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J Thorac Cardiovasc Surg 1994;107:1416-1422
© 1994 Mosby, Inc.
SURGERY FOR CONGENITAL HEART DISEASE |
San Francisco, Calif., and Boston, Mass.
Supported by a grant from the National Institutes of Health (NIHRO1HL 43357-01) and by a grant from the American Heart Association (13-456-901).
Presented in part at the World Congress of Pediatric Cardiology and Cardiac Surgery, Paris, France, June 21-25,1993.
Received for publication July 9, 1993. Accepted for publication Nov. 8, 1993. Address for reprints: Frank L. Hanley, MD, Division of Cardiothoracic Surgery, M593, 505 Parnassus Ave., University of California, San Francisco, San Francisco, CA 94143-0118.
Abstract
Cardiac bypass in late-gestation fetal lambs causes severe placental vasoconstriction, which leads to fetal death from hypoxemia and respiratory acidosis. This response can be blocked by the administration of indomethacin; however, a fatal metabolic acidosis then gradually develops in the fetus. Because the fetus is known to mount an intensive catecholamine response to stress, and because the fetal myocardium is particularly sensitive to increased afterload, we hypothesized that elevated afterload as a result of fetal stress contributes to diminished cardiac output after bypass. Twenty fetal lambs at 80% gestation underwent 30 minutes of normothermic cardiac bypass at flow rates of 200 to 500 ml/kg per minute. All ewes received general anesthesia with ketamine. In 10 fetuses general anesthesia was specifically designed not to inhibit the release of stress-related catechols (ketamine); the remaining 10 fetuses received a "high" (cisterna magna) total spinal anesthetic with tetracaine, to block the fetal stress response. In each anesthetic group, 5 of the 10 lambs received indomethacin. During operation, normal hemodynamics were preserved in the spinal anesthetic group. Cardiac output, placental blood flow, and arterial carbon dioxide tension were all improved relative to results in the ketamine group. When spinal anesthesia and indomethacin are both given, hemodynamics also approach normal after bypass, and gas exchange is further improved. These data suggest that the inhibition of the stress response by spinal anesthesia improves the hemodynamic status of the fetus during operation and, in combination with indomethacin, allows maintenance of near-normal placental function after fetal cardiac bypass. Similar responses may also be possible in human fetuses with use of a high-dose narcotic technique. (J THORAC CARDIOVASC SURG 1994;107:1416-22)
Intrauterine correction of selected congenital cardiac defects may have significant benefits over postnatal repair. Such repairs will require the availability of fetal extracorporeal circulation. The early experience with cardiac bypass in fetal lambs demonstrated the development of placental dysfunction during and after bypass (as evidenced by hypercapnia and hypoxia), which ultimately caused fetal death within 30 to 90 minutes of the cessation of bypass. 
1,2 This placental dysfunction was found to be the result of elevated placental vascular resistance, which led to extremely diminished placental blood flow (PBF). The vasoconstrictive response could be attentuated (but not obliterated) by the administration of high doses of sodium nitroprusside to the fetus during bypass, 3 but the nonspecific smooth muscle relaxation had the disadvantage of causing greatly elevated fetal pulmonary blood flow, ultimately at the expense of fetal systemic and placental perfusion. Subsequent studies demonstrated that vasoactive cyclooxygenase products are released as mediators of the placental vasoconstrictive response; their release can be blocked by the administration of indomethacin. 4 When indomethacin is given to the fetus before bypass, fetal arterial oxygen tension (PO 2) and carbon dioxide tension (PCO 2) are maintained near normal during and for several hours after bypass, but a severe metabolic acidosis gradually develops in the fetus, 3 which is ultimately fatal.
A massive catecholamine-mediated response to surgical stress is known to develop in the sheep fetus when conventional anesthesia is used. 6,7 Similar catecholamine responses to surgical stress have been shown in human premature neonates of comparable gestational ages. 8 This results in increased afterload, which is known to cause marked myocardial depression in the immature heart. We have previously demonstrated that the hemodynamic effects of this stress response to fetal operation can be avoided by the use of a total spinal anesthetic. 9 We hypothesized that a significant portion of the detrimental fetoplacental reaction to cardiac bypass was also stress-mediated and that, when compared with conventional anesthesia, the use of a total spinal anesthetic would result in improved cardiac output (CO) and PBF before and after bypass. Because we have previously demonstrated an endogenous placental vascular response to bypass, 10 this study was designed to test our hypothesis both with and without indomethacin.
