Elective high-frequency oscillatory versus conventional ventilation in preterm infants: a systematic review and meta-analysis of individual patients' data.

BACKGROUND: Population and study design heterogeneity has confounded previous meta-analyses, leading to uncertainty about effectiveness and safety of elective high-frequency oscillatory ventilation (HFOV) in preterm infants. We assessed effectiveness of elective HFOV versus conventional ventilation in this group. METHODS: We did a systematic review and meta-analysis of individual patients' data from 3229 participants in ten randomised controlled trials, with the primary outcomes of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age, death or severe adverse neurological event, or any of these outcomes. FINDINGS: For infants ventilated with HFOV, the relative risk of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age was 0.95 (95% CI 0.88-1.03), of death or severe adverse neurological event 1.00 (0.88-1.13), or any of these outcomes 0.98 (0.91-1.05). No subgroup of infants (eg, gestational age, birthweight for gestation, initial lung disease severity, or exposure to antenatal corticosteroids) benefited more or less from HFOV. Ventilator type or ventilation strategy did not change the overall treatment effect. INTERPRETATION: HFOV seems equally effective to conventional ventilation in preterm infants. Our results do not support selection of preterm infants for HFOV on the basis of gestational age, birthweight for gestation, initial lung disease severity, or exposure to antenatal corticosteroids. FUNDING: Nestlé Belgium, Belgian Red Cross, and Dräger International.

Extremes of age are associated with differences in the expression of selected pattern recognition receptor genes and ACE2, the receptor for SARS-CoV-2: implications for the epidemiology of COVID-19 disease.

BACKGROUND: Older aged adults and those with pre-existing conditions are at highest risk for severe COVID-19 associated outcomes. METHODS: Using a large dataset of genome-wide RNA-seq profiles derived from human dermal fibroblasts (GSE113957) we investigated whether age affects the expression of pattern recognition receptor (PRR) genes and ACE2, the receptor for SARS-CoV-2. RESULTS: Extremes of age are associated with increased expression of selected PRR genes, ACE2 and four genes that encode proteins that have been shown to interact with SAR2-CoV-2 proteins. CONCLUSIONS: Assessment of PRR expression might provide a strategy for stratifying the risk of severe COVID-19 disease at both the individual and population levels.

Early inhaled nitric oxide therapy in premature newborns with respiratory failure.

BACKGROUND: The safety and efficacy of early, low-dose, prolonged therapy with inhaled nitric oxide in premature newborns with respiratory failure are uncertain. METHODS: We performed a multicenter, randomized trial involving 793 newborns who were 34 weeks of gestational age or less and had respiratory failure requiring mechanical ventilation. Newborns were randomly assigned to receive either inhaled nitric oxide (5 ppm) or placebo gas for 21 days or until extubation, with stratification according to birth weight (500 to 749 g, 750 to 999 g, or 1000 to 1250 g). The primary efficacy outcome was a composite of death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age. Secondary safety outcomes included severe intracranial hemorrhage, periventricular leukomalacia, and ventriculomegaly. RESULTS: Overall, there was no significant difference in the incidence of death or bronchopulmonary dysplasia between patients receiving inhaled nitric oxide and those receiving placebo (71.6 percent vs. 75.3 percent, P=0.24). However, for infants with a birth weight between 1000 and 1250 g, as compared with placebo, inhaled nitric oxide therapy reduced the incidence of bronchopulmonary dysplasia (29.8 percent vs. 59.6 percent); for the cohort overall, such treatment reduced the combined end point of intracranial hemorrhage, periventricular leukomalacia, or ventriculomegaly (17.5 percent vs. 23.9 percent, P=0.03) and of periventricular leukomalacia alone (5.2 percent vs. 9.0 percent, P=0.048). Inhaled nitric oxide therapy did not increase the incidence of pulmonary hemorrhage or other adverse events. CONCLUSIONS: Among premature newborns with respiratory failure, low-dose inhaled nitric oxide did not reduce the overall incidence of bronchopulmonary dysplasia, except among infants with a birth weight of at least 1000 g, but it did reduce the overall risk of brain injury. (ClinicalTrials.gov number, NCT00006401 [ClinicalTrials.gov].).

