kuwait medical journalpublisher: the kuwait medical journal (ku issn-0023-5776) is a quarterly...

REVIEW ARTICLE

Pediatric viral respiratory infections in Saudi Arabia: Narrative and descriptive revisits for the etiology, epidemiology and clinical phenotypes with diagnostic challenges highlights 118Ayed A Shati, Abdelwahid S Ali, Ahmed M Al-Hakami, Ali A Asseri, Saleh M Al-Qahatani

ORIGINAL ARTICLES

Evaluation of atrial conduction characteristics in adult patients with asthma 129Sadettin Selcuk Baysal, Mehmet Has

Complications and specimen quality in transrectal ultrasound guided prostate biopsy: Comparison of 16G and 18G needles 134Ahmet Murat Bayraktar, Erkan Olcucuoglu, Eray Hasirci, Ismail Nalbant, Suleyman Yesil

Factors influencing the acceptance of prenatal testing by pregnant women 138Mehmet Dolanbay, Mehmet Serdar Kutuk, Aysecan Terzioglu, Mahmut Tuncay Ozgun, Asli Subasioglu

The biofilm formation properties of the S. epidermidis isolates obtained from conjunctiva and multi-drug resistance 143Sertac Argun Kivanc, Volkan Kilic, Berna Akova, Merih Kivanc

Comparison of femoral nerve block and fascia iliaca compartment block for postoperative analgesia following total knee arthroplasty 151Semih Baskan, Duygu Kayar, Dilsen Ornek, Ismail Aytac, Mehmet Gamli, Mustafa Baydar

Influenza vaccine: Immunization rates, knowledge and attitudes of healthcare workers in Jordan 156Lana Alhalaseh, Nada Yasein

Can serum NSE and S100-β protein levels predict central nervous system injury in patients with carbon dioxide retention? 164Harun Gunes, Muhammed M Candar, Ayhan Saritas

Retrospective analysis of anesthetic management in the cerebral aneurysm treatment: Issues in the course of endovascular versus surgical treatment 169Gulcin Hilal Alay, Nadide Aysun Postaci, Ismail Aytac, Fahri Acar, Dilsen Ornek , Bayazit Dikmen

Finite element analysis of biomechanical variation of subchondral bone in osteoarthritis 175Hainan Chen, Wei Jiang, Qirong Dong, Kan Yang

Caesarean section: Sixteen-years’ trend, risk factors and attitudes of females delivered at King Abdulaziz UniversityHospital, Jeddah, Saudi Arabia 183Nahla Khamis Ibrahim, Khadeja Ayoub, Sara Ali Sawan, Maha Saleh Al-Jdani, Nedaa Mohamed Bahkali

Incidence of malnutrition in patients with maintenance hemodialysis – a single centre experience 191Bhavana Shailendranath, Prashant G Kedlaya, Renuka Satish

Effect of positive end-expiratory pressure on right heart function in mechanically ventilated patients: An ultrasonography based study 198Yong Zhao, Hong Zhang, Dan Zhang

JUNE 2020VOLUME 52 NUMBER 2

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CASE REPORTS

Humeral biepicondylar fracture in a child without elbow dislocation: A rare case and review of literature 204Ibrahim Karaman, Ali Eray Gunay, Ibrahim Halil KafadarTraumatic isolated dislocation of the trapeziometacarpal joint: A rare case report 207Ibrahim Karaman, Ali Eray Gunay, Cemil Yildirim TurkStone formation on a surgical tack migrated to the bladder 7 years after laparoscopic incontinence surgery 211Senol Tonyali

LETTER TO THE EDITOR

Frequency of lymphopenia: A summative analysis on cases with COVID-19 214 Beuy Joob, Viroj Wiwanitkit

SELECTED ABSTRACTS OF ARTICLES PUBLISHED ELSEWHERE BY AUTHORS IN KUWAIT 215

FORTHCOMING CONFERENCES AND MEETINGS 217

WHO-FACTS SHEET 223

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Palmer AM, Schiding JK, et al. Regulation of interstitial excitatory amino acid concentrations after cortical contusion injury. Brain Res. 2002;935(1-2):40-6.Book: Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA.

Medical microbiology. 4th ed. St. Louis: Mosby; 2002.Book chapter: Meltzer PS, Kallioniemi A, Trent JM. Chromosome alterations in human solid tumors. In: Vogelstein B, Kinzler KW, editors. The genetic basis of human cancer. New York: McGraw-Hill; 2002. p. 93-113.

Weblinks: eatright.org [Internet]. Chicago: Academy of Nutrition and Dietetics; c2016 [cited 2016 Dec 27]. Available from: http://www.eatright.org/.

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KUWAIT MEDICAL JOURNAL June 2020iv

OUR GRATITUDE

The Editorial Board of the Kuwait Medical Journal

gladly expresses its gratitude to

The Kuwait Foundation for the Advancement of Sciences

(KFAS)

for the financial support accorded to this journal

during the year 2012

KUWAIT MEDICAL JOURNAL 118June 2020

Review Article

Kuwait Medical Journal 2020; 52 (2): 118 - 128

Pediatric viral respiratory infections in Saudi Arabia: Narrative and descriptive revisits for the

etiology, epidemiology and clinical phenotypes with diagnostic challenges highlights

ABSTRACT

KEY WORDS: children, Middle East, respiratory infections, Saudi Arabia, viruses

Ayed A Shati1, Abdelwahid S Ali2, Ahmed M Al-Hakami2, Ali A Asseri1, Saleh M Al-Qahatani1 1Department of Child Health, College of Medicine, King Khalid University, Abha, Saudi Arabia

2Department of Microbiology and Clinical Parasitology, College of Medicine, King Khalid University, Abha, Saudi Arabia

Address correspondence to:Dr. Ayed Abdullah Shati, Department of Child Health, College of Medicine, King Khalid University, Abha, Saudi Arabia. Tel: +966555752063; Mob: +966172417750; E-mail: [email protected]

Objective: To review, describe and narrate the etiology, epidemiology and clinical phenotypes of pediatric viral respiratory infections (PVRIs) in Saudi Arabia (KSA)Design: A comprehensive electronic search of the literature for PVRIs in KSASetting: An electronic search in PubMed, SCOPUS, Google Scholar and MEDLINESubjects: Articles published up till 2019 and those that dealt with the detection of viruses from clinical specimensInterventions: Retrieved articles were subtly studied. Data obtained included the virus reported, year of publication, diagnostics, region or city, research purpose, the season of infection and hospital of admission (if any).Main outcome measure(s): The etiology, epidemiological features and clinical phenotypes associated with the PVRIs in each study were recorded and analyzed.Result(s): The first report for PVRIs in KSA was in 1988.

Up to 2019, 35 studies were published in the topic. The highest number of reports was for respiratory syncytial viruses (n=17, 48.6%), while bocaviruses are the least reported viruses (n=3, 8.6%). Clinical presentations reported suggested both upper and lower respiratory tract infections. PVRIs were reported from Riyadh, Al-Qassim, Jazan, Jeddah, Dammam, Najran, Taif and Abha. Immunofluorescence assays, enzyme-linked immunosorbent assay, polymerase chain reaction and virus isolation were employed.Conclusion(s): In this review communication, we described the etiology, epidemiology and clinical phenotypes of PVRIs in KSA reported from 1988 through 2019. We also showed some challenges associated with the diagnostic protocols employed. Directions for future research in this topic, particularly towards diagnostics and preventive medicine, were also recommended.

INTRODUCTIONIt is well-established that respiratory tract

infections are major causes of morbidities and mortalities among children worldwide[1]. A recent World Health Organization (WHO) report revealed that 18% of deaths among children under five years are attributable to pneumonia[2,3]. Among the different causes of respiratory infections, viruses were known to constitute the major etiological factor responsible for acute respiratory infections (ARIs) in pediatrics globally[4,5]. In poor and developing countries, these

infections resulted in far higher mortality rates in children as compared to those in resource- rich countries. Inadequate data about the public health impacts and economic losses of these infections in developed countries are available[6-8]. These data are always critically essential for the design and development of efficient protective measures and treatment protocols. The viruses which are known to be responsible for ARIs in infants and children included influenza viruses, human respiratory syncytial virus (HRSV), human metapneumovirus (HMPV), human

June 2020119 Pediatric viral respiratory infections in Saudi Arabia: Narrative and descriptive revisits for the etiology...

coronaviruses (HCoVs), human parainfluenza viruses (HPIV), human adenoviruses (HAdVs), and human bocaviruses (HBoVs).

Although the burden and public health implications of influenza infections are yet to be known in many parts of the world, particularly in resource-poor countries, it has been shown that influenza is characterized by high incidence rates and hospitalizations in the tropics and subtropics[8]. The global incidences and mortalities due to influenza in children less than five years was also estimated and noted to be significantly high in terms of number of deaths, particularly in the developing countries[8-10]. In many epidemiological studies, HMPV were recognized as potential etiologic agents for acute lower respiratory tract infections (ALRTIs), namely bronchopneumonia and bronchiolitis, in children[11-16]. Although the life-threatening effects of HMPV infections in children were known in some cases, the fatalities were usually seen associated with other underlying chronic conditions such as chronic lung disease of prematurity, asthma[17], cancer[18] and immunosuppression[19,20]. Following intensive literature revisits and personal communications, there were no obvious distinctions in the epidemiological and clinical patterns between HRSV and HMPV infections in pediatric patients. Both viruses cause severe and ALRTIs in infants and children, and both represent primary reasons for emergency department visits and hospitalization[18,20]. However, HMPV infections were observed to occur in relatively older children, as compared to HRSV[17]. HCoVs were also noted, causing numerous seasonal clinical respiratory infections in children since ancient times[21]. The epidemiological patterns of these HCoVs-associated diseases were observed undergoing regular changes every time and the respiratory infections attributable to HCoVs were observed not only confined to upper respiratory tract infections (URTIs), but they are also seen to cause pneumonia in infants and children[22]. Several reports describing the role of HCoVs in the lower respiratory tract infections (LRTIs) with their clinical presentations and complications in the pediatrics were also published[23-25]. HCoV-severe acute respiratory syndrome (HCoV-SARS) has emerged as the first HCoV identified responsible for severe, acute and fatal respiratory infection in children in many parts of the world[26,27]. Recently, HCoV- Middle East Respiratory Syndrome (HCoV-MERS) has also emerged from KSA and proven as a potential etiologic agent for severe URTIs and LRTIs in children and young adults[28]. Although HAdVs were primarily recognized to cause mild URT and LRT infections in young children, severe infections of HAdVs during epidemics were also noted in immunocompromised patients[29]. Several serotypes of HAdVs were isolated

from children suffering from ALRTIs. It has been suggested that the epidemiological parameters of the infections including incidences, prevalences, morbidities and mortalities due to HAdVs are highly virus type dependent[30]. HPIVs were also recognized to be associated with URT and LRT illnesses in children with their pathology, symptomatology and epidemiology dependent on the virus serotype, age and season[31]. Among the four genotypes of HBoVs known so far, HBoV-1 is the predominant genotype known to infect the respiratory tract of children[32,33]. Throughout the years, human rhinoviruses (HRVs), were known as a significant cause of the “common cold” in children and adults worldwide, with considerable economic burdens incurred due to medical visits, schooling and work absenteeism[34]. Other viruses causing respiratory infections in children and reported at various points of time include Nipah and Hindra viruses[35].

Taken all together, viral respiratory infections are considered as major health concerns in pediatric practice in many parts of the world, particularly in developing and resource-poor countries. As diagnostic testing is improved, more respiratory viruses are expected to be explored. This review intended to focus on the clinical phenotypes and epidemiological pictures of pediatric viral respiratory infections (PVRIs) in Saudi Arabia (KSA) concerning the previously published reports in that respect. We would also like to cast some light on the diagnostic and medical intervention challenges.

METHODSSearch methodology

In this study, we performed a comprehensive electronic search of the literature for PVRIs in KSA in PubMed, SCOPUS, Google Scholar and MEDLINE databases. The keywords used in the search include Saudi Arabia, respiratory, children, infants and viruses (the word “virus” was used at times and the virus name was specified at other times). The search considered articles from ancient times up to 2019. The retrieved articles were carefully read to help in further search for additional articles. The only considered and documented studies are those that dealt with the detection and/or isolation of viruses from clinical specimens of the patients and published in peer-reviewed journals.

Data retrieval and analysisThe clinical and epidemiological features associated

with PVRIs in each study were recorded and analyzed. The elements recorded included the author(s) who conducted the research, year of publication, the virus reported to cause the infection, diagnostic technique employed, region or city of the study, the research purpose, the season of the infection and the hospital


of patient admission (if any). A narrative description of the situations was then generated in this manuscript using this data.

LITERATURE REVIEWEpidemiology and clinical phenotypes of PVRIs

The previous reports for the detection of different respiratory viruses among pediatric patients in KSA from 1988 - 2019 are demonstrated in Table 1. The total number of reports of respiratory viruses in children in different cities of KSA is determined (Fig. 1). The geographical distribution of these infections in the different cities and regions of the country is also retrieved from the data obtained (Fig. 2). Detailed descriptions for the etiology, epidemiology and clinical features of the PVRIs in infants and children in KSA, as retrieved from the previously published research, are made in the following presentations:

InfluenzaInfluenza is a highly contagious disease caused

by influenza viruses type A, B and C (IAV, IBV and ICV). These viruses are characterized by segmented RNA genomes and antigenic diversities. They were classified with the family Orthomyxoviridae. IAV causes pandemics and epidemics worldwide; those belonging to group B cause epidemics and outbreaks; while those belonging to group C cause sporadic and mild respiratory infections[36]. In KSA, the first report for influenza was made in 1988, when a cross-sectional epidemiological study was carried out to determine the viral etiology of tonsillitis among children in Riyadh[37].

In another study, a significant percentage of infants and children attending the emergency or pediatric clinics of King Faisal Specialist Hospital (KFSH) in Riyadh also reported positive to influenza viruses in 1998[38]. IAV and IBV were also detected in 2005 in the nasopharyngeal secretions of young children admitted with acute LRTIs to Buraidah Maternity and Pediatric Hospital (BMPH) in Al-Qasim (central province of KSA)[39].

Additionally, during the swine flu global pandemic in 2009, AlMazroa and co-workers published a comprehensive report showing a significant number of cases affected with swine flu virus (A-H1N1) among children aged 1 - 10 years in different regions and localities of KSA. These children included both Saudi nationals and imported cases, and concluded that influenza A-H1N1 constitute a considerable threat to KSA people at the time of the study[40]. In another epidemiological study, six cases of IAV and one case of IBV were also diagnosed using multiplex RT-PCR among children at Najran Maternity and Children Hospital (NMCH) in Najran (southern region of KSA), without adequate description to the clinical and epidemiological patterns of these infections being reported[41]. In a comprehensive surveillance study in Jazan (southwestern region of KSA), IAV and IBV were also detected among pediatric patients without the determination of virus subtypes[42]. In a more recent study, the influenza virus A-H1N1 was isolated from children suspected with HCoV-MERS and presented to John Hopkins Aramco Healthcare facilities in Dammam (the eastern region of KSA)[43]. In this study,

VirusNo. of reports

Regions of reports Years of reports ReferencesSingle (%)a Combined (%)b Total (%)c

Influenza (A & B)HRSV

HMPVHCoVs

HAdVs

HPIVs

HRVsHBoVs

2 (28.6)

9 (52.9)

2 (33.3)6 (60.0)

0 (0.0)

2 (20.0)

0 (0.0)2 (66.7)

5 (71.4)

8 (47.1)

4 (66.7)4 (40.0)

8 (100)

8 (80.0)

4 (100)1 (33.3)

7 (20.0)

17 (48.6)

6 (17.1)10 (28.6)

8 (22.9)

10 (28.6)

4 (11.4)3 (08.6)

Riyadh, Jeddah, Madinah, Dammam, Najran, JazanRiyadh, Jazan, Najran, Al-Qasim, Abha

Riyadh, Najran, Abha, Riyadh, Najran, Jazan, Jeddah, DammamRiyadh, Abha, Al-Qasim, NajranRiyadh, Al-Qasim, Najran

Najran, Riyadh, JazanTaif, Najran, Dammam

1988, 1998, 2005, 2010, 2014, 2017, 20181988, 1993, 1996, 1998, 2005, 2006, 2009, 2014, 2015, 2016, 2017, 2018 2011, 2014, 2016, 2017, 2018, 20192011, 2012, 2014, 2015, 2016, 2017, 2019 1988, 1998, 2005, 2014, 2017

1988, 1998, 2005, 2012, 2013, 2014, 20162014, 20172013, 2014, 2015

37*- 43

37, 38, 41, 42, 45- 57

41, 50, 60- 6228, 41, 42, 50, 60, 64- 7037- 39, 41, 47, 51, 53, 7337- 39, 41, 47, 50, 53, 75- 7741, 42, 51, 7341, 80, 81

Table 1: The reports of different respiratory viruses in Saudi Arabia among pediatric patients from 1988 - 2019

HRSV: Human respiratory virus; HMPV: Human metapneumovirus; HCoVs: Human coronaviruses; HAdVs: Human adenoviruses; HPIVs: Human parainfluenza viruses; HRVs: Human rhinoviruses; HBoVs: Human bocavirusesThe presented data are expressed as numbers and percentages (%).aSingle report means the study reported only one single virus type; combined report means the study reported more than one virus type.bThe percentages of single and combined reports were calculated from the total number of reports for each virus individually.cThe percentages of the total reports of each virus were calculated from the total number reports for all viruses noticed in this review (35 reports). * The reference number as given in the reference list.

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Fig 1: Report rates of pediatric respiratory viruses in different cities of KSA Riyadh (central province); Dammam (eastern province); Al-Qasim (northern province); Abha (Asir region, southern province); Jeddah (western province); Najran (Najran region, southern province); Jazan (southwestern region); Taif (western province)Rates were calculated as percentages from number of reports in each region out of the total number of reports in the kingdom (35 reports)

Fig 2: Geographic distribution of viral respiratory infections in children and infants in Saudi Arabia through 1988-2019HRSV: human respiratory virus; HMPV: human metapneumovirus; HCoVs: human coronaviruses; HAdVs: human adenoviruses; HPIVs: human parainfluenza viruses; HRVs: human rhinoviruses; HBoVs: human bocaviruses

Pediatric viral respiratory infections in Saudi Arabia: Narrative and descriptive revisits for the etiology...


the authors declared higher incidence among patients came from Ras Tanura city (far eastern region of KSA; Fig. 2).

In total, a considerable number of reports about influenza infections among pediatric patients in KSA was noted in the literature. The majority of the available data were those published during the global “avian flu” pandemic in 2005 - 2006 and the global “swine flu” pandemic in 2009 - 2010. Despite all these reports, we believe that adequate data pertaining to the virology, clinical phenotypes and epidemiological aspects of influenza viruses in KSA, among adult populations in general and children in specific, are still lacking.

Human respiratory syncytial virus (HRSV)HRSV was confirmed in many studies and surveys

as the leading cause of respiratory tract infections in infants and young children throughout the world. HRSV is a non-segmented, negative-sense, single-stranded RNA enveloped virus belonging to the family Pneumoviridae and the genus pneumovirus[44]. As compared to influenza, more studies were conducted to detect HRSV from children in different cities and regions of KSA, namely Riyadh[37,38,45-51], Najran[41], Jazan[42], Al-Qasim[52] and Abha[53]. In all of these studies, no detailed clinical presentations or specific epidemiological patterns for HRSV infections were described; however, bronchopneumonia (BP) and bronchiolitis were reported as the leading cause of morbidities and hospitalization. It was also revealed that the infections of HRSV peak in winters and autumn seasons. Deaths attributable to these infections among infants were also recorded, though dearth. The genetic analysis of HRSV group B (HRSV-B) strains circulating in KSA was also studied in 2014 by Almajhdi and co-researchers[54]. This study helped to cast some light on the circulation pattern and molecular characteristics of HRSV- B strain in the KSA.

Medical intervention of HRSV infectivity among children in KSA remains the most crucial concern to health practitioners and the public. Special attention was particularly directed towards hospitalized RSV- infected premature infants and children suffering from chronic lung disease or congenital heart disease. Palivizumab (Synagis, Medimmune) is a humanized monoclonal antibody, which is a combination of human (95%) and murine (5%) antibody sequences. In KSA, Palivizumb was used for the prevention of severe RSV infections in high-risk groups of children[55,56]. It was well-documented that Palivizumb is an effective agent for the prevention of RSV mortalities and fatalities. However, the notable possible drawbacks associated with this medication include the expense and extensiveness of use without rationality.

Conclusively, the different studies concerning the treatment of children against HRSV using different types of medicines and regimens in KSA were recently reviewed by Alharbi and co-researchers in 2018[57].

Human metapneumovirus (HMPV)HMPV was first recognized and described in

Netherlands in 2001 by van den Hoogen and others[58]. It is a negative sense, single-stranded RNA enveloped virus and classified as a member of the Paramyxoviridae family, pneumovirinae subfamily and pneumovirus genus[59]. In KSA, HMPV was first detected in 2011 among Saudi children hospitalized with ARI in Riyadh[60]. Afterward, the virus was also detected among children who presented with ARTIs to NMCH in Najran, with brief explanations of the clinical and epidemiological correlates of the infections[41]. The authors identified the virus in infants in both single viral infections and viral co-infections. HMPV was also isolated during an investigation in a cohort of children suffering severe LRTIs and hospitalized at a tertiary referral center in Riyadh in 2016[50]. The epidemiology and some genetic properties of that isolated virus were also studied[61]. That is considered the first report addressing the HMPV genotypes circulation in the KSA. HMPV was also detected in a retrospective study performed to determine the viral etiological agents causing RTIs among pediatric patients admitted to the Department of Pediatrics, King Abdul-Aziz Medical City (KAMC) in Riyadh[51].

In a recent publication, we reported the incidence of HMPV in the Aseer region (southern provinces of KSA) among children who attended the pediatric emergency rooms and were hospitalized in Aseer Central Hospital with acute bronchiolitis and BP[62]. In that study, we reported for the first time the large population of virus-infected children in the area, particularly in Abha city and the vicinity. In the previously published articles, reverse transcriptase PCR (RT-PCR) and direct fluorescent antibody (DFA) test were employed for the detection of the virus nucleic acid and antigens respectively, in the nasopharyngeal secretions from infected children. Apart from the previously mentioned reports of HMPV infections, the virus was not detected in any other region or city of the Kingdom. The role of HMPV in respiratory infections in pediatric medicine in the western, eastern and northern regions of KSA was not determined yet. The risk factors associated with the severity of HMPV in children in the KSA were not precisely known up to date. In conclusion, meager studies regarding the virus distribution, prevalence, clinical presentations and medical interventions of HMPV in KSA were made so far, and much research work is worthy in these aspects.

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Human coronaviruses (HCoVs)Human coronaviruses (HCoVs) are a well-known

cause for URT and LRT infections in all age groups. They are positive-sense, single-stranded RNA viruses classified in the family Coronaviridae[63]. Before HCoV-SARS and HCoV-MERS, which cause severe and acute respiratory infections, four other HCoVs were recognized to be responsible for mild respiratory infections in adults and children namely HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1. The first report for HCoVs infections among children in KSA was made by Al-Hajjar and co-workers in 2011[60]. In this study, HCoV-NL63 was isolated from children less than 16 years old hospitalized with ART illness during autumn and winter at KFSH in Riyadh. HCoV-NL63 and HCoV-OC43 were also detected among children presented with acute LRT infections and showing symptoms of bronchiolitis and pneumonia in Najran region of KSA in 2014[41]. In another cross-sectional study carried out to determine the prevalence of viruses causing ARTIs among hospitalized children in Riyadh area, a considerable number of them were diagnosed with HCoVs[50]. The HCoVs serotypes detected in this study were not specified and were most prevalent in infants less than six months old. Non-MERS HCoVs were also detected in nasopharyngeal swabs collected from asymptomatic outpatients less than 15 years old in Jazan province[42]. Despite the wide spread of HCoV-SARS during the global disease pandemic in 2003, no single report about the virus infectivity in children in KSA was made. As the HCoV-MERS originated from Jeddah (western region of KSA) in 2012[28], plenty of reports, thereafter, describing the virological, epidemiological and clinical characteristics of the virus were made in KSA at large. Primarily, a single pediatric case (out of 47 sampled patients), laboratory confirmed positive to HCoV-MERS was identified by Assiri and co-workers throughout KSA as a first report, in 2013[64]. Consequently, HCoV-MERS was also reported among eleven pediatric patients in Riyadh in 2014[65]. In this report, the clinical presentations and outcomes of the patients were adequately described; nine cases were asymptomatic, whereas two cases were admitted to the ICUs suffering severe respiratory infections, with one of whom died. A case report describing a complicated HCoV-MERS infection in a 9-month-old child admitted to the pediatric ICU of Prince Sultan Military Medical City in Riyadh, with infantile nephrotic syndrome that resulted in death, was also published by Thabet and his team in 2015[66]. In a comprehensive search in the literature made by Al-Tawfiq and co-researchers in 2016; a conclusion was drawn to indicate that low number of MERS pediatric cases were evident in KSA and the reasons for this low prevalence was unknown[67]. In this report, the

symptoms, mean age of infection and source of infection among pediatric patients were described to an optimal level. The various scientific elements of HCoV-MERS infectivity for children were also recently reviewed by Al-Sehaibany in 2017, when he concluded that MERS is a disease of adults, where few cases among children were known with different clinical manifestations and lower mortality rates as compared to infection in adults[68]. Conclusively, despite the intensive studies for detection of HCoV-MERS among adults in KSA and surrounding countries, a limited number of cases were reported for this virus in children. However, in recent publications, it had been reported that the proportion of asymptomatic cases among pediatric confirmed HCoV-MERS cases was significantly high[69,70].

Human adenoviruses (HAdVs)Human adenoviruses (HAdVs) were known to have

a significant contribution in PVRIs. HAdVs infections were observed as mild and indistinguishable from other viral respiratory infections in children on their pathology and clinical grounds[71]. However, acute and severe URT and LRT infections attributable to HAdVs were also noted among pediatric patients[71,72]. Since 1988 up to date, only nine studies discussing the incidences and other clinical and epidemiological parameters of adenoviral infections in children in KSA were made. In a serological and virological investigation by Hossain et al in 1988, the first report for HAdVs infections in children in KSA was made. They showed that HAdVs were the leading cause of tonsillitis among Saudi children during the study period[37]. About ten years later, adenovirus infections were also reported in children who attended the emergency of pediatric wards at KFSH and Research Center in Riyadh[38]. In the same year, HAdVs infections were also detected among Saudi children under five years who presented to King Khalid University Hospital (KKUH) in Riyadh with complaints of ARTIs[47]. In another prospective study, adenoviruses were also detected in the nasopharyngeal aspirates of children hospitalized due to severe bronchiolitis in Abha city[53]. In that study, the clinical features and risk factors of adenovirus-associated bronchiolitis were described to an adequate level. They specified the risk factors including prematurity, chronic lung diseases, atopic dermatitis, pure formula feeding, passive smoking and age. Also, Meqdam and coauthors reported the role of HAdVs in the ALRTIs among infants and young children admitted to BMPH in Al-Qassim[39]. Adenoviruses were also identified as a significant cause of respiratory infections in children less than five years in Najran city, and mainly observed to be associated with bronchiolitis and acute wheezing episodes[41]. In two recent epidemiological studies, the role of HAdVs



in ARTIs among pediatric patients presenting to the King Fahad City[73] and KAMC[51] in Riyadh was also confirmed.

Human parainfluenza viruses (HPIVs)HPIVs are genetically and antigenically grouped

into four types namely HPIV-1, HPIV-2, HPIV-3 and HPIV-4. They are enveloped viruses with single-stranded, negative-sense RNA genomes and belong to the Paramyxoviridae family, paramyxovirinae subfamily and paramyxovirus genus[74]. HPIV-1, 2 and 3 were first reported in KSA among Saudi children below 15 years of age, who were suffering from acute tonsillitis in Riyadh[37]. HPIV-3 was particularly diagnosed in children presented to KKUH[47], and KFSH and Research Center[38] in Riyadh. HPIVs were also confirmed in another study among children suffering acute LRTIs in Al-Qassim, without specification for the virus type and clinical description of the infection[39]. In Abha city, HPIV-1, HPIV-2 and HPIV-3 were also isolated from children less than two years of age, who were diagnosed with bronchiolitis[53]. The first molecular epidemiological study in KSA was carried out to screen HPVI-3 in nasopharyngeal secretions collected from children hospitalized in Riyadh with acute respiratory diseases using nested RT-PCR[75]. In another similar study, HPIV-2 was also isolated from children in Riyadh[76]. Al-Ayed and co-workers also identified HPIV-1 and HPIV-3 in children less than five years old with ARTIs in Najran[41]. Although HPIVs were widely seen as infectious to URT, in a retrospective study performed at the Departments of Pediatrics, Pathology and Microbiology of KKUH in Riyadh, a small portion of children less than one-year-old were observed as suffering bronchiolitis and pneumonia due to HPIV-1, 2 and 3 infections[77]. In another epidemiological investigation among hospitalized children at a tertiary referral center in Riyadh, HPIVs were also detected in the nasopharyngeal aspirates using monoplex RT-PCR[50]. In that study, HPIVs were seen mostly prevalent in infants less than six months during winter.

In conclusion, HPIV-1 and HPIV-3 were the most commonly observed viruses causing RTIs among children in KSA. There were many factors reported to predispose the children to these infections, such as overcrowding, non-breast feeding and environmental smoke. Symptoms associated with HPIVs have also been correlated with the age of the child and virus type.

Human rhinoviruses (HRVs)HRVs were first identified in the 1950s and known

as the most predominant cause of URTIs. HRVs are non-enveloped viruses, with positive-sense, single-

stranded RNA genomes, and classified in the family Picornaviridae and the genus enterovirus[78]. Although HRVs were known since early days to cause respiratory infections among pediatric patients in many parts of the world, they have only recently been identified in KSA. The first report for HRVs was made in 2014 when recognized as one of the viral etiologies of respiratory infections in children in Najran in 2014[41]. Later, three reports were made for HRVs in 2017; two in Riyadh[51,73] and one in Jazan[42]. In all these studies, HRVs had seen to constitute the primary cause of RTIs among the tested children. Their epidemiological pattern and infectivity was noted to peak in winter, with serious clinical consequences in infants and young children. Dual infections with other viruses such as HRSV, HCoVs, HAdVs, HMPV and influenza were more likely to occur, as retrieved from these studies. In conclusion, a limited number of studies discussing the clinical and epidemiological elements of HPIVs were published in KSA.

Human bocaviruses (HBoVs)HBoV is a parvovirus first identified in 2005

and known as a causative agent of respiratory tract infections[32]. Four HBoV subtypes were recognized so far, namely HBoV-1, HBoV-2, HBoV-3 and HBoV-4. HBoV-1 was isolated from infants with respiratory manifestations including cough, dyspnea, wheezing and suffering from rhinitis, pharyngitis, pneumonia and otitis media. HBoVs are classified with the family Parvoviridae, subfamily Parvovirinae, genus Bocavirus[79]. Following a systematic search in the literature, only three reports for HBoV infections among pediatric patients in KSA were noticed. The first report for HBoV in KSA was made by Abdel-Moneim and co-workers in 2013 in Taif city (western region of KSA) when they detected the virus in 22% of the tested children with respiratory distress[80]. In that study, the authors confirmed that the circulating HBoV genotype among the tested patient was HBoV-1. They also showed that co-infection with other viruses was seen in the majority of samples. The second report was from Najran in 2014[41], while the third report for HBoV in KSA was made by Bubshait and his group in 2015 among children admitted to King Fahad University Hospital in Dammam. They reported five positive cases for HBoV, with their clinical presentations varying from mild to severe disease[81].

Diagnostic challenges The PVRIs in KSA have been reported for

thirty years. Several methods and techniques were employed for the diagnosis of these infections. Viral antigen detection using DFA, ELISA and virus propagation in cell cultures were the commonly

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performed methodologies[37,38,53,77]. However, epidemiological studies for investigations of viral etiologies of respiratory tract infections later relied mainly on the PCR and RT-PCR for detection of DNA and RNA viruses, respectively[41,42,50,81]. These molecular methods were seen to significantly increase the viral detection sensitivities and specificities. A great debate for the reliability of these tests was raised, since positive reactions for asymptomatic patients were observed. The debate was also raised due to positive reactions observed for bronchiolitis cases associated with viruses which were well known to cause URTIs[51].

One of the great difficulties and challenges associated with the diagnostic concerns in the different regions of KSA was convincing the children, their parents, or representatives with sampling (pharyngeal swabs and aspirates, blood), particularly for research purposes. Another significant concern for health specialists and practitioners is the distribution of diagnostic logistics among the different regions and provinces of the kingdom. More focus and attention, as per the diagnostic facilities, are directed towards the central province of the kingdom (Riyadh area) with limited resources available at the peripheral regions. That had been obvious and affected the screening program during the HCoV-MERS epidemic in 2012 & 2013, when samples for virus detection had to be sent to central laboratories in Riyadh. Challenges associated with the availability of diagnosticians and laboratory technical staff were also raised on many occasions, since the qualified personnel are not available in all regions.

CONCLUSIONS· A total number of 35 studies were retrieved

from the literature that reported the detection of respiratory viruses in infants and children in KSA from 1988 until 2019.

· HRSVs are the most commonly reported virus involved in respiratory infections among pediatric patients in KSA, while HBoVs are the least reported viruses.

· The highest number (68.6%) of reports for PVRIs was observed from Riyadh region (including Riyadh city). This is presumably attributable to the fact that Riyadh, as the capital city of KSA, encompasses a high number of hospitals and medical cities as compared to other regions. Additionally, better diagnostic and research facilities are available in the research centers and university laboratories in Riyadh.

Directions for future researchAfter careful analysis and subtle investigations

in the previously published work in the topic, the following elements should have special emphasis in future research attempts: · Detailed description of the epidemiological

patterns of these viruses among different populations of children should be documented.

· Nationwide surveillance studies to reveal the exact prevalence of these viruses among newborns, infants and children in the country are recommended.

· The exact morbidities and long-term consequences of the early life infection with these viruses, especially among the high-risk groups (e.g., children with chronic lung disease and high risk of pulmonary asthma) should be determined.

ACKNOWLEDGMENTConflict of interest: The authors declare no conflict of interest.

Funding: The research was funded by the deanship of scientific research, King Khalid University, Abha, Saudi Arabia with project No. 190.

Authors ContributionAAS: literature search, data extraction and

recording, manuscript writing and revision, tables and figures preparation. ASA: literature search, data extraction and recording, manuscript writing and revision. AMH: manuscript writing and revision. AAA: manuscript revision, editorial and language. SMA: manuscript revision, editorial and language.

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KUWAIT MEDICAL JOURNAL June 2020129

Original Article


Evaluation of atrial conduction characteristics in adult patients with asthma

ABSTRACT

KEY WORDS: asthma, atrial conduction abnormality, atrial fibrillation, P-wave dispersion, tissue Doppler imaging

Sadettin Selcuk Baysal1, Mehmet Has2

1Department of Cardiology, Şanlıurfa Mehmet Akif İnan Training and Research Hospital, 63300, Şanlıurfa, Turkey2Department of Chest Diseases, Şanlıurfa Mehmet Akif İnan Training and Research Hospital, 63300, Şanlıurfa, Turkey

Objective: The electrophysiological properties of the right atrium could be impaired by right ventricular dysfunction, pulmonary hypertension and atrial enlargement in asthma. We aimed to evaluate atrial conduction abnormalities obtained by Doppler tissue imaging and electrocardiogram analysis in adult patients with asthma.Design: Cross-sectional observetional studySetting: Şanlıurfa Mehmet Akif İnan Training and Research Hospital, Şanlıurfa, Turkey Subjects: Study consisted of 90 (57 men, 25.7 ± 4.2 years) patients with asthma and 90 (59 men, 25.0 ± 4.0 years) healthy controlsIntervention: Twelve lead surface electrocardiogram, pulmonary function tests and echocardiographic imaging were performed and recorded.

Main outcome measures: Atrial conduction times were measured.Results: Intra-right atrial conduction time (IRCT-echo) (11.9 ± 2.7 and 8.8 ± 2.4; p ˂0.001), inter-atrial conduction time (IACT-echo) (25.7 ± 4.1 and 22.0 ± 3.1; p ˂0.001) and P wave dispersion (PWD) (39.8 ± 10.4 and 36.2 ± 6.2; p ˂0.001) were significantly increased in patients with asthma than controls. IACT-echo was positively correlated with IRCT-echo and intra-left atrial conduction time (ILCT-echo) (r = 0.687, p ˂0.001 and r = 0.660, p ˂0.001, respectively).Conclusions: IRCT-echo, IACT-echo and PWD measurements are higher in asthmatic patients in our study. IACT-echo was significantly correlated with IRCT-echo and ILCT-echo.

Address correspondence to:Dr. Sadettin Selcuk Baysal, Şanlıurfa Mehmet Akif İnan Eğitim Araştırma Hastanesi, Esentepe 63300, Şanlıurfa, Turkey. Tel (work): +90 414 3186000; Cell: +90 535 9696274; Fax: +90 414 3186812; E-mail: [email protected]

INTRODUCTIONAsthma is a chronic disease in which inflammation

causes airway obstruction and spasms of bronchi. The prevalence of this disorder is approximately 300 million people[1]. The relationship between asthma and as cardiovascular disease has been reported in previous studies[2]. Asthma is also associated with increased risk of cardiac arrhythmias, including atrial fibrillation (AF)[3]. Although the mechanism of the relationship between AF and asthma is not fully understood, inflammation is incriminated in the pathogenesis of both asthma and AF[4]. Structural changes in right atrium induced by increased pulmonary artery pressure is also one of the possible mechanisms leading to AF in asthma[4].

Atrial conduction abnormalities are associated

with increased risk of AF development[4]. These abnormalities could be measured by using electrocardiography (ECG) and tissue Doppler imaging (TDI). Atrial electromechanical delay (AED) and P wave dispersion (PWD) measurements could reflect the atrial conduction prolongation, which may trigger AF[5-7].

To the best of our knowledge, this is the first study evaluating the atrial conduction times detected by TDI and ECG in adult patients with asthma.

SUBJECTS AND METHODSThis is a cross-sectional study performed in Mehmet

Akif Inan Training and Research Hospital between September 2016 and August 2017. One hundred


patients were enrolled in the study group. They were evaluated at our outpatient pulmonology clinic with dyspnea and diagnosed with bronchial asthma according to Global Initiative for Asthma guidelines at the first time[1]. The control group consisted of 90 age and sex-matched volunteers without any disease. Patients who were diagnosed with asthma were referred to our cardiology outpatient clinic for further medical evaluation including medical history, physical examination, ECG and echocardiography. Diagnosis of asthma depended on clinical symptoms, physical examination and pulmonary function tests. All subjects underwent pulmonary function tests which were performed by the same technician according to the European Respiratory Society consensus standards[8]. Patients who had a history of cardiovascular or any other systemic diseases, use of medical drugs (especially systemic steroids), smoking, aged under 18 years or over 65 years were excluded. Ten subjects were excluded finally; five had a smoking history and five had poor echocardiographic image quality. The local ethics committee approved the study and written informed consent was obtained from all participants after explaining the details of the study.

Echocardiography Two-dimensional, M-mode, pulsed and color

Doppler echocardiographic imaging was performed using Philips iE33 ultrasound system (Andover, Md., USA) with 2–4 MHz transducer by the same experienced cardiologist, who was blinded to the clinical status of all patients. Single derivation ECG was simultaneously recorded during imaging. Cardiac chamber dimensions and wall thickness were measured from parasternal long axis and apical four-chamber views. Echocardiographic examinations were performed according to the criteria of the American Society of Echocardiography guidelines[9]. Peak systolic velocity (Sm), early diastolic velocity (Em), late diastolic velocity (Am) and isovolumetric relaxation time (IVRT) were measured from the mitral, lateral, septal and tricuspid lateral annuluses. The myocardial performance index (MPI), an index of combined systolic and diastolic function, was calculated from the pulsed-wave tissue Doppler recordings for the right and left ventricles[9].

Atrial electromechanical delay measurementsTDI was performed with a transducer frequency

of 3 MHz by adjusting the spectral pulsed Doppler signal filters until a Nyquist limit of 15 - 20 cm/s was reached and using minimal optimal gain. The monitor sweep speed was set at 50 - 100 mm/s. The sampling window was positioned at level of left ventricle (LV) lateral mitral annulus, septal mitral annulus and right ventricle (RV) lateral tricuspid annulus in the

apical four chamber view. The time interval from the onset of the P wave on the surface ECG recording simultaneously during TDI to the beginning of Am, which is named PA, was obtained from the lateral mitral annulus (lateral PA), septal mitral annulus (septal PA) and RV lateral tricuspid annulus (RV PA). The difference between septal PA and RV PA was defined as the intra-right atrial conduction time (IRCT-echo), the difference between lateral PA and septal PA was defined as the intra-left atrial conduction time (ILCT-echo) and the difference between lateral PA and RV PA was defined as the inter-atrial conduction time (IACT-echo)[9,10].

P-wave dispersion measurementAll standard 12-lead ECG were obtained

simultaneously using a recorder set at a 50 mm/s paper speed and 1mV/cm standardization (Hewlett Packard, Pagewriter). ECG intervals were blindly analyzed by two cardiologists and the average of these two measurements was taken. To minimize errors, analysis was performed using calipers and a magnifying lens. A 12 lead surface ECG was used to measure the maximum (Pmax) and minimum (Pmin) P-wave durations. The difference between Pmax and Pmin was defined as PWD.

Statistical analysisSPSS for Windows software (ver. 21.0; SPSS Inc.,

Chicago, IL, USA) was used for all statistical study. The Shapiro-Wilks test was used to evaluate the normality of the distribution of continuous variables. Mean ± standard deviation was used for the data. The independent t-test was used to compare normally distributed continuous variables between different groups. Pearson’s correlation coefficients were used to estimate the relationship between parameters. A p-value of ˂ 0.05 was considered statistically significant.

RESULTSBaseline demographic features are similar between

case and control groups. There is no significant difference between asthma and control groups in age (25.7 ± 4.2 and 25.0 ± 4.0; p: 0.29), body mass index (25.3 ± 1.9 and 24.8 ± 2.0; p: 0.12), systolic blood pressure (121.7 ± 6.2 and 120.9 ± 6.5; p: 0.37) and diastolic blood pressure (76.6 ± 6.6 and 75.8 ± 6.0; p: 0.56). The demographic and spirometry results were shown in Table 1.

All echocardiographic measurements were listed in Table 2. Left ventricle end-diastolic diameter, interventricular septal wall thickness, left ventricular ejection fraction, left atrial diameter, right atrial diameter, mitral inflow parameters, tricuspid inflow parameters, mitral Sm, mitral Em, mitral Am, LV MPI, LV IVRT and RV Sm were similar between case and

June 2020131

control groups. RV Em (11.9 ± 2.0 and 12.9 ± 2.3 cm/s; p ˂0.001), RV Am (11.4 ± 1.9 and 12.2 ± 1.9 cm/s; p ˂ 0.001), tricuspid annular plane systolic excursion (TAPSE) (24.9 ± 2.0 and 25.7 ± 2.1 mm; p = 0.01), pulmonary artery acceleration time (PAAT) (130.3 ± 9.8 and 134.5

Patients (n = 90)

Controls (n = 90) p-value

Age (years)Male (n)BMI (kg/m2)SBP (mmHg)DBP (mmHg)Heart rate (beats/minute)PEFFEV1FVCFEV1/ FVC

25.7 ± 4.257

25.3 ± 1.9121.7 ± 6.276.6 ± 6.6

77 ± 1084.2 ± 13.092.4 ± 12.988.2 ± 9.1

98.6 ± 11.2

25.0 ± 4.059

24.8 ± 2.0120.9 ± 6.575.8 ± 6.0

75 ± 985.2 ± 6.296.5 ± 8.791.0 ± 8.0

101.3 ± 9.8

0.290.910.120.370.560.330.060.01*0.03*0.08

BMI: body mass index; DBP: diastolic blood pressure; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; PEF: peak expiratory flow; SBP: systolic blood pressure*p-value is statistically significant

Table 1: Demographic characteristics and spirometry results of study population

Patients (n = 90)


LV EDD (mm)IVS thickness (mm)LV EF (%)LA diameter (mm)RA diameter (mm)Mitral E (cm/s)Mitral A (cm/s)Mitral E/ADT (ms)IVRT (ms)Tr. E (cm/s)Tr. A (cm/s)Tr. E/ALV Sm (cm/s)LV Em (cm/s)LV Am (cm/s)LV IVRT (ms)LV MPIRV Sm (cm/s)RV Em (cm/s)RV Am (cm/s)RV IVRT (ms)RV MPITAPSE (mm)PAAT (ms)

45.2 ± 3.49.4 ± 0.5

65.1 ± 3.434.9 ± 2.131.6 ± 2.482.8 ± 9.366.3 ± 9.6

1.27 ± 0.25212.7 ± 16.4

88.1 ± 8.368.3 ± 9.7 53.0 ± 8.8

1.31 ± 0.249.6 ± 2.3

11.6 ± 2.410.9 ± 2.782.1 ± 9.9

0.33 ± 0.0513.1 ± 3.111.9 ± 2.011.4 ± 1.947.7 ± 8.8

0.36 ± 0.0724.9 ± 2.0

130.3 ± 9.8

44.7 ± 3.39.4 ± 0.4

65.9 ± 3.035.1 ± 2.331.4 ± 2.184.0 ± 8.865.4 ± 8.5

1.30 ± 0.23209.4 ± 15.3

86.1 ± 7.768.7 ± 8.052.1 ± 7.1

1.34 ± 0.239.9 ± 2.0

12.0 ± 2.211.0 ± 2.4

81.0 ± 10.40.32 ± 0.0513.5 ± 2.312.9 ± 2.312.2 ± 1.943.2 ± 6.0

0.32 ± 0.0525.7 ± 2.1

134.5 ± 9.1

0.320.640.140.590.430.380.480.380.230.100.770.440.460.440.170.810.470.270.28

˂0.001*˂0.001*˂0.001*˂0.001*0.01*

˂0.001*

Am: late myocardial diastolic velocity; DT: deceleration time; EF: ejection fraction; Em: early myocardial diastolic velocity IVRT: isovolumetric relaxation time; IVS: interventricular septum; LA: left atrium; LV: left ventricle; LV EDD: LV end-diastolic dimension; MPI: myocardial performance index; PAAT: pulmonary artery acceleration time; RA: right atrium; RV: right ventricle; TAPSE: tricuspid annular plane systolic excursion; Tr.: Tricuspid; Sm: systolic myocardial velocity*p-value is statistically significant

Table 2: Echocardiographic parameters of study population

± 9.1; p ˂0.001) were significantly lower in patients than controls; however, RV MPI (0.36 ± 0.07 and 0.32 ± 0.05; p ˂0.001) and RV IVRT (47.7 ± 8.8 and 43.2 ± 6.0; p˂0.001) were higher in subjects with asthma than controls.

P wave and AED measurements were represented in Table 3. PWD (39.8 ± 10.4 and 36.2 ± 6.2; p ˂0.001), lateral PA (62.8 ± 5.0 and 56.7 ± 4.0; p ˂0.001), septal PA (49.0 ± 4.4 and 43.6 ± 4.4; p ˂0.001), RV PA (37.0 ± 4.9 and 34.7 ± 4.0; p˂0.001), IACT-echo (25.7 ± 4.1 and 22.0 ± 3.1; p ˂0.001) and IRCT-echo (11.9 ± 2.7 and 8.8 ± 2.4; p ˂0.001) were higher in asthmatic patients compared to healthy subjects. Pmax, Pmin, and ILCT-echo values did not differ between groups.

