Jay S. Greenspan

Partial liquid ventilation with perflubron in premature infants with severe respiratory distress syndrome

Background The intratracheal administration of a perfluorocarbon liquid during continuous positive-pressure ventilation (partial liquid ventilation) improves lung function in animals with surfactant deficiency. Whether partial liquid ventilation is effective in the treatment of infants with severe respiratory distress syndrome is not known. Methods We studied the efficacy of partial liquid ventilation with perflubron in 13 premature infants with severe respiratory distress syndrome in whom conventional treatment, including surfactant therapy, had failed. Partial liquid ventilation was initiated by instilling perflubron during conventional mechanical ventilation to a volume approximating the functional residual capacity. Infants were considered to have completed the study if they received partial liquid ventilation for at least 24 hours. Results Ten infants received partial liquid ventilation for 24 to 76 hours. In the other three infants, partial liquid ventilation was discontinued within four hours in fa...

Liquid assisted ventilation: An alternative ventilatory strategy for acute meconium aspiration injury

Evidence of surfactant inactivation by meconium has led to the use of exogenous surfactant therapy in the management of meconium aspiration syndrome (MAS). Liquid assisted ventilation has been shown to improve the cardiopulmonary function in lungs with high surface tension. We compared exogenous surfactant therapy with liquid assisted ventilation in the management of experimental acute meconium aspiration injury. Thirty‐two newborn lambs were ventilated at peak inspiratory pressures of 13–16 cm H2O, positive end expiratory pressure of 3–4 cm H2O, fractional inspired oxygen concentration (F1O2) of 1.0, and a respiratory frequency range between 30 and 35 breaths/min. Baseline arterial blood gases, pulmonary function, and arterial blood pressure measurements were taken. All lambs were given 2–3 ml/kg of an unfiltered 25% meconium solution. Lambs were then randomized into either gas‐ventilated meconium control, or one of three treatment groups: 1) surfactant; 2) partial liquid ventilation (PLV); or 3) total liquid ventilation (TLV) for 4 hours after meconium injury. All treated groups demonstrated a significant increase in arterial oxygenation (P < 0.05); surfactant and PLV‐treated lambs demonstrated significantly decreased arterial PCO2 (P < 0.05). Compliance in all groups increased compared with injury values; compliance of the TLV group increased more than in all other treatment groups (P < 0.05). In addition, lung histology of the TLV group demonstrated clear, intact alveolar epithelium and homogeneously expanded alveoli, while no such improvement was evident in the other groups. These data suggest roles for both exogenous surfactant therapy and liquid assisted ventilation techniques in the management of MAS. Pediatr Pulmonol. 1996; 21:316–322.

Sublingual Buprenorphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Trial

OBJECTIVE. In utero exposure to drugs of abuse can lead to neonatal abstinence syndrome, a condition that is associated with prolonged hospitalization. Buprenorphine is a partial μ-opioid agonist used for treatment of adult detoxification and maintenance but has never been administered to neonates with opioid abstinence syndrome. The primary objective of this study was to demonstrate the feasibility and, to the extent possible in this size of study, the safety of sublingual buprenorphine in the treatment of neonatal abstinence syndrome. Secondary goals were to evaluate efficacy relative to standard therapy and to characterize buprenorphine pharmacokinetics when sublingually administered. METHODS. We conducted a randomized, open-label, active-control study of sublingual buprenorphine for the treatment of opiate withdrawal. Thirteen term infants were allocated to receive sublingual buprenorphine 13.2 to 39.0 μg/kg per day administered in 3 divided doses and 13 to receive standard-of-care oral neonatal opium solution. Dose decisions were made by using a modified Finnegan scoring system. RESULTS. Sublingual buprenorphine was largely effective in controlling neonatal abstinence syndrome. Greater than 98% of plasma concentrations ranged from undetectable to ∼0.60 ng/mL, which is less than needed to control abstinence symptoms in adults. The ratio of buprenorphine to norbuprenorphine was larger than that seen in adults, suggesting a relative impairment of N-dealkylation. Three infants who received buprenorphine and 1 infant who received standard of care reached protocol-specified maximum doses and required adjuvant therapy with phenobarbital. The mean length of treatment for those in the neonatal-opium-solution group was 32 compared with 22 days for the buprenorphine group. The mean length of stay for the neonatal-opium-solution group was 38 days compared with 27 days for those in the buprenorphine group. Treatment with buprenorphine was well tolerated. CONCLUSIONS. Buprenorphine administered via the sublingual route is feasible and apparently safe and may represent a novel treatment for neonatal abstinence syndrome.

Revised dose schema of sublingual buprenorphine in the treatment of the neonatal opioid abstinence syndrome.

