Asian Cardiovasc Thorac Ann 2007;15:218-224
© 2007 Asia Publishing EXchange Ltd
Pharmacological Prevention of the Deleterious Effects of Cardiopulmonary Bypass
Seyed A Hassantash, MD,
Gholam R Omrani, MD1,
Nozar Givtaj, PhD1,
Maryam Afrakhteh, MD
Modarres Cardiovascular Research Center, Shahid Beheshti University of Medical Sciences
1 Shahid Radjaii Medical Center, Tehran, Iran
For reprint information contact: Seyed A Hassantash, MD, Tel/Fax: 98 21 2208 3106, Email: sahassan{at}pol.net, Modarres Cardiovascular Research Center, Modarres Medical Center, Sa’Adat Abad, Tehran 19814, Iran.
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ABSTRACT
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Indomethacin is a known immune modulator that inhibits cyclooxygenase. Studies indicate that ketoconazole, a selective lipoxygenase and thromboxane A2 synthetase inhibitor, can prevent activation of the inflammatory cascade by inhibition of proinflammatory mediators. This study was designed to determine if ketoconazole or indomethacin could reduce the adverse effects of extracorporeal circulation. As a double-blind prospective study, 76 patients were randomized into 3 groups according to preoperative medication: indomethacin, ketoconazole, and placebo groups, with 25, 26, and 25 patients, respectively. Four types of parameters were evaluated preoperatively and up to 24 hr after cardiac surgery in all patients: inflammatory (complement C3 and C4, C-reactive protein, immunoglobulins); hematologic; coagulation; and physiologic (blood loss, fluid and blood components received, weight gain, and duration of ventilation). Statistical analyses showed similar patient profiles in each group. Complement C4 decreased in all groups postoperatively, but significantly less in the indomethacin group ( p < 0.01). Ketoconazole reduced postoperative bleeding ( p < 0.0001) as well as the incidence of re-operation for bleeding ( p = 0.05). It was concluded that indomethacin decreases complement (specifically C4) consumption during cardiopulmonary bypass, and ketoconazole may reduce postoperative bleeding by limiting coagulation abnormalities in cardiac surgery patients.
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INTRODUCTION
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Cardiopulmonary bypass (CPB) is associated with profound deleterious effects in patients undergoing cardiac surgery, including acute lung, heart, and other organ injuries due to neutrophil-mediated activation.1 This by itself causes a reduction in arterial oxygen tension that may induce respiratory insufficiency and altered hemodynamics because of myocardial depression. The effect of the CPB machine on the production of inflammatory substances has been identified as the key mediator of the acute-phase response.2 On the other hand, activation of the arachidonic cascade promotes increased postoperative bleeding and extends inflammatory activation.3 Indomethacin, a cyclooxygenase inhibitor (Figure 1
), given perioperatively, is believed to ameliorate the decline in systemic oxygenation associated with CPB.1 Synthesis of proinflammatory substances was significantly counteracted by this drug as immunomodulation therapy after CPB.2,4
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Figure 1. Arachidonic acid cascade and generation of mediators by inflammatory cells. 6-Keto PGF1a = 6-ketoprostaglandin F1a, PGD = prostaglandin D, PGE2 = prostaglandin E2, PGF = prostaglandin F, PGI2 = prostaglandin I2.
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Ketoconazole, a potent lipoxygenase and thromboxane synthetase inhibitor (Figure 1
), has not been evaluated in cardiac surgery. There are several reports of its effectiveness in modifying activation of the immune system and coagulation problems, mainly in injured patients. This drug may prevent adult respiratory distress syndrome and decrease mortality in high-risk septic patients.5,6 Implementation of a prophylactic ketoconazole protocol for patients in intensive care was associated with a higher rate of prescription of this medication and a lower rate of adult respiratory distress syndrome.7 Ketoconazole significantly inhibits alveolar macrophage production of leukotriene B4, thromboxane B2, and procoagulant activity (independent effects on 5-lipoxygenase and thromboxane synthetase), which are of benefit in preventing acute respiratory failure in trauma patients.3 The data indicate that in such patients, thromboxane-mediated cardiac depression and increased leukocyte-mediated permeability of capillaries are inhibited by ketoconazole.8 As the pathways of the consequences of trauma are similar to those of CPB, we assessed these medications in adult cardiac surgical patients.