Patients (n = 90)


Pmax (ms)Pmin (ms)PWD (ms)Lateral PA (ms)Septal PA (ms)RV PA (ms)IACT-echo (ms)IRCT-echo (ms)ILCT-echo (ms)

98.7 ± 11.858.8 ± 7.839.8 ± 10.462.8 ± 5.049.0 ± 4.437.0 ± 4.925.7 ± 4.111.9 ± 2.713.8 ± 3.0

96.0 ± 11.159.8 ± 8.836.2 ± 6.256.7 ± 4.043.6 ± 4.434.7 ± 4.022.0 ± 3.18.8 ± 2.413.1 ± 2.9

0.120.42˂0.001*˂0.001*˂0.001*˂0.001*˂0.001*˂0.001*0.12

IACT: inter-atrial conduction time; ILCT: intra-left atrial conduction time; IRCT: intra-right atrial conduction time; Pmax: maximum P wave duration; Pmin : minimum P wave duration; PWD: P wave dispersion; RV: right ventricle *p-value is statistically significant

Table 3: P-wave dispersion and the atrial electromechanical delay findings of study population

IACT-echo was positively correlated with IRCT-echo and ILCT-echo (r = 0.687, p ˂0.001 and r = 0.660, p ˂0.001, respectively). There was a weak but significant correlation between PWD and IRCT-echo (r = 0.218, p = 0.004).

DISCUSSIONIn our study, we found higher IRCT-echo and

IACT-echo measurements in asthmatic adult patients. However, similar ILCT-echo values were observed in these patients. Moreover, higher PWD values were detected in this population. To the best of our knowledge, this is the first study demonstrating an increase in PWD and right atrial conduction time in adult asthmatic population. IACT-echo was significantly correlated with IRCT-echo and ILCT-echo.

It was reported that asthma is associated with an increased risk for AF, although the exact mechanism hasn’t been fully understood[4,11]. Also, the adult asthmatic patients were observed to have more tachycardia and premature ventricular contractions



than patients without asthma[3]. Pathogenesis of asthma is chronic inflammation of airways causing reversible obstruction. Chronic inflammation may be one of the possible explanations for increased arrhythmias in asthma[4,12]. Pulmonary hypertension (PHT) is one of the risk factor of AF. In asthma, recurrent hypoxemia and chronic inflammation may lead to pulmonary vasoconstriction, causing the development of pulmonary hypertension. This could result in right heart enlargement and right ventricular hypertrophy[4,13]. In later stages of the disease, both systolic and diastolic RV dysfunction occurs and this will impair the left ventricle functions due to increased RV afterload. All these structural and hemodynamic changes may trigger arrhythmias in asthmatic patients[14].

In our study, we found that asthma has a negative role in right ventricular functions. TAPSE, an echocardiographic indicator of RV function, and PAAT, an indicator of PHT, were significantly lower in asthmatic patients. Also, TDI parameters such as RV Em and RV Am were significantly decreased; and RV MPI and RV IVRT were significantly increased in subjects with asthma. These findings suggested that subclinical RV functional impairment started in patients with asthma in our study population. Previous study reports support our findings[15,16]. RV dysfunction was thought to be a potential risk factor for the development of AF[17,18]. This could be one of the underlying mechanisms leading to increased AF incidence in asthmatic patients.

It has been reported that increased AED measurements obtained by TDI were independent predictors of AF occurrence[5,19,20]. Atrial stretch due to increased RV afterload causes morphological changes in right atrium. This makes changes in electroanatomical substrate, which leads to delay in electrical conduction and development of re-entrant circuits in the atrium[21]. This is one of the possible explanations of AF development. It was shown that right atrial conduction time was increased in pediatric asthmatic patients[10]. In adult population, we also observed right atrial conduction delay in our study. The IACT-echo and IRCT-echo measurements were higher in asthmatic patients than control subjects. However, we didn’t see any statistical difference in ILCT-echo. Çiftel et al[10] reached similar results as our study in pediatric asthmatic population. We also found a significant correlation between IACT-echo and IRCT-echo and ILCT-echo.

PWD reflects the inhomogeneous and delayed conduction of sinus impulses. Increased PWD is associated with higher risk of AF. Atrial stretch due to increased afterload, electrolyte imbalance and sympathetic activity stimulation are the reasons for

increased PWD[5,6,10]. In previous studies with pediatric asthmatic patients, no significant change was found in P-wave durations (Pmax, Pmin) and PWD[10,22]. However, in our study, we found higher PWD measurements in asthmatic subjects than controls in adult population. Higher disease duration could be the reason why significantly increased PWD values were observed in adult asthmatics.

Cross-sectional design of the study and lack of follow-up for detecting arrhythmias are the main limitations of this study. Manual evaluation of ECG parameters, lack of intra-rater and inter-rater variability calculation and measurement of conduction intervals without electrophysiological study (the gold standard technique) were the other limitations of our study.

CONCLUSIONIRCT-echo and IACT-echo measurements are

prolonged in asthmatic patients in our study. IRCT-echo is associated with subclinical RV dysfunction in patients with asthma. PWD is higher in asthmatic patients. IACT-echo was significantly correlated with IRCT-echo and ILCT-echo. These results may be the underlying mechanisms to explain the impaired atrial electrophysiological properties in patients with asthma which may result in AF development. Longer prospective studies are needed to explain the exact pathophysiology of atrial arrhythmias observed in asthma.

ACKNOWLEDGMENTSource of funding: All support for this study came from institutional and departmental resources.

Conflict of interest: The authors declare that they have no conflict of interest.

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1. Beghé B, Fabbri LM, Contoli M, Papi A. Update in Asthma 2016. Am J Respir Critl Care Med 2017; 196(5):548-557.

2. Wang L, Gao S, Yu M, Sheng Z, Tan W. Association of asthma with coronary heart disease: A meta analysis of 11 trials. PloS one 2017; 12(6):e0179335.

3. Warnier MJ, Rutten FH, Kors JA, Lammers JWJ, de Boer A, Hoes AW, et al. Cardiac arrhythmias in adult patients with asthma. J Asthma 2012; 49(9):942-946.

4. Chan WL, Yang KP, Chao TF, Huang CC, Huang PH, Chen YC, et al. The association of asthma and atrial fibrillation - A nationwide population-based nested case-control study. Int J Cardiol 2014; 176(2):464-469.

5. Omi W, Nagai H, Takamura M, Okura S, Okajima M, Furusho H, et al. Doppler tissue analysis of atrial electromechanical coupling in paroxysmal atrial fibrillation. J Am Soc Echocardiogr 2005; 18(1):39-44.

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6. Abou R, Leung M, Tonsbeek AM, Podlesnikar T, Maan AC, Schalij MJ, et al. Effect of aging on left atrial compliance and electromechanical properties in subjects without structural heart disease. Am J Cardiol 2017; 120(1):140-147.

7. Eweda I, Abul-Saud M, Fouad H, Hanna RN, Nammas W. P wave dispersion and atrial electromechanical delay: do they vary with the extent of mitral annular calcification? Acta Cardiol 2016; 71(4):449-455.

8. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J 2005; 26(2):319-338.

9. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2016; 17(12):1321-1360.

10. Çiftel M, Yılmaz O, Kardelen F, Kahveci H. Assessment of atrial electromechanical delay using tissue Doppler echocardiography in children with asthma. Pediatr Cardiol 2014; 35(5):857-862.

11. Bin Salih SA, Showlag MS, Al-Qahtani MA, Taha A, Yousuf M, Abdullah M. Clinical characteristics of patients with atrial fibrillation at a tertiary care hospital in the central region of Saudi Arabia. J Fam Community Med 2011; 18(2):80-84.

12. Murphy DM, O’Byrne PM. Recent advances in the pathophysiology of asthma. Chest 2010; 137(6):1417-1426.

13. Decloedt A, Borowicz H, Slowikowska M, Chiers K, van Loon G, Niedzwiedz A. Right ventricular function during acute exacerbation of severe equine asthma. Equine Vet J 2017; 49(5):603-608.

14. MacNee W. Pathophysiology of cor pulmonale in

chronic obstructive pulmonary disease. Part One. Am J Respir Crit Care Med 1994; 150(3):833-852.

15. Ozdemir O, Ceylan Y, Razi CH, Ceylan O, Andiran N. Assessment of ventricular functions by tissue Doppler echocardiography in children with asthma. Pediatr Cardiol 2013; 34(3):553-559.

16. Shedeed SA. Right ventricular function in children with bronchial asthma: a tissue Doppler echocardiographic study. Pediatr Cardiol 2010; 31(7):1008-1015.

17. Mita N, Kuroda M, Miyoshi S, Saito S. Association of preoperative right and left ventricular diastolic dysfunction with postoperative atrial fibrillation in patients undergoing lung surgery: a prospective observational study. J Cardiothorac Vasc Anesth 2017; 31(2):464-473.

18. Shimony A, Afilalo J, Flynn AW, Langleben D, Agnihotri AK, Morin JF, et al. Usefulness of right ventricular dysfunction to predict new-onset atrial fibrillation following coronary artery bypass grafting. Am J Cardiol 2014; 113(6):913-918.

19. De Vos CB, Weijs B, Crijns HJ, Cheriex EC, Palmans A, Habets J, et al. Atrial tissue Doppler imaging for prediction of new-onset atrial fibrillation. Heart 2009; 95(10):835-840.

20. Hizal F, Ozturk S, Baltaci D, Donmez I, Alçelik A, Ayhan S, et al. Detection of atrial electromechanical dysfunction in obesity. Acta Cardiol 2015; 70(6):678-684.

21. Schotten U, Neuberger H-R, Allessie MA. The role of atrial dilatation in the domestication of atrial fibrillation. Prog Biophys Mol Biol 2003; 82(1-3):151-162.

22. Yücel O, Yildiz M, Altinkaynak S, Cevirme AS. P-wave dispersion and P-wave duration in children with stable asthma bronchiale/Stabil astimli çocuklarda P dalga dispersiyonu ve P dalga süresi. Anadolu Kardiyoloji Dergisi 2009; 9(2):118-122.



Original Article


Complications and specimen quality in transrectal ultrasound guided prostate biopsy:

Comparison of 16G and 18G needles

ABSTRACT

KEY WORDS: biopsy, needle size, prostate, transrectal ultrasound

Ahmet Murat Bayraktar1, Erkan Olcucuoglu2, Eray Hasirci3, Ismail Nalbant4, Suleyman Yesil5

1Clinic of Urology, Konya Training and Research Hospital, Konya, Turkey2Clinic of Urology, Türkiye Yüksek Ihtisas Training and Research Hospital, Ankara, Turkey

3Clinic of Urology, Baskent University Medical Faculty, Ankara, Turkey4Clinic of Urology, Ordu University Medical Faculty, Ordu, Turkey

5Clinic of Urology, Gazi University Medical Faculty, Ankara, Turkey

Objectives: To evaluate specimen quality, pathological results, complications and pain in transrectal ultrasound (TRUS) guided prostate biopsy using 16 gauge (G) or 18G biopsy needlesDesign: Retrospective studySetting: Türkiye Yüksek Ihtisas Training and Research Hospital, Ankara, Turkey Subjects: Retrospective analysis of 243 TRUS guided prostate biopsies between March 2011 and April 2016Interventions: Group 1 (n=121) underwent TRUS guided prostate biopsy using a 16 G needle and Group 2 (n=122) underwent TRUS guided prostate biopsy with an 18 G-needle. Main outcome measures: We compared two biopsy needle sizes (16G vs 18G) in relation to sample quality, prostate cancer detection rate, pain, bleeding and infection rates in 243 patients. Core fragmentation and short specimen length (<10mm) rate were the sample

quality criteria. Pain was evaluated using visual analog scale (VAS).Results: There were no statistically significant differences in mean patient ages, prostate-specific antigen values and prostate volumes between groups 1 and 2. Sixteen gauge needles caused significantly less fragmentation of the biopsy cores when compared to 18G needles (p=0.00), but no statistically significant difference between two groups was recorded for pathological results (p=0.72) and shorter specimen length (p=0.567). Haematuria, rectal bleeding and infection were similar in both groups. Mean VAS score of group 1 was significantly greater than that of group 2 (3.19 vs 2.66;p=0.027). Conclusion: Though thicker needles provided better sampling quality, the cancer detection rate was not altered by the needle size. Also, even though complication rates were similar for different needle sizes, the 18G needles were better tolerated.

Address correspondence to:Ahmet Murat Bayraktar, Konya Training and Research Hospital, Konya, Turkey. Tel: +90 5336095220; Fax: +90 3323241854; E-mail: [email protected]

INTRODUCTIONThe main method of diagnosing prostate cancer

is by performing prostate biopsy (PB). While finger-guided and lesion-focused techniques were used in the past, it has recently become a standard diagnostic method to perform systematic prostate biopsies under the guidance of transrectal ultrasound (TRUS)[1]. Over the years, various biopsy schemes have been proposed to make PB more accurate and to avoid error in diagnosis. Currently, with the opinion that sextant biopsy (the first described method) is inadequate

for diagnosis, there is still no consensus about the optimal number of cores and core localization[1,2]. The diagnostic accuracy of PB may be increased by increasing the volume of the tissue and sampling quality[3]. For this purpose, it is recommended to use larger needles that can receive larger volumes of tissue, but it is thought that the risk of complications such as pain and bleeding may increase as a result[4]. Today, 16G and 18G needles are widely used in PB. When compared with 18G needle, 16G biopsy needle can theoretically take larger and better quality samples

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and make more accurate pathologic evaluation due to its larger calibre, but there aren’t enough studies in the literature that compare the two different PB needles.

In this study, we aimed to compare 18G and 16G PB needles in terms of prostate cancer detection rate; morbidities such as pain, bleeding and infection; and sampling quality in TRUS-guided PB.

SUBJECTS AND METHODSClinical and pathological data from 243 patients

who underwent 16 cores TRUS-guided transrectal PB because of elevated prostate-specific antigen (PSA) level between March 2011 and April 2016 were analyzed retrospectively. Patients with total PSA levels between 4 and 10 ng/ml, who had no history of anticoagulant or antiplatelet drug use, bleeding disorder and prostatic surgery were included in the study. Patients with suspicious lesions detected on rectal examination or TRUS were excluded. One hundred and twenty-one patients underwent PB with 16G needle between March 2011 and February 2013 while 122 underwent PB with 18G needle between March 2013 and April 2016.

Prostatic biopsies were performed by two experienced urologists. All patients were started on ciprofloxacin 500 mg twice daily one day before the procedure for prophylaxis and continued until three days after the procedure. All patients were given detailed information about the PB and signed a consent form. PB was routinely performed in the lateral decubitus position following rectal enema. Periprostatic nerve block was performed by injecting a total of 10 ml 2% prilocaine into the junctional area between seminal vesicles and the prostate, including 5 ml on each side. Prostatic volume was then calculated by the ellipsoid formula using 6.5-Hz ultrasound probe. All patients underwent a total of 16 cores PB using 25 cm 16G or 18G biopsy needles from both right and left lobes of the prostate including two lateral peripheral (basal, midgland), three far lateral peripheral (basal, midgland apical) and three medial (basal, midgland, apical). Each sample was sent for pathological examination in separate bottles containing 10% formalin.

Severity of pain during prostatic biopsy was graded from 0 to 10 by using the visual analog scale (VAS). Evaluation of morbidity was generally made one week after the procedure. Hematuria and rectal bleeding was evaluated using Clavien-Dindo classification of surgical complication[5] which was systematized for PB by Cicione and colleagues[6]. According to this system, rectal bleeding that occurs after biopsy is classified as follows; grade 0: no or very little bleeding; grade 1: bleeding that stops by compressing rectal mucosa without requiring endoscopic treatment, electrolyte infusion or hemostatic medication; and grade 2:

bleeding that requires endoscopic or pharmacological treatment. Fever of 38 °C and above that occured within 48 hours after the procedure and that required parenteral antibiotic treatment was considered as procedure-induced infection. The following criteria were used to evaluate the sampling quality: having fragmented cores and shorter length of prostatic tissue in non-fragmented cores (core length <10 mm)[4,6].

Data from patients who underwent biopsies with 18G and 16G needles were compared in terms of age, prostatic volume, total and free PSA, treatment induced pain (VAS), the quality of the sampling, detection rate of prostate cancer and morbidity. Since the study is retrospective, there is no ethical commitee approval and patient’s consent in our study.

Statistical analysisIndependent sample t-test and chi-square test were

used for statistical analysis. All data were analyzed using SPSS (Statistical Package for the Social Sciences, Inc., Chicago, IL, USA) 16.0 for Windows programme.

RESULTSData from a total of 243 patients including 121

patients who underwent biopsy with 16G PB needle (Group 1) and 122 patients with 18G PB needle (Group 2) were analyzed. There was no statistically significant difference between the groups in terms of patient age, prostatic volume, total and free PSA values (Table 1).

Baseline demographics

Group 1(n = 121)

Group 2(n = 122)

p-value

Age (years)Mean ± SDRange

Vp (cc)Mean ± SDRange

Total PSA (ng/ml)Mean ± SDRange

Free PSA (ng/ml)Mean ± SDRange

64.38 ± 7.048 - 78

52.16 ± 22.0115 - 115

6.90 ± 2.034.14 – 9.89

1.37 ± 0.580.16 – 3.19

65.0 ± 7.9456 – 76

56.47 ± 20.4230 – 150

7.15 ± 1.884.06 – 9.96

1.53 ± 0.760.26 – 3.04

0.33

0.228

0.441

0.22

Table 1: Age, prostatic volume, total and free PSA values in two groups

Vp: Prostatic volume; SD: Standard deviation; PSA: Prostate specific antigen

After pathological evaluation, benign pathology was detected in 140 (57.6%), prostate cancer in 80 (32.9%) and atypical small acinar proliferation (ASAP) in 23 (9.4%). There was no statistically significant difference between the groups in terms of cancer, benign pathology and ASAP detection rates (p = 0.72) (Table 2).

Mean VAS scores for pain were 3.19 ± 1.58 and 2.66 ± 1.23 in Groups 1 and 2, respectively and the difference

Complications and specimen quality in transrectal ultrasound guided prostate biopsy: Comparison of ...


was statistically significant (p = 0.027). There was no statistically significant difference between the groups in terms of complications (p = 0.842) (Table 3).

Pathologyn(%)

Group 1(n = 121)

Group 2(n = 122)

Benign Prostate cancerASAP

68 (56.1%)39 (32.2%)14 (11.5%)

72 (59.01%)41 (33.6%)9 (7.37%)

Complication Group 1(n = 121)

Group 2(n = 122)

HematuriaGrade 0Grade 1Grade 2

Rectal bleedingGrade 0Grade 1Grade 2

Infection

112 (92.56%)9 (7.43%)

0

112 (92.56%)9 (7.43%)

02 (1.65%)

115 (94.45%)7(5.73%)

0

116 (95.08%)6 (4.91%)

02 (1.63%)

Table 2: Pathology reports of two groups (chi-square test)

Table 3: Comparison of the complications in two groups. (chi-square test)

Table 4: Comparison of sampling quality of two groups (chi-square test)

Sample quality Group 1(n = 121)

Group 2(n = 122) p-value

Fragmentation1 core2 cores3 cores4 cores5 cores6 cores

<10 mm sample1 core2 cores3 cores4 cores

17 (14.04%)20 (16.52%)10 (8.26%)5 (4.13%)5 (4.13%)

0

46 (38.01%)19 (15.7%)5 (4.13%)

0

66 (54.09%)22 (18.03%)10 (8.19%)3 (2.45%)2 (1.63%)2 (1.63%)

36 (29.50%)17 (13.9%)10 (8.19%)2 (1.63%)

0.00

0.567

When compared to 18G needles, 16G needles were found to cause less fragmentation (p = 0.00), but the difference in sampling rate of <10 mm length was not statistically significant between the groups (p = 0.567) (Table 4).

DISCUSSION Today, TRUS-guided PB is the main diagnostic

method used in the diagnosis of prostate cancer. In various studies, as the first identified scheme for PB, sextant biopsy has been reported to overlook the existing cancer in up to 30% of the cases[2,7]. Therefore, the common view is that sextant biopsy is inadequate and outdated in the diagnosis of prostate cancer[1]. Effectiveness of different biopsy schemes have been

investigated in order to reach the correct diagnosis. While different PB schemes were identified by increasing the number of cores, there is still no biopsy scheme that is generally standardized and accepted. Scattoni et al[8] investigated the ideal number of cores in PB for the diagnosis of prostate cancer in their study and they concluded the most ideal core number as between 10 to 16 depending on digital rectal examination findings, prostate size and age. In another study, saturation (20 cores and more) biopsy was concluded to be unnecessary for first time biopsies due to increase in morbidity[9]. Therefore, it is reasonable to perform saturation biopsy in patients with previously negative biopsies and rising or persistent high PSA levels. Although it is not a generally accepted scheme, it is recommended to take biopsies from between 10 and 18 cores as lateral as possible for the first biopsy[1]. In our own practice, we usually carry out a total of 16 cores sampling including six far lateral peripheral, four lateral peripheral and six medial.

The second way to increase the reliability of prostate biopsy is providing the pathological specimen in adequate quantity and quality. Theoretically, if the needle used for this purpose is longer or larger in caliber, the samples taken in each core would be in larger volume and better quality. Supporting this hypothesis, Dogan et al[10] reported that tissues obtained in biopsies using longer needles (end cut, 33 mm) were superior in quantity and quality, while cancer detection rate was not different when compared with the needles in the standard size (side notch, 22 mm). However, Özden et al[11] concluded that taller needles (end-cut, 33 mm) did not provide any advantage in sampling quality compared with the standard needle.

Recently, standard (side-notch) 16G and 18G biopsy needles are widely used in PB. When compared, 16G and 18G needles are equal in length while 16G needle is thicker and has more volume by up to 1.5 times. Therefore, it can theoretically be expected to obtain larger tissues in quality and volume in biopsies with 16G needle. At the same time, increasing the thickness of the biopsy needle may lead to an increase in complications. Helbich et al[12] compared 16G and 18G needles in breast biopsies and concluded that 16G needle has reached better sampling quantity and quality. In this topic, there are only a few number of studies in the literature. Inal et al[13] compared their PB outcomes of 103 patients conducted with 16G needle and 101 patients with 18G needle. They concluded better sampling quality in the first group while prostate cancer detection rates, complications and VAS pain scores were not different from the second group. Cicione et al[6] investigated the effects of PB with 16G and 18G needles on cancer detection rate, sampling quality and morbidity; no significant differences were reported in any of these three criteria.

p-value

0.72

p-value

0.842

ASAP: atypical small acinary proliferation

June 2020137

In our study, 16G needle led to less core fragmentation when compared with 18G. However, there were no significant differences between the number of cores containing samples less than 10 mm. Even though sample quality is better with the 16G needle, there was no statistically significant difference between the two groups in terms of prostate cancer and ASAP detection rates.

We also observed that our patients had difficulty in tolerating PB as the needle size increased. VAS pain scores were significantly higher in 16G needle biopsy group. This can be a result of ineffectiveness of peri-prostatic block on rectal mucosa and contact of the thicker needle with the rectal mucosa. Intrarectal pomads and gels with local anesthetics in addition to the peri-prostatic block can be useful in patients during biopsy with thicker needle. Giannarini et al[14] concluded less pain scores in patients who underwent PB with peri-prostatic block in combination with intrarectal lidocaine-prilocaine cream, when compared with peri-prostatic block alone.

In our study, complication rates such as hematuria, rectal bleeding and infection were not significantly different between the two groups. Bleeding that required endoscopic or pharmacological treatment (grade 2) were not observed in both groups. Infection that required parenteral antibiotic therapy was observed only in four patients, two in each group. In parallel with our results, previous studies reported no increase in complications in transrectal PB with thicker needles[6,7,13]. Giovanni et al[4] also reported that increase in needle size did not result in a change in the complication rate of transperineal PB.

CONCLUSION We conclude that thicker needles did not provide

any significant advantage. Though thicker needles provided better sampling quality, the cancer detection rate was not altered by the needle size. Also, even though complication rates were similar for different needle sizes, the 18G needles were better tolerated. Further prospective and randomized trials with larger series are required to determine if 16G needle provides any advantage.

ACKNOWLEDGMENTConflicts of interest: The authors declare no

conflicts of interest.

REFERENCES

1. Heidenreich A, Bellmunt J, Bolla M, Joniau S, Mason M, Matveev V, et al. EAU guidelines on prostate cancer. Part 1. Screening,diagnosis and treatment of clinically localised disease. Eur Urol 2011; 59(1):61-71.

2. Eichler K, Hempel S, Wilby J, Myers L, Bachmann LM, Kleijnen J, et al. Diagnostic value of systematic biopsy methods in the investigation of prostate cancer: a systematic review. J Urol 2006; 175(5):1605-1612.

3. Ficarra V, Martignoni G, Novella G, Cerruto MA, Galfano A, Novara G, et al. Needle core length is a quality indicator of systematic transperineal prostate biopsy. Eur Urol 2006; 50(2):266-271.

4. Giovanni S, Sighinolfi MC, Francesco F, Stefano DS, Salvatore M, Paterlini M, et al. Does needle caliber affect pain and complication rates in patients undergoing transperineal prostate biopsy? A prospective, randomized trial. Asian J Androl 2009; 11(6):678-682.

5. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6,336 patients and results of a survey. Ann Surg 2004; 240(2):205-213.

6. Cicione A, Cantiello F, De Nunzio C, Tubaro A, Damiano R. Prostate biopsy quality is independent of needle size: A randomized single-center prospective study. Urol Int 2012; 89(1):57-60.

7. McCormack M, Duclos A, Latour M, McCormack MH, Liberman D, Djahangirian O, et al. Effect of needle size on cancer detection, pain, bleeding and infection in TRUS-guided prostate biopsies: a prospective trial. Can Urol Assoc J 2012; 6(2):97-101.

8. Scattoni V, Raber M, Abdollah F, Roscigno M, Deho F, Angiolilli D, et al. Biopsy schemes with the fewest cores for detecting 95% of the prostate cancers detected by a 24-core biopsy. Eur Urol 2010; 57(1):1-8.

9. Pepe P, Aragona F. Saturation prostate needle biopsy and prostate cancer detection at initial and repeat evaluation. Urology 2007; 70(6):1131-1135.

10. Dogan HS, Eskicorapci SY, Ertoy-Baydar D, Akdogan B, Gunay LM, Ozen H. Can we obtain better specimens with an end-cutting prostatic biopsy device? Eur Urol 2005; 47(3):297-301.

11. Özden E, Göğüş Ç, Tulunay Ö, Baltaci S. The long core needle with end-cut technique for prostate biopsy: Does it really have advantages when compared with standard needles? Eur Urol 2004; 45:287-291.

12. Helbich TH, Rudas M, Haitel A, Kohlberger PD, Thurnher M, Gnant M, et al. Evalutation of needle size for breast biopsy: comparison of 14-, 16-, and 18- gauge biopsy needles. AJR Am J Roentgenol 1998; 171(1):59-63.

13. Inal GH, Oztekin VC, Uğurlu O, Kosan M, Akdemir O, Cetinkaya M. Sixteen gauge needles improve specimen quality but not cancer detection rate in transrectal ultrasound-guided 10-core prostate biyopsies. Prostate Cancer Prostatic Dis 2008; 11(3):270-273.

14. Giannarini G, Autorino R, Valent F, Mogorovich A, Manassero F, De Maria M, et al. Combination of perianal-intrarectal lidocaine-prilocaine cream and periprostatic nerve block for pain control during transrectal ultrasound guided prostate biopsy: a randomized, controlled trial. J Urol 2009; 181(2): 585-593.

Complications and specimen quality in transrectal ultrasound guided prostate biopsy: Comparison of ...


Original Article


Factors influencing the acceptance of prenatal testing by pregnant women

ABSTRACT

KEY WORDS: amniocentesis, genetic counselling, invasive prenatal testing

Mehmet Dolanbay1, Mehmet Serdar Kutuk1, Aysecan Terzioglu2, Mahmut Tuncay Ozgun1, Asli Subasioglu3

1Department of Obstetrics and Gynecology, Erciyes University Faculty of Medicine, Kayseri, Turkey2Koc University, School of Nursing and Health Sciences, Istanbul, Turkey

3Department of Genetics, Erciyes University Faculty of Medicine, Kayseri, Turkey

Objectives: To analyze the factors influencing the maternal uptake of invasive prenatal testingDesign: Retrospective clinical studySetting: Erciyes University Obstetric Clinic Perinatology Unit, TurkeySubjects: A total of 1412 referred patients, of whom 291 were offered invasive prenatal testing (20.6%)Intervention(s): 143 women (49.1%) opted for invasive testing (group 1) and 148 women (50.9%) declined (group 2).Main outcome measure(s): We compared the distribution of invasive test uptake relevant to the maternal age, obstetric history, educational level, abnormal screening tests, structural malformations and living area.Results: We offered an invasive prenatal testing to 291 women out of 1412 patients (20.6%) for various reasons. Among

them, 143 women (49.1%) opted for invasive testing and 148 women (50.9%) declined. Abnormal prenatal screening tests were found to have no effect on the uptake of invasive testing by women of advanced maternal age. The only demographic parameter that affects the uptake of invasive testing was the location, and women who were living in the rural areas had a higher rate of uptake (p: 0.026). No statistically significant difference was detected for the uptake of test with respect to age, educational level or previous pregnancy loss (p >0.05).Conclusions: The uptake of invasive diagnostic tests by pregnant women is determined by the complex network of personal and social factors rather than screening tests and maternal age. Therefore, antenatal screening, and genetic counselling program taking into account these factors should be implemented.

Address correspondence to:Mehmet Dolanbay, MD, Department of Obstetrics and Gynecology, Faculty of Medicine, Erciyes University, Gevher Nesibe Hospital, 38039 Kayseri, Turkey. Tel: +905333681211; Fax: +90 3522222376; E-mail: [email protected]

INTRODUCTIONPrenatal screening can identify a high- risk

subgroup for chromosomal trisomies within a population of pregnant women, and thus provides an individualized risk estimation of having a child with one of these disorders. In accordance with the local guidelines, screening may be performed in the first or second trimester, and it involves the use of biochemical tests on maternal serum and or ultrasound (US) scanning of the foetus. The subgroup of women with an increased risk can be offered a prenatal diagnostic testing in order to provide a certain diagnosis.

Every chromosomal disorder is potentially detectable in utero. Thus, any pregnant woman could undergo an invasive procedure to exclude

these conditions, with near 100% certainty. The most common indications that justify prenatal invasive testing are: (1) advanced maternal age; (2) previous pregnancy with autosomal trisomy; (3) parental chromosomal rearrangement; (4) abnormal US findings during the current pregnancy; and (4) increased risk, as calculated from non- invasive screening results, nuchal translucency and maternal serum analyses. The analysis of the foetal chromosomes can be performed using a sample obtained by amniocentesis (AS), chorionic villus sampling (CVS), and cordocentesis, all of which carry a risk of miscarriage reported to be around 0.5% for CVS 1% for AS, respectively[1]. However, for some women, the potential risk of pregnancy loss associated with these diagnostic tests is

June 2020139

too great to warrant an invasive diagnostic test[2,3].The anthropologist Rayna Rapp contends that the mothers and other family members develop multiple forms of strategies and negotiations with the medical doctors in this issue, based on their views on health risks, abortion, kinship and disability[4]. In Turkey, termination of the pregnancy after 10 weeks of gestation can be performed in life threatening congenital anomalies, chromosomal anomalies and when the life of the mother is in danger due to pregnancy complications. However, appropriate legal procedures should be completed before the termination of pregnancy.

Genetic counselling provides patients with the information that allows them to choose the option which best supports their personal values and opinions. We reviewed our patients testing decision following their genetic counselling for a variety of high-risk conditions of foetal chromosomal anomalies. We evaluated the maternal attitude towards the uptake of invasive diagnostic testing from 2010 to 2012 in our regional patient population, from Kayseri and neighbouring cities.

SUBJECTS AND METHODSThis retrospective cohort analysis evaluated

pregnant women who had high risk for chromosomal abnormalities in May 2010 - May 2012 at Erciyes University, Obstetrics and Gynecology, Prenatal Diagnosis Unit. Erciyes University is a tertiary referral center providing care to approximately 2,100,000 women in Kayseri and surrounding cities.

During the study period, the genetic counselling session were performed by two experienced perinatologists (MSK and MTO), who also did the US examinations. Patients signed a written informed consent for examination and we received approval of the study protocol from local institute ethical committee. At the first visit, the patients were asked their age, education, area of living, history of a previous baby with chromosomal abnormality and recurrent fetal loss. The educational level is grouped as uneducated / primary school (low), high school (middle) and university (high). The living areas of the patients were grouped as urban and rural.

The women, who attended our antenatal follow- up clinics during the first three months, are offered first trimester screening that includes nuchal translucency, pregnancy-associated plasma protein-A and free B- hCG. The women who were first seen after the first trimester were routinely offered quadruple or triple test (Alpha Feto Protein, Beta human chorionic gonadotropin, Inhibin A, Estriol). The same screening program was implemented by the local clinics, and no sequential or contingent approach for screening was adopted in our region. A high risk was defined as the combined risk value greater than 1 / 300 at the first

trimester screening, and 1 / 270 in the second trimester tests[1-5]. Women of advanced maternal age (AMA) were informed of the fact that screening tests have limited value in detecting chromosomal abnormality in their age groups (> 35 years) and that normal results do not rule out chromosomal disease. Therefore, invasive testing was offered to all women of AMA irrespective of their screening results. Invasive prenatal testing was also offered to all women who had a previous history of a child with chromosomal abnormality, structural malformation or abnormal USG findings/marker that associated with chromosomal abnormality (nuchal fold thickening, mild ventriculomegaly, nasal bone hypoplasia, echogenic bowel, echogenic focus in the heart).

All invasive diagnostic testing were also performed by the two operators (MSK and MTO). The information regarding the invasive procedure and 1% risk of abortion was also provided before the procedure. Their queries were answered and, if the women opted for the procedure, an informed consent was obtained.

To compare the distributions of invasive test uptake relevant to the maternal age, obstetric history, educational level, abnormal screening tests, structural malformations and living area, chi-square test were used. SPSS 15.0 was used for the analysis of data, and p <0.05 was admitted as statistically significant.

RESULTSIn this study, 1412 women were referred to our

tertiary prenatal diagnosis center. The median age of the women who were offered invasive prenatal testing was 32.8 ± 6.67 years (range: 17 - 47 years). Patient characteristics in the study group are shown in Table 1. We offered invasive prenatal testing to 291

Demographic parameters N ± Standard Deviation

Maternal age (years) (mean ± SD)Gravida (mean ± SD)Nulliparity (%)Twin pregnancy (%)Previous pregnancy loss (%)Assisted reproduction (%)

32.8 ± 6.67 (17-47)2.9 ± 1.75 (0-10)

75/291 (25.7)11/291 (3.7)98/291 (33.6)19/291 (6.5)

Table 1: Patient characteristics in study group

women (291/1412, 20.6%) due to the various reasons cited above. Among them, 143 women (49.1%) opted for invasive testing and 148 women (50.9%) declined. The indications for referrals (first trimester screening test risk, second trimester screening test risk, suspicious congenital malformation, isolated AMA and previous pregnancy with autosomal trisomy) are shown in Table 2. Fifty-one women were referred to us with abnormal first trimester screening test results (51/291, 17.5%), 61 with abnormal second trimester screening test results (61/291, 21%), and 76 women



(76/291, 26.1%) were referred for suspicious structural malformations. Seventeen women had a previous child with chromosomal abnormality (17/291, 5.8%). Isolated advanced maternal age was the indication for referral in 86 women (86/291, 29.5%). A total of 148 women, who were over 35 years old, had either structural malformation or abnormal screening tests (148/291, 50.8%). Thirty-four women of AMA also had abnormal screening tests (34/148, 22.9%). The effects of abnormal screening tests on the uptake of invasive testing in the AMA group are shown in Table 3.

Demographic parameters Invasive testing done n (%)

Invasive testing rejected n (%) p-value

Application reasonFirst trimester screening test riskSecond trimester screening test riskSuspicious congenital malformationIsolated advanced maternal agePrevious pregnancy with autosomal trisomy

Previous fetal lossOne or more than oneNo history of foetal loss

Living areaCountry sideCity centre

ParityNulliparousMultiparous

Maternal age (years)>35<35

Educational levelLowMiddleHigh

32 (62.7)27 (44.3)34 (44.7)43 (50.0)7 (41.2)

44 (44.9)99 (51.3)

43 (60.6)100 (45.5)

38 (50.7)105 (48.6)

75 (50.7)68 (47.6)

86 (48.9)33 (47.1)24 (53.3)

19 (37.3)34 (55.7)42 (55.3)43 (50.0)10 (58.8)

54 (55.1)94 (48.7)

28 (39.4)120 (54.5)

37 (49.3)111 (51.4)

73 (49.3)75 (52.4)

90 (51.1)37 (52.9)21 (46.7)

0.248

0.302

0.027

0.759

0.594

0.805

Table 2: Distribution according to maternal age, obstetric history, educational level and living area at presentation and uptake of invasive tests

Risk factors

Invasive testing done n (%)

Invasive testing

rejected n (%)

p-value

Advanced maternal age (AMA)AMA + high risk maternal serum screening tests

75 (50.7)

20 (58.8)

73 (49.3)

14 (41.2)0.229

Table 3: Analysis of uptake of an invasive test at advanced maternal age.

In the abnormal screening group, women were more inclined for invasive testing when the abnormal screening test was performed in the first trimester than in second trimester; however the difference is not statistically significant (p = 0.248). The only demographic parameter that affects the uptake of invasive testing was location; and women who were living in rural areas had a higher rate of uptake (p = 0.026). No statistically significant

difference was detected for the uptake of test with respect to age, educational level and previous pregnancy loss (p >0.05).

DISCUSSIONThe identification of foetal aneuploidy requires the

incorporation of various risk factors like maternal age and maternal screening results. The family members’ evaluation of the risk of aneuploidy varies depending on their socioeconomic background and education level, as well as any past experience regarding such tests. Genetic counselling for the expectant mother is crucial on such a sensitive issue. Different families may interpret the risk differently and may react differently to similar situations.

Maternal age is an important factor for determining the risk of having a baby with chromosomal abnormality[6]. The American College of Obstetrics and Gynaecology (ACOG) guidelines recommend offering prenatal diagnostics testing for fetal aneuploidy to all pregnant women who will be aged 35 or older at the time of delivery[7]. In some countries, prenatal screening tests are offered to all women including women of AMA. However, diagnostic sensitivity of the screening tests in these age groups is notoriously low with nearly 20% false positivity[8], so that the invasive tests are the only reliable methods for excluding chromosomal abnormalities. The effect of maternal age on uptake of invasive tests had been studied by Nakata et al in a very large population. Their study showed that average AS and CVS uptake increased with increased maternal age, irrespective of

June 2020141

other factors[9]. On the other hand, Sharda S et al did not show a significant correlation between maternal age and invasive test uptake[10]. Similarly, our results showed no statistical difference between women over and under 35 years of age.

In the past ten years, different methods have been suggested to reduce the need for invasive prenatal tests. Nakata et al surveyed the trend in uptake of invasive tests between 2001- 2007 and concluded that implementation of screening tests reduced the invasive procedures, and this trend reversed after 2008, probably due to ACOGs recommendation supporting routine first trimester screening that lead to increased detection of high risk pregnancies[9]. Similarly, Sharda et al reported that the detection of soft markers by the second trimester US was associated with higher acceptance of amniocentesis[10]. Conversely, Wray et al detected a dramatically decreased uptake of invasive testing after the implementation of first trimester screening[11]. Since our study covers the last three years, it is not possible to comment on general trends for the uptake of invasive testing. However, the addition of screening tests had no significant effect on the uptake of invasive testing among the women of AMA.

The effects of ethnic, social, religious and cultural factors on the perception of health, health risks, and the medical/surgical intervention have been studied by obstetrics/gynaecology specialists and medical anthropologists[4-12]. The anthropologists Rayna Rapp and Faye Ginsburg contend that the conceptions of abortion, kinship and disability do not only belong to the cultural realm of beliefs and values, but they are also shaped by concrete economic and social factors, such as the practical logistics of taking care of a child with a disability. Similarly, our study showed that the location of the family is the only significant factor affecting uptake rate. Families who live in rural areas have more financial and social problems in taking care of their disabled children, and can hardly benefit from the special centers for this purpose, which are mostly located in the major cities of Turkey. In contrast, the urban families benefit from a wide array of possibilities, such as regular medical counselling, and governmental and non-governmental organisations for social and medical assistance. Moreover, people in rural areas are much less covered and/or temporarily covered by social security system, which leads them to view having a disabled child as a major financial burden.

The definition of abnormality is also strongly conditioned by social and cultural factors, and the concept of risk is shaped by personal, traditional and religious beliefs, and life experiences. Therefore, the choice of parents in a given population is expected to differ in accordance with their socio-economic profile, religious views, and educational level. For instance, a

study conducted by Vergani et al in Italy demonstrated that the uptake was highly related to women’s a priori opinions about testing and the negative ‘a priori’ attitude towards amniocentesis in particular was the single most important determinant of rejecting the invasive test[13]. Similarly, Kuppermann et al and Baker et al found that African-American women were less likely to undertake the invasive antenatal testing than women of other ethnic groups in their study[14-15]. In fact, the great majority of studies evaluating maternal attitude towards invasive testing are coming from North America, Europe, China, and Israel[9,13-20]. Therefore, this is the first medical study evaluating the uptake of the invasive test in a Muslim population (99%). Previously, Muhsen et al determined that the Israeli-Arab Muslim women with AMA were less likely to undergo an invasive test than other Israeli women[21]. Our results showed that nearly half of all women opted for the invasive test, and this ratio was comparable to other studies. Can Acıksoz, who interviewed the women faced with the decision of undergoing an amniocentesis during their pregnancy in Istanbul, argues that many pregnant women closely follow the foreign and Turkish internet sites, where lay people and medical experts discuss these issues in a less formal manner, and shape their decision accordingly. Acıksoz also notes that the images of “Chernobyl babies”, the malformed foetuses and newborn babies after the Chernobyl nuclear disaster, were displayed quite extensively in the Turkish media since the late 1980s, since Turkey was one of the countries affected by that disaster[22]. Accordingly, those images shaped the collective memory and created a long-term fear and anxiety of having a baby with a genetic disease. The women viewed the genetic evaluations as nerve-wracking tests to pass or fail, and emphasized that they remained undecided on whether to take those tests for several days. Some of them confessed that they delegated this major responsibility by letting their doctors decide for them, or preferred to tackle the daunting problem of disability after childbirth, if the baby is born disabled.

Our experience showed that counselling about invasive testing is difficult, even for women having multiple risk factors for chromosomal abnormality, as many lay people do not understand the concept of probability[23,10]. In Turkey, there are no legal restrictions that regulate antenatal screening for chromosomal abnormalities, and the current practise is largely based on expert opinion and institutional practise. Since the combination of screening modalities even in high risk pregnant women does not change the maternal attitude towards invasive testing, it would be reasonable to embrace a less vigorous and more cost-effective screening approach for chromosomal abnormalities.



CONCLUSIONThe uptake of invasive diagnostic tests by the

future mother is determined by a complex network of personal and social factors, the majority of which could not be revealed here. In order to delineate relationship between these factors, qualitative studies which will be designed to assess the deeper stratum of personal and social issues are needed. The cooperation between perinatologists and social scientists in this area would provide new perspectives, and contribute greatly to the existing literature.

ACKNOWLEDGMENTAll the authors of this study would like to declare

the absence of any potential conflicts of interest, directly or due to relationships with commercial or corporate interests.

This study was not supported by any person or institution.

REFERENCES

1. Tabor A, Vestergaard CH, Lidegaard Ø. Fetal loss rate after chorionic villus sampling and amniocentesis: an 11-year national registry study. Ultrasound Obstet Gynecol 2009; 34(1):19-24.

2. Rapp R. Amniocentesis in sociocultural perspective. J Genet Couns 1993; 2(3):183-196.

3. Lippman-Hand A, Fraser FC. Genetic counseling: provision and reception of information. Am J Med Genet 1979; 3(2):113-127.

4. Rapp R. Testing the Women, Testing the Fetus; The Social Impact of Amniocentesis in America (The Anthropology of Everyday Life). Routledge, Taylor & Frances. New York & London, 1999.

5. Palomaki GE, Knight GJ, McCarthy JE, Haddow JE, Donhowe JM. Maternal serum screening for Down syndrome in the United States: a 1995 survey. Am J Obstet Gynecol 1997; 176(5):1046-1051.

6. Hook EB, Schreinemachers DM, Willey AM, Cross PK. Rates of mutant structural chromosome rearrangements in human fetuses: data from prenatal cytogenetic studies and associations with maternal age and parental mutagen exposure. Am J Hum Genet 1983; 35(1):96-109.

7. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 27: Clinical management guidelines for obstetricians-gynecologists: prenatal diagnosis of fetal chromosomal abnormalities. Obstet Gynecol 2001; 97(5 Pt 1):1-12.

8. Ormond KE. Disclosing genetic research results: examples from practice. Am J Bioeth 2006; 6(6):30-32.

9. Nakata N, Wang Y, Bhatt S. Trends in prenatal screening and diagnostic testing among women referred for advanced maternal age. Prenat Diagn 2010; 30(3):198-206.

10. Sharda S, Phadke SR. Uptake of invasive prenatal diagnostic tests in women after detection of

soft markers for chromosomal abnormality on ultrasonographic evaluation. J Perinatol 2007; 27(9):550-555.

11. Wray AM, Ghidini A, Alvis C, Hodor J, Landy HJ, Poggi SH. The impact of first-trimester screening on AMA patients’ uptake of invasive testing. Prenat Diagn 2005; 25(5):350-353.

12. Rapp R, Ginsburg F. Enabling Disability: Rewriting Kinship, Reimagining Citizenship. Public Culture 2001; 13(3):533-556.

13. Vergani P, Locatelli A, Biffi A, Ciriello E, Zagarella A, Pezzullo JC, et al. Factors affecting the decision regarding amniocentesis in women at genetic risk because of age 35 years or older. Prenat Diagn 2002; 22(9):769-774.

14. Kuppermann M, Learman LA, Gates E, Gregorich SE, Nease RF Jr, Lewis J, et al. Beyond race or ethnicity and socioeconomic status: predictors of prenatal testing for Down syndrome. Obstet Gynecol 2006; 107(5):1087-1097.

15. Baker CL, Feldman B, Shalhoub AG, Ayoub MA, Krivchenia EL, Yaron Y, et al. Demographic factors for utilization of invasive genetic testing after multifetal pregnancy reduction. Fetal Diagn Ther 2003; 18(3):140-143.

16. Marini T, Sullivan J, Naeem R. Decisions about amniocentesis by advanced maternal age patients following maternal serum screening may not always correlate clinically with screening results: need for improvement in informed consent process. Am J Med Genet 2002; 109(3):171-175.

17. Urban MF, Stewart C, Ruppelt T, Geerts L. Effectiveness of prenatal screening for Down syndrome on the basis of maternal age in Cape Town. S Afr Med J 2011; 101(1):45-48.