AIMSnMore than half of infants exposed to opioids in utero develop neonatal abstinence syndrome (NAS) of severity to require pharmacological therapy. Current treatments are associated with prolonged hospitalization. We sought to optimize the dose of sublingual buprenorphine in the treatment of NAS.nnnDESIGNnRandomized, Phase 1, open-label, active-control clinical trial comparing sublingual buprenorphine to oral morphine.nnnSETTINGnLarge, urban, tertiary care hospital.nnnPARTICIPANTSnTwenty-four term infants requiring pharmacological treatment for NAS.nnnMEASUREMENTSnOutcomes were neonatal safety, length of treatment and length of hospitalization.nnnFINDINGSnSublingual buprenorphine was safe and effective. Infants treated with buprenorphine had a 23-day length of treatment compared to 38 days for those treated with morphine (P = 0.01), representing a 40% reduction. Length of hospital stay in the buprenorphine group was reduced 24%, from 42 to 32 days (P = 0.05).nnnCONCLUSIONSnSublingual buprenorphine was safe in NAS, with a substantial efficacy advantage over standard of care therapy with oral morphine.

Early caffeine therapy for prevention of bronchopulmonary dysplasia in preterm infants

Abstract Objective: To determine if an early commencement of caffeine is associated with improved survival without bronchopulmonary dysplasia (BPD) in preterm infants. Methods: Retrospective data analysis from the Alere Neonatal Database for infants weighing ≤1250u2009g, and treated with caffeine within the first 10 days of life. The neonatal outcomes were compared between the infants who received early caffeine (0–2 days) with the infants who received delayed caffeine (3–10 days). Results: A total of 2951 infants met the inclusion criteria (early caffeine 1986, late caffeine 965). The early use of caffeine was associated with reduction in BPD (OR 0.69, 95%u2009CI 0.58–0.82, pu2009<u20090.001) and BPD or death (OR 0.77, 95%u2009CI 0.63–0.94, pu2009=u20090.01). Other respiratory outcomes also improved with the early commencement of caffeine. The frequency of severe intraventricular hemorrhage and patent ductus arteriosus was lower and the length of hospitalization was shorter in infants receiving early caffeine therapy. However, early use of caffeine was associated with an increase in the risk of nectrotizing enterocolits (NEC) (OR 1.41, 95%u2009CI 1.04–1.91, pu2009=u20090.027). Conclusion: Early commencement of caffeine was associated with improvement in survival without BPD in preterm infants. The risk of NEC with early caffeine use requires further investigation.

Development of children born to mothers with cancer during pregnancy: comparing in utero chemotherapy-exposed children with nonexposed controls

OBJECTIVEnCancer is diagnosed in approximately 1 per 1000 pregnant women. Lifesaving cancer therapy given to the mother during pregnancy appears in conflict with the interest of the developing fetus. Often, termination of pregnancy is suggested but has not been proven in any type of cancer to improve maternal prognosis, while very few studies have documented the long-term effects of in utero chemotherapy exposure on child outcome. To counsel patients about the risk of continuing a pregnancy while undergoing cancer treatment, we performed developmental testing to provide more detailed follow-up on children exposed in utero to chemotherapy.nnnSTUDY DESIGNnMother-infant pairs, enrolled in the Cancer and Pregnancy Registry, were offered developmental testing for children who were ≥18 months of age. Based on age, the Bayley Scales of Infant Development-Third Edition, the Wechsler Preschool and Primary Scale of Intelligence-Revised, the Wechsler Intelligence Scale for Children, Third Edition, or the Wechsler Individual Achievement Test was administered. All parents or primary caregivers completed the Child Behavior Checklist, a parent questionnaire to assess behavior and emotional issues. Results of children exposed to chemotherapy before delivery were compared with children whose mothers were also diagnosed with cancer during pregnancy but did not receive chemotherapy before delivery.nnnRESULTSnNo significant differences were noted in cognitive skills, academic achievement, or behavioral competence between the chemotherapy-exposed group and the unexposed children. Of children, 95% scored within normal limits on cognitive assessments; 71% and 79% of children demonstrated at or above age equivalency in mathematics and reading scores, respectively; and 79% of children scored within normal limits on measures of behavior. Older children had significantly higher rates of internalizing behavior problems.nnnCONCLUSIONnWe could not demonstrate a significant difference in cognitive ability, school performance, or behavioral competence for children exposed to chemotherapy in utero compared with nonexposed controls. The majority of these children scored within normal limits on all developmental measures. Premature birth was more prevalent in the chemotherapy-exposed group yet did not predict developmental outcome. Older children in the sample demonstrated higher rates of internalizing behavior problems.

Estimating pediatric inpatient medication use in the United States

We demonstrated the feasibility of developing national estimates of pediatric inpatient medication use by analyzing data from a large administrative database.

