Asian Cardiovasc Thorac Ann 2007;15:39-44
© 2007 Asia Publishing EXchange Ltd
Antithrombin and Protein C in Systemic Inflammatory Response Syndrome
Islam Massad, MD,
Hamdi Abu-Ali, MD,
Christine Biron-Andreani, MD1,
Marie-Christine Picot, MD1,
Philippe trinh-Duc, MD1
Division of Cardiac Anesthesia, Department of General Surgery, Anesthesia and Intensive Care, Jordan University Hospital, University of Jordan Amman, Jordan
1 Department of Anesthesia and Intensive Care Medicine, Arnaud de Villeneuve Hospital, Montpellier University Hospital, Montpellier, France
For reprint information contact: Islam Massad, MD, Tel: 962 6 535 3444 Ext 2420, Fax: 962 6 582 3684, Email: islam_wafa{at}yahoo.com, Department of Anesthesia and Intensive Care, Jordan University Hospital, PO Box 13046, Amman 11942, Jordan.
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ABSTRACT
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Coronary artery bypass grafting with cardiopulmonary bypass can induce systemic inflammatory response syndrome. To assess the prevalence of preoperative antithrombin and protein C deficiencies in relation to the incidence of this syndrome, antithrombin and protein C levels were measured in 130 patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Systemic inflammatory response syndrome developed in 36 (27.7%) patients who were predominantly male, had a lower EuroSCORE, longer cardiopulmonary bypass time, higher pre-bypass temperature, and shorter activated coagulation time. Logistic regression showed that predictive factors included bypass duration and pre-bypass temperature; however, low antithrombin levels appeared to be a negative predictive factor. Antithrombin levels were < 80% in 33.8% of patients, and 11.6% had protein C levels < 80%. Postoperative antithrombin and protein C deficiencies are not uncommon in adults undergoing cardiac surgery with cardiopulmonary bypass, but detection of these deficits did not identify patients at increased risk of systemic inflammatory response syndrome.
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INTRODUCTION
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In some patients, cardiac surgery with cardiopulmonary bypass (CPB) and aortic cross clamping induces systemic inflammatory response syndrome (SIRS) with organ dysfunction, which is the strongest predictor of mortality in cardiac surgical patients.1 The likely causes of this syndrome include contact activation of the immune system after blood exposure to the foreign surfaces of the CPB circuit, ischemia-reperfusion injury following aortic cross clamping, and endotoxin translocation due to splanchnic hypoperfusion.2 During CPB, the high dose of heparin does not fully block the coagulation-activating mechanisms, resulting in some thrombin production. Subsequently, thrombin activates platelets, provokes consumption of coagulation factors, produces endothelial tissue plasminogen activator, and stimulates cells participating in the inflammatory response. Heparin itself is not an anticoagulant and requires the availability of plasma proteins, mainly antithrombin (AT). Moreover, AT inhibits contact and complement activation and controls inflammatory reactions: stimulation of prostacyclin production, and inhibition of leucocyte rolling and interleukin (IL)-6 synthesis.3 Acquired AT deficiency is not uncommon and may occur either alone or in combination with a deficiency of protein C (PC) which inhibits thrombin formation and plays a major role during the inflammatory processes by blocking neutrophil interaction with selectins, as well as interfering with cytokine elaboration by monocytes.4 The aims of this study were to estimate the prevalence of preoperative AT and PC deficiencies, and to assess their potential roles in the occurrence of post-CPB SIRS.
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PATIENTS AND METHODS
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The protocol for this study was approved by our institutional review board, and informed consent was obtained from all patients. The study comprised 130 adults undergoing first-time elective coronary artery bypass grafting (CABG) using normothermic CPB. Patients were excluded if aprotinin was used, if they had an inflammatory or infectious disease, or if they were taking any kind of anti-inflammatory treatment. Aspirin was discontinued one week before surgery.
