Hypothermia for hypoxic ischemic encephalopathy in infants > or =36 weeks.
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ABSTRACT:
SUBMITTER: Higgins RD
PROVIDER: S-EPMC2813680 | biostudies-other | 2009 Oct
REPOSITORIES: biostudies-other
Publications
Hypothermia for hypoxic ischemic encephalopathy in infants > or =36 weeks.
Higgins Rosemary D RD Shankaran Seetha S
Early human development 20090917 10 Suppl
Hypoxic ischemic encephalopathy is a serious condition affecting infants which can result in death and disability. This is a summary of pathogenesis of HIE, animal studies of cooling for hypoxic and ischemic models, human hypothermia trials, and the American Academy of Pediatrics publication on hypothermia for HIE. Hypothermia for neonatal HIE is continuing to evolve as a therapy. Studies, gaps in knowledge and opportunities for research are presented herein. ...[more]
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Project description:Moderate to severe hypoxic-ischemic injury in newborn infants, manifested as encephalopathy immediately or within hours after birth, is associated with a high risk of either death or a lifetime with disability. In recent multicenter clinical trials, hypothermia initiated within the first 6 postnatal hours has emerged as a therapy that reduces the risk of death or impairment among infants with hypoxic-ischemic encephalopathy. Prior to hypothermia, no therapies directly targeting neonatal encephalopathy secondary to hypoxic-ischemic injury had convincing evidence of efficacy. Hypothermia therapy is now becoming increasingly available at tertiary centers. Despite the deserved enthusiasm for hypothermia, obstetric and neonatology caregivers, as well as society at large, must be reminded that in the clinical trials more than 40% of cooled infants died or survived with impairment. Although hypothermia is an evidence-based therapy, additional discoveries are needed to further improve outcome after HIE. In this article, we briefly present the epidemiology of neonatal encephalopathy due to hypoxic-ischemic injury, describe the rationale for the use of hypothermia therapy for hypoxic-ischemic encephalopathy, and present results of the clinical trials that have demonstrated the efficacy of hypothermia. We also present findings noted during and after these trials that will guide care and direct research for this devastating problem.
| S-EPMC2897079 | biostudies-other
Project description:BackgroundErythropoietin is neuroprotective in animal models of neonatal hypoxic-ischemic encephalopathy. We previously reported a phase I safety and pharmacokinetic study of erythropoietin in neonates. This article presents the neurodevelopmental follow-up of infants who were enrolled in the phase I clinical trial.MethodsWe enrolled 24 newborns with hypoxic-ischemic encephalopathy in a dose-escalation study. Patients received up to six doses of erythropoietin in addition to hypothermia. All infants underwent neonatal brain magnetic resonance imaging (MRI) reviewed by a single neuroradiologist. Moderate-to-severe neurodevelopmental disability was defined as cerebral palsy with Gross Motor Function Classification System levels III-V or cognitive impairment based on Bayley Scales of Infant Development II mental developmental index or Bayley III cognitive composite score.ResultsOutcomes were available for 22 of 24 infants, at mean age 22 months (range, 8-34 months). There were no deaths. Eight (36%) had moderate-to-severe brain injury on neonatal MRI. Moderate-to-severe disability occurred in one child (4.5%), in the setting of moderate-to-severe basal ganglia and/or thalamic injury. Seven infants with moderate-to-severe watershed injury exhibited the following outcomes: normal (three), mild language delay (two), mild hemiplegic cerebral palsy (one), and epilepsy (one). All 11 patients with a normal brain MRI had a normal outcome.ConclusionsThis study is the first to describe neurodevelopmental outcomes in infants who received high doses of erythropoietin and hypothermia during the neonatal period. The findings suggest that future studies are warranted to assess the efficacy of this new potential neuroprotective therapy.
