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Sedative-analgesic medications in critically ill adults: Properties, dosage regimens, and adverse effects

Authors
Karen J Tietze, PharmD
Barry Fuchs, MD
Section Editors
Polly E Parsons, MD
Michael Avidan, MD
Deputy Editor
Geraldine Finlay, MD

INTRODUCTION

Distress, due to pain, fear/anxiety, dyspnea, or delirium is common among critically ill patients, especially those who are intubated or are having difficulty communicating with their caregivers [1]. Distress may manifest clinically as agitation that is often associated with ventilator asynchrony and vital sign abnormalities. Regardless, distress needs to be treated to comfort the patient, ameliorate agitation that may interfere with supportive care, and attenuate increases in sympathetic tone, which may have untoward physiological effects [2].

Common sedative-analgesic medications used to treat distress in critically ill adults are reviewed here. Identifying the cause of distress and using this information to select the optimal sedative-analgesic agent is discussed separately. (See "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal".)

The management of pain and neuromuscular blockade in critically ill patients is also described separately. (See "Pain control in the critically ill adult patient" and "Use of neuromuscular blocking medications in critically ill patients".)

ANALGESICS

Pain can be managed in the intensive care unit (ICU) with opioid analgesic and nonopioid analgesic agents. The choice of agent should be directed at the etiology of pain, but opioids are, in general, frequently administered for the management of pain in mechanically ventilated patients.

Opioid analgesics — Morphine sulfate, fentanyl, and hydromorphone are the intravenous opioids that are most commonly used to manage distress due to pain in critically ill patients. Oral opioids such as oxycodone, methadone, and morphine are also given to patients where oral or enteral administration is preferred. Remifentanil is also an option; advantages include its rapid onset of action and prompt clearance that are independent of hepatic and renal function, although there is debate as to whether its use is associated with a higher risk of tolerance [3-5].

                                   

