Golde G. Dudell

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

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 [Fio 2] 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 Pao 2 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.

Patent ductus arteriosus in neonates with severe respiratory disease

Daily aortic contrast echo studies were carried out in 200 neonates with severe respiratory disease to determine the natural history of the ductus arteriosus during the first days of life and the effect of patency on subsequent morbidity and mortality. Decisions related to surgical or pharmacologic closure of a PDA were not based on the results of the contrast echo studies. The risk that intervention would be required was greater in infants weighing less than 1500 gm (P less than 0.005) and in patients in whom the ductus had not closed spontaneously by day 3 (P less than 0.001) regardless of birth weight. The clinical course in infants with a PDA on the third day of life revealed a lower survival rate (P less than 0.005), a greater requirement for prolonged respiratory support (P less than 0.005), and a higher incidence of bronchopulmonary dysplasia (P less than 0.005) in all birth weight categories. Ductal patency often was not associated with early clinical manifestations. No infant who had a negative echo study on the third day of life subsequently developed signs or symptoms of patent ductus arteriosus. We conclude that patency of the ductus arteriosus is a negative prognostic factor in the severely ill neonate with respiratory distress.

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.

Predictors of early childhood outcome in candidates for extracorporeal membrane oxygenation

OBJECTIVE To examine the effect of neonatal risk factors and treatment strategy on pulmonary, growth, and neurodevelopmental outcome of candidates for extracorporeal membrane oxygenation (ECMO). DESIGN We prospectively assessed growth and neurodevelopmental outcome in a cohort of 190 neonates who had severe respiratory failure, no major congenital anomalies, and met institutional criteria for the use of ECMO. The relationships among perinatal risk factors, neonatal outcome, postnatal growth, and neurodevelopmental outcome were studied by univariate and multivariate analyses. RESULTS Compared with 52 infants successfully treated with conventional or high-frequency ventilation, the 138 ECMO survivors were more mature, had earlier, more severe pulmonary disease, and were more likely to have meconium aspiration. The ECMO survivors had significantly fewer ventilator days (9 vs 11), hospital days (23 vs 29), and less (12% vs 25%) chronic lung disease (CLD). At 12 to 30 months, mean developmental scores of ECMO survivors were similar to those of infants who survived without ECMO. Infants with CLD had significantly lower motor scores (86 +/- 23 vs 100 +/- 19) and were more likely to have cerebral palsy (27% vs 6%) than those without CLD. The risk of adverse neurodevelopmental outcome was independently increased by CLD (odds ratio, 2.4; confidence interval, 1.2 to 4.6) and moderate or severe neonatal neuroimaging abnormalities (odds ratio, 6.4; confidence interval, 1.9 to 21.9). CONCLUSIONS Neonatal ECMO candidates treated with ECMO did as well or better than neonates whose conditions were managed with alternate treatment strategies. Adverse neurodevelopmental outcome was predicted by moderate or severe neonatal neuroimaging abnormalities and CLD, not by treatment with ECMO.

A comparison of venovenous and venoarterial extracorporeal membrane oxygenation in the treatment of neonatal respiratory failure.

OBJECTIVE To compare the efficacy of venovenous to venoarterial bypass in an unselected cohort of infants with refractory cardiorespiratory failure. DESIGN Retrospective cohort analysis. SETTING Two tertiary hospitals capable of providing extracorporeal life support for neonates with acute respiratory failure. PATIENTS All San Diego Regional Extracorporeal Membrane Oxygenation (ECMO) Program patients treated after the adoption of a policy which eliminated traditional restrictions to venovenous support. INTERVENTIONS Venoarterial or venovenous extracorporeal life support. MEASUREMENTS AND MAIN RESULTS Fifty-four infants were treated with venovenous bypass; 30 were treated with venoarterial bypass due to unsuccessful placement of the double lumen venovenous catheter or inability to exclude congenital heart disease before cannulation. No patient required conversion from venovenous to venoarterial ECMO. There were no differences in birth weight, gestational age, diagnosis, or pre-ECMO condition in the two groups. Patients who met ECMO criteria early were more likely to be successfully cannulated with a double-lumen venovenous catheter. Severe hemodynamic compromise was present before cannulation in a comparable percentage of venovenous and venoarterial patients. During venovenous bypass, mean Pao2 values were lower but remained in the normoxic range; Paco2 values, ventilatory setting, intravascular volume requirements, inotropic support, and mean duration of ECMO support were not different. The frequency rate of patient and mechanical complications were also comparable, except that the frequency of intravascular thrombosis was significantly lower in patients receiving venovenous ECMO. Survival, the frequency rate of chronic lung disease, and neurodevelopmental outcome were similar in the two groups. CONCLUSIONS We conclude that venovenous ECMO using a double-lumen venovenous catheter can provide results comparable with venoarterial bypass without the need for carotid artery ligation in an unselected population of neonatal ECMO candidates. In our experience, reported contraindications to venovenous ECMO did not prove to be valid.

