Effects of bumetanide on neonatal seizures: A systematic review of animal and human studies.

BACKGROUND: Bumetanide, an inhibitor of the sodium-potassium-chloride cotransporter-1, has been suggested as an adjunct to phenobarbital for treating neonatal seizures. METHODS: A systematic review of animal and human studies was conducted to evaluate the efficacy and safety of bumetanide for neonatal seizures. PubMed, Embase, CINAHL and Cochrane databases were searched in March 2023. RESULTS: 26 animal (rat or mice) studies describing 38 experiments (28 in-vivo and ten in-vitro) and two human studies (one RCT and one open-label dose-finding) were included. The study designs, methods to induce seizures, bumetanide dose, and outcome measures were heterogeneous, with only 4/38 experiments being in animal hypoxia/ischaemia models. Among 38 animal experiments, bumetanide was reported to have antiseizure effects in 21, pro-seizure in six and ineffective in 11. The two human studies (n = 57) did not show the benefits of bumetanide as an add-on agent to phenobarbital in their primary analyses, but one study reported benefit on post-hoc analysis. Overall, hearing impairment was detected in 5/37 surviving infants in the bumetanide group vs. 0/13 in controls. Four of the five infants with hearing impairment had received aminoglycosides concurrently. Other adverse effects reported were diuresis, mild-to-moderate dehydration, hypotension, and electrolyte disturbances. The studies did not report on long-term neurodevelopment. The certainty of the evidence was very low. CONCLUSION: Animal data suggest that bumetanide has inconsistent effects as an antiseizure medication in neonates. Data from human studies are scarce and raise some concerns regarding ototoxicity when given with aminoglycosides. Well conducted studies in animal models of hypoxic-ischaemic encephalopathy are urgently needed. Future RCTs, if conducted in human neonates, should have an adequate sample size, assess neurodevelopment, minimize using aminoglycosides, be transparent about the potential ototoxicity in the parent information sheet, conduct early hearing tests and have trial-stopping rules that include hearing impairment as an outcome.

Why do neonates receive antiseizure medications?

BACKGROUND: Continuous conventional video-electroencephalography (cVEEG), the gold standard, is not routinely available for monitoring neonatal seizures in Australia. Therefore, seizures are monitored with clinical observation and amplitude-integrated electroencephalography (aEEG), which may result in under- or over-treatment with antiseizure medications (ASMs). We aimed to investigate ASM usage and its relation to the "cVEEG-confirmed seizures" (cVEEG seizures) in the at-risk infants admitted to a tertiary referral neonatal intensive care unit (NICU). METHODS: The study was a part of a diagnostic study comparing cVEEG with aEEG for the detection of neonatal seizures. Thirty-six infants ≥35 weeks gestational age and at risk of seizures and admitted to NICU were recruited after informed parental consent. The infants were monitored and treated with ASMs based on clinical observation and aEEG findings. A simultaneous cVEEG, not available for clinical decision making, was recorded for 24-h and interpreted at a later date. Data regarding ASM usage and seizure burden on cVEEG were collected. Spearman's Rho coefficient was used to assess the correlation between the number of doses of ASMs administered and seizure burden on cVEEG. RESULTS: cVEEG recordings of 35 infants were available for analysis. The gestational age of the infants ranged from 36 to 42 weeks, and the most common diagnosis was hypoxic-ischemic encephalopathy. Twelve infants received ASMs during the 24-h study period, of which five (42%) did not have cVEEG seizures. Maximum cVEEG seizure burden was 8.3 h, and maximum number of ASMs used was three. The correlation between the number of doses of ASMs administered in an infant and the seizure burden on cVEEG was low (Spearman's Rho: 0.44; p = .148). CONCLUSION: Treatment of neonatal seizures based on clinical observation and aEEG, without cVEEG, results in unnecessary or inadequate exposure to ASMs for many infants.

Vitamin A supplementation in very-preterm or very-low-birth-weight infants to prevent morbidity and mortality: a systematic review and meta-analysis of randomized trials.

