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Ann Thorac Surg 1996;62:83-90
© 1996 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Inotropes in the Hypoplastic Left Heart Syndrome: Effects in an Animal Model

Division of Thoracic and Cardiovascular Surgery, University of Louisville School of Medicine, Louisville, Kentucky

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Despite substantial changes in the surgical treatment of children born with the hypoplastic left heart syndrome, overall mortality remains high. Although further improvements in outcomes appear to depend on more effective perioperative care, few experimental data exist to guide appropriate pharmacologic therapy in these infants. Because different inotropic agents may have different effects on the ratio of pulmonary to systemic flow (Q_p/Q_s), we hypothesize that they may not be equally effective at increasing oxygen delivery.

Methods. In neonatal piglets (n = 6; 3.5 to 6.5 kg), we placed an innominate artery-to-pulmonary artery shunt, created an atrial septal defect, and then occluded right ventricular outflow. We examined the effects of a number of commonly used inotropic agents, administering high and low concentrations of dopamine (5 and 15 µg • kg^-1 • min^-1), dobutamine (5 and 15 µg • kg^-1 • min^-1), and epinephrine (0.05 and 0.1 µg/min).

Results. Dobutamine at 15 µg • kg^-1 • min^-1 increased the Q_p/Q_s ratio from 1.03 ± 0.6 at baseline to 2.52 ± 0.55 (p < 0.05) and decreased oxygen delivery from 50 ± 4.3 to 36 ± 1.7 mL/min (p < 0.1). The arterial-venous oxygen difference increased as oxygen delivery went down, going from 44% ± 1% to 48% ± 2% (p < 0.1). Epinephrine at 0.1 µg • kg^-1 • min^-1 decreased the Q_p/Q_s ratio from 1.23 ± 0.21 to 0.82 ± 0.08 (p < 0.05) and increased oxygen delivery from 40 ± 9.7 to 56 ± 1.7 mL/min (p < 0.05). Systemic venous oxygen saturation increased from 36% ± 4.8% to 50% ± 8.6% (p < 0.05). Although dopamine decreased the Q_p/Q_s ratio and increased oxygen delivery, these changes were not statistically significant.

Conclusions. Dopamine, dobutamine, and epinephrine all increased cardiac output but had substantially different effects on the Q_p/Q_s ratio and on oxygen delivery, possibly due to differential effects on systemic and pulmonary vascular resistances. This suggests that inotropic agents may not be equally beneficial in the clinical setting. Systemic venous oxygen saturation and the arteriovenous oxygen difference may help determine if a given inotrope improves oxygen delivery.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 90.

Although dramatic advances have been made in the surgical treatment of the hypoplastic left heart syndrome, this relatively common set of defects remains highly lethal [1]. Surgical therapy is complex and often involves multiple staged procedures [2]. This lesion remains the most common cardiac cause of neonatal death, and some operative series still report mortality rates of 40% to 45% [3].

Infants with the hypoplastic left heart syndrome often have pronounced hemodynamic instability, and this is a major contributor to the high mortality rate seen. Although improvements in perioperative care could potentially lead to better outcomes, experimental models of the hypoplastic left heart syndrome are needed to help develop better management strategies. Our group recently developed an animal model of the univentricular circulation that allows for systematic examination of therapeutic interventions [4]. We have previously used this model to describe the effects of respirator and ventilator manipulations on univentricular physiology [5]. In this study we investigated the consequences of inotropic interventions.

Inotropic agents are potentially beneficial in infants with the hypoplastic left heart syndrome, but their actions have not been fully characterized. Data from experiments in adults may not accurately describe the actions of these medications in younger patients, as numerous studies have demonstrated that inotropes have altered efficacy in children [6]. In addition, the few studies that have examined the actions of inotropic agents in the young have focused on defects other than the hypoplastic left heart syndrome, and may not reflect how the drugs act in this anomaly [7]. The arrangement of the systemic and pulmonary circulations in this defect, with their resistances in parallel rather than in series, may cause inotropic medications to have altered actions.

