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Patterns and Potential Value of Cardiac Troponin I Elevations After Pediatric Cardiac Operations
Patterns and Potential Value of Cardiac Troponin I Elevations After Pediatric Cardiac Operations Russel Hirsch, MBChB, Catherine L. Dent, MD, Mary K. Wood, RN, Charles B. Huddleston, MD, Eric N. Mendeloff, MD, David T. Balzer, MD, Yvonne Landt, MS, Curtis A. Parvin, PhD, Michael Landt, PhD, Jack H. Ladenson, PhD, and Charles E. Canter, MD Department of Pediatrics and Divisions of Cardiothoracic Surgery and Laboratory Medicine, Washington University School of Medicine, St. Louis, Missouri
Background. Perioperative myocardial injury is a major determinant of postoperative cardiac dysfunction for congenital heart disease, but its assessment during this period is difficult. The objective of this study was to determine the suitability of using postoperative serum concentrations of cardiac troponin I (cTnI) for this purpose. Methods. Cardiac troponin I levels were measured serially in the serum of patients undergoing uncomplicated repairs of atrial septal defect (n 5 23), ventricular septal defect (n 5 16) or tetralogy of Fallot (n 5 16). The concentrations were correlated with intraoperative parameters (cardiopulmonary bypass time, aortic crossclamp time, and cardiac bypass temperature), and postoperative parameters (magnitude of inotropic support, duration of intubation, and postoperative intensive care and hospital stay). Results. Postoperative absolute cTnI levels were lesion specific, with a pattern of increase and decrease similar
for each lesion. For the total cohort, significant correlations between postoperative cTnI levels at all times (r 5 0.43 to 0.83, p < 0.05) until 72 hours were noted for all parameters, except for cardiac bypass temperature. When evaluated as individual procedure groups, no significant relationships were noted in the atrial septal defect group, whereas postoperative cTnI levels were more strongly correlated with all intraoperative and postoperative parameters in the ventricular septal defect group than in the tetralogy of Fallot group. Conclusions. This study suggests that cTnI values immediately after operation reflect the extent of myocardial damage from both incisional injury and intraoperative factors. Cardiac tropinin I levels in the first hours after operation for congenital heart disease are a potentially useful prognostic indicator for difficulty of recovery.
P
skeletal forms of the protein, assay of cTnI can be used with a high degree of sensitivity and specificity in detecting myocardial damage, even with concomitant skeletal muscle injury [6 –9]. We undertook the prospective evaluation of serum cTnI levels in infants and children undergoing uncomplicated repair of congenital heart disease to establish patterns of elevation and to evaluate the relationship of those elevations with outcome as an indication of the degree of myocardial damage.
erioperative myocardial injury is a major determinant of cardiac dysfunction after operation for congenital heart disease [1, 2]. However, during the postoperative period, evaluation of the degree of myocardial damage is difficult to ascertain, and reliance on clinical parameters and hemodynamic measurements is required. There is no accurate biochemical marker that reflects the extent of myocardial injury resulting from intraoperative procedures, operation, or complications that may have arisen during repair of congenital cardiac lesions [3, 4]. This study was performed to determine whether postoperative measurement of cardiac troponin I (cTnI) could serve as the index biochemical marker to reflect intraoperative myocardial damage, and thus provide a prognostic indicator for difficulty of recovery. Cardiac troponin I is found only within myocardial cells where it serves as a potent inhibitor of actin–myosin cross-bridge formation [5]. Because the monoclonal antibodies developed for assay of cTnI have no detectable cross-reactivity with the
Accepted for publication Dec 29, 1997. Address reprint requests to Dr Hirsch, Division of Pediatric Cardiology, Department of Pediatrics, St. Louis Children’s Hospital, One Children’s Pl, St. Louis, MO 63110.
© 1998 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
(Ann Thorac Surg 1998;65:1394 –9) © 1998 by The Society of Thoracic Surgeons
Material and Methods Patient Population All patients undergoing elective repair of congenital heart defects requiring cardiopulmonary bypass were prospectively enrolled in the study protocol from January to December 1995. Only patients who had repair of secundum type atrial septal defects (ASD), paramembranous ventricular septal defects (VSD), and tetralogy of Fallot (TOF) were included in this analysis. Other surgical procedures were not analyzed as the numbers in each category were small. To establish baseline cTnI levels in 0003-4975/98/$19.00 PII S0003-4975(98)00228-8
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Table 1. Demographic Information and Intraoperative and Postoperative Outcome Variables Variables No. Age (mo) Weight (kg) % Male Duration of CPB (min) Duration of ACC (min) CPB temperature (°C)a Inotrope scoreb Duration intubation (h) Duration ICU stay (days) Duration hospital stay (days)
ASD
VSD
TOF
23 73.6 6 64.1 25.4 6 20.5 57 32.2 6 13.8
16 29.6 6 46.8 11.6 6 13.3 50 71.3 6 14.1
16 12.8 6 13.2 7.4 6 3.3 56 121.9 6 28.2
15.7 6 8.4
45.8 6 12.4
73.5 6 18.8
32.9 6 1.7
28.3 6 2.1
25.7 6 9.1
0 1.7 6 1.5
174 6 203.2 27.6 6 26.5
764.3 6 738.7 66.8 6 35.3
1.1 6 .3
3.1 6 2.7
4.7 6 2.1
3.6 6 1.6
5.3 6 2.8
8.3 6 1.8
a b Lowest measured rectal temperature. Inotrope score 5 sum of the doses of inotropes multiplied by the number of hours that each drug was used.
