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Association between sedation–analgesia and neurodevelopment outcomes in neonatal hypoxic-ischemic encephalopathy

Journal of Perinatology volume 38, pages 1060–1067 (2018)Cite this article

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Abstract

Objective

To evaluate the association between sedation–analgesia (SA) during initial 72 h and death/disability at 18 months of age in neonatal hypoxic-ischemic encephalopathy (HIE).

Design

This was a secondary analysis of the NICHD therapeutic hypothermia (TH) randomized controlled trial in moderate or severe HIE. Receipt of SA and anticonvulsant medications at five time points were considered: prior to and at baseline, 24, 48, and 72 h of TH or normothermia. Disability was defined as mental developmental index <85, cerebral palsy, blindness, hearing impairment, or Gross Motor Function Classification System 2–5.

Results

Of the 208 RCT participants, 38 (18%) infants had no exposure to SA or anticonvulsants at any of the five time points, 20 (10%) received SA agents only, 81 (39%) received anticonvulsants only, and 69 (33%) received both SA and anticonvulsants. SA category drugs were not administered in 57% of infants while 18% received SA at ≥3 time points; 72% infants received anticonvulsants during 72 h of intervention. At 18 months of age, disability among survivors and death/disability was more frequent in the groups receiving anticonvulsants, with (48 and 65%) or without (37 and 58%) SA, compared to groups with no exposure (14 and 34%) or SA (13 and 32%) alone. Severe HIE (aOR 3.60; 1.59–8.13), anticonvulsant receipt (aOR 2.48; 1.05–5.88), and mechanical ventilation (aOR 7.36; 3.15–17.20) were independently associated with 18-month death/disability, whereas TH (aOR 0.28; 0.13–0.60) was protective. SA exposure showed no association with outcome.

Conclusions

The risk benefits of SA in HIE need further investigation.

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References

  1. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic-ischemic encephalopathy. Cochrane Database Syst Rev. 2013;1:CD003311.

    Google Scholar 

  2. Thoresen M, Satas S, Loberg EM, Whitelaw A, Acolet D, Lindgren C, et al. Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective. Pediatr Res. 2001;50:405e11.

    Article  Google Scholar 

  3. Haaland K, Loberg EM, Steen PA, Thoresen M. Posthypoxic hypothermia in newborn piglets. Pediatr Res. 1997;41:505e12.

    Article  Google Scholar 

  4. Chakkarapani E, Dingley J, Liu X, Hoque N, Aquilina K, Porter H, et al. Xenon enhances hypothermic neuroprotection in asphyxiated newborn pigs. Ann Neurol. 2010;68:330e41.

    Article  Google Scholar 

  5. Gunn AJ, Thoresen M. Hypothermic neuroprotection. NeuroRx. 2006;3:154e69.

    Article  Google Scholar 

  6. Wassink G, Lear CA, Gunn KC, Dean JM, Bennet L, Gunn AJ. Analgesics, sedatives, anticonvulsant drugs, and the cooled brain. Semin Fetal Neonatal Med. 2015;20:109–14.

    Article  Google Scholar 

  7. DellAnna AM, Taccone FS, Halenarova K, Citerio G. Sedation after cardiac arrest and during therapeutic hypothermia. Minerva Anestesiol. 2014;80:954–62.

    CAS  Google Scholar 

  8. Simbruner G, Mittal RA, Rohlmann F, Muche R. neo.nEURO.network trial participants. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. 2010;126:e771–8.

    Article  Google Scholar 

  9. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009;361:1349–58.

    Article  CAS  Google Scholar 

  10. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. National Institute of Child Health and Human Development Neonatal Research Network Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353:1574–84.

    Article  CAS  Google Scholar 

  11. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005;365:663–70.

    Article  Google Scholar 

  12. Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, et al. Infant Cooling Evaluation Collaboration. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med. 2011;165:692–700.

    Article  Google Scholar 

  13. Zhou WH, Cheng GQ, Shao XM, Liu XZ, Shan RB, Zhuang DY, et al. and China Study Group. Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China. J Pediatr. 2010;157:367–72.

    Article  Google Scholar 

  14. Róka A, Melinda KT, Vásárhelyi B, Machay T, Azzopardi D, Szabó M. Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy. Pediatrics. 2008;121:e844–9.

