| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J Thorac Cardiovasc Surg 2003;125:1242-1251
© 2003 The American Association for Thoracic Surgery
Surgery for Congenital Heart Disease |
From the Division of Cardiac Surgery, Kobe Children's Hospital, Kobe, Japan,a and the Kobe University Graduate School of Medicine, Kobe, Japan.b
Received for publication May 30, 2002. Revisions requested July 8, 2002; revisions received Aug 11, 2002. Accepted for publication Aug 16, 2002. Address for reprints: Masahiro Yamaguchi, MD, Kobe Children's Hospital, Division of Cardiothoracic Surgery, 1-1-1 Takakuradai, Sum ku, Kobe, Hyogo 654-0081, Japan.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionAppendix: DiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix: DiscussionReferences |
|---|
1-3 Previously, we also have shown that hypothermia is important for myocardial protection in pediatric heart surgery, especially in cyanotic heart diseases in which the noncoronary collateral vessel flow may contribute to myocardial rewarming and in that way increase ischemic injury. 4 Although hypothermia reduces oxygen demands, thereby prolonging tolerable ischemic arrest time, hypothermia is also reported to be associated with detrimental effects on enzymatic and metabolic function. 5
Recent evidence obtained in adult patients demonstrated that warm heart surgery might provide better protection for surgical ischemia/reperfusion injury. 5 Teoh and associates 6 demonstrated in a prospective, randomized trial in patients undergoing elective coronary artery bypass that terminal warm blood cardioplegia (TWBCP) enhanced myocardial protection afforded by intermittent cold blood cardioplegia. TWBCP is now often used in adult heart surgery but is rarely used in pediatric heart surgery. 7 Because developmental differences exist in myocardial metabolism and response to ischemia/reperfusion, 1 the effects of TWBCP in pediatric heart surgery need to be elucidated. The purpose of this study was to determine the cardioprotective effects and the mechanisms of TWBCP in pediatric heart surgery.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix: DiscussionReferences |
|---|
|
Protocol of myocardial protection
Myocardial protection was achieved with intermittent cold blood cardioplegia with topical heart cooling in all patients. Cardioplegic solution of 300 mL/m2 of body surface area was initially infused into the aortic root at 30 mm Hg to achieve cardiac arrest, with subsequent doses of 150 mL/m2 of body surface area every 20 minutes. Blood cardioplegia was made by mixing a hyperkalemic crystalloid solution 8 with oxygenated blood in a 1:2 dilution and cooled to 9°C. At the start of reperfusion, the aorta was partially declamped for 3 minutes, and the aortic root pressure was kept less than 30 mm Hg to reduce reperfusion injury; then the aorta was fully declamped. In group T, an additional 300 mL/m2 of body surface area of warm (35°C) blood cardioplegia was infused into the aortic root at a pressure of 30 mm Hg just before declamping the aorta. The composition of terminal warm blood cardioplegia was the same as the cold blood cardioplegia, other than temperature, and is shown in Table 2.
