The Explained Variance and Discriminant Accuracy of APACHE IVa Severity Scoring in Specific Subgroups of ICU Patients

Robert A Raschke MD^1,2

Richard D Gerkin MD¹

Kenneth S Ramos MD^1,2

Michael Fallon MD²

Steven C Curry MD^1,2

Division of Clinical Data Analytics and Decision Support and the Department of Medicine

University of Arizona College of Medicine-Phoenix.

Phoenix, AZ USA

(Click here for accompanying editorial)

Abstract

Objective: The Acute Physiology and Chronic Health Evaluation (APACHE) is a severity scoring system used to predict healthcare outcomes and make inferences regarding quality of care. APACHE was designed and validated for use in general ICU populations, but its performance in specific subgroups of ICU patients is unproven. Quantitative performance referents for severity scoring systems like APACHE have not been established. This study compares the performance of APACHE IVa in several common subgroups of ICU patients to the performance of APACHE IVa and a referent scoring system applied in a general ICU population.

Design: Observational cohort.

Setting: Seventeen ICUs.

Patients: Adult patients meeting criteria for APACHE IVa scoring.

Intervention: We designed a “two-variable severity score” (2VSS) to provide “weak” reference values for explained variance (R²) and discriminant accuracy to use in our comparisons. R² and AUROC were calculated for 2VSS and APACHE IVa outcome predictions in the overall cohort, and for APACHE IVa in subgroups with sepsis, acute myocardial infarction, coronary artery bypass grafting, stroke, gastrointestinal bleeding, trauma, or requiring mechanical ventilation. APACHE IVa subgroup performance was compared to APACHE VIa and 2VSS performance in the overall cohort.  

Measurements and Main Results: APACHE IVa out-performed 2VSS in our cohort of 66,821 ICU patients (R²: 0.16 vs 0.09; AUROC: 0.89 vs 0.77). However, APACHE IVa performance was significantly diminished in subgroups with sepsis, coronary artery bypass grafting, gastrointestinal bleeding or requiring mechanical ventilation compared to its performance in the overall cohort analysis. APACHE IVa performance in patients undergoing CABG (R²: 0.03, AUROC: 0.74) failed to surpass 2VSS performance referents.

Conclusions:  The performance of severity scoring systems like APACHE might be insufficient to provide valid inferences regarding quality of care in select patient subgroups. Our analysis of 2VSS provides quantitative referents that could be useful in defining acceptable performance.

Introduction

The Acute Physiology and Chronic Health Evaluation (APACHE) has undergone iterative refinement over the past 40 years and is currently the most widely used severity scoring system in the United States (1-3). APACHE provides a score based on the patient’s age, vital signs and laboratory values on the first ICU day and chronic health conditions. This score is used in combination with the patient’s admission diagnosis and other information to calculate predicted hospital and ICU mortality and length-of-stay (LOS), and days of mechanical ventilation. Ratios derived from these calculations, such as the standardized mortality ratio (observed/predicted mortality) and observed/predicted LOS are used by the Centers for Medicare and Medicaid Services, managed care plans, health insurance plans and consumers to benchmark and compare the quality of care provided by physicians, hospitals and healthcare systems. APACHE was updated and revalidated using large clinical databases in 2001-2003, yielding APACHE version IV (1,2) and in 2006-2008, yielding APACHE version IVa (4). 

The use of severity scoring systems such as APACHE to make inferences regarding quality of care is susceptible to bias if the regression models employed do not adequately characterize severity of illness. This is a particular liability when applied to a different population of patients than those for whom the system was originally developed and validated (3,5). This is likely because the optimal set of predictor variables in a severity scoring system is specific to the patient population of interest. The optimal predictor variables for patients with pneumococcal pneumonia might include factors such as prior pneumococcal exposure history, the specific competency of the patient’s immune response against pneumococcus, ciliary function of the lower respiratory tract, current cardiopulmonary capacity, and bacterial virulence factors.  The optimal set of specific predictor variables in patients with stroke or trauma are likely quite different. APACHE uses a set of predictor variables empirically found to be predictive in heterogeneous populations of general ICU patients, but these may not necessarily provide acceptable severity-adjustment for specific subpopulations of ICU patients.

The performance of severity scoring systems is typically assessed using statistical tests that include Pearson’s R-squared (R²) - which describes the “explained variance” of the system for prediction of continuous outcomes like LOS, and the area under the receiver operating curve (AUROC) - which describes the “discriminant accuracy” of the system for prediction of discrete outcomes such as mortality. APACHE IV has yielded an R² of 0.21 for LOS prediction, and AUROC of 0.88 for mortality prediction in a cohort of 131,000 general ICU patients (1,2). However, R² as low as 0.03 and AUROC as low as 0.67 have been reported for APACHE IV outcome predictions in different reference populations, such as those with surgical sepsis (6,7). The performance of the current version, APACHE IVa, is unpublished for many important subgroups of ICU patients.

