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Right arrow Congenital - cyanotic

Ann Thorac Surg 2006;81:264-271
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Twenty-Four Hour Cardiopulmonary Stability in a Model of Assisted Newborn Fontan Circulation

Cynthia D. Myers, MD a , Kelly Mattix, MD a , Robert G. Presson, Jr, MD b , Palaniswamy Vijay, PhD a , Domingo Maynes, BS a , Kenneth N. Litwak, DVM, PhD c , John W. Brown, MD a , Mark D. Rodefeld, MD a , *

a Section of Cardiothoracic Surgery, Department of Surgery, Indiana University School of Medicine and James Whitcomb Riley Hospital for Children, Indianapolis, Indiana
b Department of Anesthesiology, Indiana University School of Medicine and James Whitcomb Riley Hospital for Children, Indianapolis, Indiana
c Department of Surgery, University of Louisville, Louisville, Kentucky

Accepted for publication June 22, 2005.

* Address correspondence to Dr Rodefeld, Section of Cardiothoracic Surgery, Department of Surgery, Indiana University School of Medicine, Emerson Hall 215, 545 Barnhill Dr, Indianapolis, IN 46202 (Email: rodefeld{at}iupui.edu).

Presented at the Forty-first Annual Meeting of The Society for Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
BACKGROUND: Morbidity and mortality after stage-1 palliation of hypoplastic left heart syndrome is high as a result of adverse physiologic conditions imposed by the systemic-to-pulmonary arterial shunt. Conversion to a systemic venous source of pulmonary blood flow (Glenn/Fontan) substantially decreases instability and mortality risk. Cavopulmonary assist has the potential to eliminate critical dependence on the problematic systemic arterial shunt. We studied this support modality during a 24-hour period in a neonatal animal model of univentricular Fontan circulation.

METHODS: Lambs (8.1 ± 0.9 kg, 8.3 ± 2.1 days, n = 7) underwent total cavopulmonary diversion. A miniature centrifugal pump was used to assist cavopulmonary flow. Control animals (6.6 ± 1.0 kg, 7.3 ± 2.1 days, n = 11) underwent placement of monitoring lines only. Hemodynamic and gas exchange data were measured. Within-group and between-group comparisons were made using two-way repeated measures analysis of variance.

RESULTS: After an initial phase of reactivity, pulmonary vascular resistance returned to low levels and was not significantly different from baseline values after hour 13 or significantly different from control values after hour 4. Systemic venous pressure remained low. Oxygenation and ventilation remained normal with no histologic evidence of parenchymal lung injury.

CONCLUSIONS: Pump-assisted cavopulmonary diversion is well tolerated up to 24 hours in the neonatal period. Despite initial reactivity, pulmonary vascular resistance trended toward normal and approached control values. Cavopulmonary assist holds the potential to serve as a bridge to neonatal Fontan repair of single ventricle. Chronic studies are warranted to determine the duration and rate of weaning of support to transition to an unassisted univentricular Fontan circulation.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
In neonatal palliation of single-ventricle cardiac anomalies, a systemic-to-pulmonary arterial shunt is necessary to provide a high-pressure source of pulmonary blood flow because of the potential for elevated pulmonary vascular resistance (PVR). Unfortunately, use of a systemic-to-pulmonary shunt creates undesirable pathophysiologic consequences including potentially unstable parallel systemic and pulmonary circulations, severe hypoxemia, volume overload to the single ventricle, and impaired diastolic coronary perfusion. In response to these problems, alternative strategies for palliation of hypoplastic left heart syndrome are emerging [1, 2]. To circumvent critical dependence on a systemic arterial shunt, we have investigated the concept of temporarily supporting cavopulmonary flow in a neonatal animal model of univentricular Fontan circulation using either a paracardiac centrifugal or catheter-based implantable axial flow pump [3, 4].

