Effect of Hydrocortisone Therapy Initiated 7 to 14 Days After Birth on Mortality or Bronchopulmonary Dysplasia Among Very Preterm Infants Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Dexamethasone initiated after the first week of life reduces the rate of death or bronchopulmonary dysplasia (BPD) but may cause long-term adverse effects in very preterm infants. Hydrocortisone is increasingly used as an alternative, but evidence supporting its efficacy and safety is lacking. Objective: To assess the effect of hydrocortisone initiated between 7 and 14 days after birth on death or BPD in very preterm infants. Design, Setting, and Participants: Double-blind, placebo-controlled randomized trial conducted in 19 neonatal intensive care units in the Netherlands and Belgium from November 15, 2011, to December 23, 2016, among preterm infants with a gestational age of less than 30 weeks and/or birth weight of less than 1250 g who were ventilator dependent between 7 and 14 days of life, with follow-up to hospital discharge ending December 12, 2017. Interventions: Infants were randomly assigned to receive a 22-day course of systemic hydrocortisone (cumulative dose, 72.5 mg/kg) (n = 182) or placebo (n = 190). Main Outcomes and Measures: The primary outcome was a composite of death or BPD assessed at 36 weeks' postmenstrual age. Twenty-nine secondary outcomes were analyzed up to hospital discharge, including death and BPD at 36 weeks' postmenstrual age. Results: Among 372 patients randomized (mean gestational age, 26 weeks; 55% male), 371 completed the trial; parents withdrew consent for 1 child treated with hydrocortisone. Death or BPD occurred in 128 of 181 infants (70.7%) randomized to hydrocortisone and in 140 of 190 infants (73.7%) randomized to placebo (adjusted risk difference, -3.6% [95% CI, -12.7% to 5.4%]; adjusted odds ratio, 0.87 [95% CI, 0.54-1.38]; P = .54). Of 29 secondary outcomes, 8 showed significant differences, including death at 36 weeks' postmenstrual age (15.5% with hydrocortisone vs 23.7% with placebo; risk difference, -8.2% [95% CI, -16.2% to -0.1%]; odds ratio, 0.59 [95% CI, 0.35-0.995]; P = .048). Twenty-one outcomes showed nonsignificant differences, including BPD (55.2% with hydrocortisone vs 50.0% with placebo; risk difference, 5.2% [95% CI, -4.9% to 15.2%]; odds ratio, 1.24 [95% CI, 0.82-1.86]; P = .31). Hyperglycemia requiring insulin therapy was the only adverse effect reported more often in the hydrocortisone group (18.2%) than in the placebo group (7.9%). Conclusions and Relevance: Among mechanically ventilated very preterm infants, administration of hydrocortisone between 7 and 14 days after birth, compared with placebo, did not improve the composite outcome of death or BPD at 36 weeks' postmenstrual age. These findings do not support the use of hydrocortisone for this indication. Trial Registration: Netherlands National Trial Register Identifier: NTR2768.

Neuroimaging and neurodevelopmental outcome of preterm infants with a periventricular haemorrhagic infarction located in the temporal or frontal lobe.