ACC 5 aortic cross-clamp; ASD 5 atrial septal defect; CPB 5 cardiopulmonary bypass; ICU 5 intensive care unit; TOF 5 tetralogy of Fallot; VSD 5 ventricular septal defect. Values are mean 6 standard deviation.
patients who had uncomplicated surgical procedures, the following exclusion criteria were applied: previous cardiothoracic procedures; postoperative complications resulting in surgical reexploration or pericardiocentesis within 48 hours of operation; and tachyarrythmias resulting in the institution of antiarrythmic therapy. The study was conducted in accordance with a protocol approved by the Human Studies Committee of Washington University, and informed consent was obtained for all participating patients.
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tied and cut. All TOF repairs included a transannular patch of glutaraldehyde-treated pericardium in addition to the described VSD closure. After completion of the surgical repair and removal of the aortic cross-clamp, rewarming was instituted and standard deairing maneuvers were performed. Patients were weaned from cardiopulmonary bypass with inotropic support as dictated by the hemodynamic state and at the surgeon’s discretion. With stable hemodynamics achieved, modified ultrafiltration was performed before decannulation of the bypass circuit. The chest was then closed in routine fashion once meticulous hemostasis was achieved.
Postoperative Care All patients were admitted to the pediatric intensive care unit for further management. Standard postoperative care was performed. Decisions regarding inotropic support and airway and ventilator management were based on hemodynamic status and clinical judgment. Clinicians involved with patient care were blinded to the serum cTnI levels.
Protocol Nonheparinized blood samples were drawn from patients immediately before operation, on arrival in the intensive care unit, at 12-hour intervals for the first 24 hours, and then every 24 hours until they were discharged from the intensive care unit. The blood samples were centrifuged at 2,000 g for 15 minutes, stored at 270°C, thawed once, and then analyzed in batches. Assays were performed by individuals blinded to the clinical status of the patients or their inclusion in the study. The cTnI concentration was measured by a sandwich immunoassay in a preliminary research application that recognizes two different epitopes of cTnI and has no detectable cross-reactivity with skeletal muscle troponin [10]. The limit of detection for this assay is 1.5 ng/mL.
CARDIAC TROPONIN I.
Surgical Technique Cardiopulmonary bypass with moderate hypothermia was used in all cases with bicaval and ascending aortic cannulation. Immediately after placement of the aortic cross-clamp, prompt diastolic arrest was achieved using antegrade, cold blood cardioplegia (ratio of blood to cardioplegia 4:1). Cardioplegia was given in a volume of 10 to 20 mL/kg for the initial arresting dose, with subsequent doses of 5 to 10 mL/kg given at 20-minute intervals throughout the cross-clamp period. Myocardial cooling was augmented with the administration of topical iced slush. The ASD and VSD repairs were performed by a standard transatrial approach. Depending on the size of the defect, ASDs were repaired by either direct suture or pericardial patch technique. The VSD repairs were achieved by first encircling the defect with a series of interrupted, pledgeted mattress sutures. These were then sequentially passed through a piece of Dacron patch cut appropriately to match the size of the defect. The patch was then lowered onto the defect and all sutures were
Fig 1. Cardiac troponin I (cTnI)-elevation at postoperative time intervals in patients after atrial septal defect (ASD), ventricular septal defect (VSD), and tetralogy of Fallot (TOF) repairs.
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Table 2. Correlation Coefficients Between 24-Hour Postoperative Cardiac Troponin I Elevation and Intraoperative and Postoperative Variables Variable
ASD (p)
VSD (p)
TOF (p)
Cohort (p)
Duration of CPB Duration of ACC Lowest CPB temperaturea Inotrope scoreb Duration of intubation Duration of ICU stay Duration of hospital stay
0.21 (NS) 0.02 (NS) 0.07 (NS) ... 0.06 (NS) 0.10 (NS) 0.19 (NS)
0.78 (0.002) 0.65 (0.02) 0.26 (NS) 0.74 (,0.0001) 0.91 (,0.0001) 0.74 (0.004) 0.80 (0.001)
0.83 (0.01) 0.52 (NS) 0.07 (NS) 0.47 (NS) 0.61 (0.05) 0.83 (0.01) 0.61 (0.05)
0.80 (,0.0001) 0.72 (,0.0001) 0.69 (,0.0001) 0.69 (,0.0001) 0.83 (,0.0001) 0.82 (,0.0001) 0.77 (,0.0001)
a
Lowest measured rectal temperature.
b
Inotrope score 5 sum of the doses of inotrope/s multiplied by the number of hours that each drug was used.
ACC 5 aortic cross-clamp; ASD 5 atrial septal defect; CPB 5 cardiopulmonary bypass; (p . 0.05); TOF 5 tetralogy of Fallot; VSD 5 ventricular septal defect.
This value is equivalent to a value of 0.4 ng/mL with the commercially available assay (Dade International, Miami, FL). DATA COLLECTION. Intraoperative data (duration of cardiopulmonary bypass [CPB] and aortic cross-clamp, and lowest measured rectal temperature during cardiopulmonary bypass) and postoperative clinical information (length of intubation, inotropic requirement, and length of intensive care and hospital stay after operation) were collected for each patient. Inotrope use was defined as a continuous infusion of dopamine, dobutamine, amrinone, or epinephrine. The absolute use of inotropic agent was expressed arbitrarily as the sum of the product of the dose of inotropes multiplied by the number of hours that each drug was used, in accordance with other studies evaluating inotrope dose and duration of use [11, 12].
Statistical Analysis Data are expressed as mean values 6 standard deviation. Linear regression was used to determine the relationship between postoperative cTnI elevation for each group (ASD, VSD, and TOF repairs), and both the intraoperative variables and postoperative outcome parameters. Significance was determined by p values less than 0.05. All data were analyzed with Statview software (Abacus Concepts, Berkeley, CA).
