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Ann Thorac Surg 2002;74:1998-2002
© 2002 The Society of Thoracic Surgeons

Original article: cardiovascular

Cardiac troponin I in neonates undergoing the arterial switch operation

Hajime Imura, PhDa, Paul Modi, FRCSa, Ashwinikumar Pawade, FRCSa, Andrew J. Parry, FRCSa, M.-Saadeh Suleiman, PhDa, Gianni D. Angelini, FRCSa*, Massimo Caputo, MDa

a Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol, United Kingdom

Accepted for publication July 12, 2002.

* Address reprint requests to Dr Angelini, Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
e-mail: g.d.angelini{at}bristol.ac.uk


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Cardiac troponin I (TnI) is a sensitive and specific marker of myocardial injury, but little is known about its release after complex congenital heart surgery. We investigated whether TnI correlates with early clinical outcome in neonates undergoing the arterial switch operation (ASO) for transposition of the great arteries (TGA).

METHODS: Troponin I was measured serially up to 48 hours postoperatively in 31 neonates undergoing the ASO alone (simple TGA) and 9 neonates undergoing the ASO combined with other procedures (complex TGA) (eg, closure of a ventricular septal defect) and correlated with intraoperative and postoperative clinical parameters.

RESULTS: There was no mortality. Troponin I peaked at either 4 or 12 hours postoperatively in all patients (median for simple TGA = 3.4 ng/mL, interquartile range 2.4 to 4.6; median for complex TGA = 4.7 ng/mL, interquartile range 3.2 to 6.8, p = 0.20). Peak TnI correlated with the durations of inotropic support (r = 0.54, p < 0.001), ventilation (r = 0.51, p < 0.01), and intensive care unit stay (r = 0.50, p < 0.01). The duration of cardiopulmonary bypass, aortic cross-clamping, and circulatory arrest did not correlate with the peak or total TnI release. The duration of aortic cross-clamping correlated poorly with the duration of inotropic support (r = 0.40, p < 0.05). The complex TGA group had longer aortic cross-clamp times, required more postoperative inotropic support, and had significantly higher total TnI release compared with the simple TGA group.

CONCLUSIONS: There are weak but statistically significant correlations between peak TnI and clinical outcome. Complexity of the defect and ischemic times may be as useful to predict outcome in this group of patients.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Since its introduction, the arterial switch operation (ASO) has become the surgical treatment of choice for neonates with transposition of the great arteries (TGA) with favorable early and long-term clinical outcomes [1]. The procedure is associated with lower perioperative mortality than many other congenital cardiac operations despite being technically more challenging and time-consuming. Perioperative myocardial injury is a major determinant of postoperative cardiac dysfunction after pediatric open-heart surgery [2]. Cardiac troponin I (TnI) is a specific and sensitive marker of myocardial cell injury after pediatric open-heart surgery and the absolute levels have been shown in infants and children to be dependent on pathology, to correlate very well with the extent of perioperative myocardial damage, and to allow anticipation of the postoperative course [3, 4]. However, few reports have focused on markers of myocardial injury in neonates and their relation to clinical outcome.

In this study, we analyzed the severity of myocardial injury in neonates undergoing repair of a single pathology (TGA) by measuring serial postoperative TnI release. The relationship between TnI release and intraoperative and postoperative measurements was then assessed to establish whether TnI can be used as a predictor of early clinical outcome for this group of patients.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Forty consecutive neonates undergoing the ASO for TGA were prospectively recruited from January 1999 to October 2001. Patient characteristics are shown in Table 1. A ventricular septal defect (VSD) was present in 9 patients, 2 of whom also had a hypoplastic aortic arch. Coronary anatomy was classified according to Yacoub and Radley-Smith [5]. Approval from the local Hospital Ethics Committee and informed consent was obtained from the parents/guardians of all patients.


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  		Table 1. Characteristics of Patients With Simple and Complex TGA

 
Operative procedure
Anesthetic and operative techniques were standardized for all patients. A slow induction with sevoflurane and 50% air-O2 followed by fentanyl (25 to 50 mg/kg) was used. Morphine (0.5 mg/kg) was infused during cardiopulmonary bypass and neuromuscular blockade was achieved with pancuronium bromide (0.1 to 0.15 mg/kg). Alpha stat acid–base management was adopted. Heparin (3 mg/kg) was administered to maintain an activated clotting time of 480 seconds or longer.

