Feasibility of minimal enteral nutrition in neonates with perinatal asphyxia during therapeutic hypothermia: A randomized controlled trial.

Therapeutic hypothermia for birth asphyxia in low-resource settings: a pilot randomised controlled trial

Therapeutic hypothermia (TH) is the standard treatment for moderate to severe hypoxic-ischemic encephalopathy (HIE) in developed countries, but data on its safety and efficacy in low-middle-income countries are limited and often conflicting. The impact of enteral feeding during TH remains inadequately explored. We aimed to examine TH's effects on mortality and brain injury and evaluate the safety and effectiveness of minimal enteral feeding during TH. Here, we report our single-center experience with TH over a 10-year period". A total of 187 neonates with moderate to severe HIE who underwent cooling were included in this retrospective study. Post-rewarming MRI scans were scored using a validated MRI scoring system. The primary outcomes were mortality and composite outcomes of mortality and brain injury. The mortality rate was 3% in moderate and 25% in severe cases (p < 0.001). Overall, 85% (160/187) of neonates received minimal enteral nutrition. Multivariate regression analysis revealed that the severity of HIE at admission (OR 3.4 (1.03-11.6); p < 0.04) and gestational age (OR: 0.624 (0.442-0.882); p < 0.008) were independent predictors of composite outcomes of death and brain injuries. MRI score was a strong predictor of mortality (AUC: 0.89; p < 0.001) and of ability to orally feed at discharge (AUC: 0.73; p < 0.001). Mortality rates associated with TH in infants with moderate-severe HIE align with those in high-income countries, and minimal enteral feeding during TH is safe. The severity of HIE, MRI scores, and feeding status are important predictors of outcomes.

Commentary on: Malla RR, Asimi R, Teli MA, Shaheen F, Bhat MA. Erythropoietin monotherapy in perinatal asphyxia with moderate to severe encephalopathy: a randomized placebo-controlled trial. Journal of Perinatology 2017; 37: 596-601. PMID 28277490. Erythropoietin (EPO) works by a number of mechanisms that gives it neuroprotective properties including decreasing neuronal apoptosis in the acute phase and enhancing angiogenesis and neurogenesis for long-term brain healing 1. Malla et al. 2 demonstrate improved neurologic outcomes in patients treated with EPO monotherapy vs placebo when treating moderate or severe hypoxic ischaemic encephalopathy (HIE). A study carried out in China by Zhu et al. 3 comparing EPO vs placebo, also without adjunctive therapeutic hypothermia (TH), showed similar results. Importantly, these studies showed a significant improvement in neurologic outcome in patients with moderate but not severe encephalopathy. There was also no difference in mortality between the placebo and EPO groups. This differs from trials with TH, the current standard of care in most resource-rich areas, which show a similar reduction in combined mortality and morbidity, but also demonstrate a reduction in mortality [RR–0.75 (95% CI: 0.64, 0.88) [Table 1.2, reference (4)] and disability [RR–0.77 (95% CI: 0.63, 0.94) [Table 1.3, reference (4)], when stratified by moderate or severe encephalopathy (data not shown) (4). These differences could be attributed to the larger sample size of patients in the Cochrane review 4 compared to the single-center study 2 and are certainly reflected in the forest plots when looking at individual trials 4. In settings where TH is widely available, there is significant interest in the potential benefits of EPO as an adjunct therapy to TH. A phase I trial by Wu et al. 5 showed that a presumably effective dosing regimen of EPO could be safely given to neonates undergoing TH for HIE. In a phase II trial, Wu et al. 6 showed that infants treated with EPO as an adjunct to TH had less MRI brain injury and improved motor outcomes at 1 year of age. Currently, there are three phase III clinical trials underway (HEAL, PAEAN and Neurepo) comparing mortality and neurodevelopmental disability in term infants with HIE treated with EPO+ TH vs TH alone 7. These may reaffirm the safety of EPO as adjunct therapy to TH and substantiate evidence that it improves neurologic outcome. The number needed to treat (NNT) to prevent the composite measure of death or moderate or severe disability in this EPO monotherapy study was four 2, which is lower than most trials using TH alone, with an NNT of 7–9 1; however, the number of patients studied to date is far fewer. There has never been a head to head trial comparing EPO monotherapy vs TH. Given the findings of Malla et al. 2, is it an investigation worth considering given the resource intensity associated with TH compared to EPO monotherapy? Perhaps more importantly, would this ever be ethically feasible given the lack of clinical equipoise for the proven effectiveness of TH – although TH as compared to placebo has not been studied in the developing world either. Therefore, if the addition of EPO as an adjunct to TH in the current phase three trials fails to show a benefit, there may be an opportunity to ask this question again. The more challenging issue will be if adjunct EPO therapy does show incremental benefit compared to placebo, does that close the door on a head to head EPO vs TH? The use of simulation models may help to tease out some of the incremental cost-benefit challenges and potentially lay groundwork for a head to head trial. Careful consideration, however, must be given to the benefits of TH beyond neuroprotection that EPO may not offer (i.e. cardiovascular, gastrointestinal system, etc.). https://ebneo.org/2017/12/does-erythropoietin-monotherapy-reduce-mortality-or-moderatesevere-disability-in-neonates-with-hypoxic-ischemic-encephalopathy/ None. No relevant conflict of interests to declare.

