Troponin Measurement in the Critically Ill: Potential to Reduce Mortality
Our cardiology consult service is frequently asked to evaluate critically ill patients found to have an elevated cardiac troponin (cTn). What the concerned primary team wants to know is this: Does my patient require urgent revascularization for presumed coronary arterial plaque rupture?
Myocardial injury identified by elevated serum cTn but not caused by plaque rupture is termed Type II myocardial infarction (MI).1 The mechanism of cTn release in the critically ill is not known but is thought to be related to myocardial oxygen supply/demand mismatch and is commonly observed in the intensive care unit (ICU). Existing literature provides little guidance on how to manage patients with Type II MI. This is in contrast to Type I MI, which has well-developed management strategies. Type I MI is primarily caused by coronary arterial plaque rupture and is associated with symptoms due to angina and/or electrocardiographic changes. Type I MI is potentially fatal in the absence of appropriate treatment, which includes urgent revascularization, beta-blockers, aspirin, and statins, where appropriate.2,3
Critically ill patients with Type II MI often do not demonstrate signs and symptoms of acute coronary syndrome (ACS), which may be absent or masked by sedation or the underlying illness. If coronary angiography is considered, comorbidities such as hypotension, renal failure, or sepsis often tilt the risk/benefit ratio toward risk. Limited data have shown that plaque rupture is uncommon in this group,4 causing us to question the utility of urgent angiography in the majority of such patients.
Despite the absence of clinical ACS, patients with cTn elevation may have a mortality risk two- to fourfold higher than comparably ill patients with no cTn elevation.5,6 Beta-blockers, statins, and aspirin are often prescribed on the assumption that silent coronary disease has caused ischemic imbalance despite the fact that, until recently, no studies have shown any benefit with this approach.
To address this question, our group performed a retrospective investigation of nearly 20,000 ICU patients using the Veterans Administration Inpatient Evaluation Center, a quality management database designed to measure risk-adjusted mortality in inpatient care. Our aim was to determine whether beta-blockers, aspirin, and statins were associated with 30-day mortality reduction.7 In a mixed population of medical and surgical ICU patients without ACS, we found that 1) cTn was an independent predictor of 30-day mortality after adjusting for multiple variables and 2) beta-blocker, aspirin, and statin use was associated with 30-day mortality reductions in a cTn-dependent manner. Statins given within 24 hours of cTn measurement in patients with no or intermediate elevations of cTn had lower mortality than patients not taking statins (odds ratio [OR] 0.66; 95% confidence interval [CI], 0.53-0.82; p < 0.001); beta-blockers were not beneficial. In contrast, patients with high cTn had lower mortality if they had taken beta-blockers or aspirin within 24 hours of cTn measurement compared with patients not taking beta-blockers (OR 0.80; 95% CI, 0.68-0.94; p = 0.0077) or aspirin (OR 0.81; 95% CI, 0.69-0.96; p = 0.013); statins were not beneficial. This was observed when patients with prior cardiac diagnoses were included or excluded. This suggests that early cTn measurement may guide medical management of critically ill patients without ACS.
The following commentary discusses the limitations of our study and gaps in knowledge that must be addressed. We discuss cTn as a biomarker of severity of illness, the patient population involved, and medication delivery.
Severity of Illness
After adjusting for multiple variables, we found that cTn was an independent predictor of mortality, which aligns with a significant body of existing literature in which cTn levels positively correlate with severity of illness and mortality.5,8-10 Our study included a large sample size and excluded patients with a prior diagnosis of coronary artery disease for whom beta-blockers, statins, and aspirin would provide mortality benefit; we believe this provides a more accurate reflection of the significance of cTn elevation in non-cardiac critically ill patients. We hypothesize from this that cTn levels may be a harbinger of multi-organ failure and may be a tool to use in conjunction with severity of illness scoring to identify patients at increased risk. There are several caveats.
First, we are proposing to use cTn measurements in a linear scale to predict risk of mortality and benefit of medical intervention. This is a very different concept from the current use of cTn in the diagnosis of acute MI due to plaque rupture. The prevalence of elevated cTn in critically ill sepsis patients alone may be as high as 61%.5 If cTn were routinely measured in all critically ill patients, a method to determine which, if any, patients would benefit from urgent revascularization would be needed. Given the high prevalence of cTn in the critically ill population, this could dramatically change the practice of critical care medicine.
Second, in our investigation alone there were 12 different assays used to measure cTnI, each with different sensitivity and cut-off values for the diagnosis of acute MI. To allow comparison across all Veterans Administration ICUs, we "binned" results across institutions into one of three categories based on the assay used:
- "No cTn" (less than the lower limit of detectability)
- "Intermediate cTn" (between less than the lower limit of detectability and the 10% coefficient of variation)
- "High cTn" (above the 10% coefficient of variation)
In this way, we attempted to normalize cTnI values across institutions. If a "cutoff value" (above which beta-blockers and aspirin have benefit but below which statins reduce mortality) is found, it would be advantageous if a standardization process could be developed for cTnI measurements.
