The use of erythropoietin and magnesium sulphate for the management of hypoxic-ischaemic encephalopathy in Lagos, Nigeria: A randomized control trial

EBNEO Commentary: Safety and efficacy of erythropoietin in neonates with hypoxic-ischaemic encephalopathy.

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.

Purpose: Erythropoietin (EPO) is a promising neuroprotective drug. We investigated whether EPO has beneficial effects on neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy (HIE).Methods: We retrospectively reviewed the data of 56 infants with HIE born at or after 35 weeks of gestation who were admitted to Inha University Hospital between 2012 and 2021. Patients were divided into two groups based on EPO use and compared. In the EPO group, patients were administered 1,000 U/kg of EPO on days 1, 2, 3, 5, and 7, starting within 24 hours after birth. The primary outcome was death or neurodevelopmental impairment (NDI) at the age of 12 months.Results: EPO was administered to 38 infants, and 18 did not receive EPO. Only 37.5% of patients with HIE (21/56) and 60% of patients with moderate-to-severe HIE (21/35) received therapeutic hypothermia. Among all patients with HIE, death or NDI (21.1 % vs. 50.0%; odds ratio [OR], 0.09; 95% confidence interval [CI], 0.01 to 0.78; P=0.029) and brain injury on imaging (42.1% vs. 83.3%; OR, 0.16; 95% CI, 0.03 to 0.92; P=0.040) were significantly lower in the EPO group than in the control group. Among patients with moderate-to-severe HIE, brain injury on imaging (54.2% vs. 90.9%; OR, 0.04; 95% CI, 0.002 to 0.700; P=0.027) was significantly lower in the EPO group than in the control group.Conclusion: EPO administration significantly reduced mortality and NDI in infants with HIE. EPO can be considered an adjunctive therapeutic agent for neonatal HIE.

To evaluate whether magnesium sulfate and therapeutic hypothermia in combination decreases mortality and/or major neurodevelopmental disability at 1 y of age among term neonates with hypoxic-ischemic encephalopathy. A total of 134 term neonates were randomized to receive intravenous magnesium sulfate at a dose of 250mg/kg (at 8mg/kg/min) once daily for 3 d starting within 6h after birth along with therapeutic hypothermia in the intervention group and therapeutic hypothermia alone in the comparator group. The primary outcome was the composite outcome of mortality and/or major neurodevelopmental disability (Developmental Assessment Scale for Indian Infants score < 70) at 1 y of age. A total of 115 infants were included in the primary analysis. The composite primary outcome occurred in 14 (24%) infants in the intervention group and 19 (33%) infants in the comparator group, and the difference was not statistically significant (p = 0.30; relative risk 0.72; 95% confidence interval 0.40-1.30). The secondary outcomes including neonatal mortality, major neurodevelopmental disability at 1 y of age, neurological status at discharge, level of oxidative stress markers, and adverse effects including hypotension and respiratory depression requiring support were also comparable between the groups. The combination of magnesium sulfate and therapeutic hypothermia did not improve the composite outcome of neonatal mortality and/or major neurodevelopmental disability at 1 y of age. Clinical Trials Registry of India (CTRI/2018/06/014594), prospectively registered.

Adjuvant High-Dose Erythropoietin With Delayed Therapeutic Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy

Erythropoietin (EPO) seems to have a good application prospect both in experimental models and patients with hypoxic ischaemic encephalopathy (HIE). Data regarding the effect of EPO on death or neurodevelopmental impairment are conflicting. A search was conducted by two investigators involved in this research in PubMed, Embase, and Cochrane databases for studies in English, in Wanfang, VIP, and Cnki databases for Chinese studies (all last launched on 2022/08/31). Ultimately, we identified 11 original studies, including the EPO group (n = 636) and the control group (n = 626). Odds ratio (OR) and weighted mean difference were calculated using a random effects or fixed effects model, depending on the data type and heterogeneity of the included studies. 1. The comparison of effectiveness of EPO treatment on HIE: (1) With respect to death, data showed no significant difference between EPO and control groups (OR = 0.97, 95% CI, 0.66-1.43; P = 0.88); Considering the additional effect of mild hypothermia treatment (MHT), no significant difference was found between EPO + MHT/control + MHT groups either (OR = 1.09, 95% CI, 0.69-1.73; P = 0.72); With respect to the interference of different routes of medication administration, Meta-analysis further showed no difference between intravenous EPO/control groups (OR = 1.13, 95% CI, 0.70-1.82; P = 0.62). (2) With respect to cerebral palsy, the analysis showed no significant difference (OR = 0.76, 95% CI, 0.50-1.15; P = 0.20); Considering the effect of MHT and routes of medication administration, data further showed no difference between EPO group and control group (OR = 1.26, 95% CI, 0.73-2.19; P = 0.41). (3) Regarding epilepsy, no significant difference was found (OR = 0.49, 95% CI, 0.20-1.19; P = 0.12). MR abnormality was less common in EPO group (OR = 0.39, 95% CI, 0.19-0.79; P = 0.008). 2. The comparison of possible adverse events of EPO: EPO treatment would not increase the risk of thrombocytopenia, hypotension, and hepatic and kidney injury. This meta-analysis showed that EPO treatment is not beneficial for reducing death and improving neurological impairment, though it would not increase the risk of adverse events.

BackgroundNeonatal hypoxic–ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic–ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown.MethodsIn a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic–ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.ResultsOf 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P=0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57).ConclusionsThe administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic–ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.)

ABSTRACTBackground: Different methods have been used for therapeutic hypothermia for neonates with moderate-to-severe hypoxic ischaemic encephalopathy (HIE). As standard cooling devices are expensive, there is a need to establish the safety and efficacy of low-cost devices such as ice packs (IP) and phase changing material (PCM).Aim: To assess the efficacy and safety of therapeutic hypothermia (TH) and the clinico-laboratory profile of neonates who underwent cooling with IP or PCM.Methods: The study was retrospective. TH for moderate-to-severe HIE was initiated with IP between 2012 and 2014 and with PCM (MiraCradleTM) from September 2014. A standard protocol for inclusion and management during TH was used for all newborns. All data were collected by means of a local cooling registry.Results: Sixty-two cooled newborns (IP 29, PCM 33) were included in the study. Mean gestational age was 38.6 (1.7) weeks and mean birthweight 2920.6 g (450.7); 66.1% were inborn and 91.9% had moderate encephalopathy. Mean (SD) core temperature during cooling was 33.47°C (0.33) for PCM and 33.44°C (0.34) for IP. Adverse events observed during TH were thrombocytopenia (54.8%), coagulopathy (30.6%), shock (30.6%), skin changes (12.9%) and persistent pulmonary hypertension (8.1%). Forty-nine infants were discharged, two died and 11 were discharged against medical advice. TH was prematurely stopped in seven newborns with serious adverse events such as disseminated intravascular coagulation (DIC), gangrene and arrhythmia (IP 5, PCM 2).Conclusion: Low-cost devices are safe and effective alternatives for maintaining TH in low-resource settings with adequate monitoring.Abbreviations: DAMA, discharged against medical advice; DIC, disseminated intravascular coagulation; HELIX, Hypothermia for Encephalopathy in Low- and Middle-Income Countries Trial; HIE, hypoxic ischaemic encephalopathy; IP, ice packs; LMIC, low- and middle-income countries; NICHD, National Institute of Child Health and Human Development; PCM, phase changing; TH, therapeutic hypothermia (TH); TOBY, total body hypothermia for neonatal encephalopathy.

