Heart & Lung 44 (2015) 75e81

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Heart & Lung

journal homepage: www.heartandlung.org

The prognostic significance of troponin elevation in patients with

sepsis: A meta-analysis
Olusegun Sheyin, MD *, Oluwaseun Davies, MD, MPH, Wenlan Duan, MD,
Xavier Perez, MD, MPH
Department of Medicine, Harlem Hospital Center, in affiliation with the College of Physicians and Surgeons of Columbia University, New York, USA

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To confirm the association between troponin elevation in patients with sepsis and mortality.
Received 13 August 2014 Background: Cardiac troponins are sensitive and specific biomarkers of myocardial injury; however their
Received in revised form prognostic significance in patients with sepsis is still debated.
10 October 2014
Methods: PubMed and Ovid MEDLINE were searched for original articles using MeSH terms ‘Troponin’
Accepted 11 October 2014
and ‘Sepsis.’ Studies reporting on mortality in patients with sepsis, severe sepsis or septic shock who had
Available online 18 November 2014
troponin measured were eligible for inclusion. Meta-analysis was conducted with Review Manager.
Results: Seventeen studies, with total sample size of 1857 patients were included. Elevated troponin was
Keywords:
Troponin
found to be significantly associated with mortality (Risk ratio: 1.91; 95% CI: 1.65e2.22; p < 0.05).
Sepsis Conclusions: Troponin elevation in patients with sepsis confers poorer prognosis and is a predictor of
Prognosis mortality. Further studies are needed to see if more aggressive treatment of this subset of patients, or
Shock utilizing new therapeutic approaches will improve mortality.
Mortality Ó 2015 Elsevier Inc. All rights reserved.
Meta-analysis

Background
Sepsis is the most common cause of morbidity and mortality in
intensive care units in the United States, with hospital mortality
rate of 18e30%, depending on the series.1 The mortality rate is even
higher in patients with severe sepsis and septic shock, in whom
rates of 28.3e41.1% have been reported.2 With increasing avail-
ability of evidence-based therapies, the mortality rate of severe
sepsis decreased from 39% to 27%.3 However, an increase in the
number of sepsis cases has resulted in increasing number of sepsis-
related deaths, estimated at 215,000 annually in the United
States.1,3
Cardiovascular abnormalities are frequent in sepsis and septic
shock and may result in non-coronary artery disease-related
myocardial injury.4 Troponin is a protein found in skeletal and
heart muscle fibers which regulates muscular contraction. It is
made up of three sub-units: troponin C (which binds to calcium to
produce a conformational change in troponin I), troponin T (which
binds to tropomyosin), and troponin I (which binds to actin).
* Corresponding author. Department of Medicine, Harlem Hospital Center, 506
Lenox Avenue, New York, NY 10037, USA. Tel.: þ1 212 939 2291; fax: þ1 212
939 2263.
E-mail address: oas2120@columbia.edu (O. Sheyin).
Cardiac-specific troponins I and T are found only in the heart and
are normally present in very small to undetectable quantities in the
blood. However, when there is damage to heart muscle cells,
cardiac-specific troponins I and T are released into circulation and
can be measured by immunoassay methods. Hence cardiac tropo-
nins have emerged as sensitive and specific markers of myocardial
injury facilitating early risk stratification.5
Troponin (cardiac troponin) elevation among patients with
sepsis is common, but its role in risk stratification of patients with
sepsis is still debated. Many studies have reported increased mor-
tality in septic patients with troponin elevation,6e11 while others
did not.12e14 This may be as a result of differences in the type of
infection, troponin assays, cut-off thresholds for troponin elevation,
or differences in the time when troponins were measured.
Furthermore, the studies which failed to find a significant associ-
ation between troponin elevation and mortality may have been
inadequately powered to reach statistical significance. A meta-
analysis on the prognostic value of troponin in sepsis was pub-
lished by Bessière and colleagues which showed that elevated
troponin in patients with sepsis is associated with increased mor-
tality.15 However, the meta-analysis included mostly studies with
small sample sizes and did not conduct sub-group analysis based
on the presence of septic shock. In addition, two recently published
relatively large studies (total of 500 subjects) were not included in
the original meta-analysis (Rosjo et al, 2011 and Tiruvoipati et al,

0147-9563/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.hrtlng.2014.10.002

