- Email: [email protected]
Challenge of Neonatal Myocardial Protection
2286
CORRESPONDENCE
time to extubation, and length of stay in the intensive care unit. Despite, increased redosing interval, we demonstrate stability or improvement of these factors. Furthermore, we studied cardiac troponin t (cTnT) postoperative peak level following WBM with a 35–40-min redosing interval. There was no significant difference in cTnT peak level among 81 patients with single-dose WBM (up to 35 min of aortic cross clamping) and a control group composed of 47 patients undergoing surgery without cardioplegia (beating heart or closed heart surgery). When one or two repeated doses were necessary, cTnT peak levels were 2.17 2.29 mg/L (up to 70–80 minutes of aortic cross clamping) and 3.79 3.00 mg/L (up to 105–120 min of aortic cross-clamping). These results compare favorably with data from the literature [4]. We demonstrate that redosing intervals equivalent to those commonly used for cold cardioplegia were safe during warm myocardial ischemia. These data were reported in international meetings, and their publication is underway. Yves Durandy, MD Marina Rubatti, MD Pediatric Cardiac Surgery CCML 133 Avenue de la Resistance 92350 Le Plessis Robinson, France e-mail: [email protected]
Ann Thorac Surg 2013;96:2283–90
levels and ventricular systolic elastance occurred after 20 min of normothermic ischemia [5], and ischemic periods of up to 40 min resulted in myocardial acidosis, increased release of lactate, creatine kinase, and troponin [6]. Lichtenstein and colleagues [7] reported results from 720 coronary bypass patients showing that the odds of myocardial infarction, low cardiac output or death rose 1.05-fold (95% confidence interval, 1.00–1.11) with each minute of normothermic myocardial ischemia. As such, WBC was protective provided that any single ischemic period was less than 13 min [7]. There is no such evidence in neonates. Although it has been suggested that the relative deficiency in 5’ nucleotidase of the neonatal heart improves high-energy phosphate homeostasis and ischemic tolerance, this is not true in patients with cyanotic heart diseases [8]. It is likely that the best reinfusion regimen of WBC in neonates is yet to be established. Mirela Bojan, MD, MSc Philippe Pouard, MD Anesthesia and Critical Care Necker–Enfants Malades Hospital Assistance Publique–Hopitaux de Paris 149, rue de Sevres Paris, France 75015 e-mail: [email protected]
References 1. Bojan M, Peperstraete H, Lilot M, Tourneur L, Vouh e P, Pouard P. Cold histidine-tryptophan-ketoglutarate solution and repeated oxygenated warm blood cardioplegia in neonates with arterial switch operation. Ann Thorac Surg 2013;95:1390–6. 2. Durandy Y, Hulin S. Intermittent warm blood cardioplegia in the surgical treatment of congenital heart disease: clinical experience with 1400 cases. J Thorac Cardiovasc Surg 2007;133:241–6. 3. Rubatti M, Durandy Y. Prolonged warm ischemia for transfusion-free arterial switch and ventricular septal defect surgery in a 4,5-Kg baby. Perfusion 2012;27:230–4. 4. Taggart DP, FRCS, Hadjinikolas L, Hooper J, et al. Effects of age and ischemic times on biochemical evidence of myocardial injury after pediatric cardiac operations. J Thorac Cardiovasc Surg 1997;113:728–35.
