Cardiac troponin I in pediatrics: Normal

values and potential use in the

assessment of cardiac injury
Russel Hirsch, MBChB, Y v o n n e Landt, MS, Sharon Porter,
Charles E. Canter, MD, Allan S. Jaffe, MD, J a c k H, Ladenson, PhD,
James W. Grant, MD, a n d M i c h a e l Landt, PhD
From the Departments of Pediatrics, Pathology, and Medicine, and the Divisionof Labora-
tory Medicine of Washington UniversitySchool of Medicine, St. Louis,Missouri,and the Car-
diovascular Division,State Universityof New York Health Center, Syracuse

Objective: To establish normal values and determine the impact of congenital or

acquired heart disease on serum cardiac troponin I (cTnl).
Methods: Concentrations of cTnl were measured in two groups of children. Group
A represented ambulatory pediatric patients with no apparent cardiac disease
(n = 120) and patients in stable condition with known congenital or acquired car-
diac abnormalities (n = 96); group B was composed of patients admitted to inten-
sive care units with normal echocardiograms (n = 16), with abnormal echocar-
diograms (n = 36), and those with blunt chest trauma who were thought to have
cardiac contusions (n = 7).
Results: The cTnl concentrations were generally less than 2.0 ng/ml in group A and
frequently below the level of detection for the assay (1.5 ng/ml). There was no
statistical difference between the two outpatient subgroups (p = 0.66). Nine
intensive care patients had cTnl values greater than 2.0 ng/ml. Six of these
patients, all with abnormal echocardiograms, had values less than 7.7 ng/ml. All
improved and had subsequent normal cTnl concentrations. None of the three re-
maining patients (two with systemic illness [trauma and sepsis] and one with se-
vere pulmonary hypertension), all with values greater than 8.0 ng/ml, survived.
Three of the four patients with high likelihood of cardiac contusion had cTnl con-
centrations greater than 2.0 ng/ml (including one patient who died).
Conclusions: Cardiac troponin-I values are generally not elevated in children with
stable cardiac disease or general pediatric conditions. In the context of severe
acute illness, significant elevation of cTnl may be an indicator of poor outcome.
Elevation of cTnl may also have diagnostic value in cases when cardiac contu-
sion is suspected. (J Pediatr 1997; 130:872-7)

The recent development of sensitive and specific assay pro- dial infarction, especially in postoperative patients, and-in the
cedures for the cardiac troponins has markedly improved the detection of cardiac contusion where the MB isoenzyme of
diagnosis of myocardial injury in adults.I, 2 Cardiac troponin
I measurements have proved useful in diagnosing myocar- See commentary, p. 853.

Submitted for publication June 21, 1996; accepted Nov. 15, 1996.
Dr. Jaffe and Dr. Ladenson are consultants to Dade International. I cTnI Cardiactroponin I [
CK-MB Creatine kinase, MB isoenzyme
Reprint requests: Michael Landt, PhD, Department of Pediatrics,
Washington University School of Medicine, One Children's Place,
St. Louis, MO 63110. creatine kinase can be elevated as a result of skeletal muscle
Copyright © 1997 by Mosby-Year Book, Inc. damage. 2-6
0022-3476/97/$5.00 + 0 9/21/79370 The reason for this improved accuracy is that release of

