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Ann Thorac Surg 2000;70:765-770
© 2000 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Reducing postischemic reperfusion damage in neonates using a terminal warm substrate-enriched blood cardioplegic reperfusate

^a Division of Pediatric Cardiovascular Surgery, The Heart Institute for Children, Hope Children’s Hospital, Oak Lawn, USA
^b The University of Illinois at Chicago, Chicago, Illinois, USA

Address reprint requests to Dr Allen, Heart Institute for Children, Hope Children’s Hospital, 4440 W 95th St, Oak Lawn, IL 60453

Presented at the Poster Session of the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Ft. Lauderdale, FL, Jan 31–Feb 2, 2000.

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. In adult cardiac operations, a warm cardioplegic reperfusate ("hot shot") before removing the aortic cross-clamp improves postbypass myocardial function and metabolic recovery. This modality, however, is rarely used in infants, despite the fact that postbypass cardiac dysfunction remains problematic, especially in cyanotic ("stressed") patients.

Methods. To produce stress, 15 neonatal piglets underwent 60 minutes of ventilator hypoxia (fraction of inspired oxygen, 8% to 10%). All piglets then received similar protection with multidose cold blood cardioplegic solution during 70 minutes of arrest and were separated into three groups to examine the role of a warm reperfusate as well as possible augmentation by aspartate and glutamate enrichment. In 5 piglets (group 1), the cross-clamp was simply removed; in 5 (group 2), an unsupplemented warm blood cardioplegic reperfusate was given; and in 5 (group 3), the warm reperfusate was enriched with aspartate and glutamate. Myocardial function was assessed using pressure-volume loops and expressed as a percentage of control.

Results. Compared with hearts receiving reperfusion with unmodified blood (group 1), a warm unsupplemented cardioplegic reperfusate (group 2) slightly improved systolic contractility (end-systolic elastance, 41% versus 50%; p < 0.05 versus group 1) and preload recruitable stroke work (41% versus 52%; p < 0.05 versus group 1), reduced diastolic stiffness (263% versus 245%; p < 0.05 versus group 1), and increased adenosine triphosphate (10.7 versus 11.9 µg/g tissue, p < 0.05 versus group 1). However, if aspartate and glutamate was included in the warm reperfusate (group 3), there was complete recovery of systolic function (end-systolic elastance, 105% ± 3%; p < 0.001 versus all groups) and preload recruitable stroke work (103% ± 2%; p < 0.001 versus all groups), a minimal rise in diastolic stiffness (154% ± 7%; p < 0.001 versus all groups), and preservation of adenosine triphosphate (15.5 ± 0.5 µg/g; p < 0.001 versus all groups).

Conclusions. A warm cardioplegic reperfusate helps reduce the reperfusion injury, resulting in improved myocardial function and metabolic recovery in hypoxic (stressed) neonatal hearts, and this effect is maximized if the reperfusate is enriched with aspartate and glutamate, which completely preserves myocardial function.

	Introduction

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Reperfusion after temporary myocardial ischemia has been shown to cause irreversible cellular changes and troublesome arrhythmias that were not present during circulatory interruption [1, 2]. This potential for reperfusion damage exists after almost all cardiac operations, because the coronary circulation usually must be temporarily interrupted to perform the repair. If a reperfusion injury does occur, it may contribute to the impaired cardiac performance that develops immediately after operation, and to the eventual myocardial fibrosis that may result after surgical correction of congenital or acquired cardiac diseases [1–4].

Previous studies in adults have shown that the fate of the myocardium jeopardized by global ischemia is determined more by careful control of the conditions of reperfusion and the composition of the reperfusate then by the duration of ischemia itself [1, 2, 5]. A warm reperfusate or "hot shot" is therefore used clinically in most adults undergoing cardiac operations to modify the reperfusion injury, resulting in improvement of postoperative function and decreased mortality [1, 2, 4]. This modality, however, is rarely used in infants despite the fact that postoperative myocardial dysfunction is a major cause of morbidity and mortality [3, 6–8]. This is especially true in cyanotic infants, as they are more sensitive to myocardial ischemia. This study uses hypoxic ("stressed") hearts to examine the role of the terminal reperfusate in limiting reperfusion damage at the end of myocardial arrest. It also investigates amino acid enrichment of the reperfusate solution, as aspartate and glutamate supplementation have been shown to be beneficial after ischemia [1, 3, 7, 9, 10].

