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Ann Thorac Surg 1998;66:1507-1513
© 1998 The Society of Thoracic Surgeons

Strategies of myocardial protection for operation in chronic model of cyanotic heart disease

^a Division of Cardiovascular Surgery, University of British Columbia, Vancouver, British Columbia, Canada

Address reprint requests to Dr Jamieson, Department of Surgery, University of British Columbia, 910 West 10th Ave, Room 3100, Vancouver, BC, Canada V5Z 4E3

Presented at the Thirty-fourth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 26–28, 1998.

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Cyanotic congenital hearts have an increased susceptibility to ischemia and subsequent reperfusion. The role of platelet-activating factor antagonism and mechanical neutrophil depletion with leukocyte-depleting filters for control of ischemia-reperfusion injury was assessed in corrective surgical procedures for cyanotic heart disease.

Methods. A swine model of cyanotic heart disease was evaluated with three study groups: a control group; a group given a platelet-activating factor antagonist (PAFA group); and a group with leukocyte-depleting filtration (LDF group). The cyanotic model was created with a left atrial appendage–pulmonary artery fistula with peripheral banding through a left anterior thoracotomy in weanling swine. The experimental procedure was performed 5 to 7 weeks later when body weight was greater than 20 kg and oxygen saturation was 85% or less. The corrective procedure was performed through a median sternotomy on cardiopulmonary bypass with repair of the shunt. Myocardial protection was accomplished with hypothermic blood-crystalloid (4:1) cardioplegia; the period of ischemic arrest was 90 minutes. In the PAFA group, the platelet-activating factor antagonist CV-6209 was delivered intravenously 15 to 20 minutes before aortic cross-clamping. In the LDF group, Pall leukocyte-depleting filters were used in the CPB arterial line. Hemodynamic data were taken before operation and 10 and 30 minutes after CPB with impedance ventriculography.

Results. There were four deaths in the control group within 30 minutes after CPB; all animals in the treated groups survived longer than 60 minutes (p < 0.05). The ventricular assessment of end-systolic elastance revealed superior performance in the LDF group 30 minutes after CPB compared with the control group (p < 0.05) (controls, 4.0 ± 9; PAFA group, 6.5 ± 3.7; and LDF group, 12.0 ± 4.6).

Conclusions. Both leukocyte-depleting filters and platelet-activating factor antagonism provided myocardial protection, and the filters afforded superior postoperative myocardial contractility.

	Introduction

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Corrective surgical procedures for cyanotic congenital heart disease are frequently complicated by postoperative low-output syndrome. The repair of cyanotic heart defects requiring cardiopulmonary bypass (CPB) is now more frequent in infants and neonates. Consequently optimization of myocardial protection is of utmost importance.

Increased susceptibility of cyanotic hearts to ischemia and subsequent reperfusion has been demonstrated [1–4]. Activated neutrophils have been implicated as having a major role in the development of myocardial injury, particularly during ischemia and subsequent reperfusion [5]. Leukocyte depletion has been shown to improve ventricular performance early after ischemia in models of global myocardial ischemia [6, 7]. Platelet-activating factor is a potent inflammatory mediator and is one of several mediators released by activated neutrophils. Platelet-activating factor promotes the release of oxygen free radicals and lysosomal enzymes [8, 9]. The actions of both neutrophil activation and subsequent release of platelet-activating factor influence particularly the myocardium during reperfusion. The antagonism of platelet-activating factor has been demonstrated to have a beneficial effect in reducing the manifestations of ischemia and reperfusion [10, 11].

This study was conducted to assess measures to control reperfusion injury in a chronic cyanotic animal model simulating clinical congenital heart disease. The interventional therapies examined were leukocyte-depleting polyester filters (LDF) in the CPB line and infusion of the platelet-activating factor antagonist (PAFA) CV-6209 to prevent activation of polymorphonuclear leukocytes. The goal of the study was to enable improvement in myocardial protection during cardiac operations for neonates with cyanosis. The effect of cyanosis and hypertrophy on the neonatal, immature as well as mature myocardium poses a formidable challenge in selecting appropriate myocardial protection for such corrective surgical procedures.