|
Measurements
Myocardial temperature was measured at the ventricular septum near the cardiac apex just before release of the aortic crossclamp using a needle thermistor. Hemodynamic measurements included heart rate, blood pressure, and left atrial pressure. Arterial and coronary sinus blood samples were taken at 0, 10, 20, 30, 45, and 60 minutes after the aortic crossclamp release and analyzed for blood gas and lactate. Oxygen content was calculated from the hemoglobin (Hb), the So2, and the Po2 according to the equation: O2 content = 1.34 x Hb x So2 + 0.0031 x Po2
Myocardial oxygen extraction and myocardial lactate extraction were calculated as the difference between the arterial and coronary sinus content. Lactate extraction rate was calculated by the equation: Lactate extraction rate = (La - Lcs) x 100/La
As a marker of myocardial injury, serum concentration of cardiac troponin T and heart-type fatty acid binding protein (h-FABP) were measured. Cardiac troponin T was measured at 0, 1, 3, 6, and 18 hours after the aortic crossclamp release, and h-FABP at 0, 1, 2, and 3 hours. Cardiac troponin T was measured with an enzyme immunoassay and h-FABP with a sandwich enzyme immunoassay with two different anti-h-FABP monoclonal antibodies. 9
Assessment of clinical outcome
Intraoperative and postoperative clinical parameters were used to assess clinical outcome. Intraoperative parameters included heartbeat recovery after release of the aortic crossclamp, either spontaneously or with electrical defibrillation, and intraoperative requirement of pacing and inotropes for weaning patients from cardiopulmonary bypass. Postoperative parameters included duration and maximum doses of inotropic support, duration of ventilatory support, intensive care unit stay, and mortality rate. Dopamine was the catecholamine of the first choice and dobutamine was the second. When dopamine and dobutamine failed to provide sufficient inotropic support, epinephrine was used.
Statistics
Data were collected prospectively and analyzed for all 103 patients recruited. Statistical analysis was performed using SAS version 6.12 software package (SAS Institute, Cary, NC). The mean ± the standard error of the mean for all data was calculated for all variables. Intragroup analysis was performed by a two-tailed paired t test or repeated measures analysis of variance with Bonferroni posthoc test as appropriate. Intergroup analysis was performed by a two-tailed unpaired t test or repeated measures analysis of variance with Bonferroni post-hoc test as appropriate. A Fisher's exact test was used for categorical variables.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix: DiscussionReferences |
|---|
|
|
|
|
|
|
|
|
|
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix: DiscussionReferences |
|---|
We have used cardiac troponin T and h-FABP as a marker of myocardial injury because recent reports have suggested that both troponin T and h-FABP are more sensitive and specific to myocardial injury compared with creatine kinase-MB isoenzyme. 9,10 Troponin T is one of three components of troponin that is a major accessory protein associated with actin filaments and mediates Ca2+ regulation of muscle contraction. 11 Because most cardiac troponin T is myofibril bound, its release in serum is expected to correlate with the extent of myocardial necrosis. Furthermore, its release beyond several hours is reported to derive from myofibril-bound troponin T that is compartmented in the cell, but not from cytosolic troponin T that is released earlier after ischemic events. 12 Our data showed that serum concentration of troponin T was significantly decreased with TWBCP at 6 and 18 hours after reperfusion compared with the control, indicating TWBCP significantly reduced myocardial necrosis resulting in decreased release of myofibril-bound troponin T into the serum.
Human h-FABP is a cytoplasmic protein abundant in the myocardial cells, has a lower molecular weight (14.9 kDa) compared with creatine kinase-MB isoenzyme (80 kDa) and troponin T (32 kDa), and is the key fatty acid carrier protein in the cytosol. 13 H-FABP is released from cells into the circulation shortly after the onset of cell injury because of its low molecular weight and cytosolic location. 9 Our data showed that h-FABP was significantly decreased at 2 and 3 hours after reperfusion in group T compared with group C, indicating that less myocardial injury, not always necrosis, occurred with TWBCP.
In physiological conditions, fatty acids, lactate, and glucose are taken from blood into myocardial cells and used as myocardial metabolic substrates. Of these, fatty acids represent the principal metabolic substrate in myocardial cells; however, during ischemia, fatty acid oxidation is inhibited and glycolytic adenosine triphosphate (ATP) production predominates, resulting in lactate production and release into the extracellular space. 14 Namely, lactate release from the ischemic myocytes is considered as an index of anaerobiosis. Myocardial lactate extraction rate stayed negative in group C, indicating that the amount of lactate production through the anaerobic glycolysis was greater than the amount of lactate used for aerobic energy production. These data indicate continued anaerobic energy metabolism and prolonged impairment of normal aerobic metabolism during the first 60 minutes of reperfusion in hearts receiving cold blood cardioplegia and topical cardiac cooling only. In contrast, our data show that myocardial lactate extraction rate was increased at all time points in group T compared with group C, and the crossover point of lactate extraction rate from negative to positive was observed at 30 minutes of reperfusion. This indicates that lactate consumption and production were equilibrated at 30 minutes of reperfusion in hearts receiving TWBCP, and thereafter lactate extraction became positive. This crossover point shows that myocardial tissue starts to use lactate as a substrate via oxidative phosphorylation. 14 These data demonstrate that TWBCP accelerates the recovery of aerobic energy metabolism.
