Michael D. Schreiber

INHALED NITRIC OXIDE AND PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN

Background Persistent pulmonary hypertension of the newborn causes systemic arterial hypoxemia because of increased pulmonary vascular resistance and right-to-left shunting of deoxygenated blood. Inhaled nitric oxide decreases pulmonary vascular resistance in newborns. We studied whether inhaled nitric oxide decreases severe hypoxemia in infants with persistent pulmonary hypertension. Methods In a prospective, multicenter study, 58 full-term infants with severe hypoxemia and persistent pulmonary hypertension were randomly assigned to breathe either a control gas (nitrogen) or nitric oxide (80 parts per million), mixed with oxygen from a ventilator. If oxygenation increased after 20 minutes and systemic blood pressure did not decrease, the treatment was considered successful and was continued at lower concentrations. Otherwise, it was discontinued and alternative therapies, including extracorporeal membrane oxygenation, were used. Results Inhaled nitric oxide successfully doubled systemic oxygenation in 16 of 30 infants (53 percent), whereas conventional therapy without inhaled nitric oxide increased oxygenation in only 2 of 28 infants (7 percent). Long-term therapy with inhaled nitric oxide sustained systemic oxygenation in 75 percent of the infants who had initial improvement. Extracorporeal membrane oxygenation was required in 71 percent of the control group and 40 percent of the nitric oxide group (P=0.02). The number of deaths was similar in the two groups. Inhaled nitric oxide did not cause systemic hypotension or increase methemoglobin levels. Conclusions Inhaled nitric oxide improves systemic oxygenation in infants with persistent pulmonary hypertension and may reduce the need for more invasive treatments.

Increased Arterial pH, Not Decreased PaCO2, Attenuates Hypoxia-Induced Pulmonary Vasoconstriction in Newborn Lambs

ABSTRACT. Mechanically induced hyperventilation is used in the treatment of newborn infants with persistent pulmonary hypertension syndrome to induce respiratory alkalosis, which may attenuate their pulmonary vasoconstriction. Whether this treatment is effective because of the increase in arterial pH or the decrease in PaCO2 was investigated in nine sedated, mechanically ventilated newborn lambs with hypoxia-induced pulmonary vasoconstriction. We found that respiratory alkalosis and metabolic alkalosis were equally effective in attenuating hypoxia-induced pulmonary vasoconstriction, but that hypocapnia (low PaCO2 with a normal arterial pH) was ineffective. These results indicate that increased arterial pH, not decreased PaCO2, attenuates hypoxia-induced pulmonary vasoconstriction in newborn lambs and possibly the pulmonary vasoconstriction in newborn infants with persistent pulmonary hypertension syndrome.

Just, in Time: Ethical Implications of Serial Predictions of Death and Morbidity for Ventilated Premature Infants

OBJECTIVES. For a cohort of extremely premature, ventilated, newborn infants, we determined the power of either serial caretaker intuitions of “die before discharge” or serial illness severity scores to predict the outcomes of death in the NICU or neurologic performance at corrected age of 2 years. METHODS. We identified 268 premature infants who were admitted to our NICU in 1999–2004 and required mechanical ventilation. For each infant on each day of mechanical ventilation, we asked nurses, residents, fellows, and attending physicians the following question: “Do you think this child is going to live to go home or die before hospital discharge?” In addition, we calculated illness severity scores until either death or extubation. RESULTS. A total of 17066 intuition profiles were obtained on 5609 days of mechanical ventilation in the NICU. One hundred (37%) of 268 profiled infants had ≥1 intuition of die before discharge. Only 33 infants (33%) with an intuition of die actually died in the NICU. Of 48 infants with even 1 day of corroborated intuition of die in the NICU, only 7 (14%) were alive with both Mental Developmental Index and Psychomotor Developmental Index scores of >69, and only 2 (4%) were alive with both Mental Developmental Index and Psychomotor Developmental Index Scores of >79 at corrected age of 2 years. On day of life 1, the Score for Neonatal Acute Physiology II value for nonsurvivors (38.2 ± 18.1) was significantly higher than that for survivors (26.3 ± 12.7). However, this difference decreased steadily over time as scores improved for both groups. CONCLUSIONS. Illness severity scores become progressively less helpful over time in distinguishing infants who will either die in the NICU or survive with low Mental Developmental Index/Psychomotor Developmental Index scores. Serial caretaker intuitions of die before discharge also fail to identify prospective nonsurviving infants. However, corroborated intuitions of die before discharge identify a subset of infants whose likelihood of surviving to 2 years with both MDI and PDI >80 is approximately 4%.

