The incidence of septic shock has increased drastically during past years. Septic shock patients have mortality rate of about 60% and an excess risk of death of about 25% when compared with non-septic patients 1. Sepsis patients frequently develop endothelial damage and a hypercoagulable state related to the systemic inflammatory response syndrome 2. In these severe situations, patients present acquired antithrombin III (AT) deficiency with plasma AT level lower than 80% either due to increased consumption related to disseminated intravascular coagulopathy (DIC) or induced by decreased liver synthesis, or increased vascular permeability and degradation by elastase 3. A striking correlation between AT activity and survival in sepsis has been demonstrated 4567. Patients with multiple organ failure induced by septic shock need aggressive life support such as vasopressors, mechanical ventilation and/or renal supportive therapy. Continuous renal replacement therapy (CRRT) requires careful anticoagulation to prevent the blood from clotting while avoiding bleeding complications. Heparin treatment, especially in combination with extracorporeal circulation, may also lead to significant AT consumption 8, then to premature filter clotting despite adequate anticoagulation 9. In 2000 Williams and colleagues 10 showed, in a randomized trial in patients requiring cardiopulmonary bypass, that heparin resistance was frequently associated with AT deficiency. Treating this deficiency with AT concentrate was more effective and faster for obtaining adequate anticoagulation than using additional heparin. Cardiopulmonary bypass is a traumatic procedure that is associated with platelet and coagulation defects, and with systemic inflammation, as described in septic shock. Thus we proposed that AT supplementation in the subset of septic shock patients undergoing CRRT might increase filter lifespan and improve the efficacy of this system of renal support.

A total of 2,662 admissions of patients without septic shock were made in our ICUs over the study period. Ages and SAPS II scores were 54.8 ± 22.5 years and 38.6 ± 21.4, respectively, and the crude ICU mortality rate was 20.6%. During the same period, 230 admissions (7.9% of ICU admissions) concerned patients with septic shock (age 58.7 ± 20.2 years; SAPS II score 57.1 ± 22.0; ICU mortality 58.3%). Of these, 106 subjects (46%; age 59.6 ± 14.5 years; SAPS II score 58.2 ± 16.3) needed CRRT for a median duration of 4 days (range 1 to 9), with a crude filter clotting rate of 22% and a crude ICU mortality of 60% (Table 1). After exclusion of patients as described in Materials and methods (see Figure 2), 78 (74%) septic shock patients requiring CRRT were eligible for analysis.

In univariate analysis (Table 1), groups were similar for demographic data and co-morbidities. Modalities of CRRT, such as hemofiltration (36 patients) or hemodiafiltration (42 patients), did not differ between periods. Patients were more severely ill in the period 2003 to 2004, as assessed by higher SAPS II and SOFA scores at ICU admission. The number of overt DICs did not differ between the two periods, and AT activity was similar to baseline in both intervals; however, the mean AT activity reached a normal level within 24 hours after AT supplementation during the intervention period, and differed significantly from that of controls (95 ± 20% for cases, 55 ± 12% for controls; p = 0.001). During the intervention period, the median dose of AT received per patient was 50 IU/kg (range 50 to 150). Nineteen patients received a single dose, 13 received two AT doses, and 6 needed three AT infusions once daily, each dose being 50 IU/kg. AT supplementation was not associated with an increased risk of major bleeding events (n = 3 for cases; n = 2 for controls). The heparin dose required to achieve the targeted increase in APTT was lower during the intervention period (p = 0.0086). The frequency of post-filter protamine infusion was equal between groups (four controls versus five cases). Median lengths of CRRT and ultrafiltration rate were similar, but the filter clotting rate was significantly lower (p = 0.0018) and the ratio of delivered to prescribed ultrafiltration was significantly greater (p = 0.0032) in patients supplemented with AT.

