Whole-Body Hypothermia for Term and Near-Term Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Controlled Trial
TL;DR: Therapeutic hypothermia reduced the risk of death or major sensorineural disability at 2 years of age and appears to be safe when commenced within 6 hours of birth at the hospital of birth in term and near-term newborns with hypoxic-ischemic encephalopathy.
Abstract: Objective: To determine the effectiveness and safety of moderate whole-body hypothermia in newborns with hypoxic-ischemic encephalopathy born in hospitals with and without newborn intensive care facilities or complicated hypothermia equipment.
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TL;DR: Although two small randomised controlled trials demonstrated neither evidence of benefit or harm, current evidence is inadequate to assess either safety or efficacy of therapeutic hypothermia in newborn infants with hypoxic ischaemic encephalopathy.
Abstract: Background Newborn animal and human pilot studies suggest that mild hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae, without adverse effects. Objectives To determine whether therapeutic hypothermia in encephalopathic asphyxiated newborn infants reduces mortality and long-term neurodevelopmental disability, without clinically important side effects. Search strategy The standard search strategy of the Neonatal Review Group as outlined in the Cochrane Library (Issue 2, 2003) was used. Randomised controlled trials evaluating therapeutic hypothermia in term newborns with hypoxic ischaemic encephalopathy were identified by searching the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue Issue 2, 2003), MEDLINE (1966 to July 2003), previous reviews including cross-references, abstracts, conferences, symposia proceedings, expert informants and journal hand searching. Selection criteria Randomised controlled trials comparing the use of therapeutic hypothermia with normothermia in encephalopathic newborn infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies were included. The primary outcome measure was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling and 'early' indicators of neurodevelopmental outcome. Data collection and analysis Three reviewers independently selected, assessed the quality of and extracted data from the included studies. Authors were contacted for further information. Meta-analyses were performed using relative risk and risk difference for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals. Main results Two randomised controlled trials were included in this review, comprising 50 term infants with moderate/ severe encephalopathy and evidence of intrapartum asphyxia. There was no significant effect of therapeutic hypothermia on the combined outcome of death or major neurodevelopmental disability in survivors followed. No adverse effects of hypothermia on short term medical outcomes or on some 'early' indicators of neurodevelopmental outcome were detected. Reviewer's conclusions Although two small randomised controlled trials demonstrated neither evidence of benefit or harm, current evidence is inadequate to assess either safety or efficacy of therapeutic hypothermia in newborn infants with hypoxic ischaemic encephalopathy. Therapeutic hypothermia for encephalopathic asphyxiated newborn infants should be further evaluated in well designed randomised controlled trials.
1,878 citations
TL;DR: The following guidelines are a summary of the evidence presented in the 2015 International Consensus on Cardiopulmo nary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations (CoSTR).
Abstract: The following guidelines are a summary of the evidence presented in the 2015 International Consensus on Cardiopulmo nary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations (CoSTR).1,2 Throughout the online version of this publication, live links are provided so the reader can connect directly to systematic reviews on the International Liaison Committee on Resuscitation (ILCOR) Scientific Evidence Evaluation and Review System (SEERS) website. These links are indicated by a combination of letters and numbers (eg, NRP 787). We encourage readers to use the links and review the evidence and appendices.
These guidelines apply primarily to newly born infants transitioning from intrauterine to extrauterine life. The recommendations are also applicable to neonates who have completed newborn transition and require resuscitation during the first weeks after birth.3 Practitioners who resuscitate infants at birth or at any time during the initial hospitalization should consider following these guidelines. For purposes of these guidelines, the terms newborn and neonate apply to any infant during the initial hospitalization. The term newly born applies specifically to an infant at the time of birth.3
Immediately after birth, infants who are breathing and crying may undergo delayed cord clamping (see Umbilical Cord Management section). However, until more evidence is available, infants who are not breathing or crying should have the cord clamped (unless part of a delayed cord clamping research protocol), so that resuscitation measures can commence promptly.
