A multicentre neonatal interventional randomised controlled trial of nebulized surfactant for preterm infants with respiratory distress: Neo-INSPIRe trial protocol.

INTRODUCTION: Respiratory distress syndrome in preterm infants is an important cause of morbidity and mortality. Less invasive methods of surfactant administration, along with the use of continuous positive airway pressure (CPAP), have improved outcomes of preterm infants. Aerosolized surfactant can be given without the need for airway instrumentation and may be employed in areas where these skills are scarce. Recent trials from high-resourced countries utilising aerosolized surfactant have had a low quality of evidence and varying outcomes. METHODS AND ANALYSIS: The Neo-INSPIRe trial is an unblinded, multicentre, randomised trial of a novel aerosolized surfactant drug/device combination. Inclusion criteria include preterm infants of 27-34+6 weeks' gestational age who weigh 900-1999g and who require CPAP with a fraction of inspired oxygen (FiO2) of 0.25-0.35 in the first 2-24 h of age. Infants are randomised 1:1 to control (CPAP alone) or intervention (CPAP with aerosolized surfactant). The primary outcome is the need for intratracheal bolus surfactant instillation within 72 h of age. Secondary outcomes include the incidence of reaching failure criteria (persistent FiO2 of > 0.40, severe apnoea or severe work of breathing), the need for and duration of ventilation and respiratory support, bronchopulmonary dysplasia and selected co-morbidities of prematurity. Assuming a 40% relative risk reduction to reduce the proportion of infants requiring intratracheal bolus surfactant from 45 to 27%, the study will aim to enrol 232 infants for the study to have a power of 80% to detect a significant difference with a type 1 error of 0.05. ETHICS AND DISSEMINATION: Ethical approval has been granted by the relevant human research ethics committees at University of Cape Town (HREC 681/2022), University of the Witwatersrand HREC (221112) and Stellenbosch University (M23/02/004). TRIAL REGISTRATION: PACTR202307490670785.

Therapeutic hypothermia for hypoxic ischaemic encephalopathy using low-technology methods: a systematic review and meta-analysis.

UNLABELLED: A systematic review and meta-analysis were performed to determine the effect of therapeutic hypothermia using low-technology methods, in settings with facilities for intensive care, in term or near-term infants with hypoxic-ischaemic encephalopathy on mortality, neurological morbidity at discharge and neurological morbidity at 6-24 months. CONCLUSION: Meta-analysis of three randomised controlled studies showed that low-technology therapeutic hypothermia in an intensive care setting significantly reduced the mortality and the neurological morbidity in survivors at discharge.

Neonatal encephalopathy due to suspected hypoxic ischemic encephalopathy: pathophysiology, current, and emerging treatments.

BACKGROUND: Neonatal encephalopathy (NE) due to suspected hypoxic-ischemic encephalopathy (HIE), referred to as NESHIE, is a clinical diagnosis in late preterm and term newborns. It occurs as a result of impaired cerebral blood flow and oxygen delivery during the peripartum period and is used until other causes of NE have been discounted and HIE is confirmed. Therapeutic hypothermia (TH) is the only evidence-based and clinically approved treatment modality for HIE. However, the limited efficacy and uncertain benefits of TH in some low- to middle-income countries (LMICs) and the associated need for intensive monitoring have prompted investigations into more accessible and effective stand-alone or additive treatment options. DATA SOURCES: This review describes the rationale and current evidence for alternative treatments in the context of the pathophysiology of HIE based on literatures from Pubmed and other online sources of published data. RESULTS: The underlining mechanisms of neurotoxic effect, current clinically approved treatment, various categories of emerging treatments and clinical trials for NE are summarized in this review. Melatonin, caffeine citrate, autologous cord blood stem cells, Epoetin alfa and Allopurinal are being tested as potential neuroprotective agents currently. CONCLUSION: This review describes the rationale and current evidence for alternative treatments in the context of the pathophysiology of HIE. Neuroprotective agents are currently only being investigated in high- and middle-income settings. Results from these trials will need to be interpreted and validated in LMIC settings. The focus of future research should therefore be on the development of inexpensive, accessible monotherapies and should include LMICs, where the highest burden of NESHIE exists.

Early clinical signs in neonates with hypoxic ischemic encephalopathy predict an abnormal amplitude-integrated electroencephalogram at age 6 hours.

