definitieve binnenwerk opmaak

The wave called delirium, from onset to consequences

Chantal Jochemina Slor

© 2013 Chantal Jochemina Slor, Alkmaar, The Netherlands

Printed by: Ipskamp Drukkers, EnschedeCover Design: Trent Mitchell Photography, AustraliaLay-out: Legatron Electronic Publishing, Rotterdam

Publication of this thesis was financially supported by: Afdeling Geriatrie MCAMCA Gemini Groep

The wave called delirium, from onset to consequences

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam

op gezag van de Rector Magnificus

prof. dr. D.C. van den Boom

ten overstaan van een door het college voor promoties ingestelde

commissie, in het openbaar te verdedigen in de Agnietenkapel

op 15 november 2013, te 14.00 uur

door

Chantal Jochemina Slor

geboren te Purmerend

Promotores: Prof. dr. W.A. van Gool Prof. dr. P. Eikelenboom

Copromotores: Dr. J.F.M. de Jonghe Dr. R.W.M.M. Jansen

Overige leden: Prof. dr. D.H. Linszen Prof. dr. R.C. Oude Voshaer Prof. dr. S.E.J.A. de Rooij Prof. dr. B.A. Schmand Prof. dr. M.L. Stek

Faculteit der Geneeskunde

ConTenTS

Chapter 1: General Introduction 7

Part I: Anaesthesia and inflammatory markers for deliriumChapter 2: Anesthesia and postoperative delirium in elderly hip-surgery patients 17

Chapter 3: The trajectory of CRP levels in elderly hip fracture patients 33 with postoperative delirium 33

Part II: Clinical symptomatology Chapter 4: Predicting delirium duration in elderly hip-surgery patients. 49 Does early symptom profile matter? 49

Chapter 5: Delirium motor subtypes in elderly hip fracture patients: 65 risk factors, outcomes and longitudinal stability

Part III: The consequences of postoperative delirium: cognitive and affective functioningChapter 6: Validation and psychometric properties of the delirium motor 81 subtype scale in elderly hip fracture patients (Dutch version)

Chapter 7: The neuropsychological sequelae of delirium in elderly patients 93 with hip-fracture three months after hospital discharge

Chapter 8: Affective functioning after delirium in elderly hip fracture patients 111

Chapter 9: General discussion 129

Chapter 10: Summary 143

Chapter 11: Samenvatting 149 Supplement 1 155

Dankwoord 158

Curriculum Vitae 160

1Chapter

General Introduction

8

Chapter 1

PrefACeDelirium is a common and serious postoperative complication in hospitalized elderly patients. The characterizing features of delirium are the acute onset of disturbances in consciousness and the fluctuating of symptoms within 24 hours. Patients suffer from disturbances in consciousness and attention. This neuropsychiatric syndrome is usually considered a brief transient state, compared to dementia, which is usually considered a chronic state. However, delirium can persist and/or have long-term negative outcomes like cognitive deterioration and institutionalization.1-3 Although delirium as a clinical disorder is well known since ancient times, it was a negelected topic in the medical research till 20 years ago. Since then research on delirium has expanded, focusing on risk factors, assessment, prevention and underlying pathologic mechanisms among others. Although our knowledge on several aspects of delirium has increased, there are still many gaps in our understanding of its pathogenesis, recognition and treatment. The focus of this thesis has been threefold. First, we wanted to increase knowledge on risk factors of delirium, secondly we aimed to study phenomenology and the trajectory of delirium symptoms, and finally we sought to characterise the (long-term) outcomes after delirium has resolved. In elderly patients it is usually not possible to link delirium to only one causal factor. It is the understanding that delirium is most often a multifactorial syndrome, an interrelationship between predisposing and precipitating factors.4 The prevalence of delirium depends on the study population, and is especially high in acute medical and surgery settings. The incidence of in-hospital delirium ranges from 6% to 56%, and postoperative delirium occurs in 15% to 62% of elderly patients.5,6 Cognitive impairment and advanced age are well known predisposing risk factors for delirium.7 Presence of precipitating factors, such as (bladder) infections, severe illness or surgery, increase the risk of development of delirium. Anesthesia is considered as a possible precipitating factor for postoperative delirium, assuming that the physiologic effects on cerebral blood flow, metabolism and oxygen delivery would differ between regional and general anesthesia, with the latter having more chance on development of postoperative delirium. However, next to anesthesia also the surgical procedure itself can be a precipitaing factor in postoperative delirium. Recent research indicates that surgical procedures lead to increased levels of proinflammatory cytokines, which can induce delirium in susceptible patients.8,9 Both aging and neurodegenerative disease are accompanied by impaired immune function resulting in a heightened inflammatory state under normal conditions and an exaggerated inflammatory response in reaction to inflammatory stimulation.10,11 This pro-inflammatory state may explain why older and cognitively impaired individuals are more susceptible to delirium in the presence of precipitating factors that may elicit an inflammatory response, such as surgical procedures.

9

General introduction

1In addition to predisposing and precipating factors for the risk of development of delirium, it is also interesting to know whether these factors are associated with duration of the episode with delirium. Severity and symptom profile at the onset of delirium might be predictive of the course of delirium. The clinical diagnosis of delirium is based on the key features of delirium and exclusion of conditions that mimick delirium. The diagnosis is further complicated by the fact that delirium itself has different phenotypes. For example, delirium is often accompanied by changes in motor activity and has been classified into two motor subtypes, i.e. hyperactive and hypoactive. 12 Later on, the mixed category was added to recognise cases when elements of both subtypes occur within a short time frame.13 Studies suggest that these subtypes may have important differences in pathophysiology, treatment needs and prognosis.14 The hypoactive, quiet, delirium subtype is most likely to be missed or misdiagnosed.15,16 However, much remains unknown about the different subtypes and their stability across the delirium episode or their outcomes. Study results on differences in risk factors and prognosis between motor subtypes are inconsistent.17,18 This might be related to differences in clinical populations studied, or also by the use of different methods for defining clinical subtypes.19

Until recently it was assumed that elimination of the underlying causal factor would lead to successful recovery. However, recent research suggests that delirium contributes to poor outcomes, such as poor cognitive or affective functioning and, in elderly patients, to increased cognitive deterioration.20-22 Although it is well accepted that delirium is associated with negative long-term consequences such as impaired cognition in global terms,3 less is known about the long-term impact on specific domains of cognitive and affective functioning. If long-term disturbances in cognitive and affective functioning are associated with delirium this my be a rationale for adequate treatment and follow-up assessment of patients who had delirium, in order to diminish the possible interference with recovery or rehabilitation.23

AImS And ouTlIne of The TheSISA major part of the delirium research in elderly patients has been in heterogeneous populations. Patients develop delirium in the presence of an underlying medical condition which was the reason for hospital admission, which hinders baseline assessment of predisposing factors. The research in this thesis was done in a homogeneous group with baseline data available, as well as longitudinal and follow-up data on several factors.The general aim of this thesis was threefold. We wanted to increase our knowledge on several aspects of delirium: (1) predisposing and precipitating factors, (2) phenomenology and symptoms throughout the delirium episode, and (3) conclude with the (long-term) outcomes of delirium.

10

Chapter 1

The first part of this thesis focuses on precipitating factors of delirium. It remains unclear if anaesthesia technique or the surgical procedure itself is a precipitating factor of delirium. Chapter 2 of the thesis is concerned with the effect of general anaesthesia on postoperative delirium in a large homogenous patient group. We compared patients having general anaesthesia with patients undergoing regional anaesthesia, while also considering predisposing factors of delirium. Also, effects of classes of medications on postoperative delirium were explored. In Chapter 3 we examined CRP levels, from before the start of full syndromal delirium and across days after surgery. Several studies have examined the association between levels of CRP and delirium, although not all studies found differences.24-26 We did a time-course study, and examined the level of CRP at baseline, before surgery, and several consecutive days after surgery The aim of Chapter 4 was to identify patient characteristics that are associated with prolonged delirium. Because delirium duration has been associated with an 11% increased risk of death for every 48 hours that delirium lasts,27 we wanted to gain more insight into the determinants of delirium duration beyond the first two days. Since we had daily delirium assessments available, we also explored if different lengths of delirium episodes have different characteristics throughout the episode. Thereafter, this thesis is directed at the presentation of delirium. We investigated motor subtypes of delirium, their risk factors and outcomes, and most importantly their stability across the delirious episode (Chapter 5). Hypoactive delirium has been associated with worse outcomes, but this association is not consistently found throughout different studies.18, 28-30 Few studies examined motor subtypes of delirium in hip surgery patients.30-32 Moreover, the available longitudinal data on delirium motor subtypes comes mostly from studies in palliative care patients.33,34 Different methods have been used to identify motor subtypes of delirium, which may differ in pathophysiology, treatment needs and prognosis. The Delirium Motor Subtype Scale (DMSS) was developed to capture all the previous different approaches to subtyping into one new instrument and emphasize disturbances of motor activity rather than associated psychomotor symptoms.19,35 We translated this scale developed to identify different delirium motor subtypes and investigated the psychometric properties of this translation in a Dutch elderly hip fracture population (Chapter 6). The third part addresses the long-term outcomes of delirium and consists of two studies. Chapter 7 describes a 3-month follow-up study of elderly hip fracture patients. Patients were presented a comprehensive neuropsychological test battery in order to evaluate cognitive functioning at follow-up, and consider different cognitive domains. In this study we examined the role of inattention, as an important sign of persistent delirium36 and depression,37 as important features of the neuropsychological profile of patients who have had delirium three months earlier during their hospital admission. Chapter 8 is concerned with the association between affective functioning and delirium.

11


1We simultaneously investigated anxiety and depression levels, and post-traumatic stress disorder symptoms three months after hospital discharge, and their association with delirium. In an attempt to clarify why previous studies have found contradicting results, this study used a variety of measurements for each symptom domain, including screening questionnaires and structured diagnostic interviews. A general discussion and summary of the main findings of this thesis is provided in Chapter 9 and 10. A summary of the thesis in Dutch in Chapter 11 concludes this thesis.

12

Chapter 1

referenCeS

1. Adamis D, Treloar A, Martin FC, Macdonald, A.J. A brief review of the history of delirium as a mental disorder. Hist Psychiatry 2007; 18:459-469.

2. Cole MG. Persistent delirium in older hospital patients. Curr Opin Psychiatry 2010; 23:250-254.

3. Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. JAMA 2010; 304:443-451.

4. Inouye SK, Charpentier PA. Preciptating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA 1996; 275(11):852-857.

5. Saxena S, Lawley D. Delirium in the elderly: a clinical review. Postgrad Med J 2009; 85(1006):405-413.

6. Fong TG, Tulebaev SR, Inouye SK. Delirium in elderly adults: diagnosis, prevention and treatment. Nat Rev Neurol 2009; 5(4):210-220.

7. 7. Dasgupta M, Dumbrell AC. Preoperative risk assessment for delirium after noncardiac surgery. J Am Geriatr Soc 2006; 54;1578-1589.

8. Rudolph JL, Ramlawi B, Kuchel GA, McElhaney JE, Xie D, Sellke FW et al. Chemokines are associated with delirium after cardiac surgery. J Gerontol A Biol Sci Med Sci 2008; 63(2):184-189.

9. Simone MJ, Tan ZS. The role of inflammation in the pathogenesis of delirium and dementia in older adults. CNS Neurosci Ther 2011; 17(5):506-513.

10. Eikelenboom P, Hoogendijk WJ, Jonker C, van Tilburg W. Immunological mechanisms and the spectrum of psychiatric syndromes in Alzheimer’s disease. J Psychiatr Res 2002; 36(5):269-280.

11. Gaykema RP, Balachandran MK, Godbout JP, Johnson RW, Goehler LE. Enhanced neuronal activation in central autonomic network nuclei in aged mice following acute peripheral immune challenge. Neurosci 2007; 131(1-2):137-142.

12. Lipowski ZJ. Transient cognitive disorder in the elderly. Am J Psychiatry 1983;140: 1426-14362.

13. Lipowski ZJ. Delirium in the elderly patient. N Engl J Med 1989; 320;578-582.

14. Meagher D. Motor subtypes of delirium: past, present and future. Int Rev Psychiatry 2009; 21: 59-73.

15. Farrell KR, Ganzini L. Misdiagnosing delirium as depression in medically ill elderly patients. Arch Intern Med 1995; 155(22):2459-2464.

16. Meagher D, Leonard M. The active management of delirium: Improving detection and treatment. Advances in Psychiatric Treatments 2008; 14: 292-301.

17. Marcantonio E, Ta T, Duthie E, Resnick NM. Delirium severity and psychomotor types: their relationship with outcomes after hip fracture repair. J Am Geriatr Soc 2002; 50:850-857.

18. Kobayashi K, Takeuchi O, Suzuki M, Yamaguchi N. A retrospective study of delirium subtype. Japanese Journal of Psychiatry and Neurology 1992; 46:911-917.

19. Meagher DJ, Moran M, Raju B, Gibbons D, Donnelly S, Saunders J, Trzepacz PT. Motor symptoms in 100 patients with delirium versus control subjects: comparison of subtyping methods. Psychosomatics 2008; 49:300-308.

20. Fong TG, Jones RN, Shi P, et al. Delirium accelerates cognitive decline in Alzheimer disease. Neurology 2009; 72(18):1570-1575.

21. Gunther ML, Morandi A, Krauskopf E, Pandharipande P, Girard TD, Jackson JC et al. The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study. Crit Care Med 2012; 40(7):2022-2032.

22. Davydow DS. Symptoms of depression and anxiety after delirium. Psychosomatics 2009; 50:309-316.

23. Lenze EJ, Munin MC, Dew MA, Rogers JC, Seligman K, Mulsant BH et al. Adverse effects of depression and cognitive impairment on rehabilitation participation and recovery from hip fracture. Int J Geriatr Psychiatry 2004; 19(5):472-478.

13


124. Lee HJ, Hwang DS, Wang SK, Chee IS, Baeg S, Kim JL. Early assessment of delirium in elderly patients

after hip surgery. Psychiatry Investig 2011; 8:340-347.

25. Cerejeira J, Nogueira V, Luís P, Vaz-Serra A, Mukaetova-Ladinska EB. The cholinergic system and inflammation: common pathways in delirium pathophysiology. J Am Geriatr Soc 2012; 60:669-675.

26. van Munster BC, Korevaar JC, de Rooij SE, Levi M, Zwinderman AH. The association between delirium and the apolipoprotein E epsilon4 allele in the elderly. Psychiatr Genet 2007; 17:261-266.

27. González M, Martínez G, Calderón J, Villarroel L, Yuri F, Rojas C et al. Impact of delirium on short-term mortality in elderly inpatients: a prospective cohort study. Psychosomatics 2009; 50: 234-238.

28. Kiely DK, Jones RN, Bergmann MA, Marcantonio ER. Association between psychomotor activity delirium subtypes and mortality among newly admitted postacute facility patients. J Gerontol 2007; 62A:174-179.

29. Camus V, Gonthier R, Dubos G, Schwed P, Simeone I. Etiologic and outcome profiles in hypoactive and hyperactive subtypes of delirium. Journal Geriatr Psychiatry Neurol 2000; 13:38-42.

30. Santana-Santos F, Wahlund LO, Varli F, Tadeu Velasco I, Eriksdottier Jonhagen M. Incidence, clinical features and subtypes of delirium in elderly patients treated for hip fractures. Dement Geriatr Cogn Disord 2005; 20:231-237.


32. Meagher DJ, Leonard M, Donnelly S, Conroy M, Adamis D, Trzepacz PT. A longitudinal study of motor subtypes in delirium: frequency and stability during episodes. J Psychosom Res 2012; 72:236-241.

33. Liptzin B, Levkoff SE. An empirical study of delirium subtypes. Br J Psychiatry 1992; 161:843–845.

34. Leonard M, Godfrey A, Silberhorn M, Conroy M, Donnelly S, Meagher D et al. Motion analysis in delirium: a novel method of clarifying motoric subtypes. Neurocase 2007; 13:272-277.

35. Meagher D, Moran M, Raju B, Leonard M, Donnelly S, Saunders J et al. A new data-based motor subtype schema for delirium. J Neuropsychiatry Clin Neurosci. 2008; 20:185-193.

36. Meagher DJ, Leonard M, Donnelly S, Conroy M, Saunders J, Trzepacz PT. A comparison of neuropsychiatric and cognitive profiles in delirium, dementia, comorbid delirium-dementia and cognitively intact controls. J Neurol Neurosurg Psychiatry 2010; 81(8):876-881.

37. Herrmann LL, Goodwin GM, Ebmeier KP. The cognitive neuropsychology of depression in the elderly. Psychol Med 2007; 37(12):1693-1702.

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2Chapter

Anesthesia and postoperative delirium in elderly hip-surgery patients

Chantal J. SlorJos F.M. de Jonghe Ralph VreeswijkErwin GrootTjeerd v.d. PloegWillem A van GoolPiet EikelenboomMarc SnoeckBen SchmandKees J. Kalisvaart

J Am Geriatr Soc. 2011; 59(7):1313-1319

18

Chapter 2

ABSTrACTBackground: Anesthetic agents and several classes of medication may be risk factors for postoperative delirium. The aim of this study was to examine effects of general anesthesia on the risk of incident postoperative delirium in older hip-surgery patients.methods: Secondary analysis of haloperidol prophylaxis for delirium clinical trial data. Predefined risk factors for delirium were assessed prior to surgery. Primary outcome was postoperative delirium. Study outcome was compared across patient groups who received either general or regional anesthesia, and for individuals receiving various perioperative medications (benzodiazepines, anticholinergics, and opioids), using multivariable logistic regression after controlling for potential confounders. Subgroup analyses based on baseline cognitive impairment and delirium risk were also undertaken.results: A total of 60/526 patients (11.4%) had incident postoperative delirium, 337/526 (64.1%) received general anesthesia and 189/526 (35.9%) regional anesthesia. 18/189 (9.5%) general anesthesia patients developed postoperative delirium, vs. 42/337 (12.5%) regional anesthesia patients (OR=0.81, CI 0.43 – 1.52 adjusted P=.51). Results were stratified for baseline cognitive impairment, age, acute admission, perioperative medication and other delirium risk factors. Delirium was not independently associated with specific drugs nor the medication classes opioids, benzodiazepines and anticholinergics. Conclusion: This study found that general anesthesia has no distinct effect on incident postoperative delirium in geriatric hip-surgery patients. This also holds for patients suffering from cognitive impairment or who are otherwise at risk for postoperative delirium. Perioperative use of narcotics, benzodiazepines and anticholinergic agents was not associated with incident delirium in this cohort of elderly hip fracture patients.

19


2

InTroduCTIonDelirium is a serious, common postoperative complication in elderly patients, with occurrence rates as high as half of the patients.1,2 Postoperative delirium is associated with high mortality, cognitive deterioration and a high rate of institutionalization.3 Pathogenesis of delirium remains for the most part unexplained, although different risk factors have been identified.1,4 Potential risk factors for delirium after hip surgery include general anesthesia and perioperative medications used. Contrary to popular belief, there is little evidence that general anesthesia is associated with delirium after hip surgery.5,6 Most studies do not link general anesthesia with postoperative delirium.7-9 A recent structured clinical update by Bryson and Wyand included eight trials that evaluated the relationship between type of anesthesia and postoperative delirium.9 Seven trials found that general anesthesia did not increase the risk of postoperative delirium as compared to regional anesthesia. One trial (n=60) showed that patients who had received regional anesthesia had poorer immediate post-operative cognitive performance than patients who had received general anesthesia.10 However, these studies have not stratified patients according to low, intermediate or high risk for developing postoperative delirium. Moreover, the majority of trials did not use validated instruments for diagnosing delirium, included relatively small patient numbers, and used different diagnostic concepts. Few studies have examined the association between perioperative use of medications and postoperative delirium in geriatric hip-surgery patients. Benzodiazepines such as lorazepam, and opioids may increase the risk of postoperative delirium in ICU patients.11-16 ICU patients are often on mechanical ventilation. Sedation and prolonged intubation during mechanical ventilation are associated with negative outcomes and are potential risk factors for delirium.17 Therefore, these results cannot readily be generalized to hip-surgery patients. Though medications administered during surgery are potential precipitating or preventive factors for postoperative delirium, their effects on outcome have not previously been studied in detail. Different factors may underlie relationships between general anesthesia, anesthetics and delirium. Older patients are likely to be more sensitive to adverse side effects of certain anesthetics and analgesics compared to younger patient groups.18 Specific characteristics of anesthetic and analgesic drugs represent potential precipitating factors for postoperative delirium in geriatric patients. The increased sensitivity is thought to be causally related to the relative decrease in cholinergic activity that accompanies the physiologic changes of the body in normal aging. An imbalance in acetylcholine mediated neural systems has been associated with delirium.19 Though some progress has been made, the precise mechanisms of delirium are yet to be identified. This study examined the effect of general anesthesia on postoperative delirium in a large homogenous patient group. Study outcomes were also stratified for patients with

20

Chapter 2

delirium risk factors, examining risk of delirium associated with general anesthesia in hip-surgery patients with or without cognitive impairment. Effects of classes of medications on postoperative delirium were explored. Understanding the role of anesthetic technique and perioperative medications as risk factors for POD may further increase our knowledge of potential methods to prevent POD.

meThodSethical ConsiderationsThe study was undertaken in accordance with the Declaration of Helsinki and the guidelines on Good Clinical Practice. Approval of the regional research ethics committee was obtained. All patients or their relatives gave fully informed written consent.

Study design and objectivesStudy data on case mix variables were collected as part of a randomized, placebo-controlled, double-blind, clinical trial of low-dose haloperidol prophylaxis for post-operative delirium in elderly hip-surgery patients who were at intermediate or high risk for this complication. The study sample represents a prospective cohort study, which has been described previously.4,20 Hip-surgery patients (n=603) aged 70 and older were screened for risk factors for postoperative delirium in a randomized, double-blind, placebo-controlled clinical trial (RCT).20 A total of 430 patients at intermediate or high risk for delirium were randomized to pre-surgery prophylactic treatment with either haloperidol or placebo. Patients in the haloperidol group received a dose of 0.5 mg three times a day. Daily screening for postoperative delirium was carried out according to DSM IV and Confusion Assessment Method (CAM) criteria.21,22 The intervention showed no difference in the incidence of postoperative delirium between the haloperidol and placebo group. In addition to the predefined predictive risk factors cognitive impairment, visual impairment and severity of illness,1 other risk factors for delirium, particularly age and acute admission to hospital, were identified.4

In this study postoperative delirium was compared across patient groups with general versus regional anesthesia and across patients groups with or without specific perioperatively administered drugs grouped according to class. Data was collected prospectively, without knowledge of primary outcome for participants. We controlled for potential confounders of effects by examining baseline patient characteristics between patients with and without delirium as well as patients with general and regional anesthesia; baseline characteristics included demographics, admission type, well-known risk factors for delirium and perioperative medication. Data of haloperidol and placebo treated patients were pooled, and group assignment was analyzed as a potential confounder of results.

21


2

ParticipantsParticipants were recruited among patients admitted for hip surgery to a 915 bed teaching hospital in Alkmaar, The Netherlands. The study period was from August 2000 to August 2002. 603 patients aged 70 or over, admitted for either acute or elective hip surgery, were screened for inclusion in the study. Participants were classified at baseline as low, intermediate or high risk for delirium. This was done according to the presence of four predictive risk factors as described by Inouye et al.:1 cognitive impairment, visual impairment, index of dehydration and severity of illness. These factors were measured using the Mini Mental State Examination,23 the standardized Snellen test,24 ratio blood urea nitrogen (BUN) to creatinine and by the APACHE II score25 which was determined by chart review. A risk factor was present in each of the following situations: an MMSE score of <24 on a scale of 0 to 30, APACHE II score of >16 on a scale of 0 to 70, binocular near vision worse than 20/70 after correction (Snellen Test), and a ratio of blood urea nitrogen to creatinine ≥18. The presence of one or two risk factors was defined as ‘intermediate risk’ for delirium, while three or more was defined as ‘high risk’ for delirium.4

Exclusion criteria were: delirium at admission, inability to participate in interviews (profound dementia, language barrier, intubation, respiratory isolation, aphasia, coma or terminal illness), a delay of surgery of more than 72 hours after admission, use of cholinesterase inhibitors, parkinsonism, levodopa treatment, epilepsy or a prolonged QTc interval of 460 ms or higher for men and 470 ms or higher for women on their electrocardiogram. Figure 1 shows the flow chart of the patients participating in this study. A total of 526/603 (87.2%) patients had complete data on anesthesia type and anesthetics used. Patients with incomplete data more often had lower MMSE scores (P=.04), lower visual acuity scores (P=.048), were older (P=.004) and were more often acutely admitted (P=.004) compared to those with complete data. Incidence of delirium was not significantly different in patients with complete or incomplete data

meASuremenTS And ProCedureSMembers of the research team not involved in the clinical care of the patients carried out all assessments.25 The research team consisted of research nurses and experienced geriatricians, who were trained extensively and followed standard procedures. Data were collected on standardized patient record forms and thoroughly checked on errors and validity. Data on type of anesthesia and perioperatively used medication were independently retrieved from anesthetic records. All drugs administered as premedication, during surgery, and in the post anesthesia care unit (PACU) were recorded. Only usage or non-usage of medication was registered; administered dosages were not recorded.

22

Chapter 2

Registration of perioperative medication was carried out blinded to the outcome of the original study of Kalisvaart et al.20 The standard procedure following hip fracture was spinal anesthesia. Patients preferring otherwise received general anesthesia, unless there were contraindications.

figure 1. Flow Diagram of the Study.

Patients not meeting inclusion criteria (n=78)Refused to be screened/part (n=36)Discharged without surgery (n=13)Parkinsonism (n=6)On antipsychotic drugs (n=4)Not testable (n=8)Surgery before testing (n=6)Extreme liver failure (n=1)Delirium at admission (n=1)Missed by emergency department (n=3)

Low-risk patients (n=121)Refused to participate intaking medication (n=52)

Original studyPatients admitted

(n=681)

Eligible Patients(n=603)

n=430 randomizedn=173 not randomized

Files could not beretrieved (n=77)

Regional Anesthesia( n=337)

n=111 haldoln=134 placebo

n=92 not randomized

Present study (n=526)


n=153 not randomized General Anesthesia( n=189)


n=61 not randomized

outcomeThe primary outcome was postoperative delirium occurring within a period of 5 days postoperatively. Criteria for the diagnosis of the syndrome were based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)21 and the Confusion Assessment Method (CAM).22 To achieve the DSM-IV and CAM diagnoses, patients were assessed daily by means of the Mini Mental State Examination (MMSE), Digit Span test (assessment of attention, range 0 (no attention) to 42 (good attention) and the Delirium Rating Scale, revised version (DRS-R-98).26 A CAM score indicative of delirium was followed by a DSM-IV diagnosis made by the geriatrician.

23


2

Statistical AnalysisStatistical evaluations were performed with SPSS for Windows, version 14.0. Means or proportions were used to describe demographic and clinical characteristics of the study sample. Baseline characteristics were compared across patients with or without delirium using Chi-square, Fisher exact test or t-test. Baseline characteristics were also compared between patients with general and regional anesthesia, in order to explore differences in characteristics between both groups. Associations between delirium and anesthetic technique, and delirium and three medication classes, were examined using chi-square or Fisher exact test and by calculating odds ratios and confidence intervals. The three selected medication classes were benzodiazepines (diazepam, lorazepam, midazolam, oxazepam and temazepam), anticholinergic agents (atropine and ipratropium) and opioids (alfentanil, morphine, nalbuphine, piritramide and sufentanil). Subsequently, potential independent predictors of delirium were entered in logistic regression models (backward elimination, P<.10) to calculate adjusted odds ratios (ratio is the chance of developing postoperative delirium). Age and predefined risk factors APACHE II, MMSE and Snellen test were entered in the analysis as continuous variables, and type of admission, anesthetic technique and the three medication classes were entered as dichotomous variables. As a further stratification procedure associations between delirium and anesthetic technique were examined within each risk factor group (MMSE<24, APACHE>16, acute admission, visual acuity >20/70, dehydration, female and total number of risk factors present) separately. In an intermediate multivariate analysis we controlled for potential interaction effects of the intervention by including patients receiving treatment or placebo, and excluding haloperidol treated patients.

reSulTSPrimary outcomeA total of 18/60 (30%) delirium patients had general anesthesia, compared to 171/466 (36.7%) non-delirious patients, indicating no effect of type of anesthesia on primary outcome (OR=0.74, CI 0.41 – 1.33 P=.31). Based on an average 1.5 years age difference between the two groups, patients with regional anesthesia were at a slightly higher risk of delirium compared to those with general anesthesia as evidenced (Table 1). However, no effect of anesthesia type was found on study outcome after controlling for age differences, as well as after controlling for differences in perioperative medication. Both groups were similar on the distribution of other baseline delirium risk factors

24

Chapter 2

Table 1. Delirium Risk Factors between Anesthesia Groups.

Characteristic General Anesthesia

n=189

regional Anesthesia

n=337

or (95% CI) for developing

delirium

Age* 76.7 ± 5.5 78.2 ± 6.0 0.96 ( 0.93 – 0.99 )

Female° 148 (78.3) 262 (77.7) 1.03 ( 0.67 – 1.59 )

Mini-Mental State Examination score*¶ 25.4 ± 4.1 25.4 ± 3.9 1.01 ( 0.97 – 1.05 )

APACHE II score*§ 13.0 ± 3.0 13.0 ± 3.1 1.01 ( 0.95 – 1.07 )

Visual acuity*# 0.43 ± 0.16 0.41 ± 0.16 2.70 ( 0.86 – 8.43 )

Blood urea nitrogen/creatinine ratio*¥ 12.6 ± 4.0 12.8 ± 3.8 0.99 ( 0.94 – 1.03 )

Geriatric Depression Scale-15 score*† 1.2 ± 1.5 1.1 ± 1.5 1.06 ( 0.94 – 1.19 )

Barthel Index Score*¢ 18.6 ± 3.5 19.0 ± 2.8 0.96 ( 0.91 – 1.03 )

Acute admission (fracture)° 36 (19) 72 (21.4) 1.16 ( 0.74 – 1.81 )

Haloperidol prophylaxe° 71 (37.6) 111 (32.9) 1.23 ( 0.85 – 1.78 )

Predefined risk factors° (dichotomous values):

Mini-Mental State Examination score <24 40 (21.2) 84 (24.9) 0.81 ( 0.53 – 1.24 )

APACHE II score >16 20 (10.6) 53 (15.7) 0.63 ( 0.37 – 1.10 )

Vision score worse than 20/70 19 (10.1) 44 (13.1) 0.74 ( 0.42 – 1.32 )

Age ≥80 55 (29.1) 121 (35.9) 0.73 ( 0.50 – 1.08 )

Blood urea nitrogen/creatinine ratio ≥18 130 (68.8) 223 (66.2) 1.13 ( 0.77 – 1.65 )

Data are presented as mean ± SD or n (%) unless otherwise indicated.*=continous variables, °=dichotomous variables.OR=odds Ratio, the chance of developing postoperative delirium, CI=confidence intervalAPACHE II=Acute Physiological and Chronic Health Evaluation II ¶ Range 0 (severe cognitive impairment) to 30 (no cognitive impairment).§ Range 0 (no acute health problems) to 70 (severe acute health problems).# Range 20/20 (no visual impairment) to 20/800 (severe visual impairment).¥ Ratio ≥18 indicating dehydration.† Range 0 (depression not likely) to 15 (depression very likely).¢ Range 0 (severe disability) to 20 (no disability).

Anesthesia was not a precipitating event in at risk patients, as evidenced by no increased risk of postoperative delirium after general anesthesia in cognitively impaired patients, nor across patients at low, intermediate and high risk of delirium (Table 2).

Outcome and agents used perioperativelyPooled analysis according to medication class shows that patients without postoperative delirium more often received a benzodiazepine (394/466, 84.5%) compared to patients with delirium (36/60, 60%) (P<.001). However, controlling for predefined risk factors indicated that the use of benzodiazepine was not an independent predictor of primary outcome (OR=0.73, CI 0.35 – 1.51 P=.39). A total of 46/60 (76.7%) delirious patients received an opioid, versus 373/466 (80%) non-delirious patients (P=.54) and 8/60 (13.3%)

25


2

delirious patients received an anticholinergic agent, versus 38/466 (8.2%) non-delirious patients (P=.18) A total of 344/526 (65.4%) patients received no treatment or placebo. In the intermediate analysis anesthesia technique was not independently associated with postoperative delirium (Adjusted OR = 0.53, CI 0.21 – 1.31 , P=.0.16).

Table 2. Interaction between Risk Factors and Anesthetic Technique.

GA and delirium/GA

rA and delirium/rA

or (95% CI) for developing delirium

risk factor

MMSE <24 8/40 (20%) 29/84 (34.5%) 0.47 ( 0.19 – 1.16 )

APACHE >16 6/20 (30%) 14/53 (26.4%) 1.19 ( 0.38 – 3.71 )

Visual acuity worse than 20/70 4/19 (21.1%) 8/44 (18.2%) 1.20 ( 0.31 – 4.60 )

Dehydration 13/130 (10%) 28/223 (12.6%) 0.77 ( 0.39 – 1.55 )

Age ≥80 7/55 (12.7%) 26/121 (21.5%) 0.53 ( 0.22 – 1.32 )

Acute Admission 11/36 (30.6%) 19/72 (26.4%) 1.23 ( 0.51 – 2.96 )

Female 11/134 (8.2%) 16/216 (7.4%) 1.12 ( 0.50 – 2.49 )

Number risk factors 1

0 2/41 (4.9%) 3/74 (4.1%) 1.21 ( 0.19 – 7.58 )

1 6/103 (5.8%) 14/164 (8.5%) 0.66 ( 0.25 – 1.78 )

2 6/33 (18.2%) 13/65 (20%) 0.89 ( 0.30 – 2.60 )

3 3/8 (37.5%) 9/26 (34.6%) 1.13 ( 0.22 – 5.86 )

4 1/4 (25%) 3/8 (37.5%) 0.56 ( 0.04 – 8.09 )

Data are presented as n (%) within each group unless otherwise indicated.

n/n=people with delirium and risk factor within anesthesia technique group/total number of people with risk factor within anesthesia technique group

POD=postoperative delirium, GA=general anesthesia, RA=regional anesthesia1 Inouye SK, Viscoli CM, Horwitz RI, Hurst LD, Tinetti ME. A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med 1993; 119; 474-481.

dISCuSSIon This study examined the relationship between postoperative delirium, anesthesia and perioperative medication exposure. The risk of postoperative delirium was not increased in general anesthesia patients compared to patients receiving regional anesthesia. Moreover, the risk of delirium associated with general anesthesia was not increased in patients with baseline cognitive impairment, nor was it increased after stratification for other baseline delirium risk factors. The use of narcotics, benzodiazepines and anticholinergic agents was not independently associated with delirium. Strengths of this

26

Chapter 2

study are the large sample size and the relatively homogeneous study population, which included patients who were or were not at risk of delirium; the use of standardized and valid methods for diagnosing delirium; and pre-surgery assessment of validated delirium risk factors. The absence of a distinct association between general anesthesia and delirium is an important finding. In this study, 9.5% of patients with general anesthesia had delirium compared to the overall figure of 11.4%. In agreement with the overall trend, cognitively impaired patients were not at an increased risk of delirium after general anesthesia compared to regional anesthesia. In contrast with widespread popular belief, general anesthesia seems to be safe when it comes to the risk of delirium, even in elderly hip-surgery patients who are at risk of developing this serious complication. Our findings with respect to oucome following general anesthesia are consistent with previous reports comparing delirium risk depending on anesthesia type.7-9 Papaioannou et al.7 found no association between postoperative delirium and general anesthesia in patients (n= 47) undergoing different classes of surgery. In a randomized trial by Williams-Russo et al.,8 patients (n=262) older than 40 years undergoing knee-replacement surgery were assigned to receive epidural or general anesthesia, and patients in the latter group were not more likely to suffer from postoperative delirium. However, trials included relatively small patient groups or used different classes of surgery and none stratified study outcomes for patients with risk factors for delirium, particularly cognitive impairment. Studies examining effects of peri-operative drugs on postoperative delirium in hip-surgery patients are lacking. Exposure to benzodiazepine and opioid medication has been associated with increased delirium risk27 but these findings must be interpreted with caution because of wide confidence intervals and different study populations. For the most part, there still is insufficient information on the pathophysiology of postoperative delirium. Impaired cholinergic function has been suggested as the common final pathway leading to delirium. We did find a higher percentage of patients receiving anticholinergics in the delirium group compared to non-delirium patients. However, this did not reach significance which might be explained by the small sample. Although our results are consistent with other studies, we used a particularly rigorous approach to explore short-term outcomes of anesthesia. We clinically assessed patients on admission prior to surgery and included a large number of patients in one well-defined class of surgery, including many who were not at risk for delirium. Furthermore, in our study the diagnosis of postoperative delirium was based on clinical patient interviews and DSM IV criteria, and we used validated diagnostic instruments and delirium rating scales. By doing so, we were able to examine both the effects of anesthesia type, medication, and baseline risk factors on delirium in a single multivariate analysis. This study has a number of noteworthy limitations including study power and the relevance of these results to the practice of anesthesia in patients prone to delirium. This

27


2

was a single site study and involved a secondary analysis, as part of a randomized trial not specifically designed to examine the relationship between anesthesia and delirium risk. As such, anesthetic technique was not standardized, Moreover, patients receiving regional anesthesia were older than the patients receiving general anesthesia, but age effects were controlled for in multivariate analysis. Differences in prescribed perioperative drugs between anesthesia groups were also examined. Controlling for medication effects did not change the effect of anesthesia technique on primary outcome. Both anesthesia groups were comparable with regard to other delirium risk factors. An additional possibility is that patients with intact cognitive function may have been more likely to select regional rather than general anesthesia but MMSE scores did not differ between the regional and anesthesia group, moreover we controlled for the potential differences, also MMSE score, in our primary and secondary analysis. We therefore believe that these findings do not reflect a referral bias to either general or regional anesthesia. This study was underpowered to examine effects of specific medications. Analysis was restricted to three well known drug classes. Other classes of medication, particularly sedative-hypnotics and β-blockers may be associated with postoperative delirium.28,29 Postoperative medication use and many other in-hospital events can be associated with postoperative delirium. A recent study found evidence that limiting sedation depth during spinal anesthesia decreases the prevalence of delirium.30 This indicates that other in-surgery factors might be associated with postoperative delirium. This exploratory aspect of the study can be useful for generating hypotheses about delirium associated with peri-operative agents. More precise documentation of drug dosage is required to estimate the precise anticholinergic activity of each drug, as this may have a mediating effect. We did not examine drug dosage for logistic reasons, but did include an examination of three classes of medication in this large patient sample. To summarize, because of limited study power, conclusions on the potential effects of perioperative agents on study outcome are preliminary, and the inclusion of RCT patients does not invalidate study results and conclusions. This study suggests that the risk of developing delirium in patients receiving general anesthesia for hip-surgery may be overstated. The general understanding in the medical field s that regional anesthesia is preferred over general anesthesia because of perceived delirium risk, especially in patients already vulnerable to developing postoperative delirium. Contrary to this view, our study adds to the growing body of evidence that type of anesthesia does not increase delirium risk, even among a patient population at relatively high risk for postoperative delirium. It also highlights the relative importance of predisposing factors over precipitating events in delirium pathogenesis whereby a number of well recognised risk factors are most relevant to the risk of developing delirium and these may outweigh the impact of peri-operative events.