| S-EPMC4402201 | biostudies-literature
Project description:To examine the predictive ability of stage of hypoxic-ischemic encephalopathy (HIE) for death or moderate/severe disability at 18 months among neonates undergoing hypothermia.Stage of encephalopathy was evaluated at <6 hours of age, during study intervention, and at discharge among 204 participants in the National Institute of Child Health and Human Development Neonatal Research Network Trial of whole body hypothermia for HIE. HIE was examined as a predictor of outcome by regression models.Moderate and severe HIE occurred at <6 hours of age among 68% and 32% of 101 hypothermia group infants and 60% and 40% of 103 control group infants, respectively. At 24 and 48 hours of study intervention, infants in the hypothermia group had less severe HIE than infants in the control group. Persistence of severe HIE at 72 hours increased the risk of death or disability after controlling for treatment group. The discharge exam improved the predictive value of stage of HIE at <6 hours for death/disability.On serial neurologic examinations, improvement in stage of HIE was associated with cooling. Persistence of severe HIE at 72 hours and an abnormal neurologic exam at discharge were associated with a greater risk of death or disability.
| S-EPMC3299861 | biostudies-other
Project description:OBJECTIVES:Therapeutic hypothermia is standard of care in management of moderate/severe hypoxic-ischemic encephalopathy. Persistent pulmonary hypertension of the newborn is associated with hypoxic-ischemic encephalopathy and is exacerbated by hypoxemia and hypercarbia. Gas exchange is assessed by arterial blood gas analysis (with/without correction for body temperature), pulse oximetry, and end-tidal CO2. DESIGN:A retrospective chart review. SETTINGS:Regional perinatal center in Western New York. PATIENTS:Fifty-eight ventilated neonates with indwelling arterial catheter on therapeutic hypothermia. INTERVENTION:None. MEASUREMENT AND MAIN RESULTS:We compared pulse oximetry, PaO2, end-tidal CO2, and PaCO2 during hypothermia and normothermia in neonates with hypoxic-ischemic encephalopathy using 1,240 arterial blood gases with simultaneously documented pulse oximetry. During hypothermia, pulse oximetry 92-98% was associated with significantly lower temperature-corrected PaO2 (51 mmHg; interquartile range, 43-51) compared with normothermia (71 mmHg; interquartile range, 61-85). Throughout the range of pulse oximetry values, geometric mean PaO2 was about 23% (95% CI, 19-27%) lower during hypothermia compared with normothermia. In contrast, end-tidal CO2 accurately assessed temperature-corrected PaCO2 during normothermia and hypothermia. CONCLUSIONS:Hypothermia shifts oxygen-hemoglobin dissociation curve to the left resulting in lower PaO2 for pulse oximetry. Monitoring oxygenation with arterial blood gas uncorrected for body temperature and pulse oximetry may underestimate hypoxemia in hypoxic-ischemic encephalopathy infants during whole-body hypothermia, while end-tidal CO2 reliably correlates with temperature-corrected PaCO2.
| S-EPMC6366447 | biostudies-literature
Project description:Dexmedetomidine is a promising sedative and analgesic for newborns with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Pharmacokinetics and safety of dexmedetomidine were evaluated in a phase I, single-center, open-label study to inform future trial strategies. We recruited 7 neonates ?36 weeks' gestational age diagnosed with moderate-to-severe HIE, who received a continuous dexmedetomidine infusion during TH and the 6?h rewarming period. Time course of plasma dexmedetomidine concentration was characterized by serial blood sampling during and after the 64.8?±?6.9 hours of infusion. Noncompartmental analysis yielded descriptive pharmacokinetic estimates: plasma clearance of 0.760?±?0.155?L/h/kg, steady-state distribution volume of 5.22?±?2.62?L/kg, and mean residence time of 6.84?±?3.20?h. Naive pooled and population analyses according to a one-compartment model provided similar estimates of clearance and distribution volume. Overall, clearance was either comparable or lower, distribution volume was larger, and mean residence time or elimination half-life was longer in cooled newborns with HIE compared to corresponding estimates previously reported for uncooled (normothermic) newborns without HIE at comparable gestational and postmenstrual ages. As a result, plasma concentrations in cooled newborns with HIE rose more slowly in the initial hours of infusion compared to predicted concentration-time profiles based on reported pharmacokinetic parameters in normothermic newborns without HIE, while similar steady-state levels were achieved. No acute adverse events were associated with dexmedetomidine treatment. While dexmedetomidine appeared safe for neonates with HIE during TH at infusion doses up to 0.4??g/kg/h, a loading dose strategy may be needed to overcome the initial lag in rise of plasma dexmedetomidine concentration.
