Effect of therapeutic hypothermia initiated after 6 hours of age on death or disability among newborns with hypoxic-ischemic encephalopathy a randomized clinical trial

Abbot R. Laptook, Seetha Shankaran, Jon E. Tyson, Breda Munoz, Edward F. Bell, Ronald N. Goldberg, Nehal A. Parikh, Namasivayam Ambalavanan, Claudia Pedroza, Athina Pappas, Abhik Das, Aasma S. Chaudhary, Richard A. Ehrenkranz, Angelita M. Hensman, Krisa P. Van Meurs, Lina F. Chalak, Shannon E.G. Hamrick, Gregory M. Sokol, Michele C. Walsh, Brenda B. PoindexterRoger G. Faix, Kristi L. Watterberg, Ivan D. Frantz, Ronnie Guillet, Uday Devaskar, William E. Truog, Valerie Y. Chock, Myra H. Wyckoff, Elisabeth C. McGowan, David P. Carlton, Heidi M. Harmon, Jane E. Brumbaugh, C. Michael Cotten, Pablo J. Sánchez, Anna Maria Hibbs, Rosemary D. Higgins

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

IMPORTANCE Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. OBJECTIVE Toestimatetheprobabilitythathypothermiainitiatedat6to24hoursafterbirthreduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS A randomized clinical trialwas conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. INTERVENTIONS Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). MAIN OUTCOMES AND MEASURES The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. RESULTS Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95%CI, -1%to 17%). Bayesian analysis using a neutral prior indicated a 76%posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95%credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3%less than noncooled infants was 71%, 64%, and 56%, respectively. CONCLUSIONS AND RELEVANCE Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76%probability of any reduction in death or disability, and a 64%probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness.

Original languageEnglish (US)
Pages (from-to)1550-1560
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume318
Issue number16
DOIs
StatePublished - Oct 24 2017

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Brain Hypoxia-Ischemia
Induced Hypothermia
Randomized Controlled Trials
Newborn Infant
Hypothermia
Parturition
Bayes Theorem
Brain Diseases
Pregnancy
Random Allocation
Sample Size
Uncertainty

ASJC Scopus subject areas

  • Medicine(all)

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Effect of therapeutic hypothermia initiated after 6 hours of age on death or disability among newborns with hypoxic-ischemic encephalopathy a randomized clinical trial. / Laptook, Abbot R.; Shankaran, Seetha; Tyson, Jon E.; Munoz, Breda; Bell, Edward F.; Goldberg, Ronald N.; Parikh, Nehal A.; Ambalavanan, Namasivayam; Pedroza, Claudia; Pappas, Athina; Das, Abhik; Chaudhary, Aasma S.; Ehrenkranz, Richard A.; Hensman, Angelita M.; Van Meurs, Krisa P.; Chalak, Lina F.; Hamrick, Shannon E.G.; Sokol, Gregory M.; Walsh, Michele C.; Poindexter, Brenda B.; Faix, Roger G.; Watterberg, Kristi L.; Frantz, Ivan D.; Guillet, Ronnie; Devaskar, Uday; Truog, William E.; Chock, Valerie Y.; Wyckoff, Myra H.; McGowan, Elisabeth C.; Carlton, David P.; Harmon, Heidi M.; Brumbaugh, Jane E.; Cotten, C. Michael; Sánchez, Pablo J.; Hibbs, Anna Maria; Higgins, Rosemary D.

In: JAMA - Journal of the American Medical Association, Vol. 318, No. 16, 24.10.2017, p. 1550-1560.