The pharmacokinetics and safety of micafungin, a novel echinocandin, in premature infants.

BACKGROUND: : Candidal fungal infection rates in neonates are increasing and are a significant cause of mortality, especially in low birth weight infants. Micafungin is an echinocandin that works by inhibiting 1,3-beta-D-glucan synthase, an enzyme responsible for fungal cell wall synthesis. The objective of this study was to determine the safety and pharmacokinetics of micafungin in premature infants. METHODS: : This was a phase I, single-dose, multicenter, open-label, sequential-dose trial of intravenous micafungin investigating 3 doses (0.75 mg/kg, 1.5 mg/kg and 3.0 mg/kg) in 18 premature infants weighing >1000 g (n = 6 in each dosage group). A further 5 infants (500-1000 g) were enrolled in the 0.75 mg/kg dosage group only. RESULTS: : The mean +/- standard deviation gestational age in the >1000 g dosage group was 26.4 +/- 2.4 weeks and, on entry, patients had one or more of a variety of underlying conditions, including sepsis, pneumonia and other infections caused by Candida or other species. Micafungin pharmacokinetics in preterm infants appears linear. However, premature infants >1000 g on average displayed a shorter half-life (8 hours) and a more rapid rate of clearance (approximately 39 mL/h per kg) compared with published data in older children and adults. All doses of micafungin were well tolerated and no serious drug-related adverse events were observed. CONCLUSIONS: : Single doses of micafungin, ranging up to 3.0 mg/kg, appear well tolerated in premature infants weighing >1000 g. The drug's elimination half-life and total plasma clearance in preterm infants appear dissimilar to published values for these parameters in older children and adults. The reason(s) for this apparent difference remain to be investigated.

Implementing feeding guidelines for NICU patients<2000 g results in less variability in nutrition outcomes.

BACKGROUND: We devised a consistent approach to instituting and advancing enteral nutrition among neonatal intensive care unit (NICU) patients<2000 g birth weight. We then assessed variability in feeding-related outcomes during a period before (period 1) vs after (period 2) implementing these guidelines. METHODS: Using data from period 1 vs period 2, we statistically compared the equivalence of variance, focusing on certain feeding-related outcomes. Specific outcomes we chose to examine were (1) day of life when the first enteral feedings were given, (2) number of days during the entire hospitalization when no feedings were given, (3) number of days parenteral nutrition (PN) was administered, and (4) day of life when feedings of 80 mL/k/d and 100 kcal/k/d enteral were achieved. RESULTS: Fifty-eight patients<2000 g were admitted to the NICU in period 1, of which 56 survived to discharge home. In period 2, 68 patients<2000 g were admitted and 66 survived to discharge. Demographic features of the patients in periods 1 and 2 did not differ. In both periods, feedings were begun on a median of day 1. However, in period 1 the range was from day 0 to day 24, and in period 2, the range was from day 0 to day 6 (equivalence of variance p<.001). After feedings were initiated, they were withheld for a median of 2 days (range, 0-23) during the remainder of the hospitalization in period 1 vs a median of 1 day (range, 0-12) in period 2 (p<.001). During period 1, PN was used for a median of 10 days (range, 0-72) vs 7 (range, 0-47) in period 2 (p=.001). During period 1, more variability occurred in the day of life when 80 mL/k/d and 100 kcal/k/d were achieved (both p<.001). No differences were seen in necrotizing enterocolitis, intestinal perforation, mortality, or length of hospital stay. CONCLUSIONS: Implementing feeding guidelines was associated with significantly less variability in feeding-related outcomes. We speculate that this is a reflection of better feeding tolerance, which resulted from a more consistent approach to initiating and advancing enteral feedings.

Enteral administration of a simulated amniotic fluid to very low birth weight neonates.

