Differences in demographics and outcomes based on method of consent for a randomised controlled trial on heat loss prevention in the delivery room.

OBJECTIVE: Informed consent is standard in research. International guidelines allow for research without prior consent in emergent situations, such as neonatal resuscitation. Research without prior consent was incorporated in the Vermont Oxford Network Heat Loss Prevention Trial. We evaluated whether significant differences in outcomes exist based on the consent method. DESIGN: Subgroup analysis of infants enrolled in a randomised controlled trial conducted from 2004 to 2010. SETTING: A multicentre trial with 38 participating centres. PARTICIPANTS: Infants born 24-27 weeks of gestation. 3048 infants assessed, 2231 excluded due to fetal congenital anomalies, failure to obtain consent or gestation less than 24 weeks. 817 randomised, 4 withdrew consent, total of 813 analysed. MAIN OUTCOME MEASURE: The difference in mortality between consent groups. RESULTS: No significant differences were found in mortality at 36 weeks (80.2%, 77.4%, p=0.492) or 6 months corrected gestational age (80.7%, 79.7%, p=0.765). Infants enrolled after informed consent were more likely to have mothers who had received antenatal steroids (95.2%, 84.0%, p<0.0001). They also had significantly higher Apgar scores at 1 (5.0, 4.4, p=0.019), 5 (7.3, 6.7, p=0.025) and 10 min (7.5, 6.3, p=0.0003). CONCLUSIONS AND RELEVANCE: Research without prior consent resulted in the inclusion of infants with different baseline characteristics than those enrolled after informed consent. There were no significant differences in mortality. Significantly higher Apgar scores in the informed consent group suggest that some of the sicker infants would have been excluded from enrolment under informed consent. Research without prior consent should be considered in neonatal resuscitation research.

Levels of Care for Perinatal Health.

Since its inception in the 1970s, the stratification of perinatal health care into complexity-based levels has resulted in improved outcomes. Recent trends toward de-regionalization based on financial incentives, however, threaten to undermine these gains and should be addressed.

Parallel Exploratory RCT of Polyethylene Wrap for Heat Loss Prevention in Infants Born at Less than 24 Weeks' Gestation.

BACKGROUND: The treatment effect of occlusive wrap applied immediately after delivery in infants born 24-28 weeks' gestation has been studied, but the effect is not known in infants born at less than 240/7 weeks' gestation. OBJECTIVES: To determine if the use of occlusive wrap applied immediately after birth in infants born at less than 240/7 weeks' gestation results in any differences in outcomes when compared to non-wrapped infants. METHODS: Parallel exploratory randomized controlled trial with a convenience sample of 28 inborn infants born at less than 240/7 weeks' gestation enrolled during the duration of the HeLP trial. Infants were randomized to either the wrap or standard of care (no wrap) group. RESULTS: Twenty-eight infants (wrap n = 14; no wrap n = 14) were randomized and data on all infants was available for intention-to-treat analysis. There were no differences in baseline population characteristics. There was no statistically significant difference in mortality (n = 8/14 wrap, 8/14 no wrap). There was no statistically significant difference in baseline temperature (35.9°C, SD = 1.12, wrap vs. 35.1°C, SD = 1.16, no wrap, p = 0.16) or post-stabilization temperature (36.4°C, SD = 0.84, wrap vs. 36.1°C, SD = 1.2, no wrap, p = 0.56). There was a trend towards increased baseline temperature in the wrap group. CONCLUSION: Application of occlusive wrap to infants born at less than 240/7 weeks' gestation immediately after birth did not reduce mortality or effect baseline or post-stabilization temperature in this small exploratory study. This small sample provides the first estimate of treatment effect for this high-risk population.

Randomized trial of occlusive wrap for heat loss prevention in preterm infants.