BACKGROUND: An early clinical score predicting an abnormal amplitude-integrated electroencephalogram (aEEG) or moderate-severe hypoxic ischemic encephalopathy (HIE) may allow rapid triage of infants for therapeutic hypothermia. We aimed to determine if early clinical examination could predict either an abnormal aEEG at age 6 hours or moderate-severe HIE presenting within 72 hours of birth. METHODS: Sixty infants ≥ 36 weeks gestational age were prospectively enrolled following suspected intrapartum hypoxia and signs of encephalopathy. Infants who were moribund, had congenital conditions that could contribute to the encephalopathy or had severe cardio-respiratory instability were excluded. Predictive values of the Thompson HIE score, modified Sarnat encephalopathy grade (MSEG) and specific individual signs at age 3-5 hours were calculated. RESULTS: All of the 60 infants recruited had at least one abnormal primitive reflex. Visible seizures and hypotonia at 3-5 hours were strongly associated with an abnormal 6-hour aEEG (specificity 88% and 92%, respectively), but both had a low sensitivity (47% and 33%, respectively). Overall, 52% of the infants without hypotonia at 3-5 hours had an abnormal 6-hour aEEG. Twelve of the 29 infants (41%) without decreased level of consciousness at 3-5 hours had an abnormal 6-hour aEEG (sensitivity 67%; specificity 71%). A Thompson score ≥ 7 and moderate-severe MSEG at 3-5 hours, both predicted an abnormal 6-hour aEEG (sensitivity 100 vs. 97% and specificity 67 vs. 71% respectively). Both assessments predicted moderate-severe encephalopathy within 72 hours after birth (sensitivity 90%, vs. 88%, specificity 92% vs. 100%). The 6-hour aEEG predicted moderate-severe encephalopathy within 72 hours (sensitivity 75%, specificity 100%) but with lower sensitivity (p = 0.0156) than the Thompson score (sensitivity 90%, specificity 92%). However, all infants with a normal 3- and 6-hour aEEG with moderate-severe encephalopathy within 72 hours who were not cooled had a normal 24-hour aEEG. CONCLUSIONS: The encephalopathy assessment described by the Thompson score at age 3-5 hours is a sensitive predictor of either an abnormal 6-hour aEEG or moderate-severe encephalopathy presenting within 72 hours after birth. An early Thompson score may be useful to assist with triage and selection of infants for therapeutic hypothermia.

Early clinical predictors of a severely abnormal amplitude-integrated electroencephalogram at 48 hours in cooled neonates.

AIM: There is a need to identify infants with hypoxic ischaemic encephalopathy who have a poor outcome despite therapeutic hypothermia. A severely abnormal amplitude-integrated electroencephalogram at 48 h predicts death or disability. Our aim was to determine whether clinical assessment at age 3-5 h predicts a severely abnormal amplitude-integrated electroencephalogram at 48 h or death in cooled infants. METHODS: Forty-one cooled infants, ≥36 weeks' gestation, with moderate-to-severe hypoxic ischaemic encephalopathy, were prospectively enrolled. Infants who were moribund, had congenital conditions associated with encephalopathy or had severe cardio-respiratory instability were excluded. The predictive abilities of the Thompson encephalopathy score and individual signs at age 3-5 h were assessed. RESULTS: All infants with a Thompson score ≥16 at 3-5 h had a severely abnormal amplitude-integrated electroencephalogram at 6 h and an abnormal short-term outcome. At 48 h, 75% had a severely abnormal aEEG or died vs. 18% with a score <16 (p = 0.004). Multivariate analysis did not find a significant independent association with any of the individual signs. CONCLUSION: The Thompson score could be useful to identify infants who will have a poor outcome despite cooling. A score ≥16 should be validated as a prespecified variable in prospective studies.

Defining hypoxic ischemic encephalopathy in newborn infants: benchmarking in a South African population.