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Fifteen neonatal (5- to 18-day-old) piglets (3.5 to 5 kg) were premedicated with 40 mg/kg ketamine intramuscularly and anesthetized with 30 mg/kg phenobarbital intraperitoneally, followed by 5 mg/kg intravenously each hour, and the lungs were ventilated by means of a tracheotomy using a volume ventilator (Servo 900B, Siemens/Elema, Solna, Sweden). All animals received humane care in compliance with the principles ("Principles of Laboratory Animal Care") formulated by the National Society for Medical Research, and "Guide for the Care and Use of Laboratory Animals," prepared by the National Academy of Sciences and published by the National Institutes of Health publication 96–03, revised 1996. The experimental preparation, including cannulation for cardiopulmonary bypass (CPB) and blood sample procurement, is comparable to that previously described [10].

Experimental protocol
Hypoxic (stress) injury
All piglets underwent 60 minutes of ventilator hypoxia as previously described by lowering the fraction of inspired oxygen to 8% to 10%, producing an arterial partial pressure of oxygen of 25 to 35 mm Hg and an oxygen saturation of 65% to 70% [11, 12]. At the end of 60 minutes, piglets were placed on CPB at an inspired oxygen fraction of 100% for 5 minutes to produce a reoxygenation injury [10, 13, 14].

Cardioplegia administration
Cardioplegic solutions (CAPS Service, Research Medical Inc, Salt Lake City, UT) are shown in Tables 1 and 2. Five minutes after initiating CPB, all piglets (groups 1 through 3) underwent 70 minutes of cardioplegic arrest using a protocol consisting of 5 minutes of warm (37°C) induction with substrate-enriched blood cardioplegic solution (Table 1), followed by 4 minutes of cold multidose blood cardioplegic solution (Table 2) and a 2-minute cold multidose infusion every 20 minutes. After 70 minutes of cardioplegic arrest, piglets were then divided into three groups depending on the method of reperfusion (see below). Cardioplegic solution was always infused at a continuously measured aortic root pressure of 40 to 50 mm Hg. Immediately after cross-clamping the aorta, all piglets were cooled to a systemic temperature of 26°C, and warming to 37°C was begun 16 minutes before aortic unclamping. All piglets were weaned form CPB with no inotropic support 30 minutes after aortic unclamping. After arterial blood gases, Ca²⁺, and K⁺ were normalized, final functional and biochemical measurements were made 30 minutes later.

Uncontrolled reperfusion (group 1)
In 5 piglets, the cross-clamp was simply removed, and unmodified blood was allowed to reperfuse the heart.

Warm cardioplegic reperfusate (group 2)
In 5 piglets, a terminal warm (37°C) cardioplegic reperfusate (hot shot) without amino acid enrichment was given for 4 minutes before removing the aortic cross-clamp.

Aspartate- and glutamate-enriched warm reperfusate (group 3)
In 5 piglets, the 4-minute terminal warm (37°C) cardioplegic reperfusate was enriched with 13 mmol each of aspartate and glutamate.

Myocardial performance
Functional measurements were determined using pressure-volume loops as previously described and are expressed as percent recovery of baseline values with each piglet acting as its own control [10, 11]. After final hemodynamic measurements, transmural left ventricular biopsy samples were obtained. Endocardial and epicardial portions were separated, frozen quickly in liquid nitrogen, and stored for biochemical analysis.