Risk factors affecting school readiness in premature infants with respiratory distress syndrome.

OBJECTIVE: With advances in neonatal care, more children born prematurely are successfully reaching school age. It is unknown how many will be ready for school and what factors affect school readiness. Our objective was to assess readiness of children born prematurely for entry into public school, and determine risk factors associated with lack of school readiness in this population. METHODS: This was a single-center prospective cohort study. Follow- up data were collected for 135 of 167 (81%) surviving premature infants with RDS requiring surfactant-replacement therapy. The children were seen between July 2005 and September 2006 (average age: 5.7 ± 1.0 years) and underwent standardized neurodevelopmental and health assessments and socioeconomic status classification. A 4-level school-readiness score was constructed by using each childs standardized scores on assessments of basic concepts (Bracken School-Readiness Assessment), perceptual skills (Visual-Motor Integration Test), receptive vocabulary (Peabody Picture Vocabulary Test, Third Edition), daily living functional skills (Pediatric Functional Independence Measure), and presence of sensory impairments or autism. Proportional odds models were used to identify risk factors predicting lower school-readiness levels. RESULTS: Mean birth weight was 1016 ± 391 g, and mean gestational age was 27.5 ± 2.6 weeks. Ninety-one (67%) children were school-ready. Using multivariate analysis, male gender, chronic lung disease, and severe intraventricular hemorrhage or periventricular leukomalacia were associated with lower school-readiness levels. However, the most powerful factor determining school-readiness level was low socioeconomic status. CONCLUSION: Interventions targeting neonatal morbidities may be much less effective at improving overall performance at school age compared with the effect of the impoverished social environment.

Increased Indomethacin Dosing for Persistent Patent Ductus Arteriosus in Preterm Infants: A Multicenter, Randomized, Controlled Trial

OBJECTIVE We conducted a multicenter, randomized, controlled trial to determine whether higher doses of indomethacin would improve the rate of patent ductus arteriosus (PDA) closure. STUDY DESIGN Infants (<28 weeks gestation) who received a conventional, prophylactic 3-dose course of indomethacin were eligible if they had continued evidence of persistent ductus patency on an echocardiogram obtained before the third prophylactic indomethacin dose. Infants (n = 105) were randomized to receive an extended 3-day course of either low-dose (0.1 mg/kg/d) or higher-dose (0.2 or 0.5 mg/kg/d) indomethacin. An echocardiogram was obtained 24 hours after the last dose of study drug. RESULTS Despite increasing serum indomethacin concentrations by 2.9-fold in the higher-dose group, we failed to detect a significant decrease in the rate of persistent PDA (low = 52%; higher = 45%, P = .50). The higher-dose group had a significantly higher occurrence of serum creatinine >2 mg/100 mL (low = 6%, higher = 19%, P < .05) and moderate/severe retinopathy of prematurity (ROP) (low = 15%, higher = 36%, P < .025). The incidence of moderate/severe ROP was directly related to the poststudy indomethacin concentrations (odds ratio = 1.75, confidence interval: 1.15-2.68, P < .01). CONCLUSION Increasing indomethacin concentrations above the levels achieved with a conventional dosing regimen had little effect on the rate of PDA closure but was associated with higher rates of moderate/severe ROP and renal compromise.

Effect of high-dose dopamine on urine output in newborn infants

: To achieve adequate arterial BP, adequate capillary filling time, and adequate peripheral pulses, hypotensive newborn infants often require higher doses of dopamine that reportedly reduce urine output in adults. Whether these larger doses of dopamine also reduce urine output in newborns is not known. Therefore, we determined the effects of administering high-dose dopamine (more than 20 micrograms/kg X min) on the urine output of 15 newborn infants. Five infants were studied prospectively and ten retrospectively. In the prospective study, urine output was determined as the dose of dopamine was increased; in the retrospective study, urine output was determined as the infants were being weaned from high doses of dopamine. Both data sets demonstrate that administering high-dosage dopamine does not reduce the urine output of sick newborn infants. Therefore, we conclude that doses of dopamine previously reported to decrease urine output in adults do not do so in sick newborn infants. Consequently, when necessary, high doses of dopamine may be used in sick newborn infants to achieve cardiovascular stability without reducing urine output.