The mechanisms of TWBCP by which TWBCP affords cardioprotection in adult patients have been shown to include the following: (1) warm blood accelerates recovery of temperature-dependent enzymatic and metabolic function and provides oxygen; (2) high potassium prolongs electromechanical arrest to decrease energy demands; (3) low calcium prevents intracellular calcium overload, which is believed to be the major cause of ventricular contracture and reperfusion injury; (4) alkalotic solution counteracts tissue acidosis and optimizes enzymatic and metabolic function; and, (5) high osmolarity counteracts tissue edema. 2,6,15-17 We have used the same solution as cold blood cardioplegia for TWBCP by just warming cold blood cardioplegia to 35°C. The composition of our TWBCP solution meets the requirement of above-mentioned proposed mechanisms. At 18 mmol/L, the level of K+ was high enough to keep the heart from recurring electromechanical activities, and none of the hearts showed any electromechanical activities during TWBCP infusion.
Because TWBCP is given at the end of global ischemia just before reperfusion, TWBCP is expected to reduce reperfusion injury after ischemia. At the onset of reperfusion after the aortic crossclamp release, we routinely reduced coronary artery perfusion pressure to less than 30 mm Hg by partially declamping the aorta for 3 minutes and Ca2+ concentration to less than 0.7 mmol/L with citrate-phosphate-dextrose to prevent intracellular calcium accumulation in all patients. Therefore, the major differences in the composition of reperfused solution between the two groups were in potassium concentration, pH, and osmolarity. TWBCP included significantly higher concentration of potassium, higher pH, and higher osmolarity compared with circulating blood at the onset of reperfusion. Thus, we speculate that cardioprotection with TWBCP was achieved with prolonging electromechanical arrest and counteracting myocardial tissue acidosis and edema.
Our results show that TWBCP improved lactate metabolism and reduced myocardial injury and necrosis, and with such mechanisms TWBCP had favorable effects on clinical outcome parameters. The improved lactate metabolism indicates improved aerobic production of high-energy phosphates that would presumably occur through prolonging the electromechanical arrest by high potassium, which reduces energy demands, and through counteracting tissue acidosis. Intracellular acidosis activates Na+-H+ exchanger leading to increased Na+ concentration in the cytosol, which would further activate Na+-K+ pump to decrease intracellular Na+ concentration with the consumption of ATP and Na+-Ca2+ exchanger, leading to increased intracellular Ca2+ concentration. 18 To reduce intracellular Ca2+ concentration, ATP would be consumed further to activate Ca2+ pumps on the sarcolemma and sarcoplasmic reticulum. Thus, these two constituents of TWBCP, high potassium and high pH, would contribute to the reduced myocardial injury and necrosis by preservation and resynthesis of high-energy phosphates.
The mean age of the patients in this study was 5.6 ± 0.4 years, and only 3 neonates were included. Therefore, we could not draw any conclusions in terms of the effect of TWBCP on neonatal hearts, which obviously needs to be elucidated. However, we examined the patients whose ages were equal to or less than 2 years (Table 5
and Figures 5 and 6). Interestingly, our data showed that the crossover point of lactate extraction rate in group T was observed at 20 minutes of reperfusion, which was 10 minutes earlier compared with the entire study group, indicating that the recovery of lactate extraction might be quicker with TWBCP in the younger hearts compared with the older hearts. Cardiac troponin T was decreased with TWBCP at any time point and the difference between the groups seemed more prominent (Figure 6), although no statistical significance was observed as a result of the small number. These data suggest that immature hearts might be provided better myocardial protection by TWBCP compared with mature hearts.