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Literature review current through: Nov 2016. | This topic last updated: Wed Jul 27 00:00:00 GMT+00:00 2016.
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References
Top
  1. Hansen-Flaschen J. Improving patient tolerance of mechanical ventilation. Challenges ahead. Crit Care Clin 1994; 10:659.
  2. Lewis KS, Whipple JK, Michael KA, Quebbeman EJ. Effect of analgesic treatment on the physiological consequences of acute pain. Am J Hosp Pharm 1994; 51:1539.
  3. Kim SH, Stoicea N, Soghomonyan S, Bergese SD. Intraoperative use of remifentanil and opioid induced hyperalgesia/acute opioid tolerance: systematic review. Front Pharmacol 2014; 5:108.
  4. Rivosecchi RM, Rice MJ, Smithburger PL, et al. An evidence based systematic review of remifentanil associated opioid-induced hyperalgesia. Expert Opin Drug Saf 2014; 13:587.
  5. Ishii H, Petrenko AB, Kohno T, Baba H. No evidence for the development of acute analgesic tolerance during and hyperalgesia after prolonged remifentanil administration in mice. Mol Pain 2013; 9:11.
  6. Salpeter SR, Buckley JS, Bruera E. The use of very-low-dose methadone for palliative pain control and the prevention of opioid hyperalgesia. J Palliat Med 2013; 16:616.
  7. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41:263.
  8. Carson SS, Kress JP, Rodgers JE, et al. A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients. Crit Care Med 2006; 34:1326.
  9. Lonardo NW, Mone MC, Nirula R, et al. Propofol is associated with favorable outcomes compared with benzodiazepines in ventilated intensive care unit patients. Am J Respir Crit Care Med 2014; 189:1383.
  10. Nelson LE, Guo TZ, Lu J, et al. The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway. Nat Neurosci 2002; 5:979.
  11. Deambrogio V, Gatti G, Mongio F, et al. [A case of superficial lymph node tuberculosis]. Minerva Med 1991; 82:507.
  12. Zecharia AY, Nelson LE, Gent TC, et al. The involvement of hypothalamic sleep pathways in general anesthesia: testing the hypothesis using the GABAA receptor beta3N265M knock-in mouse. J Neurosci 2009; 29:2177.
  13. Jurd R, Arras M, Lambert S, et al. General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit. FASEB J 2003; 17:250.
  14. Asserhøj LL, Mosbech H, Krøigaard M, Garvey LH. No evidence for contraindications to the use of propofol in adults allergic to egg, soy or peanut†. Br J Anaesth 2016; 116:77.
  15. Dziedzic A. Is Propofol Safe For Food Allergy Patients? A Review of the Evidence. SAAD Dig 2016; 32:23.
  16. Fulton B, Sorkin EM. Propofol. An overview of its pharmacology and a review of its clinical efficacy in intensive care sedation. Drugs 1995; 50:636.
  17. Carrasco G, Molina R, Costa J, et al. Propofol vs midazolam in short-, medium-, and long-term sedation of critically ill patients. A cost-benefit analysis. Chest 1993; 103:557.
  18. Hug CC Jr, McLeskey CH, Nahrwold ML, et al. Hemodynamic effects of propofol: data from over 25,000 patients. Anesth Analg 1993; 77:S21.
  19. Riker RR, Glisic EK, Fraser GL. Propofol infusion syndrome: difficult to recognize, difficult to study. Crit Care Med 2009; 37:3169.
  20. Diprivan package insert. Astra Zeneca. August 2005.
  21. Bennett SN, McNeil MM, Bland LA, et al. Postoperative infections traced to contamination of an intravenous anesthetic, propofol. N Engl J Med 1995; 333:147.
  22. Mirenda J. Prolonged propofol sedation in the critical care unit. Crit Care Med 1995; 23:1304.
  23. Blakey SA, Hixson-Wallace JA. Clinical significance of rare and benign side effects: propofol and green urine. Pharmacotherapy 2000; 20:1120.
  24. Nates J, Avidan A, Gozal Y, Gertel M. Appearance of white urine during propofol anesthesia. Anesth Analg 1995; 81:210.
  25. Ho KM, Ng JY. The use of propofol for medium and long-term sedation in critically ill adult patients: a meta-analysis. Intensive Care Med 2008; 34:1969.
  26. McKeage K, Perry CM. Propofol: a review of its use in intensive care sedation of adults. CNS Drugs 2003; 17:235.
  27. Kam PC, Cardone D. Propofol infusion syndrome. Anaesthesia 2007; 62:690.