AIM: The aim of the study was to compare clinical and neuroimaging characteristics and neurodevelopmental outcome in preterm infants with a periventricular haemorrhagic infarction (PVHI) located in the temporal or frontal periventricular white matter. METHOD: The study was a retrospective hospital-based study of preterm infants with a frontal PVHI (n=21; 11 males, 10 females; mean birthweight 1527g; mean gestational age 30.3wks) or temporal PVHI (n=13; five males, eight females; mean birthweight 1205g; mean gestational age 30.2wks) admitted to the neonatal intensive care unit between 1990 and 2012. The clinical course, results of neuroimaging studies, and neurodevelopmental outcomes of preterm infants with a gestational age less than 34 weeks with a confirmed PVHI on early cranial ultrasonography and/or magnetic resonance imaging were reviewed. For assessment of neurodevelopmental outcome we used the Griffiths Mental Development Scales, the Movement Assessment Battery for Children, the Gross Motor Function Classification System, the Wechsler Preschool and Primary Scale of Intelligence, the Child Behavior Checklist, and ophthalmological assessment. An unfavourable neurodevelopmental outcome was defined as moderately or severely atypical neurological examination during the last visit: presence of cerebral palsy, epilepsy, a hearing or visual impairment, and/or atypical cognitive development (Griffiths Mental Development Scales developmental quotient or Wechsler Preschool and Primary Scale of Intelligence <85). RESULTS: Unfavourable outcome was observed in 12 out of 13 children with a temporal PVHI compared with six out of 21 children with a frontal PVHI (p=0.002). Only one of the included infants with a PVHI in the temporal white matter developed cerebral palsy, which was due to a parietal PVHI in the contralateral hemisphere. Cognitive impairment was noted in seven infants with a frontal PVHI and five with a temporal PVHI. There were more infants with a temporal PVHI who developed visual impairment (n=5) or behavioural problems (n=7) compared with those with a frontal PVHI (visual impairment (n=2), behavioural problems (n=3). INTERPRETATION: PVHI located in the temporal or frontal lobe is almost invariably related to a typical motor outcome, but carries a risk of cognitive, behavioural, and visual problems, especially in infants with a PVHI located in the temporal lobe.

Hydrocortisone treatment for bronchopulmonary dysplasia and brain volumes in preterm infants.

OBJECTIVE: To assess whether there was an adverse effect on brain growth after hydrocortisone (HC) treatment for bronchopulmonary dysplasia (BPD) in a large cohort of infants without dexamethasone exposure. STUDY DESIGN: Infants who received HC for BPD between 2005 and 2011 and underwent magnetic resonance imaging at term-equivalent age were included. Control infants born in Geneva (2005-2006) and Utrecht (2007-2011) were matched to the infants treated with HC according to segmentation method, sex, and gestational age. Infants with overt parenchymal pathology were excluded. Multivariable analysis was used to determine if there was a difference in brain volumes between the 2 groups. RESULTS: Seventy-three infants treated with HC and 73 matched controls were included. Mean gestational age was 26.7 weeks, and mean birth weight was 906 g. After correction for gestational age, postmenstrual age at time of scanning, the presence of intraventricular hemorrhage, and birth weight z-score, no differences were found between infants treated with HC and controls in total brain tissue or cerebellar volumes. CONCLUSIONS: In the absence of associated parenchymal brain injury, no reduction in brain tissue or cerebellar volumes could be found at term-equivalent age between infants with or without treatment with HC for BPD.

Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (the SToP-BPD study); a multicenter randomized placebo controlled trial.

BACKGROUND: Randomized controlled trials have shown that treatment of chronically ventilated preterm infants after the first week of life with dexamethasone reduces the incidence of the combined outcome death or bronchopulmonary dysplasia (BPD). However, there are concerns that dexamethasone may increase the risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. So far no randomized controlled trial has investigated its efficacy when administered after the first week of life to ventilated preterm infants. METHODS/DESIGN: The SToP-BPD trial is a randomized double blind placebo controlled multicenter study including 400 very low birth weight infants (gestational age < 30 weeks and/or birth weight < 1250 grams), who are ventilator dependent at a postnatal age of 7 - 14 days. Hydrocortisone (cumulative dose 72.5 mg/kg) or placebo is administered during a 22 day tapering schedule. Primary outcome measure is the combined outcome mortality or BPD at 36 weeks postmenstrual age. Secondary outcomes are short term effects on the pulmonary condition, adverse effects during hospitalization, and long-term neurodevelopmental sequelae assessed at 2 years corrected gestational age. Analysis will be on an intention to treat basis. DISCUSSION: This trial will determine the efficacy and safety of postnatal hydrocortisone administration at a moderately early postnatal onset compared to placebo for the reduction of the combined outcome mortality and BPD at 36 weeks postmenstrual age in ventilator dependent preterm infants.

Ultrasound measurements of the lateral ventricles in neonates: why, how and when? A systematic review.

