Therapeutic hypothermia in neonatal hypoxic encephalopathy: A systematic review and meta-analysis.
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SUBMITTER: Mathew JL
PROVIDER: S-EPMC8994481 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Therapeutic hypothermia in neonatal hypoxic encephalopathy: A systematic review and meta-analysis.
Mathew Joseph L JL Kaur Navneet N Dsouza Jeanne M JM
Journal of global health 20220409
<h4>Background</h4>Therapeutic hypothermia (TH) is regarded as the most efficacious therapy for neonatal hypoxic encephalopathy. However, limitations in previous systematic reviews and the publication of new data necessitate updating the evidence. We conducted this up-to-date systematic review to evaluate the effects of TH in neonatal encephalopathy on clinical outcomes.<h4>Methods</h4>In this systematic review and meta-analysis, we searched Medline, Cochrane Library, Embase, LIVIVO, Web of Scie ...[more]
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Project description:Although selective or whole body cooling combined with optimal intensive care improves outcomes following neonatal encephalopathy in high-income countries, the safety and efficacy of cooling in low-and middle-income countries is not known.We performed a systematic review and meta-analysis of all published randomised or quasi-randomised controlled trials of cooling therapy for neonatal encephalopathy in low-and middle-income countries.Seven trials, comprising a total of 567 infants were included in the meta-analysis. Most study infants had mild (15%) or moderate encephalopathy (48%) and did not receive invasive ventilation (88%). Cooling devices included water-circulating cooling caps, frozen gel packs, ice, water bottles, and phase-changing material. No statistically significant reduction in neonatal mortality was seen with cooling (risk ratio: 0.74, 95% confidence intervals: 0.44 to 1.25). Data on other neonatal morbidities and long-term neurological outcomes were insufficient.Cooling therapy was not associated with a statistically significant reduction in neonatal mortality in low-and middle-income countries although the confidence intervals were wide and not incompatible with results seen in high-income countries. The apparent lack of treatment effect may be due to the heterogeneity and poor quality of the included studies, inefficiency of the low technology cooling devices, lack of optimal neonatal intensive care, sedation and ventilatory support, overuse of oxygen, or may be due to the intrinsic difference in the population, for example higher rates of perinatal infection, obstructed labor, intrauterine growth retardation and maternal malnutrition. Evaluation of the safety and efficacy of cooling in adequately powered randomised controlled trials is required before cooling is offered in routine clinical practice in low-and middle-income countries.
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Project description:BackgroundNeonatal hypoxic ischaemic encephalopathy due to perinatal asphyxia, can result in severe neurodevelopmental disability or mortality. Hypothermia is at present the only proven neuroprotective intervention. During hypothermia, the neonate may need a variety of drugs with their specific pharmacokinetic profile. The aim of this paper is to determine the effect that hypothermia for neonates suffering from hypoxic ischaemic encephalopathy has on the pharmacokinetics and to what extent dosing regimens need adjustments.MethodA systematic search was performed on PubMed, Embase and Cochrane Library of literature (2000-2020) using a combination of the following search terms: therapeutic hypothermia, neonate, hypoxic ischemic encephalopathy and pharmacokinetics. Titles and abstracts were screened, and inclusion/exclusion criteria were applied. Finally, relevant full texts were read, and secondary inclusion was applied on the identified articles.ResultsA total of 380 articles were retrieved, and 34 articles included after application of inclusion/exclusion criteria and duplicate removal, two additional papers were included as suggested by the reviewers. Twelve out of 36 studies on 15 compounds demonstrated a significant decrease in clearance, be it that the extent differs between routes of elimination and compounds, most pronounced for renal elimination (phenobarbital no difference, midazolam metabolite -21%, lidocaine -24%; morphine -21% to -47%, gentamicin -25% to -35%, amikacin -40%) during hypothermia. The data as retrieved in literature were subsequent compared with the dosing regimen as stated in the Dutch paediatric formulary.ConclusionDepending on the drug-specific disposition characteristics, therapeutic hypothermia in neonates with hypoxic ischaemic encephalopathy affects pharmacokinetics.
