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Original Article

Purified antithrombin supplementation in coronary revascularisation operations

Rossi, M.*; Ranucci, M.; Soro, G.; Schiavello, R.; Guarneri, S.

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European Journal of Anaesthesiology: June 2007 - Volume 24 - Issue - p 71-76
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Abstract

Introduction

During cardiac operations with cardiopulmonary bypass (CPB), antithrombin (AT) is consumed, and at the end of the operation a decrease of about 30% of functional activity is usual [1-3]. Moreover, a consistent rate of coronary patients reach the operating theatre with sub-normal values of AT, due to the preoperative use of unfractionated or low molecular weight heparin: these patients often demonstrate a reduced heparin responsiveness, sometimes leading to a “heparin resistance” pattern, defined as a failure to obtain satisfactory anticoagulation after a loading dose of intravenous unfractionated heparin [4-7]. Purified AT supplementation has been proposed as a treatment for heparin resistance [8-10]; AT supplementation demonstrated beneficial effects in limiting the haemostatic system activation [11] and improving the postoperative outcome of coronary patients preoperatively suffering from unstable angina [12]; finally, it was recently demonstrated that patients with low levels of AT at the end of cardiac operations had more thrombotic-haemorragic complications [13]. So far, however, there is not enough information about the impact of purified or recombinant AT supplementation in patients undergoing coronary revascularisation with CPB, being at risk for low intraoperative AT levels and/or heparin resistance.

The aim of the present study is to investigate the effects of purified AT supplementation in a population of patients with low preoperative AT levels or demonstrating a heparin resistance pattern, in comparison with a control group not receiving AT supplementation.

Methods

This is a retrospective study conducted in two Institutions. During the last year, the two Institutions introduced a policy of routine correction of preoperatively low (<80%) levels of AT activity and approached heparin resistant patients by supplementing AT before CPB. Heparin resistance was defined as the failure to reach an activated clotting time (ACT) longer than 480 seconds after a loading dose of 450 IU/kg of unfractionated intravenous heparin. After 2 months of this policy, 89 patients undergone coronary revascularisation with CPB had received purified AT intraoperatively, and formed the AT group.

A control group was created using a propensity score analysis based on data collected in the previous year before the new policy was established. A group of 89 patients not receiving purified AT was created and constituted the control group.

All the patients were treated with the same anaesthesia technique (totally intravenous anaesthesia with remifentanil and midazolam plus cisatracurium for muscle relaxation, or balanced anesthesia with sufentanil, propofol and sevoflurane plus vecuronium bromide). CPB was established via a standard median sternotomy, aortic root cannulation and single atrial cannulation for venous return. Body temperature during CPB was maintained between 30 °C and 37 °C. Antegrade intermittent cold crystalloid, cold blood cardioplegia or warm blood cardioplegia, were used according to the surgeon's preference. The circuit was primed with 700 ml of a gelatin solution (Eufusin; Bieffe Medical, Modena, Italy), or 1000 ml of 6% hydroxi-ethil-hetastarch solution (Voluven, Fresenius Kabi, Verona, Italy) and 200 ml of trihydroxymethylaminomethane solution. Roller or centrifugal pumps were used. The pump flow was settled at 2.4 L/m{L-End} 2, and the target mean arterial pressure at 60 mmHg.

Anticoagulation

Aprotinin was not used in any patient due to its unavailability on the Italian market.

  1. Control group. Baseline activated clotting time (ACT) was determined by blood sampling immediately after the induction of anesthesia. An initial dose of 300 IU per kilogram of body weight of porcine intestinal heparin was injected into a central venous line 10 minutes before the initiation of CPB. After this loading dose the ACT was measured and, if the value was >480 seconds, CPB was initiated; otherwise, a second dose of 150 IU/kg was administered. A first ACT measurement was determined after 5-10 minutes from the initiation of CPB, and subsequent determinations have been carried out every 20 minutes. An ACT of 480 seconds or greater was considered satisfactory during CPB. At the end of CPB, heparin was reversed by protamine chloride at a 1 : 1 ratio of the loading dose, regardless of the total heparin dosage. A further dose of protamine (0.5 mg/kg) could be given if the ACT did not close to the baseline value. No purified AT was administered; heparin resistance was treated with increasing heparin doses.
  2. AT - treated group. Preoperatively low levels (<80%) of AT activity were corrected by giving purified AT (Anbin{L-End} ®, Grifols, Barcelona) according to the formula:
  3. In these patients, purified AT was administered immediately after the induction of anaesthesia.
  4. Heparin resistance was treated with a dose of 1,000 or 2,000 IU of purified AT according to the ACT obtained and the body weight, given prior to CPB initiation. Subsequently, the ACT determination was repeated, and if the value was >480 seconds, CPB was initiated.
  5. Heparin was reversed with protamine as in the control group.