UNLABELLED: Germinal matrix-intraventricular haemorrhage and subsequent post-haemorrhagic ventricular dilatation (PHVD) are frequently encountered complications in preterm neonates. As progressive dilatation of the lateral ventricles may be associated with elevated intracranial pressure, ultrasound measurements of ventricular size play a major role in the evaluation of neonates at risk of ventricular dilatation as well as in assessing the effect of intervention for PHVD. A systematic search was carried out in Medline and Embase to identify neonatal and foetal ultrasound studies on lateral ventricular size. This review presents an overview of the available data concerning neonatal reference values for lateral ventricular size, the influence of gender, ventricular asymmetry and the effect of the mode of delivery on the phenomenon of ventricular reopening following birth. CONCLUSION: Serial cranial ultrasound measurements of the lateral ventricles play a key role in the early recognition and therapeutic evaluation of post-haemorrhagic ventricular dilation and can be of prognostic value in neonates with ventricular dilatation.

Long-term effects of neonatal hydrocortisone treatment for chronic lung disease on the developing brain and heart.

Despite modern perinatal intensive care techniques, chronic lung disease remains a problem in preterm-born infants. The most commonly and almost exclusively prescribed drug to treat this disorder is dexamethasone. Corticosteroids improve short-term respiratory function; however, many side-effects have been reported and the adverse long-term effects of dexamethasone on neurodevelopment are particularly alarming. Hydrocortisone could be a suitable alternative for dexamethasone, if equally effective with fewer side-effects. This review evaluates the current literature on neonatal hydrocortisone treatment for chronic lung disease with regards to long-term neurodevelopmental outcome and cardiovascular effects. The neurodevelopmental studies do not show any adverse effects of hydrocortisone on neurocognitive and motor outcome, nor on incidence of brain abnormalities on magnetic resonance imaging or on long-lasting programming effects on the hypothalamus-pituitary-adrenal axis. At school age, cardiovascular stress response was the same in hydrocortisone-treated children compared with a reference group. Hydrocortisone seems a safe alternative to dexamethasone, but more double-blind randomised studies are needed.

Neurodevelopmental outcome of preterm infants with severe intraventricular hemorrhage and therapy for post-hemorrhagic ventricular dilatation.

OBJECTIVE: To evaluate the neurodevelopmental outcome of preterm infants with a grade III or IV hemorrhage and to assess the effect of routine low-threshold therapy of post-hemorrhagic ventricular dilatation (PHVD) on neurodevelopmental outcome. STUDY DESIGN: Of the 214 preterm infants (< or = 34 weeks gestational age), 94 (44%) had a grade III intraventricular hemorrhage (IVH), and 120 (56%) had a grade IV hemorrhage. We evaluated the natural evolution of IVH, the need for intervention for PHVD, and neurodevelopmental outcome at 24 months corrected age. RESULTS: PHVD developed significantly more often in the surviving infants with a grade III hemorrhage (53/68, 78%) than in infants with a grade IV hemorrhage (40/76, 53%; P = .002). Intervention for PHVD was required significantly more often in the grade III group, than in the grade IV group (P < .001). In the grade III group, cerebral palsy developed in 5 of the 68 surviving infants (7.4%), compared with 37 of the 76 infants (48.7%) with a grade IV hemorrhage (P < .001). The mean developmental quotient (DQ) in the grade III group was 99, and in the grade IV-group it was 95 at 24 months corrected age. CONCLUSIONS: Short-term neurodevelopmental outcome of preterm infants with grade III or IV hemorrhage was better than reported earlier. Requiring intervention for PHVD only had a negative effect on DQ in infants with a grade IV hemorrhage. Infants with cerebral palsy had significantly lower DQs, irrespective of the severity of IVH.

Neonatal hydrocortisone treatment: neurodevelopmental outcome and MRI at school age in preterm-born children.