Approximately 10% of newborns require some assistance to begin breathing at birth. Less than 1% require extensive resuscitation measures,4 such as cardiac compressions and medications. Although most newly born infants successfully transition from intrauterine to extrauterine life without special help, because of the large total number of births, a significant number will require some degree of resuscitation.3
Newly born infants who do not …
622 citations
TL;DR: The vast majority of newborn infants do not require intervention to make these transitional changes, but the large number of births worldwide means that many infants require some assistance to achieve cardiorespiratory stability each year.
Abstract: ### Newborn Transition
The transition from intrauterine to extrauterine life that occurs at the time of birth requires timely anatomic and physiologic adjustments to achieve the conversion from placental gas exchange to pulmonary respiration. This transition is brought about by initiation of air breathing and cessation of the placental circulation. Air breathing initiates marked relaxation of pulmonary vascular resistance, with considerable increase in pulmonary blood flow and increased return of now-well-oxygenated blood to the left atrium and left ventricle, as well as increased left ventricular output. Removal of the low-resistance placental circuit will increase systemic vascular resistance and blood pressure and reduce right-to-left shunting across the ductus arteriosus. The systemic organs must equally and quickly adjust to the dramatic increase in blood pressure and oxygen exposure. Similarly, intrauterine thermostability must be replaced by neonatal thermoregulation with its inherent increase in oxygen consumption.
Approximately 85% of babies born at term will initiate spontaneous respirations within 10 to 30 seconds of birth, an additional 10% will respond during drying and stimulation, approximately 3% will initiate respirations after positive-pressure ventilation (PPV), 2% will be intubated to support respiratory function, and 0.1% will require chest compressions and/or epinephrine to achieve this transition.1–3 Although the vast majority of newborn infants do not require intervention to make these transitional changes, the large number of births worldwide means that many infants require some assistance to achieve cardiorespiratory stability each year.
Newly born infants who are breathing or crying and have good tone immediately after birth must be dried and kept warm so as to avoid hypothermia. These actions can be provided with the baby lying on the mother’s chest and should not require separation of mother and baby. This does not preclude the need for clinical assessment of the baby. …
612 citations
Wayne State University1, RTI International2, Brown University3, Stanford University4, University of Cincinnati5, Duke University6, University of Texas Health Science Center at Houston7, Case Western Reserve University8, Yale University9, University of Alabama at Birmingham10, University of Texas Southwestern Medical Center11, University of California, San Diego12, University of Miami13, Indiana University14, Emory University15, University of Rochester16, University of New Mexico17, National Institutes of Health18
TL;DR: The rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant.
Abstract: Background We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic–ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available. Methods In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70. Results Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) ...
528 citations
TL;DR: Total body cooling and selective head cooling are effective methods in treating newborns with moderate to severe HIE and Clinicians should consider offering therapeutic hypothermia as part of routine clinical care to these newborns.
Abstract: Objective To establish the evidence of therapeutic hypothermia for newborns with hypoxic ischemic encephalopathy (HIE). Data Sources Cochrane Central Register of Controlled Trials, Oxford Database of Perinatal Trials, MEDLINE, EMBASE, and previous reviews. Study Selection Randomized controlled trials that compared therapeutic hypothermia to normothermia for newborns with HIE. Intervention Therapeutic hypothermia. Main Outcome Measures Death or major neurodevelopmental disability at 18 months. Results Seven trials including 1214 newborns were identified. Therapeutic hypothermia resulted in a reduction in the risk of death or major neurodevelopmental disability (risk ratio [RR], 0.76; 95% CI, 0.69-0.84) and increase in the rate of survival with normal neurological function (1.63; 1.36-1.95) at age 18 months. Hypothermia reduced the risk of death or major neurodevelopmental disability at age 18 months in newborns with moderate HIE (RR, 0.67; 95% CI, 0.56-0.81) and in newborns with severe HIE (0.83; 0.74-0.92). Both total body cooling and selective head cooling resulted in reduction in the risk of death or major neurodevelopmental disability (RR, 0.75; 95% CI, 0.66-0.85 and 0.77; 0.65-0.93, respectively). Conclusion Hypothermia improves survival and neurodevelopment in newborns with moderate to severe HIE. Total body cooling and selective head cooling are effective methods in treating newborns with HIE. Clinicians should consider offering therapeutic hypothermia as part of routine clinical care to these newborns.