Buprenorphine for the Treatment of the Neonatal Abstinence Syndrome

BACKGROUND Current pharmacologic treatment of the neonatal abstinence syndrome with morphine is associated with a lengthy duration of therapy and hospitalization. Buprenorphine may be more effective than morphine for this indication. METHODS In this single‐site, double‐blind, double‐dummy clinical trial, we randomly assigned 63 term infants (≥37 weeks of gestation) who had been exposed to opioids in utero and who had signs of the neonatal abstinence syndrome to receive either sublingual buprenorphine or oral morphine. Infants with symptoms that were not controlled with the maximum dose of opioid were treated with adjunctive phenobarbital. The primary end point was the duration of treatment for symptoms of neonatal opioid withdrawal. Secondary clinical end points were the length of hospital stay, the percentage of infants who required supplemental treatment with phenobarbital, and safety. RESULTS The median duration of treatment was significantly shorter with buprenorphine than with morphine (15 days vs. 28 days), as was the median length of hospital stay (21 days vs. 33 days) (P<0.001 for both comparisons). Adjunctive phenobarbital was administered in 5 of 33 infants (15%) in the buprenorphine group and in 7 of 30 infants (23%) in the morphine group (P=0.36). Rates of adverse events were similar in the two groups. CONCLUSIONS Among infants with the neonatal abstinence syndrome, treatment with sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than treatment with oral morphine, with similar rates of adverse events. (Funded by the National Institute on Drug Abuse; BBORN ClinicalTrials.gov number, NCT01452789.)

Neonatal non-invasive respiratory support: Physiological implications†‡

The introduction of assisted ventilation for neonatal pulmonary insufficiency has resulted in the successful treatment of many previously fatal diseases. During the past three decades, refinement of invasive mechanical ventilation techniques has dramatically improved survival of many high‐risk neonates. However, as with many advances in medicine, while mortality has been reduced, morbidity has increased in the surviving high‐risk neonate. In this regard, introduction of assisted ventilation has been associated with chronic lung injury, also known as bronchopulmonary dysplasia. This disease, unknown prior to the appearance of mechanical ventilation, has produced a population of patients characterized by ventilator or oxygen dependence with serious accompanying pulmonary and neurodevelopmental morbidity. The purpose of this article is to review non‐invasive respiratory support methodologies to address the physiologic mechanisms by which these methods may prevent the pathophysiologic effects of invasive mechanical ventilation. Pediatr Pulmonol. 2012. 47:837–847.

Effects of Multiple Ventilation Courses and Duration of Mechanical Ventilation on Respiratory Outcomes in Extremely Low-Birth-Weight Infants

IMPORTANCEnExtubation failure is common in extremely preterm infants. The current paucity of data on the adverse long-term respiratory outcomes associated with reinitiation of mechanical ventilation prevents assessment of the risks and benefits of a trial of extubation in this population.nnnOBJECTIVEnTo evaluate whether exposure to multiple courses of mechanical ventilation increases the risk of adverse respiratory outcomes before and after adjustment for the cumulative duration of mechanical ventilation.nnnDESIGN, SETTING, AND PARTICIPANTSnWe performed a retrospective cohort study of extremely low-birth-weight (ELBW; birth weight <1000 g) infants born from January 1, 2006, through December 31, 2012, who were receiving mechanical ventilation. Analysis was conducted between November 2014 and February 2015. Data were obtained from the Alere Neonatal Database.nnnEXPOSURESnThe primary study exposures were the cumulative duration of mechanical ventilation and the number of ventilation courses.nnnMAIN OUTCOMES AND MEASURESnThe primary outcome was bronchopulmonary dysplasia (BPD) among survivors. Secondary outcomes were death, use of supplemental oxygen at discharge, and tracheostomy.nnnRESULTSnWe identified 3343 ELBW infants, of whom 2867 (85.8%) survived to discharge. Among the survivors, 1695 (59.1%) were diagnosed as having BPD, 856 (29.9%) received supplemental oxygen at discharge, and 31 (1.1%) underwent tracheostomy. Exposure to a greater number of mechanical ventilation courses was associated with a progressive increase in the risk of BPD and use of supplemental oxygen at discharge. Compared with a single ventilation course, the adjusted odds ratios for BPD ranged from 1.88 (95% CI, 1.54-2.31) among infants with 2 ventilation courses to 3.81 (95% CI, 2.88-5.04) among those with 4 or more courses. After adjustment for the cumulative duration of mechanical ventilation, the odds of BPD were only increased among infants exposed to 4 or more ventilation courses (adjusted odds ratio, 1.44; 95% CI, 1.04-2.01). The number of ventilation courses was not associated with increased risk of supplemental oxygen use at discharge after adjustment for the length of ventilation. A greater number of ventilation courses did not increase the risk of tracheostomy.nnnCONCLUSIONS AND RELEVANCEnAmong ELBW infants, a longer cumulative duration of mechanical ventilation largely accounts for the increased risk of chronic respiratory morbidity associated with reinitiation of mechanical ventilation. These results support attempts of extubation in ELBW infants receiving mechanical ventilation on low ventilator settings, even when success is not guaranteed.