It has been proposed that AUROC results in the range of 0.70-0.80 indicate “good” discriminant accuracy, and values in the range of 0.80-0.90 are taken to be “very good” or “excellent” (3,8,9), but these subjective ratings have no clear mathematical justification. AUROCs as high as 0.80 have been achieved by scoring systems that utilized only 1-3 predictor variables (10-14). It does not seem plausible that so few variables could acceptably characterize the complex nature of severity-of-illness. R² and AUROC do not have established and well-justified performance thresholds and are therefore of limited value in determining whether a severity scoring system provides valid inferences regarding quality of care.  

Therefore, we first set out to quantify performance thresholds for R² and AUROC by designing a severity score which only incorporated two predictor variables, to intentionally limit the explained variance and discriminant accuracy of the system. This method was previously recommended by the RAND Corporation for assessing severity scoring systems like APACHE because it provides a population-specific referent of unacceptable performance to which the system of interest can be compared (10). We subsequently compared the statistical performance of our two-variable severity score (2VSS) to that of APACHE IVa (which incorporates 142 variables) in a large cohort of ICU patients, and in several common subgroups. Our hypothesis was that APACHE IVa would have diminished and possibly unacceptable explained variance and discriminant accuracy in certain specific subgroups.

Methods

Our Institutional Review Board provided exemption from human research requiring informed consent. Consecutive patients >16 years of age admitted to any ICU in 17 Banner Health acute care hospitals between January 1, 2015 and September 31, 2017 were eligible for inclusion in our cohort of ICU patients. The hospitals ranged from a 44-bed critical access facility to a 708-bed urban teaching hospital in the southwestern United States. The ICUs included general medical-surgical units, as well as specialty-specific cardiovascular, coronary, neurological, transplant and surgical-trauma ICUs. Only the first admission for each patient was included. Patients were excluded if they were admitted as a transfer from another hospital ICU, their ICU LOS was < four hours, or records were missing data required to calculate predicted outcomes using APACHE IVa methodology.

Data used to calculate the acute physiology score (APS) were collected by direct electronic interface between the Cerner Millennium^® electronic medical record and Philips Healthcare Analytics. The worst physiological values occurring during the first ICU day were extracted electronically for Acute Physiology Score (APS) calculation using commercial software provided by the Phillips eICU^® program. Chronic health conditions required for APACHE score calculations and admission information needed for calculation of expected mortality (including admission diagnosis) were entered by nurses who staff our critical care telemedicine service. Observed and predicted ICU and hospital LOS, ventilator days, and ICU and hospital mortality were provided by Philips Healthcare using proprietary APACHE IVa methodology (Cerner Corp. Kansas City, MO).

The 2VSS incorporated only the patient’s age and requirement for mechanical ventilation (yes/no) and used multiple linear regression for prediction of LOS and ventilator days, and multiple logistic regression for prediction of mortality. In contrast, APACHE IVa incorporates 142 variables (27 in the APACHE score, plus 115 admission diagnostic categories) and uses disease-specific regression models serially revised and revalidated in large patient populations (1-3). The two variables incorporated in our 2VSS have been shown to contribute only 10% of the discriminant accuracy of APACHE IV for predicting ICU mortality (1). Therefore, we posited that the best observed AUROC and R² achieved by 2VSS in our cohort analysis could reasonably determine referents of unacceptable performance for comparison with APACHE IVa performance in the analysis of our cohort and in specific subgroups.

Cohort analysis: We used APACHE IVa and the 2VSS to predict five outcomes in our cohort of ICU patients: ICU and hospital LOS, ventilator days, and ICU and hospital mortality. R² was calculated for LOS and ventilator days, and AUROC for mortality outcomes. APACHE IVa results were compared to those of 2VSS. Differences between AUROC results were determined to be statistically significant by comparison of 95% confidence intervals calculated using a nonparametric method based on the Mann-Whitney U-statistic. The highest R² and AUROC achieved by 2VSS in the ICU cohort were used to establish referents of unacceptable performance in all subsequent comparisons.

Subgroup analyses: R² and AUROC were then calculated for APACHE IVa outcome prediction in seven subgroups of ICU patients, including those with admission diagnoses of sepsis, acute myocardial infarction, coronary artery bypass grafting (CABG - with or without other associated cardiac procedures such as valve replacement), stroke, gastrointestinal bleeding, trauma, or requirement of mechanical ventilation. The performance of APACHE IVa in each subgroup was compared to the performance of APACHE IVa and 2VSS in the cohort analysis.

Results

71,094 patients were admitted to study ICUs during the study period. Of these, 2,545 were excluded due to ICU LOS < four hours, 1,379 due to missing data required to calculate APACHE IVa predicted outcomes, and 349 due to transfer from another ICU. The remaining 66,821 patients were included in the analysis. The mean age was 65.7 years (SD 16.3). The most common ICU admission diagnoses were: infections 21.0% (16.8 % due to sepsis); cardiac 14.8% (4.6% due to acute myocardial infarction); cardiothoracic surgery 8.8% (3.8% due to CABG); neurological 8.7% (4.1% due to stroke); pulmonary 7.3%; vascular 5.8%; trauma 5.7%; and gastrointestinal 4.8% (4.0% due to GI bleeds), metabolic/endocrine 4.6%; toxicological 4.5%; cancer 3.8%; and general surgery 3.2%.