28

Chapter 2

referenCeS

1. Inouye SK, Viscoli CM, Horwitz RI, Hurst LD, Tinetti ME. A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med 1993; 119:474-481.

2. Dasgupta M., Dumbrell AC. Preoperative risk assessment for delirium after noncardiac surgery. J Am Geriatr Soc 2006; 54:1578–1589.


4. Kalisvaart KJ, Vreeswijk R, de Jonghe JFM, van der Ploeg T, van Gool WA, Eikelenboom P. Risk factors and prediction of postoperative delirium in elderly hip-surgery patients: implementation and validation of a medical risk factor model. J Am Geriatr Soc 2006; 54:817-822.

5. Edelstein DM, Aharonoff GB, Karp A, Capla EL, Zuckerman JD, Koval KJ. Effect of postoperative delirium on outcome after hip fracture. Clin Orthop Relat Res 2004; 195-200.

6. Gustafson Y et al. Acute confusional states in elderly patients treated for femoral neck fracture. J Am Geriatr Soc 1988;36:525-530.

7. Papaioannou A, Fraidakis O, Michaloudis D, Balalis C, Askitopoulou H. The impact of the type of anaesthesia on cognitive status and delirium during the first postoperative days in elderly patients. Eur J Anaesthesiol 2005; 22:492-499.

8. Williams-Russo P, Sharrock NE, Mattis S, Szatrowski TP, Charlson ME. Cognitive effects after epidural vs general anesthesia in older adults. JAMA 1995; 274:44-50.

9. Bryson GL, Wyand A. Evidence-based clinical update: General anesthesia and the risk of delirium and postoperative cognitive dysfunction. Can J Anaesth 2006;53:669-677.

10. Crul BJ, Hulstijn W, Burger IC. Influence of the type of anaesthesia on post-operative subjective physical well-being and mental function in elderly patients. Acta Anaesthesiol Scand 1992; 36:615-20.

11. Marcantonio ER, Juarez G, Goldman L, Mangione CM, Ludwig LE, Lind L, Katz N, Cook EF, Orav EJ, Lee TH. The relationship of postoperative delirium with psychoactive medications. J Am Geriatr Soc 1994; 19:1518-1522.

12. Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P, Margolis BD, Byrne DW, Ely EW, Rocha MG. Dexemetomidine vs midazolam for sedation of critically ill patients. JAMA 2009; 301:489-499.

13. Pisani MA, Murphy TE, Araujo KLB, Slattum P, Ness van PH, Inouye SK. Benzodiazepine and opioids use and the duration of intensive care unit delirium in an older population. Crit Care Med 2009; 37:1-7.

14. Chang Y, Tsai Y, Lin P, Chen M, Liu C. Prevalence and risk factors for post-operative delirium in a cardiovascular intensive care unit. Am J Crit Care 2008; 17:567-557.

15. Pandharipande P, Shintani A, Peterson J, Pun BT, Wilkinson GR, Dittus RS, Bernard, GR, Ely EW. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 2006; 104:21-26.

16. Pandharipande PP, Cotton BA, Shintani A, Thompson J, Pun BT, Morris JA, Dittus R, Ely EW. Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients. J Trauma 2008; 65:34-41.

17. Detroyer E, Dobbels F, Verfaillie E, Meyfroidt G, Sergeant P, Milisen K. Is preoperative anxiety and depression associated with onset of delirium after cardiac surgery in older patients? A prospective cohort study. J Am Geriatr Soc 2008; 56:2278-2284.

18. Cook DJ, Rooke GA. Priorities in perioperative geriatrics. Anesth Analg 2003; 96:1823-1836.

19. Cancelli I, Beltrame M, Gigli GL, Valente M.Drugs with anticholinergic properties: cognitive and neuropsychiatric side-effects in elderly patients. Neurol Sci 2009; 30:87-92.

29


2

20. Kalisvaart KJ, de Jonghe JFM, Bogaards MJ, Vreeswijk R, Egberts TCG, Burger BJ, Eikelenboom P, van Gool WA. Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: A randomized placebo-controlled study. J Am Geriatr Soc 2005; 53:1658-1666.

21. American Psychiatric Association: DSM-IV-TR. Washington DC: American Psychiatric Association, 2000.

22. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: The confusion assessment method. A new method for detection of delirium. Ann Intern Med 1990; 113:941-948.

23. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189-198.

24. Hetherington R. The Snellen chart as a test of visual acuity. Psychol Forsch 1954; 24:349-357.

25. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13:818-829.

26. Trzepacz PT, Baker RW, Greenhouse J. A symptom rating scale for delirium. Psychiatry Res 1988; 23:89-97.

27. Clegg A, Young YB. Which medications to avoid in people at risk of delirium: a systematic review. Age Ageing 2010; 0:1-7.

28. Katznelson R, Djaiani G, Mitsakakis N, Lindsay TF, Tait G, Friedman Z, Wasowicz M, Beattie WS. Delirium following vascular surgery: increased incidence with preoperative beta-blocker administration. Can J Anaesth. 2009; 56:793-801.

29. Hall JB, Schweickert W, Kress JP. Role of analgesics, sedatives, neuromuscular blockers, and delirium.Crit. Care Med 2009; 37:416-21.

30. Sieber FE, Zakriya KJ, Gottschalk A, Blute M, Lee HB, Rosenberg PB, Mears SC. Sedation depth during spinal anesthesia and the development of postoperative delirium in elderly patients undergoing hip fracture repair. Mayo Clin Proc. 2010; 85:18-26.

30

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3Chapter

The trajectory of CRP levels in elderly hip fracture patients with postoperative delirium

Chantal J. SlorJoost WitloxRené W.M.M. JansenAlexander P.J. HoudijkWillem A van GoolJos F.M. de JonghePiet Eikelenboom

Manuscript in preparation

34

Chapter 3

ABSTrACTBackground: Many important precipitating risk factors for delirium such as infection and surgery are accompanied by an inflammatory response. Inflammatory mediators themselves can affect neuronal and synaptic function thereby inducing delirium in susceptible individuals. Less is known about the time course of these inflammatory markers and their role in the development and outcomes of delirium.methods: A prospective cohort study of elderly patients undergoing hip fracture surgery. Baseline characteristics were assessed preoperatively. During hospital admission presence of delirium was assessed daily according to CAM criteria. This study compared C-reactive protein (CRP) levels across time (baseline, postoperative day 1 until postoperative day 5) between people with and without postoperative delirium. results: 41 out of 121 patients developed postoperative delirium after hip surgery. Longitudinal analysis using the Generalised Estimating Equations method (GEE) identified that a higher CRP level was associated with postoperative delirium. CRP levels were higher from postoperative day 2 through postoperative day 5 in patients with postoperative delirium. No significant differences in CRP levels (baseline, postoperative day 1 through 5) were found between patients with short (1-2 days) and more prolonged delirium group (≥3 days). Also no significant correlation was found between the highest CRP level and pre-fracture cognitive or illness severity.Conclusion: The findings in this study suggest that delirium is associated with an increased inflammatory response. The results suggest that CRP is not an early diagnostic marker of delirium, however that this marker does increase after the appearance of delirium and remains elevated throughout the delirium episode.

35


3

InTroduCTIonMany important precipitating risk factors for delirium such as infection and surgery are accompanied by an inflammatory response. Peripherally produced inflammatory mediators can activate microglia cells in the brain which release a range of inflammatory mediators that can affect neuronal and synaptic function thereby inducing delirium in susceptible individuals.1,2

Cognitive impairment and advanced age are well known predisposing risk factors for delirium.3 Aging and neurodegenerative disease are accompanied by impaired immune function resulting in an increased neuro-inflammatory state under normal conditions1 which can develop into an exaggerated inflammatory response in reaction to systemic inflammation.4 This pro-inflammatory state may explain why older and cognitively impaired individuals are particularly susceptible to delirium in the presence of precipitating factors that elicit an inflammatory response. Cross-sectional studies have linked delirium to elevated levels of proinflammatory cytokines or C-reactive protein (CRP).5-7 However, not all studies found an association between delirium and (preoperative) levels of CRP which is induced by cytokines such as interleukin 6 (IL-6).8,9 In keeping with the senescence of the immune system, it can be hypothesised that patients with delirium show a different trajectory of CRP levels over time. These differences may also underpin the inconsistent findings of cross-sectional studies. Studies in orthopaedic surgery patients have found an association between delirium and increased levels of CRP.10-12

The aim of the present study was to examine the time course of CRP levels over multiple days, in elderly hip fracture patients with and without postoperative delirium. Secondly, we examined the association between CRP and delirium severity, cognitive impairment, illness severity and delirium duration.

meThodobjectives and study designTo describe the time course of CRP levels over multiple days in patients with and without postoperative delirium. CRP was determined at baseline and from postoperative day 1 through 5. Potential risk factors for delirium were assessed preoperatively. Presence of delirium was assessed daily from time of admission until the fifth postoperative day. The time course of CRP levels and baseline risk factors were compared across patients who did or did not develop delirium postoperatively. Delirium was diagnosed according to the criteria of the Confusion Assessment Method (CAM) criteria which consists of an acute onset and fluctuating course of symptoms, inattention, and either disorganized thinking and/or altered level of consciousness.13 The CAM algorithm was rated daily on the basis of an interview with the patient, brief cognitive assessment with the MMSE and the expanded digit span test, discussion with treating

36

Chapter 3

hospital staff, and screening of medical and nursing records for signs of delirium.14,15 The CAM remains the most widely used screening test, has good psychometrics, has been validated in several languages and replicated in multiple settings. A diagnosis of delirium was always confirmed by a psychiatrist or geriatrician. Baseline assessments were completed within 12 hours of admission and before surgery. This consisted of patient and proxy interviews, assessment of delirium, and inspection of all available medical records. We documented the following demographic variables: age, gender, educational level and living situation. To assess mental status we used the Mini Mental State Examination (MMSE) as a measure of baseline cognitive functioning on a scale of 0 (poor) to 30 (good) with scores lower than 24 indicating cognitive impairment.14 The 16 item Informant Questionnaire on Cognitive Decline in the Elderly Short-Form (IQCODE-N) was used as an estimate of pre-fracture cognitive decline and was scored by a close relative or caregiver on a scale of 16 (improvement) to 70 (decline).16 A score higher than 57 (i.e. mean item score of 3.6) indicates cognitive decline.17 Depressive symptoms were assessed with the Geriatric Depression Scale 15 (GDS-15) a 15 item self-rating scale for depression with higher scores indicating depression.18 Burden of illness included the number and type of medical co-morbidities and medications before hospital admission. We also reviewed the medical record to document the American Society of Anesthesiologists (ASA) physical status classification system (range of 1 (normal health patient) to 5 (moribund patient)) and the Acute Physiology Age and Chronic Health Examination (APACHE II) score (range of 0 (no acute health problems) to 70 (severe acute health problems)).19,20 Functional status comprised pre-fracture living arrangement, visual acuity, activities of daily living (ADL) and instrumental activities of daily living (IADL). Visual acuity was assessed with the standardized Snellen test for visual impairment and visual impairment was defined as binocular near vision, after correction, worse than 20/70.21 Pre-fracture ADL functioning was determined with the Barthel Index (BI) which is scored by a close relative or caregiver on a scale from 0 (dependence) to 20 (independence).22 IADL was also assessed by a close relative or caregiver on the Lawton IADL scale with a range of 8 (no disability) to 31 (severe disability).23

For determination of concentrations of CRP blood samples were drawn into plain tubes (Vacutainer SST, Becton Dickinson, Plymouth, UK). Blood samples were centrifuged at 2500g within 4 hours after collection in order to separate serum from the cellular fraction. CRP concentrations were assayed with C-reactive Protein Reagent (Beckman Coulter Inc, Fullerton, California, USA) on a Synchron DxC 800 analyzer (Beckman Coulter Inc, Fullerton, California, USA). Normal reference values were assessed as CRP <5 mg/L. Also, we compared the CRP levels of incident delirium cases experiencing short delirium episodes (1 or 2 days) with patients who experienced more prolonged delirium (≥3 days). The primary outcome was duration of delirium. The highly fluctuating nature of delirium makes reliably defining recovery difficult, such that a standard definition

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is lacking. We followed a conservative approach to define recovery of delirium as two subsequent days without delirium according to the Confusion Assessment Method (CAM).13 Duration of delirium was the number of days from the first delirium day until recovery (2 consecutive days of no delirium according to CAM criteria). A recent review of treatment for delirium which considered available evidence for defining ‘recovery’ concluded that because of the fluctuating course of delirium, recovery is best defined conservatively and in the manner used herein.24 Patients with no data available on the two days after the last delirious day could not be allocated to one of the duration groups. In this instance we could not define the exact count of delirious days according to the definition used for recovery. A single day without delirium but followed by further delirium was considered part of the delirium episode. Finally, we examine the association between CRP levels and delirium severity pre fracture cognitive decline and illness severity. Delirium severity was measured using the Revised Delirium Rating Scale 98 (DRS-R98), a 16-item rating scale comprised of thirteen severity items and 3 diagnostic items. The item-scores range of 0 (no severity) to 3 (maximum severity). Possible total severity scores range of 0 (no severity) to 39 (maximum severity).25 The IQCODE-N was used as an estimate of pre-fracture cognitive decline and the Acute Physiology Age and Chronic Health Examination (APACHE II) was used as a measure of illness severity.16,20

Statistical analysisStatistical calculations were performed using SPSS for Windows, version 14 (SPSS; Inc. Chicago, Il). Categorical variables were analysed using Chi-Square or Fisher Exact tests. Continuous variables were tested with Mann-Whitney-U tests or t-tests depending on the sample size and distribution and skewness of the data. The assumption of a normal distribution of data was tested with the Kolmogrov-Smirnov test. We used Generalized Estimating Equations model analyses to examine the association between delirium and CRP. The GEE method takes into account the fact that observations within a subject are correlated and estimates the population average across time. We controlled for the effect of age, gender, treatment (taurine or placebo), IQCODE-N, Barthel Index and APACHE-II score in the initial model. Thereafter, we dropped non-significant variables in order to find the most parsimonious model. We also examined each day separately with a Mann-Whitney analysis for the association between delirium and CRP, and to give a graphic representation of the longitudinal trajectory of the CRP and level in each group (delirium and non-delirium). Linear mixed models were used to examine the association between DRS-R98 severity scores and CRP levels, also in two separate analyses. We controlled for the same variables as in the GEE, and sought the most parsimonious model. The association between the highest CRP and IQCODE-N and APACHE-II scores were investigated with the Pearson product-moment correlation.

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reSulTSA flowchart of the patient selection process is shown in Figure 1. A total of 121 were available for analysis, 41/121 (34%) patients developed postoperative delirium. Characteristics of the patients who developed delirium postoperatively and patients who did not are described in Table 1. Patients who developed postoperative delirium had more evidence of prefracture cognitive decline (IQCODE-N continous, P=<.001; dichotomous, P=<.001) and cognitive impairment at baseline (MMSE, continous, P=.01; dichotomous, P=.01) compared to patients who did not.


Number in trial n=122

- No postoperative delirium (n=80) - Postoperative delirium (n=41)

Number with available CRP samples(n=118)

Total number of patients with hip-fracture

n=257

Number excluded n=1- No postoperative delirium assessment n=1

Excluded (n=135)- Not able (profound dementia, aphasia, coma) n=64

- Not willing (n=20)- Renal failure (n=20)- No operation or transfer to other hospital (n=13)

- No acute trauma, total hip prothesis, pathological fracture (n=11)

- Missed (n=4)- Language barrier (n=3)

The Generalized Estimating Equations model with data on CRP levels (baseline, and postoperative day 1 through postoperative day 5) was performed with postoperative delirium as a dependent variable, in the initial model we controlled for gender, age, ADL functioning, pre-existing cognitive impairment, physical status and treatment (placebo or taurine). The final most parsimonious GEE model is shown in Table 2 (637 observations, 114 patients included). Delirium was associated with a higher CRP level. The trajectory of the CRP levels is shown in Figure 2. Compared with non-delirious controls patients that developed delirium after surgery had significantly higher CRP levels from postoperative day 2 through postoperative day 5 (Table 3). Median levels and inter quartile range (IQR) of CRP for the delirium and no-delirium group are also shown in Table 3.

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Table 1. Baseline Characteristics of Patients With and Without Postoperative Delirium.

delirium n=41 (34%)

no deliriumn= 80 (66%)

P-Value

Age (years) 85.4 ± 5.6 83.6 ± 5.2 .07

Female gender n/N (%) 29/41 (71) 59/80 (74) .72

Living independently, n/N (%) 31/41 (76) 70/80 (88) .10

Low educational level, n/N (% ) 17/37 (46) 26/69 (38) .41

Visual impairment*, n/N (%) 3/35 (9) 4/78 (5) .68

APACHE II† score 13.3 ± 2.1 13.0 ± 1.8 .33

ASA‡ group I; II; III, n/N 8/40; 18/40; 14/40 25/80; 40/80; 15/80 .12

Number of co-morbid diseases 2.2 ± 1.4 2.3 ± 1.7 .98

Number of medications at home 5.1 ± 3.3 4.7 ± 4.0 .58

IQCODE-N§ score 3.8 ± 0.5 3.4 ± 0.5 <.001

IQCODE-N§ score >3.6, n/N 24/38 (63) 14/76 (18) <.001

MMSE|| score 22.9 ± 3.7 24.7 ± 3.5 .01

MMSE|| score <24, n/N 21/37 (57) 23/76 (30) .01

GDS¶ score 2.7 ± 1.9 2.6 ± 2.6 .92

BI# score 16.3 ± 3.1 17.7 ± 3.4 .05

Lawton IADL** score 14.9 ± 5.9 13.0 ± 5.9 .12

Values are expressed as means ± SD or n/N is number with characteristic/total number with available data, (%) is percentage.Visual impairment measured with the standardized Snellen test for visual impairment and defined as binocular near vision worse than 20/70 after correction. APACHE II is Acute Physiological and Chronic Health Evaluation II, range 0 (no acute health problems) to 70 (severe acute health problems).ASA is American Society of Anesthesiologists physical status classification system, range 1 (normal health patient) to 5 (moribund patient).IQCODE-N is Informant Questionnaire on Cognitive Decline in the Elderly - Short Form, range 16 (cognitive improvement) to 80 (severe cognitive decline), mean score >3,6 indicates cognitive decline. MMSE is Mini Mental State Examination, range 0 (severe cognitive impairment) to 30 (no cognitive impairment), score <24 indicates cognitive impairment.GDS is Geriatric Depression Scale, range 0 (depression not likely) to 15 (depression very likely). BI is Barthel Index, range 0 (severe disability) to 20 (no disability).Lawton IADL is Lawton Instrumental Activities of Daily Living scale, range 8 (no disability) to 31 (severe disability).

Mixed model analysis with data across days (baseline, postoperative day 1 through 5) found that a higher DRS-R98 severity scores were associated with a higher CRP levels. In the final model pre-existing cognitive impairment and ADL functioning also remained associated with the DRS-R98 severity score (Table 4). We also repeated the model in the delirious sample only, CRP and DRS-R98 severity score remained associated. No significant differences in CRP levels (baseline, postoperative day 1 through 5) were found between the short (1-2 days) and more prolonged delirium group ( ≥3 days) on each examined day.

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Also, no significant correlation was found between the highest CRP level and pre-fracture cognitive decline (n=38, r=.20, P=.23) or illness severity (n=39, r=-.09, P=.60).

figure 2. Trajectory of CRP Levels between Patients with and without Postoperative Delirium.

Table 2. Generalised Equation Estimation (GEE) model CRP level and Postoperative Delirium.

β Se df Wald x2 95% CI P-value

IQCODE-N score -1.6 0.5 1 -0.7 -2.5 – -0.7 <.001

CRP level -2.0E-7 9.5E-8 1 4.3 -3.8E-7 – -1.1E-8 .04

Intercept 6.4 1.6 1 15.3 3.2 – 9.6 <.001

SE=Standard ErrorC.I.=Confidence Interval E with a minus sign signals the number of places the decimal point has to be moved to the left.IQCODE- =Informant Questionnaire on Cognitive Decline in the Elderly – Short Form, range 16 (cognitive improvement) to 80 (severe cognitive decline), mean score.

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Table 3. Median and IQR of CRP within the Postoperative Delirium Group and Control Group.

Postoperative delirium

CrP baseline

CrP day 1

CrP day 2

CrP day 3

CrP day 4

CrP day 5

Yes N 41 39 40 36 37 34

Median 4 94.0 178.5 170 133 85

Percentiles 25 2 61 150 136 90 63

50 4 94 179 170 133 85

75 11 148 231 212 189 120

No N 77 76 73 71 71 69

Median 3 80.5 141 133 102 62

Percentiles 25 1 48 86 85 60 35

50 3 81 141 133 102 62

75 7.5 145 191 185 141 93

Yes vs. No P-value .33 .42 .001 .01 .02 .01

Days=postoperative days

Table 4. Linear Mixed Model CRP level and DRS-R98 severity score.

estimate Se df t 95% CI P-value

IQCODE-N score 4.1 0.8 171 5.4 2.6 – 5.7 <.001

CRP level 0.02 0.003 587 6.6 0.01 – 0.02 <.001

BI score -0.4 0.1 169 -3.5 -0.6 – -0.2 .001

Intercept -2.4 4.1 170 -0.6 -10.5 – 5.7 0.6

SE=Standard ErrorC.I.=Confidence Interval E with a minus sign signals the number of places the decimal point has to be moved to the left.IQCODE-N=Informant Questionnaire on Cognitive Decline in the Elderly - Short Form, range 16 (cognitive improvement) to 80 (severe cognitive decline), mean score.BI=Barthel Index, range 0 (severe disability) to 20 (no disability).

dISCuSSIonThis study examined the time course of CRP levels over multiple days and the association between postoperative delirium and CRP in an elderly hip surgery population. In addition, the association between CRP levels and delirium severity, cognitive impairment, illness severity and delirium duration were investigated. We found that postoperative delirium and delirium severity was associated with higher CRP levels. CRP levels increased on postoperative day 2 and also remained higher in postoperative delirium patients. No significant differences in CRP levels were found between short and more prolonged

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delirium, nor between the highest CRP level and pre-fracture cognitive decline or illness severity. The main finding of this study is an increased level of inflammatory markers after surgery with a higher level of these markers associated with postoperative delirium. This finding is consistent with other studies that identified an association between an increased level of CRP and delirium in hip surgery patients.10-12 One study examined CRP levels in elderly patients undergoing elective arthroplasty.11 They used a cut-off score of 5 ng/mL or greater for CRP, and measured the CRP level preoperatively and on the first postoperative day. No significant difference was found in the proportion of patients with this level of CRP in the group with and without postoperative delirium. This is consistent with our finding that CRP levels were higher starting from postoperative day 2 in patients who developed postoperative delirium. However, Cerejeira et al. found that patients who developed postoperative delirium had a greater production of CRP and proinflammatory to anti-inflammatory ratio after surgery.11 Another study conducted multiple measurements of the level of CRP postoperatively, although not on a daily basis.10 These authors described higher levels of CRP both 24 hours and 2-3 days after surgery in elderly patients who had undergone hip joint surgery. Also, those who developed delirium had higher APACHE II scores compared to those who did not develop delirium. However, comparison of CRP levels between both groups were only performed with univariate analysis. A third study also found an association between CRP levels and delirium in elderly hip fracture patients.12 Postoperatively, CRP levels were higher in patients with an impaired mental status (MMSE score ≤23) compared to cognitively normal patients. A separate comparison of CRP levels between the delirium group and patients with no complications showed that CRP kinetics curves were higher for those patients who developed delirium. However, it remains unclear which information was used for the CAM algorithm and also if the delirium assessments were conducted concurrently with the sampling of CRP levels. The findings in the present study are consistent with these studies, CRP levels increase after surgery and remained at a higher level compared to the preoperative level for an extended time. In contrast to previous research we used daily CRP and delirium assessments and also multivariate, longitudinal analysis to control for important factors such as physical and mental status. In our study we did not find a difference in preoperative CRP levels between patients who developed delirium or not after surgery. Most other studies, with a single exception,7 did not find a difference in CRP levels before surgery between patients who did and did not develop delirium thereafter.9,12, 26

Previous studies have suggested that anesthetic technique and other perioperative factors are not associated with postoperative delirium in orthopaedic patients.11,27 The present findings suggest that the stress response associated with the surgical procedure may increase the risk of delirium. Surgical trauma has been associated with the activation

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of the peripheral innate immune system, cytokine release and impairment of cognitive function.28-32 Several animal studies have shown that activation of the immune system, such as the stress response to surgery, results in an exaggerated inflammatory response in the hippocampus in aged organisms, which is followed by performance deficits in hippocampal-mediated cognitive tests in aged, rather than younger, animal compared to younger animals.28, 33-37 It has also been suggested that systemic inflammation activates vascular endothelial cells and perivascular cells in the human brain.38 A postmortem study in human brain tissue found that systemic inflammation was associated with higher intensity of CRP in the vasculature. The level of CRP in patients who developed delirium remained higher during the following days compared to control patients in our study. Prolonged increase of CRP levels may be associated with cognitive impairment, which in turn may reflect cerebral vascular damage and white matter pathology.39 In the aged organism, which is more vulnerable to impaired cognitive function after a peripheral immune challenge, this neuroinflammatory response can also be more persistent.35 It has been suggested that CRP might serve as a marker to assist early diagnosis of delirium, assuming that levels of CRP might already increase in the prodromal phase.10 A study with elderly hip joint surgery patients stated that CRP levels within 24 hours after surgery and within 48-72 hours after surgery showed statistically significant differences in the delirium group.10 However compared to the non delirium group they found no difference in CRP level before surgery, at this time no patients were delirious since they excluded preoperative delirium. It is also difficult to disentangle the relevance of CRP levels to the prodromal phase and full delirium, since all were in the same group for analysis. Moreover, the level of CRP was not measured on the same day of assessment as the K-DRS-98 in all subjects. Our study results suggest that CRP is not an early marker for diagnosis of delirium. We found no differences in preoperative levels between the delirium and the non-delirium group. The difference in levels of CRP was evident from postoperative day 2 and onwards. Since the majority of our patients developed delirium on the first postoperative day this is not supportive of CRP as an early marker for diagnosis of delirium. Conversely, cytokine levels might be considered as a possible early marker.5,6 It has been shown that IL-6 levels are already higher directly after surgery and also 24 hours after surgery in patients with postoperative confusion compared to patients without postoperative confusion.5 Moreover, IL-6 is known to induce the expression of CRP, which suggests that a change in cytokine levels precede a change in the level of CRP. The current study was conducted in a relatively homogeneous patient population. A strength of this study is the inclusion of longitudinal systematic assessments of both presence of delirium and CRP levels. In contrast to other studies we found that the level of CRP was not an early diagnostic marker of delirium, but increased and remained at a higher level after delirium emerged. We were able to control for important factors such as the cognitive and physical status while investigating the association between CRP and

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postoperative delirium. We used standardized and validated instruments with systematic, simultaneous measurements of CRP level and delirium. The limitations are that the study population is not a pure observational cohort. Taurine was administered to a part of the sample. However, we controlled for treatment allocation in multivariate analysis, and found no association between treatment and CRP levels. To conclude, the findings in this study suggest that delirium is associated with an increased inflammatory response. The level of CRP does not seem to be an early diagnostic marker for delirium, but rather is elevated soon after the emergence of delirium. This work, along with other recent studies, raises the possibility that inflammatory mechanisms may underpin the long-term negative consequences of delirium, including persistent cognitive impairment.

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1. Eikelenboom P, Hoogendijk WJ, Jonker C, van Tilburg W. Immunological mechanisms and the spectrum of psychiatric syndromes in Alzheimer’s disease. J Psychiatr Res 2002; 36:269-280.

2. van Gool WA, van de Beek D, Eikelenboom P. Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet 2010; 375:773-775.

3. Dasgupta M, Dumbrell AC. Preoperative risk assessment for delirium after non-cardiac surgery: a systematic review. J Am Geriatr Soc 2006; 54:1578-1589.

4. Godbout JP, Johnson RW. Age and neuroinflammation: a lifetime of psychoneuroimmune consequences. Neurol Clin 2006; 24:521-538.

5. Kudoh A, Takase H, Katagai H, Takazawa T. Postoperative interleukin-6 and cortisol concentrations in elderly patients with postoperative confusion. Neuroimmunomodulation 2005; 12:60-66.

6. van Munster BC, Korevaar JC, Zwinderman AH, Levi M, Wiersinga WJ, De Rooij SE. Time-course of cytokines during delirium in elderly patients with hip fractures. J Am Geriatr Soc 2008; 56:1704-1709.

7. Macdonald A, Adamis D, Treloar A, Martin F. C-reactive protein levels predict the incidence of delirium and recovery from it. Age Ageing 2007; 36:222-225.

8. Adamis D, Treloar A, Darwiche FZ, Gregson N, Macdonald AJ, Martin FC. Associations of delirium with in-hospital and in 6-months mortality in elderly medical inpatients. Age Ageing 2007; 36:644-649.

9. Lemstra AW, Kalisvaart KJ, Vreeswijk R, van Gool WA, Eikelenboom P. Pre-operative inflammatory markers and the risk of postoperative delirium in elderly patients. Int J Geriatr Psychiatry 2008; 23:943-948.

10. Lee HJ, Hwang DS, Wang SK, Chee IS, Baeg S, Kim JL. Early assessment of delirium in elderly patients after hip surgery. Psychiatry Investig 2011; 8:340-347.

11. Cerejeira J, Nogueira V, Luís P, Vaz-Serra A, Mukaetova-Ladinska EB. The cholinergic system and inflammation: common pathways in delirium pathophysiology. J Am Geriatr Soc 2012; 60:669-675.

12. Beloosesky Y, Hendel D, Weiss A, Hershkovitz A, Grinblat J, Pirotsky A, Barak V. Cytokines and C-reactive protein production in hip-fracture-operated elderly patients. J Gerontol A Biol Sci Med Sci 2007; 62:420-426.

13. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med 1990; 113:941-948.


15. Lindeboom J, Matto D. Digit series and Knox cubes as concentration tests for elderly subjects. Tijdschrift voor Gerontologie en Geriatrie 1994; 25:63-68.

16. Jorm AF, Jacomb PA. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): socio-demographic correlates, reliability, validity and some norms. Psychol Med 1989; 19:1015-1022.

17. de Jonghe JF, Schmand B, Ooms ME, Ribbe MW. Abbreviated form of the Informant Questionnaire on cognitive decline in the elderly. Tijdschr Gerontol Geriatr 1997; 28:224-229.

18. Sheikh JI, Yesavage JA. Geriatric depression scale (GDS): recent findings and development of a shorter version. Clinical Gerontologist 1986; 37:819-820.

19. American Society of Anesthesiologists: ASA Physical Status Classification System. http://www.asahq.org/Home/For-Members/Clinical-Information/ASA-Physical-Status- Classification-System.

20. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Critical Care Medicine 1985; 13:818-829.

21. Hetherington R. The Snellen chart as a test of visual acuity. Psychologische Forschung 1954; 24:349-357.

22. Mahoney FI, Barthel DW. Functional evaluation: The Barthel Index. Maryland State Medical Journal 1965; 14:61-65.

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23. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969; 9:179-186.

24. Meagher D, McLoughlin L, Leonard M, Hannon N, Dunne C, O’Regan N. What do we really know about the treatment of delirium with antipsychotics? Ten key issues for delirium pharmacotherapy. Am J Ger Psychiatry (in press).

25. Trzepacz PT, Mittal D, Torres R, Kanary K, Norton J, Jimerson N. Validation of the Delirium Rating Scale-revised-98: comparison with the delirium rating scale and the cognitive test for delirium. The Journal of Neuropsychiatry & Clinical Neurosciences 2001; 13:229-242.

26. van Munster BC, Korevaar JC, de Rooij SE, Levi M, Zwinderman AH. The association between delirium and the apolipoprotein E epsilon4 allele in the elderly. Psychiatr Genet 2007; 17:261-266.

27. Slor CJ, de Jonghe JF, Vreeswijk R, Groot E, Ploeg TV, van Gool WA, Eikelenboom P, Snoeck M, Schmand B, Kalisvaart KJ. Anesthesia and postoperative delirium in older adults undergoing hip surgery. J Am Geriatr Soc 2011; 59:1313-1319.

28. Cibelli M, Fidalgo AR, Terrando N, Ma D, Monaco C, Feldmann M, Takata M, Lever IJ, Nanchahal J, Fanselow MS, Maze M. Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol 2010; 68:360-368.

29. Rosczyk HA, Sparkman NL, Johnson RW. Neuroinflammation and cognitive function in aged mice following minor surgery. Exp Gerontol 2008; 43:840-846.

30. Vizcaychipi MP, Lloyd DG, Wan Y, Palazzo MG, Maze M, Ma D. Xenon pretreatment may prevent early memory decline after isoflurane anesthesia and surgery in mice. PLoS One 2011; 6:e26394.

31. Kamer AR, Galoyan SM, Haile M, Kline R, Boutajangout A, Li YS, Bekker A. Meloxicam improves object recognition memory and modulates glial activation after splenectomy in mice. Eur J Anaesthesiol 2012; 29:332-337.

32. Buchanan JB, Sparkman NL, Chen J, Johnson RW. Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice. Psychoneuroendocrinology 2008; 33:755-765.