METHODS
Anesthesia and monitoring
Twenty mixed-breed pregnant ewes (120 to 126 days gestation) were fasted for 24 hours. Maternal anesthesia was induced with ketamine 30 to 40 mg/kg intramuscularly and was maintained with ketamine 300 to 500 mg/hr by continuous intravenous infusion. The ewes' lungs were ventilated with 100% oxygen via an endotracheal tube; min ute ventilation was adjusted to keep the arterial PCO 2 in the (gravid) physiologic range of 25 to 30 torr. A large-bore intravenous catheter was placed in the external jugular vein, and fluids were administered liberally to keep the ewe's hematocrit below 25% to maintain adequate uterine perfusion. A femoral arterial line was placed percutaneously for blood gas sampling and hemodynamic monitoring, and the bladder was catheterized to monitor urine output. Fetal lambs were alternately assigned to one of four groups: conventional general anesthesia with ketamine, with or without indomethacin, and total spinal anesthesia with or without indomethacine.
Operation
A midline laparotomy was done; the uterus was exposed and the number and orientation of the fetuses were determined. Fetal weight was estimated by palpation. A small (3 to 4 cm) hysterotomy was made over a fetal hindlimb for the administration of ketamine (50 mg/kg intramuscularly) or over the neck for the introduction of tetracaine (2 mg/kg) into the cisterna magna. A hindlimb (through a separate small hysterotomy in the lambs receiving spinal anesthesia) was then gently removed from the uterus, and the femoral artery and lateral tarsal vein were cannulated proximally with 5F umbilical vessel catheters. The venous catheter was advanced into the inferior vena cava and was used for the injection of radiolabeled microspheres. The arterial catheter was advanced into the descending aorta and was used for hemodynamic and blood gas monitoring, as well as for reference sample withdrawal at the time of microsphere injections. The hindlimb was replaced in the uterus, and the hysterotomy was closed. A second hysterotomy was made overlying a forelimb. In fetuses undergoing microsphere studies, a catheter was placed in the axillary artery to be used for hemodynamic monitoring and as a reference sample withdrawal catheter during microsphere injections. Fetal lambs assigned to receive indomethacin were then given a single dose of the drug (0.5 mg/kg intravenously). A fetal neck incision was made, and the internal jugular vein and common carotid artery were carefully exposed. The jugular vein was cannulated toward the heart with a 12F or 10F Bio-Medicus (Medtronic Bio-Medicus, Eden Prarie, Minn.) venous cannula. The carotid artery was similarly cannulated with a 12F, 10F, or 8F Bio-Medicus arterial cannula.
Cardiac bypass
A Bio-Medicus centrifugal pump was primed with heparinized donor venous blood. The circuit included a pump and reservoir; the placenta was perfused and was used as the only oxygenator. Pump flow rates were 200 to 500 ml/kg per minute. After a 30-minute bypass period, the fetus was weaned from bypass and was given volume (donor blood) as required. The cannulas were removed, and the uterus and abdomen were closed.
Euthanasia
After a 6-hour observation period after bypass, or at the time of fetal death, the ewe and surviving fetuses were killed with an overdose of ketamine followed by intravenous KCl. The fetus and placenta were removed from the uterus. Fetal autopsy was done, and the locations of the infusion and withdrawal catheters were confirmed.
All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health. The experimental protocol was reviewed and approved by the Children's Hospital of Boston Committee on the Care and Use of Laboratory Animals.
Data accumulation
Maternal and fetal heart rate and blood pressure were continuously monitored with Statham transducers and a Hewlett-Packard 78342A monitor (Hewlett-Packard, Inc., Andover, Mass.). Maternal and fetal arterial blood gases and hematocrit were measured every 15 to 30 minutes on a Ciba-Corning 280 blood gas system (Ciba Corning Diagnostics Corp., Medfield, Mass.). All samples for analysis of fetal blood gases were drawn from the descending aorta.
