Increased blood troponin levels in ICU patients

Nikolaos Markoua, Leonidas Gregorakosb and Pavlos Myrianthefsb

a
ICU, Thriasio Hospital and bAthens University School
of Nursing, ICU at Agioi Anargyroi General Hospital,
Athens, Greece

Correspondence to Nikolaos Markou, 24 Sholiou St,

15342 Agia Paraskevi, Greece
Tel: +30 6973404627;
e-mail: nikolaos_markou@hotmail.com
Current Opinion in Critical Care 2011,
17:454463

Purpose of review
Cardiac troponins in serum have become the biomarkers of choice for the diagnosis of
myocardial infarction. Yet, troponin can also be elevated by a multitude of causes in the
absence of overt myocardial ischemia. Such nonspecific elevations are particularly
common in the critically ill. This article aims to provide information on the significance of
troponin elevations in unselected critically ill patients and in patients with sepsis or
septic shock.
Recent findings
Recent studies reconsider the possible association of troponin elevations with
myocardial infarction in unselected critically ill patients. There are also more data on the
prognostic significance of troponin in this population. In patients with sepsis, recent
studies suggest that troponin may be a reliable index of sepsis-induced myocardial
dysfunction, although the implications of this finding in the management of sepsis
remain unclear for the time being. Troponin also appears to be a predictor of short and
possibly also long-term outcome in septic patients. The advent of newer assays with
even higher sensitivity, may lead to further redefinition of the role of troponin in the ICU.
Summary
Troponin is frequently elevated in critically ill patients. More research is needed on the
diagnostic and prognostic significance and possible clinical applications of troponin
measurements in patients with sepsis and critical illness.
Keywords
critical illness, diastolic dysfunction, myocardial infarction, prognosis, sepsis, systolic
dysfunction, troponin
Curr Opin Crit Care 17:454463
2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
1070-5295

Introduction
Serum levels of cardiac troponins T and I (cTnT, cTnI)
represent an exquisite marker of myocardial injury, with
high myocardial tissue specificity and high sensitivity.
Thus troponins have succeeded creatine phosphokinaseMB (CPK-MB) as the preferred biomarkers for the
diagnosis of myocardial infarction (MI) and for risk
stratification in acute coronary syndromes (ACS) [13].
Currently, for types 1 and 2 of MI, diagnosis requires a
changing pattern of cardiac troponin (a rise or fall within
hours), with at least one value above the upper reference
limit of the assay [1,2,4]. With sensitive assays now in use,
up to 80% of patients presenting with MI can be identified
within 23 h, whereas exclusion of MI can take as little as
6 h [5]. The recent development of newer assays with even
lower cut-off points, promises further improvement in the
early diagnosis and risk stratification of acute MI [6,7].
Yet, an elevated troponin does not automatically
equate with diagnosis of MI as it may also be associated
with a multitude of nonischemic causes (given below)
[2,3,8,9].
1070-5295 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

Elevations of troponin in the absence of overt ischemic

heart disease:
(1) Cardiac contusion.
(2) Ablation, pacing, cardioversion, endomyocardial
biopsy.
(3) Congestive heart failure (acute, chronic).
(4) Aortic dissection, aortic valve disease or hypertrophic cardiomyopathy.
(5) Tachyarrhythmias or bradyarrhythmias.
(6) Apical ballooning syndrome.
(7) Rhabdomyolysis.
(8) Pulmonary embolism.
(9) Severe pulmonary hypertension.
(10) Renal failure.
(11) Acute neurological disease (stroke, subarachnoid
hemorrhage).
(12) Infiltrative myocardial diseases: amyloidosis, hemochromatosis, sarcoidosis, scleroderma.
(13) Myocarditis or myocardial extension of pericarditis
or endocarditis.
(14) Drug toxicity: adriamycin, 5-fluorouracil, herceptin,
snake venoms.
DOI:10.1097/MCC.0b013e3283491f0d

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Increased blood troponin levels in ICU patients Markou et al. 455

(15) Critically ill patients especially with respiratory failure or sepsis.

