Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. The I-NO/PPHN Study Group.

OBJECTIVES: To assess the dose-related effects of inhaled nitric oxide (I-NO) as a specific adjunct to early conventional therapy for term infants with persistent pulmonary hypertension (PPHN), with regard to neonatal outcome, oxygenation, and safety. METHODS: Randomized, placebo-controlled, double-masked, dose-response, clinical trial at 25 tertiary centers from April 1994 to June 1996. The primary endpoint was the PPHN Major Sequelae Index ([MSI], including the incidence of death, extracorporeal membrane oxygenation (ECMO), neurologic injury, or bronchopulmonary dysplasia [BPD]). Patients required a fraction of inspired oxygen [FIO2] of 1.0, a mean airway pressure >/=10 cm H2O on a conventional ventilator, and echocardiographic evidence of PPHN. Exogenous surfactant, concomitant high-frequency ventilation, and lung hypoplasia were exclusion factors. Control (0 ppm) or nitric oxide (NO) (5, 20, or 80 ppm) treatments were administered until success or failure criteria were met. Due to slowing recruitment, the trial was stopped at N = 155 (320 planned). RESULTS: The baseline oxygenation index (OI) was 24 +/- 9 at 25 +/- 17 hours old (mean +/- SD). Efficacy results were similar among NO doses. By 30 minutes (no ventilator changes) the PaO2 for only the NO groups increased significantly from 64 +/- 39 to 109 +/- 78 Torr (pooled) and systemic arterial pressure remained unchanged. The baseline adjusted time-weighted OI was also significantly reduced in the NO groups (-5 +/- 8) for the first 24 hours of treatment. The MSI rate was 59% for the control and 50% for the NO doses (P = .36). The ECMO rate was 34% for control and 22% for the NO doses (P = .12). Elevated methemoglobin (>7%) and nitrogen dioxide (NO2) (>3 ppm) were observed only in the 80 ppm NO group, otherwise no adverse events could be attributed to I-NO, including BPD. CONCLUSION: For term infants with PPHN, early I-NO as the sole adjunct to conventional management produced an acute and sustained improvement in oxygenation for 24 hours without short-term side effects (5 and 20 ppm doses), and the suggestion that ECMO use may be reduced.

Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn.

OBJECTIVE: Because of case reports describing hypoxemia on withdrawal of inhaled nitric oxide (I-NO), we prospectively examined this safety issue in newborns with persistent pulmonary hypertension who were classified as treatment successes or failures during a course of I-NO therapy. METHODS: Randomized, placebo-controlled, double-masked, dose-response clinical trial at 25 tertiary centers from April 1994 to June 1996. Change in oxygenation and outcome (death and/or extracorporeal membrane oxygenation) during or immediately after withdrawing I-NO were the principal endpoints. Patients (n = 155) were term infants, <3 days old at study entry with echocardiographic evidence of persistent pulmonary hypertension of the newborn. Exclusion criteria included previous surfactant treatment, high-frequency ventilation, or lung hypoplasia. Withdrawal from treatment gas (0, 5, 20, or 80 ppm) started once treatment success or failure criteria were met. Withdrawal of treatment gas occurred at 20% decrements at <4 hours between steps. RESULTS: The patient profile was similar for placebo and I-NO groups. Treatment started at an oxygenation index (OI) of 25 +/- 10 (mean +/- SD) at 26 +/- 18 hours after birth. For infants classified as treatment successes (mean duration of therapy = 88 hours, OI <10), decreases in the arterial partial pressure of oxygen (PaO(2)) were observed only at the final step of withdrawal. On cessation from 1, 4, and 16 ppm, patients receiving I-NO demonstrated a dose-related reduction in PaO(2) (-11 +/- 23, -28 +/- 24, and -50 +/- 48 mm Hg, respectively). For infants classified as treatment failures (mean duration of therapy = 10 hours), no change in OI occurred for the placebo group (-13 +/- 36%, OI of 31 +/- 11 after the withdrawal process); however a 42 +/- 101% increase in OI to 46 +/- 21 occurred for the pooled nitric oxide doses. One death was possibly related to withdrawal of I-NO. CONCLUSION: For infants classified as treatment successes, a dose response between the I-NO dose and decrease in PaO(2) after discontinuing I-NO was found. A reduction in I-NO to 1 ppm before discontinuation of the drug seems to minimize the decrease in PaO(2) seen. For infants failing treatment, discontinuation of I-NO could pose a life-threatening reduction in oxygenation should extracorporeal membrane oxygenation not be readily available or I-NO cannot be continued on transport.

Group B Streptococcus-induced acidosis in newborn swine: regional oxygen transport and lactate flux.

