Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy a randomized clinical trial

Seetha Shankaran, Abbot R. Laptook, Athina Pappas, Scott A. McDonald, Abhik Das, Jon E. Tyson, Brenda B. Poindexter, Kurt Schibler, Edward F. Bell, Roy J. Heyne, Claudia Pedroza, Rebecca Bara, Krisa P. Van Meurs, Cathy Grisby, Carolyn M Petrie Huitema, Meena Garg, Richard A. Ehrenkranz, Edward G. Shepherd, Lina F. Chalak, Shannon E G Hamrick & 157 others Amir M. Khan, Anne Marie Reynolds, Matthew M. Laughon, William E. Truog, Kevin C. Dysart, Waldemar A. Carlo, Michele C. Walsh, Kristi L. Watterberg, Rosemary D. Higgins, Michael S. Caplan, Richard A. Polin, Martin Keszler, Betty R. Vohr, Angelita M. Hensman, Elisa Vierira, Emilee Little, Ross Sommers, Birju Shah, Nicholas Guerina, Leslie T. McKinley, Melinda Caskey, Andrea Halbrook, Robert T. Burke, Anna Maria Hibbs, Nancy S. Newman, Eugenia K. Pallotto, Howard W. Kilbride, Cheri Gauldin, Anne Holmes, Kathy Johnson, Suhas G. Kallapur, Barbara Alexander, Estelle E. Fischer, Teresa L. Gratton, Lenora Jackson, Jennifer Jennings, Kristin Kirker, Greg Muthig, Sandra Wuertz, Ronald N. Goldberg, Joanne Finkle, Kimberley A. Fisher, Sandra Grimes, Carl L. Bose, Janice Bernhardt, Cindy Clark, Barbara J. Stoll, David P. Carlton, Ellen C. Hale, Yvonne Loggins, Stephanie Wilson Archer, Gregory M. Sokol, Leslie Dawn Wilson, Dianne E. Herron, Susan Gunn, Lucy Smiley, Sudarshan R. Jadcherla, Pablo J. Sánchez, Patricia Luzader, Christine A. Fortney, Gail E. Besner, Nehal A. Parikh, Dennis Wallace, Kristin M. Zaterka-Baxter, Margaret Crawford, Jenna Gabrio, Marie G. Gantz, Jamie E. Newman, Jeanette O Donnell Auman, Tracy L. Nolen, David K. Stevenson, M. Bethany Ball, Marian M. Adams, Alexis S. Davis, Carol Kibler, Jeffrey R. Parker, Melinda S. Proud, Ronald J. Wong, Namasivayam Ambalavanan, Monica V. Collins, Shirley S. Cosby, Uday Devaskar, Teresa Chanlaw, Rachel Geller, Dan L. Ellsbury, Tarah T. Colaizy, Jane E. Brumbaugh, Karen J. Johnson, Donia B. Campbell, Jacky R. Walker, Jonathan M. Klein, Jeffrey L. Segar, John M. Dagle, Julie B. Lindower, Steven J. McElroy, Glenda K. Rabe, Robert D. Roghair, Lauritz R. Meyer, Cary R. Murphy, Vipinchandra Bhavsar, Robin K. Ohls, Conra Backstrom Lacy, Sandra Beauman, Carol Hartenberger, Barbara Schmidt, Haresh Kirpalani, Sara B. De Mauro, Aasma S. Chaudhary, Soraya Abbasi, Toni Mancini, Dara M. Cucinotta, Nirupama Laroia, Carl T. D'Angio, Ronnie Guillet, Satyan Lakshminrusimha, Karen Wynn, Holly I M Wadkins, Ann Marie Scorsone, Patrick Conway, Michael G. Sacilowski, Stephanie Guilford, Ashley Williams, Myra Wyckoff, Luc P. Brion, Diana M. Vasil, Lijun Chen, Emma Ramon, Kathleen A. Kennedy, Georgia E. McDavid, Julie Arldt-McAlister, Katrina Burson, Carmen Garcia, Karen Martin, Shawna Rodgers, Patti L Pierce Tate, Sharon L. Wright, Beena G. Sood, John Barks, Maria Batts, Lilia De Jesus, Kimberly Hayes-Hart, Mary E. Johnson, Girija Natarajan, Lisa Sulkowski, Laura Sumner, Nicole Walker, Kathleen Weingarden, Mary Christensen, Stephanie A. Wiggins, Christine A. Gleason, Robert J. Boyle, Traci Clemons, Mary E. D'Alton, Carol K. Redmond, Michael G. Ross, Steven J. Weiner, Marian Willinger

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

IMPORTANCE: Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44%to 55%; longer cooling and deeper cooling are neuroprotective in animal models.