BACKGROUND: A previous systematic review showed that intramuscular vitamin A supplementation reduced the risk of bronchopulmonary dysplasia (BPD) in very-low-birth-weight (VLBW) infants. However, more recent studies have questioned this finding. OBJECTIVES: Our objective was to synthesize current evidence on vitamin A supplementation in very-preterm (<32 wk gestational age) or VLBW infants and investigate the factors that may modify its efficacy. METHODS: A systematic review was conducted using the Cochrane systematic review methodology. We included randomized controlled trials investigating vitamin A supplementation for reducing morbidity and mortality in very-preterm or VLBW infants. Certainty of evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) recommendations. Prespecified subgroup analyses assessed factors that may modify the effects of vitamin A supplementation. RESULTS: We included 17 studies (n = 2471) in the qualitative and 15 studies (n = 2248) in the quantitative synthesis. Moderate-certainty evidence suggested a beneficial effect of vitamin A for decreasing the risk of BPD at 36 wk postmenstrual age (RR: 0.83; 95% CI: 0.74, 0.93; numbers needed to treat for an additional beneficial outcome: 16; 95% CI: 9, 53; 9 studies, n = 1752; P = 0.002). Subgroup analysis suggested that the beneficial effect was limited to infants with baseline vitamin A intake <1500 IU · kg-1 · d-1. Both enteral and parenteral routes were effective. Vitamin A supplementation did not have adverse effects and did not alter mortality before discharge (12 studies, n = 1917) or neurodevelopmental outcomes at 18-22 mo (1 study, n = 538). CONCLUSIONS: The benefit of vitamin A supplementation for reducing BPD is likely to be limited to infants with baseline vitamin A intake <1500 IU · kg-1 · d-1 and is not affected by the route of administration.

Effect of Enteral Vitamin A on Fecal Calprotectin in Extremely Preterm Infants: A Nested Prospective Observational Study.

BACKGROUND: Vitamin A has anti-inflammatory and immune-modulating properties. We aimed to assess whether enteral water-soluble vitamin A supplementation in extremely preterm infants decreases fecal calprotectin, a marker of intestinal inflammation. METHODS: This was a prospective observational study nested in a randomized, double-blind, placebo-controlled clinical trial investigating enteral vitamin A (5,000 IU/day) for reducing the severity of bronchopulmonary dysplasia (BPD) in extremely preterm infants. Fecal calprotectin levels were measured using enzyme-linked immunosorbent assay after 28 days of Vitamin A or placebo supplementation. RESULTS: Fecal calprotectin was measured in 66 infants (Vitamin A: 33, Placebo: 33). The mean (standard deviation) gestational age (25.5 [1.55] vs. 25.8 [1.48]; p = 0.341) (week), birth weight (810 [200] vs. 877 [251]; p = 0.240) (gram), and factors influencing fecal calprotectin levels were comparable between the vitamin A versus placebo group infants. All infants were exclusively fed with mother's or donor's human breast milk if mother's milk was unavailable using a standardized feeding regimen and received prophylactic probiotic supplementation. Fecal calprotectin levels (median; 25th-75th centiles) (micrograms/gram of feces) were not significantly different between vitamin A (152; 97-212) and placebo groups (179; 91-313) (p = 0.195). Two infants in the vitamin A group developed definite necrotizing enterocolitis compared to none in the placebo group. Incidence of BPD at 36 weeks postmenstrual age was similar between the groups (vitamin A: 18/33, placebo: 13/33, p = 0.218). CONCLUSION: Enteral supplementation with water-soluble vitamin A did not affect fecal calprotectin levels in extremely preterm infants. Studies with a larger sample size are required to confirm the findings.

Simplified bedside assessment of pulmonary gas exchange in very preterm infants at 36 weeks' postmenstrual age.

