Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 8  |  Issue : 1  |  Page : 12-20

Pentoxifylline is better than ketamine in modulating the systemic inflammatory response in patients undergoing coronary artery bypass grafting


1 Departement of Anesthesia, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Departement of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt

Date of Submission06-Aug-2013
Date of Acceptance10-Oct-2013
Date of Web Publication21-Jul-2014

Correspondence Address:
Abdelhay Ebade
MD, Assistant Professor of Anesthesia, Faculty of Medicine, Cairo University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-9090.137230

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  Abstract 

Objective
The aim of this study was to evaluate the effect of using pentoxifylline (PTX) and ketamine on serum levels of interleukin (IL)-6, IL-10, and malondialdehyde (MDA) during coronary artery bypass grafting surgery.
Patients and methods
The study included 60 patients, 39 men and 21 women, with a mean age of 48.6 ± 9.1 years and a mean ejection fraction (EF) of 56.7 ± 3.8%. Patients were randomly allocated into three equal groups: the control group received placebo infusion; the ketamine group received 0.5 mg/kg ketamine as an intravenous bolus dose administered after induction of anesthesia, followed by continuous infusion with 1.25 μg/kg/min ketamine until weaning from cardiopulmonary bypass (CPB); and the PTX group received 5 mg/kg PTX as an intravenous bolus dose administered after induction of anesthesia, followed by continuous infusion with 1.5 mg/kg/h PTX until weaning from CPB. Blood samples were collected from the patients after induction of anesthesia (baseline; T 0 ) and 4 h (T 1 ), 24 h (T 2 ), and 48 h (T 3 ) after aortic declamping for estimation of serum IL-6, IL-10, and MDA levels using ELISA.
Results
All patients showed a steadily progressive increase in serum IL-6 levels; however, both ketamine and PTX had a blunting effect on IL-6 release, manifested as nonsignificantly (P3 = 0.262 and 0.794, respectively) higher serum levels estimated at T 1 compared with T 0 , with significantly (P3 = 0.0006) lower levels compared with those in the control group. All patients showed significantly (P3 = 0.001, 0.005, and 0.028 in control, ketamine, and PTX groups, respectively) higher serum IL-6 levels at T 3 compared with T 2 , which were significantly (P3 = 0.0004, 0.0006, and 0.001 in control, ketamine, and PTX groups, respectively) higher than those at T 1 . The PTX group showed significantly lower IL-6 levels at T 2 compared with the ketamine group (P2 = 0.018). Serum IL-10 levels were significantly (P3 = 0.029, 0.0005, and 0.0007 in control, ketamine, and PTX groups, respectively) higher at T 1 compared with T 0 , with significantly higher levels in the ketamine (P1 = 0.031) and PTX (P1 = 0.0009) groups compared with the control group. Serum IL-10 levels were significantly higher in the control (P3 = 0.041), ketamine (P3 = 0.001), and PTX (P3 = 0.009) groups at T 2 compared with T 1 , with significantly higher levels in the ketamine (P1 = 0.0006) and PTX (P1 = 0.0007) groups compared with the control group and significantly higher levels in the PTX (P1 = 0.002) group compared with the ketamine group. Serum IL-10 levels were significantly lower in the control (P3 = 0.001) and ketamine (P3 = 0.0009) groups, with nonsignificantly lower (P3 = 0.136) levels in the PTX group, at T 3 compared with T 2 , with significantly higher levels in the ketamine (P1 = 0.002) and PTX (P1 = 0.0005) groups compared with the control group and significantly higher levels in the PTX (P1 = 0.0007) group compared with the ketamine group. Serum MDA levels were significantly (P3 = 0.0004, 0.0005, and 0.0004 in control, ketamine, and PTX groups, respectively) higher at T 1 compared with T 0 , with significantly higher levels in the ketamine (P1 = 0.021) and PTX (P1 = 0.0009) groups compared with the control group and significantly higher levels in the ketamine group (P2 = 0.001) compared with the PTX group. Serum MDA levels were significantly higher in the control (P3 = 0.006) and ketamine (P3 = 0.049) groups, but nonsignificantly higher in the PTX (P3 = 0.681) group, at T 2 compared with T 1 , with significantly lower levels in the PTX group (P1 = 0.003) and nonsignificantly (P1 = 0.219) lower levels in the ketamine group compared with the control group and significantly lower levels in the PTX (P2 = 0.002) group compared with the ketamine group. Serum MDA levels were nonsignificantly lower in the control (P3 = 0.732), ketamine (P3 = 0.164), and PTX (P3 = 0.128) groups at T 3 compared with T 2 , with nonsignificantly (P3 = 0.678) higher levels in the ketamine group but significantly higher (P1 = 0.003) levels in the PTX group compared with the control group and significantly lower levels in the PTX (P1 = 0.028) group compared with the ketamine group.
Conclusion
Using of PTX or ketamine could ameliorate the systemic inflammatory response, as well as oxidative stress response, in patients undergoing coronary artery bypass grafting with CPB and could shift the immune response to surgery toward the anti-inflammatory side. However, such effects were more pronounced with PTX than with ketamine.