A DOUBLE MASKED, RANDOMIZED, PLACEBO CONTROLLED, DOSE-RESPONSE STUDY OF INHALED NITRIC OXIDE FOR THE TREATMENT OF PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN (PPHN). • 851

A DOUBLE MASKED, RANDOMIZED, PLACEBO CONTROLLED, DOSE-RESPONSE STUDY OF INHALED NITRIC OXIDE FOR THE TREATMENT OF PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN (PPHN). • 851

Radiology Casebook: Gastric Perforation with Sebserosal Dissection of Air

A female weighing 1640 gm at 32 weeks’ gestation was delivered to a 33-year-old mother (gravida 7, para 3, full-term, 4 preterm, 0 abortions, with 3 living children) by cesarean section for oligohydramnios and preterm labor. Apgar scores were 8 at 1 minute and 9 at 5 minutes. The infant was intubated in the delivery room and transported to the neonatal intensive care unit. Umbilical artery and venous catheter were placed; surfactant was given endotracheally for respiratory distress syndrome, demonstrated by chest radiography. The infant did well and weaned quickly to minimal ventilator settings. Despite aggressive use of fluids and dopamine, there was persistent hypotension with mean arterial pressures of 24 to 28 mm Hg. A single dose of dexamethasone (0.5 mg/kg) was given following which the hypotension resolved. A tracheal aspirate sent shortly after birth grew Enterobacter cloacae, and the infant was treated with cefotaxime and gentamicin. There were no other signs of sepsis, and the blood culture was negative. On day of life 3 the infant was noted to develop acute abdominal distention. She appeared otherwise well at this time. A nasogastric tube was placed to low-intermittent suction but failed to decompress the abdomen. An abdominal radiograph showed what appeared to be a large stomach bubble with no bowel gas noted beyond the pylorus. An abdominal radiograph from the second day of life demonstrated a large “stomach bubble” that would not decompress despite nasogastric suctioning (Figure 1). Due to persistent distention, the infant underwent an upper gastrointestinal series that showed complete gastric outlet obstruction (Figure 2).

Withdrawal of Inhaled Nitric Oxide From Term Newborns With Persistent Pulmonary Hypertension (Pphn): A Randomized, Double Masked, Placebo Controlled, Dose-Response Study. † 1637

Because of concerns about hypoxemia upon withdrawal of inhaled nitric oxide(NO) therapy for PPHN, we prospectively examined this safety issue as part of a multicenter trial. Study patients (n=155) were term, ≤72 hrs old, and started on inhaled NO when the FIO2 requirement was 1.0 on conventional ventilation. Lung hypoplasia, surfactant therapy and concurrent high frequency ventilation were entry exclusion criteria. Placebo (N2 vehicle) or fixed doses of NO (5,20, or 80 ppm) were administered until treatment (Rx) success (OI<10), or Rx failure criteria. Withdrawal of Rx gas (strict masking) was performed by 20% decrements, arterial blood gases were recorded before and 1/2 hr after a decrement, and no vent changes were made for this 1/2 hr. Investigator compliance for this Rx withdrawal protocol was 91%(63/69) and 29% (25/86) for patients with Rx success and failure criteria, respectively. For all patients (Rx successes and failures), Rx gas was discontinued after an exposure of 84±7 hrs; the OI was 12±2(mean ± SE) at this time. Table