INTRODUCTION: We aimed to develop and validate a prediction table for a simplified measure of rightward shift of the fetal oxyhaemoglobin saturation (SpO2) versus inspired oxygen pressure (PIO2) curve as an objective marker of lung disease severity in very preterm infants, independent of unit altitude or oxygen prescribing policies. METHODS: Very preterm infants (n=219) had an oxygen reduction test at median (IQR) test age of 354 (345-360) weeks' postmenstrual age (PMA). Shift was derived from at least three paired SpO2 versus PIO2 measurements using a computer algorithm, using the fetal oxyhaemoglobin dissociation curve as the reference. Linear regression of resultant shift values enabled construction of a table to predict shift using a single paired SpO2 versus PIO2 measurement, validated subsequently in a separate infant cohort using Bland-Altman analysis. Receiver operating curve analysis provided threshold values equating to a clinical diagnosis of mild bronchopulmonary dysplasia (BPD) or moderate to severe BPD. RESULTS: The median (IQR) age of 63 infants in the validation cohort was 360 (356-362) weeks' PMA. Mean difference (95% CI) between predicted and measured shift was 2.1 (-0.8% to 4.9%) with wide limits of agreement (-20.7% to 24.8%). Predicted shift >10.1 kPa identified mild BPD with 71% sensitivity and 88% specificity while values>13.0 kPa identified moderate to severe BPD with 81% sensitivity and 100% specificity. DISCUSSION: Shift predicted from a single paired SpO2 versus PIO2 measurement using our validated table enables objective bedside screening of lung disease severity in very preterm infant cohorts at 36 weeks' PMA.

Enteral Vitamin A for Reducing Severity of Bronchopulmonary Dysplasia: A Randomized Trial.

BACKGROUND AND OBJECTIVES: Evidence suggests that intramuscular vitamin A reduces the risk of bronchopulmonary dysplasia (BPD) in preterm infants. Our objective was to compare enteral water-soluble vitamin A with placebo supplementation to reduce the severity of BPD in extremely preterm infants. METHODS: We conducted a double-blind randomized controlled trial in infants <28 weeks' gestation who were to receive either enteral water-soluble vitamin A (5000 IU per day) or a placebo. Supplementation was started within 24 hours of introduction of feeds and continued until 34 weeks' postmenstrual age (PMA). The primary outcome was the severity of BPD, assessed by using the right shift of the pulse oximeter saturation versus the inspired oxygen pressure curve. RESULTS: A total of 188 infants were randomly assigned. The mean ± SD birth weight (852 ± 201 vs 852 ± 211 g) and gestation (25.8 ± 1.49 vs 26.0 ± 1.39 weeks) were comparable between the vitamin A and placebo groups. There was no difference in the right shift (median [25th-75th percentiles]) of the pulse oximeter saturation versus inspired oxygen pressure curve (in kilopascals) between the vitamin A (11.1 [9.5-13.7]) and placebo groups (10.7 [9.5-13.1]) (P = .73). Enteral vitamin A did not affect diagnosis of BPD or other clinical outcomes. Plasma retinol levels were significantly higher in the vitamin A group versus the placebo group on day 28 and at 34 weeks' PMA. CONCLUSIONS: Enteral water-soluble vitamin A supplementation improves plasma retinol levels in extremely preterm infants but does not reduce the severity of BPD.

Saliva for Assessing Vitamin A Status in Extremely Preterm Infants: A Diagnostic Study.

BACKGROUND: Salivary measurement of hormones and vitamins is gaining prominence as a minimally invasive procedure with the negligible potential for harm. We aimed to assess the utility of saliva for assessing vitamin A status in extremely preterm infants. METHODS: Paired saliva and blood samples were collected at 4 weeks of age from infants born <28 weeks of gestation using a proprietary polymer swab. Plasma retinol was measured using high-performance liquid chromatography, and salivary retinol was measured using enzyme-linked immunosorbent assay. RESULTS: Thirty infants were recruited with a median (IQR) gestation and birth weight of 26.2 weeks (24.8-27.2) and 865 g (718-1,002), respectively. An adequate volume of saliva (>50 µL) was obtained in 68%. There was no significant correlation (Spearman's correlation coefficient = 0.16, p = 0.3) between individual plasma and salivary retinol levels. Bland-Altman analysis showed wide limits of agreement (-113 to +119%) between individual plasma and salivary retinol levels. CONCLUSION: Individual vitamin A status cannot be determined reliably from saliva in extremely preterm infants using current collection materials and analysis techniques.