Reply To the Editor:
MISCELLANEOUS
We thank Dr Durandy and Dr Rubatti [1] for their interest in our study on histidine tryptophan ketoglutarate and warm blood cardioplegia (WBC) in neonates [2]. We are also grateful to Dr Durandy for supporting the spread of intermittent WBC worldwide. About 75 to 85 neonatal arterial switch operations are performed at the Necker University Hospital each year, and WBC has been used for 12 years, since Dr Durandy demonstrated the safety of a modified Calafiore method in pediatric cardiac surgery. This technique represents a wide range of regimens in the hands of the different physicians. However, it is important to emphasize that intermittent warm cardioplegia is also intermittent warm ischemia, and that oxygen debt occurs after 3.5 min of warm ischemia [3]. Experimental work has addressed the time-dependent metabolic and functional changes during normothermic myocardial ischemia. Both cardiac lactate release and MVO2 increased in a linear fashion with periods of ischemia of between 1 and 10 min [3], and ischemic periods longer than 10 min resulted in a drop in myocardial oxygenation, as assessed by near-infrared spectroscopy [4]. A significant drop in adenosine triphosphate Ó 2013 by The Society of Thoracic Surgeons Published by Elsevier Inc
References 1. Durandy Y, Rubatti M. Warm blood microplegia redosing interval in pediatric surgery (letter). Ann Thorac Surg 2013;96:2285–6. 2. Bojan M, Peperstraete H, Lilot M, Tourneur L, Vouh e P, Pouard P. Cold histindine-tryptophan-ketoglutarate solution and repeated oxygenated warm blood cardioplegia in neonates with arterial switch operation. Ann Thorac Surg 2013;95: 1390–6. 3. Landymore RW, Marble AE, Eng P, et al. Myocardial oxygen consumption and lactate production during antegrade warm blood cardioplegia. Eur J Cardiothorac Surg 1992;6:372–6; discussion 376. 4. Kawasuji M, Yasuda T, Tomita S, et al. Near-infrared monitoring of myocardial oxygenation during intermittent warm blood cardioplegia. Eur J Cardiothorac Surg 1997;12: 236–41. 5. de Oliveira NC, Boeve TJ, Torchiana DF, et al. Ischemic intervals during warm blood cardioplegia in the canine heart evaluated by phosphorus 31-magnetic resonance spectroscopy. J Thorac Cardiovasc Surg 1997;114:1070–9; discussion 1079–80. 6. Carrier M, Tourigny A, Thoribe N, et al. Effects of cold and warm blood cardioplegia assessed by myocardial pH and release of metabolic markers. Ann Thorac Surg 1994;58:764–7. 7. Lichtenstein SV, Naylor CD, Feindel CM, et al. Intermittent warm blood cardioplegia. Warm Heart Investigators. Circulation 1995;92:II341–6. 8. Imura H, Caputo M, Parry A, et al. Age-dependent and hypoxia-related differences in myocardial protection during pediatric open heart surgery. Circulation 2001;103:1551–6.
Challenge of Neonatal Myocardial Protection To the Editor: The article of Bojan and associates [1] demonstrated different strategies for intraoperative myocardial protection in neonates undergoing the arterial switch operation. Warm blood cardioplegia (WBC) was compared with histidine-tryptophan0003-4975/$36.00
Ann Thorac Surg 2013;96:2283–90
Sabrina Lueck, MD University of Bonn Department of Cardiac Surgery Sigmund-Freud-Str 25 Bonn 53127, Germany e-mail: [email protected] Emanuela Angeli, MD, PhD Policlinico S. Orsola-Malpighi Cardiochirurgia Pediatrica e dell’Eta Evolutiva Bologna, Italy
References 1. Bojan M, Peperstraete H, Lilot M, Tourneur L, Vouh e P, Pouard P. Cold histidine-tryptophan-ketoglutarate solution and repeated oxygenated warm blood cardioplegia in neonates with arterial switch operation. Ann Thorac Surg 2013;95: 1390–6. 2. Viana FF, Shi WY, Hayward PA, et al. Custodiol versus blood cardioplegia in complex cardiac operations: an Australian experience. Eur J Cardiothorac Surg 2013;43:526–31.
2287
3. Angeli E. The crystalloid cardioplegia: advantages with a word of caution. Ann Fr Anesth Reanim 2011;30:17–9. 4. Sawa Y, Matsuda H, Shimazaki Y, et al. Comparison of single dose versus multiple dose crystalloid cardioplegia in neonate. Experimental study with neonatal rabbits from birth to 2 days of age. J Thorac Cardiovasc Surg 1989;97:229–34. 5. Kong JH, Kim DH, Chang BH. Comparison of cardioprotection between histidine-tryptophan-ketoglutarate cardioplegia and DelNido cardioplegia in isolated rat hearts. Korean J Thorac Cardiovasc Surg 2003;36:799–811.