OBJECTIVE: To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.

DESIGN, SETTING, ANDPARTICIPANTS: Arandomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.

INTERVENTIONS: Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours.

MAIN OUTCOMES AND MEASURES: The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonateswere enrolled, then after every subsequent 25 neonates. The trialwas closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours' vs 120 hours' duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes).

RESULTS The NICU: death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95%CI, 0.92-2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95%CI, 0.69-2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1%in the 120 hours group vs 3%in the 72 hours group (RR, 0.25 [95%CI, 0.07-0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%.

CONCLUSIONS AND RELEVANCE: Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01192776.

Original languageEnglish
Pages (from-to)2629-2639
Number of pages11
JournalJournal of the American Medical Association
Volume312
Issue number24
DOIs
StatePublished - Dec 24 2014

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Brain Hypoxia-Ischemia
Neonatal Intensive Care Units
Randomized Controlled Trials
Safety
Hypothermia
Medical Futility
Clinical Trials Data Monitoring Committees
Odds Ratio
National Institute of Child Health and Human Development (U.S.)
Hemorrhage
Acidosis
Cardiac Arrhythmias
Patient Care
Thrombosis
Animal Models
Clinical Trials
Mortality
Research

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy a randomized clinical trial. / Shankaran, Seetha; Laptook, Abbot R.; Pappas, Athina; McDonald, Scott A.; Das, Abhik; Tyson, Jon E.; Poindexter, Brenda B.; Schibler, Kurt; Bell, Edward F.; Heyne, Roy J.; Pedroza, Claudia; Bara, Rebecca; Van Meurs, Krisa P.; Grisby, Cathy; Huitema, Carolyn M Petrie; Garg, Meena; Ehrenkranz, Richard A.; Shepherd, Edward G.; Chalak, Lina F.; Hamrick, Shannon E G; Khan, Amir M.; Reynolds, Anne Marie; Laughon, Matthew M.; Truog, William E.; Dysart, Kevin C.; Carlo, Waldemar A.; Walsh, Michele C.; Watterberg, Kristi L.; Higgins, Rosemary D.; Caplan, Michael S.; Polin, Richard A.; Keszler, Martin; Vohr, Betty R.; Hensman, Angelita M.; Vierira, Elisa; Little, Emilee; Sommers, Ross; Shah, Birju; Guerina, Nicholas; McKinley, Leslie T.; Caskey, Melinda; Halbrook, Andrea; Burke, Robert T.; Hibbs, Anna Maria; Newman, Nancy S.; Pallotto, Eugenia K.; Kilbride, Howard W.; Gauldin, Cheri; Holmes, Anne; Johnson, Kathy; Kallapur, Suhas G.; Alexander, Barbara; Fischer, Estelle E.; Gratton, Teresa L.; Jackson, Lenora; Jennings, Jennifer; Kirker, Kristin; Muthig, Greg; Wuertz, Sandra; Goldberg, Ronald N.; Finkle, Joanne; Fisher, Kimberley A.; Grimes, Sandra; Bose, Carl L.; Bernhardt, Janice; Clark, Cindy; Stoll, Barbara J.; Carlton, David P.; Hale, Ellen C.; Loggins, Yvonne; Archer, Stephanie Wilson; Sokol, Gregory M.; Wilson, Leslie Dawn; Herron, Dianne E.; Gunn, Susan; Smiley, Lucy; Jadcherla, Sudarshan R.; Sánchez, Pablo J.; Luzader, Patricia; Fortney, Christine A.; Besner, Gail E.; Parikh, Nehal A.; Wallace, Dennis; Zaterka-Baxter, Kristin M.; Crawford, Margaret; Gabrio, Jenna; Gantz, Marie G.; Newman, Jamie E.; Auman, Jeanette O Donnell; Nolen, Tracy L.; Stevenson, David K.; Ball, M. Bethany; Adams, Marian M.; Davis, Alexis S.; Kibler, Carol; Parker, Jeffrey R.; Proud, Melinda S.; Wong, Ronald J.; Ambalavanan, Namasivayam; Collins, Monica V.; Cosby, Shirley S.; Devaskar, Uday; Chanlaw, Teresa; Geller, Rachel; Ellsbury, Dan L.; Colaizy, Tarah T.; Brumbaugh, Jane E.; Johnson, Karen J.; Campbell, Donia B.; Walker, Jacky R.; Klein, Jonathan M.; Segar, Jeffrey L.; Dagle, John M.; Lindower, Julie B.; McElroy, Steven J.; Rabe, Glenda K.; Roghair, Robert D.; Meyer, Lauritz R.; Murphy, Cary R.; Bhavsar, Vipinchandra; Ohls, Robin K.; Lacy, Conra Backstrom; Beauman, Sandra; Hartenberger, Carol; Schmidt, Barbara; Kirpalani, Haresh; De Mauro, Sara B.; Chaudhary, Aasma S.; Abbasi, Soraya; Mancini, Toni; Cucinotta, Dara M.; Laroia, Nirupama; D'Angio, Carl T.; Guillet, Ronnie; Lakshminrusimha, Satyan; Wynn, Karen; Wadkins, Holly I M; Scorsone, Ann Marie; Conway, Patrick; Sacilowski, Michael G.; Guilford, Stephanie; Williams, Ashley; Wyckoff, Myra; Brion, Luc P.; Vasil, Diana M.; Chen, Lijun; Ramon, Emma; Kennedy, Kathleen A.; McDavid, Georgia E.; Arldt-McAlister, Julie; Burson, Katrina; Garcia, Carmen; Martin, Karen; Rodgers, Shawna; Tate, Patti L Pierce; Wright, Sharon L.; Sood, Beena G.; Barks, John; Batts, Maria; De Jesus, Lilia; Hayes-Hart, Kimberly; Johnson, Mary E.; Natarajan, Girija; Sulkowski, Lisa; Sumner, Laura; Walker, Nicole; Weingarden, Kathleen; Christensen, Mary; Wiggins, Stephanie A.; Gleason, Christine A.; Boyle, Robert J.; Clemons, Traci; D'Alton, Mary E.; Redmond, Carol K.; Ross, Michael G.; Weiner, Steven J.; Willinger, Marian.

