Iatrogenic Withdrawal Syndrome: a Review of Pathophysiology, Prevention, and Treatment

  • Jessica M. LaRosaEmail author
  • Linda Aponte-Patel
Intensive Care Medicine (E Cheung and T Connors, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Intensive Care Medicine


Purpose of Review

Iatrogenic withdrawal syndrome (IWS) is the direct result of sedative agents utilized to facilitate pediatric intensive care. The purpose of this review is to overview how sedative agents result in IWS and overview the assessment tools, prevention strategies, and treatments for the condition.

Recent Findings

Since the development of validated withdrawal assessment tools, there has been a focus on identifying IWS risk. The most significant IWS risk factors are duration of exposure to sedatives and total cumulative doses of these agents. Given these risk factors, there has been an effort to develop strategies to prevent IWS, which have not proven to be efficacious thus far. The utilization of these risk factors in the development of sedation tapering protocols has been successful in reducing the amount of exposure children have to sedative agents.


Iatrogenic withdrawal syndrome is common and is a necessary consequence of sedation needed in order to safely and effectively care for critically ill children. Newly identified risk factors may be helpful in expeditious tapering of sedatives without inducing withdrawal symptoms.


Iatrogenic withdrawal syndrome Analgesia Sedation Pediatric intensive care Abstinence syndrome 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Sury MR, Billingham I, Russell GN, Hopkins CS, Thornington R, Vivori E. Acute benzodiazepine withdrawal syndrome after midazolam infusions in children. Crit Care Med. 1989;17(3):301–2.Google Scholar
  2. 2.
    Arnold JH, Truog RD, Orav EJ, Scavone JM, Hershenson MB. Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation. Anesthesiology. 1990;73(6):1136–40.Google Scholar
  3. 3.
    Tobias JD. Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med. 2000;28(6):2122–32.Google Scholar
  4. 4.
    Harris J, Ramelet AS, van Dijk M, Pokorna P, Wielenga J, Tume L, et al. Clinical recommendations for pain, sedation, withdrawal and delirium assessment in critically ill infants and children: an ESPNIC position statement for healthcare professionals. Intensive Care Med. 2016;42(6):972–86.Google Scholar
  5. 5.
    Vet NJ, Kleiber N, Ista E, de Hoog M, de Wildt SN. Sedation in critically ill children with respiratory failure. Front Pediatr. 2016;4:89.Google Scholar
  6. 6.
    Anand KJ, Ingraham J. Pediatric. Tolerance, dependence, and strategies for compassionate withdrawal of analgesics and anxiolytics in the pediatric ICU. Crit Care Nurse. 1996;16(6):87–93.Google Scholar
  7. 7.
    Best KM, Boullata JI, Curley MA. Risk factors associated with iatrogenic opioid and benzodiazepine withdrawal in critically ill pediatric patients: a systematic review and conceptual model. Pediatr Crit Care Med. 2015;16(2):175–83.Google Scholar
  8. 8.
    Katz R, Kelly HW, Hsi A. Prospective study on the occurrence of withdrawal in critically ill children who receive fentanyl by continuous infusion. Crit Care Med. 1994;22(5):763–7.Google Scholar
  9. 9.
    Biswas AK, Feldman BL, Davis DH, Zintz EA. Myocardial ischemia as a result of severe benzodiazepine and opioid withdrawal. Clin Toxicol (Phila). 2005;43(3):207–9.Google Scholar
  10. 10.
    Carnevale FA, Ducharme C. Adverse reactions to the withdrawal of opioids and benzodiazepines in paediatric intensive care. Intensive Crit Care Nurs. 1997;13(4):181–8.Google Scholar
  11. 11.
    da Silva PS, Reis ME, Fonseca TS, Fonseca MC. Opioid and benzodiazepine withdrawal syndrome in PICU patients: which risk factors matter? J Addict Med. 2016;10(2):110–6.Google Scholar
  12. 12.