  28. Pothineni NV, Hayes K, Deshmukh A, Paydak H. Propofol-related infusion syndrome: rare and fatal. Am J Ther 2015; 22:e33.
  29. Wong JM. Propofol infusion syndrome. Am J Ther 2010; 17:487.
  30. Diedrich DA, Brown DR. Analytic reviews: propofol infusion syndrome in the ICU. J Intensive Care Med 2011; 26:59.
  31. Fong JJ, Sylvia L, Ruthazer R, et al. Predictors of mortality in patients with suspected propofol infusion syndrome. Crit Care Med 2008; 36:2281.
  32. Crozier TA. The 'propofol infusion syndrome': myth or menace? Eur J Anaesthesiol 2006; 23:987.
  33. Roberts RJ, Barletta JF, Fong JJ, et al. Incidence of propofol-related infusion syndrome in critically ill adults: a prospective, multicenter study. Crit Care 2009; 13:R169.
  34. Iyer VN, Hoel R, Rabinstein AA. Propofol infusion syndrome in patients with refractory status epilepticus: an 11-year clinical experience. Crit Care Med 2009; 37:3024.
  35. Lusedra package insert. Eisai R&D management C., Ltd. 10/09.
  36. Candiotti KA, Gan TJ, Young C, et al. A randomized, open-label study of the safety and tolerability of fospropofol for patients requiring intubation and mechanical ventilation in the intensive care unit. Anesth Analg 2011; 113:550.
  37. Shehabi Y, Ruettimann U, Adamson H, et al. Dexmedetomidine infusion for more than 24 hours in critically ill patients: sedative and cardiovascular effects. Intensive Care Med 2004; 30:2188.
  38. Buck ML, Willson DF. Use of dexmedetomidine in the pediatric intensive care unit. Pharmacotherapy 2008; 28:51.
  39. Chen K, Lu Z, Xin YC, et al. Alpha-2 agonists for long-term sedation during mechanical ventilation in critically ill patients. Cochrane Database Syst Rev 2015; 1:CD010269.
  40. Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA 2012; 307:1151.
  41. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; 301:489.
  42. Adams R, Brown GT, Davidson M, et al. Efficacy of dexmedetomidine compared with midazolam for sedation in adult intensive care patients: a systematic review. Br J Anaesth 2013; 111:703.
  43. Torbic H, Papadopoulos S, Manjourides J, Devlin JW. Impact of a protocol advocating dexmedetomidine over propofol sedation after robotic-assisted direct coronary artery bypass surgery on duration of mechanical ventilation and patient safety. Ann Pharmacother 2013; 47:441.
  44. Klompas M, Li L, Szumita P, et al. Associations Between Different Sedatives and Ventilator-Associated Events, Length of Stay, and Mortality in Patients Who Were Mechanically Ventilated. Chest 2016; 149:1373.
  45. Turunen H, Jakob SM, Ruokonen E, et al. Dexmedetomidine versus standard care sedation with propofol or midazolam in intensive care: an economic evaluation. Crit Care 2015; 19:67.
  46. Patanwala AE, Erstad BL. Comparison of Dexmedetomidine Versus Propofol on Hospital Costs and Length of Stay. J Intensive Care Med 2016; 31:466.
  47. Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007; 298:2644.
  48. Ji F, Li Z, Nguyen H, et al. Perioperative dexmedetomidine improves outcomes of cardiac surgery. Circulation 2013; 127:1576.
  49. Ji F, Li Z, Young N, et al. Perioperative dexmedetomidine improves mortality in patients undergoing coronary artery bypass surgery. J Cardiothorac Vasc Anesth 2014; 28:267.
  50. MacLaren R, Preslaski CR, Mueller SW, et al. A randomized, double-blind pilot study of dexmedetomidine versus midazolam for intensive care unit sedation: patient recall of their experiences and short-term psychological outcomes. J Intensive Care Med 2015; 30:167.
  51. Reade MC, Eastwood GM, Bellomo R, et al. Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With Agitated Delirium: A Randomized Clinical Trial. JAMA 2016; 315:1460.
  52. Zaal IJ, Devlin JW, Peelen LM, Slooter AJ. A systematic review of risk factors for delirium in the ICU. Crit Care Med 2015; 43:40.
  53. Serafim RB, Bozza FA, Soares M, et al. Pharmacologic prevention and treatment of delirium in intensive care patients: A systematic review. J Crit Care 2015; 30:799.
