efficacy of the 980 nm laser diode compared to 75% glucose...

ORIGINAL ARtIcLe

Efficacy of the 980 nm laser diode compared to 75% glucose in sclerosing and occluding rabbit ear veinsEficiência do laser diodo 980 nm em comparação à da glicose a 75% na esclerose e oclusão de veias da orelha de coelhos

Paulo Roberto da Silva Lima1, Marcelo Araújo2, Guilherme Benjamin Brandão Pitta3, Andressa Feitosa Bezerra de Oliveira4, Guilherme Costa Guedes Pereira5, José Carlos Costa Baptista-Silva6

Abstract

Background: The laser is a new treatment to varicose veins and there is several myths and doubts in relation to its efficacy; then, there is the need to compare it with the most commonly sclerosing solution (hypertonic glucose) used in our specialty. Objective: To compare the efficiency of the diode laser 980nm to the glucose 75% in the occlusion of veins from the ear of rabbits. Methods: Aleatory trial in laboratory animals during 21 days. The sample consisted of ears from male adult rabbits. Group L (laser): 15 ears treated with laser; group G (glucose 75%): 15 ears treated with glucose 75%. Primary variables: sclerotic and/or occluded veins. Complementary variables: volume of the managed substance, complications and weight of rabbit. The sample size was estimated in 30 ears. The statistical analysis was carried out by Fisher’’s exact test associated to the Relative Risk (RR), calculating the confidence interval of 95% for the mentioned variables.Results: The incidence of sclerosis or venous occlusion in group G was 53% (8/15; 95%CI: 27-79) and in group L was 20% (3/15; 95% CI: 4-49). Two-tailed p was 0.1281, RR using the approximation of Katz was 2.66; 95%CI: 0.87-8.15.Conclusion: The efficiency of the diode laser 980 nm in comparison to glucose 75% in occlusion of veins in this experimental model was equivalent.

Keywords: sclerotherapy; laser therapy; glucose; rabbits.

Resumo

Contexto: Por ser o laser um método novo no tratamento das varizes, há muitos mitos e dúvidas com relação à sua eficácia; assim, surgiu a necessidade de compará-lo a substância esclerosante mais utilizada em nosso meio (glicose hipertônica). Objetivo: Comparar a eficiência do laser diodo 980 nm à glicose 75% na oclusão de veias em orelha de coelho. Métodos: Ensaio aleatório em animais de laboratório por 21 dias. A amostra consistiu de orelhas de coelhos machos adultos. Grupo L (laser): 15 orelhas tratadas com laser; grupo G (glicose 75%): 15 orelhas tratadas com glicose a75%. Variáveis primárias: veias esclerosadas e/ou ocluídas. Variáveis complementares: volume da substância administrada, complicações e peso. O tamanho da amostra foi estimado em 30 orelhas. Foi realizado o teste exato de Fisher associado ao Risco Relativo (RR), calculando-se o intervalo de confiança (IC) de 95% para as variáveis acima.Resultados: A incidência de esclerose ou oclusão venosa no grupo G foi de 53% (8/15; IC95%: 27-79) e no grupo L, 20% (3/15; IC95%: 4-49). O p bicaudal foi de 0,1281, o RR usando a aproximação de Katz foi de 2,66; IC95%: 0,87-8,15.Conclusão: A eficiência do laser diodo 980 nm em comparação à da glicose 75% na oclusão de veias para o modelo experimental estudado foi equivalente.

Palavras-chave: escleroterapia; terapia a laser; glucose; coelhos.

1Member of the Brazilian Society of Angiology and Vascular Surgery (SBACV); Post-graduation student (Master’s degree) at Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brazil.2 PhD in Cardiovascular surgery, UNIFESP, São Paulo (SP), Brazil; Assistant professor at Universidade Estadual de Santa Cruz (UESC), Ilhéus (BA), Brazil.3 PhD in Cardiovascular surgery, UNIFESP, São Paulo (SP), Brazil; Adjunct professor at Universidade Estadual de Ciências da Saúde de Alagoas (UNCISAL), Maceió (AL), Brazil.4 Full professor at Department of Morphology, Universidade Federal da Paraíba (UFPB), João Pessoa (PB), Brazil. 5 Pathologist at Hospital Universitário of UFPB, João Pessoa (PB), Brazil; Head Pathologist at Clínica de Patologia HISTO, João Pessoa (PB), Brazil.6 PhD in Medicine; Associate professor at the Department of Surgery, Escola Paulista de Medicina, UNIFESP, São Paulo (SP), Brazil.Conflict of interest: nothing to declareSubmitted on: 31.10.2010 Accepted on: 12.04.2011J Vasc Bras. 2011;10(2):110-118.