To investigate the mechanism of metabolic acidosis resulting from group B streptococcal sepsis, oxygen metabolism and lactate flux of the cerebrum, hindlimb, liver, splanchnic organs, and systemic vascular bed as a whole were examined. Nine 3- to 5-day-old awake and spontaneously breathing piglets were studied before and after 3, 4, and 5 h of continuous live group B Streptococcus infusion. After 5 h, oxygen delivery was decreased to all organs and to the whole systemic vascular bed. Increased oxygen extraction compensated for reduced oxygen delivery in the liver and splanchnic organs; however, it only partially offset reduced oxygen delivery to the hindlimb and systemic vascular bed. Cerebral oxygen extraction did not increase. As a result, oxygen uptake was reduced in the cerebrum, hindlimb, and systemic vascular bed. At 5 h of bacterial infusion, arterial lactate concentration was increased with regional lactate efflux from the cerebrum and hindlimb and influx to the liver (P less than 0.05 vs. zero or no net flux). We conclude that group B Streptococcus-induced metabolic acidosis is associated with regional lactate efflux from vascular beds in which oxygen uptake is reduced. We speculate that the quantity of net lactate efflux from vascular beds with insufficient oxygen uptake exceeds the net influx into organs such as the liver, resulting in metabolic acidosis.

Effects of hypercarbia on autoregulation of brain blood flow and cerebral metabolism in newborn piglets.

We tested the hypothesis that, in newborn piglets, hypercarbia impairs autoregulation of total and regional brain blood flow at the lower limb of the autoregulatory curve. Cerebral oxygen metabolism was measured in the same piglets to relate changes in metabolism to blood flow. Instrumented hypercarbic (n = 9) and normocarbic (n = 8) newborn piglets exposed to phlebotomy were studied during normotension and graded hypotension with mean arterial blood pressures of 55-41, 40-31 and < 30 mmHg. In the hypercarbic piglets, total brain blood flow decreased (P < 0.01) from the hypercarbic-normotensive value of 187 +/- 15 mliter min-1 100 g-1 to 139 +/- 18, 66 +/- 11 and 34 +/- 6 at mean arterial blood pressures of 55-41, 40-31 and < 30 mmHg, respectively; in the normocarbic piglets, total brain blood flow did not change from the normotensive value (70 +/- 11 mliter min-1 100 g-1) until the mean arterial blood pressure was < 30 mmHg, when brain blood flow had decreased (P < 0.01) to 49 +/- 8 mliter min-1 100 g-1. In the hypercarbic piglets, all brain regions (cerebrum, caudate nucleus, cerebellum, brainstem and medulla) demonstrated similar response patterns to that of total brain blood flow during hypotension. Thus, during hypercarbia, none of the brain regions demonstrated autoregulation. In the normocarbic piglets, cerebral blood flow decreased (P < 0.01) from the normocarbic-normotensive value of 74 +/- 6 mloter min-1 100 g-1 to 51 +/- 8 and 37 +/- 7 at mean arterial blood pressures of 40-31 and < 30 mmHg, respectively, and blood flow to the caudate nucleus, cerebellum and brainstem did not decrease significantly, and in fact increased (P < 0.01) to the medulla during hypotension. Although cerebral oxygen metabolism was compromised in the hypercarbic and normocarbic piglets, the relationship between metabolism and blood flow was altered such that the cerebral metabolic rate of oxygen per unit of blood flow was lower in the hypercarbic than the normocarbic piglets. We conclude that hypercarbia impairs total and regional brain blood flow autoregulation in newborn piglets.

Association of patent ductus arteriosus and phototherapy in infants weighing less than 1000 grams.

To determine the relationship of phototherapy and patent ductus arteriosus, we analyzed prospectively collected data on 295 infants with birth weight of 501 to 999 gm admitted from 1984 through 1988. Seventy-four percent were evaluated by an imaging study to aid in the detection of a silent patent ductus arteriosus. Overall incidence of patent ductus arteriosus in the study population was 63%. Infants who received phototherapy (n = 128) had an increased incidence of patent ductus arteriosus compared with those who did not receive phototherapy (76% vs 53%). There was an association of patent ductus arteriosus and phototherapy (p < 0.05) when we analyzed the data with a stepwise regression model that controlled for the effects of gestational age, birth weight, gender, race, diagnosis of hyaline membrane disease, mechanical ventilation, patent ductus arteriosus imaging studies, prophylactic indomethacin, peak total and indirect bilirubin values, and the occurrence of abnormal serum sodium values. We conclude that the use of phototherapy is associated with an increased incidence of patent ductus arteriosus in extremely low birth weight infants.

Thromboxane and pulmonary morphometry in the development of the pulmonary hypertensive response to group B streptococcus.