OBJECTIVE: To determine whether the application of occlusive wrap applied immediately after birth will reduce mortality in very preterm infants. STUDY DESIGN: This was a prospective randomized controlled trial of infants born 24 0/7 to 27 6/7 weeks' gestation who were assigned randomly to occlusive wrap or no wrap. The primary outcome was all cause mortality at discharge or 6 months' corrected age. Secondary outcomes included temperature, Apgar scores, pH, base deficit, blood pressure and glucose, respiratory distress syndrome, bronchopulmonary dysplasia, seizures, patent ductus arteriosus, necrotizing enterocolitis, gastrointestinal perforation, intraventricular hemorrhage, cystic periventricular leukomalacia, pulmonary hemorrhage, retinopathy of prematurity, sepsis, hearing screen, and pneumothorax. RESULTS: Eight hundred one infants were enrolled. There was no difference in baseline population characteristics. There were no significant differences in mortality (OR 1.0, 95% CI 0.7-1.5). Wrap infants had statistically significant greater baseline temperatures (36.3°C wrap vs 35.7°C no wrap, P < .0001) and poststabilization temperatures (36.6°C vs 36.2°C, P < .001) than nonwrap infants. For the secondary outcomes, there was a significant decrease in pulmonary hemorrhage (OR 0.6, 95% CI 0.3-0.9) in the wrap group and a significant lower mean one minute Apgar score (P = .007) in the wrap group. The study was stopped early because continued enrollment would not result in the attainment of a significant difference in the primary outcome. CONCLUSION: Application of occlusive wrap to very preterm infants immediately after birth results in greater mean body temperature but does not reduce mortality.

Study protocol for multicentre randomized controlled trial of HeLP (Heat Loss Prevention) in the delivery room.

INTRODUCTION: Immediate postnatal hypothermia is an independent risk factor for death in premature newborns. Three randomized controlled trials (RCTs) and five historical controlled trials show statistically significant differences in admission temperature between infants wrapped in occlusive skin wrap and unwrapped infants. This paper presents a study protocol for The Vermont Oxford Network (VON) Heat Loss Prevention (HeLP) Trial, a multicentre RCT of two interventions (standard of care vs. occlusive wrap) that investigates the effect of polyethylene occlusive wrap applied immediately after birth on mortality in infants born 24 + 0/7 to 27 + 6/7 week gestation. METHODS: Inclusion criteria include: infants 24 + 0/7 to 27 + 6/7 weeks gestational age and a firm decision prior to birth to provide full resuscitative measures. Exclusion criteria comprise infants born with blistering skin conditions or congenital anomalies that are not covered by skin. The primary outcome measure is all-cause mortality until discharge from the hospital or at six months corrected gestational age. The secondary outcome measures include baseline and post-stabilization axillary temperatures, acidosis, hypotension, hypoglycaemia, seizures in the first 12h, patent ductus arteriosus, and respiratory distress syndrome. Long-term follow-up at 18 to 24 months corrected age will be assessed with the combined risk of death and major neurosensory disability as the primary outcome. DISCUSSION: Key covariates and protocol deviations are addressed and steps to monitor these are described. Wrapping may prove an inexpensive and easy method to benefit premature newborns in level I and II nurseries, in both developed and developing countries, as well as large tertiary care centres. REB APPROVAL: Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada-355-2003 University of Alberta, Edmonton, Alberta, Canada-Pro00003810 Vermont Oxford Network, Burlington, Vermont, USA-CHRMS: M04-295.

Dexmedetomidine versus standard therapy with fentanyl for sedation in mechanically ventilated premature neonates.

OBJECTIVE: To compare the efficacy and safety of dexmedetomidine and fentanyl for sedation in mechanically ventilated premature neonates. METHODS: This was a retrospective, observational case-control study in a level III neonatal intensive care unit. Forty-eight premature neonates requiring mechanical ventilation were included. Patients received fentanyl (n=24) or dexmedetomidine (n=24) for pain or sedation. Each group also received fentanyl and lorazepam boluses as needed for agitation. The primary outcomes were efficacy and frequency of acute adverse events associated with each drug. Days on mechanical ventilation, stooling patterns, feeding tolerance, and neurologic outcomes were also evaluated. RESULTS: There were no significant differences in baseline demographics between the dexmedetomidine and fentanyl patients. Patients in the dexmedetomidine group required less adjunctive sedation and had more days free of additional sedation in comparison to fentanyl (54.1% vs. 16.5%, p<0.0001). There were no differences in hemodynamic parameters between the 2 groups. Duration of mechanical ventilation was shorter in the dexmedetomidine group (14.4 vs. 28.4 days, p<0.001). Meconium passage (7.5 vs. 22.4 days, p<0.0002) and time from initiation to achievement of full enteral feeds (26.8 vs. 50.8 days, p<0.0001) were shorter in the dexmedetomidine group. Incidence of culture-positive sepsis was lower in the dexmedetomidine group (48% vs. 88%). The incidence of either severe intraventricular hemorrhage or periventricular leukomalacia was not statistically significantly reduced (2% vs. 7%). CONCLUSIONS: Dexmedetomidine was safe and effective for sedation in the premature neonates included in this study. Prospective randomized-controlled trials are needed before routine use of dexmedetomidine can be recommended.