872
The Journal of Pediatrics
Volume 130, Number 6
cTIfl into the blood appears to be highly specific for cardiac
injury. Cardiac troponin I is found only within the myocar-
dial cell and is a potent inhibitor of the process of actin-my-
osin cross-bridge formation] Fetal hearts contain two cTnI
isoforms: the adult cardiac isoform and an isoform similar
to that found in adult slow-twitch skeletal muscle. The
slow-twitch isoform is the predominant form in both rat and
human fetal hearts, but with maturation, the slow-twitch
isoform is replaced until at birth only the adult cardiac iso-
form is detectable, s This serves as the basis for a growing
number of literature reports about the specificity and sensi-
tivity of cTnI as a marker for cardiac injury. 9
There is a need in pediatrics for a sensitive and specific
test that would allow for the identification of myocardial cell
damage in either isolated conditions or associated with other
pathologic conditions. The clinical tests routinely used for
adults may not have the same sensitivity or specificity in
children. The utility of measuring serum cTnI for diagnostic
or screening purposes in a pediatric population is not yet
known. Normal values have not been established, and the
impact of congenital or acquired heart disease on serum cTnl
values is unclear. This study was conducted to clarify these
issues.
METHODS
Patient population. Initial studies surveyed cTnI con-
centrations in two broad population groups (designated A
and B) in relation to a variety of general pediatric diseases
between Janum2¢ 1994 and December 1995.
Group A patients included ambulatory pediatric patients,
further subdivkied into two groups: group A1, 120 ambula-
tory pediatric patients (73 boys/47 girls, mean age 11.6
months, range 0 to 29 months) without apparent heart dis-
ease, but with a variety of other pediatric diseases (clinic pa-
tients); and group A2, 96 patients (50 boys~46 girls, mean age
47 months, range 0 to 228 months) with known congenital
and acquired cardiac diseases at various stages during their
courses (patients in nonacute condition arriving for ongoing
therapy or surgical repair).
Blood samples from these patients were collected when
either routine laboratory tests were performed or in con-
junction with preoperative evaluations.
Group B patients included 59 inpatients in a multidisci-
plinary pediamc intensive care or neonatal intensive care
setting who were included after the performance of echocar-
diography. The decision to request an echocardiogram in any
patient was made,, by clinicians independent of knowledge of
the study. Group B was further subdivided into three groups
according to the results of their echocardiograms: group B1,
16 patients (10 boys/6 girls, mean age 26.2 months, range 0
to 204 months) shown to have no anatomic cardiac abnor-
malities; group B2, 36 patients (17 boys/19 girls, mean age
3.1 months, range 0 to 96 months) with cardiac abnormal-
Hirsch et al. 873
ities of varying severity; and group B3, 7 patients (4 boys/3
girls, mean age 126 months, range 44 to 220 months) with
blunt chest trauma. These patients were suspected of having
sustained cardiac contusions based on the nature of their in-
jury (obvious blunt trauma to the chest area, pulmonary
contusion on chest radiograph, and hemodynamic instabil-
ity). They were classified as high likelihood or low likeli-
hood of contusion by a clinician, unaware of their cTnI val-
ues, on the basis of their injuries and echocardiographic and
electrocardiographic findings.
Blood samples from these patients were collected when
specimens for other laboratory evaluations were being
obtained, and within 36 hours of admission.
All studies were conducted in accordance with a protocol
approved by the Human Studies Committee of Washington
University.
Cardiac troponin I. Concentration of cTnI was assayed
by a sandwich immnnoassay in a preliminary research
application that recognizes two different epitopes of cTnI
and has no detectable cross-reactivity with skeletal muscle
troponin I. J The limit of detection for this assay is 1.5 ng/ml.
This value is equivalent to a value of 0.4 ng/ml with the
commercially available assay (Dade International). Labora-
tory personnel performing the assay were unaware of the
clinical status of the patients.
Echoeardiography. Apart from the ambulatory pediatric
patients (group A1), all patients had two-dimensional
echocardiograms (Hewlett-Packard Sonos model 1500) per-
formed with standard views recommended by the American
Society of Echocardiography.10 Patients in the intensive care
unit (group B) had these evaluations performed within 24
hours of admission, and usually within 12 hours of blood
sampling for cTnI. Echocardiographic interpretation was
performed by a senior staff cardiologist who was unaware of
the indication for the test or knowledge of patients' inclusion
in the study.
Electrocardiography. Patients with suspected cardiac
contusion underwent 12-lead electrocardiography (Mar-
qnette Electronics, Mac Vu electrocardiogram) within 24
hours of admission, with standard 12-lead placement. Inter-
pretation was performed by a senior staff cardiologist
unaware of inclusion criteria for the study.
Statistical analysis. Statistical differences were assessed
by the Wilcoxon Rank Sum Test (significant values p <0.05).
RESULTS
Serum cTnI values were less than 2.0 ng/ml in 117 of the
120 ambulatory patients without cardiac disease (group A1)
and were frequently below the level of detection for the as-
say, regardless of diagnosis (Table IA). There was no age
dependency evident in the cTnI values in these patients.
Three patients from this group had levels measured between
2.0 and 4.8 ng/mi. Review of the patients' medical histories
874 Hirsch et al. The Journal of Pediatrics
June 1997

