Ann Thorac Surg 2006;81:257-263
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Neonatal Cavopulmonary Assist: Pulsatile Versus Steady-Flow Pulmonary Perfusion
Cynthia D. Myers, MD
a
,
Jack H. Boyd, MD
a
,
Robert G. Presson, Jr, MD
b
,
Palaniswamy Vijay, PhD
a
,
Aaron C. Coats, BS
a
,
John W. Brown, MD
a
,
Mark D. Rodefeld, MD
a
,
*
a Department of Surgery, Section of Cardiothoracic 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
Accepted for publication July 5, 2005.
* Address correspondence to Dr Rodefeld, Section of Cardiothoracic Surgery, Indiana University School of Medicine, Emerson Hall 215, 545 Barnhill Dr, Indianapolis, IN 46202 (Email: rodefeld{at}iupui.edu).
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Abstract
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BACKGROUND: Morbidity and mortality associated with single-ventricle physiology decrease substantially once a systemic venous, rather than systemic arterial, source of pulmonary blood flow is established. Cavopulmonary assist has potential to eliminate critical dependence on the problematic systemic-to-pulmonary shunt as a source of pulmonary blood flow in neonates. We have previously demonstrated feasibility of neonatal cavopulmonary assist under steady-flow conditions. We hypothesized that pulsatile pulmonary perfusion would further improve pulmonary hemodynamics.
METHODS: Lambs (weight 7.2 ± 1.1 kg, age 7.9 ± 1.5 days) underwent total cavopulmonary diversion using bicaval venous-to-main pulmonary artery cannulation. A miniature centrifugal pump was used to augment cavopulmonary flow. Pulsatility was created with an intermittently compressed compliance chamber in the circuit. Hemodynamic and gas exchange data were measured for 8 hours. Pulsatile (n = 6), steady-flow (n = 13), and control (n = 6) groups were compared using two-way analysis of variance with repeated measures.
RESULTS: All animals remained physiologically stable with normal gas exchange function. Mean pulmonary arterial pressure was elevated in pulsatile and steady-flow groups compared with the control group and within-group baseline values. Pulmonary vascular resistance was elevated initially in both assist groups but decreased significantly over the last 4 hours of the study and normalized after hour 4 in the pulsatile perfusion group. Pulmonary vascular resistance also normalized to control in the steady-flow group after hour 7.
CONCLUSIONS: Both steady-flow and pulsatile pulmonary perfusion demonstrated normalization of pulmonary vascular resistance to control in a neonatal model of univentricular Fontan circulation. These results suggest that there is no benefit to pulsatile flow in this model.
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Introduction
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For 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 owing to 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 (HLHS) 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 an implantable axial flow pump or paracardiac centrifugal pump under steady-flow conditions [3, 4].
In a univentricular circulation, the conversion of pulmonary perfusion from a systemic arterial to a systemic venous source shifts pulmonary blood flow from a pulsatile to a steady-flow pattern. Previous studies have documented lower pulmonary vascular resistance in lung preparations perfused by pulsatile versus steady flow [5–8], possibly mediated by several different mechanisms including endothelial-dependent nitric oxide (NO) release [9, 10]. We sought to examine the relative role that pulsatile pulmonary perfusion plays on pulmonary hemodynamics and NO release during cavopulmonary assist in the newborn lung. We hypothesized that pulsatile, in contrast to steady-flow perfusion, would yield pulmonary hemodynamics that more closely approximate the normal neonatal two-ventricle circulation and thus favor conditions for normal reduction of PVR after birth.
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Material and Methods
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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 1.0 and 0.7% to 1.5% isoflurane. Ventilation was maintained at 32 to 38 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 PaCO2 of 30 to 35 mm Hg. Normothermia was maintained at 38.5°C. A femoral arterial line (Intracath 16G; Becton Dickinson, Sandy, UT) was placed for systemic blood pressure monitoring. A femoral venous line (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 lines (Intracath) were placed in the left atrial appendage, distal main pulmonary artery, and proximal superior vena cava. An ultrasonic flowprobe (model 12A; Transonic Systems, 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 lactate values, and serum for NO concentration analysis were also obtained. Mean circulatory filling pressure, a measure of stressed systemic volume status, was measured by recording inferior vena caval pressure after 7 seconds of induced ventricular fibrillation [11]. Animals were then systemically administered heparin (sodium heparin, 150 units/kg).
Group I: Control
For group I, control (n = 6, age 7.3 ± 0.5 days, weight 6.9 ± 1.4 kg), median sternotomy and placement of intracardiac pressure lines was performed as in the other groups. A pursestring suture was placed in the right atrial appendage and a decompression cannula (Left heart vent catheter, 13F; Medtronic, Minneapolis, MN) was introduced through the right atrium into the right ventricle as a sham procedure to provide cardiac stimulation equivalent to cavopulmonary assist conditions. The cannula was occluded to prevent outflow.
Group II: Steady-Flow Cavopulmonary Assist
For group II (n = 13, age 6.8 ± 4.0 days, weight 5.6 ± 1.5 kg), pursestring sutures were placed in the superior vena cava, inferior vena cava, proximal main pulmonary artery, and right atrial appendage. A decompression cannula was introduced through the right atrial appendage into the right ventricle for egress of thebesian and coronary venous blood. Bicaval venous and pulmonary arterial cannulation was performed, as previously described [4]. The cannulas were connected to a miniature centrifugal pump (Paraflow; A-Med Systems, West Sacramento, CA) and the circuit was primed (volume 45 mL). The pump was activated and flow was gradually increased over several minutes, titrating pump output to match baseline cardiac output. Caval occlusion tourniquets were tightened to produce inflow occlusion to the right heart, and a vascular clamp was placed across the proximal main pulmonary artery to prohibit right ventricular contribution to pulmonary blood flow.
Group III: Pulsatile Cavopulmonary Assist
For group III (n = 6, age 8.3 ± 1.9 days, weight 7.6 ± 0.7 kg), pulsatile flow was created by the addition of a compliant silicone reservoir (R-38 ECMO Assist Reservoir [35 mL priming volume]; Medtronic) to the circuit beyond the pump outflow (Fig 1). Pulsatility, as measured by the pulmonary arterial catheter, was generated by rapid intermittent compression of the reservoir, and was adjustable for both rate and pulse pressure by altering the rate and extent of compression. Pulsatility was initiated within 5 minutes after establishing cavopulmonary assist, and was maintained continuously throughout the data collection period. Pulse pressure and pulsatility rate were set to match baseline pulmonary arterial pulse pressure and hourly assessed heart rate (±5%, nonphasic to systemic pressure waveform). Pump output was titrated to match baseline cardiac output. For pulsatile flow, higher pump revolutions per minute were required to generate flow equivalent to steady-flow conditions owing to increased circuit impedence.
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Fig 1. Experimental preparation. Intermittent mechanical pulsation of a silicone compliance reservoir (arrows) resulted in transmission of a pulsatile pressure waveform to the pulmonary artery. Inset: representative digitized pulmonary arterial waveforms (I = control, normal pulmonary arterial waveform; II = steady-flow cavopulmonary assist; III = pulsatile cavopulmonary assist).
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Postintervention Management
Measurable surgical blood loss was replaced 1:1 with fresh heparinized adult sheep homologous whole blood. Maintenance intravenous fluids were administered to account for surgical trauma and insensible loss. Additional fluids were administered if inferior vena caval pressure decreased to a value less than baseline or if reduced venous drainage was apparent by a reduction in pump flow rate without a change in pump speed. Inotropic support and bicarbonate therapy were not utilized. Activated clotting time was maintained greater than 1.5 times baseline. A surface electrocardiogram and systemic arterial waveform were continuously monitored (HP7354C physiologic monitor; Hewlett-Packard, Palo Alto, CA). Hemoglobin was measured with an OSM3 hemoximeter (Radiometer, Westlake, OH) calibrated for measurement of sheep hemoglobin. Arterial blood gases, corrected for hemoglobin level, were measured using an ABL 500 blood gas analyzer (Radiometer). Arterial lactate values were measured using a YSI 2300 Stat Plus glucose and lactate analyzer (YSI, Yellow Springs, OH). Hemodynamic data and arterial blood gases were measured at hourly intervals for 8 hours after initiation of cavopulmonary assist. Serum was collected hourly for NO concentration analysis. Postintervention mean circulatory filling pressure was measured at 8 hours.
Plasma Nitric Oxide Concentration
Nitric oxide was measured as product of nitrate metabolites, nitrate (NO3
–) and nitrite (NO2
–). Arterial blood samples were centrifuged (4,000g x 20 min). Plasma was immediately frozen at –70C until assays were performed. The plasma was diluted 1:1 in reaction buffer, ultrafiltrated through a 10,000 MWCO filter, and incubated with nitrate reductase converting nitrates into nitrites. Griess reagent was used to form a purple azo derivative, which was quantified by absorbance at 548 nm.
Statistical Analysis
Results are reported as mean ± SD. All pairwise comparisons within and between control, steady-flow, and pulsatile groups, including time factor for all hourly time points from baseline to 8 hours, were performed by two-way analysis of variance (ANOVA) with correction for repeated measures using the Holm-Sidak post-hoc test. Significance was defined as p < 0.05. Data for time points baseline, 1 hour, and 8 hours are presented in Table 1. 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 "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 85-23, revised 1985).
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Results
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Systemic Hemodynamics
At baseline, relatively minor differences in hemodynamic variables were observed between groups (Table 1). A decrease in diastolic blood pressure occurred to a similar degree in all three groups over the entirety of the study; however, a more abrupt decrease was observed in the first postintervention hour in the pump-assist groups (II and III; Fig 2). Systemic venous pressure and mean circulatory filling pressure increased significantly over 8 hours in the pump-assist groups (II and III). This is secondary to a slightly higher volume requirement in both pump-assist groups. Systemic venous pressures did not exceed normal physiologic levels in any group nor did they approach levels characteristic of univentricular Fontan circulation.
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Fig 2. Systemic blood pressure. Systolic and diastolic blood pressures are shown. Time 0 indicates initiation of cavopulmonary assist (B = baseline). Error bars represent SE. *Significant difference from time 0 for both pulsatile group (diamonds) and steady-flow group (squares [p  0.002]). (Triangles = control; h = hour.)
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Pulmonary Hemodynamics
Pulmonary arterial pressure increased early in both pump-assist groups and remained significantly elevated throughout the data collection period (Fig 3). The increase was modest, however. After 8 hours, mean pulmonary arterial pressure was 23.3 mm Hg and 21.7 mm Hg in the steady-flow and pulsatile groups, respectively, compared with 16.7 mm Hg in the control group (Table 1). Importantly, increases in pulmonary arterial pressure did not exceed one-half systemic pressure or compromise pump-assisted flow. Consequently, preload to the systemic ventricle was maintained and cardiac output was preserved. By two-way ANOVA, mean pulmonary arterial pressure was the only parameter to show a significant group effect for time (p = 0.013).
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Fig 3. Mean pulmonary arterial pressure. Time 0 indicates initiation of cavopulmonary assist (B = baseline). Error bars represent SE. (Triangles = control; diamonds = pulsatile; squares = steady flow; h = hour.)
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In control animals, a steady but nonsignificant increase in PVR was observed over the duration of the study, likely in response to anesthetic, surgical trauma, and mechanical ventilation. Interestingly, the response of PVR to cavopulmonary assist in both experimental groups was characterized by an initial rapid elevation immediately upon initiation of pump flow (time 0), followed by a decrease at hour 1, then a second more gradual and sustained increase over hours 2 to 3 (Fig 4). This bimodal response was consistently observed in both pump-assist groups. Subsequently, the assist groups had a consistent decrease in PVR beginning at hour 4. Pulmonary vascular resistance in the pulsatile group was not significantly different from control or baseline after hour 4. Pulmonary vascular resistance in the steady-flow group remained significantly elevated from its baseline throughout the entire study and from control values through hour 7. No between-group differences were seen at any time point between the pulsatile and steady flow groups.
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Fig 4. Pulmonary vascular resistance (PVR) calculated as (PPA– PLA)80/systemic blood flow (calculated as cardiac output/weight, and expressed as mL·min–1·kg–1) and expressed as 103dyn·s·cm–5·kg. Time 0 indicates initiation of cavopulmonary assist. Error bars represent SE. Steady-flow PVR values (squares) remained significantly elevated from baseline (B) values throughout all time points. Pulsatile flow PVR values (diamonds) were not significantly different from baseline or control values (triangles) after hour 4. (h = hour.)
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Gas Exchange Function
Pulmonary gas exchange function remained comparably excellent in all groups throughout the postintervention period (Table 2). Ventilator adjustments did not deviate more than 10% from baseline settings, and peak airway pressures remained less than 25 cmH20. Neither pulmonary edema nor hemorrhage was observed and airway secretions were negligible. Arterial pH remained within the normal range or became slightly alkalotic secondary to moderate hypocapnia. High partial pressures of oxygen were maintained to highlight that this would not acutely compromise hemodynamic stability, a concern encountered in classic stage I Norwood physiology.
Plasma NO Concentration
Plasma NO concentration decreased with time after hour 1 in all three groups (Fig 5). Overall, NO levels were highest under steady-flow conditions, with significance in comparison to control seen at hours 1 and 4. Under pulsatile conditions, NO concentration closely paralleled control levels and was never significantly different.
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Fig 5. Nitric oxide concentrations represented as ratio to baseline values. Cavopulmonary assist was initiated at time 0. Error bars represent SE. *Significant difference between steady-flow (squares) and control (triangles) concentrations. Nitric oxide levels were highest under steady-flow conditions, with significance in comparison with control seen at hours 1 and 4. (Diamonds = pulsatile; h = hour.)
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Comment
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For neonatal palliation of single-ventricle cardiac anomalies, a substantive source of pulmonary blood flow (systemic arterial shunt) is required in order to overcome potentially elevated PVR. After the risk for pulmonary vascular reactivity has subsided, the source of pulmonary blood flow can be safely transferred to a systemic venous source with takedown of the shunt and creation of a cavopulmonary connection. Systemic-to-pulmonary arterial shunts, however, induce pathophysiologic conditions which diametrically oppose maintenance of low PVR and normal maturation of the newborn transitional pulmonary circulation. Paradoxically, these are the very conditions that shunts are intended to overcome. Long-term, the elevated PVR observed late in univentricular Fontan patients may be in part a reflection of their initial staging operations in which a systemic arterial source of pulmonary blood flow was utilized [12]. Placement of systemic arterial shunts is associated with 10% mortality, excluding patients with HLHS, who are at even higher risk [13]. Despite refinement in technique and management, hospital and interim mortality rates for stage I palliation of HLHS remain high [13,14]. In contrast, morbidity and mortality decrease dramatically after conversion to a systemic venous source of pulmonary blood flow [15, 16], suggesting that poor outcomes are linked to the systemic arterial shunt. The recently described right ventricle-to-pulmonary artery shunt improves diastolic coronary perfusion in these patients, but it does not correct the problems of parallel circulations, hypoxemia, or volume overload to the single ventricle, and requires a ventriculotomy [2].
To address these problems, we have investigated the concept of assisting cavopulmonary flow whereby a univentricular circulation is supported with a temporary pulmonary ventricle, replicating two-ventricle physiology [3]. Maintenance of low systemic venous pressure limits systemic venous volume redistribution and its complications, while transpulmonary flow, ventricular preload, and cardiac output are preserved; each of these factors is suboptimal in unsupported or failing univentricular Fontan circulations [17, 18]. In newborn lambs with an assisted univentricular circulation, pulmonary hemodynamics and gas exchange function remain stable, despite modestly increased PVR [4].
Limited data in newborn animals suggest that pulsatility may be beneficial for neonatal pulmonary blood flow [5]. Although a trend toward benefit of pulsatility was observed at certain time points, the statistical findings of this study show no difference in pulmonary hemodynamics between pulsatile and steady-flow conditions. The response of the pulmonary vasculature to cavopulmonary assist was biphasic; initial reactivity followed by normalization to control levels (Fig 4). Reactivity in response to pump perfusion is not unexpected in the neonatal lung. The bimodal reactivity profile was consistently observed; it is unclear whether single or multiple mechanisms are responsible. Importantly, the initial sharp increase in PVR emphasizes the relaxed basal tone of the newborn pulmonary vasculature. In 1-week-old lambs, despite persistence of fetal levels of smooth muscle in the resistance arterioles [19], mean pulmonary arterial pressure was only 13 mm Hg at baseline conditions, equivalent to normal adult pulmonary arterial pressure.
Two key mechanisms have been proposed to account for decreased PVR in pulsatile versus steady-flow lung perfusion conditions: endothelial-mediated vasorelaxation [12, 20], and a direct mechanical effect producing vascular recruitment or increased effective vessel luminal diameter, or both [5, 7, 21]. A clinical study of Glenn cavopulmonary shunts with accessory pulsatile flow derived from a right ventricular source demonstrated decreased pulmonary endothelial-mediated vasorelaxation in relation to decreasing pulsatility [20]. Pulmonary endothelial dysfunction has been demonstrated in a clinical series of single-ventricle patients without pulsatile pulmonary blood flow as evidenced by a fall in PVR in response to exogenous NO [12]. Capillary recruitment in response to pulsatile flow has been directly observed using videomicroscopy in mature dogs [21]. A study in neonatal lambs indirectly suggested that increased pulmonary vascular recruitment is responsible for improved pulmonary hemodynamics with pulsatile flow [5]. We did not observe a significant difference in pulmonary arterial pressure between flow groups (Fig 3). That argues against predominance of a recruitment effect. In the neonatal lung, pulmonary capillary recruitment may be nearly maximal regardless of flow conditions [22].
Several issues inherent to our model may have attenuated the effect seen with pulsatile flow. First, a nonphysiologic, blunted pulmonary arterial pulse waveform was utilized, which may have decreased potential vascular recruitment (Fig 1). The energy equivalent pressure of the experimental pulmonary arterial waveform pattern was not calculated to objectively quantify pulsatile flow, but is predictably less than that seen with true physiologic waveforms [23]. Second, initial pump flow in both experimental groups was steady. Although pulsatility was quickly initiated, the brief period of steady-flow may have further intensified pulmonary vasoreactivity. Third, the difference between pulsatile and steady-flow perfusion may have been limited by hyperoxic conditions [24]. Absent these limitations, it is possible that a difference may have been observed between experimental groups.
Comparison with the control group differentiated the systemic hemodynamic sequelae of pump-assisted cavopulmonary flow versus inhaled anesthetic, especially with respect to diastolic blood pressure. Diastolic blood pressure is an important consideration because one of the postulated benefits of cavopulmonary assist is preservation of normal coronary perfusion by avoiding the diastolic run-off associated with a systemic-to-pulmonary shunt. Without a clear anatomic cause, the decline in diastolic blood pressure had previously been a concern in this model [4]. A similar decrease in diastolic blood pressure was observed in all three groups (Fig 2), and therefore the anesthetic regimen appears to be responsible for much of the decrease in systemic blood pressure. However, the abrupt decline in diastolic blood pressure unique to the pump-assist groups (II and III) in the first hour of pulmonary perfusion cannot be attributed to anesthetic. We speculate that this decrease in systemic vascular resistance may have been mediated by a humoral inflammatory response to the extracorporeal circuit.
Nitric oxide has been shown to be a key modulator of pulmonary vasomotor tone during the transition to extrauterine life [25]. Furthermore, shear stress in neonates increases pulmonary endothelial NO release [26]. Our results suggest that NO alone is not enough to produce the observed changes in pulmonary hemodynamics with time and indicate that other variables influence vascular tone. We observed a trend toward decreasing NO release over the last half of the study in all three groups (Fig 5), and speculate that this is the result of anesthetic and surgical manipulation producing systemic and pulmonary endothelial dysfunction or reduction in perfused surface area, or both. Interestingly, NO release was highest under steady-flow conditions. Despite higher NO levels, this group had the highest PVR. Furthermore, NO levels did not parallel changes in PVR and recover to baseline values, suggesting that other factors, such as additional endothelial mediators or mechanical effects, may contribute proportionately more to the observed changes in vascular tone.
In summary, normalization of PVR and preserved gas exchange function support both pulsatile and steady-flow cavopulmonary assist as potential therapeutic modalities in the neonate. These findings further suggest that lack of pulsatility is not detrimental to pulmonary hemodynamics in an assisted neonatal cavopulmonary circulation. Chronic studies to evaluate gas exchange function, pulmonary hemodynamics, and maturation of the newborn transitional pulmonary vasculature in response to cavopulmonary assist over a longer period are warranted.
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Acknowledgments
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This study was supported by a grant from the Riley Children's Foundation, Indianapolis, Indiana.
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References
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Abstract
Introduction