We used our porcine model of the univentricular heart to measure the hemodynamic changes that accompanied the administration of high and low concentrations of dopamine, dobutamine, and epinephrine. We also used the model to examine changes in the ratios of pulmonary to systemic flow (Q_p/Q_s ratio) and on oxygen delivery, as we hypothesized that the different agents may have different effects on the Q_p/Q_s ratio and therefore on oxygen delivery.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Animals
Neonatal pigs (n = 6; age, 1 to 2 weeks; weight, 3.5 to 6.5 kg) were used. All animals were examined intraoperatively to rule out the presence of a patent ductus arteriosus. All animals were cared for in accordance with the guidelines published by the National Institutes of Health ("Guide for the Care and Use of Laboratory Animals," NIH publication 85-23, revised 1985). Additionally, all aspects of animal care were in accordance with the standards of the Institutional Animal Care and Use Committee of the University of Louisville.

Procedure
The details of the operative preparation were described elsewhere [4]. Briefly, each piglet was anesthetized with ketamine (30 mg/kg intravenously) and acepromazine (2 mg/kg intravenously). Continuous anesthesia was maintained with pentobarbital (5 mg • kg^-1 • h^-1 intravenously).

Both groins were dissected, and systemic arterial blood pressure was monitored with a 5F micromanometer-tipped catheter (Millar Inc, Houston, TX) placed into the middescending thoracic aorta via the femoral artery. The other femoral artery was cannulated to measure arterial blood gases. A fluid-filled catheter was placed into the midinferior vena cava via the femoral vein to monitor central venous pressure.

With the animal in supine position, a median sternotomy was performed. The pericardium was tacked up to form a well. One thousand units of heparin was given intravenously, and a 6-mm reinforced Gore-Tex (W. L. Gore & Assoc, Flagstaff, AZ) graft was placed from the innominate artery to the common trunk of the pulmonary artery. This was anastomosed end-to-end to the innominate artery and end-to-side to the pulmonary artery.

After the graft was completed, transit time flow probes (Triton, Inc, San Diego, CA) were placed on the proximal aorta, to measure left ventricular outflow, and around the innominate artery just proximal to the graft, to measure flow through the graft, ie, pulmonary artery blood flow. A 5F micromanometer tip catheter (Millar, Inc) was passed from the infundibular portion of the right ventricle into the common trunk of the pulmonary artery to continuously monitor pulmonary artery pressure.

A 4F Rashkind septostomy catheter (Bard Inc, Billerica, MA) was then passed transvenously via the remaining femoral vein to create a nonrestrictive atrial septal defect. The Rashkind catheter was then advanced into the right ventricle. The balloon was inflated and the catheter was slowly withdrawn, thereby snaring the chordae tendineae of the tricuspid valve. By repeatedly tearing the chordae tendineae, we rendered the tricuspid valve incompetent.

By occluding the right ventricular outflow tract, we completed the univentricular circuit. All systemic venous return was routed across the atrial septal defect into the left atrium. Pulmonary flow was maintained by that portion of the left ventricular outflow that exited the innominate artery and traversed the 6-mm Gore-Tex graft to the pulmonary artery. Right ventricular distention was prevented by having rendered the tricuspid valve incompetent.

All pressure and flow measurements were displayed on a Hewlett-Packard monitor and simultaneously recorded on a Gould recorder (model TA-11; Gould, Inc, Valley View, OH). Arterial blood gases were measured on a blood and electrolyte analyzer (Nova Biomedical, Norwood, MA). Venous oxygen saturations were measured using an oximetric catheter (Opticath; Abbott Labs, North Chicago, IL) placed in the midabdominal inferior vena cava and were continuously recorded on a Abbott Labs recorder.