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Project description:Hypoxia-ischemia before or around the time of birth occurs in approximately 2/1000 live births and is associated with a high risk of death or lifelong disability. Therapeutic hypothermia is now well established as standard treatment for infants with moderate to severe hypoxic-ischemic encephalopathy but is only partially effective. There is compelling preclinical and clinical evidence that hypothermia is most protective when it is started as early as possible after hypoxia-ischemia. Further improvements in outcome from therapeutic hypothermia are very likely to arise from strategies to reduce the delay before starting treatment of affected infants. In this review, we examine evidence that current protocols are reasonably close to the optimal depth and duration of cooling, but that the optimal rate of rewarming after hypothermia is unclear. The potential for combination treatments to augment hypothermic neuroprotection has considerable promise, particularly with endogenous targets such as melatonin and erythropoietin, and noble gases such as xenon. We dissect the critical importance of preclinical studies using realistic delays in treatment and clinically relevant cooling protocols when examining combination treatment, and that for many strategies overlapping mechanisms of action can substantially attenuate any effects.
| S-EPMC4568393 | biostudies-literature
Project description:Early induced therapeutic hypothermia represents the cornerstone treatment in neonates with probable hypoxic-ischemic encephalopathy. The selection of patients for treatment usually involves meeting criteria indicating evidence of perinatal hypoxia-ischemia and the presence of moderate or severe encephalopathy. In this review, we highlight the variability that exists between some of the different regional and national eligibility guidelines. Determining the potential presence of perinatal hypoxia-ischemia may require either one, two or three signs amongst history of acute perinatal event, prolonged resuscitation at delivery, abnormal blood gases and low Apgar score, with a range of cutoff values. Clinical neurological exams often define the severity of encephalopathy differently, with varying number of domains required for determining eligibility and blurred interpretation of findings assigned to different severity grades in different systems. The role of early electrophysiological assessment is weighted differently. A clinical implication is that infants may receive different care depending on the location in which they are born. This could also impact epidemiological data, as inference of rates of moderate-severe encephalopathy based on therapeutic hypothermia rates are misleading and influenced by different eligibility methods used. We would advocate that a universally endorsed single severity staging of encephalopathy is vital for standardizing management and neonatal outcome. IMPACT: Variability exists between regional and national therapeutic hypothermia eligibility guidelines for neonates with probable hypoxic-ischemic encephalopathy. Differences are common in both criteria indicating perinatal hypoxia-ischemia and criteria defining moderate or severe encephalopathy. The role of early electrophysiological assessment is also weighted unequally. This reflects in different individual care and impacts research data. A universally endorsed single severity staging of encephalopathy would be crucial for standardizing management.
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Project description:Background: To evaluate the safety and neurological outcomes of therapeutic hypothermia to neonatal hypoxic-ischemic encephalopathy (HIE). Materials and Methods: Medical records of 61 neonates with moderate to severe HIE were retrospectively enrolled and divided into a therapeutic hypothermia group (n = 36) and conventional therapy group (n = 25). Results: No significant difference in the incidence of severe adverse events was found between the two groups. Minimum and maximum voltages of amplitude-integrated electroencephalography (aEEG) recording results showed statistically significant differences in therapeutic hypothermia group after 72 h. The neonatal behavioral neurological assessment (NBNA) on the 28th day after birth and Bayley Scales of Infant Development, second edition (BSID II) scores at 18 months old were significant higher in the therapeutic hypothermia group than the conventional therapy group. Conclusion: Therapeutic hypothermia for neonates with moderate to severe HIE improved the development of the nervous system in 0-18-month-old infants and showed a predominant role in reducing death and major neuron development-associated disabilities.