18. Kaiser AS, Ferris LE, Katz R, Pastuszak A, Llewellyn-Thomas H, Johnson JA, et al. Psychological responses to prenatal NTS counseling and the uptake of invasive testing in women of advanced maternal age. Patient Educ Couns 2004; 54(1):45-53.

19. Lo TK, Lai FK, Leung WC, Lau WL, Tang LC, Chin RK. A new policy for prenatal screening and diagnosis of Down syndrome for pregnant women with advanced maternal age in a public hospital. J Matern Fetal Neonatal Med 2010; 23(8):914-919.

20. Nazaré B, Fonseca A, Gameiro S, Canavarro MC, Dattilio FM. Amniocentesis due to advanced maternal age: The role of marital intimacy in couples’ decision-making process. Contemporary Family Therapy 2011; 33(2):128-142.

21. Muhsen K, Na’amnah W, Lesser Y, et al. Determinates of underutilization of amniocentesis among Israeli Arab women. Prenat Diagn 2010; 30(2):138-143.

22. Açıksöz C. [The Story of a Test: A Short History of Amniocentesis in Istanbul]. Istanbul 2004; 48:119-121.

23. Phadke SR, Thakur S, Sankar VH. Utility of information brochure as a part of pretest counselling for Down Syndrome screening: Indian scenario. Perinatology 2005; 7:176-182.


Original Article


The biofilm formation properties of the S. epidermidis isolates obtained from conjunctiva

and multi-drug resistance

ABSTRACT

KEY WORDS: congo red agar, eye, ica gene, microtiter plate, ocular surface

Sertac Argun Kivanc1, Volkan Kilic2, Berna Akova1, Merih Kivanc2 1Department of Ophthalmology, Bursa Uludağ University, School of Medicine, Bursa, Turkey2Department of Biology, Eskisehir Technical University, Faculty of Science, Eskisehir, Turkey

Objective: Biofilm was shown on ocular abiotic surfaces such as contact lenses, intra-ocular lenses, glaucoma shunts and corneal sutures. The aim of this study is to compare success of Microtiter plate (MTP) and Congo Red Agar (CRA) methods in showing biofilm formation of S.epidermidis isolates that were obtained from conjunctiva regarding presence of icaA gene locus and multi-drug resistance. Design: Interventional Setting: Department of Biology, Faculty of Science, Eskisehir Technical UniversitySubjects: S. epidermidis isolates obtained from conjunctivas of healthy patientsInterventions: MTP and CRA methods and antibiotic susceptibility tests were done and scanning electron microscopy was performed.Main outcome measures: Biofilm forming capacity, multidrug resistance states and bacterial adhesion of S.

epidermidis Results: Nine isolates were found as strong biofilm producers with MTP and CRA methods. There were six icaA negative isolates, one of which was not a biofilm producer. From the icaA and icaD positive isolates, 13 were biofilm negative with MTP method and seven were biofilm negative with CRA method. Eighteen isolates were determined as resistant to three or more antibiotics. Ten of 18 isolates were strong biofilm producer with MTP and eight of 18 isolates were strong biofilm producer with CRA. Biofilm producer isolates were found to be resistant to antibiotics.Conclusion: It is noted that biofilm formation capacity of S. epidermidis isolates that were obtained from ocular surface were determined and multidrug resistance were estimated more successfully with MTP method. However, there is no method which can successfully detect biofilm formation capacity with 100% accuracy.

Address correspondence to:Prof. Dr. Merih Kivanc, Department of Biology, Eskisehir Technical University, Faculty of Science, 26470 Eskişehir, Turkey. Tel: +90 222 3350580 / 4725; Fax: +90 222 3204910; E-mail: [email protected]

INTRODUCTIONStaphylococci are opportunistic pathogens for

humans and animals, and colonize in various parts of the human body. Slime factor generation and biofilm formation are among the factors of pathogenicity[1]. It was shown that staphylococci were able to hold onto medical devices through these slime properties. Staphylococcus epidermidis is frequently isolated during infections associated with medical devices. S. epidermidis is part of the normal skin flora and mucous membranes, but can enter into the body while attaching bio-materials or during operation. In recent

years, with the increasing use of medical materials such as intravascular catheters, vascular grafts, sutures and orthopaedic devices, S. epidermidis has become the most frequently isolated bacteria in nosocomial and biomaterial-based infections[2,3]. As the eye was first shown on ocular abiotic materials such as contact lenses, intraocular lenses, glaucoma shunts, corneal sutures and scleral cerclage bands, biofilm was also associated with some chronic infections such as diffuse lamellar keratitis and infectious crystal keratopathy, as well as ocular abiotic materials such as contact lenses, intraocular lenses, glaucoma shunts, corneal sutures


and scleral cerclage bands[4-7]. S. epidermidis is one of the most frequently isolated microorganisms from acute onset endophthalmitis after cataract surgery[7]. Biofilm formation is one of the most important mechanisms that determine the disease-causing capacity of species. Biofilm-forming microorganisms form the basis of persistent and chronic infections. Biofilm is a colony formed by microorganisms living in a matrix embedded in a polysaccharide matrix, which adheres to a living or inanimate surface. Biofilm is a consortium of various chemical substances, such as exopolysaccharides, proteins, teichoic acids and extracellular DNA, which are formed by bacteria species, strains and environmental conditions (Fig 1). The biofilm-forming bacteria are resistant to antibiotics, disinfectants, phagocytosis and other components of the innate adaptive immune and inflammatory defense system of the host[8]. The production of polysaccharide intercellular adenine (PIA) through enzymes encoding the intercellular adhesion (ica) operon is by far the best-understood mechanism of biofilm development in staphylococci. In particular, icaA and icaD have an important role in the production of S. epidermidis for slime production[9]. In recent years, the identification of S. epidermidis biofilm formation has gained importance in eye infections[3]. Biofilm production can be accomplished by phenotypic methods such as the microtiter plate (MTP) test developed by Christensen et al[10], by the Congo red agar (CRA) test as described by Freeman et al[11], and by the molecular[12] identification of the ica locus. Our aim in this study was to find the most successful method in determining the biofilm development properties of S. epidermidis isolates isolated from the ocular surface, and thus estimating the multiple antibiotic resistance cases. MTP and CRA methods were compared with the presence of the ica gene locus and antibiotic resistance status.

MATERIALS AND METHODSMaterials

In previous studies, icaA and icaD isolated and identified from the conjunctiva of 42 S. epidermidis isolates, whose characteristics were shown in Table 1, was obtained from Eskisehir Technical University Faculty of Science, Department of Biology,

Microbiology Laboratory and used in various studies. Only one of the isolates (CA 11.1) was positive for the biofilm associated protein (bap) gene. The S. epidermidis ATCC 12228 which does not produce biofilms, and the S. epidermidis ATCC 35984 which produces strong biofilms, were used as controls.

MethodsThe potential of S. epidermidis isolates for biofilm

formation was determined by MTP and CRA method.

Determination of biofilm production by MTP methodFresh cultures of microorganisms were prepared

by incubating them in tryptic soy broth (TSB) at 37 °C for 24 hours. These cultures were diluted at the rate of 1:100 with TSB medium containing 2% glucose and transferred to 200 μl of 96 well flat-bottomed ELISA petri. Plates were incubated at 37 °C for 24 hours. At the end of the incubation period, samples were read at 490 nm wavelength with the help of spectrophotometer (Shimadzu, UV-2101PC). After the reading, the nutrient media in the plate was drained and the plate was washed twice with sterile distilled water. 200 μl of 95% ethanol was transferred onto the plate and allowed to stand for 15 minutes. The plate was then evacuated and allowed to air dry for 45 minutes. After the wells were dried, 150 μl of a 1% crystal violet dye solution was added and allowed to stand for five minutes to penetrate into the cells. The dye in the plate was then drained and washed twice with sterile distilled water. Finally, 160 μl of 33% acetic acid was added to the plate and the samples were read with a spectrophotometer [Shimadzu, UV-2101PC) at a wavelength of 570 nm. As a result of the processing, evaluation was made according to changes in color and spectrophotometer values before and after dyeing. According to the results obtained from the MTP method, classification was made in 4 ways[13]:

Optical Density (OD) ≤ Optical Density Limit (ODc): no biofilm formation (-);

ODc ≤ OD ≤ 2 x ODc: weak biofilm (+); 2 x ODc ≤ OD ≤ 4 x ODc: intermediate biofilm (++); 4 x ODc <OD: strong biofilm (+++).All these tests were repeated three times and the

averages were taken.

Fig 1: Biofilm formation stages

June 2020145

Determination of biofilm formation in CRAActivated S. epidermidis cultures in TSB were

inoculated into petri dish containing CRA and the plates were incubated at 37 °C for 24 hours. The morphological appearance of the developing colonies at the end of the incubation period was examined. It was evaluated that the black colonies were positive; the pinkish red colonies which did not change color were negative[11].

Determining the antibiotic sensitivityAntibiotic resistance status of the 42 S. epidermidis

strains was investigated using the Kirby-Bauer disk diffusion method and the Mueller Hinton agar (Merck, Turkey) strain in accordance with the recommendations of the Clinical and Laboratory Standards Institute (CLSI)[14]. In susceptibility tests, cefoxitin (30 μg), ciprofloxacin (5 μg), gentamicin (10 μg), lomefloxacin (10 μg), ceftazidime (30 μg), cefuroxime (30 μg),

The biofilm formation properties of the S. epidermidis isolates obtained from conjunctiva and multi-drug ...

KA 2 HPCA 4.1KA 4.3 HPCA 6.2PCA 6.3PCA 9.6PCA 10.1KA 10.3KA 10.7KA 10.8PCA 11.1KA 11.1 HPCA 11.2PCA 11.2HKA 12.1KA 14.5KA 14.6KA 14.8SKA 14.8BPCA 15.2KA 15.3KA 15.4KA 15.6KA 15.8PCA 17.1KA 17.3KA 17.7KA 17.1KA 17.9PCA 22.2KA22.2ZH[+)PCA 29.1SDA 39.1SDA 44.1SDA 44 [2)SDA 45KA 48.2 H[-)PCA 495PCA4-14PCA8-1

++++++-+++++++++++++++++++++++++-----+++++

++++-+++++++++++++++++++++++++++++++++++++

SRSSSSSRSISISSSSSRSIRSSRRSRRSRSSRSSSRSRRSR

RRIISSRSRRSRSRSIRRSSRSSRRIRRIIRIRSSRRSRRRR

SSSSSSRRSSSSSRSSSSSRRSSRRIRRIIRSSSSSRRRIRR

IRSISSRRRRSSSSSRRSSSRRSSRISRRRSSSSSSSIRRRS

SSSSSSSSSSSISSSSSSSSSSSSISSSSISSSSSSSSSSSS

SSSSSSSSSSSRSSSSSSSSSSSSSSSRSRSSSRRSRSSSSS

SSSSSSSSSSSRSSSSSSSSRSSRSSSSSSSSSSSSRSRRSS

SSSSSSSSSSSSSSSSSSSISISSRRSRSRSSSSSSSRIIRS

RSSSSSRSRRSSSSRSRSSSRRSSRRSSRRSSSSSSSSRRRS

SSSSSRSSSSSSRSIIRSSIRRSSRIIIISSSRSSSRRRRRS

23---14333-3121142-172-37236252-3111637663

+++--++--++-

++++++

---+---

++++-

++++++

++++++

++++

--++++

+++++

++++++

+

+++++++++++

-+++

+-+

+++++-+-+---++++++

++++++++

++++

+--+++++++

++++++

+

Isol

ates

IcaA

IcaD

Cef

urox

ime

Met

hici

llin

Cef

tazi

dim

e

Cip

roflo

xaci

n

Gen

tam

icin

Am

ikac

in

Vank

omic

in*

Gat

iflok

saci

n

Lom

eflok

saci

n

Mok

siflo

xcin

Resi

stan

t ant

ibio

tic n

umbe

r

MTP

CRA

Table 1: IcaA and IcaD genes, antibiotic susceptibility and biofilm formation status of S. epidermidis isolates.

*Minimum inhibitory concentration values were used; MTP: Microtiter plate; CRA: Congo Red Agar


amikacin Moxifloxacin (5μg) antibiotic discs (Bioanalyse, Turkey) were used. Minimum inhibitory concentration (MIC) values of vancomycin (Sigma-Aldrich, Turkey) were determined by microdilution broth method according to CLSI standards. MIC values were interpreted as ≤4: sensitive, ≥32: resistant.

Isolates that were resistant to three or more antibiotics were described as multidrug resistant isolates.

Scanning Electron MicroscopyBacterial adhesion was examined by scanning

electron microscopy and by making some changes according to Okajima et al[15]. S. epidermidis isolates were incubated in TSB containing 2% glucose at 37 °C for 24 hours. Subsequently, the developing culture was diluted 1:100 and placed in 12 wells of polystyrene plaques. After incubation at 37 °C for 24 hours, the wells were drained and washed three times with sterile PBS. Plates were fixed with 2.5% glutaraldehyde in 0.2M sodium cacodylate buffer (pH 7.2) followed by post-fixation with 1% OsO4. Washing was repeated 2 - 3 times with cacodylate buffer. Dehydration with alcohol was performed. After the alcohol series, they were immediately dried in the Critical Point Dryer. The samples were then coated with gold for 1 minute at 40 mA and examined by scanning electron microscopy.

Statistical analysisSPSS 22 (IBM) computer program was used for

statistical analysis. Fisher’s exact probability test and Pearson’s chi-square test were used to compare the MTP and CRA methods with each other and with the absence of ica gene loci. Multinominal regression analysis was performed on multidrug resistance with the MTP and CRA method and biofilm positivity and icaA gene locus positivity. In the statistical tests, p-value was considered to be significant below 0.05.

RESULTSIn our study, S. epidermidis isolates isolated from

42 ocular surfaces were evaluated in terms of biofilm formation by isolate using the MTP (Figure 2) and CRA (Figure 3) methods. The biofilm formation status of the isolates obtained in the test is given in Table 2. Thirty-three isolates (21.2%), which were determined to produce biofilm by the CRA method did not produce biofilm by the MTP method. Of the 28 isolates identified as biofilm by the MTP method, no biofilm was detected in 2 of them (7.1%) by the CRA method. This difference was statistically significant (p = 0.003, Fisher’s exact test). It was found that nine isolates (21.4%) produced strong biofilm with both MTP and CRA methods. Scanning electron microscopy also revealed a three-dimensional biofilm structure in the biofilm-positive isolates after twenty-four hours of

incubation. It was found that there were unoccupied cells on the surface of the non-biofilm isolates (Figure 4A). It was observed that the bacteria were surrounded by gelatinous material (Figure 4B).

Fig 2: Biofilm formation in micro-titrate plaque

Fig 3: Determination of biofilm production by CRA method. A.biofilm negative, B.Mild biofilm, C. Strong biofilm

Method BiofilmMTP

TotalPositive Negative

CRA PositiveNegativeTotal

26228

7714

33942

Table 2: Number of biofilm positive and negative isolates with MTP and CRA methods.

MTP: microtiter plate; CRA: congo red agar

While one of the negative isolates did not form a biofilm, four of them produced a weaker biofilm and one of them a strong one (Table 1). In the case of isolates that were negative for icaA and negative for icaD, while a weak biofilm formation was detected by the MTP method, strong biofilm formation was detected by the CRA method. It was observed that strong biofilm formation occurred in both methods, in the case of icaA, icaD and bap positive isolates. Thirteen (30.95%) and seven (16.67%) of the isolates

A B C

June 2020147

with icaA and icaD-positive by the MTP method and the CRA method were negative, respectively (Table 1). When evaluated separately for both methods, it was found that the distribution of the isolates, which were positive and negative, was similar in terms of biofilm formation (p ≥0.05).

It was found that 20 isolates were resistant to three or more antibiotics. Thirteen (65%) of these isolates produced strong biofilm by at least one of the methods (MTP or CRA). It was found that 11 isolates were resistant to four or more antibiotics and eight of these isolates produced strong biofilm by at least one of the methods. However, it was found that 22 isolates were resistant to two antibiotics or less and six of them were strong biofilm producer isolates (p = 0.029; Fischer exact test) (Table 3). When we look at antibiotic resistance, it was found that strains that form biofilms in both methods were more resistant to antibiotics. It was found that the biofilm formation by the MTP method was significant (p = 0.012; B 0.051% 95 CI 0.005-0.515) when the multinominal regression test for the presence of the icaA gene locus for multidrug resistance (three and over antibiotic resistance) and biofilm development for the MTP and CRA were evaluated.

Fig 4: Scanning electron microscopy photography of biofilm formation. A. Planktonic cells, B. Biofilm formation

Number of resistant antibiotic

Isolate number

Moderate or strong biofilm producer isolates Rate

N N MTP CRABy at least one of the methods

(%)

2≤*3≥* 4≥5≥6≥7

222011873

1118762

675540

6138762

276572888566

N: number; MTP: microtiter plate; CRA: congo red agar*Statistically significant difference (p value=0.029) between 3≥ and 2≤ antibiotic resistance

Table 3: Relation between multidrug resistance rate and biofilm formation

In both methods, it was observed that resistance to methicillin, ciprofloxacin and lomefloxacin in biofilm-forming strains was similar. Eighteen of the strains (42.86%) were resistant to methicillin and 13 (20.57%) to cefuroxime and lomefloxacin. The resistance of amikacin, vancomycin and gatifiloxacin were similar and six (14.28%) strains presented resistance. These strains are the strains in which biofilm formation was



detected by both methods. No gentamicin resistance was detected in the strains. It was found that multiple antibiotic resistance was high in the icaA positive isolates, which was found to produce biofilms by both methods. Lomefloxacin and moxifloxacin-resistant strains produced statistically significant level of biofilms in the MTP (p = 0.049; p = 0.015; Pearson Chi-square test, respectively). No similar result was found for the CRA method.

Multiple antibiotic resistance was detected in an isolate that was icaA negative and did not produce any biofilm. It was found that the biofilm, which was negative for icaA, was positive by the MTP method and the isolate which was negative by the CRA method was resistant to three antibiotics. Two isolates that were icaA negative, but were found as positive by both methods, showed resistance only to amikacin. Resistance to six antibiotics was detected in the isolate which was negative to icaA but found to have strong biofilm by both methods.

DISCUSSIONBiofilm is defined as a colony formed by

microorganisms that are completely different in terms of genetic structure and protein synthesis embedded in an organic exopolysaccharide matrix adhered to a living or inanimate surface and immobilized on each other, on a solid surface or an interfacial surface (Figure 1). Today, it is accepted that microorganisms are in colonies using complex intercellular communication systems to facilitate adaptation to the changing environmental conditions[16]. Presently, two methods (MTP and CRA) are frequently used to determine whether strains produce biofilms. Christensen et al[10] developed the MTP test; in this test, dark colored wells on the microtiter plate indicate strong biofilm formation, while light colored and colorless wells indicate that biofilm formation is either weak or no formation has occurred, respectively (Figure 2). Freeman et al described the CRA test; in this test, if the colonies are black, it is considered that biofilm formation is strong (Figures 3 A-C). Congo red is a coloring matter consisting of a combination of benzidine and naphthionic acid. The mechanism of the CRA in the formation of biofilm is not fully explained, but it shows affinity for Congo red polysaccharides. Since the biofilm is composed of the polysaccharide structure, the colonies appear dark when combined with Congo red. In the colonies that do not form biofilm, light color is seen.

In our study, it was found that 66.67% of 42 S. epidermidis strains isolated from the ocular surface were positive by the MTP method and 78.57% by the CRA method. Statistically, there was a significant difference between the two methods. It was found that the MTP was a more effective method in determining

biofilm and determining multiple drug resistance. Ju´arez-Verdayes et al[17] reported that 66% of

the S. epidermidis isolates isolated from bacterial conjunctivitis, corneal ulcer and endophthalmitis cases formed biofilms. Cantalanotti et al[18] reported that 74% of the S. epidermidis isolates isolated from the samples using bilateral conjunctival soft contact lenses were biofilm generators. Arciola et al[19] found that nine of the 15 isolates of the S. epidermidis isolated from prosthetic infections (60%) were biofilm-positive. Unlike our findings, some researchers reported lower rate of biofilm formation by both methods. Hou et al[20] reported that the clinical isolates of S. epidermidis had a slime-positive rate of 34.38% with the CRA method and 28.13% with the MTP plaque method. Nayak et al[21] reported that while 42.9% of the 382 pathogenic S. epidermidis isolates isolated from the corneal ulcers produced slime, 24.1% of 87 S. epidermidis isolates which were isolated from healthy eyes also produced slime. Özgüneş et al[22] reported that 22% of the 50 coagulase negative isolates they isolated from clinical specimens were slime positive. Scanning electron microscopy images of the biofilm-forming and non-biofilm isolates revealed biofilm structure in bacteria surrounded by the gelatinous material around the biofilm-positive isolates (Figure 4B). The isolates that did not form biofilms were identified to have discrete cells on the surface (Figure 4A).

In a similar study, Hou et al[20] also came up with these types of findings. ica ADBC operon and its product PIA are responsible for biofilm formation in staphylococci. The ica ADBC operon is responsible[23] for the synthesis of poly- N-acetyl-beta-1-6-glucosamine oligomers in the PIA formation in the intercellular adhesion portion of the biofilm formation in staphylococci. The ica genes allow for the synthesis of the ß-1-6 glycosaminoglucan chain, a polysaccharide substance in S. epidermidis. It was found that the icaA and icaD genes were more important in the biofilm formation of S. epidermis. The task of the icaA and icaD genes is to synthesize the sugar oligomers using UDP-N-acetylglucosamine as substrate. While icaA alone exhibited low N-acetylglucosamine transferase activity, significant increase in enzyme activity in the presence of the icaD gene was observed[24].

In our study, while one of the isolates negative for icaA did not form a biofilm, four formed a weak and one a strong biofilm. While weak biofilm formation was detected by the MTP method in the isolates with icaA positive and icaD negative, strong biofilm formation was detected by the CRA method. The formation of biofilms in the icaA or icaD deficiency can be explained by the formation of different carbohydrate biofilms. It is because the biofilm forming monomers may differ. In the case of icaA, icaD and bap positive isolates, on the other hand, strong biofilm formation was observed

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in both methods. It was found that 13 (30.95%) of the icaA and icaD positive isolates were negative by the MTP method and seven (16.67%) were negative by the CRA method (Table 1). Hou et al[20] reported that the eight isolates did not form biofilm despite the presence of the icaA gene. This can be explained by the fact that the presence of genetic biofilm formation capacity of the bacteria does not mean that they will always produce biofilms. While Hou et al[20] reported similar findings, Suzuki et al[25] reported that all of the isolates identified positively by the CRA method were icaA positive. On the other hand, although the isolate Duggirala et al[26] obtained from the corneal scrape was icaA gene negative, it was found that the biofilm was positive with the CRA method. These studies suggest that biofilm has a complex structure that is influenced by many factors.

Bacteria in the biofilm have antibiotic and phagocytosis resistance and have the capacity to maintain their presence. Due to the limited diffusion of antibiotics within the biofilm, different growth rates of bacteria in the biofilm and micro-environmental changes affect the effectiveness of antibiotics[27]. Biofilm infections are usually asymptomatic in the first period. Planktonic (free-form) micro-organisms that periodically detach from the biofilm when host defense resistance drops can lead to acute infection. Protective doses of antibiotics do not affect biofilm, even though they control these microorganisms[28].

In our study, it was found that methicillin, ciprofloxacin, and lomefloxacin resistance were similar in strains that formed the biofilms in both methods. It was found that 18 (42.86%) of the strains were resistant to methicillin 13 (20.57%) to cefuroxime and lomefloxacin. It was revealed that the biofilm-forming isolates had similar amikacin, vancomycin and gatifiloxacin resistance, and six (14.28%) strains presented resistance. These strains are the strains in which biofilm formation is identified by both methods. Gentamicin resistance has not been detected in the strains. It was found that 18 isolates were resistant to three or more antibiotics. Ten isolates, on the other hand, it was revealed, were resistant to four or more antibiotics. It was found that 10% of these isolates produced strong biofilm by the MTP method and 8% by the CRA method. On the other hand, 7% and 5% of these isolates produced strong biofilms by the MTP and the CRA methods, respectively. When we examine the antibiotic resistance, it was found that the strains that formed biofilms in both methods were more resistant to antibiotics. Similarly, Bozkurt et al[29] reported that there was higher antibiotic resistance in slime positive strains. In contrast to our findings, in the Staphylococcus strains Yasar et al[30] isolated from the clinical specimens, they found no

reduced sensitivity or resistance to glycopeptides. When antibiotic resistance of the slime-positive and negative strains was compared, the expected high resistance was not observed in the positive ones. It was reported that methicillin resistance and overall antibiotic resistance were higher in the slime negative staphylococci. Resistance to four or more antibiotics was detected in the 19.04% of the biofilm-forming isolates and 4.38% of the non-biofilm isolates. Nayak et al[21] on the other hand, reported that they found multiple antibiotic resistance in 39.6% of slime-positive isolates and 22.4% of slime-negative isolates. The microorganisms in biofilm are more resistant to antimicrobial agents in comparison to the planktonic forms. Any microorganism that is not resistant to antimicrobial agents in any way can become resistant by forming a biofilm and become sensitive again when detached from the biofilm. When we look at isolates that did not have the icaA gene available, it was found that biofilm formation was low by both methods.

CONCLUSIONIt is clearly seen that biofilm formation plays an

important role in the development of resistance to antibiotics in vitro. In the present study, even though it was seen that biofilm formation was more successful with the MTP method and multidrug resistance could be predicted more successfully, no one single method was 100% successful in determining the biofilm forming strain.

ACKNOWLEDGMENTThe present study was supported under the

1306F164 project by the Anadolu University research fund.

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2. Sudağıdan M, Erdem I, Cavuşoğlu C, Ciftçiloğlu M. Investigation of the surface properties of Staphylococcus epidermidis strains isolated from biomaterials. Mikrobiyol Bült 2010; 44:93-103.

3. Bilman FB, Can F, Kaya M, Yazıcı AC. Kateter ile ilişkili hastane enfeksiyonlarından izole edilen metisiline direncli Stafilokoklarda biyofilm ile ilişkili antibiyotik duyarlılığının araştırılması. Mikrobiyoloji Bült 2013; 47:401-416.

4. Ahmad S, Ashraf H, Akram SM. Adhesion of Biofilm forming Staphylococcus epidermidis strains on Intraocular Lenses – An Update, In: Méndez-Vilas A editor. The Battle against Microbial Pathogens: Basic Science, Technological Advances and Educational Programs. Badajoz, Spain. Formatex; 2015. p.357-363.



5. Taban M, Behrens A, Newcomb RL, Nobe MY, Saedi G, Sweet PM, et al. Acute endophthalmitis following cataract surgery: a systematic review of the literature. Arch Ophthalmol 2005; 123(5):613-620.

6. West ES, Behrens A, McDonnell PJ, Tielsch JM, Schein OD. The incidence of endophthalmitis after cataract surgery among the U.S. Medicare population increased between 1994 and 2001. Ophthalmology 2005; 112(8):1388-1394.

7. Zegans, ME, Becker, HI, Budzik J, O’Toole G. The role of bacterial biofilms in ocular infections. DNA Cell Biol 2002; 21(5-6):415-420.

8. Fulcher TP, Dart JK, McLaughlin-Borlace L, Howes R, Matheson M, Cree I. Demonstration of biofilm in infectious crystalline keratopathy using ruthenium red and electron microscopy. Ophthalmology 2001; 108(6):1088-1092.

9. Arciola CR, Baldassarri L, Montanaro L. Presence of icaA and icaD genes and slime production in a collection of staphylococcal strains from catheter-associated infections. J Clin Microbiol 2001; 39(6):2151-2156.

10. Christensen GD, Simpson WA, Younger JJ, Baddour LM, Barrett FF, Melton DM, et al. Adherence of coagulase-negative staphylococci to plastic tissue culture plates: a quantitative model for the adherence of staphylococci to medical devices. J Clin Microbiol 1985; 22(6):996-1006.

11. Freeman DJ, Falkiner FR, Keane CT. New method for detecting slime production by coagulase-negative staphylococci. J Clin Pathol 1989; 42(8):872-874.

12. Arciola CR, Campoccia D, Gamberini S, Cervellati M, Donati E, Montanaro L. Detection of slime production by means of an optimised Congo red agar plate test based on a colourimetric scale in Staphylococcus epidermidis clinical isolates genotyped for ica locus. Biomaterials 2002; 23(21):4233-4239.

13. Stepanovic S, Vukovic D, Dakic I, Savic B, Svabic-Vlahovic M. A modified microtiter-plate test for quantification of staphylococcal biofilm formation. J Microbiol Methods 2002; 40(2):175-179.

14. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. 24th Informational Supplement,CLSI Document M100-S24. CLSI, Wayne, PA. 2014.

15. Okajima Y, Kobayakawa S, Tsuji A, Tochikubo T. Biofilm formation by Staphylococcus epidermidis on intra ocular lens material. Invest Ophthalmol Vis Sci 2006; 47(7):2971-2975.

16. Goldstone RJ, Popat R, Fletcher MP, Crusz SA, Diggle SP. Quorum sensing and social interactions in microbial biofilms In Lear G, Lewis G editors. Microbial biofilms Current research and applications. Caister Academic Press. 2012; p.1-25.

17. Juarez-Verdayes MA, Reyes-Lopez MA, Cancino-Diaz ME, Munoz-Salas S, Rodriguz-Martinez S, de la Serna FJ, et al. Isolation, vancomycin resistance

and biofilm production of Staphylococcus epidermidis from patients with conjunctivitis, corneal ulcers, and endophthalmitis. Rev Latinoam Microbiol 2006; 48(3-4):238-246.

18. Catalanotti P, Lanza M, Del Prete A, Lucido M, Catania MR, Galle F, et al. Slime-producing Staphylococcus epidermidis and S. aureus in acute bacterial conjunctivitis in soft contact lens wearers. New Microbiol 2005; 28(4):345-354.

19. Arciola CR, Campoccia D, Gamberini S, Donati ME, Pirini V, Visai L, et al. Antibiotic resistance in exopolysaccharide-forming Staphylococcus epidermidis clinical isolates from orthopaedic implant infections. Biomaterials 2005; 26(33):6530-6535.

20. Hou W, Sun X, Wang Z, Zhang Y. Biofilm-forming capacity of Staphylococcus epidermidis, Staphylococcus aureus, and Pseudomonas aeruginosa from ocular infections. Invest Ophthalmol Vis Sci 2012; 53(9):5624-5631.

21. Nayak N, Satpathy G, Vajpayee RB, Mrudula S. Phenotypic and plasmid pattern analysis of Staphylococcus epidermidis in bacterial keratitis. Indian J Ophthalmol 2007; 55(1):9-13.

22. Özgüneş İ, Yıldırım D, Çolak H, Durmaz G, Usluer G, Akgün Y. Koagülaz negatif Stafilokokların patojenitesi ve antibiyotik duyarlılığı ile slime pozitifliği arasındaki ilişki. Hastane infek. Derg 2000; 4:106-111.

23. Patti JM, Allen BL, McGavin MJ, Hook M. MSCRAMM-mediated adherence of microorganisms to host tissue. Ann Rev Microbiol 1994; 48:585-617.

24. Cramton SE, Gerke C, Schnell NF, Nichols WW, Götz F. The intercellular adhesion (ica) locus is present in Staphylococcus aureus and is required for biofilm formation. Infect Immun 1999; 67(10):5427-5433.

25. Suzuki T, Kawamura Y, Uno T, Ohashi Y, Ezaki T. Prevalence of Staphylococcus epidermidis strains with biofilm-forming ability in isolates from conjunctiva and facial skin. Am J Ophthalmol 2005; 140(5):844-850.

26. Duggirala A, Kenchappa P, Sharma S, Peeters JK, Ahmed N, Garg P, et al. High-resolution genome profiling differentiated Staphylococcus epidermidis isolated from patients with ocular infections and normal individuals. Invest Ophthalmol Vis Sci 2007; 48(7):3239-3245.

27. Stewart PS, Costerton JW. Antibiotic resistance of bacteria in biofilms. Lancet 2001; 358(9276):135-138.

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29. Bozkurt H, Kurtoğlu MG, Bayram Y, Keşli R, Berktas M. Correlation of slime production investigated via three different methods in coagulase-negative staphylococci with crystal violet reaction and antimicrobial resistance. J Int Med Res 2009; 37(1):121-128.

30. Yaşar KK, Bilir YA, Pehlivanoğlu F, Şengöz G. Stafilokok suşlarında slaym faktör pozitifliği, metisilin ve antibiyotik direnci. ANKEM Derg 2011; 25:89-93.


Original Article


Comparison of femoral nerve block and fascia iliaca compartment block for postoperative analgesia following total knee arthroplasty

ABSTRACT

KEY WORDS: fascia iliaca compartment block, femoral nerve block, postoperative analgesia, total knee arthroplasty

Semih Baskan, Duygu Kayar, Dilsen Ornek, Ismail Aytac, Mehmet Gamli, Mustafa BaydarDepartment of Anaesthesiology and Reanimation, Ankara Numune Training and Education Hospital, Ankara, Turkey

Objectives: To compare the analgesic efficacy of a femoral nerve block (FNB) and a fascia iliaca compartment block (FICB) in patients undergoing primary unilateral total knee arthroplasty (TKA) Design: Prospective randomised trialSetting: Orthopaedic operating rooms and services of Ankara Numune Education and Research Hospital, TurkeySubjects: Sixty patients of both genders, aged 40 - 70 years, with an American Society of Anaesthesiology physical status of I, II or III undergoing primary unilateral TKA for osteoarthritis, osteonecrosis or rheumatoid arthritisInterventions: TKA was performed under spinal anaesthesia on all patients with a 25G spinal needle and 3 ml of 0.5% bupivacaine. After surgery, the sealed envelope method was used to randomly assign patients to the FNB (Group 1, n = 30) or FICB (Group 2, n = 30) group, and blocks were

performed using ultrasound guidance.Main outcome measures: The Visual Analog Scale (VAS) from 0 to 10 points measured at 1, 2, 8, 12 and 24 hours postoperatively. Motor and sensory blocks were also evaluated.Results: At all the measurement intervals, the VAS pain scores were higher in patients who had received FICB. At two and eight hours after surgery, patients in FICB group required additional analgesics at a significantly higher rate than those in the FNB group (p<0.05).The time to ambulation was longer in patients in the FNB group.Conclusion: In our study, both methods were found to be efficacious in providing satisfactory postoperative analgesia. However, patients who had FICB mobilised earlier and required earlier analgesic administration compared to the FNB group.

Address correspondence to:Ismail Aytac, Ankara Numune Education and Research Hospital, Hacettepe Mahallesi Talatpaşa Bulvarı No:44 Altındağ, P.O 06100, Ankara, Turkey. Tel: 03125084000; Fax: 03123114340; E-mail: [email protected]

INTRODUCTIONTotal knee arthroplasty (TKA) is a common

surgical procedure frequently associated with severe postoperative pain. Effective analgesia plays a vital role in faster and improved recovery. Postoperative pain relief is a vital criterion for patients undergoing major orthopaedic surgeries[1]. Adequate pain relief has a considerable role in patient recovery, enhancing functional recovery, including the timely recovery of knee mobility, and reducing postoperative morbidity. Effective pain relief results in a reduced risk of postoperative complications such as thromboembolism and hospital-acquired in fections[2] by facilitating

earlier mobilisation. Inadequate analgesia may lead to patient distress, suboptimal knee mobilisation and postoperative complications. These factors may delay rehabilitation and prolong hospital stay[3].

Recently, regional nerve blocks have gained popularity in TKA, as they have the advantage of being able to anaesthetise a large area while being remote from the operative field and spinal cord[4]. Peripheral neural blockade, specifically femoral nerve blockade, has been shown to provide effective analgesia following TKA[5-7]. The knee joint is innervated primarily by the femoral nerve but also receives branches of the obturator and sciatic nerves.


Direct femoral nerve blocks (FNBs) have a recognised incidence of femoral nerve injury and the potential for injury to the femoral vessels[8,9]. It has been proposed that the fascia iliaca compartment block (FICB) avoids these complications by anaesthetising the femoral nerve at a site remote from important neurovascular structures while still providing adequate analgesia[10]. Ultrasound guidance for peripheral nerve blockades, which is intended to improve the block success rate, is increasingly used.

The aim of this study was to compare the analgesic efficacy of FNB and FICB in patients undergoing primary unilateral TKA.

SUBJECTS AND METHODSThis prospective, randomised study was approved

by the Institutional Ethics Committee. The study included 60 patients of both genders, 40 - 70 years old, with an American Society of Anaesthesiology (ASA) physical status of I, II or III undergoing primary unilateral TKA for osteoarthritis, osteonecrosis or rheumatoid arthritis.

Exclusion criteria included obese patients where the block might be anatomically difficult to perform; patients undergoing bilateral TKA; patients with infection at the site of the block; patients receiving routine nonsteroidal anti-inflammatory drugs; narcotic users and those with an allergy to any of the drugs used in this study; a higher ASA physical status; neuromuscular disease; sensory disturbances of the legs; severe diabetes; heart failure (American Heart Association Classification N3); renal impairment (estimated glomerular filtration rate <60 ml.min−1 · 1.73 m−2); liver dysfunction (Child–Pugh Classification Class B or C) or an inability to understand the Visual Analog Scale (VAS).

Informed consent was obtained from all the participants. The patients were randomly allocated using the sealed envelope method to either the FNB (Group 1, n = 30) or FICB (Group 2, n = 30) group. In the operating room, a subarachnoid block was administered to all patients under strict aseptic procedures according to local policy with a 25G spinal needle. After confirming clear cerebrospinal fluid flow, 3 ml of 0.5% bupivacaine was injected. After checking the level of the block, surgery was allowed to commence. The vital signs of the patient were monitored throughout the procedure. At the end of surgery, FNB or FICB was performed under strict aseptic conditions under ultrasound guidance by an experienced anaesthetist when the sensory block regressed to the T12 dermatome.

FNBThe patient was placed in the supine position, the

skin was disinfected, and sterile draping was applied.

A linear US probe (HFL38, 6-13MHz Logiq e, General Electric, USA) was sheathed and placed on the inguinal crest with a slight anterior tilt. The femoral artery and the nerve were identified. A 5 cm needle (21G, Locoplex, Vygon, Ecouen, France) was inserted lateral to the probe and advanced with an in-plane approach towards the femoral nerve. The needle was inserted in-plane from lateral to medial and advanced towards the lateral aspect of the femoral nerve. For all patients, 20 ml of 0.25% bupivacaine was administered to perform the ultrasound-guided FNB.

FICBThe patient was placed in the supine position, the

skin was disinfected, and sterile draping was applied. The femoral artery and vein, femoral nerve, iliopsoas muscle, iliacus muscle and fascia iliaca were identified using a 6-13 MHz linear ultrasound transducer between the anterior-superior iliac spine and the pubic tubercle. The transducer was moved laterally until the sartorius muscle was identified. When the target injection site was determined, a 21-gauge, 10-cm needle (21G, Locoplex, Vygon, Ecouen, France) was inserted in-plane from lateral to medial at the level of the femoral crease to cross the fascia iliaca at the junction of the sartorius and iliacus muscles. As the needle passed through the fascia iliaca, the fascia was first seen to be indented by the needle. As the needle eventually pierced through the fascia, a pop could be felt, and the fascia appeared to “snap” back on the ultrasound image. After negative aspiration, 2 mL of local anaesthetic was injected to confirm the proper injection plane between the fascia and the iliopsoas muscle. Two experienced operators agreed on the needle placement and on the dissemination of local anaesthetic (LA). If the injection resulted in the separation of the fascia iliaca with the LA in the medial-lateral direction from the point of injection, the block was evaluated as successful. When the medial-lateral spread of LA was not achieved with a single injection, additional injections were made.

The primary outcome measure was pain score measured at rest on a VAS from 0 to 10 points at 1, 2, 8, 12 and 24 hours postoperatively. The occurrence of postoperative complications within 48 hours after surgery (new arrhythmia, hypotension with systolic blood pressure <80 mmHg, hypoxia with SpO2 <95%, nausea, vomiting, dizziness, itching, numbness) were recorded and investigated. If nausea or vomiting occurred after surgery, 10 mg metoclopramide was injected intravenously. Patients were instructed to press a call button when they felt postoperative pain, and the pain onset time was recorded. To investigate the duration of the motor nerve paralysis associated with the anaesthesia or nerve block, the time required for the patient to perform plantar flexion or

June 2020153

dorsiflexion of the ankle after surgery was recorded. Patient satisfaction with postoperative analgesia was evaluated by the patients on the VAS 48 hours postoperatively. All evaluations were performed with both subjects and observers blinded to the method of analgesia. All complications were recorded. Prior to discharge, the patients were asked to assess their satisfaction with their anaesthetic experience on a four-point categorical scale (1 = outstanding; 2 = very good; 3 = satisfactory; 4 = unsatisfactory).

Statistical analysisAnalysis of the study data was made using SPSS

19.0 statistics software. Descriptive statistical methods (number, percentage, mean and standard deviation) were used in the evaluation of the qualitative data; and the Pearson chi-square test in comparisons of the qualitative data. Conformity of the data to normal distribution was tested with the Kolmogorov-Smirnov test. In the evaluation of quantitative data showing normal distribution, the independent samples t-test was used. A value of p <0.05 was accepted as statistically significant.

RESULTSTable 1 shows that there was no statistically

significant difference between the groups in terms of demographic parameters (p >0.05).

DemographicsFemoral(n = 30)n (%)

Fascia Iliaca(n = 30)n (%)

p-value

GenderMale Female

Age Height Weight (kg)BMI Operating timeASA IIIIIBlood loss

8 (26.7)22 (73.3)65.0 ± 9.2

161.3 ± 9.386.0 ± 14.333.3 ± 6.2

98.8 ± 19.026 (86.7)4 (13.3)

965.0 ± 208.9

2 (6.7)28 (93.3)63.9 ± 7.4

159.2 ± 5.681.5 ± 11.332.2 ± 4.3

96.5 ± 21.127 (90.0)3 (10.0)

918.3 ± 179.8

0.080

0.6110.2950.1850.4300.6541.000

0.358

Table 1 : Comparison of demographic values

BMI: body mass index; ASA: American Society of Anesthesiologists

A statistically significant difference was found between the groups with regards to the VAS pain scores at the 2nd, 8th, 12th and 24th hours after surgery (Table 2; p <0.05). At all the measurement intervals, the VAS pain scores of patients were higher in the FICB group than in the FNB group. No statistically significant differences were found between groups with respect to the VAS pain scores upon recovery and at the 1st hour (p >0.05).

Table 3 shows that a statistically significant difference was determined between the groups in

VAS Femoral(n = 30)

Fascia Iliaca(n = 30) p-value

Recovery 1st hour2nd hour8th hour12th hour24th hour

1.3 ± 2.42.0 ± 2.52.2 ± 2.22.9 ± 2.12.6 ± 2.02.2 ± 2.1

2.2 ± 2.82.6 ± 2.63.4 ± 2.44.7 ± 1.93.9 ± 2.23.5 ± 2.3

0.1550.3960.0370.0010.0200.019

Table 2: Comparison of VAS between the groups

VAS: visual analog scale

ambulation time (p <0.05). The time to ambulation was longer in the patients who had FNB. No statistically significant difference was determined between the groups with respect to satisfaction, as seen in Table 4 (p >0.05).

Ambulation time Femoral(n = 30)


Hour 44.1 ± 7.0 39.8 ± 9.4 0.028

Table 3: Comparison of ambulation time of the patients between the groups

Evaluation of Satisfaction

Femoral(n = 30)


n % n %

Patient satisfactionGood Moderate Poor

Surgeon SatisfactionGoodModeratePoor

2442

2442

80.013.36.7

80.013.36.7

2073

2082

66.723.310.0

66.726.76.7

0.501

0.428

Table 4: Comparison of patient and surgeon satisfaction between the groups

Tables 5 and 6 summarise sensory and motor examinations, respectively. A statistically significant difference was determined between the groups in the sensory examination values on recovery and at the 1st and 2nd hours following surgery (p <0.05). At all the measurement intervals where a difference was found, the values of the patients in FNB group were significantly higher. No statistically significant difference in sensory examination was determined between the groups at the 8th, 12th and 24th hours (p >0.05).

A statistically significant difference was found between the groups in the motor examination values upon recovery and at the 1st and 2nd hours (p <0.05). At all the measurement intervals where a difference was found, the values of the patients in the FNB group

Comparison of femoral nerve block and fascia ıliaca compartment block for postoperative analgesia following ...


were higher. No statistically significant difference was determined between the groups with respect to the motor examination at the 8th, 12th and 24th hours (p >0.05).

Table 7 shows that a statistically significant difference was determined between the two groups with regards to requests for additional analgesia at the 2nd and 8th hours (p <0.05). At all the measurement intervals where a difference was found, the values of the FICB patients were higher. No statistically significant difference was determined between the groups for the need for additional analgesia upon recovery and at the 1st, 12th and 24th hours (p >0.05).

Sensory Examination

Femoral(n = 30)


Recovery 1st hour2nd hour8th hour

12th hour24th hour

0.9 ± 0.90.8 ± 0.80.4 ± 0.60.0 ± 0.20.0 ± 0.00.0 ± 0.0

0.4 ± 0.60.3 ± 0.60.0 ± 0.00.0 ± 0.00.0 ± 0.00.0 ± 0.0

0.0340.0060.0010.3211.0001.000

Motor Examination

Femoral(n = 30)



12th hour24th hour

0.5 ± 0.70.4 ± 0.60.2 ± 0.50.0 ± 0.20.0 ± 0.00.0 ± 0.0

0.1 ± 0.30.0 ± 0.00.0 ± 0.00.0 ± 0.00.0 ± 0.00.0 ± 0.0

0.0020.0000.0400.3211.0001.000

Table 5: Comparison of sensory examination between the groups

Table 6: Comparison of motor examination between the groups

Additional Analgesia

Femoral(n = 30)



12th hour24th hour

2.0 ± 0.21.7 ± 0.51.6 ± 0.51.4 ± 0.51.4 ± 0.51.6 ± 0.5

1.8 ± 0.41.9 ± 0.31.9 ± 0.31.6 ± 0.51.4 ± 0.51.7 ± 0.5

0.0880.1210.0190.0390.7980.292

Table 7: Comparison of time of administration of additional analgesic between the groups

DISCUSSIONThe time to ambulation was longer in the patients

in the FNB group. At all the measurement times, the VAS pain scores of patients with FICB were higher than those of patients with FNB. In the sensory and motor examinations at all the measurement intervals where a difference was found, the values of the patients with FNB were higher. Analgesic requirements for breakthrough pain were higher in the FICB group.

In our study, the demand for additional postoperative analgesia in patients treated by femoral

block was less in the FNB group, but the time to ambulation and recovery from the motor and sensory blocks was longer than that in the FICB group.

TKA is one of the most frequently performed major orthopaedic surgical procedures. The majority of the patients suffer from severe postoperative pain if not adequately addressed. To ensure a successful outcome, postoperative pain control is one of the most important factors. Effective postoperative analgesia increases patient satisfaction, facilitates rehabilitation and shortens hospital stay[11-15].

Among the various postoperative analgesic techniques in practice to provide effective analgesia following TKA, central and/or peripheral nerve blocks are extremely efficacious. A central neuraxial block provides effective analgesia. The femoral nerve, together with contributions from the sciatic and obturator nerves at the posterior and medial aspects respectively, provides sensory innervation of the knee. These are the three nerves targeted by peripheral nerve block techniques for major knee surgery.