We also examined the patients with cyanosis separately (Table 6 and Figures 7 and 8). Our data showed that no significant differences in lactate extraction were observed between the groups after up to 45 minutes, and the crossover point in group T was observed between 45 and 60 minutes of reperfusion, indicating that the effect of TWBCP on lactate metabolism was less evident and the recovery of lactate extraction was slower in patients with cyanosis compared with the entire study group. The underlying mechanisms of delayed recovery of lactate extraction could be impaired aerobic energy metabolism or reduced lactate washout 19 from the hypertrophied myocardium in patients with cyanosis. No significant differences in cardiac troponin T were observed between the groups at any time point. These data suggest that cyanotic hearts might be less benefited by TWBCP compared with acyanotic hearts. However, the effects and the mechanisms of TWBCP on cyanotic hearts remain to be elucidated.
In conclusion, our data indicate that TWBCP has cardioprotective effects in children and adolescents, as it does in adults, and TWBCP affords an additional myocardial protection by improvement in aerobic energy metabolism and reduction of myocardial injury or necrosis, suggesting that TWBCP would allow for enhanced myocardial protection in pediatric heart surgery and should be used routinely as in adult heart surgery.
|
Appendix: Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix: DiscussionReferences |
|---|
A terminal warm cardioplegic reperfusate is a routine part of most adult heart procedures. In contrast, a warm blood cardioplegic reperfusate is rarely used in infants, perhaps because of the belief that the infant heart is more tolerant to ischemia. Dr Toyoda and his colleagues are to be commended for investigating this question with a randomized clinical trial. These studies are often difficult because, unlike the experimental laboratory where variables can be precisely controlled and measured, the preoperative state of patients is not uniform, and the postoperative measurements are less precise. This usually makes it difficult to demonstrate differences unless they are profound. In spite of these problems, their data support several experimental studies and demonstrate that a terminal warm cardioplegic reperfusate is beneficial in the clinical pediatric population.
Numerous studies have documented a higher mortality and morbidity rate in infants with cyanotic hearts, and these hearts are often less tolerant to ischemia and more dependent on the method of myocardial protection. Did you notice any differences between patients with and without cyanosis?
Reperfusion injury is often related to the length of ischemia and, therefore, crossclamp time. Was there any difference in the outcome variables between groups as a function of crossclamp time?
The average age of these patients was 5.5 years, and therefore many of these hearts may not be significantly different from adults. Can you please comment on this therapy in your younger patients? Did you notice any difference between the younger and older patients in the efficacy of this treatment?
We recently demonstrated a modest improvement in neonatal piglets receiving a terminal warm cardioplegic reperfusate after cold cardioplegic arrest. However, we noted the beneficial effect was markedly enhanced when the amino acid aspartate and glutamate were added. Indeed, this improvement was significantly greater than when these same amino acids were added to the terminal reperfusate in adult hearts, implying that they were more effective in younger patients. Do you have any experience with the use of amino acids, and could you please comment?
In summary, this is an important study because it is only one of a small number of studies that have examined a specific myocardial protection strategy in the pediatric population. I believe it is only from studies such as this that we will be able to determine the optimal method of protecting the pediatric heart, instead of blindly, and often uncritically, adopting adult cardioplegic strategies.
Dr Toyoda. In this study, we had only 3 neonates, so we couldn't draw any conclusions for neonatal hearts. However, we examined the patients whose ages were less than 2 years.