| S-EPMC8505668 | biostudies-literature
Project description:Opinion statementNeonatal Hypoxic-ischemic encephalopathy in full term infants has been associated with a high risk for morbidity and mortality. The patho-physiology of brain injury following hypoxia-ischemia, noted in preclinical models, is a cascade of events resulting from excitotoxic and oxidative injury culminating in cell death. Hypothermia has been noted to be protective by inhibiting various events in the cascade of injury. Major randomized clinical trials in neonatal HIE have demonstrated reduction in death and disability and continued safety and efficacy of neuroprotection in childhood. There is now clinical and imaging evidence for hypothermia as neuroprotection. Hypothermia should be offered to term infants with either severe acidosis at birth or resuscitation needing continued ventilation and evidence of either moderate or severe encephalopathy within 6 hours of birth. The target temperature should be 33° to 34 °C and duration of cooling should be 72 hours, as per the published trials. Rewarming should be slow, at 0.5 °C per hour. Infants should have serial neurological examinations during and at the end of cooling and at discharge. Multiorgan function should be supported and hypocarbia should be avoided during ventilator therapy. If available, the amplitude integrated EEG should be obtained prior to cooling and following rewarming. All infants should have magnetic resonance brain imaging studies within 1 to 2 weeks of age. Information from the neurological examination, aEEG and MRI studies will be helpful in discussing prognosis with parents. All infants should be followed for a minimum of 18 months to evaluate growth parameters and neurodevelopment al outcome.
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Project description:Background and Objective: There remains an unmet clinical need for markers that predict outcomes in the hypothermia-treated (HT) infants with HIE. The aim of this meta-analysis was to investigate the prognostic accuracy of currently available clinical tests performed in the immediate post-natal period for predicting neurological outcomes between 18 months and 3 years of age in HT near-term and term infants with perinatal asphyxia and HIE. Methods: A comprehensive review of the Embase, Cochrane library, and PubMed databases was performed to identify studies that evaluated the prognostic value of clinical tests for neurological outcomes in HT near-term and term infants with perinatal asphyxia and hypoxic-ischemic encephalopathy. Pooled sensitivity and specificity with corresponding 95% confidence intervals and area under the receiver operating characteristic (ROC) curve (AUC) were calculated. Results: Of the 1,144 relevant studies, 26 studies describing four clinical tests conducted in 1458 HT near-term or term infants were included. For predicting an unfavorable neurological outcome, of the imaging techniques, MRI within 2 weeks of birth performed best on sensitivity 0.85 (95% CI 0.79-0.89), specificity 0.72 (95% CI 0.66-0.77), and AUC 0.88; among the neurophysiological tests, multichannel EEG (Electroencephalogram) demonstrated the sensitivity 0.63 (95% CI 0.49-0.76), specificity 0.82 (95% CI 0.70-0.91), and AUC 0.88, and for aEEG (amplitude-integrated electroencephalography) background pattern pooled sensitivity, specificity and AUC were 0.90 (95% CI 0.86-0.94), 0.46 (95% CI 0.42-0.51), and 0.78 whereas for SEPs (Somatosensory evoked potentials), pooled sensitivity and specificity were 0.52 (95% CI 0.34-0.69), 0.76 (95% CI 0.63-0.87), and AUC 0.84, respectively. Conclusions: In the wake of the era of TH, MRI and neurophysiological tests (aEEG or EEG) were promising predictors of adverse outcomes, while SEPs need high-quality studies to confirm the findings. Continued follow-up of the children and well-designed large prospective studies are essential to determine whether these benefits are maintained in later childhood.
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Project description:Pathophysiologic mechanisms involved in neonatal hypoxic ischemic encephalopathy (HIE) are associated with complex changes of blood flow and metabolism. Therapeutic hypothermia (TH) is effective in reducing the extent of brain injury, but it remains uncertain how TH affects cerebral blood flow (CBF) and metabolism. Ten neonates undergoing TH for HIE and seventeen healthy controls were recruited from the NICU and the well baby nursery, respectively. A combination of frequency domain near infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) systems was used to non-invasively measure cerebral hemodynamic and metabolic variables at the bedside. Results showed that cerebral oxygen metabolism (CMRO2i) and CBF indices (CBFi) in neonates with HIE during TH were significantly lower than post-TH and age-matched control values. Also, cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO2) were significantly higher in neonates with HIE during TH compared with age-matched control neonates. Post-TH CBV was significantly decreased compared with values during TH whereas SO2 remained unchanged after the therapy. Thus, FDNIRS-DCS can provide information complimentary to SO2 and can assess individual cerebral metabolic responses to TH. Combined FDNIRS-DCS parameters improve the understanding of the underlying physiology and have the potential to serve as bedside biomarkers of treatment response and optimization.