In 14 lambs, radiolabeled microspheres (chosen from 125I, 51Cr, 141Ce, 113Sn, 85Sr, 95Nb, and 46Sc) were used to determine fetal CO, PBF, and individual organ blood flows before and after neck cannulation, 1 hour after cessation of bypass, and 3 to 5 hours after bypass. Microspheres were injected into the inferior vena cava in a quantity that ensured at least 400 microspheres per organ counted. 11 A dual-catheter withdrawalsystem 5,7 was used that allowed quantitation of all flows except pulmonary blood flow, which is normally quite low in the fetus. The fetal organs and placenta were dissolved overnight in a solution of 2N KOH in methanol at 60° C. Individual organ and placental radioactivity were counted in a LKB Wallac 1282 gamma counter (Wallac, Inc., Gaithersburg, Md.), with the aid of a Dell system 200 computer (Dell Computer Corp., Austin, Tex.). CO, individual organ blood flows, and PBF were calculated as previously described. 5,11
Statistical methods
The blood gas data were analyzed by a multiple linear regression implementation of analysis of variance. 12 This statistical method has the advantage that it can be used in cases of missing data and allows simultaneous analysis of continuous and categorical data. In this study we designed the regression equation as follows:
where Y is the dependent variable of interest (arterial PCO 2, arterial PO 2, and pH) and a0 is the intercept of the equation. T is the time in minutes (with T = 0 being the initiation of bypass), I is a dummy variable assigned a value of 1 if indomethacin was administrated and 0 if not, S is a dummy variable assigned a value of 1 for spinal anesthesia and -1 for ketamine. The interactive effect of spinal anesthesia and indomethacin administration, represented by aisIS, is also included. Dummy variables F1 through F16 code for the 20 animals and represent the inter animal variability, which was considered only as a set. This coding technique makes the intercept of the equation (a0) the mean value of the dependent variable over all the animals (both anesthesia protocols) without indomethacin. By this technique we were able to construct highly significant regression equations for all three dependent variables. A p value of 0.05 or lower was considered statistically significant.
Because the flow data were taken at only four time points and there were no missing data among the animals undergoing microsphere studies, we used a three-factor repeated-measures analysis of variance to analyze the PBF and CO data.
RESULTS
Maternal heart rate (HR) and blood pressure (MAP) were normal throughout the study period (HR 70 to 130 beats/min, MAP 80 to 120 mm Hg); fetal HR and MAP remained normal (HR 140 to 180 beats/min, MAP 40 to 55 mm Hg) in all groups until immediately before fetal death. Fetal arterial blood gas values (Table I) were initially within the normal range: our linear regression model predicted a mean PCO 2 at the start of bypass of 44.8 ± 0.8 mm Hg. With time, there was a rise in arterial PCO 2 (Fig. 1), with a predicted slope of 2.3 ± 0.2 mm Hg/hour. Administration of indomethacin caused a predicted drop in PCO 2 of 3.17 ± 0.88 mm Hg, and ketamine anesthesia was associated with a PCO 2 that was 11.2 mm Hg greater than that with spinal anesthesia (Table I). The interaction between indomethacin and spinal anesthesia predicted a small additional drop in PCO 2. All of these changes were highly statistically significant (Table I). There was also a significant drop in arterial pH that was related to choice of anesthesia but was not associated with indomethacin and a small improvement in arterial PO 2 when indomethacin was given (Table I).
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(Table II) to be initially within the normal range, 7,9-11,13,14 although before bypass there was a trend toward a lower CO and PBF (and an associated higher arterial PCO 2) in the ketamine group both with and without indomethacin. This supports our previous work, 9 in which use of a total spinal anesthetic allowed improved CO and gas exchange function during fetal surgical stress. After bypass, there is a significant drop in the proportion of CO going to the placenta in all treatment groups, which is associated with ketamine (p = 0.012) but is unrelated to the administration of indomethacin (p = 0.43). Similarly, there are trends toward improved total PBF (p = 0.073) and placental (p = 0.12) and systemic vascular resistance (p = 0.18) with spinal anesthesia.