    Article  Google Scholar 

  15. Pappas A, Shankaran S, Laptook AR, Langer JC, Bara R, Ehrenkranz RA, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Hypocarbia and adverse outcome in neonatal hypoxic-ischemic encephalopathy. J Pediatr. 2011;158:752–8.

    Article  Google Scholar 

  16. Palisano R, Rossenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol. 1997;39:214–23.

    Article  CAS  Google Scholar 

  17. Deakin CD, Nolan JP, Soar J, Sunde K, Koster RW, Smith GB, et al. European Resuscitation Council Guidelines For Resuscitation 2010 Section 4. Adult advanced life support. Resuscitation. 2010;81:1305–52.

    Article  Google Scholar 

  18. Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, et al. American Heart Association. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122:S768–86.

    Article  Google Scholar 

  19. Chamorro C, Borrallo JM, Romera MA, Silva JA, Balandín B. Anesthesia and analgesia protocol during therapeutic hypothermia after cardiac arrest: a systematic review. Anesth Analg. 2010;110:1328–35.

    Article  CAS  Google Scholar 

  20. Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, et al. THAPCA Trial Investigators Therapeutic hypothermia after out-of-hospital cardiac arrest in children. N Engl J Med. 2015;372:1898–908.

    Article  Google Scholar 

  21. Guerra GG, Robertson CMT, Alton GY, Joffe AR, Cave DA, Yasmin F, et al. Neurotoxicity of sedative and analgesia drugs in young infants with congenital heart disease: 4-year follow-up. Pediatr Anesth. 2014;24:257–65.

    Article  Google Scholar 

  22. Walsh-Sukys MC, Tyson JE, Wright LL, Bauer CR, Korones SB, Stevenson DK, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics. 2000;105:14–20.

    Article  CAS  Google Scholar 

  23. Anand KJ, Whit Hall R, Desai N, Shephard B, Bergqvist LL, Young TE, et al. NEOPAIN Trial Investigators Group Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet. 2004;363:1673–82.

    Article  CAS  Google Scholar 

  24. Roze JC, Denizot S, Carbajal R, Ancel PY, Kaminski M, Arnaud C, et al. Prolonged sedation and/or analgesia and 5-year neurodevelopment outcome in very preterm infants. Arch Pediatr Adolesc Med. 2008;162:728–33.

    Article  Google Scholar 

  25. MacGregor R, Evans D, Sudgen D, Gaussen T, Levene M. Outcome at 5-6 years of prematurely born children who received morphine as neonates. Arch Dis Child Fetal Neonatal Ed. 1998;79:F40–F43.

    Article  CAS  Google Scholar 

  26. de Graaf J, van Lingen RA, Simons SH, Anand KJ, Duivenvoorden HJ, Weisglas-Kuperus N, et al. Long-term effects of routine morphine infusion in mechanically ventilated neonates on children’s functioning: five-year follow-up of a randomized controlled trial. Pain. 2011;152:1391–7.

    Article  Google Scholar 

  27. Hu S, Sheng WS, Lokensgard JR, Peterson PK. Morphine induces apoptosis of human microglia and neurons. Neuropharmacology. 2002;42:829–36.

    Article  CAS  Google Scholar 

  28. Handelmann GE, Dow-Edwards D. Modulation of brain development by morphine: effects on central motor systems and behavior. Peptides. 1985;6(Suppl. 2):29–34.

    Article  CAS  Google Scholar 

  29. Attarian S, Tran LC, Moore A, Stanton G, Meyer E, Moore RP. The neurodevelopmental impact of neonatal morphine administration. Brain Sci. 2014;4:321–34.

    Article  Google Scholar 

  30. Festekjian A, Ashwal S, Obenaus A, Angeles DM, Denmark TK. The role of morphine in a rat model of hypoxic-ischemic injury. Pediatr Neurol. 2011;45:77e82.