429 citations
References
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TL;DR: A five‐level classification system analogous to the staging and grading systems used in medicine, which has application for clinical practice, research, teaching, and administration is developed.
Abstract: To address the need for a standardized system to classify the gross motor function of children with cerebral palsy, the authors developed a five-level classification system analogous to the staging and grading systems used in medicine. Nominal group process and Delphi survey consensus methods were used to examine content validity and revise the classification system until consensus among 48 experts (physical therapists, occupational therapists, and developmental pediatricians with expertise in cerebral palsy) was achieved. Interrater reliability (kappa) was 0.55 for children less than 2 years of age and 0.75 for children 2 to 12 years of age. The classification system has application for clinical practice, research, teaching, and administration.
5,582 citations
"Whole-Body Hypothermia for Term and..." refers methods in this paper
...Major sensorineural disability comprised neuromotor delay (cerebral palsy [CP] in which the child was not walking [moderate CP] or was unlikely to walk [severe CP] at 2 years, a Psychomotor Development Index score on the Bayley Scales of Infant Development II [BSID-II] of less than −2 SDs, a Motor Composite Scale score on the BSID-III of less than −2 SDs, or a disability level on the Gross Motor Function Classification System [GMFCS] of 2-5), developmental delay (a Mental Development Index score on the BSID-II of less than −2 SDs or a Cognitive Scale score or a Language Composite Scale score on the BSID-III of less than −2 SDs), blindness (vision worse than 20/200 in both eyes), and/or deafness requiring amplification or worse (ie, the infant does not respond to amplification and is in need of a cochlear implant).(23-26) Fifteen survivors were assessed with the BSID-III, which was introduced in 2006....
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TL;DR: The proportion of child deaths that occurs in the neonatal period (38% in 2000) is increasing, and the Millennium Development Goal for child survival cannot be met without substantial reductions in neonatal mortality.
3,481 citations
Additional excerpts
...5) Apgar score, median (IQR) At 1 min 1 (0-2) 1 (0-2) At 5 min 3 (1-4) 3 (1-4) At 10 min 4 (3-5) 4 (3-5) Resuscitation Ventilation 110 (100) 111 (100) Cardiac compressions 69 (62....
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Book•
01 Jan 1980
TL;DR: The Fourth Edition of Statistical Methods for Survival Data Analysis is an ideal text for upper-undergraduate and graduate-level courses on survival data analysis and is an excellent resource for biomedical investigators, statisticians, and epidemiologists, as well as researchers in every field in which the analysis of survival data plays a role.
Abstract: Praise for the Third Edition. . . an easy-to read introduction to survival analysis which covers the major concepts and techniques of the subject. Statistics in Medical ResearchUpdated and expanded to reflect the latest developments, Statistical Methods for Survival Data Analysis, Fourth Edition continues to deliver a comprehensive introduction to the most commonly-used methods for analyzing survival data. Authored by a uniquely well-qualified author team, the Fourth Edition is a critically acclaimed guide to statistical methods with applications in clinical trials, epidemiology, areas of business, and the social sciences. The book features many real-world examples to illustrate applications within these various fields, although special consideration is given to the study of survival data in biomedical sciences.Emphasizing the latest research and providing the most up-to-date information regarding software applications in the field, Statistical Methods for Survival Data Analysis, Fourth Edition also includes:Marginal and random effect models for analyzing correlated censored or uncensored dataMultiple types of two-sample and K-sample comparison analysisUpdated treatment of parametric methods for regression model fitting with a new focus on accelerated failure time modelsExpanded coverage of the Cox proportional hazards modelExercises at the end of each chapter to deepen knowledge of the presented materialStatistical Methods for Survival Data Analysis is an ideal text for upper-undergraduate and graduate-level courses on survival data analysis. The book is also an excellent resource for biomedical investigators, statisticians, and epidemiologists, as well as researchers in every field in which the analysis of survival data plays a role.