Reply To the Editor: We thank Dr Lueck and Dr Angeli [1] for their interest in our study [2]. The literature reports good results with crystalloid and blood, hypothermic and normothermic, and intracellular and extracellular solutions of cardioplegia, likely because of the 90% drop in the myocardial oxygen consumption already provided by the electromechanical arrest of the heart [3]. However, one cannot state that warm blood cardiopegia (WBC) and histidine tryptophan ketoglutarate (HTK) provide similar myocardial protection based on the study by Viana and colleagues [4]. Although the rates of mortality and postoperative circulatory assist requirement were similar with WBC and HTK, such comparisons were underpowered in both our study and the study by Viana and colleagues [4]. The probability to show a difference in mortality was 0.35 in the study by Viana and colleagues [4] and was 0.67 in our study, and the probability to show a difference in extracorporeal membrane oxygenation requirement was 0.12. Therefore, our conclusion was based on differences in troponin-I release, a marker of myocardial ischemia. Viana and colleagues [4] did not analyze troponin concentrations, but demonstrated a higher incidence of ventricular tachycardia and fibrillation with HTK, a previously reported finding [5] linked with inadequate myocardial protection [6]. In neonates, Angeli [7] reported troponin-I concentrations of 1.2 to 3 mg/mL with HTK, 2 105-fold higher (a typographic error?) than the mean concentrations of 5 to 15 ng/mL that we reported with WBC. Our WBC technique appeared confusing to Dr Lueck and Dr Angeli; however, a simple calculation allows one to infer the potassium concentration in the delivered cardioplegia at approximately 13.3 mmol/L, which is not fundamentally different from 9 mmol/L with HTK. We admit that the reinfusion of cardioplegia results in better metabolic clearance, in reduced accumulation of Naþ during ischemia via the Naþ/Hþ exchanger, and in less Caþ loading upon reperfusion [8]. Therefore, we cannot agree with Dr Lueck’s assumption that the WBC reinfusion resulted in a simple washout of troponin, which may have influenced subsequent troponin release. Finally, we find it hazardous to extrapolate to human neonates the results of experimental work in neonatal rabbits undergoing surgery at 15 C. Overall, we believe there are insufficient data to support the use of HTK cardioplegia with reinfusion intervals of up to 3 h in neonatal cardiac surgery. Mirela Bojan, MD, MSc Philippe Pouard, MD Anesthesia and Critical Care Necker–Enfants Malades Hospital Assistance Publique–Hopitaux de Paris 149, rue de Sevres Paris, France 75015 e-mail: [email protected]
MISCELLANEOUS
ketoglutarate (HTK) solution. Their results were contrary to others published recently confirming that protection by HTK is not only convenient and simple, but also at least as safe as WBC [2]. Because only 30 HTK patients were compared with 188 WBS patients, a propensity matching was necessary, controlling statistical errors. In a first approximation, mortality rates would have shown a significant superiority of WBC, but after matching, mortality rates differed no longer significantly. The same argument was valid for the comparison of extracorporeal membrane oxygenation requirement postoperatively. Nevertheless, some critical remarks about the manuscript must be emphasized: Bojan and coworkers [1] stated that WBC consisted of oxygenated blood and a potassium-rich solution in a ratio of 60:1, being administered every 10 to 12 minutes. If these data were no transcription error, such a cardioplegic solution only represents a simple potassium arrest. In Figure 1, cardiac troponin-I release was higher in the HTK group but it decreased more rapidly, and at postoperative day 2 it was even lower than in the WBC group. The outliers in the HTK group were due to the high number of patients with high-risk anatomy. Interestingly, a previous study showed even lower levels of troponin-I release in neonates with arterial switch operation [3]. Additionally, some basic remarks on pathophysiologic processes are necessary: troponin-I release mainly depends on myocardial ischemic stress. Indeed, every readministration of WBC disrupts ischemia for some minutes, depending on the ratio of myocardial energy demand to oxygen supply by the solution. Thus the ischemic stress of the HTK group was distinctly higher, as HTK was applied only initially. Furthermore, by every cardioplegic reperfusion troponin is principally washed out. Along with biochemical parameters in animal experiments, scorings describing mitochondrial damage and intracellular edema demonstrated that in neonatal hearts, single-dose application of cardioplegia is by far superior to multidose delivery independent of whether blood-containing or crystalloid solutions are used [4, 5]. Considering these data mentioned above, the HTK solution fulfils the following requirement: effective myocardial protection by only a single application even for long-lasting cross clamping (<3 hours) in human neonates.
