Nirupama Laroia

Early CPAP versus surfactant in extremely preterm infants

BACKGROUND There are limited data to inform the choice between early treatment with continuous positive airway pressure (CPAP) and early surfactant treatment as the initial support for extremely-low-birth-weight infants. METHODS We performed a randomized, multicenter trial, with a 2-by-2 factorial design, involving infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to CPAP treatment initiated in the delivery room, with subsequent use of a protocol-driven limited ventilation strategy. Infants were also randomly assigned to one of two target ranges of oxygen saturation. The primary outcome was death or bronchopulmonary dysplasia as defined by the requirement for supplemental oxygen at 36 weeks (with an attempt at withdrawal of supplemental oxygen in neonates who were receiving less than 30% oxygen). RESULTS A total of 1316 infants were enrolled in the study. The rates of the primary outcome did not differ significantly between the CPAP group and the surfactant group (47.8% and 51.0%, respectively; relative risk with CPAP, 0.95; 95% confidence interval [CI], 0.85 to 1.05) after adjustment for gestational age, center, and familial clustering. The results were similar when bronchopulmonary dysplasia was defined according to the need for any supplemental oxygen at 36 weeks (rates of primary outcome, 48.7% and 54.1%, respectively; relative risk with CPAP, 0.91; 95% CI, 0.83 to 1.01). Infants who received CPAP treatment, as compared with infants who received surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P<0.001), required fewer days of mechanical ventilation (P=0.03), and were more likely to be alive and free from the need for mechanical ventilation by day 7 (P=0.01). The rates of other adverse neonatal outcomes did not differ significantly between the two groups. CONCLUSIONS The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants. (ClinicalTrials.gov number, NCT00233324.)

Target ranges of oxygen saturation in extremely preterm infants.

BACKGROUND Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes. METHODS We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant. RESULTS The rates of severe retinopathy or death did not differ significantly between the lower-oxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P=0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P<0.001). There were no significant differences in the rates of other adverse events. CONCLUSIONS A lower target range of oxygenation (85 to 89%), as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors. The increase in mortality is a major concern, since a lower target range of oxygen saturation is increasingly being advocated to prevent retinopathy of prematurity. (ClinicalTrials.gov number, NCT00233324.)

Electrographic seizures in neonates correlate with poor neurodevelopmental outcome

Objective: To quantify the number, duration, and intensity of electrographic seizures (ESz) in neonates and to compare the outcome of neonates with ESz with those who were at risk but did not have ESz recorded. Methods: The EEG and outcome data were reviewed from 68 infants who met at-risk criteria for neonatal seizures and underwent prolonged continuous EEG monitoring. Forty infants had ESz. The control group contained 28 infants monitored for at least 18 hours and found not to have ESz. Outcomes for both groups were evaluated using hospital and follow-up clinic records and a standardized telephone interview. Results: The etiology of ESz included asphyxia (n = 23), stroke (n = 7), and other (n = 10, intraparenchymal, subdural, and subarachnoid bleeding; meningitis; sepsis; hyponatremia; and unknown). The cumulative recorded ESz duration was 8 minutes to 30 hours. Forty-three percent of infants with ESz spent 38 minutes to 32 hours in electrographic status. Despite doses of 40 mg/kg of phenobarbital and 20 mg/kg of phenytoin, 30% of infants continued to have ESz. Ten infants with ESz and one without died from causes related to neurologic instability. The occurrence of ESz was correlated with microcephaly (p = 0.04), severe cerebral palsy (CP) (p = 0.03), and failure to thrive (p = 0.03). In the subgroup of infants with asphyxia, those with ESz were more likely to die of neurologic causes (p = 0.02) and have microcephaly (p = 0.05) or severe CP (p = 0.04). Additionally, those with the greatest number of ESz were more likely to have these severe outcomes. Conclusion: The authors’ data indicate an association between the amount of electrographic seizure activity and subsequent mortality and morbidity in at-risk infants in general and in infants with perinatal asphyxia. Only with more effective treatment of neonatal electrographic seizures can their potential contribution to poor neurodevelopmental outcome, independent of degree of insult, be ascertained.