Cardiopulmonary bypass was established between ascending aortic and right atrial or bicaval cannulation. A single dose of cold (4° to 6°C) crystalloid St Thomas’ I cardioplegia and topical cooling with ice slush were used for myocardial protection in all patients (20 mmol/L KCl, 16 mmol/L MgCl2, 2 mmol/L CaCl2, 147 mmol/L NaCl, 1 mmol/L procaine HCl; Martindale Pharmaceuticals, Romford, UK) [6]. Cardioplegic arrest was achieved by an antegrade infusion of 25 mL/kg for more than 4 minutes. Correction of type C coronary anatomy was as described by Asou and associates [7]. Deep hypothermic circulatory arrest (rectal temperature 18° to 22°C) was used to close atrial septal defects. Ventricular septal defects when present were exposed and closed through the right atrium (two cases were closed under circulatory arrest). Hypoplastic aortic arch repair was performed by direct anastomosis of the descending aorta to the ascending aorta during deep hypothermic circulatory arrest. Patients with a diagnosis of TGA and VSD or hypoplastic aortic arch were classified as complex cases, whereas those with TGA alone were classified as simple cases.

Postoperative management and assessment of clinical outcome
All patients were admitted to the pediatric intensive care unit (ICU) after surgery and managed by intensivists and pediatric cardiologists blinded to the TnI results. Decisions regarding inotropic support and ventilation were based on unit protocol, hemodynamic status (eg, low mixed venous saturation, high lactic acidosis), and clinical judgment.

Outcome variables
The effects of preoperative and intraoperative parameters on TnI release were investigated. Preoperative variables included coronary anatomy and associated cardiac anomalies while intraoperative variables were cardiopulmonary bypass (CPB), aortic cross-clamp, and circulatory arrest times, as well as the lowest rectal temperature.

Intraoperative and postoperative clinical measurements were used as indices of clinical outcome. These included the intraoperative use of inotropic agents to wean neonates from CPB and the durations of inotropic and ventilatory support, and ICU and hospital stay. Dopamine (5 µg · kg-1 · min-1) was routinely infused to discontinue CPB and this dose was then titrated to the hemodynamic and clinical state of the patient in accordance with unit protocol. Postoperative inotropic support was considered as either minimal (dopamine <= 5 µg · kg-1 · min-1) or clinically significant (dopamine > 5 µg · kg-1µg · min-1 with or without other inotropic agents such as adrenaline, noradrenaline, or milrinone).

Measurement of cardiac troponin I
Serum concentrations of TnI were determined before surgery, and at 1, 4, 12, 24, and 48 hours postoperatively, using the ACCESS Immunoassay System (Beckman Instruments Inc., Minnesota). This system uses a sandwich immunoassay technique that recognizes two different epitopes of TnI and has no detectable cross-reactivity with skeletal muscle troponin. The assays were performed by a laboratory technician blinded to the clinical status of the patients or their inclusion in the study. Total TnI release in the first 48 hours postoperatively was calculated using the area under the curve.

Statistical analysis
Summary descriptive statistics were calculated for simple and complex groups separately. The Mann-Whitney rank sum test was used to compare the characteristics of the two groups. Spearman’s rank correlation was used to assess the relationship between peak TnI and measures of clinical outcome. The level of significance was set at 0.05. All data were analyzed using Statview version 5.0.1 (SAS Institute Inc, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
No hospital deaths or major postoperative complications were recorded. Coronary anatomy was classified as A in 23, B in 1, C in 3, D in 9 and E in 2. Two cases did not fall within this classification system (both inverted). Postoperative echocardiography revealed satisfactory correction in all patients with no significant pulmonary valve stenosis, aortic valve regurgitation, or residual VSD. Patient characteristics are shown in Table 1.

Troponin I and clinical outcome variables
Troponin I peaked at 4 or 12 hours postoperatively in all patients (median for simple TGA = 3.4 ng/mL, interquartile range 2.4 to 4.6; median for complex TGA = 4.7 ng/mL, interquartile range 3.2 to 6.8, p = 0.20) and declined over the following 48 hours (Fig 1). The peak TnI level correlated with the total TnI release (r = 0.83, p < 0.0001).



