Prognostic Value of Initial Elevation in Cardiac Troponin I Level in Critically Ill Patients Without Acute Coronary Syndrome

In a prospective observational study, all patients admitted to either the ICU or the CCU during 115 consecutive days were screened for eligibility. Inclusion criteria included at least 1 elevated serum level of CTnI within 24 hours of admission to the ICU or CCU, with the highest CTnI level within the stated time window recorded for the study’s results. Patients were excluded if they had ACS as indicated by medical history, physical examination, clinical features, cardiac biomarkers, and electrocardiographic findings as defined by the American College of Cardiology and the American Heart Association^12,24  anytime during their current admission; were less than 18 years old; or declined to participate in the study. Patients with a known history of ACS were eligible for enrollment only if the ACS had occurred more than 10 days before the patient was examined in the emergency department, because serum levels of CTnI can remain elevated for up to 10 days after a myocardial ischemic event.¹⁰  Patients were divided into 2 groups on the basis of their highest CTnI level: if the peak serum level was more than 0.049 ng/mL, they were enrolled in the elevated CTnI group (CTnI-positive); if the level was 0.049 ng/mL or less, they were placed into the normal CTnI group (CTnI-negative).

The Access AccuTnI Reagent (Beckman Coulter Inc) was used to detect CTnI. The functional sensitivity, defined as the lowest CTnI concentration measurable with an assay coefficient of variation or total imprecision of 20% or less for the presence of a myocardial infarction, is 0.046 ng/mL,²²  which is close to the assay’s cutoff value for the detection of a CTnI level considered elevated (CTnI-positive). The sensitivity of different methods of measurement vary.^11,12  In several studies,²⁵  the functional sensitivity of other assays with a similar coefficient of variation (≤20%) was 0.03 ng/mL. However, the cross-reactivity of the Access AccuTnI Reagent with cardiac troponins C and T subunits, creatine kinase MB, actin, myosin, tropomyosin, and myoglobin is 0.001% or less,²⁶  and as a result the assay is highly specific for CTnI. The detectable range of the assay is 0.01 to 100 ng/mL.²⁶  The lowest median detection limit of the immunoassay reported is 0.004 ng/mL.²⁶  The third universal definition of myocardial infarction defines an increased concentration of cardiac troponins as a value exceeding the 99th percentile of the concentration of a normal reference population consisting of apparently healthy volunteers free from heart disease.²⁷  Apple²⁸  recommends that the concentration of cardiac troponin to be considered indicative of myocardial infarction be based on a level that must be measured with an imprecision less than or equal to a 10% coefficient of variation.

The following data were collected for each patient within 24 hours of admission to the ICU or CCU: demographic information (eg, age); where they were admitted from; admitting diagnosis; medical history for specific diseases (eg coronary artery disease); current smoking status; presence of an implantable cardioverter defibrillator; peak CTnI and creatine kinase MB levels; serum levels of sodium, potassium, urea nitrogen, glucose, and creatinine; platelet and white blood cell counts; the need for invasive mechanical ventilation or hemodialysis; presence of sepsis or shock; use of intravenous vasopressors; and prophylaxis status for venous thromboembolism. All laboratory data were obtained at the same time as the CTnI and creatine kinase MB levels. If completed, the initial electrocardiographic findings were also assessed to determine if the patient met the exclusion criteria for ACS. The following data were collected daily until discharge: mortality, ICU length of stay, hospital length of stay, use of intravenous vasopressors, and respiratory status. The primary outcome was hospital mortality due to any cause. Secondary outcomes included ICU and hospital lengths of stay; admitting diagnosis of sepsis, shock, acute renal failure, or acute respiratory failure; use of intravenous vasopressors; incidence of intubation; successful extubation if the patient was intubated; and disposition at discharge.

Continuous variables are reported as median and interquartile range; categorical variables are reported as proportions with matching percentages. For univariate comparison of categorical variables between the CTnI-positive group and the CTnI-negative group, the Fisher exact test was used. The Mann-Whitney test was used for categorical independent variables with continuous dependent variables between both groups, with disposition at discharge analyzed with the multiple regression test in relationship to all baseline continuous variables, including CTnI levels. Spearman rank correlation was used to assess for correlation between continuous variables. The unpaired Kruskal-Wallis test was used for analysis of disposition of patients after discharge from the hospital. All tests were 2-tailed except for the Kruskal-Wallis test. A significance level of .05 was used for all analyses. For relative risk, 95% CIs were calculated. Analyses were performed by using SPSS, version 16.0, software (IBM SPSS).

During the study period, 90 patients qualified for inclusion in the study. Of these, 40 (44%) were in the CTnI-positive group and 50 (56%) in the CTnI-negative group. The median CTnI levels were 0.08 and 0.01 ng/mL, respectively (P < .001; Table 2). Baseline characteristics were similar in both groups except that compared with the CTnI-negative patients, CTnI-positive patients had a higher median white blood cell count (P = .02), were less likely to be admitted from home (P = .009), and were more likely to have underlying COPD (P = .04).