CORRESPONDENCE
CORRESPONDENCE
time to extubation, and length of stay in the intensive care unit. Despite, increased redosing interval, we demonstrate stability or improvement of these factors. Furthermore, we studied cardiac troponin t (cTnT) postoperative peak level following WBM with a 35–40-min redosing interval. There was no significant difference in cTnT peak level among 81 patients with single-dose WBM (up to 35 min of aortic cross clamping) and a control group composed of 47 patients undergoing surgery without cardioplegia (beating heart or closed heart surgery). When one or two repeated doses were necessary, cTnT peak levels were 2.17 2.29 mg/L (up to 70–80 minutes of aortic cross clamping) and 3.79 3.00 mg/L (up to 105–120 min of aortic cross-clamping). These results compare favorably with data from the literature [4]. We demonstrate that redosing intervals equivalent to those commonly used for cold cardioplegia were safe during warm myocardial ischemia. These data were reported in international meetings, and their publication is underway. Yves Durandy, MD Marina Rubatti, MD Pediatric Cardiac Surgery CCML 133 Avenue de la Resistance 92350 Le Plessis Robinson, France e-mail: [email protected]
Ann Thorac Surg 2013;96:2283–90
levels and ventricular systolic elastance occurred after 20 min of normothermic ischemia [5], and ischemic periods of up to 40 min resulted in myocardial acidosis, increased release of lactate, creatine kinase, and troponin [6]. Lichtenstein and colleagues [7] reported results from 720 coronary bypass patients showing that the odds of myocardial infarction, low cardiac output or death rose 1.05-fold (95% confidence interval, 1.00–1.11) with each minute of normothermic myocardial ischemia. As such, WBC was protective provided that any single ischemic period was less than 13 min [7]. There is no such evidence in neonates. Although it has been suggested that the relative deficiency in 5’ nucleotidase of the neonatal heart improves high-energy phosphate homeostasis and ischemic tolerance, this is not true in patients with cyanotic heart diseases [8]. It is likely that the best reinfusion regimen of WBC in neonates is yet to be established. Mirela Bojan, MD, MSc Philippe Pouard, MD Anesthesia and Critical Care Necker–Enfants Malades Hospital Assistance Publique–Hopitaux de Paris 149, rue de Sevres Paris, France 75015 e-mail: [email protected]
References 1. Bojan M, Peperstraete H, Lilot M, Tourneur L, Vouh e P, Pouard P. Cold histidine-tryptophan-ketoglutarate solution and repeated oxygenated warm blood cardioplegia in neonates with arterial switch operation. Ann Thorac Surg 2013;95:1390–6. 2. Durandy Y, Hulin S. Intermittent warm blood cardioplegia in the surgical treatment of congenital heart disease: clinical experience with 1400 cases. J Thorac Cardiovasc Surg 2007;133:241–6. 3. Rubatti M, Durandy Y. Prolonged warm ischemia for transfusion-free arterial switch and ventricular septal defect surgery in a 4,5-Kg baby. Perfusion 2012;27:230–4. 4. Taggart DP, FRCS, Hadjinikolas L, Hooper J, et al. Effects of age and ischemic times on biochemical evidence of myocardial injury after pediatric cardiac operations. J Thorac Cardiovasc Surg 1997;113:728–35.
