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Interact CardioVasc Thorac Surg 2009;8:17-21. doi:10.1510/icvts.2008.189373 © 2009 European Association of Cardio-Thoracic Surgery
Clinical benefit of cardiac ischemic postconditioning in corrections of tetralogy of FallotDepartment of Cardiothoracic Surgery, Xiang Ya Hospital, Central South University, Changsha, Hunan, 410008, P.R.China Received 28 July 2008; received in revised form 22 September 2008; accepted 24 September 2008
*Corresponding author. Tel.: +86-731-4310800; fax: +86-731-4327247.
The postoperative course of cyanotic patients is generally more complicated than in acyanotic patients. The ischemic postconditioning provides protection from myocardial injury. We conducted a randomized trial to evaluate the clinical benefits of postconditioning in patients undergoing repair of tetralogy of Fallot. Ninety-nine patients with tetralogy of Fallot were randomly assigned to ischemic postconditioning group (n=48) or control group (n=51). The postconditioning was performed by intermittent aortic clamping after reperfusion. The morbidity, mortality, ventilation time, length of ICU stay, inotropic score, release of troponin I and lactate were assayed. There was one death in postconditioned group and two in control. Major non-fatal morbidity was reduced in postconditioned patients (12.5%, 6/48) compared with control (33.3%, 17/51, P=0.016). The troponin I was significantly lower (P=0.026) with reduced inotrope score (P=0.001) and lactate release (P=0.019) in postconditioned patients. The ventilation time was significantly reduced in postconditioned patients compared with control (14±15 h vs. 25±28 h, P=0.024). There was a significant decrease in the ICU stay in the postconditioned patients (P=0.048). The study suggests that ischemic postconditioning may provide clinical benefits with respect to the morbidity, ventilation time, ICU stay, requirement of inotrope in patients undergoing repair for tetralogy of Fallot.
Key Words: Myocardial protection; Postconditioning; Ischemia; Reperfusion; Tetralogy of Fallot
The postoperative course of cyanotic patients is more complicated than that of acyanotic patients. The morbidity was from 20% to 40% in tetralogy of Fallot (TOF) repair [1–3]. The ischemic postconditioning (PostC) referring to multiple brief periods of ischemia-reperfusion performed just after the prolonged ischemic insult had been proved experimentally to have strong endogenous myocardial protection by reducing reperfusion injury [4]. The PostC also has been proved to exist in humans in the setting of percutaneous coronary intervention [5]. We previously reported that two cycles of ischemic postconditioning by intermittent aortic cross-clamping after cold blood cardioplegic arrest in the repair for TOF can reduce significantly the postoperative requirement of inotrope and release of creatine kinase-MB, cardiac troponin I (cTnI) [6]. However, the clinical benefits of PostC remain to be determined. The aim of present study was to evaluate the clinical benefits of PostC in patients with TOF undergoing surgical correction.
2.1. Patients One hundred and eight patients with TOF were referred to hospital for surgery between December 2006 and May 2008. Of these, six were unsuitable for repair and three were refused to surgery. The remaining 99 patients were enrolled for the study. The ethics committee of the hospital approved the study and written informed consent was obtained from adult patients or their parents for children. The patients were randomized into a control group (n=51) and a postconditioning (PostC) group (n=48). The patients in PostC group were divided into two subgroups, two cycles of PostC group (2 PostC, n=23) or three cycles of PostC group (3 PostC, n=25) by randomized number table before surgery. The surgeon performing the operation knew group allocation just before aortic cross de-clamping. The anesthesiologist did not know grouping before the postconditioning protocol was performed. The ICU team caring for postoperative patients, data collectors and laboratory staff were also blinded to group allocation. Inclusion criteria were patients undergoing elective complete repair of TOF. Exclusion criteria were as follows: without other major anomalies, McGoon index <1.0, palliative procedure; concomitant infection such as infective endocarditis; emergency surgery; with pulmonary atresia; hemodynamic instability with inotropic support before surgery. Preoperative liver and renal functions in both groups were normal. The preoperative clinical data are summarized in Table 1.