In accordance with the sensory innervation, lumbar plexus and sciatic block will provide effective postoperative analgesia for TKA. However, blocking the plexus and sciatic nerve is a relatively difficult technique, requiring expertise, difficulty in positioning and the potential for complications from use of high doses of local anaesthesia. Combined lumbar plexus and sciatic nerve block can lead to prolonged motor block with delayed mobilisation. Several studies have shown that despite performing a femoral block below the inguinal, it is often associated with blockade of the obturator nerve.

Although the obturator nerve is far more consistently involved with lumbar plexus blocks than with either infra-inguinal technique[5], it is not clear that obturator block translates into improved patient recovery after TKA[5,16]. Magnetic resonance imaging studies have suggested that the local anaesthetic solution predominantly spreads caudally after ‘3-in-1’ block using a peripheral nerve stimulator, blocking the femoral and lateral femoral cutaneous nerves and the anterior branch of the obturator nerve[5,16], although there is some evidence that the latter nerves are more reliably blocked with the more lateral, blind, ‘double-pop’ FICB[5,16].

CONCLUSIONIn our study, both methods were found to be

successful in providing effective postoperative analgesia. However, ambulation in the FICB group occurred earlier than in the FNB group and was associated with faster analgesic needs. In summary, both methods can be performed to provide equally effective analgesia for patients undergoing TKA with comparable safety margins. We found no significant

June 2020155

differences between the two techniques with regard to operability, analgesic effect, and complications in patients undergoing TKA.

REFERENCES

1. Capdevila X, Barthelet Y, Biboulet P, Ryckwaert Y, Rubenovitch J, d’Athis F. Effects of perioperative analgesic technique on the surgical outcome and duration of rehabilitation after major knee surgery. Anesthesiology 1999; 91(1):8-15.

2. Imani F, Safari S. “Pain Relief is an Essential Human Right”, We should be concerned about it. Anesth Pain Med 2011; 1(2):55-57.

3. Safa B, Gollish J, Haslam L, McCartney CJ. Comparing the effects of single shot sciatic nerve block versus posterior capsule local anesthetic infiltration on analgesia and functional outcome after total knee arthroplasty: a prospective, randomized, double-blinded, controlled trial. J Arthroplasty 2014; 29(6):1149-1153.

4. Singelyn FJ, Deyaert M, Joris D, Pendeville E, Gouverneur JM. Effects of intravenous patient-controlled analgesia with morphine, continuous epidural analgesia, and continuous three-in-one block on postoperative pain and knee rehabilitation after unilateral total knee arthroplasty. Anesth Analg 1998; 87(1):88-92.

5. Fowler SJ, Symons J, Sabato S, Myles PS. Epidural analgesia compared with peripheral nerve blockade after major knee surgery: a systematic review and meta-analysis of randomized trials. Br J Anaesth 2008; 100(2):154-164.

6. Capdevila X, Pirat P, Bringuier S, Gaertner E, Singelyn F, Bernard N, et al. Continuous peripheral nerve blocks in hospital wards after orthopedic surgery: A multicenter prospective analysis of the quality of postoperative analgesia and complications in 1,416 patients. Anesthesiology 2005; 103(5):1035-1045.

7. Vloka JD, Hadzić A, Drobnik L, Ernest A, Reiss W, Thys DM. Anatomical landmarks for femoral nerve block: a comparison of four needle insertion sites. Anesth Analg 1999; 89(6):1467-1470.

8. Auroy Y, Benhamou D, Bargues L, Ecoffey C, Falissard B, Mercier FJ, et al. Major complications of regional anesthesia in France: The SOS Regional Anesthesia Hotline Service. Anesthesiology 2002; 97(5):1274-1280.

9. Auroy Y, Narchi P, Messiah A, Litt L, Rouvier B, Samii K. Serious complications related to regional anesthesia: results of a prospective survey in France. Anesthesiology 1997; 87(3):479-486.

10. Lopez S, Gros T, Bernard N, Plasse C, Capdevila X. Fascia iliaca compartment block for femoral bone fractures in prehospital care. Reg Anesth Pain Med 2003; 28(3):203-207.

11. Allen HW, Liu SS, Ware PD, Nairn CS, Owens BD. Peripheral nerve blocks improve analgesia after total knee replacement surgery. Anesth Analg 1998; 87(1):93-97.

12. Hirst GC, Lang SA, Dust WN, Cassidy JD, Yip RW. Femoral nerve block. Single injection versus continuous infusion for total knee arthroplasty. Reg Anesth 1996; 21(4):292-297.

13. Wang H, Boctor B, Verner J. The effect of single-injection femoral nerve block on rehabilitation and length of hospital stay after total knee replacement. Reg Anesth Pain Med 2002; 27(2):139-144.

14. Weber A, Fournier R, Van Gessel E, Gamulin Z. Sciatic nerve block and the improvement of femoral nerve block analgesia after total knee replacement. Eur J Anaesthesiol 2002; 19(11):834-836.

15. Tanikawa H, Sato T, Nagafuchi M, Takeda K, Oshida J, Okuma K. Comparison of local infiltration of analgesia and sciatic nerve block in addition to femoral nerve block for total knee arthroplasty. J Arthroplasty 2014; 29(12):2462-2467.

16. Chan EY, Fransen M, Parker DA, Assam PN, Chua N. Femoral nerve blocks for acute postoperative pain after knee replacement surgery. Cochrane Database Syst Rev 2014 May 13;(5):CD009941.

Comparison of femoral nerve block and fascia ıliaca compartment block for postoperative analgesia following ...


Original Article


Influenza vaccine: Immunization rates, knowledge and attitudes of healthcare workers in Jordan

ABSTRACT

KEY WORDS: attitude, healthcare workers, immunization rate, influenza vaccine, knowledge

Lana Alhalaseh, Nada YaseinDepartment of Family and Community Medicine, School of Medicine, University of Jordan, Amman, Jordan

Objectives: To determine the rate of infleunza vaccination among Jordanian healthcare workers (HCWs) and to study the factors affecting these rates, including their knowledge and attitudes toward influenza infection and immunizationDesign: Cross-sectional studySetting: Jordan University Hospital, a university-affiliated academic centerSubjects: A convenience sample of 744 HCWs recruited after the 2015/2016 influenza season. They included 322 physicians, 156 other medical staff (nurses, pharmacists, technicians, etc.), and 266 non-medical hospital staff.Intervention: A personal interview of HCWs by trained research assistants, using a validated questionnaireMain outcome measures: Demographic characteristics, vaccination rates, knowledge and attitudes of participants, and perceived barriers to vaccination were analyzed.Results: The overall one-year immunization rate was 30.8%

(95% CI: 27.5% - 34.2%) with no significant differences across different job categories. Vaccinated participants achieved a higher mean knowledge score (±SD) compared to their unvaccinated counterparts (5.86 ± 1.15 vs 5.32 ± 1.38 out of 7; p <0.001). The majority of HCWs knew about the importance of receiving the influenza vaccine to protect themselves (89%) and their patients (83%). They cited their job as HCWs and direct contact with severely ill patients as the main reasons for getting vaccinated. The most common barrier to getting vaccinated was having a “strong immune system”. Conclusions: This is the first study in Jordan addressing influenza vaccine among HCWs. It is found that despite having sufficient knowledge on influenza infection and vaccination, and the availability of free vaccine, influenza vaccine coverage remains low among HCWs due to inconsistencies between knowledge and practice.

Address correspondence to:Lana Alhalaseh, MD, MCFP (COE), PO Box 851182 Sweifieh, 11185 Amman, Jordan. Tel: +962-799188896; Fax: +962-6-5355 522; E-mail: [email protected]

INTRODUCTIONInfluenza is a highly contagious upper respiratory

tract disease with high rates of morbidity and mortality, causing up to 500,000 deaths per year worldwide, especially among high-risk groups such as the elderly, immunocompromised, and critically ill patients in healthcare settings[1]. The influenza vaccine has been reported to prevent influenza-related respiratory tract infection, pneumonia, hospitalizations, and mortality by 56%, 53%, 50%, and 68%, respectively[2].

Multiple studies have shown that healthcare workers (HCWs), i.e, persons who provide services, work, volunteer, or train in a healthcare setting, are at increased risk of contracting influenza, and when infected, they can transmit it to their vulnerable

patients[3]. Annual vaccination has been shown to decrease the incidence of influenza infection among HCWs and their patients[4,5]. The World Health Organization, along with other major healthcare organizations worldwide, recommend annual influenza vaccination for all HCWs[3,6-8]. Notably, vaccination of 80% of HCWs may be necessary to achieve herd immunity[9,10]. Despite these longstanding recommendations, the overall rate of influenza vaccination among HCWs remains below the recommended targets throughout pandemic and non-pandemic influenza seasons.

Barriers to immunization range from fear of needles to misconceptions about the influenza vaccine[11,12]. Extensive studies regarding influenza vaccination

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among HCWs have been conducted in Western countries, whereas only a few studies have been conducted in Middle Eastern countries, including Saudi Arabia, Oman, Emirates, Kuwait, Turkey, and Lebanon[13-18]. In Jordan, only two studies have been conducted that included the general population and did not specifically target HCWs[19,20].

This study aimed to determine: (1) the rate of voluntary immunization with the influenza vaccine among HCWs at Jordan University Hospital; (2) the knowledge and attitudes of HCWs regarding the benefits and risks of influenza vaccination; (3) the reasons identified by HCWs for electing or declining immunization; and (4) the appropriate policies to promote acceptable vaccine use.

SUBJECTS AND METHODSStudy design and participants

This cross-sectional study was carried out at Jordan University Hospital, a 550-bed university-affiliated teaching hospital and a tertiary referral center with 2500 employees including, among other staff, 630 physicians, 731 nurses, and 64 pharmacists[21]. Four research assistants, trained by the principal investigator to collect the data through personal interviews, were available during the working hours of the months of March and April, 2016. The hospital floors were divided among the research assistants to prevent duplication of information. The sample size necessary to reach the study objectives was estimated considering a type one error of 0.05, a confidence level of 0.95, a 33% vaccination rate based on our pilot study, and a 0.05 precision level. This showed that a minimum of 340 workers would need to be surveyed. Given that reports suggest a 30% response rate to surveys, it was considered necessary to approach 1500 employees[22]. Of those, 744 eligible HCWs consented to participate in the study with a response rate of 49.6%. Employees who were away during the working hours of these months, those who refused to participate, and those with a contraindication to the influenza vaccine were excluded from the study. Study participants were stratified into three categories: physicians, medical staff, and non-medical staff. The physician group included interns, residents, fellows, specialists, and consultants. The medical staff group included nurses, pharmacists, laboratory and radiology technicians, physiotherapists, and occupational therapists, while the non-medical staff group included accountants, porters, and housekeeping and administrative staff. The study protocol was approved by the Institutional Review Board committee at Jordan University Hospital. All collected data were treated as confidential, and the questionnaires were kept in the principal investigator’s office.

Study instrumentThe questionnaire was developed after reviewing

the scientific literature on the subject. In particular, the questionnaire was based on that used in the study by Khazaeipour et al [23]. The questions were modified by the principal investigator to satisfy the study objectives, and they were tested for validity by three family practice consultants on three separate occasions. Each time, minor changes were made in the layout and the Arabic phrasing of the questions to ensure better understanding. A pilot study was conducted on 50 participants who were not included in the main study. The overall internal reliability (Cronbach’s alpha) was measured at r = 0.7 and was considered acceptable.

The questionnaire had three parts. The first part included questions regarding demographic characteristics, including age, sex, marital status, smoking status, level of education, and questions regarding the frequency of availed immunization in the past three years. The second part included Likert-type questions assessing the HCWs’ knowledge of influenza infection and vaccination, including the risk and severity of influenza infection among HCWs and the efficacy of the influenza vaccine and its side effects and complications. The third part of the questionnaire assessed the attitudes of the respondents toward the vaccine in terms of reasons to get vaccinated and barriers that prevented them from getting vaccinated.

Statistical analysisData were analyzed using SPSS version 23 (SPSS

Inc., Chicago, IL). P-values less than 0.05 were considered significant. Descriptive statistics were used to describe sample characteristics and variables of the study. All Likert-type questions were grouped into two categories: agree and disagree. The total knowledge score then was calculated by summing the total number of correct answers. It ranged between 0 and 7.

Because the data were not normally distributed (Shapiro-Wilk, p = 0.001), the association of demographic variables with the median knowledge score was assessed using Wilcoxon-Mann Whitney-U test for dichotomous variables (gender, marital, smoking and vaccination), whereas Kruskal-Wallis test was used for the polychotomous variables (age groups, levels of education, and job groups). While the Mann-Whitney-U test looks for significance in the difference between medians, we have presented means instead of medians because the knowledge score had only seven whole numbers. Thus, the medians for even significantly different groups were often the same. Presenting the means provides more information, in this case, than presenting the medians. On the other hand, studying the association between vaccination status in relation to the following variables: demographic variables,



item-specific knowledge questions, reasons to get vaccinated and barriers to vaccination, was performed using cross-tabulation, where Chi square test was reported for dichotomous variables and Chi square for linear trend was used for polychotomous variables. When the results of the analyses using the above-mentioned tests showed differences, pair-wise post-hoc comparisons were performed using the Bonferroni procedure.

RESULTSSubject characteristics

A total of 744 HCWs included 43% physicians, 21% medical staff, and 36% non-medical staff agreed to participate in the study. Of those, 59% were men and 41% were women (Table 1).

Vaccination uptake A total of 386 (52%, 95% confidence interval (CI):

48.3% - 55.5%) HCWs had availed of the influenza vaccine in the previous three years, whereas 229 (30.8%, 95% CI: 27.5% - 34.5%) availed of the vaccine during the 2015/2016 influenza season.

There were no significant differences in vaccination rates across different job categories (p = 0.874), age groups (p = 0.274), or levels of education (p = 0.850), as shown in Table 1.

Knowledge and attitudes of participantsThe mean (±SD) knowledge score was 5.49 ± 1.34

out of 7. Vaccinated participants achieved significantly higher mean knowledge scores compared to unvaccinated counterparts (5.86 ± 1.15 vs. 5.32 ± 1.38, p < 0.001). No significant differences were noted in the mean knowledge scores between the physician and medical staff groups (p = 1.00), but both groups scored significantly higher than the non-medical staff group (p <0.001 and p = 0.002, respectively). Moreover, mean knowledge scores were significantly higher in females, unmarried and non-smokers (Table 1).

Table 2 shows the participants’ basic knowledge of influenza infection and vaccination.

Participants who availed the vaccine, compared with those who declined it, were more likely to answer almost all knowledge questions more correctly. Noteworthy, both groups agreed on the importance of the influenza vaccine in preventing seasonal influenza, but those who declined the vaccine did not know enough about its importance in preventing pandemic influenza (p = 0.013).

Meanwhile, post hoc tests showed that physicians were more likely to know about the seriousness of infleunza and its complications, compared to the medical staff group (p = 0.01), and the non-medical group (p = 0.0001). They were also more appreciating

Demographic variables Subgroupn (%)

Mean knowledge score (± SD) p-value

Proportion vaccinated

n (%)p-value

Age (years) 20 - 2930 - 3940 - 49+50

Sex MaleFemale

Marital status Married Single/other

SmokingYesNo

Level of education SchoolCollegeBachelor degreeHigher education

Job category Physicians Medical house staffNon-medical staff

Vaccinated in 2015-2016 YesNo

270 (36)224 (30)180 (24)70 (10)

442 (59.4)302 (40.6)

544 (73)200 (27)

217 (29)527 (71)

97 (13)140 (18.8)304 (40.9)203 (27.3)

322 (43.3)156 (20.9)266 (35.8)

229 (30.8)515 (69.2)

5.60 (1.30)5.52 (1.34)5.33 (1.41)5.31 (1.23)

5.38 (1.35)5.64 (1.32)

5.40 (1.40)5.72 (1.12)

5.17 (1.40)5.61 (1.29)

5.24 (1.24)5.17 (1.50)5.62 (1.27)5.63 (1.33)

5.68 (1.23)5.62 (1.30)5.17 (1.43)

5.86 (1.15)5.32 (1.38)

0.089

0.003*

0.013*

<0.001*

0.001*

<0.001*

<0.001*

73 (27.0)75 (33.5)60 (33.3)21 (30.0)

136 (30.8)89 (29.5)

182 (33.5)47 (23.5)

77 (35.5)151 (28.7)

31 (32.0)45 (32.1)84 (27.6)69 (34.0)

95 (29.5)58 (37.2)76 (28.6)

--

0.274

0.760

0.009*

0.055

0.850

0.874

--

Table 1: Demographic characteristics of the study participants according to knowledge score and vaccination status

* p-value <0.05

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to the increased risk of contracting influenza among HCWs than the medical staff group (p = 0.0001) who, in turn, was more likely to agree than the non-medical group (p = 0.02). In the question about the prevalence of systemic side effects, the medical staff group were more likely to believe that side effects of the vaccine were very common, compared to the physician (p = 0.002) and non-medical staff groups (p= 0.03).

Figure 1 shows the participants’ attitudes towards the influenza vaccine. The most common reasons to avail of the vaccine were: direct contact with critically-ill patients (88.2%), and working as a HCW (83.6%). Compared to unvaccinated participants, vaccinated counterparts were significantly more likely to avail of the vaccine due to the following reasons: working as a HCW (p = 0.0001), being in direct contact with critically ill patients (p = 0.0001), recommended in the guidelines (p = 0.001), a personal history of a bad flu (p = 0.0001), prevention of absenteeism from work (p

= 0.001), and the presence of reported death due to influenza (p = 0.0004).

Physicians were more likely, compared to non-medical staff, to list “working as a health care professional” as a reason to avail of the vaccine (p = 0.007).

Perceived barriers to vaccinationBarriers to getting vaccinated are detailed in Table

3. The most common barriers to availing the influenza vaccine were having a “strong immune system” and “infrequently contracting the flu”. Compared with the physician group, medical staff were more likely to elicit both barriers as reasons for declining vaccination (p <0.0001 and 0.01; respectively). They were also more likely to enlist their concern about the side effects of the vaccine (p = 0.004) as a barrier to vaccination.

Around 55% of the participants considered vaccine availability a barrier to vaccination, especially

Knowledge questionsCorrect answers Total (%)

Proportion vaccinated

n (%)

Proportion unvaccinated

n (%)p- value

Influenza and its complications are very serious among high-risk patients HCWs' risk of contracting influenza is higher than the general population’s Influenza vaccine is effective in preventing seasonal influenza infection Influenza vaccine is effective in preventing the 2009 H1N1 infectionHCWs should receive the influenza vaccine to protect themselves HCWs should receive the influenza vaccine to protect their patients The percentage of vaccine recipients experiencing systemic side effects is uncommon

658 (88.4)610(82.0)686 (92.2)336 (45.2)663 (89.1)616 (82.8)512 (68.8)

214 (93.4)202 (88.2)217 (94.8)119 (52.0)220 (96.1)203 (88.6)168 (73.4)

444 (86.2)408 (79.2)469 (91.1)217 (42.1)443 (86.0)413 (80.2)344 (66.8)

0.004*0.003*0.0830.013*0.001*0.005*0.074*

Table 2: Basic knowledge of influenza infection and influenza vaccine among healthcare workers according to vaccination status

* p-value <0.05

Direct contact with critically ill patients

If you are a healthcare professional

Death-related news in the media

Don’t want to miss work due to influenza

Have had a bad flu previously

Having a chronic illness/poor health

Recommended in the guidelines or by doctors

Fig 1: Reasons to avail of the vaccine



vaccinated HCWs (p = 0.035). Interestingly, physicians were more likely to elicit this factor as a barrier compared to the medical staff (p = 0.048).

Regarding the cost of the vaccine as a barrier to vaccination, there was no statistically significant difference between vaccine recipients and non-recipients. Noteworthy, 48.2% (n = 110) of the vaccinated HCWs were vaccinated for free through the hospital’s Infection Prevention and Control Department, whose personnel administer the vaccine to HCWs for free throughout the flu season. Another 40.4% (n = 92) had the cost partially covered by their medical insurance. Only 11.4% (n = 26) of the employees paid for the vaccine themselves.

DISCUSSIONInfluenza vaccination of HCWs is an evidence-

based intervention that has been suggested as an effective strategy to lower the rates of nosocomial transmission of influenza to patients at high risk of complications[24]. This paper offers the first insight into HCWs’ knowledge and attitude toward the influenza vaccine in Jordan.

The results of this study show that the total vaccination rate remained low (30.8%) among all categories of HCWs during the 2015/2016 influenza season. The rate of HCWs availing of the influenza vaccine varies among different countries, ranging from 7.5% to 63%[25]. Compared with that in Jordan, higher rates have been reported in the USA (72%), Oman (46.4%), Kuwait (67.2%), Iran (67%) and Spain (50.7%), whereas similar rates were found in Saudi Arabia[9,13-15,22,23]. Meanwhile, lower rates were noted in the UAE (24.7%), Qatar (19.4%), Turkey (12.7–23%), Italy (16.7–24%), Israel (16.4%), and Greece (17%)[15,17,26-31].

The low rates of vaccination in our institution might be explained by several reasons related to knowledge and attitude gaps that were apparently affecting our HCWs’ decision to decline the vaccine, despite having a good total knowledge score and the availability of free vaccine through the hospital. The most common misconceptions seen in our study were a perceived “strong” immune system and the rarity of contracting the influenza infection. Similar knowledge gaps

have also been illustrated in different studies[2,32-36]. Indeed, HCWs were found to have altruistic views of vaccination where they tend not to consider themselves as needing vaccination, seeing themselves as strong and healthy compared to their patients[37].

Other misconceptions regarding vaccine’s safety and, to a lesser extent efficacy, were also seen in our study. For example, 69% knew that side effects of the vaccine are uncommon, and, at the same time, 58% elicited their concern about these side effects as a barrier to vaccination. This discrepancy could be due to a perceived seriousness of these “uncommon” side effects. It also suggests that although education on the influenza vaccine is important, it does not always result in vaccination[25]. To further support this notion, note that significantly more of those who had been vaccinated gave a correct answer to almost all the knowledge questions compared to those who had not been vaccinated. A reverse causality could be present in this association, by which those who are vaccinated receive education about the vaccine at the time of vaccination. This shows the need to have other measures undertaken to promote vaccine uptake in an organized institutional system, such as providing modeling and support for influenza vaccination by institutional leaders.

Meanwhile, concerns regarding vaccine efficacy were prevalent in only 22% of our cohort, particularly among unvaccinated HCWs, who addressed this concern as a barrier that impeded vaccination. Specifically, almost 55% of the HCWs believed that the seasonal influenza vaccine distributed during the 2015/2016 season did not have a protective benefit against the 2009 H1N1 strain. This knowledge gap is particularly alarming considering the high rate of influenza A (H1N1)pdm09 in Jordan in 2009, and knowing that the (H1N1)pdm09 virus continues to circulate as a seasonal influenza virus that causes illness and death worldwide every year[38]. These hesitant attitudes toward vaccine safety and efficacy are also corroborated by other studies worldwide[14,25,32,39] and it has been shown that addressing such issues, rather than focusing on the vaccine rejection rates, will help in understanding the main reasons behind HCWs

Most commonly listed barriers Totaln (%)

Proportion vaccinatedn (%)

Proportion unvaccinatedn (%) p- value

Having a “strong immune system” Do not usually contract influenzaConcern about side effectsAvailability of vaccineCostDon't like needlesLack of benefit

572 (76.9)564 (75.8)429 (57.7)407 (54.7)283 (38.0)255 (34.3)166 (22.3)

175 (76.4)166 (73.1)127 (55.9)139 (60.7)84 (36.7)77 (33.9)33 (14.5)

397 (77.8)398 (78.0)302 (58.9)268 (52.3)199 (38.7)178 (34.8)133 (25.9)

0.6690.1460.4580.035*0.5980.8100.001*

Table 3: Barriers to availing of the influenza vaccine as listed by vaccine recipients and vaccine non-recipients

* p-value <0.05

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declining vaccination, and lead to the development of appropriate strategies to encourage vaccination and maintain optimal coverage[37].

Furthermore, availability of the vaccine was a major barrier to immunization among our HCWs, especially among physicians, while cost of the vaccine was not, despite the fact that less than half of the vaccinated employees got their vaccine for free. Research has indicated that cost and availability of the influenza vaccine are the most common barriers to influenza vaccination, especially among busy physicians; hence, providing free and accessible vaccines is the most important reason for availing the influenza vaccine[7,13,15,18,40]. In particular, the Advisory Committee on Immunization Practices has recommended measures to improve the rates of vaccination among HCWs with busy schedules, such as the use of a mobile cart to vaccinate HCWs in the workplace, and increased availability of vaccinating personnel after regular daytime working hours. Since these measures have proven effective in increasing the rates of vaccination among HCWs, they should be considered by our local policy makers[7].

As such, we propose that an effective program, carried out throughout the influenza season, to increase the rate of influenza vaccination among HCWs must: (I) provide annual targeted education addressing the knowledge gaps specific to each HCWs subgroup; (II) provide free vaccines at convenient times and locations, including the cafeteria and hallways, and during physicians’ rounds; (III) recommend that HCWs who decline the vaccination must sign declination statements; and (IV) implement surveillance measures to estimate the impact of local vaccination programs.

The following are the strengths and limitations of this study. The study was conducted in the largest academic hospital in Jordan, serving more than 500,000 patients a year. On the other hand, the possibility of selection bias and other unknown differences between respondents and non-respondents cannot be excluded from this cross-sectional survey. However, considering that a total of 744 HCWs were recruited in this study, we believe that we have captured a wide range of opinions that may reflect real differences between vaccinated and unvaccinated HCWs.

Our findings may be of a limited generalisation because we sampled HCWs working at a single healthcare institution, and we cannot be certain these results are applicable to other groups of HCWs throughout the country.

CONCLUSIONThis is the first study in Jordan that addresses the

influenza vaccine uptake among healthcare workers

and highlights the different factors affecting these rates in the first and largest academic institution in Jordan. The rates of influenza vaccination among Jordanian HCWs remain low despite having a good total knowledge score and the availability of free vaccine. To improve the number of HCWs receiving influenza vaccine, enforcement of knowledge and dispelling myths about the vaccine should be undertaken by physicians and decision makers. Furthermore, inconsistencies between knowledge and practice should be acted upon, and different barriers to immunization peculiar to each specific category of HCWs should be addressed in a way pertinent to that particular group of HCWs in order to improve vaccine uptake across all categories of HCWs, especially those with the closest contact with patients.

In fact, these results should not be limited to Jordan University Hospital and they should be taken into consideration by the Ministry of Health when framing policies at the national level, as the hospital serves half a million patients yearly coming from both urban and rural areas throughout the country, in addition to international patients coming from all over the Arab World, especially the neighboring countries. In addition, these results could be of particular significance to HCWs from other countries with similar risks of acquiring and transmitting infectious diseases, particularly influenza. Thus, further studies are needed at the national level to corroborate our study and help outline local and regional preventive health strategies.

ACKNOWLEDGMENTSThis work was funded by the Deanship of Academic

Research at the University of Jordan.

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13. Alshammari TM, AlFehaid LS, AlFraih JK, Aljadhey HS. Health care professionals’ awareness of, knowledge about and attitude to influenza vaccination. Vaccine 2014; 32(45):5957-5961.

14. Rehmania R, Memon JI. Knowledge, attitudes and beliefs regarding influenza vaccination among healthcare workers in a Saudi hospital. Vaccine 2010; 28(26):4283-4287.

15. Abu-Gharbieh E, Fahmy S, Rasool BA, Khan S. Influenza vaccination: Healthcare workers attitude in three Middle East countries. Int J Med Sci 2010; 7(5):319-325.

16. Arda B, Durusoy R, Yamazhan T, Sipahi OR, Tasbakan M, Pullukcu H, et al. Did the pandemic have an impact on influenza vaccination attitude? A survey among health care workers. BMC Infect Dis 2011; 11:87.

17. Savas E, Tanriverdi D. Knowledge, attitudes and anxiety towards influenza A/H1N1 vaccination of healthcare workers in Turkey. BMC Infect Dis 2010; 10:281.

18. Romani MH, Musharrafieh UM, Lakkis NA, Hamadeh

GN. Family physicians beliefs and attitudes regarding adult pneumococcal and influenza immunization in Lebanon. Fam Pract 2011; 28(6):632-637.

19. Assaf A, Hammad EA, Haddadin RN. Influenza vaccination coverage rates, knowledge, attitudes, and beliefs in Jordan: A comprehensive study. Viral Immunol 2016; 29(9):516-525.

20. Abu-rish EY, Elayeh ER, Mousa LA, Butanji YK, Albsoul-Younes AM. Knowledge, awareness and practices towards seasonal influenza and its vaccine: implications for future vaccination campaigns in Jordan. Fam Pract 2016; 33(6):690-697.

21. Jordan University Hospital. About us. (Accessed August 29, 2017 at http://hospital.ju.edu.jo/medical/juhospital/Lists/HospPages_List/Disp_page.aspx?UrlTitle=aboutus)

22. Domínguez A, Godoy P, Castilla J, Soldevila N, Toledo D, Astray J, et al. Knowledge of and attitudes to influenza vaccination in healthy primary healthcare workers in Spain, 2011-2012. PLoS One 2013; 8(11):e81200.

23. Khazaeipour Z, Ranjbarnovin N, Hoseini N. Influenza immunization rates, knowledge, attitudes and practices of health care workers in Iran. J Infect Dev Ctries 2010; 4(10):636-644.

24. Corace KM, Srigley JA, Hargadon DP, Yu D, MacDonald TK, Fabrigar LR, et al. Using behavior change frameworks to improve healthcare worker influenza vaccination rates: A systematic review. Vaccine 2016; 34(28):3235-3242.

25. Aguilar-Díaz Fdel C, Jiménez-Corona ME, Ponce-de-León-Rosales S. Influenza vaccine and healthcare workers. Arch Med Res 2011; 42(8):652-657.

26. Shahbic HE, Said HA. Flu vaccine among health workers in Qatar. Saudi Med J 2010; 31(10):1157-1160.

27. Torun SD, Torun F. Vaccination against pandemic influenza A/H1N1 among healthcare workers and reasons for refusing vaccination in Istanbul in last pandemic alert phase. Vaccine 2010; 28(35):5703-5710.

28. Albano L, Matuozzo A, Marinelli P, Di Giuseppe G. Knowledge, attitudes and behavior of hospital health-care workers regarding influenza A/H1N1: a cross sectional survey. BMC Infect Dis 2014; 14:208.

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30. Dubnov J, Kassabri W, Bisharat B, Rishpon S. Influenza vaccination coverage determinants among employees of the Nazareth Hospital in Israel. Isr Med Assoc J 2010; 12(6):338-341.

31. Rachiotis G, Mouchtouri VA, Kremastinou J, Gourgoulianis K, Hadjichristodoulou C. Low acceptance of vaccination against the 2009 pandemic influenza A(H1N1) among healthcare workers in Greece. Euro Surveill 2010; 15(6):19486.

32. Ajenjo MC, Woeltje KF, Babcock HM, Gemeinhart N, Jones M, Fraser VJ. Influenza vaccination among healthcare workers: Ten-year experience of a large healthcare organization. Infect Control Hosp Epidemiol 2010; 31(3):233-240.

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33. Prematunge C, Corace K, McCarthy A, Nair RC, Roth V, Suh KN, et al. Qualitative motivators and barriers to pandemic vs. seasonal influenza vaccination among healthcare workers: A content analysis. Vaccine 2014; 32(52):7128-7134.

34. Blank PR, Schwenkglenks M, Szucs T. Vaccination coverage rates in eleven European countries during two consecutive influenza seasons. J Infect 2009; 58(6):446-458.

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Original Article


Can serum NSE and S100-β protein levels predict central nervous system injury in patients with carbon dioxide retention?

ABSTRACT

KEY WORDS: carbon dioxide retention, central nervous system injury, hypercapnia, neuron-specific enolase, S100-β

Harun Gunes, Muhammed M Candar, Ayhan SaritasDepartment of Emergency Medicine, Duzce University School of Medicine, Duzce, Turkey

Objectives: To evaluate whether serum neuron specific enolase (NSE) or S100-β protein levels are helpful in predicting central nervous system (CNS) injury in patients with carbon dioxide (CO2) retentionDesign: A case-control studySetting: This study was performed in the Emergency Department of a University Hospital which functions as the only tertiary center in the city.Subjects: One hundred patients who were admitted to the emergency department and seen to have an arterial partial carbon dioxide pressure above 45 mmHg were included as the study group and 48 healthy volunteers as the control group.Interventions: NoneMain outcome measures: Possible elevations in serum NSE and/or S100-β protein levels in the study group were

main outcome measures. The levels of these markers were measured using enzyme-linked immunoassay kits, and mean values of these parameters were compared between the study and the control groups.Results: Mean NSE level was found to be 69.45 ± 36.39 ng/ml, and mean S100-β level was 160.57 ± 54.05 pg/ml in the study group. Mean NSE and S100-β levels of the control group were 30.99 ± 20.04 ng/ml and 129.31 ± 415.17 pg/ml, respectively. Mean NSE levels differed significantly between the study and control groups; however, mean S100-β levels did not.Conclusions: The results of the present study suggest that NSE can be used to predict CNS injury in patients with CO2 retention, but S100-β protein cannot. New studies including larger number of patients are needed to obtain more accurate results on this topic.

Address correspondence to:Ayhan Saritas, MD, Assoc. Prof, Department of Emergency Medicine, Duzce University School of Medicine , 81620 Duzce, Turkey. Tel: +905059439833; E-mail: [email protected]

INTRODUCTIONCarbon dioxide (CO2) retention may be defined

as decreased removal of CO2 through the lung due to some pathologic conditions[1]. CO2 retention may be seen in acute or chronic diseases of various organ systems, of which the respiratory system is the most significant one[2,3]. It was shown that CO2 retention together with hypoxia, which is generally present concurrently, leads to central nervous system (CNS) injury. This effect of hypercapnia is thought to be associated with enhanced apoptosis secondary to mitochondrial dysfunction, increased generation of reactive oxygen species and resultant higher level of oxidative stress[4-6]. Some biomarkers which can help

physicians to predict CNS injury in patients with CO2 retention are needed. Several proteins like glial fibrillary astrocytic protein, N-methyl-D-aspartate receptor, nucleoside diphosphate kinase A and S100-β have been studied to predict neuronal injury in patients with hemorrhagic stroke, and neuron-specific enolase (NSE) is considered to be a biochemical marker of brain injury in cerebral infarction[7,8]. NSE and S100-β protein are two of the potentially useful biomarkers which may have some role in estimation of CNS injury related to hypercapnia. NSE is an enzyme dimer which serves as a gamma-gamma enolase in glucose metabolism of the brain[9]. It has been shown that NSE levels increase in the case of ischemic stroke,

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meningoencephalitis, status epilepticus and head trauma. Besides, serum NSE levels were found to be correlated with the level of brain injury[10]. S100-β is an intracellular calcium-binding protein dimer[11]. The level of this biomarker was shown to be elevated in patients with meningoencephalitis and head trauma, and CNS tumors like glioma, melanoma and schwannoma[12,13]. However, as far as we know, there are no studies in the literature evaluating usefulness of the serum levels of either NSE or S100-β in patients with CO2 retention. Hence, we aimed in the current study to investigate whether serum levels of these two markers can be used to predict CNS injury associated with hypercapnia.

SUBJECTS AND METHODSOne hundred patients having an arterial partial

CO2 pressure (PaCO2) above 45 mmHg on admission to the emergency department were included in this case-control study as the study group, and 48 healthy volunteers were included as the control group. All subjects were above 18 years of age. Local Clinical Trials Ethics Committee approved the study. All participants gave informed consent for the study. Demographic features including age, sex and past medical history; Glasgow coma scale score (GCS) on admission and arterial blood gas analysis parameters including PaCO2, pH, partial oxygen pressure and oxygen saturation were recorded for each patient.

Patients included in the study group were divided into three subgroups according to their PaCO2 levels:Group I: 45 mmHg < PaCO2 < 60 mmHgGroup II: 60 mmHg ≤ PaCO2 < 80 mmHgGroup III: 80 mmHg ≤ PaCO2

Six ml of venous blood was taken from each patient upon seeing his/her PaCO2 is above 45 mmHg, and also from the participants in the control group for measurement of NSE and S100-β protein levels. Blood samples were centrifuged at 4000 rpm for 10 minutes in NF 048 Microliter and Hematocrit Centrifuge Machine (Nüve Industrial Equipments Manufacturing and Trade Inc., Ankara, Turkey, 2008) after waiting for two hours, and stored at -20 °C until assayed. Enzyme-linked immunoassay kits were used in the measurement of NSE and S100-β protein levels (h-NSE ELISA for measurement of NSE levels, DiaMetra srl Unipersonale Management and Coordination: Immunodiagnostic Systems [IDS] Ltd, Perugia, Italy, production date: March 2013; and S100-β ELISA for measurement of S100-β levels, DiaMetra srl Unipersonale Management and Coordination: Immunodiagnostic Systems (IDS) Ltd, Perugia, Italy, production date: March 2013). Epoch Microplate Spectrophotometer device (BioTek Instruments Inc., Winooski, USA, 2009) was used in the measurement of NSE and S100-β protein levels, and the data was transferred to digital media by using

Gen5 Data Analysis Software, which belongs to the same company.

Statistical analysisThe data derived from the study was analyzed using

Statistical Package for the Social Science for Windows v21.0 (SPSS Inc., New York, USA). Kolmogorov-Smirnov test was used to investigate whether NSE and S100-β levels were distributed normally. Since NSE and S100-β levels were not distributed normally, the significance of the difference between the study and the control groups was investigated using Mann-Whitney U test, and the difference between the three sub-groups of the study group with Kruskal-Wallis one way analysis of variance. Possible relationships between PaCO2, NSE, S100-β levels and GCS were evaluated using Spearman’s rho correlation. The categorical variables were evaluated using Pearson’s chi-square (Fischer’s exact chi-square) test; a p-value of <0.05 was considered to be statistically significant.

RESULTSThe mean age of the participants in the study group

and the control group was 72.65 ± 10.48 years and 45.38 ± 12.63 years, respectively. Most of the participants were male in both the study group and the control group (62% and 62.5%, respectively). The study group and the control group were similar regarding gender distribution (p> 0.05). Most of the patients included in the study group had a history of chronic obstructive pulmonary disease (67%), coronary artery disease (62.5%), hypertension (58.3%) and diabetes mellitus (56%). Demographic features of the study group and the control group are given in Table 1.

Mean NSE level was found to be 69.45 ± 36.39 ng/ml, and mean S100-β level was 160.57 ± 54.05 pg/

Feature Study Group(n = 100)

Control Group(n = 48)

Age (year)

Gender MaleFemale

Past medical historyCOPDCADHTDMCHFCRFCVDMalignancy

72.65 ± 10.48(min:45, max:96)

62%38%

67%62.5%58.3%56%

29.2%20%19%14%

45.38 ± 12.63(min:19, max:63)

62.5%37.5%None

min: minimum; max: maximum; COPD: chronic obstructive pulmonary disease; CAD: coronary artery disease; HT: hypertension; DM: diabetes mellitus; CHF: congestive heart failure; CRF: chronic renal failure; CVD: cerebrovascular disease

Table 1: Demographic features of the study and the control groups

Can serum NSE and S100-β protein levels predict central nervous system injury in patients with carbon ...


ml in the study group. Mean NSE and S100-β levels of the control group were 30.99 ± 20.04 ng/ml and 129.31 ± 415.17 pg/ml, respectively. For mean NSE levels, the difference between the study group and the control group was significant (p <0.001). However, the difference between mean S100-β levels of the study and the control groups was not significant (p = 0.118, Figure 1).

300 -

200 -

100 -

0 -

Controls Patients Groups

Subgroups of the study group

NSE (ng/ml)p-value

S100-β (pg/ml)p-valueMedian

(min-max) SEM Median(min-max) S.E.M.

Group I (n = 50)Group II (n = 33)Group III (n = 17)

9.23 (0.19-1390)6.02 (0-3320)

15.73 (1.51-43.94)

31.18100.25

2.86

NSNSNS

0 (0-3453.08)0 (0-2319.19)

11.12 (0-3028.82)

76.3471.94181.14

NSNSNS

NSE: neuron specific enolase; min: minimum; max: maximum; SEM: standard error of mean; NS: no significance

Table 2: NSE and S100-β levels of subgroups of the study group

Patient numbers included in the sub-groups of the study group were as follows: Group I had 50 patients; Group II had 33 patients, and Group III had 17 patients.

Mean PaCO2 was found to be 64.4 ± 14.73 mmHg (range: 46 - 110 mmHg) in the study group. There were no significant differences between mean NSE and S100-β levels of the study group and those of its subgroups. When the subgroups of the study group were compared for median NSE, the highest level was observed in Group III (15.73 ng/ml), while Group I had the lowest level (6.02 ng/ml). Median S100-β level

was 0 pg/ml in both Group I and Group II; and that of Group III was 11.2 pg/ml. Neither NSE nor S100-β levels differed significantly between the subgroups of the study group (p> 0.05) (Table 2).

PaCO2 values were found to be correlated with neither NSE nor S100-β levels in the study group (p=0.748; p = 0.263, respectively). GCS score on admission correlated with PaCO2 level in the study group. It was seen that GCS decreased as the PaCO2 increased (p <0.001). Neither NSE nor S100-β levels were found to be related to the GCS score in the study group (p = 0.533; p = 0.953, respectively).

DISCUSSIONCO2 is an end-product of cellular respiration which

is needed by nearly all living organisms to produce energy. Normal range of PaCO2 in humans is 35 to 45 mmHg[14]. CO2 retention is a result of physio-pathologic processes leading to decreased removal of CO2 through the lung. PaCO2 level is one of the major determinants of respiratory functions regulated by various organ systems, of which CNS is the most significant one[15]. However, CNS cannot trigger an appropriate regulator response when PaCO2 reaches extreme levels, and a cascade of harmful events begins, which eventually results in neuronal death in the CNS. Findings suggesting CNS injury like neuronal swelling, disruption of cytoplasmic organelles, signs of accelerated apoptosis and increase in water content of the cells were observed in rats exposed to a hypoxic and hyper-carbic environment[5].

Intracellular proteins pass to cerebrospinal fluid (CSF), and then to the blood stream, when CNS injury and cellular death occur. NSE and S100-β are two of the potentially useful biomarkers which have been evaluated for use in the prediction of CNS injury in such conditions. Levels of these proteins in the CNS tissue of rats exposed to chronic hypoxia and hypercapnia were found to be decreased in a study by Yu et al[6]. Although CNS injury was found to be correlated with not only NSE but also S100-β levels in that study, a relationship between CNS injury and NSE levels was only found in the current study. However, we measured serum levels of these markers, while their levels were directly measured in the CNS

Fig 1: NSE and S100-β levels of the study group and the control group. Mean NSE levels of the study group was found to be significantly higher than that of the control group, but mean S100-β levels did not differ significantly between the groups.

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tissue in the subject study. Additionally, the study by Yu et al investigated effects of chronic hypoxia and hypercarbia on the CNS, whereas we took blood samples in the acute period and investigated short-term effects. We suggest that the difference between the findings of these two studies may be attributed to these methodological differences.

There are several studies investigating NSE and S100-β levels in various conditions[16-20]. There are also several studies showing that cerebral ischemia elevates NSE and S100-β levels[17,19,21]. NSE was found to be significantly correlated with infarct volume in patients with cerebral infarction[19]. It was suggested that significantly elevated levels of NSE can be demonstrated as a consequence of ischemia-induced cytoplasmic loss of NSE in CNS neurons[21]. Kaca-Oryńska et al[16] found significantly higher NSE and S100-β levels in ischemic stroke patients. The current study also showed significantly higher levels of NSE in patients with CO2 retention compared to those measured in the control group; however, a similar elevation in S100-β levels could not be demonstrated. Some possible explanations for that situation may include the following:

S100-β, which is an intracellular calcium-binding protein, needs to enter the blood stream by passing through the blood brain barrier (BBB) after passing to CSF to have a measurable increase in its serum levels. Our patients were brought to the emergency department due to a respiratory or cardiac pathology just after PaCO2 levels begin to elevate, and venous blood samples were taken a few minutes after admission. So, serum S100-β level might not have started to increase yet when the blood sample was taken. The reason for that delay may be the BBB which S100-β molecules should pass through to enter the blood stream. Our patients did not have serious inflammatory problems like meningitis, encephalitis and brain abscess which may affect permeability of BBB. Molecular weight of the biggest molecule which can directly pass BBB by membrane diffusion was found to be 7.800 daltons[22], whereas the molecular weight of S100-β is 21.000 daltons[23]. Hence, it has to use an active transport mechanism to pass the BBB, and elevation of its serum level may be delayed due to saturation of transport mechanisms, even if its concentration in CSF reaches a considerably high level. Serena et al[24] reported that they took blood samples approximately 6.3 hours after stroke due to delay in elevation of serum levels caused by BBB. Hardemark et al[17] saw a relatively slower increase in S100-β and NSE levels in CSF after middle cerebral artery occlusion (MCA) compared to that seen after trauma, and a peak was observed after 2 to 4 days in an experimental model. Besides, NSE concentration was slightly higher

than S100-β level after MCA occlusion. It was seen that NSE level was above the normal value in 93.5% of stroke patients; however, the level of S100-β protein was elevated in only 63.1% of them in the study by Kaca-Oryńska et al[16], who took venous blood samples on the 4th day after admission. NSE levels were found to be elevated more prominently in our study, similar to the results of Hardemark et al[17] and Kaca-Oryńska et al[16].

In the present study, in which patients were divided into subgroups with respect to their PaCO2 levels, no significant correlations were found between PaCO2 values and NSE or S100-β levels of each subgroup. An increase in NSE and S100-β levels was notable as PaCO2 elevated, but this increase did not reach statistical significance. Thus, we can state that a thoroughly remarkable relationship was present between CO2 retention and both NSE and S100-β levels, but a linear correlation does not exist. Similarly, NSE and S100-β levels do not have a linear correlation; group III had the highest median NSE and S100-β levels but group I and group II had a median S100-β level of zero, which may be attributed to possible factors leading to delayed elevation of serum S100-β levels mentioned above (e.g. effect of BBB). Besides, group I had a higher median NSE than group II. This finding seems a bit strange at first glance, but there may be some explanation of this situation. When the PaCO2 values begin to rise and CNS injury ensues, the body may activate some protective mechanisms to restrict the damage. A lower median NSE level observed in group II compared to that observed in group I may occur as a result of these protective mechanisms. As it was mentioned above, the highest value of median NSE was observed in group III, which was the group with the highest PaCO2. When the protective mechanisms of the body begin to fail due to significantly elevated PaCO2 levels, a rapid increase in the development of CNS injury causing the highest NSE levels in group III may occur.

Our study has some limitations. The first is the timing of venous blood sampling. S100-β levels might be not elevated yet in some patients because blood samples were taken within a few minutes after admission. More accurate results might be obtained if blood samples were taken at a later point in time. We could not follow such a strategy because our patients did not stay in the emergency department for more than a few hours; they had been admitted to a ward, critical care unit or intensive care unit or referred to another medical facility in a few hours. The second limitation is the small number of subjects included in the study and the control groups. The third one is the presence of several co-morbid diseases each patient included in the study group had, which made it impossible to create a pure CO2 retention group.

Can serum NSE and S100-β protein levels predict central nervous system injury in patients with carbon ...


