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Eur J Cardiothorac Surg 1999;14:243-249
© 1999 Elsevier Science NL

Myocardial protection by pressure- and volume-controlled continuous hypothermic coronary perfusion in combination with Esmolol and nitroglycerine for correction of congenital heart defects in pediatric risk patients¹

^a Clinic of Cardiac Surgery, University of Cologne, Cologne, Germany
^b Clinic of Pediatric Cardiology, University of Cologne, Cologne, Germany

Received 23 February 1998; received in revised form 18 May 1998; accepted 16 June 1998.

Corresponding author. Maria-Hilf-Strasse 3, 50677 Köln, Germany. Tel.: +49 0221 325669.

	Abstract

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Objective: This study assesses the technical applicability and the clinical value of the continuous coronary perfusion with oxygenated blood as a method for myocardial protection used for congenital heart surgery in pediatric risk patients. Methods: Thirty non-consecutive pediatric risk patients aged from 1 month to 16 years (mean 3.9 years; 11/30 patients aged <6 months) underwent open heart procedures on the beating heart for simple and complex cardiac malformations using a self designed perfusion system with pressure- and volume-controlled continuous hypothermic coronary perfusion (PVC-CONTHY-CAP) in combination with ultra-short ß1-receptor blockade (Esmolol) and nitroglycerine for myocardial protection. The following procedures were done: VSD patch closure (n=6), repair of total a-v canal with `double patch' (n=4), total repair of tetralogy of Fallot (n=7), correction of truncus arteriosus communis type IV (n=1), mitral valve reconstruction (n=4), total cavo-pulmonary connection (n=4), and Rastelli procedure (n=4). Results: The mean cardio-pulmonary bypass time was 131.5 min (range: 44–245 min), the mean coronary perfusion time: 90.1 min (range: 13–202 min). The weaning off extracorporeal circulation was uneventful in all patients, in 21 patients with low-dose and in nine patients with moderate catecholamine support; the mean weaning time was 25 min (range: 7–58 min). The post-operative mean peak creatine kinase (CK-MB) value was 58 U/l, (range: 14–202 U/l). The mean ICU stay in the cardiac surgery unit was 2.9 days, (range: 1–10 days). The mean post-operative mechanical ventilatory support was 2 days (range: 6 h–9 days). Six patients developed thrombocytopenia with values <40 tsd/µl, four patients renal dysfunction, two patients ascites, five patients heart rhythm disturbances, one patient neurological deficits. In three patients (VSD closure: n=2; age: 1 and 2 months; total a-v-canal: n=1; age: 3 months) re-do procedures for significant intraventricular shunt had to be done, in one patient implantation of a permanent pacemaker system was necessary. One patient died due to multiple organ failure after uneventful surgery (total cavo-pulmonary connection for single ventricle). Conclusions: PVC-CONTHY-CAP can be successfully used for repair of simple and complex congenital cardiac malformations. However, in children less than 3 months of age, the transatrial repair of intraventricular defects is technically much more demanding and challenging than under conventional cardioplegic arrest and is possibly accompanied by an increased incidence of residual or recurring intraventricular shunts.

Key Words: Myocardial protection • Coronary perfusion • ß1 receptor blockade • Nitroglycerine • Congenital heart defects

	Introduction

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Generally, the myocardial management with currently used cardioplegic cardioplegic principles offers a good protection against ischemic damage [1] [2]. However, in some individual cases, the cardioplegic principles may not completely protect myocardium leading to post-operative deterioration of ventricular function and, occasionally, to a deleterious outcome [3] [4].

Especially for cases with limited tolerance for ischemia i.e. compromised hearts by volume overload, hypertrophy or cyanosis, methods with aerobic myocardial protection by continuous coronary perfusion with oxygenated blood [5] [6] [7] may promise a better option, provided that some disadvantages of this old concept [8] [9] are eliminated or, at least, reduced.

Therefore, we modified this old concept of myocardial protection and designed a protocol for pressure- and volume-controlled continuous hypothermic coronary perfusion in combination with an ultra-short acting ß1-receptor blocker Esmolol (Brevibloc) and nitroglycerine. Using this protocol we operated on more than 200 patients, our first clinical experience with 100 consecutive patients, including children, was reported elsewhere [10] [11].

Here, we report on our experiences with this technique used for correction of simple and complex congenital malformations in pediatric patients with risk constellations.