(16) Burns, especially more than 30% of body surface
area (BSA).
(17) Extreme exertion.
It should be noted that in most of these cases troponin
elevation probably still signifies myocardial injury (but
not necessarily necrosis) [4]. Thus diagnosis of myocardial necrosis of ischemic cause in a patient with
increased troponin depends on the clinical context
(symptoms of ischemia, ECG findings, imaging) [1,2].
Increased troponin levels in the absence of ACS should
prompt an evaluation for an alternative, nonthrombotic
mechanism of troponin elevation and direct management
at the underlying cause [6].
A recent study highlights that troponin elevations may
often be unrelated to MI even in acute patients presenting with increased clinical likelihood for MI: among 991
consecutive troponin-positive patients presenting with a
clinical suspicion of ACS to the emergency department,
83% of the troponin elevations were retrospectively
attributed to MI, 7.9% were related to other cardiac
causes, and 9.1% to noncardiac diseases. The leading
noncardiac causes were pulmonary embolism, renal failure, pneumonia, and sepsis [10]. The specificity for MI
of low-level troponin elevations (one to five times the
upper limit of normal) is probably much lower (49%)
[11]. It seems that with sensitive troponin assays currently in use such low-level elevations represent a gray
zone, when evaluation of the clinical context as well as of
changes of troponin over time becomes even more
imperative for correct diagnosis.
It is well recognized that the levels of troponin are of
prognostic significance in ACS [4]. This prognostic significance seems also to extend to patients with acute
noncoronary events (e.g. pulmonary embolism) and to
patients with chronic heart failure and chronic renal
failure [4,9]. Interestingly, in the study of Ilva et al.
[10] noncardiac patients with elevated troponin I at
admission showed significantly higher in-hospital
mortality (26.7 vs. 13.4%) compared to cardiac patients.
The use of recent high-sensitivity assays with very low
cut-offs may aggravate the problem of specificity for MI,
but on the contrary it may offer valuable prognostic
information. It has been recently shown that most
patients with stable coronary artery disease and preserved
left-ventricular function have detectable levels of troponin with a high-sensitivity troponin T assay, whereas
elevated values are found in 11.1% of patients. In these
patients, troponin concentrations were independently
associated with long-term incidence of cardiovascular
death and heart failure. This association persisted even

Key points
 Troponin elevation is common in critically ill
patients and is not specific for myocardial ischemia.
 In these patients, regardless of the presence of
myocardial ischemia, elevation of troponin seems
to be associated with both short- and long-term
prognosis.
 In patients with sepsis, elevations of troponin seem
to be associated with reversible sepsis-induced
myocardial infarction.
for values of troponin within normal range of the assay
and below the limit of detection of conventional cardiac
troponin T assays [12].
Cardiac troponin elevation is common in the ICU and can
be observed in up to 4050% of critically ill patients.
The interpretation, clinical significance and appropriate
management of an elevated troponin measurement in
critically ill patients are uncertain. In these patients,
the pretest probability for ACS is much lower than in
coronary care, whereas nonischemic causes of troponin
elevation (shock, sepsis, pulmonary embolism, renal
failure) are very often encountered. Regardless of cause,
elevated levels of troponin are probably of prognostic
value in critically ill patients, although such associations
are less unequivocal than in ACS [13,14].
We will review the significance of troponin elevations in
the general critically ill patient, with particular emphasis
in more recent findings. We will not discuss the role of
troponin in trauma, cardiac and noncardiac surgery, the
postsurgical setting, revascularization processes or in the
coronary care unit, neither its significance in entities
such as stroke, pulmonary embolism, chronic obstructive
pulmonary disease (COPD), decompensated heart failure
or renal failure.

Troponin in mixed critical care patients

Troponin is commonly increased in critically ill patients,
although the exact frequency varies considerably
between studies, because of differences in patient selection, case-mix, heterogeneity of assays and different
cut-off values [1531,32,33]. A few years ago, a
meta-analysis of 20 studies with a total of 3278 critically
ill patients, reported that elevated troponin was present
with a median frequency of 43% [interquartile range
(IQR) 2159%]. Elevated cardiac troponin (cTn) levels
were more frequently found among patients admitted
with sepsis or septic shock. The median frequency of
elevated troponin measurement was higher among
medical ICU patients, somewhat lower in mixed
medical-surgical ICU patients and even lower in surgical-trauma ICU patients [15]. It should be noted that