In: Journal of the American Medical Association, Vol. 312, No. 24, 24.12.2014, p. 2629-2639.

Research output: Contribution to journalArticle

Shankaran, S, Laptook, AR, Pappas, A, McDonald, SA, Das, A, Tyson, JE, Poindexter, BB, Schibler, K, Bell, EF, Heyne, RJ, Pedroza, C, Bara, R, Van Meurs, KP, Grisby, C, Huitema, CMP, Garg, M, Ehrenkranz, RA, Shepherd, EG, Chalak, LF, Hamrick, SEG, Khan, AM, Reynolds, AM, Laughon, MM, Truog, WE, Dysart, KC, Carlo, WA, Walsh, MC, Watterberg, KL, Higgins, RD, Caplan, MS, Polin, RA, Keszler, M, Vohr, BR, Hensman, AM, Vierira, E, Little, E, Sommers, R, Shah, B, Guerina, N, McKinley, LT, Caskey, M, Halbrook, A, Burke, RT, Hibbs, AM, Newman, NS, Pallotto, EK, Kilbride, HW, Gauldin, C, Holmes, A, Johnson, K, Kallapur, SG, Alexander, B, Fischer, EE, Gratton, TL, Jackson, L, Jennings, J, Kirker, K, Muthig, G, Wuertz, S, Goldberg, RN, Finkle, J, Fisher, KA, Grimes, S, Bose, CL, Bernhardt, J, Clark, C, Stoll, BJ, Carlton, DP, Hale, EC, Loggins, Y, Archer, SW, Sokol, GM, Wilson, LD, Herron, DE, Gunn, S, Smiley, L, Jadcherla, SR, Sánchez, PJ, Luzader, P, Fortney, CA, Besner, GE, Parikh, NA, Wallace, D, Zaterka-Baxter, KM, Crawford, M, Gabrio, J, Gantz, MG, Newman, JE, Auman, JOD, Nolen, TL, Stevenson, DK, Ball, MB, Adams, MM, Davis, AS, Kibler, C, Parker, JR, Proud, MS, Wong, RJ, Ambalavanan, N, Collins, MV, Cosby, SS, Devaskar, U, Chanlaw, T, Geller, R, Ellsbury, DL, Colaizy, TT, Brumbaugh, JE, Johnson, KJ, Campbell, DB, Walker, JR, Klein, JM, Segar, JL, Dagle, JM, Lindower, JB, McElroy, SJ, Rabe, GK, Roghair, RD, Meyer, LR, Murphy, CR, Bhavsar, V, Ohls, RK, Lacy, CB, Beauman, S, Hartenberger, C, Schmidt, B, Kirpalani, H, De Mauro, SB, Chaudhary, AS, Abbasi, S, Mancini, T, Cucinotta, DM, Laroia, N, D'Angio, CT, Guillet, R, Lakshminrusimha, S, Wynn, K, Wadkins, HIM, Scorsone, AM, Conway, P, Sacilowski, MG, Guilford, S, Williams, A, Wyckoff, M, Brion, LP, Vasil, DM, Chen, L, Ramon, E, Kennedy, KA, McDavid, GE, Arldt-McAlister, J, Burson, K, Garcia, C, Martin, K, Rodgers, S, Tate, PLP, Wright, SL, Sood, BG, Barks, J, Batts, M, De Jesus, L, Hayes-Hart, K, Johnson, ME, Natarajan, G, Sulkowski, L, Sumner, L, Walker, N, Weingarden, K, Christensen, M, Wiggins, SA, Gleason, CA, Boyle, RJ, Clemons, T, D'Alton, ME, Redmond, CK, Ross, MG, Weiner, SJ & Willinger, M 2014, 'Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy a randomized clinical trial', Journal of the American Medical Association, vol. 312, no. 24, pp. 2629-2639. https://doi.org/10.1001/jama.2014.16058
