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Pediatr Crit Care Med 2014;15:e66-e71 244 Markovitz BP Proving propofol safe for continuous sedation in the PICU is an impossible task Pediatr Crit Care Med 2014;15:577 245 Cawley MJ, Guse TM, Laroia A, Haith LR, Ackerman BH Propofol withdrawal syndrome in an adult patient with thermal injury Pharmacotherapy 2003;23:933-939 246 Gao M, Rejaei D, Liu H Ketamine use in current clinical practice Acta Pharmacol 2016;37(7):865 247 Scheier E, Gadot C, Leiba R, Shavit I Sedation with the combination of ketamine and propofol in a pediatric ED: a retrospective case series analysis Am J Emerg Med 2015;33(6):815-7 248 Dewhirst E, et al Cardiac arrest following ketamine administration for rapid sequence intubation J Intensive Care Med 2013;28:375-379 249 Roy TM, Pruitt VL, Garner PA, et al The potential role of anesthesia in status asthmaticus J Asthma 1992;29:73-77 250 Smith JA, Santer LJ Respiratory arrest following intramuscular ketamine injection in a 4-year-old child Ann Emerg Med 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randomized controlled trial Surv Anesthesiol 2016;60(5):204-205 257 Watt I, Ledingham IM Mortality amongst multiple trauma patients admitted to an intensive therapy unit Anaesthesia 1984;39:973-978 258 Chitilian HV, Eckenhoff RG, Raines DE Anesthetic drug development: novel drugs and new approaches Surg Neurol Int 2013; 4(suppl 1):S2-S10 259 Stabernack CR, et al Absorbents differ enormously in their capacity to produce compound A and carbon monoxide Anesth Analg 2000;90:1428-1435 260 Sponheim S, Skraastad O, Helseth E, et al Effects of 0.5 and 1.0 MAC isoflurane, sevoflurane and desflurane on intracranial and cerebral perfusion pressures in children Acta Anaesthesiol Scand 2003;47:932-938 261 Petersen KD, Landsfeldt U, Cold GE, et al Intracranial pressure and cerebral hemodynamic in patients with cerebral tumors: a randomized prospective study of patients subjected to craniotomy in propofol-fentanyl, isoflurane-fentanyl, or sevoflurane-fentanyl anesthesia Anesthesiology 2003;98:329-336 262 Fraga M, Rama-Maceiras P, Rodino S, et al The effects of isoflurane and desflurane on intracranial pressure, cerebral perfusion pressure, and cerebral arteriovenous oxygen content difference in normocapnic patients with supratentorial brain tumors Anesthesiology 2003;98:1085-1090 263 Tanigami H, Yahagi N, Kumon K, et al Long-term sedation with isoflurane in postoperative intensive care in cardiac surgery Artif Organs 1997;21:21-23 264 Arnold JH, Truog RD, Rice SA Prolonged administration of isoflurane to pediatric patients during mechanical ventilation Anesth Analg 1993;76:520-526 265 Johnston RG, Noseworthy TW, Friesen EG, et al Isoflurane therapy for status asthmaticus in children and adults Chest 1990;97:698-701 266 Fujino Y, Nishimura M, Nishimura S, et al Prolonged administration of isoflurane to patients with severe renal dysfunction Anesth Analg 1998;86:440-441 267 Kong KL, Willatts SM Isoflurane sedation in pediatric intensive care Crit Care Med 1995;23:1308-1309 268 Parnass SM, Feld JM, Chamberlin WH, et al Status asthmaticus treated with isoflurane and enflurane Anesth Analg 1987;66:193-195 269 Wheeler DS, Clapp CR, Ponaman ML, et al Isoflurane therapy for status asthmaticus in children: a case series and protocol Pediatr Crit Care Med 2000;1:55-59 270 Higuchi H, Maeda S, Ishii-Maruhama M, Honda-Wakasugi Y, Yabuki-Kawase A, Miyawaki T Intellectual disability is a risk factor for delayed emergence from total intravenous anaesthesia: Intellectual disability and emergence J Intellect Disabil 2018;62:217-224 271 Yoshikawa F, Tamaki Y, Okumura H, et al Risk factors with intravenous sedation for patients with disabilities Anesth Prog 2013;60:153-161 272 Sciandra D, Wiryawan B, Joshi P, Heard CMB Dexmedetomidine for the difficult to sedate PICU patient Anesthesiology, 2008;109:A498 273 Lee J, Loepke AW Does pediatric anesthesia cause brain damage? - Addressing parental and provider concerns in light of compelling animal studies and seemingly