All patients were premedicated with oral midazolam, and anesthesia was induced using a totally intravenous technique with midazolam, sufentanil, and pancuronium bromide. Radial artery and central venous pressures were monitored along with all other routine parameters. Normothermic CPB, which is the routine practice for conventional CPB procedures in our hospital, was carried out with a centrifugal pump (Medtronic-BioMedicus, Inc., Eden Prairie, MN, USA), a hollow-fiber membrane oxygenator (D903 Dideco, Mirandola, Italy), an arterial filter, and standard tubing. The circuit was primed with 1,700 mL of Ringer’s lactate solution, 50 mL of sodium bicarbonate 4.2%, and 5,000 IU of bovine heparin. During CPB, non-pulsatile flow > 2.4 L·min–1·m–2 was used, pH was regulated according to the alpha-stat concept, and rectal temperature was maintained at 37°C by active warming. During aortic cross clamping, intermittent cold blood cardioplegia was injected into the ascending aorta. Before and after CPB, a cell saver (Dideco Compact) was used to collect blood from the operating field, which was processed as soon as the collected volume exceeded 700 mL, and retransfused. A heparin bolus (Choay, Sanofi-Synthelabo, Paris, France) of 300 IU·kg–1 was given 5 min before aortic cannulation. The kaolin-activated clotting time (ACT) was measured (HemoTec; Medtronic, Minneapolis, MN, USA) 5 min after CPB initiation; the target value was 450 sec. If this value was not achieved, an additional 100 IU·kg–1 of heparin was administered. The protamine dose corresponded to 70% of the total heparin dose. Fifteen minutes after protamine administration, a high-range heparinase test (HemoTec) was carried out to measure the residual free heparin and determine whether another dose of protamine was needed.
Before surgery, biometric data, risk factors, and cardiac status were recorded. EuroSCORE was calculated.5 During surgery, CPB and aortic cross clamp times, lowest rectal temperature, total heparin and protamine doses, and shortest ACT during CPB were noted. To investigate whether hemodynamic instability had any postoperative clinical impact, we used the following markers: administration of vasopressor or inotropics before or after CPB, the area under the curve of pump flow index, arterial pressure, and SvO2, and the under-threshold levels (2.4 L·min–1·m–2 for flow, 60 mm Hg for pressure, and 65% for SvO2). While in the intensive care unit, SIRS was diagnosed if two or more of the following signs were found: body temperature abnormalities (> 38°C or < 36°C), leukocytosis or leukopenia (leukocyte count > 12,000 or < 4,000 ), heart rate > 90 beats·min–1, respiratory rate > 20 breaths·min–1, pCO2 < 32 mm Hg, based on the clinical criteria of the American College of Chest physicians and the Society of Critical Care Medicine.6 Severe SIRS was defined as SIRS associated with organ dysfunction. To determine organ dysfunction, the criteria were: for cardiovascular system dysfunction, the use of vasopressors after adequate fluid replacement, to maintain mean arterial pressure > 70 mm Hg; for respiratory system dysfunction, PaO2 to FiO2 ratio < 250; for renal dysfunction, urine output < 0.5 mL·kg–1 for more than an hour and postoperative increase of creatinine > 20%; and for hematological dysfunction, platelet count < 80,000·mm–3. Systemic inflammatory response syndrome criteria were assessed in all patients on the morning of the first postoperative day, taking into account the entire postoperative course between intensive care unit admission until the time of evaluation. Transient tachycardia or hyperventilation caused by nurse interventions or inadequate analgesia were excluded.
The preoperative AT and PC levels were measured in routine blood samples collected from all the patients. Venous blood was collected from an antecubital vein into 0.105 mmol·L–1 trisodium citrate tubes for hemostasis parameters. Antithrombin and PC levels were determined using Coamatic antithrombin and protein C (Chromogenix, Molndal, Sweden). Analyses were performed in duplicate. The lower reference limit was 80% for AT and PC.
For continuous variables, the distributions were tested with the Kolmogorov-Smirnov test. Continuous variables were expressed as mean ± standard deviation, and compared using Student’s t test or the Wilcoxon test. Categorical variables were expressed as percentages and analyzed by the chi-squared or Fisher’s exact test. A p value < 0.05 was considered significant. To examine the independent effects of the significant variables on the occurrence of SIRS, multivariate analyses using logistic regression were performed with stepwise selection of variables. The a-to-enter and a-to-exit were set, respectively, at 0.10 and 0.05. To assess the predictive ability of the model, the concordance rate between predicted and observed responses was calculated. Statistical analyses were performed using SAS software version 8.0 (SAS Institute, Cary, NC, USA).