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PATIENTS AND METHODS
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This study was carried out in a double-blind prospective randomized manner. Adult cardiac surgery patients undergoing myocardial revascularization and/or valve surgery were randomized according to their hospital number. There were 76 patients enrolled in the study from January to the end of May 2002. The exclusion criteria were age < 15 years, emergency surgery, aspirin < 7 days preoperatively, and congenital defect operations. The study was approved by the research committee of the institution. Patients were informed of the details of the study, and gave written consent. Twenty-five patients received a placebo (group C), 25 received 100 mg of indomethacin (group I), and 26 received 400 mg of ketoconazole (group K). These medications were administered 12 and 2 hr preoperatively, and 8 hr postoperatively. Other than one administrator, the therapy team and the statistician were blinded to the medication received by the patient. The hospital’s pharmacy dispensed the drugs. Regular medications were continued up to the morning of the operation. Adverse effects of both drugs were monitored during the study.
The procedure was the same in all 3 groups. After premedication with diazepam (10–15 mg), anesthesia was induced with fentanyl (40 µg·kg–1), and maintained with additional fentanyl up to a total dose of 100 µg·kg–1. Muscle relaxation was achieved with pancuronium bromide (1.3 mg·kg–1). All patients received cefazolin (1 g) intravenously preoperatively and every 8 hr for 4 additional doses. Steroids were not given to any of the patients perioperatively. All underwent CPB with moderate systemic hypothermia. Hollow-filter membrane oxygenators, hard-shell reservoirs, 40 µm in-line arterial filters (Medtronic, Minneapolis, MN, USA), a CPB machine (Cobe Cardiovascular, Arvada, CO, USA), roller pumps, and a 2-stage right atrial cannula were used in the circuit, which was primed with 1.5 L of Ringer’s lactate containing mannitol (12.5 g) and sodium bicarbonate (50 mEq). Five minutes after heparinization (300 IU·kg–1), CPB was initiated at a flow rate of 2.2 L·m–2·min–1. Patients were cooled to 28°C; at that temperature, flow was adjusted to 50 mL·kg–1·min–1. The mean arterial pressure was maintained at 50 to 70 mm Hg by administration of phenylephrine, trinitroglycerin, or nitroprusside, as necessary. The activated clotting time was maintained at more than 4 times the baseline measurement by additional doses of heparin, as required. Heparin was reversed with protamine after termination of CPB. Myocardial protection consisted of antegrade cold blood cardioplegia supplemented with topical ice slush.
Blood was withdrawn from the radial arterial line. The factors evaluated can be classified into 4 types. The first type was markers of the inflammatory response to the process of cardiac surgery. These included C-reactive protein (CRP), complement 3 and 4 (C3, C4), and immunoglobulin (Ig) A, G, and M. They were determined just preoperatively, immediately after weaning off the CPB machine, and 6, 12, and 18 hr postoperatively. Blood for determination of C3 was drawn into tubes, serum was separated by centrifugation and kept at –70°C until the time of the test. Concentrations of C3 and C4 in plasma were determined by single radial immunodiffusion. An immunoturbidimetric technique was used for assessment of CRP and immunoglobulin levels. The second type of test was hematologic: complete blood count, serum glutamic oxaloacetic transaminase, serum glutamate pyruvate transaminase, total and direct bilirubin, alkaline phosphatase, and lactate dehydrogenase; these tests were performed immediately after blood withdrawal. Hepatic toxicity, known to be associated with ketoconazole, was also monitored by these tests preoperatively and 24 hr after surgery (there was no case in this series). The 3rd type of test evaluated coagulation parameters: prothrombin time, partial thromboplastin time, fibrinogen, platelet count, and platelet aggregation tests; preoperatively, 6 and 12 hr postoperatively. The 4th type of test comprised clinical and physiologic parameters: blood loss, weight gain, fluid or blood requirement, duration of respiratory support, length of hospital stay, and re-operation for excessive postoperative bleeding.