ambivalent human data Korean J Anesthesiol 2018;71:255-273 274 Ikonomidou C, Bosch F, Miksa M, et al Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain Science 1999;283:70-74 275 Sanders RD, et al Impact of anaesthetics and surgery on neurodevelopment: an update Br J Anaesth 2013;110(suppl 1):i53-i72 276 Bartels M, Althoff RR, Boomsma DI Anesthesia and cognitive performance in children: no evidence for a causal relationship Twin Res Hum Genet 2009;2:246-253 277 Sun LS, Li G, Miller TLK, et al Association between a single general anesthesia exposure before 35 months and neurocognitive outcomes in later childhood JAMA 2016;315:2312-2320 278 Warner DO, Zaccariello MJ, Katusic SK Neuropsychological and behavioral outcomes after exposure of young children to procedures requiring general anesthesia: The Mayo Anesthesia Safety in Kids (MASK) Study Anesthesiology 2018;129(1):89-105 279 Davidson AJ, Disma N, de Graaff Jurgen C, et al Neurodevelopmental outcome at years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial Lancet 2016;387:239-250 e7 280 McCann ME, de Graaff JC, Dorris L, et al Neurodevelopmental outcome at years of age after general anaesthesia or awakeregional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial Lancet 2019;393:664-677 281 Hansen TG Anesthesia-related neurotoxicity and the developing animal brain is not a significant problem in children Paediatr Anaesth 2015;25:65-72 282 Walia H, Whitaker E, Pearson G, Tobias JD General anesthesia with dexmedetomidine and remifentanil in a 3-year-old child: an alternative anesthetic regimen to allay parental concerns of the potential neurocognitive effects of general anesthesia J Med Case Rep 2016;7:109-113 283 Kamat PP, Kudchadkar SR, Simon HK Sedative and anesthetic neurotoxicity in infants and young children: not just an operating room concern J 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Response Report: Summary with Critical Appraisal Dexmedetomidine for Sedation in the ICU or PICU: A Review of CostEffectiveness and Guidelines Ottawa, ON: Canadian Agency for Drugs and Technologies in Health; 2014 e8 Abstract: A wide selection of sedation and analgesia options is available in the pediatric intensive care unit There is no ideal sedative agent for all patients, but most children well with a combination of opiates (fentanyl or morphine) and supplementation with benzodiazepines either by infusion (midazolam) or on an as-required basis (lorazepam) to provide adjunct anxiolysis and amnesia Dexmedetomidine is being used increasingly as an adjunct in place of benzodiazepines When the ability to perform a rapid neurologic examination is necessary, use of short-acting agents—such as remifentanil, propofol, or isoflurane—may be warranted All sedative agents result in tolerance with prolonged use The clinician must be aware that withdrawal may occur with the prolonged use of these agents (i.e., more than 3–5 days) Key words: opioids, benzodiazepines, pediatric intensive care unit, morphine, fentanyl, dexmedetomidine, propofol, isoflurane, ketamine, etomidate, iatrogenic withdrawal syndrome, delirium 133 Tolerance, Dependency, and Withdrawal JOSEPH D TOBIAS PEARLS • Physical dependency and withdrawal have been documented in all agents used for sedation and analgesia in the pediatric intensive care unit, including benzodiazepines, barbiturates, opioids, dexmedetomidine, propofol, and the inhalational anesthetic agents Regardless of the agent administered, withdrawal will occur once the sedative or analgesic medication has been administered by continuous infusion for more than to days Delaying the onset and magnitude of tolerance and physical dependency may be feasible with the use of newer practices, such as drug holidays or rotating sedation regimens • • Data demonstrating the potential deleterious physiologic effects of untreated pain combined with ongoing humanitarian concerns have led to increased attention on the need to provide compassionate care for patients in the pediatric intensive care unit (PICU) setting Many of these initiatives have