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J Thorac Cardiovasc Surg 1996;112:437-449
© 1996 Mosby, Inc.

SURGERY FOR CONGENITAL HEART DISEASE

FETAL MODEL OF SINGLE VENTRICLE PHYSIOLOGY: HEMODYNAMIC EFFECTS OF OXYGEN, NITRIC OXIDE, CARBON DIOXIDE, AND HYPOXIA IN THE EARLY POSTNATAL PERIOD

Supported in part by funding from the National Institutes of Health: 2 RO1 HL43357.

Presented in part at the Sixty-seventh Annual Scientific Session of the American Heart Association, Dallas, Tex., November 13-17, 1994.

Received for publication Sept. 21, 1995; revisions requested Nov. 29, 1995; revisions received Feb. 9, 1996 Accepted for publication Feb. 13, 1996. Address for reprints: V. Mohan Reddy, MD, 505 Parnassus Ave., M593, San Francisco, CA 94143-0118.

Abstract

Background:In patients with single ventricle physiology, the distribution of flow to the systemic and pulmonary circulations, which are in parallel, largely depends on the relative resistances in the respective vascular beds. Although neonatal palliation in patients with single ventricle physiology has become more common, medical management during the perinatal and perioperative periods is often based primarily on personal and institutional experience and is complicated by the transition to postnatal life and the effects of cardiopulmonary bypass. The lack of an animal model that suitably mimics single ventricle physiology has impeded progress in this area. Objective:The purpose of the current study was to investigate the effects of respiratory manipulations on pulmonary hemodynamics in the early neonatal period in a reproducible model of single ventricle physiology created in utero. Methods:A 10 mm Damus-Kaye-Stansel aortopulmonary anastomosis was created in fetal sheep (n= 14) at 140 ± 1.2 days' gestation, with pulmonary blood flow provided through a 5 mm aortopulmonary shunt after ligation of the main pulmonary artery distally. Two to 3 days after delivery at term, lambs (n= 11) underwent an open sternotomy and 30 minutes of deep hypothermic circulatory arrest. Both before and after bypass, respiratory manipulations, including administration of nitric oxide (80 ppm), 100% oxygen, 10% oxygen, and 5% carbon dioxide, were performed and hemodynamic variables were measured. Results:Nitric oxide and oxygen caused a decrease in pulmonary vascular resistance and an increase in the pulmonary/systemic blood flow ratio, both before and after bypass. Hypoxia and carbon dioxide produced a significant rise in pulmonary vascular resistance and a significant drop in the ratio of pulmonary to systemic blood flow. Conclusions:Oxygen, nitric oxide, and carbon dioxide all appear to be useful means of manipulating pulmonary vascular resistance and pulmonary/systemic blood flow ratio in neonatal lambs with single ventricle physiology, but further investigation is necessary to understand their dose responsive effects and the effects of prolonged administration. (J THORACCARDIOVASCSURG1996;112:437-49)

Patients born with congenital heart lesions characterized by one functioning ventricle, and hence parallel systemic and pulmonary circulations, often depend for their pulmonary blood flow on systemic–pulmonary arterial communications, via either a patent ductus arteriosus or a surgically created shunt. In this setting, pulmonary and systemic blood flows (Qp and Qs, respectively) are a function of relative resistances in the respective vascular beds and are among the primary determinants of systemic arterial oxygen saturation. ¹ An important goal in the preoperative and postoperative management of these patients is to minimize the total volume work of the single ventricle and preserve adequate systemic oxygen delivery by achieving a critical balance between Qp and Qs. Various ventilatory adjustments, inhalational agents, and pharmacologic agents are commonly used to achieve such a balance. ^1,2 Although the effects of inspired gases, pH, and other pharmacologic agents on pulmonary vasculature are well understood in the in-series two-ventricle circulation, ^3-9 little such information is available in the setting of single ventricle physiology. Therefore controversies exist in the management of patients with single ventricle physiology, because often the decisions are based on individual institutional experiences ^10-12 derived from monitoring physiologic variables that only indirectly reflect the changes in the systemic (SVR) and pulmonary (PVR) vascular resistances. Recently reported experimental ¹³ and mathematical ¹⁴ models of single ventricle physiology have provided some insight into the management of these patients. However, these models do not adequately account for the transitional physiology, either because they were created postnatally ¹³ or because they are purely theoretical. ¹⁴ We have recently established a reliable fetal animal model of single ventricle physiology. In the current report we examine the effects of inhalational agents, including nitric oxide, 100% oxygen, 10% oxygen, and 5% carbon dioxide, on pulmonary and systemic hemodynamics in this model.

