Ann Thorac Surg 1995;59:695-698
© 1995 The Society of Thoracic Surgeons
Effects of Halothane on the Immature Lamb Heart
Deborah A. Davis, MD,
Giovanni Speziali, MD,
L. Craig Wagerle, PhD,
James L. Heckman, PhD,
Pierantonio A. Russo, MD
Departments of Anesthesia and Critical Care, Surgery, and Physiology, Temple University School of Medicine, Pediatric Heart Institute, St Christopher's Hospital for Children, Philadelphia, Pennsylvania
Accepted for publication November 25, 1994.
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Abstract
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The choice of anesthesia during pregnancy and fetal operations is controversial. Halothane frequently is used, but its direct effects on fetal cardiac performance are unknown. The effects of halothane on fetal cardiac mechanics were studied in 8 fetal lamb hearts (135 days' gestation) using a modified Langendorff model connected to a membrane oxygenator. The perfusate consisted of oxygenated maternal blood at a constant flow temperature, hematocrit value, and glucose level. Coronary blood flow, left ventricular systolic pressure, left ventricular end-diastolic pressure, and the developed left ventricular pressure at a fixed volume were evaluated at baseline and after the addition of incremental concentrations of halothane to the perfusate through the oxygenator. Perfusate halothane levels were maintained in a clinical range. Systolic and diastolic cardiac function were adversely affected by the administration of even low doses of halothane, despite a concomitant increase in coronary blood flow. Because of the immaturity of their calcium transport system, fetal hearts may be particularly sensitive to the known calcium channel–blocking properties of halothane.
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Introduction
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In utero surgical management of congenital defects is becoming a clinical reality [1–4]. Although cardiac surgical procedures in human fetuses have not yet been performed, percutaneous balloon angioplasty procedures have been attempted [5]. In cases in which postnatal repairs traditionally carry a poor prognosis, intrauterine intervention can be an appropriate alternative. Recent advances in noncardiac fetal operations have suggested the feasibility and possible advantages of fetal surgical intervention for certain cardiac lesions [6–8].
Halothane has been one of the anesthetic agents used for fetal procedures, both in experimental models and clinical procedures [9, 10]. Its advantages are that it is an effective tocolytic, reducing the risk of premature labor after uterine manipulation, and that it can readily cross the placenta, providing both anesthesia and analgesia to the fetus. However, halothane may have a negative inotropic effect, due in part to its reported role as a calcium channel blocker at the cardiac cell membrane level [11].
The purpose of this study was to determine the direct effects of halothane on fetal cardiac function, which we hypothesized would be greatly altered by even low doses of halothane. Our hypothesis is based on the knowledge that the sarcoplasmic reticulum of the fetal heart is not fully developed, requiring the fetal heart to depend largely on extracellular calcium for activation of its contractile machinery [12]. Fetal cardiac function could be greatly depressed by any agent such as halothane, which significantly reduces calcium flux across the sarcolemma. The fetal isolated heart model was selected so that the direct actions of halothane on the heart could be determined. This study could not be done using in utero fetuses because of the effects of halothane on uterine blood flow and on the fetal vasculature, and because reflex and hormonal changes can accompany the hypotension produced by halothane. Knowledge of the direct effects of halothane on the fetal heart is essential if halothane is to be considered for use in fetal cardiac surgical procedures.
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Material and Methods
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This study was performed according to protocols approved by the Institutional Animal Use and Care Protocol Committee of Temple University School of Medicine. Eight pregnant ewes at 135 days' gestation were anesthetized with ketamine (10 mg/kg intramuscularly), intubated, and maintained on a volume ventilator with maintenance anesthesia consisting of a gas mixture of 30% oxygen and 70% nitrous oxide. Additional doses of ketamine (5 mg/kg intravenously) were administered as required to maintain the desired state of anesthesia in the mother. The ewe was fully heparinized (3 mg/kg) and the modified Langendorff circuit was primed with maternal blood obtained by cannulation of the right carotid artery. A median laparotomy was performed and the fetal lamb was extracted through a small hysterotomy. A fetal median sternotomy was performed, the pericardium opened, and the heart exposed. The innominate artery was cannulated and ligated, and then divided distal to the cannulation site. The tip of the cannula was positioned in the fetal ascending aorta, and the proximal end was connected to the Langendorff apparatus. The superior and inferior venae cavae were divided, and the aortic arch was ligated between the innominate and left carotid artery and divided distally. The pericardial reflections and the pulmonary veins were divided, and the beating heart was suspended by the arterial cannula. Perfusion was started as soon as the heart was completely empty after the venae cavae were divided. Two stimulating electrodes were connected to the right appendage using clips, and the heart was paced at a fixed rate of 180 beats/min. A left atriotomy was performed so that a latex balloon could be inserted into the left ventricle. A catheter-tipped pressure transducer (Millar Instruments, Houston, TX) was placed in the lumen of the balloon to record intraventricular pressure to desired values. The balloon was large enough so that its unstressed volume was greater than any end-diastolic volume achieved during the experiment. Therefore, the properties of the balloon did not contribute to the properties of the ventricle that we were investigating. A pursestring suture was tied around the mitral annulus to keep the balloon in place.