OBJECTIVE: To reduce feeding intolerance among very low birth weight neonates. STUDY DESIGN: A total of 10 neonates with birth weights of 750 to 1250 g were given oral-gastric boluses (2.5 ml/kg every 3 hours) of a solution patterned after amniotic fluid. When milk feedings were begun the milk was mixed with the test solution. The solution was given at a constant daily dose of 20 ml/kg/day while the volumes of milk feedings were gradually increased. When milk feedings reached 80 ml/kg/day the test solution was discontinued. A comparison group consisted of neonates who met study criteria but were cared for during the period immediately preceding the study. The outcome was the number of calories taken enterally over the first 21 days of life. RESULTS: The test solution was begun an average of 27 hours after birth (range, 4 to 45). In the test group the first milk feedings were introduced 74 hours after birth (range, 18 to 144), which was similar to the time milk was introduced in the comparison subjects (79 hours; range, 18 to 168). After milk feedings were started, the test patients had a total of four NPO days (0.4 NPO days per patient) during their first 21 days, while the comparison group had 34 NPO days (3.4 NPO days per patient). During the first 14 days of life the test solution recipients had a median of 26.5 enteral cal/kg/day (range, 4.3 to 68.9), while the comparison neonates had 8.5 (range, 0.2 to 25; p < 0.05). During the first 21 days of life the test solution recipients had a median of 56.9 enteral cal/kg/day (range, 11.5 to 89.4), while the comparison neonates had 19.2 (range, 0.9 to 52.8; p < 0.05). CONCLUSION: In all, 10 VLBW infants tolerated the test solution for periods up to 14 days with no significant adverse effects. A randomized trial to determine whether this solution reduces feeding intolerance among VLBW neonates should be conducted.

Reported medication use in the neonatal intensive care unit: data from a large national data set.

OBJECTIVES: The objectives were (1) to identify the drugs reported most commonly during NICU care, (2) to examine how different methods of documenting drug use could influence prioritization of drugs for future research aimed at evaluating safety and efficacy, (3) to describe the demographic differences in the population samples for some specific medications, (4) to identify which reported medications are used for patient populations with >20% mortality rates, and (5) to examine how reports of drug use change over time. METHODS: A retrospective review of a large national data set was performed. RESULTS: The 10 medications reported most commonly for the NICU were ampicillin, gentamicin, ferrous sulfate, multivitamins, cefotaxime, caffeine citrate, furosemide, vancomycin, surfactant, and metoclopramide. Medications used for patient populations with >20% mortality rates included amphotericin, clonazepam, dobutamine, epinephrine, ethacrynic acid, insulin, lidocaine, metolazone, milrinone, inhaled nitric oxide, nitroglycerin, octreotide, pancuronium, phenytoin, sodium nitroprusside, sodium polystyrene sulfonate (Kayexalate), tris-hydroxymethylaminomethane acetate buffer, and tolazoline. Several of these drugs (eg, amphotericin B and bumetanide) were used primarily for extremely premature neonates, and this usage might explain the high mortality rates for the population of neonates treated with these medications. Other medications (clonazepam, milrinone, inhaled nitric oxide, and phenytoin) were used primarily for near-term and term infants. The explanation for the high mortality rates for these neonates is less clear and may be related primarily to the severity of illness for which the medications are used. Utilization rates for several different medications (eg, cisapride, metoclopramide, and dexamethasone) changed by >50% during the past 5 years. CONCLUSIONS: Data reported here are the first from a large national data set on the use of different medications for neonates admitted for intensive care and should be helpful in establishing priority agendas for future drug studies in this population.

Empiric use of ampicillin and cefotaxime, compared with ampicillin and gentamicin, for neonates at risk for sepsis is associated with an increased risk of neonatal death.