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  		Fig 1. Time-dependent release of troponin I (TnI). • = complex transposition of the great arteries; {circ} = simple transposition of the great arteries.p< 0.01, simple versus complex. (* = p= 0.005;Post-op= postoperative;Pre-op= preoperative.)

 
Peak TnI correlated with the durations of inotropic support (r = 0.54, p < 0.001), ventilation (r = 0.51, p < 0.01), and ICU stay (r = 0.50, p < 0.01) (Fig 2). Two complex cases that had high maximum TnI values and also long durations of inotropic support, ventilation, and ICU stay stand out clearly from the rest of the patients in the graphs. Both patients had TGA associated with a VSD, but 1 of them (who had the highest maximum TnI level and worst outcomes) had inverted coronary arteries, a cross-clamp time above the 80th percentile, and failed to wean from CPB at the first attempt due to suprasystemic pulmonary artery pressures caused by tenting of the left pulmonary artery by the aorta after the Lecompte maneuver—this was resolved by placing an interposition graft into the left pulmonary artery. The other patient was ventilated and on inotropic support preoperatively and also had an interrupted aortic arch, type D coronary anatomy, and the second longest cross-clamp duration (88 minutes).



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  		Fig 2. Relationship of peak troponin I (TnI) to the duration of (A) inotropic support, (B) ventilation, and (C) intensive care unit (ICU) stay. The best-fit line has been plotted and Spearman’s rank correlation coefficient shown. • = complex transposition of the great arteries; {circ} = simple transposition of the great arteries.

 
The duration of aortic cross-clamping correlated with the duration of inotropic support (r = 0.40, p < 0.05). The duration of CPB or circulatory arrest was not correlated with clinical outcome. The duration of CPB, aortic cross-clamping, and circulatory arrest did not correlate with the peak or total TnI release.

Complex versus simple transposition of the great arteries
Complex cases had longer aortic cross-clamp times (medians of 72 versus 54 minutes, p = 0.003), required more inotropic support (medians of 72 versus 49 hours, p = 0.04), and significantly higher concentrations of dopamine to wean from CPB (medians of 10.0 versus 7.5 µg · kg-1 · min-1, p = 0.02) than simple cases (see Table 1). No differences were noted in ICU or hospital stay. Repair of complex TGA resulted in significantly higher total but not peak TnI release compared with simple TGA (total, 100 versus 76 ng · h/mL, p = 0.04; peak, medians of 4.7 versus 3.4 ng/mL, p = 0.20).

Neonates who received clinically significant postoperative inotropic support had higher peak and total TnI release compared with patients who received only minimal inotropic support (median for peak 4.5 ng/mL [IQR 3.6 to 5.3] versus 2.4 ng/mL [IQR 1.8 to 3.2], respectively, p less than 0.001; median for total 95.6 ng h/mL [IQR 76.1 to 132.2] versus 59.1 ng h/mL [IQR 54.6 to 71.7], respectively, p = 0.001).

Coronary anatomy
No significant differences were noted in peak or total TnI or the durations of inotropic support, ventilation, ICU, or hospital stay between neonates with A and non-A coronary anatomy.


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
This study has demonstrated weak but statistically significant correlations between the peak TnI and the durations of postoperative inotropic support, ventilation, and ICU stay in neonates undergoing the arterial switch operation. Two neonates had particularly high peak TnI values needing long durations of inotropic support and ventilation who both required correction of complex defects, had long cross-clamp times, and had non-A coronary anatomy. The complex TGA group overall had longer aortic cross-clamp times, required more postoperative inotropic support and had higher total TnI release compared with the simple TGA group. Neonates who received clinically significant postoperative inotropic support had higher peak and total TnI release compared with those who received minimal inotropic support.

The fact that there was no evidence that TnI release (peak or total) was related to aortic cross-clamp or cardiopulmonary bypass times in the whole group may be explained by the fact that myocardial protection was adequate during cardioplegic arrest.