33. Cao XZ, Ma H, Wang JK, Liu F, Wu BY, Tian AY, Wang LL, Tan WF. Postoperative cognitive deficits and neuroinflammation in the hippocampus triggered by surgical trauma are exacerbated in aged rats. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:1426-1432.

34. He HJ, Wang Y, Le Y, Duan KM, Yan XB, Liao Q, Liao Y, Tong JB, Terrando N, Ouyang W. Surgery upregulates high mobility group box-1 and disrupts the blood-brain barrier causing cognitive dysfunction in aged rats. CNS Neurosci Ther 2012; 18:994-1002.

35. Barrientos RM, Hein AM, Frank MG, Watkins LR, Maier SF. Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats. J Neurosci 2012; 17:14641-14648.

36. Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 2005; 25:9275-9284.

37. Godbout JP, Chen J, Abraham J, Richwine AF, Berg BM, Kelley KW, Johnson RW. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J 2005; 19:1329-1331.

38. Uchikado H, Akiyama H, Kondo H, Ikeda K, Tsuchiya K, Kato M, Oda T, Togo T, Iseki E, Kosaka K. Activation of vascular endothelial cells and perivascular cells by systemic inflammation-an immunohistochemical study of postmortem human brain tissues. Acta Neuropathol 2004; 107:341-351.

39. Wersching H, Duning T, Lohmann H, Mohammadi S, Stehling C, Fobker M, Conty M, Minnerup J, Ringelstein EB, Berger K, Deppe M, Knecht S. Serum C-reactive protein is linked to cerebral microstructural integrity and cognitive function. Neurology 2010; 74:1022-1029.

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4Chapter

Predicting delirium duration in elderly hip-surgery patients. Does early symptom profile matter?

Chantal J. SlorJoost WitloxDimitrios AdamisDavid J. MeagherTjeerd v.d. PloegRene W.M.M. JansenMireille F. M. van StijnAlexander P.J. HoudijkWillem A van GoolPiet EikelenboomJos F.M. de Jonghe

Current Gerontology and Geriatrics Research, vol. 2013, Article ID 962321, 9 pages, 2013. doi:10.1155/2013/962321

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ABSTrACTBackground: Features that may allow early identification of patients at risk of prolonged delirium, and therefore of poorer outcomes, are not well understood. The aim of this study was to determine if pre-operative delirium risk factors and delirium symptoms (at onset and clinical symptomatology during the course of delirium) are associated with delirium duration.methods: This study was conducted in prospectively identified cases of incident delirium. We compared patients experiencing delirium of short duration (1 or 2 days) with patients who had more prolonged delirium (≥3 days) with regard to DRS-R-98 (Delirium Rating Scale Revised-98) symptoms on the first delirious day. Delirium symptom profile was evaluated daily during the delirium course.results: In a homogenous population of 51 elderly hip-surgery patients, we found that the severity of individual delirium symptoms on the first day of delirium was not associated with duration of delirium. Pre-existing cognitive decline was associated with prolonged delirium. Longitudinal analysis using the Generalised Estimating Equations method (GEE) identified that more severe impairment of long-term memory across the whole delirium episode was associated with longer duration of delirium.Conclusion: Pre-existing cognitive decline rather than severity of individual delirium symptoms at onset, is strongly associated with delirium duration.

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InTroduCTIonPostoperative delirium is a common complication in elderly hip-fracture patients, that is associated with high mortality, cognitive deterioration and a high rate of subsequent institutionalization.1-3 Delirium follows a variable course, ranging from a brief transient state to more persistent illness that can evolve into long-term cognitive impairment.4,5 Factors that may allow earlier identification of patients who are at risk of more prolonged delirium are not well understood.6,7 Although studies over the past decade have improved our understanding of the phenomenology of delirium, little is known about the association between specific delirium symptoms and duration of delirium.8

Few studies have examined delirium symptoms as a risk factor for an extended duration of the delirious episode. Previous studies have used the Delirium Rating Scale (DRS)9 to measure the severity of delirium symptoms.10,11 Rudberg et al. (1997) found that patients experiencing delirium of a single day’s duration did not differ from more persistent (multiple days) cases with regard to individual DRS item scores on the first day of delirium.10 Conversely, Wada and Yamaguchi (1993), who also used the DRS, found that more severe cognitive impairment, sleep-wake cycle disturbances and mood lability were associated with longer delirium episodes (>1 week vs ≤1 week).11 However, these studies used the original DRS which focuses upon a relatively narrow range of delirium symptoms compared to the revised version (DRS-R-98), and/or did not control for factors such as pre-existing cognitive problems, including dementia. This is a significant shortcoming of previous research since dementia may be a predictor of illness duration,12,13 in addition to being an important risk factor for delirium.14 Most studies that investigated delirium duration restricted delirium monitoring to specific time-intervals. The risk of mortality is increased by 11% for every additional 48 hours that delirium persists.15 This makes it imperative to gain more insight into the determinants of delirium duration. Moreover, frequent (e.g. daily) assessments make it possible to determine the character of delirium is related to episode duration. In this prospective observational study we investigated a homogenous cohort of elderly hip surgery patients aged 75 or older, who were carefully monitored on a daily basis for the occurrence of delirium. The aim of the present study was to identify patient characteristics that are associated with prolonged delirium, and explore how delirium symptomatology evolves over time.

meThodS ethical ConsiderationsThe study was undertaken in accordance with the Declaration of Helsinki and the guidelines on Good Clinical Practice. Approval of the regional research ethics committee was obtained. Patients or their relatives gave fully informed written consent.

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Study design and objectivesThis was a prospective cohort study in elderly hip fracture patients. Evaluating the relationship between patient characteristics and delirium was a pre-specified aim of this study. Patient characteristics and risk factors for delirium were assessed preoperatively. Presence and severity of delirium were assessed daily. Since all participants were at high risk for delirium (i.e. age 75 years or older, and acute hospital admission) all patients received routine care with prophylactic treatment of 0.5 mg haloperidol, three times daily, from time of admission until postoperative day three, unless contraindications regarding its use were present.16 We investigated the association between delirium symptoms on the first delirious day, with subsequent duration of the delirious episode. We compared incident delirium cases experiencing short delirium episodes (1 or 2 days) with patients who experienced more prolonged delirium (≥3 days). Thereafter, we investigated the association between delirium symptom profile over time and duration in days until recovery. For this longitudinal analysis, data on DRS-R-98 item scores gathered over all days of active delirium was included. ParticipantsThe study was conducted in a series of consecutively admitted elderly hip fracture patients to a teaching hospital in Alkmaar, the Netherlands. Eligibility was checked for all patients 75 years and older admitted for primary surgical repair of hip fracture. From March 2008 to March 2009, 192 hip fracture patients were eligible, they fulfilled criteria for participation and provided consent. A subgroup of this study cohort, 122 patients, also participated in a clinical trial that compared the effectiveness of taurine versus placebo in reducing morbidity and one-year mortality in elderly hip fracture patients (Clinicaltrials.gov; registration number NCT00497978; This project has been the subject of a previous report17). The 122 patients who participated in the RCT were younger compared to the rest of the 192 eligible patients. Patients were ineligible to participate in the study if they had no surgery, had a malignancy, had a previous hip-fracture on the identical side, were in contact isolation, incapable of participating in interviews (language barrier, aphasia, coma), had no acute trauma, were transferred to another hospital or received a total hip prosthesis. For the current analysis we also excluded cases who died during hospitalization, were already delirious before surgery or could not be allocated to one of the duration groups according to the definition of recovery. The people who died during admission were more often male, had a history of previous delirium and more dependent in their activities of daily living compared to the rest of the 192 eligible patients. Preoperative delirium cases were excluded because we focused upon a well defined homogeneous group of incident

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delirium and the presence of preoperative delirium includes cases where delirium may have contributed to falls and need for subsequent hip-fracture surgery. Patients with no data available on the two days after the last delirious day could not be allocated to one of the duration groups. In this instance we could not define the exact count of delirious days according to the definition used for recovery.

meASuremenTS And ProCedureSBaseline assessmentBaseline assessment was completed within 12 hours of admission and prior to surgery. This comprised delirium assessment, patient and proxy interviews and questionnaires, and inspection of the medical record to assess for risk factors for delirium. Preoperative cognitive functioning was assessed with the Mini Mental State Examination (MMSE) on a scale of 0 to 30 with scores lower than 24 indicating cognitive impairment.18 Prefracture cognitive decline was estimated with the short version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE-N), scored by a close relative or caregiver. This measures pre-existing cognitive decline during the past 10 years on a scale of 16 (improvement) to 70 (decline).19 A total score higher than 57 (i.e. a mean item-score higher than 3.6) indicates cognitive decline.20 For the IQCODE-N proxies were asked to describe the patient’s condition a week before the fracture as to determine function unbiased by the event of hip fracture itself or any acute or sub-acute event leading to hip fracture. Burden of illness included the number and type of medical co-morbidities and medications before hospital admission. Demographic factors included age and gender. Data on medication was collected as part of the prospective data collection and checked again afterwards by medical record review. We also reviewed medical records to document the Acute Physiology Age and Chronic Health Examination (APACHE II) score (range of 0 (no acute health problems) to 70 (severe acute health problems)).21 Functional status comprised pre-fracture living arrangement, visual acuity, activities of daily living (ADL) and instrumental activities of daily living (IADL). Visual acuity was assessed with the standardized Snellen test for visual impairment22 and visual impairment was defined as binocular near vision, after correction, worse than 20/70. Pre-fracture ADL functioning was determined with the Barthel Index (BI) which is scored by a close relative or caregiver on a scale from 0 (dependence) to 20 (independence).23 IADL was also assessed by a close relative or caregiver on the Lawton IADL scale with a range of 8 (no disability) to 31 (severe disability).24

outcomeThe primary outcome was duration of delirium. The highly fluctuating nature of delirium makes for problems in reliably defining recovery and therefore a standard definition is lacking. A recent review of treatment for delirium which considered available evidence

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Chapter 4

for defining ‘recovery’ concluded that because of the fluctuating course of delirium, recovery is best defined conservatively and in the manner used herein.25 We followed a conservative approach to define recovery of delirium as two subsequent days without delirium according to the Confusion Assessment Method (CAM).26 For some analyses (specified below) delirium duration was used as a continuous variable, whereas we also used a dichotomy with incident cases who were delirious for 1 or 2 days labeled as ‘short delirium’ with the remaining cases who were delirious for three days or more, labeled as prolonged delirium. A single day without delirium but followed by further delirium was considered part of the delirium episode. Delirium was defined according to the Confusion Assessment Method (CAM) and validated with a diagnosis based on DSM IV criteria.26,27 The CAM consists of acute onset and fluctuating course of cognitive function, inattention, and either disorganized thinking, and/or altered level of consciousness. Delirium severity was measured using the Delirium Rating Scale Revised-98 (DRS-R-98), a 16-item rating scale comprised of thirteen severity items and 3 diagnostic items. The item-scores range of 0 (no severity) to 3 (maximum severity). Possible total severity scores range of 0 (no severity) to 39 (maximum severity).28 Presence and severity of delirium were assessed within 12 hours after admission and before surgery and continued daily after delirium onset or until the fifth postoperative day for delirium onset. Delirium usually presents itself within the first few days after surgery, if delirium onset is after this time-frame it is mostly caused by secondary complications (e.g. urinary tract infection).29-34 The CAM and DRS-R-98 rating were based on all available information ,collected by trained research assistants, including (i) brief formal cognitive testing with the MMSE, (ii) patient and hospital staff interviews, and (iii) scrutiny of the medical and nursing records.

data AnalysisData analysis was performed using SPSS for Windows, version 19 (SPSS; Inc. Chicago, Il). Comparisons of group characteristics were made using chi-square or Fisher’s exact test for differences in proportions, t-testing for differences in means, and nonparametric tests for rank differences. The univariate significant baseline variables between the short and prolonged delirium group were analyzed with binary logistic regression using the backward Wald method, in order to select the control variables for the first and second part of the research question. For the first research question (the prediction of short vs. prolonged delirium duration by the initial severity of DRS-R-98 items and baseline characteristics) binary logistic regression with the backward Wald method was used. Delirium duration was the binary dependent variable (short (≤2 days) vs. long (≥3 days)).

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At first we applied a logistic regression model with only the scores (range 0 to 3) on the 13 DRS-R-98 severity items on the first day of delirium. Afterwards the same model was repeated but including the covariates: age, sex and prior cognitive decline (IQCODE >3.6). The variables were checked for collinearity (Collinearity Statistics; Tolerance and Variance Inflation Factor (VIF) were performed, all variables entered into the model had a VIF less than 10 and Tolerance more than 0.1.). For the second research question (clinical symptomatology during the course of delirium) a Generalized Estimating Equations model was used to analyze longitudinal data for patterns of individual items from the DRS-R-98 (items 1-13) between cases with different delirium duration until recovery (range from 1 through 9 days). All available DRS-R-98 item scores (1-13) from first day of delirium until the defined end of the delirium episode were included as independent variables. The continuous dependent variable was duration, measured as the sum of the delirium days from the first day of delirium until the end of delirium. Because it is factually a count variable, following a Poisson distribution, we treated this as such. The GEE method takes into account the fact that observations within a subject are correlated and estimates the population average across time. All scale items were included in each analysis although only those that were significantly different are shown in the results tables. Results were classified as significant if the P-value was less than 0.05.

reSulTSAfter excluding ineligible patients (n=73), patients who died in hospital (n=12) and prevalent cases (n=23) there were 57/157 (36.3%) incident delirium cases (Figure 1). Six cases were excluded, since they could not be defined with certainty as belonging to the short or prolonged delirium group because of missing data. The second research question involved exclusion of another 8 cases because of missing data that impeded determining exact duration of delirium according to our definition of recovery. Treatment (taurine or placebo) had no effect on daily CAM diagnosis, DRS-R-98 total scores and delirium duration, so this was not entered as a control variable in further analysis. Logistic regression analysis with baseline characteristics identified IQCODE score >3.6 as the only significant factor, so this was entered as a control variable in further analysis. The average age of the 13 male and 38 female patients was 85.1 ± 5.4 (mean ± standard deviation). A total of 22/51 cases (43.1%) had short delirium (1 or 2 days) and 29/51 cases (56.9%) had prolonged delirium (≥3 days). Within the prolonged delirium 20/28 cases could be further defined with regard to exact duration (3 days: n=6; 4 days; n=4; 5 days: n=3; 6 days: n=3; 7 days: n=1; 8 days: n=1 and 9 days: n=2). A significantly greater (P=.003) proportion of patients within the prolonged delirium group (26/29 cases: 89.7%) compared to the short delirium group 11/22 cases (50%) had an IQCODE>3.6. A further comparison of the short and prolonged delirium group on other variables

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is depicted in Table 1. The use (yes or no) of medication classes (Sedative-Hypnotics, Antipsychotics, Opioids, Beta-blocking agents, Anti-depressants, Anti-histamines for systemic use, Antiparkinson agents, Corticosteroids for systemic use, non-steroidal anti-inflammatory agents, Anti-epileptics, Diuretics and H2-Antagonists did not differ significantly between the short and prolonged delirium group

Table 1. Baseline Clinical and Demographic Characteristics of Patients in the Short and Prolonged Delirium Group.

Characteristic Short delirium Prolonged delirium

n = 22 n = 29 or (95% CI) P-value

Age* 84.6 ± 4.7 85.6 ± 5.9 1.04 (0.93 – 1.15 ) 0.50

Female° 17 (77.3) 21 (72.4) 1.30 (0.36 – 4.69 ) 0.69

Mini-Mental State Examination (MMSE) score *¶ 23.0 ± 3.1 19.6 ± 5.5 0.84 ( 0.71 – 0.99 ) 0.02

APACHE II score*§ 13.3 ± 3.0 13.9 ± 3.1 1.14 ( 0.87 – 1.49 ) 0.34

Snellen Test* 31.6 ± 18.1 38.6 ± 35.5 1.01 ( 0.98 – 1.04 ) 0.41

Barthel ADL Index Score *¢ 17.4 ± 3.0 14.0 ± 4.1 0.76 ( 0.62 – 0.93 ) 0.003

Lawton IADL score * ≈ 14.8 ± 5.8 18.6 ± 8.3 1.08 ( 0.99 – 1.17 ) 0.08

Geriatric Depression Scale-15 score*† 6.4 ± 1.1 6.4 ± 1.7 0.98 ( 0.61 – 1.59 ) 0.95

CRP value * 12.7 ± 25.2 13.4 ± 28.5 1.00 ( 0.98 – 1.02 ) 0.76

History of Previous Delirium ° 0 (0) 12 (46.2) N.A. 0.001

IQCODE-N >3.6 ° 11 (50) 26 (89.7) 8.7 ( 2.02 – 37.26 ) 0.002

Number of concomitant diseases at admission * 2.4 ± 1.5 3.2 ± 2.5 1.20 ( 0.90 – 1.60 ) 0.18

Number of medication at admission * 4.2 ± 2.4 5.6 ± 3.8 1.15 ( 0.95 – 1.38 ) 0.12

MMSE score on the first day of delirium *¶ 18.1 ± 6.3 15.1 ± 6.0 0.92 ( 0.83 – 1.03 ) 0.13

DRS-R-98 score on the first day of delirium *¥

18.6 ± 6.4 20.6 ± 6.5 1.05 ( 0.96 – 1.15 ) 0.28

Data are presented as mean ± SD or n (%) unless otherwise indicated.

*=continous variables, °=dichotomous variables

OR=odds Ratio, the chance of developing prolonged delirium, CI = confidence interval

APACHE II=Acute Physiological and Chronic Health Evaluation II

IQCODE-N=Informant Questionnaire on Cognitive Decline in the Elderly, >3.6 indicates pre-existent cognitive decline

DRS-R-98=Delirium Rating Scale Revised-98¶ Range 0 (severe cognitive impairment) to 30 (no cognitive impairment).§ Range 0 (no acute health problems) to 70 (severe acute health problems).¢ Range 0 (severe disability) to 20 (no disability).

≈ Range 8 (no disability) to 31 (severe disability)† Range 0 (depression not likely) to 15 (depression very likely).¥ Range 0 (no delirium symptoms) to 39 (maximum severity)

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Prevalent delirium (n=23)

Patients (n=180)

De�nition: Short vs. Prolonged Delirium (n=51)

Short Delirium (1-2 days) (n=22)Prolonged Delirium (≥3 days)

(n=29)


(n=265)

Died during admission(n=12)


Patients (n=157)Never delirious

(n=100)Incident delirium

(n=57)De�nition: Count Delirium Days until

Recovery (n=42)1 day=122 days=103 days=64 days=45 days=36 days=37 days=18 days=19 days=2

Patients not meeting inclusion criteria (n=73)

Discharged without surgery (n=16)Previous identical hip-fracture (n=6)

Malignancy (n=2)Transfer to another hospital (n=6)

Total hip-prosthesis (n=4) No acute trauma(n=9)

Not testable (n=15)Missed by emergency department (n=6)

Refused to participate (n=8)Contact-isolation (n=1)

Table 2 shows a descriptive analysis of the presence (score ≥1) of delirium symptoms within the short and prolonged delirium group on the first day. Disturbed orientation and attention were prominent features in both groups. Only visuospatial functioning differed significantly (OR 5.3, 95% CI 1.28 – 21.57, P=.02). Figure 2 displays the mean scores on DRS-R-98 items on the first day of delirium within the short and prolonged delirium group. None of the individual item scores differed significantly between the groups. Logistic regression analysis indicated that more severe motor retardation on the DRS-R-98 was associated with prolonged delirium (OR 1.88, 95% CI 1.03 – 3.42, P=.04). The model’s R2 (Nagelkerke) was 0.16 and percentage of correctly classified patients was 61.5% (1-2 days: 0%, ≥3 days: 100%). After controlling for time-invariate variables (gender, age, and pre-existent cognitive decline) none of the DRS-R-98 items on the first day of delirium were associated with delirium duration. Only pre-existent cognitive decline (IQCODE >3.6) was associated with prolonged delirium (OR 0.1, 95% CI 0.02 – 0.61, P=.01). The model’s R2 (Nagelkerke) was 0.24 and the overall percentage of correctly classified patients was 74.4% (1-2 days: 46.7%, ≥3 days: 91. 7%).

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Table 2. Presence Of Individual DRS-R-98 Delirium Symptoms On First Day Of Delirium.

drS-r-98 Item Short delirium (n=22)

Prolonged delirium(n=29)

P-value

1. Sleep-wake cycle disturbance 21 (95.5%) 29 (100%) 0.43

2. Perceptual disturbances and hallucinations 8/21 (38.1%) 13/27 (48.1%) 0.49

3. Delusions 11/21 (52.4%) 14/27 (51.9%) 0.97

4. Affective Lability 15 (68.2%) 15/28 (53.6%) 0.30

5. Language problems 18 (81.8%) 22 (75.9%) 0.74

6. Thought process abnormalities 19 (86.4%) 27 (93.1%) 0.64

7. Motor agitation 14 (63.6%) 20 (69%) 0.69

8. Motor retardation 11/21 (52.4%) 20 (69%) 0.23

9. Orientation problems 22 (100%) 28 (96.6%) 1.00

10. Attention deficits 22 (100%) 28 (96.6%) 1.00

11. Short-term memory impairment 20/21 (95.2%) 27/28 (96.4%) 1.00

12. Long-term memory impairment 12/18 (66.7%) 22/28 (78.6%) 0.37

13. Visuospatial impairment 9/18 (50%) 21/25 (84%) 0.02

Data are presented as n (%), or n/n (%) in case of missing data.

figure 2. Mean DRS-R-98 Item Scores for Short (1-2 days) vs. Prolonged (≥3 days) Delirium on the First Delirious Day.

0

0,5

1

1,5

2

2,51

2

3

4

5

6

78

9

10

11

12

131. Sleep-wake cycle 2. Hallucinations 3. Delusions 4. A�ective lability 5. Language 6. Thought process 7. Motor agitation 8. Motor retardation 9. Orientation 10. Attention 11. Short-term memory 12. Long-term memory 13. Visuospatial impairment

Short Prolonged

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The longitudinal analysis, with data on DRS-R-98 item scores gathered over all the delirium days gave the final most parsimonious GEE model (113 observations, 38 patients included) that is shown in Table 3. A higher score on long-term memory (DRS-R-98 item 12) was associated with a longer duration of delirium until recovery considering all assessments within the delirium episode.

Table 3. Generalised Equation Estimation (GEE) model for DRS items 1-13 for different lengths of delirium episodes until recovery (count of days). n=113 included observations.

β Se df Wald x2 95% CI p

DRS-R-98 item 6Thought Process Abnormalities

-7.9E-6 6.30E-6 1 1.558 -2.03E-5, 4.5E-6 0.21

DRS-R-98 item 9Orientation

-6E-6 8.88E-6 1 0.456 -2.34E-5, 1.14e-5 0.50

DRS-R-98 item 10Attention

-5.17E-6 8.83E-6 1 0.343 -2.25E-5, 1.21E-5 0.56

DRS-R-98 item 11Short-term memory

-1.08E-6 9.67E-6 1 0.012 -2.01E-5, 1.79E-5 0.91

DRS-R-98 item 12Long-term memory

1.45E-5 7.20E-6 1 4.044 3.67E-7, 2.86E-5 0.04

DRS-R-98 item 13Visuospatial impairment

8.86E-6 1.16E-5 1 0.580 -1.40E-5, 3.17E-5 0.45

Constant 1.21 0.11 1 119.487 0.99, 1.42 0.000

SE=Standard ErrorC.I.=Confidence Interval, E with a minus sign signals the number of places the decimal point has to be moved to the left.

dISCuSSIonThis study is one of the few to describe the predictive value of delirium symptomatology in the early phase of the delirium episode for subsequent duration. In a homogenous population of elderly hip-surgery patients, we found that the severity of individual delirium symptoms at the first day of delirium was not associated with short or prolonged delirium. Initially motor retardation was identified as a predictor for longer delirium duration (≥3 days), but when controlling for gender, age and pre-existing cognitive decline, only pre-existing cognitive impairment was associated with prolonged delirium. In addition more severe impairment of long-term memory (a it was also measured with DRS-98 R item 12) across the whole delirium episode was associated with longer duration of delirium.

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Pre-existing cognitive impairment is thought to be more common in hypoactive delirium, although there is quite limited data to support this observation.35 Our data indicate that the observed relationship between relatively hypoactive clinical profile (as measured on item 8 of the DRS-R98) and more prolonged delirium is confounded by the relationship between motor retardation and pre-existing cognitive impairment. This observation supports clinical experience where delirium superimposed on dementia is more likely to be hypoactive and resolves more slowly. There have been few studies investigating the predictive value of delirium symptoms on the first day of delirium and findings have been inconsistent. Rudberg et al. (1997) determined the duration within a mixed sample of 64 general medical and surgical patients who were found to have delirium.10 Similar to our findings, there was no difference between delirium lasting a single day versus that of more prolonged cases in relation to individual delirium symptoms. They did find that the multiple day cases had higher DRS total scores on the first day. In contrast, Wada and Yamaguchi11 found that poor cognitive status, sleep-wake cycle disturbances and mood lability were associated with delirium lasting more than a week. However, in our study item 12 (long term memory) was the only predictive item from DRS-R-98 for delirium duration such that participants with more severe long term memory problems experienced more prolonged delirium. However, the two previous mentioned studies measured symptoms with the original 10-item DRS, which includes a more restricted range of symptoms than the revised DRS-R-98 which captures a wider range of cognitive and neuropsychiatric disturbances that occur in delirium and is widely used in the assessment of delirium severity and in phenomenological studies. In addition, both patient populations were highly heterogeneous and not only limited to only postoperative delirium and focused only on univariate analysis without controlling for confounding factors, like pre-existing cognitive decline. The study by Wada and Yamaguchi described delirium duration according to a general category (≤1 week vs. >1 week).11 However, we found that almost half of the delirious patients experienced a delirium episode of 1 to 2 days. Rudberg et al. also found a high percentage of cases (69%) with a single day of delirium in their sample.10 Recent work has highlighted the impact of short periods of delirium upon outcomes and emphasises the importance of daily assessments in studies of delirium.15

Our work includes some significant strengths that include the use of daily measurements with the DRS-R-98. Moreover, given the challenges in longitudinal studies of handling the effects of drop-outs, interdependence of ratings across visits within patients, and individual patient variability in delirium severity over time, we used the GEE modeling method because it manages these issues in longitudinal data sets and is therefore particularly suited to investigating the course of delirium, considering its fluctuating nature.

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Pre-existing cognitive decline is thought to be associated with more prolonged delirium. It has been postulated that this reflects the effects of uncontrolled neuro-inflammation contributing to delirium symptoms.36 Experimental findings and neuropathological observations suggest that activation of microglia is pivotal for mediation of the acute behavioural and cognitive effects of systemic inflammation.36 A mild systemic inflammatory response suffices to increase the production of pro-inflammatory cytokines within the brain when microglia are already “primed” by chronic pathologic events as chronic neurodegeneration or advanced age.37 After hip surgery the release of pro-inflammatory cytokines as a consequence of fracture and surgery induces a systemic inflammatory response. Since inflammatory markers have been shown to be elevated in dementia as well as MCI,38-40 it follows that pre-existing cognitive impairment might not only increase the chance of developing delirium, but also prolong it. This work also has some limitations. The present study was naturalistic in design. Patients received optimal care, which incorporates extensive general geriatric care and haloperidol as a prophylactic interventions in high risk patients and delirium treatment according to study site protocol. Both are known to impact positively upon the course of delirium. Although we cannot exclude the effect haloperidol might have had on motor symptom profile in this population, similar longitudinal work in a palliative care setting suggests a limited relationship between motor activity and use of antipsychotic agents.41 Furthermore, since all patients in our sample were high-risk for delirium and thus all received haloperidol prophylaxis, any likely effects would be likely to be similar for all the patients in our sample. Although a sub-sample of the patients participated in a clinical trial, analysis showed that study treatment (taurine/placebo) did not have effect on study outcomes. Also, delirium treatment was delivered according to a standard protocol and this did not differ between the sample participating in the clinical trial and the naturalistic cohort. The exclusion of participants who could not be classified regarding the duration of delirium episode might reduce the strength of this study. This study is not the first to define two consecutive negative delirium assessments as resolution of the delirium episode.42 However, to allow for greater confidence, we repeated the analysis twice. First, the analysis was repeated with the excluded patients added to the short delirium group, because we had data of at least 1 or 2 delirious days. Second, the prolonged delirium group was limited to patients who could be exactly defined according to duration of the delirium episode in exact count of days, similar to the short delirium group. This did not change the results evident in the initial analysis. This study excluded preoperative delirium cases and focused upon incident delirium cases, a well defined and homogeneous group of elderly hip fracture patients. Preoperative delirium cases might have experienced hip fracture because of their confusion, and subsequent other causes. Lee et al. (2011) demonstrated that delirium duration can last as

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long as 4 weeks or longer.13 The main cause of this prolonged delirium was preoperative delirium. The duration of delirium has been noted to be shorter, suggesting that preoperative delirium may include a different group who warrant separate study. The sample size was relatively small as it was limited to incident cases of delirium. The main finding that cognition rather than delirium profile is associated with delirium duration was demonstrated by two separate methods. The GEE method is an innovative statistical analysis used for longitudinal data analysis, the small sample size is less important with this analysis because we have a relative large number of observations due to the use of daily assessments. In conclusion, this study explores the relationship between baseline status and early symptoms of delirium with delirium duration in a homogenous population using validated measurement-scales. Pre-existing cognitive decline, a concept intertwined with dementia, rather than specific delirium symptoms, was the principal predictor of delirium duration.

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4. Jackson JC, Gordon SM, Hart RP, Hopkins RO, Ely EW. The association between delirium and cognitive decline: a review of the empirical literature. Neuropsychol Rev 2004; 14:87-98.

5. MacLullich AM, Beaglehole A, Hall RJ, Meagher DJ. Delirium and long-term cognitive impairment. Int Rev Psychiatry 2009; 21:30-42.

6. Edelstein DM, Aharonoff GB, Karp A, Capla EL, Zuckerman JD, Koval KJ. Effect of postoperative delirium on outcome after hip fracture. Clin Ortop Relat Res 2004; 422:195-200.

7. Nightingale S, Holmes J, Mason J, House A. Psychiatric illness and mortality after hip fracture. Lancet 2001; 21:1264-1265.

8. Gupta N, de Jonghe J, Schieveld J, Leonard M, Meagher D. Delirium phenomenology: what can we learn from the symptoms of delirium? J Psychosom Res 2008; 5:215-222.

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12. McCusker J, Cole M, Dendukuri N, Han L, Belzile E. The course of delirium in older medical inpatients: a prospective study. J Gen Intern Med 2003; 18:696-704.

13. Lee KH, Ha YC, Lee YK, Kang H, Koo KH. Frequency, Risk Factors, and Prognosis of Prolonged Delirium in Elderly Patients After Hip Fracture Surgery. Clin Orthop Relat Res 2011; 15;469:2612-2620.

14. Robinson TN, Raeburn CD, Tran ZV, Angles EM, Brenner LA, Moss M. Postoperative delirium in the elderly: risk factors and outcomes. Ann Surg 2009; 249:173-178.

15. González M et al. Impact of delirium on short-term mortality in elderly inpatients: a prospective cohort study. Psychosomatics 2009; 50:234-238.

16. Kalisvaart KJ et al. Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study. J Am Geriatr Soc 2005; 53:1658-1666.

17. Witlox J et al. Cerebrospinal fluid β-amyloid and tau are not associated with risk of delirium: a prospective cohort study in older adults with hip fracture. J Am Geriatr Soc 2011; 59:1260-1267.



20. de Jonghe JF, Schmand B, Ooms ME, Ribbe MW. Abbreviated form of the Informant Questionnaire on cognitive decline in the elderly. Tijdschr Gerontol Geriatr 1997; 28:224-229.

21. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system. Crit Care Med 1985; 13:818-829.

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24. Lawton MP, Brody EM: Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969; 9:179-186.



27. American Psychiatric Association: DSM-IV-TR. Washington DC: American Psychiatric Association, 2000.

28. Trzepacz PT, Mittal D, Torres R, Kanary K, Norton J, Jimerson N. Validation of the Delirium Rating Scale-revised-98: comparison with the delirium rating scale and the cognitive test for delirium. J Neuropsychiatry Clin Neurosci 2001; 13:229-242.

29. Lee HJ, Hwang DS, Wang SK, Chee IS, Baeg S, Kim JL. Early assessment of delirium in elderly patients after hip surgery. Psychiatry Investig 2011; 8:340-347.

30. Tognoni P et al. Preoperative risk factors for postoperative delirium (POD) after urological surgery in the elderly. Arch Gerontol Geriatr 2011; 52:166-169.

31. Katznelson R et al. Hospital administrative database underestimates delirium rate after cardiac surgery. Can J Anaesth 2010;7:898-902.

32. Lemstra AW, Kalisvaart KJ, Vreeswijk R, van Gool WA, Eikelenboom P. Pre-operative inflammatory markers and the risk of postoperative delirium in elderly patients. Int J Geriatr Psychiatry 2008; 23:943-948.

33. Santana Santos F, Wahlund LO, Varli F, Tadeu Velasco I, Eriksdotter Jonhagen M. Incidence, clinical features and subtypes of delirium in elderly patients treated for hip fractures. Dement Geriatr Cogn Disord 2005; 20:231-237.

34. de Jonghe et al. Early symptoms in the prodromal phase of delirium: a prospective cohort study in elderly patients undergoing hip surgery. Am J Geriatr Psychiatry 2007; 15:112-121.

35. Meagher D. Motor subtypes of delirium: past, present and future. International Review of Psychiatry 2009; 21(1):59-73.


37. Cunningham, C. Systemic inflammation and delirium: important co-factors in the progression of delirium. Biochemical Society Transactions 2011; 39:945-953.

38. Licastro F et al. Increased plasma levels of interleukin-1, interleukin-6 and alpha-1- antichymotrypsin in patients with Alzheimer’s disease: peripheral inflammation or signals from the brain? J Neuroimmunol 2000; 103:97-102.

39. Alvarez A, Cacabelos R, Sanpedro C, Garcia-Fantini M, Aleixandre M. Serum TNF-levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol Aging 2007; 28:533-536.

40. Trollor JN et al. Systemic inflammation is associated with MCI and its subtypes: the Sydney Memory and Aging Study. Dement Geriatr Cogn Disord 2010; 0:569-578.

41. Meagher D, Leonard M, Donnelly S, Conroy M, Adamis D, Trzepacz PT. A Longitudinal Study of Motor Subtypes in Delirium: Relationship with Other Phenomenology, Etiology, Medication Exposure and Prognosis. Journal of Psychosomatic Research 2011; 71:395-403.

42. Fann JR, Alfano CM, Burington BE, Roth-Roemer S, Katon WJ, Syrjala KL. Clinical presentation of delirium in patients undergoing hematopoietic stem cell transplantation. Cancer 2005; 15:810-20.

5Chapter

Delirium motor subtypes in elderly hip fracture patients: risk factors, outcomes and longitudinal stability

Chantal J. SlorDimitrios AdamisRené W.M.M. JansenDavid J. MeagherJoost WitloxAlexander P.J. HoudijkJos F.M. de Jonghe

Journal of Psychosomatic Research 2013;74:444-9.

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ABSTrACTBackground: Delirium is often accompanied by changes in motor activity but the longitudinal expression of these features and etiological and prognostic significance of clinical subtypes defined by motor activity is unclear. methods: A prospective cohort study of elderly patients undergoing hip fracture surgery. Baseline characteristics were assessed preoperatively. During hospital admission presence of delirium was assessed daily according to CAM criteria. This study compared baseline characteristics and outcomes according to longitudinal pattern of motor subtype expression (predominantly hyperactive, predominantly hypoactive, predominantly mixed, no motor subtype and variable). Motor subtype categorization was performed with the DRS-R98. We also investigated the longitudinal stability of motor subtypes across the delirium episode. results: 62 patients had experienced in-hospital delirium postoperatively. The full course of the delirium episode could be defined for 42/62 (67.7%) patients. Of the patients with multiple days of delirium only 4/30 (13.3%) patients had a consistent motor subtype profile throughout the delirium episode, while 26/30 (86.7%) patients had a variable course. Of the patients with multiple days of delirium, 5/30 (16.7%) were predominantly hypoactive in profile, 7/30 (23.3%) predominantly hyperactive, 6/30 (20%) predominantly mixed, 1/30 (3.3%) had no motor subtype and 11/30 (36.7%) had a variable profile. Baseline characteristics and outcomes did not differ between the groups. Conclusion: The majority of elderly hip fracture patients in this homogenous sample experienced variable expression of motor subtype over the course of their delirium episodes. The subtype categorization according to dominant motor subtype across the delirium episode identified groups with similar characteristics and outcomes.