Inter-rater reliability of amplitude-integrated EEG for the detection of neonatal seizures.

BACKGROUND: Amplitude-integrated electroencephalogram (aEEG) is being used increasingly for seizure detection in neonates. However, data regarding inter-rater reliability among neonatologists for the use of aEEG for the detection of neonatal seizures is lacking. METHODS: Term and late-preterm infants at risk of seizures were monitored simultaneously with 24-h video-electroencephalography (vEEG) and aEEG. vEEG was interpreted by an experienced neurologist. Five neonatologists with experience in aEEG interpretation from four different neonatal units interpreted aEEG recordings independently. The Brennan and Prediger kappa coefficient and Intra-class Correlation Coefficients (ICC) were used to assess inter-rater reliability between the neonatologists. RESULTS: Thirty-five infants at risk of seizure with gestational age at birth 35-42 weeks were recruited for the study after informed parental consent. vEEG detected seizures in seven infants with a total of 169 individual seizure episodes. Neonatologists detected seizures in 10 to 15 infants on aEEG. The sensitivities for the detection of individual seizures by neonatologists ranged from 18% to 38%. The inter-rater reliability for detection of: individual seizure was "fair" (kappa = 0.37; 95% CI: 0.32-0.42), infant with seizure was "moderate" (kappa = 0.60; 95% CI: 0.44-0.75), duration of individual seizure (ICC: 0.22; 95% CI: 0.18-0.28) and total duration of seizures in an infant (ICC: 0.46; 95% CI: 0.30-0.63) was "poor". The neonatologists missed 77-90% of the duration of seizures. CONCLUSION: The inter-rater reliability of aEEG for the detection of neonatal seizures was suboptimal. Even when interpreted by experienced and trained clinicians, seizure detection with aEEG has limitations and can miss large number and duration of seizures.

Developmental dysplasia of the hip in preterm breech infants.

BACKGROUND: Whether preterm infants born with breech presentation are at similar risk of developmental dysplasia of the hip (DDH) as the term breech infants is not known. The information will be vital for DDH screening guidelines. METHODS: A retrospective audit of infants born in the breech position was performed to compare the incidence of DDH in the following gestational age groups: 23-27, 28-31, 32-36 and ≥37 weeks. RESULTS: A total of 1144 neonates were included in the study. The incidence of DDH did not differ between the groups (11.6%, 9.4%, 13.6% and 11.5%, in 23-27, 28-31, 32-36 and ≥37 weeks, respectively, p=0.40). Sixty infants required intervention for DDH. Multiple logistic regression after correcting for potential confounders showed that gestational age group did not influence the risk of DDH, and requirement of therapy. CONCLUSION: Preterm infants born with breech presentation appear to have a similar incidence of DDH to term breech infants. .

Current Practice of Therapeutic Hypothermia for Mild Hypoxic Ischemic Encephalopathy.

CONTEXT: Therapeutic hypothermia is the recommended treatment for neonates with moderate or severe hypoxic ischemic encephalopathy (HIE). There is an increasing trend to use therapeutic hypothermia even in infants with mild hypoxic ischemic encephalopathy, even though there is little evidence to support/refute this. OBJECTIVE: To estimate the incidences of mild hypoxic ischemic encephalopathy among infants who received therapeutic hypothermia, and its short- and long-term outcomes. DATA SOURCES AND STUDY SELECTION: PubMed, Embase, CINAHL, and Cochrane library were searched to identify observational studies reporting on therapeutic hypothermia in term and near-term infants with mild hypoxic ischemic encephalopathy. The JBI (Joanna Briggs Institute) tools were used to assess the risk of bias in the included studies. Random effects meta-analysis was conducted to find out the percentage of cooled infants who had only mild hypoxic ischemic encephalopathy. RESULTS: A total of 3590 citations were screened, of which 13 were included. Of the 2783 infants who received therapeutic hypothermia, 573 had mild hypoxic ischemic encephalopathy. Meta-analysis found that 22% of the infants who underwent therapeutic hypothermia had only mild hypoxic ischemic encephalopathy (95% confidence interval: 16%-27%; I2 statistic = 90.5%). Five studies provided information on adverse effects of therapeutic hypothermia in mild hypoxic ischemic encephalopathy. The reported adverse effects were extreme hypothermia, bradycardia, hypoglycemia, sepsis, skin necrosis, pulmonary hypertension, and systemic hypotension. Limitation: The limitations included relatively small sample size and the lack of data for short- and long-term neurodevelopmental outcome. CONCLUSIONS: A significant proportion of infants who received therapeutic hypothermia had mild hypoxic ischemic encephalopathy. Randomized trials are urgently needed to evaluate the efficacy and safety of therapeutic hypothermia in infants with mild hypoxic ischemic encephalopathy.