All statistical analyses of the laboratory tests were performed using Kruskal-Wallis and Mann-Whitney tests because the data were not normally distributed. Comparison of the groups with regard to age, CPB and aortic cross clamp times, amount of bleeding or fluid/blood components given postoperatively were determined by the analysis of variance method. The chi-squared and likelihood-ratio chi-squared tests were used for other evaluations. Values are reported as mean ± standard error of the mean.
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RESULTS
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The characteristics and operative variables were similar in the 3 groups of patients (Table 1). The CPB times in the 3 groups were similar (group K vs C, p = 0.3; group I vs C, p = 0.8). Although aortic cross clamp times tended to be longer in the ketoconazole group, the differences between groups were not significant (group K vs C, p = 0.9; group I vs C, p = 0.7). There were no other significant confounding factors such as preoperative heparin or perioperative aprotinin (no cases) in the 3 groups. No adverse effect related to the medications was observed in any patient.
Plasma levels of the complement anaphylatoxins C3 and C4 decreased during CPB in all 3 groups and rose gradually postoperatively, but they were still subnormal at the last blood withdrawal 18 hr after surgery (Figures 2 and 3). Note that the preoperative levels are given in the figure legends, and the subsequent levels can be calculated from the changes shown in the figures. C4 consumption was significantly decreased at all time points in group I ( p < 0.01). The decline in the C3 level was much less (a favorable effect) in groups K and I. However, only for C3 measurements at 12 hr postoperatively was the level in group K significantly closer to normal compared to the control group ( p = 0.01). The CRP level dropped significantly at the time of weaning from CPB, but it increased dramatically after 2 hr and was up to 9 times the preoperative levels after 18 hr (Figure 4). The changes were not different in the 3 groups. The decline in IgA, IgG, and IgM levels was similar to the changes in complement, and the differences among the 3 groups did not reach statistical significance (Figures 5, 6, and 7).
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Figure 2. Change in C3 levels due to cardiopulmonary bypass. The difference between the ketoconazole and control groups 12 hours after surgery was statistically significant ( p = 0.01). Mean preoperative values: 119.5 ± 9.7, 84.9 ± 5.4, 91.5 ± 5.3 mg·dL–1 for the ketoconazole, indomethacin, and control groups, respectively.
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Figure 3. Change in C4 levels due to cardiopulmonary bypass. The indomethacin group was associated with significantly less C4 consumption compared to the control group ( p < 0.01). Mean preoperative values: 36.7 ± 2.8, 21.5 ± 1.6, 28.1 ± 1.9 mg·dL–1 for the ketoconazole, indomethacin, and control groups, respectively.
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Figure 4. Change in C-reactive protein levels due to cardiopulmonary bypass. Mean preoperative values: 9.6 ± 1.8, 9.3 ± 2, 9.9 ± 2.8 mg·L–1 for the ketoconazole, indomethacin, and control groups, respectively.
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Figure 5. Change in immunoglobulin (Ig) A levels due to cardiopulmonary bypass. Mean preoperative values: 355.3 ± 35.2, 322.4 ± 28.6, 330.4 ± 29.5 mg·dL–1 for the ketoconazole, indomethacin, and control groups, respectively.
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Figure 6. Change in immunoglobulin (Ig) G levels due to cardiopulmonary bypass. Mean preoperative values: 1,293 ± 75.7, 1,317 ± 71.2, 1,636 ± 97 mg·dL–1 for the ketoconazole, indomethacin, and control groups, respectively.
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Figure 7. Change in immunoglobulin (Ig) M levels due to cardiopulmonary bypass. Mean preoperative values: 216.1 ± 18.6, 204 ± 23.3, 220.8 ± 24 mg·dL–1 for the ketoconazole, indomethacin, and control group, respectively.