Table IA. Ambulatory pediatric patients (group A1) Table lB. Ambulatory cardiology patients (group A2)
(n = 120) (n = 96)

Diagnosis cTnl -<2 Diagnosis cTnl -<2

Gastrointestinaldisorders Left-to-right shunts
Diarrhea 14 Atrial septal defect 22
Vomiting 11 Ventricular septal defect 12
Failure to thrive 6 Atrioventricularcanal 4
Constipation 6 Patent ductus arteriosus 3
Hepatitis 4 Cyanotic lesions
Short gut syndrome 3 Tetralogy of Fallot 12
Gastroesophagealreflux 4 Transposition of great arteries 4
Neurologic disorders Complete mixing lesions
Seizures* 21 Tricuspid/pulmonaryatresia 13
Cerebral palsy 5 Truncus arteriosus 1
Developmental delay 3 Valve disease
Hydrocephalus 2 Pulmonary stenosis 11
Renal disorders Aortic stenosis 3
Urinary tract infection 7 Aortic insufficiency 1
Multicystic-dysplastickidney 4 Mitral insufficiency 1
Nephritis 4 Cardiomyopathy
Hydronephrosis 3 Dilated 1
Reflux 1 Hypertrophic 1
Pulmonary disorders Restrictive 1
Pneumonia 6 Miscellaneous
Bronchopulmonary dysplasia 4 Left ventricular aneurysm 1
Metabolic disorders Concentrationsof cTnI were measuredin nanogramsper milliliter.
Diabetes 7
Rickets 1
Congenital adrenal hyperplasia 1
Orthopedic disorder
Genu valgum? ng/ml) in these four patients decfined to less than 2.0 ng/ml
within 36 hours of the initial measurement. Two of these
Concentrationsof cTnI were measuredin nanogramsper milliliter.
*Two other patients in group A1 had cTnI concentrationsof 2 to 8 ng/ml. patients required inotropic support to maintain normal
-?Theone patientin group A1 with this diagnosishad a cTnI concentration hemodynamic parameters (one patient with birth asphyxia
of 2 to 8 ng/rrd. and the other with congestive heart failure as a result of a
cerebral arteriovenous malformation). A third patient with
hypoplastic left heart syndrome received intravenously ad-
did not reveal a common link or suspicion of cardiac disease, ministered prostaglandin E to maintain patency of the duc-
and subsequent echocardiograms performed in two of these tus arteriosus before surgical intervention. She, as well as the
three patients were normal. All 96 ambulatory patients with fourth newborn patient with elevated cTnI values who had
known cardiac disease (group A2) had cTnI values less than a diagnosis of a subdural hematoma and a coronary fistula,
2.0 ng/ml (Table IB). Mean cTnI values in group A2 com- had stable hemodynamic status. The fifth patient was a 13-
pared with group A1 were statistically similar (p = 0.66). year-old with Down syndrome and severe pulmonary hy-
Intensive care patients (group B) were designated as car- pertension. She arrived at the hospital in extremis as a result
diac and noncardiac groups on the basis of echocardio- of severe right ventricular failure and despite maximal med-
graphic findings (Tables IIA and IIB). The cTnI concentra- ical intervention, died within 36 hours of admission. Her
tions in the 16 patients with normal echocardiograms (group initial cTnI concentration was 13.7 ng/ml, with subsequent
BI) were all less than 2.0 ng/ml, with the exception of one values all greater than 5.0 ng/ml.
patient with a value of 8.2 ng/ml. This patient had systemic Seven patients were evaluated for cardiac contusion after
sepsis and multiorgan failure, and cTnI remained above 2.0 sustaining blunt chest trauma (group B3), Four of these pa-
ng/ml until death (3 days after the initial level was obtained). tients were considered to have a high likelihood of cardiac
Of the 36 patients with abnormal echocardiograms (group contusion on the basis of the nature of their injuries,
B2), 5 were found to have cTnI values greater than 2.0 ng/ml echocardiographic and electrocardiographic results, and
(range 2.2 ng/ml to 13.7 ng/ml). Four of these patients were their clinical course~ Of these, three had cTnI values greater
newborn infants. The cTnI values (range 2.2 ng/ml to 7.6 than 2.0 ng/ml (Table III). One patient with severe multi-
The Journal of Pediatrics Hirsch et aI. 875
Volume 130, Number 6

