Hypothermia combined with neuroprotective adjuvants shortens the duration of hospitalization in infants with hypoxic ischemic encephalopathy: Meta-analysis

Abstract

Objective: Therapeutic hypothermia (TH) is the current standard of care for neonatal hypoxic-ischemic encephalopathy (HIE), yet morbidity and mortality remain significant. Adjuvant neuroprotective agents have been suggested to augment hypothermic-mediated neuroprotection. This analysis aims to identify the classes of drugs that have been used in combination with hypothermia in the treatment of neonatal HIE and determine whether combination therapy is more efficacious than TH alone.Methods: A systematic search of PubMed, Embase and Medline from conception through December 2022 was conducted. Randomized- and quasi-randomized controlled trials, observational studies and retrospective studies evaluating HIE infants treated with combination therapy versus TH alone were selected. Primary reviewers extracted information on mortality, neurodevelopmental impairment and length of hospitalization for meta-analyses. Effect sizes were pooled using a random-effects model and measured as odds ratio (OR) or mean difference (MD) where applicable, and 95% confidence intervals (CI) were calculated. Risk of bias was assessed using the tool from the Cochrane Handbook for Systematic Reviews of Interventions.Results: The search strategy collected 519 studies, 16 of which met analysis inclusion criteria. HIE infants totaled 1,288 infants from included studies, 646 infants received some form of combination therapy, while 642 received TH alone. GABA receptor agonists, NMDA receptor antagonists, neurogenic and angiogenic agents, stem cells, glucocorticoids and antioxidants were identified as candidate adjuvants to TH that have been evaluated in clinical settings compared to TH alone. Length of hospitalization was significantly reduced in infants treated with combination therapy (MD −4.81, 95% CI [−8.42. to −1.19], p = .009) compared to those treated with TH alone. Risk of mortality and neurodevelopmental impairment did not differ between combination therapy and TH alone groups.Conclusion: Compared to the current standard of care, administration of neuroprotective adjuvants with TH reduced the duration of hospitalization but did not impact the risk of mortality or neurodevelopmental impairment in HIE infants. Meta-analysis was limited by a moderate risk of bias among included studies and small sample sizes. This analysis highlights the need for preclinical trials to conduct drug development studies in hypothermic settings to identify relevant molecular targets that may offer additive or synergistic neuroprotection to TH, and the need for larger powered clinical trials to determine the dose and timing of administration at which maximal clinical benefits are observed for adjuvant neuroprotectants.

Neonatal magnesium sulphate for neuroprotection: A systematic review and meta‐analysis

“…A recent systematic review and meta‐analysis demonstrated the breadth of neuroprotective adjuvants to therapeutic hypothermia evaluated in RCTs to date, including γ‐aminobutyric acid receptor agonists (phenobarbital, topiramate), n ‐methyl‐ d ‐aspartic acid receptor antagonists (magnesium sulphate, xenon), neurogenic and angiogenic agents (darbepoetin alpha, erythropoietin), umbilical cord blood cells, glucocorticoids (hydrocortisone), and antioxidants (melatonin) 67 . As recognized by others, 68, 69 magnesium sulphate is not the sole, or indeed favoured agent, in the current quest for an adjuvant to augment therapeutic hypothermia‐mediated neuroprotection.…”

Hipotermia terapéutica como neuroprotección en neonatos con encefalopatía hipóxica-isquémica

“…La encefalopatía hipóxica isquémica tiene gran relevancia en la discapacidad a nivel mundial, el uso de la tecnología ha favorecido el uso de métodos diagnósticos como la resonancia magnética que confirma que los neonatos no presentan una atrofia cerebral concreta lo que se presume que estas lesiones son causadas en la labor de parto (Ovali, 2022) en el avance clínico demuestran la relevancia del uso de la hipotermia terapéutica como un factor que disminuye la discapacidad grave (parálisis cerebral)(Chin Journal Scientific MQRInvestigar 1379 tasa de discapacidad grave varía entre 42-100 % por lo que el uso de este plan terapéutico podría ayudar a reducir los picos de prevalencia de la discapacidad (Garfinkle et al, 2013). Se ha determinado que la secretoneurina un polipéptido es la encargada del proceso de la angiogénesis así como otros procesos como una citoquina quimiotáctica, angiogénica y en el sistema nervioso; por ejemplo en el caso del sistema nervioso la secretoneurina ayuda a la liberación de la dopamina, en la isquémica existen concentraciones altas en el tejido cerebral y en el suero produciendo un colapso de sangre en el cerebro teniendo un aumento de secreción sérica de secretoneurina en muchos de los casos estos niveles altos han sido encontrados en pacientes que han sufrido una reanimación cardiopulmonar siendo un biomarcador para pronosticar un daño neurológico, en el caso de los recién nacidos este neuropéptido puede ser de gran utilidad utilizado como un biomarcador en la identificación de una encefalopatía hipóxico isquémico después de una asfixia perinatal ya que estos niveles se encuentran en concentraciones más altas en comparación con los recién nacidos a término y sanos, sin embargo se considera necesario realizar estudios más avanzados permitan demostrar si este puede ser un biomarcador completo para un diagnóstico eficaz de la EHI (21)(22)(23)(24).…”

The association between plasma IgG N-glycosylation and neonatal hypoxic–ischemic encephalopathy: a case-control study

“…Although hypothermic therapy is effective for neonatal HIE, the window of opportunity for treatment is narrow ( Walas et al, 2020 ). Hypothermic therapy at 33–34°C for 72 h within 6 h of birth has been shown to be effective in reducing the risk of death or neurological disability ( Mietzsch et al, 2020 ; Ovcjak et al, 2022 ). Therefore, clinicians must make a definitive diagnosis and take therapeutic measures within 6 h of birth.…”