led to increased use of sedative and analgesic agents during mechanical ventilation in infants and children Although the judicious use of sedative and analgesic agents is mandatory to ensure effective anxiolysis and analgesia, new consequences have emerged from such practices, including physical dependency, tolerance, and withdrawal These problems require definition and effective treatment strategies to limit their impact on the patient, length of hospitalization, and perhaps even outcome The development of an effective approach to identifying, preventing, and treating tolerance and physical dependency requires a consensus on the definitions of these terms.1 Tolerance is a decrease in a drug’s effect over time, generally with the need to increase the dose to achieve the same effect Tolerance is related to changes at or distal to the receptor, generally at the cellular level Tolerance may be divided into various subtypes: Innate tolerance refers to a genetically predetermined lack of sensitivity to a medication related to a lack of or alteration in receptors or their subcellular components Pharmacokinetic (dispositional) tolerance refers to changes in a medication’s effects because of alterations in distribution or metabolism • • • When transitioning from intravenous to oral medications and weaning the amount of medication administered, the use of formal scoring systems to identify withdrawal is recommended In the majority of clinical scenarios, once physical dependency has occurred, withdrawal can be prevented by switching to an orally equivalent agent of the same class, such as methadone for the opioids, lorazepam for the benzodiazepines, and clonidine for dexmedetomidine To facilitate care and avoid variations in practice, it is suggested that each institution develop specific protocols for the oral agent to be used, conversion from intravenous to oral doses, and tapering regimen Learned tolerance refers to a reduction in a drug’s effect as a result of learned or compensatory mechanisms An example of this is learning to walk a straight line while intoxicated by repeated practice at the task Pharmacodynamic tolerance occurs when drug effect is diminished, although the plasma concentration of the drug remains constant For the purpose of this discussion, it is pharmacodynamic tolerance that is generally the most relevant to the PICU population For the remainder of this chapter, it will be referred to simply as tolerance Withdrawal includes the physical signs and symptoms that manifest when the administration of a medication (for our purposes, the sedative or analgesic agent) is abruptly discontinued in a patient who is physically tolerant The symptomatology of withdrawal varies from patient to patient and may be affected by several factors, including the agent involved as well as the patient’s age, cognitive state, and associated medical conditions Physiologic (physical) dependence is the need to continue a sedative or analgesic agent to prevent withdrawal Psychologic dependence is the need for a substance because of its euphoric effects Addiction is a complex pattern of behaviors characterized by the repetitive, compulsive use of a substance, antisocial or criminal behavior to obtain the drug, and a high incidence of relapse after treatment Psychologic dependency and addiction are extremely rare after the appropriate use of sedative or analgesic agents to treat pain or to relieve anxiety in the PICU setting 1611 ... remains constant For the purpose of this discussion, it is pharmacodynamic tolerance that is generally the most relevant to the PICU population For the remainder of this chapter, it will be referred... a reduction in a drug’s effect as a result of learned or compensatory mechanisms An example of this is learning to walk a straight line while intoxicated by repeated practice at the task Pharmacodynamic... Pract 2015;2015:831260 253 Kenyon CJ, McNeil LM, Fraser R Comparison of the effects of etomidate, thiopentone and propofol on cortisol synthesis Br J Anaesth 1985;57:509-511 254 Crozier TA, Flamm