3,307 citations
"Whole-Body Hypothermia for Term and..." refers methods in this paper
...A gamma distribution was also investigated, but this model did not converge.(33) Children with missing values for a particular outcome or covariate were not included in analyses using that outcome and/or covariate....
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Wayne State University1, Yale University2, University of Texas at Austin3, RTI International4, University of Cincinnati5, Case Western Reserve University6, National Institutes of Health7, University of California, San Diego8, University of Alabama9, University of Miami10, Duke University11, Stanford University12, Emory University13, Indiana University – Purdue University Indianapolis14, University of Rochester15
TL;DR: Whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic–ischemic encephalopathy and there was no increase in major disability among survivors.
Abstract: background Hypothermia is protective against brain injury after asphyxiation in animal models. However, the safety and effectiveness of hypothermia in term infants with encephalopathy is uncertain. methods We conducted a randomized trial of hypothermia in infants with a gestational age of at least 36 weeks who were admitted to the hospital at or before six hours of age with either severe acidosis or perinatal complications and resuscitation at birth and who had moderate or severe encephalopathy. Infants were randomly assigned to usual care (control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (hypothermia group). Neurodevelopmental outcome was assessed at 18 to 22 months of age. The primary outcome was a combined end point of death or moderate or severe disability. results Of 239 eligible infants, 102 were assigned to the hypothermia group and 106 to the control group. Adverse events were similar in the two groups during the 72 hours of cooling. Primary outcome data were available for 205 infants. Death or moderate or severe disability occurred in 45 of 102 infants (44 percent) in the hypothermia group and 64 of 103 infants (62 percent) in the control group (risk ratio, 0.72; 95 percent confidence interval, 0.54 to 0.95; P=0.01). Twenty-four infants (24 percent) in the hypothermia group and 38 (37 percent) in the control group died (risk ratio, 0.68; 95 percent confidence interval, 0.44 to 1.05; P=0.08). There was no increase in major disability among survivors; the rate of cerebral palsy was 15 of 77 (19 percent) in the hypothermia group as compared with 19 of 64 (30 percent) in the control group (risk ratio, 0.68; 95 percent confidence interval, 0.38 to 1.22; P=0.20). conclusions Whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic–ischemic encephalopathy.
2,311 citations
"Whole-Body Hypothermia for Term and..." refers background or result in this paper
...The lack of a significant effect of hypothermia on the other components of 2-year sensorineural outcomes is also consistent with the CoolCap and National Institute of Child Health and Human Development (NICHD) trials.(16,20) However, the largest trial (the Total Body Hypothermia for Neonatal Encephalopathy [TOBY] trial) reported a significant reduction in CP in cooled surviTable 2....
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...They also show that this secondary neuronal injury can be prevented or reduced by a mild reduction in brain temperature.9-13 Accumulating evidence supports the neuroprotective benefit of therapeutic hypothermia in term newborns with HIE.14-20 Commencing therapeutic hypothermia before 6 hours of age is considered critical; however, few babies throughout the world are admitted to tertiary neonatal intensive care units (NICUs) before this time....
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...Published online April 4, 2011. doi:10.1001/archpediatrics.2011.43 P ERIPARTUM ASPHYXIA COMPLI-cated by hypoxic-ischemicencephalopathy (HIE) re-mains an important cause ofmortality worldwide1-3 and of long-term sensorineural impairments and disabilities.4-8 Animal models demonstrate a therapeutic “window of opportunity” of approximately 6 hours after hypoxia-ischemia in the newborn before the delayed phase of neuronal loss....
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...Slight overshoot below 33°C was common duringtheinitiationphase,similartotheothertrials,(14,20) even when a servomechanism was used.(20) 39...
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...Althougheducationwasprovidedtoparticipatingcenters and retrieval services, this may represent the lack of a standardizedneurologicassessment tool toassessencephalopathy for the ICE trial, compared with the TOBY trial,(14) and the lack of formal certification of the transport medical staff who assessed encephalopathy at the birth hospital, as in the NICHD trial.(20) It may also represent the pragmatic nature of the ICE trial, which was performed in multiple centers andenvironments, and the imprecision in the diagnosis of encephalopathy....
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