To minimize the effect on TnI release due to pathology, we have looked at a single pathology previously not assessed. We also restricted our interest to TnI, a marker of myocardial injury as opposed to other markers of general illness such as lactate and mixed venous oxygen saturation, because there is direct coronary manipulation during the ASO. Our own data [8] and that of Hirsch and coworkers [9] suggests that TnI release is lesion-specific and is a reliable predictor of clinical outcome after repair of VSDs and tetralogy of Fallot, but not atrial septal defects. During a routine ASO, there is no direct myocardial damage in terms of stitches being placed through the septum or a ventriculotomy. Thus, if coronary reimplantation can be performed adequately and in the presence of sufficient cardioplegic protection, myocardial damage should be minimized and thus there should not be too much TnI release. It may also be that during surgical repair a threshold level of myocardial damage (and therefore TnI release) has to occur before functional impairment is manifested with requirement for higher degrees of inotropic support, longer durations of mechanical ventilation, and resultant prolongation of ICU stay [9].

Complex anatomy, coronary anomalies, prolonged CPB and circulatory arrest times have been reported as risk factors for mortality and morbidity after the ASO [10, 11]. Complex TGA was associated with a poorer clinical outcome and greater TnI levels. This may purely be a consequence of longer myocardial ischemia or local damage to the peri-VSD cardiomyocyte population during placement of sutures. In our series, coronary anomalies were not associated with significantly greater TnI release or worse clinical outcome.

A potential limitation of this study is that outcome variables such as the duration of inotropic support and ventilation can be subjective according to the intensivist managing the patient. Clinician bias is, however, unlikely to have been a confounding factor given that the postoperative management was strictly in accordance with unit protocol and the TnI results were not available to the intensivist. Also, the sample size of the complex group was relatively small, thus limiting the power of the study to detect differences between the simple and complex groups.

In conclusion, this study has demonstrated weak but statistically significant correlations between the peak TnI and the durations of postoperative inotropic support, ventilation, and ICU stay in neonates undergoing the arterial switch operation. Other simpler markers such as the complexity of the heart defect and cross-clamp time may be as useful to predict outcome in this group of patients.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
The British Heart Foundation and the National Heart Research Fund supported this work.

We would like to thank Dr B. Reeves for statistical advice, M. Ginty for expert technical assistance, and the staff of the pediatric intensive care unit and ward 32, Bristol Royal Hospital for Children.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. von Bernuth G. 25 years after the first arterial switch procedure: mid-term results. Thorac Cardiovasc Surg 2000;48:228-232.[Medline]
  2. Bull C., Cooper J., Stark J. Cardioplegic protection of the child’s heart. J Thorac Cardiovasc Surg 1984;88:287-293.[Abstract]
  3. Immer F.F., Stocker F., Seiler A.M., et al. Troponin-I for prediction of early postoperative course after pediatric cardiac surgery. J Am Coll Cardiol 1999;33:1719-1723.[Abstract/Free Full Text]
  4. Immer F.F., Stocker F.P., Seiler A.M., Pfammatter J.P., Printzen G., Carrel T.P. Comparison of troponin-I and troponin-T after pediatric cardiovascular operation. Ann Thorac Surg 1998;66:2073-2077.[Abstract/Free Full Text]
  5. Yacoub M.H., Radley-Smith R. Anatomy of the coronary arteries in transposition of the great arteries and methods for their transfer in anatomical correction. Thorax 1978;33:418-424.[Abstract/Free Full Text]
  6. Jonas R.A. Myocardial protection for neonates and infants. Thorac Cardiovasc Surg 1998;46(Suppl 2):288-291.
  7. Asou T., Karl T.R., Pawade A., Mee R.B. Arterial switch: translocation of the intramural coronary artery. Ann Thorac Surg 1994;57:461-465.[Abstract]
  8. Modi P, Imura H, Angelini GD, et al. Pathology-related troponin I release and clinical outcome after pediatric open-heart surgery. J Card Surg 2002; in press
  9. Hirsch R., Dent C.L., Wood M.K., et al. Patterns and potential value of cardiac troponin I elevations after pediatric cardiac operations. Ann Thorac Surg 1998;65:1394-1399.[Abstract/Free Full Text]
  10. Daebritz S.H., Nollert G., Sachweh J.S., Engelhardt W., von Bernuth G., Messmer B.J. Anatomical risk factors for mortality and cardiac morbidity after arterial switch operation. Ann Thorac Surg 2000;69:1880-1886.[Abstract/Free Full Text]
  11. Wernovsky G., Mayer J.E., Jr, Jonas R.A., et al. Factors influencing early and late outcome of the arterial switch operation for transposition of the great arteries. J Thorac Cardiovasc Surg 1995;109:289-302.[Abstract/Free Full Text]



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