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

456 Cardiovascular system

many of the studies in this meta-analysis concerned not

only unselected critically ill patients but cohorts with
more specific problems (trauma, sepsis, COPD). Table 1
presents data from studies of troponin in unselected
critically ill patients [1631,32,33]. Troponin levels
seem to be higher in more severe disease [22,30,34].
Associations have also been reported with age, cardiovascular risk factors and previous cardiovascular history
[30].
Troponin elevation in these patients is not necessarily
indicative of ACS, as many of the entities listed above are
also commonly observed in the ICU. On the other hand,
aggravation of pre-existing coronary artery disease in the
context of extreme stress associated with critical illness
can also lead to increases in troponin because of MI [35].
It has been observed that among patients admitted
to the ICU for gastrointestinal bleeding, those with risk
factors for ischemic heart disease developed ACS more
frequently than those without [36]. It can be easily
postulated that an imbalance in pro and anticoagulant
mechanisms can predispose to thrombotic (type 1) MI
in these patients, whereas endothelial dysfunction might
also play a role in limiting coronary blood flow in patients
with critical coronary lesions. In addition, tachycardia,
hypoxemia, diminished oxygen delivery, may tip the
balance of regional myocardial oxygen consumption over
the critical edge. Thus, in some cases, troponin elevation
might represent not only plaque rupture (type 1 MI) but
also a type 2 MI due to underlying coronary artery disease
and increased myocardial oxygen demand [27,28,35].
Nevertheless, the exact contribution of MI or ACS to
troponin increase in unselected critically ill patients
remains debatable.
In an older prospective study by Ammann et al. [22] in
58 consecutive patients admitted to the ICU for reasons
other than ACS, flow-limiting coronary artery disease
could be excluded with stress echocardiography or
autopsy in 72% of troponin-positive patients. On the
contrary, studies with prospective screening of critically
ill patients with 12-lead electrocardiography (ECG)
and troponin measurements conclude that troponin
elevations are associated with events of myocardial
ischemia in approximately 50% of cases [20,31,32].
Booker et al. [20] prospectively screened 76 consecutive
patients admitted to a general ICU with 12-lead ECGs for
the first 2448 h of admission and troponin assays 812 h
after the ECG monitoring period. ECG-defined ischemic
events together with troponin I elevation were observed
in six patients, who accounted for 50% of all troponinpositive results [20].
Lim et al. [31,32] applied on all patients admitted to a
general ICU over a 2-month period a systematic screen-

ing protocol (with troponin T and 12-lead ECG) over the

whole duration of hospitalization. Patients were screened
at ICU admission and then once daily for the first week;
on alternate days for up to 1 month; then weekly until
ICU death or discharge or for a maximum of 2 months.
Two adjudicators retrospectively reviewed patient charts
to determine the likely cause of troponin elevation. It
should be noted that in their institution patients with
primary cardiac diagnoses but requiring mechanical
ventilation or inotropes/vasopressors were admitted to
the ICU and not to the coronary care unit and thus were
not excluded from the study. Cardiovascular diagnosis
was present in 13.8% of patients but only one of nine
patients with cardiovascular diagnosis had an admission
diagnosis of acute MI, whereas the other eight were
surgical patients.
Of 103 patient admissions, 52 (50.5%) had one or more
elevated troponin measurements. Troponin elevation
was attributed to MI in 53.1% of patients, sepsis in
18.4%, renal failure in 12.2%, and to other causes in
16.3% (cardiac contusion/cardiopulmonary resuscitation
in 6.1%, COPD in 6.1%, congestive heart failure in 4.1%).
Of patients with MI, 61.5% were adjudicated as having
type 1 MI (plaque rupture) on the basis of a history of
coronary artery disease with typical ECG evidence of
progression of infarction (Q waves). A 38.5% of patients
were adjudicated as having type 2 MI (no risk factors or
history of coronary artery disease and presence of a
condition possibly associated with supplydemand
imbalance in the coronary circulation for example
hypotension, hypovolemia, supraventricular tachycardia).
Interestingly, no significant difference in hospital
mortality was observed between the two types of MI
(25 vs. 40%), although this lack of significance may be
associated with limited number of events [32].
Diagnosis of MI in these prospective studies was based
on current guidelines, recommending a rise and/or fall in
serum levels of troponin, together with evidence of
myocardial ischemia (clinical, electrocardiographical or
by imaging of new regional wall motion abnormalities)
[2,3]. Yet, diagnosing MI in unselected critically ill
patients remains a challenge. In these patients, not only
is chest pain a rare finding and the significance of troponin
elevation unclear, but interpretation of 12-lead ECG can
be problematic, as even ST-segment elevation has
been reported to be a nonspecific finding that is frequently the result of a variety of nonischemic processes
[20,37,38,39].
Rennyson et al. [39] retrospectively studied all cases with
electrocardiographic ST-segment elevation in an ICU: in
23 patients with ST elevation and borderline elevation of
troponin, who should have been classified as MI according
to current guidelines, echocardiographic evaluation could