Table IIA. Intensive care patients with normal Table lIB. Intensive care patients with abnormal
echocardiograms (group B1) (n = 16) echocardiograms (group B2) (n = 36)

Diagnosis cTnl <2 Diagnosis cTnl <2

Gastrointestinal disorders Left-to-fight shunts
Diarrhea 1 Patent ductus arteriosus I1
Neurologic disorders Ventricular septal defect 4
Seizures 3 Atrial septal defect 2
Pulmonary disorders Atrioventricular canal 1
Respiratory distress syndrome 4 Cyanotic lesions
Pneumonia 3 Transposition of great arteries 3
Asthma 2 Complete mixing lesions
Trauma Tricuspid/pulmonary atresia 2
Femur fracture 1 Hypoplastic left heart syndrome*
Miscellaneous Valve disease
Persistent fetal circulation 1 Ebstein anomaly 2
Sepsis/multiorgan failure* Mitral insufficiency 1
Concentrationsof cTnI were measured in nanogramsper milliliter. Cardiomyopathy
*The one patient in group B1 with this diagnosishad a cTnI concentration Dilated 2
of 2 to 8 ng/ml. Miscellaneous
Cor tfiatriatum l
Coronary fistula*
organ trauma had an initial cTnI value of 10.3 ng/ml. She Pulmonary vein stenosis 1
died within 5 hours of admission as a result of her injuries. Pulmonary hypertension?
Superior vena cava thrombus 1
All patients in the subgroup considered to have low likeli- Arteriovenous malformation*
hood of cardiac contusion had cTnI values less than 2.0 ng/ Birth asphyxia*
ml. Concentrationsof cTnI were measuredin nanogramsper milliliter.
*The patientin group B2 with this diagnosishad a cTnI concentrationof 2
DISCUSSION to 8 ng/ml.
?The patient in group B2 with this diagnosishad a cTnI concentrationof
We have shown that cTnI values are usually less than 2.0 greater than 8 ng/ml.
ng/ml in the absence of discernible myocardial damage in a
wide variety of different pediatric conditions. This finding
was consistent in infants and children with hemodynamically have potential value as a diagnostic tool for cardiac contu-
stable cyanotic and acyanotic congenital, and nonacute ac- sion in children, as it does in adults. 4 Contusion is a difficult
quired heart disease. It is also evident from our results that but important diagnosis to establish, because it may alter
moderate elevation of cTnI (<8.0 ng/ml) is rare in a pediat- immediate management decisions. 12 When trauma is mas-
ric population, except in critically ill patients. All three crit- sive, it is often impossible to determine whether hemody-
ically ill patients in our study with cTnI elevations greater namic instability is a result of depressed myocardial function
than 8.0 ng/ml died within 72 hours. These results are sim- from contusion or from concomitant injury. In such settings,
ilar to those observed in critically ill adults in whom eleva- it would obviously be useful to be able to assess the presence
tions of cTnI are a potent prognostic factor. 1~ For two of and extent of cardiac trauma by a simple biochemical test.
these patients, multiorgan involvement was the cause of However, because of the frequent accompaniment of signif-
death (systemic sepsis and multiorgan trauma), whereas the icant multiorgan and skeletal muscle injuries, elevation of
third had a primarily cardiac cause resulting in final decom- the MB isoenzyme of creatine kinase is not specific for car-
pensation. The significance of moderate elevation of cTnI diac injury in this setting, resulting in diagnostic confusionS3;
seen in neonates who are critically ill is uncertain. It is pos- hence the appeal of a sensitive assay for cTnI with myocar-
sible that small degrees of myocardial damage associated dial specificity. However, the major limitation in establish-