Past models of unsupported univentricular Fontan physiology have required nonphysiologic volume loading to a systemic venous pressure of 20 to 25 mm Hg to maintain pulmonary perfusion and cardiac output. Long-term stability was not possible because of complications of systemic venous and capillary hypertension in a systemic circulation that had not been previously exposed to high pressure [5, 6]. Other models have applied pulmonary circulatory assist after right ventricular exclusion, but none have yielded long-term stability or have been performed in newborns [7, 8]. The current experiment was designed to assess the hemodynamic response in a neonatal model of assisted univentricular Fontan circulation for an intermediate time frame. We hypothesized that pulmonary hemodynamics and gas exchange function would remain normal in an animal receiving assisted cavopulmonary flow, and that systemic venous pressure would remain in the physiologic range.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Discussion
 Acknowledgments
 References
 
Newborn lambs underwent mask induction, followed by endotracheal intubation, and mechanical ventilation using a Servo 900C volume-cycled respirator (Siemens, Danvers, MA) with inspired O2 fraction of 0.3 and 1% to 1.5% isoflurane. Ventilation was maintained at 30 to 35 breaths per minute with tidal volumes 12 to 15 mL/kg and 4 cm H2O positive end-expiratory pressure. Minor ventilator adjustments were made to maintain mild hypocapnia with a goal arterial partial pressure of carbon dioxide of 30 to 35 mm Hg. After obtaining intravenous access, 5 mg/kg ketamine and 0.5 mg/kg xylazine were infused for 20 minutes, followed by an infusion at 5 mg/kg per hour and 0.5 mg/kg per hour, respectively, to maintain anesthesia throughout the remainder of the study. Isoflurane was then decreased to 0.5% to 1% until completion of the surgical procedure.

A femoral arterial catheter (Intracath 16-gauge; Becton Dickinson, Sandy, UT) was placed for systemic blood pressure monitoring. A femoral venous catheter (Intracath) was advanced to the infradiaphragmatic vena cava for measurement of systemic venous pressure. The heart was exposed through a median sternotomy, and the pericardium was suspended. The azygous vein and ductus arteriosus were ligated. Pressure monitoring catheters (Intracath) were placed in the left atrial appendage and distal main pulmonary artery. An ultrasonic flow probe (series 12A, Transonic Systems Inc, Ithaca, NY) was placed around the ascending aorta. Baseline systemic arterial pressure, pulmonary arterial pressure, left atrial pressure, systemic venous pressure, and cardiac output were measured. Baseline activated clotting time, arterial blood gas, and arterial lactate values were also obtained. Additionally, blood was drawn for serum nitric oxide (NO) concentration analysis at baseline. Mean circulatory filling pressure (MCFP), a measure of stressed systemic volume status, was measured by recording inferior vena caval pressure after 7 seconds of induced ventricular fibrillation [9]. The heart was defibrillated, and animals were systemically heparinized (sodium heparin, 150 U/kg).

Control animals (6.6 ± 1.0 kg, 7.3 ± 2.1 days, n = 11) underwent median sternotomy and placement of intracardiac pressure catheters and aortic flow probe only. In the assisted Fontan animals (8.1 ± 0.9 kg, 8.3 ± 2.1 days, n = 7), a multiperforated venous cannula (A-med Systems Inc, West Sacramento, CA) was introduced through the right atrial appendage with its tip situated in the midportion of the right ventricle to drain both right atrium and ventricle. The proximal main pulmonary artery was cannulated with an angled inflow cannula (A-med Systems). Both cannulas were connected to a miniature centrifugal pump (Paraflow, A-med Systems), and the circuit was primed by backfilling with autologous blood (45 mL). The pump was activated, and flow was gradually increased during several minutes. A tourniquet was placed around the proximal main pulmonary artery and tightly snared to prohibit right ventricular contribution to pulmonary blood flow. Bilateral pleural drains were placed, and the chest was closed to maintain negative intrapleural pressure. A suprapubic cystostomy was performed for measurement of urine output.

Postintervention Management
Activated clotting time was maintained greater than 1.5 times baseline in both groups. A surface electrocardiogram and systemic arterial waveform were continuously monitored. Hemodynamic data and arterial blood gases were measured at hourly intervals for 24 hours. Measurable surgical blood loss was replaced 1:1 with maternal fresh packed red blood cells. Maintenance intravenous fluids, packed red blood cells, fresh plasma, and inotropic medications (dopamine, dobutamine, epinephrine) were administered as necessary to optimize cardiac output near baseline. Systemic venous pressure was the primary determinant of intravascular volume status and was validated with MCFP at the beginning and end of the study. Inotrope scores were calculated using the following formula: 1 µg · kg–1 · min–1 dopamine = 1 point, 1 µg · kg–1 · min–1 dobutamine = 1 point, 0.01 µg · kg–1 · min–1 epinephrine = 1 point [10]. Hourly inotrope scores were averaged for 24 hours to provide a mean inotrope score.

Hemoglobin was measured with an OSM3 hemoximeter (Radiometer, Westlake, OH) calibrated for sheep hemoglobin. Arterial blood gases, corrected for hemoglobin level, were measured with an ABL500 blood gas analyzer (Radiometer). Arterial lactate values were measured using a YSI 2300 Stat Plus glucose and lactate analyzer (YSI, Yellow Springs, OH). Serum was collected every 3 hours for NO concentration analysis. Postintervention MCFP was measured at the conclusion of the study.

Pulmonary Vascular Reactivity
Pulmonary vascular tone was assessed serially at hours 3, 9, 15, and 21 in response to hypoxia (fraction inspired oxygen, 0.15), U-46619 (thromboxane receptor agonist; Cayman Chemical, Ann Arbor, MI), and inhaled NO (INO Therapeutics, Inc, Clinton, NJ). Baseline pulmonary hemodynamics were recorded just before starting the challenges. Hypoxia was maintained for 10 minutes. U-46619 was infused at 0.5 µg · kg–1 · min–1 for 5 minutes. Inhaled NO 40 ppm was delivered for 10 minutes. Absolute change in pulmonary arterial pressure was compared within and between groups for all challenges [11, 12].

Plasma Nitric Oxide Concentration
Nitric oxide was measured as the product of nitrate metabolites, nitrates, and nitrites. Arterial blood samples were collected every 3 hours and centrifuged (4,000 g for 20 minutes). Plasma was immediately frozen at –70°C until assays were performed. Samples at baseline and hours 0, 3, 9, and 24 were analyzed. Plasma was diluted (1:1) in reaction buffer, ultrafiltered through a 10,000 MWCO filter, and then incubated with nitrate reductase, converting nitrates (NO3 –) into nitrites (NO2 –). Griess reagent was used to form a purple azo derivative, which was quantified by absorbance at 548 nm.

Lung Histology
Lung specimens, collected from representative animals at completion of the study, were preserved in 10% formalin. Tissue was embedded in paraffin, sectioned, and stained with hematoxylin and eosin.

Statistical Analysis
Results are reported as mean ± standard deviation. Data from all animals was analyzed by pairwise comparisons within and between control and assisted Fontan groups, including time factor for all hourly time points from baseline to 24 hours, performed by two-way analysis of variance with correction for repeated measures using Holm-Sidak post hoc test. Pulmonary vascular reactivity data and plasma NO concentration data were also analyzed using two-way repeated measures analysis of variance with the Holm-Sidak post hoc test. Significance was defined as p equal to 0.05 or less. Statistical analysis was performed with Sigmastat software (Systat, Richmond, CA).

The experimental protocol was approved by the Animal Care and Use Committee of the Indiana University School of Medicine. Animals received humane care in accordance with the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 86-23, revised 1996).


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Discussion
 Acknowledgments
 References
 
Systemic Hemodynamics
At baseline and at 24 hours, there were no significant differences between groups for any hemodynamic variable (Table 1). Cardiac index was maintained for 24 hours. A decrease in diastolic blood pressure occurred in both groups, but this was significant only in the control group. Left atrial pressure, systemic venous pressure, and MCFP increased significantly during 24 hours in both groups, but no difference was seen between groups at 24 hours. Baseline MCFP was 7 ± 1 mm Hg and 8 ± 1 mm Hg in the control and Fontan groups, respectively, in comparison to values at 24 hours of 11 ± 3 mm Hg and 10 ± 2 mm Hg, respectively. Probability values for within-group comparisons of MCFP from baseline to 24 hours were less than 0.001 and 0.024 for control and Fontan groups, respectively, and the between-group values at baseline and 24 hours were 0.749 and 0.384, respectively. Systemic venous pressure did not exceed physiologic levels in either group. Mean inotrope scores were higher in the assisted Fontan group than the control group (6.0 ± 3.1 versus 3.6 ± 2.2, respectively, p = 0.016).


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  		Table 1. Hemodynamic and Respiratory Data a
 
Pulmonary Hemodynamics
Pulmonary arterial pressure and PVR (Fig 1) increased substantially in the assisted Fontan group after initiation of pump flow, as expected in the setting of reactive newborn transitional pulmonary vasculature. Pulmonary vascular resistance increased significantly during the first 3 hours after pump initiation. This reflects an increase in pulmonary arterial pressure, with a maximal mean pressure of 30.9 mm Hg measured at hour 2, and an initial decrease in cardiac index (estimate of pulmonary blood flow). After hour 3, however, PVR and pulmonary arterial pressure exhibited an equally dramatic decrease. By hour 14, PVR was not significantly different from baseline, and after hour 5 was not significantly different from control values. In the control group, a significant increase in pulmonary arterial pressure from baseline was seen consistently throughout all hours of the study, and a significant increase in PVR was also observed starting in hour 2, presumably in response to anesthesia, surgical trauma, and mechanical ventilation. Pulmonary vascular resistance decreased and was not significantly different from baseline after hour 7 in the control group.



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  		Fig 1. Pulmonary vascular resistance, calculated as (pulmonary arterial pressure minus left atrial pressure) times 80 divided by cardiac index and expressed as 103 dyne · s · cm–5 · kg. Time 0 indicates initiation of assisted Fontan. The assisted Fontan group (solid line) was significantly different from baseline for hours 0 to 14. The control group (dashed line) was significantly different from baseline for hours 2 to 7. Between-group significance was observed for hours 1 to 5. (B = baseline.)

 
Pulmonary Vascular Reactivity
Hypoxia induced a decreasing magnitude of reactivity during the course of the study as demonstrated by significantly smaller changes in pulmonary arterial pressure at hour 21 in comparison to hour 3 in both groups (control p = 0.001 and Fontan p < 0.001; Fig 2A). No between-group differences were seen with hypoxia (p 0.090 to 0.924). There were no within-group differences in change in pulmonary arterial pressure at any time points in response to U-46619 (p 0.067 to 0.857), but significant differences were observed between groups at hour 3 (p = 0.001) and hour 9 (p = 0.004), which normalized to control at hour 15 (p = 0.096) and hour 21 (p = 0.308; Fig 2B). Inhaled NO significantly decreased pulmonary arterial pressure in both groups, but no within-group (p 0.097 to 0.876) or between-group differences (p 0.409 to 0.691) were observed.



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  		Fig 2. Pulmonary vascular reactivity in control (solid bars) and assisted Fontan (open bars) groups. (A) Response to hypoxia. (B) Response to U-46619. *p = 0.001, p = 0.004 indicates between-group significance at hours 3 and 9, respectively.

 
Gas Exchange Function
Pulmonary gas exchange function remained comparably normal in both groups throughout the postintervention period (Table 1). Physiologic arterial partial pressure of oxygen values were maintained throughout the study, although arterial partial pressure of oxygen in the assist group significantly decreased during 24 hours. Peak airway pressure remained less than 30 cm H2O in all studies. Positive end-expiratory pressures of 8 to 10 mm Hg were occasionally used to overcome atelectasis. Neither pulmonary edema nor hemorrhage was observed, and airway secretions were negligible. On histologic evaluation, no microscopic evidence of edema or other interstitial change was observed after 24 hours of cavopulmonary assist. Arterial pH remained within the normal range or was slightly alkalotic secondary to moderate hypocapnia. Arterial lactate values increased in both groups, but there was not a significant difference observed within or between groups.

Plasma Nitric Oxide Concentration
No statistical difference was observed between groups at any time point (p ≥ 0.407).


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Discussion
 Acknowledgments
 References
 
In staged palliation of functional single ventricle, morbidity and mortality decrease dramatically after conversion to a systemic venous source of pulmonary blood flow [13]. This suggests that poor outcomes are linked to the systemic-to–pulmonary arterial shunt. Placement of systemic arterial shunts is associated with 10% mortality, excluding patients with hypoplastic left heart syndrome, who are at even higher risk [14]. Despite refinement in technique and management, hospital and interim mortality rates for stage I palliation of hypoplastic left heart syndrome remain high [15, 16]. The systemic-to–pulmonary arterial shunt creates conditions (hypoxemia, pulmonary blood flow to systemic blood flow ratio greater than 1, high-pressure source) that diametrically oppose normal transitional pulmonary vascular maturation and maintenance of low PVR [17]. Long-term, the elevated PVR observed late in univentricular Fontan patients is in part a reflection of their initial staging operation in which a systemic arterial shunt was used [18]. The shunt may not only make the patient a worse candidate for eventual Fontan conversion, but may undermine the goal of minimizing PVR for optimal Fontan circulation in the long term. The recently described right ventricle–to–pulmonary artery conduit addresses the problem of impaired diastolic coronary perfusion, but it does not address the problems of parallel systemic and pulmonary circulations, hypoxemia, or volume overload to the single ventricle [2]. Furthermore, it has the concerning disadvantage of requiring a ventriculotomy, which may impair ventricular function [19].

To address these problems, we have investigated the concept of assisting cavopulmonary flow to support a univentricular circulation, thereby replicating two-ventricle physiology [3]. Low systemic venous pressure is maintained, limiting volume redistribution into the highly compliant systemic venous territory and complications of systemic capillary hypertension, while transpulmonary flow, ventricular preload, and cardiac output are preserved. Each of these factors is suboptimal in unsupported or failing univentricular Fontan circulations [20]. In newborn lambs with an assisted univentricular circulation at 8 hours, we have previously demonstrated that systemic and pulmonary hemodynamics and gas exchange function remain stable, despite modestly increased PVR [4]. In the current protocol, in contrast to the prior study, intravenous fluids (crystalloid, packed red blood cells, and plasma) and inotropic medications (dopamine, dobutamine, and epinephrine) were administered as deemed necessary to optimize cardiac output and systemic perfusion for the intermediate duration of the study [3,4]. Fluid administration was similar between groups as indicated by MCFP. The assisted single-ventricle group, however, required a higher level of inotropic agent administration.

Pulmonary hemodynamics were assessed to evaluate response to mechanically assisted pulmonary blood flow. Both PVR and vascular reactivity normalized to control values, although adaptation was not complete as indicated by persistently elevated pulmonary arterial pressure. The response profile to inhaled NO demonstrates that the increase in pulmonary tone is responsive to medical management. In contrast to a systemic arterial source of pulmonary blood flow, cavopulmonary assist creates conditions (normoxia, pulmonary blood flow to systemic blood flow ratio equal to 1, low-pressure source) that strongly favor normal transitional pulmonary vascular maturation and maintenance of low PVR [17]. Based on these observations, we predict that pulmonary hemodynamics would further normalize under chronic conditions. Therapeutic modification of pulmonary vascular tone would presumably provide additional benefit to overcome early endothelial dysfunction and optimize the pulmonary vasculature to facilitate weaning and eventual discontinuation of cavopulmonary assist during a chronic time period.

Pulmonary vascular reactivity assessment is well documented in clinical and preclinical studies in response to many different types of stimuli, including oxygen, hypoxia, acetylcholine, NO, and U-46619 [11, 12, 18]. As a correlate to the PVR profile during 24 hours, reactivity to hypoxia was highest early as indicated by a significant decrease in absolute change in pulmonary arterial pressure at subsequent intervals. U-46619 was especially sensitive in eliciting between-group differences with time; reactivity was significantly different at 3 and 9 hours but was not significant at 15 and 21 hours.

A chronic animal model of unsupported Fontan physiology has never been produced. This is because of the complex requirement for single-ventricle cardiac anatomy and the interdependent problems of systemic venous hypertension and pulmonary arterial hypotension. Successfully achieving 24-hour stability in this study, while maintaining pulmonary perfusion and low systemic venous pressure, is attributed to use of a device to essentially replicate two-ventricle physiology. Opposed to ventricular support, cavopulmonary assist requires a minimal pressure gradient (5 to 10 mm Hg) to maintain systemic venous perfusion of the pulmonary vascular bed. Rather than temporarily substituting for an impaired ventricle until satisfactory recovery permits withdrawal of the device, cavopulmonary assist is unique in that it acts as a bridge for the transition from an assisted to an unassisted univentricular Fontan circulation in which no power source exists to replace the device. The timing and ideal age for this transition remain to be determined.

There are several theoretical advantages to early establishment of Fontan circulation. Most significantly, inherently unstable Norwood physiology can be avoided by circumventing use of a systemic arterial shunt. The number of operations required to achieve complete palliation may be reduced while the physiologic margin of stability is improved. It is unknown whether neonates may be physiologically predisposed to better tolerate the systemic consequences of a univentricular circulation. In support of this idea, the accepted age for Fontan repair has evolved to relatively young ages and morbidity has declined [21]. Systemic venous pressure is elevated in the fetus from placental umbilical venous flow; thus, the younger patient may be predisposed to better tolerate elevated systemic venous pressure [22, 23]. Furthermore, transcapillary fluid movement and lymphatic flow are higher in the young, which may provide a defense against systemic capillary hypertension and tissue edema formation that is not present in older age groups [24, 25].

This study has several limitations. Small group size (n = 7 for assisted Fontan and n = 11 for control) likely limited the ability to detect between-group differences. Systemic arterial and venous pressures were significantly higher in the assisted Fontan group compared with control animals. This may reflect bias in resuscitation between groups. Despite no difference in MCFP, the difference in systemic venous pressure between groups indicates more aggressive fluid administration to the assisted Fontan group. The modest rise in filling pressures in this model is not overly concerning because the systemic circulation would eventually need to adapt to higher systemic venous pressure to successfully transition to an unsupported univentricular circulation. Additionally, diastolic blood pressure was better preserved in the assisted Fontan group, possibly indicating a bias toward inadequate resuscitation of the control group. This study also did not account for an autonomic response to an empty right atrium and ventricle.

In conclusion, cardiopulmonary stability can be maintained in a model of newborn assisted Fontan circulation for an intermediate time frame in which PVR and reactivity normalize to control values and gas exchange function is preserved. These results support feasibility of assisted Fontan circulation as a bridge to newborn Fontan repair of single-ventricle heart disease. Chronic studies will further assess this strategy and more clearly define the time course of pulmonary and systemic adaptation to Fontan physiology.


   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
Acknowledgments
 References
 
DR MARSHALL L. JACOBS (Philadelphia, PA): I congratulate you on a very, very fine presentation of this most recent study in a series that I guess Dr Rodefeld and associates have worked on over the last couple of years.

I have three questions for you.

In the previous studies—the first I guess was not done in a newborn animal model and then the second one was—one of the issues concerning the data, while the authors asserted hemodynamic stability, is there seemed to be progressively falling hematocrit and substantial volume requirements over the duration of the experimental period. And in those earlier studies, ongoing and progressive lactic acidosis. You indicated that the lactic acidosis was not a problem in this study. And in that regard my question would be what about the volume requirement and falling hematocrit? And if you have somehow circumvented those problems, it would certainly be of interest to know how you modified the model and its management to address those issues.

My second question is really more general. I think it's demonstrated very nicely that you've managed to support the circulation here with right heart bypass and with an impeller pump to drive blood through the pulmonary circulation. And even after the early peak in the pulmonary vascular resistance, you demonstrated very nicely that it came down and stabilized at a level of about 6 Woods units. Six Woods units is sort of at the upper limit of where we would conventionally consider converting to a Fontan circulation even in a more mature individual where issues of reactivity of the pulmonary vasculature would be less applicable. I don't question for a moment that you successfully managed to drive blood through the lungs at this resistance and without the expense of too high a venous pressure, but your conclusion in terms of prospects for future neonatal Fontan surgery must somehow be considered in the context of the likelihood of a successful Fontan with a pulmonary vascular resistance of 6 Woods units.

DR MYERS: To address your first question regarding volume requirements and decreasing hematocrit in our previous studies, resuscitation has been required to maintain stability. What we have shown is that systemic venous pressure has remained within the physiologic range, though at the high end. This is less concerning to us knowing that venous hypertension will be required at the time of conversion to unassisted cavopulmonary blood flow via the Fontan connection.

The etiology of the falling hematocrit is another issue that wasn't addressed with this study. We administered blood through the course of the study to replace blood loss and maintain hematocrit.

DR JACOBS: I guess another way of asking my question in terms of simple data point is how much more did these experimental neonatal animals weigh at the end of the 24-hour support period than at the start of that time? Did they leak and become terribly edematous?

DR MYERS: We did not weigh the animals at the end of the support period. There were some minor signs of edema.

In regard to your second question, that the pulmonary vascular resistance observed is too high, we expect the pulmonary vasculature to continue to mature over the course of the neonatal period and that pulmonary vascular resistance will continue to decrease under conditions of cavopulmonary assist. We would not anticipate converting from assisted to unassisted cavopulmonary flow until we had achieved a lower pulmonary vascular resistance.

DR OLAF REINHARTZ (Stanford, CA): I noticed that you used a centrifugal pump, and I would be interested in knowing what kind of centrifugal pump. In the previous studies of your group, you used the hemopump, an axial flow pump. Why did you switch? And the second question: PVR (pulmonary vascular resistance) in these animals normalized later, but why do you think it initially increased? Was it just reactivity to the tubing, to the foreign material?

DR MYERS: In regard to your first question, we used the A-med Paraflow centrifugal pump. This is the pump we had used in our prior newborn animal study with an 8-hour support duration. We did use an axial flow pump in the initial studies with adult animals, but we switched from the axial flow pumps because they could not produce the lower limit of flow required for pulmonary perfusion in a newborn animal.

In regard to your second question, why we see increased pulmonary vascular resistance, we hypothesize that it is a reaction to the mechanically assisted pump flow in the already reactive pulmonary vasculature of the newborn. We did see that the pulmonary vascular resistance normalized throughout the period of the study.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
References
 
This study was supported by grants from the Riley Children's Foundation (No. 05–01), Indianapolis, Indiana, INO Therapeutics, Inc, Clinton, NJ, and National Institutes of Health grant HL080089.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 

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