    Cote CJ, Notterman DA, Karl HW, Weinberg JA, McCloskey C. Adverse sedation events in pediatrics: a critical incident analysis of contributing factors. Pediatrics. 2000;105(4 Pt 1):805–14.Google Scholar
  13. 13.
    Anand KJ, Willson DF, Berger J, Harrison R, Meert KL, Zimmerman J, et al. Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics. 2010;125(5):e1208–25.Google Scholar
  14. 14.
    Hartman ME, McCrory DC, Schulman SR. Efficacy of sedation regimens to facilitate mechanical ventilation in the pediatric intensive care unit: a systematic review. Pediatr Crit Care Med. 2009;10(2):246–55.Google Scholar
  15. 15.
    Vet NJ, Brussee JM, de Hoog M, Mooij MG, Verlaat CW, Jerchel IS, et al. Inflammation and organ failure severely affect midazolam clearance in critically ill children. Am J Respir Crit Care Med. 2016;194(1):58–66.Google Scholar
  16. 16.
    Lo JCK, A. D. . Benzodiazepines and muscle relaxants. Essentials of pharmacology for anesthesia, pain medicine, and critical care. New York, NY: Springer Science Business Media; 2015. p. 167–78.Google Scholar
  17. 17.
    Mazlot JX. Pharmacology. Gregory's pediatric anesthesia. 2011. 5 ed. New York, NY: Blackwell Publishing Ltd; 2011. p. 168–204.Google Scholar
  18. 18.
    Blumer JL. Clinical pharmacology of midazolam in infants and children. Clin Pharmacokinet. 1998;35(1):37–47.Google Scholar
  19. 19.
    Biggio G, Dazzi L, Biggio F, Mancuso L, Talani G, Busonero F, et al. Molecular mechanisms of tolerance to and withdrawal of GABA(a) receptor modulators. Eur Neuropsychopharmacol. 2003;13(6):411–23.Google Scholar
  20. 20.
    Wafford KA. GABAA receptor subtypes: any clues to the mechanism of benzodiazepine dependence? Curr Opin Pharmacol. 2005;5(1):47–52.Google Scholar
  21. 21.
    Salinas OJM, K. C. . Opiate agonist, mixed agonists/antagonists, and antagonists for acute pain management. Essentials of pharmacology for anesthesia, pain medicine, and critical care. New York, NY: Springer Science Business Media; 2015. p. 167–78.Google Scholar
  22. 22.
    Liu JG, Anand KJ. Protein kinases modulate the cellular adaptations associated with opioid tolerance and dependence. Brain Res Brain Res Rev. 2001;38(1–2):1–19.Google Scholar
  23. 23.
    Compton P, Geschwind DH, Alarcon M. Association between human mu-opioid receptor gene polymorphism, pain tolerance, and opioid addiction. Am J Med Genet B Neuropsychiatr Genet. 2003;121B(1):76–82.Google Scholar
  24. 24.
    McRorie TI, Lynn AM, Nespeca MK, Opheim KE, Slattery JT. The maturation of morphine clearance and metabolism. Am J Dis Child. 1992;146(8):972–6.Google Scholar
  25. 25.
    Sharma A, Tallchief D, Blood J, Kim T, London A, Kharasch ED. Perioperative pharmacokinetics of methadone in adolescents. Anesthesiology. 2011;115(6):1153–61.Google Scholar
  26. 26.
    Alam A, Suen KC, Hana Z, Sanders RD, Maze M, Ma D. Neuroprotection and neurotoxicity in the developing brain: an update on the effects of dexmedetomidine and xenon. Neurotoxicol Teratol. 2017;60:102–16.Google Scholar
  27. 27.
    Gertler R, Brown HC, Mitchell DH, Silvius EN. Dexmedetomidine: a novel sedative-analgesic agent. Proc (Bayl Univ Med Cent). 2001;14(1):13–21.Google Scholar
  28. 28.
    Vilo S, Rautiainen P, Kaisti K, Aantaa R, Scheinin M, Manner T, et al. Pharmacokinetics of intravenous dexmedetomidine in children under 11 yr of age. Br J Anaesth. 2008;100(5):697–700.Google Scholar
  29. 29.
    Buck ML. Dexmedetomidine use in pediatric intensive care and procedural sedation. J Pediatr Pharmacol Ther. 2010;15(1):17–29.Google Scholar
  30. 30.
    Jamadarkhana S, Gopal S. Clonidine in adults as a sedative agent in the intensive care unit. J Anaesthesiol Clin Pharmacol. 2010;26(4):439–45.Google Scholar
  31. 31.