Protocol
Once the univentricular preparation was completed and stable conditions had been present for at least 10 minutes, baseline measurements were obtained. Baseline ventilator settings consisted of inspired oxygen fraction (FiO₂) of 1.0 and positive end-expiratory pressure of 0 cm H₂O.

Individual inotropic agents were then administered. The drugs used were epinephrine at concentrations of 0.05 and 0.1 µg • kg • min^-1, dobutamine at 5 and 15 µg • kg^-1 • min^-1, and dopamine at 5 and 15 µg • kg^-1 • min^-1. The order of drug administration varied between experiments. Drugs were administered at an FiO₂ of 1.0 and 0.5.

Each agent was given for at least 10 minutes, until equilibrium conditions were present. Measurements were then taken. Before administering another drug, we obtained repeat baseline measurements. These readings were taken after administration of the initial drug had been stopped for at least 15 minutes and an equilibrium condition had again been reached.

Data Analysis and Statistics
Pulmonary flow and aortic flow were measured directly. Systemic flow was calculated as aortic flow minus pulmonary flow, as all pulmonary flow was derived from the innominate artery via the innominate artery-to-pulmonary artery graft. The Q_p/Q_s ratio was then determined by dividing pulmonary flow by the derived systemic flow. Pulmonary vascular resistance (PVR) was determined as

Central venous pressure was used in these calculations because an earlier study using this model demonstrated CVP to be equal to left atrial pressure, given the nonrestrictive atrial septal defect incorporated in the preparation. Systemic vascular resistance (SVR) was defined as

Oxygen delivery was calculated as systemic arterial content times systemic arterial flow, where

Results were analyzed using nonlinear regression analysis and goodness of fit test using a computerized statistical package (Excel; Microsoft Corp, Redwood, WA). One-way analysis of variance was used to analyze differences between means, with significance set at p less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Hemodynamics
Table 1 shows the hemodynamic effects of each agent. Epinephrine tended to increase mean systemic arterial pressure, but not to a statistically significant degree. No agent increased pulmonary artery pressure to a significant degree, although dopamine tended to increase it. All three agents increased cardiac output, although only epinephrine induced statistically significant changes at an FiO₂ of 1.0, whereas all three agents did at an FiO₂ of 0.5.

View larger version (27K): [in this window] [in a new window]   Fig 1. . Effects of inotropes on the pulmonary-to-systemic flow (Qp/Qs) ratio. Epinephrine decreases Qp/Qs, whereas dobutamine increases it. Dopamine does not lead to significant changes, although its actions appear similar to those of epinephrine. (FiO2 = inspired oxygen fraction;*p < 0.05 compared with baseline.)

The bottom panel of Figure 1 shows that although dopamine decreased Q_p/Q_s at both levels of FiO₂, the decrease failed to reach statistical significance.

Resistance
Figure 2 shows the relationship of the various inotropic agents and SVR and PVR. Epinephrine produced no significant changes in SVR (Fig 2, upper panel). Pulmonary vascular resistance increased, but not to a statistically significant level. This was true at both levels of FiO₂.

View larger version (34K): [in this window] [in a new window]   Fig 2. . Effects of inotropes on resistances. Dobutamine at high doses increased systemic vascular resistance, whereas dopamine increased pulmonary vascular resistance. (FiO2 = inspired oxygen fraction;*p < 0.05 compared with baseline.)

There was no significant change in SVR due to dopamine (Fig 2, lower panel), but PVR was increased significantly at both levels of FiO₂ (p < 0.1).

Oxygen Delivery
Figure 3 shows the effects of the inotrope-induced changes in the Q_p/Q_s ratio on oxygen delivery. The upper panel shows that epinephrine increased oxygen delivery at an FiO₂ of 1.0 (p < 0.05). Epinephrine also increased oxygen delivery at an FiO₂ of 0.5, but this did not reach statistical significance.