Table 1 compares the explained variance (R²) and discriminant accuracy (AUROC) of APACHE IVa and 2VSS outcome predictions in the ICU cohort.

Table 1. Comparison of APACHE IVa to a 2-variable severity score (2VSS) for outcome prediction in a cohort of 66,821 ICU patients. 

Bold font represents the best performance achieved by the 2VSS by R2 and AUROC.

The highest R² achieved by 2VSS was for ICU LOS (R² = 0.09) and the highest AUROC for ICU mortality (AUROC = 0.77).

Subgroup results for APACHE IVa are shown in Table 2.

Table 2. Performance of APACHE IVa outcome prediction in selected subgroups in descending order of discriminant accuracy for ICU mortality. (Click here for enlarged Table 2)

Bold font indicates performance statistically no better than the best performance of 2VSS in the ICU cohort.

*Indicates statistically significantly-reduced performance compared to APACHE IVa in the inclusive ICU cohort (non-overlapping 95% confidence intervals).

Abbreviations: Vent = patients requiring mechanical ventilation; AMI = acute myocardial infarction; GI = gastrointestinal, CABG = coronary artery bypass grafting.

AUROC for APACHE IVa mortality predictions (hospital and ICU mortality) ranged from 0.74-0.90 and were statistically-significantly diminished in subgroups of patients with sepsis, GI bleeds, CABG or mechanical ventilation compared to APACHE IVa performance in the cohort analysis. R² for APACHE IVa prediction of ventilator days was less than 0.09 (the performance referent established by 2VSS) in subgroups of patients with trauma, stroke, acute myocardial infarction, sepsis, GI bleeds and CABG. APACHE IVa predictions of ICU LOS, ventilator days, ICU mortality and hospital mortality for patients who underwent CABG yielded: R² 0.03, R² 0.02, AUROC 0.74 and AUROC 0.75, respectively – all failing to exceed the performance referents established by our cohort analysis by 2VSS.

Discussion

Our study employed empirically-derived, quantitative referents of unacceptable severity-adjustment performance: R² < 0.09 and AUROC < 0.77. APACHE IVa significantly surpassed these referents in all comparisons made in the analysis of our inclusive cohort of ICU patients. R² values for APACHE IVa indicate that it explains about 15- 25% of the variance in hospital and ICU LOS and about 10% of the variance in ventilator days and that it provides discriminant accuracy >0.85 for mortality prediction in this general ICU population. These findings are consistent with previous reports of APACHE IV performance in other large cohorts of ICU patients (1,2,4,15).

However, APACHE IVa performance was significantly diminished in specific subgroups of ICU patients – notably those with sepsis, GI bleeding, requiring mechanical ventilation and undergoing CABG. Values for R² for the prediction of ventilator days in several subgroups were as low as 0.02 – explaining only 2% of the observed variance in ventilator days. Hospital mortality prediction for patients with sepsis yielded an AUROC 0.79 – barely superior to the referent AUROC of 0.77 achieved by 2VSS, and arguably only because of our large sample size. APACHE IVa prediction of ICU LOS, vent days, ICU mortality and hospital mortality in patients undergoing CABG all failed to exceed the performance referents set by 2VSS. 

Few published studies are available to provide meaningful comparisons with the subgroup results from our study. Most describe smaller patient populations outside the U.S. (6,16,17,18). Previous use of APACHE IV to predict outcomes in patients with sepsis reported AUROCs ranging from 0.67 to 0.94 (6,16,19). APACHE IV uses a specific logistic modeling technique and has been specifically validated for CABG patients, but CABG-specific R² and AUROC were not reported (20). No previous study compared APACHE IVa performance in subgroups with that in a general population of ICU patients using quantitative performance referents.

Our findings are important because although general severity scoring systems like APACHE IVa are not optimized for use in specific ICU patient subgroups, they are often used in this manner to make implications regarding quality of care (6,16-19,21-26). In addition to the subgroups discussed above, previous studies have employed general severity scoring system to predict outcomes in subgroups of patients with acute coronary syndrome (17), acute kidney failure (21), malignancy (22), organ transplantation (23), ECMO (24), cardiac surgery (25) and survivors of cardiac arrest (4,26). Many of these studies report AUROCs inferior to our 2VSS referent (6,19,20,23-26). Diagnosis-specific scoring systems, such as the Cardiac Surgery Score (CASUS), generally have provided superior discriminant accuracy in the specific subsets of patients they were designed to serve (27-29).