BACKGROUND: We reported previously that the use of cephalosporin among premature neonates increased the risk of subsequent fungal sepsis. As a result, we recommended that ampicillin and gentamicin be used as empiric coverage for early-onset neonatal sepsis while culture results are awaited. OBJECTIVES: To describe antibiotic use during the first 3 days after birth for neonates admitted to the NICU and to evaluate the outcomes for neonates treated with 2 different antibiotic regimens. METHODS: We assembled a cohort of inborn neonates, from our deidentified administrative database, who had documented exposure to ampicillin during the first 3 days after birth. Infants treated concurrently with cefotaxime or gentamicin were evaluated, to identify the factors that were associated independently with death before discharge, with both univariate and multivariate analyses. RESULTS: There were 128,914 neonates selected as the study cohort; 24,111 were treated concurrently with ampicillin and cefotaxime and 104,803 were treated concurrently with ampicillin and gentamicin. Logistic modeling showed that neonates treated with ampicillin/cefotaxime were more likely to die (adjusted odds ratio: 1.5; 95% confidence interval: 1.4-1.7) and were less likely to be discharged to home or foster care than were neonates treated with ampicillin/gentamicin. This observation was true across all estimated gestational ages. Other factors that were associated independently with death included immature gestational age, need for assisted ventilation on the day of admission to the NICU, indications of perinatal asphyxia or major congenital anomaly, and reported use of ampicillin/cefotaxime. CONCLUSIONS: For patients receiving ampicillin, the concurrent use of cefotaxime during the first 3 days after birth either is a surrogate for an unrecognized factor or is itself associated with an increased risk of death, compared with the concurrent use of gentamicin.

A randomized, multicenter masked comparison trial of poractant alfa (Curosurf) versus beractant (Survanta) in the treatment of respiratory distress syndrome in preterm infants.

We compared the onset of clinical response and safety of two surfactants, poractant alfa (Curosurf, Chiesi Pharmaceuticals, Parma, Italy) and beractant (Survanta, Ross Laboratories, Columbus, OH), for treatment of respiratory distress syndrome (RDS) in preterm infants weighing 750 to 1750 g at birth and <35 weeks gestation. The study was performed as a 20-center prospective, randomized, masked comparison trial. Preterm infants (n = 293) with RDS were randomized to receive an initial dose of either 100 (n = 96) or 200 (n = 99) mg/kg of poractant alfa or 100 ( n = 98) mg/kg of beractant. All repeat dosing was given at 100 mg/kg. The onset of clinical response after the first dose was studied by comparing changes in the fraction of inspired oxygen (F IO(2)) between 0 and 6 hours measured using the area under the curve (F IO(2) AUC (0-6)); other outcomes were assessed for the entire cohort at 28 days and for infants born at < or = 32 weeks gestation at 36 weeks postconceptional age. We found that the mean F IO(2) AUC (0-6) values for the 100 and 200 mg/kg poractant alfa groups were both significantly lower than the mean F IO(2) AUC (0-6) values for the beractant group ( p < 0.005) but were not different from each other. Other outcomes were not different among the three groups for the entire cohort, but in infants born at < or = 32 weeks gestation, mortality up to 36 weeks postconceptional age was significantly less in the 200 mg/kg poractant alfa group than in either the beractant group (3% versus 11%; p = 0.034) or in the 100 mg/kg poractant alfa group (3% versus 11%; p = 0.046). Need for more than one dose of surfactant was significantly lower in infants treated with an initial dose of 200 mg/kg poractant alfa in comparison to the beractant-treated group ( p < 0.002). Treatment with poractant alfa (200 mg/kg initial dose) resulted in rapid reduction in supplemental oxygen with fewer additional doses of surfactant versus treatment with beractant in infants <35 weeks gestation with RDS, and significantly reduced mortality ( p <0.05) than either beractant or poractant alfa (100 mg/kg dosing) in infants < or =32 weeks gestation with RDS.

Treatment of neonatal pain without a gold standard: the case for caregiving interventions and sucrose administration.

Although many different neonatal pain assessment scales are used in clinical research, no gold-standard instrument exists. The multitude of pain assessment scales used has, in fact, threatened the validity of many studies and confused the construct of pain. This integrative review of the neonatal pain literature provides the recommendations from practice guidelines and the current evidence for modifying the pain response prior to and during common painful procedures.