	Material and methods

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Patients
Between April, 1996 and December, 1996, 30 non-consecutive pediatric patients at risk (age: 1 month–16 years; mean 3.9 years); 11/30 patients aged <6 months) were operated on by one surgeon (A.B.) for simple and complex cardiac malformations under conditions of beating heart using PVC-CONTHY-CAP for myocardial protection. All patients could be grouped according to the underlying cardiac malformations: ventricular septal defect (VSD) (n=6), total a-v canal (TAVC) (n=4), tetralogy of Fallot (TOF) and one case of truncus arteriosus communis type IV acc. to Collett and Edwards (n=8), mitral valve insufficiency (MI) (n=4), single ventricle (SV) (n=4) and transposition of the great arteries (TGA) with VSD and left ventricular outflow tract obstruction (LVOTO) (n=4).

Each patient was enrolled in the study on the basis of cumulated hazard function of all potential patient-specific incremental risk factors for early (hospital) death and organ dysfunction considered in the current literature as valid [12]. The incremental risk factor for cardiac death or dysfunction was introduced as a main and obligatory inclusion criterion for patient selection.

We accepted the incremental risk factor for cardiac dysfunction as equivalent to the incremental risk factor for cardiac death since it correlates indirectly with the probability of post-operative cardiac death e.g. pre-operative congestive heart failure correlates with the incidence of post-operative low output syndrome (LOS) and, on the other hand, LOS correlates with acute post-operative cardiac death [12].

No patient with the given risk profile was primarily excluded from the study and no patient among those initially enrolled in the study was secondarily excluded from further investigations.

The incremental risk factors for organ dysfunction and early death with particular emphasizing risk factors for cardiac death/dysfunction are summarized in Table 1.

Briefly, conventional cardiopulmonary bypass (CPB) is established by cannulation of the distal segment of the ascending aorta and selective cannulation of both venae cavae. Additionally, coronary sinus is drained to avoid hemolysis and to facilitate operative conditions. For controlled coronary perfusion, a perfusion cannula provided with pressure transducer for intraaortic pressure measurement is placed into the proximal segment of the ascending aorta and connected to a branch line of a main perfusion line of the CPB circuit. The perfusate is cooled down by an integrated heat exchanger. The full CPB is established, the ascending aorta cross-clamped between the two perfusion cannulas and controlled continuous coronary perfusion, gradually increasing the perfusion volume, started. The temperature of the perfusate is maintained at 32°C, the aortic root pressure at approximately 40–70 mmHg, the perfusion flow between 0.8–1.0 ml/g heart muscle (hm) per min. Simultaneously, Esmolol and nitroglycerine infusions are started via coronary perfusion line by a bolus (Esmolol: 0.07 mg/g hm; nitroglycerine: 0.001 mg/kg b.w.) followed by continuous application (Esmolol: 0.05 mg/ml CAP per min; nitroglycerine: 0.01 mg/kg per h). The level of Esmolol application is guided by heart frequency with a target value of 40 beats/min; in some individual cases, for an adequate bradycardia effect, additional Esmolol bolus application is required. After accomplishing the surgical procedure, the aortic clamp is removed, and dopamine infusion with initial dose of 2–4 µg/kg per min is started.

	Results

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The risk profile for each individual patient group is summarized in Table 1. In the VSD-group, each patient had between two and four (mean 3.1) incremental risk factors for organ dysfunction including one incremental risk factor for cardiac dysfunction, as well as one incremental risk factor for early death, respectively. In the TAVC-, TOF-, MI-, SV- and TGA-groups, each patient had between one and three (mean 2.8) incremental risk factors for organ dysfunction, and between one and five (mean 2.8) incremental risk factors for death including at least one incremental risk factor for cardiac death, respectively.

In Table 2, for each individual patient group, mean age, diagnosis, type of surgical repair as well as intra- and post-operative data are given.

The mean CPB time for all patients was 131.5 min (range: 44–245 min), the mean coronary perfusion (CAP) time 90.1 min (range: 13–202 min). The mean CPB- and CAP-times for each individual group are summarized in Table 2. The weaning from CPB was uneventful in all patients – in 21 patients with low dose (up to 5 µg/kg per min) dopamine, in seven patients with moderate (between 5 and 10 µg/kg per min) dopamine and/or dobutamine support, and in two patients, administration of epinephrine (0.05–0.1 µg/kg per min) was necessary. The mean weaning time from extracorporeal circulation for all patients was 25 min (range: 7–58 min). The mean weaning times for each individual group are presented in Table 2. The post-operative mean peak CK-MB value was 58 U/l, (range 14–202 U/l). The mean ICU stay on cardiac surgery unit until transfer into pediatric ICU for all patients was 2.9 days, (range: 1–10 days). Data for each individual group are presented in Table 2. The mean post-operative mechanical pulmonary ventilation time for all patients was 2.0 days (range: 6 h–9 days), in 13 patients for 24 hours or less, in eight patients between 1 and 4 days, in nine patients between 4 and 9 days.