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76 O. Sheyin et al. / Heart & Lung 44 (2015) 75e81
2012).13,16 Hence, we set out to perform an updated meta-analysis
to determine if a decisive conclusion can be made on the associa-
tion between troponin elevation in patients with sepsis and
mortality.
Methods
Study research
We conducted a systematic review and meta-analysis, using
methods that are in accordance with the Meta-analysis of
Observational Studies in Epidemiology (MOOSE) group’s
recommendations.17
A systematic literature search of Ovid MEDLINE and Pubmed
was conducted to identify all studies involving humans published
up to February 2014, comparing outcome in patients with sepsis
with and without troponin elevation. Search criteria combined
Medical Subject Headings (MeSH) terms ‘Troponin’ and ‘Sepsis.’
The search was not restricted to any language. We subsequently
searched and evaluated all reference lists of eligible articles ob-
tained from the electronic search to ensure identification of all
published studies on the subject.
Study selection, data extraction, and outcome measures
Two investigators independently read the results from elec-
tronic search to identify and scrutinize those articles relevant to
this systematic review based on title or title and abstract. Relevant
articles from the list of references of the reviewed papers obtained
from the electronic search were also retrieved to determine eligi-
bility for inclusion in this meta-analysis. Full articles were then
retrieved for further assessment, and disagreements were resolved
by consensus and by discussion with a third investigator. A form
was designed to describe the characteristics of studies to be
included or excluded as set out in the recommendations in the
Cochrane Handbook for Systematic Reviews of Interventions
5.0.2.18 The outcome measure for this analysis was all cause
mortality.
We designed a form to extract data on the following: total
number of patients in each study and the number with and without
positive troponin; the number of patients who died in each group
(positive troponin and negative troponin groups); the type of
troponin measured; the follow-up period; mean age; gender ratio;
proportion of patients in septic shock; exclusion of patients with
confounding co-morbidities; conduction of multivariate analysis;
and the setting and country of the study.
Selection criteria
We applied the following screening criteria to determine qual-
itative eligibility: original article; observational study or clinical
trial conducted on patients at least 18 years of age; blood sampling
for troponin was performed; follow-up for at least 7 days or to
hospital mortality; and a sample size greater than or equal to 10
patients.
Studies were included if they reported on patients with a
diagnosis of sepsis, severe sepsis or septic shock as defined by the
American College of Chest Physicians/Society of Critical Care
Medicine consensus conference19,20; and information can be ob-
tained on mortality among patients with and without positive
troponin. In studies in which data was missing, the authors were
contacted to provide the missing information. Studies in which the
authors failed to respond were not included in the meta-analysis.
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Quality assessment
The selected studies were evaluated for their methodological
quality utilizing elements from the MOOSE checklist17 by sys-
tematically noting whether there was: (1) blinding of the physi-
cians involved in direct care of the septic patients to the troponin
result at study entry; (2) multivariate analysis on possible pre-
dictors of study results; and (3) inclusion of patients with
comorbidities (e.g. renal failure, ischemic heart disease, pulmo-
nary embolism, myocarditis or chronic heart failure) that may
influence troponin levels and accuracy. The included studies were
then divided into three categories based on quality: (1) high
quality if at least two of the three criteria were clearly described
and accounted for; (2) low quality if only one criteria was
described and accounted for; and (3) uncertain risk of material
bias if none of the criteria was described (Table 1).
Statistical analysis
The pooled prevalence and its 95% confidence interval (95% CI)
were computed by weighted averages in which the weight of each
study is its sample size. Mantel Haenszel calculations were used to
calculate the pooled risk ratios (RR) according to the random effects
model. We assessed heterogeneity between trial results using
Cochran’s Q statistic and I2 statistic. Heterogeneity was considered
present at p < 0.10 and I2 > 50%.21 Sensitivity analyses were per-
formed by repeating analysis: (1) excluding any large studies to see
how they influence the results; (2) taking account of study quality
and sample size; (3) according to the type of troponin measured
(troponin I or troponin T); and (4) comparing patients with sepsis
and septic shock. Finally, a funnel plot was calculated to assess for
publication bias, looking for asymmetry on visual inspection. An-
alyses were conducted using Review Manager (RevMan; Cochrane
Collaboration), version 5.2.11 software.
Results
Baseline characteristics
A total of 221 citations were obtained from our electronic
search. After reading titles and abstracts, eighteen potentially
relevant studies were identified for further review. Five studies
were removed because of failure to obtain missing information
from the authors.22e26 Using backtracking, four additional studies
were added (Fig. 1). Seventeen studies, published between 1998
and 2012, with sample size range of 10e598 patients, mean age
range 30e70 years, male gender range 44e75 % were included,
encompassing a total of 1857 patients (Table 1).
Fifteen studies were prospective,6e11,14,16,27,29e31,33,34 while
two were retrospective in nature.13,28 The largest of the studies is
a retrospective study of 598 patients with severe sepsis in whom
troponin I was measured.28 Multivariate statistical analysis
adjusting for known cardiovascular risk factors were performed
in seven studies,6,13,14,16,27,28,31 encompassing 1497 patients.
Fifteen studies were set in the Intensive Care Unit (ICU),
6e11,13,14,16,28e32
while two were set in a general medicine unit.27,33
The proportion of the patients who were admitted in septic shock
ranged from 24.8 to 100%, and the most frequent source of sepsis
was pulmonary infection. Seven studies were conducted in
Europe,7,9e11,16,32 three in North America,6,30,31 two in South
America,29,34 two in Asia27,33 and two in Australia.8,13 One study
(PROWESS trial) utilized data from a registry of patients from 11
countries28 (Table 1).
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Table 1
Characteristics of included studies.

Author, year Patients Age, SD (years) Male (%) Exclusion of Series Patients Origin of sepsis (%) Factors positive in Follow-up Study Setting, country
[reference] (n) patients with admitted multivariate analysis (days) quality
co-morbiditiesa in shock (%) (score)
Amman et al (2003)7 58 55  21 48 Yes Prospective 41 NA e 30 Low (1) ICU, Switzerland
Amman et al (2001)10 20 66.1  8.2 75 Yes Prospective 40 Pulmonary (55) e Hospital High (2) ICU, Switzerland
discharge
Bouhemad 54 56  17 76 Yes Prospective 100 Pulmonary (46) e 10 days Low (1) ICU, France
et al (2008)32 Abdominal (26)
Brivet et al (2006)14 136 70.3  15 75 Yes Prospective 65.4 Pulmonary (60.3) SAPS II, tropo () Hospital High (2) ICU, France
discharge
Choon-ngarm 40 60  19.7 N/A Yes Prospective 100 Pulmonary (57.5) e NA Low (1) Department of
et al (2008)33 Urinary (22.5) medicine, Thailand

O. Sheyin et al. / Heart & Lung 44 (2015) 75e81

Fernandes 10 30.1  5.6 60 Yes Prospective NA Peritonitis (40) e NA High (2) ICU, Brazil
et al (1999)29 Skin (20)
Issa et al (2008)34 23 51.3  18.6 60.9 Yes Prospective 82 Pulmonary (43.5) e ICU Low (1) ICU, Brazil
discharge
John et al (2007)31 105 57  15.0 59 No Prospective 68 NA Age, MODS, APACHE II, tropo (þ) 28 Low (1) ICU, USA
John et al (2010)28 598 60  17.5 56 No Retrospectiveb NA NA Treatment, age, race, functional 28 Low (1) ICU, PROWESS
dependency status, APACHE II, trial, 11 countries
activated partial thromboplastin
time, IL-6, tropo (þ)
Kang et al (2009)27 121 66.1  11.8 44 Yes Prospective 24.8 Pulmonary (66) Age, diabetes, septic shock, 90 High (2) Internal medicine
Urinary (11.5) tropo (þ) (ESRD), Korea
Mehta et al (2004)6 37 68.5  14.2 54 Yes Prospective 100 NA Tropo (þ), APACHE II, anion gap, Hospital High (2) ICU, USA
lactate (þ) discharge
Rosjo et al (2011)16 207 65 (range 56e76) 68 Yes Prospective NA NA SAPS II score, tropo (þ) Hospital High (2) ICU, Finland
discharge
30
Scott et al (2008) 66 64.6  17 59 No Prospective 64 Abdomen (53) e Hospital Uncertain (0) ICU, USA
Pulmonary (20) discharge
Necrotizing
fasciitis (12)
Spies et al (1998)9 26 59.6 (Range 21e89) 58 Yes Prospective NA Peritonitis (38) e 7 Low (1) ICU, Germany
Pulmonary (27)
b
Tiruvoipati 293 70 (Range 59e78) 50.2 No Retrospective NA NA Mean BP, temperature, lactate, Hospital Low (1) ICU, Australia
et al (2012)13 SAPS II score discharge
Turner et al (1999)8 15 63.8  16.1 NA Yes Prospective 100 Pulmonary (53) e 30 Low (1) ICU, Australia
ver Elst et al (2000)11 46 66 (range 54e74) 65 Yes Prospective 100 Pulmonary (74) e NA Low (1) ICU, Belgium
Peritonitis (13)