EEG Background as Predictor of Electrographic Seizures in High‐Risk Neonates

Summary: Purpose: Experience with continuous EEG monitoring in 29 consecutive infants at risk of neonatal seizures demonstrated that background abnormalities on the initial EEG were strongly associated with electrographic seizures in the subsequent 18–24 h. To test this association prospectively, we examined the relationship between EEG background and the presence of electrographic seizures in the next 22 at‐risk infants monitored for seizures.

DEXTROMETHORPHAN AMELIORATES EFFECTS OF NEONATAL HYPOXIA ON BRAIN MORPHOLOGY AND SEIZURE THRESHOLD IN RATS

Hypoxic injury to the brain is mediated in part by NMDA receptors. Therefore, NMDA receptor blockade with dextromethorphan (DM), a non-competitive channel blocker, was hypothesized to ameliorate injury even when given after the hypoxic insult. Rats were exposed to 8% oxygen for 3 h on postnatal day 7. Within 20 min of exposure, animals received 30 mg/kg i.p. DM or normal saline. Littermates maintained in room air for 3 h also received DM or saline. At 14 days of age, 7 days after exposure, cortical thickness and hippocampal area were measured. At 70-90 days of age, approximately two months after exposure, in a separate group of rats, seizure threshold using pentylenetetrazol (PTZ) and passive avoidance learning and retention were determined. There were no gross changes in cellular morphology and no evidence for cellular necrosis in any of the exposure groups. However, cortical thickness was decreased in animals exposed to hypoxia. DM administration prevented this decrease. Hippocampal area was unaffected. Seizure susceptibility in adulthood was increased in animals exposed to hypoxia in the neonatal period. DM prevented the decrease in seizure threshold. There was no difference in passive avoidance learning or retention as a function of neonatal exposure condition. Mild to moderate hypoxia, previously thought not to produce any histologic changes, causes significant short-term loss of cortical thickness and long-term decrease in seizure threshold. DM appears to ameliorate these effects even when given after the hypoxic insult. These results implicate the glutamate receptor system in the pathophysiology of hypoxia damage and suggest that treatment with a glutamate receptor blocker when neonatal asphyxia is suspected would help ameliorate the consequences of such an insult.

Auditory toxicity in late preterm and term neonates with severe jaundice

Jaundice may cause auditory toxicity (auditory neuropathy and hearing loss). However, total serum bilirubin (TSB) does not discriminate neonates at risk for auditory toxicity. We compared TSB, bilirubin:albumin molar ratio (BAMR), and unbound bilirubin for their association with auditory toxicity in neonates with severe jaundice (TSB ≥342μmol/L, or that met exchange transfusion).

Chronic Auditory Toxicity in Late Preterm and Term Infants With Significant Hyperbilirubinemia

UB (but not TSB or BAMR) is associated with chronic auditory toxicity in late preterm and term infants with hyperbilirubinemia. BACKGROUND AND OBJECTIVES: Significant hyperbilirubinemia (SHB) may cause chronic auditory toxicity (auditory neuropathy spectrum disorder and/or sensorineural hearing loss); however, total serum bilirubin (TSB) does not discriminate neonates at risk for auditory toxicity. Our objective was to compare TSB, bilirubin albumin molar ratio (BAMR), and unbound bilirubin (UB) for their association with chronic auditory toxicity in neonates with SHB (TSB ≥20 mg/dL or TSB that met criteria for exchange transfusion). METHODS: Infants ≥34 weeks’ gestational age (GA) with SHB during the first 2 postnatal weeks were eligible for a prospective longitudinal study in India. Comprehensive auditory evaluations were performed at 2 to 3 months of age by using auditory brainstem response, tympanometry, and an otoacoustic emission test and at 9 to 12 months of age by using audiometry. The evaluations were performed by an audiologist unaware of the degree of jaundice. RESULTS: A total of 93 out of 100 infants (mean GA of 37.4 weeks; 55 boys, 38 girls) who were enrolled with SHB were evaluated for auditory toxicity. Of those, 12 infants (13%) had auditory toxicity. On regression analysis controlling for covariates, peak UB (but not peak TSB or peak BAMR), was associated with auditory toxicity (odds ratio 2.41; 95% confidence interval: 1.43–4.07; P = .001). There was significant difference in the area under the receiver operating characteristic curves between UB (0.866), TSB (0.775), and BAMR (0.724) for auditory toxicity (P = .03) after controlling for covariates. CONCLUSIONS: Unconjugated hyperbilirubinemia indexed by UB (but not TSB or BAMR) is associated with chronic auditory toxicity in infants ≥34 weeks’ GA with SHB.