Physiologic measurements
Coronary vascular resistance
Coronary vascular resistance (CVR) was determined as previously described during the terminal warm cardioplegic infusion in groups 2 and 3 by measuring coronary sinus pressure and cardioplegic flow once a constant infusion rate with an aortic root pressure between 40 and 50 mm Hg was achieved [10].

Myocardial oxygen consumption
Myocardial oxygen consumption (MO₂) was determined in piglets receiving a cardioplegic reperfusate (groups 2 and 3), during the 4 minutes of reperfusion, as described previously [15]. The cumulative 4-minute MO₂ was determined by the sum of the individual 1-minute values and expressed per 100 g of heart tissue, which was determined by weighing the left ventricle at the conclusion of the experiment.

Biochemical analysis
Adenosine pool
Myocardial samples were crushed in a liquid nitrogen-cooled mortar and pestle and lyophilized. The adenosine pool was determined as described previously, and adenosine triphosphate (ATP) levels expressed as micrograms per gram of dry tissue [10].

Myeloperoxidase activity
Quantitative myeloperoxidase activity was determined as described previously [12]. Enzyme activity is expressed as the change in optical density units per minute per milligram of tissue protein.

Myocardial water
Ventricular samples were placed in preweighed vials and dried to a constant weight at a temperature of 85°C. The percent myocardial water was calculated as previously described [10, 11].

Statistics
Data were analyzed using JMP V2.0 (SAS Institute, Inc, Cary, North Carolina) on a Macintosh IIVX computer (Apple Inc, Cupertino, CA). Paired Student’s t test and one-way analysis of variance was used for comparison of variables among experimental groups. If the analysis of variance revealed a significant interaction, pairwise tests of individual group means were compared by means of multiple comparisons (Tukey’s test) using a level of significance of p less than 0.05 and p less than 0.01. Group data are expressed as mean ± standard error of the mean.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
There was no difference among groups for prehypoxic (baseline) values (slopes) of left ventricular contractility (38 ± 2 mm Hg/mL), diastolic compliance (0.05 ± 0.01), or preload recruitable stroke work (69 ± 2 [mmHg · mL/mL]). All piglets remained stable during 60 minutes of hypoxia.

Hemodynamic and physiologic measurements
Results are depicted in Figures 1–4. There was no change or difference in the x-axis intercept point (V₀) for end-systolic elastance (before, 6.4 ± 0.1; after, 6.5 ± 0.1) or preload recruitable stoke work (before, 10.1 ± 0.1; after, 10.2 ± 0.2) between prehypoxic (baseline) and post-CPB values in any experimental group. Therefore, the change in slope of end-systolic elastance and preload recruitable stroke work can be interpreted to express variability in the contractile state of the myocardium compared with baseline values. Compared with hearts reperfused with unmodified blood (uncontrolled reperfusion, group 1), use of a terminal warm cardioplegic reperfusate without amino acids (group 2) partially modified the reperfusion injury, resulting in slightly improved post-CPB systolic contractility (41% ± 2% versus 52% ± 2%; p < 0.001) and preload recruitable stroke work (41% ± 2% versus 50% ± 2%; p < 0.001), and less diastolic stiffness (263% ± 4% versus 245% ± 5%; p = 0.04; Fig 2). In contrast, the reperfusion injury was avoided if the terminal cardioplegic reperfusate was enriched with amino acids (group 3), resulting in complete recovery of systolic contractility (105% ± 3%; p < 0.001 versus all groups) and preload recruitable stroke work (103% ± 2%; p < 0.001 versus all groups) and a minimal rise in diastolic stiffness (154% ± 7%; p < 0.001 versus all groups). Myocardial oxygen consumption was higher when the terminal cardioplegic reperfusate was enriched with the amino acids aspartate and glutamate (7.3 ± 0.2 versus 4.3 ± 0.2 mL · 100 g^-1 · 4 min^-1; p < 0.001; Fig 3 ), suggesting increased metabolic activity. Coronary vascular resistance was also lower (Fig 4 ), implying improved vascular function.