As shown in Figure 3, the survival curve for filters in patients supplemented or not with AT concentrates differed significantly between periods. The median filter lifespan in patients who received AT was 44.5 hours (95% CI 34.5 to 48.0), which was significantly longer than the 32.5 hours (95% CI 26.5 to 36.0) in patients who received heparin alone (p = 0.0045 by the log-rank test).

By multivariable analysis adjusted for age, fibrinogen level, heparin dose, platelet count and the need for mechanical ventilation, AT supplementation was independently associated with a decrease in membrane failure, whereas higher SAPS II and femoral angioaccess were identified as independent predictors of clotting (Table 2).

Despite a greater severity of illness during the intervention period, the median lengths of ICU stay and the ICU mortalities did not differ significantly. When adjusted for the severity of illness, mortality for patients treated with AT did not differ significantly from that calculated in control patients (the risk-adjusted mortality rate was 1.1 for cases and 1.4 for controls, with overlapping confidence intervals). However, the observed hospital mortality rate was significantly higher than predicted mortality estimated by SAPS II during the period 2001 to 2002 (95% CI significantly different from 1), whereas the observed hospital mortality rate remained similar to the expected rate during the intervention period.

The recent conference on CRRT 16 failed to reach a consensus on the preferred anticoagulant for most CRRT patients. Systemic anticoagulation with unfractionated heparin remains the treatment of choice. Some authors have reported encouraging results with the concomitant administration of prostaglandin E₁ 17, or fresh frozen plasma 18 and unfractionated heparin, to keep the circuit open. However, prostaglandin E₁ requires adequate experience to avoid side effects, and transfusion with fresh frozen plasma presents the same risks as transfusion with red blood cells and is not routinely recommended during septic shock to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedure 19. More recently, a randomized trial has suggested the superiority of regional citrate anticoagulation over unfractionated heparin 20. In this study, the median hemofilter survival time increased markedly from 38.3 hours in the heparin group to 124.5 hours in the citrate group. Decreasing AT levels were identified as independent predictors of hemofilter failure, and citrate anticoagulation was associated with a greater increase in AT over time after adjustment for temporal changes in illness severity. Finally, these results advocated the use of regional citrate as anticoagulation of choice in patients receiving CRRT, and highlighted the key role of AT levels to predict filter lifespan as described by others 8921.

There are conflicting data on the use of AT in sepsis or extracorporeal circulation. On the one hand, the body of literature currently does not support the routine use of AT in sepsis patients despite encouraging results from experimental studies 22. In 1998, a meta-analysis based on four double-blind placebo-controlled trials of patients with severe sepsis documented a non-significant 22% decrease in death rate in treated patients 23. More recently, the KyberSept trial found no effect of AT on 28-day all-cause mortality in patients with severe sepsis or septic shock, despite a possible treatment benefit in the subgroup of patients not receiving concomitant heparin 24. In this latter study, AT was associated with an increased risk of hemorrhage when it was administered with heparin. On the other hand, in heparin-resistant patients undergoing cardiac surgery with cardiopulmonary bypass, there are recent data suggesting that normalizing AT during extracorporeal circulation may modulate thrombin generation, decrease levels of fibrin monomer and D-dimer 25, restore heparin responsiveness, and then promote therapeutic anticoagulation 2627.

Our observational study confirms the high incidence of septic shock patients with a lack of AT activity as well as the strong association between AT deficiency, heparin resistance and premature circuit coagulation. It also suggests that AT supplementation can effectively prevent the occurrence of clotting, at least in part by potentiation of the heparin effect on thrombin and factor Xa. This is substantiated by the decrease in heparin dose needed to achieve targeted APTT during the second two-year period. Finally, our results suggest that low AT levels have first to be supplemented to take advantage of a new membrane generation such as heparin-bonded filters.