Effect of routine probiotic, Lactobacillus reuteri DSM 17938, use on rates of necrotizing enterocolitis in neonates with birthweight < 1000 grams: a sequential analysis.

BACKGROUND: Necrotizing enterocolitis (NEC) is a disease in neonates, often resulting in death or serious medical or neurodevelopmental complications. The rate of NEC is highest in the smallest babies and many efforts have been tried to reduce the rate of NEC. In neonates born below 1500 grams, the rate of NEC has been significantly reduced with the use of various probiotics. This study examines the impact of routine use of a probiotic, Lactobacillus reuteri DSM 17938 (BioGaia®), on the rate of NEC in neonates at highest risk for developing NEC, those with birth weight ≤1000 grams. METHODS: This is a retrospective cohort study comparing the rates of NEC in neonates with birth weight ≤ 1000 grams. The groups are separated into those neonates born from January 2004 to June 30, 2009, before introduction of L. reuteri , and neonates born July 2009 through April 2011 who received routine L. reuteri prophylaxis. The chart review study was approved by our institutional review board and exempted from informed consent.Neonates were excluded if they died or were transferred within the first week of life. The remainder were categorized as having no NEC, medical NEC, surgical NEC, or NEC associated death. Since no major changes occurred in our NICU practice in recent years, and the introduction of L. reuteri as routine prophylaxis was abrupt, we attributed the post-probiotic changes to the introduction of this new therapy. Rates of NEC were compared using Chi square analysis with Fisher exact t-test. RESULTS: Medical records for 311 neonates were reviewed, 232 before- and 79 after-introduction of L. reuteri prophylaxis. The incidence of NEC was significantly lower in the neonates who received L. reuteri (2 of 79 neonates [2.5%] versus 35 of 232 untreated neonates [15.1%]). Rates of late-onset gram-negative or fungal infections (22.8 versus 31%) were not statistically different between treated and untreated groups. No adverse events related to use of L reuteri were noted. CONCLUSIONS: Prophylactic initiation of L. reuteri as a probiotic for prevention of necrotizing enterocolitis resulted in a statistically significant benefit, with avoidance of 1 NEC case for every 8 patients given prophylaxis.

Oseltamivir dosing for influenza infection in premature neonates.

Under the Emergency Use Authorization issued in April 2009, oseltamivir can be used to treat 2009 influenza A (H1N1) virus infection in children aged <1 year. No data exist on the dosing of oseltamivir in premature babies. A hospital health care worker inadvertently exposed 32 neonatal intensive care unit babies to 2009 influenza A (H1N1); a protocol was expeditiously implemented to collect samples for pharmacokinetics and dosage evaluation. Results suggest 1.0 mg/kg/dose twice daily in premature babies produces oseltamivir carboxylate exposures similar to that in older children receiving 3.0 mg/kg/dose twice daily. These results provide initial guidance on dosing oseltamivir in this vulnerable population.

Indomethacin pharmacodynamics are altered by surfactant: a possible challenge to current indomethacin dosing guidelines created before surfactant availability.