Efficacy of 980 nm laser diode compared to glucose in vein occlusion - Lima PRS et al. J Vasc Bras 2011, Vol. 10, Nº 2 111

Introduction

Telangiectasias or microvaricose veins are vessels measuring 0.1 to 1 mm in diameter1,2. The CEAP classification was adopted in 1994 aiming at a uniform terminology for venous insufficiency as to Clinical presentation, Etiology, Anatomy and Pathophysiology3-5.

In Brazil, the prevalence of C2 and C3 varicose veins is 37.9%6. In a study conducted in outpatient clinics of the Brazilian Public Health System in the city of Belo Horizonte (MG), the prevalence of chronic venous insufficiency was 50% in patients older than 15 years7.

Currently, sclerotherapy is accepted and performed as the ideal treatment for microvaricose veins8 or CEAP C1. However, the performance of this therapy still has some controversial issues, such as the choice of the ideal sclerosing agent.

The sclerosing solutions currently available are divided in three categories: osmotic, detergent and chemical. Hyperosmotic agents cause dehydration of endothelial cells, with consequent destruction and disintegration. Osmotic agents such as hypertonic saline solution and hypertonic glucose provide slow destruction, hence they are considered to be less capable of producing endothelial desquamation and inflammation, in comparison to detergent agents. The efficacy of hypertonic glucose is 54%9. Such agents tend to deposit few red blood cells on the endothelium, thus reducing the incidence of tissue pigmentation 10,11.

The most widely used detergent agents in Brazil are ethanolamine oleate (EO) and polidocanol (POL). They dissolve and interfere in the lipids of the cell surface, and their effect propagates beyond the site of injection.

Chemical solutions dissolve the intercellular cement and cause endofibrosis. Chromated glycerin (Scleremo®) and polyiodinated iodine (Variglobin®) are the most widely used agents in sclerotherapy of vessels with more than 8 mm in diameter12,13.

As a new addition to the treatment of varicose veins, we now have laser (light amplification stimulated emission of radiation) therapy. It has been used for benign vascular lesions because of the possible advantages over other treatments, such as absence of hyperpigmentation due to deposits of hemosiderin; it is a non-invasive and faster method; and absence of telangiectatic matting, hematoma or allergic reaction14.

The types of laser now used to treat benign vascular lesions also have disadvantages: non-selective action and pain of moderate intensity14. The existing controversy in literature whether the laser has more or less safety

and efficacy in comparison with traditional sclerosing treatments made us to raise the key question of this study: how effective is the 980 nm laser diode compared with 75% glucose to sclerose veins?

The hypothesis is that the 980 nm laser diode is more effective than 75% glucose. Hence, the objective of this study was to compare the efficacy of the 980 nm laser diode with 75% glucose in sclerosing ear veins of rabbits.

Methods

The study was approved by the Animal Ethics Committee of Universidade Federal da Paraíba (protocol 0105/08, 5/20/2008), by the Ethics Committee of Universidade Estadual de Ciências da Saúde de Alagoas (protocol 47-A, 6/18/2008) and by the Ethics Committee of Universidade Federal de São Paulo (protocol 1483/09, 10/16/2009).

The current laws of research laboratory animal management were observed.

There was no conflict of interest in this research, for it was financed by the researcher, who also paid for the laser device.

Study design

Randomized trial with laboratory animals for 21 days.

Location

Experimental research laboratory of pharmaceutical technology, Campus I of UFPB, João Pessoa (PB), Brazil.

Sample

Thirty young adult rabbits (Oryctolagus cuniculus) were used as animal models and divided into two groups. In compliance with literature reports, they weighed more than 2 kg15-20. Their right lateral auricular veins were used. The animals were from the vivarium of UFPB, and they were divided into two groups:a) Group G: 15 animals whose lateral auricular veins were

treated with 75% glucose.b) Group L: 15 animals whose lateral auricular veins were

treated with the 980 laser diode.

Inclusion criteria

Thirty Oryctolagus cuniculus adult rabbits were included in the study (12 months old, more than 2 kg).

Efficacy of 980 nm laser diode compared to glucose in vein occlusion - Lima PRS et al.J Vasc Bras 2011, Vol. 10, Nº 2112

Exclusion criteria

Rabbits that did not present perfect ears or marginal dorsal ear veins were excluded from the sample.

Sampling

The animals were randomly allocated to each group (15 individuals)21 by means of assigned lists named from G1 to G15 (glucose group) and L1 to L15 (laser group).