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Liver function tests were the same in all groups. There was only a slight increase in the results obtained 18 hr after surgery compared to preoperative samples in all groups. There was also no difference in complete blood counts in the 3 groups. Changes in laboratory values for the coagulation system were not significantly different in the 3 groups. There was a slight increase in prothrombin time and partial thromboplastin time, and a decrease in platelet and fibrinogen levels at 6 and 12 hr after surgery compared to preoperative values. No cases of adult respiratory distress syndrome or readmission to the intensive care unit because of respiratory problems occurred in this series. The duration of mechanical ventilation and total intubation time were the same in all groups. The amount of crystalloid fluid (group C = 2,942 mL, group I = 3,190 mL, group K = 3,395 mL, p = 0.1), fresh frozen plasma (group C = 776 mL, group I = 569 mL, group K = 588 mL, p = 0.1), and the total urinary output (group C = 2,696 mL, group I = 2,600 mL, group K = 2,641 mL, p = 0.1) were similar in the 3 groups in the first 24 hr after surgery. The difference between total fluid intake and output was slightly less in the indomethacin group (group C = 1,725 mL, group I = 1,442 mL, group K = 1,920 mL).
There was significantly less ( p < 0.0001 for group K vs C) bleeding in the ketoconazole group (group C = 1,020 mL, group I = 1,234 mL, group K = 543 mL), and fewer patients ( p = 0.05, Fisher’s exact test) required re-operation for excessive postoperative bleeding (group C = 4 patients, group I = 2 patients, group K = 0 patients). The lengths of stay in the intensive care unit (2 days) and hospital (9 days) were not significantly different among the groups.
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DISCUSSION
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Blood contact with synthetic surfaces during extracorporeal circulation causes a systemic inflammatory reaction involving multiple humoral and cellular mediators of inflammation. Early studies focused on the role of complement activation during CPB, but it is now clear that CPB causes activation of the kinin, fibrinolytic, arachidonic acid, and coagulation cascades, as well as generation of numerous cytokines.9,10 Minimization of the damaging effects of CPB is an important future direction. Blockade of the individual humoral amplification cascades has always been the hope of investigators in this area.
During CPB, neutrophils may be activated by C3a, C5a, kallikrein, platelet-activating factor, and leukotriene B4, and also by direct contact of blood with synthetic surfaces.9,10 The complement system involves a group of circulating glycoproteins, which is a fundamental component of the body’s response to immunologic, traumatic, or foreign body injury. Two pathways exist for activation of the complement sequence. The classic pathway is usually initiated via interaction with antibody-antigen complexes. However, it is mainly the alternative pathway that is primarily activated during CPB. Chenoweth and colleagues9 demonstrated that levels of the complement anaphylatoxin C3a increase shortly after the onset of CPB, with continuing production throughout the duration of bypass. In our study, consumption of C3, the precursor of C3a, was used to evaluate C3a production. As expected, C3 decreased in all groups during extracorporeal circulation (especially due to hemodilution) and started to rise toward the preoperative level after surgery. The consumption was much less in groups K and I (positive trend), but this did not become statistically significant, probably due to the small number of patients enrolled in the study. Another study with a larger number of patients may clarify this issue. Increased levels of the anaphylatoxin C4a indicate activation of the classic pathway (e.g., following administration of protamine).11,12 Again, we measured C4, the precursor of C4a, which was significantly consumed and diluted during surgery. The decreased consumption in groups K and I shows the inhibitory effect of these medications on this wing of immunity activation in patients undergoing CPB. This effect was significant in group I, but again a larger number of patients may be needed to evaluate the effect of ketoconazole. It must be noted that hemodilution was one reason for the decreasing levels of C4, but this mechanism was equal in all 3 groups. Thus, comparison of the groups with each other will reflect the other mechanisms responsible for the changes.