We believe that general severity scoring systems like APACHE IVa are at an inherent disadvantage in the prediction of outcomes in specific subgroups of ICU patients, because they employ general predictor variables empirically-chosen to work best in heterogeneous patient populations. The APACHE score for example comprises 27 parameters, including vital signs, laboratory values, and specific chronic health items, with a few additional clinical variables added for patients undergoing CABG. As the field of precision medicine has emerged, a rapidly-growing literature describes the use of highly-specific biomarkers, proteomic assays, genomic microarrays and whole-genome sequencing in disease-specific outcome predictions (30-38).  As the science of precision medicine advances, it’s likely that we will develop more precise methods of outcome prediction for specific subgroups of patients that are likely to surpass the performance of general severity scoring systems based only on clinical variables and routine laboratory tests. 

Our study illustrates some features of the explained variance and discriminant accuracy of current severity scoring systems. Our finding that R² does not generally exceed 0.25 is consistent with the findings of other investigators in regards to other well-validated severity scoring systems (2,11,39). This indicates that less than 25% of the between-patient variability in ICU or hospital LOS is explained by current scoring systems. There are two possible explanations for this finding. Either current severity scores are not well-designed to predict LOS, or LOS is inherently not very dependent on severity-of-illness. Our findings imply that ratios of observed/predicted LOS, or observed/predicted ventilator days calculated using current severity scoring systems, may be vulnerable to significant residual bias.  

The differences in the discriminant accuracy achieved by 2VSS and APACHE IVa were surprisingly narrow (e.g., AUROC 0.77 vs. 0.89 for ICU mortality), suggesting that the relationship between AUROC and system complexity is non-linear. We recently performed a Monte Carlo simulation that showed that AUROC increases quadratically in diminishing increments as explanatory power is added to a mortality prediction model, and that the model can achieve an AUROC of 0.85 when only half of important predictor variables have been incorporated (40). This suggests that even the best current severity scoring systems, achieving AUROCs near 0.85, may leave many important aspects of severity-of-illness unaccounted for.

Based on our study results and review of the literature, we suggest that an AUROC ≤ 0.80 represents unacceptable discriminant accuracy in relation to severity scoring systems. This proposition is more conservative than previously-described subjective rating scales (3,8,9), but consistent with published examples of severity scoring systems that are inherently unlikely to yield acceptable discriminant accuracy. Systems incorporating only 1-3 variables have achieved AUROCs of 0.70-0.80, including one intentionally-designed to perform poorly (AUROC 0.70) (10), and others based only on: categorical self-assessment of health (i.e. as poor, good, excellent) (AUROC 0.74) (12), age (AUROC 0.76) (13) or hypotension, tachypnea and altered mentation (AUROC 0.80) (14). Furthermore, a model based only on administrative variables yielded an AUROC 0.81 (41) despite the inaccuracies inherent in such data (42).

Our proposed performance threshold for AUROC implies that organ failure scores, such as the sequential organ failure assessment (SOFA) and the multiple organ dysfunction score (MODS), generally fail to provide acceptable discriminant accuracy (43,44) to mitigate bias in outcome comparisons used to make inferences regarding quality of care.  Outdated versions of severity scoring systems, such as the mortality probability model (MPM) and APACHE II, may achieve discriminant accuracy in the marginal range, with AUROCs of 0.80-0.84 (3,14,45). Well-designed contemporary severity scoring systems, such as APACHE IV, MPM-III, the simplified acute physiology score (SAPS-3), the Veterans Affairs intensive care unit risk adjustment model (1,3,5,9,15,46,47) and several newer machine-learning models (48,49) generally achieve AUROCs ranging from 0.84-0.89 when applied to general patient populations for which they were designed and validated.

Conclusions

Our study suggests that the explained variance and discriminant accuracy of general severity adjustment scoring systems like APACHE might be significantly reduced when they are used to predict outcomes in specific subgroups of ICU patients, and therefore caution should be exercised in making inferences regarding quality of care based on these predictions. Further studies are needed to establish absolute performance criteria for severity scoring systems.

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Acknowledgements

We would like to acknowledge the work of Maria Calleja and Banner Health Clinical Performance Analytics in providing the data used in our analysis.

Author’s contributions

Conception and design: RAR, RDG, KSR, MF, SCC

Data collection: RAR

Statistical analysis: RDG, RAR

Interpretation: RAR, RDG, KSR, MF, SCC

Writing the manuscript: RAR, RDG, KSR, MF, SCC

Guarantor taking full responsibility for integrity of the study: RAR

The authors have no conflicts of interest to report and there was no direct funding for this project.

Abbreviation List

• 2VSS: two-variable scoring system
• APACHE: Acute Physiology and Chronic Health Evaluation
• APS: acute physiology score
• AMI: acute myocardial infarction
• AUROC: area under the receiver operating curve
• CABG: coronary artery bypass grafting
• CASUS: cardiac surgery score
• GI: gastrointestinal
• ICU: intensive care unit
• LOS: length of stay
• MODS: multiple organ dysfunction score
• MPM: mortality probability model
• RAND (corporation): research and development
• R²: Pearson’s coefficient of determination
• SAPS: simplified acute physiology score
• SOFA: sequential organ failure assessment

Cite as: Raschke RA, Gerkin RD, Ramos KS, Fallon M, Curry SC. The explained variance and discriminant accuracy of APACHE IVa severity scoring in specific subgroups of ICU patients. Southwest J Pulm Crit Care. 2018;17:153-64. doi: https://doi.org/10.13175/swjpcc108-18 PDF

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Bryan White, MD¹

George Broderick, MD¹

¹Cardiology Division, Department of Internal Medicine, Wright State University Boonshoft School of Medicine, Dayton, Ohio.