  54. Venn RM, Bradshaw CJ, Spencer R, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia 1999; 54:1136.
  55. Mueller SW, Preslaski CR, Kiser TH, et al. A randomized, double-blind, placebo-controlled dose range study of dexmedetomidine as adjunctive therapy for alcohol withdrawal. Crit Care Med 2014; 42:1131.
  56. Gagnon DJ, Riker RR, Glisic EK, et al. Transition from dexmedetomidine to enteral clonidine for ICU sedation: an observational pilot study. Pharmacotherapy 2015; 35:251.
  57. Dasta JF, Kane-Gill SL, Durtschi AJ. Comparing dexmedetomidine prescribing patterns and safety in the naturalistic setting versus published data. Ann Pharmacother 2004; 38:1130.
  58. Venn M, Newman J, Grounds M. A phase II study to evaluate the efficacy of dexmedetomidine for sedation in the medical intensive care unit. Intensive Care Med 2003; 29:201.
  59. Holliday SF, Kane-Gill SL, Empey PE, et al. Interpatient variability in dexmedetomidine response: a survey of the literature. ScientificWorldJournal 2014; 2014:805013.
  60. Sichrovsky TC, Mittal S, Steinberg JS. Dexmedetomidine sedation leading to refractory cardiogenic shock. Anesth Analg 2008; 106:1784.
  61. Möhler H, Richards JG. The benzodiazepine receptor: a pharmacological control element of brain function. Eur J Anaesthesiol Suppl 1988; 2:15.
  62. Arendt RM, Greenblatt DJ, deJong RH, et al. In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution. J Pharmacol Exp Ther 1983; 227:98.
  63. Ziegler WH, Schalch E, Leishman B, Eckert M. Comparison of the effects of intravenously administered midazolam, triazolam and their hydroxy metabolites. Br J Clin Pharmacol 1983; 16 Suppl 1:63S.
  64. Greenblatt DJ. Clinical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet 1981; 6:89.
  65. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002; 30:119.
  66. Kollef MH, Levy NT, Ahrens TS, et al. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest 1998; 114:541.
  67. Pandharipande P, Shintani A, Peterson J, et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 2006; 104:21.
  68. Jones C, Bäckman C, Capuzzo M, et al. Precipitants of post-traumatic stress disorder following intensive care: a hypothesis generating study of diversity in care. Intensive Care Med 2007; 33:978.
  69. Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004; 291:1753.
  70. Pisani MA, Murphy TE, Araujo KL, et al. Benzodiazepine and opioid use and the duration of intensive care unit delirium in an older population. Crit Care Med 2009; 37:177.
  71. Zaal IJ, Devlin JW, Hazelbag M, et al. Benzodiazepine-associated delirium in critically ill adults. Intensive Care Med 2015; 41:2130.
  72. Litchfield NB. Complications of Intravenous Diazepam - Adverse Psychological Reactions. (An assessment of 16,000 cases). Anesth Prog 1980; 27:175.
  73. Thurston TA, Williams CG, Foshee SL. Reversal of a paradoxical reaction to midazolam with flumazenil. Anesth Analg 1996; 83:192.
  74. Fulton SA, Mullen KD. Completion of upper endoscopic procedures despite paradoxical reaction to midazolam: a role for flumazenil? Am J Gastroenterol 2000; 95:809.
  75. Diazepam injection [Baxter Healthcare Corporation] United States Food and Drug Administration approved prescribing information. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1045 (Accessed on May 12, 2010).
  76. Tayar J, Jabbour G, Saggi SJ. Severe hyperosmolar metabolic acidosis due to a large dose of intravenous lorazepam. N Engl J Med 2002; 346:1253.
  77. Cawley MJ. Short-term lorazepam infusion and concern for propylene glycol toxicity: case report and review. Pharmacotherapy 2001; 21:1140.
  78. Wilson KC, Reardon C, Theodore AC, Farber HW. Propylene glycol toxicity: a severe iatrogenic illness in ICU patients receiving IV benzodiazepines: a case series and prospective, observational pilot study. Chest 2005; 128:1674.
  79. Wilson KC, Reardon C, Farber HW. Propylene glycol toxicity in a patient receiving intravenous diazepam. N Engl J Med 2000; 343:815.
  80. Arroliga AC, Shehab N, McCarthy K, Gonzales JP. Relationship of continuous infusion lorazepam to serum propylene glycol concentration in critically ill adults. Crit Care Med 2004; 32:1709.