Keywords: Coronary artery bypass grafting, IL-10, IL-6, ketamine, malondialdehyde, pentoxifylline


How to cite this article:
Ebade A, Shehata M. Pentoxifylline is better than ketamine in modulating the systemic inflammatory response in patients undergoing coronary artery bypass grafting. Egypt J Cardiothorac Anesth 2014;8:12-20

How to cite this URL:
Ebade A, Shehata M. Pentoxifylline is better than ketamine in modulating the systemic inflammatory response in patients undergoing coronary artery bypass grafting. Egypt J Cardiothorac Anesth [serial online] 2014 [cited 2021 Jun 19];8:12-20. Available from: http://www.ejca.eg.net/text.asp?2014/8/1/12/137230


  Introduction Top


Proinflammatory and anti-inflammatory cytokines such as interleukin (IL)-6, IL-8, and IL-10 play a dominant role as local or systemic regulators in the acute inflammatory response. Inhibition of IL-6 with monoclonal antibodies leads to a marked attenuation in the inflammatory response [1],[2],[3]. Tissue injury causes the release of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and IL-1β, which are involved in many aspects of inflammation [4],[5],[6].

The produced TNF-α triggers the release of a cascade of cytokines that mediate the release of prostaglandins and sympathomimetic amines. Indeed, TNF-α stimulates the production of IL-1β and IL-6, which in turn stimulate the production of cyclooxygenase products and IL-8/neutrophil chemoattractant-1, thereby enhancing the production of sympathomimetic amines [7],[8]. IL-6 is also able to promote Th2 phenotypic responses and its actions can be classified as both proinflammatory and anti-inflammatory. The local balance between IL-6 and IL-10 is an important determinant of subsequent immune responses [9].

The coronary artery bypass grafting (CABG) procedure is a strong inflammatory stimulus that causes a substantial rise in circulating C-reactive protein, fibrinogen, and IL-6 levels. High-plasma IL-6 concentrations were in turn significantly associated with postoperative fever, atrial fibrillation, prolonged endotracheal intubation time, and duration of intensive care stay [10],[11],[12],[13],[14].

The N-methyl-d-aspartate receptor antagonist, ketamine, has an anti-inflammatory role in low dose, causing a significant reduction in proinflammatory mediators such as C-reactive protein and IL-6 in cardiac surgery using cardiopulmonary bypass (CPB) [15],[16],[17].

Pentoxifylline (PTX) is a methylxanthine. It inhibits tumor necrosis factor synthesis through inhibition of phosphodiesterase and by increasing intracellular cyclic adenosine monophosphate levels. It depresses TNF production by macrophages at the transcription level and has a potential to attenuate the inflammatory responses that occur during CPB. PTX also decreases neutrophil activation, which plays a central role in the pathogenesis of adult respiratory distress syndrome and multiple organ failure [18],[19],[20].