The blood from the venous reservoir was pumped by means of a roller pump to the oxygenator–heat exchanger and into the arterial cannula. An overflow tubing kept the perfusion pressure constant by a hydrostatic mechanism. Blood from the overflow cannula was returned to the venous reservoir together with the coronary venous and thebesian blood. A halothane vaporizer (Fluotec) was attached to the oxygenator. Coronary blood flow was measured by means of an in-line flow probe (Transonics, Ithaca, NY). Side ports in the perfusion system allowed for periodic sampling of the halothane concentrations (Fig 1
). Serum analysis for the halothane concentration was performed using an electron-capture detection method (National Medical Laboratories, Willow Grove, PA). Five sets of data were collected for each experiment: the baseline value, and the serum level after exposure to 0.5%, 1%, 1.5%, and 2% halothane. Because of differences in heart sizes and hence their ability to accommodate different volumes, our experimental protocol was to vary the left ventricular (LV) volume until a desired LV end-diastolic pressure of 5 mm Hg was achieved, and then to vary the halothane concentration while keeping the LV volume constant. This approach was used to document the direct effects of halothane on the LV inotropic state. The peak systolic pressure and end-diastolic pressure were measured directly. The difference between these two pressures determined the developed pressure. Variables that were kept constant included the coronary artery perfusion pressure, perfusate temperature, perfusate hematocrit value, perfusate glucose concentration, electrolyte composition, activated clotting time, gas flow, and perfusion flow through the oxygenator.
Data were analyzed using a repeated-measures analysis of variance, followed by the Student-Newman-Kiels test when appropriate. The values reported are the mean ± the standard error of the mean.
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Results
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Administration of halothane to the perfusate by means of the oxygenator was associated with a rapid onset of changes in the fetal cardiac mechanics. Significant decreases were noted in the LV systolic pressure at all halothane levels compared with the baseline measurements, including when halothane administration had been stopped, though this pressure was significantly better than those associated with the four halothane concentrations (Fig 2).
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Fig 2. . Effects of various concentrations of halothane on coronary blood flow (CBF), end-diastolic pressure (EDP), systolic pressure (LV sys), and developed pressure (LVDP). Values are the mean ± the standard error of the mean. Asterisk denotes statistical significance at p < 0.05.
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In the studies of end-diastolic pressure, data for 2 animals were discarded from statistical analysis because of technical difficulties. Of the remaining 6 animals, 5 had evidence of increasing end-diastolic pressure with increasing doses of halothane, but 1 did not. In all of the experiments, cessation of halothane administration resulted in a decrease in the end-diastolic pressure. With regard to the LV developed pressure, significant decreases in pressure occurred at all levels of halothane. Once halothane was removed from the circuit, there was significant recovery of the developed pressure, though not completely back to the baseline value.
Coronary blood flow increased with the administration of halothane and then decreased to the baseline value as the halothane concentrations were incrementally lowered. All effects were dose related and reversible once halothane was washed out of the circuit.
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Comment
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If we are to consider managing a fetus surgically, it is essential that we understand the nature of fetal cardiac mechanics and the mechanisms involved in optimizing fetal cardiac function. Cardiac preload, as defined by a length–tension mechanism, represents the capacity to increase cardiac function from baseline by increasing diastolic volume. Although some studies have demonstrated little or no preload reserve in fetal myocardium, others have demonstrated a significant reserve in the fetal heart [13, 14]. The conflicting findings from these studies may stem from the difficulty in studying the fetal heart. Using a modified, isolated isovolumic fetal lamb heart preparation allows one to evaluate the extent of cardiac preload reserve and to independently assess variables of cardiac function as they are affected by halothane. This preparation eliminates the hormonal and neural influences on cardiac mechanics.
Use of an isolated heart preparation has certain advantages when studying the effects of anesthetic agents on fetal cardiac mechanics. Variables such as changes in uteroplacental perfusion caused by aortocaval compression, maternal hypotension, hypoxemia, and maternal hypercapnia or hypocapnia may all affect fetal hemodynamic characteristics. With these variables removed, the direct effects of halothane on cardiac pressure–volume relationships and on coronary blood flow can be studied. Although previous studies have demonstrated how fetal cardiovascular mechanics were altered when general anesthesia was provided to the mother, often it was not clear whether these effects were secondary to changes in uterine perfusion or to other variables directly affecting the fetus [15]. Our study demonstrated that halothane in and of itself can directly cause myocardial depression.