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Prospective,
consecutive
Prospective,
consecutive
Prospective,
case control,
consecutive
Prospective,
consecutive
Prospective,
consecutive
Retrospective,
nonconsecutive
Prospective, consecutive.
CAD excluded with stress
ECHO or autopsy
Prospective, consecutive

Prospective, consecutive

Prospective, nonconsecutive
(81% of all ICU admissions)
Retrospective, nonconsecutive
132/221
Prospective, consecutive

Guest et al. [16]

Klein Gunnewiek and

van de Leur [19]
Booker et al. [20]

Quenot et al. [24]

Lim et al. [25]

cTnT

101 General ICU

Retrospective,
nonconsecutive

Prospective, consecutive

2078 Medical ICU

103 Medical surgical ICU

14% had cardiovascular
diagnosis on admission,
1 had MI

cTnT

cTnT

cTnT

cTnI

cTnI

cTnI

cTnT

cTnI

215 Medical ICU

132 Medical ICU

93 Medical-surgical ICU

217 Medical ICU

cTnI

47

32

45

55

Not specified

16

32

71 (0 in controls)

16

15

Frequency of
elevated cTn (%)

Association with hospital

mortality (unadjusted analysis)
Increased ICU mortality in
unadjusted analysis
Association with ICU,
hospital mortality
(univariate analysis)
Increased ICU mortality,
Increased hospital mortality
Increased hospital mortality

No association with mortality

ICU mortality increased

(univariate analysis)
Hospital mortality no effect
in multivariate analysis
Hospital mortality no
effect (univariate analysis)

Association of cTn
with mortality

Increased ICU and

hospital LOS

Increased ICU LOS

No association
with LOS

ICU LOS increased

LOS (unadjusted
analysis)

Not independent predictor of

ICU or hospital mortality
Admission
31
Unadjusted association with ICU
but not hospital mortality
No association
Admission (within 6 h)
27, 3
Association in univariate analysis
with ICU LOS
but not
independent predictor of
28-day mortality
Daily
38
Associated with 1-month,
6-month and 2-year mortality
in univariate but not multivariate
analysis
As needed
Early sampling: 42; In univariate analysis, association
late sampling: 12
with ICU but not hospital
mortality. Not independent
predictor of survival
Admission
61, 4
Independent association with:
30-day mortality, in-hospital
mortality, long-term mortality
Independent predictor of hospital
Screened at ICU admission 50.5
mortality but not of ICU mortality
and then once daily for the
first week; on alternate
days for up to 1 month;
then weekly until ICU
death or discharge for
a maximum of 2 months
Admission
42, 3
Independent association with:
30-day mortality, in-hospital
mortality, long-term mortality

Day of admission

Admission

Admission

cTnI, cTnT Enrollment, 3, 12, 24,

46, 96, 192 h

58 Medical ICU
108 Medical ICU

cTnI

cTnI

869 Surgical ICU

76 Medical-surgical

Admission, next morning

and 24 h later
812h after 2448 h
of EKG monitoring
Not specified

Daily

109 Cases and 58 controls cTnI

(healthy volunteers)
medical-surgical ICU
34 Surgical
cTnT

Daily

Sampling protocol

Daily

cTnI

cTn type

cTnI

260 Medical ICU

209 Medical ICU

Number and
type of patients

Early sampling (<48 h):

Retrospective. Patients with
171; late sampling
expected stay in ICU > 72 h;
(>48 h): 136; medicalnonconsecutive
surgical ICU
Retrospective,
929 Medical ICU
nonconsecutive

LOS, length of stay. Data from [1631,32,33].

Vasile et al. [33]

Lim et al. [31,32]

Babuin et al. [30]

Lim et al. [29]

Landesberg et al. [28] Prospective. Patients with

known stable CAD or
high risk for CAD

King et al. [27]

Minkin et al. [26]

Wu et al. [23]

Ammann et al. [22]

Relos et al. [21]

Noble et al. [18]

Kollef et al. [17]