Regardless of baseline characteristics, hospital mortality was significantly higher in the CTnI-positive group than in the CTnI-negative group: 35% vs 12%, respectively; relative risk (RR), 1.35; 95% CI, 1.05–1.73; P=.01 (Table 3). CTnI-positive patients were also more likely than CTnI-negative patients to be intubated anytime during the current admission period: 41% vs 17%, respectively; RR, 1.34; 95% CI, 1.02–1.76; P=.02. The 2 groups did not differ significantly in median length of stay in the ICU or CCU (4 vs 3 days; P=.52), median hospital length of stay (9 vs 8 days; P=.44), admission because of sepsis (38% vs 22%; RR, 1.23; 95% CI, 0.94–1.66; P=.16), shock (40% vs 20%; RR, 1.04; 95% CI, 0.99–1.78; P=.06), or acute renal failure (10% vs 6%; RR, 1.04; 95% CI, 0.92–1.18; P= .48), and the use of intravenous vasopressors (38% vs 18%; RR, 1.31; 95% CI, 0.99–1.72; P= .06). Among the patients who survived until hospital discharge, CTnI-negative patients (46%) were more likely than CTnI-positive patients (25%) to be discharged to home directly from the hospital (RR, 0.72; 95% CI, 0.52–0.98; P = .04), although multiple regression analysis indicated no significant difference between CTnI levels and other baseline continuous variables for hospital disposition (R²=0.111; P>.05 for all variables assessed).

ICU or CCU length of stay correlated positively with sepsis (P=.006), shock (P=.005), and use of intravenous vasopressors (P = .001; Table 4). No significant positive correlation was detected between CTnI level and ICU or CCU length of stay (ρ= 0.156; P = .14). No significant difference was detected for other clinical variables for length of stay in the ICU or CCU. In addition, no statistical significant difference was detected between any clinical variables and overall hospital length of stay (Table 5).

In our study, elevated serum levels of CTnI were associated with higher hospital mortality among non-ACS critically ill patients. This finding agrees with the results of other studies.^21,22,29  Of the 90 patients included in our study, 44% had an abnormal CTnI levels similar to levels reported by Lim et al.²⁹  The exact pathophysiological mechanism of CTnI elevation among non-ACS critically ill patients remains unclear. Potential mechanisms^9,30–36  include underlying coronary artery disease; small-vessel thrombosis due to low levels of activated protein C, leading to myocardial necrosis and depressed left ventricular ejection fraction; tachycardia and hypotension associated with septic shock; and use of intravenous vasopressors. The prevalence of underlying coronary artery disease and other chronic preexisting conditions did not differ between the 2 groups, although significantly more patients in the CTnI-positive group had a history of COPD. COPD often results in poor systemic and myocardial oxygenation, which may result in cardiac-demand ischemia and ultimately decrease functionality of CTnI.⁸  Using a combination of coronary angiography, dobuta-mine stress echocardiography, and autopsy studies, Ammann et al³⁷  detected no flow-limiting coronary artery disease or small-vessel thrombosis in 72% of critically ill non-ACS patients with sepsis and CTnI elevation. Therefore, the theoretical mechanisms for CTnI elevation are not supported by our findings or by the results of Ammann et al.

Use of intravenous vasopressors has been associated with elevated CTnI levels³²  and may reflect low levels of irreversible or reversible myocardial ischemia associated with dopamine and intravenous norepinephrine.³⁸  However, in our study, the 2 groups of patients did not differ in the use of vasopressors despite a positive correlation between vasopressor use and ICU length of stay (ρ=0.331; P=.001). In critically ill patients without ACS, possible alternative causes for elevation in CTnI include sepsis, acute renal failure, and acute respiratory failure, and, as mentioned earlier, these conditions are significant independent predictors of in-hospital mortality among hospitalized nursing home residents.⁵  However, we found no significant difference for these variables between the 2 groups of patients in our study.

Other causes for CTnI elevation in non-ACS patients relevant to an ICU include COPD and asthma exacerbations, renal failure, heart failure, and presence of an implantable cardioverter defibrillator.³⁹  We found no significant difference between our 2 groups for any of these causes except underlying COPD, which was more prevalent in the CTnI-positive group (P=.04), although the need for intubation among COPD patients and successful extubation were similar between both groups (Table 2). Pulmonary embolism is also known to cause CTnI elevation, although this embolism is difficult to diagnose because of its nonspecific signs and symptoms and the lack of sensitivity, specificity, or both among the diagnostic tests currently available.⁴⁰  For instance, although the D-dimer test is highly sensitive and the results are helpful in the diagnosis of both deep vein thrombosis and pulmonary embolism, the test lacks specificity because D-dimer levels may be elevated as a result of any situation that involved fibrin formation and degradation, such as recent surgery or trauma and inflammatory conditions.⁴⁰  We used computed tomo graphy pulmonary angiography to screen 7 patients in the CTnI-positive group and 13 in the CTnI-negative group for pulmonary embolism; we found only 1 confirmed case, in the CTnI-positive group. Although our 2 groups of patients did not differ in the use of pharmacological prophylactic agents, mechanical prophylactic devices (eg, sequential compression device), and no prophylaxis for venous thromboembolism, pulmonary embolism may occur with any of the 3 methods, even when both pharmacological and mechanical prophylaxis are used simultaneously.⁴¹ 