	Material and methods

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Twenty-five weanling swine with creation of a chronic cyanotic state were entered into the study. The swine were intubated and supported with a volume-limited respirator with oxygen administration. General anesthetics included ketamine hydrochloride (20 mg/kg) and maintenance isoflurane (0.5% to 2.0%). This anesthesia protocol was used for both surgical procedures on the same animal. Electrocardiograms were monitored for both procedures.

The animals received humane care in compliance with the "Guide to the Care and Use of Experimental Animals" published by the Canadian Council on Animal Care. The experimental protocol was designed and performed in accordance with the principles of the Canadian Council on Animal Care and was approved by The University of British Columbia Committee on Animal Care.

Development of cyanotic model
The cyanotic model was made in weanling swine (weighing 11 to 12 kg) by creating a fistula (4 x 6 mm) between the pulmonary artery and the left atrial appendage through a limited left thoracotomy in the anterior third intercostal space. The fistula was formed by direct anastomosis using vascular clamps with partial occlusion of the pulmonary artery. A pulmonary band of umbilical tape (55 to 60 mm in length) was placed distal to the fistula and only in contact with the arterial wall. All animals recovered from the preliminary procedure, and cyanosis developed over the next 5 to 7 weeks as the pulmonary artery was gradually restricted in growth by the band and an increasing right-to-left shunt facilitated the development of the cyanotic state. The end point of the development of cyanosis was an oxygen saturation of 85% or less.

Corrective surgical procedure
The interventional procedure of global ischemia and correction of the anatomic defect was performed at the 5- to 7-week period with the animals in the desaturated state. The animals were anesthetized and maintained in the same manner as for the procedure to develop the cyanotic model. The left internal thoracic artery was catheterized for pressure recording and arterial blood sampling through a median sternotomy, and the heart was exposed. A Millar transducer-tipped catheter was placed in the right atrium for central venous pressure monitoring. A pulmonary flotation Swan-Ganz catheter was put through the right ventricle to facilitate monitoring of filling pressures. An eight-electrode–equipped conductance catheter (Webster Laboratories, Baldwin Park, CA) together with a Millar transducer-tipped catheter was placed in the left ventricle through the apex for monitoring pressure–volume loops.

After systemic heparinization (300 IU/kg intravenously), the animal was placed on CPB by means of left carotid artery cannulation and double-stage right atrial cannulation. Cardiopulmonary bypass was maintained with aortic cross-clamping, and the heart was subjected to 90 minutes of ischemic arrest at 8°C with hypothermic blood-crystalloid (4:1) cardioplegia (Tyers cardioplegic solution). The fistula was closed directly during ischemic arrest through a pulmonary arteriotomy. The systemic temperature during global ischemic arrest was kept at 30°C. Anesthesia was maintained after the weaning of the animal from CPB to allow completion of functional assessment prior to termination of the experiment and death of the animal. The heart was reperfused for 20 minutes, and then the animal was weaned from CPB. Arterial blood gases were analyzed throughout the procedure and corrected to pH 7.4 with sodium bicarbonate, if necessary.

Measurements
The ventricular function studies employed intracardiac impedance ventriculography and Millar pressure micromanometry to generate pressure–volume loops. The pressure–volume loops were determined by real-time volumes from caval occlusion plotted against the simultaneous measurement of ventricular pressure using the concept of preload-recruitable stroke work. End-systolic elastance (absolute end-systolic pressure–volume slope or Emax) (Fig 1) and diastolic compliance as a measure of chamber wall stiffness were determined. The various pressure readings, stroke volume, and left ventricular stroke work were obtained directly from the pressure–volume loop. The dynamic variables of cardiac output, cardiac index, stroke volume index, left ventricular stroke work index, systemic vascular resistance, and pulmonary vascular resistance were calculated by standard formulas. The diastolic compliance curve assessed by linear regression analysis of end-diastolic pressure–volume data was used to calculate the slope and x-intercept. The computer system incorporated the Crystal Biotech System and DataFlow software version 2.516 (Crystal Biotech, Northboro, MA) and a Leycom Sigma 5-DF signal conditioner-processor (Leycom, Degstgust, the Netherlands).