Results Patient Population and Outcome Variables Between January and December 1995, 61 children underwent surgical repair of either an ASD (n 5 23), VSD (n 5 19), or TOF (n 5 19). Six patients with complications were excluded, leaving 55 patients in the study cohort (Table 1). The 6 excluded subjects included 3 with postoperative junctional tachycardia, 2 from the VSD group and 1 from the TOF group. Hemodynamically significant pericardial effusions were diagnosed and drained in 1 patient each from the VSD and TOF groups, and another patient in the TOF group was diagnosed postoperatively with respiratory syncytial virus bronchiolitis, resulting in prolonged ventilation and hospitalization. None of the ASD patients were excluded from study.
ICU 5 intensive care unit;
NS 5 not significant
All patients were found to have anatomy consistent with their preoperative evaluation and surgical repairs proceeded as planned in all patients. The duration of CPB, aortic cross-clamp, intensive care unit and hospital stay were shortest for the ASD patients, and longest for the TOF group (Table 1). No inotropes were used postoperatively in the ASD patients, but their use was greatest in the TOF group (Table 1). No patients required epinephrine.
Pattern of Cardiac Troponin I Level Elevation All preoperative cTnI concentrations were within normal limits and were frequently less than the level of detection for the assay [13]. Mean preoperative cTnI levels were less than 1.5 ng/mL for all three groups. Absolute postoperative cTnI concentrations were lesion specific with a similar pattern of rise and fall for each group with peak levels noted in the immediate postoperative period (Fig 1). No patients were noted to have 12-hour levels greater than the initial postoperative level.
Relationship of Cardiac Troponin I Level to Outcome Variables The correlation coefficients between postoperative cTnI concentrations and intraoperative and postoperative variables were determined separately for the three procedure groups and for the total cohort (r values at 24 hours are shown in Table 2). In the ASD group, no significant correlation coefficients were noted between postoperative cTnI elevation and outcome parameters at any time (r 5 0.12 to 0.44; p 5 0.13 to 0.99). In the VSD group, significant correlation coefficients (r 5 0.57 to 0.91; p 5 ,0.0001 to 0.04) were noted between postoperative cTnI elevation (0 to 72 hours) and all parameters except for CPB temperature. The only significant relationship for that parameter occurred at 12 hours after operation (r 5 0.55; p 5 0.03). In the TOF group, significant correlation coefficients (r 5 0.49 to 0.85; p 5 0.01 to 0.05) were noted between postoperative cTnI elevation (0 to 72 hours) and the parameters of duration of CPB, aortic cross-clamp, intensive care unit and hospital stay; exceptions were duration of CPB at 12 hours (r 5 0.42; p 5 0.2), aortic cross-clamp
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duration at 12 and 24 hours (r 5 0.37 and 0.52; p 5 0.2 and 0.11, respectively), and duration of hospital stay at 0 hours (r 5 0.17; p 5 0.56). No significant correlation coefficients were noted between postoperative cTnI elevations at any time and the categories of lowest CPB temperature, inotrope use, or duration of intubation (except at 24 hours in the last category; r 5 0.61; p 5 0.05). In the total cohort, significant correlation coefficients (r 5 0.43 to 0.83; p , 0.0001 to 0.01) were noted between postoperative cTnI elevation (0 to 72 hours) and all intraoperative and postoperative parameters, with the exception of lowest CPB temperature at 48 and 72 hours (r 5 0.19 and 0.25; p 5 0.2 and 0.49, respectively). Plots of these parameters versus concentration of cTnI at 24 hours (Figs 2, 3) demonstrate overlap and variability of cTnI concentrations within and between the different procedure groups. This reflects differences in patient-topatient surgical technique, and individual differences in patient responses to myocardial trauma and myocardial protection. Thus, although some difference in cTnI concentrations could be attributed to the generally longer CPB and aortic cross-clamp times for TOF versus VSD versus ASD repairs, cTnI also appears to reflect the difficulty of postoperative recovery of an individual patient with a VSD or TOF. Regression equations for cTnI elevation at different times versus intraoperative and postoperative outcome variables with correlation coefficients greater than 0.8 are shown in Table 3.
Comment
Fig 2. Distribution of cardiac troponin I (cTnI) concentration at 24hour postoperative time relative to the intraoperative variables. (CPB 5 cardiopulmonary bypass; X-Clamp 5 aortic cross-clamp.)
Cardiac troponin I is one component of a complex of three separate proteins that, together with tropomysin, confers calcium sensitivity to the process of actin–myosin cross-bridge formation in the myocardial cell. Found exclusively in the myocardial cell, it is a potent inhibitor of those interactions [5]. Assay for cTnI is sensitive and specific, with no detectable cross-reactivity with skeletal muscle troponin. The level of cTnI is a more sensitive index of myocardial cell damage than either creatine kinase MB fraction or myoglobin level in the postoperative pediatric population [1]. In adults it has been shown to have diagnostic utility for myocardial infarction and contusion [6, 8, 10]. There is little known about the relationship between the absolute elevation of cTnI and the degree of myocardial damage incurred during the repair of congenital cardiac defects, or in turn, how that relates to myocardial recovery after operation [1]. When myocardial cell damage occurs in the context of infarction or contusion, cell death results in the release of the contractile regulatory proteins that are then measurable in serum. In the same manner, trauma to the myocardium during operation, either as a result of direct surgical incision or secondary to technical procedures such as aortic cross-clamping or CPB, will result in myocardial cell damage and release of the same proteins. Our results suggest that elevation of cTnI level after operation reflects myocardial damage from both inci-
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Fig 3. Distribution of cardiac troponin I (cTnI) concentration at 24-hour postoperative time relative to postoperative variables. (ICU 5 intensive care unit; *summation of the product of the dose of inotropes and the number of hours the inotrope was received.)
