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Antithrombin Levels, Morbidity, and Mortality in a Surgical Intensive Care Unit

Section Editor(s): Takala, JukkaSakr, Yasser MB BCh*; Reinhart, Konrad MD*; Hagel, Stefan MD*; Kientopf, Michael MD; Brunkhorst, Frank MD*

doi: 10.1213/01.ane.0000275194.86608.ac
Critical Care and Trauma: Research Report
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SDC

BACKGROUND: Antithrombin (AT) levels have been suggested as being predictive of outcome in intensive care unit (ICU) patients with septic shock. We investigated the time course of AT levels in a surgical ICU and tested the hypothesis that AT levels may be associated with morbidity and increased mortality rates in a cohort of surgical ICU patients.

METHODS: Three-hundred-twenty-seven consecutive patients admitted to the ICU with an estimated length of stay more than 48 h were included. AT levels were measured daily.

RESULTS: On admission to the ICU, AT levels were below the lower limit of normal in 84.1% (n = 275) of patients and increased significantly by 48 h after admission to reach normal values by the 7th ICU day in patients who never had sepsis (n = 208). This increase in AT levels was delayed in patients with sepsis. Patients with severe sepsis (n = 55) had consistently lower AT levels compared with other patients. Patients with lower AT levels were more likely to need blood products and had a greater maximum degree of organ dysfunction in the ICU than did other patients. The ICU length of stay was similar, regardless of the AT level on admission. Admission AT levels were not associated with increased ICU mortality in a multivariable analysis.

CONCLUSIONS: AT levels are low on admission to the ICU, regardless of the presence of sepsis. Although associated with the degree of organ dysfunction and the severity of sepsis, AT levels were not independently associated with worse outcome in this group of surgical ICU patients.

IMPLICATIONS: Although antithrombin levels are often low in sepsis, such levels are not related to outcome.

From the *Department of Anesthesiology and Intensive Care, and †Institute of Clinical Chemistry and Laboratory Medicine, Friedrich-Schiller-University Hospital, Jena, Germany.

Accepted for publication May 16, 2007.

Supported by competitive, peer-reviewed R&D grants from the Thuringian Ministry of Science (TMWFK).

Address correspondence and reprint requests to Konrad Reinhart, MD, Department of Anesthesiology and Intensive Care, Friedrich-Schiller-University, Erlanger Allee 103, 07743 Jena, Germany. Address e-mail to konrad.reinhart@med.uni-jena.de.

Antithrombin (AT) is a single-polypeptide, hepatically synthesized, serine protease inhibitor with a molecular weight of approximately 58 kDa (1). AT inhibits multiple components of the intrinsic, extrinsic, and common coagulation pathways, including factors IIa, XIIa, XIa, IXa, Xa, and kallikrein. The resting plasma concentration of AT is approximately 110–140 mg/L, with a serum half-life of 36–48 h (2).

Acute inflammation, as a response to severe infection or trauma, results in systemic activation of the coagulation system (3,4). Cytokines have been shown to play an important mediatory role through the activation of the tissue factor–factor VIIa (extrinsic) pathway (5,6), with subsequent consumption of anticoagulation factors, including AT. Several studies have reported low AT levels, not only in patients with sepsis syndromes but in other groups of patients admitted to the intensive care unit (ICU) (7,8). Patterns of AT levels in various groups of surgical ICU patients have been reported (9), but the possible association of AT levels with outcome was not characterized in that study due to the small number of patients studied.

A potential role for AT levels as a predictor of outcome in patients with septic shock has been suggested (2), and low AT levels have been associated with an increased risk of infections and death in patients after trauma (7). However, the association between AT levels and subsequent morbidity and mortality in the ICU is not consistent in the literature (8,10).

We therefore investigated the time course of AT levels in a surgical ICU and tested the hypothesis that AT levels may be associated with morbidity and increased mortality rates in a cohort of surgical ICU patients.

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METHODS

The study was approved by the IRB of Friedrich Schiller University hospital, and informed consent was obtained from all patients or their next of kin. All consecutive patients admitted to our surgical ICU between January and November 2001 with an estimated ICU length of stay (ICU LOS) more than 48 h were included. Exclusion criteria were as follows: patients younger than 18 yr, patients with advanced malignancies or other conditions with shortened life expectancy (<4 wk), pregnancy, previous inclusion in the study, and patients in whom decisions to withhold or withdraw life-sustaining treatments were established within the first 24 h of ICU admission.

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Data Collection and Blood Sampling

The Acute Physiology and Chronic Health Evaluation II score (11) and the simplified acute physiology score II (SAPS II) (12) were obtained within 24 h of admission. The sequential organ failure assessment (SOFA) score (13) was calculated daily. The maximum SOFA score (SOFAmax) was defined as the highest SOFA score reached during the ICU stay, and was used to express the worst organ dysfunction/ failure status attained during the ICU stay. Data recorded on admission included age, gender, referring facility, primary and secondary admission diagnoses, associated comorbidities, and surgical procedures preceding admission. The presence of systemic inflammatory response syndrome criteria, organ failure and/or infection was recorded daily, together with laboratory indices of organ dysfunction/failure (including platelet count, serum total bilirubin, serum creatinine, and serum lactate concentration).