Initiation of therapeutic hypothermia (TH) within 6h of life is a major concern for treating neonatal hypoxic ischemic encephalopathy (HIE). We aimed to determine clinical and healthcare organizational factors associated with delayed TH in a French population-based cohort of neonates with moderate/severe HIE. Time to reach a rectal temperature of 34°C defines optimal and delayed (within and over 6h, respectively) TH. Clinical and healthcare organizational factors associated with delayed TH were analysed among neonates born in cooling centres (CCs) and non-cooling centres (non-CCs). Among 629 neonates eligible for TH, 574 received treatment (91.3%). TH was delayed in 29.8% neonates and in 20.3% and 36.2% of those born in CCs and non-CCs, respectively. Neonates with moderate HIE were more exposed to delayed TH in both CCs and non-CCs. After adjustment for HIE severity, maternal and neonatal characteristics and circumstances of birth were not associated with increased risk of delayed TH. However, this risk was 2 to 5 times higher in maternities with < 1999 annual births, when the delay between birth and call for transfer (adjusted odds ratio [aOR] 2.47, 95% confidence interval [CI] [1.03 to 5.96]) or between call for transfer and admission (aOR 6.06, 95%CI [2.60 to 14.12]) was > 3h and when an undesirable event occurred during transfer (aOR 2.66, 95%CI [1.11 to 6.37]. Conclusion: Increasing early identification of neonates who could benefit from TH and access to TH in non-CCs before transfer are modifiable factors that could improve care of neonates with HIE. Trial registration: The trial was registered at ClinicalTrials.gov (NCT02676063). What is Known: • International recommendations are to initiate therapeutic hypothermia before 6 h of life in neonates with moderate or severe hypoxic ischemic encephalopathy. What is New: •In this French population-based cohort of infants with hypoxic ischemic encephalopathy, nearly one-third of neonates eligible for treatment did not have access to hypothermia in the therapeutic window of 6 h of life. . • Among infants born in non-cooling centres, healthcare organizational factors involved in delayed care were the small size of maternities (1999 annual births), a time interval of more than 3 h between birth and call for transfer and between call for transfer and admission in neonatology, and the occurrence of an undesirable event during transfer.

Therapeutic hypothermia reduces risk of death and disability in infants with moderate to severe hypoxic ischemic encephalopathy (HIE). Randomized clinical trials of therapeutic hypothermia to date have not included infants with mild HIE because of a perceived good prognosis. To test the hypothesis that children with mild HIE have worse neurodevelopmental outcomes than their healthy peers. Analysis of pooled data from 4 prospective cohort studies in Cork, Ireland, and Stockholm, Sweden, between January 2007 and August 2015. The dates of data analysis were September 2017 to June 2019. Follow-up was performed at age 18 to 42 months. In this multicenter cohort study, all children were born or treated at the tertiary centers of Cork University Maternity Hospital, Cork, Ireland, or Karolinska University Hospital, Stockholm, Sweden. In all, 690 children were eligible for this study. At discharge, all children were categorized into the following 5 groups using a modified Sarnat score: healthy controls, perinatal asphyxia (PA) without HIE, mild HIE, moderate HIE, and severe HIE. Cognitive, language, and motor development were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-III). The BSITD-III scores are standardized to a mean (SD) of 100 (15), with lower scores indicating risk of developmental delay. Of the 690 children eligible for this study, 2-year follow-up data were available in 471 (mean [SD] age at follow-up, 25.6 [5.7] months; 54.8% male), including 152 controls, 185 children with PA without HIE, and 134 children with HIE, of whom 14 had died. Infants with mild HIE (n = 55) had lower cognitive composite scores compared with controls, with a mean (SD) of 97.6 (11.9) vs 103.6 (14.6); the crude mean difference was -6.0 (95% CI, -9.9 to -2.1), and the adjusted mean difference was -5.2 (95% CI, -9.1 to -1.3). There was no significant difference in the mean cognitive composite scores between untreated children (n = 47) with mild HIE and surviving children with moderate HIE (n = 53) treated with therapeutic hypothermia, with a crude mean difference for mild vs moderate of -2.2 (95% CI, -8.1 to 3.7). This study's findings suggest that, at age 2 years, the cognitive composite scores of children with a history of mild HIE may be lower than those of a contemporaneous control group and may not be significantly different from those of survivors of moderate HIE treated with therapeutic hypothermia.