OBJECTIVES: There are few population-based studies of hypoxic ischemic encephalopathy (HIE) in sub-Saharan Africa, and the published criteria that are used to define and grade HIE are too variable for meaningful comparisons between studies and populations. Our objectives were (1) to investigate how the incidence of HIE in our region varies with different criteria for intrapartum hypoxia and (2) to determine how encephalopathy severity varies with different grading systems. METHOD: We reviewed the records of infants with a diagnosis of HIE born between September 2008 and March 2009 in public facilities in the Southern Cape Peninsula, South Africa.The incidence of HIE was calculated according to four definitions of intrapartum hypoxia and graded according to three methods. RESULTS: Depending on which defining criteria were applied,the incidence of HIE varied from 2.3 to 4.3 per 1000 live births, of mild HIE ranged from 0.4 to 1.3 per 1000 live births, and of moderate-severe HIE ranged from 1.5 to 3.7 per 1000 livebirths. Ninety-seven of the 110 (88%) infants reviewed had at least one intrapartum-related abnormality. Only 62 (56%) infants had a blood gas performed in the fi rst hour of life. CONCLUSION: The incidence and grade of HIE can vary more than 2-fold in the same population, depending on which defining criteria are used. Consensus definitions are needed for benchmarking.

Growth velocity of extremely low birth weight preterms at a tertiary neonatal unit in South Africa.

INTRODUCTION: There is wide variation in the feeding practices of extreme low birth weight (ELBW) preterms often guided by tradition and resources. The feeding regimen at Groote Schuur Hospital (GSH) nursery, a tertiary neonatal unit, follows a restricted use of parenteral nutrition and concentrates on early introduction of breast milk. There is a need to determine whether this approach achieves acceptable growth velocity. OBJECTIVES: This study aims to describe the growth velocity of ELBW babies at GSH. DESIGN: This was a retrospective cohort study. METHODOLOGY: Infant hospital records of all ELBW babies born at GSH from 1 March to 31 August 2010 were accessed from a previously collected database and relevant data extracted. Growth data were collected from birth to 8 weeks postnatal age or discharge, whichever came first. RESULTS: Ninety-one ELBW babies were born during the study period. Forty were excluded from the study. Thirty died before discharge, and 10 were excluded for other reasons. The mean (SD) gestation of the cohort was 28.5 (1.6) weeks, and the median (range) birth weight was 875 (640-995) g. The overall mean (SD) growth velocity was 14 (2.9) g/kg/day. There was no statistically significant association between the growth velocity and the type of feed given, days to establishing full enteral feeds, time to regaining birth weight, HIV exposure status, intra-uterine growth restriction or exposure to antenatal steroids. CONCLUSION: In our cohort of ELBW infants, growth velocity was within the range currently deemed acceptable by international consensus.

Placental weights of neonates born with symptomatic congenital syphilis.

Background: Syphilis during pregnancy remains an important global health concern causing miscarriage, stillbirth, preterm birth and neonatal death. As part of the fetal infection, placental changes occur which may include a heavier placenta than expected. Methods: A cohort of 50 neonates with symptomatic congenital syphilis has previously been described. This cohort was admitted to Groote Schuur neonatal unit in Cape Town South Africa from 2011 to 2013. For this study, the placental weights of the neonates were analyzed and compared to population based placental centiles. Results: There was data for 37 placentae. Heavy placentae (>90th centile) occurred in 76% of placentae in the study. All 6 infants with birth weights ≥2,500 g had heavy placentae. There was no correlation between placental centile and death. Conclusion: Heavy placenta are an important and frequent finding with symptomatic congenital syphilis, especially in the larger neonates.

Therapeutic hypothermia and hypoxic ischemic encephalopathy: opinion and practice of pediatricians in South Africa.

BACKGROUND: Recent newborn resuscitation guidelines recommend therapeutic hypothermia (TH) as a treatment to reduce long-term neurological deficit in hypoxic ischemic encephalopathy (HIE) survivors. In South Africa, varied resource constraints may present difficulties in the implementation of TH. OBJECTIVE: To determine the opinions and practice of South African pediatricians, regarding TH and the management of HIE. METHODS: We invited 288 South African pediatricians and neonatologists to participate in a web-based survey by e-mail. Practitioners were identified using the Medpages™ database. RESULTS: Responses were received from 37.8% of the e-mails. Seventy-six percent of respondents stated that hypothermia was either effective or very effective while 4% stated TH was ineffective in the management of HIE. Only 42% of respondents offered TH and a further 9% transferred patients to other units for cooling. Twenty-four percent had not implemented TH nor planned to introduce it into practice in the near future. Ninety-eight percent of respondents stated TH should be the standard of care in tertiary neonatal units. CONCLUSION: Most pediatricians in South Africa who responded to the survey stated that TH is effective to reduce the neurological deficit in HIE, however, less than half offered it as a treatment.

A randomised controlled trial of high vs low volume initiation and rapid vs slow advancement of milk feeds in infants with birthweights ≤ 1000 g in a resource-limited setting.