Does bronchopulmonary dysplasia contribute to the occurrence of cerebral palsy among infants born before 28 weeks of gestation

Objective To evaluate the relationships among cerebral palsy (CP) phenotypes and bronchopulmonary dysplasia (BPD) severity and, in the process, to generate hypotheses regarding causal pathways linking BPD to CP. Study design We studied 1047 infants born before the 28th week of gestation. Receipt of supplemental oxygen at 36 weeks postmenstrual age (PMA), with or without the need for mechanical ventilation (MV) at 36 weeks PMA, defined two levels of BPD. At 24 months, the children underwent neurologic examinations and CP diagnoses were made using an algorithm based on topographic localisation. Results The 536 infants with BPD were at increased risk of all three CP phenotypes. In time-oriented multivariable analyses that adjusted for potential confounders, receipt of supplemental oxygen without MV at 36 weeks PMA (BPD) was not associated with increased risk of any CP phenotype. In contrast, BPD accompanied by MV at 36 weeks PMA (BPD/MV) was associated with a nearly sixfold increased risk of quadriparesis and a fourfold increased risk of diparesis. Conclusions Combined treatment with both MV and supplemental oxygen at 36 weeks PMA strongly predicts the more common bilateral CP phenotypes. BPD without MV at 36 weeks PMA was not significantly associated with any form of CP.

Leukotriene Inhibition Prevents and Reverses Hypoxic Pulmonary Vasoconstriction in Newborn Lambs

ABSTRACT: The effects of the leukotriene antagonist FPL 57231 on the circulation were studied in spontaneously breathing normoxic and hypoxic newborn lambs in order to evaluate the role of leukotrienes in the perinatal control of hypoxic pulmonary vasoconstriction. Hypoxia produced a 58% increase in pulmonary arterial pressure (p < 0.05) and a 37% increase in pulmonary vascular resistance (p < 0.05). Hypoxic pulmonary vasoconstriction was abolished by the prior infusion of FPL 57231. Pulmonary arterial pressure increased by only 8% and pulmonary vascular resistance decreased by 10% from normoxia. The infusion of FPL 57231 during hypoxia-induced pulmonary vasoconstriction reversed the increase in pulmonary arterial pressure (p < 0.05) and pulmonary vascular resistance (p < 0.05). The hypoxia-induced increase in cardiac output was maintained during the infusion of FPL 57231. Leukotrienes may play a significant role in the mediation of hypoxic pulmonary vasoconstriction. Leukotriene inhibition with FPL 57231 may be useful in the management of infants with persistent pulmonary hypertension syndrome.

Systemic Inflammation, Intraventricular Hemorrhage, and White Matter Injury

To see if the systemic inflammation profile of 123 infants born before the 28th week of gestation who had intraventricular hemorrhage without white matter injury differed from that of 68 peers who had both lesions, we compared both groups to 677 peers who had neither. Cranial ultrasound scans were read independently by multiple readers until concordance. The concentrations of 25 proteins were measured with multiplex arrays using an electrochemiluminescence system. Infants who had both hemorrhage and white matter injury were more likely than others to have elevated concentrations of C-reactive protein and interleukin 8 on days 1, 7, and 14, and elevated concentrations of serum amyloid A and tumor necrosis factor–α on 2 of these days. Intraventricular hemorrhage should probably be viewed as 2 entities: hemorrhage alone and hemorrhage with white matter injury. Each entity is associated with inflammation, but the combination has a stronger inflammatory signal than hemorrhage alone.

Predicting school readiness from neurodevelopmental assessments at age 2 years after respiratory distress syndrome in infants born preterm

Aim  To determine whether neurodevelopmental outcomes at the age of 2 years accurately predict school readiness in children who survived respiratory distress syndrome after preterm birth.