2.3. Anesthesia and surgical techniques During the surgical procedure, the anesthetic technique was similar in both groups. The operations were performed using standard hypothermic cardiopulmonary bypass (28 °C–31 °C) with intermittent perfusion of cold blood cardioplegia in a ratio of 1:4 (modified St Thomas cardioplegia: autologous blood). The aprotinin (5x105 U/kg) administered to the priming volume (from 2008, aprotinin was not used). All operations were performed by the same surgical team using standard surgical methods in both groups. The limited right ventricular outflow incision of 1–2 cm below the pulmonary ring was made for all patients in both groups to enlarge the right ventricular outflow tract and to close the ventricular septal defects. If necessary, a transannular patch using fresh autologous pericardium was employed. 2.4. Cardiac ischemic postconditioning protocol Cardiac ischemic postconditioning was achieved by intermittent aortic cross clamping at 30 s after aortic de-clamping (Fig. 1a). The aorta was occluded for 30 s rendering myocardial ischemia. The superior vena cava and inferior vena cava still were snared, aortic root strong suction was established during aortic cross-clamping to ensure to empty the heart, and thereafter, the aortic clamp was released for 30 s for reperfusion. This cycle was repeated twice in 2 PostC subgroup or three times in 3 PostC subgroup.
2.5. Postoperative care After surgery, all patients were admitted to the intensive care unit (ICU). The patients received the similar postoperative care as determined by the caring physicians. The inotropic support was given on the basis of hemodynamic and clinical conditions. The dopamine was used as first-line inotropic therapy for patients needing such support. The initial dose was 5 µg/kg/min, and then the dose was titrated according to the hemodynamic parameter. If needed, epinephrine was added for sufficient hemodynamic support. The ICU and hospital discharge criteria were standardized in all patients. The primary endpoints were ventilation time, length of ICU stay, postoperative 30-day mortality and major morbidity (non-fatal complication) including low cardiac output, bleeding requiring reopening, major arrhythmia, prolonged ventilation time, hypoxemia, renal failure, retubation and infection. The secondary endpoints were the postoperative inotropic requirement, the release of cTnI and the blood lactate. The inotropic score [7] for the first 24 h postoperatively was calculated with the formula: [(dopamine+dobutamine)x 1]+(milrinonex20)+[(epinephrine+norepinephrine+isoproterenol)]x100. Blood samples were obtained preoperatively (baseline), 4 h, 8 h and 20 h after aortic de-clamping for determination of cTnI by enzyme-linked immunosorbent assay (normal reference value in our hospital is  0.15 ng/ml). The arterial blood lactate was measured serially during the first 24 h after admission to the ICU.
All patients who survived surgery were followed up for at least 30 days after operation. Echocardiography was used to evaluate the surgical result after the operation.
Statistical analysis was performed with the SPSS13.0 software (SPSS Inc, Chicago, IL). The differences were assessed by unpaired Student's t-test for parametric data, Mann–Whitney test for non-parametric data. The repeated-measures analysis of variance (ANOVA) was used to evaluate differences over time between groups for cTnI, blood lactate and post-hoc tests were used to compare these parameters at each time point between groups. Categorical data were analyzed using Fisher's exact test or  2-test as appropriate. The forward stepwise logistic regression was performed to identify risk factors for postoperative morbidity. A P<0.05 were considered significant.
3.1. Mortality and morbidity There were two deaths in control (3.9%, 95% CI: 1–14%); one died of severe low cardiac output syndrome on the first postoperative day. The other died of sudden cardiac arrest on the second day after operation. One in the postconditioned group died of multiple organ failure caused by a brain complication on the 10th postoperative day (2.1%, 95% CI: 0–11%). There was no significant difference in operative mortality between the two groups (P=1.0, Table 2).
The non-fatal complications occurred in 17 patients in the control (33.3%, 95% CI: 19–54%), 6 in the PostC group (12.5%, 95% CI: 5–25% vs. control, P=0.016, Table 2). After exclusion of technique-related complications, the morbidity accounts for 27.5% (n=14, 95% CI: 17–43%) in controls and 6.3% (n=3, 95% CI: 2–17% P=0.006) in the PostC group. The forward stepwise logistic regression revealed the PostC was an independent protective factor for morbidity (OR=0.08, 95% CI: 0.022–0.26, P<0.001). The transannular patchings were risk factors for morbidity (OR=3.02, 95% CI: 1.3–8.0, P=0.023). 3.2. Ventilation time and ICU stay The ventilation time and the ICU stay were significantly less in postconditioned group than in control (P=0.024 and P=0.048, respectively, Table 1). The length of ICU stay was strongly associated with the ventilation time (r=0.861, P<0.001). The multivariate linear regression analysis showed that the morbidity was an independent risk predictor of ventilation time (OR=24.9, P<0.001). The dopamine dose in the PostC group was reduced significantly by approximately 40% less than in control (P<0.001, Table 1). Adrenaline was employed in 3 (6.3%) postconditioned patients and 13 (25%) control patients, respectively (P=0.012). The preoperative cTnI was similar in both groups. The significant increase occurred postoperatively in both groups (P=0.002). However, the cTnI release was significantly lower in the postconditioned group than in control (P=0.032). The significant differences between the groups were found at 4 h intervals after aortic declamping (P=0.026, Fig. 1b). The blood lactate during bypass was not significantly different between the two groups. A significant increase in lactate was observed in the control and postconditioned group (time effect, P=0.001, Fig. 1c) after operation. The peak lactate in both groups was presented at 9 h after operation. However, the lactate in the PostC group was significantly less than in control. According to the area under curve of lactate release, the lactate in the PostC group was reduced by approximately 30% less than in control (P=0.019). The significant differences between groups were found at 6 and 9 h, respectively, after operation. The morbidity was reduced in two subgroups of postconditioned patients compared with in control. Both subgroups had less peak cTnI release (data not shown) and less inotropic requirement than in control (Table 3). Although the ventilation time and ICU stay were reduced in the 2 PostC group compared with control, the difference did not reach statistical significance. Only patients with 3 PostC had significantly reduced ventilation time (P=0.006) and ICU stay compared with control (P=0.031, Table 3).