Shankaran, Seetha ; Laptook, Abbot R. ; Pappas, Athina ; McDonald, Scott A. ; Das, Abhik ; Tyson, Jon E. ; Poindexter, Brenda B. ; Schibler, Kurt ; Bell, Edward F. ; Heyne, Roy J. ; Pedroza, Claudia ; Bara, Rebecca ; Van Meurs, Krisa P. ; Grisby, Cathy ; Huitema, Carolyn M Petrie ; Garg, Meena ; Ehrenkranz, Richard A. ; Shepherd, Edward G. ; Chalak, Lina F. ; Hamrick, Shannon E G ; Khan, Amir M. ; Reynolds, Anne Marie ; Laughon, Matthew M. ; Truog, William E. ; Dysart, Kevin C. ; Carlo, Waldemar A. ; Walsh, Michele C. ; Watterberg, Kristi L. ; Higgins, Rosemary D. ; Caplan, Michael S. ; Polin, Richard A. ; Keszler, Martin ; Vohr, Betty R. ; Hensman, Angelita M. ; Vierira, Elisa ; Little, Emilee ; Sommers, Ross ; Shah, Birju ; Guerina, Nicholas ; McKinley, Leslie T. ; Caskey, Melinda ; Halbrook, Andrea ; Burke, Robert T. ; Hibbs, Anna Maria ; Newman, Nancy S. ; Pallotto, Eugenia K. ; Kilbride, Howard W. ; Gauldin, Cheri ; Holmes, Anne ; Johnson, Kathy ; Kallapur, Suhas G. ; Alexander, Barbara ; Fischer, Estelle E. ; Gratton, Teresa L. ; Jackson, Lenora ; Jennings, Jennifer ; Kirker, Kristin ; Muthig, Greg ; Wuertz, Sandra ; Goldberg, Ronald N. ; Finkle, Joanne ; Fisher, Kimberley A. ; Grimes, Sandra ; Bose, Carl L. ; Bernhardt, Janice ; Clark, Cindy ; Stoll, Barbara J. ; Carlton, David P. ; Hale, Ellen C. ; Loggins, Yvonne ; Archer, Stephanie Wilson ; Sokol, Gregory M. ; Wilson, Leslie Dawn ; Herron, Dianne E. ; Gunn, Susan ; Smiley, Lucy ; Jadcherla, Sudarshan R. ; Sánchez, Pablo J. ; Luzader, Patricia ; Fortney, Christine A. ; Besner, Gail E. ; Parikh, Nehal A. ; Wallace, Dennis ; Zaterka-Baxter, Kristin M. ; Crawford, Margaret ; Gabrio, Jenna ; Gantz, Marie G. ; Newman, Jamie E. ; Auman, Jeanette O Donnell ; Nolen, Tracy L. ; Stevenson, David K. ; Ball, M. Bethany ; Adams, Marian M. ; Davis, Alexis S. ; Kibler, Carol ; Parker, Jeffrey R. ; Proud, Melinda S. ; Wong, Ronald J. ; Ambalavanan, Namasivayam ; Collins, Monica V. ; Cosby, Shirley S. ; Devaskar, Uday ; Chanlaw, Teresa ; Geller, Rachel ; Ellsbury, Dan L. ; Colaizy, Tarah T. ; Brumbaugh, Jane E. ; Johnson, Karen J. ; Campbell, Donia B. ; Walker, Jacky R. ; Klein, Jonathan M. ; Segar, Jeffrey L. ; Dagle, John M. ; Lindower, Julie B. ; McElroy, Steven J. ; Rabe, Glenda K. ; Roghair, Robert D. ; Meyer, Lauritz R. ; Murphy, Cary R. ; Bhavsar, Vipinchandra ; Ohls, Robin K. ; Lacy, Conra Backstrom ; Beauman, Sandra ; Hartenberger, Carol ; Schmidt, Barbara ; Kirpalani, Haresh ; De Mauro, Sara B. ; Chaudhary, Aasma S. ; Abbasi, Soraya ; Mancini, Toni ; Cucinotta, Dara M. ; Laroia, Nirupama ; D'Angio, Carl T. ; Guillet, Ronnie ; Lakshminrusimha, Satyan ; Wynn, Karen ; Wadkins, Holly I M ; Scorsone, Ann Marie ; Conway, Patrick ; Sacilowski, Michael G. ; Guilford, Stephanie ; Williams, Ashley ; Wyckoff, Myra ; Brion, Luc P. ; Vasil, Diana M. ; Chen, Lijun ; Ramon, Emma ; Kennedy, Kathleen A. ; McDavid, Georgia E. ; Arldt-McAlister, Julie ; Burson, Katrina ; Garcia, Carmen ; Martin, Karen ; Rodgers, Shawna ; Tate, Patti L Pierce ; Wright, Sharon L. ; Sood, Beena G. ; Barks, John ; Batts, Maria ; De Jesus, Lilia ; Hayes-Hart, Kimberly ; Johnson, Mary E. ; Natarajan, Girija ; Sulkowski, Lisa ; Sumner, Laura ; Walker, Nicole ; Weingarden, Kathleen ; Christensen, Mary ; Wiggins, Stephanie A. ; Gleason, Christine A. ; Boyle, Robert J. ; Clemons, Traci ; D'Alton, Mary E. ; Redmond, Carol K. ; Ross, Michael G. ; Weiner, Steven J. ; Willinger, Marian. / Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy a randomized clinical trial. In: Journal of the American Medical Association. 2014 ; Vol. 312, No. 24. pp. 2629-2639.