Study design

Reference

Table 1 Troponin in unselected critically ill patients

Increased blood troponin levels in ICU patients Markou et al. 457

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458 Cardiovascular system

detect regional or global wall motion abnormalities in only

four cases. Given the fact that the prevalence of both
troponin elevation and of ECG abnormalities in the
ICU is high and that both findings are relatively nonspecific for MI, there is high probability that at least some
patients in the cohort of Lim et al. [32] with both elevated
troponin and ECG abnormalities did not actually have MI.
Unluckily, neither Booker et al. nor Lim et al. routinely
performed echocardiograms as part of their screening
protocol, whereas angiography was also not part of the
protocol. Thus an unequivocal determination of the exact
frequency of MI in the ICU setting is not possible
at present.
Lim et al. [31] report that in less than half of their MI
patients was a clinical diagnosis possible by ICU staff and
only screening provided 62.2% of MIs ultimately diagnosed. They conclude that MI in the ICU can be an
elusive diagnosis in the absence of systematic screening
with troponin and ECGs. An alternative explanation
might be that their screening protocol resulted in overdiagnosis of MI. Yet, if the findings of Lim et al. are
confirmed by further studies, and the prevalence of MI in
unselected critically ill patients is indeed as high as that
reported by these investigators, then one can ask whether
all critically ill patients should undergo screening (with
troponin and ECG or imaging) for MI. For the time
being, the answer is probably negative: it is currently
unknown whether higher detection rates of MI will
translate into better clinical outcomes through targeted
therapy. The results of the study by Lim et al. also do not
support a strategy of systematic screening: there was
no difference in outcome between patients with MI
detected by staff and MI detected solely by screening.
With clinicians blinded as to the screening diagnosis
which did not affect patient management in their cohort,
this casts doubt to the hypothesis that a diagnosis of MI
can improve outcome in the critically ill [31]. On the
contrary, further prospective studies with screening
(including troponin, ECG and probably echocardiography as well) to further clarify the cause of troponin
elevations in the ICU would be highly welcome.

The prognostic significance of troponin in

unselected critically ill patients
There is no unanimity on the prognostic significance
of troponin in unselected critically ill patients [1631,
32,33] (Table 1). Some investigators report that
troponin is an independent predictor of ICU or hospital
mortality [24,30,31,33] and others find no association
whatever [18,19]. Other studies report associations with
mortality, but they either do not control for other variables [16,2023,26] or these associations do not persist in
multivariate analysis [17,25,27].

Associations have also been reported with length of ICU

[16,21,24] and hospital stay [24,40], although in this case
there is no adjustment for other variables.
A meta-analysis concluded that troponin was a univariate
predictor of death in the ICU (eight studies with no
adjustment for confounding variables, with a total of
1019 patients), whereas cumulative data from six more
studies with adjustment for confounding variables (a total
of 1706 patients) demonstrated that troponin was an
independent predictor of death [odds ratio (OR) 2.5;
95% confidence interval (CI) 1.93.4]. Moreover, this
meta-analysis concluded that troponin was associated
with an increased length of ICU stay of 3.0 days and
an increased length of hospital stay of 2.2 days (unadjusted data) [15].
Reaffirmation of a prognostic significance for troponin is
provided by a large retrospective study by Babuin et al.
[30]. They reviewed the files of 1657 consecutive unselected patients admitted to medical ICU, 929 of whom
had a cTnT measurement within 6 h of admission.
Cardiovascular causes of admission were not excluded.
Troponin was elevated in 61.3% of the patients, with
mostly small to modest increases. Troponin was an independent predictor of 30-day and in-hospital mortality
with no difference observed between cardiovascular
and noncardiovascular admissions.
A recent retrospective study of 240 critically ill patients
with normal (<0.1 ng/ml) or intermediate (0.11.49 ng/ml)
cTnI levels, concludes that even borderline elevations
of cTnI are independently associated with in-hospital
mortality and length of ICU stay (but not length of
hospital stay, readmission rate, or postdischarge mortality
at 6 months) [40].
Surprisingly, in the study of Babuin et al. [30] elevated
cTnT on admission was independently associated with
long-term mortality even at 3 years of follow-up, with no
difference observed between cardiovascular and noncardiovascular admissions. Two more retrospective studies
from the same group [33,41] support an association of
troponin at admission to the ICU with long-term outcome. Elevated troponin upon admission was independently associated with in-hospital, short-term and longterm mortality (up to 3 years follow-up) in a cohort of
2078 patients who had troponin measurement out of a
total of 4433 consecutive admissions to the ICU for a
respiratory condition [33]. In another retrospective
cohort of 754 patients who had troponin measurements
out of a total of 1076 consecutive ICU admissions for
acute gastrointestinal bleeding, troponin levels on admission were independently associated with long-term
mortality (though not with short-term mortality) [41].
These findings suggest that even after hospital discharge