CONCLUSIONThe results of the present study suggest that NSE

can be used to predict CNS injury in patients with CO2 retention, but S100-β cannot. New studies including larger number of patients are needed to obtain more accurate results on this topic.

ACKNOWLEDGMENTSWe would like to thank the Scientific Research

Projects Foundation of Duzce University for their financial support to the study.

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3. Feller-Kopman DJ, Schwartzstein RM. Mechanisms, causes, and effects of hypercapnia. (Accessed March 28, 2017, Available from: http://www.uptodate.com/contents/mechanisms-causes-and-effects-of-hypercapnia/.) Accessed 28 March 2017.

4. Douglas RM, Ryu J, Kanaan A, Del Carmen Rivero M, Dugan LL, Haddad GG, et al. Neuronal death during combined intermittent hypoxia/hypercapnia is due to mitochondrial dysfunction. Am J Physiol Cell Physiol 2010; 298(6):C1594-1602.

5. Yu LS, Fan YY, Ye G, Li J, Feng XP, Lin K, et al. Curcumin alleviates brain edema by lowering AQP4 expression levels in a rat model of hypoxia-hypercapnia-induced brain damage. Exp Ther Med 2016; 11(3):709-716.

6. Yu LS, Wang LX, Xu ZJ. [Changes of the brain NSE, S100 and effect of ligustrazine in rats of chronic hypoxia and hypercapnia.] Zhongguo Ying Yong Sheng Li Xue Za Zhi 2002; 18(2):114-116. Article in Chinese.

7. Marginean IC, Stanca DM, Vacaras V, Soritau O, Margiean M, Muresanu DF. Plasmatic markers in hemorrhagic stroke. J Med Life 2011; 4(2):148-150.

8. Bharosay A, Bharosay VV, Varma M, Saxena K, Sodani A, Saxena R. Correlation of Brain Biomarker Neuron Specific Enolase (NSE) with degree of disability and neurological worsening in cerebrovascular stroke. Indian J Clin Biochem 2012; 27(2):186-190.

9. Azapağasi E, Alehan F, Saygi S, Bayraktar N, Yazici AC. Serum concentrations of neuron-specific enolase in pediatric migraine. Turk J Pediatr 2012; 54:150-155.

10. Song TJ, Choi YC, Lee KY, Kim WJ. Serum and cerebrospinal fluid neuron-specific enolase for diagnosis of tuberculous meningitis. Yonsei Med J 2012; 53(6):1068-1072.

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hypoxic-ischemic encephalopathy in newborns. Front Neurol 2012; 3:144.

12. Beer C, Blacker D, Bynevelt M, Hankey GJ, Puddey IB. Systemic markers of inflammation are independently associated with S100B concentration: results of an observational study in subjects with acute ischaemic stroke. J Neuroinflammation 2010; 7:71.

13. Calcagnile O, Unden L, Unden J. Clinical validation of S100B use in management of mild head injury. BMC Emerg Med 2012; 12:13.

14. Crystal GJ. Carbon Dioxide and the heart: Physiology and clinical implications. Anesth Analg 2015; 121(3):610-623.

15. Berger AJ, Mitchell RA, Severinghaus JW. Regulation of respiration (third of three parts). N Engl J Med 1977; 297(4):194-201.

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17. Hardemark HG, Ericsson N, Kotwica Z, Rundstrom G, Mendel-Hartvig I, Olsson Y, et al. S-100 protein and neuron-specific enolase in CSF after experimental traumatic or focal ischemic brain damage. J Neurosurg 1989; 71(5 Pt 1):727-731.

18. Martens P, Raabe A, Johnsson P. Serum S-100 and neuron-specific enolase for prediction of regaining consciousness after global cerebral ischemia. Stroke 1998; 29(11):2363-2366.

19. Cunningham RT, Watt M, Winder J, McKinstry S, Lawson JT, Johnston CF, et al. Serum neurone-specific enolase as an indicator of stroke volume. Eur J Clin Invest 1996; 26(4):298-303.

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Original Article


Retrospective analysis of anesthetic management in the cerebral aneurysm treatment: Issues in the course of endovascular versus surgical treatment

ABSTRACT

KEYWORDS: Anesthesia, aneurysm, endovascular treatment, interventional neuroradiology, neurosurgical

Gulcin Hilal Alay, Nadide Aysun Postaci, Ismail Aytac, Fahri Acar, Dilsen Ornek, Bayazit DikmenDepartment of Anaesthesiology and Reanimation, Ankara Numune Training and Education Hospital, Ankara, Turkey

Objective: To compare endovascular and surgical treatments for intracranial aneurysm in terms of anesthetic management, length of stay in the intensive care unit (ICU), morbidity, and mortalityDesign: Retrospective studySetting: Interventional radiology and neurosurgery operation theatre, Ankara Numune Education and Research Hospital, Ankara, TurkeySubjects: We included 143 patients who underwent endovascular or surgical management for intracranial aneurysms between January 2013 and December 2013.Interventions: Information taken from anesthesiology department database recordsMain outcome measures: Anesthetic agents, duration of anesthesia, controlled hypotension, invasive monitoring methods, length of stay in the post-anesthetic care unit or ICU, complications, and time to discharge were evaluated.Results: Of all patients, 54.5% (n = 78) underwent an

elective procedure and the remainder 45.5% (n = 65) had emergency treatment. In most patients with subarachnoid bleeding (n = 67), surgery was performed in the early phase (n = 36; 53.7%) rather than the late phase (n = 31; 46.3%; p <0.001). Although there was no significance between the treatment groups in terms of the occurrence of vasospasm, hydrocephalus was more frequently present in the endovascular group than in the surgery group (p = 0.018). There was significant difference between the groups in terms of the time to discharge, the length of stay in the ICU, and the duration of anesthesia (p <0.005). Although more complications occurred in the surgical group patients, there was no significant difference between groups in mortality. Conclusions: In these patients, advances in endovascular techniques will enable less invasive monitoring, fewer surgical traumas and postoperative complications, and a shorter period of anesthesia.

Address correspondence to:Ismail Aytac, Ankara Numune Education and Research Hospital, Hacettepe Mahallesi Talatpaşa Bulvarı No:44 Altındağ, P. Kodu 06100, Ankara, Turkey. Tel: 0 312 508 40 00; Fax: 0 312 311 43 40; E-mail: [email protected]

INTRODUCTIONEndovascular and surgical procedures are

commonly applied to treat intracranial aneurysms. The assessment of the effectiveness of these treatment modalities shows that each method has its own advantages and disadvantages, and sometimes, they may complement each other[1,2]. The advantages of surgical treatment include the elimination of bleeding risk by protecting the main vessel and its branches during clamping of the aneurysm, as well as the elimination of the balloon-like mass of the aneurysm. In addition,

during surgery, blood in the subarachnoid area can be drained to reduce vasospasm and hydrocephalus. However, a disadvantage of surgical treatment is that it requires craniotomy and brain retraction. The main advantages of the endovascular technique are that it is a rapid and less invasive procedure. It is more appropriate for patients who have concomitant diseases, and provides better results for aneurysms located on the posterior side, which are difficult to reach via the surgical approach. However, about 10% of patients undergoing endovascular treatment using


coils may require additional endovascular or surgical treatment sometime in the future[3].

It is considered that the treatment of aneurysms by the endovascular technique can be performed under local anesthesia and sedation or under general anesthesia; however, it is preferred that the anesthetic technique provides deep anesthesia, immobility, physiological stability, and the ability to perform the procedure without complications[3]. The depth of anesthesia emergence should also be considered in terms of post-procedural neurological examination.

The present study aims to provide a retrospective comparison of endovascular and surgical methods used to treat intracranial aneurysms with regard to the duration of anesthesia, the length of stay in the intensive care unit (ICU), and postoperative morbidity and mortality.

SUBJECTS AND METHODSThis retrospective study investigated the data

of patients who received endovascular or surgical treatment for intracranial aneurysms performed between 1 January, 2013 and 31 December, 2013 in the department of Anesthesiology and Reanimation at the Ankara Numune Education and Research Hospital. The study protocol was approved by the local ethics committee.

The data were derived from the patients’ preoperative and intraoperative forms and hospital files. Demographic data, as well as information on American Society of Anesthesia (ASA) classification, preoperative Glasgow Coma Scale, World Federation of Neurological Surgeons Grading System for Subarachnoid Hemorrhage Scale (WFNS), medical history, and emergence from the procedure were retrieved from the hospital files. Results of preoperative digital subtraction angiography and computerized tomography were evaluated for the presence of vasospasm and hydrocephalus, respectively.

Details on the anesthetic agent used, duration of anesthesia, agents used to control hypotension, colloidal solutions used during the procedures, and invasive monitoring methods (central venous catheterization and arterial catheterization) were recorded. In the postoperative period, we examined the length of stay in the post-anesthetic care unit (PACU) or ICU, complications (motor and sensory dysfunctions, hematoma, respiratory failure, brain death and death), and the time to discharge. The number of intubated patients arriving at the PACU or ICU was also recorded. Operations performed during the first 72 hours and after the seventh day were categorized as early and late surgery, respectively.

Characteristics Endovascular treatment (n = 73)

Surgical treatment(n = 70)

Age (years)Gender (males/females)n(%)ASA I/II/III/IV n(%)

Additional diseases n (%)GCS

preoperativePostoperative

GCS (median-IQR)preoperativepostoperative

Elective/emergency treatment n (%)Time to acceptance for operation (day/min-max)Time to acceptance for operation median(IQR)Duration of anesthesia (min-max)Duration of anesthesia median(IQR)Subarachnoid bleeding, n (%)Cerebral vasospasm, n(%)Hydrocephalus, n (%) Re-operation, n (%) Postoperative complications, n (%)Length of stay in intensive care unit, days (min-max)Length of stay in intensive care unit days median (IQR)Discharge from hospital (day)Mortality n (%)

57 (± 45.6)37/36(50.6%/49.3)

2/ 43/ 25/ 3(2.7/58.9/34.2/4.1%)

54(73.9%)

15 (8-15)14 (3-15)

15(0)15(0)

18/55 (25%/75%)*8.6 (1-34)

7(10)192 (90-570)*

180(60)35 (48%)13 (18%)9 (12.3%)8 (11%)

14 (19.2%)3.6 (1-33)

1(1)10.9 (1-120)

8 (11%)

47 (± 12.12)49/37(57%/43%)

1/ 43/ 22/ 4(1.4/61.4/31.4/5.7%)

55(78.5%)

14 (4-15)14 (3-15)

15(0)15(1)

60/10 (86%/14%)9.1 (1-29)

8(7)363 (180-660)

360(120)32 (46%)18 (26%)

1 (1.43%) p=0.018†

22 (31.4%)24 (34.3%)†

4.9 (1-72) *3(5)

10.4 (3-37)†

3 (4.3%)

Data are mean + standard deviation, n (%), (minimum-maximum). p <0.001; †p <0.05 between groups; ASA: American Society of Anesthesiology; GCS: Glasgow Coma Scale

Table 1: Demographic data, ASA classification, and preoperative and postoperative characteristics of the two treatment groups (N = 143)

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Statistical analysisStatistical analysis was performed using SPSS for

Windows version 16. The number and percentage are presented to describe quantitative variables. Mean and standard deviation values are presented for quantitative variables with a normal distribution, and median values (min-max, interquartile ranges) are presented for quantitative variables without a normal distribution. For group comparisons, the Chi-square test was used for quantitative data, the Kruskal-Wallis test for non-parametric data, and the Mann-Whitney U-test was used for comparisons. A p-value <0.05 was considered statistically significant.

RESULTSThis retrospective study evaluated 143 patients.

Table 1 presents the demographic data, the information on ASA classifications, and the preoperative/postoperative evaluations. Of all patients, 56 (39%) were female, 87 (61%) were male (F/M ratio: 0.6); mean age was 48 years, and 109 patients had other concomitant diseases. Subarachnoid bleeding was present in 53.5% of the female and 42.5% of the male patients. Although 54.5% (n = 78) of the patients underwent an elective procedure, 45.5% (n = 65) underwent emergency treatment (p <0.001) (Table 1). In most patients with subarachnoid bleeding, surgery was performed in the early phase (n = 36; 53.7%) rather than the late phase (n = 31; 46.3%). Although there was no significant difference between the groups in terms of the presence of vasospasm, more hydrocephalus

Details of anesthetia Endovascular treatment

Surgical treatment

Inhalational agentsSevofluraneIsofluraneDesfluraneNitric oxide Total intravenous anesthesia

Induction agentsPropofolThiopental

Central venous catheterization Subclavian veinInternal jugular vein Femoral vein

Arterial catheterizationRadial arteryDorsalis pedis arteryBrachial artery

Drug infusionsRemifentanylEsmelolNitroglycerinDopamine

73 (100%)0000

62 (84.9%)11 (15.1%)

01 (1.4%)

0

68 (93.2%)2 (2.7%)1 (1.4%)

01 (1.4%)2 (2.7%)2 (2.7%)

56 (80%)8 (11.43%)3 (4.29%)

50 (71.4%)3 (4.29%)

50 (71.4%)20 (28.6%)

67 (95.7%)0

3 (4.3%)

59 (84.3%)4 (5.7%)4 (5.7%)

28 (40%)7 (10%)1 (1.4%)2 (2.9%)

Table 2: Details of anesthetic methods used during endovascular and surgical procedures

Data are numbers of patients (%)

was present in patients undergoing the endovascular approach compared to those undergoing surgery (p = 0.018) (Table 1). There was no significant difference between the treatment groups (or between early vs. late surgery) in terms of mortality, the time to discharge, and the length of stay in the ICU (p >0.05). Of all patients, 73 (51%) had endovascular treatment and 70 (49%) had surgical treatment. Posterior cerebral artery aneurysms were significantly prevalent in the endovascular group than in the surgery group (n = 29 and n = 4 respectively, p <0.001), whereas middle cerebral artery aneurysms were prevalent in the surgery group (n = 40 and n = 16 respectively, p <0.001). There was no significant difference between treatment groups in the WFN scale. Although the average age was higher in the endovascular group than in the surgery group, the difference was not significant. For both treatment groups, the anesthetic technique applied was general anesthesia with endotracheal intubation. The duration of anesthesia was significantly shorter in the endovascular group (192 min) than in the surgical group (363 min) (p <0.001). Details on the anesthetic method used for both groups are presented in Table 2. Body temperature was not routinely monitored in either group; after surgery, patients were passively warmed in their hospital bed. Total intravenous anesthesia (TIVA) was applied to three patients in the surgical group, but not to any patient in the endovascular group. These latter patients also received Bispectral Index monitoring and somatosensory evoked potential monitoring.

Treatment group No. of patients

Preoperative subarachnoid

bleeding

Result

Endovascular treatment (n = 73)Surgical treatment(n = 70)

2(2.7%)

2(2.9%)

1/0

0/1

Discharge

Discharge

Table 3: Patients admitted to the intensive care unit and intubated postoperatively

Invasive arterial monitoring was applied in 71 patients (97.2%) in the endovascular group and in 67 patients (95.7%) in the surgical group (Table 2). Central vein catheterization was not performed in the endovascular group, with the exception of one patient who earlier had internal jugular vein catheterization. No complications related to arterial or venous catheterization were encountered in this study period. In the endovascular treatment group, 35 patients received intra-arterial nimodipine. Fifty-nine patients in the surgical group and no patient in the endovascular group had infusion of colloidal fluid (p <0.001).

Retrospective analysis of anesthetic management in the cerebral aneurysm treatment: Issues in the course ...


All patients undergoing endovascular treatment were administered heparin empirically without measuring the activated coagulation time (ACT). After the procedure, protamine sulfate was administered to three patients after measuring the ACT.

Four patients (two in the endovascular and two in the surgical group) were admitted to the ICU after the procedures (Table 3). Table 4 presents data on the patients re-operated at our center. There was a significant difference between the treatment groups in terms of postoperative complications and the length of stay in the ICU. More postoperative complications were encountered in the surgical treatment group, and the length of stay in the ICU was longer in patients treated surgically than in those treated with the endovascular approach. However, there was no significant difference between the groups in mortality. The time to discharge from hospital was significantly shorter in the surgical treatment group (10.4 days; range: 3 - 37) than in the endovascular group (10.9 days; range: 1 – 120; p <0.05).

Second treatment group Endovascular treatment

Surgical treatment

Second endovascular treatment Second surgical treatment

7 (46.7%)8 (53.3%)

7 (53.9%)6 (46.1%)

Table 4: Patients undergoing a second operation in the first 30 days postoperatively

DISCUSSIONCurrently, intracranial aneurysms are treated

either surgically or endovascularly using coils. However, few studies have compared the anesthetic method used for intracranial aneurysms treated either surgically or endovascularly[4].

In the present study, differences in anesthetic management were found between the two treatment groups. Although the ratio for emergency operation was significantly higher in the endovascular group than in the surgery group, there was no significant difference in the incidence of subarachnoid hemorrhage between the two groups. The duration of anesthesia was shorter in the endovascular group but the length of stay in the ICU was longer. However, postoperative complications were observed in significantly fewer patients in the endovascular treatment group than in the surgery group. Application of invasive monitoring and the use of intraoperative colloidal fluids were higher in the surgical group.

Liu et al compared endovascular coiling and microsurgical clipping in patients with ruptured intracranial aneurysms (133 patients; 39% female, 61% male) in their study, surgical clipping was applied to 62.7% of the patients and endovascular coiling to 37.3%

of the patients[4]. In the present study, 68 patients (38% female, 62% male) had a ruptured aneurysm, and 48.5% of these patients were treated surgically while 51.5% were treated with the endovascular approach.

The anesthetic method chosen for endovascular treatment varies between institutions. Generally, the neuroradiologist’s opinion is followed. In our hospital, during the study period investigated, general anesthesia was preferred for the endovascular procedure. As an induction agent, propofol was used in 85% of the endovascular procedures, and thiopental was used in 87% of the surgical procedures. In addition, thiopental was routinely used during temporary clipping of aneurysms. Propofol was preferred for the endovascular treatment probably because this procedure takes less time than a surgery and because of its ready to use nature. Sevoflurane was used as the inhalation agent in all endovascular procedures. For all the surgical cases, sevoflurane (80%), isoflurane (11.4%), and desflurane (4.3%) were used. In addition, 4.3% of the surgical patients received TIVA (a combination of propofol and remifentanil). Although the application of general anesthesia with both TIVA and inhalation anesthetics is recommended, there is no consensus on the superior method of the two. However, nitrous oxide should be avoided, as it can cause micro-emboli formation[3,5]. Isoflurane, sevoflurane, and desflurane are less likely to increase cerebral blood flow than other anesthetic agents[6,7]. However, desflurane can disturb cerebral autoregulation[8].

In the present study, induced hypertension was not applied in any of the surgically treated patients. It has been suggested that brain perfusion pressure should be normal (or even above normal) after acute central nervous system damage and during neurosurgical procedures. This suggestion is probably related to the fact that cerebral blood flow decreases in some areas of the brain, especially following head injury and subarachnoid hemorrhage[9]. Hypertension may be used to increase cerebral blood flow during temporary artery occlusion. In the present study, more vasoactive agents were used in the endovascular treatment group than in the surgical group. The main reason for this is the use of intra-arterial nimodipine by the neuroradiologists during the procedure.

Normovolemic hemodilution using colloidal solutions reportedly improves blood flow to brain regions that are less well perfused by reducing blood viscosity[10,11]. Also, normovolemic hemodilution reportedly ameliorates cerebral blood flow and reduces the infarcted area[12]. In the present study, patients who received starch solutions had more postoperative complications and a longer stay in the ICU than patients who did not receive starch solutions.

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Postoperative complications were motor and sensory dysfunctions, intracranial hematoma, respiratory failure, and brain death.

The application of central venous catheterization during surgical treatment of cerebral aneurysms depends on medical history, localization and the number of aneurysms, the use of inotropic agents, and the anesthetist’s preference. If peripheral catheterization is adequate, there is no need to place a central catheter for neurosurgical procedures[1]. We found that central venous catheterization was preferred in our center for the surgical treatment group (n = 67; 95.7%) with no associated complications. However, bleeding complications and pneumothorax can occur with jugular venous catheterization and subclavian venous catheterization, respectively[13]. Routine arterial catheterization is advised during surgical or endovascular treatment of intracranial aneurysms. The main goals of arterial pressure control during neuroradiologic procedures are to achieve adequate brain perfusion pressure, prevent vessel rupture, avoid cerebral edema, and help the neuroradiologist perform the procedure by controlling hemodynamic parameters[14].

Most of the randomized prospective studies comparing endovascular and surgical treatment were performed in the International Subarachnoid Aneurysm Trial[15]. That study concluded that although the microsurgical technique had advantages over the endovascular approach by providing exact occlusion and reducing the incidence of re-bleeding, ischemic attacks occurred more often with this technique. The re-bleeding incidence was higher in patients having undergone endovascular embolization. However, there was no significant difference between the two groups in terms of mortality rate due to re-bleeding[15].

In our study, the length of stay in the ICU was significantly longer in patients who had endovascular embolization than in patients who underwent surgical treatment. Recently, studies have compared the length of stay in the ICU[16,17]. One of them compared coil embolization to surgical clipping. The total time of the procedure (in ruptured aneurysm coiling procedure: 145 min vs. clipping procedure: 203 min) and the length of stay in the ICU (coiling procedure: 5.3 days vs. clipping procedure: 6 days) were significantly shorter in patients treated with endovascular embolization than in those treated with surgical clipping. In addition, the length of stay in hospital was significantly shorter with the coiling procedure (in ruptured aneurysms coiling: 21.4 days, clipping: 26.8 days; in unruptured aneurysms coiling: 9.2 days, clipping: 17.5 days)[17].

We found no significant difference between patients who had early surgical procedure and

patients who had late surgical procedure in terms of mortality, time to hospital discharge, and the length of stay in the ICU. However, the incidence to apply early surgical procedure was significantly higher in patients with subarachnoid bleeding. In our study, there were fewer postoperative complications in patients who underwent endovascular procedures. This may be due to the shorter period of anesthesia and fewer surgical traumas in patients undergoing endovascular treatment.

Limitations of the present study are that owing to the retrospective design of the study, only recorded complications were investigated, and some complications may have been missed.

CONCLUSIONSThis study indicates that advances in the

endovascular procedure technique will allow for less invasive monitoring, shorter anesthesia duration, fewer surgical traumas, fewer postoperative complications, and a reduced need for intensive care.

ACKNOWLEDGMENTSConflict of interest and financial support

The authors declare to have no conflicts of interest. No financial support was received for this study.

REFERENCES

1. Avitsian R, Schubert A. Anesthetic considerations for intraoperative management of cerebrovascular disease in neurovascular surgical procedures. Anesthesiol Clin 2007; 25(3):441-463.

2. Shivashankar R, Miller T, Jindal G, Simard JM, Aldrich EF, Gandhi D. Treatment of cerebral aneurysms—surgical clipping or endovascular coiling: The guiding principles. Semin Neurol 2013; 33(5):476-487.

3. Berlis A. Endovaskulare ein griffe in der interventionellen neuroradiologie. Neue Aspekte. Der Anaesthesist 2013; 62:692-706.

4. Liu B, Wei W, Wang YL, Yang XY, Zhu T, Yue SY, et al. Individualized treatment of ruptured intracranial aneurysms by microsurgical clipping and endovascular coiling: results from a consecutive series of 212 patients. Chin Med J (Engl) 2012; 125(19):3584-3586.

5. Varma MK, Price K, Jayakrishnan V, Manickam B, Kessell G. Anaesthetic considerations for interventional neuroradiology. Br J Anaesth 2007; 99(1):75-85.

6. Ornstein E, Young WL, Fleischer LH, Ostapkovich N. Desflurane and isoflurane have similar effects on cerebral blood flow in patients with intracranial mass lesions. Anesthesiology 1993; 79(3):498-502.

7. Scheller MS, Tateishi A, Drummond JC, Zornow MH. The effects of sevoflurane on cerebral blood flow, cerebral metabolic rate for oxygen, intracranial pressure, and the electroencephalogram are similar to those of isoflurane in the rabbit. Anesthesiology 1988; 68(4):548-551.

Retrospective analysis of anesthetic management in the cerebral aneurysm treatment: Issues in the course ...


8. Bedforth NM, Girling KJ, Skinner HJ, Mahajan RP. Effects of desflurane on cerebral aurtoregulation. Br J Anaesth 2001; 87(2):193-197.

9. Bouma GJ, Muizelaar JP, Stringer WA, Choi SC, Fatouros P, Young HF. Ultra-early evaluation of regional cerebral blood flow in severely head-injured patients using xenon-enhanced computerized tomography. J Neurosurg 1992; 77(3):360-368.

10. Oskuorian RJ Jr, Martin NA, Lee JH, Glenn TC, Guthrie D, et al. Multimodal quantitation of the effects of endovascular therapy for vasospasm on cerebral blood flow, transcranial doppler ultrasongraphic velocities and cerebral artery diameters. Neurosurgery 2002; 51(1):30-43.

11. Chang HS, Hongo K, Nakagawa H. Adverse effects of limited hypotensive anesthesia on the outcome of patients with subarachnoid hemorrhage. J Neurosurg 2000; 92(6):971-975.

12. Foroohar M, Macdonald RL, Roth S, Stoodley M, Weir B. Intraoperative variables and early outcome after aneurysm surgery. Surg Neurol 2000; 54(4):304-315.

13. Kaur R, Mathai AS, Abraham J. Mechanical and infectious complications of central venous catheterizations in a tertiary-level intensive care unit in northern India. Indian J Anaesth 2012; 56(4):376-381.

14. Türeci E. Anaesthesia in interventional neuroradiology. Turk J Anaesth Reanim 2001; 29:231-238.

15. Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, et al. International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 2002; 360(9342):1267-1274.

16. Sharma M, Brown B, Madhugiri V, Cuellar-Saenz H, Sonig A, Ambekar S, et al. Unruptured intracranial aneurysms: comparison of perioperative complications, discharge disposition, outcome, and effect of calcification, between clipping and coiling: a single institution experience. Neurol India 2013; 61(3):270-276.

17. Brunken M, Kehler U, Fiehler J, Leppien A, Eckert B. [Coiling vs. clipping: hospital stay and procedure time in intracranial aneurysm treatment.] Rofo 2009; 181(10):989-995. [Article in German]


Original Article


Finite element analysis of biomechanical variation of subchondral bone in osteoarthritis

ABSTRACT

KEY WORDS: biomechanics, finite element analysis, occurrence, osteoarthritis

Hainan Chen1, Wei Jiang2, Qirong Dong1, Kan Yang3

1Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China2Department of Rehabilitation, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China

3Department of Orthopaedics, the Seventh People’s Hospital of Suzhou, Suzhou 215004, China

Objective: This study aimed to investigate the changes in mechanical properties of subchondral bone in the early stage of knee instability and the intervention effects of diphosphate. Design: Control experimentSetting: Department of Orthopedics, The Second Hospital Affiliated to Soochow University, Suzhou, ChinaSubjects: Sixty healthy male New Zealand white rabbits were divided into model, diphosphate, and control groups.Intervention: Statistical analysis and comparisonMain outcome measures: The obtained 2D image files were

then used for the finite element analysis.Results: Several parameters of the 12- and 4-week groups were compared. Results showed that bone volume fraction, bone density, elastic modulus, reaction force, and von Mises stress were all increased (p <0.01). In the early stage of knee instability, the elastic modulus significantly decreased. The diphosphate could significantly improve the elastic modulus of the subchondral bone by preventing bone resorption. Conclusions: The changes in the mechanical properties of the subchondral bone showed a significant role in the occurrence and development of osteoarthritis.

Address correspondence to:Qirong Dong, Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China. Tel: +86 512 67784116; Fax: +86 512 68284303; E-mail: [email protected]

INTRODUCTIONOsteoarthritis (OA) is a common disease in

older people[1]. It is characterized by joint pain and dysfunction[2]. However, its pathogenesis remains unclear, and many factors are involved. Biological and mechanical factors are considered to be the two major risk factors[3]. In recent years, the role of mechanical factors in OA have received increasing attention. Moreover, several studies about the effects of cell biomechanics[4], material biomechanics[5], and subchondral bone biomechanics in OA have been conducted[6-8], and research methods have been constantly updated[9]. OA can lead to anatomical variations of subchondral trabecular bone in the femoral head and changes of trabecular 3D structure, which affect the mechanical properties of the subchondral bone[10]. By establishing a rabbit OA model, the author used micro-CT to perform the 3D reconstruction of subchondral bone. Subsequently, the finite element calculation was conducted, and

the mechanical changes of the subchondral bone were observed. Meanwhile, bisphosphonate (Bis) intervention was also applied to investigate the effects of mechanical changes in the subchondral bone on OA progress.

MATERIALS AND METHODSExperimental animals and grouping

Sixty healthy male New Zealand white rabbits (provided by the Animal Center, School of Medicine of Suzhou University) weighing 2.71 ± 0.29 kg were placed in individual cages. The rabbits were provided granulated diet and free access to drinking water. The ambient temperature was 22 ± 1 °C, with alternate natural light-dark cycles every 12 hours. The rabbits were divided into model (n = 24), Bis (n = 24), and control groups (n = 12) by using a table of random digits. This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National


Institutes of Health. The animal use protocol has been reviewed and approved by the Institutional Animal Care and Use Committee of Soochow University.

Model duplication and specimen collectionAll animals underwent knee-skin preparation one

day before the modeling and were weighed before the surgery. About 20 g/L sodium pentobarbital (Sigma Co., San Francisco, USA) was injected through an ear vein at a dose of 30 mg/kg to induce anesthesia. The animal was then disinfected and covered with an operation sheet. A medial patellar incision was made to expose the joint cavity. Joint cavity incision was conducted on the model and Bis groups. Subsequently, the anterior cruciate ligament was cut (confirmed by the drawer test). About 5 mm of the ligament was cut off from the middle segment, and the incision was sutured layer by layer. The same joint cavity incision was performed on the control group, except that the anterior cruciate ligament was only exposed instead of cut, and the incision was sutured layer by layer. The rabbits were intraperitoneally injected with cefazolin sodium (500 mg/d) (Shandong Lukang Pharmaceutical Group Co., Ltd., Shandong, Chinese) for five days postoperatively to prevent infection. The injured limb was not fixed, and the animals were bred separately and allowed free movement. The Bis group was subcutaneously injected daily with 0.01 mg/kg Bis (risedronate sodium; LKT Laboratories Co., Minnesota, USA), whereas the model and control groups were subcutaneously injected with equal volume of isotonic saline. The rabbits were then killed at each predetermined time point (4th, 8th, and 12th weeks after the surgery) by air embolism. The surgical side of the knee (2 cm above and below the reserved knee plane) was cut following the removal of the soft tissues. The knee was cryopreserved at −20 °C for 48 hours and then examined using micro-CT (GE Healthcare, London Ontario, Canada).

Gross scoring and Mankin scoringGross morphological evaluation was performed on

the intra- and extra-lateral condyle cartilages of femurs. The evaluation was classified into 5 grades according to the OA standard: grade 1 (0 point): the surface was normal and smooth, without damage; grade 2 (1 point): the articular cartilage was rough, gray colored, with small cracks; grade 3 (2 points): the articular surface was erosive, with large cracks, and the cartilage defects reached the middle layer of cartilage surface; grade 4 (3 points): the ulcers and defects of articular cartilage reached the deep layer of cartilage; and grade 5 (4 points): the cartilage exfoliated, and the subchondral bone was exposed. The tissue samples were stained with hematoxylin and eosin (HE) and then observed under a microscope. Scoring was conducted referring to the Mankin scoring criteria.

Micro-CT examination and finite element analysisThe joint sample of the rabbit knee was evenly

placed in the examination slot of the micro-CT system and then bundled to prevent movement. The scan was performed along the long axis of the specimen, with a scanning protocol of 45 μm, 24R, and 18 minutes. The scanning parameters were as follows: scan resolution, 45 μm; rotation angle, 360°; rotation angle increment, 0.5°; interlayer spacing, 20 μm; tube voltage, 80 kV; tube current, 450 μA; exposure time, 2960 ms; and scanning time, 18 minutes. Five hundred different sectional images (1024×1024 pixels) of the same sample were obtained, and the segmentation value was set at 1000 to complete the image binarization. The complete bone tissue of the sample was set as the region of interest (ROI) for further 3D reconstruction. 3D visualization was then performed on the selected ROI intra-bone. Micview V2.1.2 3D reconstruction processing software and ABA special bone analysis software were used for quantitative analysis.

The specific measurement parameters were as follows: bone volume fraction (BVF), namely, the division of bone volume by the total volume, and expressed as %; and volumetric bone mineral density (vBMD), namely, the apparent density of porous trabecular bone, reflecting the overall bone mineral density in the region, and expressed as mg/mm3. 2D images in DICOM format were obtained from micro-CT and then imported into Mimics V10.01 software for fitting and threshold setting. The grid redraw module was used to generate the grid, and the Mimics main interface generated the surface mesh model, which was then transmitted into Ansys V10 for the body mesh processing. The obtained body mesh model was finally materialized in Mimics. A total of 10 types of materials were selected, with each representing the material properties of each section. Geomagic Studio 11.0 software was used to repair and optimize the generated models. The Homminga et al[11] formula is as follows:

Eelement = Etissued (GVelement) γ, where Eelement is the relative gray value based on

each finite element (GVelement); the normal range is from 0 (bone marrow) to 1 (bone). This formula was used to convert the elastic modulus (EM) into the tissue’s elasticity modulus. The normal gray value was 1754 mgHA/cm3 (equivalent to 12000 CT). Given that the femoral condyle is composed of dense and cancellous pine mass, the dense mass is anisotropic and the cancellous mass is isotropic. Therefore, the simplified material model was unified to the isotropic linear materials. The elastic modulus (Etissued) and index (γ) were determined based on the image resolution and structure size; according to literature, Etissued was set at 15 GPa, γ = 1.7[12]. The apparent EM was reversely calculated using a computer, with a Poisson’s ratio

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of 0.3. The boundary condition was set as the stress applied, which made the femoral condyle realize 1% longitudinal compression. Thus, the reaction force (RF) and average von Mises stress, which could induce 1% deformation, were obtained.

Statistical analysisThe data were expressed as x ± s. SPSS 13.0

statistical software was used for all statistical analyses. ANOVA was performed for intergroup comparison. A p-value <0.05 was considered statistically significant.

RESULTSGeneral observation and OA scoring of cartilages

The knee joint cavity of the control group had no joint effusion. The joint fluid was small and clear, and the joint exhibited no swelling and synovial hyperplasia. In addition, no osteophyte formation was observed. The articular cartilages of the femoral condyle and tibial plateau were blue and white, and bright and smooth, respectively. At the 4th week, joint effusion and synovial hyperplasia appeared in two cases of the model group, and the articular surface was erosive and rough. At the 12th week, the synovium exhibited nodular hyperplasia, and the synovial fluid was cloudy. The surface of the two femoral articular condyle exhibited large cracks and ulcers. The cartilage damages of the Bis group were significantly reduced than those of the model group at the 4th and 12th weeks, as shown in Table 1.

Group Number Postoperative 4th week

Postoperative 12th week

ModelBisControl

12126

0.88 ± 0.6409a

0.38 ± 0.5176b

0.13 ± 0.3536

3.25 ± 0.7071ad

1.63 ± 0.7440c

0.38 ± 0.5176

Bis: bisphosphonateCompared with the control group, a p <0.01; compared with the model group, b p <0.05, c p <0.01; compared with the 4th week, d p <0.01

Table 1: OA scores of the three groups ( ±s)

Mankin scoring of articular cartilage injuryThe tissue samples were stained with HE and then

observed under a microscope. Scoring was performed referring to the Mankin scoring criteria, as shown in Table 2. The control side exhibited normal articular cartilage at the 4th and 12th weeks, and the Mankin scores were 0 - 1 point. HE staining showed that the chondrocytes were uniformly distributed, with clear layers and neat arrangements. The tidal line was intact. Moreover, the toluidine blue staining was uniform, and no staining loss was observed. At the 4th week, the model group exhibited a non-flat cartilage surface. The chondrocytes showed compensatory proliferation and were disorganized; some even appeared in clusters.

The chondrocytes with larger volume exhibited a tendency to migrate toward the cartilage surface. Mild loss of toluidine blue staining was observed. At the 12th week, the damages of the articular cartilage were severe, and the tidal line disappeared. Pathological changes, such as disappearance of cartilage and exposure of subchondral bone, were found. Osteophyte formation also occurred. The toluidine blue staining disappeared. Compared with the Bis and control groups, the model group showed cartilage degeneration (p <0.01), which further aggravated at the 12th week (p <0.01). The degeneration at the 12th week was significantly worse than that at the 4th week, (p <0.01). The Bis group exhibited less degeneration than the model group at the 4th and 12th weeks (p <0.01) and showed no statistical significance with the control group.

Structures and mechanical parametersThe BVF, bone trabecular number (Tb.N), bone

trabecular thickness (Tb.Th), bone trabecular separation (Tb.Sp), and bone density of the 60 specimens were obtained through micro-CT examination. The finite element software was used to calculate the EM, RF, and average von Mises stress. At postoperative 4th week, the BVF, EM, RF, and average von Mises stress of the model group were decreased when compared with those of the Bis and control groups; the model group was significantly lower than the Bis and control groups (p <0.01). These parameters were also decreased in the Bis group when compared with those of the control group, but the difference was not statistically significant. The bone density of the model group was significantly lower than that of the control and Bis groups (p <0.01). However, the comparison between the Bis and control groups exhibited no statistically significant difference (Table 3). At the 12th week, the BVF and BMD of the model group was significantly increased than those of the control and Bis groups (p <0.01), whereas the EM, RF, and von Mises stress were decreased (p <0.05) (Table 4). The Bis group was also lower than the control group, but the difference was not statistically significant. The BVF, BMD, EM, RF, and von Mises stress at the 12th week were increased when compared with those at the 4th week (p <0.01)

Group Number Postoperative 4th week

Postoperative 12th week

ModelBisControl

12126

4.53 ± 0.1444a

1.98 ± 0.1931b

1.41 ± 0.0207

8.56 ± 1.6832ad

2.50 ± 0.1581c

1.40 ± 0.1681

Bis: bisphosphonateCompared with the control group, a p <0.01; compared with the model group, b p <0.05, c p <0.01; compared with the 4th week, d p <0.01

Table 2: Mainkin scores of the three groups ( ±s)



(Table 5). Meanwhile, the 2D DICOM images and 3D reconstruction images exhibited that the osteophytes of the model group were significantly proliferated than those of the Bis and control groups (Figure 1).

Correlation comparisonAt postoperative 4th week, the EM of the model

group was negatively correlated with Mankin scores (r = -0.835, p <0.01), but positively correlated with BMD (r = 0.848, p <0.01) and volume fraction (r = 0.893, p <0.01). At postoperative 12th week, the EM of the model group was negatively correlated with Mankin scores (r = -0.883, p <0.01), but positively correlated with BMD (r = 0.861, p <0.01) and volume fraction (r = 0.817, p <0.01).

DISCUSSIONBecause of its special structure, the subchondral

bone has special functions in joint movements. This bone absorbs the stress placed on the articular

surface and then distributes it to the backbone and its surrounding tissues, thus buffering the shocks from the joints and protecting the articular cartilage and other vital organs. Meanwhile, the subchondral bone maintains the unique shapes of different joints, making it easier to perform their functions. All these functions require the subchondral bone to have sufficient strength (i.e., the ability to resist damages when bearing the loadings) and stiffness (i.e., the ability to resist deformation under the extra loadings)[13].

Numerous measurement methods and mechanical property studies of knee subchondral bone are available. A bone density detection instrument was commonly used to detect subchondral bone density. Through this evaluation, the relationships between the subchondral bone density and articular cartilage damage were investigated. Mckinley et al[14] used high-resolution digital imaging and built-in software to measure the sclerotic model of subchondral bone of human cadavers. They found that the stress on the

VM (MPa) Animal numberThe postoperative 4th week

BVF (%) vBMD (mg/mm3) EM (MPa) RF (N) VM (MPa )

ModelBis

Controlp-value

12126

26.44 ± 1.8130.03 ± 2.4234.10 ± 1.78

p <0.05a

p <0.01b

p <0.05c

298.66 ± 4.68305.38 ± 2.40308.52 ± 2.21

p <0.05a

p <0.01b

175.46 ± 1.55227.96 ± 1.87230.54 ± 1.73

p <0.01a

p <0.01b

368.41 ± 1.72383.52 ± 1.54390.90 ± 7.74

p <0.01a

p <0.01b

9.41 ± 1.6216.42 ± 1.6318.33 ± 1.59

p <0.01a

p <0.01b

Bis: bisphosphonate; BVF: bone volume fraction; vBMD: volumetric bone mineral density; EM: elastic modulus; RF: reaction force; VM: von Mises stressNote: Among the p-values, a: comparison between the model group and the bis group; b: comparison between the model group and the control group; c: comparison between the bis group and the control group.

Table 3: Comparison of distal femoral microstructures and mechanical parameters of the three groups on the postoperative 4th week ( ±s)

Group Animal numberThe postoperative 12th week


ModelBis

Controlp-value

12126

41.21 ± 2.2136.13 ± 2.1635.00 ± 2.86

p <0.01a

p <0.01b

319.59 ± 4.08310.71 ± 1.80308.57 ± 2.91

p <0.01a

p <0.01b

270.32 ± 1.65227.36 ± 1.60229.48 ± 1.85

p <0.01a

p <0.01b

374.25 ± 1.68382.34 ± 6.83388.49 ± 1.55

p <0.05a

p <0.01b

11.55 ± 1.1816.44 ± 1.4318.43 ± 1.39

p <0.01a

p <0.01b

Group Animal number

The postoperative 12th week


The postoperative 4th weekThe postoperative 12th weekp-value

1212

26.44 ± 1.8141.21 ± 2.21

< 0.01

298.66 ± 4.68319.59 ± 4.08

< 0.01

175.46 ± 1.55270.32 ± 1.65

< 0.01

368.41 ± 1.72374.25 ± 1.68

< 0.01

9.41 ± 1.6211.55 ± 1.18

< 0.05

Bis: bisphosphonate; BVF: bone volume fraction; vBMD: volumetric bone mineral density; EM: elastic modulus; RF: reaction force; VM: von Mises stress Note: Among the p-values, a: comparison between the model group and the bis group; b: comparison between the model group and the control group.

Table 4: Comparison of distal femoral microstructures and mechanical parameters of the three groups on the postoperative 12th week ( ±s)

Table 5: Comparison of distal femoral microstructures and mechanical parameters of the model group between the postoperative 4th and 12th week ( ±s)

Bis: bisphosphonate; BVF: bone volume fraction; vBMD: volumetric bone mineral density; EM: elastic modulus; RF: reaction force; VM: von Mises stress

June 2020179

Fig 1: 3D reconstruction figures of knee at different times. A: 2D DICOM and 3D reconstruction images of knee joint of the control group. A1: 2D DICOM; A2: Normal position; A3: Right side. B: 2D DICOM and 3D reconstruction images of knee joint of the model group. B1: Osteophyte in 2D DICOM; B2: Osteophyte in normal position; B3: Osteophyte exhibited in lateral position. C: 2D DICOM and 3D reconstruction images of knee joint of the Bis group. C1: Osteophyte in 2D DICOM; C2: Osteophyte in normal position; C3: Osteophyte in lateral position.



peri-joint trabecular bone is increased because of the sclerosis of the subchondral bone, exhibiting weakened cushioning and protective effects on the articular cartilage. This phenomenon indirectly results in cartilage destruction. A hydraulic mechanical material testing machine was used to prepare a special stainless steel cylindrical indenter and load the oppression on the experimental zone of subchondral bone of the rabbit tibial plateau. The results indicated that the stiffness and strength of rabbit knee in the entire procedure changed from low to high in the early stage of instability. Meanwhile, he studied the correlations between the EM changes and articular cartilage damages. With the development and application of non-invasive and higher resolution equipment, such as CT and MRI, as well as the continuous innovation of computer software, the 3D finite element method is widely applied in biomechanical studies. Previously, this method was used in spine research and then gradually applied to mechanical studies of the skull, pelvis, and limb joints. The development of micro-CT, which is suitable for small animal studies, such as bone anatomy, including teeth, and bone specimens, as well as the limb bones of live animals, greatly contributes to research about bone structures and mechanical properties for clinical and basic needs[15-17].

In this experiment, an unstable model of the rabbit knee was first established. The femoral distal articular bone was then intercepted, and micro-CT scanning was conducted. Mimics software fitting was used for the images obtained to initially form the 3D model, which was then imported into the Geomagic software for refinement and formation of the 3D solid model that could be recognized by the finite element analysis software. This 3D solid model of bone tissues was then calculated using Ansys software. Subsequently, reverse engineering was performed to calculate the relevant data. Through fixing the nodes, the restraints were loaded to observe the experimental indicators. The results indicated that in the early stage of knee instability (4 weeks after the surgery), the comparison between the model and Bis groups revealed that BVF and BMD, which could reflect the bone mass, were significantly reduced (p <0.01). The EM, RF, and von Mises stress were also significantly reduced; the Bis group was also lower than the control group, but the difference was not significant. This result indicates that in the early OA stage, the knee was unstable because the cruciate ligament was cut off. Thus, the joint was affected by abnormal forces. Moreover, the subchondral bone exhibited structural changes, and the bone mass was reduced. The EM, RF, and von Mises stress, which could reflect the mechanical strength of subchondral bone, were slightly reduced. At 12 weeks after the surgery, although the BVF, BMD, EM, RF, and von Mises stress were still lower than those of the control group (p <0.05), they were significantly

improved than those at postoperative 4th week. The bone density of certain specimens was even higher than that of the control group. This finding reveals that the structure and mechanical strength of subchondral bone in the entire process changed from low to high in the early OA stage, namely, the compliance was initially increased then decreased; these results are similar to those reported in literature[15]. Meanwhile, the early EM value of the OA model was related to the articular cartilage scoring, BVF of subchondral bone, and bone density. EM was negatively correlated with Mankin scores at the 4th week, but positively correlated with BVF and BMD of subchondral bone. At the 12th week, EM was negatively correlated with Mankin scores, but positively correlated with BVF and BMD of subchondral bone. This demonstrates the relationship of mechanical properties and structures of subchondral bone in the early OA stage, i.e., more bone mass indicates better bone structure and mechanical properties, and reflects the changes in OA.

The exact mechanism of mechanical property changes of subchondral bone is not completely elucidated. Fazzalari et al[17-20] believed that abnormal stress causes subchondral bone micro-fractures. These micro-fractures result in bone remodeling, as well as simultaneous activation of osteoblasts and osteoclasts and secretion of various proteases and cytokines, which lead to subchondral bone resorption, bone mass destruction, and trabecular bone fracture. Thus, abnormal stress inevitably causes the reduction of mechanical properties. Meanwhile, bone repair begins, but the destruction and repair are uneven. Calcium deposition is not sufficient, thus decreasing bone density. With the development of disease, repair and calcium deposition are increased, resulting in accelerated subchondral bone remodeling and evident reconstruction, which leads to bone sclerosis. At this time, the EM, bone density, and stress intensity are increased. However, because of excessive subchondral bone sclerosis, its capacity of buffering the joint also drops, so that its stress reverse reaction on the articular cartilage increases, which further promotes articular cartilage destruction. In this study, the general observations were consistent with the aforementioned findings. Regarding the sequence of these changes, namely, whether the cartilage changes first, then affects the subchondral bone, or the subchondral bone changes first, then affects the cartilage, or these two change at the same time, remains unclear[21-23]. However, studies reported that the changes of subchondral bone are observed prior to the cartilage in the OA animal models of primates and the spontaneous OA model of guinea pigs[24].