@article{34870cf9f08b4b2cbff8df53d4fbbd40,
title = "Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy a randomized clinical trial",
abstract = "IMPORTANCE: Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44{\%}to 55{\%}; longer cooling and deeper cooling are neuroprotective in animal models.OBJECTIVE: To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.DESIGN, SETTING, ANDPARTICIPANTS: Arandomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.INTERVENTIONS: Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours.MAIN OUTCOMES AND MEASURES: The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonateswere enrolled, then after every subsequent 25 neonates. The trialwas closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours' vs 120 hours' duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes).RESULTS The NICU: death rates were 7 of 95 neonates (7{\%}) for the 33.5°C for 72 hours group, 13 of 90 neonates (14{\%}) for the 32.0°C for 72 hours group, 15 of 96 neonates (16{\%}) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17{\%}) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95{\%}CI, 0.92-2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95{\%}CI, 0.69-2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1{\%}in the 120 hours group vs 3{\%}in the 72 hours group (RR, 0.25 [95{\%}CI, 0.07-0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2{\%}.CONCLUSIONS AND RELEVANCE: Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01192776.",
author = "Seetha Shankaran and Laptook, {Abbot R.} and Athina Pappas and McDonald, {Scott A.} and Abhik Das and Tyson, {Jon E.} and Poindexter, {Brenda B.} and Kurt Schibler and Bell, {Edward F.} and Heyne, {Roy J.} and Claudia Pedroza and Rebecca Bara and {Van Meurs}, {Krisa P.} and Cathy Grisby and Huitema, {Carolyn M Petrie} and Meena Garg and Ehrenkranz, {Richard A.} and Shepherd, {Edward G.} and Chalak, {Lina F.} and Hamrick, {Shannon E G} and Khan, {Amir M.} and Reynolds, {Anne Marie} and Laughon, {Matthew M.} and Truog, {William E.} and Dysart, {Kevin C.} and Carlo, {Waldemar A.} and Walsh, {Michele C.} and Watterberg, {Kristi L.} and Higgins, {Rosemary D.} and Caplan, {Michael S.} and Polin, {Richard A.} and Martin Keszler and Vohr, {Betty R.} and Hensman, {Angelita M.} and Elisa Vierira and Emilee Little and Ross Sommers and Birju Shah and Nicholas Guerina and McKinley, {Leslie T.} and Melinda Caskey and Andrea Halbrook and Burke, {Robert T.} and Hibbs, {Anna Maria} and Newman, {Nancy S.} and Pallotto, {Eugenia K.} and Kilbride, {Howard W.} and Cheri Gauldin and Anne Holmes and Kathy Johnson and Kallapur, {Suhas G.} and Barbara Alexander and Fischer, {Estelle E.