View larger version (23K): [in this window] [in a new window]   Fig 1. (A) End-systolic elastance (Emax) is the slope of line A, which is plotted for the point of end-systole of each cardiac cycle. End-diastole of each cardiac cycle is plotted on line B. The slope and x-intercept of line B are presented as the diastolic function variables. The Emax is generated directly by the Crystal Biotech Dataflow software, and the slope and x-intercept are calculated by Statistical Analysis System software from the transferred data from the Crystal Biotech Dataflow software. (B) Left ventricular stroke work (LVSW) and stroke volume (SV) were plotted by the Crystal Biotech Dataflow software. Left ventricular stroke work was calculated as the loop area, and SV was the volume difference.

Rejection criteria
Seven animals in the experimental protocol were not included in the functional assessment. The causes for rejection included cardiac arrest before CPB, major volume sequestration during CPB, pulmonary edema occurring during CPB, inspiratory airway pressure greater than 35 mm Hg after CPB, and bleeding causing unstable hemodynamics during and after CPB.

Statistical analysis
The study groups were randomized, and data were collected by operating room research staff. Statistical analysis was performed using Statistical Analysis System software (SAS Institute, Cary, NC) and a personal computer. Data were expressed as the mean ± the standard deviation of the original values. Data analysis was performed with a two-way analysis of variance, and between-group differences were specified with Duncan’s multiple range test. The values before and after CPB were conformed with repeated-measures analysis of variance. In addition, multivariate analysis of variance simultaneously evaluated the hemodynamic factors. Significance was assumed for a p value of less than 0.05.

	Results

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There were no significant differences between groups in regard to demographic data. Of all the animals, 7 (78%) of 9 in the control group, 5 (63%) of 8 in the PAFA group, and 6 (75%) of 8 in the LDF group were included in the study. Oxygen saturation evaluation showed significant (p < 0.05) differences before and after operation but no differences between groups (Fig 2). All animals were treated similarly during CPB, and there were no significant differences between the three groups (Table 1).

View larger version (41K): [in this window] [in a new window]   Fig 2. Oxygen saturation was significantly increased after operation (10 min and 30 min) compared with the preoperative value (100% oxygen with swine under anesthesia) (PRE). There were no significant differences between groups. (Control = no treatment during corrective surgical procedure; LDF = leukocyte-depleting filter group; PAFA = platelet-activating factor antagonist group; Room Air = room air before operation.)

Defibrillation was required in 12 of 18 swine before weaning from CPB: all 7 (100%) in the control group, 1 (20%) of 5 in the PAFA group, and 4 (67%) of 6 in the LDF group (p < 0.05). Fourteen of the 18 swine required inotropic support with dopamine hydrochloride postoperatively: all 7 in the control group, 4 (80%) of 5 in the PAFA group, and 3 (50%) of 6 in the LDF group (p = not significant). The total dose of dopamine was significantly greater in the control group (46.63 ± 43.66 mg) compared with the PAFA group (11.04 ± 9.09 mg) and the LDF group (6.52 ± 7.76 mg) (Fig 3).

View larger version (10K): [in this window] [in a new window]   Fig 3. Dopamine requirement was significantly greater in the control group than in the other two groups. The numbers in parentheses are swine requiring inotropic support. (LDF = leukocyte-depleting filter group; PAFA = platelet-activating factor antagonist group.)

There were trends for cardiac output, cardiac index, left ventricular minute work index, and pulmonary capillary wedge pressure. The first three were depressed at 10 minutes after CPB, and recovered at 30 minutes in the LDF and PAFA groups but not in the control group. Pulmonary capillary wedge pressure was elevated in the control group, but there were no significant differences between groups.