In this study, it was also observed that the structural characteristics and mechanical indexes of subchondral bone in the bisphosphonates group were significantly higher than those in the model group, indicating that

June 2020181

bisphosphonates can significantly protect the structure and mechanical properties of subchondral bone. As the third generation of bisphosphonates, sodium rizonium is a synthetic pyrophosphate analogue. The difference in the chemical structure between bisphosphonates and pyrophosphate lies in the substitution of P - O - P bond for P - C - P bond. This substitution makes it resistant to the action of the hydrolase without biodegradation, and its hydroxyl group and 2 phosphate groups make it highly compatible to the bone matrix. The author believed that osteoclasts are target cells of bisphosphonates, which can significantly inhibit the bone resorption of osteoclasts, promote the apoptosis of osteoclasts and inhibit the formation of osteoclasts. Our results also showed that bisphosphonates can effectively inhibit bone destruction, protect the mechanical properties of subchondral bone, reduce bone remodeling and protect articular cartilage. Our previous study[25] showed that the BVF of bone trabecula, Tb.N and Tb.Th of the subchondral bone in rabbit gonarthrosis model at postoperative 4 weeks were significantly reduced as compared with those of the control group, while the Tb.Sp was increased and the vBMD decreased, which indicated that there is abnormal force on articular surface caused by various pathogenic factors in early stage of OA. The bone trabecula of subchondral bone is damaged by repeated overload pressure, and then causes edema, hemorrhage and necrosis of bone marrow locally. The repeated microdamage of the subchondral bone and calcified cartilage initiate the process of bone remodeling, activate osteoclast, decompose a variety of osseous enzymes, promote local osteolysis and destroy the structure of the trabecular bone. At the same time, the neovascularization and the activated osteoblasts promote the formation of new bone and the production of osteoid, but the calcification is not enough, presenting as the decrease of the volume fraction, trabecular bone volume, thickness and bone mineral density. Since the bone density of the subchondral bone is reduced and the structure is destroyed, the mechanical properties will inevitably decrease. The buffer capacity of subchondral bone is not enough for the force from the cartilage, so that the articular cartilage cannot be well protected. The microstructural parameters of the bisphosphonates group were statistically different from that of the model group, indicating the protective effect of bisphosphonates on the destruction of subchondral bone tissue. Meanwhile, we compared bone mineral density and bone trabecular structure between 4 and 12 weeks, and found that BVF, Tb.N, TbTh and vBMD were increased significantly at 12 weeks (p <0.05), while the bone trabecular space was decreased (p <0.01). There was no significant difference between the bisphosphonates group and the control group, suggesting an obvious bone destruction in early OA and an accelerated

bone formation in the later stage. Early OA showed accelerated bone remodeling with insufficient calcification, destroyed bone trabecular structure and reduced mechanical properties. However, with the repair and reconstruction of subchondral bone in the later stage, the subchondral bone was hardened, resulting in increased hardness of subchondral bone. The uneven hardness of the subchondral bone changed the stress balance of articular cartilage and aggravated the cartilage damage. However, there was a significant difference in various parameters between the bisphosphonates group and the model group, indicating that bisphosphonates could protect the subchondral bone tissue which had been damaged. The general observation of the articular cartilage of the bisphosphonates group in the same period was obviously better than that of the model group, also proving that bisphosphonates can be used as a potential therapeutic drug for OA. The mechanism of sodium rizonium protecting the subchondral bone may be that bisphosphonates can inhibit the enzymolystic effect of a variety of matrix metalloproteinase, cathepsin K and other proteases produced by osteoclasts on the subchondral bone. In addition, bisphosphonates can promote the apoptosis of macrophages, inhibit bone remodeling of subchondral bone, and reduce the destruction of subchondral bone, thereby reducing the occurrence of subchondral osseosclerosis.

The accuracy of the finite element analysis mainly depends on two aspects: the coincidence degree of model and actual tissue and the choice of loading constraints. In the present study, high-resolution micro-CT was used to examine the rabbit knee joint. This technique could reflect the trabecular bone structure from the microstructural aspect. The loading conditions should be in line with the actual situation as much as possible. Although the muscles around the joint are neglected in the finite element analysis, and the complexity of the actual joint movement is not completely considered, this method possesses evident advantages. It can overcome the effects of conventional experiment objects, design methods, and other factors on the results, as well as exclude errors due to different experimental conditions. In this method, one or several parameters can be changed to observe their effects on the entire system. In addition, calculation can be repeated, which is cost-efficient. In this study, the parameters were designed according to the reported standard[26]. This could ensure the accuracy and versatility of the model, establishing a good foundation for further studies.

CONCLUSIONThe changes in the mechanical properties of the

subchondral bone showed a significant role in the occurrence and development of osteoarthritis.



ACKNOWLEDGMENTConflict of interest: All authors have no conflict of

interest regarding this paper.

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Original Article


Caesarean section: Sixteen-years’ trend, risk factors and attitudes of females delivered at King Abdulaziz

University Hospital, Jeddah, Saudi Arabia

ABSTRACT

KEY WORDS: attitudes, cesarean section, risk factors, trend

Nahla Khamis Ibrahim1,2, Khadeja Ayoub3, Sara Ali Sawan3, Maha Saleh Al-Jdani3, Nedaa Mohamed Bahkali4

1Department of Community Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia2Department of Epidemiology, High Institute of Public Health, Alexandria University, Alexandria, Egypt

3Interns, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia4Department of Obstetrics & Gynecology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia

Objective: To determine sixteen-years’ trend of cesarean section (CS), risk factors and attitudes towards it among females delivered at King Abdulaziz University Hospital (KAUH), JeddahDesign: Two study designs were conducted during 2016. A retrospective study was done through reviewing of delivery records (2000-2015). The second design was a matched case-control study.Setting: Obstetrics & Gynecology Department of KAUHSubjects: For the retrospective study, females delivered during the 16 years were scrutinized. For the case-control study, 300 postpartum randomly selected females were recruited (150 cases delivered by CS, and an equal number of controls with vaginal delivery) matched by age and parity. Intervention: Reviewing delivery records, an interviewing questionnaire with females, and clinical record abstraction forms. Descriptive and inferential statistics were done.Main outcome measures: Trend, risk factors and attitudes towards CS

Results: An increasing CS trend was obvious (129.5% increase); from 13.86% (2000) to 31.81% (2015). CS delivery was significantly associated with high income, increased weight, smoking, gestational diabetes mellitus, and previous CS(s). Non-cephalic (breech and shoulder) presentation, multiple pregnancies, preterm delivery, fetal distress and low Bishop Score were important risk factors of CS. The most frequent CS indications were history of previous CS, fetal distress and maternal emergencies. CS was done according to mother’s opinion for 3.7%. Regarding attitudes, females delivered by CS perceived it as a safer and more convenient delivery than controls. Conclusion: Increasing rates of CS prevailed at KAUH. Females with high risk factors require adequate antenatal follow-up. Implementation of programs such as labor induction in low-risk pregnancies is recommended. Increased awareness about CS complicity and advantage of vaginal delivery is needed.

Address correspondence to:Nahla Khamis Ibrahim, M.B.B.Ch, MPH, Dr.PH (Epidemiology), DHPE (Medical Education), JMHPE (Maastricht/SCU), King Abdulaziz University, Jeddah, Box: 42806, Postal code: 21551, Kingdom of Saudi Arabia. E-mail: [email protected]

INTRODUCTIONThe increasing rates of cesarean section (CS)

represents a worldwide escalating epidemic[1,2]. The number of babies delivered by CS is rapidly growing both in developed and the developing countries. The rate of CS ranged from 12% - 86% in the industrialized countries[3]. In the developing nations, CS rates ranged between 2 - 39%[3]. The countries with the highest CS rates as reported in 2016 were Brazil (55.6%) and

Dominican Republic (56.4%) from South America and the Caribbean, Egypt (51.8%) from Africa, Iran and Turkey from Asia (47.9% and 47.5%, respectively), Italy (38.1%) from Europe, United States (32.8%) from Northern America, and New Zealand (33.4%) from Oceania[4]. CS is a common obstetric procedure[5] and the reasons behind its continuous increasing rates appeared to be multiple, complex and, may be in many cases, specific to the country[1,2]. The increasing trend


of CS may be attributed to maternal, foetal, obstetric and organizational factors[6,7]. In some cases, women may request cesarean delivery without medical need[8].

There are many concerns regarding the escalating rise in CS rates due to potential maternal and perinatal risks, the probability of obstetric complications in upcoming pregnancies and financial issues[9]. The increased rates of CS lead to increased scar pregnancies, which can have lethal consequences and may affect infant immune system[2]. Females previously delivered by CS may be more liable to postpartum haemorrhage and retained placenta. Uterine rupture and placenta previa are well-known and potentially life-threatening complications of previous CS, but are fortunately still rare conditions[10].

The World Health Organization has stated that maximum CS percentage should be 15%, and that no region in the world is justified with having a caesarean rate greater than 10% to 15%[9]. Although the rate of CS is escalating, no adequate studies were done about the trend, risk factors and attitudes of mothers towards CS in university hospitals in Jeddah, Saudi Arabia. Therefore, such a study is needed.

The study was done to determine the 16 years’ trend of CS (2000 - 2015), and to identify the risk factors and attitudes towards CS among females who delivered by both CS and vaginal delivery (VD) in the University Hospital from Jeddah.

SUBJECTS AND METHODS Two study designs were conducted:

1. A retrospective record review study (16-years’ trend of CS): All records of deliveries done in the Obstetrics & Gynaecology Department of the University Hospital during a 16 year period (2000 - 2015) were reviewed.

Data was collected through a pre-constructed clinical data abstraction sheet. It was used to collect information about the numbers and methods of deliveries (CS or VD). The types of CS such as upper segment, transverse and lower segment CS (LSCS) were also recorded. Similarly, the types of VD such as spontaneous VD (SVD), breach and assisted deliveries (ventouse and forceps) were also noted.

2. A matched case-control study: Eligibility criteria for enrolment in this part of the study included all females in the reproductive age, who attended the Gynaecology and Obstetrics Department of the University Hospital for labour during the year 2016, mentally sound, who were willing to participate in the study, and to write the informed written consent.

Cases: Females who fulfilled the eligibility criteria and delivered by CS.

Controls: Females who fulfilled eligibility criteria and had a VD.

A systemic random sample method was used. Every 7th file of the postpartum females, who fulfilled the eligibility criteria were included. For each selected

Fig 1: Sixteen years’ trend of vaginal and caesarean section deliveries among females delivered at King Abdulaziz University Hospital from year 2000 to 2015

Perc

enta

ge

June 2020185

female delivered by CS (case), one female delivered by VD (control) was taken and matched by age and parity.

The sample size for the case-control part was calculated through EpiTools epidemiological calculators[11].

It was assumed that expected proportion of exposure among the control group was 60%, odds ratio (OR) was 2, the power of the sampling equals 80%. At 1.96 confidence level, the calculated sample size was 300, divided into 150 in each group.

A data collection sheet was used for the case-control study and it contained: Ø An interviewing questionnaire: A validated,

anonymous, interviewing questionnaire with females was used. Two experts examined the face and content validity. The internal constituency reliability was assessed by Cronbach’s α test and was 0.82.

Post-partum females from both the case and control groups were asked about the personal and socio-demographic information. History of chronic diseases was taken. Gynecological, obstetric history and history of the current pregnancy were determined. In addition, the attitudes of all females towards delivery by CS were assessed. Ø Clinical record abstraction form: It was

fulfilled through reviewing the hospital files of the selected females for collecting data about the weight, height, gestational age (GA), presence of gestational diabetes mellitus (GDM) and hypertension. The types of CS or VD were taken. Data about the presentation and child’s Apgar score (after one minute) was also collected. Bishop Score was recorded (if data was

present). It is based on the consistency, effacement, dilation, and position of cervix. It assessed also the foetal station (how far up the birth canal the baby’s head is)[12].

Statistical analysisData was analysed using SPSS 20 (SPSS Inc.,

Chicago, IL). The rate of CS was calculated as the number of caesarean births divided by total live births. Bishop score[12] was calculated and categorized into those having a score of ≥6 (labour is likely to start without induction), and those who obtained a score ≤ 5 (labour is unlikely to start without induction).

Apgar score was categorized. Descriptive and inferential statistics were done. Body mass index was calculated. Chi square, OR and 95% confidence intervals (CIs) were calculated. All p-values <0.05 was considered significant.

RESULTSFor the retrospective study, the sixteen years’ trend

of all deliveries is presented in Table 1 and Figure 1. The total cumulative numbers of deliveries done during the period was 66,000. The rate of VD decreased from 86.14% during 2000 to 68.19% in 2015. On the other hand, the rate of CS increased from 13.86% to 31.81% during the same years, respectively (129.5% increase). CS accounted for 21.2%, and SVD with cephalic presentation represented 75.42% of all deliveries done during the 16-year period. SVD with babies in breach presentation accounted for 1.2%. Assisted VDs were done by ventouse and forceps for 2.1% and 0.08% of females, respectively.

YearTotal

deliveries

Vaginal deliveries CS

SVD Assisted vaginal delivery Breach Allvaginal No %

SVD % Ventouse % Forceps % Breach. % %

2000200120022003200420052006200720082009201020112012201320142015Total

3145379041654927471738993834391943984243423847604599431937243323

66,000

2625312733373960372530843000296733153165310834243331303924262146

49779

83.4682.5080.1280.3778.9679.0978.2575.7175.3874.5973.3471.9372.4370.3665.1564.5875.42

24415383

106929692969094

13111388

10573

1377

0.030.080.020.120.040.050.100.100.2

0.090.040.060.040.070.030.152.1

1316224412423231555

0.030.080.020.120.040.050.100.100.270.090.040.060.040.070.030.150.08

595948555529294346524544355110742799

1.881.561.151.121.170.740.761.101.051.231.060.920.761.182.871.261.2

86.1485.2282.5783.382.4382.2581.6179.2578.8878.0376.6675.6775.6973.6570.8668.1978.8

4365607268238296927058139299329891158111811381085105713990

13.8614.7817.4316.717.5717.7518.3920.7521.1221.9723.3424.3324.3126.3529.1431.8121.20

Table 1: Sixteen-year trend of types of deliveries between females delivered at the University Hospital (2000 to 2015)

SVD: spontaneous vaginal delivery

Caesarean section: Sixteen-years’ trend, risk factors and attitudes of females delivered at King Abdulaziz ...


Regarding case-control part of the study, the mean age of all 300 females was 30.09 ± 5.16 years. Based on matching criteria, there is no statistical significant difference between cases and controls regarding age or parity (p >0.05). Regarding types, LSCS was the most common type of CS (97.3%). Only two cases (1.3%) were delivered through transverse CS incision, and one case (0.7%) had complication and delivered by emergency caesarean hysterectomy.

Results revealed that all cases of placenta previa (8 cases), preeclampsia (5 cases), cord prolapse and placenta abortion were delivered by CS (4 cases for each). It was found that 18.3% of females were primigravida. The cephalic presentation represented 88%, while non-cephalic (breech and shoulder) accounted for 12% of all presentations. GDM occurred among 8.3% of all females from both groups.

Table 2 illustrates that there is no statistically significant association between the type of delivery and each females’ occupation and education (p >0.05). However, females who had enough income delivered more frequently by CS compared to others, with a statistically significant difference (p <0.05). Overweight and obese mothers were 2.25 times more prone to CS delivery compared to others (OR = 2.25; 95% CI: 1.23

- 4.10). Smokers had higher rates of CS compared to others, with statistically significant difference (p <0.05). Shorter GA at birth (≤ 32 weeks) was associated with more CS delivery (p <0.05)

Table 3 revealed that females who delivered by previous CS had an increased risk of delivery by the same method in the current pregnancy (X2 = 116.15, p <0.001). Furthermore, mothers who suffered from GDM in the current pregnancy were about three times more at risk of having CS delivery (current) compared to others (OR = 2.79; 95% CI: 1.13 - 6.88). Hypertensive females had a higher rate of delivery by CS compared to others (p <0.05).

Regarding foetal presentation, CS was done for 97.2% of women who had their foetus in the non-cephalic presentations compared to only 43.6% for females whose foetus was in the cephalic presentation (OR = 45.35; 95% CI: 6.12 - 335.95). Mothers who delivered twins were about eight times more liable to CS delivery (OR = 8.22; 95% CI: 1.8 5- 36.62). Those who delivered a distressed baby (confirmed by first minute Apgar score ≤ 6) had higher rate of CS compared to others. Females who had a pre-term delivery (GA ≤32 weeks) had a higher susceptibility to CS compared to others (p <0.05).

VariableCase

(Caesarean Section)Control

(Vaginal delivery) X2 p-value OR 95% CINo. Percentage No. Percentage

Mother’s age < 35≤ 35

Education< University ≥ University

OccupationProfessionalNon-Professional

IncomeNot enough Enough or more

SmokingYesNo

BMIOverweight & obeseNormal

Current gestational age≤ 32 weeks> 32 weeks

Follow-up regularly during this pregnancyYesNo

GravidityPrimigravidaMultigravida

11634

7872

25125

13137

12138

12320

11139

12624

21129

49.253.1

5248

16.783.3

8.791.3

75.048.6

54.234.5

78.648.6

50.846.2

38.252.7

12030

7872

30120

28122

4146

10438

3147

12228

34116

50.846.9

5248

2080

18.781.3

25.051.4

45.865.5

21.451.4

49.253.8

61.847.3

0.32

0.00

0.56

6.36

4.23*

7.17

4.80*

0.37

3.76

0.573

1.000

0.456

0.012

0.040

0.007

0.029

0.542

0.05

0.85

1.00

0.80

0.41

3.17

2.25

3.88

1.21

0.55

0.49 -1.48

0.64 – 1.57

0.45 – 1.44

0.21 – 0.83

1.01 - 10.08

1.23 – 4.10

1.06 -14.19

0.66 - 2.19

0.31-1.01

Table 2: Comparisons between females delivered by caesarean section and by vaginal deliveries according to personal, socio-demographic factors, obstetric history and measurements

* Fisher’s exact testOR: odds ration; CI: confidence interval

June 2020187

The most common indications for CS (Table 4) were having a history of previous CS (26%), foetal distress (24.7%) and mother’s emergency (22.3%). Furthermore, opinions of doctors and mothers accounted for 14% and 3.7%, respectively.

Table 5 demonstrates the attitudes of females in both case and control groups towards CS. A higher percentage of females who delivered by CS agreed that CS is a safer method of giving birth than others (X2 =13.79, p <0.01). Similarly, there is a statistically significant difference between opinions of both groups concerning CS as a more convenient method of delivery (p <0.05).

DISCUSSIONCS is one of the most frequently performed

surgical obstetric operations[13]. Results of the retrospective part of our study showed an increasing CS trend overtime. The rate was 13.86% during 2000 and increased to 31.81% in 2015 (129.5% increase).

VariableCase

(Caesarean Section)Control

(Vaginal delivery) X2 p-value OR 95% CINo. Percentage No. Percentage

Mode of previous deliveries (245 had previous deliveries)

All deliveries were by CSBoth CS & vaginal deliveries All deliveries were vaginal RC

Gestational diabetes mellitusYes No

Hypertension YesNo

Presentation Non-cephalic (breech & shoulders) Cephalic

Current gestational age≤ 32 weeks> 32 weeks

Multiple pregnancies TwinsSingle

Foetal distress (Apgar score after 1 minute)≤ 6<6

History of taking drugs YesNo

Exaggerated pregnancy symptomsYesNo

Bishop score (done for 92 cases only)< 6≥ 6

653430

18132

12138

35115

11139

15135

30120

47103

47103

912

95.682.922.1

72.048.0

75.048.6

97.243.6

78.648.6

88.247.7

85.745.3

58.846.8

52.848.8

81.814.8

37

106

7143

4146

1149

3147

2148

5145

33117

42108

269

4.417.177.9

28.052.0

25.051.4

2.856.4

21.451.4

11.852.3

14.354.7

41.253.2

47.251.2

18.285.2

116.15*

5.28

4.23*

36.49*

4.80*

10.54*

20.22

3.34

0.40

24.68*

0.000

0.02

0.04

0.000

0.02

0.001

0.000

0.068

0.53

0.000

67.5617.16

2.79

3.17

45.35

3.88

8.22

7.25

1.62

1.17

25.87*

22.46-260.96.91-42.59

11.13 - 6.88

1.01 - 10.08

6.12–335.95

1.06 - 14.19

1.85 - 36.62

2.73 - 19.26

0.96 - 2.72

0.72 - 1.93

4.97–134.76

Table 3: Comparisons between females delivered by caesarean section and by vaginal deliveries regarding current obstetric history

* Fisher’s exact testRC: Referent Category; OR: odds ratio; CI: confidence interval

Causes of caesarean section No. Percentage

Maternal & foetal causes Previous CSFoetal distressMother's emergencyOpinion of doctorBaby in breechPrecious babyMechanical impendenceDilation problemsCephalo-pelvic disproportion Opinion of mother

Obstetric causesMultiple pregnancyPlacenta previaPreeclampsiaCord prolapseplacental abruptionPregnancy after infertilityGenital herpes

78746742313020151211

11854441

26.024.722.314.010.310.06.75.04.03.7

3.72.71.71.31.31.30.3

Table 4: Indication of cesarean section delivery among females attended labour at King Abdulaziz University Hospital


CS: caesarean sectionNB: Each item was separately collected


QuestionAgree No opinion Disagree X2

(p)No. Percentage No. Percentage No. Percentage

CS is an easier way of giving birthCSVD

CS is a more convenient way of birthingCSVD

CS is safer than vaginal deliveryCSVD

CS is no longer seen as major surgeryCSVD

CS is portrayed by media as a better way of delivery than the vaginal

CSVD

4134

3317

245

6143

5541

27.322.7

22.011.3

163.3

40.728.7

36.727.3

158

1720

1719

2424

3670

10.05.3

11.313.4

11.312.7

1616.0

2446.7

93108

100113

109126

6583

5939

62.072.0

66.775.3

72.784.0

43.353.3

39.326

3.09 (0.14)

6.16 (0.04)

13.79 (0.001)

5.03 (0.07)

3.99 (0.14)

Table 5: Opinions of females delivered by cesarean section or vaginal delivery towards cesarean section

Similarly, several other studies have reported increasing CS trends[1,13-17]. On the other hand, Costa et al[9] conducted a retrospective study at a teaching hospital from Portugal and revealed decreasing CS rates overtime; from 30.9% in 2005 to 27.6% in 2011. The cause behind this discrepancy may be attributed to their implementation of departmental policies as external fetal version program, labor induction after the 41 gestational weeks in pregnancy with low-risk, etc.[9].

In the current study, the cumulative 16-years CS rate was 21.2%, which agrees with 16-years rate (1997-2012) of Lurie et al[18].

Regarding our case control study, 97.3% of females in CS group delivered by LSCS, which agrees with results of Gupta et al from India[19]. In addition, history of previous CS was the first indication of its current conduction, followed by foetal distress and mother’s emergency. We found that all cases of maternal emergencies (placenta previa, pre-eclampsia, cord prolapse and placenta abrrtion) were delivered by CS. These results are aligned with findings of one-year retrospective study carried out by Abebe et al from Ethiopia in 2016[3].

In the current study, older women had a slightly higher rate of CS delivery, which agrees with a study from the UK[20]. Older females are more likely to have pregnancy complications[7]. However, there was no significant difference between the age of females delivered by CS or VD in our study, which agrees with results of Dias et al from Brazil[21] and Chanthasenanont et al from Iran[22]. Furthermore, we found that increasing family income was associated with increased CS delivery, which agrees with results of Al Busaidi et al from Oman[14].

In our study, previous CS was associated with much increased risk of current CS, which may be due

to persistence of the indication for conduction. This result agrees with many other findings[3,7,14,20,22].

Our results showed that females with shorter GA (preterm labour) were significantly at an increased risk for CS, which agrees with the results of Patel et al from UK[20]. Furthermore, most of the cases with multiple-pregnancies (twins) in our study were delivered by CS, which coincides with other researches[3,23].

Concerning child presentation, our results found that mothers whose babies were in the non-cephalic presentation were about 45 times more prone to CS delivery compared to others, which agrees with two UK studies[20,24].

Results of the current study showed that overweight and obese mothers had higher susceptibility to CS delivery. It was found from results of a meta-analysis from 2014 that obese women are more likely to have macrosomic babies, and therefore more likely to have CS[25]. This finding may be because obesity can be associated with other pregnancy problems such as pre-eclampsia, diabetes mellitus and GDM[14]. Similar findings were reported from Peru[1], Oman[14] and China[26]. Furthermore, our findings illustrated that mothers with GDM had about a threefold increase in risk of CS delivery compared to others. Similar results were obtained from the studies of Oman[14], UK[20] and Portugal[27]. Hypertension was also associated with CS in our study, which coincides with the Omani study[14].

In the current work, CS rate increased among smokers compared to non-smokers, which coincides with the results of another study done by Lurie et al[28]. They concluded that foetal compromise can occur during labour, leading to increased rates of operative delivery among female smokers.

Our results revealed presence of significant association between low Bishops score and CS, which agrees with results from Iran[12] and Turkey[29].

CS: caesarean section; VD: vaginal delivery

June 2020189

Low Apgar score (≤ 6) was significantly associated with CS delivery in our study, which coincides with results from another study done by Gasim in Al-Khobar, KSA, which indicated that CS was conducted more in foetal distress[23].

Regarding attitudes, a higher percentage of females delivered by CS in our study agreed that CS is an easier, safer and more convenient way of giving birth compared to the control group. Women who preferred CS from another Saudi study done by Gari et al[30], and those from an Iranian ethnographic study reported that they preferred CS as it is less painful[31]. Ashimi et al found that a majority of their Nigerian pregnant females are willing to undergo and repeat CS if it is indicated[32]. However, a study of Adageba et al from Ghana showed that the majority of women in their study preferred VD unless CS is necessary[33].

CONCLUSIONAn increasing trend of CS prevailed among females

delivered at the University Hospital during the 16 years (2000 to 2015). CS was associated with females who had enough income, smokers, with higher body mass index, GDM and hypertension. It was also associated with preterm delivery, non-cephalic presentation, multiple pregnancies, foetal distress, and with low Bishop Score. The most frequent CS indications were previous CS, foetal distress and maternal emergencies. Opinion of doctors and mothers accounted for 14% and 3.7% of CS, respectively. Regarding attitudes, females in CS group perceived it as a safer and more convenient way of delivery compared to those in the control group. Preventing the escalating trend of CS is needed through sound provision of antenatal care. Females with high risk factors require adequate follow-up. Implementation of programs such as external fetal version program and labor induction in low-risk pregnancies is recommended. Providing sound, detailed educational CS messages is needed for both physicians and females.

ACKNOWLEDGMENTWe would like to thank all the participants in the

study, all the students who helped in data collection, and all administrators who facilitated it.

Conflict of interests: None

REFERENCES

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2. Saleh AM, Dudenhausen JW, Ahmed B. Increased rates of cesarean sections and large families: a potentially dangerous combination. J Perinat Med 2017; 45(5):517-521.

3. Abebe FE, Gebeyehu AW, Kidane AN, Eyassu GA. Factors leading to cesarean section delivery at Felegehiwot referral hospital, Northwest Ethiopia: a retrospective record review. Reprod Health 2016; 13:6.

4. Betrán AP, Ye J, Moller AB, Zhang J, Gülmezoglu AM, Torloni MR. The increasing trend in caesarean section rates: Global, regional and national estimates: 1990-2014. PloS one 2016; 11(2):e0148343.

5. Mhaske N, Agarwal R, Wadhwa RD, Basannar DR. Study of the risk factors for cesarean delivery in induced labors at term. J Obstet Gynaecol India 2015; 65(4):236-240.

6. Al Rowaily MA, Alsalem FA, Abolfotouh MA. Cesarean section in a high-parity community in Saudi Arabia: clinical indications and obstetric outcomes. BMC Pregnancy Childbirth 2014; 14:92.

7. Cnattingius R, Höglund B, Kieler H. Emergency cesarean delivery in induction of labor: an evaluation of risk factors. Acta Obstet Gynecol Scand 2005; 84(5):456-462.

8. Tully KP, Ball HL. Misrecognition of need: Women’s experiences of and explanations for undergoing cesarean delivery. Soc Sci Med 2013; 85:103-111.

9. Costa A, Policiano C, Clode N, Graca LM. Indications for cesarean deliveries during a 7-year period in a tertiary hospital. Acta Med Port 2013; 26(6):649-654.

10. Belachew J, Eurenius K, Mulic-Lutvica A, Axelsson O. Placental location, postpartum hemorrhage and retained placenta in women with a previous cesarean section delivery: a prospective cohort study. Ups J Med Sci 2017; 122(3):185-189.

11. Sergeant, ESG, Epitools epidemiological calculators. Ausvet Pty Ltd. index_accord.htm, 2018., (Accessed 1 February 2018) at http://epitools.ausvet.com.au.

12. Khazardoost S, Ghotbizadeh Vahdani F, Latifi S, Borna S, Tahani M, Rezaei MA, et al. Pre-induction translabial ultrasound measurements in predicting mode of delivery compared to bishop score: a cross-sectional study. BMC Pregnancy Childbirth 2016; 16(1):330-335.

13. Bahadori F, Hakimi S, Heidarzade M. The trend of caesarean delivery in the Islamic Republic of Iran. East Mediterr Health J 2014; 19 Suppl 3:S67-70.

14. Al Busaidi I, Al-Farsi Y, Ganguly S, Gowri V. Obstetric and non-obstetric risk factors for cesarean section in Oman. Oman Med J 2012; 27(6):478-481.

15. Walker R, Turnbull D, Wilkinson C. Increasing cesarean section rates: exploring the role of culture in an Australian community. Birth 2004; 31(2):117-124.

16. Chong C, Su LL, Biswas A. Changing trends of cesarean section births by the Robson Ten Group Classification in a tertiary teaching hospital. Acta Obstet Gynecol Scand 2012; 91(12):1422-1427.

17. Mylonas I, Friese K. Indications for and risks of elective cesarean section. Dtsch Arztebl Int 2015; 112(29-30):489-495.

18. Lurie S, Shalev A, Sadan O, Golan A. The changing indications and rates of cesarean section in one academic center over a 16-year period (1997-2012). Taiwan J Obstet Gynecol 2016; 55(4):499-502.

19. Gupta P, Jahan I, Jograjiya GR. Is vaginal delivery safe after previous lower segment caesarean section in developing country? Niger Med J 2014; 55(3):260-265.



20. Patel RR, Peters TJ, Murphy DJ; ALSPAC Study Team. Prenatal risk factors for Caesarean section. Analyses of the ALSPAC cohort of 12,944 women in England. Int J Epidemiol 2005; 34(2):353-367.

21. Dias MAB, Domingues RMSM, Schilithz AOC, Nakamura-Pereira M, do Carmo Leal M. Factors associated with cesarean delivery during labor in primiparous women assisted in the Brazilian Public Health System: data from a National Survey. Reprod Health 2016; 13(Suppl 3):114-117.

22. Chanthasenanont A, Pongrojpaw D, Nanthakomon T, Somprasit C, Kamudhamas A, Suwannarurk K. Indications for cesarean section at Thammasat University Hospital. J Med Assoc Thai 2007; 90(9):1733-1737.

23. Gasim TG. Preterm singleton breech delivery in a teaching hospital of Saudi Arabia: vaginal versus cesarean delivery. J Family Community Med 2008; 15(2):65-70.

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26. Xiong C, Zhou A, Cao Z, Zhang Y, Qiu L, Yao C, et al. Association of pre-pregnancy body mass index, gestational weight gain with cesarean section in term

deliveries of China. Sci Rep 2016; 6:37168.27. Gorgal R, Gonçalves E, Barros M, Namora G,

Magalhães A, Rodrigues T, et al. Gestational diabetes mellitus: a risk factor for non-elective cesarean section. J Obstet Gynaecol Res 2012; 38(1):154-159.

28. Lurie S, Ribenzaft S, Boaz M, Golan A, Sadan O. The effect of cigarette smoking during pregnancy on mode of delivery in uncomplicated term singleton pregnancies. J Matern Fetal Neonatal Med 2014; 27(8):812-815.

29. Çelik HG, Bestel A, Çelik E, Aydın AA. Why do multiparous women with a history of vaginal delivery give birth by cesarean section? J Turk Ger Gynecol Assoc 2016; 17(4):209-213.

30. Gari A, Al-Esemi A, Al-Gailani A, Al-Shafi D, Al-Malki H, Al-Saadi M. Cesarean section on demand: Is it a choice among women in Saudi Arabia? Jordan Medical Journal 2015; 49(3):175-182.

31. Zakerihamidi M, Latifnejad Roudsari R, Merghati Khoei E. Vaginal delivery vs. cesarean section: A focused ethnographic study of women’s perceptions in the north of Iran. Int J Community Based Nurs Midwifery 2015; 3(1):39-50.

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Original Article


Incidence of malnutrition in patients with maintenance hemodialysis – a single centre experience

ABSTRACT

KEY WORDS: counselling, hemodialysis, nutritional, status

Bhavana Shailendranath, Prashant G Kedlaya, Renuka SatishDepartment of Nephrology, St. John’s Medical College Hospital, Bengaluru, Karnataka, India

Objective: Malnutrition embarks as a significant criterion to portray patients on hemodialysis. The main aim was to find out the incidence of malnutrition among maintenance hemodialysis patients using a panel of nutritional markers.Design: A retrospective study on maintenance hemodialysis patients for one year on interval of three month follow-up basis.Setting: Department of Nephrology, St. John’s Medical College Hospital, Bengaluru, IndiaSubjects: Adult patients (aged ³18 and £65 years) who were on regular hemodialysis (n=90). Interventions: The samples were assessed for anthropometry, haematochemical parameters, dietary pattern, appetite status and subjective global assessment.Main outcome measure: Assessment of nutritional status among hemodialysis patientsResults: The mean age was 49.67±13.17 years and 68% were males. Each anthropometric measure was nearly

similar at each time point indicative of non-detriment in body composition, which symbolizes good nutritional status. Body mass index was within the ideal range all through study duration. Based on biochemical investigational parameters, there was significant change over time from baseline to end of study for serum albumin, serum calcium, serum phosphorus and urea reduction ratio towards improvement phase. Other biochemical parameters showed no statistical significance, with means being consistent over the time during the study period, suggesting continuance of health status and adherence to 3 D’s of therapy. Appetite status assessment scoring showed improvement from baseline to end of study, hence good eating ability was supported with improved overall nutritional status. Conclusion: With adequate dietary intake, there was maintenance of nutritional status blended with effective periodic educational programs.

Address correspondence to:Dr. Bhavana Shailendranath, Renal Nutritrionist, Department of Nephrology, St. John’s Medical College Hospital, Sarjapur Road, Bengaluru – 560 034, Karnataka, India. Tel: +91 9448023748; Fax: 080 25503694; E-mail: [email protected]

INTRODUCTIONNutritional status determines the nutritional

health of an individual, describing the wellness of nutrients that are being met in the form of food. It is not only influenced by living situation, availability of food and their choices, but also the state of health of that individual depicting the body’s absorption and utilization of nutrients. A complete evaluation of nutritional status involves a combination of anthropometric, biochemical, clinical and dietary measurements[1]. Chronic kidney disease (CKD) is a public health problem. The incidence and prevalence of end stage renal disease has become more evident in this era of modern medicine. Malnutrition is a

significant co-morbidity of CKD, including patients on hemodialysis (HD) or peritoneal dialysis therapy[2,3]. Malnutrition is a frequent complication affecting quality of life since it is associated with increased risk of morbidity and mortality among maintenance hemodialysis (MHD) patients[4]. There is paucity of Indian dialysis patients’ data on quality of life and associated survival related to poor nutrition and dialysis noncompliance[5]. Periodic evaluation and monitoring of nutritional status is found to be the vital component of nutrition care in patients with kidney disease. To ascertain nutritional status, the nutrition care plan involves an array of indexes, each representing a specific data category measured


independently and evaluated collectively[2,3]. As per the definition of protein energy malnutrition (PEM), there is a lack in supply of sufficient energy or protein to meet the body’s metabolic demands as a result of either an inadequate dietary intake of protein, intake of poor quality dietary protein, increased demands due to disease condition or increased nutrient losses. Many studies have reported the presence of PEM at the initiation of dialysis therapy due to change in body composition at pre-dialysis CKD stages[6]. There are many contributing factors for protein energy wasting among dialysis populace, but those of concern are inadequate food intake and abnormal nutrient metabolism, which may be associated with underlying psychological distress, barriers and burden of illness[7].

Hence, a one year retrospective study was conducted to assess the incidence of malnutrition among MHD patients.

SUBJECTS AND METHODSSample selection

One-hundred patients regularly visiting the dialysis center at St. John’s Medical College Hospital were enrolled in the study. They were studied prospectively for one year on an interval of three monthly follow-up basis, i.e., initial month (baseline), third month, sixth month, ninth month and twelfth month (end of study (EOS)). The study samples were undergoing regular twice/thrice weekly HD sessions. By the end of the study period, ten subjects could not complete the research program due to unavoidable reasons like change in dialysis centre, lost to follow up, change in dialysis modality and death. Finally, the study sample size was minimized to 90 subjects who successfully accomplished the requirements of research protocol. Institutional Ethical Committee approval was obtained for the conduct of the study. A one to one interview schedule method was used for data collection to obtain accurate and appropriate information. A window period of ±7 days was employed at each scheduled visit for each individual after their enrollment into the study.

The criterion considered for patient selection included:

Inclusion criteria1. Subjects with CKD stage V on MHD of either

gender with ³18 to £65 years of age2. Subjects who have undergone ³3 months of HD

and permanent dialysis access AV fistula / AV graft

3. Subjects who were willing to undergo regular tests4. Subjects who were voluntarily willing to

participate in the research program and signed informed consent.

Exclusion criteria1. Those subjects suffering from severe cardiac and

liver failure2. Subjects who were retroviral positive3. Subjects diagnosed to have tuberculosis or

malignancy4. Those planned for renal transplantation in near

future

General observationsThe basic information was collected as per the

following;Socio-Demographics data along with details of

dialysis modality

Anthropometric statusOne of the methods of assessing nutritional status

was by physical examination and was performed after one hour of post dialysis session on non-vascular side. Anthropometric assessment status included measurements and recordings of subjects at baseline visit and at each follow-up visit until end of the study visit. Anthropometric status of both male and female subjects were included as mentioned below;· Primary anthropometric measurements –

i. Weight (kg)ii. Height (cm)iii. Mid arm Circumference (MAC-cm)iv. Four sites of skin fold thickness (mm) at biceps,

triceps, subscapular and suprailiac· Derived from primary anthropometric

measurement details – i. Body mass index (BMI - kg/m2)ii. Arm muscle area (AMA – cm2)iii. Total body percent fativ. Fat free mass (FFM-kg)v. Fat mass (FM-kg). Body composition parameters were analyzed using

bioelectrical impedance and skinfold calipers and the inference values were considered as per actuals. Body fat was analyzed using Holtain skin fold calipers and body composition using Multivariate Maltron BioScan 920-2 Bioelectrical impedance. Body composition techniques were used to diagnose protein depletion and to monitor efficacy of nutritional therapies using KDOQI guidelines for anthropometry[8].

Biochemical investigation statusThe biochemical laboratory tests were performed

on a sub-sample of the study population (n = 30) during each study visit. Adequacy of dialysis was calculated using urea reduction ratio (URR) at every study visit.

Dietary patternDetailed information about the eating pattern was

obtained.

June 2020193

Appetite assessmentA detailed profile on barriers and facilitators of

adequate food consumption for the past one week duration was assessed.

The subjects were exposed to intervention program of education modules developed through lecture method, individual and group (patient and care givers) counselling sessions, visual aids, interaction sessions, demonstrations and group discussions.

Subjective Global Assessment (SGA)A short form 36 scoring was considered for

nutritional status assessment for all study patients every six months.

Statistical methodsData are presented in continuous variables as mean

± standard deviation for the normally distributed variables; otherwise median and inter-quartile range was used. Categorical variables were reported using number and percentages. Repeated measures ANOVA, which analyzes the equality of means, was carried out to assess the time effect and interaction effect of outcome which was applied to analyze anthropometry, biochemical investigations and total dietary and appetite scoring. Cochran’s Q test was used to analyze SGA. A p-value £0.05 was considered for statistical significance. All the analysis was done using SPSS version 18.0.

RESULTSThe data in Table 1 provides the demographic

profile of the respondents. Nearly two-thirds (45%) of the study population were in the age group of 56 to 65 years and 68% of the study population belonged to the male gender. The mean age was found to be 49.67 ± 13.17 years.

The anthropometric indices mentioned in Table 2 depicted that there was no significant change in the

CharacteristicsRespondents

(N = 90)

No Percentage

Age Group (years)18 - 3031 – 4546 – 5556 - 65

GenderMaleFemale

11172240

6129

12192445

6832

Table 1: Sociodemographic profile

mean measurements of MAC, BMI, AMA, FFM, FM and total body percent fat over the study period. The mean value of each anthropometric parameter was nearly similar at each time point, indicative of non-detriment in body composition. BMI of the study group were in the ideal range as per Asia Pacific standard all through the study duration.

Table 3 highlights the biochemical findings which reveals that there was a significant change over time from baseline to EOS in haematochemical parameters like serum calcium, phosphorus, serum albumin and URR. Serum calcium and phosphorus stores were in sufficient parametric data to predict bone health status. Though there was not much variation in the means of albumin, calcium and phosphorus levels, their statistical significance posed good control of essential indices. Other biochemical parameters showed no significance and the means were consistent over time during study period. All biochemical indices were in the required reference range, which reflected their good nutritional status and adherence to 3D’s of therapy (diet, drug and dialysis) during the study period and was attained by regular interaction.

It was evident from Table 4 that the dynamics of dietary pattern and the subjects’ food habits reflected on their food intake along with dialysis regimen. Majority

CategoryRespondents (n = 90)

p-value0 MonthMean (SD)

3 MonthMean (SD)

6 MonthMean (SD)

9 MonthMean (SD)

12 MonthMean (SD)

Mid Arm Circumference(cm)Body Mass Index (kg/m2)Arm Muscle Area (cm2)Skin fold Calipers

Fat Free Mass (kg) Fat Mass (kg) Percentage of body fat

Bioelectrical Impedance AnalysisFat Free Mass (kg) Fat Mass (kg) Percentage of body fat

25.25 (3.95)21.25 (3.97)30.56 (11.66)

41.68 (7.84)14.30 (7.31)23.94 (7.37)

47.35 (9.03)8.78 (5.68)18.99 (7.24)

25.28 (4.01)21.29 (3.96)30.69 (11.91)

41.76 (7.94)14.34 (7.18)23.94 (7.38)

47.28 (9.30)8.63 (5.65)18.94 (7.24)

25.26 (3.96)21.30 (3.96)31.81 (14.89)

41.67 (8.18)14.33 (7.17)23.93 (7.33)

47.56 (8.83)8.65 (5.50)18.97 (7.22)

25.26 (4.01)21.32 (3.96)30.73 (11.99)

41.73 (8.22)14.34 (7.17)23.92 (7.34)

47.64 (8.88)8.52 (5.42)18.99 (7.24)

25.28 (3.99)21.34 (3.93)30.80 (11.98)

41.89 (7.94)14.36 (7.17)23.83 (7.32)

47.55 (9.06)8.68 (5.54)18.89 (7.19)

0.32 NS0.55 NS0.33 NS

0.43 NS0.75 NS0.45 NS

0.46 NS0.35 NS0.75 NS

Table 2: Body composition of the subjects

NS: Non-significant



of the respondents were non-vegetarians, had better food intake post dialysis and preferred to liberalise their dietary restrictions at pre-dialysis session. Most of them felt taste was a predominant factor for their non-adherence to renal diet prescription and they preferred hot platter.

Table 5 concentrated mainly on the appetite pattern of the samples which included feeling full of a meal, hunger, food taste, meal pattern, nausea and mood swings. There was a statistical mean significance in total appetite assessment scoring which showed an increasing trend over the time, projecting improvement of appetite status [Baseline = 21.66 ± 3.62; 6th month = 23.42 ± 2.35; EOS = 24.66 ± 2.23]. There was a good response for appetite which showed improvement from poor to average, and then to good criteria, with statistical significance. It was also seen that there was a higher number of cases who

reported no weight change over time during every study visit; hence, the respondents were maintaining their health status during the study period. A trend of three meal pattern with acceptable food taste was observed among a majority of the study population. Improvement in appetite status was found beneficial with counselling rendered at every study visit. Irrespective of the cause of native kidney disease, our samples exhibited same kind of dietary and appetite pattern.

There was a shift in the nutritional status from severely malnourished to mildly to moderately malnourished and then to well-nourished group among the study population depicting gradual improvement during study duration (Fig. 1).

Significant outcome was obtained between SGA and serum albumin levels and frequency of dialysis (Table 6). There was enhancement in nourishment

Category 0 MonthMean (SD)

3 MonthMean (SD)

6 MonthMean (SD)

9 MonthMean (SD)

12 MonthMean (SD) p-value

Haemoglobin (g/dL)Calcium (mg/dL)Phosphorus (mg/dL)Albumin (g/dL)Potassium (mEq/L)Urea Reduction Ratio (%)

009.25 (01.52)008.17 (00.77)004.48 (01.31)003.49 (00.44)005.49 (00.71)066.52 (09.30)

009.04 (01.58)008.28 (00.65)004.52 (01.44)003.49 (00.35)005.53 (00.74)066.20 (08.48)

009.16 (01.50)008.36 (00.57)004.64 (01.41)003.41 (00.34)005.49 (00.69)069.59 (08.64)

009.29 01.33)008.40 00.64)004.42 (01.31)003.47 00.32)005.55 00.60)068.86 08.51)

009.44 (01.35)008.33 (00.64)004.16 (01.26)003.57 (00.38)005.42 (00.64)069.99 (08.06)

0.17 NS0.02, S0.01, S0.005, S0.62 NS0.02, S

Table 3: Biochemical parameters of the subjects

NS: Non-significant, S: Significant

Respondents (N = 90)

Characteristics 0 Month 3 Month 6 Month 9 Month 12 Month

No. % No. % No. % No. % No. %

Dietary HabitsVegetarianNon VegetarianEggitarian

Post dialysis – food intakeAppetite improved and intake was better

Prior dialysis – food intakeLiked to eat before dialysisLiked to eat during dialysisDid not like to eat

Reason for Non-Adherence to dietAppearanceSmell and flavourTasteTexture Family support

Preference for food intakeHot food To have along with other family members

Hindrance for food intakeUnable to chewFull bellyChronic constipation

126711

80

501921

1712591004

5110

040303

137512

89

562123

1913661104

5711

040303

096813

86

631413

1510661104

5410

030303

107614

96

701614

1711731204

6011

030303

106911

90

720909

1110710803

6509

030502

117712

100

801010

1211790903

7210

030602

116910

90

780507

0907780803

7206

030401

127711

100

870607

1008870903

8007

030401

126810

90

820503

1007790803

7306

030200

137611

100

910603

1108880903

8107

030200

Table 4: Dietary pattern

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Characteristics

Respondents (N = 90)p-valueBaseline

(0 Month)3rd Month Followup

6th Month Followup

9th Month Followup

12th month(EOS)

No. % No. % No. % No. % No. %

Appetite in past 4 weeksPoorAverageGood

Change in appetiteIncreasedDecreasedNo change

Weight Change in last 3 MonthsGainLossNo change

063252

171162

312930

073657

191269

353233

023058

281250

292041

023365

311356

322246

022563

240858

271845

022870

270964

302050

021771

280557

201456

021979

310663

221662

031275

180567

190863

031384

200674

210970

<0.001, S

0.11, NS

0.002, S

Table 5: Assessment of appetite status

NS: Non-significant, S: Significant

Fig.1: Subjective Global Assessment scoring

ParameterHypothesis Test Exp(B) 95% Wald Confidence

Interval for Exp(B)

B Std. Error Wald Chi-Square df Sig. Lower Upper

Serum Albumin levelBody mass indexArm muscle areaGender

MaleFemale

Age (yrs)

1.5350.1070.012

0.713Reference

0.003

0.50130.06670.0185

0.4950.