with these elevations do increase risk and may have ing serum cTnI measurement as a sensitive diagnostic tool
long-term sequelae. Nevertheless, further prospective study in pediatric patients with cardiac contusion is the lack of an
is needed to clarify this issue, and to determine whether el- adequate gold standard for comparison. ~4 In adults, compar-
evation of cTnI above a threshold level has significance as ison with total creatine kinase, CK-MB, and electrocardio-
a prognostic factor. graphic and echocardiographic abnormalities has established
The modest correlation of cTnI with blunt chest trauma cTnI in diagnosing cardiac contusions. 4 Ongoing studies are
presented in this series of patients suggests that cTnI may now aimed at addressing these issues in pediatric patients.
876 Hirsch et al.
T a b l e Ill. Patients with blunt chest trauma (group B3) (n = 7)
Patient Likelihoodof
No. contusion Echocardiogram
1 High Normal
2 High Flattened septal motion
3 High Flattened septal motion
4 High Global myocardial
dysfunction
5 Low Normal
6 Low Normal
7 Low Normal
Plasma cTnI is a sensitive and specific marker of myocar-
dial cell injury in adults, especially in patients with ischemic
heart disease, z, 4,15 The monoclonal antibodies developed
for the assay of cTnI have no detectable cross-reactivity with
the skeletal muscle forms of the protein. Cardiac troponin I
has comparable sensitivity to CK-MB measurement for di-
agnosis of myocardial infarction, but offers improved spec-
ificity because of the exclusive cardiac source, whereas the
presence of small amounts of CK-MB in skeletal muscle can
generate false-positive or confusing results? Cardiac ische-
mia as a result of coronary artery disease is rare in children.
Nevertheless, there are multiple instances in both congenital
and acquired pediatric heart disease in which myocardial
damage and cell necrosis is the ultimate pathophysiologic
phenomenon resulting in cardiac decompensation and cfin-
ical presentation. These include varied congenital pathologic
conditions such as anomalous origin of coronary arteries and
neonatal myocardial infarction, acquired diseases such as
Kawasaki disease with the long-term sequelae of coronary
aneurysms and coronary stenoses, and processes such as an-
thracycline cardiotoxicity in the treatment of malignan-
cies.16-18Further, necrosis in certain conditions such as acute
myocarditis may be limited or occur over an extended period
that diagnostic elevations of CK-MB are not achieved. The
sensitivity of CK-MB fraction as a diagnostic marker in
children is lower than in adults, because developmental ex-
pression of the B subunit results in increased concentration
of CK-MB in skeletal muscle. 19 As a result, the origin of the
enzyme in patients who are frequently undergoing instru-
mentation and procedures as part of their diagnostic evalu-
ation is often unclear. The advent of a sensitive assay for
cTnI thus offers the possibility of detecting lesser degrees of
myocardial cell damage in these conditions that uniquely af-
fect the pediatric population. Elevation of cTnI may also
prove useful in the selection of donor hearts for transplan-
tation, allowing for rapid biochemical screening of poten-
tially suitable grafts. 2°
We thank Marsha Kuhns for technical assistance.
The Journal of Pediatrics
June 1997
cTnl
Electrocardiogram (ng/ml) Outcome
Ventricularbigeminy 1.6 Alive
Normal 2.1 Alive
Normal 3.8 Alive
Normal 10.3 Dead
Normal <1.5 Afire
Normal 1.8 Alive
Normal <1.5 Alive
REFERENCES
1. Bodor GS, Porter S, Landt Y, Ladenson JH. Development of
