Risks/Outcomes/Predictors
Troponin-I as a prognosticator of mortality in severe sepsis patients,☆☆,

https://doi.org/10.1016/j.jcrc.2009.12.001Get rights and content

Abstract

Purpose

The purpose of this retrospective study was to evaluate cardiac troponin-I (cTnI) as a 28-day mortality prognosticator and predictor for a drotrecogin alfa (activated) (DrotAA) survival benefit in recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis patients.

Methods

Cardiac troponin-I was measured using the Access AccuTnI Troponin I assay (Beckman Coulter, Fullerton, CA). There were 598 patients (305 DrotAA, 293 placebo) with baseline cTnI data (cTnI negative [<0.06 ng/mL], n = 147; cTnI positive [≥0.06 ng/mL], n = 451).

Results

Cardiac troponin-I–positive patients were older (mean age, 61 vs 56 years; P = .002), were sicker (mean Acute Physiology and Chronic Health Evaluation II, 26.1 vs 22.3; P < .001), had lower baseline protein C levels (mean level, 49% vs 56%; P = .017), and had higher 28-day mortality (32% vs 14%, P < .0001) than cTnI-negative patients. Elevated cTnI was an independent prognosticator of mortality (odds ratio, 2.020; 95% confidence interval, 1.153-3.541) after adjusting for other significant variables. Breslow-Day interaction test between cTnI levels and treatment was not significant (P = .65).

Conclusion

This is the largest severe sepsis study reporting an association between elevated cTnI and higher mortality. Cardiac troponin-I elevation was not predictive of a survival benefit with DrotAA treatment.

Introduction

Biomarkers are important tools in the quest to treat patients quickly and efficiently, especially in critical illness where time could be a limiting factor. Compared with other diagnostic tools, biomarkers may provide an efficient way for clinicians to quickly formulate different diagnoses, guide therapy, and provide prognostic values [1]. Cardiac biomarkers are some of the more well-documented biomarkers currently in use, with the ability of cardiac troponin T and cardiac troponin I (cTnI) measurements to predict outcome and guide the therapeutic management of patients with acute coronary syndromes [2]. Specifically, cTnI has been shown to be an indicator of myocardial injury and is an accepted prognosticator of myocardial infarction (MI) [3], [4]. Although cTnI is cardiac-specific, its release seems not to be limited to cardiac-related events, but is also detectable in other critical clinical conditions, such as trauma, pulmonary embolism, and severe sepsis.

Recent studies have begun examining the role of cTnI in sepsis and septic shock. In a prospective case-control study by Ammann et al [5], of the 20 patients with sepsis, septic shock, or systemic inflammatory response syndrome and without underlying acute coronary syndromes, 85% of the patients had elevated cTnI, whereas no patient in the control group of the study had elevated cTnI (P < .0001). In another prospective study, Arlati et al [6] showed that cTnI was elevated in 11 of 19 sepsis patients. Other sepsis studies, with similarly small numbers of patients (<105), showed that sepsis patients with elevated troponin levels had higher Acute Physiology Age and Chronic Health Evaluation (APACHE) II scores and higher mortality [7], [8], [9].

Severe sepsis is the leading cause of death in the noncoronary intensive care unit (ICU) and the 10th leading cause of death overall [10], [11], [12]. Drotrecogin alfa (activated) (DrotAA) is approved by the United States Food and Drug Administration for the reduction of mortality in adult patients with severe sepsis and high risk of death. Approval for DrotAA was based on the pivotal phase 3 study, recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS), that enrolled 1690 patients (850 DrotAA, 840 placebo) [13]. This current retrospective study (abstract recently published by Heiselman et al [14]) used a subset of the PROWESS severe sepsis patients (n = 598) and evaluated cTnI as a prognosticator of 28-day mortality as well as a predictor for a survival benefit with DrotAA treatment.

Section snippets

Patient population

From July 1998 through June 2000, 1690 severe sepsis patients were enrolled in PROWESS, a randomized, double-blind, placebo-controlled phase 3 trial for evaluating DrotAA treatment. The PROWESS trial was conducted at 164 centers in 11 countries [13]. The institutional review board at each center approved the protocol, written informed consent was obtained from all participants or their authorized representatives, and the study was conducted according to the principles of the Declaration of

Troponin-I as prognosticator of mortality

Of the 598 patients, 147 patients (71 placebo, 76 DrotAA) were cTnI and 451 (222 placebo, 229 DrotAA) were cTnI+ at baseline. The median baseline level of cTnI in the 598 patients was 0.15 ng/mL (range, 0.01-353 ng/mL).

There were significant differences in baseline characteristics between the cTnI+ and cTnI groups (Table 1). The cTnI+ group was slightly older and had worse baseline disease severity (more patients had APACHE II scores ≥25, more organ dysfunction and vasopressor use, and higher

Discussion

In evaluating serum samples from a large cohort of patients with severe sepsis, we were hoping to address 2 questions: (1) Is cTnI a marker of disease severity in severe sepsis? (2) Could troponin be used to guide therapy? This is the largest study (n = 598) to date wherein baseline cTnI measurement was used as a prognostic marker in patients with severe sepsis. Elevated cTnI values were observed in 75% (451 of 598) of patients, which is consistent with previous studies of severe sepsis

Conclusion

We found, in a subset of patients from the PROWESS trial, that elevated cTnI was associated with a higher mortality. Using multivariable analysis, troponin was an independent prognosticator of mortality, but was not a predictor of the survival benefit observed with DrotAA administration. This study further supports the association between increased cTnI levels and increased hospital and ICU lengths of stay.

Acknowledgments

This study was funded by Eli Lilly and Company. Drs John, Woodward, Wang, Yan, Kinasewitz, and Heiselman, and Ms Fisher contributed to the interpretation of the data and the drafting of the manuscript. Dr Wang performed the statistical analyses for the manuscript. All authors reviewed and approved the final version of the manuscript. The authors wish to acknowledge the following Lilly colleagues for their assistance: Suzane Um for managing and coordinating the entire sample and clinical data

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    Work was performed at Eli Lilly and Company, Cardiovascular/Critical Care, Lilly Corporate Center, Indianapolis, IN 46285.

    ☆☆

    Financial support was provided by Eli Lilly and Company.

    Disclosures: Dr Kinasewitz is a speaker for Eli Lilly's lecture bureau. Drs Woodward, Wang, Yan, and Heiselman and Ms Fisher are employees and shareholders of Eli Lilly and Company. Eli Lilly and Company is the maker of drotrecogin alfa (activated).

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