    Article  Google Scholar 

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Acknowledgements

Participating NRN sites collected data and transmitted it to RTI International, the data coordinating center (DCC) for the network, which stored, managed, and analyzed the data for this study. On behalf of the NRN, Dr. Abhik Das (DCC Principal Investigator) and Mr. Scott A McDonald (DCC Statistician) had full access to all of the data in the study, and with the NRN Center Principal Investigators take responsibility for the integrity of the data and accuracy of the data analysis. We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study: NRN Steering Committee Chairs: Alan H Jobe, MD PhD, University of Cincinnati (2003–2006); Michael S Caplan, MD, University of Chicago, Pritzker School of Medicine (2006–present). Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904)—Betty R Vohr, MD; William Oh, MD; Angelita M Hensman, RN BSN; Bonnie E Stephens, MD; Theresa M Leach, MEd CAES; Lucy Noel; Victoria E Watson, MS CAS. Case Western Reserve University, Rainbow Babies & Children’s Hospital (U10 HD21364 and M01 RR80)—Michele C Walsh, MD MS; Avroy A Fanaroff, MD; Deanne E Wilson-Costello, MD; Nancy Bass, MD; Harriet G Friedman MA; Nancy S Newman, BA RN; Bonnie S Siner, RN. Cincinnati Children’s Hospital Medical Center and University of Cincinnati Medical Center (U10 HD27853 and M01 RR8084)—Kurt Schibler, MD; Edward F Donovan, MD; Kate Bridges, MD; Kimberly Yolton, PhD; Jean J Steichen, MD; Barbara Alexander, RN; Cathy Grisby, BSN CCRC; Holly L Mincey, RN BSN; Jody Hessling, RN; Teresa L Gratton, PA. Duke University School of Medicine, University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (U10 HD40492 and M01 RR30)—Ronald N Goldberg, MD; C Michael Cotten, MD MHS; Kathryn E Gustafson, PhD; Ricki F Goldstein, MD; Kathy J Auten, MSHS; Katherine A Foy, RN; Kimberley A Fisher, PhD FNP-BC IBCLC; Sandy Grimes, RN BSN; Melody B Lohmeyer, RN MSN. Emory University, Grady Memorial Hospital and Emory University Hospital Midtown (U10 HD27851 and M01 RR39)—Barbara J Stoll, MD; David P Carlton, MD; Lucky Jain, MD; Ira Adams-Chapman, MD; Ann M Blackwelder, RNC BS MS; Ellen C Hale, RN BS CCRC; Sobha Fritz, PhD; Sheena Carter, PhD; Maureen Mulligan LaRossa, RN. Eunice Kennedy Shriver National Institute of Child Health and Human Development—Linda L Wright, MD; Elizabeth M McClure, MEd; Stephanie Wilson Archer, MA. Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856 and M01 RR750)—Brenda B Poindexter, MD MS; James A Lemons, MD; Anna M Dusick, MD FAAP; Diana D Appel, RN BSN; Jessica Bissey, PsyD HSPP; Dianne E Herron, RN; Lucy C Miller, RN BSN CCRC; Leslie Richard, RN; Leslie Dawn Wilson, BSN CCRC. RTI International (U10 HD36790)—W Kenneth Poole, PhD; Jane Hammond, PhD; Jeanette O’Donnell Auman, BS; Margaret Crawford, BS; Betty K Hastings; Jamie E Newman, PhD MPH; Carolyn M Petrie Huitema, MS; Kristin M Zaterka-Baxter, RN BSN. Stanford University and Lucile Packard Children’s Hospital (U10 HD27880 and M01 RR70)—Krisa P Van Meurs, MD; David K Stevenson, MD; M Bethany Ball, BS CCRC; Maria Elena DeAnda, PhD; Barry E Fleisher, MD; Anne M DeBattista, RN PNP; Joan M Baran, PhD; Julie C Lee-Ancajas, PhD. University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216 and M01 RR32)—Waldemar A Carlo, MD; Namasivayam Ambalavanan, MD; Myriam Peralta-Carcelen, MD MPH; Kathleen G Nelson, MD; Monica V Collins, RN BSN MaEd; Shirley S Cosby, RN BSN; Vivien A Phillips, RN BSN; Laurie Lou Smith, EdS NCSP; Fred J Biasini, PhD; Kirstin J Bailey, PhD. University of California-San Diego Medical Center and Sharp Mary Birch Hospital for Women (U10 HD40461)—Neil N Finer, MD; David Kaegi, MD; Maynard R Rasmussen, MD; Yvonne E Vaucher, MD MPH; Martha G Fuller, RN MSN; Radmila West PhD; Kathy Arnell, RNC; Chris Henderson, RCP CRTT; Wade Rich, BSHS RRT. University of Rochester Medical Center, Golisano Children’s Hospital (U10 HD40521 and M01 RR44)—Dale L Phelps, MD; Gary J Myers, MD; Diane Hust, MS RN CS; Linda J Reubens, RN CCRC. University of Miami Holtz Children’s Hospital (U10 HD21397 and M01 RR16587)—Shahnaz Duara, MD; Charles R Bauer, MD; Sylvia Hiriart-Fajardo, MD; Mary Allison, RN; Maria Calejo, MS; Ruth Everett-Thomas, RN MSN; Silvia M Frade Eguaras, MA; Susan Gauthier, BA. University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children’s Medical Center Dallas (U10 HD40689 and M01 RR633)—Pablo J Sánchez, MD; R Sue Broyles, MD; Abbot R Laptook, MD; Charles R Rosenfeld, MD; Walid A Salhab, MD; Roy J Heyne, MD; Cathy Boatman, MS CIMI; Cristin Dooley, PhD LSSP; Gaynelle Hensley, RN; Jackie F Hickman, RN; Melissa H Leps, RN; Susie Madison, RN; Nancy A Miller, RN; Janet S Morgan, RN; Lizette E Torres, RN; Alicia Guzman; Elizabeth Heyne, PA-C; Linda A Madden, BSN RN CPNP; Sally Adams, PNP. University of Texas Health Science Center at Houston Medical School, Children’s Memorial Hermann Hospital, and Lyndon Baines Johnson General Hospital/Harris County Hospital District (U10 HD21373 and M01 RR2588)—Kathleen A Kennedy, MD MPH; Jon E Tyson, MD MPH; Esther G Akpa, RN BSN; Patty A Cluff, RN; Patricia W Evans, MD; Claudia I Franco, RN BSN; Charles Green, PhD; Anna E Lis, RN, BSN; Georgia E McDavid, RN; Patti L Pierce Tate, RCP; Nora I Alaniz, BS; Pamela J Bradt, MD MPH; Magda Cedillo; Susan Dieterich, PhD; Margarita Jiminez, MD; Terri Major-Kincade, MD MPH; Brenda H Morris, MD; M Layne Poundstone, RN BSN; Stacey Reddoch, BA; Saba Siddiki, MD; Maegan C Simmons, RN; Laura L Whitely, MD; Sharon L Wright, MT; Lourdes M Valdés PhD. Wayne State University, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (U10 HD21385)—Rebecca Bara, RN BSN; Yvette R Johnson, MD MPH; Laura A Goldston, MA; Geraldine Muran, RN BSN; Deborah Kennedy, RN BSN; Patrick J Pruitt, BS. Yale University, Yale-New Haven Children’s Hospital (U10 HD27871, M01 RR125, and UL1 RR24139)—Richard A Ehrenkranz, MD; Patricia Gettner, RN; Monica Konstantino, RN BSN; JoAnn Poulsen, RN; Elaine Romano, MSN; Joanne Williams, RN BSN; Susan DeLancy, MA CAS.