The effect of surfactant administration for respiratory distress syndrome (RDS) on indomethacin (INDO) pharmacodynamics and dosing requirements for patent ductus arteriosus (PDA) closure and renal toxicity was evaluated. A 22-year prospective cohort study including 442 INDO-treated patients given 466 INDO treatment courses. The database included demographic information, medical problems, and medications. Neonates with a PDA confirmed by echocardiography were treated with INDO, 0.25-0.3 mg/kg. Subsequent INDO dosing was based on a combined pharmacokinetic/pharmacodynamic (PK/PD) approach. Data were fit to an Emax model and ANOVA was used to compare mean closure levels between groups. PDA closure was successful in 405 of 442 patients (91.6%) and in 434 of 466 treatment courses (93.1%) using an individualized PK/PD dosing approach. Renal toxicity was documented in 56 of 442 patients (12.7%) or 56 of 466 treatment courses (12.0%). Patients not treated with synthetic surfactant trended toward lower mean INDO concentrations at PDA closure compared to patients treated with synthetic surfactant (1.65 vs. 2.01 mg/l; P > 0.05) and significantly lower mean INDO concentrations at PDA closure compared to patients treated with natural surfactant (1.65 vs. 2.15 mg/l; P < 0.002). This requires an increased total dose of ~0.3 mg/kg or an individual dose increase of 0.1 mg/kg. Administration of natural or synthetic surfactant for RDS may increase the INDO concentrations and doses needed for PDA closure in premature infants.

Low-dose aminophylline for the treatment of neonatal non-oliguric renal failure-case series and review of the literature.

OBJECTIVE: Aminophylline is a methylxanthine with multiple physiologic actions. At low doses, aminophylline can antagonize adenosine and improve renal function via increased glomerular filtration rate. Despite its clinical use, little data exists in neonates for this indication. Therefore, the objective of this report is to describe the impact of aminophylline on renal function indices in a series of neonates with acute renal failure. MATERIALS AND METHODS: This was a retrospective chart review of 13 neonates with acute renal failure who received aminophylline during a 15-month study period. Aminophylline was administered at 1 mg/kg intravenously or orally every twelve hours. Forty-six percent (n = 6) of the patients received a 5 mg/kg loading dose before initiation of maintenance therapy. Most patients had already received other treatments for renal failure, including diuretics and dopamine. RESULTS: Resolution of acute renal failure (with normalization of serum creatinine and blood urea nitrogen) was documented in 10 patients (77%). Four of the thirteen patients died from complications due to their prematurity. Failure of low-dose aminophylline was observed in 3 of the 4 patients who died. CONCLUSIONS: Low-dose aminophylline in neonates with acute renal failure is associated with an improvement in renal function indices.

Heat loss prevention for preterm infants in the delivery room.

OBJECTIVE: Preterm infants are prone to hypothermia immediately following birth. Among other factors, excessive evaporative heat loss and the relatively cool ambient temperature of the delivery room may be important contributors. Most infants <29 weeks gestation had temperatures <36.4 degrees C on admission to our neonatal unit (NICU). Therefore we conducted a randomized, controlled trial to evaluate the effect of placing these infants in polyurethane bags in the delivery room to prevent heat loss and reduce the occurrence of hypothermia on admission to the NICU. METHODS: After parental consent was obtained, infants expected to be <29 weeks gestation were randomized to intervention or control groups just prior to their birth. Infants randomized to the intervention group were placed in polyurethane bags up to their necks immediately after delivery before being dried. They were then resuscitated per NRP guidelines, covered with warm blankets, and transported to the NICU, where the bags were removed and rectal temperatures were recorded. Control infants were resuscitated, covered with warm blankets, and transported without being placed in polyurethane bags. Delivery room temperatures were recorded so this potentially confounding variable could be assessed. RESULTS: Intervention patients were less likely than control patients to have temperature < 36.4 degrees C on admission , 44 vs 70% (p<0.01) and the intervention group had a higher mean admission temperature, 36.5 degrees C vs 36.0 degrees C (p<0.003). This effect remained significant (p<0.0001) when delivery room temperature was controlled in analysis. Warmer delivery room temperatures (>/=26 degrees C) were associated with higher admission temperatures in both intervention and control infants, but only the subgroup of intervention patients born in warmer delivery rooms had a mean admission temperature >36.4 degrees C. CONCLUSIONS: Placing infants <29 weeks gestation in polyurethane bags in the delivery room reduced the occurrence of hypothermia and increased their NICU admission temperatures. Maintaining warmer delivery rooms helped but was insufficient in preventing hypothermia in most of these vulnerable patients without the adjunctive use of the polyurethane bags.