Reply To the Editor:
MISCELLANEOUS
We thank Dr Durandy and Dr Rubatti [1] for their interest in our study on histidine tryptophan ketoglutarate and warm blood cardioplegia (WBC) in neonates [2]. We are also grateful to Dr Durandy for supporting the spread of intermittent WBC worldwide. About 75 to 85 neonatal arterial switch operations are performed at the Necker University Hospital each year, and WBC has been used for 12 years, since Dr Durandy demonstrated the safety of a modified Calafiore method in pediatric cardiac surgery. This technique represents a wide range of regimens in the hands of the different physicians. However, it is important to emphasize that intermittent warm cardioplegia is also intermittent warm ischemia, and that oxygen debt occurs after 3.5 min of warm ischemia [3]. Experimental work has addressed the time-dependent metabolic and functional changes during normothermic myocardial ischemia. Both cardiac lactate release and MVO2 increased in a linear fashion with periods of ischemia of between 1 and 10 min [3], and ischemic periods longer than 10 min resulted in a drop in myocardial oxygenation, as assessed by near-infrared spectroscopy [4]. A significant drop in adenosine triphosphate Ó 2013 by The Society of Thoracic Surgeons Published by Elsevier Inc
References 1. Durandy Y, Rubatti M. Warm blood microplegia redosing interval in pediatric surgery (letter). Ann Thorac Surg 2013;96:2285–6. 2. Bojan M, Peperstraete H, Lilot M, Tourneur L, Vouh e P, Pouard P. Cold histindine-tryptophan-ketoglutarate solution and repeated oxygenated warm blood cardioplegia in neonates with arterial switch operation. Ann Thorac Surg 2013;95: 1390–6. 3. Landymore RW, Marble AE, Eng P, et al. Myocardial oxygen consumption and lactate production during antegrade warm blood cardioplegia. Eur J Cardiothorac Surg 1992;6:372–6; discussion 376. 4. Kawasuji M, Yasuda T, Tomita S, et al. Near-infrared monitoring of myocardial oxygenation during intermittent warm blood cardioplegia. Eur J Cardiothorac Surg 1997;12: 236–41. 5. de Oliveira NC, Boeve TJ, Torchiana DF, et al. Ischemic intervals during warm blood cardioplegia in the canine heart evaluated by phosphorus 31-magnetic resonance spectroscopy. J Thorac Cardiovasc Surg 1997;114:1070–9; discussion 1079–80. 6. Carrier M, Tourigny A, Thoribe N, et al. Effects of cold and warm blood cardioplegia assessed by myocardial pH and release of metabolic markers. Ann Thorac Surg 1994;58:764–7. 7. Lichtenstein SV, Naylor CD, Feindel CM, et al. Intermittent warm blood cardioplegia. Warm Heart Investigators. Circulation 1995;92:II341–6. 8. Imura H, Caputo M, Parry A, et al. Age-dependent and hypoxia-related differences in myocardial protection during pediatric open heart surgery. Circulation 2001;103:1551–6.
Challenge of Neonatal Myocardial Protection To the Editor: The article of Bojan and associates [1] demonstrated different strategies for intraoperative myocardial protection in neonates undergoing the arterial switch operation. Warm blood cardioplegia (WBC) was compared with histidine-tryptophan0003-4975/$36.00
Ann Thorac Surg 2013;96:2283–90
Sabrina Lueck, MD University of Bonn Department of Cardiac Surgery Sigmund-Freud-Str 25 Bonn 53127, Germany e-mail: [email protected] Emanuela Angeli, MD, PhD Policlinico S. Orsola-Malpighi Cardiochirurgia Pediatrica e dell’Eta Evolutiva Bologna, Italy
References 1. Bojan M, Peperstraete H, Lilot M, Tourneur L, Vouh e P, Pouard P. Cold histidine-tryptophan-ketoglutarate solution and repeated oxygenated warm blood cardioplegia in neonates with arterial switch operation. Ann Thorac Surg 2013;95: 1390–6. 2. Viana FF, Shi WY, Hayward PA, et al. Custodiol versus blood cardioplegia in complex cardiac operations: an Australian experience. Eur J Cardiothorac Surg 2013;43:526–31.
2287
3. Angeli E. The crystalloid cardioplegia: advantages with a word of caution. Ann Fr Anesth Reanim 2011;30:17–9. 4. Sawa Y, Matsuda H, Shimazaki Y, et al. Comparison of single dose versus multiple dose crystalloid cardioplegia in neonate. Experimental study with neonatal rabbits from birth to 2 days of age. J Thorac Cardiovasc Surg 1989;97:229–34. 5. Kong JH, Kim DH, Chang BH. Comparison of cardioprotection between histidine-tryptophan-ketoglutarate cardioplegia and DelNido cardioplegia in isolated rat hearts. Korean J Thorac Cardiovasc Surg 2003;36:799–811.