The current comparative study aims to evaluate the effect of preoperative priming with a continuous intraoperative infusion of PTX and ketamine on the release of inflammatory and anti-inflammatory cytokines and on oxidative stress during CABG with CPB.


  Patients and methods Top


The current prospective comparative study was conducted after approval of the study protocol by the local ethics committee and obtaining informed consent from the patients; it was carried out between September 2010 and December 2012. Sixty patients assigned for elective CABG with CPB were enrolled in the study. Patients with left main coronary artery disease, EF less than 50%, renal or hepatic dysfunction, known hypersensitivity to the studied drugs, scheduled for an emergency operation, and with chronic obstructive pulmonary disease were not enrolled in the study. In addition, patients with infections, inflammatory diseases, or maintained on immunosuppressant drugs or steroid therapy were excluded from the study.

All operations were performed by the same surgical team. The patients were divided into three groups: the control group (n = 20), which received placebo infusion; the ketamine group (n = 20); and the PTX group (n = 20). The ketamine group received an intravenous bolus of 0.5 mg/kg ketamine after induction, followed by 1.25 μg/kg/min ketamine till weaning from CPB, whereas the PTX group received an intravenous bolus dose of 5 mg PTX (Trental ampoule, 100 mg in 5 ml; Sanofi Aventis, Germany), followed by 1.5 mg/kg/h PTX for the same time period as ketamine.

Patients were premedicated with 0.03-0.05 mg/kg midazolam on arrival at the operating room. The radial artery was cannulated, standard monitors were attached, and anesthesia was induced using 3-5 mg/kg thiopental sodium with 3-5 μg/kg fentanyl and 0.1 mg/kg pancuronium. Controlled mechanical ventilation was applied to keep PaCO 2 levels between 35 and 45 mmHg. Anesthesia was maintained with sevoflurane, using a mixture of oxygen and air (1 : 1), boluses of pancuronium, and boluses of fentanyl when needed.

Heparin sulfate was administered at a dose of 4 mg/kg and supplemented as needed to keep the activated clotting time greater than 400 s before the start of CPB. CPB was established using a membrane oxygenator, a roller pump, and a nonpulsatile flow with a flow rate of 2.4 l/min/m 2 . Anesthesia was maintained on CPB using 3-4 mg/kg/h propofol; systemic temperature was allowed to drift to 34-35°C. Blood cardioplegia was prepared from equal volumes of normal saline and blood (1 : 1). Its composition was 30 mEq/l potassium chloride, 120 mg/l lidocaine, and 26 mEq/l sodium bicarbonate. Cardioplegia was administered initially at a dose of 10 ml/kg, followed by 5 ml/kg every 20-30 min. When inotropic support was needed, 3-5 μg/kg/min dobutamine was used.

Intraoperative hemodynamic data including heart rate, systolic blood pressure and diastolic blood pressure, and central venous pressure changes were determined at the time of induction of anesthesia, after CPB weaning, and every 2 h thereafter. The number of grafted vessels, aortic cross-clamping time, CPB time, and total operative time were also recorded.

Blood samples were collected from patients after induction of anesthesia (baseline; T 0 ) and 4 h (T 1 ), 24 h (T 2 ), and 48 h (T 3 ) after aortic declamping. Temperature, heart rate, partial pressure of oxygen (PaO 2 ) levels, white blood cell counts, and neutrophil counts were recorded during the period of collection of blood samples. Blood samples were allowed to clot and then centrifuged at 3000 rpm for 10 min; the supernatant was separated, transferred into pyrogen-free Eppendorf tubes, and stored at -80°C until ELISA was carried out.

Measurement of IL-6 [21] and IL-10 [22] levels by ELISA

Commercial kits (Boehringer GmbH, Mannheim, Germany) were used for all ELISA assays. Immunoreagent solution was prepared by adding 50 μl of peroxidase-conjugated detection antibody to 0.9 ml of incubation buffer, and 50 μl of biotin antibody was added to this mixture. Twenty microliters of each supernatant was added into the microtiter plate provided, and 200 μl of immunoreagent was pipetted into all wells containing the test samples. The microtiter plate was then covered tightly with adhesive foil and incubated for 2 h at room temperature on a shaker at 250 rpm. The incubation buffer was removed by tapping, and the wells were rinsed three times with washing buffer. The washing solution was removed and 200 μl of substrate solution was added to the wells. The microtiter plate was covered again with the adhesive foil and incubated in the same manner for another 20-30 min at room temperature. Fifty microliters of stop solution was added to each well, and after incubation for 1 min the plate was read at 450 nm using a spectrophotometer; the optical density was read from the standard curve.