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Increased blood troponin levels in ICU patients Markou et al. 459

there might be an opportunity to intervene in patients

who were troponin-positive on admission to the ICU, in
an effort to improve long-term outcome.
An older study by Lim et al. suggests that the prognostic
significance of troponin elevations in the ICU may vary
depending on the cause of troponin elevation, for example
myocardial ischemia vs. nonischemic origin: they concluded that MI during ICU stay is an independent predictor of hospital mortality [odds ratio (OR) 3.2], whereas
an isolated increase in troponin was not independently
predictive of ICU or hospital mortality [25]. Later highquality prospective data from the same group [31,32]
indeed confirmed that prognostic significance depends on
the cause of troponin elevation, but the implications
on prognosis were different, with troponin elevation in
the absence of MI appearing to favor a worse outcome. In
this cohort, ICU mortality was 2.0% for patients with no
troponin elevation, 23.1% in patients with MI, and 39.1%
in patients with troponin elevation not due to MI. Elevated
troponin in the absence of MI was independently associated with hospital (but not ICU) mortality. Associations
of elevated troponin in the presence of MI with mortality
did not persist in multivariate analysis [31].

Troponin in sepsis
Troponin elevation is a common finding in patients with
sepsis [4257,58,59] (Table 2). Troponin levels in
these patients seem to be associated with disease severity
[4247,50,58,59] and presence of shock [47,55,59],
whereas a study of hospitalized bacteremic patients
also reports associations with kidney function, severity
of the underlying infection, and underlying cardiac
disease [60].
The close association of high-sensitivity troponin T
(hs-TnT) with N-terminal pro b-type natriuretic peptide
(NT-proBNP) suggests myocardial origin of troponin
elevation in sepsis [59]. Although some septic patients
with elevated troponin may have either nonspecific ECG
changes [46,50] or regional wall motion abnormalities
[47], on the whole, neither objective testing [22,45,46]
nor the high occurrence of elevated troponin in a population of pediatric sepsis [48] supports the concept that
flow-limiting coronary artery disease is the main cause of
troponin release in sepsis. Troponin release in this
population is most probably the result of low-grade
cytokine-mediated cardiomyocyte injury with transient
loss in membrane integrity and troponin leakage. Sepsisrelated factors like apoptosis, increase in intracellular
calcium, oxidative stress or uncoupling of oxidative phosphorylation may also contribute, whereas microvascular
thrombotic injury or systemic hypotension resulting in
suboptimal coronary artery blood flow cannot be excluded
as additive factors in some cases [6163,64].

A recent study concludes that thrombus-associated myocardial damage is unlikely to have a major role in troponin
release in sepsis. The authors studied 38 consecutive
patients with sepsis without evidence of ACS, 58% of
whom were cTnI-positive. Extensive investigation of
coagulation parameters could not demonstrate differences
between cTnI-positive and negative patients in the extrinsic, intrinsic or common pathway of coagulation [64].
It has long been observed that troponin may be associated
with nonischemic systolic dysfunction, mainly in patients
with sepsis [43,45,47,49] but also in unselected critically ill
patients [22]. The more recent findings of Bouhemad et al.
[54,65] expand this association to nonischemic diastolic
dysfunction as well, with troponin featuring as a reliable
index of sepsis-induced myocardial dysfunction.
Bouhemad et al. studied prospectively 54 patients with
septic shock: at days 1, 2, 3, 4, 7, and 10 after onset of
septic shock they performed echocardiography with
tissue Doppler and measurement of cTnI and cytokines.
An increase in cTnI was observed in 22 patients, half of
whom had both systolic and diastolic dysfunction
together with acute and left-ventricular dilation, whereas
the rest had isolated impairment of left-ventricular relaxation. Echocardiographic findings in patients with
increased cTnI were reversible with reversal of shock.
Improvement of diastolic dysfunction went in parallel with
a progressive decrease in cTnI values and with decreases in
tissue necrosis factor-alpha (TNF-a), IL-8, and IL-10.
The observed improvement in impaired myocardial performance after disease recovery, speaks against major
myocardial cell death in sepsis. On the contrary, patients
with normal cTnI values had either normal systolic and
diastolic function, or in some cases, diastolic dysfunction
that persisted after reversal of shock (and most probably
pre-existed) [54,65]. Associations with mortality were not
assessed in this cohort [54,65], but according to other
investigators diastolic dysfunction is an independent
predictor of hospital survival in septic shock [57].
Although measurements of troponin may facilitate recognition of sepsis-induced myocardial dysfunction, the lack
of established treatment for this entity limits the role of
troponin in the management of sepsis at this time. On the
contrary, troponin can be utilized in the context of
future therapeutic trials in order to target patients with
possible sepsis-induced myocardial dysfunction.
A single-center study by John et al. [50] suggests that
troponin can be used to guide treatment with activated
protein C (APC). In this study patients were prospectively defined but cTnI was measured at the discretion of
the primary physician. The same study group in a retrospective analysis of data from the PROWESS study could
not replicate this finding [58]. Further study is needed