Research output: Contribution to journalArticle

Laptook, AR, Shankaran, S, Tyson, JE, Munoz, B, Bell, EF, Goldberg, RN, Parikh, NA, Ambalavanan, N, Pedroza, C, Pappas, A, Das, A, Chaudhary, AS, Ehrenkranz, RA, Hensman, AM, Van Meurs, KP, Chalak, LF, Hamrick, SEG, Sokol, GM, Walsh, MC, Poindexter, BB, Faix, RG, Watterberg, KL, Frantz, ID, Guillet, R, Devaskar, U, Truog, WE, Chock, VY, Wyckoff, MH, McGowan, EC, Carlton, DP, Harmon, HM, Brumbaugh, JE, Cotten, CM, Sánchez, PJ, Hibbs, AM & Higgins, RD 2017, 'Effect of therapeutic hypothermia initiated after 6 hours of age on death or disability among newborns with hypoxic-ischemic encephalopathy a randomized clinical trial', JAMA - Journal of the American Medical Association, vol. 318, no. 16, pp. 1550-1560. https://doi.org/10.1001/jama.2017.14972
Laptook, Abbot R. ; Shankaran, Seetha ; Tyson, Jon E. ; Munoz, Breda ; Bell, Edward F. ; Goldberg, Ronald N. ; Parikh, Nehal A. ; Ambalavanan, Namasivayam ; Pedroza, Claudia ; Pappas, Athina ; Das, Abhik ; Chaudhary, Aasma S. ; Ehrenkranz, Richard A. ; Hensman, Angelita M. ; Van Meurs, Krisa P. ; Chalak, Lina F. ; Hamrick, Shannon E.G. ; Sokol, Gregory M. ; Walsh, Michele C. ; Poindexter, Brenda B. ; Faix, Roger G. ; Watterberg, Kristi L. ; Frantz, Ivan D. ; Guillet, Ronnie ; Devaskar, Uday ; Truog, William E. ; Chock, Valerie Y. ; Wyckoff, Myra H. ; McGowan, Elisabeth C. ; Carlton, David P. ; Harmon, Heidi M. ; Brumbaugh, Jane E. ; Cotten, C. Michael ; Sánchez, Pablo J. ; Hibbs, Anna Maria ; Higgins, Rosemary D. / Effect of therapeutic hypothermia initiated after 6 hours of age on death or disability among newborns with hypoxic-ischemic encephalopathy a randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2017 ; Vol. 318, No. 16. pp. 1550-1560.
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abstract = "IMPORTANCE Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. OBJECTIVE Toestimatetheprobabilitythathypothermiainitiatedat6to24hoursafterbirthreduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS A randomized clinical trialwas conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. INTERVENTIONS Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). MAIN OUTCOMES AND MEASURES The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. RESULTS Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57{\%}) and 55 of 85 (65{\%}) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4{\%}) and 22 of 79 noncooled infants (27.9{\%}) (absolute difference, 3.5{\%}; 95{\%}CI, -1{\%}to 17{\%}). Bayesian analysis using a neutral prior indicated a 76{\%}posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95{\%}credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1{\%}, 2{\%}, or 3{\%}less than noncooled infants was 71{\%}, 64{\%}, and 56{\%}, respectively. CONCLUSIONS AND RELEVANCE Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76{\%}probability of any reduction in death or disability, and a 64{\%}probability of at least 2{\%} less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness.",
author = "Laptook, {Abbot R.} and Seetha Shankaran and Tyson, {Jon E.} and Breda Munoz and Bell, {Edward F.} and Goldberg, {Ronald N.} and Parikh, {Nehal A.} and Namasivayam Ambalavanan and Claudia Pedroza and Athina Pappas and Abhik Das and Chaudhary, {Aasma S.} and Ehrenkranz, {Richard A.} and Hensman, {Angelita M.} and {Van Meurs}, {Krisa P.} and Chalak, {Lina F.} and Hamrick, {Shannon E.G.} and Sokol, {Gregory M.} and Walsh, {Michele C.} and Poindexter, {Brenda B.} and Faix, {Roger G.} and Watterberg, {Kristi L.} and Frantz, {Ivan D.} and Ronnie Guillet and Uday Devaskar and Truog, {William E.} and Chock, {Valerie Y.} and Wyckoff, {Myra H.} and McGowan, {Elisabeth C.} and Carlton, {David P.} and Harmon, {Heidi M.} and Brumbaugh, {Jane E.} and Cotten, {C. Michael} and S{\'a}nchez, {Pablo J.} and Hibbs, {Anna Maria} and Higgins, {Rosemary D.}",
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TY - JOUR

T1 - Effect of therapeutic hypothermia initiated after 6 hours of age on death or disability among newborns with hypoxic-ischemic encephalopathy a randomized clinical trial

AU - Laptook, Abbot R.

AU - Shankaran, Seetha

AU - Tyson, Jon E.

AU - Munoz, Breda

AU - Bell, Edward F.

AU - Goldberg, Ronald N.

AU - Parikh, Nehal A.

AU - Ambalavanan, Namasivayam

AU - Pedroza, Claudia

AU - Pappas, Athina

AU - Das, Abhik

AU - Chaudhary, Aasma S.

AU - Ehrenkranz, Richard A.

AU - Hensman, Angelita M.

AU - Van Meurs, Krisa P.

AU - Chalak, Lina F.

AU - Hamrick, Shannon E.G.

AU - Sokol, Gregory M.

AU - Walsh, Michele C.

AU - Poindexter, Brenda B.

AU - Faix, Roger G.

AU - Watterberg, Kristi L.

AU - Frantz, Ivan D.

AU - Guillet, Ronnie

AU - Devaskar, Uday

AU - Truog, William E.

AU - Chock, Valerie Y.

AU - Wyckoff, Myra H.

AU - McGowan, Elisabeth C.

AU - Carlton, David P.

AU - Harmon, Heidi M.

AU - Brumbaugh, Jane E.

AU - Cotten, C. Michael

AU - Sánchez, Pablo J.

AU - Hibbs, Anna Maria

AU - Higgins, Rosemary D.

PY - 2017/10/24

Y1 - 2017/10/24

N2 - IMPORTANCE Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. OBJECTIVE Toestimatetheprobabilitythathypothermiainitiatedat6to24hoursafterbirthreduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS A randomized clinical trialwas conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. INTERVENTIONS Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). MAIN OUTCOMES AND MEASURES The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. RESULTS Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95%CI, -1%to 17%). Bayesian analysis using a neutral prior indicated a 76%posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95%credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3%less than noncooled infants was 71%, 64%, and 56%, respectively. CONCLUSIONS AND RELEVANCE Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76%probability of any reduction in death or disability, and a 64%probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness.

AB - IMPORTANCE Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. OBJECTIVE Toestimatetheprobabilitythathypothermiainitiatedat6to24hoursafterbirthreduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS A randomized clinical trialwas conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. INTERVENTIONS Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). MAIN OUTCOMES AND MEASURES The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. RESULTS Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95%CI, -1%to 17%). Bayesian analysis using a neutral prior indicated a 76%posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95%credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3%less than noncooled infants was 71%, 64%, and 56%, respectively. CONCLUSIONS AND RELEVANCE Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76%probability of any reduction in death or disability, and a 64%probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness.

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