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Delirium motor subtypes: risk factors, outcomes, longitudinal stability

5

InTroduCTIon Delirium is associated with long-term negative outcomes, including cognitive deterioration and institutionalization.1 It is often accompanied by changes in motor activity. Two principal patterns of motor behaviour are recognised, i.e. hyperactive and hypoactive.2 A third category, mixed, accounts for cases where elements of both subtypes occur within a short time frame.3 The aetiological and prognostic significance of motor subtypes defined according to these patterns is unclear. Previous studies have found different results concerning the aetiology, occurrence, characteristics and outcomes associated with motor subtypes.4 Some suggest that hypoactive delirium is associated with poorer prognosis,5,6 while others suggest poorer outcomes for patients with hyperactive or mixed subtype, or no difference in outcomes.7-11 Also, many patients with no motor subtype have less severe or subsyndromal delirium.12 There have been few studies of motor subtypes of delirium in hip surgery patients, and existing work has been cross-sectional in design.7,10,13 Different subtyping methods have been used including the Memorial Delirium Assessment Scale (MDAS), the Liptzin and Levkoff classification system, the criteria described by Lipowski.3,14,15 More recently, studies in other (non-hip surgery) populations have applied bio-electronic measures such as accelerometer and actigraphy in an effort to enhance the reliability of motor subtype attribution.16-18 Findings in hip fracture patients have varied; one study identified better outcomes in the form of nursing home placement and death at 1 month in hypoactive patients compared to patients with any hyperactivity.7 In another elderly hip fracture population no differences were found between the motor subtypes in relation to comorbidity, ASA, length of hospitalization and mortality at 6 months.10 However, these different findings may reflect methodological differences (e.g. in relation to subtyping method used), but may also relate to the limitations of basing subtype categorization on a single cross-sectional assessment. If motor subtype is not consistent over the course of a delirium episode, then accurate investigation of differences between motor subtypes requires longitudinal assessment. The available longitudinal data on delirium motor subtypes is based mainly upon research in palliative care patients.12,19 This study categorized patients into five groups based upon biweekly assessments for three weeks: no subtype throughout (6%), hypoactive subtype throughout (28%), mixed subtype throughout (18%), hyperactive subtype throughout (10%) and variable subtype (38%).19 Thus the majority of patients (62%) had a stable pattern, with hypoactive subtype being the most common stable pattern.12 Another study in a medical intensive care unit (MICU) population found that the majority of assessments were of the mixed type, according to the Richmond Agitation-Sedation Scale (RASS).20 However, the RASS is a general measure of agitation and sedation rather than an actual subtyping method. There have been other longitudinal

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Chapter 5

studies investigating motor symptoms rather than actual motor subtypes.21-23 Some of this work suggests that motor symptoms, especially hypoactivity, are relatively stable across assessments,21,2 while another study reported that most assessments had mixed features.23 Therefore, we conclude that longitudinal data on motor subtypes in delirium is lacking and has only been reported in a palliative care population. Moreover, information regarding daily expression of motor subtypes is lacking. The aim of the present study was to examine the association between patient characteristics, outcomes and motor subtype of delirium in an elderly hip-fracture population. This study differentiated between hypoactive, hyperactive, mixed and no motor subtype and applied daily assessments to investigate the longitudinal course of motor subtypes in delirium. To our knowledge this is the first such report in an elderly hip fracture population.

meThodSethical considerationsThis study was conducted in accordance with the Declaration of Helsinki and the guidelines on Good Clinical Practice. Approval of the regional research ethics committee was obtained. All patients gave written informed consent.

Study design and objectives The study was conducted in a series of consecutively admitted elderly hip fracture patients to a teaching hospital in Alkmaar, the Netherlands (Clinicialtrials.gov; registration number NCT00497978 and has been the subject of previous reports24,25). Patients were deemed ineligible to participate in the study if they did not undergo surgery, had a malignancy, had a previous hip-fracture on the identical side, were in contact isolation, incapable of participating in interviews (language barrier, aphasia, coma), had no acute trauma or received a total hip prosthesis. A standardized baseline assessment was completed prior to surgery to document patient characteristics, risk factors for delirium, and global cognitive performance. During hospital admission presence of delirium was assessed daily from time of admission until the fifth postoperative day or discharge, and where delirium occurred assessments continued until it remitted for three consecutive days or until discharge.

Baseline (preoperative) assessmentThe baseline assessment was completed within 12 hours of admission and before surgery. It consisted of patient and proxy interviews, assessment of delirium, and inspection of all available medical records. We documented the following demographic variables: age, gender, and history of previous delirium. To assess mental status we used the Mini Mental State Examination (MMSE) as a measure of baseline cognitive functioning on a scale of 0

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5

(poor) to 30 (good) with scores lower than 24 indicating cognitive impairment.26 The 16 item Informant Questionnaire on Cognitive Decline in the Elderly Short-Form (IQCODE-N) was used as an estimate of pre-fracture cognitive decline and was scored by a close relative or caregiver on a scale of 16 (improvement) to 70 (decline).27 A score higher than 57 (i.e. mean item score of 3.6) indicates cognitive decline.28 Burden of illness included the number of medical co-morbidities and medications before hospital admission. We also reviewed the Acute Physiology Age and Chronic Health Examination (APACHE II) score (range of 0 (no acute health problems) to 70 (severe acute health problems)).29 Functional status comprised pre-fracture living arrangement, visual acuity, activities of daily living (ADL) and instrumental activities of daily living (IADL). Pre-fracture ADL functioning was determined with the Barthel Index (BI) which is scored by a close relative or caregiver on a scale from 0 (dependence) to 20 (independence).30 IADL was also assessed by a close relative or caregiver on the Lawton IADL scale with a range of 8 (no disability) to 31 (severe disability).31

Delirium was diagnosed according to the criteria of the Confusion Assessment Method (CAM) which consists of an acute onset and fluctuating course of symptoms, inattention, and either disorganized thinking and/or altered level of consciousness.32 The CAM algorithm was rated daily on the basis of an interview with the patient, brief cognitive assessment with the MMSE and the expanded digit span test,33 discussion with treating hospital staff, and screening of medical and nursing records for signs of delirium. The CAM remains the most widely used screening test, has good psychometrics, has been validated in several languages and replicated in multiple settings.34 A diagnosis of delirium was always confirmed by a psychiatrist or geriatrician. Delirium severity was measured daily using the Delirium Rating Scale Revised-98 (DRS-R98), a 16-item rating scale comprised of thirteen severity items and 3 diagnostic items, which captures the previous 24 hours. The item-scores range of 0 (no severity) to 3 (maximum severity). Possible severity total scores range of 0 (no severity) to 39 (maximum severity).35 Delirium assessment continued daily at fixed time points until delirium remitted for three consecutive days or until discharge.

OutcomesThe following outcomes were compared between patients with different longitudinal motor subtype patterns of delirium: length of hospitalization (number of days), death in hospital, delirium severity, length of the delirium episode (number of days) and reduction in level of functional independence ( living situation after hospital discharge and after 3 months). Delirium severity was measured according to the average total DRS-R98 severity score (items 1-13) during delirium.35 The average scores both with and without the motor items, items 7 and 8, were compared between motor subtype groups. Also, the highest DRS-R98 total severity score and the DRS-R98 total severity scores on the first delirious day

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were compared between the groups. Duration of delirium was the number of days from the first delirium day until recovery (2 consecutive days of no delirium according to CAM criteria). A recent review of treatment for delirium which considered available evidence for defining ‘recovery’ concluded that because of the fluctuating course of delirium, recovery is best defined conservatively and in the manner used herein.36 The relationship between delirium subtype and delirium severity and duration were investigated in patients who could be defined in relation to the outcome (i.e. resolution) of their delirious episode. Living situation was categorized in decreasing order of independence into: independent living, protected housing, home for the elderly, and nursing home. The situation three months after hospital discharge was compared to the living situation before admission for patients who participated in the follow-up assessment. The longitudinal course of motor subtypes over the delirium episode was investigated in patients where the full course of the episode could be defined (i.e. evidence of two consecutive days of no delirium). The variability of motor subtype expression was assessed in patients who had a minimum of 2 days delirium.

delirium motor subtype definition Delirium was classified into four clinical subtypes (hypoactive, hyperactive, mixed and no motor symptoms) according to motor activity profile as assessed with item 7 (agitation) and item 8 (retardation) of the DRS-R98.35 Hypoactive delirium is defined as a score of 1-3 on DRS-R98 item 8 (motor retardation) and a score of 0 on DRS-R98 item 7 (motor agitation). Hyperactive delirium is defined as a score of 1-3 on DRS-R98 item 7 and a score of 0 on DRS-R98 item 8. The mixed subtype is defined as scores of 1-3 on both DRS-R98 item 7 and 8. No motor subtype equates with scores of 0 on both items. Dominant motor subtype profile was determined across the full episode of delirium. We identified profiles where the profile was predominantly hypoactive, hyperactive, mixed or no motor subtype. Profiles where no one subtype dominated were categorized as a variable profile.

Statistical AnalysisStatistical analyses were performed using SPSS for Windows, version 19 (SPSS; Inc. Chicago, Il., USA). Descriptive statistics are provided to characterize patients with different dominant delirium motor profiles (hypoactive, hyperactive, mixed, no motor subtype and variable profiles). Quantitative variables are presented as mean (standard deviation (SD)) or median (inter-quartile range (IQR)). Chi-Square or Fisher Exact tests were used to analyze categorical variables. The assumption of normality was tested with the Kolmogorov-Smirnov test. Continuous variables were analyzed with Mann-Whitney U tests or Kruskall-Wallis tests for between group comparisons.

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reSulTSThe final patient sample consisted of 62 patients who experienced in-hospital delirium postoperatively (Figure 1). This sample consisted of 42/62 (67.7%) patients where the full course of the delirium episode could be defined. Of the 30/42 (71.4%) patients with multiple days of delirium, 5/30 (16.7%) had a predominantly dominant hypoactive profile, 7/30 (23.3%) had a predominantly dominant hyperactive profile, 6/30 (20%) had a predominantly mixed profile, 1/30 (3.3%) had dominant no motor subtype and 11/30 (36.7%) had a variable profile.

figure 1. Flowchart of the Study.

Prevalent delirium(n=23)

Patients (n=169)

Patients not meeting inclusion criteria (n=73)Discharged without surgery (n=16)Previous identical hip-fracture (n=6)

Transfer to another hospital (n=6)Malignancy (n = 2)

Total hip-prosthesis (n = 4) No acute trauma(n = 9)

Not testable (n = 15)Missed by emergency department (n=6)


Never delirious (n=107)Full course of the episode could not be de�ned

(n=20)Patients with 1 day of delirium (n=12)

Dominant Motor Subtype duringDelirium Episode (n=30)

Hypoactive (n=5)Hyperactive (n=7)

Mixed (n=6)No motor subtype (n=1)

Variable (n=11)


(n=265)


Patients (n=169)Never delirious (n=107)Incident delirium (n=62)

longitudinal stability Motor subtype profile throughout the course of delirium is shown in Figure 2. 42/62 (67.7%) patients with in-hospital postoperative delirium had a well-defined endpoint of delirium. 30/42 (71.4%) had a delirium episode longer than one day. Of these patients with more than one day of delirium, only 4/30 (13.3%) patients had a constant motor subtype profile throughout the delirium episode, while 26/30 (86.7%) patients had a

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variable course. All 4 patients with a stable pattern had a delirium episode of only 2 days, all other patients with a variable pattern had 2 or more days of delirium. The 26 patients with a variable course had a total of 112 assessments. Subtype categories at these visits were 28/112 (25%) hypoactive, 30/112 (26.8%) hyperactive, 41/112 (36.6%) mixed and 13/112 (11.6%) had no motor symptoms present.

figure 2. Occurrence of Motor Subtypes during the course of Delirium for each Patient (n=42).

Hypoactive subtype Hyperactive subtype Mixed subtype No motor subtype

Assessments

Patients

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5

Baseline Characteristics and outcomesThe baseline characteristics of the 30 patients categorized according to dominant motor subtype profiles are presented in Table 1. Characteristics did not differ significantly between motor subtype groups.

Table 1. Baseline Characteristics between Dominant Motor Subtype Groups.

hypoactiveSubtype

(n=5)

hyperactiveSubtype

(n=7)

mixedSubtype

(n=6)

no motor Subtype

(n=1)

Variable motor

Subtype (n=11)

P-value

demographics

Age (years) 87.8 ± 4.5 83.9 ± 3.7 85.8 ± 5.9 82.0 86.3 ± 5.3 .38

Female gender n/N (%) 4/5 (80) 5/7 (71.4) 3/6 (50) 1/1 (100) 10/11 (90.9) .40

History of Delirium n/N (%) 0/4 (0) 0/7 (0) 3/6 (50) 1/1 (100) 2/10 (20) .05

mental status

MMSE total score 22.6 ± 3.0 23.7 ± 2.6 18.8 ± 5.6 20.0 22.6 ± 2.0 .94

IQCODE-N 3.6 ± 0.5 3.9 ± 0.5 4.4 ± 0.4 4.6 3.9 ± 0.7 .74

DRS-R98 total severity score 7.2 ± 4.2 5.0 ± 2.0 10.8 ± 3.6 13.0 7.0 ± 3.8 1.00

functional status

Living independently, n/N (%) 3/4 (75) 4/5 (80) 1/4 (25) 0/1 (0) 6/7 (85.7) .17

BI 13.8 ± 4.1 17.6 ± 2.1 16.0 ± 3.9 9.0 15.1 ± 5.1 .44

Lawton IADL 16.0 ± 7.0 9.9 ± 5.2 16.3 ± 8.1 28.0 18.5 ± 6.2 .44

Burden of illness

APACHE II 14.0 ± 3.5 14.0 ± 1.3 13.3 ± 2.3 8.0 13.6 ± 1.8 .74

Number of co-morbid diseases at home

1.8 ± 1.5 2.1 ± 2.0 2.5 ± 1.8 2.0 2.7 ± 2.3 .44

Number of medications at home

5.6 ± 3.8 5.1 ± 4.1 3.8 ± 2.5 8.0 4.6 ± 4.3 .51

Values are expressed as means ± SD or n/N is number with characteristic/total number, (%) is percentage.MMSE is Mini Mental State Examination, range 0 (severe cognitive impairment) to 30 (no cognitive impairment), score <24 indicates cognitive impairment.IQCODE-N is Informant Questionnaire on Cognitive Decline in the Elderly - Short Form, range 16 (cognitive improvement) to 80 (severe cognitive decline), mean score >3,6 indicates cognitive decline. Delirium Rating Scale Revised-98 (DRS-R98), range 0 (no severity) to 39 (maximum severity).BI is Barthel Index, range 0 (severe disability) to 20 (no disability).Lawton IADL is Lawton Instrumental Activities of Daily Living scale, range 8 (no disability) to 31 (severe disability).APACHE II is Acute Physiological and Chronic Health Evaluation II, range 0 (no acute health problems) to 70 (severe acute health problems).

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Outcome measures according to motor subtype profiles are shown in Table 2. Follow-up data 3 months after hospital discharge was available for 13 patients. No significant differences were evident between the motor subtype groups.

Table 2. Outcome Variables between Dominant Motor Subtype Groups.

hypoactiveSubtype

(n=5)

hyperactiveSubtype

(n=7)

mixedSubtype

(n=6)

no motor Subtype

(n=1)

Variable motor subtype(n=11)

P-value

Decreased independency in living situation n/N (%)

4/4 (100) 1/5 (20) 2/4 (50) - 5/7 (71.4) .09

Number of days in hospital 9.4 ± 4.6 11.9 ± 6.2 23.8 ± 15.9 13.0 16.6 ± 8.6 .07

Died during hospitalization n/N (%)

N.A N.A N.A N.A N.A N.A

Length of delirium episode (days)

4.4 ± 2.5 4.0 ± 2.8 6.0 ± 1.5 4.0 2.7 ± 0.9 .22

DRS-R98 mean severity score during episode (without motor items)

17.8 ± 2.5 16.6 ± 3.9 17.0 ± 3.8 11.3 16.4 ± 5.8 .66

DRS-R98 mean severity score during episode (with motor items)

20.2 ± 2.7 18.6 ± 4.0 19.6 ± 3.9 12.0 18.6 ± 6.4 .58

DRS-R98 highest score during delirium episode

24.6 ± 2.7 24.3 ± 5.6 26.0 ± 5.0 15.0 23.0 ± 7.4 .91

DRS-R98 total severity score at first delirious day

20.0 ± 5.8 22.7 ± 7.5 21.0 ± 5.5 15.0 18.5 ± 7.5 .83

Decreased independency in living situation from baseline to 3 months after hospital discharge; (data on 13 patients, who had follow-up data 3 months after hospital discharge available).Delirium Rating Scale Revised-98 (DRS-R98), severity items 1-13, range 0 (no severity) to 39 (maximum severity).

dISCuSSIonThis study examined motor profile and its relationship to other clinical characteristics and outcomes in an elderly hip fracture population with postoperative in-hospital delirium. Subtype categorization according to dominant motor subtype across the delirium episode identified groups that did not differ significantly in characteristics or outcomes. Notably, longitudinal assessment indicated that most patients had a variable course, with few patients having a consistent motor profile throughout their delirium episode. This challenges the validity of existing knowledge of motor subtypes which is almost exclusively derived from cross-sectional studies which have limited meaning if the majority of patients have variable motor subtypes across their delirium course as was evident in this study.

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Relatively little is known about the longitudinal trajectory of motor subtypes in delirium. We investigated the longitudinal course of motor subtypes for each patient and found that many patients transitioned several times during the delirium episode with, for example, 87% changing motor subtype category between the first and second day of delirium. Previous longitudinal work in palliative care patients found that most patients (62%) had a stable pattern, with hypoactive subtype being the most common stable pattern (29%).12 The observed variability was related to the number of assessments, since patients with a variable subtype course had significantly more visits than the patients with a stable pattern. This pattern was also evident in the study reported herein where patients with more data showed a more variable pattern. A study in MICU patients also performed daily assessments and reported that the majority of assessments were of the mixed subtype.20 However, they did not report on subtype stability over time. Thus it appears that the stability of motor subtypes may vary across populations but further work is needed, applying consistent subtyping methods to different populations. This study used a very active screening procedure which has good capacity to detect most if not all cases of delirium, including more easily missed hypoactive cases, which is a common problem in delirium research. This strengthens reliability of the percentages of delirium motor subtypes found in our study. We cannot exclude the possibility that the unstable course of motor subtypes in our study is associated with medication changes. However, the degree of variability was so marked that this factor alone is unlikely to fully account for the pattern and a previous study in palliative care patients using general estimating equations analysis found few associations existed between motor subtype (stable hypoactive, stable hyperactive, stable mixed, stable no subtype and variable course) and medication exposure or etiologies.19 Moreover, subtype transitions in the variable course group were uncommonly (14/102) preceded by a change to psychotropic medication apart from the finding that almost half of the transitions into the hypoactive subtype were preceded by increased benzodiazepine dosing.19 Further research is needed in populations other than palliative care patients to explore the stability of motor subtypes and to explore their relevance to other clinical characteristics and outcomes when longitudinal expression is considered. The variability in course of motor subtypes has potential implications for treatment since use of antipsychotic and other interventions is focused principally upon patients with hyperactive and mixed presentations. However, our data suggest that the majority of patients with hypoactive profiles will also experience hyperactivity at some point during their delirium episode and thus these interventions should be carefully considered in all patients. In conclusion, we found that the majority of elderly hip fracture patients in this homogenous sample experienced variable expression of motor subtype over the course of their delirium episodes. In addition, different dominant motor subtype profiles shared

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comparable cognitive and other clinical features and outcomes. These observations highlight the similarity across the clinical subtypes of this generally heterogeneous syndrome and the need to consider all therapeutic options relevant to delirium, regardless of clinical presentation. This work highlights the importance of longitudinal assessment in studies of clinical profile in delirium where the variability in presentation over time is considerable.

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13. Van Munster BC, Korevaar JC, Zwinderman AH, Levi M, Wiersinga WJ, de Rooij SE. Time course of cytokines during delirium in elderly patients with hip fractures. JAGS 2008; 56;1704-1709.

14. Breibart W, Rosenfeld B, Roth A, Smith MJ, Cohen K, Passik S. The Memorial Delirium Assessment Scale. J Pain Symptom Manage 1997; 13:128-137.

15. Liptzin B, Levkoff SE. An empirical study of delirium subtypes. Br J Psychiatry 1992; 161:843-845.

16. Leonard M et al. Motion analysis in delirium: a novel method of clarifying motoric subtypes. Neurocase 2007; 13:272-277.

17. Godfrey A, Conway R, Leonard M, Meagher D, Olaighin GM. Motion analysis in delirium: a discrete approach in determining physical activity for the purpose of delirium motoric subtyping. Med Eng Phys 2010; 32:101-110.

18. Eeles EM, Tahir TA, Johansen A, Bisson JI, Hubbard RE. Comparison of clinical assessment and actigraphy in the characterization of delirium. J Psychosom Res 2009; 67:103-104.

19. Meagher DJ, Leonard M, Donnelly S, Conroy M, Adamis D, Trzepacz PT. A longitudinal study of motor subtypes in delirium: relationship with other phenomenology, etiology, medication exposure and prognosis. J Psychosom Res 2011; 71:395-403.

20. Peterson JF et al. Delirium and its motoric subtypes: a study of 614 critically ill patients. JAGS 2006; 54:479-484.

21. Fann JR, Alfano CM, Burington BE, Roth-Roemer S, Katon WJ, Syrjala KL. Clinical presentation of delirium in patients undergoing hematopoietic stem cell transplantation. Cancer 2005; 103:810-820.

22. Marcantonio ER, Simon SE, Bergmann MA, Jones RN, Murphy KM, Morris JN. Delirium symptoms in post-acute care: Prevalent, persistent, and associated with poor functional recovery. JAGS 2003; 51:4-9.

23. Peterson JF, Truman B, Shintani A, Thomason JW, Jackson J, Ely EW. The prevalence of delirium subtypes in medical ICU patients. JAGS 2003; 51:S174.

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24. Witlox J et al. Cerebrospinal fluid β-amyloid and tau are not associated with risk of delirium: a prospective cohort study in older adults with hip fracture. J Am Geriatr Soc 2011; 59:1260-1267.

25. Slor CJ et al. Affective functioning after delirium in elderly hip fracture patients. Int Psychogeriatr 2012; 30:1-11.



28. de Jonghe JF, Schmand B, Ooms ME, Ribbe MW. [Abbreviated form of the Informant Questionnaire on cognitive decline in the elderly]. Tijdschr Gerontol Geriatr 1997; 28:224-229.

29. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13:818-829.

30. Mahoney FI, Barthel DW. Functional evaluation: The Barthel Index. Md State Med J 1965; 14:61-65.



33. Lindeboom J, Matto D. [Digit series and Knox cubes as concentration tests for elderly subjects]. Tijdschr Gerontol Geriatr 1994; 25:63-68.

34. Wei LA, Fearing MA, Sternberg EJ, Inouye SK. The Confusion Assessment Method: a systematic review of current usage. Journal of the American Geriatrics Society 2008; 56:823-830.

35. Trzepacz PT, Mittal D, Torres R, Kanary K, Norton J, Jimerson N. Validation of the Delirium Rating Scale-revised-98: comparison with the delirium rating scale and the cognitive test for delirium. J Neuropsychiatry Clin Neurosci 2001; 13; 229-242.


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Validation and psychometric properties of the delirium motor subtype scale in elderly hip fracture patients (Dutch version)

Chantal J. SlorDimitrios AdamisRené W.M.M. JansenDavid J. MeagherJoost WitloxAlexander P.J. HoudijkJos F.M. de Jonghe

Accepted for publication in Archives of Gerontology and Geriatrics

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ABSTrACTBackground: Motor disturbances are common in delirium. Different methods have been used to identify motor subtypes of delirium, which possibly differ in pathophysiology, treatment needs and prognosis. The Delirium Motor Subtype Scale (DMSS) was developed to capture all the previous different approaches to subtyping into one new instrument and emphasize disturbances of motor activity rather than associated psychomotoric symptoms. methods: We investigated the reliability and validity of the DMSS Dutch version. Elderly patients who had undergone hip fracture surgery received the Dutch version of the DMSS and the Delirium Rating Scale revised 98. A diagnosis of delirium was defined according to the Confusion Assessment Method. results: Among 146 patients, 46 (32%) patients were diagnosed with delirium (mean age 86.3 years SD 5.2). The internal consistency of the DMSS was acceptable (Cronbach’s alpha=0.72). If an item was removed at random the internal consistency of the scale remained the same. Similarly the concurrent validity of DMSS was good (Cohen’s kappa=0.73) while for each motor subtype the Cohen’s kappa ranged from 0.58 to 0.85. The sensitivity and specificity of DMSS to detect each subtype ranged from 0.56 to 1 and from 0.88 to 0.98 respectively.Conclusion: This study suggests that the Dutch version of the Delirium Motor Subtype Scale is a reliable and valid instrument. Assessments on each patient were generally performed by the same rater, although this could imply correlation between the ratings, the DMSS and DRS-R-98 items are different. Second, the decided cut-off scores for the DRS-R-98 might have had some influence on the results. Despite these limitations, the translated scale can differentiate different motor subtypes within an elderly hip-fracture patient sample. The DMSS has scientific validity that could allow for greater precision in further research on motor subtypes.

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Validation and psychometric properties of the delirium motor subtype scale (Dutch version)

6

InTroduCTIonDelirium is a complex neuropsychiatric syndrome that is common in hip surgery patients and is associated with long-term negative outcomes that include cognitive deterioration, institutionalization and mortality.1 It is characterized by acute onset, fluctuation in consciousness and inattention, along with a range of neuropsychiatric and cognitive symptoms. Disturbances in motor activity are almost invariably present in full syndromal illness and follow two principal patterns involving hyperactivity and hypoactivity.2,3 These features can present as a variety of clinical subtypes, hyperactive, hypoactive, and mixed subtype, where elements of both hyperactivity and hypoactivity occur within short time frames.4 Studies suggest that these subtypes may have important differences in pathophysiology, treatment needs and prognosis.5 In addition, a key difference is that hypoactive presentations are more frequently not recognised and/or misdiagnosed in clinical practice.6 However, results remain inconsistent since other studies have found poorer prognosis for the hyperactive or mixed subtype.7,8 These inconsistencies are related to differences in clinical populations studied, but are also impacted upon by the use of different methods for defining clinical subtypes.3 Motor subtypes of delirium have been identified with symptom checklists,9,10 motor items from delirium severity rating scales7,11,12

or based on clinical impression.13 The DRS-R-98 has been translated into the Dutch language and can be used to distinguish delirium motor subtypes.12 All these previous subtyping methods have included psychobehavorial disturbances supposedly associated with motor activity levels, such as changes to affect, sleep, or psychotic symptoms. To capture all these different elements and approaches within a single 30-item instrument The Delirium Motoric Checklist was developed.3 This instrument combined features from three psychomotor subtyping schemas.9,10, 14 Subsequently this was reduced to an 11-item Delirium Motor Subtype Scale (DMSS) based upon relative specificity of items for delirium vs. non-delirious controls and also according to correlation of items with independently assessed motor activity as per items 7 and 8 of the DRS-R-98.3,15 This new tool emphasises disturbances of motor activity rather than associated psychomotoric symptoms in motor subtyping.5 It is a simple instrument, designed for both medical and non-medical staff and suggested to have good concurrent and predictive validity.16,17 Also, DMSS-defined motor subtypes (hypoactive, hyperactive, mixed and no subtype) have been shown to match electronic measure of motion, although the principal differences were between hyperactive and hypoactive patients, and less significant differences regarding the mixed motor profile were found.18 The DMSS can allow for more precise diagnosis of clinical subtypes of delirium, which in turn can allow more focused research of delirium pathophysiology and treatment.15 While initial studies of the DMSS validity are promising, studies have been limited to palliative care settings, and validity needs to be established in other patient samples, including elderly hip fracture patients.

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Few studies have examined motor subtypes of delirium in hip surgery patients.7,19-21 These have used a variety of methods to identify motor subtypes including the Memorial Delirium Assessment Scale (MDAS), the classification system developed by Liptzin and Levkoff and the criteria as described by Lipowski.4,9,22 Some of these studies in hip fracture patients found no differences between motor subtypes, while others did find significant associations. The aim of the present study was to report on the reliability and validity of the Delirium Motor Subtype Scale Dutch version in a sample of hospitalized elderly hip-fracture patients with delirium. To the best of our knowledge it is the first time delirium subtypes after hip surgery were examined in great detail using the DMSS.

meThodSethical considerationsThis study was conducted in accordance with the Declaration of Helsinki and the guidelines on Good Clinical Practice. Approval of the regional research ethics committee was obtained. All patients gave written informed consent.

Study design and objectives The study was conducted in a series of consecutively admitted elderly hip fracture patients to a teaching hospital in Alkmaar, the Netherlands (Clinicialtrials.gov; registration number NCT00497978; Research on delirium has been published previously23). Patients were ineligible to participate in the study if they had no surgery, had a malignancy, had a previous hip-fracture on the identical side, were in contact isolation, incapable of participating in interviews (language barrier, aphasia, coma), had no acute trauma or received a total hip prosthesis.

Baseline (preoperative) assessmentThe baseline assessment was completed within 12 hours of admission and before surgery. It consisted of patient and proxy interviews, assessment of delirium, and inspection of all available medical records. Demographic variables such as age and gender were also documented. Assessments were performed by trained and experienced members of the research team. A diagnosis of delirium was defined according to the criteria of the Confusion Assessment Method (CAM) which consists of an acute onset and fluctuating course of cognitive function, inattention, and either disorganized thinking and/or altered level of consciousness.24 The CAM algorithm was rated on the basis of an interview with the patient and hospital staff, brief cognitive assessment with the MMSE and the expanded digit span test, and screening of the medical and nursing records for signs of delirium.25,26 During hospital admission presence of delirium was assessed daily from time of admission until

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the fifth postoperative day or discharge. In identified cases of delirium assessments were conducted until remission for three consecutive days (CAM negative) or until discharge.

Translation of the dmSSThe DMSS was translated into Dutch by two members of the research staff experienced in delirium research. The translators were native Dutch speakers, both fluent in English. Back-translation was done by native English speakers, also fluent in Dutch. The final translation was approved by David Meagher, one of the developers of the original DMSS.

delirium motor subtype definition Delirium was classified into hypoactive, hyperactive, mixed and no motor subtype according to two methods (1) the DMSS, and (2) using the motor items of the DRS-R-98.15,27 The DMSS and Delirium Rating Scale Revised-98 (DRS-R-98) were assessed daily. The Delirium Motor Subtype Scale (DMSS) is a scale using 11 motor items derived from items used in previous motor subtyping methods but with relative specificity for delirium.15 It can be rated by any healthcare professional who is familiar with patient behaviour and can be used to rate the previous 24 hours or more. Each symptom is rated as absent (score 0) or present (score 1). DMSS hyperactive subtype was deemed present if there was definite evidence in the previous 24 hours (and this should be a deviation from pre-delirious baseline) of at least two of the following symptoms (items 1-4): increased quantity of motor activity, loss of control of activity, restlessness and wandering. Hypoactive subtype was deemed present if there was definite evidence in the previous 24 hours (and this should be a deviation from pre-delirious baseline) of two or more of the following symptoms (items 5-11): decreased amount of activity, decreased speed of actions, reduced awareness of surroundings, decreased amount of speech, decreased speed of speech, listlessness and reduced alertness/withdrawal. At least one of either decreased amount of activity or speed of actions must be present. Mixed Motor Subtype was present if there was evidence of both hyperactive and hypoactive subtype criteria in the previous 24 hours. If there was evidence of neither hyperactive or hypoactive subtype in the previous 24 hours this was classified as no motor subtype. As a comparison DRS-R-98 defined motor subtypes were used. For subtype classification with the Delirium Rating Scale Revised-98 (DRS-R-98) items 7 (motor agitation) and 8 (motor retardation) were used.27 Hypoactive delirium is defined as a score of 1-3 on DRS-R-98 item 8 (motor retardation) and a score of 0 on DRS-R-98 item 7 (motor agitation). Hyperactive delirium is defined as a score of 1-3 on DRS-R-98 item 7 and a score of 0 on DRS-R-98 item 8. The mixed subtype is defined as scores of 1-3 on both DRS-R-98 item 7 and 8. The no motor subtype had scores of 0 on both items.

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Statistical AnalysisStatistical analyses were conducted using SPSS version 20. The following analyses were performed with the sample of delirious patients. Cronbach’s alpha was used to estimate the internal consistency of the DMSS. To estimate the concurrent validity of the groups of the four motor subtypes, as defined by the DMSS. The motor subtypes were compared with the motor subtypes as defined by the DRS-R-98 items 7 (motor agitation) and 8 (motor retardation), using the Cohen’s kappa statistic. To graphically represent the relationships between each one of the DMSS motor categories with the comparable motor category, as it has been defined by the DRS-R-98, a correspondence analysis was used. Correspondence analysis is a graphical technique to represent the rows and columns of a two way (in this case the DMSS and DRS-R-98 motor categories) contingency table in a joint plot.

reSulTS 146 patients were included of which 46 (31.5%) patients were diagnosed with delirium on the first postoperative day. Analyses were performed with data on this first postoperative day to minimise loss of data due to attrition and to include more delirious participants, since this day had the highest delirium frequency. descriptive statisticsThe mean age of the 46 patients was 86.3 years (SD: 5.2, range 73-97 ). The sample consisted of 29 (63%) female patients. The number of delirious participants within each delirium motor subtype according to the DMSS and the DRS-R-98 ratings are shown in Table 1. Of the 100 non-delirious patients, 7% was categorized as hypoactive, 6% was hyperactive, none were mixed and 87% was classified as no motor subtype according to the DMSS. The same non-delirious sample was classified with the DRS-R-98 into 15% hypoactive, 17% hyperactive, 3% mixed and 65% no motor subtype.

reliability analysisThe internal consistency of the scale was assessed with the Cronbach’s alpha. The Cronbach’s alpha for the 11 items in the sample of delirious participants (n=46) was 0.72. As the scale itself consists of two different parts no split-half method was used. However, if an item was removed at random the internal consistency of the scale remained the same. This is an indication that the scale can be reduced to a smaller number of items. Because the measured target (motor activity) can change from one day to another no test-retest reliability analysis was performed.

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Table 1. Number of Delirious Patients within each Motor Subtype based on DMSS and DRS-R-98.

dmSS motor Subtypes

hypoactiveSubtype

hyperactive Subtype

mixed Subtype

no motor Subtype

Total

drS-r-98 motor Subtypes

Hypoactive Subtype n=11 n=0 n=1 n=1 n=13

Hyperactive Subtype n=0 n=14 n=0 n=0 n=14

Mixed Subtype n=4 n=3 n=9 n=0 n=16

No Motor Subtype n=0 n=0 n=0 n=3 n=3

Total n=15 n=17 n=10 n=4 n=46

DMSS is Delirium Motor Subtype Scale.DRS-R-98 is Delirium Rating Scale Revised-98.

Concurrent ValidityThe psychometric properties of the DMSS were evaluated in the group of delirious participants (n=46). Overall Cohen’s kappa was 0.73 and Cramer’s V was 0.78. The agreement between the DMSS and DRS-R-98 on motor subtype categorization, and the sensitivity and specificity, for the delirious group are shown in Table 2.

Table 2. Agreement, Sensitivity and Specificity of the Scale in the Delirium Sample (n=46).

Kappa value Sensitivity (CI) Specificity (CI)

Hypoactive Subtype 0.69 0.84 (CI: 0.54 – 0.97)

0.88 (CI: 0.71 – 0.96)

Hyperactive subtype 0.85 1 (CI: 0.73 – 1)

0.90 (CI: 0.74 – 0.97)

Mixed Subtype 0.58 0.56 (CI: 0.31 – 0.80)

0.97(CI: 0.80 – 1)

No Motor Subtype 0.85 1 (CI: 0.31 – 1)

0.98 (CI: 0.86 – 1)

CI=Confidence Interval

Correspondence analysisA two dimensions solution explained the relationship between the categories of each scale (cumulative proportion of inertia 95%) best. Figure 1 shows the relations between the categories (motor subtypes) of each scale. Points that are close together are more

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similar than points that are far apart. From the graph it can be seen that both scales identify the four subtypes very well.

figure 1. Correspondence Analysis – Relationship between DMSS and the DRS-R-98 defined Motor Subtype Categories.

dISCuSSIonThis study examined validity and psychometric properties of the Dutch version of the Delirium Motor Subtype Scale in a sample of hospitalized elderly hip-fracture patients with and without delirium. We found that the translated scale had acceptable psychometric properties. The Dutch DMSS had good agreement with the DRS-R-98 on motor subtype identification, which confirms the findings in the initial study on the DMSS.15 However, in contrast to the DRS-R-98 method of subtype attribution, the DMSS had greater specificity for delirium as evidenced by the substantially lower attribution of motor subtypes in non-delirious patients. The DRS-R-98 was used as a reference measure of motor activity in this study. The Dutch version of the DRS-R-98 has been found to distinguish hypoactive and non-hypoactive subtypes.12 Although uncertainty remains about optimal cut-off scores and the DMSS is relatively more precise regarding the particular aspects of motor activity that can define subtypes and is also designed for use by a range of healthcare staff, rather than those with delirium-expertise as recommended for the DRS-R-98. Further research can be

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supported by the use of more ‘objective’ measures of motor activity, such as actigraphy / electronic motion analysis. Studies of delirious patients indicate that different motor activity patterns can be distinguished by this means.18,28-30 However, it remains unclear whether the three motor subtypes represent distinct categories, since less significant differences have been found for the mixed subtype.18 Further research with both these ‘objective’ measures of motor activity and motor ratings and categorization like the DMSS can advance our knowledge on this subject. Delirium was originally classified into two motor subtypes, i.e. hyperactive and hypoactive.31 A third category, mixed, was subsequently added in recognition that elements of both subtypes can appear within short time frames.4 The status of mixed motor subtype has been uncertain. Previous work with palliative care patients indicated that this subtype was common, associated with more severe overall delirium and stable over time in a large percentage of patients.2 This supports mixed motor subtype as a separate motor category, and not just a reflection of the fluctuating nature of delirium or a transitional phase between hypoactive and hyperactive subtypes. However, this study highlights that there is much lower concordance between the DMSS and DRS-R-98 methods regarding the attribution of mixed rather than other clinical subtypes and suggests that its delineation may require further revision informed by studies in other clinical populations and using electronic motion analysis. The ‘no motor subtype’, without substantial motor activity disturbances present, is suggested to reflect less severe, subsyndromal or even questionable delirium.2 This is in keeping with the method by which the DMSS items were selected i.e. according to relative specificity of motor symptoms for delirium vs. non-delirious controls. Of note, more than 90% of delirious patients met criteria for either hypoactive, hyperactive or mixed motor subtypes whilst in contrast 87% of non-delirious patients were deemed ‘no subtype’ emphasising the relative specificity of the motor activity items in the DMSS for delirium. The relative homogeneity of the hip surgery sample in our study made it very suitable to study motor subtypes without the potential confounding effects of different underlying somatic illnesses. Longitudinal research might also increase our understanding of the existence of different motor subtype categories. Since most studies are cross-sectional there is limited knowledge regarding the stability of motor subtypes over the course of delirium. Recent work with palliative care patients indicated that the mixed subtype is common and stable throughout the delirium episode in almost two-thirds of the patients who present with mixed profile on the first assessment.2 Further research in different populations can explore the stability of motor subtypes over time, using instruments such as the DMSS for subtype categorization. A limitation of this study is that the assessments on each patient were generally performed by the same rater. This might challenge the validity, because the ideal would be independent assessments. Although this could imply correlation between the ratings,

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the DMSS and DRS-R-98 items are different. Thus the good agreement between both scales on subtype identification found in this study supports the validity of the Dutch version of the DMSS. Since there is no overall agreement on optimal cut-off scores for the DRS-R-98 when used for motor subtyping, the decided cut-off scores might have had some influence on the results. A cut-off score of 2 might have increased the specificity for the mixed subtype, but would reduce the coverage of delirium with many patients falling in to the no subtype category. In conclusion, the findings in this study suggest that the translated version of the DMSS is a valid and reliable instrument. It can differentiate different motor subtypes within an elderly hip-fracture patient sample. The DMSS has scientific validity that could allow for greater precision in studies exploring important issues such as detection, pathophysiology, treatment and prognosis of motor subtypes. Further use of this instrument, including studies with longitudinal design, can advance our knowledge on the different delirium motor subtypes.

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referenCeS

1. Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. Journal of the American Medical Association 2010; 304:443-451.

2. Meagher DJ, Leonard M, Donnelly S, Conroy M, Adamis D, Trzepacz PT. A longitudinal study of motor subtypes in delirium: frequency and stability during episodes. Journal of Psychosomatic Research 2012; 72:236-241.

3. Meagher DJ et al. Motor symptoms in 100 patients with delirium versus control subjects: comparison of subtyping methods. Psychosomatics 2008; 49:300-308.

4. Lipowski ZJ. Delirium in the elderly patient. New England Journal of Medicine 1989; 320:578-582.

5. Meagher D. Motor subtypes of delirium: past, present and future. International Review of Psychiatry 2009; 21:59-73.

6. Meagher D, Leonard M. The active management of delirium: Improving detection and treatment. Advances in Psychiatric Treatments 2008; 14:292-301.

7. Marcantonio E, Ta T, Duthie E, Resnick NM. Delirium severity and psychomotor types: their relationship with outcomes after hip fracture repair. Journal of the American Geriatrics Society 2002; 50:850-857.

8. Kobayashi K, Takeuchi O, Suzuki M, Yamaguchi N. A retrospective study of delirium subtype. Japanese Journal of Psychiatry and Neurology 1992; 46:911-917.

9. Liptzin B, Levkoff SE. An empirical study of delirium subtypes. British Journal of Psychiatry 1991; 161:843-845.

10. O’Keeffe ST, Lavan JN. Clinical significance of delirium subtypes in older people. Age and Ageing 1999; 28:115-119.

11. Platt MM, Breitbart W, Smith M, Marotta, R, Weisman H, Jacobsen PB. Efficacy of neuroleptics for hypoactive delirium. Journal of Neuropsychiatry and Clinical Neurosciences 1994; 6:66.

12. de Rooij SE, van Munster BC, Korevaar JC, Casteelen G, Schuurmans MJ, van der Mast RC, Levi M. Delirium subtype identification and the validation of the Delirium Rating Scale--Revised-98 (Dutch version) in hospitalized elderly patients. International Journal of Geriatric Psychiatry 2006; 21:876-882.

13. Van der Cammen TJM, Tiemeier H, Engelhart MJ, Fekked D. Abnormal neurotransmitter metabolite levels in Alzheimer patients with a delirium. International Journal of Geriatric Psychiatry 2006; 21:838-843.

14. Lipowski ZJ. (1980). Delirium: Acute Brain Failure in Man. New York, Oxford University Press.

15. Meagher D et al. A new data-based motor subtype schema for delirium. Journal of Neuropsychiatry and Clinical Neurosciences 2008; 20:185-193.

16. Leonard M et al. Motion analysis in delirium: a novel method of clarifying motoric subtypes. Neurocase 2007; 13:272-277.

17. Meagher D, Leonard M, Donnelly S, Conroy M, Adamis D, Trzepacz PT. A Longitudinal Study of Motor Subtypes in Delirium: Relationship with Other Phenomenology, Etiology, Medication Exposure and Prognosis. Journal of Psychosomatic Research 2011; 71:395-403.

18. Godfrey A, Leonard M, Donnelly S, Conroy M, O’Laighin G, Meagher D. Validating a new clinical subtyping scheme for delirium with electronic motion analysis. Psychiatry Research 2010; 178:186-190.

19. Santana-Santos F, Wahlund LO, Varli F, Tadeu Velasco I, Eriksdottier Jonhagen M. Incidence, clinical features and subtypes of delirium in elderly patients treated for hip fractures. Dementia and Geriatric Cognitive Disorders 2005; 20:231-237.

20. Van Munster, BC, Korevaar JC, de Rooij SE, Levi M, Zwinderman AH. The association between delirium and the apolipoprotein E epsilon 4 allele in the elderly. Psychiatric Genetics 2007; 17:261-266.

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21. Van Munster BC, Korevaar JC, Zwinderman AH, Levi M, Wiersinga WJ, de Rooij SE. Time course of cytokines during delirium in elderly patients with hip fractures. Journal of the American Geriatrics Society 2008; 56:1704-1709.

22. Breibart W, Rosenfeld B, Roth A, Smith MJ, Cohen K, Passik S. The Memorial Delirium Assessment Scale. Journal of Pain and Symptom Management 1997; 13:128-137.

23. Witlox J et al. Cerebrospinal fluid β-amyloid and tau are not associated with risk of delirium: a prospective cohort study in older adults with hip fracture. Journal of the American Geriatrics Society 2011; 59:1260-1267.

24. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Annals of Internal Medicine 1990; 113:941-948.

25. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 1975; 12:189-198.


27. Trzepacz PT, Mittal D, Torres R, Kanary K, Norton J, Jimerson N. Validation of the Delirium Rating Scale-revised-98: comparison with the delirium rating scale and the cognitive test for delirium. Journal of Neuropsychiatry and Clinical Neurosciences 2001; 13:229-242.

28. Van Uitert M, de Jonghe A, de Gijsel S, van Someren EJ, de Rooij SE, van Munster BC. Rest-activity patterns in patients with delirium. Rejuvenation Research 2011; 14:483-490.

29. Osse RJ, Tulen JH, Bogers AJ, Hengeveld MW. Disturbed circadian motor activity patterns in postcardiotomy delirium. Psychiatry and Clinical Neurosciences 2009; 63:56-64.

30. Honma H et al. Motor activity rhythm in dementia with delirium. Psychiatry and Clinical Neurosciences 1998; 52:196-198.

31. Lipowski ZJ. Transient cognitive disorder in the elderly. American Journal of Psychiatry 1983; 140:1426-1436.

7Chapter

The neuropsychological sequelae of delirium in elderly patients with hip-fracture three months after hospital discharge

Joost WitloxChantal J SlorRené WMM JansenKees J KalisvaartMireille FM van StijnAlexander PJ HoudijkPiet EikelenboomWillem A van GoolJos FM de Jonghe

International Psychogeriatrics 2013; 25:1521-1531

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ABSTrACTBackground: Delirium is a risk factor for long-term cognitive impairment and dementia. Yet, the nature of these cognitive deficits is unknown as is the extent to which the persistence of delirium symptoms and presence of depression at follow-up may account for the association between delirium and cognitive impairment at follow-up. We hypothesized that inattention, as an important sign of persistent delirium and/or depression, is an important feature of the cognitive profile 3 months after hospital discharge of patients who suffered in-hospital delirium.methods: Prospective cohort study. Fifty-three patients 75 years and older admitted for surgical repair of acute hip fracture. Before surgery baseline characteristics, depressive symptomatology, and global cognitive performance were documented. Presence of delirium was assessed daily during hospital admission and 3 months after hospital discharge when patients underwent neuropsychological assessment. results: Of twenty-seven patients with in-hospital delirium, five were still delirious after three months. Patients with in-hospital delirium (but free of delirium at follow-up) showed poorer performance than patients without in-hospital delirium on tests of global cognition and episodic memory, even after adjustment for age, gender, and baseline cognitive impairment. In contrast, no differences were found on tests of attention. Patients with in-hospital delirium showed an increase of depressive symptoms after three months. However, delirium remained associated with poor performance on a range of neuropsychological tests among patients with few or no signs of depression at follow-up.Conclusion: Elderly hip fracture patients with in-hospital delirium suffer from impairments in global cognition and episodic memory three months after hospital discharge. Our results suggest that inattention, as a cardinal sign of persistent delirium or depressive symptomatology at follow-up cannot fully account for the poor cognitive outcome associated with delirium.

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The neuropsychological sequelae of delirium three months after hospital discharge

7

InTroduCTIonDelirium is a severe neuropsychiatric syndrome characterized by an acute decline in attention and cognition (American Psychiatric Association 2000). 1 Although delirium is often viewed as a transient and reversible cognitive disorder research has shown that delirium is associated with long-term cognitive impairment and dementia (Jackson et al. 2004; MacLullich et al. 2009; Witlox et al. 2010).2-4

Neuropsychological test batteries are considered the ‘gold standard’ for investigating cognitive functioning. Yet, most studies that examined the association of delirium with cognitive impairment merely used screening instruments which are inappropriate for fully characterizing and quantifying defects in specific cognitive domains (Jackson et al. 2004).2 Therefore, the precise nature of the cognitive impairments and the extent to which particular cognitive domains are affected after delirium remains uncertain (MacLullich et al. 2009).3

A better understanding of the nature of the cognitive impairments following delirium might help to ascertain the value of different hypotheses that have been proposed to explain the relationship between delirium and cognitive impairment at follow-up. Delirium may persist for months and patients with cognitive impairment at follow-up may in fact suffer from persistent delirium (Cole et al. 2009). 5 Alternatively, patients with cognitive impairment at follow-up may have depression or suffer from neurodegenerative disease (Krogseth et al. 2011; Lenze et al. 2007).6,7 The few studies that examined the neuropsychological profiles of elderly patients after an episode of delirium (Benoit et al. 2005; Jankowski et al. 2011; Katz et al. 2001) have not adequately addressed the possibility that the presence of delirium symptoms or depression may have influenced performance on cognitive tests at follow-up.8-10

The aim of the present study was to evaluate cognitive performance at follow-up in elderly hip fracture patients who did or did not suffer from in-hospital delirium. We used a comprehensive neuropsychological approach and examined to what extent inattention, as an important sign of persistent delirium (Meagher et al. 2010)11 and depression (Herrmann et al. 2007),12 is an important feature of the neuropsychological profile of patients who have had delirium three months earlier during their hospital admission.

meThodSParticipantsThis is a prospective cohort study that was nested within in a clinical trial that compared the effectiveness of taurine versus placebo in reducing morbidity and one-year mortality in elderly hip fracture patients aged 75 years and older (Clinicaltrials.gov; registration number NCT00497978). Examining neuropsychological function, three months after hospital discharge, was a pre-specified secondary aim of the trial.

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Approval of the regional research ethics committee was obtained. All patients gave signed informed consent. Patients were recruited from a series of consecutively admitted elderly hip fracture patients to a non-academic teaching hospital in Alkmaar, the Netherlands. Eligibility was checked for all patients 75 years or older admitted for primary surgical repair of hip fracture. Patients were not eligible if they had no acute trauma, received a total hip prosthesis, had a pathological fracture, were not capable (e.g. dementia in the medical case notes, aphasia, coma) or not willing to provide informed consent or had contraindications regarding the administration of taurine (i.e. renal impairment defined as a creatinine clearing less than 30 ml/min). As these patients are at high risk for developing delirium all patients received routine care with prophylactic treatment of 0.5 mg haloperidol, three times daily, from time of admission until postoperative day three, unless contraindications regarding its use were present (Kalisvaart et al. 2005).13

All patients who developed delirium during hospital admission were asked to participate in the follow-up. A subgroup of patients without delirium was selected to participate as controls based on random selection by a computer generated randomization code. Because we were specifically interested in the effects of in-hospital delirium on neuropsychological test performance three months after hospital discharge we excluded patients with clinically manifest delirium at follow-up (Figure 1).

Baseline (preoperative) assessmentBaseline assessment was completed within 12 hours after hospital admission and before surgery. The following demographic variables were documented; age, gender, and educational level. Cognitive functioning was assessed with the Mini Mental State Examination (MMSE) (Folstein et al. 1975) 14, and pre-existent cognitive decline with the Informant Questionnaire on Cognitive Decline in the Elderly Short-Form (IQCODE-N) (de Jonghe et al. 1997;Jorm and Jacomb 1989).15,16 The Geriatric Depression Scale (GDS) was used a self-inventory of depressive symptomatology (Sheikh and Yesavage 1986; Stek et al. 2004).17,18 The number and type of medical co-morbidities and medications at home, the American Society of Anesthesiologists (ASA) physical status classification system (American Society of Anesthesiologists 2010),19 and the Acute Physiology Age and Chronic Health Examination (APACHE II) (Knaus et al. 1985) score 20 were abstracted from the medical record. Visual acuity was assessed with the standardized Snellen test for visual impairment (Hetherington 1954).21 Pre-fracture (I)ADL functioning was assessed by a close relative or caregiver with the Barthel Index (BI) (Mahoney and Barthel 1965)22 and the Lawton IADL scale (Lawton and Brody 1969).23 Delirium was defined according to the criteria of the Confusion Assessment Method (CAM) which consists of an acute onset and fluctuating course of cognitive function, inattention, and either disorganized thinking and/or altered level of consciousness (Inouye et al. 1990).24 The CAM algorithm was rated on the basis of an interview with the patient and hospital staff, brief cognitive assessment

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with the MMSE and the expanded digit span test (Lindeboom and Matto 1994),25 and screening of the medical and nursing records for signs of delirium. Presence of delirium was assessed daily from time of hospital admission until at least the fifth postoperative day. For the IQCODE-N, BI, and Lawton IADL, proxies were asked to describe the patient’s condition a week before the fracture as to determine function unbiased by the event of hip fracture itself or any acute or sub-acute event leading to hip fracture.

Three month follow-up assessmentA neuropsychological test battery was administered three months after hospital discharge by two trained neuropsychologists. The neuropsychological battery was designed to assess multiple cognitive domains and contained standardized and validated instruments. It also included the MMSE, the expanded digit span test and the GDS, and took approximately one hour to complete. Most patients were examined at home; some patients preferred to visit the hospital. The CAM was used to screen for delirium at follow-up. CAM positive patients at follow-up were those that demonstrated an acute change or fluctuation in their mental status plus the accompanying inattention and disorganized thinking and/or altered level of consciousness. The Dutch version of the National Adult Reading Test (DART) was used to measure pre-morbid verbal intelligence (Nelson 1991;Schmand et al. 1992).26,27 The DART requires patients to read aloud 50 words with irregular pronunciation. Episodic memory was examined with the Dutch version of Verbal Learning Test; i.e. the Groningen Fifteen Words Test (Brand and Jolles 1985; van der Elst et al. 2005).28,29 Fifteen words are presented orally and the patient is asked to repeat as many words as possible when the presentation stops. After five trials a 20 minute delay is interspersed at the end of which the patient is asked to recall and recognize the previously learned words (delayed recall). We analyzed: (1) the total number of correctly recalled words summed over five trials; (2) the number of correctly recalled words after the delay; and (3) the number of correctly recognized target and non-target words. Attention and concentration was first assessed with the expanded digit span test. In this test the examiner reads a string of digits which the patient has to repeat in either the same (forward) or the reverse (backward) order (Lindeboom and Matto 1994).25 The forward and backward tests were analyzed separately with the forward span measuring concentration, and the backward span measuring working memory (Lezak et al. 2004).30

Second, the Expanded Mental Control Task (EMCT) which consists of 12 word lists and arithmetic progressions that the patient has to recite within a certain amount of time was administed (Lindeboom et al. 1993).31 The following measures of the EMCT were analyzed: (1) the combined total score; (2) total time needed to complete all items; and

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(3) total number of errors. Third, a computerized simple reaction time task (RT) was used in which the patient had to press the space bar as quickly as possible when the word “YES” appeared in the screen. The time between stimuli presentation varied randomly between 1-3 seconds. Forty trials were administered and we analyzed (1) mean reaction time; (2) intra-trial variability of reaction times, i.e. standard deviation of reaction times; and (3) number of premature responses, i.e. response during the inter-stimulus interval. The Clock Drawing test measures visuoconstructive function. Patients are asked to draw a clock and set the hands of the clock at ten past eleven. Points are given for: (1) drawing a closed circle; (2) correct ordering of the numbers within the clock; (3) correct spatial location of the numbers within the clock; and (4) inserting the hands at the correct time (Pinto and Peters 2009).32

We administered the Dutch version of the Controlled Oral Word Association Test (COWAT) to examine executive function (Schmand et al. 2008).33 This verbal fluency task requires patients to name as many words as possible within 60 seconds beginning with a target letter specified by the examiner. Proxies were asked to complete the IQCODE-N for the second time with reference to the situation 3 months after hospital discharge.

outcomePerformance on neuropsychological tests three months after hospital discharge.

Statistical AnalysisStatistical calculations were performed using SPSS for Windows, version 14 (SPSS; Inc. Chicago, Il., USA). Quantitative variables are presented as mean (standard deviation (SD)) or median (inter-quartile range (IQR)). Chi-Square or Fisher Exact tests were used to analyze categorical variables. Continuous variables were analyzed with student t-tests or Mann-Whitney U tests for between group comparisons and paired t-tests or Wilcoxon’s signed ranks tests for within group comparisons. The assumption of normality was tested with the Kolmogrov-Smirnov test. To examine whether delirium is associated with neuropsychological test performance independent of important covariates we fitted a multiple linear regression model for those neuropsychological measures that were associated with delirium in univariate analyses. In the multivariate models we entered delirium as an independent variable together with age, gender, baseline MMSE, and treatment allocation. These covariates were selected a priori based on their potential to influence neuropsychological test performance. Besides the demographic variables age and gender, educational level has also been shown to affect neuropsychological test performance (van der Elst et al. 2005).29 However, education was not included as a covariate into our regression models for two reasons: (a) preliminary analyses showed that the results remained unchanged

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whether or not the variable ‘level of education’ was included in the models; and (b) given our sample size we aimed to restrict the number of independent variables to a maximum of five. In the regression models that are presented in the results section we entered the baseline MMSE, and not the baseline IQCODE-N, as a measure of pre-existent cognitive impairment. Compared with the IQCODE-N (which measures intra-individual changes in cognitive functioning) the MMSE provides a score that can more easily be compared between patients. We performed sensitivity analyses to examine whether inclusion of the IQCODE-N (instead of the MMSE) produced similar results. The baseline measures of the GDS and IQCODE-N were entered as covariates, instead of the MMSE, in the multivariate models that examined the association between delirium during hospitalization and the GDS and IQCODE-N at follow-up. The core assumptions of linear regression modelling were tested for each model. Statistical significance was set at P<.05.

reSulTSA total of 53 patients with and without delirium during hospitalization underwent comprehensive neuropsychological testing three months after hospital discharge (Figure 1).

figure 1. Flow Chart.

Number of patients with hipfracture

March 2008 – March 2009n =257

Number in trial n=122

- Declined to participate in FU n=8 - Died before FU n=10 - No operation n=1

- Not able (profound dementia, profound dementia, aphasia, coma) n=64

- Not willing n=20- Renal failure n=20- No operation or transfer to other hospital n=13

- No acute trauma, total hip prothesis, pathological # n=11

- Missed n=4- Language barrier n=3

Number in analyses n=22

Not invited for FU n=39

Deliriumn=46

Controln=76

Delirium at FU n=5

Number in analyses n=26

Deliriumn=27

Controln =26

- Declined to participate in FU n=7- Died before FU n=2 - No operation n=1

FU=Follow-up

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Five patients (all of whom also experienced delirium in the hospital) were diagnosed with delirium at follow-up according to CAM criteria. Thus, 48 patients free from clinically manifest delirium at follow-up of whom 22 had previously experienced delirium were available for our analyses. Ten of 22 (45%) patients with previous delirium scored one or two points on the CAM at follow-up compared with 3/26 (12%) controls. According to the CAM 8/22 (36%) patients with in-hospital delirium were inattentive at follow-up compared with 2/26 (8%) controls (P=.03). No patient displayed disorganized thinking or an altered level of consciousness at follow-up. The duration between hospital discharge and neuropsychological assessment was on average 81 days and did not differ between both groups (t(46)=.05, P=.96).

Preoperative comparisons between groupsBaseline characteristics of patients with and without in-hospital delirium are presented in Table 1. Baseline cognitive impairment, as evidenced by low MMSE and high IQCODE-N scores, was poorer in patients with delirium as compared with those without. Also, patients in the delirium group were more dependent in (I)ADL functioning at home. Other baseline characteristics did not differ significantly between both groups.

Table 1. Baseline Characteristics of Patients With and Without In-hospital Delirium.

delirium n=22

no deliriumn=26

P-Value

demographic

Age (years) 84.3 ± 5.0 82.2 ± 6.0 .20

Gender n/N (% female) 16/22 (73) 20/26 (77) .74

Low educational level, n/N (% ) 9/22 (41) 9/26 (36) .73

mental status

MMSE|| 22.9 (4.0) 25.4 (3.1) .02

Cutoff < 24, n/N(%) 10/21 (48) 5/25 (20)

IQCODE-N§ 3.8 (.54) 3.3 (.37) >.001

Cutoff > 3.6, n/N(%) 13/21 (62) 2/24 (8)

Expanded digit span forward^ 11.5 (1.8) 11.4 (2.7) .85

Expanded digit span backward^ 5.9 (1.9) 7.1 (1.9) .06

Affective status

GDS¶ score 2.3 (1.3) 2.2 (1.8) .79

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delirium n=22

no deliriumn=26

P-Value

Burden of illness

APACHE II† 13.2 (1.4) 12.9 (1.8) .45

ASA‡ group, n/N (%)

Group I;

II;

III;

5/22 (23)

13/22 (59)

4/22 (18)

8/26 (31)

13/26 (50)

5/26 (19)

.79

Number of co-morbid diseases 2.0 (1.0 – 3.0) 1.0 (1.0 – 2.3) .85

Number of medications at home 4.5 (3.4) 4.2 (3.1) .78

functional status

Living independently, n/N (%) 4/22 (18) 0/26 (0) .02

Visual impairment*, n/N (%) 2/19 (11) 0/26 (0) .09

BI# 18.0 (14.0 – 20.0) 20.0 (18.8 – 20.0) .04

Lawton IADL** 15.1 (4.1) 12.0 (5.2) .04

Values are expressed as means ± SD or median (IQR), n/N is number with characteristic/total number, (%) is percentage.||MMSE is Mini Mental State Examination, range 0 (severe cognitive impairment) to 30 (no cognitive impairment), score <24 indicates cognitive impairment.§ IQCODE-N is Informant Questionnaire on Cognitive Decline in the Elderly - Short Form, range 16 (cognitive improvement) to 80 (severe cognitive decline), mean score >3,6 indicates cognitive decline. ^ Expanded digit span test, range 0 (poor performance) to 21 (very good performance), forward measures concentration, backward measures working memory. ¶ GDS is Geriatric Depression Scale, range 0 (depression not likely) to 15 (depression very likely), score > 4 indicates depression.† APACHE II is Acute Physiological and Chronic Health Evaluation II, range 0 (no acute health problems) to 70 (severe acute health problems).‡ ASA is American Society of Anesthesiologists physical status classification system, range 1 (normal health patient) to 5 (moribund patient).* Visual impairment measured with the standardized Snellen test for visual impairment and defined as binocular near vision worse than 20/70 after correction. # BI is Barthel Index, range 0 (severe disability) to 20 (no disability).** Lawton IADL is Lawton Instrumental Activities of Daily Living scale, range 8 (no disability) to 31 (severe disability).

follow-up comparisons between groupsAt follow-up, patients with in-hospital delirium performed poorer on tests of global cognitive performance (MMSE), episodic memory, and attention than controls (Table 2). Moreover, patients with in-hospital delirium also showed more signs of depression (GDS) and cognitive decline (IQCODE-N) at follow-up than controls (Table 2). After adjustment for relevant confounders the association between in-hospital delirium and global cognitive performance (MMSE), episodic memory, and depressive symptoms (GDS) remained significant (Table 3). When sensitivity analyses were performed in which the baseline MMSE was substituted by the baseline IQCODE-N the association between in-hospital delirium and the MMSE at follow-up did not remain significant (data not shown).

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Table 2. Global Cognitive and Affective Performance and Neuropsychological Test Scores at Three Months Follow-up of Patients With and Without In-hospital Delirium.

delirium n=22

no deliriumn=26

P-Value

MMSE || 23.1 (4.5) 26.8 (2.7) .002

IQCODE-N§ 4.0 (.67) 3.3 (.43) .001

GDS¶ 5.1 (3.5) 2.5 (2.1) .004

Expanded digit span forward^ 10.5 (2.7) 10.5 (2.8) .96

Expanded digit span backward^ 5.5 (2.5) 6.6 (1.9) .11

DART† 71.2 (15.8) 62.6 (16.9) .10

Fifteen Words Test total recall 20.3 (5.9) 29.7 (8.2) <.001

Fifteen Words Test delayed recall 1.1 (1.7) 5.1 (2.9) <.001

Fifteen Words Test delayed recall 22.1 (3.8) 26.5 (3.2) .001

EMCT‡ total 17.7 (5.8) 20.3 (2.8) .09

EMCT‡ total time (seconds) 272 (123) 224 (80) .16

EMCT‡ total error 6.5 (1.8 – 15.0) 3.0 (1.5 – 7.5) .11

Clock drawing 2.0 (1.0 – 3.0) 3.5 (2.0 – 4.0) .06

COWAT* total 19.2 (8.1) 23.5 (11.0) .25

RT# total error 1.0 (.0 – 6.0) 1.0 (.0 – 3.5) .43

RT# mean (milliseconds) 543 (383 – 911) 338 (283 – 457) .01

RT# standard deviation (milliseconds) 355 (112 – 608) 126 (80 – 225) <.05

BI ^^ 17.0 (12.5 – 20.0) 19.0 (17.8 – 20.0) .23

Lawton IADL** 19.9 (6.4) 16.2 (6.4) .14

Values are expressed as means ± SD or median (IQR).|| MMSE is Mini Mental State Examination, range 0 (severe cognitive impairment) to 30 (no cognitive impairment), score <24 indicates cognitive impairment.§ IQCODE-N is Informant Questionnaire on Cognitive Decline in the Elderly - Short Form, range 16 (cognitive improvement) to 80 (severe cognitive decline), score >57 (i.e. mean score >3,6) indicates cognitive decline. ¶ GDS is Geriatric Depression Scale, range 0 (depression not likely) to 15 (depression very likely), score >4 indicates depression.^ Expanded digit span test, range 0 (poor performance) to 21 (very good performance), forward measures concentration, backward measures working memory.† DART is Dutch Adult Reading Test, a measure of pre-morbid verbal intelligence, range 0 (no words correctly pronounced) to 100 (all words correctly pronounced).‡ EMCT is Expanded Mental Control Task measures attention, range total score 0 (poor performance) to 24 (very good performance).* COWAT is Controlled Oral Word Association Test, a measure of executive function with higher scores indicating a better performance.# RT is simple Reaction Time task, a measure of attention.^^ BI is Barthel Index, range 0 (severe disability) to 20 (no disability).** Lawton IADL is Lawton Instrumental Activities of Daily Living scale, range 8 (no disability) to 31 (severe disability).

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7

Tabl

e 3.

Mul

tiple

Lin

ear R

egre

ssio

n M

odel

s of

Neu

rops

ycho

logi

cal T

est S

core

s Si

gnifi

cant

ly A

ssoc

iate

d w

ith In

-hos

pita

l Del

irium

in U

niva

riate

Ana

lyse

s.

3 m

onth

s fo

llow

-up

mSS

efi

ftee

n W

ords

Tes

tto

tal r

ecal

lfi

ftee

n W

ords

Tes

t de

laye

d re

call

fift

een

Wor

ds T

est

reco

gnit

ion

reac

tion

Tim

em

ean

reac

tion

Tim

eSt

anda

rd d

evia

tion

βP-

valu

er²

βP-

valu

er²

βP-

valu

er²

βP-

valu

er²

βP-

valu

er²

βP-

valu

er²

Age

(yea

rs)

-.14

.23

-.15

.25

-.12

.36

-.14

.26

.37

.01

.30

.06

Gen

der

.04

.72

.31

.01

.29

.02

.58

<.0

01.1

3.3

6.1

0.5

0

MM

SE b

asel

ine

.54

<.0

01.3

5.0

08.3

7.0

06.2

0.1

0-.2

7.0

6-.2

9.0

7

Del

irium

-.29

.02

-.40

.003

-.44

.001

-.41

.001

.26

.07

.09

.57

Trea

tmen

t gro

up.0

1.9

1-.1

4.2

5.0

1.9

3-.0

03.9

8-.1

3.3

5.1

6.2

8

.56

.56

.59

.65

.43

.29

3mon

ths

follo

w-u

pG

dS

IQCo

de-

n

βP-

valu

er²

βP-

valu

er²

Age

(yea

rs)

.20

.15

Age

(yea

rs)

.13

.06

Gen

der

.17

.19

Gen

der

.04

.58

GD

S ba

selin

e.4

6.0

01IQ

COD

E-N

bas

elin

e.8

3<

.001

Del

irium

.39

.006

Del

irium

.14

.10

Trea

tmen

t gro

up.0

09.9

4Tr

eatm

ent g

roup

-.04

.54

.42

.84

Abb

revi

atio

ns: M

MSE

, Min

i Men

tal S

tate

Exa

min

atio

n; IQ

COD

E-N

, Inf

orm

ant Q

uest

ionn

aire

on

Cogn

itive

Dec

line

in th

e El

derly

- Sh

ort F

orm

; GD

S, G

eria

tric

Dep

ress

ion

Scal

e.

104

Chapter 7

Preoperative to follow-up comparisonsThe degree of change in the MMSE over the course of three months between patients with and without in-hospital delirium was not significant (Table 4). However, a comparison within groups revealed that the MMSE of control patients improved over time (t(24)=-4.5, P<.001) while no change was observed in the delirium group (t(20)=-.1, P=.92). In contrast, the degree of change over time in the IQCODE-N between both groups was significant (Table 3) with more deterioration notable in the delirium group (t(15)=-3.2, P=.006) but not in the control group (t(25)=-.46, P=.65). None of the between- and within group analyses performed on the expanded digit span test showed any significant differences between patients with and without in-hospital delirium (data not shown). A preoperative to follow-up comparison of depressive symptomatology (GDS) between patients with and without in-hospital delirium was significant (Table 4) with patients who experienced in-hospital showing an increase of depressive symptoms (t(17)=-3.7, P=.002) while no change was observed among controls (t(24)=-.6, P=.55).

Table 4. Degree of Change Between Baseline and Three Months Follow-up for Patients With and Without In-hospital Delirium.

delirium no delirium P-Value

MMSE Δ .1 (4.2) 1.6 (1.8) .13

IQCODE-N Δ -.23 (.29) -.02 (.27) .02

Expanded Digit Span forward Δ -1.0 (3.1) -.4 (2.2) .47

Expanded Digit Span backward Δ -.7 (2.1) -.4 (2.1) .62

GDS Δ 2.7 (3.1) .2 (1.7) .005

Values are expressed as means ± SD; abbreviations: MMSE=Mini Mental State Examination; IQCODE-N=Informant Questionnaire on Cognitive Decline in the Elderly – Short Form; GDS, Geriatric Depression Scale.

exploratory subgroup analysesAmong patients who were free of any delirium symptoms at follow-up (i.e. CAM score of null), patients with in-hospital delirium still performed poorer on the total and delayed recall measure of the Fifteen Words test than non-delirious controls. Among patients with few to no symptoms of depression at follow-up (i.e. GDS<4), patients with in-hospital delirium performed poorer on tests of global cognition, episodic memory, attention and constructional praxis than non-delirious controls. Finally, patients who previously experienced in-hospital delirium and who did not showed any signs of cognitive impairment at baseline (i.e. MMSE>23 and IQCODE-N<3.6)

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7

performed significantly worse on all measures of the Fifteen Words Test than patients without previous cognitive impairment and delirium.

dISCuSSIonThis study evaluated the impact of in-hospital delirium on neuropsychological function three months after hospital discharge in a group of elderly hip fracture patients. In-hospital delirium was found to be independently associated with impairments on tests of global cognition and episodic memory at follow-up. Strengths of the current study include the systematic and simultaneous assessment of delirium, cognitive impairment, and depression at follow-up using standardized and validated instruments. A limitation of this study is the small patient number. Although this study would ideally have been performed in a larger and purely observational cohort, our multivariate models show highly significant associations between in-hospital delirium and poorer cognitive performance at follow-up. Nevertheless, future studies of larger cohorts would be better able to exclude potential type II errors and provide more robust and definitive conclusions. Such studies would also better able to take into account the interactions between delirium and numerous other determinants of cognitive impairment. Interestingly, patients with in-hospital delirium were more often labeled as ‘inattentive’ according to the CAM than controls at follow-up whereas no difference in attention performance was seen on the more objective neuropsychological tests. This discrepancy may be explained by a tendency of raters to label the observed cognitive impairments as having an attentional component when the cognitive deficits are more severe, as they are for patients with previous delirium. Several hypotheses have been proposed to explain the association between delirium and cognitive impairment. One of these explanations suggests that the high prevalence of cognitive impairment at follow-up among patients with previous delirium may reflect persistence of delirium instead (Cole et al. 2009). 5 Indeed, according to the CAM elderly hip fracture patients who earlier experienced in-hospital delirium were most likely to show signs of inattention – the cardinal and required symptom of (persistent) delirium (American Psychiatric Association 2000;World Health Organization 1993)34 – at follow-up. However, when important baseline characteristics were taken into account differences between both groups in attentional performance could not be observed on the more objective neuropsychological tests. This may imply that the poorer cognitive performance at follow-up of patients who earlier experienced delirium cannot be fully explained by the persistence of a key symptom of delirium. This suggestion is substantiated by our subgroup analyses that showed that patients with in-hospital delirium, but without delirium symptoms at follow-up (i.e. CAM score of null), performed poorer on a episodic memory test than controls who never experienced delirium.

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On the contrary, our study also clearly demonstrates that the persistence of delirium can affect cognitive outcome at follow-up in some patients, as almost 20% of our patients with in-hospital delirium was excluded because of persistent (or recurrent) delirium three months after hospital discharge. When explaining the association between delirium and cognitive impairment at follow-up the interrelationship between delirium and depression may also be of relevance. Depression is a known risk factor for delirium in elderly hip fracture patients (Olofsson et al. 2005). 34 In turn, delirium has been associated with higher depressive symptom levels months after hip fracture (Lenze et al. 2007) 7, and importantly, depression can markedly affect cognitive function (Herrmann et al. 2007).12 To date few if any studies have examined the association between delirium and cognitive impairment at follow-up while simultaneously documenting the presence of mood disturbances. Contrary to previous investigations (Olofsson et al. 2005)35 depression was not a risk factor for in-hospital delirium in our study. However, patients with in-hospital delirium did show an increase in depressive symptoms at follow-up that may (partially) explain their poorer performance on neuropsychological tests. Yet, the neuropsychological profile of depression in late life is typically characterized by diminished processing speed and impaired executive function (Herrmann et al. 2007).12 In contrast, our delirium patients showed disproportionate memory disturbances. In addition, in patients with few or no depressive symptoms present at follow-up, in-hospital delirium remained associated with poorer performance on a range of neuropsychological tests. These results suggest that an increase of depressive symptoms at follow-up among patients with previous delirium cannot fully explain their poorer cognitive functioning. As a consequence, studies that include patients with reversible causes of cognitive impairment, such as persistent delirium and depression, may systematically overestimate the strength of the relationship between delirium and newly acquired long-term cognitive impairment or dementia. If the presence of delirium symptoms or worsening of depressive symptomatology at follow-up cannot fully explain poor cognitive outcome of individuals with previous delirium what other explanations can be considered? Delirium may unmask early or subclinical dementia or may initiate or accelerate a process of cognitive decline. In most dementias there is a disproportionate disturbance on tests of global cognition and episodic memory with relatively preserved attentional capacities. Thus, the neuropsychological profile of our patients with previous delirium may seem consistent with the presence or development of a dementia syndrome. However, to test the hypothesis that delirium actually initiates neurodegeneration requires a (seemingly) non-demented population at baseline. Because pre-existent cognitive impairment is an important predisposing risk factor for delirium in elderly individuals (Dasgupta and Dumbrell 2006)36 our findings of poor cognitive performance at follow-up among patients with in-hospital delirium may

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merely reflect the presence (or acceleration) of baseline cognitive impairment. Indeed, many of our patients who did develop delirium showed signs of pre-fracture cognitive decline. Therefore, we adjusted our multivariate models for baseline cognitive impairment and also repeated our analyses in a subgroup of patients that did not showed any sign of cognitive impairment at baseline. The results of these analyses suggest that delirium may be more than a marker of pre-existent cognitive decline, although the exact mechanism through which delirium is associated with later cognitive deterioration remains unclear. Factors that precipitate delirium may incite a sequence of events in the brain which may contribute to the development or acceleration of cognitive impairment. Microglia and aberrant stress responses have been suggested to play a role in this detrimental process (Cunningham et al. 2009;MacLullich et al. 2008;van Gool et al. 2010).37-39

In conclusion, the current investigation provides evidence of the poor cognitive and affective prognosis of elderly people after delirium and adds to a growing body of evidence that suggests that delirium is associated with various forms of poor long-term outcomes (Witlox et al. 2010).4 Future studies with multiple and longer follow-up periods will be needed to draw definitive conclusions as to whether cognitive dysfunction at follow-up after delirium follows a static, fluctuating, gradually resolving or progressive course. Moreover, intervention studies are needed to investigate whether the sequelae associated with delirium can be averted.

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2. Jackson JC, Gordon SM, Hart RP, Hopkins RO, Ely EW. The association between delirium and cognitive decline: a review of the empirical literature. Neuropsychology Review 2004; 14(2):87-98.

3. MacLullich AM, Beaglehole A, Hall RJ, Meagher DJ. Delirium and long-term cognitive impairment. International Review of Psychiatry 2009; 21(1):30-42.

4. Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. Journal of the American Medical Association 2010; 304(4):443-451.

5. Cole MG, Ciampi A, Belzile E, Zhong L. Persistent delirium in older hospital patients: a systematic review of frequency and prognosis. Age and Ageing 2009; 38(1):19-26.

6. Krogseth M, Wyller TB, Engedal K, Juliebo V. Delirium is an important predictor of incident dementia among elderly hip fracture patients. Dementia and Geriatric Cognitive Disorders 2011; 31(1):63-70.

7. Lenze EJ et al. Onset of depression in elderly persons after hip fracture: implications for prevention and early intervention of late-life depression. Journal of the American Geriatrics Society 2007; 55(1):81-86.

8. Benoit AG at al. Risk factors and prevalence of perioperative cognitive dysfunction in abdominal aneurysm patients. Journal of Vascular Surgery 2005; 42(5):884-890.

9. Jankowski CJ et al. Cognitive and functional predictors and sequelae of postoperative delirium in elderly patients undergoing elective joint arthroplasty. Anesthesia and Analgesia 2011; 112(5):1186-1193.

10. Katz IR, Curyto KJ, TenHave T, Mossey J, Sands L, Kallan MJ. Validating the diagnosis of delirium and evaluating its association with deterioration over a one-year period. American Journal of Geriatric Psychiatry 2001; 9(2):148-159.

11. Meagher DJ, Leonard M, Donnelly S, Conroy M, Saunders J, Trzepacz PT. A comparison of neuropsychiatric and cognitive profiles in delirium, dementia, comorbid delirium-dementia and cognitively intact controls. Journal of Neurology, Neurosurgery and Psychiatry 2010; 81(8):876-881.

12. Herrmann LL, Goodwin GM, Ebmeier KP. The cognitive neuropsychology of depression in the elderly. Psychological Medicine 2007; 37(12):1693-1702.

13. Kalisvaart KJ et al. Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study. Journal of the American Geriatrics Society 2005; 53(10):1658-1666.

14. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 1975; 12(3):189-198.

15. Jorm AF, Jacomb PA. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): socio-demographic correlates, reliability, validity and some norms. Psychological Medicine 1989; 19(4):1015-1022.

16. de Jonghe JF, Schmand B, Ooms ME, Ribbe MW. Abbreviated form of the Informant Questionnaire on cognitive decline in the elderly. Tijdschrift voor Gerontologie en Geriatrie 1997; 28(5):224-229.

17. Sheikh JI, Yesavage JA. (1986). Geriatric depression scale (GDS): recent findings and development of a shorter version. 819-820.

18. Stek ML, Gussekloo J, Beekman AT, van Tilburg W, Westendorp RG. Prevalence, correlates and recognition of depression in the oldest old: the Leiden 85-plus study. Journal of Affective Disorders 2004; 78(3):193-200.

19. American Society of Anesthesiologists. ASA Physical Status Classification System. In [www.asahq.org/clinical/physicalstatus.html]. Accessed January 2012.

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20. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Critical Care Medicine 1985;13(10):818-829.

21. Hetherington R. The Snellen chart as a test of visual acuity. Psychologische Forschung 1954; 24(4):349-357.

22. Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Maryland State Medical Journal 1965; 14:61-65.

23. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969; 9(3):179-186.

24. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Annals of Internal Medicine 1990; 113(12):941-948.

25. Lindeboom J, Matto D. Digit series and Knox cubes as concentration tests for elderly subjects. Tijdschrift voor Gerontologie en Geriatrie 1994; 25(2):63-68.

26. Nelson HE. (1991). The revised National Adult Reading Test- Test Manual. In NFER-Nelson Publishing Company: Windsor.

27. Schmand B, Lindeboom J, van Harskamp F. (1992). De Nederlandse Leestest voor Volwassenen. [The Dutch Adult Reading Test.]. In Swets and Zeitlinger: Lisse.

28. Brand N, Jolles, J. Learning and retrieval rate of words presented auditorily and visually. Journal of General Psychology 1985; 112(2):201-210.

29. van der Elst EW, Van Boxtel MP, Van Breukelen GJ, Jolles J. Rey’s verbal learning test: normative data for 1855 healthy participants aged 24-81 years and the influence of age, sex, education, and mode of presentation. Journal of the International Neuropsychological Society 2005; 11(3):290-302.

30. Lezak MD, Howieson DB, Loring DW. (2004). Orientation and Attention. In Neuropsychological Assessment, Lezak MD, Howieson DB, Loring DW (eds). Oxford University Press, Inc: New York, 337-374.

31. Lindeboom J, Koene T, Matto D. The diagnostic value of tests for mental control. Tijdschrift voor Gerontologie en Geriatrie 1993; 24(3):105-109.

32. Pinto E, Peters R. Literature review of the Clock Drawing Test as a tool for cognitive screening. Dementia and Geriatric Cognitive Disorders 2009; 27(3):201-213.

33. Schmand B, Groenink SC, van den Dungen M. Letter fluency: psychometric properties and Dutch normative data. Tijdschrift voor Gerontologie en Geriatrie 2008; 39(2):64-76.

34. World Health Organization. (1993). International statistical classification of diseases and related health problems. World Health Organization: Geneva.

35. Olofsson B, Lundstrom M, Borssen B, Nyberg L, Gustafson Y. Delirium is associated with poor rehabilitation outcome in elderly patients treated for femoral neck fractures. Scandinivian Journal Caring Sciences 2005; 19(2);119-127.

36. Dasgupta M, Dumbrell AC. Preoperative risk assessment for delirium after noncardiac surgery: a systematic review. Journal of the American Geriatrics Society 2006; 54(10):1578-1589.

37. Cunningham C et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biological Psychiatry 2009; 65(4):304-312.

38. MacLullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C. Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. Journal of Psychosomatic Research 2008; 65(3):229-238.

39. van Gool WA, van de Beek D, Eikelenboom P. Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet 2010; 375(9716):773-775.

8Chapter

Affective functioning after delirium in elderly hip fracture patients

Chantal J. SlorJoost WitloxRené W.M.M. JansenDimitrios AdamisDavid J. MeagherEsther TiekenAlexander P.J. HoudijkWillem A van GoolPiet EikelenboomJos F.M. de Jonghe

Int Psychogeriatrics 2013;25(3):445-455.

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ABSTrACTBackground: Delirium in elderly patients is associated with various long-term sequelae that include cognitive impairment and affective disturbances, although the latter is understudied. methods: A prospective cohort study of elderly patients undergoing hip fracture surgery. Baseline characteristics, affective and cognitive functioning were assessed preoperatively. During hospital admission presence of delirium was assessed daily. Three months after hospital discharge, affective and global cognitive functioning was evaluated again in patients free from delirium at the time of this follow-up. This study compared baseline characteristics and affective functioning between patients with and without in-hospital delirium. We investigated whether in-hospital delirium is associated with increased anxiety and depressive levels, and posttraumatic stress disorder symptoms three months after discharge. results: Among 53 eligible patients, 23 (43.4%) patients experienced in-hospital delirium after hip fracture repair. Patients who had experienced in-hospital delirium showed more depressive symptoms at follow-up after three months compared to the 30 patients without in-hospital delirium. This association persisted in a multivariate model controlling for age, baseline cognition, baseline depressive symptoms and living situation. The level of anxiety and symptoms of post-traumatic stress disorder (PTSD) at follow-up did not differ between both groups.Conclusion: This study suggests that in-hospital delirium is associated with an increased burden of depressive symptoms three months after discharge in elderly patients who were admitted to the hospital for surgical repair of hip fracture. Symptoms of depression in patients with previous in-hospital delirium cannot be fully explained by persistent (sub)syndromal delirium or baseline cognitive impairment.

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InTroduCTIonPostoperative delirium is a common neuropsychiatric complication in hospitalized elderly patients, with an incidence up to 56% after hip-surgery.1 This acute disorder is characterized by a decline in attention and cognition. Psychotic symptoms may occur, such as delusions and hallucinations, as well as mood instability. Although delirium is usually considered a brief transient state, it can persist and/or have long-term negative outcomes like cognitive deterioration and institutionalization.2-4

Much less is known about the impact of delirium upon affective functioning. Preoperative delirium is an identified risk factor for delirium, but what about postoperative delirium as a risk factor for depression afterwards.5 Previous work suggest that approximately 50% of the patients who experience in-hospital delirium have clinically significant depressive symptoms after hospital discharge, while other work suggests that depressive symptoms may be evident up to 2 years afterwards.6-9 Screening for depression after hip fracture found that the majority cases emerge within the first ten weeks.10 A review from Davydow9 identified eight studies relating to delirium and affective disturbances, of which four studies found an association between in-hospital delirium and subsequent depressive symptoms, two of the studies concerned delirium after hip fracture. Almost all of these studies are based on screening questionnaires only, with the exclusion of one study that used a semi-structured diagnostic interview in a cardiac surgery population. This review also noted that the existing studies were incapable of differentiating between depression after in-hospital delirium or a possible persisting delirium. A study on treatment and prevention of depression, as measured with the GDS, after hip surgery reported no significant effect of their interventions at follow-up assessments. If indeed delirium are subsequently associated with clinically manifest depression, this raises the question as to why intervention had no effect. In the case of increased depressive symptoms without full syndromal depression present, it might be that usual interventions are inappropriate. Yet, increased depressive symptoms after delirium are still of importance, because it interferes with rehabilitation after hip surgery.11

Anxiety levels, PTSD symptoms and their association with delirium have been investigated in different populations, other than hip fracture patients. In a study of 52 hematopoietic cell transplantation (HTC) patients, aged between 22 and 62 years, no association was found between delirium and anxiety levels at 6 months to 1 year follow-up.12 A limitation of this study is that the original Delirium Rating Scale was used for delirium diagnosis, which includes a relatively narrow range of delirium symptoms. A study with 34 burn victims found that affective distress during delirium correlated with worse psychopathological adjustment. Since burn injury can be considered as a traumatizing event in itself and this study population was also relatively young, the association between delirium and long-term psychiatric symptoms in elderly patients

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remains unclear.13 In the study on HTC patients delirium was associated with more symptoms of PTSD at 1-year follow-up, whereas no association was found with PTSD in intensive care unit (ICU) patients requiring mechanical ventilation.12,14

The aim of the present study was to examine affective functioning at follow-up, three months after hospital discharge, in elderly hip fracture patients with and without in-hospital delirium. This is the first study that simultaneously investigates anxiety and depression levels, and post-traumatic stress disorder symptoms three months after hospital discharge, and their association with delirium, in elderly hip fracture patients. The 3 months time period is relevant, since onset of depression has been suggested to be at its highest risk within the first ten weeks after hip fracture. In an attempt to clarify why previous studies have found contradicting results, this study used a variety of measurements for each symptom domain, including screening questionnaires and structured diagnostic interviews. meThodSethical considerationsThis study was conducted in accordance with the Declaration of Helsinki and the guidelines on Good Clinical Practice. Approval of the regional research ethics committee was obtained. All patients gave written informed consent including permission for the follow-up part of this study.

Study design and objectives The study was conducted in a series of consecutively admitted elderly hip fracture patients to a teaching hospital in Alkmaar, the Netherlands. Eligibility was checked for all patients 75 years and older admitted for primary surgical repair of hip fracture, from March 2008 to March 2009. A subgroup of this study cohort also participated in a clinical trial that compared the effectiveness of taurine versus placebo in reducing morbidity and one-year mortality in elderly hip fracture patients (Clinicaltrials.gov; registration number NCT00497978; Research on delirium has been published previously.15

Patients were ineligible to participate in the study if they had no surgery, had a malignancy, had a previous hip-fracture on the identical side, were in contact isolation, incapable of participating in interviews (language barrier, aphasia, coma), had no acute trauma, were transferred to another hospital or received a total hip prosthesis. Examining affective functioning three months after hospital discharge in patients who did or did not develop delirium during hospitalization was a pre-specified secondary aim of the study. All patients with delirium during hospital admission were asked to participate in the follow-up. Based on random selection by a computer generated randomization code a subgroup of patients without delirium during hospitalization were

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selected and invited to participate as controls. Declination to participate in the follow-up study did not significantly differ between people with and without in-hospital delirium. Because we were specifically interested in the effects of postoperative in-hospital delirium on affective functioning three months after hospital discharge, we excluded patients with prevalent delirium (already delirious at admission) from all the analysis. At the follow-up assessment we excluded patients who were still delirious from the analysis. An additional analysis was performed where we excluded patients with subsyndromal delirium. Definition of (full syndromal) delirium and subsyndromal delirium were based on Confusion Assessment Method (CAM) criteria).16 Patients who met full Confusion Assessment Method (CAM) criteria were classified as delirious (CAM item 1 and 2 plus either 3 or 4). Those patients with two CAM criteria but without full criteria were classified as having subsyndromal delirium.17 Before surgery a standardized baseline assessment had been completed to document patient characteristics, risk factors of delirium, and global cognitive performance. During hospital admission presence of delirium was assessed daily from time of admission until the fifth postoperative day or discharge, in case of delirium until it remitted for three consecutive days or until discharge. At the follow-up assessment patients were asked about additional hospitalizations or possible delirium episodes between discharge and follow-up. Three months after discharge patients underwent a comprehensive assessment that included among others the repetition of several tests presented at baseline. Baseline characteristics and neuropsychiatric test scores were compared between patients with and without in-hospital delirium. When applicable, we compared baseline and follow-up scores within groups. We also performed additional analyses to further examine the association between delirium and affective functioning in specific subgroups. Since participants were at high risk for delirium during hospitalization (i.e. age 75 years or older, and acute hospital admission) they all received routine care, according to hospital guidelines, with prophylactic treatment of .5 mg haloperidol, three times daily, from time of admission until postoperative day three, unless contraindications regarding its use were present.18

Baseline (preoperative) assessmentThe baseline assessment was completed within 12 hours of admission and before surgery. It consisted of patient and proxy interviews, assessment of delirium, and inspection of all available medical records. We documented the following demographic variables: age, gender, and educational level. To assess mental status we used the Mini Mental State Examination (MMSE) as a measure of baseline cognitive functioning on a scale of 0 (poor) to 30 (good) with scores lower than 24 indicating cognitive impairment.19 The 16 item Informant Questionnaire on Cognitive Decline in the Elderly Short-Form (IQCODE-N) was used as an estimate of pre-fracture cognitive decline and was scored by a close relative or caregiver on a scale of 16 (improvement) to 70 (decline).20 A score higher than 57 (i.e.

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mean item score of 3.6) indicates cognitive decline.21 We used the Hospital Anxiety and Depression Scale Part A (HADS-A) to measure anxiety levels.22 This screening tool consists of seven questions, on a four-point (1-4) scale. The maximum score is 28, with higher scores indicating more anxiety. Depressive symptoms were assessed with the Geriatric Depression Scale 15 (GDS-15) a 15 item self-rating scale for depression with higher scores indicating depression.23 Based on the items of the GDS we also calculated a separate core depression (items 1, 3-8,10-12,14-15) and apathy (items 2, 9 and 13) score.24 Burden of illness included the number and type of medical co-morbidities and medications before hospital admission. We also reviewed the medical record to document the American Society of Anesthesiologists (ASA) physical status classification system (range of 1 (normal health patient) to 5 (moribund patient)) and the Acute Physiology Age and Chronic Health Examination (APACHE II) score (range of 0 (no acute health problems) to 70 (severe acute health problems)).25,26 Functional status comprised pre-fracture living arrangement, visual acuity, activities of daily living (ADL) and instrumental activities of daily living (IADL). Visual acuity was assessed with the standardized Snellen test for visual impairment and visual impairment was defined as binocular near vision, after correction, worse than 20/70.27 Pre-fracture ADL functioning was determined with the Barthel Index (BI) which is scored by a close relative or caregiver on a scale from 0 (dependence) to 20 (independence).28 IADL was also assessed by a close relative or caregiver on the Lawton IADL scale with a range of 8 (no disability) to 31 (severe disability).29

A diagnosis of delirium was defined according to the criteria of the Confusion Assessment Method (CAM) which consists of an acute onset and fluctuating course of cognitive function, inattention, and either disorganized thinking and/or altered level of consciousness.16 The CAM algorithm was rated on the basis of an interview with the patient and hospital staff, brief cognitive assessment with the MMSE and the expanded digit span test, and screening of the medical and nursing records for signs of delirium.30 CAM positive patients were those that demonstrated an acute change or fluctuation in their mental status plus the accompanying inattention and disorganized thinking and/or altered level of consciousness. Delirium severity was measured using the Delirium Rating Scale Revised-98 (DRS-R-98), a 16-item rating scale comprised of thirteen severity items and 3 diagnostic items. The item-scores range of 0 (no severity) to 3 (maximum severity). Possible total severity scores range of 0 (no severity) to 39 (maximum severity).31 Delirium assessments continued until delirium remitted for three consecutive days or until discharge. In case of the IQCODE-N, BI, and Lawton IADL, proxies were asked to describe the patient’s condition a week before the fracture as to determine function unbiased by the event of hip fracture itself or any acute or sub-acute event leading to hip fracture.

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follow-up assessment at three monthsThe CAM was used to screen for delirium symptoms at follow-up and to exclude patients with persistent (i.e. from hospital discharge until follow-up) or recurring delirium. Several neuropsychiatric questionnaires were administered three months after hospital discharge by two trained neuropsychologists. The questionnaires were selected to assess several affective domains and contained standardized and validated instruments. The collection consisted of the following tests: The Mini-International Neuropsychiatric Interview (M.I.N.I.), The Post-Traumatic Stress Syndrome Scale 10 (PTSS-10), the HADS-A and the GDS-15.32,33 It took approximately 1 hour to complete the whole follow-up assessment. Most patients were examined at home, but some patients preferred to visit the hospital. The M.I.N.I. was used to assess the presence of a depressive episode, generalized anxiety disorder and posttraumatic stress disorder according to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM IV) criteria.34 Each domain is assessed with several yes/no questions. In addition to the M.I.N.I. the rating scale PTSS-10 was used to assess the presence of posttraumatic stress disorder. The PTSS-10 is a self-report questionnaire assessing symptoms related to post-traumatic stress disorder. The PTSS-10 consists of 10 items, each of which ranges from 1 point (none) to 7 points (always). The 10 symptoms are: sleeping problems, nightmares, gloom, jumpiness, the need to draw back from contact with other people, irritability, mood swings, the feeling of guiltiness, fear of locations or situations that remind the patient of the fall or hospitalization, and tensed muscles. The total score ranges from 10 to 70, with higher scores indicating more symptoms; scores of 35 or above are considered indicative of PTSD.35,36

outcomeScores on neuropsychiatric questionnaires three months after hospital discharge.

Statistical AnalysisStatistical calculations were performed using SPSS for Windows, version 19 (SPSS; Inc. Chicago, Il., USA). Descriptive statistics are provided to characterize patients with and without previous delirium. Quantitative variables are presented as mean (standard deviation (SD)) or median (inter-quartile range (IQR)). We presented raw test scores of neuropsychological tests. Chi-Square or Fisher Exact tests were used to analyze categorical variables. The assumption of normality was tested with the Kolmogrov-Smirnov test. Continuous variables were analyzed with student t-tests or Mann-Whitney U tests for between group comparisons and paired t-tests or Wilcoxon’s signed ranks tests for within group comparisons. To examine whether delirium is associated with scores on neuropsychiatric questionnaires independent of important covariates we fitted a multiple linear regression model for those affective measures that were associated with delirium in univariate analyses. In the multivariate models we entered delirium

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as an independent variable together with age, baseline MMSE score (continuous variable), living independently (yes/no) and baseline measure of the outcome variable. These covariates were selected based on their potential to influence delirium and neuropsychiatric symptoms. Given our sample size we aimed to restrict the number of independent variables to a maximum of 5. We repeated the analysis with the variable treatment allocation (taurine or placebo for the patients who participated in the RCT). In the regression models that are presented in the results section we entered the MMSE, and not the IQCODE-N, as a measure of pre-existent cognitive impairment. Compared with the IQCODE-N (which measures intra-individual differences) the MMSE provides a score that can more easily be compared between patients. The core assumptions of linear regression modelling were tested for each model: linearity of the relationship between dependent and independent variables, independence of the errors, constant variance of the errors and normality of the error distribution. Statistical significance was set at P<.05.

reSulTSThe final patient sample consisted of 53 patients of whom 23 (43.4%) experienced in-hospital delirium (Figure 1).



No delirium n=30

Prevalent delirium(n=23)

Delirium n=23

Died during admission(n=12)

Patients not meeting inclusion criteria (n=73)

Discharged without surgery (n=16)Previous identical hip-fracture (n=6)

Malignancy (n=2)Transfer to another hospital (n=6)

Total hip-prosthesis (n=4) No acute trauma(n=9)

Not testable (n=15)Missed by emergency department (n=6)



(n=265)


Prevalent delirium (n=23)


Declined to participaten=8

Died before follow-up n=10

No operation n=1Delirium at follow-up (n=5)

Declined to participate n=7Died before follow-up n=2

No operation n=1

At random selected toinvite for follow-up

At random selected toinvite for follow-up

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Table 1. Baseline Characteristics of Patients With and Without In-hospital Delirium.

delirium (n=23) no delirium (n=30) P-Value

demographic

Age (years) 84.3 ± 5.1 82.5 ± 6.1 .25

Female gender n/N (%) 17/23 (73.9) 24/30 (80) .60

Low educational level, n/N (% ) 9/23 (39.1) 11/29 (37.9) .93

Affective functioning

GDS score 2.5 ± 1.7 2.4 ± 1.8 .78

HADS-A score 8.8 ± 1.7 9.8 ± 2.5 .15

mental status

MMSE total score 22.9 ± 3.8 25.3 ± 3.1 .02

Cutoff < 24, n/N(%) 11/22 (50) 6/28 (21.4) .03

IQCODE-N 3.9 ± 0.6 3.3 ± 0.5 .002

Cutoff > 3.6, n/N(%) 14/22 (63.6) 4/30 (13.3) < .001

functional status

Living independently, n/N (%) 17/23 (73.9) 30/30 (100) .004

Visual impairment, n/N (%) 0/20 (0) 0/30 (0) -

BI 17.2 ± 3 18.2 ± 3.3 .08

Lawton IADL 15.5 ± 5 12.8 ± 5.4 .09

Burden of illness

APACHE II 13.2 ± 1.3 13.0 ± 1.8 .69

ASA group, n/N (%)

Group I;

II;

III;

5/20 (25)

12/20 (60)

3/20 (15)

8/26 (30.8)

13/26 (50)

5/26 (19.2)

.80

Number of co-morbid diseases 2.2 ± 1.5 2.4 ± 2.0 .98

Number of medications at home 4.6 ± 3.4 4.4 ± 3.1 .79

Psychotropics at admission 7/23 (30.4) 8/30 (26.7) .76

Treatment (taurine) 12/20 (60) 12/26 (46.2) .35

Values are expressed as means ± SD or n/N is number with characteristic/total number with available data, (%) is percentage.GDS is Geriatric Depression Scale, range 0 (depression not likely) to 15 (depression very likely). HADS-A is Hospital Anxiety and Depression Scale Part A to measure anxiety levels. Seven questions with a four-point (1-4) scale. The maximum score is 28.MMSE is Mini Mental State Examination, range 0 (severe cognitive impairment) to 30 (no cognitive impairment), score <24 indicates cognitive impairment.IQCODE-N is Informant Questionnaire on Cognitive Decline in the Elderly - Short Form, range 16 (cognitive improvement) to 80 (severe cognitive decline), mean score >3,6 indicates cognitive decline. Visual impairment measured with the standardized Snellen test for visual impairment and defined as binocular near vision worse than 20/70 after correction. BI is Barthel Index, range 0 (severe disability) to 20 (no disability).Lawton IADL is Lawton Instrumental Activities of Daily Living scale, range 8 (no disability) to 31 (severe disability).APACHE II is Acute Physiological and Chronic Health Evaluation II, range 0 (no acute health problems) to 70 (severe acute health problems).ASA is American Society of Anesthesiologists physical status classification system, range 1 (normal health patient) to 5 (moribund patient).Treatment, taurine or placebo for patients who participated in the RCT.

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The baseline characteristics of the 23 patients with and 30 without in-hospital delirium are presented in Table 1. Patients who developed in-hospital delirium were more cognitively impaired and more often institutionalized compared to patients who remained free from delirium postoperatively. Anxiety and depressive symptoms at admission did not differ between the patients with and without delirium, and no patient had a GDS-15 score higher than 7, indicative of more severe depressive symptoms.

Three months after hospital dischargeAt follow-up patients who had experienced in-hospital delirium had more depressive symptoms as reflected in the higher GDS-15 total scores and they remained more cognitively impaired compared to patients without delirium (Table 2).

Table 2. Characteristics at Three months Follow-up of Patients With and Without In-hospital Delirium.

Characteristic at follow-up: In-hospitaldelirium (n=23)

no deliriumduring admission

(n=30)

P-Value

GDS total score 4.9 ± 3.4 3.0 ± 2.7 .03

HADS-A total score 11.7 ± 3.9 10.5 ± 3.0 .23

PTSS-10 total score 19 ± 5.3 17.8 ± 5.3 .27

M.I.N.I. Major Depressive Episode with melancholic features

2/21 (9.5) 3/27 (11.1) 1.00

M.I.N.I. Major Depressive Episode 5/21 (23.8) 4/27 (14.8) .48

M.I.N.I. Generalized Anxiety Disorder 1/20 (3.7) 1/27 (3.7) 1.00

M.I.N.I. Posttraumatic stress disorder 0/20 (0) 0/27 (0) -

Values are expressed as means ± SD or n/N is number with characteristic/total number with available data, (%) is percentage.GDS is Geriatric Depression Scale, range 0 (depression not likely) to 15 (depression very likely). HADS-A is Hospital Anxiety and Depression Scale Part A to measure anxiety levels. Seven questions with a four-point (1-4) scale. The maximum score is 28. PTSS=10 is The Post-Traumatic Stress Syndrome Scale 10, range 10 to 70, with higher scores indicating more symptoms; scores of 35 or above are considered indicative of PTSD.M.I.N.I is Mini-International Neuropsychiatric Interview.

Further analysis showed that patients with in-hospital delirium scored higher on the core depressive symptoms of the GDS (P=.02), and not on the total score of the apathy items, compared to patients without in-hospital delirium at follow-up. Figure 2 shows the relative frequency of the GDS total scores at follow up within the delirium and control group. This figure shows that the scores of the non-delirious patients are centred within a lower range compared to the delirious patients, indicating that the difference between both groups are not caused by outliers.

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figure 2. Relative Frequency of GDS Total Scores Within Each Group.

Repetition of this analysis without patients who had subsyndromal delirium during hospitalization or at follow-up showed that patients with in-hospital delirium (n=18) had again significantly more depressive symptoms at follow-up compared to patients without delirium (n=23) (P=.004). 5/23 patients with in-hospital delirium had subsyndromal delirium at follow-up, and 7/30 patients without full-syndromal delirium did experience subsyndromal delirium during hospitalization. At follow-up the HADS-A score did not differ between patients with and without in-hospital delirium. Patients with and without delirium did not differ on diagnoses of generalized anxiety disorder and major depressive episode according to the M.I.N.I. However, almost half (47.1%) of the patients that had been delirious previously, did have three or more depressive symptoms according to the M.I.N.I compared to 5/20 (25%) patients without in-hospital delirium, this difference was not significant. Patients with and without delirium did not differ on PTSS-10 total scores. Also, no patients were diagnosed with posttraumatic stress disorder according to the M.I.N.I. Within group analysis Within group analysis showed that both in the post-delirium group (P=.003) and the control group (P=.04) HADS-A scores increased from baseline to follow-up. Depressive

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symptoms showed a significant increase from baseline to follow-up within the post-delirium group(P=.007), while no significant change was noted among controls who had remained free from delirium.

multivariate analysisIn multivariate analysis we examined the association between in-hospital delirium and GDS-15 scores at follow-up. We adjusted for age, MMSE at baseline, GDS-15 at baseline and living situation. In-hospital delirium remained associated with higher GDS-15 scores at 3 months follow-up (Table 4), also when excluding the apathy associated items from the score (B 1.72, 95% CI 0.42 – 3.02, P=.01). Repeating the multivariate analysis with treatment allocation to either taurine or placebo as a covariate did not change the results.

Table 3. Multiple Linear Regression Models of GDS Scores at Follow-up and In-hospital Delirium.