Reply To the Editor: We thank Dr Lueck and Dr Angeli [1] for their interest in our study [2]. The literature reports good results with crystalloid and blood, hypothermic and normothermic, and intracellular and extracellular solutions of cardioplegia, likely because of the 90% drop in the myocardial oxygen consumption already provided by the electromechanical arrest of the heart [3]. However, one cannot state that warm blood cardiopegia (WBC) and histidine tryptophan ketoglutarate (HTK) provide similar myocardial protection based on the study by Viana and colleagues [4]. Although the rates of mortality and postoperative circulatory assist requirement were similar with WBC and HTK, such comparisons were underpowered in both our study and the study by Viana and colleagues [4]. The probability to show a difference in mortality was 0.35 in the study by Viana and colleagues [4] and was 0.67 in our study, and the probability to show a difference in extracorporeal membrane oxygenation requirement was 0.12. Therefore, our conclusion was based on differences in troponin-I release, a marker of myocardial ischemia. Viana and colleagues [4] did not analyze troponin concentrations, but demonstrated a higher incidence of ventricular tachycardia and fibrillation with HTK, a previously reported finding [5] linked with inadequate myocardial protection [6]. In neonates, Angeli [7] reported troponin-I concentrations of 1.2 to 3 mg/mL with HTK, 2 105-fold higher (a typographic error?) than the mean concentrations of 5 to 15 ng/mL that we reported with WBC. Our WBC technique appeared confusing to Dr Lueck and Dr Angeli; however, a simple calculation allows one to infer the potassium concentration in the delivered cardioplegia at approximately 13.3 mmol/L, which is not fundamentally different from 9 mmol/L with HTK. We admit that the reinfusion of cardioplegia results in better metabolic clearance, in reduced accumulation of Naþ during ischemia via the Naþ/Hþ exchanger, and in less Caþ loading upon reperfusion [8]. Therefore, we cannot agree with Dr Lueck’s assumption that the WBC reinfusion resulted in a simple washout of troponin, which may have influenced subsequent troponin release. Finally, we find it hazardous to extrapolate to human neonates the results of experimental work in neonatal rabbits undergoing surgery at 15 C. Overall, we believe there are insufficient data to support the use of HTK cardioplegia with reinfusion intervals of up to 3 h in neonatal cardiac surgery. Mirela Bojan, MD, MSc Philippe Pouard, MD Anesthesia and Critical Care Necker–Enfants Malades Hospital Assistance Publique–Hopitaux de Paris 149, rue de Sevres Paris, France 75015 e-mail: [email protected]
MISCELLANEOUS
ketoglutarate (HTK) solution. Their results were contrary to others published recently confirming that protection by HTK is not only convenient and simple, but also at least as safe as WBC [2]. Because only 30 HTK patients were compared with 188 WBS patients, a propensity matching was necessary, controlling statistical errors. In a first approximation, mortality rates would have shown a significant superiority of WBC, but after matching, mortality rates differed no longer significantly. The same argument was valid for the comparison of extracorporeal membrane oxygenation requirement postoperatively. Nevertheless, some critical remarks about the manuscript must be emphasized: Bojan and coworkers [1] stated that WBC consisted of oxygenated blood and a potassium-rich solution in a ratio of 60:1, being administered every 10 to 12 minutes. If these data were no transcription error, such a cardioplegic solution only represents a simple potassium arrest. In Figure 1, cardiac troponin-I release was higher in the HTK group but it decreased more rapidly, and at postoperative day 2 it was even lower than in the WBC group. The outliers in the HTK group were due to the high number of patients with high-risk anatomy. Interestingly, a previous study showed even lower levels of troponin-I release in neonates with arterial switch operation [3]. Additionally, some basic remarks on pathophysiologic processes are necessary: troponin-I release mainly depends on myocardial ischemic stress. Indeed, every readministration of WBC disrupts ischemia for some minutes, depending on the ratio of myocardial energy demand to oxygen supply by the solution. Thus the ischemic stress of the HTK group was distinctly higher, as HTK was applied only initially. Furthermore, by every cardioplegic reperfusion troponin is principally washed out. Along with biochemical parameters in animal experiments, scorings describing mitochondrial damage and intracellular edema demonstrated that in neonatal hearts, single-dose application of cardioplegia is by far superior to multidose delivery independent of whether blood-containing or crystalloid solutions are used [4, 5]. Considering these data mentioned above, the HTK solution fulfils the following requirement: effective myocardial protection by only a single application even for long-lasting cross clamping (<3 hours) in human neonates.
CORRESPONDENCE