Measurement of serum MDA levels [23] by ELISA assay

Commercial kits (Boehringer GmbH) were used for all ELISA assays. Seven wells were prepared for standard and one well for blank; 100 μl each of dilutions of standard, blank, and samples were added into the appropriate wells. Thereafter, the plate was covered and incubated for 2 h at 37°C. The liquid of each well was removed without washing and 100 μl of detection reagent and working solution were added to each well; the plate was then covered and incubated for 1 h at 37°C. The solution was aspirated, the wells were washed, and the remaining liquid was removed from all wells completely by snapping the plate on to absorbent paper; the wash was repeated three times and after the last wash the plate was inverted and blotted against absorbent paper. Detection reagent B working solution was added to each well and the plate was incubated for 30 min at 37°C after covering it with the plate sealer. The aspiration/wash process was repeated five times; 90 μl of substrate solution was added to each well and the plate was covered and incubated for 15-25 min at 37°C. The plate was protected from light; substrate solution was added and the liquid turned blue; 50 μl of stop solution was added to each well, causing the liquid to turn yellow. A microplate reader was used to measure optical density at 450 nm immediately.

Statistical analysis

Obtained data are presented as mean ± SD, ranges, numbers, and ratios. Results were analyzed using the Wilcoxon rank test for unrelated data (Z-test) and the χ2 -test. Statistical analysis was carried out using SPSS (version 15, 2006; SPSS Inc., Chicago, Illinois, USA) for Windows statistical package. P-value less than 0.05 was considered statistically significant.

Power analysis

If the true serum IL-6 mean difference between the PTX-treated and ketamine-treated populations is similar to our calculated difference at T 1 , T 2 , and T 3 , which is 3.6, 7.4, and 7.7 ng/ml, respectively, we will be able to reject the null hypothesis with 13.2, 28.9, and 8.7% power.

If the true serum IL-10 mean difference between the PTX-treated and ketamine-treated populations is similar to our calculated difference at T 1 , T 2 , and T 3 , which is 7.6, 10.8, and 12.5 ng/ml, respectively, we will be able to reject the null hypothesis with 89.4, 72.5, and 96.9% power.

If the true MDA mean difference between the PTX-treated and ketamine-treated populations is similar to our calculated difference at T 1 , T 2 , and T 3 , which is 0.126, 0.095, and 0.125 nmol/ml, respectively, we will be able to reject the null hypothesis with 97.1, 83.3, and 96.6% power. Student's t-test was used in the analysis with a type I error probability of 0.05. Calculations were performed using PS Power and Sample Size Calculations Software, version 2.1.30 for MS Windows (William D. Dupont and Walton D. Vanderbilt, USA).


  Results Top


This study included 60 patients, 39 men and 21 women, with a mean age of 48.6 ± 9.1 years (range: 32-67 years). The mean BMI of enrolled patients was 30.6 ± 2.1 kg/m 2 . The mean EF was 56.7 ± 3.8% (range: 51-65%); 25 patients (41.6%) had an EF of less than 55%, 19 patients (31.7%) had EF in range of 55-60%, and 16 patients (26.7%) had an EF of greater than 60%. There was nonsignificant difference between studied groups as regards patient demographics and clinical profile [Table 1].
Table 1: Demographics and clinical profile