²Cardiology Division, Department of Internal Medicine, University of Nevada School of Medicine, Las Vegas, Nevada.

³Department of Cardiovascular Medicine, University of Toledo Health Science Campus, Toledo, Ohio.

⁴Department of Cardiology, Ochnser Heart and Vascular Institute, New Orleans, Louisiana.

Abstract

Background: In acute coronary syndrome, elevated troponins are associated with worse clinical outcomes. We examined the relationship between the level of troponin elevation and the presence of a flow-limiting lesion for patients with no history of coronary disease admitted with NSTE-ACS.

Methods: From January of 2010 until April of 2013, 561 patients received coronary angiography for new-onset NSTE-ACS. The Mann-Whitney Test, chi-square test, and Spearman correlation were used to examine relationships. Inferences were made at the 0.05 level of significance. The independent samples t test and the chi square test were used to identify predictors of LV systolic dysfunction- LVSD.

Results: The 430 patients with a flow-limiting coronary lesions had a higher troponin I level than the 131 patients without obstructive coronary disease (5.69 ng/ml vs. 2.85 ng/ml, p=0.002). Further, within troponin categories, those in the greater than 5.0 ng/ml group were more likely to have angiographically significant CAD than those in the less than 0.5 ng/ml group (p=0.012). Elevated troponins were also associated with increased thrombus burden, worse systolic function, higher complexity of the lesions, and worse post intervention TIMI flow. Cardiac troponin >5ng/ml [odds ratio=2.13 (95%CI=1.22 to 3.70) p=0.008] and DM [odds ratio=1.74 (95%CI=1.02 to 2.97) p=0.042] were independent predictors of LVSD. Advanced LM disease and age were marginally significant.

Conclusion: The degree of cardiac troponin I elevation should be incorporated into the risk stratification models of NSTE-ACS to promptly triage high-risk patients to early invasive strategies and tailored anticoagulant therapy to reduce troponin elevation and improve myocardial perfusion.

Background

Cardiac troponin is the main biomarker of myocardial ischemia. In acute coronary syndrome, elevated troponin levels are associated with complex obstructive coronary anatomy and impaired myocardial tissue perfusion. Elevated troponins can identify high-risk patients with non-ST elevation acute coronary syndrome (NSTE-ACS), who may benefit from early invasive management. However, the degree of troponin elevation has not been incorporated in risk stratification models for NSTE-ACS. To triage patients for conservative versus invasive management strategies, we need to define the significance of the magnitude of troponin elevation following NSTE-ACS (1).

NSTE-ACS is the most common form of acute coronary syndrome. Troponin elevation signifies a delayed presentation in ST elevation MI not so for NSTE-ACS. The determination of ischemic injury timing becomes more challenging when NSTE-ACS patient present with variable levels of troponin elevation.

Thus, we examined the relationship between troponin levels and the extent of coronary disease and myocardial dysfunction, as assessed by coronary angiography, in a subset of patients with no history of coronary disease admitted with NSTE-ACS.

Methods

Study design

This is a retrospective study of a cohort admitted to a university-affiliated teaching hospital with highly specialized cardiovascular care over a period of 40 months. The data for this study were obtained from the National Cardiovascular Data Registry (NCDR) database and electronic chart review of study participants.

Serum cardiac troponin levels were measured using a high-sensitivity enzyme-linked immune-absorbent assay kit (VITROS® Troponin I ES Assay, © Ortho Clinical Diagnostics, Johnson & Johnson -Hong Kong- Ltd. 2003-2014). A level greater than 0.033 ng/ml is considered above the reference range and represents a positive test value. The highest troponin I level prior to coronary angiography was used in the analyses.

Selection of study participants

The study investigated the association of cardiac troponin I levels and the presence of a flow-limiting coronary arterial lesion; a flow-limiting lesion was defined as an angiographically significant coronary lesion warranting percutaneous and/or surgical revascularization. The study only included patients with new-onset (de novo) NSTE-ACS. Patients with a history of coronary artery disease, heart failure, and cardiac bypass were excluded.

Study Objectives and Data Analysis

In addition to determining the association between cardiac troponin I levels and the presence of flow-limiting coronary artery disease, the study also examined the relationship between cardiac troponin I levels and various other factors, including vascular anatomy, lesion complexity, success of percutaneous intervention (based on the post-intervention Thrombolysis In Myocardial Infarction - TIMI - study grading system of the coronary blood flow), and incidence of Left Ventricular Systolic Dysfunction (LVSD), defined by an ejection fraction of less than 40% on left ventriculogram, in de-novo NSTE-ACS patients.