Magnesium sulfate and risk of hypoxic-ischemic encephalopathy in a high-risk cohort

BackgroundPerinatal asphyxia, more appropriately known as hypoxic-ischemic encephalopathy (HIE), is a condition characterized by clinical and laboratory evidence of acute or sub-acute brain injury resulting from systemic hypoxemia and/or reduced cerebral blood flow. HIE is a common and devastating clinical condition in resource-poor countries with poor treatment outcome. This paper describes the protocol for an ongoing study that aims to evaluate the neuroprotective effects of Erythropoietin (EPO) as compared to routine care in the management of moderate to severe HIE among term infants.MethodsThis study is a double-blind randomized controlled trial that will be conducted in the neonatal wards of the Lagos University Teaching Hospital (LUTH), Lagos, Nigeria, over a two-year period after ethical approvals and consents. One hundred and twenty-eight term newborns (≥ 37 weeks gestation) diagnosed with moderate/ severe HIE at admission will be allocated by randomization to receive either EPO or normal saline. All the participants will be offered standard care according to the unit protocol for HIE. Baseline investigations and close monitoring of the babies are done until discharge. Participants are followed up for 2 years to monitor their outcome (death or neurological development) using standard instruments.DiscussionPrevious trials had shown that EPO confers neuroprotective benefits and improve neurological and behavioral outcome in infants with HIE both singly or as an adjuvant to therapeutic hypothermia. This study hypothesized that administering EPO to newborns with moderate /severe HIE can positively influence their clinical and neurological outcomes and will provide evidence to either support or disprove the usefulness of Erythropoietin as a sole agent in the treatment of HIE, especially in resource-limited environment with the highest burden of the disease.Trial registrationThe study has been registered with the Pan African Clinical trials registry on the 2nd of December 2018, with registration number PACTR201812814507775.

Background Although shown to reduce death or disability in moderate-to-severe hypoxic ischaemic encephalopathy (HIE), therapeutic hypothermia (TH) has recently been associated with an increase in adverse events in low- and middle-income countries (LMIC). Aim To determine the clinical characteristics, complications and short-term outcome in neonates receiving TH in King Edward Memorial Hospital, Mumbai, India. Methods A retrospective single-centre study of neonates with moderate-to-severe HIE who received TH from 1 January 2018 to 31 December 2021 was undertaken. TH was provided as per the unit’s protocol using either a servo-controlled device or a phase-changing material (PCM). Results One hundred and fifty-five neonates were included with 94.2% intramural births. Mean gestation and birthweight were 38.6 (1.5) weeks and 2776.7 (431) g, respectively. HIE staging was moderate in 87.1% and severe in 12.9%, with a mean cord pH of 6.93 (0.14) and seizures in 38.7%. Adverse events included shock (50.3%), clinically significant bleeding (16%), acute kidney injury (6.7%), culture-positive sepsis (11.6%), persistent pulmonary hypertension (9%), bradycardia (9%), food intolerance (14.9%) and premature termination (7.1%). A servo-controlled device (15.5%) or PCM (84.5%) was used, with comparable adverse events. 84.5% of the neonates were discharged, 7.1% discharged against medical advice and 8.4% died. Detailed neurological assessment at discharge/discharge against medical advice suggested neurological impairment in 128 (87.1%) neonates. Conclusion Adverse events during TH range from asymptomatic laboratory abnormalities to life-threatening complications, which are manageable in well equipped units. Neurological impairment at discharge in neonates who received cooling mandates strict neurological follow-up. Abbreviations: aEEG: amplitude-integrated EEG; AKI: acute kidney injury; BW: birthweight; EEG: electro-encephalogram; GA: gestational age; HELIX: hypothermia for encephalopathy in low- and middle-income countries; HIE: hypoxic ischaemic encephalopathy; IVH: intraventricular haemorrhage; LMIC: low- and middle-income countries; NICHD: National Institute of Child Health and Human Development; NICU: neonatal intensive care unit; PPHN: persistent pulmonary hypertension of newborn; PCM: phase-changing material; SGA: small-for-gestational age; TH: therapeutic hypothermia.