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Hemodynamic data of all patients showed a nonsignificant difference between studied groups [Table 2]. The mean ischemia time was 56.5 ± 10.8 min (range: 35-75 min), the mean CPB time was 74 ± 10 min (range: 50-90 min), and the mean total operative time was 177.3 ± 18.3 min (range: 140-210 min). The mean number of grafted vessels was 4 ± 0.8 vessels (range: three to five vessels). There was a nonsignificant difference between the studied groups as regards operative and postoperative data. No postoperative fever, new Q-wave in postoperative ECG, or mortality was reported. No postoperative dysfunction of the lungs, kidney, or liver was reported. Only four patients (6.7%) required reoperation, all of which were uneventful. The mean duration of postoperative mechanical ventilation was 4.9 ± 0.8 h (range: 3-6 h) and the mean duration of intensive care unit stay was 64 h. The mean amount of chest tube drainage was 1167.7 ± 142.5 ml (range: 900-1450 ml; [Table 3]).
Table 2: Hemodynamic data

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Table 3: Operative and postoperative data of studied patients

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Throughout the study period, all patients showed nonsignificant changes in temperature [Table 4] and total leukocytic count, with nonsignificant differences in neutrophil percentage [Table 5]. In addition, the ratio of partial pressure of oxygen to the faction of inspired oxygen (PaO 2 /FiO 2 ) showed a nonsignificant difference among the studied groups throughout the study period [Table 6].
Table 4: Body temperature estimated at different time points

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Table 5: Leukocytic count at different time points

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Table 6: Ratio of partial pressure of oxygen to faction of inspired oxygen (PaO2/FiO2) estimated at different time points

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No difference was observed in the baseline level of IL-6, IL-10, and MDA among the three groups. In both the ketamine and PTX groups, serum IL-6 levels were significantly (P<0.05) lower than that in the control group, with nonsignificantly (P > 0.05) higher levels at T 1 compared with T 0 . IL-6 levels estimated at T 2 and T 3 were significantly higher compared with those at T 0 and T 1 , with significantly higher T 3 levels compared with T 2 levels. The mean serum IL-6 levels were significantly higher at T 2 , but nonsignificantly higher at T 1 and T 3 , in the ketamine group compared with the PTX group [Table 7].
Table 7: Serum levels of interleukin-6 (ng/ml) at different time points

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Serum IL-10 levels were significantly (P<0.05) higher in the PTX group compared with the control and ketamine groups. All patients showed a peak level of IL-10 at T 2 , which declined at T 3 , with significantly (P < 0.05) lower serum IL-10 levels at T 3 compared with T 2 in the control and ketamine groups; however, the difference was nonsignificant (P > 0.05) with PTX [Table 8].

PTX showed significant control of MDA levels. The levels of MDA were significantly lower in the PTX group compared with the control and ketamine groups at T 1 , T 2 , and T 3 , whereas they were significantly lower at T 1 , but nonsignificantly lower at T 2 and T 3 , in the ketamine group compared with the control group [Table 9].
Table 8: Serum levels of interleukin-10 (ng/ml) at different time points

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Table 9: Serum levels of malondialdehyde (nmol/ml) at different time points

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  Discussion Top


The current study showed a blunting effect of PTX and ketamine on the release of inflammatory cytokines with concomitant pronounced release of anti-inflammatory cytokines, an effect that was manifested more with PTX than with ketamine. These data indicate a modulatory effect of PTX on the immune response to surgery, which is more pronounced than that of ketamine.

These data illustrate the effect of both bolus dose and PTX infusion on cytokine release associated with surgical interference and are in accordance with the results of multiple previous clinical trials. Coimbra et al. [24] reported that PTX downregulates neutrophil activation and proinflammatory mediator synthesis with markedly decreased TNF-α production in patients with hemorrhagic shock treated with PTX added to resuscitation fluid. Izadpanah et al. [25] reported that intravenous infusion with PTX, administered preoperatively, induced significantly lower postoperative plasma levels of TNF-α and IL-6 compared with placebo, and PTX could be administered to reduce inflammatory changes. Gupta et al. [26] found PTX significantly reduced circulating levels of vascular cell adhesion molecule-1 and interferon-γ-induced protein, significantly improved endothelial function during the 8-week trial, and may reverse HIV-related endothelial dysfunction by directly inhibiting the endothelial leukocyte adhesion pathway.