Furthermore, as recently described by Lima and colleagues 28, our study confirms the difficulties in predicting outcome by using scoring systems at ICU admission in patients with acute renal failure. Mortality was underestimated by SAPS II in the control group of the present study and not in the treatment group. This could indicate changes in the management of treated patients that resulted in an improved outcome. The potential impact of AT supplementation must therefore be interpreted with caution. However, because patients were more severely ill during the intervention period, the benefit of AT on survival might have been underestimated, and AT might contribute to an improvement in outcome as assessed by the reduction of mortality adjusted for the severity of illness. In our study the ultrafiltration rate was about 35 ml/kg per hour and did not differ significantly between periods. However, the reduced downtime in treated patients contributed to an enhancement in the daily dose of hemofiltration in patients who received AT concentrates, as assessed by the ratio of delivered to prescribed ultrafiltration. Because a beneficial impact of higher dose of hemofiltration on survival of ICU patients with acute renal failure treated by continuous hemofiltration has been well demonstrated 29, this mechanism might be involved, at least in part, in improving the adjusted mortality risk in our study.

Another finding is the association between femoral angioaccess and circuit coagulation. The femoral vein is usually considered the primary choice in emergencies, whereas internal jugular access seems preferable in the absence of life-threatening thoracic conditions. Our results further support the placement of dialysis catheters in the internal jugular vein whenever possible, to decrease the rate of complications such as clotting and to improve the efficacy of hemofiltration. This should be confirmed by a well-designed randomized trial.

Some limitations of our study have to be addressed. Because the design was single-center and retrospective, with a comparison of unmatched small historical groups despite a prospective collection of data, we recognize that the conclusions drawn from the present study might not be generalizable. We simply reported the evolution of the incidence of filter failure between two periods during which only one element had changed: the supplementation of AT in patients with an endogenous AT activity of less than 70% during CRRT.

Finally, the cost of AT supplementation is high in our study. Despite a decrease in the mean number of filters used, AT (product and analysis) plus hemofilters in the second period cost about €730 per treatment day compared with €80 per treatment day for filters alone. However, the mean cost increase of €650 per treatment day can be counterbalanced by the time saved by nurses and intensivists, and by a potential beneficial effect on outcome. Thus, although AT supplementation represents a real cost to the hospital, further randomized studies are needed to evaluate its cost-effectiveness in septic shock patients treated with continuous hemofiltration.

Our results suggest that AT administration in patients suffering from septic shock-induced multiple organ failure and requiring CRRT should be re-evaluated. As demonstrated in heparin-resistant patients necessitating cardiopulmonary bypass during cardiac surgery, AT supplementation may be used in the future as an alternative to regional citrate anticoagulation to improve the effect of heparin in patients undergoing CRRT during septic shock. Its safety, cost-effectiveness and impact on outcome remain to be determined by further double-blind, randomized, placebo-controlled multicenter trials.

• Acquired AT deficiency is frequently observed during septic shock.

• In septic shock patients undergoing CRRT, a low level of AT activity, with a threshold value of 70%, is associated with premature filter clotting.

• The body of literature does not recommend the routine use of AT concentrate to treat heparin resistance during CRRT.

• Our case-control observational study suggests that AT supplementation during CRRT restores heparin responsiveness, decreases the filter clotting rate and may improve outcome.

• Further double-blind, randomized, placebo-controlled multicenter trials are warranted to confirm these findings and determine the cost-effectiveness of AT supplementation.

APTT = activated partial thromboplastin time; AT = antithrombin III; CI = confidence interval; CRRT = continuous renal replacement therapy; DIC = disseminated intravascular coagulopathy; ICU = intensive care unit; ROC = receiver operating characteristic; SAPS II = Simplified Acute Physiology Score II; SOFA = Sequential Organ Failure Assessment.

The authors declare that they have no competing interests.

DdC conceived the original protocol, executed the study, analyzed data, and drafted the manuscript. BB, CB, CD, MR assisted in executing the study and drafting the final manuscript. PC participated in the coordination of the study. All authors read and approved the final manuscript.