  81. Yahwak JA, Riker RR, Fraser GL, Subak-Sharpe S. Determination of a lorazepam dose threshold for using the osmol gap to monitor for propylene glycol toxicity. Pharmacotherapy 2008; 28:984.
  82. Barnes BJ, Gerst C, Smith JR, et al. Osmol gap as a surrogate marker for serum propylene glycol concentrations in patients receiving lorazepam for sedation. Pharmacotherapy 2006; 26:23.
  83. Sawynok J. Topical and peripheral ketamine as an analgesic. Anesth Analg 2014; 119:170.
  84. Kundra P, Velayudhan S, Krishnamachari S, Gupta SL. Oral ketamine and dexmedetomidine in adults' burns wound dressing--A randomized double blind cross over study. Burns 2013; 39:1150.
  85. Norambuena C, Yañez J, Flores V, et al. Oral ketamine and midazolam for pediatric burn patients: a prospective, randomized, double-blind study. J Pediatr Surg 2013; 48:629.
  86. Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med 2010; 38:419.
  87. Seemüller F, Volkmer E, Vogel T, et al. Quetiapine as treatment for delirium during weaning from ventilation: a case report. J Clin Psychopharmacol 2007; 27:526.
  88. Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med 2004; 30:444.
  89. Han CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics 2004; 45:297.
  90. Kram BL, Kram SJ, Brooks KR. Implications of atypical antipsychotic prescribing in the intensive care unit. J Crit Care 2015; 30:814.
  91. Kudo S, Ishizaki T. Pharmacokinetics of haloperidol: an update. Clin Pharmacokinet 1999; 37:435.
  92. Avent KM, DeVoss JJ, Gillam EM. Cytochrome P450-mediated metabolism of haloperidol and reduced haloperidol to pyridinium metabolites. Chem Res Toxicol 2006; 19:914.
  93. Information for Healthcare Professionals: Haloperidol http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHealthcareProfessionals/ucm085203.htm (Accessed on May 12, 2010).
  94. Riker RR, Fraser GL, Cox PM. Continuous infusion of haloperidol controls agitation in critically ill patients. Crit Care Med 1994; 22:433.
  95. Fernandez F, Holmes VF, Adams F, Kavanaugh JJ. Treatment of severe, refractory agitation with a haloperidol drip. J Clin Psychiatry 1988; 49:239.
  96. Seneff MG, Mathews RA. Use of haloperidol infusions to control delirium in critically ill adults. Ann Pharmacother 1995; 29:690.
  97. Mac Sweeney R, Barber V, Page V, et al. A national survey of the management of delirium in UK intensive care units. QJM 2010; 103:243.
  98. Fish DN. Treatment of delirium in the critically ill patient. Clin Pharm 1991; 10:456.
  99. Stern TA. The management of depression and anxiety following myocardial infarction. Mt Sinai J Med 1985; 52:623.
  100. Metzger E, Friedman R. Prolongation of the corrected QT and torsades de pointes cardiac arrhythmia associated with intravenous haloperidol in the medically ill. J Clin Psychopharmacol 1993; 13:128.
  101. Wilt JL, Minnema AM, Johnson RF, Rosenblum AM. Torsade de pointes associated with the use of intravenous haloperidol. Ann Intern Med 1993; 119:391.
  102. Menza MA, Murray GB, Holmes VF, Rafuls WA. Decreased extrapyramidal symptoms with intravenous haloperidol. J Clin Psychiatry 1987; 48:278.
  103. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005; 294:1934.
  104. Gill SS, Bronskill SE, Normand SL, et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med 2007; 146:775.
  105. Schneeweiss S, Setoguchi S, Brookhart A, et al. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ 2007; 176:627.
  106. Behne M, Wilke HJ, Harder S. Clinical pharmacokinetics of sevoflurane. Clin Pharmacokinet 1999; 36:13.
  107. Bracco D, Donatelli F. Volatile agents for ICU sedation? Intensive Care Med 2011; 37:895.
  108. Mesnil M, Capdevila X, Bringuier S, et al. Long-term sedation in intensive care unit: a randomized comparison between inhaled sevoflurane and intravenous propofol or midazolam. Intensive Care Med 2011; 37:933.
  109. Richman PS, Baram D, Varela M, Glass PS. Sedation during mechanical ventilation: a trial of benzodiazepine and opiate in combination. Crit Care Med 2006; 34:1395.