In terms of the applicability of PTX in patients undergoing cardiac surgery, Groesdonk et al. [27] reported that the use of PTX may blunt the inflammatory response induced by cardiac surgery using CPB, and it has been shown that perioperative application of PTX may improve postoperative function of organs at risk, such as the kidney and liver. Iskesen et al. [28] reported a significant increase in plasma levels of TNF-α, IL-6, and IL-8 in both the control and study groups after CPB, with a greater increase in controls compared with patients who received preoperative PTX, and concluded that pretreatment with oral PTX before cardiac surgery inhibits proinflammatory cytokine release caused by CPB and has some beneficial effects in protecting the myocardium during the cardioplegic arrest period in open-heart surgery, without affecting postoperative hemodynamics. Barkhordari et al. [29] found that PTX could reduce the occurrence of acute kidney injury, as determined by attenuation of serum creatinine rise with concomitant reduction in urinary neutrophil gelatinase-associated lipocalin levels, without causing hemodynamic instability or increased bleeding.

As regards the reported attenuating effect of ketamine on inflammatory response, Bartoc et al. [17] reported that low-dose ketamine (0.5 mg/kg) attenuates increases in C-reactive protein and IL-6 levels, whereas decreases vasodilatation after CPB. Welters et al. [30] found that the levels of all cytokines increased during and after CPB; however, the increase in the levels of proinflammatory cytokines IL-6 and IL-8 at 6 h after aortic unclamping was significantly lower with ketamine compared with sufentanil, whereas the anti-inflammatory cytokine IL-10 showed higher levels with ketamine compared with sufentanil 1 h after declamping. Du et al. [31] found that postoperative IL-6 and TNF-α concentrations in patients given ketamine were lower than those in control patients who did not receive ketamine.

In contrast to the obtained results, Cho et al. [32] found that low-dose ketamine administered during anesthesia induction did not exert any evident anti-inflammatory effect in terms of reducing the serum concentrations of proinflammatory markers in low-risk patients undergoing off-pump CABG. However, such discrepancies could be attributed to the dose difference in the current study, which relies on a bolus dose of 0.5 mg/kg ketamine, followed by continuous intravenous infusion of 1.25 μg/kg/min ketamine until weaning from CPB, whereas Cho et al. [32] used a bolus dose of 0.5 mg/kg without intraoperative infusion.

Both ketamine and PTX ameliorated the ischemia reperfusion injury manifested as a significant reduction in the level of MDA, a lipid peroxidation product that peaked at 4 h sample denoting release of oxidative products during aortic cross clamping. However, this ameliorative effect was more pronounced with PTX. These findings support those documented experimentally previously. Yu et al. [33] reported that ketamine shows potent protective effects against spinal cord ischemia/reperfusion injury in the rabbit model and protects against the loss of antioxidant activity in spinal cord tissues. Ergün et al. [34] they recommended that ketamine might be preferred in certain operations with the risk for ischemia/reperfusion injury. Le Campion et al. [35] reported significant reductions in serum TNF-α, IL-6, and MDA levels in pancreatic tissue, with a significantly found that in rats treated with subanesthetic doses of ketamine, elevated malondialdehyde levels in ischemia/reperfusion injury were reversed to control levels by each dose and recommended that ketamine might be preferred in certain operations with the risk of ischemia/reperfusion injury. Ramallo et al. [36] detected burn-injury-induced oxidative stress in lung homogenates, with increased total protein, cytokine, and MDA levels on bronchoalveolar lavage, but all these parameters were decreased in animals treated with PTX.


  Conclusion Top


In patients assigned for elective CABG surgery, bolus dose and continuous intraoperative infusion of either PTX or ketamine is safe and could ameliorate the oxidative stress secondary to ischemia/reperfusion, concomitant with aortic cross clamping and release, and shift the immune response to surgery towards the anti-inflammatory side. However, such effects were more pronounced with PTX than with ketamine.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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Abstract
Introduction
Patients and methods
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