Enteral vitamin A for reducing severity of bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled trial.

BACKGROUND: Intramuscular vitamin A supplementation decreases the risk of bronchopulmonary dysplasia (BPD) in very-low-birth-weight preterm infants without significant adverse effects. However, intramuscular vitamin A supplementation is not widely accepted because of the discomfort and risk of trauma associated with repeated injections. Enteral vitamin A supplementation has not been studied adequately in the clinical trials. Enterally administered water-soluble vitamin A is absorbed better than the fat-soluble form. We hypothesised that enteral administration of a water-soluble vitamin A preparation will decrease severity of BPD compared with a control group receiving placebo. METHODS: We plan a double-blind randomised placebo-controlled trial at a tertiary neonatal-perinatal intensive care unit. Eligibility criteria include infants born at less than 28 weeks' gestational age and less than 72 h of life. Infants with major congenital gastrointestinal or respiratory tract abnormalities will be excluded. After parental consent, infants will be randomized to receive either enteral water-soluble vitamin A (5000 IU once a day) or placebo. The intervention will be started within 24 h of introduction of feeds and continued until 34 weeks' post-menstrual age (PMA). The primary outcome is severity of BPD at 36 weeks' PMA. Severity of BPD will be assessed objectively from the right-shift of the peripheral oxyhaemoglobin saturation versus partial pressure of inspired oxygen (SpO2-PiO2) curve. We require 188 infants for 80% power and 5% significance level based on an expected 20% decrease in the right shift of the SpO2-PiO2 curve in the vitamin A group (primary outcome) compared with control group at 36 weeks' PMA, and a 20% attrition rate. Secondary outcomes will be plasma and salivary concentrations of vitamin A on day 28 of the trial (first 30 infants), lung and diaphragm function, clinical outcomes at 36 week' PMA or before discharge/death, and safety of vitamin A. DISCUSSION: BPD poses a significant economic burden on the health-care system. If our study shows that enteral supplementation of water-soluble vitamin A is safe and effective for decreasing the severity of BPD, it will provide the opportunity to further evaluate a simple, globally acceptable preventive therapy for BPD. TRIAL REGISTRATION: ANZCTR; ACTRN12616000408482 (30th March 2016).

Amplitude Integrated Electroencephalography Compared With Conventional Video EEG for Neonatal Seizure Detection: A Diagnostic Accuracy Study.

This diagnostic accuracy study compared the accuracy of seizure detection by amplitude-integrated electroencephalography with the criterion standard conventional video EEG in term and near-term infants at risk of seizures. Simultaneous recording of amplitude-integrated EEG (2-channel amplitude-integrated EEG with raw trace) and video EEG was done for 24 hours for each infant. Amplitude-integrated EEG was interpreted by a neonatologist; video EEG was interpreted by a neurologist independently. Thirty-five infants were included in the analysis. In the 7 infants with seizures on video EEG, there were 169 seizure episodes on video EEG, of which only 57 were identified by amplitude-integrated EEG. Amplitude-integrated EEG had a sensitivity of 33.7% for individual seizure detection. Amplitude-integrated EEG had an 86% sensitivity for detection of babies with seizures; however, it was nonspecific, in that 50% of infants with seizures detected by amplitude-integrated EEG did not have true seizures by video EEG. In conclusion, our study suggests that amplitude-integrated EEG is a poor screening tool for neonatal seizures.