OBJECTIVE: To investigate neurodevelopment at school age in preterm infants treated with hydrocortisone for bronchopulmonary dysplasia (BPD) in the neonatal period. STUDY DESIGN: Preterm infants (n = 226; gestational age < or = 32 weeks and/or body weight < or = 1500 grams) performed subtests of the Wechsler Intelligence Scale for Children-Revised, the Visual Motor Integration test, a 15-Word Memory Test and the Movement Assessment Battery for Children at school age. Conventional MRI of the brain was obtained. Sixty-two children who received hydrocortisone for BPD (starting dose, 5 mg/kg/day; median duration, 27.5 days) were compared with 164 nontreated neonates. RESULTS: Hydrocortisone-treated infants were younger, lighter, and sicker than their non-steroid-treated counterparts. Adjustments for gestational age, body weight, sex, mechanical ventilation, and small for gestational age were made. Adjusted mean Intelligence Quotient, Visual Motor Integration test, and memory test results were the same in the hydrocortisone-treated group and the non-steroid-treated group (99 versus 101, P = .62; 97 versus 99, P = .49, 7.9 versus 7.5, P = .42, respectively). Motor function and incidence of cerebral palsy in both groups was not different (11% versus 7%, P = .97). Occurrence of brain lesions on MRI was similar for the two groups. CONCLUSIONS: Neonatal hydrocortisone treatment for BPD had no long-term effects on neurodevelopment.

Anticonvulsant effectiveness and hemodynamic safety of midazolam in full-term infants treated with hypothermia.

BACKGROUND: Midazolam is used as an anticonvulsant in neonatology, including newborns with perinatal asphyxia treated with hypothermia. Hypothermia may affect the safety and effectiveness of midazolam in these patients. OBJECTIVES: The objective was to evaluate the anticonvulsant effectiveness and hemodynamic safety of midazolam in hypothermic newborns and to provide dosing guidance. METHODS: Hypothermic newborns with perinatal asphyxia and treated with midazolam were included. Effectiveness was studied using continuous amplitude-integrated electroencephalography. Hemodynamic safety was assessed using pharmacokinetic-pharmacodynamic modeling with plasma samples and blood pressure recordings (mean arterial blood pressure) under hypothermia. RESULTS: No effect of therapeutic hypothermia on pharmacokinetics could be identified. Add-on seizure control with midazolam was limited (23% seizure control). An inverse relationship between the midazolam plasma concentration and mean arterial blood pressure could be identified. At least one hypotensive episode was experienced in 64%. The concomitant use of inotropes decreased midazolam clearance by 33%. CONCLUSIONS: Under therapeutic hypothermia, midazolam has limited add-on clinical anticonvulsant effectiveness after phenobarbital administration. Due to occurrence of hypotension requiring inotropic support, midazolam is less suitable as a second-line anticonvulsant drug under hypothermia.

Pulmonary effects of neonatal hydrocortisone treatment in ventilator-dependent preterm infants.

Background/Objective. Hydrocortisone, administered to ventilated preterm neonates to facilitate extubation, has no adverse long-term effects, but short-term pulmonary effects have not been described previously. In the present study, we analyzed effects of hydrocortisone on ventilator settings and FiO(2) in ventilator-dependent preterm infants. Patients and Methods. Fifty-five preterm children were included in this retrospective cohort study. Hydrocortisone was administered at a postnatal age of > 7 days to treat chronic lung disease (CLD). Ventilator settings before and after hydrocortisone administration were recorded as well as FiO(2) at 36 weeks' gestational age. Presence of cerebral palsy was assessed at a mean corrected age of 24.1 months. Results. Hydrocortisone administered at a median postnatal age of 14 days significantly reduced FiO(2) from a median of 0.39 to 0.30, mean airway pressure (MAP) from a median of 10.0 cm H(2)O to 7.6 cm H(2)O, and PaCO(2) from a median of 53.5 mmHg to 47 mmHg. Extubation was achieved in all patients. CLD at 36 weeks was present in 11 of the 52 patients (21.1%). None developed cerebral palsy. Conclusions. Hydrocortisone was effective in reducing the FiO(2), MAP, and PaCO(2) and facilitated extubation. Hydrocortisone was not associated with cerebral palsy.