BACKGROUND: Optimal feeding regimens for infants ≤ 1000 g have not been established and are a global healthcare concern. AIMS AND OBJECTIVES: A controlled trial to establish the safety and efficacy of high vs low volume initiation and rapid vs slow advancement of milk feeds in a resource-limited setting was undertaken. METHODS: Infants ≤ 1000 g birthweight were randomised to one of four arms, either low (4 ml/kg/day) or high (24 ml/kg/day) initiation and either slow (24 ml/kg/day) or rapid (36 ml/kg/day) advancement of exclusive feeds of human milk (mother's or donor) until a weight of 1200 g was reached. After this point, formula was used to supplement insufficient mother's milk. The primary outcome was time to reach 1500 g. RESULTS: infants were recruited (51: low/slow; 47: low/rapid; 52: high/slow; 50: high/rapid). Infants on rapid advancement regimens reached 1500 g most rapidly (hazard ratio 1.48, 95% CI 1.05-2.09, P=0.03). The rapid advancement groups also regained birthweight more rapidly (hazard ratio 1.77, 95% CI 1.26-2.50, P=0.001). There was no apparent effect of high vs low initiation volumes but there was some evidence of interaction between interventions. There were no significant differences in other secondary outcomes, including necrotising enterocolitis, feed intolerance and late-onset sepsis. CONCLUSIONS: In this small pilot study, higher initiation feed volumes and larger daily increments appeared to be well tolerated and resulted in more rapid early weight gain. These data provide justification for a larger study in resource-limited settings to address mortality, necrotising enterocolitis and other important outcomes.

Nevirapine concentrations in preterm and low birth weight HIV-exposed infants: implications for dosing recommendations.

World Health Organisation guidelines recommend nevirapine 2 mg/kg/d for HIV-exposed infants <2 kg, but 4-6 mg/kg/d for infants >2 kg. In 116 low birth weight infants, nevirapine 2 mg/kg/d until 14 days, and 4 mg/kg/d thereafter, was safe (1 mild possibly related rash) and achieved target plasma concentrations. Concentrations decreased with treatment duration. Routine dose increase at 14 days should be considered.

HIV transmission to extremely low birth weight infants.

BACKGROUND: Prematurity increases the perinatal HIV transmission rate compared with term infants. There is sparse literature documenting the risk of transmission of HIV to extremely low birth weight (ELBW) infants. OBJECTIVE: To determine the risk of perinatal transmission of HIV to ELBW infants in a tertiary neonatal unit in South Africa. METHODS: A prospective database was maintained on all inborn ELBW infants over a 1-year period from March 2010 to February 2011. Survival and DNA HIV polymerase chain reaction results at 6 weeks were recorded. RESULTS: Of the 180 ELBW infants, 51 (28%) of these babies were HIV exposed. Of these 51 infants, 37 survived until 6 weeks of age. Polymerase chain reaction testing revealed 1 HIV-positive infant for a rate of 2.7% (95% confidence interval: 0.7-14.1%). Twenty-six (72%) of the 36 mothers received antiretroviral drugs, but only 16 (44%) had been treated for more than 1 month. CONCLUSIONS: The rate of HIV transmission in this cohort of ELBW infants is very low despite only 44% of the mothers receiving adequate antiretroviral drugs. We postulate that this is due to our high (89%) cesarean section rate, universal (100%) infant prophylactic antiretroviral drugs and the use of pasteurized breast milk.

Extensive portal venous gas without obvious pneumatosis intestinalis in a preterm infant with necrotizing enterocolitis.

Portal venous gas is one of the classic radiologic features of necrotizing enterocolitis and is an uncommon isolated finding because it is most commonly seen in conjunction with pneumatosis intestinalis. In this case study, we present a preterm neonate with necrotizing enterocolitis who had extensive portal venous gas without obvious pneumatosis intestinalis.

Should neonates sleep alone?