Blood samples were collected daily; routine variables of organ dysfunction/failure were measured using automated measures in our laboratories. Lactate concentrations in arterial blood samples were measured using an automated blood gas analyzer (ABL700 Radiometer®, Copenhagen, Denmark). AT and protein C activities were determined daily for the first 2 wk of the ICU stay, chromogenically by the Coamatic®-Test (Chromogenix, Mölndal, Sweden). The detection for AT was validated to a lower detection limit of 10%. AT levels higher than 80% were considered as normal. The initial AT levels were measured within 2 h of ICU admission.

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Definitions

Sepsis, severe sepsis, and septic shock were defined according to the American College of Chest Physicians/American Society of Critical Care Medicine consensus conference criteria (14) by the attending senior intensivist. Central nervous system failure was defined as disturbed consciousness, irritability, disorientation, or delirium without evidence of drug-induced manifestations; thrombocytopenia was defined as platelet count <100 × 103/μL or >30% decline within 24 h without evidence of blood loss as an etiological factor; respiratory failure was defined as Pao2 <75 mm Hg in room air, Pao2/Fio2 <250 mm Hg; cardiovascular failure was defined as systolic blood pressure <90 mm Hg or mean arterial blood pressure <70 mm Hg for at least 1 h despite adequate fluid resuscitation; renal failure was defined as urinary output <0.5 mL · kg−1 · h−1 for at least 1 h in the absence of hypovolemia or a two-fold increase in serum creatinine; and metabolic acidosis was defined as a base excess <−5 mEq/L or a plasma lactate concentration 1.5 times more than the reference value. Patients were categorized according to the worst grade of sepsis syndrome in the ICU.

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Outcome Variables

Four outcome variables were defined a priori and included: the need for blood products during the ICU stay; ICU LOS; the maximum degree of organ dysfunction/failure as assessed by the max SOFA score; and death in the ICU.

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Statistical Analysis

Data were analyzed using SPSS 13.0 for Windows (SPSS Inc., Chicago, IL). A Kolmogorov–Smirnov test was used to verify the normality of distribution of continuous variables. A Friedman test was used to assess the evolution of AT levels within groups over time, and the differences among groups were assessed using the multifactorial analysis of variance. A Kruskal–Wallis H-test was used to compare differences among groups, and subsequent pairwise comparisons were performed using a Mann–Whitney U-test with Bonferroni correction for multiple comparisons. The predictive value of AT activity with regard to ICU outcome was calculated using a receiver operator characteristic curve, and the area under the curve (AUC) was computed. The best cutoff point was defined using the Youdin index, and sensitivity, specificity, negative predictive value, and positive predictive value were calculated. We conducted a multivariable analysis with ICU mortality as the dependent variable. Variables considered for the multivariable analysis included age, gender, source of admission, type of surgery, the occurrence of sepsis syndromes during the ICU stay, and the maximum SOFA score. The multivariable analysis was preceded by a univariate selection of potential prognostic variables (P < 0.2). Colinearity between variables was excluded before covariates were introduced in the model. A forward, stepwise approach was used for multivariable modeling, and admission and minimum AT activity were introduced separately at the final step as a categorical variable with values >80% as a reference category. Variables were retained in the multivariable model with P < 0.1. Goodness of fit was tested using a Hosmer and Lemeshow test, and odds ratios (OR) with 95% confidence interval (CI) were computed.

P < 0.05 was considered significant. Categorical data are presented as n (%) and continuous data as mean ± sd unless otherwise indicated.

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RESULTS

Characteristics of the Study Group

We enrolled 327 patients, 207 men, and 120 women, with a mean age of 63 yr. The characteristics of the study group are presented in Table 1. Seventy-four postoperative patients were referred from other facilities and did not undergo any surgical procedure in the 48 h preceding ICU admission, because of respiratory failure. Admission was due to respiratory failure (n = 24), severe sepsis (n = 9), deterioration in the level of consciousness (n = 14), trauma (n = 6), successful cardiopulmonary resuscitation (n = 4), acute renal failure (n = 5), congestive heart failure or myocardial ischemia (n = 5), gastrointestinal bleeding (n = 4), seizures (n = 2), and arrhythmia (n = 1). The median ICU LOS was 6 days (25%–75% interquartile range [IQ]: 4–13 days), and the overall ICU mortality rate was 15.0% (n = 49). Severity scores and ICU LOS varied considerably among the various subgroups (Table 2).