Financial support

Please see “Acknowledgement” section U10 HD27904; U10 HD21364; M01 RR80 and U10 HD27853; M01 RR8084; U10 HD40492 and M01 RR30; U10 HD27851 and M01 RR39; U10 HD27856 and M01 RR750; U10 HD36790; U10 HD27880 and M01 RR70; U10 HD34216 and M01 RR32; U10 HD40461; U10 HD40521 and M01 RR44; U10 HD21397 and M01 RR16587; U10 HD40689 and M01 RR633; U10 HD21373 and M01 RR2588; U10 HD21385; U10 HD27871 and M01 RR125; and UL1 RR24139.

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Authors and Affiliations

  1. Division of Neonatology, Department of Pediatrics, Wayne State University, Detroit, MI, USA

    Girija Natarajan, Seetha Shankaran & Athina Pappas

  2. Department of Pediatrics, Women and Infants Hospital, Brown University, Providence, RI, USA

    Abbot R. Laptook

  3. Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, Durham, NC, USA

    Scott A. McDonald & Abhik Das

  4. Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA

    Susan R. Hintz

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  1. Girija Natarajan
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  2. Seetha Shankaran
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for the NICHD Neonatal Research Network (NRN) Whole Body Hypothermia Subcommittee

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Correspondence to Girija Natarajan.

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Natarajan, G., Shankaran, S., Laptook, A.R. et al. Association between sedation–analgesia and neurodevelopment outcomes in neonatal hypoxic-ischemic encephalopathy. J Perinatol 38, 1060–1067 (2018). https://doi.org/10.1038/s41372-018-0126-7

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