If cTn level does correlate with effectiveness of the proposed therapies, then different mechanisms of death may be present. In milder cases of systemic illness in which cTn would be expected to be low or absent, the purported immunomodulatory effect of statins may be of greatest benefit. In more severe systemic illness, statin benefit may be lost or outweighed by the treatment effect of beta-blockers and aspirin, which could limit the negative impact of catecholamines and prevent end organ damage from microvascular obstruction.
In our retrospective investigation, we did not have access to individual records and therefore may not have excluded all patients with Type I MI in whom angiography or beta-blockers, aspirin, and statins may have provided benefit. Furthermore, a large population of ICU patients did not have cTn measured; therefore, our results cannot be extrapolated to all ICU patients. However, the severity of illness of patients who did not have cTn measured was lower than patients who underwent cTn testing. If this lower-risk group were included in our study, it may have further defined the population who may benefit from statin use.
Finally, our population included all ICU patients with a variety of diagnoses, from sepsis to post-operative patients. It is likely that mechanisms of myocardial injury for a patient with sepsis are different from a patient recovering from surgery. However, critical illness is characterized by heightened sympathetic tone, which may contribute to increased platelet aggregation and microvascular obstruction as an etiology for multi-organ failure. This certainly requires further investigation.
We utilized Barcode Medication Administration files to identify patients who had been given beta-blocker, aspirin, or statin within 24 hours of cTn measurement. We were therefore unable to discriminate between pretreatment with these medications and in-hospital initiation. We did not assess if later administration, either during the admission or at the time of discharge, would have offered benefit. We did not evaluate the effect of different dosages, non-aspirin antiplatelet agents, different classes of beta-blockers or statins, heparin use, angiotensin-converting enzyme inhibitors, or other drug-drug interactions. We also did not perform propensity matching, which would adjust for prescription bias. These are potentially important questions that a well-designed prospective randomized investigation would take into consideration.
Our study has generated a number of questions regarding appropriate management of high-risk critically ill patients with cTn elevation. What we know for certain is that any future investigation of interventions to ameliorate mortality in this high-risk group must report severity of illness as well as all medications administered. It will be important to consider standardization of cTn values across institutions; generalizability of our result according to admission diagnosis; careful exclusion of patients with plaque rupture; and confirmation that beta-blockers, aspirin, and statins are outcome modifiers in the critically ill patient in a way that reflects the severity of illness. Certainly, there is much work to be done to determine if the results of our retrospective analysis could translate into real prospective mortality reductions in this high-risk group.
- Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012;60:1581-98.
- American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions, O'Gara PT, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78-140.
- Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;64:e139-228.
- Baron T, Hambraeus K, Sundström J, et al. Type 2 myocardial infarction in clinical practice. Heart 2015;101:101-6.
- Bessière F, Khenifer S, Dubourg J, Durieu I, Lega JC. Prognostic value of troponins in sepsis: a meta-analysis. Intensive Care Med 2013;39:1181-9.
- Lim W, Cook DJ, Griffith LE, Crowther MA, Devereaux PJ. Elevated cardiac troponin levels in critically ill patients: prevalence, incidence, and outcomes. Am J Crit Care 2006;15:280-8.
- Poe S, Vandivier-Pletsch RH, Clay M, Wong HR, Haynes E, Rothenberg FG. Cardiac Troponin Measurement in the Critically Ill: Potential for Guiding Clinical Management. J Investig Med 2015;63:905-15.
- Røsjø H, Varpula M, Hagve TA, et al. Circulating high sensitivity troponin T in severe sepsis and septic shock: distribution, associated factors, and relation to outcome. Intensive Care Med 2011;37:77-85.
- Reynolds T, Cecconi M, Collinson P, Rhodes A, Grounds RM, Hamilton MA. Raised serum cardiac troponin I concentrations predict hospital mortality in intensive care unit patients. Br J Anaesth 2012;109:219-24.
- Vasile VC, Chai HS, Abdeldayem D, Afessa B, Jaffe AS. Elevated cardiac troponin T levels in critically ill patients with sepsis. Am J Med 2013;126:1114-21.
Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers, Anticoagulation Management and ACS, Nonstatins, Novel Agents, Statins, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Nuclear Imaging
Keywords: Acute Coronary Syndrome, Adrenergic beta-Antagonists, Angina Pectoris, Angiotensin-Converting Enzyme Inhibitors, Aspirin, Biomarkers, Catecholamines, Comorbidity, Coronary Angiography, Coronary Artery Disease, Critical Illness, Drug Interactions, Heparin, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypotension, Intensive Care Units, Myocardial Infarction, Platelet Aggregation, Platelet Aggregation Inhibitors, Prospective Studies, Renal Insufficiency, Retrospective Studies, Sepsis, Troponin
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