3 months follow-up GdS

B P-value r²

Age (years) .10 .14

MMSE baseline -.21 .16

Delirium 2.24 .01

Living Independently baseline -5.99 <.001

GDS baseline score .91 <.001

.48

GDS is Geriatric Depression Scale, range 0 (depression not likely) to 15 (depression very likely).MMSE is Mini Mental State Examination, range 0 (severe cognitive impairment) to 30 (no cognitive impairment), score <24 indicates. cognitive impairment.Living Independently (yes or no) before hospital admission.

dISCuSSIonThis study highlights the importance of monitoring elderly hip fracture patients after in-hospital delirium. It examined the association between in-hospital delirium after hip fracture surgery and affective functioning three months after hospital discharge. Depressive symptoms, anxiety levels and posttraumatic stress symptoms were assessed in an elderly population free from delirium at a 3-month follow-up. The main finding of this study is that the occurrence of in-hospital delirium was independently associated with increased depressive symptoms 3 months after hospital discharge. Although increased depressive symptoms at follow-up was associated with in-hospital delirium, this association did not equate with the diagnosis of major depressive

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disorder as measured with the M.I.N.I. This might explain why interventions after hip surgery had no effect on depression in a study with elderly hip fracture patients.10 Patients received six weekly sessions short after hip surgery aimed at either treatment or prevention of depression. Patients were assessed at follow-up, after six weeks, three months and six months. In this study the GDS-15 was used to identify depression and patients with delirium were excluded. In our study persistent or recurring full syndromal delirium does not explain the increased depressive symptoms, because patients with delirium at follow-up were excluded from analysis. An alternate explanation might be that the depressive symptoms might have been part of an existing subsyndromal delirium. However, repetition of the analysis in this study without patients that had subsyndromal delirium showed that patients with in-hospital delirium had again significantly more depressive symptoms at follow-up compared to patients without delirium. Experimental findings and neuropathological observations suggest that activation of microglia is pivotal for mediation of the acute behavioural and cognitive effects of systemic inflammation.37 A mild systemic inflammatory response suffices to increase the production of pro-inflammatory cytokines within the brain when microglia are already “primed” by chronic pathologic events as chronic neurodegeneration or advanced age.38 After hip surgery the release of pro-inflammatory cytokines as a consequence of fracture and surgery induces a systemic inflammatory response. In older hip-fracture patients delirium was associated with higher postoperative serum levels of proinflammatory cytokines while no differences were seen in the preoperative serum levels between the delirium and non-delirium patients.39,40 A recent study with elderly, hip-fracture patients found that depressive symptoms were associated with increased cytokine levels at 1 year follow-up.41 However, rates of delirium were not reported in this study. In animal studies the acute behavioural changes induced by a single dose of lipopolysaccharide (as a bacterial mimic) was followed by a increase of depressive-like symptoms. There was a temporal dissociation between the acute behavioural changes and the symptoms of depression with a time interval varying from hours to weeks depending on the eliciting conditions.42 The inflammation-associated depression was found to be mediated by a pro-inflammatory cytokines induced elevated activity of the tryptophan-degrading enzyme indoleamine 2,3 dioxoxygenase (IDO). Blockade of IDO activation either indirectly by the microglia inhibitor minocycline or directly by a specific IDO antagonist prevented the development of the inflammation-associated depressive symptoms. These findings indicate that the temporal dissociation between the acute behavioural changes and the depressive symptoms are based on distinct and time-related differences in the underlying biological mechanisms. In the present study we found that patients with in-hospital delirium have increased depressive symptoms three months later, in the absence of (sub)syndromal delirium. So, increased depressive symptoms after a delirious episode can not readily be explained by prolonged delirium or (sub)syndromal delirium. The animal

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studies discussed above may provide a biological rationale for this temporal dissociation in clinical symptoms. Another explanation for the increase in depressive symptoms after in-hospital delirium in elderly patients could be underlying cognitive impairments. Depression and dementia are suggested to be related, with increased prevalence of depression in people suffering from dementia.43 People with delirium were more cognitively impaired at baseline and were still more cognitively impaired three months after hospital discharge. This is why we controlled in this study for baseline cognitive functioning in multivariate analysis, after which in-hospital delirium was still associated with more depressive symptoms at follow-up. In a sub-sample of patients without evidence of cognitive impairment at baseline (MMSE >23 and IQCODE-N<3.6) again that patients with in-hospital delirium had more depressive symptoms at follow-up compared to controls. Previous research found mixed results concerning the association between delirium and anxiety levels at follow-up. Some did find an association between delirium and subsequent anxiety, others did not.44,12,13 In the present study no difference was found in anxiety levels between patients with and without in-hospital delirium three months after hospital discharge. However, anxiety levels did increase in both the delirious and control group. This might be related to the effects of hospitalization and having experienced surgery and interventions. The present study did not find an association between in-hospital delirium and PTSD symptoms at follow-up. A previous study in 90 patients undergoing hematopoietic cell transplantation did find that delirium was associated with higher levels of post traumatic stress at one year follow-up.12 The average duration of a delirium episode in this study, 2 days, and average total score of 19 on the PTSS-10 is comparable to previous research, which does not explain the current findings.14 It has been suggested that higher levels of PTSD symptoms are less likely to occur in older patients, like the patients in the present study.14 It is suggested that the development of PTSD symptoms is associated with delusional memories.45 Experiencing delusions and hallucinations during delirium might be the underlying link between in-hospital delirium and neuropsychiatric symptoms at follow-up. Further work might explore this relation more into detail by monitoring the occurrence of these symptoms during the delirious period and investigating the association with neuropsychiatric symptoms at follow-up Strengths of the current study are the detailed investigation of depressive symptoms using screening questionnaires as well as structured diagnostic interviews. We extensively investigated the possible effect of (subsyndromal) delirium, cognitive impairment and differentiated between increased depressive symptoms and actual depression. Moreover this study used standardized and validated instruments to assess affective functioning in the hospital and at follow-up. The limitations are that the sample is not a pure observational cohort. Taurine was administered to a part of the sample, which might have influenced

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outcome measures. However, treatment allocation was not associated with the incidence of delirium or affective functioning at follow-up. We controlled for treatment allocation in multivariate analysis, and found that a strong significant association between depressive symptoms at follow-up and in-hospital delirium remained. A larger cohort could however control for more factors that possibly interact with delirium and affective functioning, as well as reduce the likelihood of type II errors. To conclude, the findings in this study suggest that in-hospital delirium relates to poor affective functioning afterwards, namely increased depressive symptoms. The increase in depressive symptoms do not seem to be a reflection of an ongoing (subsyndromal) delirium, or be part of an actual major depressive disorder.

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referenCeS

1. Inouye SK, Viscoli CM, Horwitz RI, Hurst LD, Tinetti ME. A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Annals of Internal Medicine 1993; 119:474-481.

2. Adamis D, Treloar A, Martin FC, Macdonald AJ. A brief review of the history of delirium as a mental disorder. History of Psychiatry 2007; 18:459-469.

3. Cole MG. Persistent delirium in older hospital patients. Current Opinion in Psychiatry 2010; 23:250-254.

4. Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. The Journal of the American Medical Association 2010; 304:443-451.

5. Greene NH, Attix DK, Weldon BC, Smith PJ, McDonagh DL, Monk TG. Measures of executive function and depression identify patients at risk for postoperative delirium. Anesthesiology 2009; 110:788-795.

6. Dolan MM. et al. Delirium on hospital admission in aged hip fracture patients: predicition of mortality and two-year functional outcomes. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2000; 55A:527-534.

7. Olofsson B, Lundström M, Borssén B, Nyberg L, Gustafson Y. Delirium is associated with poor rehabilitation outcome in elderly patients treated for femoral neck fractures. Scandinavian Journal of Caring Sciences 2005; 19:119-127.

8. Lenze EJ et al. Onset of depression in elderly persons after hip fracture: implications for prevention and early intervention of late-life depression. Journal of the American Geriatrics Society 2007; 55,:81-86.

9. Davydow DS. Symptoms of depression and anxiety after delirium. Psychosomatics 2009; 50:309-316.

10. Burns A et al. Treatment and prevention of depression after surgery for hip fracture in older people: randomized, controlled trials. Journal of the American Geriatrics Society 2007; 55:75-80.

11. Lenze EJ et al. Adverse effects of depression and cognitive impairment on rehabilitation participation and recovery from hip fracture. International Journal of Geriatric Psychiatry 2004; 19:472-478.

12. Basinski JR, Alfano CM, Katon WJ, Syrjala KL, Fann JR. Impact of delirium on distress, health-related quality of life, and cognition 6 months and 1 year after hematopoietic cell transplant. Biology of Blood and Marrow Transplantation 2010; 16:824-831.

13. Blank K, Perry S. Relationship of psychological processes during delirium to outcome. American Journal of Psychiatry 1984; 141:843-847.

14. Girard TD et al. Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study. Critical Care 2007; 11:R28.

15. Witlox J et al. Cerebrospinal fluid β-amyloid and tau are not associated with risk of delirium: a prospective cohort study in older adults with hip fracture. Journal of the American Geriatrics Society 2011; 59:1260-1267.

16. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI.. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Annals of Internal Medicine 1990; 113:941-948.

17. Marcantonio ER et al. Outcomes of older people admitted to postacute facilities with delirium. Journal of the American Geriatrics Society 2005; 53:963-969.

18. Kalisvaart KJ et al. Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study. Journal of the American Geriatrics Society 2005;53: 1658-1666.

19. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 1975; 12:189-198.

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20. Jorm AF, Jacomb PA. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): socio-demographic correlates, reliability, validity and some norms. Psychological Medicine 1989; 19:1015-1022.

21. de Jonghe JF, Schmand B, Ooms ME, Ribbe MW. Abbreviated form of the Informant Questionnaire on cognitive decline in the elderly. Tijdschrift voor Gerontologie en Geriatrie 1997; 28:224-229.

22. Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatrica Scandinavica 1983; 67:361-370.

23. Sheikh JI, Yesavage JA. Geriatric depression scale (GDS): recent findings and development of a shorter version. Clinical Gerontologist 1986; 37:819-820.

24. Brodaty H., Altendorf A, Withall A, Sachdev P. Do people become more apathetic as they grow older? A longitudinal study in healthy individuals. International Psychogeriatrics 2010; 22:426-436.

25. American Society of Anesthesiologists: ASA Physical Status Classification System. http://www.asahq.org/Home/For-Members/Clinical-Information/ASA-Physical-Status-Classification-System.

26. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Critical Care Medicine 1985; 13:818-829.

27. Hetherington R. The Snellen chart as a test of visual acuity. Psychologische Forschung 1954; 24:349-357.

28. Mahoney FI, Barthel DW. Functional evaluation: The Barthel Index. Maryland State Medical Journal 1965; 14:61-65.



31. Trzepacz PT, Mittal D, Torres R, Kanary K, Norton J, Jimerson N. Validation of the Delirium Rating Scale-revised-98: comparison with the delirium rating scale and the cognitive test for delirium. The Journal of Neuropsychiatry & Clinical Neurosciences 2001; 13:229-242.

32. Sheehan DV et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry 1998; 59:22-33.

33. Richter JC, Waydhas C, Pajonk FG. Incidence of posttraumatic stress disorder after prolonged surgical intensive care unit treatment. Psychosomatics 2006; 47:223-230.

34. American Psychiatric Association. (2000). DSM-IV-TR. Washington DC: American Psychiatric Association.

35. Nickel M et al. The occurrence of posttraumatic stress disorder in patients following intensive care treatment: a cross-sectional study in a random sample. Journal of Intensive Care Medicine 2004; 19: 285-290.

36. Stoll C et al. Sensitivity and specificity of a screening test to document traumatic experiences and to diagnose post-traumatic stress disorder in ARDS patients after intensive care treatment. Intensive Care Medicine 1999; 25:697-704.


38. Cunningham C. Systemic inflammation and delirium: important co-factors in the progression of delirium. Biochemical Society Transactions 2011; 39:945-953.

39. van Munster BC, Korevaar JC, Zwinderman AH, Levi M, Wiersinga WJ, de Rooij SE. Time-course of cytokines during delirium in elderly patients with hip fractures. Journal of the American Geriatrics Society 2008; 56:1704-1709.

40. Cerejeira J, Nogueria V, Luis P, Vaz-Serra A, Mukaetova-Ladinska EB. The cholinergic system and inflammation: common pathways in delirium pathophysiology. Journal of the American Geriatrics Society 2012; 60:669-675.

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41. Matheny ME et al. Inflammatory cytokine levels and depressive symptoms in older women in the year after hip fracture: findings from the Baltimore Hip Studies. Journal of the American Geriatrics Society 2011; 59:2249-2255.

42. O’Connor JC et al. Lipopolyssacharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Molecular Psychiatry 2009; 14:511-522.

43. Pattanayak RD, Sagar R. Depression in dementia patients: issues and challenges for a physician. Journal of the Association of Physicians of India 2011; 59:650-652.

44. Fann JR, Alfano CM, Roth-Roemer S, Katon WJ, Syrjala KL. Impact of delirium on cognition, distress, and health-related quality of life after hematopoietic stem-cell transplantation. Journal of Clinical Oncology 2007; 25:1223-1231.

45. Jones C, Griffiths RD, Humphris G, Skirrow PM. Memory, delusions, and the development of acute posttraumatic stress disorder-related symptoms after intensive care. Critical Care Medicine 2001; 29:573-580.

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The focus of this thesis has been threefold. First, we investigated predisposing and precipitating risk factors for the development of delirium. Second, we focused on clinical symptomatology, namely duration and associated factors and motoric subtypes of delirium. The thesis concluded with studies of the (long-term) consequences of delirium, neuropsychological and affective functioning after delirium resolved. All these subject have been investigated in a relatively homogenous group, namely elderly hip surgery patients. The main advantage of such a patient group is that all patients experience the same sequence of events, and that they are relatively homogenous with respect to underlying illnesses compared to samples recruited from elderly patients acutely admitted to the hospital or patients from the ICU. Another strength of this approach was that data on different clinical factors and demographics could be collected at baseline, so we were able to investigate (and thus to control for in our analyses) the relative importance of predisposing factors over precipitating events in delirium pathogenesis. It might be that these risk factors outweigh the impact of peri-operative events, such as anaesthetic technique.

PArT 1: AneSTheSIA And InflAmmATory mArKerS for delIrIumAnesthetic technique has been suggested as precipitating factor for delirium. A theory is that the physiologic effects on cerebral blood flow, metabolism and oxygen delivery may differ between regional and general anesthesia, the latter having an increased risk of developing postoperative delirium. Also, the effects of drugs may be reduced or even eliminated with regional anesthesia. Results of previous studies are inconsistent, primarily due to the small number of patients included. A recent review concluded that postoperative delirium was not associated with anesthesia type, although a trend that postoperative cogntive dysfunction might be related to general anesthesia was found.1 We were able to investigate the association between anaesthetic technique and postoperative delirium in a homogeneous group, controlling for other important delirium risk factors. Secondly, we investigated inflammatory markers before and after surgery. We compared CRP and levels between patients who developed postoperative delirium and patient who did not. Experimental findings and neuropathological observations suggest that activation of microglia is pivotal for mediation of the acute behavioural and cognitive effects of systemic inflammation.2 A mild systemic inflammatory response suffices to increase the production of pro-inflammatory cytokines within the brain when microglia are already “primed” by chronic pathologic events as chronic neurodegeneration or advanced age.3 After hip surgery, the release of pro-inflammatory cytokines as a consequence of fracture and surgery induces a systemic inflammatory response. In older hip-fracture patients delirium was associated with higher postoperative serum levels of proinflammatory cytokines while no differences were seen in the preoperative serum levels between the delirium and non-delirium patients.4,5

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AnesthesiaIn our relatively homogeneous hip fracture sample it was found that the risk of postoperative delirium was not increased in general anesthesia patients compared to patients receiving regional anesthesia. Patients with more baseline cognitive impairment, higher age, acute admission and other delirium risk factors present had also no association between anesthetic technique and postoperative delirium. The absence of a distinct association between general anesthesia and delirium is an important finding, especially that cognitively impaired patients were not at an increased risk of delirium after general anesthesia compared to regional anesthesia. Since this was not a randomized study, it remains possible that patients with intact cognitive function may have been more likely to be selected for regional rather than general anesthesia. However, baseline MMSE scores did not differ between the regional and anesthesia group, and we controlled for potential differences, such as MMSE score. We therefore believe that these findings do not reflect a referral bias to either general or regional anesthesia. The use of narcotics, benzodiazepines and anticholinergic agents was not independently associated with delirium. We had to restrict analysis to these three well-known drug classed, because the study was underpowered to examine the effects of specific medications. Studies examining effects of peri-operative drugs on postoperative delirium in hip-surgery patients are lacking. Exposure to benzodiazepine and opioid medication has been associated with increased delirium risk, but these findings must be interpreted with caution because of wide confidence intervals and different study populations.6 Impaired cholinergic function has been suggested as the common final pathway leading to delirium. We did find a higher percentage of patients receiving anticholinergics in the delirium group compared to non-delirium patients. However, this did not reach significance, which might represent a type II error due to our small sample size. Other classes of medication, particularly sedative-hypnotics and β-blockers may be associated with postoperative delirium.7,8 Although this study did not find an association between perioperative medication, anesthetic technique and postoperative delirium, it is difficult to reach a definitive conclusion on this subject. It might be that administered dosage is also of relevance to the risk of developing delirium, which we were unable to include in our analysis. Also, medication use postoperatively might be associated with postoperative delirium. Many other in-hospital events during surgery or not, might be of more importance than the anesthetic technique itself. A recent study found evidence that limiting sedation depth during spinal anesthesia decreases the prevalence of delirium.9 This indicates that other in-surgery factors might be associated with the risk for postoperative delirium and that they may be even more important than the anesthetic technique itself.

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CrP We found an increase in the level of inflammatory markers after surgery. The increase in the CRP level with patients who developed postoperative delirium was found after surgery and stayed higher in those patients who developed delirium postoperatively. The pathogenic mechanisms underlying postoperative cognitive dysfunction remains unknown. It is suggested that the surgical trauma itself is mostly involved, more than perioperative factors such as hypoxaemia, hypotension or anesthesia.10,11 Surgical trauma has been associated with activation of the peripheral innate immune system, cytokine release and impairment of cognitive function.12-16 Several animal studies have shown that activation of the immune system, such as the stress response to surgery, results in an exaggerated inflammatory response in the hippocampus in aged organisms, which is followed by performance deficits in hippocampal-mediated cognitive tests in the aged animal compared to younger animals.11,12,17-20 In the aged organism, which is more vulnerable to impaired cognitive function after a peripheral immune challenge, this neuroinflammatory response can also be persistent.21

We found that anaesthetic technique was not associated with the development of postoperative delirium. We did find an increase in the level of inflammatory markers after surgery and that a higher level of these markers is associated with postoperative delirium. This is in accordance with the suggestion that it is the surgical procedure itself, with the accompanying stress response, that is associated with the development of delirium.

PArT 2: ClInICAl SymPTomAToloGyThe second part of the thesis concerned the clinical symptomatology of delirium. Delirium duration is suggested to be associated with mortality risk and long-term cognitive impairment in ICU patients.22-24 A study in medical and surgical ICU survivors found that longer duration of delirium was associated with smaller brain volumes up to 3 months after discharge, and that smaller brain volumes are associated with long-term cognitive impairment up to 12 months.25 Persistent delirium has also been associated with more severe cognitive and non-cognitive disturbances compared to delirium that resolved over time. This was found in a study with palliative care patients with twice-weekly evaluations.26 We investigated if duration of delirium is associated with certain delirium symptoms (profile at onset and throughout) or clinical characteristics in a homogeneous group with data on daily evaluations of delirium symptoms. One of the possible symptoms of delirium is an impaired motor function. Delirium was originally classified into two motor subtypes, i.e. hyperactive and hypoactive.27 A third category, mixed, was subsequently added in recognition that elements of both subtypes can appear within short time frames.28 The status of mixed motor subtype is still uncertain. Previous work with palliative care patients indicated that this subtype is common and associated with more severe overall delirium and stable over time in a

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large percentage of patients.29 This supports mixed motor subtype as a separate motor category, and not just a reflection of the fluctuating nature of delirium or a transitional phase between hypoactive and hyperactive subtypes. We investigated if different motoric subtypes are associated with specific characteristic and outcomes. Also, we investigated the stability of motor subtypes across the delirium episode, since there are little longitudinal data on motoric subtypes. We performed daily assessments of delirium, thus we could add to the existing longitudinal research to increase our understanding of the existence of different motor subtype categories. Since most studies are cross-sectional there is limited knowledge regarding the stability of motor subtypes over the course of delirium. Also, this study used a very active screening procedure, which reliably enabled to detect most if not all cases of delirium, including more easily missed hypoactive cases, which is a common problem in delirium research. This strengthens the reliability of the percentages of delirium motor subtypes found in our study. Thereafter, we investigated the psychometric properties of the Delirium Motor Subtype Scale (DMSS), which we translated into Dutch. Previous subtyping methods have included behavioural abnormalities supposedly associated with motor activity levels, such as changes to affect, sleep, or psychotic symptoms. The DMSS combined features from three psychomotor subtyping schemas.30-32 Subsequently this was reduced to an 11-item Delirium Motor Subtype Scale (DMSS) based upon relative specificity of items for delirium vs. non-delirious controls and also according to correlation of items with independently assessed motor activity as per items 7 and 8 of the DRS-R98.33,34 This new tool emphasises disturbances of motor activity rather than associated psychomotor symptoms in motor subtyping. 35

delirium durationAs a next step, we were interested in the predictive value of delirium symptomatology in the early phase of the delirium episode for its duration. In this thesis we used the duration of delirium in several analyses. For some analyses this implied we had to define the resolution of the delirium episode. We choose to consider 2 consecutive days of no delirium as recovery. This method is supported by a recent review of treatment for delirium, which considered available evidence for defining ‘recovery’. This review concluded that because of the fluctuating course of delirium, recovery is best defined conservatively and in the manner used in this thesis.36

We found that the severity of individual delirium symptoms at the first day of delirium was not associated with short or prolonged delirium. Pre-existing cognitive impairment, which has repeatedly proven to be of importance in relation to delirium, was the only examined variable to be associated with prolonged delirium. The finding that cognition rather than delirium profile is associated with delirium duration is replicated twice within

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this study with two independent methods. The GEE method is an innovative statistical analysis used for longitudinal data analysis, the small sample size is less important with this analysis because we have a relative large number of observations because of daily assessments. The main finding in our study was that an association exists between prolonged delirium and pre-existent cognitive decline. It has been postulated that this reflects the effects of uncontrolled neuro-inflammation contributing to delirium symptoms.2 Since inflammatory markers have been shown to be elevated in dementia as well as MCI, it follows that pre-existent cognitive impairment might not only increases the chance of developing delirium, but also prolong the episode with delirium.3,37,38

We found that almost half of the delirious patients experienced a delirium episode of 1 to 2 days. This short time-frame might suggest that this is of no relevance to the patients well-being or recovery. However, recent work has highlighted the impact of even short periods of delirium upon outcomes and therefore the importance of daily assessments in studies of delirium.23 Also delirium can be a very frightful experience, whether it lasts a day or a week.

motor subtypes: characteristics, outcomes and longitudinal stabilitySubtype categorization according to dominant motor subtype across the delirium episode identified groups that did not differ significantly in characteristics or outcomes. The evident similarity across the motor subtypes of this generally heterogeneous syndrome suggests the need to consider all therapeutic options relevant to delirium, regardless of motor presentation. Notably, longitudinal assessment indicated that most patients had a variable course, with few patients having a consistent motor profile throughout their delirium episode. This challenges the validity of existing knowledge of motor subtypes which is almost exclusively derived from cross-sectional studies, limiting the distinction of the motor types if the majority of patients have variable motor subtypes across their delirium course as was evident in this study. Relatively little is known about the longitudinal trajectory of motor subtypes in delirium. We investigated the longitudinal course of motor subtypes for each patient and found that many patients transitioned several times during the delirium episode with, for example, 87% changing motor subtype category between the first and second day of delirium. Previous longitudinal work in palliative care patients found that most patients (62%) had a stable pattern, with hypoactive subtype being the most common stable pattern (29%).29 The observed variability was related to the number of assessments, since patients with a variable subtype course had significantly more visits than the patients with a stable pattern. This pattern was also evident in the study reported herein where patients with more data showed a more variable pattern.

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The unstable course of motor subtypes in our study might be associated with medication changes. However, the degree of variability was so marked that this factor alone is unlikely to fully account for the pattern and a previous study in palliative care patients using general estimating equations analysis found few associations existed between motor subtype (stable hypoactive, stable hyperactive, stable mixed, stable no subtype and variable course) and medication exposure or etiologies.39 Moreover, subtype transitions in the variable course group were rarely (14/102) preceded by a change to psychotropic medication apart from the finding that almost half of the transitions into the hypoactive subtype were preceded by increased benzodiazepine dosing.39 Further research is needed in populations other than palliative care patients to explore the stability of motor subtypes and to explore their relevance to other clinical characteristics and outcomes when longitudinal expression is considered.

The delirium motor Subtype Scale (dutch version)In Chapter 5 we used the DRS-R98 as a reference measure of motor activity to differentiate motor subtypes. The Dutch version of the DRS-R-98 has been found to distinguish hypoactive and non-hypoactive subtypes.40 However, this instrument is not developed specifically for motor subtype categorization and uncertainty remains about optimal cut-off scores. The Delirium Motor Subtype Scale (DMSS) is relatively more precise regarding the particular aspects of motor activity that can define subtypes and is also designed for use by a range of healthcare staff, rather than those with delirium-expertise as recommended for the DRS-R98. Therefore it was decided to translate the DMSS and examine psychometric properties of the Dutch version of the Delirium Motor Subtype Scale in our sample of hospitalized elderly hip-fracture patients with and without delirium. The Dutch DMSS had good agreement with the DRS-R98 on motor subtype identification, which confirms the findings in the initial study on the DMSS.34 In contrast to the DRS-R98 method of subtype attribution, the DMSS had greater specificity for delirium as evidenced by the substantially lower attribution of motor subtypes in non-delirious patients. However, it remains unclear whether the three motor subtypes represent distinct categories, since less significant differences have been found for the mixed subtype.41 Further research with the use of more ‘objective’ measures of motor activity, such as actigraphy / electronic motion analysis, and also categorization like the DMSS can advance our knowledge on this subject.41-44

This study highlights that there is much lower concordance between the DMSS and DRS-R98 methods regarding the attribution of mixed rather than other clinical subtypes and suggests that its delineation may require further revision informed by studies in other clinical populations and using electronic motion analysis. More than 90% of delirious patients met criteria for either hypoactive, hyperactive or mixed motor subtypes whilst in contrast 87% of non-delirious patients were deemed

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‘no subtype’ emphasising the relative specificity of the motor activity items in the DMSS for delirium. This is in keeping with the method by which the DMSS items were selected i.e. according to relative specificity of motor symptoms for delirium vs. non-delirious controls.

PArT 3: The ConSeQuenCeS of PoSToPerATIVe delIrIum: CoGnITIVe And AffeCTIVe funCTIonInGAlthough delirium may resolve with time, it is suggested to be associated with long-term poor outcome. Delirium can contribute to poor cognitive and affective functioning, although not all research is consistent on this.45-49 Differences in results might be because of different patient populations, and the type of surgery or methodology. Animal studies suggest that a temporal dissociation might exist between the acute behavioural changes and the depressive symptoms, which are based on distinct and time-related differences in the underlying biological mechanisms.50 In a study with elderly hip-fracture patients it has been found that depressive symptoms were associated with increased cytokine levels as long as at 1 year follow-up.51

Also, subsyndromal delirium or persisting delirium might negatively effect cognitive functioning after 6 months.52,53 Depression might also effect cognition, so it is important to consider this interrelationships between affective and cognitive functioning when investigating the association between delirium and cognitive or affective functioning at follow-up.

Cognitive functioningIn Chapter 7 we evaluated cognitive performance, using a comprehensive neuro-psychological approach, at follow-up in elderly hip fracture patients who did or did not suffer from in-hospital delirium. In-hospital delirium was found to be independently associated with impairments on tests of global cognition and episodic memory at follow-up. This result cannot be readily explained by persistent delirium or presence of depressive symptoms as we will discuss in the following section. Patients with in-hospital delirium, but without delirium symptoms at follow-up (i.e. CAM score of null), performed worse on an episodic memory test than controls who never experienced delirium. Also, the persistence of delirium might affect cognitive outcome at follow-up in some patients, as almost 20% of our patients with in-hospital delirium was excluded because of persistent (or recurrent) delirium. Another suggested explanation is that delirium may unmask early or prodromal dementia or may initiate or accelerate a process of cognitive decline. Many of the patients in our study who developed delirium showed signs of pre-fracture cognitive decline. Therefore, we controlled for baseline cognitive impairment in multivariate models. In addition we repeated analysis in subgroups of patients that did not show any sign of

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cognitive impairment at baseline. Patients who had experienced in-hospital delirium still had a worse performance on a test which mainly measures episodic memory, compared to controls. Delirium has been associated with higher depressive symptom levels months after hip fracture, and depression can markedly affect cognitive function.54,55 Therefore, we repeated the analysis in patients with few or no depressive symptoms present at follow-up. In-hospital delirium remained associated with poorer performance on a range of neuropsychological tests. Also, delirium patients in our study showed disproportionate memory disturbances, in contrast to diminished processing speed and impaired executive function, which is more characteristic of depression in late life.55 These results suggest that an increase of depressive symptoms at follow-up among patients with previous delirium cannot fully explain their poorer cognitive functioning. To date few if any studies have examined the association between delirium and cognitive impairment at follow-up while simultaneously documenting the presence of mood disturbances.

Affective functioningIn addition to the cognitive functioning at follow-up in the previous study, we examined the association between in-hospital delirium and affective functioning three months after hospital discharge. The occurrence of in-hospital delirium was independently associated with increased depressive symptoms 3 months after hospital discharge, whereas no association was found for anxiety levels or posttraumatic stress symptoms. We found that patients with in-hospital delirium have increased depressive symptoms three months later, in the absence of (sub)syndromal delirium. So, increased depressive symptoms after a delirious episode can not readily be explained by prolonged delirium or (sub)syndromal delirium. An explanation for the increase in depressive symptoms after in-hospital delirium in elderly patients could be underlying cognitive impairment. Depression and dementia are suggested to be related, with increased prevalence of depression in people suffering from dementia.56 People with delirium were more cognitively impaired at baseline and were still more cognitively impaired three months after hospital discharge. This is why we controlled for baseline cognitive functioning in multivariate analysis, in-hospital delirium was still associated with more depressive symptoms at follow-up. In a sub-sample of patients without evidence of cognitive impairment at baseline (MMSE>23 and IQCODE-N<3.6) again that patients with in-hospital delirium had more depressive symptoms at follow-up compared to controls. In the present study no difference was found in anxiety levels between patients with and without in-hospital delirium three months after hospital discharge. However, anxiety levels did increase in both the delirious and control group. This might be related to the effects of hospitalization and having experienced surgery and interventions. The present

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study did not find an association between in-hospital delirium and PTSD symptoms at follow-up. It has been suggested that higher levels of PTSD symptoms are less likely to occur in older patients, as we found in our study.57

final concluding wordsThis thesis investigated predisposing and precipitating risk factors for the development of delirium. The second part of this thesis focused on clinical symptomatology, namely duration and associated factors and motoric subtypes of delirium. The final part investigated the neuropsychological and affective functioning after postoperative delirium. The strengths of our study are that we used a homogenous population, with baseline data available from the period before surgery and onset of delirium. This enabled us to investigate the (inter)relationship between development of delirium and predisposing factors, such as cognition and comorbidities, clinical characteristics and outcomes at a three month follow-up. Except for chapter 2 on anesthesia, all other studies were part of a randomized controlled trial comparing the effectiveness of taurine versus placebo in reducing morbidity and one-year mortality. This might be considered a weakness of our study. However, we routinely controlled for treatment modality, and this did not affect the results in any of our analyses. All the patients in our sample who were at high-risk of delirium received haloperidol prophylaxis. Haloperidol might have had an effect on motor symptom profile, but similar longitudinal work in a palliative care setting suggests a limited relationship between motor activity and use of antipsychotic agents.58 Also, if any effect existed, it will have been for all the patients in our sample and not a subgroup. This thesis investigated several aspects of delirium, from onset to outcomes. It focused on interactions between different factors and their association with delirium. It is important to unravel the underlying mechanisms and further improve prevention and therapeutic interventions, both in the acute phase and in the long term. Although it has been suggested that general anaesthesia increases the risk at delirium, we did not find an indication for this. Recently, it has been hypothesized that neuroinflammation might induce delirium, especially in individuals who are predisposed to develop delirium59,60 and it might also have a role in the development of depression and cognition afterwards.61 The role of inflammation and other suggested mechanisms need further exploration in future research.

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referenCeS

1. Mason SE, Noel-Storr A, Ritchie CW. The impact of general and regional anesthesia on the incidence of post-operative cognitive dysfunction and post-operative delirium: a systematic review with meta-analysis. J Alzheimers Dis 2010; 22:67-79.


3. Cunningham, C. Systemic inflammation and delirium: important co-factors in the progression of delirium. Biochem Soc Trans 2011; 39:945-953.

4. van Munster BC, Korevaar JC, Zwinderman AH, Levi M, Wiersinga WJ, de Rooij SE. Time-course of cytokines during delirium in elderly patients with hip fractures. J Am Geriatr Soc 2008; 56:1704-1709.

5. Cerejeira J, Nogueria V, Luis P, Vaz-Serra A, Mukaetova-Ladinska EB. The cholinergic system and inflammation: common pathways in delirium pathophysiology. J Am Geriatr Soc 2012; 60:669-675.

6. Clegg A, Young YB. Which medications to avoid in people at risk of delirium: a systematic review. Age Ageing 2010; 0:1-7.

7. Katznelson R, Djaiani G, Mitsakakis N, Lindsay TF, Tait G, Friedman Z et al. Delirium following vascular surgery: increased incidence with preoperative beta-blocker administration. Can J Anaesth 2009; 56;793-801.

8. Hall JB, Schweickert W, Kress JP. Role of analgesics, sedatives, neuromuscular blockers, and delirium. Crit Care Med 2009; 37:416-421.

9. Sieber FE, Zakriya KJ, Gottschalk A, Blute M, Lee HB, Rosenberg PB et al. Sedation depth during spinal anesthesia and the development of postoperative delirium in elderly patients undergoing hip fracture repair. Mayo Clin Proc 2010; 85:18-26.

10. Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators, International Study of Post-Operative Cognitive Dysfunction. Lancet 1998; 351:857-61.

11. Cao XZ, Ma H, Wang JK, Liu F, Wu BY, Tian AY, Wang LL, Tan WF. Postoperative cognitive deficits and neuroinflammation in the hippocampus triggered by surgical trauma are exacerbated in aged rats. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:1426-32.

12. Cibelli M, Fidalgo AR, Terrando N, et al. Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol 2010; 68:360-368.

13. Rosczyk HA, Sparkman NL, Johnson RW. Neuroinflammation and cognitive function in aged mice following minor surgery. Exp Gerontol 2008; 43:840-846.

14. Vizcaychipi MP, Lloyd DG, Wan Y, Palazzo MG, Maze M, Ma D. Xenon pretreatment may prevent early memory decline after isoflurane anesthesia and surgery in mice. PLoS One 2011; 6:e26394.

15. Kamer AR, Galoyan SM, Haile M, et al. Meloxicam improves object recognition memory and modulates glial activation after splenectomy in mice. Eur J Anaesthesiol 2012; 29:332-337.

16. Buchanan JB, Sparkman NL, Chen J, Johnson RW. Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice. Psychoneuroendocrinology 2008; 33:755-65.

17. He HJ, Wang Y, Le Y, Duan KM, Yan XB, Liao Q, Liao Y, Tong JB, Terrando N, Ouyang W. Surgery upregulates high mobility group box-1 and disrupts the blood-brain barrier causing cognitive dysfunction in aged rats. CNS Neurosci Ther 2012; 18:994-1002.

18. Barrientos RM, Hein AM, Frank MG, Watkins LR, Maier SF. Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats. J Neurosci 2012; 32:14641-8.

19. Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 2005; 25:9275-9284.

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20. Godbout JP, Chen J, Abraham J, Richwine AF, Berg BM, Kelley KW, Johnson RW. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J 2005; 19:1329-1331.

21. Barrientos RM, Frank MG, Hein AM, Higgins EA, Watkins LR, Rudy JW, Maier SF. Time course of hippocampal IL-1 beta and memory consolidation impairments in aging rats following peripheral infection. Brain Behav Immun 2009; 23:46-54.

22. Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL, Shintani AK et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med 2010; 38:1513-1520.

23. González M, Martínez G, Calderón J, Villarroel L, Yuri F, Rojas C et al. Impact of delirium on short-term mortality in elderly inpatients: a prospective cohort study. Psychosomatics 2009; 50:234-238.

24. Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness PH. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med 2009; 180:1092-1097.

25. Gunther ML, Morandi A, Krauskopf E, Pandharipande P, Girard TD, Jackson JC et al. The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study. Crit Care Med 2012; 40(7):2022-2032.

26. Meagher D, Adamis D, Trzepacz P, Leonard M. Features of subsyndromal and persistent delirium. Br J Psychiatry 2012; 200:37-44.

27. Lipowski ZJ. Transient cognitive disorder in the elderly. Am J Psychiatry 1983; 140:1426-1436.

28. Lipowski ZJ. Delirium in the elderly patient. New Engl J Med 1989; 320:578-582.


30. Liptzin B, Levkoff SE. An empirical study of delirium subtypes. Brit J Psychiatry 1992; 161:843-845.

31. O’Keeffe ST, Lavan JN. Clinical significance of delirium subtypes in older people. Age Ageing 1999; 28:115-119.

32. Lipowski ZJ. (1980). Delirium: Acute Brain Failure in Man. New York, Oxford University Press.

33. Meagher DJ, Moran M, Raju B, Gibbons D, Donnelly S, Saunders J et al. Motor symptoms in 100 patients with delirium versus control subjects: comparison of subtyping methods. Psychosomatics 2008; 49:300-308.

34. Meagher D, Moran M, Raju B, Leonard M, Donnelly S, Saunders J et al. A new data-based motor subtype schema for delirium. J Neuropsychiatry Clin Neurosci 2008; 20:185-193.

35. Meagher D. Motor subtypes of delirium: past, present and future. Int Rev Psychiatry 2009; 21:59-73.

36. Meagher D, McLoughlin L, Leonard M, Hannon N, Dunne C, O’Regan N: What do we really know about the treatment of delirium with antipsychotics? Ten key issues for delirium pharmacotherapy. Am J Ger Psychiatry (in press).

37. Licastro F, Pedrini S, Caputo L, Annoni G, Davis LJ, Ferri C et al. Increased plasma levels of interleukin-1, interleukin-6 and alpha-1-antichymotrypsin in patients with Alzheimer’s disease: peripheral inflammation or signals from the brain? J Neuroimmunol 2000; 103: 97-102.

38. Alvarez A, Cacabelos R, Sanpedro C, Garcia-Fantini M, Aleixandre M. Serum TNF- levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol Aging 2007; 28:533-536.