The LV volume–pressure relationship can be evaluated in an isolated isovolumic contracting model that is perfused and oxygenated, while variables such as heart rate, coronary perfusion pressure, and the perfusate mixture are controlled. By adding incremental doses of halothane, we demonstrated that the LV systolic pressure was significantly lowered as the dose of halothane was increased. The end-diastolic pressure increased in most of the lamb hearts as increasing doses of halothane were added. Because developed pressure is a reflection of systolic pressure minus the end-diastolic pressure, it was predictably decreased in our experiments. Halothane's negative effect on fetal cardiac function was most dramatic at the lowest concentration (0.5%), although larger doses resulted in a further depression of generated pressures; that is, the most significant effect occurred when the fetal heart was first exposed to halothane. Any isolated organ preparation is known to intrinsically degenerate over time. This may be reflected in our results, as seen in the return to baseline conditions (no halothane) when poorer cardiac function was evident.
When end-diastolic volume is held constant, changes in the LV developed pressure signify a change in the inotropic state and changes in the LV end-diastolic pressure imply a change in LV compliance [16]. The reductions in the LV developed pressure that we saw as the halothane levels were increased indicate that halothane directly decreases the inotropic state of the fetal left ventricle. Likewise, in 5 of 6 animals studied, the increase in the LV end-diastolic pressure associated with increases in the halothane levels, though not significant, suggests that halothane directly decreases fetal LV compliance.
Many investigators have studied the effects of halothane and other volatile anesthetic agents on myocardial contractility at the cellular level. Halothane's negative inotropic effect can be related in part to inhibition of the inward calcium current at the level of the sarcolemma. Halothane may alter sarcolemma function, decrease the levels of ionized calcium during systole, and modify the responsiveness of contractile proteins to activation by calcium [17]. In the fetal heart, the sarcoplasmic reticulum and the T-tubule system are not fully developed; thus, the calcium channels on the cytoplasmic membrane are the primary source of intracellular calcium. For this reason, calcium channel blockers may have a more profound effect on the fetal myocardium.
Other investigators have demonstrated halothane's depressant effect on myocardial contractility to be secondary to a decreased synthesis of adenosine triphosphate consequent to halothane's inhibitory effect on the myocardial oxidation of NADH-linked substrates [18]. This is a controversial issue, as not all investigators have made similar findings. Although a number of investigators have examined myocardial actomyosin adenosine triphosphatase for its possible role in the phenomenon of anesthetic-induced negative inotropism, most evidence seems to point to a major effect of halogenated agents on calcium influx [19].
The degree to which externally derived or internally released calcium participates in contractile force varies greatly with the species and the tissue; for example, the atrial response is different from the ventricular response. Therefore, extrapolation of observed drug effects from one species to another must take these differences into account. We chose to study the lamb because the ovine uterus most closely resembles human uterine qualities, and because the fetal lamb heart is capable of generating a significant systolic pressure–volume relationship [20].
In our work, there was evidence of myocardial depression despite a transient increase in coronary blood flow during exposure to halothane. This could be explained by the fact that, by inhibiting calcium transport, halothane depresses cardiac contractility but dilates coronary arteries. One result of this study relies on whether the fetal coronary vasculature has a flow reserve. Flow reserve is the capability of a tissue or organ to increase its blood flow by reducing its vascular resistance. Our results indicate that halothane does cause coronary flow to increase. Because the coronary perfusion pressure of the isolated heart was held constant, the increase in flow shows that, under control conditions, the coronary vasculature is not fully dilated and that there is a fetal coronary flow reserve.
Clinicians considering the use of halothane for maternal anesthesia during fetal surgical procedures should be aware of its myocardial depressant effects, particularly in a heart that has less mature calcium transport mechanisms. It is clear that what we give the mother in terms of a maternal anesthetic agent will have an effect on the fetus. There is no reliable formula that can calculate the extent of placental transfer of volatile agents, though we know it occurs. Gregory and associates [21] have demonstrated that halothane inhaled by a mother ewe is found in fetal ewe blood levels. In addition, they have calculated dose ranges and determined the fetal minimal alveolar concentration that keeps 50% of the patients from moving in response to a noxious stimuli. They did this by measuring blood levels and extrapolating the minimal alveolar concentration from these. The minimal alveolar concentration of the fetus is less than that of a newborn or the mother. In our studies, the perfusate levels in some ranges were higher than those utilized by Gregory's group. However, even at the lower dose ranges, fetal cardiac function was clearly depressed. Although the minimal alveolar concentration of sheep will differ from that of human beings, conceptually, the theory and problems will be the same among species.
In conclusion, the direct effects of halothane on mechanical performance were studied in our isolated preparation using a fetal lamb model. The mechanism responsible for the depression of generated pressures may reside at the cellular level, particularly at the level of calcium influx. Because of this demonstrable detrimental effect of halothane on fetal cardiac mechanics, it is advisable to avoid using halothane as an anesthetic agent when performing fetal surgical procedures.
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Acknowledgments
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We acknowledge the technical assistance of Mr Warren Moliken and the guidance from Jeffrey M. Dunn, MD.
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Footnotes
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Address reprint requests to Dr Davis, Department of Anesthesia and Cardiac Critical Care, St Christopher's Hospital for Children, Erie Ave at Front St, Philadelphia, PA 19134.
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References
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Abstract
Introduction