In the post-operative course, six patients developed thrombocytopenia (values <40 tsd/µl) but no bleeding or thrombotic complications were observed, four patients had renal dysfunction (one patient needed continuous veno-venous hemofiltration), two patients had ascites with need for abdominal decompression by temporary Tenckhoff-catheter implantation, five patients developed heart rhythm disturbances (four patients with paroxysmal tachyarrhythmia responsive to drug therapy and one patient with a-v block III°), in one patient diffuse cerebral ischemic insult was observed on the third post-operative day leading to neurological sequelae with a tendency to recovery (Table 3).

	Discussion

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Analysis of mortality profiles in pediatric patients undergoing open heart surgery with cardioplegic arrest reveals that the most common mode of early death is acute cardiac failure which strongly correlates with pre-operative impairment of ventricular function [12]. Even if it is true that, in patients operated on with cardioplegic arrest, the probability for cardiac death may be ischemic-time-independent [12] there is still a basic potential for ischemic injury in cardioplegic hearts, which is almost negligible in patients with simple cardiac malformations and non-compromised hearts, but serious in patients with complex malformations and severly disabled hearts [12].

Therefore, the logical concept of myocardial protection for hearts with severly impaired ventricular function should be based on the principle which eliminates, or at least reduces this basic potential for ischemic injury by providing aerobic metabolism during the surgical procedure.

Encouraged by our favourable clinical experiences with PVC-CONTHY-CAP in combination with ß-blockade and nitrates in adult patients, especially in those with severely depressed left ventricular function and acute ischemia/infarction [11], we adopted this specific technique of myocardial protection in pediatric risk patients with predominantly incremental risk of cardiac death or cardiac dysfunction.

Using this technique we followed the old but abandoned concept of aerobic myocardial protection by continuous coronary perfusion with oxygenated blood [5] [6] [7]. This concept regained new interest by the introduction of Esmolol, an ultra short ß-blocking agent, which due to its negative chrono- and inotropic effects, and due to its complex cardioprotective properties [13] [14] [15] enables technically precise and demanding procedures.

However, in contrast to the techniques recently used in adults [16] [17] and in children [18] [19], in our opinion, three components – cross clamping of the aorta, administration of nitrates, and moderate hypothermia of the coronary perfusate – seem to be necessary to counteract the hazards and overcome the limitations of the method [19] [20].

Aortic cross-clamping: (a) coronary perfusion can be permanently pressure- and volume-controlled, the heart can be perfused with hypothermic perfusate while the patient remains normothermic, thus the total CPB time can be shortened considerably. (b) The dosage of Esmolol can be markedly reduced which, in consequence, enables control of heart rate, avoiding heart arrest, myocardial edema [21] and possible hypotensive effects of Esmolol [22] during CPB. (c) Possible post-operative bronchospastic effects [23] [24] and ß1-receptor-related adverse rebound stimulation effects of renin and antidiuretic hormone [25] can be avoided. (d) Potential for intoxication with the Esmolol metabolite methanol [26] [27] especially in time-consuming procedures with long lasting perfusion times can be reduced. (e) The risk of potential deleterious cerebral air embolization is substantially reduced [19] [20].

Application of nitrates: (a) Potential perfusion deficits of subendocardial layer in the empty beating heart can be favourably influenced by a redistribution of flow in favour of the subendocardial layer [28]. (b) Cardioprotective effects by economisation of myocardial energy status due to a shift to carbohydrate metabolism can be achieved [29]. (c) Putative Esmolol-induced coronary vasoconstriction caused by ß2-receptor inhibition [23] [24] can be prevented/reduced.

Moderate hypothermia: (a) myocardial oxygen consumption [30] and endogenous catecholaminergic counter-regulation can be reduced substantially, increasing the safety margins for myocardial protection, and (b) synergistic negative chronotropic effects of Esmolol can be achieved.