The experiment was performed in the vivarium. The models were kept in cages and fed with water and rabbit food (Purina®) ad libitum before and during the experiment (Figure 1).

Procedures

The animals were sedated with an intramuscular injection of xylazine (2 to 5 mg/kg) in the lateral portion of their right thigh19,22. The hair at the dorsal portion of the right ears was carefully removed at the level of the lateral auricular vein (vena auricularis lateralis), which was chosen because of the similarity of the vein caliber to the microvaricose veins in human beings. Asepsis of the ears was performed with hydrate alcohol 70%. The models were treated with 980 nm laser diode via transdermal patches and with 75% glucose local intravenous injection.

A 980 laser diode device (Synus®) (Figure 2), with power of 30 W, spot size diameter of 2 mm, frequency of 3 Hz, and fluence of 96 J/cm2 was used in Group L via transdermal delivery. In Group G, 75% glucose was administered at the dosage of 0.25 mL on average, by

means of a 3-mL syringe and a 30-gauge ½ needle. The vessel was filled with glucose for 20 seconds20. Application site in both groups was 4 cm away from the distal portion of the ear. The laser was also applied 3 cm away from the initial application site toward the base of the ear, in a single pulse15,17,20 (Figure 3).

To prove efficacy, we considered: formation of or existing thrombus (with fibrosis) inside the vessel; vein fibrosis; endothelium decamation or inner elastic limiting membrane (microscopic structures on the vein wall) and vessel absorption.

The first and second items were examined macroscopically for the absence of blood flow at manual milking, performed from the tip toward the base of the ear, keeping the initial pressure site occluded. The other items were verified by optical microscopy, and efficacy was verified on the 21st day after treatment.

Failure of procedure was considered as the absence of vessel sclerosis.

Complications were pigmentation, depigmentation, hematoma, edema, neovascularization (nodules), ulceration, tissue necrosis, hypertrophic scar, tissue atrophy and death.

After final macroscopic assessment and collection for histology, the animals were sedated with xylezine and euthanized by the veterinarian by intravenous injection of 19.1% potassium chloride.

Surgical fragments of the veins were collected for microscopic examination 1 cm above the initial glucose and laser application site and 1 cm below the final application site of the laser by surgical excision with no. 11 scalpel blade (Figure 3). Surgical specimens were maintained in 10% formalin for 24 hours at minimum and,

Figure 1 - Rabbit cages. Figure 2 - 980 nm laser diode device (Synus®).


then, histological slides were prepared for macroscopic examination. The specimens were gradually dehydrated with 70% alcohol until absolute alcohol, diaphanized in xylol and embedded in liquid paraffin at 60oC. The paraffin blocks were transversally cut at 3 μm and put on slides (76 x 25 mm). After that, they were stained in hermatoxylin-eosin and in Masson, being set up in natural resin. The slides were prepared and examined in 40 and 100X magnification by a pathologist of UFPB.

Aiming at a blind microscopy, we changed the letters in the slides by others that could only be identified by the principal investigator. We put them in a sealed envelope that was opened at the moment of data analysis. The pathologist could not identify the sclerosing method used in each vessel.

Variables

Primary variable

Sclerosing or occluded veins are thickened and fibrous veins from an inflammatory process. Efficacy gathers the utility and the benefits of the service or intervention under ideal conditions in a research for the individual or the community, and, in this study, it was determined based on randomized controlled trials23.

Statistical method

Sample size calculation

Sample size was calculated in 86 rabbits, considering the efficacy proportion of 54% in Group G (75% glucose) and of 88.4% in Group L (laser), with 5% significance level, test power of 95% and bicaudal hypothesis test. However, since some studies in the literature have shown acceptable statistical results with smaller samples15,17-20, and to comply with COBEA guidelines, our study population was set at 30 animals. Statistical analysis was performed by Fisher’s Exact Test in association with relative risk (RR) and a 95% confidence interval24. An electronic calculator available on the internet was used for sample size calculation (http://www.lee.dante.br/pesquisa/amostragem/di_2_pro.html). Statistical analysis was performed by the software GraphPad Instat® (3.06 32 bit) for Windows.

Statistical analysis

Data were collected by means of a standard form and stored in an electronic chart (Microsoft® Excel 2007, Redmond, WA, EUA) with independent data entries.

Assessed variable

Effectiveness of 980 nm diode laser and 75% glucose in vein sclerosis and occlusion were compared to the study hypothesis.

Statistical Hypotheses

- H0: G = L (no difference between laser and glucose);- H1: G ≠ L (difference between laser and glucose).

Alpha value

Alpha value was set at 0.05 to reject the null hypothesis.