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RESULTS
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Post-CPB SIRS developed in 36 (27.7%) patients (95% confidence interval [CI]: 20%–35.4%), 21 (58%) of them had severe post-CPB SIRS with associated organ dysfunction. In this severe SIRS group, 16 patients exhibited single-organ dysfunction, 3 had double-organ dysfunction, and 2 suffered dysfunction of 3 organ systems. The most affected systems were cardiovascular (13 patients) and respiratory (11 patients). Preoperative AT and PC levels are shown in Figures 1
and 2; they were not significantly different between the group with SIRS and the non-SIRS group. When analyzed as categorical variables (< 80%, > 80%), AT levels, unlike PC levels, appeared significantly different between the two groups. Patients with preoperative AT levels below 80% were less prone to develop post-CPB SIRS. Other preoperative and intraoperative variables are shown in Table 1. Antithrombin levels, sex distribution, EuroSCORE, CPB duration, temperature, shortest ACT during CPB, and the heparin and protamine doses were all significantly different between the SIRS and non-SIRS groups. Using stepwise logistic regression, we examined the effects of the following variables on the occurrence of SIRS: AT (as a categorical variable), sex, age, CPB time, shortest ACT during CPB, and lowest rectal temperature. As EuroSCORE is a combination of different variables, we chose to test the effect of the statistically significant constituting variables. The 3 characteristics most significantly associated with the occurrence of post-CPB SIRS were CPB time (per 10 min; adjusted odds ratio 1.20, 95%CI 1.05–1.38, p = 0.01), temperature (per 0.5°C; adjusted odds ratio 1.45, 95%CI 1.02–20.7, p = 0.05), and AT (> 80%; adjusted odds ratio 0.39, 95%CI 0.15–0.97, p = 0.05). Male sex, with an adjusted odds ratio of 3.77 (95% CI 0.79–17.9), was not significant ( p = 0.09).
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Figure 1. Distribution of preoperative Antithrombin levels in 130 patients. The values above the bars correspond to the percentage of patients.
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Figure 2. Distribution of preoperative Protein C levels in 130 patients. The values above the bars correspond to the percentage of patients.
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DISCUSSION
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Although Matthai and colleagues7 reported a 9% prevalence of antithrombin deficiency (AT < 70%) in a series of 250 patients before percutaneous coronary revascularization, the prevalence of AT and PC deficiency in patients undergoing CPB surgery was unknown until now. Our finding that 33.8% and 11.6% of patients, respectively, had AT and PC levels less than 80%, indicates that preoperative AT and PC deficits are not uncommon. The second purpose of this study was to look for a relationship between deficiencies of these preoperative coagulation inhibitors and the occurrence of SIRS after conventional CABG. We chose the clinical definition of SIRS as a response to a variety of severe clinical insults.6 Cardiac surgery with CPB is clearly recognized as one of these insults, and the incidence of SIRS after CABG and CPB ranges from 10% to 43%.8,9 In this study, 28% of patients developed SIRS. We did not find any significant difference in AT and PC levels between the SIRS and non-SIRS groups. Conversely and surprisingly, SIRS was significantly more frequent in the group with preoperative AT levels higher than or equal to 80%, than in those with AT levels below 80%. This result contradicts the rationale of the present study, and goes against the conventional thinking that AT deficiency leads to higher heparin requirements.
To investigate this unexpected relationship, we studied the other variables likely to be confounding factors. EuroSCORE was significantly lower in the SIRS group, although most variables making up the EuroSCORE (renal failure, ejection fraction, chronic obstructive pulmonary disease, peripheral vascular disease, cerebrovascular disease, unstable angina, recent myocardial infarction, pulmonary hypertension) were not significantly different between the two groups. The patients in the SIRS group tended to be younger, but sex was the only component of the score to be significantly different. The predominance of younger and more male patients in the SIRS group was probably the reason why the EuroSCORE appeared lower.