For intracardiac repair, two further recommendations concerning the surgical technique seem to be relevant: (1) continuous coronary sinus drainage – to ensure a bloodless operative field for optimal visualisation and to avoid hemolysis by prolonged and exaggerated suction, and (2) left ventricular drainage – for optimal de-airing to prevent cerebral air embolization.

According to this protocol we operated on 30 pediatric patients at risk and, although our study is only observational in nature, some essential remarks on this technique concerning the quality of myocardial protection (at least in an indirect manner) as well as the conditions for surgical repair can be made.

If our hypothesis is true that the aerobic principle of myocardial protection with PVC-CONTHY-CAP – contrary to cardioplegic arrest – can reduce, or even eliminate the basic potential for ischemic damage, the advantage of continuous coronary artery perfusion will be reflected by lowering the incidence of post-operative cardiac death or dysfunction.

In this regard, the PVC-CONTHY-CAP supplemented by Esmolol and nitroglycerine has fulfilled our expectations. We observed no cardiac related deaths (one patient died due to MOF) in our heterogenous patient cohort, which is a favourable result, considering the increased expected mortality in those patients.

The weaning from CPB was uneventful in all patients, even in patients with very long CAP-times reaching values up to 160 min and more; the catecholamine demand was low and the post-operative cardiac function very satisfactory.

Regarding the conditions for cardiac repair, this technique is – when following all recommendations of our protocol – suitable for any type of intracardiac and extracardiac repair, provided that there is no need for aortic root incision e.g. arterial switch operation. The intracardiac exposure is good to excellent. The passive mode of coronary sinus drainage effectively prevents overflooding of the operative field, thus we were in no case forced to shut off the coronary artery perfusion for improving visualization during the procedure. One exception was in infants less than 3 months of age, in whom visualization of the intracardiac structures and accuracy of surgical repair were not optimal which, due to possible complications, is a clear disadvantage compared to cardioplegic arrest. In this context, some technical complications that occurred may be attributable to this technique.

In three patients (all 3 months of age or less) re-VSD with significant shunting occurred requiring re-do procedures (all re-dos performed under conditions of cardioplegic arrest). In two patients with isolated VSD, the defects of a-v canal type were closed at the primary procedure by a transatrial route after detachment of the septal tricuspid leaflet. Irrespective of the surgical technique used for closure of this specific type of VSD, the generally more difficult exposure of the ventricular septum in a small beating heart may have contributed to higher incidence of recurrent VSD.

Considering a further case with postoperative heart block III° needing a permanent pacemaker system, we would be rather reserved in recommending this technique for correction of VSD of inflow type in children less than 3 months of age.

On the other hand, if one considers the learning phase and the fact that small infants may generally have an increased incidence of residual shunt [31], the good overall clinical outcome in our specific patient cohort may perhaps justify using this technique in small infants with severely compromised hearts.

In six cases, thrombocytopenia, not associated with thrombotic or hemorrhagic events and with spontaneous recovery, was observed. Despite the beneficial effects of Esmolol on platelet aggregation by inhibitory action on neutrophils, superoxid generation and probably stimulating effects on endogenous prostacyclin synthesis during myocardial ischemia [32], a putative Esmolol-induced immune mediated thrombocytopenia cannot fully be excluded [33].

In four cases (all with cyanotic heart disease), persistent supraventricular tachyarrhythmia was observed needing class IC and III anti-arrhythmic drug therapy for conversion into sinus rhythm. One possible mechanism of induction of arrhythmia may be due to the effects of ß-adrenoceptor antagonist withdrawal on the sensitivity of ß-adrenoceptor-mediated responses [34] [35].

In conclusion, PVC-CONTHY-CAP in combination with Esmolol and nitrates provides an adequate myocardial protection in pediatric patients with compromised hearts, also in patients with complex cardiac malformations needing very time-consuming surgery. Its technically more demanding handling (additional equipment, beating heart, need for coronary sinus drainage etc.) when compared to cardioplegic arrest, may be counterbalanced by better clinical outcome.

	Footnotes

 
Presented in part at the 26th Annual Meeting of the German Society for Thoracic and Cardiovascular Surgery, Dresden, Germany, February 5 – 8, 1997, and at the 7th International Symposium on Cardiovascular Pharmacotherapy, Jerusalem, Israel, June 1 – 5, 1997.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Borowski, A. Articles by Korb, H. Search for Related Content PubMed PubMed Citation Articles by Borowski, A. Articles by Korb, H.