Comparative Efficacy and Safety of Neuroprotective Therapies for Neonates With Hypoxic Ischemic Encephalopathy: A Network Meta-Analysis

Abstract

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.

Erythropoietin monotherapy for neuroprotection after neonatal encephalopathy in low-to-middle income countries: a systematic review and meta-analysis

“…Our results are in accordance with previous meta-analyses of erythropoietin efficacy for infants with NE [ 28 , 29 ]. One meta-analysis assessed six randomised-controlled trials, the other examined 15 studies comparing five interventions.…”

Comparative effectiveness of cardiovascular, renal and safety outcomes of second‐line antidiabetic drugs use in people with type 2 diabetes: A systematic review and network meta‐analysis of randomised controlled trials

“…Network meta-analysis is now becoming increasingly popular to evaluate healthcare interventions, since it allows for the estimation of relative effectiveness of multiple interventions simultaneously. 20,21 In this study, we aim to compare the cardiovascular and renal efficacy of the available second-line anti-hyperglycaemic agents in people with type 2 diabetes, as well as the associated noncardiovascular adverse events.…”

The role of G-CSF neuroprotective effects in neonatal hypoxic-ischemic encephalopathy (HIE): current status

“…Potential neuroprotective strategies targeting different pathways leading to neuronal cell death in response to hypoxic-ischemic insult have been investigated, including hypothermia, erythropoietin, magnesium, allopurinol, xenon, melatonin, growth factors (G-CSF, SCF, Epo), barbiturates, statins, and stem cells in various animal models of neonatal HIE [ 2 , 16 – 18 ]. Therapeutic hypothermia (TH) is the most widely used standard treatment in neonatal HIE [ 19 , 20 ], by inhibiting inflammatory cascades, reduced production of reactive oxygen species, inhibited apoptosis, an endogenous neuroprotective effect, reduced concentrations of free radicals, and neurotransmitters such as glutamate, glutamine, GABA, and aspartate [ 17 , 21 , 22 ], while others report ineffectiveness and/or adverse effects [ 23 – 25 ]. For instance, Arteaga et al [ 9 ] reported that about 50% of infants treated with TH had adverse outcomes, such as cognitive impairment.…”