Objective We assessed the impact of early enteral feeding introduction during therapeutic hypothermia on time to reach full enteral feeding (FEF) and other feeding related outcomes in infants born at ≥35 weeks gestational age and diagnosed with moderate to severe Hypoxic-Ischemic Encephalopathy. Methods A prospective cohort with historical control study, conducted on infants admitted to the Alberta Children’s Hospital level III NICU in Calgary between January 2013 and December 2018. Infants were divided into 2 groups: (1) unfed group (UG), which was kept nil per os during the 72 h of therapeutic Hypothermia (TH), with subsequent introduction of feeding and gradual increase to FEF; (2) fed group (FG), which received feeding at 10 mL/kg/day during TH then increased gradually to FEF. Groups were compared for time to FEF and the type of milk they were being fed on discharge. Other gut related health risks such as NEC and sepsis were examined. Results During the study period, 146 infants received therapeutic hypothermia, of whom 75 in the UG and 71 in the FG. The FG compared to the UG received the first feed sooner after TH initiation (median 57 vs. 86.5 h, p < .001), reached FEF earlier (median 6 vs. 8 days, p = .012), had a higher rate of being fully fed in the first week of life (70 vs. 53%, p < .035), was kept NPO for shorter duration (median 2 vs. 4 days, p < .001), and had a higher rate of breast milk feeding at discharge (41 vs. 13%, p < .001). There were no cases of necrotizing enterocolitis or late onset sepsis in either group during the hospital stay. Conclusion Minimal enteral feeding during therapeutic hypothermia appears to be safe and leads to a shorter time to FEF and higher rates of breast milk feeding at discharge.

Ten years since the introduction of therapeutic hypothermia in neonates with perinatal hypoxic-ischaemic encephalopathy in Spain

Una década después de la implantación en España de la hipotermia terapéutica en el recién nacido con encefalopatía hipóxico-isquémica perinatal

Background Therapeutic hypothermia (TH) is standard of care for neonates ≥36 weeks with hypoxic-ischemic encephalopathy (HIE). Although intravenous fluid restriction is common, optimal strategies for parenteral and enteral nutrition remain unclear. This study evaluated the tolerance of parenteral nutrition (PN) and enteral feeding in neonates undergoing TH, as well as the impact of these interventions on clinical outcomes. Methods We retrospectively reviewed charts from the Florida Neonatal Neurologic Network (FN3) of neonates who underwent TH for HIE between 2012 and 2020. Collected data included demographics, neurologic assessments, nutritional strategies, laboratory values, and MRI findings. Statistical analysis was performed using one-way ANOVA, with results expressed as Kruskal-Wallis p-values. Results Of 170 neonates, 163 met inclusion criteria. Participants were categorized by nutritional approach: intravenous fluids (IVF), PN, or both. Neonates receiving PN had significantly higher blood urea nitrogen (BUN) during TH (p < 0.05), although values remained within acceptable limits. Lipid tolerance did not differ between groups. PN administration was associated with improved glucose regulation at 12 h (p < 0.05). Enteral feeding correlated with reduced brain injury on MRI and improved neurodevelopmental outcomes, including cognitive (p < 0.05) and motor (p < 0.05) function. Neonates receiving both PN and enteral feeding demonstrated significant recovery from malnutrition by the first outpatient follow-up (p < 0.05) and achieved full enteral feeds sooner (p < 0.05). Conclusions Early nutritional support, including PN and enteral feeding, appears to be well-tolerated in neonates undergoing TH for HIE. These findings suggest that providing early nutrition may enhance neurodevelopmental outcomes and promote growth during TH.