View larger version (13K): [in this window] [in a new window]   Fig 1. Recovery of left ventricular systolic function as measured by end-systolic elastance (EES) and expressed as percentage of control (baseline). *p < 0.001 versus unmodified blood; **p < 0.001 versus all groups.

View larger version (16K): [in this window] [in a new window]   Fig 2. Postbypass left ventricular diastolic compliance as measured by the end-diastolic pressure-volume relationship and expressed as a percentage of stiffness compared with control (baseline). *p = 0.04; **p < 0.001 versus all groups.

View larger version (22K): [in this window] [in a new window]   Fig 3. Myocardial oxygen consumption (MO2) during reperfusion in piglets receiving a terminal warm cardioplegic reperfusate. *p < 0.001.

View larger version (14K): [in this window] [in a new window]   Fig 4. Coronary vascular resistance (CVR) measured during delivery of the cardioplegic reperfusate in hearts receiving a terminal warm infusion (hot shot). Note that coronary vascular resistance is significantly lower in hearts receiving the terminal cardioplegic reperfusate enriched with the amino acids aspartate and glutamate. Because the myocardium is ischemic after aortic cross-clamping, the coronary vasculature should be maximally vasodilated. The lower coronary vascular resistance therefore represents preservation of vascular function. *p < 0.001.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Reperfusion injury is defined as the functional, metabolic, and structural alterations caused by reperfusion after a period of temporary ischemia [1, 2, 4]. The potential for this damage exists during most pediatric cardiac procedures, because the aorta must be clamped to produce a quiet, bloodless field. Previous studies in adults have shown that the fate of the ischemic myocardium is determined more by the method of reperfusion than the duration of ischemia itself [1, 2, 5]. The cardiac surgeon is in the unique position of counteracting this reperfusion damage because the conditions of reperfusion and the composition of the reperfusate are under his or her immediate control.

Follette and colleagues [2] were the first to show that postischemic reperfusion damage after global ischemia could be avoided in adult hearts by substituting a brief warm blood cardioplegic infusion during the initial phase of reperfusion for the unmodified blood that would normally be provided by aortic unclamping. Applying these principles, Teoh and colleagues [16] and Kirklin and Barratt-Boyes [4] found that use of a warm blood cardioplegic reperfusate improved metabolic and functional recovery, thereby decreasing mortality in adult patients undergoing cardiac operations. The use of a warm cardioplegic reperfusate, however, is rare in infants, perhaps because of the belief that the infant heart is more tolerant of ischemia [3, 7, 17]. Although this may be true in the normal (nonhypoxic) pediatric heart, several experimental and clinical studies have found that the hypoxic neonatal heart is more sensitive to ischemia than the adult [3, 6–8, 10, 18]. This may explain why postoperative left ventricular dysfunction is often seen in cyanotic children despite successful surgical correction [3, 8, 19].

As in adults, use of a nonsubstrate-enriched warm blood cardioplegic reperfusate (group 2) did improve post-CPB functional recovery in hypoxic hearts undergoing 70 minutes of arrest. However, there was still significant cellular damage, as ATP levels and the ATP/ADP ratio were depressed, and the functional improvement compared with uncontrolled reperfusion was slight. In contrast, Follette and associates [2] and others [1, 16] demonstrated a much greater improvement in adult hearts, even when the cardioplegic reperfusate was not enriched with amino acids. This supports the concept that hypoxia–reoxygenation causes a more severe injury than ischemia–reperfusion [14]. Furthermore, neonatal hearts in the present study only underwent 70 minutes of cardioplegic arrest. The fact that such a severe injury occurred after a relatively short period of ischemia confirms the recent clinical study by Taggert and coworkers [20], which demonstrated that the neonatal heart is more vulnerable to ischemia and reperfusion compared with the adult.