3.7. Follow-up There was no late mortality. One patient had a small residual ventricular septal defect in the PostC group. One patient in control had a right ventricular outflow tract obstruction with peak gradient of 32 mmHg.
The major finding of the present study is that PostC reduced the morbidity from 33% in the control to 12% in postconditioned patients undergoing TOF repair. Compared with control, there was an approximately 40% reduction in inotropes, 50% reduction in peak cTnI release and 30% reduction in postoperative blood lactate levels in the postconditioned group. These compelling results strongly suggested that PostC played an important role in reducing myocardial ischemia/reperfusion injury, and may offer clinical benefits in these patients with cyanotic congenital heart defects undergoing primary repair. It has been clearly demonstrated that PostC can provide protection from myocardial cellular injury [8] and reduced cTnI release and improved functional recovery in the isolated rat heart with cardioplegia [9]. The present results further provided evidence that cardiac ischemic postconditioning could be also initiated in the setting of cardiac surgery with cardioplegia as effective as that without cardioplegia in percutaneous coronary intervention [5, 10]. Our promising result supported that a multi-center clinical trial is deserved before PostC is employed for routine clinical recommendation. Another major finding in this study is that the time on ventilator and the length of ICU stay also significantly reduced after PostC. The ventilation time, as one of the important clinical parameters used to evaluate the effect of myocardial and pulmonary protection strategy. The reduced ventilation time in postconditioned patients perhaps results from better myocardial function preserved by postconditioning. In addition, the less morbidity in the postconditioned group also may contribute to early extubation. Another possible explanation for reduced ventilation time in PostC patients may be due to the pulmonary protection induced by cardiac PostC. The accumulated clinical and experimental data have shown that remote ischemic preconditioning can provide the protective effect on pulmonary injury [11, 12]. We reported previously that myocardial ischemic preconditioning improved the lung preservation [13]. Because of the similarity in the mechanisms of ischemic preconditioning and postconditioning [14], we cannot rule out the possibility that direct cardiac ischemic postconditioning of myocardium provided remote protection to another organ such as the lungs. Both two cycles and three cycles of PostC can provide similar protection with respect to inotrope requirement, peak cTnI release. However, although ventilation time and ICU stay in the two-cycles group were decreased compared with control, the differences were not significant. This result is consistent with our previous report [6]. The reduced ventilation time and ICU stay in the three cycles of PostC subgroup suggested that three cycles of PostC may be more favorable in improving clinical outcomes than two cycles of PostC. However, because of the small number of patients in the two subgroups, the final conclusion with respect to optimal protocols of PostC in the setting of cardiac surgery needs further investigation. There are several limitations to the present study. Firstly, the age of patients in our study is relatively old, not clinically sufficient to evaluate the effects of PostC on the neonates and young infants with TOF complex congenital heart defects. Secondly, we did not measure cardiac output due to the technical difficulty in young children. However, several direct or indirect indices of myocardial protection such as inotropic requirement, cTnI and lactate release and ventilation time, suggested that cardiac ischemic postconditioning is encouraging for cardiac surgeons due to its simplicity, cost-effectiveness, and easy to be performed in cardiac surgery. In conclusion, the present study suggests that cardiac ischemic postconditioning may improve clinical results with respect to the morbidity, ventilation time, ICU stay, release of troponin I and lactate, and requirement of inotrope in patients undergoing repair for TOF.
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Abstract
1. Introduction