Materials and methods

Surgical preparation and care
Ewes and fetuses
Fourteen mixed-breed Western ewes (140 ± 1.2 days' gestation, term = 145 to 150 days) were operated on under sterile conditions with the use of local anesthesia (2% lidocaine hydrochloride), epidural anesthesia (4 ml of 1% tetracaine hydrochloride), and intravenous sedation (50 to 100 mg ketamine hydrochloride). After placement of a central venous catheter into the maternal jugular vein, a midline laparotomy was performed, and the horn of the uterus containing the fetus was exposed. Hysterotomy was performed, the left fetal forelimb was extracted, and fetal anesthesia was administered with ketamine hydrochloride (10 mg/kg intramuscularly) and succinylcholine hydrochloride (2 mg/kg intramuscularly) to prevent fetal respiratory movements. The chest of the fetus was exposed and 1% lidocaine was injected along the line of incision. A left lateral thoracotomy was performed in the third intercostal space, after which an oblique pericardiotomy was made and the great vessels were exposed. The ascending aorta, main pulmonary artery, and brachiocephalic arterial trunk were dissected and controlled with vessel loops. The Damus-Kaye-Stansel anastomosis was performed in the following manner (Fig. 1). A side-biting vascular clamp was placed on the ascending aorta and an aortotomy was performed with a No. 11 blade knife. The aortotomy was extended to about 10 mm in length with fine scissors, and a strip of aortic wall was excised to create an oval opening in the ascending aorta. A short piece (about 10 mm length) of 10 mm polytetrafluoroethylene vascular graft* was anastomosed end to side to the ascending aorta with 7-0 Prolene sutures (Ethicon, Inc., Somerville, N.J.) with a continuous suture technique. The vascular clamp was then applied to the main pulmonary artery. A pulmonary arteriotomy was performed and a strip of the posterior pulmonary arterial wall was excised. The free end of the 10 mm graft was anastomosed end to side to the pulmonary artery. The vascular clamp was gradually released, allowing any air in the graft to escape through the suture line and needle holes, and the vascular clip was removed to establish graft patency. The main pulmonary artery was occluded distal to the Damus anastomosis with a large vascular clip. An aortopulmonary shunt was then created with a 5 mm polytetrafluoroethylene tube graft from the ascending aorta to the left pulmonary artery (Fig. 1). The thoracotomy incision was closed in layers. Warm saline solution was infused to replace the lost amniotic fluid and the uterine incision was closed. After recovery from anesthesia, the ewe was returned to the cage with free access to food and water. Antibiotics (2 million units of penicillin G procaine and 100 mg of gentamicin sulfate) were administered intravenously to the ewe during the operation and daily thereafter for 2 more days.

View larger version (26K): [in this window] [in a new window]   Fig. 1. Completed surgical procedure for in utero creation of Damus-Kaye-Stansel anastomosis to achieve single ventricle physiology. A, Aortopulmonary shunt; Ao, ascending aorta; BT, brachiocephalic trunk; C, clip ligation of main pulmonary artery; D, Damus-Kaye-Stansel anastomosis; DA, ductus arteriosus; DAo, descending aorta; LPA, left pulmonary artery; PA, main pulmonary artery.

Data acquisition
After a 30-minute recovery following instrumentation, and before and after each intervention, arterial blood gases and hemodynamic variables were measured. Arterial blood gases and pH were measured on a Corning 158 pH/blood gas analyzer (Corning Medical and Scientific, Medfield, Mass.), and hemoglobin concentration and oxygen saturation were measured by a hemoximeter (model OSM 2; Radiometer A/S, Copenhagen, Denmark). Pulmonary and systemic arterial pressures (PAP and SAP, respectively) and right and left atrial pressures were measured with Statham P23Db pressure transducers (Statham Instruments, Hato Rey, Puerto Rico). Mean pressures were obtained by electrical integration. Heart rate was measured by a cardiotachymeter triggered from the phasic systemic arterial pressure pulse wave. Qp and Qs were measured on an ultrasonic flowmeter (Transonic Systems Inc.). All hemodynamic variables were continuously recorded on a Gould multichannel electrostatic recorder (Gould Inc., Cleveland, Ohio). PVR and SVR were calculated by standard formulas relating pressure to flow and resistance (Ohm's law).

Experimental protocol
After baseline measurements of the hemodynamic variables (PAP, SAP, heart rate, Qs, Qp, and left and right atrial pressures) and systemic arterial blood gases, the following inhalational agents were administered in random order and their effects were noted:

Oxygen 100%
A 100% concentration of oxygen was administered by increasing the inspired oxygen fraction on the ventilator to 100% (oxygen concentration was checked with an oxygen sensor in the inflow circuit).

Oxygen 10% (hypoxia)
A 10% concentration of oxygen was administered by adding nitrogen to the inspired air (oxygen concentration was checked with an oxygen sensor in the inflow circuit).

Carbon dioxide 5%
A commercially prepared gas mixture of 5% carbon dioxide, 21% oxygen, and 74% nitrogen was administered.

Nitric oxide 80 parts per million
Nitric oxide was administered into the inflow circuit of the ventilator. The flow of the nitric oxide–nitrogen mixture was regulated by a Bird low-flow blender (Bird Products Corp., Palm Springs, Calif.), and delivered nitric oxide concentration (80 ppm of air) was continuously measured at the endotracheal tube by chemiluminescence (model 42H; Thermo-Environmental Instruments, Franklin, Mass.).

After administration of 100% oxygen and 5% carbon dioxide, a 10-minute period was provided for stabilization. Hemodynamic variables were measured continuously. Systemic arterial blood gases, pH, and hemodynamic variables were measured at the end of 10 minutes. After administration of 10% oxygen and nitric oxide, a 5-minute period of stabilization was allowed and the same variables were recorded. At the completion of each intervention, a 30-minute recovery period was allowed before the next intervention, and all measurements were repeated to ensure that the animal was in a steady state.

The lambs were then supported with cardiopulmonary bypass, cooled to 15º C, and the circulation was arrested for 30 minutes to mimic the clinical circumstances of a stage I Norwood procedure. The lambs were rewarmed fully and separated from bypass. After a 60-minute recovery period, all hemodynamic measurements and systemic arterial blood gases and pH levels were obtained and a stable state was established. The prebypass interventions were repeated randomly according to the same protocol. At the end of the study, the lambs were given a lethal dose of pentobarbital sodium and an autopsy was performed to confirm the placement of intravascular catheters and shunt patency. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society of 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 (NIH Publication No. 86-23, revised 1985). All protocols were approved by the Committee on Animal Research of the University of California, San Francisco.

Statistical analysis
Microsoft Excel Version 5.0 (Microsoft Corporation, Redmond, Wash.) was used to calculate descriptive and analytic statistics. The change in the variables with each intervention is expressed as percent change from the baseline preintervention value. Mean percent changes in variables from preadministration to postadministration levels (as presented in the Results section) were calculated as the average of percent changes in individual subjects. Paired two-tailed t test analysis was used to assess the significance of changes in hemodynamic variables relative to baseline preadministration levels after nitric oxide, 100% oxygen, 10% oxygen, and 5% carbon dioxide administration, both before and after bypass. The significance of differences between prebypass and postbypass mean percent change in variables after the administration of nitric oxide, 100% oxygen, 10% oxygen, and 5% carbon dioxide was also examined by means of paired two-tailed t test analysis. In all cases, presented p values reflect significance levels by two-tailed paired t test comparison, as described earlier. All p values of 0.05 or less were considered significant.

Results

Of the 14 fetuses in which the model was created, 11 were delivered normally and three were aborted within 3 days of the in utero operation. All animals remained in hemodynamically stable condition during the prebypass study, and hemodynamic and blood gas data were obtained and analyzed in all 11 animals studied. The study was discontinued in one lamb because of excessive bleeding from rupture of the graft suture line during cannulation of the ascending aorta. The other 10 animals were in hemodynamically stable condition throughout the bypass and postbypass periods and completed the study successfully. Except for postbypass nitric oxide data, which were not obtained for technical reasons in the first animal studied, postbypass hemodynamic and blood gas data were available for all 10 animals. Prebypass changes after nitric oxide, 100% oxygen, hypoxia, and 5% carbon dioxide administration were calculated from the data collected on all 11 animals. Postbypass statistics (except in the case of nitric oxide) reflect data for the 10 animals that survived bypass. Paired two-tailed t test comparison of prebypass and postbypass changes after intervention was performed with the use of data from the 10 animals that survived bypass and from nine animals for nitric oxide.

Arterial blood gases and hemoglobin
Table I shows arterial pH, carbon dioxide tension, oxygen tension, bicarbonate, oxygen saturation, and hemoglobin levels before and after administration of nitric oxide, 100% oxygen, hypoxia, and 5% carbon dioxide before and after bypass.

View larger version (34K): [in this window] [in a new window]   Fig. 2. Mean (± standard deviation) percent change in PAP after administration of nitric oxide, 100% oxygen, hypoxia, and 5% carbon dioxide before (n = 11) and after (n = 10) cardiopulmonary bypass. Percent and p values displayed directly above figure columns reflect the mean percent change and significance levels for the paired, two-tailed t test comparison between preadministration and postadministration PAP. Boxed p values indicate significance levels for paired two-tailed t test comparison between prebypass and postbypass mean percent change in PAP after administration of nitric oxide, 100% oxygen, hypoxia, and 5% carbon dioxide (n = 10). The same format applies to Figs. 3 through 9.

View larger version (28K): [in this window] [in a new window]   Fig. 3. Mean (± standard deviation) percent change in SAP after administration of nitric oxide, 100% oxygen, hypoxia, and 5% carbon dioxide before (n = 11) and after (n = 9) cardiopulmonary bypass.

View larger version (32K): [in this window] [in a new window]   Fig. 4. Mean (± standard deviation) percent change in indexed Qp after administration of nitric oxide, 100% oxygen, hypoxia, and 5% carbon dioxide before (n = 11) and after (n = 10) cardiopulmonary bypass.

View larger version (31K): [in this window] [in a new window]   Fig. 5. Mean (± standard deviation) percent change in indexed Qs after administration of nitric oxide, 100% oxygen, hypoxia, and 5% carbon dioxide before (n = 11) and after (n = 10) cardiopulmonary bypass.

Qp/Qs ratio (Fig. 6)
Nitric oxide increased Qp/Qs ratio by 7.1% (p = 0.014) before bypass and to a lesser degree after bypass (4.2%; p = 0.05). However, 100% oxygen produced a significant increase in Qp/Qs ratio both before and after bypass (prebypass: 36.6%; p = 0.001; postbypass: 21.7%; p = 0.01). Qp/Qs ratio increased significantly more with 100% oxygen than with nitric oxide before (p = 0.008) and after bypass (p = 0.009). A significant fall in Qp/Qs ratio was seen with hypoxia (prebypass: -32.2%; p < 0.0001; postbypass: -27.4%; p = 0.0003) and 5% carbon dioxide (prebypass: -26.9%; p = 0.001; postbypass: -26.2%; p = 0.0009). The effects of hypoxia and 5% carbon dioxide were not significantly different before (p = 0.28) or after bypass (p = 0.63).

View larger version (33K): [in this window] [in a new window]   Fig. 6. Mean (± standard deviation) percent change in Qp/Qs after administration of nitric oxide, 100% oxygen, hypoxia, and 5% carbon dioxide before (n = 11) and after (n = 10) cardiopulmonary bypass.

View larger version (36K): [in this window] [in a new window]   Fig. 7. Mean (± standard deviation) percent change in PVR after administration of nitric oxide, 100% oxygen, hypoxia, and 5% carbon dioxide before (n = 11) and after (n = 10) cardiopulmonary bypass.

View larger version (31K): [in this window] [in a new window]   Fig. 8. Mean (± standard deviation) percent change in SVR after administration of nitric oxide, 100% oxygen, hypoxia, and 5% carbon dioxide before (n = 11) and after (n = 10) cardiopulmonary bypass.

View larger version (36K): [in this window] [in a new window]   Fig. 9. Mean (± standard deviation) percent change in PVR/SVR after administration of nitric oxide, 100% oxygen, hypoxia, and 5% carbon dioxide before (n = 11) and after (n = 10) cardiopulmonary bypass.

Perioperative management of patients born with single ventricle physiology is aimed at achieving a critical balance between Qp and Qs to ensure adequate systemic oxygen delivery while simultaneously minimizing volume overload on the single functioning ventricle. ^1,2 Clinical strategies to achieve this goal are often institutional preferences, which are generally based on experience with blood gas measurements and final patient outcome. ^10-12 This approach tends to create controversy because institutions with different approaches ^10,12 often have equally good results. Frequently, other factors such as ventricular function and the size of the systemic-pulmonary shunt are not taken into consideration. This empiric nature of current management strategies has prompted investigators to create animal models of single ventricle physiology to investigate the hemodynamic effects of various interventions by direct methods. Recently, Mora and associates ¹³ reported an experimental model of single ventricle physiology in which they examined the effects of inspired carbon dioxide on pulmonary hemodynamics. This study supported the clinical use of inspired carbon dioxide to manipulate PVR and decrease the Qp/Qs ratio. However, one drawback of the reported model is that it was created in a 4-week-old animal that had progressed beyond the transitional phase of circulation. As such, it had lived for a considerable period with normal postnatal circulatory dynamics before it was surgically altered to mimic single ventricle physiology. Thus this model does not accurately represent a neonate with single ventricle physiology who requires intervention in the first few days of life.

We recently created a fetal model of single ventricle physiology. The main shortcoming of this model is that it has two ventricles, both of which eject into the aorta, where the mixing of systemic and pulmonary venous blood occurs. In addition, inherent to any animal model is the possibility of differences in physiologic responses between human beings and animals. Inasmuch as the perinatal circulatory physiology has been most extensively studied in the sheep, and the size of the sheep fetus is similar to that of the human fetus, we preferred the sheep fetus for the model. However, the major strength of this model is that the most important feature of single ventricle physiology, namely, parallel pulmonary and systemic circulations, is present from birth, which serves to adequately simulate the newborn infant with a single ventricle. This fetal model allows for the study of single ventricle physiology during the transitional period when most neonates undergo surgical intervention.

In the present study, as expected, 100% oxygen and nitric oxide both decreased PVR and increased Qp/Qs ratio. PVR decreased approximately 20% with oxygen and 12% to 14% with nitric oxide. The magnitude of increase in Qp/Qs ratio was significantly greater with oxygen than with nitric oxide (p = 0.008 before bypass and p = 0.009 after bypass). This difference in the effect on Qp/Qs ratio is probably due to the observed differences in the effect of 100% oxygen and nitric oxide on SVR. Nitric oxide decreased SVR, a phenomenon that has also been observed by others ¹⁵ in the setting of single ventricle physiology. However, its effect is difficult to explain, because nitric oxide is inactivated by contact with hemoglobin and thought not to have any systemic effects. On the other hand, the increase in SVR with oxygen appears to be a flow-related phenomenon resulting from steal of systemic flow into the pulmonary bed. The increase in Qp/Qs ratio with 100% oxygen is more profound than with 80 ppm nitric oxide. Nitric oxide may be useful when a mild increase in Qp/Qs ratio is adequate to achieve systemic oxygenation.

Both carbon dioxide and hypoxia (10% oxygen) increased PVR and decreased both Qp and the Qp/Qs ratio. The effects of hypoxia were significantly more pronounced than those of carbon dioxide on PVR, especially after bypass, but there was no statistically significant difference between decreases in Qp/Qs ratio produced by carbon dioxide and hypoxia. Both hypoxia and carbon dioxide decreased SVR. However, this effect could be flow related as a result of a reciprocal increase in Qs caused by elevated PVR. The effects of carbon dioxide in this study were not measured independent of pH. However, a previous study in a model of single ventricle suggests that carbon dioxide may have independent effects on pulmonary vasculature when pH is controlled. ¹³

In summary, judicious use of oxygen, nitric oxide, and carbon dioxide all appear to be useful modalities to manipulate PVR and alter Qp/Qs ratio. The model described here offers a unique tool to study single ventricle physiology. Further studies to quantitate the pulmonary vascular responses to incremental changes in inspired gases and their effects on systemic oxygen delivery will be necessary for a better understanding of single ventricle physiology in the neonatal transitional period and after bypass.

Acknowledgments

We thank Roger Chang for his technical help in conducting these studies.

Footnotes

*Gore-Tex vascular graft, registered trademark of W. L. Gore & Associates, Inc., Newark, Del.

References

1. Castaneda AR, Jonas RA, Mayer JE, Hanley FL, editors. Cardiac surgery of the neonate and infant. Philadelphia: WB Saunders, 1994:80-2.
   
2. Jobes DR, Nicolson SC, Steven JM, Miller M, Jacobs ML, Norwood WI. Carbon dioxide prevents pulmonary overcirculation in hypoplastic left heart syndrome. Ann Thorac Surg 1992;54:150-1.[Abstract/Free Full Text]
   
3. Roberts JD, Lanf P, Bigatello LM, Vlahakes GJ, Zapol WM. Inhaled nitric oxide in congenital heart disease. Circulation 1993;87:447-52.[Abstract/Free Full Text]
   
4. Rudolph AM, Yuan S. Response of the pulmonary vasculature to hypoxia and hydrogen ion concentration changes. J Clin Invest 1966;45:399-411.
   
5. Schreiber MD, Heymann MA, Soifer SJ. Increased arterial pH, not decreased Paco₂ attenuates hypoxia-induced pulmonary vasoconstriction in newborn lambs. Pediatr Res 1986;20:113-7.[Medline]
   
6. Fullerton DA, Kirson LE, St. Cyr JA, Kinnard T, Whitman GJR. Influence of hydrogen ion concentration versus carbon dioxide tension on pulmonary vascular resistance after cardiac operation. J Thorac Cardiovasc Surg 1993;106:528-36.[Abstract]
   
7. Morray JP, Lynn AM, Mansfield PB. Effect of pH and Pco₂ on pulmonary and systemic hemodynamics after surgery in children with congenital heart disease and pulmonary hypertension. J Pediatr 1988;113:474-9.[Medline]
   
8. Viitanen A, Salmenperä M, Heinonen J, Hynynen M. Pulmonary vascular resistance before and after cardiopulmonary bypass: the effect of Paco₂. Chest 1989;95:773-8.[Abstract/Free Full Text]
   
9. Malik AB, Kidd BSL. Independent effects of changes in H⁺ and CO₂ concentrations on hypoxic pulmonary vasoconstriction. J Appl Physiol 1973;34:318-23.[Free Full Text]
   
10. Iannettoni MD, Bove EL, Mosca RS, Lupinetti FM, Dorostkar PC, Ludomirsky A, et al. Improving results with first-stage palliation for hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 1994;107:934-40.[Abstract/Free Full Text]
    
11. Rossi AF, Sommer RJ, Lotvin A, et al. Usefulness of intermittent monitoring of mixed venous oxygen saturation after stage I palliation for hypoplastic left heart syndrome. Am J Cardiol 1994;73:1118-23.[Medline]
    
12. Gullquist SD, Schmitz ML, Hannon GD, et al. Carbon dioxide in the inspired gas improves early postoperative survival in neonates with congenital heart disease following stage I palliation (Norwood). Circulation 1992;86(Suppl):I360.
    
13. Mora GA, Pizarro C, Jacobs ML, Norwood WI. Experimental model of single ventricle: influence of carbon dioxide on pulmonary vascular dynamics. Circulation 1994;90[Part 2]:II43-6.
    
14. Barnea O, Austin EH, Richman B, Santamore WP. Balancing the circulation: theoretic optimization of pulmonary/systemic flow ratio in hypoplastic left heart syndrome. J Am Coll Cardiol 1994;24:1376-81.[Abstract]
    
15. Wessel DL, Adatia I, Giglia TM, Thompson JE, Kulik TJ. Use of inhaled nitric oxide and acetylcholine in the evaluation of pulmonary hypertension and endothelial function after cardiopulmonary bypass. Circulation 1993;88:2128-38.[Abstract/Free Full Text]
    

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