    Ista E, van Dijk M, Gamel C, Tibboel D, de Hoog M. Withdrawal symptoms in children after long-term administration of sedatives and/or analgesics: a literature review. “Assessment remains troublesome”. Intensive Care Med. 2007;33(8):1396–406.Google Scholar
  32. 32.
    Petursson H, Lader MH. Withdrawal from long-term benzodiazepine treatment. Br Med J (Clin Res Ed). 1981;283(6292):643–5.Google Scholar
  33. 33.
    van Engelen BG, Gimbrere JS, Booy LH. Benzodiazepine withdrawal reaction in two children following discontinuation of sedation with midazolam. Ann Pharmacother. 1993;27(5):579–81.Google Scholar
  34. 34.
    Hughes J, Gill A, Leach HJ, Nunn AJ, Billingham I, Ratcliffe J, et al. A prospective study of the adverse effects of midazolam on withdrawal in critically ill children. Acta Paediatr. 1994;83(11):1194–9.Google Scholar
  35. 35.
    Fonsmark L, Rasmussen YH, Carl P. Occurrence of withdrawal in critically ill sedated children. Crit Care Med. 1999;27(1):196–9.Google Scholar
  36. 36.
    Suresh S, Anand KJ. Opioid tolerance in neonates: mechanisms, diagnosis, assessment, and management. Semin Perinatol. 1998;22(5):425–33.Google Scholar
  37. 37.
    Franck LS, Naughton I, Winter I. Opioid and benzodiazepine withdrawal symptoms in paediatric intensive care patients. Intensive Crit Care Nurs. 2004;20(6):344–51.Google Scholar
  38. 38.
    Ista E, van Dijk M, Gamel C, Tibboel D, de Hoog M. Withdrawal symptoms in critically ill children after long-term administration of sedatives and/or analgesics: a first evaluation. Crit Care Med. 2008;36(8):2427–32.Google Scholar
  39. 39.
    French JP, Nocera M. Drug withdrawal symptoms in children after continuous infusions of fentanyl. J Pediatr Nurs. 1994;9(2):107–13.Google Scholar
  40. 40.
    Lane JC, Tennison MB, Lawless ST, Greenwood RS, Zaritsky AL. Movement disorder after withdrawal of fentanyl infusion. J Pediatr. 1991;119(4):649–51.Google Scholar
  41. 41.
    Tobias JD. Dexmedetomidine: are tolerance and withdrawal going to be an issue with long-term infusions? Pediatr Crit Care Med. 2010;11(1):158–60.Google Scholar
  42. 42.
    Weber MD, Thammasitboon S, Rosen DA. Acute discontinuation syndrome from dexmedetomidine after protracted use in a pediatric patient. Paediatr Anaesth. 2008;18(1):87–8.Google Scholar
  43. 43.
    Miller JL, Allen C, Johnson PN. Neurologic withdrawal symptoms following abrupt discontinuation of a prolonged dexmedetomidine infusion in a child. J Pediatr Pharmacol Ther. 2010;15(1):38–42.Google Scholar
  44. 44.
    Darnell C, Steiner J, Szmuk P, Sheeran P. Withdrawal from multiple sedative agent therapy in an infant: is dexmedetomidine the cause or the cure? Pediatr Crit Care Med. 2010;11(1):e1–3.Google Scholar
  45. 45.
    Whalen LD, Di Gennaro JL, Irby GA, Yanay O, Zimmerman JJ. Long-term dexmedetomidine use and safety profile among critically ill children and neonates. Pediatr Crit Care Med. 2014;15(8):706–14.Google Scholar
  46. 46.
    Shutes BL, Gee SW, Sargel CL, Fink KA, Tobias JD. Dexmedetomidine as single continuous sedative during noninvasive ventilation: typical usage, hemodynamic effects, and withdrawal. Pediatr Crit Care Med. 2018;19(4):287–97.Google Scholar
  47. 47.
    Hudak ML, Tan RC, Committee On D, Committee On F, Newborn, American Academy of P. Neonatal drug withdrawal. Pediatrics. 2012;129(2):e540–60.Google Scholar
  48. 48.
    Franck LS, Harris SK, Soetenga DJ, Amling JK, Curley MA. The Withdrawal Assessment Tool-1 (WAT-1): an assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients. Pediatr Crit Care Med. 2008;9(6):573–80.Google Scholar
  49. 49.
    Franck LS, Scoppettuolo LA, Wypij D, Curley MA. Validity and generalizability of the Withdrawal Assessment Tool-1 (WAT-1) for monitoring iatrogenic withdrawal syndrome in pediatric patients. Pain. 2012;153(1):142–8.Google Scholar
  50. 50.