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for indomethacin, by analysis of variance). DISCUSSION
Accurate echocardiographic imaging of the fetal heart and great vessels can now be done within a few weeks of the completion of primary cardiac morphogenesis, 14 which allows characterization of the natural intrauterine history of various cardiac malformations and identification of lesions that could best be managed by prenatal surgical treatment. Such procedures will require the availability of some form of fetal circulatory support.
Cardiac bypass can be done in late-gestation fetal lambs with preservation of fetal cardiac function after bypass, but early studies identified the development of placental dysfunction during and after bypass, 1,2 which caused fetal death within hours. This placental insufficiency is the result of elevated placental vascular resistance. PBF during and after bypass can be improved with the administration of sodium nitroprusside, but the applicability of this approach is limited by a significant rise in pulmonary blood flow. Further work demonstrated that administration of indomethacin to the fetus before bypass at least partially blocks the placental vasoconstriction, which implies a cyclooxygenase-mediated mechanism, but the stimuli for the release of vasoactive mediators have never been completely elucidated.
Massive catecholamine release is known to develop in the fetus when stressed. 6,7 Fetal stress caused by acute or chronic hypoxemia, hyperthermia, acidosis, or premature delivery is also associated with elevated fetal prostaglandin levels, 15-19 which may contribute to placental vasoconstriction. Recent work by us has focused on the fetal response to surgical stress and on the role that anesthetic management plays in the maintenance of fetal hemodynamic stability during operation. With conventional anesthetic techniques, stress from fetal operation results in increased afterload and, because of the fetal parallel circulation, significant redistribution of the combined ventricular output. 9 Administration of a total (cisterna magna) spinal anesthetic to the fetus at the time of operation permits maintenance of fetal CO, PBF, and gas exchange equivalent to those in the fetal lamb instrumented for long-term study. 9 This represents a marked improvement when compared with these hemodynamic and gas exchange values obtained when fetal operation is done with more conventional anesthetic techniques that are known not to block the catecholamine response to stress. The encouraging results achieved with the use of a total spinal anesthetic during fetal surgical intervention has not previously been applied to fetuses undergoing cardiac bypass. The purpose of the current study was to apply the technique of total spinal anesthesia, used to block the fetal stress response, to our fetal cardiac bypass model to investigate the contribution of fetal surgical stress to the placental dysfunction and metabolic acidosis that follow cardiac bypass.
In the current study, use of a total spinal anesthetic again allowed the fetus to maintain normal CO and PBF during operation, before bypass. After bypass, there was a much greater fall in PBF in the animals receiving ketamine than in the animals receiving spinal anesthesia (
Table II, Fig. 2), which was associated with a trend toward higher systemic and placental vascular resistances in the lambs receiving ketamine. Neither ketamine nor spinal anesthesia is a direct myocardial depressant. Ketamine is known not to block the catechol response to stress. The higher CO in the spinal group, which was associated with maintenance of normal (low) afterload, is likely to be related to inhibition of the fetal stress response. One mechanism by which PBF may be better maintained with spinal anesthesia may be by inhibiting catechol release and thereby maintaining normal afterload, allowing preservation of overall fetal CO. Alternatively, spinal anesthesia may maintain better PBF because the stress response directly inhibits PBF, possibly by stimulation of prostaglandin synthesis. The persistence of a significant drop in PBF in the lambs receiving spinal anesthesia suggests again that the stimulus is multifactorial: we have previously demonstrated that the extracorporeal circuit is another important stimulus 13 and that some placental dysfunction develops after extracorporeal circulation even in the absence of interaction with the fetus, with use of an isolated-placenta model. 10
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8,20 Studies of fetal cardiac bypass in a primate model will be needed to determine whether a narcotic anesthetic will be as effective as spinal anesthesia at preventing the stress response and preserving placental function.
Acknowledgments
We gratefully acknowledge the technical assistance of Ms. Hannah Zinn and Mr. Roosevelt Bryant.
Footnotes
References
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