Means and standard deviations are reported for continuous variables, and counts and percents for categorical variables. The independent samples Mann-Whitney Test (two groups), Kruskal-Wallis Test (three groups), one-way analysis of variance (ANOVA) with Least Significance Difference post hoc test, chi square test, and Spearman correlation were used to examine relationships. Inferences were made at the 0.05 level of significance with no corrections for multiple comparisons. Multivariable logistic regression was used to determine if troponin is an independent risk factor for LVSD. Analyses were conducted using IBM SPSS Statistics 22.0 (IBM, Armonk, NY).

Results

Baseline characteristics

From January 2010 through April 2013, 561 patients received coronary angiography for new onset NSTE-ACS. Of this total, 485 (86.5%) had left ventricular functional assessment at the time of cardiac catheterization. All patients were managed invasively.

Patients were divided into three groups according to the degree of troponin I elevation (mild <0.5 ng/ml [n = 167], moderate 0.5-5 ng/ml [n = 263], and high >5 ng/ml [n = 131]).  Table 1 shows that age differed among the three groups (p = 0.008): the moderate group was older than the mild group (mean age = 66.3±13.9 vs. 62.2±12.5) but not the high groups (64.1±13.3).  

Table 1. Characteristics of troponin groups.

Abbreviations - GFR: glomerular filtration rate; PCI: percutaneous coronary artery intervention; IABP: intra-aortic balloon pump; UH: unfractionated heparin; LMWH: low molecular weight heparin

^a The moderate group was older than the mild group (mean age = 66.3±13.9 vs. 62.2±12.5) but not the high group (64.1±13.3).

^bPatients were more likely to be Caucasian as troponin categories increased (66.5% for the <0.5 ng/ml group, 78.2% for the 0.5-5 ng/ml group, 81.5% for the >5.0 ng/ml group) and less likely to be African American as troponin categories increased (32.3% for the <0.5 ng/ml group, 21.0% for the 0.5-5 ng/ml group, 17.7% for the >5.0 ng/ml group); p value for chi square test excludes Asians and Hispanics due to low counts.

^cThe moderate and high groups had a higher euroscore than the mild group (mean euroscore = 5.44±3.3 and 5.98±6.1 vs. 4.38±2.8).

^dPatients were more likely to receive unfractionated heparin as troponin categories increased (63.4% for the <0.5 ng/ml group, 69.7% for the 0.5-5 ng/ml group, 84.2% for the >5.0 ng/ml group).

Patients were more likely to be Caucasian as troponin categories increased (66.5% for the <0.5 ng/ml group, 78.2% for the 0.5-5 ng/ml group, 81.5% for the >5.0 ng/ml group) and less likely to be African American as troponin categories increased (32.3% for the <0.5 ng/ml group, 21.0% for the 0.5-5 ng/ml group, 17.7% for the >5.0 ng/ml group).

The moderate and high groups had a higher euro-score than the mild group (mean euro-score = 5.44±3.3 and 5.98±6.1 vs. 4.38±2.8 p = 0.003). Patients were more likely to have been treated with unfractionated heparin as troponin levels increased (63.4% for the <0.5 ng/ml group, 69.7% for the 0.5-5 ng/ml group, 84.2% for the >5.0 ng/ml group (p = 0.01).

Primary outcomes

Patients with flow-limiting coronary lesions (n = 430) had higher mean troponin I levels than patients without obstructive coronary disease (n = 131) [5.69±12.57 ng/ml vs. 2.85±5.76 ng/ml, p = 0.002]. More importantly, the proportion of patients with angiographically significant CAD increased as troponin levels increased (70.7% for the <0.5 ng/ml group, 77.2% for the 0.5-5 ng/ml group, 83.2% for the >5.0 ng/ml group (p = 0.038) (Figure 1).

Figure 1. Troponin groups and the presence of flow-limiting CAD.

Secondary outcomes

Elevated troponin levels were associated with increased thrombus burden (8.34±15.44 ng/ml for patients with intracoronary thrombus vs 5.29±13.11 ng/dl for those without thrombotic lesions, p = 0.001), worse systolic function (6.62+9.77 ng/dl for those with LVEF <40% compared to 4.42+8.70 ng/dl for those with preserved LV function, p=0.003), higher complexity of the lesions (patients with high - type C – lesions, per AHA/ACC classification, had mean troponin level of 8.38±17.71 ng/ml vs 3.44±7.7 ng/ml for those with non-high - type C - lesions, p < 0.001), and worse TIMI flow (patients with TIMI grade 0 flow post-intervention had mean troponin of 49.1±71.99 ng/ml vs 5.16±10.41 ng/ml for those with TIMI grade 3 flow, p = 0.017) post intervention.

Patients with LVSD were more likely to be older, have diabetes (DM), have more advanced left main coronary disease, and have cardiac troponin levels greater than 5 ng/ml. When the statistically significant predictors for LVSD (p<0.05) from the univariate analysis were entered into a multivariable logistic regression model of analysis, cardiac troponin levels > 5ng/ml [odds ratio = 2.13 (95%CI = 1.22 to 3.70) p = .008] and DM [odds ratio = 1.74 (95%CI = 1.02 to 2.97) p = .042] were found to be independent predictors for LVSD (Table 2). Age and left main coronary disease almost reached statistical significance.