Results

Research protocol deviation

The specimens were stained in Masson’ trichrome stain aiming at a better visualization and examination of treatment effects on adjacent tissues, thrombi and tissue

Figure 3 - Application of laser and glucose, and site of biopsy for his-tology.


damages. We found intimal hyperplasia and vascular congestion in our sample, data not previously reported in the literature. Vascular congestion (Figures 4 and 5) is characterized by a great amount of red blood cells in the vessel lumen, that is not organized in thrombus, and intimal hyperplasia (Figures 6 and 7) is characterized by an organized increase in the number of cells in certain regions of the vessel wall.

Sample characteristics

The sample consisted of 30 male rabbits weighing 4,425 g on average in Group G, and 3,590 g in Group L. We used 0.25 mL of 75% hypertonic glucose in each injection.

On average, we used 4.15 mL of Xylezin in Group G and 3.55 mL in Group L for application of intramuscular sedation.

Variables

Primary variable

The incidence of sclerosis/occlusion at histological study after 21 days of observation was 53% in Group G (8/15, 95%CI=27-79), and 20% in Group L (3/15, IC95%=4-49), with a 33% difference between them.

Bicaudal test was p=0.1281 and relative risk of 2.66 by Katz approximation (95%CI=0.87-8.15) (Figure 8). Some occlusion/sclerosis were partial (Figure 9) and others were total (Figure 10), in the following distribution (Figure 11):

Figure 4 - Vascular congestion, Manson, 100x magnification. Grouping of red blood cells (arrow).

Figure 5 - Vascular HE, 100X magnification. Grouping of red blood cells (arrow).

Figure 6 - Intimal hyperplasia (arrow), Manson, 40X magnification.

Figure 7 - Intimal hyperplasia (arrow), Manson, 20X magnification.


Difference between fractions = 46%; p = 0.0253 and RR = 0.30 in the bicaudal test; 95%CI: 0.10-0.88 with Katz approximation.

c) 21 days: glucose − 6% (1/15; 95%CI: 0.1-32); laser − 13% (2/15; 95%CI: 2-40).

Difference between fractions = 7%; p = 1 and RR = 0.50 in the bicaudal test; 95%CI: 0.05-4.95 with Katz approximation.

Until the 14th day of macroscopic examination, we observed edema at the site of laser application (Figure 13), as well as some scabs (Figure 14) that disappeared during the examination.

Venous recanalization (Figures 15 and 16) was observed at histological study in 88% of Group G (7/8, 95%CI: 47-99) and in 100% of Group L (3/3, 95%CI: 29-100). The difference between fractions was of 12%, and the bicaudal test

Figure 8 - Frequency of sclerosis or occlusion (21 days) − microscopy.

Figure 11 - Frequency of partial and total sclerosis.

a) Glucose: - total sclerosis: 25% (2/8; 95%CI=3-65);- partial sclerosis: 75% (6/8; 95%CI=35-97).

b) Laser:- total occlusion: 0%;- partial occlusion: 100% (3/3; 5%CI=29-100).

Macroscopically, the groups were assessed on the 7th, 14th and 21st days after treatment, with the following results (Figure 12):a) 7 days: glucose − 20% (3/15; 95%CI=6-45); Laser −

100% (15/15; 95%CI: 76-100). Difference between fractions = 80%; p < 0.0001 and RR

= 0.20 in the bicaudal test; 95%CI: 0.07-0.55 with Katz approximation.

b) 14 days: glucose − 20% (3/15; 95%CI=6-45); laser − 66% (10/15; 95%CI: 38-88).

Figure 9 - Partial occlusion, Manson, 100X magnification, fibrosis (blue arrow); light (orange arrow).

Figure 10 - Total occlusion, Manson, 100X magnification, fibrosis (arrow).


showed p = 1 and RR = 0.87; 95%CI: 0.67-1.14, with Katz approximation.

Complementary data

Vascular congestion (Figures 4 and 5) had the following distribution:a) Group G: 87% (13/15, 95%CI: 60-98);b) Group L: 67% (10/15, 95%CI: 38-88). Bicaudal test showed p = 0.3898 and RR = 1.30 (95%CI:

0.86-1.96), with Katz approximation.

Intimal hyperplasia (Figures 6 and 7) was:a) Group G: 13% (2/15, 95%CI: 2-40);b) Group L: 7% (1/15, 95%CI: 0-32).

Figure 12 - Frequency of sclerosis and occlusion in lateral auricular veins macroscopically examined in the 7th, 14th and 21st days after laser or glucose treatment.

Figure 13 - Vein edema, laser, showed by blue marks.

Figure 14 - Scabs (arrows): laser therapy in lateral auricular vein.