AT activity determinations

AT activity was measured immediately before the induction of anesthesia and at the ICU admission, on a central venous line blood sample, through a calibration curve prepared by serial dilution of the human normal plasma pool, and expressed as percentage activity. All the determinations have been carried out in the local clinical laboratory with a coagulometer Sysmex CA-6000 (TOA Medical Electronics, Milan, Italy), and are expressed as percentage.

Data collection and definitions

For each patient, the following data were recorded:

  1. Preoperative data: AT activity; age; gender; weight; serum creatinine level; chronic obstructive pulmonary disease; previous cerebrovascular accident; previous vascular surgery; diabetes on medication; haematocrit; salycilates therapy; ticlopidine/clopidogrel therapy; warfarin therapy; low molecular weight or unfractionated heparin therapy.
  2. Operative data: redo operation; CPB duration; total heparin dose; total protamine dose.
  3. Outcome variables: blood loss in the first 12 hours; need for allogeneic blood products; surgical re-exploration due to bleeding; low cardiac output syndrome (need for major inotropic support); intra-aortic balloon pump (IABP) use rate; incidence of perioperative myocardial infarction (enzimatic criteria+new Q waves), atrial fibrillation, ventricular arrythmias, lung dysfunction, stroke, mesenteric infartion, acute renal failure (need for renal replacement therapy), mortality at 28 days. Two composite outcome indices were analyzed: overall thrombotic events (perioperative myocardial infarction, stroke and mesenteric infarction) and severe morbidity (IABP, stroke, mesenteric infarction and acute renal failure).

Statistical analysis

Patients of AT-treated group and historical controls from the two participating Centres (n = 923) have been analysed with respect to their ‘propensity’ to be an AT-treated patient. The procedure for creating an homogeneous Control group followed three steps:

Step 1: Identification of significant differences between AT- treated patients and historical controls with an univariate analysis (Pearson χ{L-End} 2 for categorical variables and unpaired Student t test for continuous variables). Seven risk factors were significant different between groups: age, preoperative AT activity levels, preoperative serum creatinine levels, unstable angina, diabetes, preoperative use of anti-platelets drugs, preoperative heparin use, CPB duration.

Step 2. Multivariate analysis of the previously identified risk factors. A stepwise logistic regression analysis was applied, with the AT treatment as dependent variable and the seven risk factors as independent variables. Five risk factors remained as independent predictors of AT treatment: preoperative AT activity level, diabetes, preoperative serum creatinine level, preoperative heparin use, and CPB duration. On the basis of the logistic equation, the propensity score for being an AT- treated patient was assessed (range 0-1).

Step 3. The AT- treated patients have been divided in quintiles with respect to their propensity score. First quintile (0-0.19), 23 patients; second quintile (0.2-0.39), 26 patients; third quintile (0.4-0.59), 13 patients; fourth quintile (0.6-0.79), 10 patients; fifth quintile (0.8-1.0), 17 patients.

The control group (C) was created by randomly including the same amount of patients to each propensity score-based quintile.

All the values in text and tables are expressed as number of patients (percentage) or as mean ± standard deviation for normally distributed or median and range for non-normally distributed variables. Differences between groups have been analyzed using an unpaired data t test and a Mann-Whitney U-test for continuous variables, and a relative risk analysis for categorical variables. A computerized SPSS program (SPSS; Chicago, Il) was used. A p value <0.05 was considered statistically significant.

Results

The AT group received an intraoperative dose of purified AT ranging from 1,000 to 5,000 IU.

Table 1 includes the data regarding the purified AT dose, the total heparin dose and the ACT value reached before establishing CPB, separately for patients receiving AT due to a low preoperative AT activity or due to heparin resistance. In this second group, AT supplementation corrected the heparin resistance pattern in all patients.

Table 1
Table 1:
Treatment data (study group). Patients have been distinguished according the indication to AT concentrate administration; given to correct preoperative low levels of AT or to correct heparin resistance.

The control group collected using a propensity score on more than 1,000 potential control patients was homogeneous to the AT group with respect to demographics, pre and intra-operative variables (Table 2). Preoperative AT activity did not significantly differ between groups; conversely, as an effect of the AT supplementation, patients in the AT group had higher values of AT activity at the end of the operation.

Table 2
Table 2:
Baseline clinical and laboratory variables in untreated (control) vs. AT-treated patients.