sional injury and factors independent of incisional injury, such as aortic cross-clamping and CPB. The wide range of cTnI levels with overlap between and within groups for the same outcome parameter results probably from variations in surgical technique and differences in patient responses to myocardial preservation. However, the consistent significant correlation between postoperative cTnI elevation and both intraoperative and postoperative parameters for the entire cohort would suggest a degree of independence from incisional injury in determining the absolute cTnI elevation. This study suggests that postoperative cTnI elevation may be a prognostic indicator for difficulty of recovery after congenital heart operation. In contradistinction to patients with a VSD or TOF, significant correlation between postoperative cTnI elevation and both intraoperative and postoperative outcomes were not found when applied to the ASD group of patients, reflecting the
minor degree of myocardial damage incurred during repair. These patients were subjected to the shortest periods of aortic cross-clamping and CPB, and the least amount of direct incisional trauma. It is conceivable that during surgical repair a threshold level of myocardial damage has to occur (and thus a threshold elevation of cTnI) before functional impairment manifest by higher degrees of inotropic support, longer duration of mechanical ventilation, and resultant prolongation of hospitalization. When studied in larger numbers and after different surgical procedures, determination of threshold levels for other congenital heart operations, such as the arterial switch procedure for transposition of the great arteries or the Fontan procedure, may aid in predicting functional impairment, and hence difficulty of recovery and duration of hospital stay. Thus, cTnI levels within the first hours after operation could help to estimate the intensity and duration of postoperative convalescence for
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Table 3. Regression Equations for Cardiac Troponin I Elevation at Different Times Versus Intraoperative and Postoperative Outcome Variables With Correlation Coefficients Greater Than 0.8 Group VSD
TOF
ASD/VSD/TOF
Category cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI
at at at at at at at at at at at at at at at
12 24 48 12 12 24 24 72 24 12 24 24 12 24 12
h h h h h h h h h h h h h h h
vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs
duration duration duration duration duration duration duration duration duration duration duration duration duration duration duration
r Value
of intubation of intubation of intubation of ICU stay from operation until discharge from operation until discharge of CPB of CPB of ICU stay of CPB of CPB of intubation of ICU stay of ICU stay from operation until discharge
ASD 5 atrial septal defect; CPB 5 cardiopulmonary bypass; Fallot; VSD 5 ventricular septal defect.
cTnI 5 cardiac troponin I;
an individual procedure. Furthermore, measurement of postoperative cTnI concentrations could provide a tool for evaluating relative myocardial damage in the development of new surgical techniques, and determining the adequacy of myocardial protection afforded by new forms of myocardial protective agents. This study population was carefully selected to provide for no unexpected findings in the measured postoperative parameters, allowing in turn for consistency in evaluating the relationship of postoperative cTnI elevation to outcome parameters. Owing to this selectivity, extrapolation of these results in determining the prognostic value of postoperative cTnI elevation after repair of other forms of congenital cardiac defects, or in the presence of hemodynamically significant complications, is limited. A further limitation to this study is the relatively small number of patients included in each of the procedure groups, which precluded the use of more complex statistical analyses or the development of predictive values of cTnI at different postoperative intervals in determining outcome. In conclusion, measurement of postoperative cTnI concentration reflects myocardial damage incurred during the uncomplicated repair of ventricular septal defects and tetralogy of Fallot. It may also be a useful indicator of the difficulty of recovery after operation. Evaluation of cTnI levels in postoperative patients can serve as a useful adjunct to current means of patient evaluation, and may serve as a marker in evaluating new surgical techniques or intraoperative myocardial protection.
We thank Marsha Kuhns for technical assistance. Doctor Ladenson is a consultant to Dade-Behring Corporation (Wilmington, DE).
Regression Equation
0.87 0.91 0.89 0.88 0.91 0.8 0.83 0.85 0.83 0.81 0.8 0.83 0.82 0.81 0.82 ICU 5 intensive care unit;
y y y y y y y y y y y y y y y
5 5 5 5 5 5 5 5 5 5 5 5 5 5 5
20.2 1 1.1x 16.1 1 1.2x 12.5 1 0.9x 16.1 1 11.1x 0.9 1 8.4x 6.2 1 7.5x 2148.7 1 1.9x 257.7 1 0.9x 28.3 1 22.2x 21.6 1 0.7x 28.5 1 0.8x 8.8 1 17.8x 14.9 1 12.7x 10.1 1 12.9x 27.6 1 10.1x
TOF 5 tetralogy of
References 1. Taggart DP, Hjadjinikolas L, Wong K, et al. Vulnerability of pediatric myocardium to cardiac surgery. Heart 1996;76:214–7. 2. Kirklin JH, Blackstone EH, Kirklin JW, McKay R, Pacifico AD, Bargeron LM. Intracardiac surgery in infants under age 3 months: incremental risk factors for hospital mortality. Am J Cardiol 1981;48:500– 6. 3. Britton CV, Hernandez 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. 4. Adams JE, Abendschein DR, Jaffe AS. Biochemical markers of myocardial injury. Is MB creatine kinase the choice for the 1990s? Circulation 1993;88:50– 63. 5. Farah CS, Reinach FC. The troponin complex and regulation of muscle contraction. FASEB J 1995;9:755– 67. 6. Adams JE, Davila-Roman VG, Delmez JA, Apple FS, Ladenson JH, Jaffe AS. Cardiac troponin-I: a marker with high specificity for cardiac injury. Circulation 1993;88:101– 6. 7. Etievent JP, Chocron S, Toubin G, et al. Use of cardiac troponin I as a marker of perioperative myocardial ischemia. Ann Thorac Surg 1995;59:1192– 4. 8. Adams JE, Davila-Roman VG, Bessy PQ, Blake DP, Ladenson JH, Jaffe AS. Improved detection of cardiac contusion with cardiac troponin I. Am Heart J 1996;131:308–12. 9. Adams JE, Sicard GA, Allen BT, et al. Diagnosis of perioperative myocardial infarction with measurement of cardiac troponin I. N Engl J Med 1994;330:670– 4. 10. Bodor GS, Porter S, Landt Y, Ladenson JH. Development of monoclonal antibodies for an assay of cardiac troponin I and preliminary results in suspected cases of myocardial infarction. Clin Chem 1992;11:2203–14. 11. Wernovsky G, Wypij D, Jonas RA, et al. Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants. A comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation 1995; 92:2226–35. 12. Kulik TJ, Moler FW, Palmisano JM, et al. Outcomeassociated factors in pediatric patients treated with extracorporeal membrane oxygenator after cardiac surgery. Circulation 1996;94(suppl 2):63– 8. 13. Hirsch R, Landt Y, Porter S, et al. Cardiac troponin I in pediatrics: normal values and potential use in the assessment of cardiac injury. J Pediatr 1997;130:872–7.