Figure 15 - Vein recanalization (arrows) Manson, 40X magnification.

Figure 16 - Vein recanalization (blue arrows), Hemossiderin (orange ar-rows), Manson, 100X magnification.


Bicaudal test showed p = 1 and RR = 2.00 (95%CI: 0.20-19.79), with Katz approximation.

Discussion

The hypothesis was that 980 nm laser diode had a 30% higher efficacy than 75% glucose, for the literature reports efficacy of 88.2%25 for laser and 54%9 for hypertonic glucose. After 21 days of treatment, the efficacy of glucose was 53%, which was also a finding by Bougeois (1984) 9, and that of laser was 20% in our study. This result differed from that of Passeron (2003), who showed an efficacy higher than 88.2%25. This author used a higher fluence than we did, so the values of his study varied from 306 to 317 J/cm2, while ours were set at 96 J/cm2, that is, the amount of energy absorbed by the vein was greater in Passeron’s study and the best results were achieved after three applications. Vural et al.20 used a fluence of 140 J/cm2 (intense pulse light) in a group, and ranging from 500 to 700 J/cm2 in another group (with the ARC system laser). We did not use fluence in our study because, in daily practice, the fluence for telangiectasias varies from 90 to 140 J/cm2, and cases of burning at 150 J/cm2 have been reported, as well as hyperpigmentation and inflammation. In addition, Goldman et al. (1990)17 used fluence of 8 to 10 J/cm2 and obtained high efficacy with laser, using the Pulsed dye LASER device.

On the 7th and 14th days, macroscopic examination showed statistical difference favorable to Group L. However, on the 21st day, this difference disappeared and histology showed no difference between groups. It is possible that the laser, by provoking temporary edema, has caused compression of the vessel that resembles an occlusion.

The 13% rate of intimal hyperplasia in Group G and 7% rate in Group L may be related to some degree of injury to the vein wall caused by the methods of treatment, because intimal hyperplasia is indeed an abnormal migration and proliferation of vascular smooth muscle cells, with deposition of with extracellular connective tissue matrix, followed by remodeling of the newly formed tissue26. We have not found studies reporting these findings (intimal hyperplasia and vascular congestion in veins26-28. After reviewing the results with the pathologist, we concluded that some degree of narrowing of the adjacent veins might have occurred, thus compromising blood flow into the area examined

Among the complications of chemical sclerotherapy reviewed by Correia and Oliveira in 2003, we observed only temporary edema in Group L, but this is a normal reaction to the procedure, so it is not adequate to classify it as a complication. Miyake et al., in 197616, stated that ulceration

in chemical sclerotherapy is related to the retrograde passage of the sclerosing agent into the arterial circulation; however, we did not observe ulcers in our sample. Goldman et al., in 198730, mentioned hemossiderin skin deposition as cause of pigmentation. We did not observe cases of pigmentation or depigmentation in our sample. We did find hemosiderin in the histological slides, but it was present on the fibrous tissue around the vessel, not in the skin.

Based on our data, we have to accept the H0 hypothesis, for the bicaudal p value was 0.1281.

Conclusion

The efficacy of the 980 nm laser diode was similar to that of 75% glucose injection in sclerosing and occluding rabbit ear veins in this experimental model.

References

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26. Davies MG. Hiperplasia da íntima: Resposta básica à lesão e reconstrução do enxerto arterial e venoso. In: Rutherford RB, editor. Cirurgia Vascular. 6a ed. Rio de Janeiro: DiLivros; 2007. p. 149-72.

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29. Correia M, Oliveira A. Complicações em escleroterapia. In: Pitta GBB, Castro AA, Burihan E, editors. Angiologia e cirurgia vascular: guia ilustrado. Maceió: UNCISAL/ECMAL & LAVA; 2003. p. 1-9.

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Correspondence: Paulo Roberto da Silva Lima

Avenida Epitácio Pessoa, 753, sala 1.001 – Bairro dos Estados CEP: 58030-904 – João Pessoa (PB), Brazil

E-mail: [email protected]

Author’s contribution: Study conception and design: PRSL, MA, GBBP, JCCBS

Data analysis and interpretation: PRSL, MA, JCCBS, GBBP Data collection: PRSL, GCGP

Writing: PRSL, MA, JCCBS, AFBO Critical analysis: MA, JCCBS, AFBO, GBBP

Final approval*: PRSL, MA, JCCBS, GBBP, AFBO, GCGP Statistical analysis: PRSL, MA, JCCBS, GBBP

Overall responsibility: PRSL Financing information: PRSL

* All authors have read and approved the final version, submitted to J Vasc Bras.

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