Association between Early Basal Ganglia and Thalami Perfusion Assessed by Color Doppler Ultrasonography and Brain Injury in Infants with Hypoxic-Ischemic Encephalopathy: A Prospective Cohort Study

Background: Therapeutic hypothermia (TH) is standard-of-care for infants with moderate and severe HIE in developed countries; TH has been shown to decrease the risk of brain injury in asphyxiated newborns. Observations were like: 1) Asses morbidity and mortality in neonates with moderate and severe birth asphyxia treated with TH and 2) Asses neurological outcome in neonates.Methods: A RCT was done in NICU of Balchikitsalaya, RNTMC, Udaipur. Phase changing material, FS 21, FS 29 used to provide TH for 72 hours, started within 6 hours of birth and neurological outcome was assessed.Results: Total 60 neonates were enrolled 30 cases given TH and 30 control not given TH. Neurological assessment on basis of Thompson scoring, done on admission, 24, 48, 72 and 96 hours for both groups. At 48 hours, mean score in controls 14.5±1.67 and cases 11.47±2.34 (p&lt;0.05). At discharge, mean score for controls was 11.31±3.67 and for cases was 5.24±2.72 (p&lt;0.005). Mortality was 4 (13.3%) in cases and 11 (36.7%) in control group. Among 45 survivors, 25 (55.5%) required anticonvulsant at discharge; 15 from controls, 10 from cases group.Conclusions: There was significant decrease in mortality in birth asphyxia babies given TH as compared to babies not given TH. Also, significant improvement in Thompson score among the cooled neonates at and after 48 hours of age suggestive of better immediate neurological outcome in these babies. Anticonvulsant’s requirement was also significantly less in therapeutic hypothermia group.

Background Aminoglycosides are administered to treat (suspected) neonatal sepsis. The pharmacokinetics (PK) of this antibiotic class are expected to be different in neonates with perinatal asphyxia (PA) treated with therapeutic hypothermia (TH). Effective exposure of the aminoglycoside amikacin in neonates is achieved using a prospectively validated population PK mod-el-derived dosing regimen.1 However, dosing adjust-ments in case of PA with TH are lacking. The aim of the current (AMICOOL) study was to further explore amikacin disposition in neonates by quantifying the impact of PA treated with TH on amikacin clearance and to provide dosing recommendations for this specific patient population. Methods Amikacin therapeutic drug monitoring data were retrospectively collected from term neonates with PA treated with TH and admitted to the neonatal inten-sive care units of VUmc Amsterdam and the University Hospitals Leuven between 2010–2015. Data were added to the original published amikacin population PK dataset.2 A data-driven covariate analysis was performed to assess the impact of PA treated with TH on amikacin clearance. Monte Carlo simulations facilitated the comparison of simulated amikacin exposures using the current dosing guidelines.1 and proposed dosing adaptations for PA treated with TH. We hereby aimed to achieve optimal amikacin trough ( 24 mg/L) levels. Stochastic simulations were used to investigate the differ-ences in exposure among typical neonates with PA and TH with varying birth weights (1965–4220 g). Results Data of 55 neonates with PA treated with TH were added to the original amikacin population PK dataset of 930 neonates.2 A 40.6% (RSE 9%) decrease in amikacin clearance for neonates with PA with TH was documented. Based on Monte Carlo simulations, the current dosing guidelines resulted in 40%–57% of neonates with PA and TH displaying amikacin trough concentrations above the toxic trough level (>5 mg/L), while an additional increase of the dosing interval with 12 hours decreased this percentage to 14%. Stochastic simulations showed that among typical neonates the percentage of patients with trough concentrations>5 mg/L ranges 14% to 25%. Conclusion In neonates with perinatal asphyxia treated with therapeutic hypothermia, amikacin clearance is reduced with 40.6%. Based on simulations, an additional prolongation of the dosing interval with 12 hours results in optimised amikacin exposure and reduces toxicity in this specific population. As a future perspective, the model-based dosing proposal needs prospective validation. Since amikacin can be used as a surrogate for glomerular filtration, clearance of other drugs using the same elimination route could also be reduced in case of perinatal asphyxia treated with therapeutic hypothermia and may require further dosing adaptations.