Context: Several interventions are available for the management of hypoxic ischemic encephalopathy (HIE), but no studies have compared their relative efficacy in a single analysis. This study aims to compare and determine the effectiveness of available interventions for HIE using direct and indirect data. Methods: Large randomized trials were identified from PubMed, EMBASE, CINAHL Plus, AMED, and Cochrane Library of Clinical Trials database from inception until June 30, 2018. Two independent reviewers extracted study data and performed quality assessment. Direct and network meta-analysis of randomized controlled trials was performed to obtained pooled results comparing the effectiveness of different therapies used in HIE on mortality, neurodevelopmental delay at 18 months, as well as adverse events. Their probability of having the highest efficacy and safety was estimated and ranked. The certainty of evidence for the primary outcomes of mortality and mortality or neurodevelopmental delay at 18 months was evaluated using GRADE criteria. Results: Fifteen studies comparing five interventions were included in the network meta-analysis. Whole body cooling [Odds ratio: 0.62 (95% credible interval: 0.46–0.83); 8 trials, high certainty of evidence] was the most effective treatment in reducing the risk of mortality, followed by selective head cooling (0.73; 0.48–1.11; 2 trials, moderate certainty of evidence) and use of magnesium sulfate (0.79; 0.20–3.06; 2 trials, low certainty of evidence). Whole body hypothermia (0.48; 0.33–0.71; 5 trials), selective head hypothermia (0.54; 0.32–0.89; 2 trials), and erythropoietin (0.36; 0.19–0.66; 2 trials) were more effective for reducing the risk of mortality and neurodevelopmental delay at 18 months (moderate to high certainty). Among neonates treated for HIE, the use of erythropoietin (0.36; 0.18–0.74, 2 trials) and whole body hypothermia (0.61; 0.45–0.83; 7 trials) were associated with lower rates of cerebral palsy. Similarly, there were lower rates of seizures among neonates treated with erythropoietin (0.35; 0.13–0.94; 1 trial) and whole body hypothermia (0.64; 0.46–0.87, 7 trials). Conclusion: The findings support current guidelines using therapeutic hypothermia in neonates with HIE. However, more trials are needed to determine the role of adjuvant therapy to hypothermia in reducing the risk of mortality and/or neurodevelopmental delay.

Background: Hypoxic-ischemic encephalopathy (HIE) is a leading cause of mortality and morbidity in neonates. Head cooling is considered the standard treatment that reduces mortality and morbidity by decreasing the adverse effects of the disease. Some medicines having neuroprotective properties may be beneficial in treating HIE. Objectives: We aimed to evaluate the effect of erythropoietin (EPO) on short-time outcomes in newborns with HIE. Methods: This study was conducted on 62 newborns with moderate to severe HIE hospitalized in Fatemieh Hospital, affiliated with Hamadan University of Medical Sciences, Hamadan, Iran, from 2019 to 2020. Eighteen patients who received head cooling plus 1000 IU/kg/d EPO were considered the intervention group and compared with 44 neonates who received only head cooling alone. Short-term outcomes, including length of stay (LOS), thrombocytopenia, seizure, need for mechanical ventilation, multiple anticonvulsant drugs, and in-hospital mortality, were compared between the groups using SPSS version 22. Results: The mean LOS was 21.2 ± 9.6 and 21.5 ± 12.3 days (P = 0.927), thrombocytopenia occurred in 27.8% and 34.1% (P = 0.629), and 84.1% - 88.9% of newborns required mechanical ventilation (P = 1.0). The seizure was observed in 93.2 -94.4% of newborns (P = 0.29), and multiple anti-seizure drugs were required in 35.3% and 48.9% of EPO and control groups retrospectively (P = 0.66). The mortality rate was significantly different between the EPO and control groups (11.1% vs 44%; P = 0.02). Conclusions: High-dose EPO can reduce the mortality rate of neonates with HIE when used in addition to head cooling compared to head cooling alone.