Patients in the AT-treated group had a shorter Intensive Care Unit (ICU) and hospital stay, but they showed an increased bleeding tendency (Table 3), even if the amount of patients transfused was similar between the two groups (Table 4). A detailed analysis of postoperative complications demonstrated that patients in the AT-treated group had a significantly reduced relative risk for developing severe morbidity after surgery (Table 4). In the control group there were two cases of stroke and one mesenteric infarction. The incidence of thrombotic events and the mortality rate at 28 days showed a trend in favour of the AT-treated group (relative risk respectively 0.42 and 0.24) without however reaching a statistical significance.

Table 3
Table 3:
Postoperative outcome (continuous variables).
Table 4
Table 4:
Postoperative outcome (binary variables).

Discussion

AT supplementation in cardiac surgery patients still has an unclear role. It has been well demonstrated that patients with low values of AT activity have a high likelihood to be heparin resistant [4-7], and that AT supplementation, in these patients, exerts a beneficial effect increasing their sensitivity to heparin [6,8-10]. This behaviour was confirmed in our study, where all the heparin-resistant patients could be effectively treated with normal doses of heparin after receiving purified AT supplementation.

Many studies have demonstrated that increasing the AT activity during CPB exerts a synergistic effect with the thrombin inhibiting effect of heparin, suggesting a possible role as modulator of the inflammatory reactions and biohumoral activation related to CPB, but conflicting results have been reported as well. Rossi and coworkers [12] could demonstrate that patients receiving purified AT demonstrate lower levels of prothrombin fragment 1.2. (PF1.2) and thrombin-antithrombin (TAT) complexes, thus revealing a better thrombin suppression during the operation. These results have been confirmed by Koster and coworkers [11] who could again demonstrate that AT-treated patients have lower intraoperative levels of PF1.2. Conversely, Slaughter and coworkers [14] found no differences in TAT complexes formation in patients intraoperatively treated with AT. None of these study, however, has the power to detect clinically relevant outcome differences, being in the range of 20 to 80 patients enrolled. In our study the population size was large enough to see a beneficial effect of AT supplementation in terms of shorter ICU and hospital lenght of stay, and lower rate of severe morbid events. The former result, if confirmed in wider groups of patients, could counterbalance the higher costs due to AT concentrates supplementation; the latter confirms the possible role of AT as antiinflammatory mediator [11-15]. We are however aware of the major limitations of our study: (a) this is a retrospective analysis with a control group created with a propensity score method. Although the two groups are homogeneous with respect to pre and intraoperative variables, a more sound statistical approach would have been represented by a prospective, randomised trial; (b) the study population is undersized to detect significant differences in terms of single complications rate: a positive trend exist for the AT-treated group with respect to the need for IABP, thrombotic stroke, and mortality, but at least 200 patients in each group would have been required to reach a statistical significance.

Besides the better general outcome of the AT-treated patients, these subjects demonstrated a significantly more pronounced bleeding tendency. The difference, however, is clinically irrelevant (120 ml in 12 hours) and did not lead to an increased transfusion rate.

AT is a natural anticoagulant which greatly increases the heparin sensitivity. In our study, we did not measure the adequate heparin dose after giving purified AT: we cannot therefore exclude that some patient received more heparin than required. As a matter of fact, the heparin dose did not changed between the two groups, therefore supporting this hypothesis. The problem of a correct heparin titration whenever supplementing AT is probably important and often underestimated. In the three studies previously quoted, the anticoagulation protocol was greatly different. Slaughter and Rossi followed a standard anticoagulation protocol, with a fixed dose of 300 IU/kg heparin and a standard ACT control. Koster followed an heparin-response management using a dedicated device (HMS Hepcon, Medtronic, Minneapolis, Minn), but determined the heparin loading dose before giving the purified AT dose. We think that future studies on AT supplementation should follow a policy of careful heparin titration before giving the loading dose, in order to avoid unjustified heparin overdoses.

As a matter of fact, previous studies addressing the role of AT supplementation in the setting of septic shock had demonstrated that the association of heparin with purified AT administration results in a higher bleeding tendency [16].

In conclusion, this study demonstrates that AT supplementation in patients with low preoperative AT values and/or in heparin resistant patients undergone coronary revascularisation with CPB results in a better postoperative outcome; however, the synergistic effect of AT and heparin may lead to an increased postoperative bleeding tendency, even if not clinically relevant. Sistematic preoperative screening of AT activity, joined to a better AT concentrates utilization, should represent an improvement of perioperative management of the coronary patient. Further prospective studies are aimed to confirm our results, enrolling enough patients to allow reliable analysis of collected data from a clinical point of view.

References

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Keywords:

antithrombin; cardiopulmonary bypass; surgery; complications

© 2007 European Society of Anaesthesiology