monoclonal antibodies for an assay of cardiac troponin-I and
preliminaryresults in suspectedcases of myocardialinfarction.
Clin Chem 1992;11:2203-14.
2. Adams JE, Davila-Roman VG, Delmez JA, Apple FS, Laden-
son JH, Jaffe AS. Cardiac troponin-I: a marker with high spec-
ificity for cardiac injury. Circulation 1993;88:101-6.
3. Etievent JP, Chocron S, Touhin G, Taberlet C, Alwan K,
Clement F, et al. Use of cardiac troponin I as a marker of pe-
rioperative myocardial ischemia. Ann Thorac Surg 1995;59:
1192-4.
4. Adams JE, Davila-Roman VG, Bessy PQ, Blake DP, Laden-
son JH, Jaffe AS. Improved detection of cardiac contusion with
cardiac troponin-I. Am Heart J 1996;131:308-12.
5. Britton CV, Hemandez A, Roberts R. Plasma creatine kinase
isoenzyme in infants and children: characterization in normal
patients and after cardiac catheterization and surgery. Chest
1980;77:758-60.
6. Adams JE, Sicard GA, Allen BT, Bridwell KH, Lenke LG,
Davila-Roman VG, et al. Diagnosis of perioperative myocar-
dial infarction with measurementof cardiac troponin I. N Engl
J Med 1994;330:670-4.
~7. Farah CS, Reinach FC. The troponin complex and regulation
of muscle contraction. FASEB J 1995;9:755-67.
8. Sasse S, Brand NJ, Kyprianou P, Dhoot GK, Wade R, Arai M,
et al. Troponin I gene expression during human cardiac devel-
opment and in end-stageheart failure. Circ Res 1993;72:932-8.
9. Adams JE, Schechtman KB, Landt Y, Ladenson JH, Jaffe AS.
Comparable detection of acute myocardial infarction by creat-
ine kinase MB isoenzyme and cardiac troponin I. CiliaChem
1994;40:1291-5.
10. Henry WL, DeMaria A, Gramiak R, King DL, Kisslo JA, Popp
RL, et al. Report of the American Society of Echocardiography
on nomenclature and standards in two-dimensionalechocardi-
ography. Circulation 1980; 62:212-7.
11. Guest TM, Ramanathan AV, Tnteur PG, Schechtman KB,
Ladenson JH, Jaffe AS: Myocardial injury in critically ill pa-
tients: a frequently unrecognized complication. JAMA 1995;
273:1945-9.
12. Baum V. Anesthetic complications during emergency noncar-
diac surgery in patients with documented cardiac contusions.J
Cardiothorac Vasc Anesth 1991;5:57-60.
13. Apple FS, Rogers MA, Sherman WM. Profile of creatine ki-
nase isoenzymes in skeletal muscles of marathon runners. Clin
Chem 1984;30:413-6.
The Journal of Pediatrics
Volume 130, Number 6
14. Langer JC, Winthrop AL, Wesson DE,'Spence L, Pearl RH,
Hoffman MA, et al. Diagnosis and incidence of cardiac injury
in children with blunt thoracic trauma. J Pediatr Surg 1989;
24:1091-4.
15. Cummins B, Auckland ML, Cummins P. Cardiac-specific
troponin-I radioimrnunoassay in the diagnosis of acute myo-
cardial infarction. Am Heart J 1987;113:1333-44.
16. Nakamura Y, Fujita Y, Nagai M, Yanagawa H, Imada Y,
Okawa S, et al. Cardiac sequelae of Kawasaki disease in chil-
dren: statistical analysis. Pediatrics 1991; 88:1144-7.
17. Goorin AM, Borow KM, Goldman A, Wilfiams RG, Hender-
son IC, Sallan SE, et al. Congestive heart failure due to adri-
amycin cardiotoxicity. Cancer 1981; 47:2810-6.
Hirsch et aL 877
18. Click RL, Holmes DR, Vlietstra RE, Kosinski AS, Kronmal
RA. Anomalous coronary arteries: location, degree of athe-
rosclerosis and effect on survival a report from the coro-
nary artery surgery study. J Am Coll Cardiol 1989;13:
531-7.
19. Eppenberger HM, Eppenberger M, Richterich R, Aebl H. The
ontogeny of creatine kinase isoenzymes. Dev Biol 1964; 10:1-
16.
20. Grant JW, Canter CE, Spray TL, Landt Y, Saffitz JE, Laden-
son JH, et al. Elevated donor cardiac troponin I, a marker of
acute graft failure in infant heart recipients. Circulation 1994;
90:2618-21.