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Prospective, consecutive

Prospective, consecutive. Case-control

Prospective, consecutive

Prospective. Enrollment not specified

Prospective; enrollment not specified

Prospective; nonconsecutive

Prospective. Consecutive patients

requiring pulmonary artery catheter
Prospective, consecutive

Prospective. Enrollment not specified

Prospective. Consecutive

ver Elst et al. [45]

Ammann et al. [46]

Mehta et al. [47]

Fenton et al. [48]

Brivet et al. [49]

John et al. [50]

Scott et al. [51]

Yucel et al. [52]

Choon-ngarm and
Partpisanu [53]
Bouhemad et al. [54]
Oliveira et al. [55]

Retrospective data from PROWESS

study. Nonconsecutive
Nonconsecutive; patients admitted
to ICU with severe sepsis

Data from [4257,58,59].

Rsj et al. [59 ]



John et al. [58 ]



Sturgess et al. [57]

Long-term follow-up for sepsis of a

cohort of 305 ESRD patients
Prospective consecutive

Surgical ICU. Septic shock 54

218 Pediatric ICU

Prospective, consecutive. Case-control

Turner et al. [44]

Kang et al. [56]

66; surgical ICU. Severe sepsis,

septic shock
40 patients admitted with sepsis
to medical-surgical ICU
40 with septic shock

Prospective. Enrollment not specified

Fernandes et al. [43]

Medical-surgical ICU 21 septic

shock
598 of 1690 patients (those who
had available results)
Subgroup from FINNSEPSIS
study 254

121 ESRD patients with sepsis

105 patients with severe sepsis

23 children with septic shock

Not specified. 118

Medical-surgical; 15 patients with

septic and 6 nonseptic shock
controls
Medical-surgical. 46 patients with
septic shock
20 patients with sepsis,
20 nonseptic critically ill controls
Medical surgical. 37 septic shock

10-medical surgical

26-surgical ICU

Prospective. Enrollment not specified

Spies et al. [42]

Number and type of patients

Study design

Reference

Table 2 Troponin in sepsis

Conventional
cTnT assay;
hs-cTnT assay

cTnI

cTnT

cTnI

cTnI.
cTnI

cTnT

cTnI

cTnI

cTnI

cTnI
cTnI

cTnI

cTnI

cTnI, cTnT

cTnI

cTnI

cTnT

cTn type

Admission to ICU, 72 h

Enrollment

Within 72 h of shock

Days 1,2, 3, 4,7, 10

Within 24 h from
enrollment
Onset of sepsis

At catheterization and
every 68 h thereafter
At admission, day 2,
day of discharge

Enrollment

Initial 72 h
Not specified

Enrollment, 24, 48 h

Within 24 from onset

Enrollment, 24 and 48 h

Every 4 h on day 1.
Then daily for 7 days
Within 12 h from
admission
Daily until end of sepsis

Sampling protocol

Admission: 42 with
fourth-generation
assay, 80 with
hs-cTnI assay

75

67

41.3

40
4.5

42, 5

Not specified

64

46

57
Not specified

43

85 vs. 0 in controls

50 cTnI, 36 cTnT

80 vs. 17 in controls

60

69

Frequency of
elevated cTn (%)

Association (univariate analysis)

after day 1 with ICU mortality
Association with mortality
(univariate analysis)
Increased (univariate analysis)
No association with hospital
mortality (multivariate analysis)
Independent association with
3-month and 6-month mortality
No association with hospital
mortality (multivariate analysis)
Independent predictor of
28-day mortality
No association with hospital
mortality (multivariate analysis)

No association with hospital

mortality (multivariate analysis)
Increased sepsis mortality
(univariate)
No association with mortality

Increased ICU mortality

(univariate)

Association with hospital

mortality (univariate analysis)
Not addressed

Increased sepsis mortality

(univariate)
Not addressed

Not addressed

Association with mortality

460 Cardiovascular system

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Increased blood troponin levels in ICU patients Markou et al. 461

to determine whether troponin can serve as a simple,

readily available marker to identify which patients with
severe sepsis will benefit from APC, or possibly from
other innovative treatments of sepsis.