Corpus callosum size in relation to motor performance in 9- to 10-year-old children with neonatal encephalopathy.

Magnetic resonance imaging studies have contributed to recognize the patterns of cerebral injury related to neonatal encephalopathy (NE). We assessed whether a smaller corpus callosum (CC) explained the difference in motor performance between school-age children with NE and controls. Frontal, middle, and posterior areas of the CC were measured in 61 9-10-y-old children with NE and in 47 controls. Motor performance was determined using the Movement Assessment Battery for Children (M-ABC). Linear regression was used to assess whether differences in M-ABC between NE children and controls could be explained by CC size. The CC of 11/30 children with NE type I according to Sarnat (NE I) and 19/36 children with NE type II according to Sarnat (NE II) showed generalized or focal thinning, compared with 8/49 controls. Children with NE II had significantly smaller middle and posterior parts and total areas of the CC. Children with NE scored significantly worse on the M-ABC than controls. The reduction in size of the posterior part of the CC partly explained the mean differences on the M-ABC. Children with NE have poorer motor skills than controls, which is partly explained by a smaller size of the CC.

Neonatal hydrocortisone treatment related to 1H-MRS of the hippocampus and short-term memory at school age in preterm born children.

Animal studies have shown that corticosteroids (dexamethasone) cause neuronal loss in the hippocampus and deficits in short term memory. Proton magnetic resonance spectroscopy can measure brain metabolites in vivo and give an indication of neuronal integrity. We investigated whether prolonged administration of hydrocortisone during the neonatal period for bronchopulmonary dysplasia (BPD) in preterm born children changes the metabolism in the hippocampus, measured at school age. Secondly, we investigated whether hippocampal metabolism and short-term memory and neurodevelopmental outcome are related. In this observational study 37 preterm born children (< or = 32 wk (range 25.0-33.0) and/or a birth weight < or = 1500 g) underwent proton spectroscopy of the hippocampus at school age. Eighteen children were treated with hydrocortisone for BPD (starting dose 5 mg/kg/d tapered over a minimum period of 22 d, median duration 28 d) and 19 never received corticosteroids during the perinatal period. N-acetyl aspartate/ Choline + Creatine/phosphocreatine (NAA/(Cho + Cr)) ratios were determined. A 15-word recall memory test and an IQ measurement were obtained on the same day. Hydrocortisone treated children were younger, lighter and sicker than their nonsteroid treated counterparts. Mean NAA/(Cho + Cr) ratios in the hippocampus were not significantly different in the hydrocortisone group compared with the non-steroid group. Performance on the 15-word memory test and IQ were similar in the two groups. There was no relation between NAA/(Cho + Cr) ratios and memory nor between NAA/(Cho + Cr) ratios and IQ. We conclude that hydrocortisone in the mentioned dose, administered in the neonatal period for BPD, does not appear to have any long-term effects on memory and/or hippocampal metabolism.

Structural and functional brain development after hydrocortisone treatment for neonatal chronic lung disease.