Table 1

Table 1

Table 2

Table 2

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Time Course of AT Levels During the ICU Stay

On admission to the ICU, AT levels were below the lower limit of normal in 84.1% (n = 275) of patients. AT levels varied according to the source of admission, type of admission, and type of surgery (Table 2). AT levels on admission were lower in patients with severe sepsis (n = 55; including 48 patients with septic shock) compared with those in patients who did not have sepsis (n = 208) (Table 2). Patients with sepsis (without sepsis-attributable organ failure, n = 64) had AT levels similar to those of patients who never had sepsis in the ICU. The time course of AT levels over the 2 wk after admission to the ICU, stratified by the presence and severity of sepsis syndromes, is presented in Figure 1.

Figure 1

Figure 1

AT levels increased significantly 48 h after admission to the ICU in patients who never had sepsis, to reach normal values by the 7th ICU day. In patients with sepsis, with or without organ failure, there was a delayed increase in AT levels until the fifth ICU day; however, the mean AT levels remained mostly below the lower limit of normal over the 2 wk after admission in these two groups. Patients with severe sepsis had consistently lower AT levels compared with the other two groups.

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Relationship Between AT Levels and Other Variables of Coagulation

During the ICU stay, AT levels were positively correlated to the platelet count (R2 = 0.27, P < 0.001), to the Quick prothrombin time (R2 = 0.17, P < 0.001), and to protein C levels (R2 = 0.4, P < 0.001). AT levels were inversely correlated to the activated partial thromboplastin time (R2 = 0.16, P < 0.001). The evolution of the Quick prothrombin time, activated partial thromboplastin time, and platelet count paralleled the evolution of AT irrespective of the presence of sepsis (Fig. 2).

Figure 2

Figure 2

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Relationship Between AT Levels and Outcome

Table 3 shows morbidity and mortality according to AT levels. The need for administration of blood products in the ICU was greater in patients with lower AT levels. The maximum degree of organ dysfunction/ failure was greater in patients with lower AT levels, and was more pronounced when either the admission or the minimum AT levels were <60%. A positive correlation was present between AT levels at any time during the ICU stay and the SOFA scores recorded on the same day (R2 = 0.15, P < 0.001). Measured on admission, lower AT levels were associated with higher cardiovascular, renal, and coagulation max SOFA subscores. The ICU LOS was similar regardless of AT levels on admission. Patients with greater SOFAmax scores had lower AT levels over the 2 wk after ICU admission.

Table 3

Table 3

Forty-nine patients (15%) died in the ICU: 29 patients with severe sepsis, 5 patients with sepsis, and 15 patients without sepsis. AT levels were consistently lower in nonsurvivors than in survivors over the 2 wk after ICU admission (Fig. 3). AT levels increased >10% over the 24 h after admission in 75 patients, decreased >10% in 69 patients, and remained unchanged in 183 patients; ICU mortality rates were 12%, 17.4%, and 13.6%, respectively (P = 0.357 among groups). In a receiver operator characteristic curve analysis (Fig. 4), SAPS II score discriminated ICU mortality (AUC: 0.78; 95% CI: 0.7–0.85) more efficiently than AT level on admission (AUC: 0.62; 95% CI: 0.52–0.71) or the minimum AT level in the ICU (AUC: 0.72; 95% CI: 0.64–0.8). The best cutoff point for AT level on ICU admission was 54%, with a sensitivity of 53%, specificity 67%, negative predictive value 89%, and positive predictive value 22%. The best cutoff for minimum AT level was 44%, with a sensitivity of 63%, specificity 75%, negative predictive value 92%, and positive predictive value 31%.

Figure 3

Figure 3

Figure 4

Figure 4

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).

Table 4

Table 4

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DISCUSSION

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 agreement with the previous literature (22–24), AT levels in our study were lower depending on the presence and severity of sepsis, and the observed increase in AT levels after 48 h of ICU admission was delayed in patients with sepsis and sepsis-induced organ failure. Likewise, Gando et al. (22) reported that patients with severe sepsis had low AT levels during their first 48 h in the ICU, and that these levels increased gradually on the third day after admission to the ICU. Hoffmann et al. (25) also reported low AT levels in patients with severe sepsis over 2 wk (n = 20). The correlation between AT and other variables of coagulation was significant, however, regardless of the presence of sepsis. Moreover, AT levels were correlated with SOFA scores in the ICU. We therefore hypothesize that organ dysfunction/failure is as important as sepsis in influencing AT levels and activating the coagulation cascades, and that AT levels may influence the degree of organ dysfunction/failure in the ICU.

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.

In a meta-analysis (31) and post hoc reports (32), supplementation with AT was shown to improve survival, but these data were not confirmed by a large phase III study (33), and the role of AT is still unclear. Our data should not be interpreted as a case against AT supplementation. The anti-inflammatory effect of AT is thought to be independent of its anticoagulation activity (34–36). Nevertheless, current evidence does not support the routine use of AT therapy in patients with sepsis. Similar observations were reported by Pettila et al. (10) and Ranucci et al. (8).

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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