In a multivariable analysis with ICU mortality as the dependent variable, SAPS II score (OR = 1.5; 95% CI: 1.08–2.12; P = 0.017), maximum SOFA score (OR = 1.32; 95% CI: 1.12–1.56; P = 0.001), and the presence of severe sepsis (OR = 2.73; 95% CI: 1.01–7.4; P = 0.001) were the only independent risk factors for ICU death (Table 4).
In this large cohort of surgical ICU patients, AT levels on admission were generally low. Patients with severe sepsis had the lowest AT levels. AT levels increased significantly over time, but this increase was delayed in the presence of sepsis and organ failure. Lower AT levels were associated with organ dysfunction/failure and AT levels were consistently lower in nonsurvivors than in survivors over the 2 wk after ICU admission; however, they discriminated nonsurvivors poorly and were not independently associated with an increased risk of ICU death.
Several factors may have contributed to the low AT levels in our study. Acute consumption of AT after activation of the coagulation system (8,15–17) and increased thrombin formation (18,19) in response to tissue injury is probably the most important factor. This consumption may be particularly aggravated in patients undergoing cardiac surgery in the presence of high heparin concentrations (8). Decreased hepatic synthesis of AT has also been observed in chronic or acutely acquired liver failure in ICU patients (20) and may be a contributing factor. An additional mechanism in patients with sepsis may be the specific inactivation of serine proteases and AT by elastase released from activated neutrophils (21).
In our study, patients referred to the ICU from the hospital floor or from other hospitals had higher AT levels on admission compared with those referred from the operating room. This highlights the importance of surgical injury as a cause of AT deficiency in this population. Neurosurgical patients had greater AT levels on ICU admission than those who had undergone cardiothoracic surgery; this suggests a possible relation between AT deficiency and the extent of the surgical procedure. A similar observation was made in a small group of surgical patients (9).
In our study, patients with lower AT levels were more likely to require administration of blood products in the ICU. This finding could be related to an inadequately suppressed thrombin activity resulting from suboptimal anticoagulation, promoting a bleeding diathesis. Alternatively, the low AT levels may be indicative of activated coagulation with clotting factor consumption, leading to clinical bleeding and, hence, the increased need for blood product transfusion. Ranucci et al. (8) similarly found that AT levels were significantly associated with higher blood loss, a more frequent incidence of allogeneic blood product use, and surgical reexploration. The ICU LOS in our study was similar, regardless of AT levels on admission. However, low AT levels were associated with a higher degree of organ dysfunction/failure as assessed by the SOFA score.
The potential role of AT levels as a predictor of outcome in septic shock patients was first suggested 2 decades ago (26), and several reports support this observation (27–29). However, evaluation of the predictive value of a single laboratory test or model requires strict methodological criteria (30). Significant differences in a single laboratory value between survivors and nonsurvivors may be present but not necessarily clinically relevant. Paradoxically, using larger sample sizes to detect possible differences in main outcome measures may actually increase the detection of clinically nonsignificant differences in secondary end points or demographic data (10). It should not be surprising, therefore, that despite the persistently lower AT levels in our survivors compared to our nonsurvivors over the 2 wk after ICU admission, these were not associated with an increased risk of ICU death in the final multivariable analysis, after adjusting for baseline characteristics, severity of illness, and degree of organ dysfunction/ failure.
Our study has some limitations. The heterogeneity of the study group may preclude the extrapolation of the results to other ICU patients with different case-mix. The multivariate analysis is also limited by the variables included in the analysis, and the effect of unmeasured variables cannot be excluded. Intraoperative events, including bleeding, vascular exposure, and extent of surgery, were not considered in our analysis, and may have contributed to the lower AT levels and the subsequent outcome. However, we adjusted for the severity of illness, baseline characteristics, and the degree of organ dysfunction/failure, which are considered major determinants of outcome in ICU patients. Finally, we included patients with an expected ICU LOS >48 h. This may have led to the exclusion of patients with a fulminating clinical course and early death, precluding the extrapolation of our results to those patients.
In conclusion, AT levels are low on admission to the ICU, regardless of the presence of sepsis syndromes. The subsequent increase in AT levels is delayed in patients with sepsis. Despite being associated with the degree of organ dysfunction and the severity of sepsis, AT levels poorly predict ICU mortality and are not independently associated with worse outcomes in this group of surgical ICU patients.
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