View larger version (28K): [in this window] [in a new window]   Fig 3. . Effects on oxygen delivery. Epinephrine increased oxygen delivery at an inspired oxygen fraction (FiO2) of 1.0 but did not reach significance at an FiO2 of 0.5. Dobutamine decreased oxygen delivery at an FiO2 of 1.0. Dopamine had no significant effects. (*p < 0.05 compared with baseline.)

Figure 4 plots the changes in the ratio of PVR to SVR as a function of drug administration. This plot demonstrates that there were significant increases in the PVR/SVR ratio when dopamine and epinephrine were given (p < 0.05), whereas no changes were seen with dobutamine.

View larger version (29K): [in this window] [in a new window]   Fig 4. . Effects of inotropes on the pulmonary vascular resistance-to-systemic vascular resistance (PVR/SVR) ratio. Epinephrine increases the PVR/SVR ratio, whereas dobutamine decreases it. Dopamine does not alter the ratio. The changes in PVR/SVR are opposite to those in the pulmonary-to-systemic flow ratio: an increase in the PVR/SVR ratio leads to a decrease in the flow ratio. This is a reflection of the parallel arrangement of the circulations. (FiO2 = inspired oxygen fraction.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

In contrast to infants with other univentricular defects, such as tricuspid atresia, children born with the hypoplastic left heart syndrome can have particularly volatile hemodynamics. This lability is present before and immediately after the initial operative intervention (the Norwood procedure). Good outcomes appear to be related to the ability to achieve a balance between the pulmonary and systemic circulations, which maintain parallel resistances after first-stage operative palliation [10]. A number of groups have reported using alterations in respiratory mechanics, including supplemental carbon dioxide and nitrogen, to stabilize hemodynamics and balance the Q_p/Q_s ratio [11].

Until very recently, new therapeutics such as these have been developed empirically, through "trial and error." Our group and a number of others have completed new animal models of a univentricular heart that raise the possibility of developing and examining perioperative therapies in an experimental framework. Norwood's group [12] used a porcine model, constructed with cardiopulmonary bypass and circulatory arrest, to examine the effects of adding supplemental carbon dioxide to the breathing circuit. Hanley and associates [13] reported using a model constructed by performing a Damus-Stansel-Kaye procedure and placing a shunt in fetal lambs to examine the consequences of addition of nitric oxide, carbon dioxide, and lowered oxygen tensions on the univentricular circuit. We have recently used our model to characterize the consequences of lowering FiO₂, adding positive end-expiratory pressure, and adding supplemental carbon dioxide.

Although pharmacologic agents, and in particular inotropes, constitute a major part of the therapy used to stabilize infants with the hypoplastic left heart syndrome, there are few experimental data to guide the application of these drugs. Experimental data may be useful, as the actions of these drugs on infants cannot be predicted from data derived from studies performed on adults [6]. Studies that have specifically examined the effects of inotropes in adults and children show a number of differences. Driscoll and associates [14] have demonstrated decreased myocardial sensitivity to dopamine in both human infants and young animal models. Zaritsky and Chernow [15] have shown how this decreased sensitivity translates into a need for higher doses of both dopamine and other inotropes to achieve the same effects in children that are seen in adults. These authors suggest that these findings may reflect incomplete sympathetic innervation and reduced norepinephrine stores in the young. As development continues and innervation increases, responses closer to those found in the adult are seen.

Recognizing the potential differences in the actions of drugs due to developmental changes in pharmacology, a number of studies have been performed to examine the effects of inotropes in younger patients, but their results may not be directly applicable to patients with the hypoplastic left heart syndrome. The findings in these studies are often conflicting, and are derived from defects that do not reproduce the unusual physiology of the univentricular circuit.

Examining a number of infants at the time of postoperative catheterization, Stephenson and colleagues [7] found that dopamine decreased SVR by a mean of 8% and increased PVR by an average of 11%. The defects encountered in this group included atrial septal defects, tetralogy of Fallot, and pulmonary hypertension. In contrast, a Japanese group [16] examining a number of infants with large ventricular septal defects before repair showed an increase in both PVR and SVR with dopamine infusion.