Effect of Dexamethasone Therapy on Serum Vitamin E Concentrations in Premature Infants with Bronchopulmonary Dysplasia

OBJECTIVE: To investigate the effect of dexamethasone therapy on serum vitamin E concentrations in premature infants with bronchopulmonary dysplasia.STUDY DESIGN: A total of 10, 24 to 29 weeks’ gestational age, infants enrolled in a prospective study designed to evaluate the effect of dexamethasone on lipid intolerance were eligible for the study. Eight of these 10 infants had serum vitamin E concentrations measured simultaneously with serum triglyceride concentrations before the start of dexamethasone therapy (baseline) and within 5 days of the initiation of dexamethasone therapy. Charts were reviewed for vitamin E intake at baseline and on dexamethasone therapy for each of these eight infants.RESULTS: All eight infants had physiological serum vitamin E concentrations (1 to 3 mg/dl) at baseline, while six of eight infants had pharmacological serum vitamin E concentrations (≥3 mg/dl) on dexamethasone therapy. All infants with an increase in serum vitamin E concentration also had a simultaneous increase in serum triglyceride concentrations with a significant correlation between vitamin E and triglyceride concentrations (Spearmans ρ=0.92). There was a significant difference in mean serum vitamin E concentration between baseline and post-dexamethasone therapy (P=0.01, Wilcoxons signed-rank test). There was no significant difference in vitamin E intake between baseline and post-dexamethasone therapy.CONCLUSION: Dexamethasone therapy in premature infants induces significant increase in serum vitamin E concentrations to pharmacological levels independent of vitamin E intake.

December 26 Highlight and Commentary Heart rate changes and the detection of seizures in the newborn

Cherian et al. report that heart rate monitoring appears to be insensitive for detecting post-asphyxial seizures in neonates. The authors found heart rate changes occurring during 21/169 seizures in 8/14 neonates with subclinical seizures following severe birth asphyxia. see page 2221 Commentary by Nirupama Laroia, MD Studies of epileptic seizures in adults show that autonomic dysregulation (changes in blood pressure and heart rate) are helpful in differentiating pseudoseizures from epileptic seizures.1 While the basic mechanism of sudden unexpected death in epilepsy (SUDEP) remains unclear, it has been postulated to be associated with rhythm …

NEONATAL ELECTRICAL SEIZURES ARE OFTEN CLINICALLY INAPPARENT AND RESISTANT TO TREATMENT. † 2240

Neonates may have electrical seizures (ES) that are clinically undetected. To identify such infants, 27 infants were monitored with continuous EEG because they were considered to be at high risk: 16 with perinatal asphyxia (5 min Apgar score ≤5 and/or cord pH≤7.2 and continuing lethargy at 2h), of which 11 had suspected clinical seizures (szs) or abnormal movements; 8 with suspected clinical szs without asphyxia; 1 with unexplained apnea at term; 1 with meningitis; 1 with cerebral anomalies. Monitoring continued for 6h-24h(mean 20h) if no ES or 13h-26h (mean 21h) after the last ES. ES were treated with phenobarbital (up to 40 mg/kg) or lorazepam (0.1 mg/kg, up to 3 doses/8h); the second drug was added if ES continued. 13 of the 27 infants had no ES. Of these, 6 had already received anticonvulsant for suspected clinical szs before monitoring; 3 with suspected clinical szs without ES were not treated with anticonvulsant. 14 infants with ES were monitored for a total of 21h-97h (mean 45h) during which 4-226 (mean 54) ES were recorded. Clinical correlates were seen for fewer than 10% of their ES and 5 of the 14 had no clinical szs noted. 5 had more than 10 clinically inapparent ES per hour. 2 of 6 treated with phenobarbital went on to lorazepam; 4 of 9 treated with lorazepam went on to phenobarbital. In 2 infants, multiple ES continued without clinical correlates despite full doses of both drugs that stopped after loading doses of phenytoin. Clinical ascertainment of neonatal seizures is difficult. Continuous EEG monitoring in high risk neonates allows detection of abnormal cortical electrical activity that is not apparent clinically. Animal studies indicate that frequent ES are deleterious to the developing brain. The frequency and duration of clinically undetected ES in neonates and their resistance to traditional anticonvulsant therapy have not been adequately emphasized.