Background. Perioperative myocardial injury is a major determinant of postoperative cardiac dysfunction for congenital heart disease, but its assessment during this period is difficult. The objective of this study was to determine the suitability of using postoperative serum concentrations of cardiac troponin I (cTnI) for this purpose. Methods. Cardiac troponin I levels were measured serially in the serum of patients undergoing uncomplicated repairs of atrial septal defect (n 5 23), ventricular septal defect (n 5 16) or tetralogy of Fallot (n 5 16). The concentrations were correlated with intraoperative parameters (cardiopulmonary bypass time, aortic crossclamp time, and cardiac bypass temperature), and postoperative parameters (magnitude of inotropic support, duration of intubation, and postoperative intensive care and hospital stay). Results. Postoperative absolute cTnI levels were lesion specific, with a pattern of increase and decrease similar
for each lesion. For the total cohort, significant correlations between postoperative cTnI levels at all times (r 5 0.43 to 0.83, p < 0.05) until 72 hours were noted for all parameters, except for cardiac bypass temperature. When evaluated as individual procedure groups, no significant relationships were noted in the atrial septal defect group, whereas postoperative cTnI levels were more strongly correlated with all intraoperative and postoperative parameters in the ventricular septal defect group than in the tetralogy of Fallot group. Conclusions. This study suggests that cTnI values immediately after operation reflect the extent of myocardial damage from both incisional injury and intraoperative factors. Cardiac tropinin I levels in the first hours after operation for congenital heart disease are a potentially useful prognostic indicator for difficulty of recovery.
P
skeletal forms of the protein, assay of cTnI can be used with a high degree of sensitivity and specificity in detecting myocardial damage, even with concomitant skeletal muscle injury [6 –9]. We undertook the prospective evaluation of serum cTnI levels in infants and children undergoing uncomplicated repair of congenital heart disease to establish patterns of elevation and to evaluate the relationship of those elevations with outcome as an indication of the degree of myocardial damage.
erioperative myocardial injury is a major determinant of cardiac dysfunction after operation for congenital heart disease [1, 2]. However, during the postoperative period, evaluation of the degree of myocardial damage is difficult to ascertain, and reliance on clinical parameters and hemodynamic measurements is required. There is no accurate biochemical marker that reflects the extent of myocardial injury resulting from intraoperative procedures, operation, or complications that may have arisen during repair of congenital cardiac lesions [3, 4]. This study was performed to determine whether postoperative measurement of cardiac troponin I (cTnI) could serve as the index biochemical marker to reflect intraoperative myocardial damage, and thus provide a prognostic indicator for difficulty of recovery. Cardiac troponin I is found only within myocardial cells where it serves as a potent inhibitor of actin–myosin cross-bridge formation [5]. Because the monoclonal antibodies developed for assay of cTnI have no detectable cross-reactivity with the
Accepted for publication Dec 29, 1997. Address reprint requests to Dr Hirsch, Division of Pediatric Cardiology, Department of Pediatrics, St. Louis Children’s Hospital, One Children’s Pl, St. Louis, MO 63110.
© 1998 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
(Ann Thorac Surg 1998;65:1394 –9) © 1998 by The Society of Thoracic Surgeons
Material and Methods Patient Population All patients undergoing elective repair of congenital heart defects requiring cardiopulmonary bypass were prospectively enrolled in the study protocol from January to December 1995. Only patients who had repair of secundum type atrial septal defects (ASD), paramembranous ventricular septal defects (VSD), and tetralogy of Fallot (TOF) were included in this analysis. Other surgical procedures were not analyzed as the numbers in each category were small. To establish baseline cTnI levels in 0003-4975/98/$19.00 PII S0003-4975(98)00228-8
Ann Thorac Surg 1998;65:1394 –9
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Table 1. Demographic Information and Intraoperative and Postoperative Outcome Variables Variables No. Age (mo) Weight (kg) % Male Duration of CPB (min) Duration of ACC (min) CPB temperature (°C)a Inotrope scoreb Duration intubation (h) Duration ICU stay (days) Duration hospital stay (days)
ASD
VSD
TOF
23 73.6 6 64.1 25.4 6 20.5 57 32.2 6 13.8
16 29.6 6 46.8 11.6 6 13.3 50 71.3 6 14.1
16 12.8 6 13.2 7.4 6 3.3 56 121.9 6 28.2
15.7 6 8.4
45.8 6 12.4
73.5 6 18.8
32.9 6 1.7
28.3 6 2.1
25.7 6 9.1
0 1.7 6 1.5
174 6 203.2 27.6 6 26.5
764.3 6 738.7 66.8 6 35.3
1.1 6 .3
3.1 6 2.7
4.7 6 2.1
3.6 6 1.6
5.3 6 2.8
8.3 6 1.8
a b Lowest measured rectal temperature. Inotrope score 5 sum of the doses of inotropes multiplied by the number of hours that each drug was used.