Animal studies have failed to yield any more consistent data. Abdul-Rasool and associates [17] found in a dog model that dopamine increased systemic vascular resistance, whereas dobutamine decreased systemic and pulmonary vascular resistance. Toorup and colleagues [18], in contrast, showed that, in lambs with a left-to-right shunt placed at the atrial level, dopamine decreased SVR, whereas dobutamine decreased both SVR and PVR. Driscoll and co-workers [19], in a study using young dogs, failed to demonstrate any change in SVR with the administration of dobutamine.

In addition to yielding conflicting results, these studies have focused on defects, such as atrial or ventricular septal defects, that have different hemodynamics than those encountered in the hypoplastic left heart syndrome. This circulation is distinct in having the pulmonary and systemic resistances in parallel, rather than in series. As a result, the ratio of flow through the two systems, the Q_p/Q_s ratio, is a direct function of the ratio of PVR to SVR. Changes in SVR or PVR induced by pharmacologic agents can have potentially large effects in this circuit, ones that may be quite distinct from those seen in other cardiac defects.

Because of these considerations, we thought it was important to use our animal model to examine the actions of inotropic agents on a univentricular heart. The drugs that we chose to examine, epinephrine, dobutamine, and dopamine, have different combinations of actions on ₁, ß₁, and ß₂ receptors. As a result, we thought they might influence SVR, PVR, and the PVR/SVR ratio differently, leading to varied effects on the Q_p/Q_s ratio.

We found that the agents we examined had dramatic and opposite effects on the Q_p/Q_s ratio, and led to contradictory effects on oxygen delivery. Although dopamine, epinephrine, and dobutamine all increased total cardiac output, only epinephrine significantly increased oxygen delivery. Dopamine had no significant impact on oxygen delivery, whereas dobutamine decreased it.

We have shown previously, in both a theoretical and an animal model, that oxygen delivery in the hypoplastic left heart syndrome is a direct function of the Q_p/Q_s ratio [20, 21]. There appears to be a fairly narrow range of Q_p/Q_s that leads to maximal oxygen delivery; Q_p/Q_s ratios either above or below this range are associated with decreased levels of oxygen delivery. In the case of inotropic medications, the ability of a drug to increase oxygen delivery seems to be determined not only by its ability to increase cardiac output but also by its effect on the Q_p/Q_s ratio. If a medication moves the Q_p/Q_s ratio towards its optimum, then oxygen delivery increases. Conversely, if a drug moves the Q_p/Q_s ratio away from the optimum, then oxygen delivery decreases, even though that drug may be increasing total cardiac output.

This is better demonstrated when comparing the effects of epinephrine and dobutamine in our model. Dobutamine increased cardiac output but decreased oxygen delivery because it moved the Q_p/Q_s ratio away from its optimum, increasing it from 1.03 ± 0.16 to 2.52 ± 0.55. Conversely, epinephrine was able to increase oxygen delivery because it not only increased cardiac output but also moved the Q_p/Q_s ratio closer to an optimum, changing it from 1.23 ± 0.21 to 0.82 ± 0.08. We have previously found, both in our theoretical and animal studies, that an optimum Q_p/Q_s ratio is seen at a value slightly less than 1.

As seen in Table 2, the changes that occurred in oxygen delivery in our model were accompanied by changes in SvO₂ and AVO₂ difference. As epinephrine increased oxygen delivery, SvO₂ increased while the AVO₂ difference decreased. When dobutamine decreased oxygen delivery, the AVO₂ difference increased. This suggests that determining SvO₂ and the AVO₂ difference may be a useful way to assess the effect of a given drug on oxygen delivery.

Our model demonstrates one manner in which the effects of the drugs can be quantitated in the clinical setting. We have previously demonstrated that SvO₂ functions as a good marker for the Q_p/Q_s ratio in an animal model [21]. In that study we found that SvO₂ reaches an optimum at approximately the same range of Q_p/Q_s values that oxygen delivery does; the plots of SvO₂ versus the Q_p/Q_s ratio and oxygen delivery versus the Q_p/Q_s ratio are very similar. The present study also demonstrated that SvO₂ and the AVO₂ difference were good markers for oxygen delivery. In a clinical setting, SvO₂ should be able to indicate whether an inotrope is successful in increasing oxygen delivery. Failure of an inotropic agent to increase SvO₂ and decrease the AVO₂ difference would indicate that the drug had not increased oxygen delivery, most likely because it had moved the Q_p/Q_s ratio away from an optimum.

Limitations
Although our model was based on a single left ventricle performing cardiac work, rather than on a right ventricle, it contained a circulation dependent on a systemic-to-pulmonary shunt. This function closely approximates the arrangement both in the preoperative hypoplastic left heart syndrome and in the heart after first-stage palliation. This circuit is of a very specific type, making the results of this study most easily extrapolated to the defects that constitute the hypoplastic left heart syndrome. The physiology of the univentricular heart defects, with parallel SVR and PVR, is relatively consistent, however, so that some insight into the full spectrum of these defects may be derived from this study.

This protocol was performed at an FiO₂ of 1.0 and 0.5. In clinical practice infants are typically maintained at a substantially lower FiO₂, typically 0.21 or less. In our model the Q_p/Q_s ratio was substantially less than that seen in human infants for an equivalent FiO₂, despite the use of a 6-mm graft in the preparation. As we encountered minimal pressure drops across the graft, the lower Q_p/Q_s ratio probably reflects differences in the pulmonary vasculature between species, or may be due to the fact that these animals do not undergo cardiopulmonary bypass. The lower Q_p/Q_s ratio in the preparation did necessitate the use of higher FiO₂ to obtain Q_p/Q_s ratios in the range seen in humans. This means that this study does not allow the direct determination of an optimal value of FiO₂ to use in humans. The overall trends and actions of the agents seen in this study should still be useful and valid, however.

Although our model suggests that there are substantial differences between inotropic agents regarding their effects on the Q_p/Q_s ratio and oxygen delivery, it may be that at least some of the data reflect species differences. There is little research to suggest that the actions of the medications that we examined are substantially different in the porcine model and in humans, although little is known about the effect of these medications in a univentricular system. These concerns notwithstanding, our data at least raise the possibility that different inotropic agents may have quite substantial differences in their effects in the neonate with the hypoplastic left heart syndrome. Further studies characterizing these medications in the human are needed.

Conclusions
In an animal model of the hypoplastic left heart syndrome, epinephrine decreased the Q_p/Q_s ratio and increased oxygen delivery, whereas dobutamine increased the Q_p/Q_s ratio and decreased oxygen delivery. Dopamine had no statistically significant effects on either the Q_p/Q_s ratio or oxygen delivery. Systemic venous oxygen saturation and the AVO₂ difference were useful in determining if an inotropic agent increased or decreased oxygen delivery. These findings suggest that inotropic agents may have substantial and opposite effects on oxygen delivery in the human infant with the hypoplastic left heart syndrome. Further examination of this hypothesis is necessary. Measuring SvO₂ and AVO₂ differences may be a useful way to determine drug effects in the clinical setting.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was supported in part by grants from the Alliant Community Trust Fund, the Louisville Institute for Heart and Lung Disease–Jewish Hospital, and the American Heart Association, Kentucky Affiliate.

Doctor Riordan is a Cardiothoracic Research Fellow, funded by Alliant Community Trust Fund.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Presented at the Forty-second Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 9-11, 1995.

Address reprint requests to Dr Austin, Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40292.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract 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 Author home page(s): Christopher J. Riordan John H. Storey Erle H. Austin, III Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Riordan, C. J. Articles by Austin, E. H. Search for Related Content PubMed PubMed Citation Articles by Riordan, C. J. Articles by Austin, E. H., III Related Collections Related Article