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Project description:ObjectiveEarly prediction of neurological deficits following neonatal hypoxic-ischemic encephalopathy (HIE) may help to target support. Neonatal animal models suggest that recovery following hypoxia-ischemia depends upon cortical bursting. To test whether this holds in human neonates, we correlated the magnitude of cortical bursting during recovery (≥postnatal day 3) with neurodevelopmental outcomes.MethodsWe identified 41 surviving infants who received therapeutic hypothermia for HIE (classification at hospital discharge: 19 mild, 18 moderate, 4 severe) and had 9-channel electroencephalography (EEG) recordings as part of their routine care. We correlated burst power with Bayley-III cognitive, motor and language scores at median 24 months. To examine whether EEG offered additional prognostic information, we controlled for structural MRI findings.ResultsHigher power of central and occipital cortical bursts predicted worse cognitive and language outcomes, and higher power of central cortical bursts predicted worse motor outcome, all independently of structural MRI findings.ConclusionsClinical EEG after postnatal day 3 may provide additional prognostic information by indexing persistent active mechanisms that either support recovery or exacerbate brain damage, especially in infants with less severe encephalopathy.SignificanceThese findings could allow for the effect of clinical interventions in the neonatal period to be studied instantaneously in the future.
| S-EPMC8407358 | biostudies-literature
Project description:BackgroundHypoxic perinatal brain injury is caused by lack of oxygen to baby's brain and can lead to death or permanent brain damage. However, the effectiveness of therapeutic hypothermia in birth asphyxiated infants with encephalopathy is uncertain. This systematic review and meta-analysis was aimed to estimate the pooled relative risk of mortality among birth asphyxiated neonates with hypoxic-ischemic encephalopathy in a global context.MethodsWe used the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines to search randomized control trials from electronic databases (PubMed, Cochrane library, Google Scholar, MEDLINE, Embase, Scopus, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and meta register of Current Controlled Trials (mCRT)). The authors extracted the author's name, year of publication, country, method of cooling, the severity of encephalopathy, the sample size in the hypothermic, and non-hypothermic groups, and the number of deaths in the intervention and control groups. A weighted inverse variance fixed-effects model was used to estimate the pooled relative risk of mortality. The subgroup analysis was done by economic classification of countries, methods of cooling, and cooling devices. Publication bias was assessed with a funnel plot and Eggers test. A sensitivity analysis was also done.ResultsA total of 28 randomized control trials with a total sample of 35, 92 (1832 hypothermic 1760 non-hypothermic) patients with hypoxic-ischemic encephalopathy were used for the analysis. The pooled relative risk of mortality after implementation of therapeutic hypothermia was found to be 0.74 (95%CI; 0.67, 0.80; I2 = 0.0%; p<0.996). The subgroup analysis revealed that the pooled relative risk of mortality in low, low middle, upper-middle and high income countries was 0.32 (95%CI; -0.95, 1.60; I2 = 0.0%; p<0.813), 0.5 (95%CI; 0.14, 0.86; I2 = 0.0%; p<0.998), 0.62 (95%CI; 0.41-0.83; I2 = 0.0%; p<0.634) and 0.76 (95%CI; 0.69-0.83; I2 = 0.0%; p<0.975) respectively. The relative risk of mortality was the same in selective head cooling and whole-body cooling method which was 0.74. Regarding the cooling device, the pooled relative risk of mortality is the same between the cooling cap and cooling blanket (0.74). However, it is slightly lower (0.73) in a cold gel pack.ConclusionsTherapeutic hypothermia reduces the risk of death in neonates with moderate to severe hypoxic-ischemic encephalopathy. Both selective head cooling and whole-body cooling method are effective in reducing the mortality of infants with this condition. Moreover, low income countries benefit the most from the therapy. Therefore, health professionals should consider offering therapeutic hypothermia as part of routine clinical care to newborns with hypoxic-ischemic encephalopathy especially in low-income countries.
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