Table 2. Independent predictors of LVSD.

Discussion

The classic definition of myocardial infarction (MI) by the World Health Organization (WHO) is based on symptoms, electrocardiographic abnormalities, and elevated cardiac enzymes. However, over the past decade the Global MI Task Force has integrated new elements to the definition of MI based on the mechanisms of myocardial injury. Obstructive coronary lesion is the most clinically relevant form of injury and results in troponin release (2,3).

Routine detection of troponin levels using high sensitivity assays that yield a continuous gradient in apparently normal subjects makes it difficult to differentiate myocardial necrosis related to plaque rupture in ACS patients from necrosis in non-ACS patients. Newby et al. discussed the impact of improved test sensitivity on the interpretation of cardiac troponin and emphasized the value of pretest probability when interpreting troponin elevation (3).

The major findings of the present study were: 1) obstructive coronary lesions (flow-limiting) related myocardial injury resulted in greater troponin elevation when compared to other etiologies of myocardial injury, 2) in the context of a flow-limiting coronary artery disease, the degree of troponin elevation implies high-risk features for invasively managed NSTE-ACS patients related to their vascular anatomy, lesion complexity, and the eventual success of percutaneous intervention, and 3) regardless of the mechanism of troponin release, a high level of troponin I was an independent predictor of LVSD in de novo NSTE-ACS patient population.

Troponin I and the presence of hemodynamically significant (flow-limiting) coronary artery disease

Troponin I is independently associated with in-hospital mortality in NSTE-ACS patients. Antman et al. reported that short-term mortality increases with rising levels of cardiac troponin I, and the highest increment in mortality was observed when levels are > 5 ng/ml (4). Additionally, Kleiman et al. (5) demonstrated that invasive management could improve mortality risk in a NSTE-ACS subset of patients with positive cardiac biomarkers.

Interestingly, analyses from the ACTION Registry (NCDR published data) indicate that single vessel flow-limiting coronary artery disease was the most common finding identified by cardiac angiography, and that percutaneous coronary artery intervention was the most common mode of treatment in invasively managed NSTE-ACS patients (6,7). We previously reported that the likelihood of hemodynamically significant coronary artery disease in invasively managed NSTE-ACS patients when the troponin level is more than 5 ng/ml was significantly higher than that in individuals with a lower troponin level (8).

Concern about elevated troponin was reflected in the guidelines that recommend incorporating risk stratification models (TIMI risk score, Grace risk score, or PURSUIT risk model) to the management strategy for NSTE-ACS patients (9). However, none of these models has integrated the additive value of the degree of troponin elevation in their risk-score calculation (10-12).

Being closely associated with mortality and the presence of flow-limiting coronary artery disease, the degree of cardiac troponin elevation should be scored properly in risk stratification modules and contemplated in the timing for invasive management of those presenting with NSTE-ACS.

Troponin I and percutaneous coronary artery interventions in NSTE-ACS

In the setting of ACS, elevated troponin is associated with impaired myocardial tissue perfusion and lower rate of coronary recanalization after percutaneous coronary intervention (13-18). Troponin elevation also signifies adverse short and long-term prognosis in this patient population (19-22). Similarly, in our study, we observed that elevated troponin was associated with increased thrombus burden, worse systolic function, higher complexity of the lesions, and worse post intervention TIMI flow.

Subgroup analysis of ACS clinical trials showed that elevated troponin identified a subset of NSTE-ACS patients who would derive benefit from the addition of antithrombotic therapy and intravenous anti-platelet therapy to a conventional regimen. This is gained via reduction of thrombus formation at the culprit lesion and facilitation of distal micro-thrombi resolution (23-26).

The current guidelines identify the value of elevated troponin when choosing anti-thrombotic therapy, with or without invasive strategy. However, there is no consensus regarding a clinically relevant level of troponin that will provide the most benefit to invasively managed NSTE-ACS patients.

Predictors of left ventricular systolic dysfunction (LVSD) in NSTE-ACS:

Ischemic cardiomyopathy is the main etiology for LVSD in the United States and North America. The development of LVSD following ACS significantly worsens short- and long-term prognosis (17,27,28).  

We targeted patients with no prior history of coronary artery disease, heart failure or cardiac surgery who were referred for coronary angiograms for a new diagnosis of NSTE-ACS to assess the predictors of LVSD. Cardiac troponin I levels >5 ng/ml were the most important predictor of LVSD following a new onset NSTE-ACS in patients with no prior history of coronary artery disease (Table 2).

The previous ACC/AHA (2012-2013) guidelines recommended early invasive strategy in NSTE-ACS patients with a systolic ejection fraction of less than 40% (9). The timing of this recommendation was revised in the most recent guidelines (29).

Using clinical characteristics and risk factors at admission to identify risk of heart failure influences therapeutic decisions and permits an individualized approach to each patient. LVSD is a major concern among invasively managed ACS patients and imposes a large economic burden on the health care system. Troponin level could be used as a cost-effective tool to stratify patients who are at risk of LVSD, allowing appropriate early measures to improve their outcome.

Troponin I and Early versus Delayed Intervention in NSTE-ACS

The optimal timing of angiography has not been conclusively established in NTE-ACS (29). In earlier randomized trials, better outcomes were obtained with an early invasive strategy in patient with troponin I elevation when compared to those with normal troponin levels (30). In other reports, investigators found that early invasive intervention was not superior to a delayed invasive approach in NSTE-ACS patients for the prevention of death or myocardial infarction, even in those with positive cardiac biomarkers (31, 32).

The most notable beneficial effect of an invasive versus a conservative strategy in the management of NSTE-ACS patients was demonstrated in the reduction of recurrent MI, although the effect on mortality was seen in high-risk patients only (29,33).  Prospective trials to determine a clinically relevant troponin level that will determine the timing of an invasive strategy and its impact on patients’ outcomes are yet to be conducted (1).

Study Limitations

Our cohort study is subject to the standard bias associated with retrospective observations including selection bias, incomplete records, and loss of patients’ long-term follow-up.

The results of our study were derived from a single-center using a particular assay kit for serum troponin testing; thus, generalizability is a concern. Follow-up of cardiac events, recurrent hospitalizations, and long-term adverse events was beyond the scope of our study.

Conclusion

The degree of cardiac troponin I elevation should be incorporated into the risk stratification models of NSTE-ACS to promptly triage high-risk patients to early invasive strategies and tailored anticoagulant therapy to reduce troponin elevation and improve myocardial perfusion.

Acknowledgement

The authors of the study would like to thank Melissa Hodges (Cardiac Clinical Nurse Specialist) for her help with data abstraction.

References

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Cite as: Abdul Jabbar A, Mufti O, Altabaqchali S, Ahsan C, Hasan M, Markert R, White B, Broderick G. High-sensitivity troponin i and the risk of flow limiting coronary artery disease in non-ST elevation acute coronary syndrome (NSTE-ACS). Southwest J Pulm Crit Care. 2017;14(6):296-307. doi: https://doi.org/10.13175/swjpcc059-17 PDF 

March 2017 Critical Care Case of the Month

Kyle J. Henry, MD

Banner University Medical Center Phoenix

Phoenix, AZ USA

History of Present Illness

A 50-year-old man presented to the emergency room via private vehicle complaining of 5 days of intermittent chest and right upper quadrant pain. Associated with the pain he had nausea, cough, shortness of breath, lower extremity edema, and palpitations. 

Past Medical History, Social History, and Family History

He had a history of hypertension and diabetes mellitus but was on no medications and had not seen a provider in years. He was disabled from his job as a construction worker. He had smoked a pack per day for 30 years. He was a heavy daily ethanol consumer. He had an extensive family history of diabetes.

Physical Examination

• Vitals: T 36.4 C, pulse 106/min and regular, blood pressure 96/69 mm Hg, respiratory rate 19 breaths/min, SpO2 98% on room air
• Lungs: clear
• Heart: regular rhythm without murmur.
• Abdomen: mild RUQ tenderness
• Extremities: No edema noted.

Electrocardiogram

His electrocardiogram is show in Figure 1.

Figure 1. Admission electrocardiogram.

Which of the following are true regarding the electrocardiogram? (Click on the correct answer to proceed to the second of seven pages)

1. The lack of Q waves in V2 and V3 excludes an anteroseptal myocardial infarction
2. The S1Q3T3 patter is diagnostic of a pulmonary embolism
3. There are nonspecific ST and T wave changes
4. 1 and 3
5. All of the above

Cite as: Henry KJ. March 2017 critical care case of the month. Southwest J Pulm Crit Care. 2017;14(3):94-102. doi: https://doi.org/10.13175/swjpcc021-17 PDF

February 2016 Critical Care Case of the Month

Thomas M. Stewart, MD

Bhargavi Gali, MD 

Department of Anesthesiology

Mayo Clinic Minnesota

Rochester, MN USA

Case Presentation

A 32 year-old, previously healthy, female hospital visitor had been participating in a family care conference regarding her critically ill grandmother admitted to the cardiac intensive care unit. During the care conference, she felt unwell and had some mild chest discomfort; she collapsed and cardiopulmonary resuscitation (CPR) was initiated (1). Upon arrival of the code team, she was attached to the monitor and mask ventilation was initiated. Her initial rhythm is shown in Figure 1.

Figure 1. Initial rhythm strip.

In addition to DC cardioversion which of the following should be administered immediately? (Click on the correct answer to proceed to the second of four panels)

1. Lidocaine
2. Magnesium sulfate
3. Procainamide
4. 1 and 3
5. All of the above

Cite as: Stewart TM, Gali B. February 2016 critical care case of the month. Southwest J Pulm Crit Care. 2016;12(2):41-5. doi: http://dx.doi.org/10.13175/swjpcc011-16 PDF