Amplitude-integrated EEG for detection of neonatal seizures: a systematic review.

PURPOSE: Amplitude-integrated electroencephalogram (aEEG) is being used increasingly for monitoring seizures in neonatal units. Its accuracy, compared with "the gold-standard" conventional elecroencephalogram (cEEG) is still not well established. We aimed to conduct a systematic review to evaluate the diagnostic accuracy of aEEG when compared with cEEG, for detection of neonatal seizures. METHOD: A systematic review was conducted using the Cochrane methodology. EMBASE, CINAHL and PubMed databases were searched in September 2014. Studies comparing simultaneous recordings of cEEG and aEEG for detection of seizures in neonatal population were included. QUADAS 2 tool was used to examine "risk of bias" and "applicability". RESULTS: Ten studies (patient sample 433) were included. Risk of bias was high in five studies, unclear in one and low in four. For the detection of individual seizures, when "aEEG with raw trace" was used, median sensitivity was 76% (range: 71-85), and specificity 85% (range: 39-96). When "aEEG without raw trace" was used, median sensitivity was 39% (range: 25-80) and specificity 95% (range: 50-100). Detailed meta-analysis could not be done because of significant clinical/methodological heterogeneity. Seizure detection was better when interpreted by experienced clinicians. Seizures with low amplitude/brief duration and those occurring away from aEEG leads were less likely to be detected. CONCLUSION: Studies included in the systematic review showed aEEG to have relatively low and variable sensitivity and specificity. Based on the available evidence, aEEG cannot be recommended as the mainstay for diagnosis and management of neonatal seizures. There is an urgent need of well-designed studies to address this issue definitively.

Intravenous levetiracetam for treatment of neonatal seizures.

In this case series we report on eight neonates with refractory seizures who received intravenous levetiracetam when seizures did not respond to two or more conventional anticonvulsants. Six of the eight neonates had an excellent response with either cessation, or reduction in seizures by at least 80%. One neonate showed a partial response while one did not have any reduction in seizure frequency. We did not encounter any adverse effects that could be attributable to levetiracetam.

Standardised parenteral nutrition.

Parenteral nutrition (PN) has become an integral part of clinical management of very low birth weight premature neonates. Traditionally different components of PN are prescribed individually considering requirements of an individual neonate (IPN). More recently, standardised PN formulations (SPN) for preterm neonates have been assessed and may have advantages including better provision of nutrients, less prescription and administration errors, decreased risk of infection, and cost savings. The recent introduction of triple-chamber bag that provides total nutrient admixture for neonates may have additional advantage of decreased risk of contamination and ease of administration.

Peritoneal drainage versus laparotomy for perforated necrotising enterocolitis or spontaneous intestinal perforation: a retrospective cohort study.

AIM: Perforated necrotising enterocolitis (NEC) and spontaneous intestinal perforation (SIP) in preterm infants are associated with high morbidity and mortality. The optimum surgical management during the acute stage remains unclear. The aim of the study was to compare the outcomes of preterm infants (gestational age at birth <30 weeks) with perforated NEC or SIP undergoing primary peritoneal drainage (PD) versus laparotomy. METHODS: This was a retrospective cohort study (January 2004 to February 2010). Initial search of hospital database followed by a review of the medical records was performed to identify eligible infants. Thirty-nine infants were included in the study. Information regarding the baseline characteristics and outcomes of interest were recorded using the medical charts, radiology and laboratory databases. NEC was differentiated from SIP based on radiological, operative and clinical findings retrospectively for this study. RESULTS: Among 39 infants, 19 underwent primary PD while 20 had primary laparotomy. Gestational age and birthweight were similar between the two groups. The composite outcome of mortality before discharge or hospital stay longer than 3 months post-term was significantly worse in PD group (74% vs. 40%, P= 0.038). CONCLUSIONS: Preterm infants undergoing PD for NEC/SIP appeared to have increased risk of adverse outcome compared with laparotomy. More randomised controlled trials are necessary to confirm these findings.