Left ventricular contractile function
The Emax, the maximum first derivative of left ventricular pressure, and the negative first derivative of left ventricular pressure were similar preoperatively. The Emax was significantly increased in the LDF group postoperatively compared with the control group and its own preoperative value (Figs 4, 5). The postoperative Emax at 10 and 30 minutes was decreased in the control group and increased in both treated groups. The maximum first derivative of left ventricular pressure was increased significantly after the corrective procedure, but there were no significant differences between groups (Table 2).

View larger version (28K): [in this window] [in a new window]   Fig 4. End-systolic elastance (Emax) was slightly decreased postoperatively in control group and was increased in platelet-activating factor antagonist group (PAFA) and leukocyte-depleting filter group (LDF). There were significant differences between the preoperative (PRE) and 10-minute postoperative (10 min) values in the filter group and the 10-minute and 30-minute postoperative (30 min) values in that group and the control group. (ANOVA = analysis of variance.)

View larger version (24K): [in this window] [in a new window]   Fig 5. Representative average curves of end-systolic elastance (Emax) before operation (PRE) and 30 minutes after cardiopulmonary bypass (30 MIN) in control group and leukocyte-depleting filter group (LDF). In the latter group, the curve shifted upward significantly as Emax increased, thus indicating greater ventricular contractility compared with the control group. (ANOVA = analysis of variance.)

View larger version (21K): [in this window] [in a new window]   Fig 6. Stroke volume–preload curves before operation (PRE) and 10 minutes after cardiopulmonary bypass (10 MIN) in control group and leukocyte-depleting filter group (LDF). In the control group, the curve shifted downward and to the right, indicating reduced stroke volume with same preload after operation. In the filter group, the curve shifted upward and to the left postoperatively, indicating increased stroke volume with same preload.

View larger version (36K): [in this window] [in a new window]   Fig 7. Representative left ventricular pressure–volume loops (Emax) and compliance curves before operation (PRE) and 30 minutes after operation (30 MIN POST) for 1 control and 1 animal with leukocyte-depleting filter (LDF). The loops were shifted to the right postoperatively in the control animal and to the left in the LDF animal. The compliance curve was shifted upward and to the right postoperatively in the LDF animal compared with its preoperative location and the control animal’s curve.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

The pathogenesis of ischemia-reperfusion injury has been studied extensively [2, 13]. Neutrophils have been implicated in the pathogenesis of reperfusion injury after hypothermic cardioplegia-protected ischemia on CPB [2, 5, 13]. Oxygen free radicals, namely, superoxide anions, hydroxyl radicals, and hypochlorous acid, are generated by the activated neutrophils. Platelet-activating factor is also involved in the activation of platelets and neutrophils in the inflammatory process and is synthesized during tissue reperfusion [8, 9]. When released into thecoronary circulation, platelet-activating factor is a mediator of oxygen free radical production from activated neutrophils during reperfusion [9].

The therapeutic modalities of leukocyte depletion on CPB and platelet-activating factor antagonism were studied in the chronic cyanotic model as protection against reperfusion injury. There is extensive literature on these management techniques but not as they relate to protection against reperfusion in chronic cyanosis.

There has been increasing interest in the application of reduction of neutrophil-mediated damage associated with CPB procedures. The effects of leukocyte depletion with LDFs on CPB have been assessed in animal models and clinically since the study by Breda and coauthors [14] published in 1985. They reported the beneficial effects on 24-hour lung preservation in an ex vivo rabbit model. The experimental models have included canine CPB, rabbit lung transplantation, bovine heart-lung transplantation, and bovine lung transplantation [6, 15].

There is conflicting evidence as to whether neutrophil counts are actually decreased with LDFs. In a neonatal swine model of 90 minutes of hypothermic ischemia, Wilson and associates [7] showed that there is sustained improvement in postischemic ventricular function despite a rapid return of neutrophils. Neutrophil-endothelial interactions were demonstrated by Kawata and colleagues [5] in an isolated neonatal lamb heart model.

