{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T15:46:29Z","timestamp":1776699989271,"version":"3.51.2"},"reference-count":51,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,5,17]],"date-time":"2019-05-17T00:00:00Z","timestamp":1558051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["K08 DA035972-01"],"award-info":[{"award-number":["K08 DA035972-01"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"name":"2017 Trailblazer Award from Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital","award":["2017 Trailblazer Award - Clinical Study"],"award-info":[{"award-number":["2017 Trailblazer Award - Clinical Study"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Prolonged sedation in infants leads to a high incidence of physical dependence. We inquired: (1) \u201cHow long does it take to develop physical dependence to sedation in previously na\u00efve full-term infants without known history of neurologic impairment?\u201d and (2) \u201cWhat is the relationship between length of sedation to length of weaning and hospital stay?\u201d. The retrospective study included full-term patients over a period of one year that were &lt;1 year of age and received opioids and benzodiazepines &gt;72 hours. Quantification of fentanyl, morphine, and midazolam were compared among three time periods: &lt;5 days, 5\u201330 days, and &gt;30 days using t-test or one-way analysis of variance. Identified full-term infants were categorized into surgical (14\/44) or medical (10\/44) groups, while those with neurological involvement (20\/44) were excluded. Physical dependence in full-term infants occurred following sedation \u22655 days. Infants with surgical disease received escalating doses of morphine and midazolam when administered &gt;30 days. A positive association between length of sedation and weaning period was found for both respiratory (p &lt; 0.01) and surgical disease (p = 0.012) groups, while length of sedation is related to hospital stay for the respiratory (p &lt; 0.01) but not the surgical disease group (p = 0.1). Future pharmacological directions should lead to standardized sedation protocols and evaluate patient neurocognitive outcomes.<\/jats:p>","DOI":"10.3390\/brainsci9050114","type":"journal-article","created":{"date-parts":[[2019,5,17]],"date-time":"2019-05-17T11:06:46Z","timestamp":1558091206000},"page":"114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Evaluation of Postnatal Sedation in Full-Term Infants"],"prefix":"10.3390","volume":"9","author":[{"given":"Jean Carmela","family":"Solodiuk","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russell William","family":"Jennings","sequence":"additional","affiliation":[{"name":"Esophageal Advance Treatment Center, Department of Surgery, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Surgery, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3943-2105","authenticated-orcid":false,"given":"Dusica","family":"Bajic","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Anaesthesia, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/S0022-3468(87)80343-3","article-title":"Pain relief for the pediatric surgical patient","volume":"22","author":"Dilworth","year":"1987","journal-title":"J. Pediatr. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1056\/NEJMra012626","article-title":"Analgesics for the treatment of pain in children","volume":"347","author":"Berde","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1097\/00003246-199402000-00027","article-title":"Opioid tolerance and dependence in infants and children","volume":"22","author":"Anand","year":"1994","journal-title":"Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e1208","DOI":"10.1542\/peds.2009-0489","article-title":"Tolerance and withdrawal from prolonged opioid use in critically ill children","volume":"125","author":"Anand","year":"2010","journal-title":"Pediatrics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"305","DOI":"10.5055\/jom.2015.0279","article-title":"Pharmacoepidemiology of opiate use in the neonatal ICU: Increasing cumulative doses and iatrogenic opiate withdrawal","volume":"11","author":"Lewis","year":"2015","journal-title":"J. Opioid Manag."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/S0022-3476(05)82419-9","article-title":"Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion","volume":"119","author":"Arnold","year":"1991","journal-title":"J. Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1016\/S0140-6736(04)16251-X","article-title":"Effects of morphine analgesia in ventilated preterm neonates: Primary outcomes from the neopain randomised trial","volume":"363","author":"Anand","year":"2004","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1016\/j.jpeds.2015.02.012","article-title":"Neonatal morphine exposure in very preterm infants-cerebral development and outcomes","volume":"166","author":"Steinhorn","year":"2015","journal-title":"J. Pediatr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1542\/peds.2004-1398","article-title":"Morphine, hypotension, and adverse outcomes among preterm neonates: Who\u2019s to blame? Secondary results from the neopain trial","volume":"115","author":"Hall","year":"2005","journal-title":"Pediatrics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1016\/j.pain.2011.02.017","article-title":"Long-term effects of routine morphine infusion in mechanically ventilated neonates on children\u2019s functioning: Five-year follow-up of a randomized controlled trial","volume":"152","author":"Simons","year":"2011","journal-title":"Pain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ntt.2011.10.008","article-title":"A pilot study of preemptive morphine analgesia in preterm neonates: Effects on head circumference, social behavior, and response latencies in early childhood","volume":"34","author":"Ferguson","year":"2012","journal-title":"Neurotoxicol. Teratol."},{"key":"ref_12","first-page":"945","article-title":"V. Guidelines for sedation and analgesia during mechanical ventilation general overview","volume":"63","author":"Shapiro","year":"2007","journal-title":"J. Trauma"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bellu, R., de Waal, K.A., and Zanini, R. (2008). Opioids for neonates receiving mechanical ventilation. Cochrane Database Syst. Rev., CD004212.","DOI":"10.1002\/14651858.CD004212.pub3"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1001\/archpedi.153.4.331","article-title":"Analgesia and sedation in preterm neonates who require ventilatory support: Results from the nopain trial. Neonatal outcome and prolonged analgesia in neonates","volume":"153","author":"Anand","year":"1999","journal-title":"Arch. Pediatr. Adolesc. Med."},{"key":"ref_15","first-page":"39","article-title":"Various factors which affect the rate of development of tolerance and physical dependence to abused drugs","volume":"54","author":"Dewey","year":"1984","journal-title":"NIDA Res. Monogr."},{"key":"ref_16","first-page":"1171","article-title":"Retrospective studies and chart reviews","volume":"49","author":"Hess","year":"2004","journal-title":"Respir. Care"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.1553-2712.2004.tb01433.x","article-title":"Advanced statistics: Understanding medical record review (MRR) studies","volume":"11","author":"Worster","year":"2004","journal-title":"Acad. Emerg. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1177\/016327879702000203","article-title":"Chart review. A need for reappraisal","volume":"20","author":"Wu","year":"1997","journal-title":"Eval. Health Prof."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3389\/fped.2016.00089","article-title":"Sedation in critically ill children with respiratory failure","volume":"4","author":"Vet","year":"2016","journal-title":"Front. Pediatr."},{"key":"ref_20","first-page":"126","article-title":"A methodology for conducting retrospective chart review research in child and adolescent psychiatry","volume":"15","author":"Gearing","year":"2006","journal-title":"J. Can. Acad. Child Adolesc. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.jclinepi.2004.07.006","article-title":"Guidelines were developed for data collection from medical records for use in retrospective analyses","volume":"58","author":"Jansen","year":"2005","journal-title":"J. Clin. Epidemiol."},{"key":"ref_22","unstructured":"Haynes, R.B., Sackett, D.L., Guyatt, G.H., and Tugwell, P. (2006). Clinical Epidemiology: How to Do Clinical Practice Research, Lippincott Williams and Wilkins. [3rd ed.]."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1097\/00002060-198906000-00010","article-title":"Research in physical medicine and rehabilitation. III. The chart review or how to use clinical data for exploratory retrospective studies","volume":"68","author":"Findley","year":"1989","journal-title":"Am. J. Phys. Med. Rehabil."},{"key":"ref_24","first-page":"1071","article-title":"Regression models for prognostic prediction: Advantages, problems, and suggested solutions","volume":"69","author":"Harrell","year":"1985","journal-title":"Cancer Treat Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1080\/10705519509540017","article-title":"Issues in applied equation modeling research","volume":"2","author":"Raykov","year":"1995","journal-title":"Struct. Equ. Modeling"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.pain.2011.10.003","article-title":"Validity and generalizability of the withdrawal assessment tool-1 (WAT-1) for monitoring iatrogenic withdrawal syndrome in pediatric patients","volume":"153","author":"Franck","year":"2012","journal-title":"Pain"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1001\/jama.2014.18399","article-title":"Protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute respiratory failure: A randomized clinical trial","volume":"313","author":"Curley","year":"2015","journal-title":"JAMA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1097\/00000542-199012000-00011","article-title":"Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation","volume":"73","author":"Arnold","year":"1990","journal-title":"Anesthesiology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1097\/CCM.0000000000000326","article-title":"Sedation, sleep promotion, and delirium screening practices in the care of mechanically ventilated children: A wake-up call for the pediatric critical care community","volume":"42","author":"Kudchadkar","year":"2014","journal-title":"Crit. Care Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1097\/PCC.0000000000000572","article-title":"Patterns of sedation weaning in critically ill children recovering from acute respiratory failure","volume":"17","author":"Best","year":"2016","journal-title":"Pediatr. Crit. Care Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1097\/PCC.0b013e318253c80e","article-title":"Opioid analgesia in mechanically ventilated children: Results from the multicenter measuring opioid tolerance induced by fentanyl study","volume":"14","author":"Anand","year":"2013","journal-title":"Pediatr. Crit. Care Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1111\/j.1460-9592.2006.02180.x","article-title":"Current United Kingdom sedation practice in pediatric intensive care","volume":"17","author":"Jenkins","year":"2007","journal-title":"Paediatr. Anaesth."