0.0165

23.61209.37902.579

00.30302.075

.

111

1.1

0.002, S0.1080.504

0.150.

0.839

4.6421.1131.012

2.0401

1.003

1.7380.9770.976

0.773.

0.971

12.4001.2681.050

5.383.

1.036

Dependent Variable: SGA; Model: Serum Albumin level, BMI, AMA, Gender, Age (yrs), Frequency of dialysis; S:Significant

Table 6: Estimation of SGA with other nutritional parameters

status of the study population. With the increase in serum albumin status which determines the visceral protein status, there was rise in well nourished status [AOR=4.62, (1.74, 12.4]. However there was a trend towards BMI for well nourished group, though not statistically significant. There was no statistical significance for AMA, gender and age indicating that there was no difference in their outcome between the

well nourished and malnourished group during the study period.

DISCUSSIONWe analysed the impact of inter-related components

of malnutrition to assess its rate of incidence among Indian subset of population in South India, Karnataka over a one-year period in a retrospective study.



Fig. 2: Interdialytic weight gain

The prevalence of malnutrition in HD patients was found to be widely between 20% and 60%[9]. However, in our study population, there was maintenance of nutritional status. Testa et al reported in their study that nearly 45% of the study samples were steadily on a high interdialytic weight gain (IDWG)[10]. Hence, high IDWG was associated with better nutritional status, which attributed to intake of fluid and sodium overload, which was on par with the present study. The samples were undergoing hemodialysis for one year and 66% of them were on a twice-weekly dialysis regimen. Majority of our subjects were in the IDWG between 3 and 4 kg, with no significant change in means over time during study period (Fig. 2).

Studies conducted by Girija et al and Tayyem et al[11,12] revealed similar anthropometric indices to those of the present study. The BMI classification (Asia-Pacific standard) was illustrated by Roy et al and showed their samples to be in normal BMI range (22%)[13], as against majority of samples from the present study. Present study conferred anthropometric parameters being consistent throughout the study period, which revealed maintenance of nutritional status among the subjects. Clinically, dialysis subjects are considered as chronically ill, but there seemed to be no sign of deterioration among the study populace, which discloses condensed interaction with them in continuance of maintaining health status during the study period.

Similar and concurrent studies’ reported findings which were on par with the present study, showing all biochemical parameters being in the normal range[12]. Present study depicted majority of study samples to be in 3.5 mg/dl as against 39% by a study conducted by Girija et al[11].

Appetite status was evaluated by Radha et al, who showed from their study that majority of their study samples had normal appetite and they attained early

satiety when food was consumed[14], which was against the present study showing a majority of subjects having normal appetite but attained slow satiety. Gastrointestinal symptoms like vomiting/nausea were not found to be a barrier for food intake among our study population as against the aforementioned study subjects who had affected food intake leading to malnutrition. The present study revealed better appetite pattern of the study populace, enabling the subjects to consume adequate diet, eventually resulting in good nourishment status supported with better SGA scoring.

CONCLUSIONSNutritional outcomes over the study duration of one

year showed the health status of the study population being consistent, which exhibited continuance of their nutritional status. Underlying barriers and burdens of the illness were overcome with effective counselling to improve their overall health status. A strong family, social and health care support can frame a backbone to enhance longevity with secured quality of life.

CONFLICT OF INTERESTThe authors declare that they have no conflict of

interest.

REFERENCES

1. Eleanor DS. Nutrition and Health, In: Eleanor DS, Sara LR, editors. William’s Essentials of Nutrition and Diet Therapy.10th Ed. U.S.A: Elsevier Mosby Publishers; 2011. p 8.

2. Sara LR. Renal Disease, In: Eleanor DS, Sara LR, editors. William’s Essentials of Nutrition and Diet Therapy, 10th Ed. U.S.A: Elsevier Mosby Publishers; 2011. p 517-539.

3. Sahay M, Sahay R, Baruah MP. Nutrition in chronic kidney disease. J Med Nutr Nutraceut 2014; 3(1):11-18.

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4. Janardhan V, Soundararajan P, Vanitha RN, Kannan G, Thennarasu P, Chacko RA, et al. Prediction of malnutrition using Modified Subjective Global Assessment-dialysis Malnutrition Score in patients on hemodialysis. Indian J Pharm Sci 2011; 73(1):38-45.

5. Veerappan I, Arvind RM, Ilayabharthi V. Predictors of quality of life of hemodialysis patients in India. Indian J Nephrol 2012; 22(1):18-25.

6. Kuhlmann MK, Kribben A, Wittwer M, Horl WH. OPTA – malnutrition in chronic renal failure. Nephrol Dial Transplant 2007; 22(3):iii13-19.

7. Nande P. Nutritional status of patients undergoing maintenance hemodialysis. J Community Nutr Health 2013; 2(2):38-47.

8. Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines for Nutrition in Chronic Renal Failure. Am J Kidney Dis 2000; 35(6 Suppl 2): S76-S85.

9. Kirushnan BB, Subba Rao B, Annigeri R, Balasubramanian S, Seshadri R, Prakash KC, et

al. Impact of malnutrition, inflammation and atherosclerosis on the outcome in hemodialysis patients. Indian J Nephrol 2017; 27(4):277-283.

10. Testa A, Beaud JM. The other side of the coin: interdialytic weight gain as an index of good nutrition. Am J Kidney Dis 1998; 31(5):830-834.

11. Girija K, Radha R. Correlation between subjective global assessment (SGA) and serum albumin in hemodialysis patients. Int J Recent Sci Res 2015; 6(2):2790-2793.

12. Tayyem RF, Mrayyan MT, Heath DD, Bawadi HA. Assessment of nutritional status among ESRD patients in Jordanian hospitals. J Ren Nutr 2008; 18(3):281-287.

13. Roy LG, Shetty MS, Urooj A. Screening of malnutrition using clinical, dietary and anthropometric variables in an Indian hemodialysis population. J Med Res 2015; Article ID 847823.

14. Radha R, Girija K. Eating disorders in hemodialysis patient. Int J Food Nutrit Sci 2013; 2(3):120-123.



Original Article


Effect of positive end-expiratory pressure on right heart function in mechanically ventilated

patients: An ultrasonography based study

ABSTRACT

KEY WORDS: heart function, mechanical ventilation, PEEP, ultrasound

Yong Zhao, Hong Zhang, Dan ZhangDepartment of Emergency, the First Affiliated Hospital of Anhui Medical University, Hefei 230032, China

Objective: To investigate the effect of positive end-expiratory pressure (PEEP) on right heart function in mechanically ventilated patients using bedside ultrasonographyDesign: Retrospective studySetting: Department of Emergency Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei, ChinaSubjects: Eighteen patients who received mechanical ventilation between December 2014 and May 2016Interventions: Different levels of PEEP were applied to patients to achieve appropriate PaO2 levels. Main outcome measures: Indices of right heart function was assessed at three different PEEP levels, ≤5 cm H2O, 5-10 cm H2O or ≥10 cm H2O. Indices included preload assessment by measurement of the area of the right atrium (RA), the diameter of the inferior vena cava (IVC) and measurement

of the central venous pressure (CVP); afterload was assessed by estimation of the pulmonary vessel resistance (PVR); right ventricular systolic function was assessed by tricuspid annular plane systolic excursion (TAPSE). Results: The IVC diameter and the CVP increased as PEEP levels increased (14.5±2.2 vs. 16.9±1.4 vs. 22.6±2.4; 7.1±1.1 vs. 7.9±1.3 vs. 13.2±2.0); the RA area decreased at the same time (36.6±2.9 vs. 32.1±2.0 vs. 25.3±3.8). These changes were statistically significant. PVR and TAPSE changed significantly at higher levels of PEEP (p<0.05). PEEP levels positively correlated with the IVC diameter and the PVR, and negatively correlated with TAPSE; coefficients of determination were 0.644, 0.759, and 0.628, respectively.Conclusions: The application of PEEP decreased the preload and increased the afterload of the right heart. Right ventricular contractility decreased significantly at higher levels of PEEP.

Address correspondence to:Yong Zhao, Department of Emergency, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China. Tel: +86 551 62922289; Fax: +86 551 62922289; E-mail: [email protected]

INTRODUCTIONIt is important to stabilize cardiopulmonary

function in critically ill patients. Cardiopulmonary interactions may be influenced by intermittent positive pressure ventilation through alterations in intrathoracic pressure[1]. The effect of tide volume variation on intrathoracic pressure and cardiac function has been previously reported[2]. However, there are few reports on the effect of positive end-expiratory pressure (PEEP) on cardiac function, especially that of the right heart. PEEP is widely used during mechanical ventilation (MV). Historically, the effect of PEEP on left heart function has been studied more than its effect

on right heart function. The pathophysiology of right ventricular failure includes increased afterload and reduced right ventricular contractility[3,4]. The venous return may decrease due to high intrathoracic pressures generated during positive pressure ventilation, leading to a fall in right ventricular output[5,6]. The application of PEEP may further reduce preload; however, it leads to an increase in the pulmonary vascular resistance (PVR) and increases afterload. Hence, it is important to assess the effect of PEEP on right heart function.

Ultrasound plays a key role in the evaluation of cardiac function. Historically, invasive techniques including the Swan-Ganz catheter were the main

June 2020199

monitoring tools used to detect cardiac function in critically ill patients[7]. However, being invasive, it carries potential risks, and cannot be applied in all critically ill patients. Recently, bedside-ultrasonography has been widely used in the assessment of critically ill patients, especially to evaluate cardiac function[8,9]. Previous studies have demonstrated the accuracy of bedside-ultrasonography and shown good correlation with invasive monitoring[10,11].

There are few studies that focus on the effect of PEEP on right heart function. We aimed to assess the influence of different levels of PEEP on right heart function by bedside ultrasonographic evaluation.

SUBJECTS AND METHODSPatients

We included 18 patients who received MV in our unit between December 2014 and May 2016. Twelve patients were diagnosed with acute respiratory distress syndrome (ARDS) according to the Berlin definition[12]. The other six patients had respiratory failure due to poisoning with anticholinesterase insecticide. All patients had acute respiratory failure with no previous history of cardiovascular or pulmonary disease and required MV because of severe hypoxemia. Midazolam, sufentanil, and etomidate were administered for tracheal intubation and to attain ventilator synchrony as required. During the course of this study, all patients remained hemodynamically stable and did not need vasopressors. This study was conducted in accordance with the declaration of Helsinki. This study was conducted with approval from the Ethics Committee of Anhui Medical University. Written informed consent was obtained from all participants or their guardians.

Ventilator settingsMV was carried out in the synchronized intermittent

mandatory ventilation mode initially using standard ventilators (Puritan Bennett 760, Covidien, USA); all patients were in the weaning phase.

We used PEEP with every mode, at a baseline level of 5 cm H2O or less. For sustained oxygen saturation greater than 90%, the level of PEEP was increased step by step from a low (5 cm H2O) to a sufficient level. The fractional inspired oxygen concentration (FiO2), and the PEEP levels were selected according to a PEEP-FiO2 table (Table 1). Depending on the response, the PEEP level was increased gradually, to a maximum

limit of 15 cm H2O. The PEEP level was classified as ≤5 cm H2O, 5 - 10 cm H2O or ≥10 cm H2O.

Ultrasonographic assessmentEchocardiographic evaluation was carried out in all

patients prior to the initiation of MV and at different levels of PEEP using a Sonosite MAXX machine (Sonosite, Seattle, USA) equipped with 2.5- and 3.5-MHz transducers. Studies were carried out with the patient in the supine position. We evaluated right heart function based on three types of indices.

The preload indexes: The area of the right atrium (RA) was measured by echocardiographic imaging at end-diastole in the apical view. The diameter of inferior vena cava (IVC) was measured in the subcostal view to estimate RA pressure.

The afterload indexes: The PVR was estimated from the peak tricuspid regurgitant velocity (TRV) and the right ventricular outflow tract time-velocity integral (TVIRVOT) in accordance with published guidelines[13], using the equation, PVR = (TRV/TVIRVOT) × 10+0.16. Color-flow Doppler examination was used to screen for the presence of valvular regurgitation in apical windows.

The index of right heart systolic function: We estimated tricuspid annular plane systolic excursion (TAPSE) in real time. On M-mode, the cursor was passed through the lateral tricuspid annulus in the apical 4-chamber view. TAPSE was estimated by measurement of the extent of longitudinal motion of the lateral tricuspid annulus at peak systole[14].

Statistical analysisStatistical analyses were performed by using the

SPSS 16.0 statistical software. Data are expressed as means ± SD, unless otherwise specified. Repeated measure analysis at different PEEP levels was done using the one-way ANOVA. The correlation of different PEEP levels with IVC, PVR and TAPSE are shown as scatter plots. The coefficients of determination were analyzed. A p-value <0.05 was considered as statistically significant.

RESULTSBaseline patient characteristics

We enrolled 18 patients in this study. Twelve patients underwent mechanical ventilation for ARDS secondary to pneumonia, severe acute pancreatitis, or

Index Number

PEEP (cmH2O)FiO2

50.3

50.4

80.4

80.5

100.5

100.6

100.7

120.7

140.7

140.8

140.9

160.9

180.9

18-241.0

Table 1: PEEP-FiO2 adjustment form

Note: 1cm H2O = 0.098kPa

Effect of positive end-expiratory pressure on right heart function in mechanically ventilated patients...


severe sepsis. The other six patients were diagnosed with acute pulmonary edema or acute respiratory failure secondary to organophosphorus pesticide poisoning. The highest levels of PEEP ranged from 12 to 15 cm H2O (13.1 ± 1.3). The duration of ventilation ranged from 6 to 20 days (9.8 ± 4.5). The Apache II scores ranged from 20 to 36 (26.1 ± 5.1). Table 2 shows baseline patient characteristics.

Arterial blood gas analysis and pulmonary mechanicsAll patients had severe hypoxemia with a low

PaO2/FiO2 ratio at baseline. The PaO2 and PaO2/FiO2 ratios improved with increasing levels of PEEP. However, the peak inspiratory pressure (PIP) and the plateau pressure (Pplat) also increased as the PEEP levels increased (25.3 ± 8.2 vs. 28.9 ± 6.3 vs. 33.2 ± 5.6; 20.1 ± 3.8 vs. 25.4 ± 4.3 vs. 29.7 ± 4.6); these changes were statistically significant (p <0.05) (Table 3).

Preload indexesThe IVC diameter and the central venous pressure

(CVP) increased with increasing PEEP levels (14.5 ± 2.2

Gender / age Diagnosis/reason for intubation Highest level of PEEP (cmH2O) Time of MV Apache II score

M/56M/32F/30M/45F/28M/50F/62M/48F/54M/60F/40F/46F/32F/40F/32M/38F/35M/50

Pneumonia/ARDSPneumonia/ARDSSAP/ARDSPneumonia/ARDSSAP/ARDSSevere sepsis/ARDSPneumonia/ARDSSAP/ARDSPneumonia/ARDSSevere sepsis/ARDSSAP/ARDSPneumonia/ARDSAOPP/acute pulmonary edemaAOPP/acute pulmonary edemaAOPP/acute pulmonary edemaAOPP/acute respiratory failureAOPP/acute respiratory failureAOPP/acute pulmonary edema

121215141212151215141215121412141212

1081597720712107126761076

232035253036302528322630222322222020

SAP: severe acute pancreatitis; AOPP: acute organophosphorus pesticide poisoning; ARDS: acute respiratory distress syndrome

Table 2: Baseline patient characteristics

Patients indexes PEEP≤5 5<PEEP≤10 10<PEEP≤15

PaO2 (mmHg)PaCO2 (mmHg)PaO2/FiO2PIP (cmH2O)Pplat (cmH2O)

47 ± 1242 ± 1178 ± 10

25.3 ± 8.220.1 ± 3.8

55 ± 10*40 ± 12

112 ± 13*28.9 ± 6.3*25.4 ± 4.3*

66 ± 13#41 ± 11

180 ± 18#33.2 ± 5.6#29.7 ± 4.6#

Compared with PEEP≤5, *P<0.05; #P<0.01.PIP: peak inspiratory pressure; Pplat: plateau pressure

Table 3: Arterial blood gas and pulmonary mechanics at different PEEP levels (cmH2O)

vs. 16.9 ± 1.4 vs. 22.6 ± 2.4; 7.1 ± 1.1 vs. 7.9 ± 1.3 vs. 13.2 ± 2.0). The RA area decreased with increasing PEEP (36.6 ± 2.9 vs. 32.1 ± 2.0 vs. 25.3 ± 3.8). The change in IVC diameter and the RA area were statistically significant (p <0.05).

Afterload indexThe PVR increased from 2.4 ± 0.2 Wood units (WU)

at baseline (PEEP ≤5 cm H2O) to 2.6 ± 0.2 WU (PEEP 5 - 10 cm H2O). The changes were not statistically significant. When the PEEP level reached >10 cm H2O, the PVR was significantly higher by 3.7 ± 0.3 WU compared to baseline and lower PEEP levels.

Right heart indexes PEEP≤5 5<PEEP≤10 10<PEEP≤15

RA area (cm2)IVC (mm)CVP (cmH2O)PVRTAPSE (mm)

36.6 ± 2.914.5 ± 2.27.1 ± 1.12.4 ± 0.217.2 ± 2.5

32.1 ± 2.0*16.9 ± 1.4*7.9 ± 1.3*2.6 ± 0.216.3 ± 2.5

25.3 ± 3.8#

22.6 ± 2.4#

13.2 ± 2.0#

3.7 ± 0.3#

11.1 ± 1.6#

RA: right atrium; IVC: the diameter of inferior vena cava; CVP: center vessel pressure; PVR: pulmonary vessel pressure; TAPSE: tricuspid annular plane systolic excursion. Compared with PEEP≤5, *p <0.05; #p <0.01

Table 4: Right heart function at different PEEP levels (cmH2O)

Right ventricular function TAPSE decreased with increasing levels of PEEP;

however, there was no significant difference between baseline (PEEP ≤5 cm H2O) and lower levels of PEEP (5–10 cm H2O). TAPSE decreased significantly at PEEP levels of >10 cm H2O (17.2 ± 2.5 vs. 16.3 ± 2.5 vs. 11.1 ± 1.6), (p <0.01) (Table 4).

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Correlation analysisThe correlation between IVC, PVR, TAPSE, and

PEEP levels are shown as scatter plots. PEEP levels showed a positive correlation with IVC and PVR and a negative correlation with TAPSE. The central line in the scatter plot is the regression line; the two lines on either side of the regression line are 95% CI of individual predicted values. The coefficients of determination were 0.644, 0.759, and 0.628 (Figure 1).

DISCUSSIONThe patients in our study had ARDS and acute

lung edema secondary to underlying disease. PEEP can prevent cyclic opening and collapse of alveoli by maintaining the alveolar pressure at end expiration[15]. PEEP may influence cardiac output, especially that of the left ventricle, through changes in intrathoracic pressure[16]. Due to its anatomical characteristics, right ventricular changes during positive pressure ventilation are less noticed compared with those of the left ventricle. As the output from the right ventricle flows into the pulmonary arteries, changes in intrathoracic pressure may influence right ventricular output through alterations in preload, afterload, and right ventricular systolic function. We used ultrasonography to verify this hypothesis.

Our patients were on MV for variable periods of time. The duration of ventilation in patients with poisoning was shorter than that in ARDS patients. There were more female patients with poisoning, which may be peculiar to China. PaO2 and PaO2/FiO2 ratios were significantly lower than normal in all patients. PIP and Pplat increased as the PEEP level increased, leading to high ventilation pressures.

CVP denotes the pressure within the RA, besides reflecting the volume status. A change in the CVP level can influence the diameter of the IVC[17]. In previous studies[18,19], the prognostic value of the IVC diameter was similar to that of RA pressure. In our study, the CVP levels and the IVC diameter were significantly different in groups with different PEEP levels. The increase in IVC diameter showed a positive correlation with the

PEEP level. The mechanism of this phenomenon may be as reported by Jellinek et al [20]. They demonstrated that positive airway pressure equally increases the mean systemic filling pressure and the RA pressure in humans, and alters venous return without changes in the pressure gradient. In our opinion, the reduction in RA area may reduce the preload to the right heart. PEEP may increase the intrathoracic pressure, leading to compression of the RA and reduction of its area. The reduction in RA area was more obvious in the high PEEP group (>10 cm H2O). As reported previously[21], we noted a decrease in atrial volumes in systole and diastole with positive pressure ventilation, with atrial volumes decreasing relatively more than ventricular volumes. The absolute and relative decrease in RA volumes was higher compared to left atrium volumes. Therefore, the influence of PEEP on RA preload may be significant.

PVR is considered to constitute the right ventricular afterload. It is a concept that relates to the pressure needed to drive blood across the lungs to the pulmonary circulation. The resistances of large and small arteries, the pulmonary microcirculation, and the veins are the main contributors to PVR. Several factors can contribute to changes in PVR. In ARDS, PVR is elevated due to hypoxic vasoconstriction and tortuosity of the medium and large intrapulmonary blood vessels[22]. PEEP affects PVR by compression of intra-alveolar capillaries by over expanded alveoli[23]. The reservoir-wave model suggested that there was a small increase in microcirculatory resistance with the application of PEEP[24]. The present study demonstrated that PVR increased significantly at PEEP levels of >10 cm H2O. However, the difference in PVR between PEEP levels of ≤5 cm H2O and 5 - 10 cm H2O was not significant. These results may indicate that compression of intra-alveolar capillaries and increase in microcirculatory resistance became significant at PEEP levels of >10 cm H2O.

The change in right ventricular function or contractility was less compared to preload and afterload changes of the right heart during mechanical

Fig 1: The PEEP correlations with IVC, PRV and TAPSE. A: The correlation between PEEP with IVC (coefficient of determination = 0.644); B: The correlation between PEEP with PRV (coefficient of determination = 0.759); C: The correlation between PEEP with TAPSE (coefficient of determination = 0.628).



ventilation. The right ventricular perfusion is dependent on the gradient between aortic pressure and the right ventricular systolic pressure; it is also influenced by the intrathoracic pressure. High levels of PEEP can worsen right ventricular ischemia[25]. A previous study demonstrated that the right ventricular free wall showed dyssynchronous contraction at the highest PEEP level reached on assessment by speckle tracking echocardiography. TAPSE is a better, non-invasive index of right ventricular function. It provides information not only on the emptying of the right ventricle, but also on the driving force which acts on the systemic venous column because systolic shortening of the right ventricle occurs from base to apex. In our study, TAPSE decreased significantly at PEEP levels of >10 cm H2O. The scatter plot revealed that the decrease in TAPSE correlated with increasing PEEP levels. This suggests that right ventricular contractility may be influenced by higher levels of PEEP.

LimitationsThere are several limitations to our study. First,

our study was limited to two main disease processes. Previous studies have shown that PVR may be higher than normal in the early stage of ARDS[21]. Besides, organophosphorus pesticide poisoning could result in myocardial injury[26]. These two factors could have contributed to the variability observed in the results. However, a clear correlation was observed between right heart function and the level of PEEP. A larger sample size is required to confirm our findings. Second, although bedside ultrasound is a convenient, non-invasive technique of hemodynamic assessment in critically ill patients, it has some limitations. A reliable ultrasonographic assessment depends on several factors including patient condition, the use of MV, and individual proficiency in carrying out the examination.

CONCLUSIONSWe demonstrated in our study that right heart

function could be reliably assessed by bed-side ultrasonography. The application of PEEP decreased the preload and increased the afterload of the right heart. Right ventricular contractility decreased significantly at higher levels of PEEP.

ACKNOWLEDGMENTConflict of interest: The authors declare no conflict

of interest.

REFERENCES

1. Lamia B, Molano LC, Muir JF, Cuvelier A. [Cardiopulmonary interactions in the course of mechanical ventilation]. Rev Mal Respir 2016; 33(10):865-876. [Article in French]

2. Liu LX, Wu JQ, Wu QY, Zhang Q, Yu B, Ge SM, et al. [The effects of different tidal volume ventilation on right ventricular function in critical respiratory failure patients]. Zhonghua Nei Ke Za Zhi 2017; 56(6):419-426.

3. Harjola VP, Mebazaa A, Čelutkienė J, Bettex D, Bueno H, Chioncel O, et al. Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology. Eur J Heart Fail 2016; 18(3):226-241.

4. Van de Veerdonk MC, Bogaard HJ, Voelkel NF. The right ventricle and pulmonary hypertension. Heart Fail Rev 2016; 21(3):259-271.

5. Berger D, Moller PW, Weber A, Bloch A, Bloechlinger S, Haenggi M, et al. Effect of PEEP, blood volume, and inspiratory hold maneuvers on venous return. Am J Physiol Heart Circ Physiol 2016; 311(3):H794-806.

6. Magder S. Volume and its relationship to cardiac output and venous return. Crit Care 2016; 20:271.

7. Rosenkranz S, Preston IR. Right heart catheterisation: best practice and pitfalls in pulmonary hypertension. Eur Respir Rev 2015; 24(138):642-652.

8. Arbo JE, Maslove DM, Beraud AS. Bedside assessment of right atrial pressure in critically ill septic patients using tissue Doppler ultrasonography. J Crit Care 2013; 28(6):1112.e1-5.

9. Saul T, Avitabile NC, Berkowitz R, Siadecki SD, Rose G, Toomarian M, et al. The inter-rater reliability of echocardiographic diastolic function evaluation among emergency physician sonographers. J Emerg Med 2016; 51(4):411-417.

10. Vermeiren GL, Malbrain ML, Walpot JM. Cardiac ultrasonography in the critical care setting: a practical approach to assess cardiac function and preload for the “non-cardiologist”. Anaesthesiol Intensive Ther 2015; 47 Spec No:s89-104.

11. Horster S, Stemmler HJ, Sparrer J, Tischer J, Hausmann A, Geiger S. Mechanical ventilation with positive end-expiratory pressure in critically ill patients: comparison of CW-Doppler ultrasound cardiac output monitoring (USCOM) and thermodilution (PiCCO). Acta Cardiol 2012; 67(2):177-185.

12. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012; 307(23):2526-2533.

13. Abbas AE, Fortuin FD, Schiller NB, Appleton CP, Moreno CA, Lester SJ. A simple method for noninvasive estimation of pulmonary vascular resistance. J Am Coll Cardiol 2003; 41(6):1021-1027.

14. Dahhan T, Siddiqui I, Tapson VF, Velazquez EJ, Sun S, Davenport CA, et al. Clinical and echocardiographic predictors of mortality in acute pulmonary embolism. Cardiaovasc Ultrasound 2016; 14(1):44.

15. Hess DR. Recruitment Maneuvers and PEEP Titration. Respir Care 2015; 60(11):1688-1704.

16. Marini M, Caretta G, Vagnarelli F, Luca F, Biscottini E ,Lavorgna A, et al. Hemodynamic effects of positive end-expiratory pressure. G Ital Cardiol (Rome) 2006; 18(6):505-512.

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17. Ciozda W, Kedan I, Kehl DW, Zimmer R, Khandwalla R, Kimchi A. The efficacy of sonographic measurement of inferior vena cava diameter as an estimate of central venous pressure. Cardiovasc Ultrasound 2016; 14(1):33.

18. Besli F, Kecebas M, Caliskan S, Dereli S, Baran I, Turker Y. The utility of inferior vena cava diameter and the degree of inspiratory collapse in patients with systolic heart failure. Am J Emerg Med 2015; 33(5):653-657.

19. Lee SL, Daimon M, Kawata T, Kohro T, Kimura K, Nakao T, et al. Estimation of right atrial pressure on inferior vena cava ultrasound in Asian patients. Circ J 2014; 78(4):962-966.

20. Jellinek H, Krenn H, Oczenski W, Veit F, Schwarz S, Fitzgerald RD. Influence of positive airway pressure on the pressure gradient for venous return in humans. J Appl Physiol (1985) 2000; 88(3):926-932.

21. Kyhl K, Ahtarovski KA, Iversen K, Thomsen C, Vejlstrup N, Engstrom T, et al. The decrease of cardiac chamber volumes and output during positive-pressure

ventilation. Am J Physiol Heart Circ Physiol 2013; 305(7):H1004-1009.

22. Ryan D, Frohlich S, McLoughlin P. Pulmonary vascular dysfunction in ARDS. Ann Intensive Care 2014; 4:28.

23. Cheifetz IM. Cardiorespiratory interactions: the relationship between mechanical ventilation and hemodynamics. Respir Care 2014; 59(12):1937-1945.

24. Bouwmeester JC, Belenkie I, Shrive NG, Tyberg JV. Partitioning pulmonary vascular resistance using the reservoir-wave model. J Appl Physiol (1985) 2013; 115(12):1838-1845.

25. Johnston WE, Vinten-Johansen J, Shugart HE, Santamore WP. Positive end-expiratory pressure potentiates the severity of canine right ventricular ischemia-reperfusion injury. Am J Physiol 1992; 262(1 Pt 2):H168-176.

26. He X, Li C, Wei D, Wu J, Shen L, Wang T. Cardiac abnormalities in severe acute dichlorvos poisoning. Crit Care Med 2011; 39(8):1906-1912.



Address correspondence to:Dr. Ibrahim Karaman, Department of Orthopaedics and Traumatology, Erciyes University Medical Faculty, TR-38039, Kayseri, Turkey. Tel: +90 352 4377163; Fax: +90 352 4375288; E-mail: [email protected]


Humeral biepicondylar fracture in a child without elbow dislocation: A rare case and review of literature

ABSTRACT

Ibrahim Karaman1, Ali Eray Gunay2, Ibrahim Halil Kafadar1

1Department of Orthopaedics and Traumatology, Erciyes University Medical Faculty, Kayseri, Turkey2Department of Orthopaedics and Traumatology, Training and Research Hospital, Kayseri, Turkey

In children, humeral biepicondylar fracture is extremely rare among traumas involving elbow region. The main goal should be to provide elbow stability in these patients. Thus, open reduction plus internal fixation should be performed

in these cases. Here, we aimed to present an 11-year-old patient with biepicondylar humeral fracture without elbow dislocation, which is rarely seen among pediatric elbow traumas.

KEY WORDS: child, elbow, epicondyle, humerus

Case Report

INTRODUCTIONThe upper extremity fractures are commonly seen

in children and a majority of these injuries occur at elbow region. Distal humerus fractures comprise approximately 90% of fractures at elbow region[1]. The most common fracture is supracondylar humerus fracture, while medial epicondylar fractures are the third most common fractures at elbow region[2]. However, biepicondylar fractures are extremely rare, and PubMed search of the term “biepicondylar fracture” revealed 6 case reports in the literature[2-7]. Thus, the case reported here will be seventh case in the literature. Mechanism of injury generally involves fall on outstretched hand. Medial epicondylar fractures occur due to traction by flexor, pronator and ulnar collateral ligament, while lateral epicondylar fractures occur due to traction force by extensor muscles associated to varus force. One-half of medial epicondylar fractures are accompanied by elbow dislocation while no elbow dislocation is seen in remaining half[8].

Here, we aimed to present an 11-year-old patient who had biepicondylar humeral fracture without elbow dislocation.

CASE REPORTAn 11-year-old presented to the emergency

department with fall on outstretched hand while playing at the park. He was assessed due to swelling and deformity at left elbow and ecchymosis at lateral epicondylar region. No additional neurovascular abnormality was detected, but there were fractures at medial and lateral epicondyles in anteroposterior and lateral direct radiographs (Figure 1). The patient underwent surgery under general anesthesia due to displaced fragments. In surgery, medial and lateral epicondyles were fixed by K-wire following open reduction (Figure 2). After surgery, long-arm splint was applied for 4 weeks. At the end of week 4, splint was removed and rehabilitation was started. At week 6, K-wires were removed. At 6th month after surgery, full elbow extension and flexion were achieved and Maya elbow score was estimated to be 100 (Figure 3). On radiographs, it was seen that union was achieved on medial epicondyle but opacities suggesting heterotopic ossification were observed at distal to medial epicondyle. The lateral epicondyle underwent lysis due to complete avascular necrosis (Figure 4).

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DISCUSSIONIn the literature, there are only a few pediatric cases

with biepicondylar humerus fracture[2-7]. Assessment and management of childhood elbow trauma is challenging due to complex anatomy of elbow and differing ossification timing of growth plates.

Primary and secondary stabilizers play different roles in elbow stability during joint movement. Primary stabilizer structure is humeroulnar joint and coronoid process is the most important component of this structure[9]. Thus, it is recommended to assess coronoid process and to ensure integrity in elbow fractures. In our case, it was seen that coronoid process was intact. Flexor, pronator, extensor muscles and ulnar collateral ligaments surrounding elbow act as secondary stabilizers[9]. The secondary stabilizers are also involved in the etiology of biepicondylar fractures. Medial epicondylar fractures generally occur due to traction of flexor-pronator muscles and ulnar collateral ligament following valgus trauma after fall on outstretched hand. On the other hand, lateral epicondylar fractures often occur due to traction of extensor muscles as well as varus and internal rotation

trauma of forearm[10]. Our patient was also exposed to a similar trauma after fall on outstretched hand when he was playing at the park. If a similar trauma occurs in an adult age; terrible triad and posterior elbow dislocation are likely to be seen. It can also be assumed that supracondylar humerus fractures may develop due to low bone quality in older ages[11].

Elbow dislocation can be seen in one-half of medial epicondylar fractures[12]. Elbow dislocation accompanied the fracture in all six cases of biepicondylar fracture reported in the literature[2-7]. However, elbow dislocation accompanying fracture was lacking in our case, contrary to cases in the literature.

Elbow instability is the major problem in biepicondylar fractures. Thus, one should aim to ensure elbow stability in these cases. Sufficient biomechanical stability couldn’t be achieved following closed reduction in general[12]. Thus, open reduction plus internal fixation should be preferred in order to ensure stability[2]. We also performed open reduction and fixation by K-wire in our case.

Given the complex anatomy and differential timing

Fig 1: Preoperative anteroposterior radiograph

Fig 2: Immediate postoperative radiographs: A) anteroposterior; B) lateral

Fig 3: Functional appearance of patient at postoperative month 6 Fig 4: Radiographs at postoperative month 6: A) anteroposterior; B) lateral

Humeral biepicondylar fracture in a child without elbow dislocation: A rare case and review of literature


of ossification in growth plates, several problems can be encountered in the assessment of pediatric patients with elbow trauma. Either imaging of intact extremity or advanced imaging modalities such as CT scan or MRI should be used to avoid misdiagnosis[13]. In our case, comparative radiographs were sufficient to establish diagnosis.

One should beware the neurological injuries associated to biepicondylar fractures. Radial and ulnar nerve injuries have been shown in biepicondylar fractures with elbow dislocation[4,14]. In our case, no neurological injury was present. We think that this was due to lack of accompanying elbow dislocation. If there is a concomitant nerve injury, exploration must be done at the time of the surgery and if necessary, microsurgical nerve repair must be done[4].

CONCLUSIONBiepicondylar elbow fractures are instable injuries

which may be accompanied by elbow dislocation and neurological injuries. Open reduction plus internal fixation should be performed in order to ensure elbow stability.

REFERENCES

1. Rasool MN. Dislocations of the elbow in children. J Bone Joint Surg Br 2004; 86(7):1050-1058.

2. Gani NU, Rather AQ, Mir BA, Halwai MA, Wani MM. Humeral biepicondylar fracture dislocation in a child: A case report and review of the literature. Cases J 2008; 1(1):163.

3. Agrawal P, Das P, Gupta V, Arora S. Unusual association of elbow dislocation with humeral biepicondylar fracture in a child: A case report and review of literature. J Clin Orthop Trauma 2017; 8(Suppl 1):S41-S44.

4. Konya MN, Aslan A, Sofu H, Yıldırım T. Biepicondylar fracture dislocation of the elbow joint concomitant with ulnar nerve injury. World J Orthop 2013; 4(2):94-97.

5. Guner S, Guner SI, Ceylan MF, Gormeli G, Gormeli CA, Onder H. Biepicondylar fracture presenting with elbow dislocation: a case report. J Med Case Rep 2012; 6:265.

6. Meta M, Miller D. Paediatric biepicondylar elbow fracture dislocation - a case report. J Orthop Surg Res 2010; 5:75.

7. Taylor GR, Gent E, Clarke NMP. Biepicondylar fracture dislocation of a child’s elbow. Injury 1997; 28(1):71-72.

8. Herring JA. Upper extremity injuries. In Tachdjian’s Pediatric Orthopaedics. Volume 3. 4th edition. Philadelphia:Elsevier; 2008:2496. ISBN 978-1-4160-2221-3.

9. O’Driscoll SW, Jupiter JB, King GJ, Hotchkiss RN, Morrey BF. The unstable elbow. Instr Course Lect 2001; 50:89-102.

10. Chessare JW, Rogers LF, White H, Tachdjian MO. Injuries of the medial epicondylar ossification center of the hemerus. Am J Roentgenol 1977; 129(1):49-55.

11. Wake H, Hashizume H, Nishida K, Inoue H, Nagayama N. Biomechanical analysis of the mechanism of elbow fracture-dislocations by compression force. J Orthop Sci 2004; 9(1):44-50.

12. Doornberg JN, van Duijn J, Ring D. Coronoid fracture height in terrible-triad injuries. J Hand Surg Am 2006; 31(5):794-797.

13. Dodds SD, Flanagin BA, Bohl DD, DeLuca PA, Smith BG. Incarcerated medial epicondyle fracture following pediatric elbow dislocation: 11 cases. J Hand Surg Am 2014; 39(9):1739-1745.

14. Petratos DV, Stavropoulos NA, Morakis EA, Matsinos GS. Median nerve entrapment and ulnar nerve palsy following elbow dislocation in a child. J Surg Orthop Adv 2012; 21(3):157-161.


Address correspondence to:Dr. Ibrahim Karaman, Department of Orthopaedics and Traumatology, Erciyes University Medical Faculty, TR-38039, Kayseri, Turkey. Tel: +90 352 4377163; Fax: +90 352 4375288; E-mail: [email protected]


Traumatic isolated dislocation of the trapeziometacarpal joint: A rare case report

ABSTRACT

Ibrahim Karaman1, Ali Eray Gunay2, Cemil Yildirim Turk1

1Department of Orthopaedics and Traumatology, Erciyes University Medical Faculty, Kayseri, Turkey2Department of Orthopaedics and Traumatology, Training and Research Hospital, Kayseri, Turkey

Isolated dislocation of trapeziometacarpal (TMC) joint is a rarely seen entity among hand injuries. It often develops after axial loading on thumb at partial flexion. It may eventually result in TMC arthritis, pain and dysfunction in thumb due to TMC joint instability if treated inadequately

or left untreated. Here, we aimed to present successful outcome in a case who presented with acute instable dislocation of TMC joint and underwent dorsoradial carpal and volar oblique ligament repair after two years of follow-up.

KEY WORDS: carpometacarpal joint, dorsoradial ligament, thumb, volar oblique ligament

Case Report

INTRODUCTIONIsolated dislocation of trapeziometacarpal (TMC)

joint is a rarely seen entity among hand injuries[1]. It often develops after axial loading on thumb at partial flexion[2]. Although reduction is easy, instability is commonly seen following reduction[1]. It may eventually result in TMC arthritis, pain and dysfunction in thumb due to TMC joint instability if treated inadequately or left untreated[3]. Despite the presence of four stabilizer structures, dorsoradial carpal ligament is considered as the primary stabilizer in TMC joint[4]. Dorsoradial carpal ligament is accepted as the primary structure that prevents dorsal dislocation of TMC joint. In addition, it is known that volar oblique ligament is involved in the anterior stabilization of TMC joint[5]. The management is still controversial in dislocation of TMC joint with no optimal treatment method established in acute cases[3]. Primarily, three therapeutic modalities are employed for management of TMC joint dislocations: closed reduction plus cast; close or open reduction plus pinning; and ligament repair plus capsulorrhaphy[1,6,7]. However, ligament repair is considered as the only treatment option in instable dislocation[3]. Here, we aimed to present successful outcome in a case who

presented with acute instable dislocation of TMC joint and underwent dorsoradial carpal and volar oblique ligament repair after two years of follow-up.

CASE REPORTA 22-year-old patient who crashed into an abiding

object while riding a bike was examined at the Emergency Department. In physical examination, it was found that the thumb of the right hand was deformed and that there was swelling and tenderness at carpometacarpal joint level (Figure 1).

In radiological assessment, it was seen that TMC joint was partially dislocated (Figure 2). Reduction in TMC joint was performed in the Emergency Department but the TMC joint was found to be unstable in Torque test. Thus, the patient underwent surgery under general anesthesia. The joint was exposed via Wagner approach and it was seen that TMC joint was displaced and that subluxation was relapsed after reduction. In addition, it was seen that dorsoradial carpal ligament was avulsed from base of metacarpal bone whereas oblique ligament was avulsed over trapezium (Figure 3). After reduction, both ligaments were repaired at avulsion site by 2.0


Anchor sutures. Then, capsulorrhaphy was performed and TMC joint was stabilized by two K-wires. The surgery was completed by closing the surgery site using the appropriate technique. The short-arm splint was applied for thumb. Postoperative radiological assessment revealed successful reduction in TMC joint (Figure 4). The K-wires were removed at week 3, while splint was removed at week 6 after surgery. Rehabilitation program was initiated thereafter. On control visit at year 2, it was observed that TMC joint was stable without degenerative changes (Figure 5) and that VAS pain score was “0” and range of motion was comparable to contralateral side.

DISCUSSIONSeveral mechanisms regarding trauma exposed

have been defined in dislocation of TMC joint. Among

Fig 1: Clinical image of TMC joint in the patient

Fig 2: Radiographic imaging. Red arrow indicates subluxation of TMC joint

Fig 3: Intra-operative image of dorsoradial carpal ligament avulsed from base of metacarpal bone and oblique ligament avulsed over trapezoid

Fig 4: Immediate postoperative radiograph

these, the most common mechanism is dislocation caused by axial loading during mild flexion of thumb[2], while the second most common mechanism is shearing force on first web[8]. In our case, dislocation occurred due to latter mechanism of injury. The injury occurred due to shearing force applied on first web by handlebar when the patient crashed into an abiding object with a bike.

June 2020209 Traumatic isolated dislocation of the trapeziometacarpal joint: A rare case report

In the dislocation of TMC joint, the diagnosis is generally made by radiographs, which also show avulsion fractures that may accompany the dislocation. Besides, instability should be assessed at clinical assessment. Torque test is widely used for this purpose[9]. Magnetic resonance imaging (MRI) can be used in acute cases, if diagnosis couldn’t be established by radiographs or those with delayed presentation[10]. The MRI will help to define injuries of capsule and ligaments that may accompany the dislocation, and it might be useful in very limited cases. In our case, radiography was sufficient to establish diagnosis. The dislocation was established and no avulsion fracture was observed on radiographs. The torque test after closed reduction showed presence of instability. No advanced imaging modality such as MRI was needed as radiographs established diagnosis. Also, computed tomography would be more helpful for diagnosis if a fracture occurred with the dislocation.

In these cases, one should be careful and may need to use different therapeutic modalities in order to achieve stable and functional joint due to anatomy of TMC joint[11]. Capsule and ligament damages can be present at varying rates in acute unstable dislocations of TMC[6]. Thus, early repair of ligaments is recommended in instable dislocations[6]. However, closed reduction plus casting or pinning can be preferred in the absence of instability[12]. We preferred open reduction and repair in dorsoradial carpal, and volar oblique ligaments as well as capsule due to instability following closed reduction. End-to-end repair is possible in primary cases, while anchor suturing provides better outcome if ligament damage occurs via avulsion injury[7]. In our case, both ligaments were repaired at avulsion site by 2.0 Anchor sutures; dorsoradial carpal ligament was avulsed from base of metacarp whereas oblique ligament was avulsed over trapezium. In addition, temporary fixation by K-wire is recommended if there is doubt in ensuring stability after ligament and capsule repair. In order to enhance stability, we also performed fixation by two K-wires, which were removed at week 3 after surgery. Ligament reconstruction will be warranted in cases with delayed presentation, failed conservative treatment or those

Fig 5: Control radiograph at late postoperative period

with instability, since primary ligament repair is impossible[13]. Ligament reconstruction is a more invasive and challenging surgical technique. Thus, one should attempt to ensure stable joint in acute cases. In the literature, there are a lot of controversies about management such as closed reduction and casting, closed reduction and pinning or open reduction and ligament reconstruction. The surgeon must decide on the treatment based on the instability of the joint and the level of injury (acute or chronic).

Prognosis will be better in cases with dislocation of TMC joint when acute treatment is provided. However, secondary arthritis development seems inevitable in cases with instability and ongoing subluxation despite treatment[8]. In our case, no arthritic change was observed after two-year follow-up, as joint stability was achieved.

CONCLUSIONAcute dislocation of TMC joint is a rare entity and

they are often unstable injuries. A stable and functional joint should be aimed due to anatomy of TMC joint. Thus, ligament repair and capsulorrhaphy should be preferred in acute instable TMC dislocation, which will provide better prognosis.

REFERENCES

1. Bosmans B, Verhofstad MHJ, Gosens T. Traumatic thumb carpometacarpal joint dislocations. J Hand Surg Am 2008; 33(3):438-441.

2. Chen VT. Dislocation of the carpometacarpal joint of the thumb. J Hand Surg (Br) 1987; 12(2):246-251.

3. Ansari MT, Kotwal PP, Morey VM. Primary repair of capsuloligamentous structures of trapeziometacarpal joint: A preliminary study. J Clin Orthop Trauma 2014; 5(4):185-192.

4. Marques P, Rodrigues PC, Rodrigues AS, Ramos PN. Traumatic isolated dislocation of the trapeziometacarpal joint: case report. Eur Orthop Traumatol 2013. doi: 10.1007/s12570-013-0198-y.

5. Strauch RJ, Behrman MJ, Rosenwasser MP. Acute dislocation of the carpometacarpal joint of the thumb: an anatomic and cadaver study. J Hand Surg Am 1994; 19(1):93-98.

6. Jakobsen CW, Elberg JJ. Isolated carpometacarpal dislocation of the thumb. Scand J Plast Reconstr Surg Hand Surg 1988; 22(2):185-186.

7. Okita G, Anayama S, Sato N, Haro H. Surgical reconstruction using suture anchor for dislocation of the carpometacarpal joint of the thumb: a case report. Arch Orthop Trauma Surg 2011; 131(2):225-228.

8. Liverneaux PA, Ichihara S, Hendriks S, Facca S, Bodin F. Fractures and dislocation of the base of the thumb metacarpal. J Hand Surg Eur Vol 2015; 40(1):42-50.

9. Eaton RG, Littler JW. Ligament reconstruction for the painful thumb carpometacarpal joint. J Bone Joint Surg Am 1973; 55(8):1655-1666.