The current investigation of protective modalities against ischemia-reperfusion injury in the chronic cyanosis model demonstrated superior myocardial performance in the group randomized to leukocyte-depletion filtration on CPB. In this study, leukocyte-depleted perfusion was shown to decrease operative morbidity and mortality, reduce inotropic drug requirement, and increase left ventricular contractility. The routine use of low-dose inotropic support to wean from CPB may have masked any small hemodynamic differences between groups. Nevertheless, Emax was significantly increased in the LDF group postoperatively compared with the control group and its own preoperative value. Our observations are supported by those of Bolling and colleagues [16] in a neonatal swine model of ventilation hypoxia followed by reoxygenation on CPB: superior systolic function, diastolic compliance, and preload-recruitable stroke work, better arterial to alveolar oxygen ratio, and less increase in pulmonary vascular resistance.

The role of platelet-activating factor antagonism in protecting against reperfusion injury to the myocardium has also been favorable [10, 11]. Sawa and associates [11] showed that with controlled reperfusion, CV-3988 was more effective than terminal leukocyte depletion, a finding suggesting that platelet-activating factor may play a more important role in myocardial reperfusion injury than neutrophils. We [10] identified the protective effect of CV-3988 in a swine model of heart-lung transplantation. The current investigation revealed contradictory evidence to that of Sawa and coworkers [11]; we found that PAFA CV-6209 was less effective than leukocyte depletion but provided a trend to effectiveness over controls. The study by Sawa and colleagues [11] did not identify the addition of CV-3988 to neutrophil depletion as providing extended improvement.

The appropriateness of cyanotic models, whether chronic or acute, does raise some concern. The model of creation of a left atrium–pulmonary artery fistula with pulmonary banding and progressive development of chronic cyanosis and ventricular hypertrophy was reported by Fujiwara and colleagues [12] in 1988 and has been used successfully by us. The other model of chronic cyanosis is that of inferior vena cava–pulmonary artery diversion with development of left ventricular dilatation but without hypertrophy [17].

Recently, one investigative group [18–20] has presented three reports using a hypoxic immature swine model. The hypoxemia model was created by decreased ventilatory oxygen fraction for up to 2 hours before CPB. In one study, Ihnken and associates [18] demonstrated that hypoxemia-reoxygenation injury occurs in immature hearts acutely reoxygenated during bypass by the elevation of conjugated dienes from oxygen free radical injury. The authors suggested that the addition of antioxidants to the prime of the CPB circuit may be beneficial for immature cyanotic hearts. In another study using the same model, Morita and coworkers [19] demonstrated that delaying reoxygenation until blood cardioplegia induction protected myocardial end-systolic elastance, reduced lipid peroxidation as measured by conjugated dienes, and preserved antioxidant reserve capacity as assessed by reduced malondialdehyde production.

Our group has suggested that the concept of controlled cardiac reoxygenation may not be effective in chronic cyanosis (Jamieson, unpublished data, 1998). In our chronic cyanotic model, both acute reoxygenation on CPB and delayed reoxygenation until after global ischemia and reperfusion had deleterious effects. Ihnken and colleagues [20] reported in 1997 that the reoxygenation injury in the hypoxemic model can be controlled by reduction of both nitric oxide and oxygen free radicals.

In conclusion, ischemia-reperfusion injury in a chronic cyanosis state can be protected against by elimination of activated leukocytes from perfusion or control of activated neutrophils by platelet-activating factor antagonism. Chronic cyanosis may deplete the myocardium of endogenous antioxidant enzyme activity, and with neutrophil activation and production of platelet-activating factor, the ischemia-reperfusion injury may be further aggravated. The use of leukocyte-depletion filtration on CPB provides more effective maintenance of myocardial contractility than platelet-activating factor antagonism.

	Acknowledgments

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This study was supported by a grant from the Heart & Stroke Foundation of British Columbia and Yukon.

We thank Pall Biomedical Canada for donating the leukocyte-depleting filters (LG6).

We thank Dr A. Karim Qayumi for his support of the experimental endeavors, and we are grateful to Pamela R. Itterman for the preparation of the manuscript.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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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 Zhang, J. Articles by McGibbon, R. Search for Related Content PubMed PubMed Citation Articles by Zhang, J. Articles by McGibbon, R.