OBJECTIVE: To clarify the mechanism of the development of a severe pulmonary hypertensive response to group B streptococcus. DESIGN: Prospective, randomized controlled trial. SUBJECTS: Twelve chronically instrumented and six age-matched uninstrumented newborn piglets. INTERVENTIONS: Six animals received eight injections of group B streptococcus over an 11-day period (control group). Six additional animals (pretreatment group) were given 3 mg/kg of dazmegrel, a thromboxane synthase blocking agent, before each dose of group B streptococcus to prevent the pulmonary hypertensive response and to control for any secondary arterial remodeling. MEASUREMENTS AND MAIN RESULTS: Hemodynamic measurements, pulmonary arterial morphometry, and thromboxane concentrations were examined in the instrumented animals. Lungs from the uninstrumented piglets were examined to determine morphometric norms for this population. The animals given only group B streptococcus developed a significant pulmonary hypertensive response after five daily doses (+6.8 +/- 2.0 [SEM] mm Hg, p < .05) which became pronounced after eight doses (+13.2 +/- 1.0 mm Hg). Pulmonary hypertension was not observed in the pretreatment group when dazmegrel was given; however, on the final day in this group, dazmegrel was withheld before group B streptococcus dosing and a significant pulmonary hypertensive response was observed (+20 +/- 1.6 mm Hg). The medial thickness of pulmonary arteries was not different between the two groups nor when compared with that of six normal, uninstrumented animals. Plasma thromboxane B2 concentrations were determined from blood samples taken before and after group B streptococcus infusion at the first, seventh and eighth (final) dosing. Thromboxane concentrations increased significantly on days 7 and 8 in the control group (578 +/- 312 to 752 +/- 372 pg/mL, 638 +/- 201 to 1462 +/- 295 pg/mL, respectively) and on day 8 in the pretreatment group (545 +/- 160 to 705 +/- 187 pg/mL). CONCLUSIONS: We conclude that the development of potentiated pulmonary hypertension is not due to pulmonary arterial remodeling, but is associated with increased thromboxane production.

The role of nitric oxide in the treatment of neonatal pulmonary hypertension.

Nitric oxide production appears to be decreased in infants with persistent pulmonary hypertension (PPHN). Inhaled nitric oxide may improve oxygenation by two mechanisms: increased pulmonary blood flow and improved ventilation-perfusion matching. Nitric oxide inhalation has been tested in newborns with PPHN, congenital heart diseases, and bronchopulmonary dysplasia. We present a review of the articles concerning inhaled nitric oxide for infants with PPHN. Overall, 59% of the neonates had an initial improvement in oxygenation in response to nitric oxide inhalation. A sustained response was observed in 60% of the infants. Patients with extrapulmonary shunting, clear chest radiographs, and adequate lung volume seem to have a better response, whereas patients with congenital diaphragmatic hernia, severe sepsis, and alveolar capillary dysplasia are more likely to fail. To define the benefit-risk ratio, six prospective randomized trials are currently in progress.

Inhaled nitric oxide in term infants with hypoxemic respiratory failure.

OBJECTIVE: To determine whether inhaled nitric oxide (NO) administered during conventional mechanical ventilation could produce improvements in oxygenation and reduce the incidence of meeting extracorporeal membrane oxygenation (ECMO) criteria in infants with hypoxemia. DESIGN: Prospective, randomized, controlled trial. Enrolled infants were assigned to conventional treatment with or without adjunctive inhaled NO. Control infants meeting failure criteria (partial pressure of arterial oxygen (PaO2)<80 mm Hg (10.7 kPa)) were allowed to cross over. Caregivers were not masked to group assignment. SETTING: Neonatal intensive care units at the University of Alabama Hospital and the Children's Hospital of Alabama, October 1993 to May 1994. PATIENTS: Newborn infants, both term and near-term, with PaO2 less than 100 mm Hg (13.3 kPa) who were receiving mechanical ventilation with 100% oxygen. Exclusion criteria included major congenital anomalies, diaphragmatic hernia, profound asphyxia, and significant bleeding. INTERVENTIONS: Inhaled NO was initiated in the NO group at a dose of 20 to 40 ppm and advanced stepwise to 80 ppm if PaO2 remained less than 100 mm Hg (13.3 kPa). OUTCOME MEASURES: Primary outcome variables were treatment failure and meeting of ECMO criteria before crossover. Improvement in oxygenation and ultimate use of ECMO or high-frequency oscillatory ventilation were secondary outcome variables. RESULTS: Seventeen neonates with hypoxemia were enrolled; 16 had echocardiographic evidence of pulmonary hypertension, and eight had extrapulmonary shunting. At 1 hour of treatment, two infants in the NO group responded with increases in PaO2 of more than 100 mm Hg (13.3 kPa); after crossover, two had increases in PaO2 of more than 10 mm Hg (1.3 kPa) and one control infant had an increase in PaO2 of more than 10 mm Hg (1.3 kPa). All control infants met failure criteria and crossed over to receive NO; two had increases in PaO2 of more than 10 mm Hg (1.3 kPa) with NO treatment. Despite initial responses, all subjects in both groups eventually met failure criteria. There were no differences between groups in primary outcome variables. CONCLUSIONS: Although inhaled NO produced a transient improvement in oxygenation in some infants, it did not reduce the incidence of meeting ECMO criteria in this population.