Therapeutic hypothermia is now proven to reduce death or disability in term and near-term born infants with moderate to severe hypoxic-ischemic encephalopathy. Nevertheless, many infants still survive with disability, despite treatment with hypothermia. Recent preclinical and clinical studies suggest that current protocols for therapeutic hypothermia are near-optimal. The obvious strategy, in addition to improving early initiation of therapeutic hypothermia after birth, is to combine hypothermia with other neuroprotective agents. We review evidence that the mechanisms of action of many promising agents overlap with the anti-excitotoxic, anti-apoptotic, and anti-inflammatory mechanisms of hypothermia, leading to a lack of benefit from combination treatment. Moreover, even apparently beneficial combinations have failed to translate in clinical trials. These considerations highlight the need for preclinical studies to test clinically realistic protocols of timing and duration of treatment, before committing to large randomized controlled trials.

Neonatal hypoxic ischemic encephalopathy (HIE) is one of the most common causes of neonatal morbidity and mortality worldwide. It has an overall mortality rate ranging from 15% to 25%, with up to 50% of survivors developing long-term neurological disabilities. Therapeutic hypothermia (TH) has been the only effective treatment for moderate to severe HIE in neonates ≥35 weeks of gestation. Infants with mild HIE previously had been excluded from studies, but a recent study reported approximately 16% developed a disability at 18 to 22 months of age. Despite treatment, up to 29% of neonates with HIE still develop adverse outcomes. To decrease the prevalence of neonatal HIE, prevention is key and a better understanding of associated maternal, perinatal, and neonatal risk factors is needed. The aim of this study was to assess trends of HIE prevalence and use of TH, mortality, and clinical neonatal outcomes. This was a cross-sectional analysis using National Inpatient Sample data sets from 2010 to 2018. Included were newborn infants diagnosed with HIE or asphyxia, who were ≥35 weeks of gestation and had a birth weight ≥2500 g. Excluded were those with congenital heart disease, congenital central nervous system anomalies, congenital lung anomalies, congenital abdominal wall defects, gastroschisis or omphalocele, multiple congenital anomalies, common syndromes, and chromosomal disorders. Of the 32,180,617 infants included in the analysis, 31,249,100 were term infants (&gt;35 weeks). The prevalence of all degrees of HIE for term infants was approximately 0.1%. There was a modest increase from 0.093% during the years 2010 and 2012 up to 0.097% during 2016 and 2018. Approximately 21% of cases were managed with TH. More infants with moderate HIE received TH than those with severe HIE (29.9% vs 19.9%; P &lt; 0.01). Fewer infants with mild or unspecified HIE received TH than those with severe HIE (17.7% and 17.3%, respectively; P &lt; 0.01). From 2010 to 2018, the use of TH increased overall and within each grade of HIE (P &lt; 0.01). The mortality rate was higher in term infants with all degrees of asphyxia than the general population (10.8% vs 0.06%; P &lt; 0.01). Over time, the mortality rate in term infants decreased from 12.3% in 2010 to 8.3% in 2018 (P &lt; 0.01). The analysis included 931,517 were late preterm infants (35–36 weeks of gestation). The combined prevalence for all grades of HIE was 0.23% and did not change significantly over the years. Approximately 21% of late preterm infants were managed with TH. More infants with moderate HIE received TH than those with severe HIE (26.9% vs 20.1%). Fewer infants with mild HIE received TH (13.2%), and no significant difference was observed in infants with unspecified HIE compared with those with severe HIE (18.7% vs 20.1%). The use of TH increased has increased in late preterm infants over the years. The strongest factors associated with HIE were placental infarction or insufficiency, placental abruption, and cord prolapse. Female infant sex, maternal Hispanic ethnicity, and maternal Asian race were associated with lower risk of HIE. In conclusion, HIE prevalence remained essentially the same at 1 per 1000 live births. Use of TH increased, and mortality decreased over time. The strongest factors associated with HIE were placental factors.