ACC 5 aortic cross-clamp; ASD 5 atrial septal defect; CPB 5 cardiopulmonary bypass; ICU 5 intensive care unit; TOF 5 tetralogy of Fallot; VSD 5 ventricular septal defect. Values are mean 6 standard deviation.
patients who had uncomplicated surgical procedures, the following exclusion criteria were applied: previous cardiothoracic procedures; postoperative complications resulting in surgical reexploration or pericardiocentesis within 48 hours of operation; and tachyarrythmias resulting in the institution of antiarrythmic therapy. The study was conducted in accordance with a protocol approved by the Human Studies Committee of Washington University, and informed consent was obtained for all participating patients.
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tied and cut. All TOF repairs included a transannular patch of glutaraldehyde-treated pericardium in addition to the described VSD closure. After completion of the surgical repair and removal of the aortic cross-clamp, rewarming was instituted and standard deairing maneuvers were performed. Patients were weaned from cardiopulmonary bypass with inotropic support as dictated by the hemodynamic state and at the surgeon’s discretion. With stable hemodynamics achieved, modified ultrafiltration was performed before decannulation of the bypass circuit. The chest was then closed in routine fashion once meticulous hemostasis was achieved.
Postoperative Care All patients were admitted to the pediatric intensive care unit for further management. Standard postoperative care was performed. Decisions regarding inotropic support and airway and ventilator management were based on hemodynamic status and clinical judgment. Clinicians involved with patient care were blinded to the serum cTnI levels.
Protocol Nonheparinized blood samples were drawn from patients immediately before operation, on arrival in the intensive care unit, at 12-hour intervals for the first 24 hours, and then every 24 hours until they were discharged from the intensive care unit. The blood samples were centrifuged at 2,000 g for 15 minutes, stored at 270°C, thawed once, and then analyzed in batches. Assays were performed by individuals blinded to the clinical status of the patients or their inclusion in the study. The cTnI concentration was measured by a sandwich immunoassay in a preliminary research application that recognizes two different epitopes of cTnI and has no detectable cross-reactivity with skeletal muscle troponin [10]. The limit of detection for this assay is 1.5 ng/mL.
CARDIAC TROPONIN I.
Surgical Technique Cardiopulmonary bypass with moderate hypothermia was used in all cases with bicaval and ascending aortic cannulation. Immediately after placement of the aortic cross-clamp, prompt diastolic arrest was achieved using antegrade, cold blood cardioplegia (ratio of blood to cardioplegia 4:1). Cardioplegia was given in a volume of 10 to 20 mL/kg for the initial arresting dose, with subsequent doses of 5 to 10 mL/kg given at 20-minute intervals throughout the cross-clamp period. Myocardial cooling was augmented with the administration of topical iced slush. The ASD and VSD repairs were performed by a standard transatrial approach. Depending on the size of the defect, ASDs were repaired by either direct suture or pericardial patch technique. The VSD repairs were achieved by first encircling the defect with a series of interrupted, pledgeted mattress sutures. These were then sequentially passed through a piece of Dacron patch cut appropriately to match the size of the defect. The patch was then lowered onto the defect and all sutures were
Fig 1. Cardiac troponin I (cTnI)-elevation at postoperative time intervals in patients after atrial septal defect (ASD), ventricular septal defect (VSD), and tetralogy of Fallot (TOF) repairs.
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Table 2. Correlation Coefficients Between 24-Hour Postoperative Cardiac Troponin I Elevation and Intraoperative and Postoperative Variables Variable
ASD (p)
VSD (p)
TOF (p)
Cohort (p)
Duration of CPB Duration of ACC Lowest CPB temperaturea Inotrope scoreb Duration of intubation Duration of ICU stay Duration of hospital stay
0.21 (NS) 0.02 (NS) 0.07 (NS) ... 0.06 (NS) 0.10 (NS) 0.19 (NS)
0.78 (0.002) 0.65 (0.02) 0.26 (NS) 0.74 (,0.0001) 0.91 (,0.0001) 0.74 (0.004) 0.80 (0.001)
0.83 (0.01) 0.52 (NS) 0.07 (NS) 0.47 (NS) 0.61 (0.05) 0.83 (0.01) 0.61 (0.05)
0.80 (,0.0001) 0.72 (,0.0001) 0.69 (,0.0001) 0.69 (,0.0001) 0.83 (,0.0001) 0.82 (,0.0001) 0.77 (,0.0001)
a
Lowest measured rectal temperature.
b
Inotrope score 5 sum of the doses of inotrope/s multiplied by the number of hours that each drug was used.
ACC 5 aortic cross-clamp; ASD 5 atrial septal defect; CPB 5 cardiopulmonary bypass; (p . 0.05); TOF 5 tetralogy of Fallot; VSD 5 ventricular septal defect.