} and Gratton, {Teresa L.} and Lenora Jackson and Jennifer Jennings and Kristin Kirker and Greg Muthig and Sandra Wuertz and Goldberg, {Ronald N.} and Joanne Finkle and Fisher, {Kimberley A.} and Sandra Grimes and Bose, {Carl L.} and Janice Bernhardt and Cindy Clark and Stoll, {Barbara J.} and Carlton, {David P.} and Hale, {Ellen C.} and Yvonne Loggins and Archer, {Stephanie Wilson} and Sokol, {Gregory M.} and Wilson, {Leslie Dawn} and Herron, {Dianne E.} and Susan Gunn and Lucy Smiley and Jadcherla, {Sudarshan R.} and S{\'a}nchez, {Pablo J.} and Patricia Luzader and Fortney, {Christine A.} and Besner, {Gail E.} and Parikh, {Nehal A.} and Dennis Wallace and Zaterka-Baxter, {Kristin M.} and Margaret Crawford and Jenna Gabrio and Gantz, {Marie G.} and Newman, {Jamie E.} and Auman, {Jeanette O Donnell} and Nolen, {Tracy L.} and Stevenson, {David K.} and Ball, {M. Bethany} and Adams, {Marian M.} and Davis, {Alexis S.} and Carol Kibler and Parker, {Jeffrey R.} and Proud, {Melinda S.} and Wong, {Ronald J.} and Namasivayam Ambalavanan and Collins, {Monica V.} and Cosby, {Shirley S.} and Uday Devaskar and Teresa Chanlaw and Rachel Geller and Ellsbury, {Dan L.} and Colaizy, {Tarah T.} and Brumbaugh, {Jane E.} and Johnson, {Karen J.} and Campbell, {Donia B.} and Walker, {Jacky R.} and Klein, {Jonathan M.} and Segar, {Jeffrey L.} and Dagle, {John M.} and Lindower, {Julie B.} and McElroy, {Steven J.} and Rabe, {Glenda K.} and Roghair, {Robert D.} and Meyer, {Lauritz R.} and Murphy, {Cary R.} and Vipinchandra Bhavsar and Ohls, {Robin K.} and Lacy, {Conra Backstrom} and Sandra Beauman and Carol Hartenberger and Barbara Schmidt and Haresh Kirpalani and {De Mauro}, {Sara B.} and Chaudhary, {Aasma S.} and Soraya Abbasi and Toni Mancini and Cucinotta, {Dara M.} and Nirupama Laroia and D'Angio, {Carl T.} and Ronnie Guillet and Satyan Lakshminrusimha and Karen Wynn and Wadkins, {Holly I M} and Scorsone, {Ann Marie} and Patrick Conway and Sacilowski, {Michael G.} and Stephanie Guilford and Ashley Williams and Myra Wyckoff and Brion, {Luc P.} and Vasil, {Diana M.} and Lijun Chen and Emma Ramon and Kennedy, {Kathleen A.} and McDavid, {Georgia E.} and Julie Arldt-McAlister and Katrina Burson and Carmen Garcia and Karen Martin and Shawna Rodgers and Tate, {Patti L Pierce} and Wright, {Sharon L.} and Sood, {Beena G.} and John Barks and Maria Batts and {De Jesus}, Lilia and Kimberly Hayes-Hart and Johnson, {Mary E.} and Girija Natarajan and Lisa Sulkowski and Laura Sumner and Nicole Walker and Kathleen Weingarden and Mary Christensen and Wiggins, {Stephanie A.} and Gleason, {Christine A.} and Boyle, {Robert J.} and Traci Clemons and D'Alton, {Mary E.} and Redmond, {Carol K.} and Ross, {Michael G.} and Weiner, {Steven J.} and Marian Willinger",
year = "2014",
month = "12",
day = "24",
doi = "10.1001/jama.2014.16058",
language = "English",
volume = "312",
pages = "2629--2639",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "24",