    Ista E, van Dijk M, de Hoog M, Tibboel D, Duivenvoorden HJ. Construction of the Sophia Observation withdrawal Symptoms-scale (SOS) for critically ill children. Intensive Care Med. 2009;35(6):1075–81.Google Scholar
  51. 51.
    Ista E, de Hoog M, Tibboel D, Duivenvoorden HJ, van Dijk M. Psychometric evaluation of the Sophia Observation Withdrawal Symptoms Scale in critically ill children. Pediatr Crit Care Med. 2013;14(8):761–9.Google Scholar
  52. 52.
    •• Best KM, Wypij D, Asaro LA, Curley MA. Randomized evaluation of sedation titration for respiratory failure study I. Patient, process, and system predictors of iatrogenic withdrawal syndrome in critically ill children. Crit Care Med. 2017;45(1):e7–e15 RESTORE Trial data which idenitied risk factors for the development of IWS. Google Scholar
  53. 53.
    •• Amigoni A, Mondardini MC, Vittadello I, Zaglia F, Rossetti E, Vitale F, et al. Withdrawal Assessment Tool-1 monitoring in PICU: a multicenter study on iatrogenic withdrawal syndrome. Pediatr Crit Care Med. 2017;18(2):e86–91 Large multicenter study utilizing WAT-1 to identify withdrawal risk factors. Google Scholar
  54. 54.
    Poh YN, Poh PF, Buang SN, Lee JH. Sedation guidelines, protocols, and algorithms in PICUs: a systematic review. Pediatr Crit Care Med. 2014;15(9):885–92.Google Scholar
  55. 55.
    Curley MA, Wypij D, Watson RS, Grant MJ, Asaro LA, Cheifetz IM, et al. Protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute respiratory failure: a randomized clinical trial. JAMA. 2015;313(4):379–89.Google Scholar
  56. 56.
    Gupta K, Gupta VK, Jayashree M, Singhi S. Randomized controlled trial of interrupted versus continuous sedative infusions in ventilated children. Pediatr Crit Care Med. 2012;13(2):131–5.Google Scholar
  57. 57.
    Vet NJ, de Wildt SN, Verlaat CW, Knibbe CA, Mooij MG, van Woensel JB, et al. A randomized controlled trial of daily sedation interruption in critically ill children. Intensive Care Med. 2016;42(2):233–44.Google Scholar
  58. 58.
    Dervan LA, Yaghmai B, Watson RS, Wolf FM. The use of methadone to facilitate opioid weaning in pediatric critical care patients: a systematic review of the literature and meta-analysis. Paediatr Anaesth. 2017;27(3):228–39.Google Scholar
  59. 59.
    Berens RJ, Meyer MT, Mikhailov TA, Colpaert KD, Czarnecki ML, Ghanayem NS, et al. A prospective evaluation of opioid weaning in opioid-dependent pediatric critical care patients. Anesth Analg. 2006;102(4):1045–50.Google Scholar
  60. 60.
    Bowens CD, Thompson JA, Thompson MT, Breitzka RL, Thompson DG, Sheeran PW. A trial of methadone tapering schedules in pediatric intensive care unit patients exposed to prolonged sedative infusions. Pediatr Crit Care Med. 2011;12(5):504–11.Google Scholar
  61. 61.
    •• Sanchez-Pinto LN, Nelson LP, Lieu P, Koh JY, Rodgers JW, Larson KA, et al. Implementation of a risk-stratified opioid weaning protocol in a pediatric intensive care unit. J Crit Care. 2018;43:214–9 Study aimed at weaning opiates based on risk stratification. Google Scholar
  62. 62.
    Fenn NE 3rd, Plake KS. Opioid and benzodiazepine weaning in pediatric patients: review of current literature. Pharmacotherapy. 2017;37(11):1458–68.Google Scholar
  63. 63.
    Dominguez KD, Crowley MR, Coleman DM, Katz RW, Wilkins DG, Kelly HW. Withdrawal from lorazepam in critically ill children. Ann Pharmacother. 2006;40(6):1035–9.Google Scholar
  64. 64.
    Lardieri AB, Fusco NM, Simone S, Walker LK, Morgan JA, Parbuoni KA. Effects of clonidine on withdrawal from long-term dexmedetomidine in the pediatric patient. J Pediatr Pharmacol Ther. 2015;20(1):45–53.Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pediatrics, New York Presbyterian Morgan Stanley Children’s Hospital of New YorkColumbia University Irving Medical CenterNew YorkUSA

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