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1097\/01.PCC.0000144710.13710.2E","article-title":"Sedation, analgesia, and neuromuscular blockade in the pediatric intensive care unit: Survey of fellowship training programs","volume":"5","author":"Twite","year":"2004","journal-title":"Pediatr. Crit. Care Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/j.neuroimage.2007.03.070","article-title":"Volumetric cerebral characteristics of children exposed to opiates and other substances in utero","volume":"36","author":"Walhovd","year":"2007","journal-title":"Neuroimage"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/nrn2598-c1","article-title":"Effects of prenatal opiate exposure on brain development\u2014A call for attention","volume":"10","author":"Walhovd","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1001\/archpedi.162.8.728","article-title":"Prolonged sedation and\/or analgesia and 5-year neurodevelopment outcome in very preterm infants: Results from the epipage cohort","volume":"162","author":"Roze","year":"2008","journal-title":"Arch. Pediatr. Adolesc. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.pain.2012.12.006","article-title":"Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age?","volume":"154","author":"Valkenburg","year":"2013","journal-title":"Pain"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1136\/adc.2008.156851","article-title":"Drug misuse in pregnancy: Losing sight of the baby?","volume":"94","author":"McGlone","year":"2009","journal-title":"Arch. Dis. Child"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.brainres.2007.12.043","article-title":"Neonatal morphine enhances nociception and decreases analgesia in young rats","volume":"1199","author":"Zhang","year":"2008","journal-title":"Brain Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.neuint.2010.06.011","article-title":"Changes in metabolic-related variables during chronic morphine treatment","volume":"57","author":"Ferenczi","year":"2010","journal-title":"Neurochem. Int."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.neuroscience.2012.07.037","article-title":"Long-term changes in reward-seeking following morphine withdrawal are associated with altered n-methyl-d-aspartate receptor 1 splice variants in the amygdala","volume":"223","author":"Anderson","year":"2012","journal-title":"Neuroscience"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e32","DOI":"10.1542\/peds.2014-0898","article-title":"Neuroimaging and neurodevelopmental outcome in extremely preterm infants","volume":"135","author":"Hintz","year":"2015","journal-title":"Pediatrics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1111\/j.1651-2227.2009.01219.x","article-title":"Adverse neurodevelopmental outcome in preterm infants: Risk factor profiles for different gestational ages","volume":"98","author":"Ralser","year":"2009","journal-title":"Acta Paediatr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1002\/ana.24601","article-title":"Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants","volume":"79","author":"Duerden","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1016\/j.athoracsur.2012.04.050","article-title":"Changing expectations for neurological outcomes after the neonatal arterial switch operation","volume":"94","author":"Andropoulos","year":"2012","journal-title":"Ann. Thorac. Surg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.athoracsur.2012.04.070","article-title":"Neurodevelopmental outcomes after regional cerebral perfusion with neuromonitoring for neonatal aortic arch reconstruction","volume":"95","author":"Andropoulos","year":"2013","journal-title":"Ann. Thorac. Surg."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/pan.12257","article-title":"Neurotoxicity of sedative and analgesia drugs in young infants with congenital heart disease: 4-year follow-up","volume":"24","author":"Robertson","year":"2014","journal-title":"Paediatr. Anaesth."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1111\/j.1460-9592.2011.03581.x","article-title":"Neurodevelopmental outcome following exposure to sedative and analgesic drugs for complex cardiac surgery in infancy","volume":"21","author":"Guerra","year":"2011","journal-title":"Paediatr. Anaesth."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Mongerson, C.R.L., Wilcox, S.L., Goins, S.M., Pier, D.B., Zurakowski, D., Jennings, R.W., and Bajic, D. (2019). Infant brain structural mri analysis in the context of thoracic noncardiac surgery and critical care. Front. Pediatr. Neurol., Accepted.","DOI":"10.3389\/fped.2019.00315"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.jpeds.2016.11.080","article-title":"Neonatal surgery for noncardiac congenital anomalies: Neonates at risk of brain injury","volume":"182","author":"Stolwijk","year":"2017","journal-title":"J. Pediatr."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e20151728","DOI":"10.1542\/peds.2015-1728","article-title":"Neurodevelopmental outcomes after neonatal surgery for major noncardiac anomalies","volume":"137","author":"Stolwijk","year":"2016","journal-title":"Pediatrics"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/9\/5\/114\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:52:54Z","timestamp":1760187174000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/9\/5\/114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,17]]},"references-count":51,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["brainsci9050114"],"URL":"https:\/\/doi.org\/10.3390\/brainsci9050114","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,17]]}}}