OBJECTIVE: There is much concern about potential neurodevelopmental impairment after neonatal corticosteroid treatment for chronic lung disease. Dexamethasone is the corticosteroid most often used in this clinical setting, and it has been shown to impair cortical growth among preterm infants. This study evaluated long-term effects of prematurity itself and of neonatal hydrocortisone treatment on structural and functional brain development using three-dimensional MRI with advanced image-processing and neurocognitive assessments. METHODS: Sixty children born preterm, including 25 children treated with hydrocortisone and 35 children not treated with hydrocortisone, and 21 children born at term were evaluated, at a mean age of 8 years, with quantitative MRI and neurocognitive assessments (Wechsler Intelligence Scales for Children-Revised [WISC-R]). Automatic image segmentation was used to determine the tissue volumes of cerebral gray matter, white matter, and cerebrospinal fluid. In addition, the volume of the hippocampus was determined manually. WISC-R scores were recorded as mean intelligence scores at evaluation. Neonatal hydrocortisone treatment for chronic lung disease consisted of a starting dose of 5 mg/kg per day tapered over a minimum of 3 weeks. RESULTS: Cerebral gray matter volume was reduced among preterm children (regardless of hydrocortisone treatment), compared with children born at term (preterm: 649 +/- 4.4 mL; term: 666 +/- 7.3 mL). Birth weight was shown to correlate with gray matter volume at 8 years of age in the preterm group (r = 0.421). Cerebrospinal fluid volume was increased among children born preterm, compared with children born at term (preterm: 228 +/- 4.9 mL; term: 206 +/- 8.2 mL). Total hippocampal volume tended to be lower among children born preterm, with a more pronounced reduction of hippocampal volume among boys (preterm: 6.1 +/- 0.13 mL; term: 6.56 +/- 0.2 mL). The WISC-R score was lower for children born preterm, compared with children born at term (preterm: 99.4 +/- 12.4; term: 109.6 +/- 8.8). Children treated with neonatal hydrocortisone had very similar volumes of gray matter (preterm with hydrocortisone: 650 +/- 7.0 mL; preterm without hydrocortisone: 640 +/- 5.6 mL), white matter (preterm with hydrocortisone: 503 +/- 6.1 mL; preterm without hydrocortisone: 510 +/- 4.9 mL), and cerebrospinal fluid (preterm with hydrocortisone: 227 +/- 7.4 mL; preterm without hydrocortisone: 224 +/- 6.0 mL), compared with untreated infants. The hippocampal volumes were similar in the 2 groups (preterm with hydrocortisone: 5.92 +/- 0.15 mL; preterm without hydrocortisone: 5.81 +/- 0.12 mL). The WISC-R score assessments were within the normal range for both groups, with no difference between the groups (preterm with hydrocortisone: 100.8 +/- 13; preterm without hydrocortisone: 98.6 +/- 12.3). CONCLUSIONS: Prematurity is associated with mild brain structural differences that persist at 8 years of age, with associated lower scores in neurocognitive assessments. The data suggest that perinatal hydrocortisone given at the described dosage has no long-term effects on either neurostructural brain development or neurocognitive outcomes.

Ultrasound abnormalities preceding cerebral palsy in high-risk preterm infants.

OBJECTIVE: To assess sequential high-resolution cranial ultrasound (US) in high-risk preterm infants to predict cerebral palsy (CP). STUDY DESIGN: Preterm infants were prospectively studied (n=2139), 1636

Cardiac arrhythmias in neonates receiving lidocaine as anticonvulsive treatment.

UNLABELLED: Lidocaine has been used in neonates as an effective drug in controlling neonatal seizures not responding to traditional anticonvulsant therapy. Little is known about the effect of lidocaine on heart rate or occurrence of cardiac arrhythmias in neonates. The purpose of the present study was to assess the incidence of cardiac arrhythmias associated with lidocaine use for neonatal seizures. A retrospective review was performed in 207 neonates who received lidocaine for treatment of neonatal seizures. All were given a loading dose of 2 mg/kg in 10 min followed by a continuous infusion of 6 mg/kg per h, tailed off over the next 48 h. A total of ten (4,8%) infants developed cardiac arrhythmias during lidocaine infusion. In five infants a bradycardia developed, associated with a prolonged QRS complex in one. In one infant a tachycardia was seen following the bolus administration. In the other four an irregular heart rate was noted. In eight infants the arrhythmias disappeared immediately following discontinuation of lidocaine. In two infants, with severe encephalopathy, who died, the association was not so clear. CONCLUSION: The present study demonstrates that continuous cardiac monitoring of neonates who receive lidocaine for neonatal seizures is indicated, as there is a risk to develop cardiac arrhythmias. Lidocaine should be discontinued immediately when a cardiac arrhythmia occurs. Lidocaine should not be given to patients with a congenital heart disease and to infants who have already been treated with diphantoine.