We had 13 patients in group C and 9 patients in group T, and similar results were observed with the incidence of spontaneous defibrillation and the inotropic support at the time of weaning from cardiopulmonary bypass. Interestingly, the effect of terminal warm blood cardioplegia on lactate metabolism was more evident in the younger patients. As you can see, the crossover point from negative to positive was observed at 20 minutes of reperfusion, which was 10 minutes earlier than that in the entire study group. Also, cardiac troponin T was significantly decreased in the terminal warm blood cardioplegia group at any time point. So, our data suggest that immature hearts might be provided better myocardial protection by terminal warm blood cardioplegia compared to older hearts.
Regarding the first question, cyanosis versus acyanosis, we had 26 patients with cyanosis in both groups, and again similar results were observed in terms of spontaneous defibrillation and inotropic support. Interestingly, in patients with cyanosis, there were no significant differences in lactate extraction up to 45 minutes between the groups, and the crossover point was observed between 45 and 60 minutes, which moved significantly to the right. Also, no significant difference in cardiac troponin T was observed between the groups.
We had 26 patients without cyanosis in group C and 25 in group T. The effect of terminal warm blood cardioplegia on lactate metabolism was more evident in patients in the acyanotic group. The crossover point was observed between 10 and 20 minutes, which was significantly earlier than that observed in patients with cyanosis. Also, cardiac troponin T was significantly decreased at 0 and 1 hour after reperfusion in patients in the acyanotic group. So, these data suggest that patients with cyanosis might be less benefited by terminal warm blood cardioplegia compared with patients in the acyanotic group. Regarding the aortic crossclamp time, we could not find any correlation between the aortic crossclamp time and the effect of terminal warm blood cardioplegia.
Finally, we didn't add amino acids to our terminal warm blood cardioplegia. I know Dr Allen and colleagues have reported the effectiveness of amino acids. In this particular study, however, we simply investigated the effect of warm blood cardioplegia with the same composition as cold blood cardioplegia.
Dr Emile A. Bacha (Chicago, Ill). Would you comment on the temperature difference between your warm cardioplegia and the temperature of the myocardium itself? You mentioned that the myocardium had a temperature of 9°C, so you're hitting myocardial cells that are 9°C with a 35°C perfusate. When we cool and warm patients, as you know, we're very careful to keep the temperature difference between perfusate and body temperature at most 10°C difference for fear of harming the cells, and I'm wondering whether you could comment on that particular aspect of your strategy.
Dr Toyoda. We measured myocardial temperature while infusing terminal warm blood cardioplegia. Myocardial temperature was increased from 9.6°C to about 20°C. But, as you can see, the functional recovery and the recovery of rhythm in patients treated with terminal warm blood cardioplegia were better than in patients without terminal warm blood cardioplegia. We didn't find any detrimental effect by this warm temperature.
Dr Richard A. Jonas (Boston, Mass). Dr Toyoda, have you considered using thermodilution cardiac output in the first 24 hours after operation to assess myocardial protection? I've been surprised at how little this has been used as a clinical tool in studies of this nature. We have found in our studies, which primarily have been looking at cerebral protection, that when we place thermodilution catheters, we obtain very reproducible results. The thermodilution catheter has been a very sensitive clinical instrument for us that has demonstrated, for example, improved myocardial protection with a higher perfusate hematocrit on bypass. Have you considered using a thermodilution catheter to measure the cardiac output?
Dr Toyoda. Instead of the thermodilution catheter, we used a left atrial line and pulmonary arterial line to measure the left atrial and pulmonary arterial pressures. Because we believe cardiac output is definitely a good marker to treat patients after operation, we will consider using the thermodilution catheter.
Dr Jonas. Okay. Well, I would put in a plea for those of you doing myocardial protection studies, it's simply a matter of placing a pulmonary artery line through the infundibulum of the right ventricle and a right atrial line. And by injection of ice saline solution, it's possible to get regular thermodilution outputs. It's certainly not a regular Swan-Ganz catheter (Baxter Healthcare Corp., Edwards Div., Irvine, Calif.) like you would use in an adult, but we found it to be an extremely low-risk test.
Dr William M. DeCampli (Philadelphia, Pa). You have to be applauded for the number of patients in your study: 100 is a great number. That also implies, however, that you probably could have used formal multivariate analysis to examine these data rather than a series of univariate studies. Your clamp times must have had a fair amount of spread, because you did some quite simple operations, atrial septal defect closures, all the way up to repairs of pulmonary atresia. So that I would think that a more formal look at whether there were significant interactions between the duration of ischemia, the total time for cardiopulmonary bypass, and the method of cardioplegia might be worth trying if you have haven't already done so.
Also, with regard to certain outcome variables, such as the incidence of using inotropes, I think that blindedness in a study like this can be very important, because no one has a very rigorous set of criteria for instituting inotropic support on weaning bypass. In a study like this, it is possible to blind that final 3 minutes with regard to whether you were actually infusing or not infusing, and it might be worth trying.
Finally, with regard to the lactate production, in a study that we had done previously we looked at the effect of blood cardioplegia on early coronary vasodilation during that terminal phase. I'm wondering if the lag in the transition point of lactate production may have been just the effect of delayed opening up of some of the distal coronary beds so that you have delayed washout of lactate, to the extent that the effect does not represent increased myocardial damage or increased lactate production so much as it represents delayed washout of lactate.
Dr Toyoda. We have not done multivariate analysis yet, so we will do that. Regarding criteria for instituting inotropic support at the time of weaning patients from cardiopulmonary bypass, we make every effort to avoid using inotropic support because we believe inotropes are harmful for myocardial cells recovering from ischemic injury. The most important thing we did was take enough time for empty beating after completion of intracardiac repair. The average time for empty beating was 34 minutes. Also, of course, we rigorously optimized rhythm, preload, and afterload before we tried to wean patients from cardiopulmonary bypass. We wean patients from cardiopulmonary bypass if systolic blood pressure is greater than 50 to 70 mm Hg, depending on a patient's age, with left atrial pressure between 10 and 12 mm Hg. We also believe that blindedness with regard to whether the patients were receiving terminal warm blood cardioplegia can be very important.
With regard to the lactate production, delayed washout could be the mechanism of this result. We didn't measure the coronary flow in this study so we couldn't comment on that. However, we believe the effect on the lactate extraction does represent, at least in part, increased myocardial damage based on clinical outcomes, as well as the results of cardiac troponin T and fatty acid binding protein.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix: DiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  N. Yoshimura, Y. Oshima, M. Yoshida, H. Murakami, H. Matsuhisa, and M. Yamaguchi Continuous Hemodiafiltration During Cardiopulmonary Bypass in Infants Asian Cardiovasc Thorac Ann, October 1, 2007; 15(5): 376 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Rergkliang, A. Chetpaophan, V. Chittithavorn, P. Vasinanukorn, and V. Chowchuvech Terminal Warm Blood Cardioplegia in Mitral Valve Replacement: Prospective Study Asian Cardiovasc Thorac Ann, April 1, 2006; 14(2): 134 - 138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Amark, H. Berggren, K. Bjork, A. Ekroth, R. Ekroth, K. Nilsson, and J. Sunnegardh Blood Cardioplegia Provides Superior Protection in Infant Cardiac Surgery Ann. Thorac. Surg., September 1, 2005; 80(3): 989 - 994. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hasegawa, M. Yamaguchi, N. Yoshimura, and Y. Okita The dependence of myocardial damage on age and ischemic time in pediatric cardiac surgery J. Thorac. Cardiovasc. Surg., January 1, 2005; 129(1): 192 - 198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hasegawa, N. Yoshimura, S. Oka, Y. Ootaki, Y. Toyoda, and M. Yamaguchi Evaluation of heart fatty acid-binding protein as a rapid indicator for assessment of myocardial damage in pediatric cardiac surgery J. Thorac. Cardiovasc. Surg., June 1, 2004; 127(6): 1697 - 1702. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG |
