|Year : 2014 | Volume
| Issue : 2 | Page : 242-249
Does type of cardioplegia affect myocardial and cerebral outcome in pediatric open cardiac surgeries?
Gamal Z. El-Morsy1, Hazem M. Abdullah2, Hany M. Abo-Haded3, Mohamed Adel F Elgamal4, Alaaeldin M. El-Deep4
1 Department of Anesthesia and Surgical ICU, Mansoura University Children Hospital, Mansoura, Egypt
2 Department of Pathology, Mansoura University Children Hospital, Mansoura, Egypt
3 Department of Pediatric Cardiology, Mansoura University Children Hospital, Mansoura, Egypt
4 Department of Pediatric Cardiac Surgery, Mansoura University Children Hospital, Mansoura, Egypt
|Date of Submission||28-Oct-2013|
|Date of Acceptance||19-Nov-2013|
|Date of Web Publication||31-May-2014|
Alaaeldin M. El-Deep
Mansoura University Children Hospital, Mansoura, Dakahleya
Source of Support: None, Conflict of Interest: None
A single-dose strategy for cardioplegia is desired in pediatric congenital cardiac surgery, especially in repair of complex congenital defects. The hypothesis of this study is that a single infusion of Bretschneider HTK solution may offer myocardial and cerebral protection superior to repeated doses of a cold oxygenated blood cardioplegic solution in pediatric congenital cardiac surgery.
Patients and methods
Sixty patients who underwent congenital cardiac repair using cardiopulmonary bypass were grouped randomly to receive either a single dose of Custodiol (group A) or repeated oxygenated blood cardioplegia (group B). Echocardiography, ECG, and microscopic examination were used to evaluate left-ventricular function and structure. Myocardial injury was assessed with creatine kinase MB and serum troponin T, whereas cerebral outcome was assessed by jugular venous oxygen saturation. Patients were also neurologically examined and studied by brain computed tomography for gross neurological manifestation of cerebral ischemia or infarction preoperative and 2 days postoperatively.
Myocardial enzymes and oxygen extraction were significantly high in group B compared with group A. Ultrastructure evaluation and cerebral outcome were significantly better in group A than in group B.
A single dose of an HTK cardioplegic solution provides better myocardial and cerebral protection than repeated doses of oxygenated blood cardioplegia during pediatric congenital cardiac surgery.
Keywords: Bretschneider, cardioplagia, cardiopulmonary bypass, cerebral protection, cold blood cardioplagia, myocardial protection
|How to cite this article:|
El-Morsy GZ, Abdullah HM, Abo-Haded HM, Elgamal MF, El-Deep AM. Does type of cardioplegia affect myocardial and cerebral outcome in pediatric open cardiac surgeries?. Ain-Shams J Anaesthesiol 2014;7:242-9
|How to cite this URL:|
El-Morsy GZ, Abdullah HM, Abo-Haded HM, Elgamal MF, El-Deep AM. Does type of cardioplegia affect myocardial and cerebral outcome in pediatric open cardiac surgeries?. Ain-Shams J Anaesthesiol [serial online] 2014 [cited 2021 Apr 11];7:242-9. Available from: http://www.asja.eg.net/text.asp?2014/7/2/242/133451
| Introduction|| |
Considerable attention has been paid to developing the best method for preserving cardiac muscle viability during cardiac surgery without detriment to myocardial function. The sequelae of myocardial edema formation and its impact on cardiac function are one of the consequences of myocardial injury following cardiopulmonary bypass (CPB) and cardioplegia .
Myocardial edema reflects the limitation of both interstitial and cellular tissue capacities to regulate its volume after ischemia and reperfusion. Impaired cell volume regulation, imbalance in fluid homeostasis, and focal structural defects in cell membrane integrity contribute toward postischemic interstitial and myocyte edema .
Blood cardioplegia, being inexpensive and simple to use, has considerably enhanced myocardial protection during ischemia by slowing the destructive myocardial changes associated with improved patient survival .
The Bretschneider HTK solution is used widely for multiorgan preservation for transplantation, but it is also recognized as a cardioplegic agent that allows single dose administration .
Monitoring of jugular venous oxygen saturation has many applications in cardiac surgery with CPB and the hypothermic technique . Measurement of the saturation of brain efferent blood provides a global estimate of cerebral oxygenation . Decrease of secondary insult to the brain has potential benefits to a range of patients with potential acute brain injuries such as cardiac bypass procedures .
There are few direct comparisons between single-dose HTK cardioplegia and repeated blood cardioplegia in clinically relevant adult patients ,,. It was proved that Custodiol HTK solution is simple to use, administered as one single dose, and it is considered to confer sufficient myocardial protection for more than 2 h of cardiac arrest. The hypothesis of this study is that a single infusion dose of Bretschneider HTK solution may offer myocardial and cerebral protection superior to repeated doses of cold oxygenated blood cardioplegic solution.
However, to our knowledge, in congenital pediatric patients, no studies have been carried out to compare the effect of multidose cold oxygenated blood cardioplegia (CBC) with a single dose of Custodiol HTK solution on the myocardial function.
The aim of this study is to compare the effect of multidose CBC with a single dose of Custodiol HTK solution on the myocardial function and cerebral oxygen extraction. The two different methods of cardioplegia were compared by evaluating left-ventricular function, myocardial tissue blood flow, and serum troponin T release. Cerebral outcome was assessed by jugular venous oxygen saturation and neurological examination for signs of cerebral ischemia or infarction.
| Patients and methods|| |
After ethical committee approval and obtaining informed written consent from the parents, 60 children aged 2-10 years of either sex who were admitted to the Cardiothoracic Surgery Unit, Mansoura University Children Hospital, from January 2011 to March 2013 for correction of congenital cardiac anomalies using CPB were enrolled in this study. Patients with redocardiac surgery or endocarditis, neurological, renal, pulmonary disease, heart failure, and moderate to severe pulmonary hypertension were excluded from this study.
All patients were subjected to a preoperative clinical examination for the assessment of cardiovascular function. Laboratory investigations including complete blood count, electrolyte, arterial blood gas and urine analysis, coagulation survey including prothrombin time, partial thromboplastin time, and bleeding time, activated clotting time, blood glucose level, and liver and renal function tests were performed. Radiological examination [including brain computed tomography (CT)], neurological examination, ECG, and echocardiographic investigations were performed. Patients were chosen randomly by a closed envelope method for either the Bretschneider HTK cardioplegia group (group A, n = 30) or the cold oxygenated blood cardioplegia group (group B, n = 30).
All patients were premedicated in the preoperative area with intramuscular 5 mg/kg ketamine and 0.015 mg/kg atropine sulfate 15 min before induction of general anesthesia. ECG, peripheral oxygen saturation, and noninvasive blood pressure were monitored. Supplemental oxygen was provided through a face mask. Two peripheral intravenous cannulae were inserted after the application of EMLA cream.
Anesthesia was induced by sevoflurane inhalation 2-3 MAC. With loss of consciousness, slow intravenous administration of fentanyl 5 μg/kg and rocuronium 0.9 mg/kg was performed to provide neuromuscular blockade and facilitate tracheal intubation. Positive pressure ventilation was started through a face mask at a rate of 25-28 breaths/min. Patients were mechanically ventilated with 50% O 2 and the end-tidal CO 2 was monitored by side-stream capnograph and maintained between 30 and 35 mmHg. Anesthesia was maintained with sevoflurane 1.5 MAC and fentanyl 0.05 μg/kg/min to maintain the entropy value between 45 and 60, with infusion requirements for rocuronium ranging from 5 to 15 μg/kg/min to maintain muscle relaxation.
A radial artery catheter (22 G) was inserted after performing Allen's test to monitor the arterial blood pressure and blood gas sampling during the entire procedure. A central venous catheter and a jugular bulb catheter (size 4 fr) were inserted under complete aseptic conditions ; a urinary catheter was placed to monitor urine output and nasopharyngeal temperatures were monitored continuously. The heart was approached through a standard median sternotomy in all patients. Perfusion was maintained at an average rate of around 2.4 l/m 2 /min. After the ascending aorta, superior vena cava and inferior vena cava were cannulated for CPB and using a membrane oxygenator and a roller pump with an arterial line filter. The α-stat CO 2 management strategy was used. The normothermic perfusion strategy (32°C) was used.
After aortic cross-clamping, the cardioplegic solution was administered. In group A (n = 30), patients were given 50 ml/kg of HTK cardioplegic solution (Custodiol; Koehler Chemi, Alsbach-Hδhnlein, Germany) once. Each liter contained 15 mmol/l sodium chloride, 9 mmol/l potassium chloride, 18 mmol/l histidine hydrochloride, 180 mmol/l histidine, 4 mmol/l magnesium chloride, 2 mmol/l tryptophan, 30 mmol/l mannitol, 0.015 mmol/l calcium chloride, and 1 mmol/l potassium hydrogen 2-ketoglutarate (osmolarity 310 mOsm/kg, pH 7.02-7.20). The cardioplegic solution was administered at a temperature of 4-8°C.
In group B (n=30), patients were administered 20 ml/kg of cold oxygenated blood cardioplegia and then 10 ml/kg/dose every 25 min. Each liter of cold oxygenated blood cardioplegia contained one-third blood component and two-thirds blood component contained the following: 179.1 mmol/l sodium, 22.2 mmol/l potassium, 18.6 mmol/l magnesium, 2.8 mmol/l calcium, 1.1 mmol/l procaine hydrochloride, 6.5 mmol/l acetate, 77.6 mmol/l chloride, and 32.8 mmol/l hydrogen carbonate (pH 7.30-7.40). The cardioplegic solution may have small variations in individual variables. The cardioplegic solution was administered at a temperature of 4-8°C. The following parameters were measured:
(1) Use of inotropic support, postarrest recovery time, 30-day mortality, and incidence of acute myocardial function. The time from the release of the aortic cross clamp until weaning from extracorporeal circulation, the use of inotropic infusions for longer than 20 min in the first 24 postoperative hours, 30-day mortality, and incidence of acute myocardial function were determined.
(2) Documentation of postoperative atrial fibrillation: A 12-lead ECG was recorded daily on the first 3 postoperative days and compared with the ECG before surgical intervention.
All patients were also monitored by telemetry continuously for the first 3 postoperative days. Patients who had one or more episodes of atrial fibrillation postoperatively without a history of atrial fibrillation preoperatively were recorded.
(3) Measurements of cardiac marker proteins: Venous blood samples were collected for measurement of creatine kinase MB (CK-MB) and troponin T levels before the operation, 6, 18, and 36 h postoperatively. The serum cardiac troponin T level was determined using an electrochemiluminescence immunoassay on the Roche Elecsys 2010 Immunoassay Analyzer (Roche Diagnostics, Mannheim, Germany). The upper normal reference limit of serum cardiac troponin T is less than 0.10 ng/ml. The serum CK-MB level was determined using an electrochemiluminescence immunoassay on the Roche Elecsys 2010 Immunoassay Analyzer. The upper normal reference limit of serum CK-MB is less than 5 ng/ml.
(4) Jugular venous blood sampling and neurological examination: Jugular venous blood samples were collected for the measurement of venous blood oxygen tension and measurement of the difference between venous blood oxygen tension and arterial oxygen tension before CPB, at the end of CPB, at the end of operation, and 6 and 24 h postoperatively. Patients were also neurologically examined by a questionnaire on age and sex and studied by brain CT for gross neurological manifestation of cerebral ischemia or infarction preoperatively and 2 days postoperatively.
(5) Left-ventricular function evaluation: Left-ventricular end-diastolic, left-ventricular end-systolic, and fractional shortening of the left ventricle were measured before surgery and 2 weeks after surgery using transesophogeal echocardiography.
(6) Tissue samples and examination: A full-thickness left-ventricular muscle biopsy was performed in 15 randomly selected patients in each group before perfusion, at the end of ischemia (immediately before removing the aortic clamp), and 30 min after reperfusion using a disposable TraveNol biopsy needle (Tru-Cut). The biopsy sites were oversewn.
(7) Ultrastructural and morphometric analysis: Microscopic studies of mitochondria were then carried out on several Epon-embedded tissue blocks from each one of the 10 selected patients from each group; other patients were not examined because of technical unavailability of the electron microscope (all patients were exposed to the same anesthetic drug) for comparison. Fresh tissue blocks were fixed overnight in 3% gluteraldehyde, postfixed in 1% osmium tetroxide in 0.05 mol/l cacodylate buffer (pH 7.3), and dehydrated in graded alcohol (70, 90, 95, and 100%). We examined semithin sections cut at 150 nm from the two patient groups stained with toluidine blue and safranin, and examined them by light microscopy. Well-fixed areas and those free from preparation artifacts and vacuoles were selected for ultrathin sections cut at 30-50 nm for electron microscopy.
Ultrathin sections were stained with uranyl acetate and lead citrate and examined using a Hitachi 7100 Electron Microscope (Hitachi High-Technologies, Hitachinaka, Japan). At least three tissue blocks from each specimen were cut and at least three sections from each block were examined; five adjacent fibers in each field from five randomly selected fields magnified 10 000-22 500 times, in a zigzag manner, from each section were examined to avoid overlapping of the fields or recounting of the same mitochondrion. Average numbers of mitochondria were counted, and the percentage was determined for whole sections and total number of blocks of each case.
Morphological abnormal mitochondria including number, shape, site (near myofibrils and paranuclear), and size were counted upon examination of these ultrathin sections in the patient group A in comparison with the patients in group B. Each one was examined individually at different magnification powers. To avoid misinterpretation of preparation or fixation artifacts, we only considered abnormal mitochondria in well-fixed fields with intact surrounding cytoplasm with no vacuoles and other intact organelles arranged in a precise manner; other adjacent mitochondria as an internal control showed slight swelling with intact unseparated inner and outer membranes and intact homogenous matrices and cristae. The morphologically abnormal mitochondria showed high-amplitude abnormal swelling without membrane separation, irregular or bizarre shapes, and average number of mitochondria in each field. In contrast, these abnormal findings were not observed in other patients examined from the other group.
(8) Comparative stereological morphometric electron: As marked differences in the shape of mitochondria may occur, no assumption was made in terms of the stereological configuration of these organelles and, thus, the area data were not converted into volume.
In all biopsies, an area (in μm 2 ) of more than 100 randomly selected mitochondria was measured using at least five micrographs.
Randomization was ensured by placing a grid with multiple preselected points over the micrographs. All mitochondria in all micrographs were measured because of marked variations in mitochondria1 size.
To quantify and compare degrees of intracellular edema, as evidenced by swelling of the subsarcolemmal cytoplasmic matrix, the relative change in the size of the subsarcolemmal areas was compared with each of the three serial biopsies. This was done by circumscribing the confines of an area bounded by
(i) The limits of the outermost myofibrillar band,
(ii) The sarcolemmal membrane, and
(iii) Perpendicular lines drawn from one to the other (on prints that had a final magnification of up to 22 400 times).
The area (in μm 2 ) recorded by the digital planimeter was then divided by the total length of the sarcolemmal membrane measured from one perpendicular line to the other and was expressed as μm 2 /cm of the sarcolemmal membrane.
Other ultrastructural modalities examined without morphometrics were autophagic vacuoles, degree of glycogen deposition, state of myofibrillar organization, and the integrity of the interstitial microvasculature. Degrees of abnormality were indicated by description.
Sample size was calculated before the study on the basis of an α error of 0.05 and a β error of 0.1 to detect 25% differences in ventricular functions between the two groups and it was found to be 17 patients in each group. Data were first tested for normality using the Kolmogorov-Smirnov test. Normally distributed continuous data were analyzed using the Student t-test. Non-normally distributed continuous and ordinal data were analyzed using the Mann-Whitney U-test. Categorical data were analyzed using the c2 or Fisher's exact test as appropriate. The results are presented as mean (SD), median (interquartile range), or number of patients as appropriate. A P value of less than 0.05 was considered statistically significant. Statistical analyses were carried out using the SPSS (version 17; SPSS Inc., Chicago, Illinois, USA) for Windows.
| Results|| |
Patient characteristics are shown in [Table 1]. There were no statistical significant differences in any of the variables presented in [Table 1]. There was no 30-day mortality in either of the groups. There was no difference in the incidence of myocardial infarction between the groups studied.
The inotropic dose needed and the duration of its usage were significantly high in group B compared with group A; however, spontaneous recovery of the heart was higher in group A compared with group B. In contrast, the incidence of atrial fibrillation (AF) and time of weaning from CPB were not significant between the groups studied [Table 2].
Creatine kinase MB and troponin T
CK-MB and troponin T levels were significantly higher in group B compared with those in group A as shown in [Table 3] and [Table 4]. The highest levels were found 6 h after the operation.
|Table 3 Preoperative and postoperative creatine kinase MB (μg/ml) values in the groups studied|
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|Table 4: Preoperative and postoperative troponin T (μg/ml) values in the groups studied|
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Left-ventricular function evaluation
The left-ventricular end-systolic dimension decreased gradually 2 weeks postoperatively in both groups when compared with the basal values [Table 5]; however, left-ventricular end-systolic dimension was significantly more lower in group A compared with group B 2 weeks postoperatively [Table 5].
|Table 5: Preoperative and 2-week postoperative left-ventricular function evaluation in the groups studied|
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Jugular venous blood sampling and neurological examination
Jugular venous oxygen saturation was significantly lower in group B compared with group A 6 h postoperatively [Table 6]. However, neurological examination and brain CT study were not significant between the groups studied [Table 7].
|Table 6: Jugular venous oxygen saturation values (%) in the groups studied|
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|Table 7: Neurological examination and brain computed tomography study of the groups studied|
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In group A, there was no increase in the average mitochondrial size in postreperfusion (biopsy) myocardial fibers compared with the average mitochondrial size in the biopsies taken before perfusion. In fact, there was a 5% decrease in the average mitochondrial area. However, group B showed an average increase of 51% in mitochondrial size from the preperfusion to postreperfusion biopsies, thus reflecting an increased propensity toward mitochondrial swelling. The differences in the average area of the mitochondria in groups A and B in the biopsies taken after reperfusion were compared; the results were highly significant (P < 0.001). None of the samples from the Custodiol group showed more than a 6% increase in mitochondrial area, reflecting the absence of significant mitochondrial swelling in this group [Figure 1].
Intracellular edema (as evidenced by subsarcolemmal swelling and cytoplasmic rarefaction) was present in 40% and absent in 60% in group A. It was present to a severe degree in 80% and to a minimal degree in 20% in group B.
All of the biopsies taken after reperfusion in group A showed a moderate or a severe decrease in cytoplasmic glycogen deposition as compared with preperfusion biopsies. However, all postreperfusion biopsies in group A showed a slight or a moderate increase in the cytoplasmic glycogen content.
Focal myofibrillar disorganization
No abnormalities of myofibrillar organization were detected in group A, whereas 60% of samples of group B showed moderate or severe focal myofibrillar disorganization.
| Discussion|| |
In this study, we used two cardioplegic solutions for myocardial preservation in congenital pediatric cardiac surgery to compare their postoperative clinical outcome.
Our study showed that protection of the myocardium for an extended period could be achieved by a single high dose of HTK. This study showed that the cardioprotective effect provided by HTK was superior to cold blood cardioplegia in pediatric open cardiac surgeries. There were no differences in the frequency of atrial fibrillation, time of weaning from extracorporeal circulation, inotropic support, or myocardial infarction between the two groups. Cardiac enzymes were significantly higher in group B compared with group A. Left-ventricular dimensions and ultrastructural studies were better in group A in comparison with group B.
The mechanism of blood cardioplegia protective effect is still unclear. In an experimental study, a direct effect on the myocardial microvasculature is suggested to be responsible. Temporary loss of myocardial capillaries and significantly higher troponin I release have been reported with crystalloid cardioplegia; meanwhile, no capillary-density modification has been associated with blood cardioplegia .
Heat-shock proteins are produced by cardiomyocytes in response to stress stimuli. The protective effects of these proteins against myocardial cell damage and ischemia might be involved in the positive effects of preconditioning. Heat-shock protein 70-1 gene (hsp70-1 gene) expression was assessed on right atrium biopsies in 59 pediatric patients during blood cardioplegia arrest. An upregulation of heat-shock protein 70-1 correlated with aortic cross-clamping time was observed during blood cardioplegia. This could also be the mechanism responsible for the protective effects of blood cardioplegia .
However, HTK is an intracellular cardioplegic solution with a low sodium concentration to arrest the heart by inhibiting the rapid phase of the action potential, which contains histidine as a buffer, ketoglutarate to improve ATP energy production during reperfusion, tryptophan to stabilize the cell membrane, and mannitol to decrease cellular edema. Aarsaether et al.  noted that protein buffers such as histidine might be superior to bicarbonate in stabilizing intracellular pH and the recovery of postischemic biochemical and mechanical parameters.
Takeuchi et al. and Liu et al., in their studies, showed that the administration of a histidine-containing cardioplegia solution promotes anaerobic glycolysis and improves the recovery of high-energy phosphates and contractile function in hypertrophied myocardium, which supports our findings. Because of these qualities and the high buffer capacity, it has been shown that one single dose of HTK is sufficient for myocardial protection up to more than 2 h of ischemia ,.
We compared the effect of HTK with that of cold blood cardioplegia on myocardial injury. There was no significant difference between the two groups in the cross-clamp time and the average time in the present study was just above 30 min in both groups, although one would expect a somewhat shorter cross-clamp time in favor of HTK in more complex and longer lasting procedures. The reason for this finding, although HTK is only administered as one single dose, is most likely that the initial time of HTK administration is between 6 and 8 min and thus longer than that for blood cardioplegia. This finding is in agreement with that of the Fannelop et al.'s  study.
Cerebral oxygen extraction was significantly high in group B compared with group A; this may be attributed to the hemodynamic stability, lesser need for inotropic, ease of weaning from CPB, and better myocardial function in group A than in group B, which maintain CPP and CBF.
Several previous studies used jugular bulb saturation for intraoperative and postoperative monitoring of patients undergoing CPB ,.
In the present study, cardiac enzymes were significantly higher in group B compared with group A. Left-ventricular dimensions and ultrastructural studies were better in group A in comparison with group B. However, some experimental studies comparing one single dose of cold HTK with multidose cold blood cardioplegia  or multidose cold St Thomas' Hospital solution  have reported that HTK provides less adequate cardioprotection, which is not in agreement with our findings. Most of the clinical studies of the cardioprotective effect of HTK solution have been carried out on patients undergoing coronary artery bypass grafting and only a relatively small number of patients have been included ,.
In contrast to our results, one retrospective study with a total of 46 patients undergoing mitral valve replacement with various additional procedures (bypass grafting, maze, tricuspid valve surgery) reported, in agreement with the present study, more spontaneous ventricular fibrillation after removal of the cross-clamp in patients receiving HTK. CK-MB and troponin T were not measured and the cross-clamp time was 20 min longer in the HTK group. Moreover, the temperature of the cardioplegic solution administered was 15°C in blood compared with 4°C in the HTK solution, making a comparison of the two cardioplegic solutions difficult .
This study did not find a significant increase in spontaneous ventricular fibrillation after cross clamp removal in the group of patients receiving HTK. An increase in fibrillation after cross-clamp removal has been linked to conduction disturbances associated with inadequate intraoperative myocardial protection caused by heterogeneous reperfusion, oxidative stress, and alteration of electrolyte concentration across the cell membranes and low ATP levels .
In agreement with a previous study by Breathen et al.  that showed that the Custodiol group had better left-ventricular contraction preservation, superior mitochondrial function, and using myocardial biopsy specimens, significantly lower markers of myocardial damage than using conventional blood cardioplegia, enzymes such as troponin and CK-MB were better in the Custodiol group.
Limitation of study
This study has some limitations. First, the surgeons were not blinded to which type of cardioplegia was being used. Second, the differences in age and cyanosis, and the varied pathologic entities involved in the study were major limitations and might have masked the effects of cardioplegia.
| Conclusion|| |
Our data have shown that HTK cardioplegia provides superior myocardial protection compared with CBC in pediatric patients undergoing simple congenital cardiac anomalies repair. The use of HTK cardioplegia was associated with less metabolic derangement and myocardial cell damage compared with CBC.
| Acknowledgements|| |
Conflicts of interest
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]