ICU: intensive care units; NA: not available; SD: standard deviation; tropo: troponin; (þ): troponin reported as independent risk factor in multivariate analysis.
a
Conditions known to increase troponin plasma levels: renal failure, dilated and ischemic heart disease, pulmonary embolism, myocarditis.
b
Retrospective analysis of prospectively collected data.

77
78 O. Sheyin et al. / Heart & Lung 44 (2015) 75e81
Fig. 1. Study selection flow diagram.
Troponin assays
Apart from the study by Issa et al,34 threshold levels defining
positive and negative results were determined in all the studies
included in this meta-analysis. Ten of the studies used thresholds
recommended by manufacturers that corresponded to any con-
centration above the 99th percentile. Three of the included studies
used troponin T alone,9,16,33 two studies used both troponin I and
T,7,11 while the remainder of the studies used troponin I alone.
Three different assays for Troponin T and at least seven for Troponin
I were utilized with different thresholds ranging from 0.014 to
0.1 mg/L for troponin T and 0.006e1.0 mg/L for troponin I. Initial
blood samples for troponin were taken during the first day in
fourteen studies,6e11,13,16,29,30,32,33 and during the first 3 days in one
study.31 In two studies, this information was unavailable.28,34
Meta-analysis
A total of 1124 patients in our meta-analysis had elevated
(positive) troponin, yielding a prevalence of 60.5%. In our pooled
analysis, 38.9% of septic patients with elevated troponin died
Fig. 2. Forest plot of studies investigating the relationship between troponin and mortality.
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compared with 22.1% of septic patients without troponin elevation
(RR: 1.91; 95% CI: 1.65e2.22), see Fig. 2. On sensitivity analysis we
observed similar results for studies that included only septic shock
patients (RR: 2.16; 95% CI: 1.56e2.97); studies using troponin T (RR:
1.84; 95% CI: 1.39e2.42); and studies using troponin I (RR: 1.97; 95%
CI: 1.66e2.33), see Figs. 3 and 4.
Sensitivity analyses
No significant heterogeneity was detected for the outcome
measure. Visual inspection of the funnel plot suggested some evi-
dence of publication bias (Fig. 5). Results were similar when ana-
lyses were compared with the fixed effects model and remained
statistically significant after removal of any trial from the pooled
result (Supplemental digital content e Table). In addition, there was
no statistical difference in results on sub-group analysis for the type
of troponin measured, studies involving patients with and without
septic shock, studies utilizing the manufacturer specified 99th
percentile cut-off for positive troponins, studies in which patients
with co-morbidities likely to influence the accuracy of troponin
levels were not excluded, and studies in which multivariate analysis
was performed.
Discussion
In this updated meta-analysis, we observed that troponin
elevation in patients with sepsis was associated with an almost
two-fold increased risk of death. With 1857 patients, this is the
largest meta-analysis to date investigating the association between
troponin elevation in patients with sepsis and mortality. On sub-
group analysis, we observed that troponin positivity predicts
mortality in patients with sepsis irrespective of the presence of
septic shock, adjustment for known cardiovascular risk factors or
the type of troponin measured (Supplemental digital content e
Table). Hence, inclusion of patients at the high end of the sepsis
spectrum (septic shock) was not the sole reason for the overall
association between troponin positivity and mortality seen.
Only one meta-analysis to date has been published on the as-
sociation between troponin elevation in patients with sepsis and
mortality.15 The prevalence of troponin elevation in patients with
sepsis was found to be 60.5%, similar to the earlier meta-analysis by
Bessière and colleagues on this topic, who reported a prevalence of
 O. Sheyin et al. / Heart & Lung 44 (2015) 75e81 79

Fig. 3. Subgroup analyses investigating the relationship between troponin and mortality according to the presence of septic shock.