As mentioned, CTnI is elevated if any mechanical or inflammatory stress is exerted on the myocardium.^8,9  In pulmonary embolism, oxygen delivery to the myocardium is decreased, and left ventricular volume decreases as a result of right ventricular distention; the decrease in left ventricular volume leads to a decrease in stroke volume.⁴²  The reduction of both oxygenation and ventricular volume result in an increase in heart rate, a type of mechanical stress, as a physiological reflex in an attempt to increase stroke volume.⁴³  Without adequate oxygenation, the increase in heart rate ultimately leads to dyspnea and demand ischemia of the myocardium, resulting in partial loss of CTnI functionality, which ultimately leads to detectable serum levels of CTnI.^8,9  Both dyspnea and tachycardia are common indications of pulmonary embolism and the need for supplemental oxygen.⁴²  Therefore, silent pulmonary embolism remains a possible cause for the increased need for intubation and mortality in the patients in our study.

Scoring systems for severity of illness, such as the APACHE II, the Simplified Acute Physiology Score (SAPS II), and the Mortality Probability Model (MPM II) may be used to predict the probability of mortality and to assess objectively the quality of care provided by an ICU.^6,7  However, use of these systems has several limitations. Unlike the APACHE II and the MPM II, the SAPS II was derived from studies of European, not North American, patients; consequently, it may not be appropriate to apply this predictor model in the United States.^6,7  When severity-of-illness scores were calculated by using each of these systems, the input data were the most abnormal serum CTnI levels obtained within the initial 24 hours after an admission to the ICU,⁶  with the exception of the MPM II, in which a value obtained after 24 hours may be incorporated. The physiological status of ICU patients can change dramatically within 24 hours, and consequently, the most abnormal value may be difficult to determine. The Glasgow Coma Scale is a component of the APACHE II, SAPS II, and MPM II scoring systems. The scale is subjective, and consistency between evaluators may be moderate at best.⁴⁴  Therefore, an objective marker such as the CTnI level may help reduce interrater variability. Theoretically, as long as the CTnI assays are identical, levels of the biomarker could be used for assessment of prognosis in critically ill patients in different institutions. However, validation of this possibility would require a multicenter study with a large number of patients.

CTnI levels are often obtained to help rule out ACS, and a CTnI-negative result might lead to a confirmation bias that the patient is not at high risk for morbidity and mortality. Although the reason CTnI-positive patients in our study had a higher incidence of in-hospital mortality and intubation and were less likely to be discharged home than were CTnI-negative patients remains unclear, the CTnI level appears to be a useful objective prognostic marker for our patients and will help us educate health care professionals and allocate resources more appropriately.

On the basis of our findings, CTnI-positive patients without ACS may require increased vigilance for signs and symptoms of respiratory distress (eg, respirations < 8/minute or > 20/minute, oxygen saturation < 85% for > 5 minutes via pulse oximetry, initiation of nonrebreathing oxygen mask, shorter response time to bedside call bell); verification of code status; and quick access to the respiratory therapy and anesthesia team, mechanical ventilators, intubation trays, and medications for rapid-sequence intubation.⁴⁵ 

Our study had several limitations. Although each severity-of-illness scoring system has its own limitations, we did not use any of these systems during the study. Hence, all patients were included rather than only the most ill. A power analysis was not performed before the start of the study. As a result, we used nonparametric tests for all analyses. This step may account for the lack of significant differences in ICU or CCU length of stay and hospital length of stay; admitting diagnosis of sepsis, shock, acute renal failure, and acute respiratory failure; and the correlation of CTnI levels with ICU or CCU length of stay. Nevertheless, significant differences in mortality and need for intubation were found in favor of the CTnI-negative group. Another potential limitation was the CTnI stratification into only 2 categories of normal and abnormal. In other studies,^22,29  CTnI levels were stratified into multiple tiers, and the investigators evaluated whether higher levels were associated with poorer clinical prognosis. Limitations of other studies include a lack of specification about the assays used, as mentioned; lack of standardization among the commercially available CTnI assays^11,12 ; conflicting results^22,29 ; and arbitrary stratification between studies.^22,26,29  Because of these limitations, we opted not to categorize our patients into more than 2 groups. Not all patients were screened for pulmonary embolism via computed tomography pulmonary angiography, although this situation may have occurred because pulmonary embolism was not considered a possibility. In addition, screening was avoided to prevent potential harm to patients whose unstable hemodynamic status precludes transfer out of the ICU or CCU to undergo such a test. Autopsy reports for confirmation of the presence of pulmonary embolism were not collected for any patient.

Elevation of CTnI within 24 hours of an ICU admission has prognostic value for hospital mortality and incidence of intubation in non-ACS critically ill patients. Further studies are needed to determine whether this finding will be applicable in other clinical settings.

This research was done at Kingsbrook Jewish Medical Center. The study was approved by the appropriate institutional review board in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments.