Arthur J. Smerling

Randomized, Double-Blind Trial of Inhaled Nitric Oxide in LVAD Recipients With Pulmonary Hypertension

BACKGROUND Pulmonary vascular resistance is often elevated in patients with congestive heart failure, and in those undergoing left ventricular assist device (LVAD) insertion, it may precipitate right ventricular failure and hemodynamic collapse. Because the effectiveness of inotropic and vasodilatory agents is limited by systemic effects, right ventricular assist devices are often required. Inhaled nitric oxide (NO) is an effective, specific pulmonary vasodilator that has been used successfully in the management of pulmonary hypertension. METHODS Eleven of 23 patients undergoing LVAD insertion met criteria for elevated pulmonary vascular resistance on weaning from cardiopulmonary bypass (mean pulmonary artery pressure > 25 mm Hg and LVAD flow rate < 2.5 L x min[-1] x m[-2]) and were randomized to receive either inhaled NO at 20 ppm (n = 6) or nitrogen (n = 5). Patients not manifesting a clinical response after 15 minutes were given the alternative agent. RESULTS Hemodynamics for the group at randomization were as follows: mean arterial pressure, 72 +/- 6 mm Hg; mean pulmonary artery pressure, 32 +/- 4 mm Hg; and LVAD flow, 2.0 +/- 0.3 L x min(-1) x m(-2). Patients receiving inhaled NO exhibited significant reductions in mean pulmonary artery pressure and increases in LVAD flow, whereas none of the patients receiving nitrogen showed hemodynamic improvement. Further, when the nitrogen group was subsequently given inhaled NO, significant hemodynamic improvements ensued. There were no significant changes in mean arterial pressure in either group. CONCLUSIONS Inhaled NO induces significant reductions in mean pulmonary artery pressure and increases in LVAD flow in LVAD recipients with elevated pulmonary vascular resistance. We conclude that inhaled NO is a useful intraoperative adjunct in patients undergoing LVAD insertion in whom pulmonary hypertension limits device filling and output.

Inhaled nitric oxide and gentle ventilation in the treatment of pulmonary hypertension of the newborn: a single-center, 5-year experience

OBJECTIVE: To evaluate the effect of inhaled nitric oxide (INO) in pulmonary hypertension of the newborn (PH) in a single center over 5 years using gentle ventilation (GV), without hyperventilation or induced alkalosis.METHODS: Data from 229 consecutive infants with PH of varied etiology treated with INO and GV, and from 67 infants with meconium aspiration syndrome (MAS) and primary PH (PPHN) treated with GV alone were reviewed over a 5-year period (86% outborn). INO was initiated at 25 ppm when PH and severe hypoxemia persisted despite maximal optimal ventilation. Hyperventilation or systemic alkalosis were not attempted.RESULTS: Mean duration of ventilation was 9.9±14 days (median 6.5 days). Average mean airway pressure (MAP) dropped from 17.7±4.3 cm H2O at the referral hospital to 13.2±2.5 cm H2O (p<0.001) following admission to our unit using conventional settings and GV, before starting INO. Mean oxygenation index (OI) dropped from 46.8±24.5 to 22.7±21.4 within 24 hours of INO therapy (p<0.001). Infants with higher baseline pH and lower baseline OI responded better to INO (p<0.02). Overall survival was 72%. Patients with MAS and PPHN had the best response, 92% survived and there was a 46% reduction in need for extracorporeal membrane oxygenation (ECMO) compared to historical pre-INO period controls (23.9% vs. 12.8%, p<0.01). In the infants treated with GV alone, the MAP dropped from 17.2±4.3 cm H2O at the referral hospital to 12.6±2.4 after GV was started in our unit.CONCLUSIONS: We conclude that INO is an effective and well-tolerated therapy for PH in infants receiving GV.

Heart transplantation in children with markedly elevated pulmonary vascular resistance: Impact of right ventricular failure on outcome

BACKGROUND Pulmonary hypertension causes increased morbidity and mortality in adults after heart transplantation. The effect of markedly elevated pulmonary vascular resistance (PVR) on post-transplant outcomes in children has not been well described. METHODS Outcomes were compared in a retrospective study between 58 children with an elevated PVR index (PVRI) ≥ 6 U/m(2) and 205 children with a PVRI < 6 U/m(2). Patients who did and did not respond to acute vasodilator testing and patients who underwent transplant before (pre-1995) and after (post-1995) the availability of inhaled nitric oxide (iNO) were compared. RESULTS The pre-transplant diagnoses, and cardiopulmonary bypass and donor ischemic times were similar between the high and low PVRI groups. High PVRI patients were older at transplant (12 ± 6.2 vs 8 ± 7.1 years, p = 0.002). The post-transplant inotrope score was higher in the high PVRI group (12 ± 12 vs 2 ± 2, p = 0.0001) and 1-year survival was worse (76% vs 81%, p = 0.03). The PVRI fell to < 6 U/m(2) with acute vasodilator testing in 21 of 49 (42%) high PVRI patients. RV failure occurred in 4 (19%) of the responders and in 14 (50%) of the non-responders (p = 0.037). One responder (5%) and 4 non-responders (14%) died of RV failure. In the period after 1995, the year iNO became clinically available, the select group of high PVRI patients who received iNO preemptively had a lower incidence of post-transplant RV failure than the group that did not receive preemptive iNO (13% vs 54%, p = 0.04). CONCLUSIONS Pre-transplant vasodilator testing identified patients at higher risk for RV failure. Patients who did not respond to vasodilator testing had an increased incidence of RV failure and death from RV failure. Preemptive use of iNO was associated with a decreased incidence of RV failure.

Endogenous nitric oxide and pulmonary vascular tone in the neonate

PURPOSE In newborns, inhaled nitric oxide (NO) has been shown to ameliorate increased pulmonary vascular resistance (PVR) precipitated by hypoxia. The role of endogenous NO production in this response is not clear. The contribution of endogenous NO to resting PVR in normoxic newborns also has not been well studied. The authors used an isolated, in situ, neonatal piglet lung-perfusion model, devoid of systemic detractors in which endogenous NO could be selectively inhibited, to determine whether (1) endogenous NO plays a role in the maintenance of PVR with normoxia, (2) endogenous NO plays a role in the response to hypoxia, and (c) inhaled NO can reverse changes induced by inhibition of endogenous NO. METHODS Sixteen neonatal piglets underwent occlusive tracheostomy and pressure-cycled ventilation. After heparinization and ligation of the ductus arteriosus, left atrial and pulmonary arterial cannulation were performed, without ischemia, via a median sternotomy. The aorta was ligated, and lung perfusion was set at 80 mL/kg/min via an extracorporeal membrane oxygenation circuit. Hematocrit (40% to 45%), pH (7.37 to 7.44), Pco2 (35 to 40 mm Hg), and peak inspiratory pressures (20 mm Hg) were constant. Pulmonary artery pressure (PPA), left atrial pressure (PLA), and circuit flow (QPA) were recorded continuously. PVR calculated as follows: PVR[(dynes x seconds x cm(-5)) x 1,000] = [(PPA-PLA/(QPA x 1,000/60)] x 1,332. The experimental animals were ventilated with normoxic gas (FIO2, 0.21), followed by hypoxic gas (FIO2, 0.07), returned to normoxia, and then divided into two groups of eight animals each. One group remained normoxemic (FIO2, 0.21; SPA02, 100%) while the other group was made hypoxemic by ventilation with hypoxic gas (FIO2, 0.07; SPA02, 50%). Endogenous NO was suppressed with L-arginine-N-omega methyl ester (L-NAME) at 40 mg/kg in both groups. Inhaled NO was given at 40 ppm in both groups. Analysis of variance for repeated measures was used to test for statistical significance. RESULTS Baseline normoxic PVR (3,403 +/- 1,169) was increased significantly by hypoxia (6,524 +/- 1,018, P < .01) and was fully resorted to baseline by normoxia (3,497 +/- 1,079; P = NS). In normoxic animals, inhibition of endogenous NO production by L-NAME increased PVR to levels similar to those seen during hypoxic stress (6,345 +/- 1,441, P < .01). Replacement of endogenous NO by inhaled NO reversed PVR to normoxic baseline values (3,986 +/- 1,363, P = NS). In hypoxic animals, inhibition of endogenous NO production by L-NAME also increased PVR from hypoxic baseline (9,655 +/- 1,642, P < .01). Replacement of endogenous NO by inhaled NO reversed PVR to hypoxic baseline (6,450 +/- 1,796, P = NS). CONCLUSION In this piglet model, endogenous NO is important in the regulation of pulmonary vascular tone during both normoxia and hypoxia. Inhaled NO completely reversed the elevations in PVR caused by inhibition of endogenous NO and may normalize PVR in diseases in which the production of endogenous NO is compromised.

Inhaled nitric oxide is not a negative inotropic agent in a porcine model of pulmonary hypertension

BACKGROUND Reports of pulmonary edema complicating inhaled nitric oxide therapy in patients with chronic heart failure and pulmonary hypertension have raised the concern that inhaled nitric oxide may have negative inotropic effects. METHODS AND RESULTS We investigated the effect of multiple doses of inhaled nitric oxide (20, 40 and 80 ppm) on left ventricular contractile state in 10 open-chest pigs. Pressure-volume loops were generated during transient preload reduction to determine the end-systolic pressure-volume relationship and the stroke work-end-diastolic volume relation. Inhaled nitric oxide had no effect on systemic vascular resistance, cardiac output, end-systolic pressure volume relationship or stroke work-end-diastolic volume relation under normal conditions. After induction of pulmonary hypertension (intravenous thromboxane A2 analog), inhalation of nitric oxide (80 ppm) resulted in a reduction in pulmonary vascular resistance (mean +/- standard error of the mean) from 10.4 +/- 3 to 6.5 +/- 2 Wood units (p < 0.001) and in pulmonary artery pressure from 44 +/- 4 to 33 +/- 4 mm Hg (p < 0.05). Left ventricular end-diastolic volume rose from 53 +/- 9 ml to 57 +/- 10 ml (p = 0.02). No statistically significant change in cardiac output or systemic vascular resistance was observed. Inhaled nitric oxide had no effect on end-systolic pressure-volume relationship or stroke work-end-diastolic volume relation. CONCLUSIONS In a porcine model of pulmonary hypertension, inhaled nitric oxide does not impair left ventricular contractile function. Therefore the cause of pulmonary edema observed in some patients receiving inhaled nitric oxide is not due to a negative inotropic action of this therapy.

Nitric oxide treatment for pulmonary hypertension after neonatal cardiac operation

This report describes a newborn with transposition of the great arteries who underwent a Blalock-Taussig shunt with transient improvement in oxygenation, but required emergent insertion of a central shunt later the same day due to progressive hypoxia and cardiac arrest. Two hours after central shunt insertion, sudden episodes of hypoxia and hypotension developed that were resistant to all pharmacologic therapy. Inhaled nitric oxide (25 ppm) was then administered with dramatic improvement in oxygenation and hemodynamics within minutes. The patients condition stabilized after these measures, and nitric oxide therapy was discontinued after 2 days.

Differential effects of inhaled nitric oxide on normoxic and hypoxic isolated in situ neonatal pig lungs perfused by extracorporeal membrane oxygenation

Inhaled nitric oxide (NO) is effective as a selective pulmonary vasodilator, but its effects on uninjured lungs subjected to normoxia and hypoxia have not been fully studied. The authors sought the response of pulmonary vascular resistance (PVR) to inhaled NO in piglet lungs devoid of ischemic injury in a model of reversible pulmonary hypertension. If the changes were dose-responsive, the authors asked whether the PVR changes were related to normoxia or hypoxia, and hypothesized that the change would be more pronounced for hypoxia than normoxia. In situ isolated piglet lungs were prepared by occlusive tracheostomy and ligation of the ductus arteriosus and aorta. Cannulae positioned in the left atrium and pulmonary artery were connected to a standard extracorporeal membrane oxygenation (ECMO) circuit, and flow was increased to approximate cardiac output. After stabilization, piglets (aged 5 to 14 days, weighing 3.2 to 6.4 kg) were divided into two groups of four each: normoxic (FIO2 0.30, normal PVR) and hypoxic (FIO2 0.07, increased PVR). NO was administered at 10 to 80 parts per million (ppm) in increments of 10 ppm, for 5 minutes at each concentration, with a return to baseline before each new dose. Flow, pulmonary arterial (PA) and left atrial (LA) pressures were continuously monitored, from which PVR was calculated (PVR = [PPA - PLA]/flow) and expressed as log delta PVR. Data were analyzed statistically by repeated measures of analysis of variance, comparing log delta PVR to baseline at each dose of NO, and comparing log delta PVR for normoxic and hypoxic lungs at each dose of NO.(ABSTRACT TRUNCATED AT 250 WORDS)