C-reactive protein was greatly elevated in our patients and showed no difference between the 3 groups. Immunoglobulin measurements also demonstrated no difference between the 3 groups. This is probably because CRP and immunoglobulins are nonspecific markers and their rise or consumption is related to multiple complex systems and cascades that are difficult to alter with medications that inhibit specific pathways. The arachidonic acid cascade is activated during CPB as a result of alterations to the cell membrane. The two major pathways of arachidonic acid metabolism are the lipoxygenase pathway producing leukotrienes and the cyclooxygenase pathway that produces either prostaglandins or thromboxane A2 through thromboxane synthetase (Figure 1). Each of these final products may cause vicious cycles of inflammatory activation and coagulation alterations.13,14 The ability to inhibit these undesired effects will help to control the deleterious effects of CPB. Prior attempts have been made with the use of steroids or a thromboxane synthetase inhibitor.14,15 These end products together with activation of other humoral cascades stimulated by CPB lead to neutrophil activation. Thus, it is not surprising that recent studies have shown that the neutrophil is an important common mediator of inflammatory tissue damage associated with CPB.9,10 Capillary permeability is increased by the generation of cytokines and as a result, generalized edema, pulmonary dysfunction, increased need for fluid administration in the postoperative period secondary to vascular volume contraction, and renal failure become likely.
Indomethacin has been shown to inhibit cyclooxygenase, therefore, it may decrease both prostaglandin and thromboxane production. Ketoconazole inhibits lipoxygenase and thromboxane synthetase selectively, and decreases production of leukotrienes and thromboxane A2 without affecting prostaglandin production (Figure 1). Indomethacin has been evaluated both in the laboratory and clinically for potential favorable effects in cardiac surgery using CPB.1,2,4,16 The efficacy of ketoconazole has never been investigated in cardiac surgery. This drug was originally known as an antifungal agent, and sometimes used as an adjunct to cyclosporine to reduce the dosage and still achieve the desired blood level in patients with transplants.17,18 A few papers, mainly in the 1990s, demonstrated a beneficial effect of this drug in trauma, both experimentally and clinically.3,5–8,19,20 The similarity of the immunological activation processes in trauma patients and those undergoing CPB (with a greater magnitude) warrants the investigation of ketoconazole in cardiac surgical patients. Evaluation of these two drugs together in this study permits us to assess their specific effects in our group of patients. Higher than usual doses, but still within safe recommended limits, were used in this study. Liver function and other tests support the absence of some of the known side effects of these medications.
No significant clinical manifestations of increased capillary permeability were noted in this study. The primary reason is that advances in medical care, techniques, and medications now available for the optimum management of cardiac surgical patients postoperatively, have already eliminated some of the harmful effects of CPB, such as lung dysfunction. Secondly, our small number of patients is insufficient to show some of the less common complications caused by CPB. Thirdly, consideration of other variables such as body weight might have given additional information.
Bleeding problems were significantly reduced by ketoconazole; this was true for both the total amount of bleeding through the drains in the first 24 hr postoperatively, and the number of patients taken back to the operating room for bleeding. We speculate that this is because of the selective inhibitory effect of this drug on thromboxane synthetase during CPB, without affecting the prostaglandin pathway. With regard to the effect of ketoconazole in reducing blood loss despite no significant differences in coagulation tests, it should be noted that the amount of post-cardiac surgery bleeding may change as the overall result of several coagulation pathways, including platelet function, hemodilution, clotting pathways, vascular and microvascular performance, and other processes. Only some of the tests related to these processes were measured in this study. Decreased bleeding in patients with similar coagulation test results demonstrates that other factors have a role in the coagulation process.
The data in this report show that C3 consumption is reduced in patients given indomethacin or ketoconazole, but C4 consumption was significantly controlled only in the indomethacin group. Bleeding complications were significantly less in the patients receiving ketoconazole. Although this study confirms previous findings of activation of the inflammatory system secondary to CPB, further studies with larger numbers of patients are necessary to characterize the precise effect of these medications. Continued investigation in this area may reveal new means of reducing the destructive effects associated with CPB.
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ACKNOWLEDGMENTS
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This study was conducted with the financial support of two grants from Shahid Radjaii Heart Institute and Modarres Cardiovascular Research Center.
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REFERENCES
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ABSTRACT
INTRODUCTION