Objectives: The aim of our study is to evaluate the effects of perinatal asphyxia and subsequent treatment with therapeutic hypothermia (TH) especially on gastrointestinal system in newborns diagnosed with moderate-to-severe Hypoxic-Ischemic Encephalopathy (HIE). The primary objective was to determine the time for initiation of enteral feeds, enhancing the feeds and achieving full feeds in a group of newborns with HIE undergoing TH with secondary objectives to determine the risk of necrotising enterocolitis (NEC), late onset sepsis and duration of hospital stay.&#x0D; Methods: This is a retrospective study done at Neonatal Intensive Care Unit (NICU), Sarji hospital, a tertiary care centre in Shivamogga, India. A review of the medical records for feeding charts of the babies who underwent TH between December 2018 and October 2021 was carried out. A total of 50 newborns either in-born (n = 3) or out-born and referred (n = 47) to our NICU were included.&#x0D; Results: Among the 50 babies (both hemodynamically stable and unstable) undergoing TH, feeds were initiated at Day 2 of life. All hemodynamically stable babies were on full feeds by 5th day of life, while 14 out of 16 unstable babies were on full feeds by 8th day of life. For the remaining 2 babies, we could achieve full feeds by 11th day of life.&#x0D; Conclusion: This study not only supports the recent studies, but also highlights the safety of achieving complete enteral nutrition in neonates (both hemodynamically stable and unstable) undergoing TH without the risk of late-onset sepsis or NEC.

Introduction: Perinatal asphyxia contributes to 20%–30% of the neonatal deaths in India. In developed countries, therapeutic hypothermia (TH) is the established standard of care in asphyxiated neonates. In this study, we present our center experience in using TH for asphyxiated neonates using servo-controlled cooling machine.Subjects and Methods: This study was conducted in Level IIB Neonatal Intensive Care Unit (NICU) of Shri B M Patil Medical College Hospital Vijayapur, Karnataka, over a period of 1 year including neonates admitted in NICU with perinatal asphyxia. Babies with perinatal asphyxia (TOBY criteria) were enrolled in the protocol group and control group. In the protocol group, babies were cooled to 33.5°C using servo-controlled cooling machine within 6 h of birth for 72 h, followed by rewarming at 0.5°C/h to 36.5°C. In the control group, babies received standard supportive care as per unit protocol. Babies were enrolled in this study after taking verbal and written consent from parents.Results: Among 210 neonates included in the study, 92 in the protocol group received TH, whereas 118 neonates were in the control group. 10 neonates died/discharge against medical advice in the Protocol group whereas 22 neonates died/discharge against medical advice in the Control group. 35% and 19% had normal neurological examination at discharge in the protocol and control group, respectively. No statistically significant differences were observed among complications associated with TH between protocol and control group except for bradycardia and thrombocytopenia.Conclusion: TH resulted in better survival and neurodevelopmental outcomes at 18 months of age in our study. Developing training programs and improving infrastructure including neonatal transport are necessary for successful implementation of TH.

Hypoxic‐ischemic encephalopathy (HIE) resulting from perinatal asphyxia presents a substantial risk of mortality and long‐term sequelae in neonates. Therapeutic hypothermia (TH) improves both short‐ and long‐term outcomes in near‐term/term neonates with moderate to severe HIE. While neonates with perinatal asphyxia and TH often require polypharmacy, the impact of both covariates on pharmacokinetics and pharmacodynamics is only partially described and quantified. In this pooled, multicenter retrospective study, longitudinal trends of human serum albumin (HSA, the major drug binding protein) and total protein (TP) concentrations in near‐term/term neonates were described using linear mixed models and compared between cohorts (TH vs control neonates, and moderate vs severe HIE TH cases). A mathematical function for HSA concentrations in neonates with HIE undergoing TH was derived (AlbuCool function). The pooled dataset to estimate these functions contained 330 TH neonates and 425 controls with 1725 and 1415 HSA observations, respectively. The median (interquartile range) HSA concentration was 27.0 (23.0‐31.0) g/L for the TH cohort, and 32.1 (28.4‐35.7) g/L for the control cohort. Estimated mean HSA concentrations were significantly lower (P < .001) in TH compared to control cases, as well as in severe compared to moderate HIE cases (P < .001) over the first 7 postnatal days. The HSA function for neonates with HIE undergoing TH was: HSA (g/L) = 32.28 − 2.94 * PNA + 0.33 * PNA2 (PNA is postnatal age). The integration of this function in pharmacokinetic models holds the promise to improve the predictive performance of these models, and consequently, the pharmacotherapy of HSA‐bound drugs in this vulnerable population.