10. Connell DA, Pike J, Koulouris G, van Wettering N, Hoy G. MR imaging of thumb carpometacarpal joint ligament injuries. J Hand Surg Br 2004; 29(1):46-54.

11. Simonian PT, Trumble TE. Traumatic dislocation of the thumb carpometacarpal joint: early ligamentous reconstruction versus closed reduction and pinning. J Hand Surg Am 1996; 21(5):802-806.

12. Watt N, Hooper G. Dislocation of the trapezio-metacarpal joint. J Hand Surg 1987; 12(2):242-245.

13. Ozer K. A new surgical technique for the ligament reconstruction of the trapeziometacarpal joint. Tech Hand Up Extrem Surg 2006; 10(3):181-186.



Stone formation on a surgical tack migrated to the bladder 7 years after laparoscopic incontinence surgery

ABSTRACT

Senol TonyaliClinic of Urology, Turkiye Yuksek Ihtisas Training and Research Hospital, 06230 Ankara, Turkey

A 53-year-old woman admitted to our outpatient urology clinic with complaints of dysuria, urgency and recurrent urinary tract infection (UTI). She had undergone an unknown laparoscopic incontinence surgery seven years ago that we considered being burch colposuspension. She had recurrent UTI for more than one year. Plain radiography showed multiple radiopaque helical materials and semi-opacity in bony pelvis. Cystoscopic evaluation revealed a 3 cm stone fixed at the dome of the urinary bladder. Stone was fragmented endoscopically using pneumonic lithotripter. After fragmentation of the stone, three tacks became apparent. The adhered tack was

removed with the aid of grasping forceps by a rotation maneuver. It was not possible to remove the embedded tacks and the operation was ended. One month later, the patient underwent cystoscopy. The bladder mucosa was exactly intact and no tack was visible.Migration of tacks into the bladder after laparoscopic incontinence surgery must be kept in mind, especially in patients with recurrent UTI and lower urinary system symptoms post-surgery. Endoscopic approach by means of a cystoscopy should be the preferred technique because of adhesion at the previous operation side. A rotation maneuver could be used to remove embedded tacks.

KEY WORDS: bladder stone, colposuspension, incontinence, surgical tack

Case Report

INTRODUCTIONBurch colposuspension has been utilized in the

treatment of stress urinary incontinence for many years. Several modified techniques have been described and materials used since the description of the procedure by Burch JC[1-3]. Various complications have been reported related to materials used to fix the paravaginal tissues to the Cooper’s ligament. Herein, we present a patient who developed a large bladder stone due to migrated surgical tack seven years after laparoscopic (L/S) colposuspension.

CASE REPORTA 53-year-old woman admitted to our outpatient

urology clinic with complaints of dysuria, urgency and recurrent urinary tract infection. She had a medical history of type 2 diabetes mellitus and asthma. She was on medication with insulin and inhaler corticosteroid. She had undergone laparoscopic burch colposuspension seven years ago at another institution. She also had recurrent urinary tract infection for more than one year and had taken several

courses of various antibiotics. Physical examination and routine blood parameters did not reveal any abnormality. Urine culture yielded >100.000 CFU/mL Escherichia coli. After ten days of antibiotherapy, there was no evidence of infection in either urinalysis or urine culture. Kidney-ureter-bladder radiography showed multiple radiopaque helical materials and semi-opacity in bony pelvis (Figure 1a). Abdominal ultrasonography revealed a 25 mm hyperecogenity suspicious of urinary bladder stone. Non-contrast abdominal computed tomography revealed 2.5 x 2.9 cm opacity consistent with urinary bladder stone and multiple opacities in millimeter size close to symphisis pubis (Figure 1b-1c). The patient was scheduled for cystoscopy and synchronous required intervention. Cystoscopic evaluation revealed a 3 cm stone fixed at the dome of the urinary bladder. Stone was fragmented endoscopically using pneumonic lithotripter. After fragmentation of the stone, three tacks became apparent. Among the three tacks, two were almost embedded into bladder mucosa and one was adhered to the bladder from one edge (Figure 2). The adhered

Address correspondence to:Senol Tonyali, MD, FEBU, Turkiye Yuksek Ihtisas Egitim ve Arastirma Hastanesi, Uroloji Klinigi 06230 Sihhiye Altindag, Ankara, Turkey. Tel: + 90 312 3061829; E-mail: [email protected]


tack was removed with the aid of grasping forceps by a rotation maneuver. It was not possible to remove the embedded tacks, and the operation was ended. The situation was discussed with the patient. The patient was scheduled for cystoscopy and informed about the possible need of an open surgical removal of the tacks. One month later, the patient underwent cystoscopy. The bladder mucosa was exactly intact and no tack was visible. Her urine analysis was also normal and she had no complaints.

Fig 1: (a) Multiple helical tacks and semi-opacity close to symhisis pubis on Kidney-Ureter-Bladder radiography; (b) Multiple echogenicities in millimeter size at anterosuperior of the urinary bladder on computed tomography; (c) A 3 cm stone seen in urinary bladder in CT.

Fig 2: Cystoscopic view of helical tack adhered to bladder wall and embedded tack nearby, which could be seen after stone fragmentation

DISCUSSIONThe Burch colposuspension, described by John

C. Burch in 1961, had been the preferred choice of treatment of stress urinary incontinence in women for many years. The main principle of the operation is fixation of perivaginal tissues to the Cooper’s ligament to restore the normal anatomy of the bladder neck[1]. Over the decades, several modifications on the procedure have been made in terms of type of surgery

(open/laparoscopic) and materials used[2-4]. In early 1990’s, L/S colcosuspension emerged as a minimal invasive technique with shorter convalescence and smaller incisions compared to open surgery. Despite its advantages, it has been related to more surgical complications and poorer outcomes[5]. One of the main difficulties encountered in L/S colcosuspension, especially by inexperienced surgeons, is placing sutures in a restricted area. Using a hernia mesh and tacker was considered to overcome the suturing difficulty[6]. Various complications have been reported in using mesh, suture or tack including migration of tack into the bladder, stone formation in the bladder, and suture, mesh and tack erosion[7-10]. Foreign bodies like sutures and tacks can act as a nidus in the urinary tract for stone formation. There are a few reports in the literature describing stone formation on sutures and tacks[7,8,10]. Arunkalaivanan[10] reported a stone 1 cm in diameter on a suture after L/S colposuspension which was removed by forceps cystoscopically. Salvarci et al[7] also reported a small stone in the bladder surrounding a tack utilized in L/S Burch colposuspension, which was extracted by means of a forceps endoscopically. In the present case, we have reported the largest stone in dimension that has ever been reported in the literature. Moreover, the stone was fragmented with a lithotripter, which made three tacks visible. A rotation maneuver was used to remove the tack embedded to the urothelium.

CONCLUSIONMigrations of tacks into the bladder after L/S

incontinence surgery must be keep in mind, especially in patients with recurrent urinary tract infection and lower urinary system symptoms post-surgery. Endoscopic approach by means of a cystoscope should be the preferred technique because of the cohesion at the previous operation side. A rotation maneuver could be used to remove embedded tacks. When cystoscopic intervention fails, the surgeon may repeat cystoscopy 4 - 6 weeks later to avoid unnecessary re-operation, in case of urothelium covering the almost embedded tackers.

June 2020213 Stone formation on a surgical tack migrated to thebladder 7 years after laparoscopic incontinence surgery

ACKNOWLEDGMENTConflict of interest: None declared.Financial support: None declared.

REFERENCES

1. Burch JC. Urethrovaginal fixation to Cooper’s ligament for correction of stress incontinence, cystocele, and prolapse. Am J Obstet Gynecol 1961; 81:281-290.

2. Fatthy H, El Hao M, Samaha I, Abdallah K. Modified Burch colposuspension: laparoscopy versus laparotomy. J Am Assoc Gynecol Laparosc 2001; 8(1):99-106.

3. Henley C. The Henley staple-suture technique for laparoscopic Burch colposuspension. J Am Assoc Gynecol Laparosc 1995; 2(4):441-444.

4. Vancaillie TG, Schuessler W. Laparoscopic bladderneck suspension. J Laparoendosc Surg 1991; 1(3):169-173.

5. Moehrer B, Ellis G, Carey M, Wilson PD. Laparoscopic colposuspension for urinary incontinence in women. Cochrane Database Syst Rev 2002;(1):CD002239.

6. Soygur T, Safak M, Yesilli C, Arikan N, Gogus O. Extraperitoneal laparoscopic bladder neck suspension using hernia mesh and tacker. Urology 2000; 56(1):121-124.

7. Salvarci A, Agrali Y. Migration of endotacker into the bladder 7 years after laparoscopic retroperitoneal Burch application. Int Braz J Urol 2015; 41(2):382-387.

8. Yesilli C, Seckiner I, Mungan NA, Akduman B. Stone formation on surgical staple in the bladder: a long-term complication of laparoscopic colposuspension. Surg Laparosc Endosc Percutan Tech 2007; 17(6):568-569.

9. Washington JL. Staple erosion into the bladder after mesh and staple laparoscopic colposuspension. A case report. J Reprod Med 2002; 47(4):325-326.

10. Arunkalaivanan AS, Smith AR. Bladder calculus after laparoscopic colposuspension. J Obstet Gynaecol 2002; 22(1):101.


Kuwait Medical Journal 2020; 52 (2): 214

Frequency of lymphopenia: A summative analysis on cases with COVID-19

Beuy Joob1, Viroj Wiwanitkit2,3

1Private Academic Consultant, Sanitation Medical Academic Center, Bangkok, Thailand2Honorary professor, Dr DY Patil University, Pune, India

3Visiting professor, Hainan Medical University, Haikou, China

COVID-19 infection is a new emerging coronavirus infection[1]. It started in China and has already caused problems in more than 50 countries in Asia, Europe, Africa, America and Australia. Typically, the new infection presents with acute febrile illness. The patient usually has respiratory problems, and severe respiratory distress might occur[2-4]. Regarding basic laboratory investigation, lymphopenia is a hematological finding from complete blood count[2-4]. Here, the authors reappraised clinical data published to summarize the frequency of lymphopenia and expected range of lymphocyte count. Based on available data of 278 cases with COVID[2-4], lymphopenia occurred in 158 cases, giving a summative frequency of lymphopenia as 56.83% (95% confidence interval: 51.3% - 62.97%). The expected range (mean ± 2 SD) of lymphocyte count is 0.84 ± 0.14 x 109/L (expected range: 0.70 – 0.98 x 109/L). It can be seen that lymphopenia might not occur in all cases (since it is usually used as a local criteria for further working up for diagnosis of COVID-19), and if the criteria of lymphopenia is used for primary recruiting for

suspicious COVID-19 cases, missed diagnosis is likely to occur.

ACKNOWLEDGMENTConflict of Interest: None

REFERENCES

1. Hsia W. Emerging new coronavirus infection in Wuhan, China: situation in early 2020. Case Study Case Rep 2020; 10:8-9.

2. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020 Feb 7. doi: 10.1001/jama.2020.1585. [Epub ahead of print]

3. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020 Feb 15; 395(10223):507-513.

4. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020 Feb 15; 395(10223):497-506.

Letter To The Editor

Address correspondence to:Beuy Joob, PhD, Private Academic Consultant, Sanitation Medical Academic Center, Sanitation 1 Road, Bangkok, Thailand. E-mail: [email protected]


Selected Abstracts of Articles Published Elsewhere by Authors in Kuwait

Kuwait Medical Journal 2020; 52 (2) : 215 - 216

Rhinoconjunctivitis among Adolescents in Kuwait and Associated Risk Factors: A Cross-Sectional Study

Ali H Ziyab 1, Yaser M Ali 2

1Department of Community Medicine and Behavioral Sciences, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait

2Department of Internal Medicine, Mubarak Al-Kabeer Hospital, Ministry of Health, Kuwait City, Kuwait Biomed Res Int 2019 Nov 11;2019:3981064. doi: 10.1155/2019/3981064. eCollection 2019.

Rhinoconjunctivitis is a public health problem that causes major illness and disability worldwide. Epidemiological studies intended to determine the burden of rhinoconjunctivitis in Kuwait are limited. Hence, this study sought to estimate the prevalence of rhinoconjunctivitis among adolescents in Kuwait and explore its association with different risk factors. Schoolchildren aged 11-14 years (n = 3,864) were enrolled in a cross-sectional study. Parents completed questionnaires regarding their children›s clinical history and symptoms of rhinoconjunctivitis and relevant exposures. Associations were assessed using Poisson regression with robust variance estimation, and adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) were estimated. The 12-month (current) prevalence estimates of rhinitis, rhinoconjunctivitis, and severe rhinoconjunctivitis were 28.6% (1,040/3,643), 13.5% (497/3,689), and 1.2% (44/3,689), respectively. The prevalence of current rhinoconjunctivitis symptoms was higher in boys compared to girls (aPR = 1.19, 95% CI: 1.01-1.41). Parental history of rhinitis and asthma showed positive associations with rhinoconjunctivitis in offspring. Trend analyses showed that rhinoconjunctivitis prevalence decreased with increasing numbers of total siblings (aPR = 0.92, P trend < 0.001) and older siblings (aPR = 0.90, P trend < 0.001). Rhinoconjunctivitis is common among adolescents in Kuwait and its epidemiology is similar to that found in western countries.

Elevated concentrations of bromate in drinking water and groundwater from Kuwait and associated exposure and health risks

Alomirah HF1, Al-Zenki SF2, Alaswad MC2, Alruwaih NA2, Wu Q3, Kannan K4

1Food and Nutrition Program, Environment and Life Sciences Research Center, Kuwait Institute for Scientific Research, P.O. Box 24885, Safat 13109, Kuwait City, Kuwait. Electronic address: [email protected].

2Food and Nutrition Program, Environment and Life Sciences Research Center, Kuwait Institute for Scientific Research, P.O. Box 24885, Safat 13109, Kuwait City, Kuwait.

3Wadsworth Center, New York State Department of Health, and Department of Environmental Health Sciences, School of Public Health, State University of New York at Albany, Albany, NY 12201, USA.

4Wadsworth Center, New York State Department of Health, and Department of Environmental Health Sciences, School of Public Health, State University of New York at Albany, Albany, NY 12201, USA. Electronic address:

[email protected].

Environ Res. 2019 Nov 1:108885. doi: 10.1016/j.envres.2019.108885. [Epub ahead of print] Drinking water is an important source of human exposure to bromate, an ubiquitous environmental contaminant and a suspect human carcinogen. Nevertheless, little is known with regard to bromate


Physical Therapists with Work-Related Musculoskeletal Disorders in the State of Kuwait: A Comparison across

Countries and Health Care Professions

Musaed Z Alnaser 1, Sameera H Aljadi 2

1Department of Occupational Therapy, Faculty of Allied Health Sciences, Kuwait University, Kuwait2Department of Physical Therapy, Faculty of Allied Health Sciences, Kuwait University, Kuwait

Work 2019;63(2):261-268. doi: 10.3233/WOR-192927.

BACKGROUNDIn the US, as the demands for rehabilitation services increase, work-related musculoskeletal disorders (WMSDs) have increased among rehabilitation practitioners. This trend has been noticed among physical therapists (PTs) in the State of Kuwait.

OBJECTIVEThe purpose of this study was to determine the prevalence and risk factors associated with WMSDs among PTs in Kuwait over a 12-month period. In addition, the result compared across countries and health care professions.

METHODSA descriptive cross-sectional design was used in this study. A self-administered questionnaire was distributed to the PT departments at Kuwait government hospitals and schools. A total of 312 returned questionnaires (69.3% response rate) were received.

RESULTSResults showed that 149 (48%) PT respondents experienced WMSDs. The lower back and muscle spasm were the most common area of the body injured and type of injury, respectively. Manual therapy techniques and patient transfers were most common activities associated with injuries.

CONCLUSIONSThe prevalence of PTs with WMSDs in Kuwait was high and similar to other studies of PTs with WMSDs working in other countries. The performance of work activities was the leading risk factor for WMSDs, and WMSDs were prevalent among industrialized, industrially developing, and underdeveloped countries. Education of PTs regarding ergonomic and biomechanical principles as well as hands-on training of patient handling are the key tools to help prevent WMSDs.

exposure from water produced by thermal desalination of seawater. The purpose of this study was to determine the occurrence of bromate in desalinated drinking water and groundwater from Kuwait and estimate associated exposure and health risks to consumers. In this study, 194 tap and ground water samples collected from Kuwait were analyzed for the presence of bromate and bromide (reduced form of bromine). Bromate was found in almost all tap water samples with a mean concentration of 19.6 μg/L, which is higher than the maximum acceptable contaminant level (MCL) of 10 μg/L. The mean concentration of bromide in tap water samples was 46.2 μg/L. In bottled water, lower mean bromate concentration was found (2.89 μg/L) with mean bromide levels at 76.1 μg/L. Saline brackish water had bromate concentration at 9.48 μg/L while bromate was not detected in saline groundwater/well water samples. The mean estimated daily intake (EDI) of bromate by the Kuwaiti population through tap water and commonly consumed bottled water was 21.7 μg/d and 3.21 μg/d, respectively. Among the five age groups, 3 to 5-year-old children had the highest EDI of bromate at 15.4 μg/d. The excess cancer risk due to ingestion of bromate in tap water was estimated to be 3.92 × 10-4, which is approximately one order of magnitude higher than the maximum acceptable level of risk (2× 10-5). This study highlights the significance of desalinated water as a source of bromate exposure.


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1. COVID-19What is a coronavirus?

Coronaviruses are a large family of viruses which may cause illness in animals or humans. In humans, several coronaviruses are known to cause respiratory infections ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). The most recently discovered coronavirus causes coronavirus disease COVID-19.

What is COVID-19?COVID-19 is the infectious disease caused by the

most recently discovered coronavirus. This new virus and disease were unknown before the outbreak began in Wuhan, China, in December 2019. COVID-19 is now a pandemic affecting many countries globally.

What are the symptoms of COVID-19?The most common symptoms of COVID-19 are

fever, dry cough, and tiredness. Other symptoms that are less common and may affect some patients include aches and pains, nasal congestion, headache, conjunctivitis, sore throat, diarrhea, loss of taste or smell or a rash on skin or discoloration of fingers or toes. These symptoms are usually mild and begin gradually. Some people become infected but only have very mild symptoms.

Most people (about 80%) recover from the disease without needing hospital treatment. Around 1 out of every 5 people who gets COVID-19 becomes seriously ill and develops difficulty breathing. Older people, and those with underlying medical problems like high blood pressure, heart and lung problems, diabetes, or cancer, are at higher risk of developing serious illness. However, anyone can catch COVID-19 and become seriously ill. People of all ages who experience fever

and/or cough associated with difficulty breathing/shortness of breath, chest pain/pressure, or loss of speech or movement should seek medical attention immediately. If possible, it is recommended to call the health care provider or facility first, so the patient can be directed to the right clinic.

What should I do if I have COVID-19 symptoms and when should I seek medical care?

If you have minor symptoms, such as a slight cough or a mild fever, there is generally no need to seek medical care. Stay at home, self-isolate and monitor your symptoms. Follow national guidance on self-isolation.

However, if you live in an area with malaria or dengue fever it is important that you do not ignore symptoms of fever. Seek medical help. When you attend the health facility wear a mask if possible, keep at least 1 metre distance from other people and do not touch surfaces with your hands. If it is a child who is sick help the child stick to this advice.

Seek immediate medical care if you have difficulty breathing or pain/pressure in the chest. If possible, call your health care provider in advance, so he/she can direct you to the right health facility.

How does COVID-19 spread?People can catch COVID-19 from others who have

the virus. The disease spreads primarily from person to person through small droplets from the nose or mouth, which are expelled when a person with COVID-19 coughs, sneezes, or speaks. These droplets are relatively heavy, do not travel far and quickly sink to the ground. People can catch COVID-19 if they breathe in these droplets from a person infected with the virus. This is why it is important to stay at least 1 meter) away from others. These droplets can land

WHO-Facts Sheet1. COVID-192. Depression

3. Musculoskeletal Cconditions4. Onchocerciasis

Compiled and edited byVineetha E Mammen


Address correspondence to: Office of the Spokesperson, WHO, Geneva. Tel.: (+41 22) 791 2599; Fax (+41 22) 791 4858; Email: [email protected]; Web site: http://www.who.int/


on objects and surfaces around the person such as tables, doorknobs and handrails. People can become infected by touching these objects or surfaces, then touching their eyes, nose or mouth. This is why it is important to wash your hands regularly with soap and water or clean with alcohol-based hand rub.

WHO is assessing ongoing research on the ways that COVID-19 is spread and will continue to share updated findings.

Can COVID-19 be caught from a person who has no symptoms?

COVID-19 is mainly spread through respiratory droplets expelled by someone who is coughing or has other symptoms such as fever or tiredness. Many people with COVID-19 experience only mild symptoms. This is particularly true in the early stages of the disease. It is possible to catch COVID-19 from someone who has just a mild cough and does not feel ill.

Some reports have indicated that people with no symptoms can transmit the virus. It is not yet known how often it happens. WHO is assessing ongoing research on the topic and will continue to share updated findings.

Protecting yourself and others from the spread COVID-19

You can reduce your chances of being infected or spreading COVID-19 by taking some simple precautions:· Regularly and thoroughly clean your hands with

an alcohol-based hand rub or wash them with soap and water. Why? Washing your hands with soap and water or using alcohol-based hand rub kills viruses that may be on your hands.

· Maintain at least 1 metre (3 feet) distance between yourself and others. Why? When someone coughs, sneezes, or speaks they spray small liquid droplets from their nose or mouth which may contain virus. If you are too close, you can breathe in the droplets, including the COVID-19 virus if the person has the disease.

· Avoid going to crowded places. Why? Where people come together in crowds, you are more likely to come into close contact with someone that has COIVD-19 and it is more difficult to maintain physical distance of 1 metre (3 feet).

· Avoid touching eyes, nose and mouth. Why? Hands touch many surfaces and can pick up viruses. Once contaminated, hands can transfer the virus to your eyes, nose or mouth. From there, the virus can enter your body and infect you.

· Make sure you, and the people around you, follow

good respiratory hygiene. This means covering your mouth and nose with your bent elbow or tissue when you cough or sneeze. Then dispose of the used tissue immediately and wash your hands. Why? Droplets spread virus. By following good respiratory hygiene, you protect the people around you from viruses such as cold, flu and COVID-19.

· Stay home and self-isolate even with minor symptoms such as cough, headache, mild fever, until you recover. Have someone bring you supplies. If you need to leave your house, wear a mask to avoid infecting others. Why? Avoiding contact with others will protect them from possible COVID-19 and other viruses.

· If you have a fever, cough and difficulty breathing, seek medical attention, but call by telephone in advance if possible and follow the directions of your local health authority. Why? National and local authorities will have the most up to date information on the situation in your area. Calling in advance will allow your health care provider to quickly direct you to the right health facility. This will also protect you and help prevent spread of viruses and other infections.

· Keep up to date on the latest information from trusted sources, such as WHO or your local and national health authorities. Why? Local and national authorities are best placed to advise on what people in your area should be doing to protect themselves.

Advice on the safe use of alcohol-based hand sanitizers

To protect yourself and others against COVID-19, clean your hands frequently and thoroughly. Use alcohol-based hand sanitizer or wash your hands with soap and water. If you use an alcohol-based hand sanitizer, make sure you use and store it carefully.

o Keep alcohol-based hand sanitizers out of children’s reach. Teach them how to apply the sanitizer and monitor its use.

o Apply a coin-sized amount on your hands. There is no need to use a large amount of the product.

o Avoid touching your eyes, mouth and nose immediately after using an alcohol-based hand sanitizer, as it can cause irritation.

o Hand sanitizers recommended to protect against COVID-19 are alcohol-based and therefore can be flammable. Do not use before handling fire or cooking.

o Under no circumstance, drink or let children swallow an alcohol-based hand sanitizer. It can be poisonous.

WHO-Facts Sheet June 2020225

o Remember that washing your hands with soap and water is also effective against COVID-19.

When and how to use masks· Before putting on a mask, clean hands with alcohol-

based hand rub or soap and water.· Cover mouth and nose with mask and make sure

there are no gaps between your face and the mask.· Avoid touching the mask while using it; if you do,

clean your hands with alcohol-based hand rub or soap and water.

· Replace the mask with a new one as soon as it is damp and do not re-use single-use masks.

· To remove the mask: remove it from behind (do not touch the front of mask); discard immediately in a closed bin; clean hands with alcohol-based hand rub or soap and water.

· If you are healthy, you only need to wear a mask if you are taking care of a person with COVID-19.

· Wear a mask if you are coughing or sneezing.· Masks are effective only when used in combination

with frequent hand-cleaning with alcohol-based hand rub or soap and water.

· If you wear a mask, then you must know how to use it and dispose of it properly.

MYTH BUSTERS1. There are currently no drugs licensed for the treatment or prevention of COVID-19

While several drug trials are ongoing, there is currently no proof that hydroxychloroquine or any other drug can cure or prevent COVID-19. The misuse of hydroxychloroquine can cause serious side effects and illness and even lead to death. WHO is coordinating efforts to develop and evaluate medicines to treat COVID-19

2. Adding pepper to your soup or other meals DOES NOT prevent or cure COVID-19

Hot peppers in your food, though very tasty, cannot prevent or cure COVID-19. The best way to protect yourself against the new coronavirus is to keep at least 1 metre away from others and to wash your hands frequently and thoroughly. It is also beneficial for your general health to maintain a balanced diet, stay well hydrated, exercise regularly and sleep well.

3. COVID-19 IS NOT transmitted through housefliesTo date, there is no evidence or information to

suggest that the COVID-19 virus transmitted through houseflies. The virus that cause COVID-19 spreads primarily through droplets generated when an infected person coughs, sneezes or speaks. You can also become infected by touching a contaminated surface and then touching your eyes, nose or mouth before washing

your hands. To protect yourself, keep at least 1-metre distance from others and disinfect frequently-touched surfaces. Clean your hands thoroughly and often and avoid touching your eyes, mouth and nose.

4. Spraying and introducing bleach or another disinfectant into your body WILL NOT protect you against COVID-19 and can be dangerous

Do not under any circumstance spray or introduce bleach or any other disinfectant into your body. These substances can be poisonous if ingested and cause irritation and damage to your skin and eyes.

Bleach and disinfectant should be used carefully to disinfect surfaces only. Remember to keep chlorine (bleach) and other disinfectants out of reach of children.

5. Drinking methanol, ethanol or bleach DOES NOT prevent or cure COVID-19 and can be extremely dangerous

Methanol, ethanol, and bleach are poisons. Drinking them can lead to disability and death. Methanol, ethanol, and bleach are sometimes used in cleaning products to kill the virus on surfaces – however you should never drink them. They will not kill the virus in your body and they will harm your internal organs.

To protect yourself against COVID-19, disinfect objects and surfaces, especially the ones you touch regularly. You can use diluted bleach or alcohol for that. Make sure you clean your hands frequently and thoroughly and avoid touching your eyes, mouth and nose.

6. Exposing yourself to the sun or to temperatures higher than 25C degrees DOES NOT prevent the coronavirus disease (COVID-19)

You can catch COVID-19, no matter how sunny or hot the weather is. Countries with hot weather have reported cases of COVID-19. To protect yourself, make sure you clean your hands frequently and thoroughly and avoid touching your eyes, mouth, and nose.

7. Do vaccines against pneumonia protect you against the new coronavirus?

No. Vaccines against pneumonia, such as pneumococcal vaccine and Haemophilus influenza type B (Hib) vaccine, do not provide protection against the new coronavirus.

The virus is so new and different that it needs its own vaccine. Researchers are trying to develop a vaccine against 2019-nCoV, and WHO is supporting their efforts.

Although these vaccines are not effective against 2019-nCoV, vaccination against respiratory illnesses is highly recommended to protect your health.


8. Can regularly rinsing your nose with saline help prevent infection with the new coronavirus?

No. There is no evidence that regularly rinsing the nose with saline has protected people from infection with the new coronavirus.

There is some limited evidence that regularly rinsing nose with saline can help people recover more quickly from the common cold. However, regularly rinsing the nose has not been shown to prevent respiratory infections.

9. Can eating garlic help prevent infection with the new coronavirus?

Garlic is a healthy food that may have some antimicrobial properties. However, there is no evidence from the current outbreak that eating garlic has protected people from the new coronavirus.

10. Does the new coronavirus affect older people, or are younger people also susceptible?

People of all ages can be infected by the new coronavirus (2019-nCoV). Older people, and people with pre-existing medical conditions (such as asthma, diabetes, heart disease) appear to be more vulnerable to becoming severely ill with the virus.

WHO advises people of all ages to take steps to protect themselves from the virus, for example by following good hand hygiene and good respiratory hygiene.

11. Are antibiotics effective in preventing and treating the new coronavirus?

No, antibiotics do not work against viruses, only bacteria.

The new coronavirus (2019-nCoV) is a virus and, therefore, antibiotics should not be used as a means of prevention or treatment.

However, if you are hospitalized for the 2019-nCoV, you may receive antibiotics because bacterial co-infection is possible.

12. Are there any specific medicines to prevent or treat the new coronavirus?

To date, there is no specific medicine recommended to prevent or treat the new coronavirus (2019-nCoV).

However, those infected with the virus should receive appropriate care to relieve and treat symptoms, and those with severe illness should receive optimized supportive care. Some specific treatments are under investigation, and will be tested through clinical trials. WHO is helping to accelerate research and development efforts with a range or partners.

2. DEPRESSION

KEY FACTS· Depression is a common mental disorder. Globally,

more than 264 million people of all ages suffer from depression.

· Depression is a leading cause of disability worldwide and is a major contributor to the overall global burden of disease.

· More women are affected by depression than men.· Depression can lead to suicide.· There are effective psychological and

pharmacological treatments for moderate and severe depression.

OverviewDepression is a common illness worldwide, with

more than 264 million people affected(1). Depression is different from usual mood fluctuations and short-lived emotional responses to challenges in everyday life. Especially when long-lasting and with moderate or severe intensity, depression may become a serious health condition. It can cause the affected person to suffer greatly and function poorly at work, at school and in the family. At its worst, depression can lead to suicide. Close to 800 000 people die due to suicide every year. Suicide is the second leading cause of death in 15-29-year-olds.

Although there are known, effective treatments for mental disorders, between 76% and 85% of people in low- and middle-income countries receive no treatment for their disorder(2). Barriers to effective care include a lack of resources, lack of trained health-care providers and social stigma associated with mental disorders. Another barrier to effective care is inaccurate assessment. In countries of all income levels, people who are depressed are often not correctly diagnosed, and others who do not have the disorder are too often misdiagnosed and prescribed antidepressants.

The burden of depression and other mental health conditions is on the rise globally. A World Health Assembly resolution passed in May 2013 has called for a comprehensive, coordinated response to mental disorders at the country level.

Types and symptoms

Depending on the number and severity of symptoms, a depressive episode can be categorized as mild, moderate or severe.

A key distinction is also made between depression in people who have or do not have a history of manic episodes. Both types of depression can be chronic (i.e. over an extended period) with relapses, especially if they go untreated.


Recurrent depressive disorder: this disorder involves repeated depressive episodes. During these episodes, the person experiences depressed mood, loss of interest and enjoyment, and reduced energy leading to diminished activity for at least two weeks. Many people with depression also suffer from anxiety symptoms, disturbed sleep and appetite, and may have feelings of guilt or low self-worth, poor concentration and even symptoms that cannot be explained by a medical diagnosis.

Depending on the number and severity of symptoms, a depressive episode can be categorized as mild, moderate or severe. An individual with a mild depressive episode will have some difficulty in continuing with ordinary work and social activities but will probably not cease to function completely. During a severe depressive episode, it is unlikely that the sufferer will be able to continue with social, work or domestic activities, except to a limited extent.

Bipolar affective disorder: this type of depression typically consists of both manic and depressive episodes separated by periods of normal mood. Manic episodes involve elevated or irritable mood, over-activity, pressure of speech, inflated self-esteem and a decreased need for sleep.

Contributing factors and prevention

Depression results from a complex interaction of social, psychological and biological factors. People who have gone through adverse life events (unemployment, bereavement, psychological trauma) are more likely to develop depression. Depression can, in turn, lead to more stress and dysfunction and worsen the affected person’s life situation and depression itself.

There are interrelationships between depression and physical health. For example, cardiovascular disease can lead to depression and vice versa.

Prevention programmes have been shown to reduce depression. Effective community approaches to prevent depression include school-based programmes to enhance a pattern of positive thinking in children and adolescents. Interventions for parents of children with behavioural problems may reduce parental depressive symptoms and improve outcomes for their children. Exercise programmes for the elderly can also be effective in depression prevention.

Diagnosis and treatment

There are effective treatments for moderate and severe depression. Health-care providers may offer psychological treatments such as behavioural

activation, cognitive behavioural therapy (CBT) and interpersonal psychotherapy (IPT), or antidepressant medication such as selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). Health-care providers should keep in mind the possible adverse effects associated with antidepressant medication, the ability to deliver either intervention (in terms of expertise, and/or treatment availability), and individual preferences. Different psychological treatment formats for consideration include individual and/or group face-to-face psychological treatments delivered by professionals and supervised lay therapists.

Psychosocial treatments are also effective for mild depression. Antidepressants can be an effective form of treatment for moderate-severe depression but are not the first line of treatment for cases of mild depression. They should not be used for treating depression in children and are not the first line of treatment in adolescents, among whom they should be used with extra caution.

WHO response

Depression is one of the priority conditions covered by WHO’s mental health Gap Action Programme (mhGAP). The Programme aims to help countries increase services for people with mental, neurological and substance use disorders through care provided by health workers who are not specialists in mental health. WHO has developed brief psychological intervention manuals for depression that may be delivered by lay workers. An example is Problem Management Plus, which describes the use of behavioural activation, relaxation training, problem solving treatment and strengthening social support. Moreover, the manual Group Interpersonal Therapy (IPT) for Depression describes group treatment of depression. Finally, Thinking Healthy covers the use of cognitive-behavioural therapy for perinatal depression.

REFERENCES

1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. (2018). Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet. DOI.

2. Wang et al. Use of mental health services for anxiety, mood, and substance disorders in 17 countries in the WHO world mental health surveys. The Lancet. 2007; 370(9590):841-50.


3. MUSCULOSKELETAL CONDITIONS

KEY FACTS· Musculoskeletal conditions are the leading

contributor to disability worldwide, with low back pain being the single leading cause of disability globally.

· Musculoskeletal conditions and injuries are not just conditions of older age; they are prevalent across the life-course. Between one in three and one in five people(including children) live with a musculoskeletal pain condition.

· Musculoskeletal conditions significantly limit mobility and dexterity, leading to early retirement from work, reduced accumulated wealth and reduced ability to participate in social roles.

· The greatest proportion of non-cancer persistent pain conditions is accounted for by musculoskeletal conditions.

· Highly prevalent among multi-morbidity health states, musculoskeletal conditions are prevalent in one third to one-half of multi-morbidity presentations, particularly in older people.

· Musculoskeletal conditions are commonly linked with depression and increase the risk of developing other chronic health conditions.

IntroductionMusculoskeletal conditions comprise more than

150 diagnoses that affect the locomotor system; that is, muscles, bones, joints and associated tissues such as tendons and ligaments, as listed in the International Classification of Diseases. They range from those that arise suddenly and are short-lived, such as fractures, sprains and strains, to lifelong conditions associated with ongoing pain and disability.

Musculoskeletal conditions are typically characterised by pain (often persistent) and limitations in mobility, dexterity and functional ability, reducing people’s ability to work and participate in social roles with associated impacts on mental wellbeing, and at a broader level impacts on the prosperity of communities. The most common and disabling musculoskeletal conditions are osteoarthritis, back and neck pain, fractures associated with bone fragility, injuries and systemic inflammatory conditions such as rheumatoid arthritis.

Musculoskeletal conditions include conditions that affect:· joints, such as osteoarthritis, rheumatoid arthritis,

psoriatic arthritis, gout, ankylosing spondylitis;· bones, such as osteoporosis, osteopenia and

associated fragility fractures, traumatic fractures;· muscles, such as sarcopenia;

· the spine, such as back and neck pain;· multiple body areas or systems, such as regional

and widespread pain disorders and inflammatory diseases such as connective tissue diseases and vasculitis that have musculoskeletal manifestations, for example systemic lupus erythematosus.

Musculoskeletal conditions are prevalent across the life-course and most commonly affect people from adolescence through to older age. The prevalence and impact of musculoskeletal conditions is predicted to rise as the global population ages and the prevalence of risk factors for noncommunicable diseases increases, particularly in low- and middle-income settings. Musculoskeletal conditions occur commonly with other noncommunicable diseases in multimorbidity health states.

Scope of the health issueMusculoskeletal conditions affect people across the

life-course in all regions of the world. Musculoskeletal conditions were the leading cause of disability in four of the six WHO regions in 2017 (ranked second in the East Mediterranean Region and third in the African Region). While the prevalence of musculoskeletal conditions increases with age, younger people are also affected, often during their peak income-earning years.

The Global Burden of Disease (GBD) study provides evidence of the impact of musculoskeletal conditions, highlighting the significant disability burden associated with these conditions. In the 2017 GBD study, musculoskeletal conditions were the highest contributor to global disability (accounting for 16% of all years lived with disability), and lower back pain remained the single leading cause of disability since it was first measured in 1990 (1). While the prevalence of musculoskeletal conditions varies by age and diagnosis, between 20%–33% of people across the globe live with a painful musculoskeletal condition.

A recent report from the United States of America suggests that one in two adult Americans live with a musculoskeletal condition – the same number as those with cardiovascular or chronic respiratory diseases combined (2).

Analysis of data from WHO’s Study on global AGEing and adult health (SAGE) point to the high prevalence of arthritis in low- and middle-income settings, particularly among those in a lower socioeconomic position (3).· WHO Study on global AGEing and adult health

(SAGE)

Signs and symptomsPain and restricted mobility are the unifying

features of the range of musculoskeletal conditions.


Pain is typically persistent for long-term conditions. In some conditions, joint deformity may occur, where early diagnosis and treatment are not available.

Prevention and managementMusculoskeletal conditions share some similar

risk factors to other noncommunicable diseases, such as inadequate physical activity, obesity, smoking and poor nutrition. While management of some musculoskeletal conditions may require specialist and/or surgical care, many musculoskeletal conditions can be managed in primary care through a combination of core non-pharmacologic interventions such as exercise, weight management, psychological therapies and pharmacologic therapies.

Social and economic implicationsThe health and broader social cost of musculoskeletal

conditions are significant. Spending on musculoskeletal conditions is challenging to measure due to the vast array of musculoskeletal conditions and limitations in health surveillance systems. Orthopaedic surgery procedures, for example total joint replacement, account for one of the greatest hospital expenditures. Data are particularly scarce in low- and middle-income areas. Musculoskeletal conditions account for the greatest proportion of lost productivity in the workplace. In 2011, musculoskeletal conditions cost US$ 213 billion – 1.4% of Gross Domestic Product (2).

WHO responseWHO recognises that musculoskeletal health

conditions contribute greatly to disability across the life-course in all regions of the world. In particular, WHO recognises that musculoskeletal conditions significantly impact functional ability. In this context, WHO is responding through the Integrated Care for Older People (ICOPE) approach, which identifies the need to improve musculoskeletal function through a range of interventions, with multimodal exercise as a key component.

Integrated Care for Older PeopleThe need to address impairments in musculoskeletal

health is also identified in WHO’s Global Programme of Work in rehabilitation, in order to improve peoples’ performance. Prevention of musculoskeletal trauma is addressed in WHO’s Global Programme of Work on road traffic injuries

REFERENCES

1. James SL, Abate D, Abate KH, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the

Global Burden of Disease Study 2017. Lancet 2018; 392: 1789-858.

2. The Impact of Musculoskeletal Disorders on Americans — Opportunities for Action. Bone and Joint Initiative USA. 2016. ( h tt p : / / w w w . b o n e a n d j o i n t b u r d e n . o r g / d o c s /BMUSExecutiveSummary2016.pdf).

3. Prevalence of arthritis according to age, sex and socioeconomic status in six low and middle income countries: analysis of data from the World Health Organization study on global AGEing and adult health (SAGE) Wave 1.

S. L. Brennan-Olsen, S. Cook, M. T. Leech, S. J. Bowe, P. Kowal, N. Naidoo, I. N. Ackerman, et al. BMC Musculoskeletal Disorders. 2017.(https://bmcmusculoskeletdisord.biomedcentral .com/articles/10.1186/s12891-017-1624-z).

4. World Health Organization. Guidelines on community-level interventions to manage declines in intrinsic capacity. Geneva: WHO; 2017 (https://www.who.int/ageing/publications/guidelines-icope/en/).

4. ONCHOCERCIASIS

KEY FACTS· Onchocerciasis, commonly known as “river

blindness”, is caused by the parasitic worm Onchocerca volvulus.

· It is transmitted to humans through exposure to repeated bites of infected blackflies of the genus Simulium

· Symptoms include severe itching, disfiguring skin conditions, and visual impairment, including permanent blindness.

· More than 99% of infected people live in 31 African countries. The disease also exists in some foci in Latin America and Yemen.

· The Global Burden of Disease Study estimated in 2017 that there were 20.9 million prevalent O. volvulus infections worldwide: 14.6 million of the infected people had skin disease and 1.15 million had vision loss

· Community-directed treatment with ivermectin is the core strategy to eliminate onchocerciasis in Africa. In the Americas the strategy is biannual large-scale treatment with ivermectin.

· Four countries have been verified by WHO as free of onchocerciasis after successfully implementing elimination activities for decades: Colombia, Ecuador, Mexico, and Guatemala

· By the end of 2017, three additional countries had stopped mass drug administration and completed 3 years of post-treatment surveillance in at least one transmission area: Bolivarian Republic of Venezuela, Uganda, and Sudan

· 1.8 million people live in areas that no longer require mass drug administration for onchocerciasis.


Onchocerciasis – or “river blindness” – is a parasitic disease caused by the filarial worm Onchocerca volvulus transmitted by repeated bites of infected blackflies (Simulium spp.). These blackflies breed along fast-flowing rivers and streams, close to remote villages located near fertile land where people rely on agriculture.

In the human body, the adult worms produce embryonic larvae (microfilariae) that migrate to the skin, eyes and other organs. When a female blackfly bites an infected person during a blood meal, it also ingests microfilariae which develop further in the blackfly and are then transmitted to the next human host during subsequent bites.

Signs and symptomsOnchocerciasis is an eye and skin disease.

Symptoms are caused by the microfilariae, which move around the human body in the subcutaneous tissue and induce intense inflammatory responses when they die. Infected people may show symptoms such as severe itching and various skin changes. Some infected people develop eye lesions which can lead to visual impairment and permanent blindness. In most cases, nodules under the skin form around the adult worms.

Geographical distribution 2017 Onchocerciasis occurs mainly in tropical areas.

More than 99% of infected people live in 31 countries in sub-Saharan Africa: Angola, Benin, Burkina Faso, Burundi, Cameroon, Central African Republic, Chad, Republic of Congo, Côte d’Ivoire, Democratic Republic of the Congo, Equatorial Guinea, Ethiopia, Gabon, Ghana, Guinea, Guinea-Bissau, Kenya, Liberia, Malawi, Mali, Mozambique, Niger, Nigeria, Rwanda, Senegal, Sierra Leone, South Sudan, Sudan, Togo, Uganda, United Republic of Tanzania.

Onchocerciasis is also transmitted in Brazil, Venezuela (Bolivarian Republic of) and Yemen.

Prevention, control and elimination programmesThere is no vaccine or medication to prevent

infection with O. volvulus.Between 1974 and 2002, disease caused by

onchocerciasis was brought under control in West Africa through the work of the Onchocerciasis Control Programme (OCP), using mainly the spraying of insecticides against blackfly larvae (vector control) by helicopters and airplanes. This has been supplemented by large-scale distribution of ivermectin since 1989.

The OCP relieved 40 million people from infection, prevented blindness in 600 000 people, and ensured that 18 million children were born free from the threat

of the disease and blindness. In addition, 25 million hectares of abandoned arable land were reclaimed for settlement and agricultural production, capable of feeding 17 million people annually.

The African Programme for Onchocerciasis Control (APOC) was launched in 1995 with the objective of controlling onchocerciasis in the remaining endemic countries in Africa and closed at the end of 2015 after beginning the transition to onchocerciasis elimination. Its main strategy has been the establishment of sustainable community-directed treatment with ivermectin (CDTI) and vector control with environmentally-safe methods where appropriate. In APOC’s final year, more than 119 million people were treated with ivermectin, and many countries had greatly decreased the morbidity associated with onchocerciasis. More than 800,000 people in Uganda and 120,000 people in Sudan no longer required ivermectin by the time that APOC closed.

In 2017, more than 145 million people were treated in Africa where the strategy of CDTI was implemented, representing more than 70% coverage of the number of people who require treatment globally. The Expanded Special Project for the Elimination of Neglected Tropical Diseases in Africa (ESPEN), set up to cover the five preventive chemotherapy NTDs, has 4 core objectives: 1. Scale up treatments towards the achievement of 100% geographic coverage, 2. Scale down: stopping treatments once transmission has been interrupted or control achieved, 3. Strengthen information systems for evidence-based action, and 4. Improve the effective use of donated medicines through enhance supply chain management. ESPEN is housed in the WHO Regional Office for Africa.

The Onchocerciasis Elimination Program of the Americas (OEPA) began in 1992 with the objective of eliminating ocular morbidity and interruption of transmission throughout the Americas by 2015 through biannual large-scale treatment with ivermectin. All 13 foci in this region achieved coverage of more than 85% in 2006, and transmission was interrupted in 11 of the 13 foci so far in 2017. Elimination efforts are now focused on the Yanomami people living in Brazil and Venezuela (Bolivarian Republic of).

On 5 April 2013, the Director-General of WHO issued an official letter confirming that Colombia has achieved elimination of onchocerciasis. Colombia was the first country in the world to be verified and declared free of onchocerciasis by WHO. This has been followed by Ecuador in September 2014, Mexico in July 2015, and Guatemala in July 2016. More than 500 000 people no longer need ivermectin in the Americas.


TreatmentWHO recommends treating onchocerciasis with

ivermectin at least once yearly for between 10 to 15 years. Where O. volvulus co-exists with Loa loa, treatment strategies have to be adjusted. Loa loa is a parasitic filarial worm that is endemic in Cameroon, the Central African Republic, Congo, the Democratic Republic of the Congo, Nigeria and South Sudan. Treatment of individuals with high levels of L. loa in the blood can sometimes result in severe adverse events. In affected countries, it is recommended to follow the Mectizan Expert Committee (MEC)/APOC recommendations for the management of severe adverse events.

WHO responseWHO headquarters provides administrative,

technical and operational research support to three regions where onchocerciasis is transmitted.

The Onchocerciasis Technical Advisory Subgroup (OTS) was organized by WHO in 2017 to provide recommendations to WHO about future policy and guideline development and priorities for research required to help programme achieve their elimination objectives. Reports from the OTS meetings can be found here.

The WHO Regional Office for Africa, which had an overall supervisory role for OCP from 1975 to 2002 and APOC from 1995 to 2015, currently supervises ESPEN which coordinates PC-NTD control and elimination activities in that region.

Through the OEPA partnership, WHO collaborates with endemic countries and international partners in the WHO Region of the Americas. Although there is no official programme to coordinate activities in the WHO Eastern Mediterranean Region, the two countries in the region collaborate on elimination activities.

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