39. Meagher DJ, Leonard M, Donnelly S, Conroy M, Adamis D, Trzepacz PT: A longitudinal study of motor subtypes in delirium: relationship with other phenomenology, etiology, medication exposure and prognosis. J Psychosom Res 2011; 71:395-403.

40. de Rooij SE, van Munster BC, Korevaar JC, Casteelen G, Schuurmans MJ, van der Mast RC et al. Delirium subtype identification and the validation of the Delirium Rating Scale--Revised-98 (Dutch version) in hospitalized elderly patients. Int J Geriatr Psychiatry 2006; 21:876-882.

41. Godfrey A, Leonard M, Donnelly S, Conroy M, O’Laighin G, Meagher D. Validating a new clinical subtyping scheme for delirium with electronic motion analysis. Psychiatry Res 2010; 178:186-190.

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42. Van Uitert M, de Jonghe A, de Gijsel S, van Someren EJ, de Rooij SE, van Munster BC. Rest-activity patterns in patients with delirium. Rejuvenation Res 2011; 14:483-490.

43. Osse RJ, Tulen JH, Bogers AJ, Hengeveld MW. Disturbed circadian motor activity patterns in postcardiotomy delirium. Psychiatry Clin Neurosci 2009; 63:56-64.

44. Honma H, Kohsaka M, Suzuki I, Fukuda N, Kobayashi R, Sakakibara S, Matubara S, Koyama T. Motor activity rhythm in dementia with delirium. Psychiatry Clin Neurosci 1998; 52:196-198.

45. Fann JR, Alfano CM, Roth-Roemer S, Katon WJ, Syrjala KL. Impact of delirium on cognition, distress, and health-related quality of life after hematopoietic stem-cell transplantation. J Clin Oncol 2007; 25:1223-1231.

46. Katz IR, Curyto KJ, TenHave T, Mossey J, Sands L, Kallan MJ. Validating the diagnosis of delirium and evaluating its association with deterioration over a one-year period. Am J Geriatr Psychiatry 2001; 9:148-159.

47. McCusker J, Cole M, Dendukuri N, Belzile E, Primeau F. Delirium in older medical inpatients and subsequent cognitive and functional status: a prospective study. CMAJ 2001; 165:575-583.

48. Koster S, Hensens AG, van der Palen J. The long-term cognitive and functional outcomes of postoperative delirium after cardiac surgery. Ann Thorac Sur 2009; 87(5):1469-74.

49. Jankowski CJ, Trenerry MR, Cook DJ, Buenvenida SL, Stevens SR, Schroeder DR et al. Cognitive and functional predictors and sequelae of postoperative delirium in elderly patients undergoing elective joint arthroplasty. Anesth Analg 2011; 112(5):1186-93.

50. O’Connor JC, Lawson MA, André C, Moreau M, Lestage J, Castanon N et al. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 2009;14(5):511-522.

51. Matheny ME, Miller RR, Shardell MD, Hawkes WG, Lenze EJ, Magaziner J et al. Inflammatory cytokine levels and depressive symptoms in older women in the year after hip fracture: findings from the Baltimore Hip Studies. J Am Geriatr Soc 2011; 59(12):2249-2255.

52. Cole MG, McCusker J, Voyer P, Monette J, Champoux N, Ciampi A et al. Subsyndromal delirium in older long-term care residents: incidence, risk factors, and outcomes. J Am Geriatr Soc 2011; 59(10):1829-36.

53. Cole MG, Ciampi A, Belzile E, Zhong L. Persistent delirium in older hospital patients: a systematic review of frequency and prognosis. Age Ageing 2009; 38(1):19-26.

54. Lenze EJ, Munin MC, Skidmore ER, Dew MA, Rogers JC, Whyte EM et al. Onset of depression in elderly persons after hip fracture: implications for prevention and early intervention of late-life depression. J Am Geriatr Soc 2007; 55(1):81-86.

55. Herrmann LL, Goodwin GM, Ebmeier KP. The cognitive neuropsychology of depression in the elderly. Psychol Med 2007; 37(12):1693-1702.

56. Pattanayak RD, Sagar R. Depression in dementia patients: issues and challenges for a physician. J Ass Physicians India 2011; 59:650-652.

57. Girard TD, Shintani AK, Jackson JC, Gordon SM, Pun BT, Henderson MS et al. Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study. Crit Care 2007; 11:R28.

58. Trollor JN, Smith E, Baune BT, Kochan NA, Campbell L, Samaras K et al. Systemic inflammation is associated with MCI and its subtypes: the Sydney Memory and Aging Study. Dement Geriatr Cogn Disord 2010; 30:569-578.

59. Maclullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C. Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J Psychosom Res 2008; 65:229-238.

60. Eikelenboom P, Hoogendijk WJ, Jonker C, van Tilburg W. Immunological mechanisms and the spectrum of psychiatric syndromes in Alzheimer’s disease. J Psychiatr Res 2002; 36:269-280.

61. Cunningham C, Campion S, Lunnon K, Murray CL, Woods JF, Deacon RM et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry 2009; 65:304-312.

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A major part of delirium research in elderly patients has been in heterogeneous populations. Patients develop delirium in the presence of an underlying medical condition which is the reason for hospital admission, which hinders baseline assessment of predisposing factors. In contrast, the research in this thesis was done in a homogeneous group with baseline data available, as well as longitudinal and follow-up data on several factors. The general aim of this thesis was threefold. We wanted to increase our knowledge on several aspects of delirium: predisposing and precipitating factors, phenomenology and symptoms throughout the delirium episode, and conclude with the (long-term) outcomes of delirium.

PArT 1: AneSTheSIA And InflAmmATory mArKerS for delIrIumDelirium is most often considered a multifactorial syndrome, an interrelationship between predisposing and precipitating factors.1 Cognitive impairment and advanced age are well known predisposing risk factors for delirium.2 Presence of precipitating factors, such as (bladder) infections, severe illness or surgery, increase the risk of development of delirium. Anesthetic technique has been suggested as precipitating factor because the physiologic effects on cerebral blood flow, metabolism and oxygen delivery might between regional and general anesthesia, with the latter having more chance on development of postoperative delirium. It has also been suggested that merely the surgical procedure itself, such as hip surgery, is a precipitating factor of delirium. A surgical procedure elicits an inflammatory response, which can induce delirium, especially in susceptible patients.3,4

In Chapter 2 we examined the effects of general anesthesia on the risk of incident postoperative delirium. Patients were 70 years or older and admitted for hip surgery. Predefined risk factors for delirium were assessed prior to surgery. A total of 60/526 patients (11.4%) had incident postoperative delirium, 337/526 (64.1%) received general anesthesia and 189/526 (35.9%) regional anesthesia. 18/189 (9.5%) general anesthesia patients developed postoperative delirium, vs. 42/337 (12.5%) regional anesthesia patients. General anesthesia had no distinct effect on incident postoperative delirium in geriatric hip-surgery patients compared to regional anesthesia. We controlled for baseline cognitive impairment, age, acute admission, gender, visual impairment, physical status and dehydration. Delirium was not independently associated with specific drugs nor the medication classes opioids, benzodiazepines and anticholinergics. Chapter 3 examined the time course of CRP levels over multiple days (baseline, postoperative day 1 through 5) and the association between postoperative delirium and CRP. Also, the association between CRP levels and delirium severity, cognitive impairment, illness severity and delirium duration were investigated. Longitudinal analysis showed that postoperative delirium was associated with a higher CRP level. Analyzing separate days showed that CRP levels were increased after surgery and that they were higher from postoperative day 2 and onwards in patients with delirium compared to patients who did not develop

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postoperative delirium. Delirium severity was associated with CRP levels. No significant differences in CRP levels were found between the short and more prolonged delirium group, nor between the highest CRP level and pre-fracture cognitive decline or illness severity.

PArT 2: ClInICAl SymPTomAToloGyThe second part of the thesis concerned the clinical symptomatology of delirium and delirium duration. Special emphasis was on the relation between symptomatology of delirium and delirium duration and predisposing factors. Severity and symptom profile at the onset of delirium might be predictive of the duration of delirium. Delirium duration is suggested to be associated with mortality risk and long-term cognitive impairment.5-7 Delirium has different phenotypes and diagnosis of delirium is based on the key features of delirium and exclusion of conditions that have great resemblance with delirium. Delirium is often accompanied by changes in motor activity, but the longitudinal expression of these features and etiological and prognostic significance of clinical subtypes defined by motor activity is unclear. The fourth chapter focused on features that may allow early identification of patients at risk of prolonged delirium, and therefore of poorer outcomes. We determined if pre-operative delirium risk factors and delirium symptoms (at onset and clinical symptomatology during the course of delirium) were associated with delirium duration. In a case control study patients having short delirium (1 or 2 days) were compared with patients who had more prolonged delirium (≥3 days) on DRS-R-98 (Delirium Rating Scale Revised-98) symptoms on the first delirious day. Delirium symptom profile was evaluated daily during the delirium course. Only pre-existent cognitive decline, not severity of individual delirium symptoms at onset, was associated with prolonged delirium. Chapter 5 compared baseline characteristics and outcomes according to longitudinal pattern of motor subtype expression (predominantly hyperactive, predominantly hypoactive, predominantly mixed, no motor subtype and variable). Motor subtype categorization was performed with the DRS-R98. We also investigated the longitudinal stability of motor subtypes across the delirium episode. The full course of the delirium episode could be defined for 42/62 (67.7%) patients who experienced in-hospital delirium postoperatively. Of the patients with multiple days of delirium only 4/30 (13.3%) patients had a consistent motor subtype profile throughout the delirium episode, while 26/30 (86.7%) patients had a variable course. Of the patients with multiple days of delirium, 5/30 (16.7%) were predominantly hypoactive in profile, 7/30 (23.3%) predominantly hyperactive, 6/30 (20%) predominantly mixed, 1/30 (3.3%) had no motor subtype and 11/30 (36.7%) had a variable profile. The subtype categorization according to dominant

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motor subtype across the delirium episode identified groups with similar characteristics and outcomes. In Chapter 6 we investigated the reliability and validity of the Delirium Motor Subtype Scale (DMSS) that was translated to Dutch. The DMSS was developed to capture all the previous different approaches to subtyping into one new instrument and emphasize disturbances of motor activity rather than associated psychomotor symptoms. Elderly patients who had undergone hip fracture surgery received the Dutch version of the DMSS and the Delirium Rating Scale revised 98. A diagnosis of delirium was defined according to the Confusion Assessment Method. The internal consistency of the DMSS was acceptable (Cronbach’s alpha=0.72). If an item was removed at random the internal consistency of the scale remained the same. Similarly the concurrent validity of DMSS was good (Cohen’s kappa=0.73) while for each motor subtype the Cohen’s kappa ranged from 0.58 to 0.85. The sensitivity and specificity of DMSS to detect each subtype ranged from 0.56 to 1 and from 0.88 to 0.98 respectively. These results suggests that the Dutch version of the Delirium Motor Subtype Scale is a reliable and valid instrument, that could allow for greater precision in further research on motor subtypes.

PArT 3: The ConSeQuenCeS of PoSToPerATIVe delIrIum: CoGnITIVe And AffeCTIVe funCTIonInGThe last section of this thesis focused on the consequences of delirium. Until recently it was assumed that when the underlying causal factor was eliminated and delirium resolved a successful recovery would follow. Although it is well documented that delirium is associated with negative long-term consequences such as impaired cognition and a high rate of institutionalization, less is known about the impact on specific domains of cognitive and affective functioning.8 It is suggested that delirium can contribute to poor cognitive and affective functioning, although not all research is consistent with this.9-13 Differences in results might be because of different patient populations, type of surgery or methodology. In Chapter 7 we investigated the long-term neuropsychological sequelae of delirium. Delirium is a risk factor for long-term cognitive impairment and dementia. Yet, the nature of these cognitive deficits is unknown as is the extent to which the persistence of delirium symptoms and presence of depression at follow-up may account for the association between delirium and long-term cognitive impairment. Before surgery baseline characteristics, depressive symptomatology, and global cognitive performance were documented. Presence of delirium was assessed daily during hospital admission and 3 months after hospital discharge when patients underwent neuropsychological assessment. Elderly hip fracture patients with in-hospital delirium suffer from impairments in global cognition and episodic memory three months after hospital discharge, even after adjustment for age, gender, and baseline cognitive impairment. In contrast, no

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differences were found on tests of attention. Our results suggest that inattention, as a cardinal sign of persistent delirium or depressive symptomatology at follow-up cannot fully account for the poor cognitive outcome associated with delirium. Chapter 8 investigated whether in-hospital delirium is associated with increased anxiety and depressive levels, and posttraumatic stress disorder symptoms three months after discharge. Patients who had experienced in-hospital delirium showed more depressive symptoms at follow-up after three months compared to the 30 patients without in-hospital delirium. This association persisted in a multivariate model controlling for age, baseline cognition, baseline depressive symptoms and living situation. The symptoms of depression in patients with previous in-hospital delirium could also not be fully explained by persistent (sub)syndromal delirium The level of anxiety and symptoms of post-traumatic stress disorder (PTSD) at follow-up did not differ between both groups.

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referenCeS

1. Inouye SK, Charpentier PA. Preciptating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA 1996; 275(11): 852-857.

2. Dasgupta M, Dumbrell AC. Preoperative risk assessment for delirium after noncardiac surgery. J Am Geriatr Soc 2006; 54;1578-1589.

3. Rudolph JL, Ramlawi B, Kuchel GA, McElhaney JE, Xie D, Sellke FW et al. Chemokines are associated with delirium after cardiac surgery. J Gerontol A Biol Sci Med Sci 2008; 63(2):184-189.

4. Simone MJ, Tan ZS. The role of inflammation in the pathogenesis of delirium and dementia in older adults. CNS Neurosci Ther 2011; 17(5):506-513.

5. Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL, Shintani AK et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med 2010; 38(7):1513-1520.

6. González M, Martínez G, Calderón J, Villarroel L, Yuri F, Rojas C et al. Impact of delirium on short-term mortality in elderly inpatients: a prospective cohort study. Psychosomatics 2009; 50:234-238.

7. Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness PH. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med 2009; 180(11):1092-1097.


9. Fann JR, Alfano CM, Roth-Roemer S, Katon WJ, Syrjala KL. Impact of delirium on cognition, distress, and health-related quality of life after hematopoietic stem-cell transplantation. J Clin Oncol 2007; 25:1223-1231.

10. Katz IR, Curyto KJ, TenHave T, Mossey J, Sands L, Kallan MJ. Validating the diagnosis of delirium and evaluating its association with deterioration over a one-year period. Am J Geriatr Psychiatry 2001; 9:148-159.

11. McCusker J, Cole M, Dendukuri N, Belzile E, Primeau F. Delirium in older medical inpatients and subsequent cognitive and functional status: a prospective study. CMAJ 2001; 165:575-583.

12. Koster S, Hensens AG, van der Palen J. The long-term cognitive and functional outcomes of postoperative delirium after cardiac surgery. Ann Thorac Sur 2009; 87(5):1469-74.

13. Jankowski CJ, Trenerry MR, Cook DJ, Buenvenida SL, Stevens SR, Schroeder DR et al. Cognitive and functional predictors and sequelae of postoperative delirium in elderly patients undergoing elective joint arthroplasty. Anesth Analg 2011; 112(5):1186-93.

11Chapter

Samenvatting

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InleIdInGDelier (ook ‘delirium’ genoemd) is een vaak voorkomende, ernstige postoperatieve complicatie bij oudere patiënten. Het bestaat uit acute, ernstige verwardheid met daarbij wisselende stoornissen in het bewustzijn en de aandacht. Dit syndroom wordt beschouwd als een kortdurende, tijdelijke stoornis. Echter, een delier kan ook langere tijd persisteren en negatieve effecten hebben op de lange termijn, zoals een verhoogde kans op dementie en slechter fysiek herstel. Hoewel het delier als klinische aandoening al sinds lange tijd bekend is, was het lange tijd zelden onderwerp van onderzoek. In de afgelopen 20 jaar is het onderzoek naar delier toegenomen en heeft het zich op verscheidene aspecten gericht, waaronder risicofactoren, diagnostiek, preventie en onderliggende pathologie. De kennis over delier is dus toegenomen, maar er is nog meer onderzoek noodzakelijk om dit syndroom in alle facetten te doorgronden, alsmede het goed te herkennen en te behandelen. Dit proefschrift richt zich op drie verschillende aspecten: de kennis over risico factoren , het beloop van delier en de symptomen, en de (lange-termijn) uitkomsten na delier. Delier ontstaat doorgaans door meerdere factoren, en wordt verondersteld een samenspel te zijn van predisponerende en precipiterende factoren. De incidentie van delier in het ziekenhuis loopt uiteen van 6% tot 56%, en postoperatief delier komt voor bij 15% tot 62% van de oudere patiënten. Cognitieve stoornissen en een hoge leeftijd zijn bekende risico factoren voor een delier. Precipiterende factoren, zoals (urineweg)infecties, ernstige ziektes of het ondergaan van een operatie verhogen de kans op het ontstaan van delier. Een mogelijke uitlokkende factor is de anesthesievorm. Een theorie is dat de fysiologische effecten op de cerebrale bloedvoorziening, metabolisme en aanleveren van zuurstof verschilt tussen regionale en algehele anesthesie, waardoor de laatstgenoemde geassocieerd zou zijn met een verhoogde kans op postoperatief delier. Er zijn aanwijzingen dat een chirurgische ingreep leidt tot een toename in proinflammatoire cytokines, wat vervolgens een delier kan veroorzaken m.n. bij kwetsbare patiënten. Zowel bij veroudering als neurodegeneratieve aandoeningen is sprake van een verstoring in het immuunsysteem. Dit resulteert in verhoogde inflammatie onder normale omstandig-heden, maar kan ook te sterk worden in reactie op inflammatoire stimulatie. De pre-inflammatoire toestand verklaart mogelijk waarom oudere en cognitief aangedane personen kwetsbaarder zijn voor delier wanneer tevens uitlokkende factoren aanwezig zijn, die een inflammatoire reactie teweegbrengen. Behalve dat deze predisponerende en precipiterende factoren de kans op het ontstaan van delier vergroten, is het effect van deze factoren op de duur van het postoperatief delier potentieel van belang. Er zijn namelijk aanwijzingen dat naarmate een delier langer aanhoudt dit een negatief effect heeft op de langere termijn. De delier duur zou bijvoorbeeld de kans op sterfte vergroten en het cognitieve en affectief functioneren negatief beïnvloeden. De klinische diagnose van delier is gebaseerd op

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een aantal kenmerkende symptomen en het uitsluiten van aandoeningen die een grote overeenkomst met delier vertonen. Echter, delier zelf heeft ook verschillende fenotypes. Het delier gaat vaak samen met veranderingen in de motoriek en wordt ook wel geclassificeerd in twee motorische subtypes, namelijk hypo- en hyperactief. Later is hier een derde, gemengde (mixed), categorie aan toegevoegd, waarbij elementen van beide subtypes zich binnen korte tijd voordoen. Eerder onderzoek suggereert dat deze subtypes verschillen in pathofysiologie, vereiste behandeling en prognose. Het hypoactieve subtype heeft meer kans om onopgemerkt te blijven of onjuist gediagnosticeerd te worden. Er is nog veel onduidelijkheid over de motorische subtypes, uitkomsten en de stabiliteit van dit subtype gedurende het delier. Onderzoeksresultaten betreffende verschillen tussen de motorische subtypes in risicofactoren en prognose zijn inconsistent. De verschillen worden mogelijk veroorzaakt door verschillende onderzoekspopulaties en/of onderzoeksmethodes. Delier is geassocieerd met verhoogde kans op mortaliteit, verpleeghuisplaatsing en dementie. Er is echter minder bekend over de lange termijn effecten op specifieke cognitieve en affectieve domeinen. Het hebben doorgemaakt van een delier, dan wel het persisteren van het delier is mogelijk geassocieerd met verminderde cognitieve functies en affectieve stoornissen, zoals depressie of angst. Indien sprake is van een associatie tussen delier en lange termijn cognitieve en affectieve stoornissen vereist dit extra oplettendheid en controle van de patiënt, omdat dit het verdere herstel en de revalidatie zou kunnen belemmeren. SAmenVATTInG Het eerste deel van dit proefschrift beschrijft predisponerende en precipiterende factoren voor delier, waarbij we ons richten op richten op de anesthesietechniek en het effect van een chirurgische ingreep. In hoofdstuk 2 hebben we onderzocht of algehele anesthesie geassocieerd is met een verhoogd risico op postoperatief delier. Patiënten waren 70 jaar of ouder, opgenomen om heup chirurgie te ondergaan. In totaal ontwikkelden 60/526 patiënten (11.4%) een delier, 337/526 (64.1%) ondergingen algehele anesthesie en 89/526 (35.9%) ondergingen regionale anesthesie. 18/189 (9.5%) algehele anesthesie patiënten kregen postoperatief een delier tegenover 42/337 (12.5%) van de regionale anesthesie patiënten. Algehele anesthesie was niet geassocieerd met een verhoogd risico op postoperatief delier in vergelijking met regionale anesthesie. We hebben hierbij gecontroleerd voor cognitieve status, leeftijd, acute opname, geslacht, gezichtsvermogen, fysieke status en dehydratie. Delier was in deze studie niet geassocieerd met perioperative toediening van opiaten, benzodiazepines of anticholinergica In hoofdstuk 3 hebben we het beloop van CRP concentraties over meerdere dagen heen bestudeerd (baseline, postoperatieve dag 1 t/m 5), en de associatie tussen postoperatief delier en CRP waardes onderzocht. Daarnaast is gekeken naar de

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associatie tussen CRP waardes en delier ernst, cognitieve stoornis, fysieke status en delier duur. Longitudinale analyse toonde een associatie tussen postoperatief delier en hogere CRP concentraties. Het onderzoeken van specifieke dagen liet zien dat CRP concentraties toenamen vanaf postoperatieve dag 2 en ook hoger bleven bij patiënten met postoperatief delier. Delier ernst was geassocieerd met hogere CRP niveaus. We vonden geen significante verschillen in CRP waardes tussen patiënten met kort en langer aanhoudend delier, of tussen de hoogste CRP concentratie en pre-existent verminderd cognitief functioneren of een globale maat voor ernst van ziekte. Het tweede deel van dit proefschrift richtte zich op het beloop van delier, de duur en klinische kenmerken. hoofdstuk 4 betrof het onderzoeken van kenmerken waardoor een vroeg onderscheid kan worden gemaakt tussen patiënten die wel en niet verhoogd risico hebben op een langer persisterend delier, en daardoor negatieve (lange termijn) consequenties. We onderzochten of preoperatieve delier risico factoren en delier symptomen (bij aanvang van het delier en gedurende het delier) geassocieerd waren met de duur van het delier. We vergeleken patiënten met kortdurend delier (1 of 2 dagen) met persisterend delier (3 dagen of langer) op de DRS-R98 (Delirium Rating Scale Revised-98) symptomen op de eerste dag van het delier. Dit symptoomprofiel werd dagelijks beoordeeld gedurende het delier. Er werd een associatie gevonden tussen langer aanhoudend delier (3 dagen of meer) en een reeds bestaande verslechtering van het cognitieve functioneren, niet met de ernst van individuele delier symptomen. hoofdstuk 5 vergeleek baseline kenmerken en uitkomsten tussen verschillende motorische subtypes. Ook hebben we gekeken naar de longitudinale stabiliteit van de classificatie in subtypes over meerdere dagen. De motorische subtypes werden gecategoriseerd aan de hand van de DRS-R98, en de longitudinale expressie (overheersend hyperactief, overheersend hypoactief, overheersend gemengd, geen motorisch subtype en het variabele subtype). De volledige delier episode kon worden bepaald voor 42/62 (67.7%) patiënten met een postoperatief delier in het ziekenhuis. Van de patiënten met meerdere dagen delier had slechts 4/30 (13.3%) patiënten een consistent motorisch subtype profiel gedurende het delier, terwijl 26/30 (86.75) een wisselend subtype profiel had. Van de patiënten met meerdere delier dagen had 5/30 (16.7%) een overheersend hypoactief profiel, 7/30 (23.3%) een overheersend hyperactief profiel, 6/30 (20%) een overheersend gemengd subtype profiel, 1 patiënt (3.3%) had geen motorisch subtype en 11/30 (36.7%) had een variabel profiel (geen van de subtypes was overheersend). De categorisatie aan de hand van overheersend motorisch subtype toonde dat de groepen verschilden in verschillende karakteristieken of uitkomsten. hoofdstuk 6 betreft de betrouwbaarheid en validiteit van de ‘Delirium Motor Sub-type Scale’ (DMSS) vertaald naar het Nederlands. De DMSS is een instrument ontwikkeld om alle voorgaande manieren van motorische subtypering samen te voegen in een nieuwe schaal om het motorisch subtype te bepalen. In tegenstelling tot voorgaande methoden

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van subtypering legt de DMSS meer nadruk op de stoornissen in de motoriek in plaats van veronderstelde geassocieerde psychomotorische symptomen. De Nederlandse versie van de DRS-R98 en de DMSS werden afgenomen bij oudere heup chirurgie patiënten. De diagnose delier werd bepaald aan de hand van de ‘Confusion Assessment Method’ (CAM). De interne consistentie van de DMSS was acceptabel (Cronbach’s alpha=0.72). ‘At random’ verwijdering van een DMSS item had geen effect op de interne consistentie van de schaal. De concurrente validiteit was goed (Cohen’s kappa=0.73), Cohen’s kappa reikte van 0.58 to 0.85 voor ieder motorische subtype. De sensitiviteit en specificiteit van de DMSS om ieder subtype (hypoactief, hyperactief, gemengd, geen motorisch subtype) te diagnosticeren varieerde van 0.56 tot 1 en van 0.88 tot 0.98. De gevonden resultaten suggereren dat de Nederlandse versie van de DMSS een betrouwbaar en valide instrument is, dat mogelijk met meer precisie subtypes kan identificeren in toekomstig onderzoek. Het onderwerp van het laatste deel van dit proefschrift heeft betrekking op de gevolgen van een delier. Hierin onderzochten we het effect van delier op het latere cognitieve en affectieve functioneren. In hoofdstuk 7 onderzochten we de associatie tussen delier en lange termijn cognitieve stoornissen. Een delier kan het begin betekenen van cognitieve achteruitgang, het versnellen of veroorzaken. Echter, de precieze aard van de cognitieve stoornissen is nog onduidelijk. Ook is het onduidelijk of persisterende delier symptomen of aanwezigheid van depressie bij follow-up een rol spelen bij de associatie tussen delier en lange termijn cognitieve stoornissen. Bij 53 oudere patiënten werd 3 maanden na ontslag uit het ziekenhuis een neuropsychologische testbatterij afgenomen. Patiënten met een persisterend delier werden geëxcludeerd uit de analyses. Patiënten die tijdens de ziekenhuisopname een delier hadden doorgemaakt presteerden slechter op taken die het episodisch geheugen testen 3 maanden later. Dit resultaat bleef bestaan na correctie voor verschillen in leeftijd, geslacht en het niveau van de cognitie bij opname. Er werd geen verschil gevonden met betrekking tot de uitvoering van aandachtstaken. Een verstoorde aandacht, wat een kern symptoom is van persisterend delier of depressie , lijkt daarom deze verminderde cognitieve functie niet te kunnen verklaren. hoofdstuk 8 beschrijft de associatie tussen delier tijdens ziekenhuisopname en de mate van gevoelens van angst en depressie, en symptomen van posttraumatische stress 3 maanden na ziekenhuisopname. Patiënten die een delier hadden doorgemaakt tijdens hun ziekenhuisopname toonden meer symptomen van depressie na 3 maanden in vergelijking met controles. Deze associatie bleef bestaan na controle voor leeftijd, niveau van cognitie bij opname, mate van symptomen van depressie bij opname en woonsituatie (mate van zelfstandigheid). Ook persisterend (sub) syndromaal delier bleek geen onderliggende verklaring voor de verhoogde symptomen van depressie bij patiënten die een delier hadden doorgemaakt. De mate van angstgevoelens en symptomen van posttraumatische stress bij follow-up verschilde niet tussen patiënten die wel en geen delier hadden doorgemaakt tijdens ziekenhuisopname.

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In hoofdstuk 9 worden de resultaten in de hiervoor genoemde onderzoeken nader besproken, alsmede de zwakke en de sterke methodologische aspecten van de studies. hoofdstuk 10 is de Engelstalige samenvatting van de hiervoor genoemde onderzoeken.

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Supplement 1

delIrIum moTor SuBTyPe SCAle (dmSS)

hyperactive Subtype if definite evidence in the previous 24 hours of (and this should be a deviation from pre-delirious baseline) at least two of: • Increased quantity of motor activity • Loss of control of activity • Restlessness • Wandering

hypoactive Subtype if definite evidence in the previous 24 hours of (and this should be a deviation from pre-delirious baseline) two or more of:* • Decreased amount of activity • Decreased speed of actions • Reduced awareness of surroundings • Decreased amount of speech • Decreased speed of speech • Listlessness • Reduced alertness/withdrawal

*Where at least one of either decreased amount of activity or speed of actions is present.

mixed motor Subtype if evidence of both hyperactive and hypoactive subtype in the previous 24 hours.

no motor Subtype if evidence of neither hyperactive or hypoactive subtype in the previous 24 hours.

Bron: Meagher D, Moran M, Raju B, Leonard M, Donnelly S, Saunders J, Trzepacz P: A new data-based motor subtype schema for delirium. J Neuropsychiatry Clin Neurosci. 2008; 20;185-193.

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Supplement 2delIrIum moTor SuBTyPe SCAle (dmSS) – nederlAndSe VerSIe

moTorISChe CheCKlIST Voor delIer

hyperactieve SubtypeIn de afgelopen 24 uur waren er duidelijke aanwijzingen (en dit moet afwijken van de situatie voor het delier) voor tenminste twee van de volgende: • Een overmaat aan activiteit, bijv. ijsberen, friemelen of overactiviteit in het algemeen. • Patiënt is niet in staat om een activiteitsniveau passend bij de omstandigheden

vast te houden. Patiënt is bijvoorbeeld niet in staat stil te zijn wanneer dit wordt verwacht.

• Patiënt klaagt over mentale rusteloosheid of komt geagiteerd over. • Patiënt zwerft rond, bijv. beweegt zich voort zonder doel of duidelijke richting.

hypoactieve SubtypeIn de afgelopen 24 uur waren er duidelijke aanwijzingen (en dit moet afwijken van de situatie voor het delier) voor tenminste twee of meer van de volgende:* • Patiënt is minder actief dan normaal of passend bij de omstandigheden, bijv. patiënt

zit stil met weinig spontane bewegingen. • Patiënt is traag in het initiëren en uitvoeren van bewegingen, bijv. lopen. • Patiënt laat te weinig emotionele reactiviteit zien ten opzichte van de omgeving,

bijv. patiënt neemt een passieve houding aan ten opzichte van zijn/haar omgeving. • Patiënt is minder spraakzaam in relatie tot de omgeving, bijv. antwoorden zijn

terughoudend of beperkt tot een minimum. • Patiënt spreekt trager dan normaal, bijv. lange pauzes en vertraging van de

daadwerkelijke taalproductie. • Patiënt is verminderd reactief ten opzichte van de omgeving, bijv. patiënt reageert

traag of minder frequent op activiteit in de directe omgeving. • Patiënt lijkt niet in contact te staan met, of zich bewust van, de omgeving of het

belang ervan.* Waar tenminste een verminderde frequentie van activiteit of een verminderde snelheid van handelen aanwezig moet zijn.

mixed Subtype In de afgelopen 24 uur waren er aanwijzingen voor zowel het hyperactieve als het hypo-actieve subtype.

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Geen motorisch Subtype In de afgelopen 24 uur waren er geen aanwijzingen voor het hyperactieve of het hypoactieve subtype.

Bron: Meagher D, Moran M, Raju B, Leonard M, Donnelly S, Saunders J, Trzepacz P: A new data-based motor subtype schema for delirium. J Neuropsychiatry Clin Neurosci. 2008; 20;185-193.

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Dankwoord

Dankwoord

Graag wil ik iedereen bedanken zonder wie dit proefschrift niet tot stand was gekomen. Daarbij wil ik een aantal mensen in het bijzonder bedanken.

Allereerst Jos, ergens lang geleden liep ik eens binnen voor een gesprek betreffende een stageplek en hier zijn we nu dan. Bedankt voor alle mogelijkheden, motivering en de ruimte om te groeien.

Joost, je hebt op zoveel manieren bijgedragen aan de totstandkoming van dit proefschrift. Ik ben je ontzettend dankbaar voor alles. Daarnaast ook bedankt voor alle gezelligheid, humor en de ‘wandelpraatjes’ tijdens dit traject.

Piet, bedankt voor de niet geringe intellectuele bijdrage aan dit proefschrift, alle (telefonische) overleg momenten waardoor ik op het ‘juiste’ spoor bleef en voor alle vriendelijkheid die je verder altijd toonde voor hoe het met me ging.

Pim, ook jij uiteraard bedankt voor het intellectueel bijdragen aan en geloven in dit proefschrift. Ook bedankt voor het helpen relativeren en overkomen van de tegengekomen hindernissen tijdens dit traject.

Rene, bedankt dat je geloofde in dit proefschrift en copromotor wilde worden, met kritiek die altijd recht door zee was.

Kees, met een scriptie betreffende anesthesie is het uiteindelijk allemaal begonnen en daarom ook mijn dank naar jou.

In het bijzonder wil ik ook twee mede-auteurs bedanken, D&D:

Dimitrios Adamis, my visit to Athens was something I will never forget. Thank you for your hospitality, your time, your contribution to this thesis in several articles, your endless willingness to explain things to me (over and over again sometimes…I remember your quote ‘why do you always make things so complicated!’) and your confidence in me. Let’s celebrate this with a drink and an episode of BB!

David Meagher, thank you for your contribution to this thesis. Your work has inspired part of this thesis and I am grateful for all the feedback, answers and ideas that you have provided.

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Graag zou ik ook de overige mede-auteurs bedanken: Marc Snoek, Erwin Groot en Ben Schmand.

Mijn dank ook naar Wolfgang Schlack en Cees-Jan Oostwouder voor hun bijdrage aan het manuscript betreffende anesthesie.

Vervolgens wil ik de mensen bedanken die hebben bijgedragen aan het verzamelen, verwerken, invoeren en analyseren van de data in deze studie: Gisela Dekker, Gem Kramer, Margreet Schoorl, Tjeerd van der Ploeg, Tjerk Schoemaker (tik m aan), Ellen Slijkerman, Esther Tieken, Milko van Langen en Ralp Vreeswijk.

Lex Houdijk en Mireille van Stijn wil ik bedanken voor de mogelijkheid om dit proefschrift te creëren met de data van de TAUP studie.

Dank naar de promotiecommissie voor de tijd die zij wilde besteden aan het lezen en beoordelen van dit proefschrift.

Uiteraard gaat mijn dank ook uit naar de patiënten en hun familie, die wilden meewerken aan dit onderzoek.

De afdeling geriatrie van het Medisch Centrum Alkmaar, en de collega’s van de verschillende betrokken afdelingen bedankt voor de mogelijkheid tot het doen van dit onderzoek.

In het bijzonder nog mijn dank naar Ellen en Leoniek, bedankt voor alle relativering, steun en een lach op zijn tijd tijdens dit hele traject.

Mijn ouders, broertje (Bert, tis gelukt, bert) en vrienden wil ik bedanken omdat ze er nog steeds voor me zijn en in me geloven. Een proefschrift tot stand brengen is al een hele klus, maar bijzondere omstandigheden maakten het er niet makkelijker op. Bedankt voor de steun, het eerlijke advies (ook al heb ik niet altijd geluisterd) en de broodnodige humor tijdens deze periode. Nibbit en Ellen, ik ben blij dat jullie enthousiast ja zeiden op mijn verzoek!

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Curriculum vitae

Curriculum Vitae

Chantal Jochemina Slor was born in Purmerend on the 18th of November 1984. She obtained her masters degree in neuropsychology in 2009 at the University of Amsterdam. She started at the Medical Center Alkmaar with an internship, as part of her study in 2008. Thereafter she continued doing her master thesis on delirium, which eventually developed into this PhD project. In this same period she worked as a psychologist at the GGZ NHN for a while and as a study co-coordinator for a clinical research trial. Currently, she is looking for a new challenge in the field of psychology.

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