This value is equivalent to a value of 0.4 ng/mL with the commercially available assay (Dade International, Miami, FL). DATA COLLECTION. Intraoperative data (duration of cardiopulmonary bypass [CPB] and aortic cross-clamp, and lowest measured rectal temperature during cardiopulmonary bypass) and postoperative clinical information (length of intubation, inotropic requirement, and length of intensive care and hospital stay after operation) were collected for each patient. Inotrope use was defined as a continuous infusion of dopamine, dobutamine, amrinone, or epinephrine. The absolute use of inotropic agent was expressed arbitrarily as the sum of the product of the dose of inotropes multiplied by the number of hours that each drug was used, in accordance with other studies evaluating inotrope dose and duration of use [11, 12].
Statistical Analysis Data are expressed as mean values 6 standard deviation. Linear regression was used to determine the relationship between postoperative cTnI elevation for each group (ASD, VSD, and TOF repairs), and both the intraoperative variables and postoperative outcome parameters. Significance was determined by p values less than 0.05. All data were analyzed with Statview software (Abacus Concepts, Berkeley, CA).
Results Patient Population and Outcome Variables Between January and December 1995, 61 children underwent surgical repair of either an ASD (n 5 23), VSD (n 5 19), or TOF (n 5 19). Six patients with complications were excluded, leaving 55 patients in the study cohort (Table 1). The 6 excluded subjects included 3 with postoperative junctional tachycardia, 2 from the VSD group and 1 from the TOF group. Hemodynamically significant pericardial effusions were diagnosed and drained in 1 patient each from the VSD and TOF groups, and another patient in the TOF group was diagnosed postoperatively with respiratory syncytial virus bronchiolitis, resulting in prolonged ventilation and hospitalization. None of the ASD patients were excluded from study.
ICU 5 intensive care unit;
NS 5 not significant
All patients were found to have anatomy consistent with their preoperative evaluation and surgical repairs proceeded as planned in all patients. The duration of CPB, aortic cross-clamp, intensive care unit and hospital stay were shortest for the ASD patients, and longest for the TOF group (Table 1). No inotropes were used postoperatively in the ASD patients, but their use was greatest in the TOF group (Table 1). No patients required epinephrine.
Pattern of Cardiac Troponin I Level Elevation All preoperative cTnI concentrations were within normal limits and were frequently less than the level of detection for the assay [13]. Mean preoperative cTnI levels were less than 1.5 ng/mL for all three groups. Absolute postoperative cTnI concentrations were lesion specific with a similar pattern of rise and fall for each group with peak levels noted in the immediate postoperative period (Fig 1). No patients were noted to have 12-hour levels greater than the initial postoperative level.
Relationship of Cardiac Troponin I Level to Outcome Variables The correlation coefficients between postoperative cTnI concentrations and intraoperative and postoperative variables were determined separately for the three procedure groups and for the total cohort (r values at 24 hours are shown in Table 2). In the ASD group, no significant correlation coefficients were noted between postoperative cTnI elevation and outcome parameters at any time (r 5 0.12 to 0.44; p 5 0.13 to 0.99). In the VSD group, significant correlation coefficients (r 5 0.57 to 0.91; p 5 ,0.0001 to 0.04) were noted between postoperative cTnI elevation (0 to 72 hours) and all parameters except for CPB temperature. The only significant relationship for that parameter occurred at 12 hours after operation (r 5 0.55; p 5 0.03). In the TOF group, significant correlation coefficients (r 5 0.49 to 0.85; p 5 0.01 to 0.05) were noted between postoperative cTnI elevation (0 to 72 hours) and the parameters of duration of CPB, aortic cross-clamp, intensive care unit and hospital stay; exceptions were duration of CPB at 12 hours (r 5 0.42; p 5 0.2), aortic cross-clamp
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duration at 12 and 24 hours (r 5 0.37 and 0.52; p 5 0.2 and 0.11, respectively), and duration of hospital stay at 0 hours (r 5 0.17; p 5 0.56). No significant correlation coefficients were noted between postoperative cTnI elevations at any time and the categories of lowest CPB temperature, inotrope use, or duration of intubation (except at 24 hours in the last category; r 5 0.61; p 5 0.05). In the total cohort, significant correlation coefficients (r 5 0.43 to 0.83; p , 0.0001 to 0.01) were noted between postoperative cTnI elevation (0 to 72 hours) and all intraoperative and postoperative parameters, with the exception of lowest CPB temperature at 48 and 72 hours (r 5 0.19 and 0.25; p 5 0.2 and 0.49, respectively). Plots of these parameters versus concentration of cTnI at 24 hours (Figs 2, 3) demonstrate overlap and variability of cTnI concentrations within and between the different procedure groups. This reflects differences in patient-topatient surgical technique, and individual differences in patient responses to myocardial trauma and myocardial protection. Thus, although some difference in cTnI concentrations could be attributed to the generally longer CPB and aortic cross-clamp times for TOF versus VSD versus ASD repairs, cTnI also appears to reflect the difficulty of postoperative recovery of an individual patient with a VSD or TOF. Regression equations for cTnI elevation at different times versus intraoperative and postoperative outcome variables with correlation coefficients greater than 0.8 are shown in Table 3.
Comment
Fig 2. Distribution of cardiac troponin I (cTnI) concentration at 24hour postoperative time relative to the intraoperative variables. (CPB 5 cardiopulmonary bypass; X-Clamp 5 aortic cross-clamp.)