}

TY - JOUR

T1 - Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy a randomized clinical trial

AU - Shankaran, Seetha

AU - Laptook, Abbot R.

AU - Pappas, Athina

AU - McDonald, Scott A.

AU - Das, Abhik

AU - Tyson, Jon E.

AU - Poindexter, Brenda B.

AU - Schibler, Kurt

AU - Bell, Edward F.

AU - Heyne, Roy J.

AU - Pedroza, Claudia

AU - Bara, Rebecca

AU - Van Meurs, Krisa P.

AU - Grisby, Cathy

AU - Huitema, Carolyn M Petrie

AU - Garg, Meena

AU - Ehrenkranz, Richard A.

AU - Shepherd, Edward G.

AU - Chalak, Lina F.

AU - Hamrick, Shannon E G

AU - Khan, Amir M.

AU - Reynolds, Anne Marie

AU - Laughon, Matthew M.

AU - Truog, William E.

AU - Dysart, Kevin C.

AU - Carlo, Waldemar A.

AU - Walsh, Michele C.

AU - Watterberg, Kristi L.

AU - Higgins, Rosemary D.

AU - Caplan, Michael S.

AU - Polin, Richard A.

AU - Keszler, Martin

AU - Vohr, Betty R.

AU - Hensman, Angelita M.

AU - Vierira, Elisa

AU - Little, Emilee

AU - Sommers, Ross

AU - Shah, Birju

AU - Guerina, Nicholas

AU - McKinley, Leslie T.

AU - Caskey, Melinda

AU - Halbrook, Andrea

AU - Burke, Robert T.

AU - Hibbs, Anna Maria

AU - Newman, Nancy S.

AU - Pallotto, Eugenia K.

AU - Kilbride, Howard W.

AU - Gauldin, Cheri

AU - Holmes, Anne

AU - Johnson, Kathy

AU - Kallapur, Suhas G.

AU - Alexander, Barbara

AU - Fischer, Estelle E.

AU - Gratton, Teresa L.

AU - Jackson, Lenora

AU - Jennings, Jennifer

AU - Kirker, Kristin

AU - Muthig, Greg

AU - Wuertz, Sandra

AU - Goldberg, Ronald N.

AU - Finkle, Joanne

AU - Fisher, Kimberley A.

AU - Grimes, Sandra

AU - Bose, Carl L.

AU - Bernhardt, Janice

AU - Clark, Cindy

AU - Stoll, Barbara J.

AU - Carlton, David P.

AU - Hale, Ellen C.

AU - Loggins, Yvonne

AU - Archer, Stephanie Wilson

AU - Sokol, Gregory M.

AU - Wilson, Leslie Dawn

AU - Herron, Dianne E.

AU - Gunn, Susan

AU - Smiley, Lucy

AU - Jadcherla, Sudarshan R.

AU - Sánchez, Pablo J.

AU - Luzader, Patricia

AU - Fortney, Christine A.

AU - Besner, Gail E.

AU - Parikh, Nehal A.

AU - Wallace, Dennis

AU - Zaterka-Baxter, Kristin M.

AU - Crawford, Margaret

AU - Gabrio, Jenna

AU - Gantz, Marie G.

AU - Newman, Jamie E.

AU - Auman, Jeanette O Donnell

AU - Nolen, Tracy L.

AU - Stevenson, David K.

AU - Ball, M. Bethany

AU - Adams, Marian M.

AU - Davis, Alexis S.

AU - Kibler, Carol

AU - Parker, Jeffrey R.

AU - Proud, Melinda S.

AU - Wong, Ronald J.

AU - Ambalavanan, Namasivayam

AU - Collins, Monica V.