BACKGROUND: Maternal-neonate separation (MNS) in mammals is a model for studying the effects of stress on the development and function of physiological systems. In contrast, for humans, MNS is a Western norm and standard medical practice. However, the physiological impact of this is unknown. The physiological stress-response is orchestrated by the autonomic nervous system and heart rate variability (HRV) is a means of quantifying autonomic nervous system activity. Heart rate variability is influenced by level of arousal, which can be accurately quantified during sleep. Sleep is also essential for optimal early brain development. METHODS: To investigate the impact of MNS in humans, we measured HRV in 16 2-day-old full-term neonates sleeping in skin-to-skin contact with their mothers and sleeping alone, for 1 hour in each place, before discharge from hospital. Infant behavior was observed continuously and manually recorded according to a validated scale. Cardiac interbeat intervals and continuous electrocardiogram were recorded using two independent devices. Heart rate variability (taken only from sleep states to control for level of arousal) was analyzed in the frequency domain using a wavelet method. RESULTS: Results show a 176% increase in autonomic activity and an 86% decrease in quiet sleep duration during MNS compared with skin-to-skin contact. CONCLUSIONS: Maternal-neonate separation is associated with a dramatic increase in HRV power, possibly indicative of central anxious autonomic arousal. Maternal-neonate separation also had a profoundly negative impact on quiet sleep duration. Maternal separation may be a stressor the human neonate is not well-evolved to cope with and may not be benign.

Is the attendance of paediatricians at all elective caesarean sections an effective use of resources?

OBJECTIVES: To determine the need for resuscitation at the birth of babies delivered by elective caesarean section (CS) and to record the time spent by doctors attending such deliveries. METHODS: Data were collected prospectively on all elective CSs performed at Groote Schuur Hospital over a 3-month period. Data collected included: total time involved for paediatrician from call to leaving theatre, management of infant (requiring any form of resuscitation), Apgar scores and neonatal outcome (e.g. admission to nursery). The CSs were classified as low-risk or high-risk (multiple pregnancy, prematurity, growth restriction, abnormal lie, general anaesthetic or known congenital abnormality). RESULTS: Data were recorded for 138 deliveries. Three were excluded as they were not elective CS. One hundred and fifteen deliveries were classified as uncomplicated and 20 as high-risk. Only 1 of the babies born from the 115 low-risk CSs needed brief resuscitation, whereas 9 of the 20 high-risk deliveries resulted in newborn resuscitation. The reasons for low-risk CS were: previous CS (81); infant of diabetic mother (IDM) and previous CS (16); IDM alone (6); estimated big baby (10); and other (2).The average time spent at each elective CS by the pediatrician was 37 minutes. CONCLUSION: For low-risk CS, the same medical attendance (i.e. a midwife) as for an uncomplicated NVD would be appropriate; this can free a doctor for other duties, and assist in de-medicalising a low-risk procedure.

Induced hypothermia for infants with hypoxic- ischemic encephalopathy using a servo-controlled fan: an exploratory pilot study.

OBJECTIVE: Several trials suggest that hypothermia is beneficial in selected infants with hypoxic-ischemic encephalopathy. However, the cooling methods used required repeated interventions and were either expensive or reported significant temperature variation. The objective of this pilot study was to describe the use, efficacy, and physiologic impact of an inexpensive servo-controlled cooling fan blowing room-temperature air. PATIENTS AND METHODS: A servo-controlled fan was manufactured and used to cool 10 infants with hypoxic-ischemic encephalopathy to a rectal temperature of 33 degrees C to 34 degrees C. The infants were sedated with phenobarbital, but clonidine was administered to some infants if shivering or discomfort occurred. A servo-controlled radiant warmer was used simultaneously with the fan to prevent overcooling. The settings used on the fan and radiant warmer differed slightly between some infants as the technique evolved. RESULTS: A rectal temperature of 34 degrees C was achieved in a median time of 58 minutes. Overcooling did not occur, and the mean temperature during cooling was 33.6 degrees C +/- 0.2 degrees C. Inspired oxygen requirements increased in 6 infants, and 5 infants required inotropic support during cooling, but this was progressively reduced after 1 to 2 days. Dehydration did not occur. Five infants shivered when faster fan speeds were used, but 4 of the 5 infants had hypomagnesemia. Shivering was controlled with clonidine in 4 infants, but 1 infant required morphine. CONCLUSIONS: Servo-controlled fan cooling with room-temperature air, combined with servo-controlled radiant warming, was an effective, simple, and safe method of inducing and maintaining rectal temperatures of 33 degrees C to 34 degrees C in sedated infants with hypoxic-ischemic encephalopathy. After induction of hypothermia, a low fan speed facilitated accurate temperature control, and warmer-controlled rewarming at 0.2 degrees C increments every 30 minutes resulted in more appropriate rewarming than when 0.5 degrees C increments every hour were used.