Cardiac troponin I is one component of a complex of three separate proteins that, together with tropomysin, confers calcium sensitivity to the process of actin–myosin cross-bridge formation in the myocardial cell. Found exclusively in the myocardial cell, it is a potent inhibitor of those interactions [5]. Assay for cTnI is sensitive and specific, with no detectable cross-reactivity with skeletal muscle troponin. The level of cTnI is a more sensitive index of myocardial cell damage than either creatine kinase MB fraction or myoglobin level in the postoperative pediatric population [1]. In adults it has been shown to have diagnostic utility for myocardial infarction and contusion [6, 8, 10]. There is little known about the relationship between the absolute elevation of cTnI and the degree of myocardial damage incurred during the repair of congenital cardiac defects, or in turn, how that relates to myocardial recovery after operation [1]. When myocardial cell damage occurs in the context of infarction or contusion, cell death results in the release of the contractile regulatory proteins that are then measurable in serum. In the same manner, trauma to the myocardium during operation, either as a result of direct surgical incision or secondary to technical procedures such as aortic cross-clamping or CPB, will result in myocardial cell damage and release of the same proteins. Our results suggest that elevation of cTnI level after operation reflects myocardial damage from both inci-
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Fig 3. Distribution of cardiac troponin I (cTnI) concentration at 24-hour postoperative time relative to postoperative variables. (ICU 5 intensive care unit; *summation of the product of the dose of inotropes and the number of hours the inotrope was received.)
sional injury and factors independent of incisional injury, such as aortic cross-clamping and CPB. The wide range of cTnI levels with overlap between and within groups for the same outcome parameter results probably from variations in surgical technique and differences in patient responses to myocardial preservation. However, the consistent significant correlation between postoperative cTnI elevation and both intraoperative and postoperative parameters for the entire cohort would suggest a degree of independence from incisional injury in determining the absolute cTnI elevation. This study suggests that postoperative cTnI elevation may be a prognostic indicator for difficulty of recovery after congenital heart operation. In contradistinction to patients with a VSD or TOF, significant correlation between postoperative cTnI elevation and both intraoperative and postoperative outcomes were not found when applied to the ASD group of patients, reflecting the
minor degree of myocardial damage incurred during repair. These patients were subjected to the shortest periods of aortic cross-clamping and CPB, and the least amount of direct incisional trauma. It is conceivable that during surgical repair a threshold level of myocardial damage has to occur (and thus a threshold elevation of cTnI) before functional impairment manifest by higher degrees of inotropic support, longer duration of mechanical ventilation, and resultant prolongation of hospitalization. When studied in larger numbers and after different surgical procedures, determination of threshold levels for other congenital heart operations, such as the arterial switch procedure for transposition of the great arteries or the Fontan procedure, may aid in predicting functional impairment, and hence difficulty of recovery and duration of hospital stay. Thus, cTnI levels within the first hours after operation could help to estimate the intensity and duration of postoperative convalescence for
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Table 3. Regression Equations for Cardiac Troponin I Elevation at Different Times Versus Intraoperative and Postoperative Outcome Variables With Correlation Coefficients Greater Than 0.8 Group VSD
TOF
ASD/VSD/TOF
Category cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI cTnI
at at at at at at at at at at at at at at at
12 24 48 12 12 24 24 72 24 12 24 24 12 24 12
h h h h h h h h h h h h h h h
vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs
duration duration duration duration duration duration duration duration duration duration duration duration duration duration duration
r Value
of intubation of intubation of intubation of ICU stay from operation until discharge from operation until discharge of CPB of CPB of ICU stay of CPB of CPB of intubation of ICU stay of ICU stay from operation until discharge
ASD 5 atrial septal defect; CPB 5 cardiopulmonary bypass; Fallot; VSD 5 ventricular septal defect.
cTnI 5 cardiac troponin I;
an individual procedure. Furthermore, measurement of postoperative cTnI concentrations could provide a tool for evaluating relative myocardial damage in the development of new surgical techniques, and determining the adequacy of myocardial protection afforded by new forms of myocardial protective agents. This study population was carefully selected to provide for no unexpected findings in the measured postoperative parameters, allowing in turn for consistency in evaluating the relationship of postoperative cTnI elevation to outcome parameters. Owing to this selectivity, extrapolation of these results in determining the prognostic value of postoperative cTnI elevation after repair of other forms of congenital cardiac defects, or in the presence of hemodynamically significant complications, is limited. A further limitation to this study is the relatively small number of patients included in each of the procedure groups, which precluded the use of more complex statistical analyses or the development of predictive values of cTnI at different postoperative intervals in determining outcome. In conclusion, measurement of postoperative cTnI concentration reflects myocardial damage incurred during the uncomplicated repair of ventricular septal defects and tetralogy of Fallot. It may also be a useful indicator of the difficulty of recovery after operation. Evaluation of cTnI levels in postoperative patients can serve as a useful adjunct to current means of patient evaluation, and may serve as a marker in evaluating new surgical techniques or intraoperative myocardial protection.
We thank Marsha Kuhns for technical assistance. Doctor Ladenson is a consultant to Dade-Behring Corporation (Wilmington, DE).
Regression Equation
0.87 0.91 0.89 0.88 0.91 0.8 0.83 0.85 0.83 0.81 0.8 0.83 0.82 0.81 0.82 ICU 5 intensive care unit;
y y y y y y y y y y y y y y y
5 5 5 5 5 5 5 5 5 5 5 5 5 5 5
20.2 1 1.1x 16.1 1 1.2x 12.5 1 0.9x 16.1 1 11.1x 0.9 1 8.4x 6.2 1 7.5x 2148.7 1 1.9x 257.7 1 0.9x 28.3 1 22.2x 21.6 1 0.7x 28.5 1 0.8x 8.8 1 17.8x 14.9 1 12.7x 10.1 1 12.9x 27.6 1 10.1x
TOF 5 tetralogy of
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