Enriching the terminal warm cardioplegic reperfusate with the amino acids aspartate and glutamate vastly improved the efficacy of the modified reperfusate, resulting in complete functional recovery. Furthermore, ATP levels, and the ATP/ADP ratio, were the same as we previously reported in hypoxic hearts undergoing no ischemia, implying cellular preservation [11, 13]. In the presence of normal mitochondrial function (preserved ATP/ADP ratio), these hearts were able to replenish the ATP levels that were reduced during aortic cross-clamping, resulting in an MO₂ during reperfusion that was almost twice the basal metabolic rate [1]. In contrast, piglets not receiving an amino acid-enriched reperfusate sustained mitochondrial damage (low ATP/ADP ratio) and were therefore unable to generate sufficient ATP to replenish depleted energy stores, resulting in a lower MO₂ during reperfusion.

In adults, aspartate and glutamate are thought to restore depleted Krebs cycle intermediates, which allows intact mitochondria to produce substantially greater amounts of ATP through aerobic metabolism [1, 3, 4, 9]. Therefore, the higher MO₂ and ATP levels in hearts receiving aspartate and glutamate (group 3) at least partially supports this hypothesis. However, the increase in MO₂ with amino acids is much less than what was seen in ischemic adult hearts [1, 9]. This suggest that amino acids may also be acting by means of another mechanism, such as preventing a white blood cell-mediated injury, or acting as an antioxidant [21]. The substantially reduced myeloperoxidase activity in these hearts supports this hypothesis, as does our previous study of substrate-enriched warm induction, in which there was no increase in MO₂ during warm induction, despite a substantial functional improvement [11]. The fact that amino acids may be acting by more than one mechanism may help explain why in the present investigation there is such a significant improvement in myocardial function with amino acid enrichment, despite only a moderate increase in MO₂.

Amino acid enrichment also reduced CVR during reperfusion. Just before reperfusion, the coronary vasculature should be vasodilated, because the heart has been ischemic for 70 minutes. The lower CVR in hearts receiving an amino acid-enriched reperfusate therefore represents preservation of normal vascular function, whereas the increased CVR without amino acids suggests a vascular injury. The only other explanation for an increase in CVR would be compression from cellular edema. However, increased edema cannot explain this finding, as myocardial water is not different between groups given a warm cardioplegia reperfusate (groups 2 and 3).

Our model of acute hypoxia does not allow for the chronic adaptive changes that may occur in cyanotic newborns. However, several studies have documented a similar oxygen-mediated injury with reoxygenation of the chronically hypoxic infant, and using the same biochemical tests, we recently documented an identical injury in the cyanotic infant [22–24]. Furthermore, this increased sensitivity of cardioplegic solutions after acute hypoxia parallels the findings in cyanotic infants and chronically hypoxic animals [3, 6, 8, 18, 25, 26]. No hearts in this investigation were normal (nonhypoxic). However, in clinical practice, congenital lesions usually result in either hypoxia or pressure-volume overload, and therefore, normal hearts are probably uncommon, especially in the neonatal population. Furthermore, Taggart and associates [20] recently found that infants undergoing corrective operations were more prone to a reperfusion injury compared with the adult. This may explain why Chaturvedi and coworkers [27], using a conductance catheter to measure pressure-volume loops, demonstrated postoperative ventricular dysfunction even in infants undergoing simple atrial septal defect repair when the heart was protected by cold cardioplegic solution alone. Use of a substrate-enriched warm cardioplegic reperfusate is therefore probably indicated in all infants.

In summary, (1) use of a warm cardioplegic reperfusate, or hot shot, helps reduce the reperfusion injury and improve post-CPB myocardial function in hypoxic (stressed) neonatal hearts, and (2) this effect is maximized if the cardioplegic solution is enriched with the amino acids aspartate and glutamate, resulting in complete preservation of myocardial function and metabolic recovery. Inasmuch as hypoxic hearts are prone to postoperative dysfunction and more sensitive to ischemia, this study suggests a terminal warm amino acid-enriched cardioplegic solution should be administered to all hypoxic infants.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Michael T. Kronon, MD, was supported in part by the Pillsbury Fellowship.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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