AU - Cosby, Shirley S.

AU - Devaskar, Uday

AU - Chanlaw, Teresa

AU - Geller, Rachel

AU - Ellsbury, Dan L.

AU - Colaizy, Tarah T.

AU - Brumbaugh, Jane E.

AU - Johnson, Karen J.

AU - Campbell, Donia B.

AU - Walker, Jacky R.

AU - Klein, Jonathan M.

AU - Segar, Jeffrey L.

AU - Dagle, John M.

AU - Lindower, Julie B.

AU - McElroy, Steven J.

AU - Rabe, Glenda K.

AU - Roghair, Robert D.

AU - Meyer, Lauritz R.

AU - Murphy, Cary R.

AU - Bhavsar, Vipinchandra

AU - Ohls, Robin K.

AU - Lacy, Conra Backstrom

AU - Beauman, Sandra

AU - Hartenberger, Carol

AU - Schmidt, Barbara

AU - Kirpalani, Haresh

AU - De Mauro, Sara B.

AU - Chaudhary, Aasma S.

AU - Abbasi, Soraya

AU - Mancini, Toni

AU - Cucinotta, Dara M.

AU - Laroia, Nirupama

AU - D'Angio, Carl T.

AU - Guillet, Ronnie

AU - Lakshminrusimha, Satyan

AU - Wynn, Karen

AU - Wadkins, Holly I M

AU - Scorsone, Ann Marie

AU - Conway, Patrick

AU - Sacilowski, Michael G.

AU - Guilford, Stephanie

AU - Williams, Ashley

AU - Wyckoff, Myra

AU - Brion, Luc P.

AU - Vasil, Diana M.

AU - Chen, Lijun

AU - Ramon, Emma

AU - Kennedy, Kathleen A.

AU - McDavid, Georgia E.

AU - Arldt-McAlister, Julie

AU - Burson, Katrina

AU - Garcia, Carmen

AU - Martin, Karen

AU - Rodgers, Shawna

AU - Tate, Patti L Pierce

AU - Wright, Sharon L.

AU - Sood, Beena G.

AU - Barks, John

AU - Batts, Maria

AU - De Jesus, Lilia

AU - Hayes-Hart, Kimberly

AU - Johnson, Mary E.

AU - Natarajan, Girija

AU - Sulkowski, Lisa

AU - Sumner, Laura

AU - Walker, Nicole

AU - Weingarden, Kathleen

AU - Christensen, Mary

AU - Wiggins, Stephanie A.

AU - Gleason, Christine A.

AU - Boyle, Robert J.

AU - Clemons, Traci

AU - D'Alton, Mary E.

AU - Redmond, Carol K.

AU - Ross, Michael G.

AU - Weiner, Steven J.

AU - Willinger, Marian

PY - 2014/12/24

Y1 - 2014/12/24

N2 - IMPORTANCE: Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44%to 55%; longer cooling and deeper cooling are neuroprotective in animal models.OBJECTIVE: To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.DESIGN, SETTING, ANDPARTICIPANTS: Arandomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.INTERVENTIONS: Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours.MAIN OUTCOMES AND MEASURES: The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonateswere enrolled, then after every subsequent 25 neonates. The trialwas closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours' vs 120 hours' duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes).RESULTS The NICU: death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95%CI, 0.92-2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95%CI, 0.69-2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1%in the 120 hours group vs 3%in the 72 hours group (RR, 0.25 [95%CI, 0.07-0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%.CONCLUSIONS AND RELEVANCE: Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01192776.

AB - IMPORTANCE: Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44%to 55%; longer cooling and deeper cooling are neuroprotective in animal models.OBJECTIVE: To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.DESIGN, SETTING, ANDPARTICIPANTS: Arandomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.INTERVENTIONS: Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours.MAIN OUTCOMES AND MEASURES: The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonateswere enrolled, then after every subsequent 25 neonates. The trialwas closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours' vs 120 hours' duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes).RESULTS The NICU: death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95%CI, 0.92-2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95%CI, 0.69-2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1%in the 120 hours group vs 3%in the 72 hours group (RR, 0.25 [95%CI, 0.07-0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%.CONCLUSIONS AND RELEVANCE: Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01192776.

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U2 - 10.1001/jama.2014.16058

DO - 10.1001/jama.2014.16058

M3 - Article

VL - 312

SP - 2629

EP - 2639

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 24

ER -