As systemic hypoperfusion during CPB could be responsible for SIRS as a result of endotoxin translocation, we looked for low flow and low perfusion pressures during CPB, using the area under the curve of pump flow index, SvO2, and arterial pressure.2 No significant difference in hemodynamic status was found between the groups. Although it is important to mention that the relationships between gut hypoperfusion, increased gut permeability, endotoxemia, and postoperative outcome are very controversial; Oudemans van Straaten and colleagues10 found a significant relation between preoperative hemodynamic condition and intestinal permeability, and between this permeability and the amount of circulating endotoxin or postoperative systemic response in CABG patients. Conversely, Myles and colleagues11 did not detect any correlation between gastric mucosal pH or endotoxin levels and post-CPB oxygen consumption, oxygen delivery, systemic vascular resistance, or serum lactate in cardiac surgery patients. Neuhof and colleagues12 concluded that cytokine generation is triggered by surgical and CPB trauma rather than by endotoxemia. These discrepancies might in part be explained by differences in methodology of gut hypoperfusion assessment, endotoxin dosage, and outcome evaluation.
In our patients, CPB duration was significantly longer in the SIRS group, and the aortic cross clamp time tended to be longer ( p = 0.06). Multivariate and logistic regression analyses confirmed that the main prognostic factor for SIRS was CPB duration; this is in accordance with the presumed pathophysiological mechanisms of SIRS and clinical observations.12–14 This might be explained by the contact of blood with the artificial surface of the CPB circuit, and ischemia-reperfusion injury which induces the secretion of proinflammatory cytokines, with significant correlation between peak concentrations of IL-6 and IL-8 and the duration of CPB.12–14
Although ACT measurement is a rough technique, it is the most widely used means of assessing anticoagulation during cardiac surgery. In this study, the shortest ACT during CPB was shorter in the SIRS group; as a result, these patients received much more heparin to achieve a good level of anticoagulation. Inflammation and coagulation activation are interconnected; proinflammatory cytokines induce tissue factor expression on the surface of the mononuclear cells, down-regulate thrombomodulin expression and fibrinolytic as well as PC pathways, altering the equilibrium between procoagulant and anticoagulant activities, which results in markedly procoagulant states.2
The normothermic technique is associated with a better postoperative respiratory index, earlier extubation, better hemodynamics, shorter CPB, and reduced requirements for defibrillation after aortic declamping, compared with hypothermia.15 Hypothermia followed by rewarming increases the inflammatory response by augmenting IL-8-induced polymorphonuclear cell degranulation.16 We recorded the lowest rectal temperature to ensure normothermic CPB. The patients got colder in the pre-CPB period (intravenous infusions, loss of heat through the surgical field), so the temperature was lowest just before the start of CPB. It was slightly but significantly higher in the SIRS group, suggesting that something happened before exposure to the trigger (CPB). Does surgical stimuli (sternotomy, mediastinal and pericardial dissection) before initiation of CPB prime the inflammatory response? Is the temperature difference between the two groups already present before surgery? It would have been interesting to measure body temperature just before the induction of anesthesia; a higher temperature in the SIRS group might suggest that these patients present a greater predisposition to the inflammatory response.
In our study, increased pre-CPB rectal temperature and preoperative AT level (equal to or higher than 80%) were found to be independently predictive of postoperative SIRS. This seems to explain the predisposition to develop an amplified inflammatory response to CPB in some patients but not others. This agrees with two reports in CABG patients on the influence of gene polymorphism on the postoperative inflammatory response.17,18 Drabe and colleagues17 found significantly higher perioperative tumor necrosis factor alpha and IL-8 release in apolipoprotein E4 allele-carrier patients compared to E4 non-carrier patients. Similarly, Schroeder and colleagues18 noticed that patients homozygous for the TNF-B2 allele showed significantly higher TNF-a and IL-8 plasma levels after CPB, compared with non-CPB patients. In contrast to our initial hypothesis, preoperative AT could be considered more a marker of proinflammatory predisposition, a kind of "acute phase protein", rather than the source of SIRS. In support of this assumption, Boeken and colleagues19 observed that patients with preoperative elevated C-reactive protein values, a well-known acute-phase protein, faced an increased risk of developing post-CPB SIRS. Moreover, CRP was recently found to correlate positively with plasma AT levels, but only in women.20
It was concluded that AT and PC deficiencies are not rare in adult patients undergoing a first elective CABG operation with CPB. Detection of these deficits does not help to identify patients at increased risk of postoperative SIRS.
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ACKNOWLEDGMENTS
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The authors wish to thank the Laboratoire Francais du Fractionnement et des Biotechnologies for financial support for these investigations.
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ABSTRACT
INTRODUCTION