Prognostic significance of troponin in septic

patients
Several [43,45,47,52], but not all [49,51,55] studies conclude that troponin is an independent predictor of
adverse short-term outcome in sepsis (Table 2), whereas
it has also been associated with length of ICU stay in
sepsis patients [47]. Reasons for differences in the predictive role of troponins in sepsis may be related to small
sample size in some studies or to differences in the
characteristics of troponin assays utilized.
Recently, three sepsis studies reporting on associations
between elevated troponin and outcome were published
[56,58,59].
The study of John et al. [58] was a retrospective analysis
of material from the PROWESS study: baseline cTnI
data were available in 598 nonconsecutive patients from
this cohort. Troponin-positive patients had a significantly
higher 28-day mortality (32 vs. 14%) and this difference
was observed in both the APC-treated and placebo-treated
groups. Elevated cTnI was also an independent predictor
of mortality (OR 2.020; 95% CI 1.1533.541) [58].
In a retrospective cohort of 121 patients with end-stage
renal disease (ESRD) and sepsis, cTnI was an independent predictor of mortality at 90 days from onset of sepsis
(OR 5.13) and of mortality at more protracted follow-up
(180 days) (hazard ratio 5.90; 95% CI 2.0616.9) [56].
It should be noted that the cut-off value for troponin
in this study was defined as the value providing the best
diagnostic accuracy for mortality based on receiver
operating characteristic curve (ROC) analysis and not
the cut-off by the manufacturer.
The study by Rsj et al. [59] reported on a subgroup of
patients from the prospective FINNSEPSIS study. From
a total of 470 patients who were enrolled with severe
sepsis or septic shock in this cohort, 254 consented for
blood sampling for troponin: cTnT levels were measured
by a novel hs-cTnT assay at two time points (inclusion
and 72 h thereafter). Results for the hs-cTnT assay were
compared to those of the established fourth-generation
cTnT assay (lower limit of detection 0.003 mg/l vs.
0.01 mg/l for fourth-generation assay). At inclusion in
the study, cTnT was detectable in 60% of patients with
the conventional assay and in 100% with the hs-cTnT
assay, whereas increased levels were found in 42% with
the standard assay and in 80% with hs-cTnT assay. At
72 h, troponin was still detected in 57% of patients with
the conventional assay and in 100% with hs-cTnT assay,

whereas it remained elevated in 7% of patients with the

conventional assay and in 79% with the hs-cTnT assay.
Survivors had higher levels of hs-cTnT on inclusion,
whereas no difference in troponin values was observed
with the conventional assay. Troponin was not independently associated with in-hospital mortality, regardless of
assay but, interestingly, hs-cTnT on inclusion was independently associated with development of shock during
hospitalization (OR 2.45; 95% CI 1.095.53) and could
predict development of septic shock with a sensitivity of
86% and specificity of 33% [59]. This role of cTnT as an
index of impending shock in early sepsis needs to be
confirmed in further studies.
The study by Rsj et al. highlights the importance of
the characteristics of troponin assays which may be a
partial explanation for the divergence of results between
existing studies of troponin in critical illness and sepsis.

Conclusion
Troponin is frequently elevated in the critically ill, and
recent data suggest that MI is the underlying (and often
unrecognized) cause of such elevations in a large proportion of these patients. Recent studies also reinforce
the impression that troponin may be an independent
predictor of short-term outcome in critical illness and
expand the predictive role of troponin to the long-term
outcome of this patient population.
In sepsis, troponin elevations do not seem to be commonly related to ACS, but are probably associated with
reversible sepsis-induced myocardial dysfunction. There
are newer data on the predictive role of troponin in sepsis,
although the verdict on this question is not unanimous.
Recent findings on troponin need to be confirmed in
larger and more systematic prospective trials enrolling
consecutive patients. More research is also needed on the
possible implications of these findings in the clinical
management of mixed critically ill patients and patients
with severe sepsis or septic shock.

Acknowledgements
Conflicts of interest
There are no conflicts of interest.

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:

of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 539).
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