| S-EPMC7060842 | biostudies-literature
Project description:Despite recent advances in neonatal care and monitoring, asphyxia globally accounts for 23% of the 4 million annual deaths of newborns, and leads to hypoxic-ischemic encephalopathy (HIE). Occurring in five of 1000 live-born infants globally and even more in developing countries, HIE is a serious problem that causes death in 25%-50% of affected neonates and neurological disability to at least 25% of survivors. In order to prevent the damage caused by HIE, our invention provides an effective whole-body cooling of the neonates by utilizing evaporation and an endothermic reaction. Our device is composed of basic electronics, clay pots, sand, and urea-based instant cold pack powder. A larger clay pot, lined with nearly 5 cm of sand, contains a smaller pot, where the neonate will be placed for therapeutic treatment. When the sand is mixed with instant cold pack urea powder and wetted with water, the device can extract heat from inside to outside and maintain the inner pot at 17°C for more than 24 hours with monitoring by LED lights and thermistors. Using a piglet model, we confirmed that our device fits the specific parameters of therapeutic hypothermia, lowering the body temperature to 33.5°C with a 1°C margin of error. After the therapeutic hypothermia treatment, warming is regulated by adjusting the amount of water added and the location of baby inside the device. Our invention uniquely limits the amount of electricity required to power and operate the device compared with current expensive and high-tech devices available in the United States. Our device costs a maximum of 40 dollars and is simple enough to be used in neonatal intensive care units in developing countries.
| S-EPMC3540914 | biostudies-literature
Project description:Perinatal hypoxic-ischemic encephalopathy is a leading cause of neonatal death and disability. Therapeutic hypothermia significantly reduces death and major disability associated with hypoxic-ischemic encephalopathy; however, many infants still experience lifelong disabilities to movement, sensation and cognition. Clinical guidelines, based on strong clinical and preclinical evidence, recommend therapeutic hypothermia should be started within 6 hours of birth and continued for a period of 72 hours, with a target brain temperature of 33.5 ± 0.5°C for infants with moderate to severe hypoxic-ischemic encephalopathy. The clinical guidelines also recommend that infants be rewarmed at a rate of 0.5°C per hour, but this is not based on strong evidence. There are no randomized controlled trials investigating the optimal rate of rewarming after therapeutic hypothermia for infants with hypoxic-ischemic encephalopathy. Preclinical studies of rewarming are conflicting and results were confounded by treatment with sub-optimal durations of hypothermia. In this review, we evaluate the evidence for the optimal start time, duration and depth of hypothermia, and whether the rate of rewarming after treatment affects brain injury and neurological outcomes.
| S-EPMC6585539 | biostudies-literature
Project description:BackgroundHypothermia initiated in the first six hours of life in term infants with hypoxic ischemic encephalopathy reduces the risk of death and severe neurological sequelae. Our study's principal objective was to evaluate transport predictors potentially influencing arrival in NICU (Neonatal Intensive Care Unit) at a temperature ≥35-<36°C.Methodology/principal findingsA multi-centric, prospective cohort study was conducted during 18 months by the three Neonatal Transport Teams and 13 NICUs. Newborns were selected for inclusion according to biological and clinical criteria before transport using passive hypothermia using a target temperature of ≥35-<36°C. Data on 120 of 126 inclusions were available for analysis. Thirty-three percent of the children arrived in NICU with the target temperature of ≥35-<36°C. The mean temperature for the whole group of infants on arrival in NICU was 35.4°C (34.3-36.5). The median age of all infants on arrival in NICU was 3h03min [2h25min-3h56min]. Three infants arrived in NICU with a temperature of <33°C and eleven with a temperature ≥37°C. Adrenaline during resuscitation was associated with a lower mean temperature on arrival in NICU.Conclusions/significanceOur strategy using ≥35-<36°C passive hypothermia combined with short transport times had little effect on temperature after the arrival of Neonatal Transport Team although did reduce numbers of infants arriving in NICU in deep hypothermia. For those infants where hypothermia was discontinued in NICU our strategy facilitated re-warming. Re-adjustment to a lower target temperature to ≥34.5-<35.5°C may reduce the proportion of infants with high/normothermic temperatures.
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Project description: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.
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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