61%. The work by Bessière and colleagues included 1227 patients
and similar to our study, also found a significantly increased risk of
mortality in patients with sepsis with positive troponins. The
studies by Brivet, Scott and Tiruvoipati failed to identify troponin
positivity to be independently associated with mortality in septic
patients. However, five of the studies included in our meta-analysis
found troponin elevation to be an independent predictor of
mortality.6,16,27,28,31
The pathophysiology of troponin elevation in sepsis is thought
to be due to myocardial dysfunction. Proposed mechanisms for
myocardial dysfunction in sepsis include demand ischemia, direct
cardiac myotoxic effects of endotoxins, cytokines or reactive oxygen
radicals, and perturbations in regional coronary blood flow.8 In a
recent study by Landesberg and colleagues, left ventricular diastolic
dysfunction and right ventricular systolic dysfunction were found
to be strongly associated with troponin positivity and mortality.35
The increased mortality observed in this group of patients may be
attributed to myocardial dysfunction, a more fulminant disease
process or underlying quiescent coronary artery disease. However,
two of the studies included in this meta-analysis excluded

Fig. 4. Subgroup analyses investigating the relationship between troponin and mortality according to the type of troponin measured.

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80 O. Sheyin et al. / Heart & Lung 44 (2015) 75e81
Fig. 5. Funnel plot of the included studies.
significant coronary artery disease in the septic patients either by
stress echocardiogram or autopsy.7,10 Hence troponin elevation in
sepsis does not seem to be solely a consequence of coronary artery
obstruction by atherosclerosis.
Serum troponin measurement can be done using cheap and
readily available assays to detect myocardial injury in patients with
sepsis. Therefore, an elevated troponin value during the first days of
admission may be a reliable test to identify septic patients who are
at high-risk for mortality and select them for more aggressive
management. Previous studies reported that septic patients with
elevated troponin levels were more likely to have left ventricular
systolic dysfunction, be in septic shock and require mechanical
ventilation.36 Early identification of this subset of patients is
important as it has been shown that early aggressive resuscitation
can improve myocardial injury and improve survival.37 Hence the
early identification of this subset of septic patients can help with
prompt emergency room triage, guide clinical decision on early
goal directed therapy and decisions on patient disposition.
In addition, further studies may be done to investigate new
therapeutic approaches in patients with sepsis to see if they confer
any morbidity and mortality benefit. The randomized control trial
ASEPSIS reported a reduction in the progression of sepsis in patients
who got atorvastatin compared to placebo but did not improve
mortality.38 Although this trial was not conducted in septic patients
with and without troponin, the findings are promising and further
multicenter trials are needed to establish whether this class of
medications will offer utility in this regard. Additional studies are also
required to determine if therapeutic interventions aimed at
improving diastolic function or right ventricular dilatation (such as
milrinone and levosimendan) can prevent troponin elevation and
mortality in severe sepsis and septic shock. However, it would be
necessary to determine an appropriate threshold concentration for
cardiac troponin that would identify septic patients at highest risk of
death. This may be a challenge considering that there are several
commercially available troponin assays, with varying sensitivities. As
seen in our analysis of studies using the manufacturer-recommended
99th percentile threshold for troponin positivity which revealed a
two-fold increased risk of mortality, it may be safe to use this
threshold to define troponin positivity for each troponin assay.
We acknowledge limitations to our meta-analysis resulting from
the data available from the included studies. First, all studies that
were included in our analysis were observational raising concerns
of confounders biasing our results. However, historically most
studies in critical care settings have been observational in nature
due to the severity of illness. In addition, a subgroup analysis
looking at studies that adjusted for known cardiovascular risk
factors still confirmed the increased risk of mortality in patients
with elevated troponin. Secondly, the vast majority of the included
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studies were performed in the ICU setting; it is unclear whether the
results from this meta-analysis may be extrapolated to patients in
other medical settings. Lastly, there was some asymmetry on visual
inspection of the Funnel plot, suggesting that publication bias may
have been present possibly due to smaller non published data
(Fig. 5). To this we must add that we performed an extensive
literature search including backtracking in addition to contacting
authors regarding unpublished data.
Conclusion
Troponin elevation in patients with sepsis confers a poorer
prognosis and is a predictor of mortality. Further studies are needed
to see if selection of this subset of patients for more aggressive
therapy, or for new therapeutic approaches targeting cardiovas-
cular protection in sepsis leads to a reduction in mortality.
Acknowledgments
We like to thank F.G. Brivet for the additional data provided from
his study.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.hrtlng.2014.10.002.
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