Iranian Journal of Psychiatry 2018. 13(1):65-79.

Adaptation of the Pharmacological Management of Delirium in ICU Patients in Iran: Introduction and Definition
mohammad arbabi, fatemeh shahhatami, mojtaba mojtahed zadeh, mostafa mohammadi, padideh ghaeli


Objective: Delirium is a brain dysfunction syndrome. In most cases, this syndrome is neither diagnosed accurately nor treated properly. The incidence of delirium by itself increases hospitalization period, mortality rate and the cost in health spectrum. If appropriate attempts are not made to treat this complication, the outcomes could become worse. Thus, the present study aimed at conducting a review on medications which are prescribed to treat delirium and establishing a general view on their advantages and disadvantages.

Method: By searching Google Scholar, PsycINFO, Scopus, and PubMed databases as well as hand searching in key journals, data were collected without time and language limitation. After collecting the data, comparing the similar or contradictory information, and sorting them, the views of specialists were inquired and duly received via email. By acquiring consensus of opinions, the secondary manuscript was written in a narrative review form.

Discussion: This narrative review paper aimed at providing a general view on defining delirium, the pathologic factors that create it, and treating this syndrome based on its development. Authentic evidence regarding delirium management was reviewed and a treatment strategy was suggested for Iranian patients.


Antipsychotics; Delirium; Intensive Care Unit; Prmacological Treatment

Full Text:



Black DW, Grant JE. DSM-5, guidebook: the essential companion to the diagnostic and statistical manual of mental disorders: American Psychiatric Pub; 2014.

Jain G, Chakrabarti S, Kulhara P. Symptoms of delirium: an exploratory factor analytic study among referred patients. General Hospital Psychiatry 2011; 33: 377-385.

Eidelman LA, Putterman D, Putterman C, Sprung CL. The spectrum of septic encephalopathy: definitions, etiologies, and mortalities. Jama 1996; 275: 470-473.

Linnoila M, Mefford I, Nutt D, Adinoff B. Alcohol withdrawal and noradrenergic function. Annals of Internal Medicine 1987; 107: 875-889.

Hall W, Zador D. The alcohol withdrawal syndrome. Lancet 1997; 349: 1897-1900.

Association AP. American Psychiatric Association Practice Guidelines for the treatment of psychiatric disorders: compendium 2006: American Psychiatric Pub; 2006.

Liptzin B, Levkoff SE. An empirical study of delirium subtypes. Br J Psychiatry 1992; 161: 843-845.

Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit: executive summary. Am J Health Syst Pharm 2013; 70: 53-58.

Robinson TN, Raeburn CD, Tran ZV, Brenner LA, Moss M. Motor subtypes of postoperative delirium in older adults. Arch Surg 2011; 146: 295-300

Shehabi Y, Riker RR, Bokesch PM, Wisemandle W, Shintani A, Ely EW. Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients. Crit Care Med 2010; 38: 2311-2318.

Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell Jr FE, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004; 291: 1753-1762.

Ely E, Gautam S, Margolin R, Francis J, May L, Speroff T, et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med 2001; 27: 1892-900.

Inouye SK, Rushing JT, Foreman MD, Palmer RM, Pompei P. Does delirium contribute to poor hospital outcomes? J Gen Intern Med 1998; 13: 234-242.

McCusker J, Cole MG, Dendukuri N, Belzile E. Does delirium increase hospital stay? J Am Geriatr Soc 2003; 51: 1539-1546.

Marcantonio ER, Simon SE, Bergmann MA, Jones RN, Murphy KM, Morris JN. Delirium symptoms in post‐acute care: Prevalent, persistent, and associated with poor functional recovery. J Am Geriatr Soc 2003; 51: 4-9.

van Zyl LT, Seitz DP. Delirium: concisely: condition is associated with increased morbidity, mortality, and length of hospitalization. Geriatrics 2006; 61: 18-21.

Inouye SK. Delirium in older persons. N Engl J Med 2006 16; 354: 1157-1165.

Potter J, George J. The prevention, diagnosis and management of delirium in older people: concise guidelines. Clin Med (Lond) 2006; 6: 303-308.

Lat I, McMillian W, Taylor S, Janzen JM, Papadopoulos S, Korth L, et al. The impact of delirium on clinical outcomes in mechanically ventilated surgical and trauma patients. Crit Care Med 2009; 37: 1898-1905.

Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med 2007; 33: 66-73.

Riker R, Shehabi Y, Bokesch P, Ceraso D, Wisemandle W, Koura F, et al. SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; 301: 489-499.

Shehabi Y, Ruettimann U, Adamson H, Innes R, Ickeringill M. Dexmedetomidine infusion for more than 24 hours in critically ill patients: sedative and cardiovascular effects. Intensive Care Med 2004; 30: 2188-2196

Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, 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: 2644-2653.

Needham DM, Korupolu R, Zanni JM, Pradhan P, Colantuoni E, Palmer JB, et al. Early physical medicine and rehabilitation for patients with acute respiratory failure: a quality improvement project. Arch Phys Med Rehabil 2010; 91: 536-542.

Schweickert WD, Pohlman MC, Pohlman AS, Nigos C, Pawlik AJ, Esbrook CL, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 2009; 373: 1874-1882.

Pandharipande P, Shintani A, Peterson J, Pun BT, Wilkinson GR, Dittus RS, et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. The Journal of the American Society of Anesthesiologists 2006; 104: 21-26.

van der Mast RC. Pathophysiology of delirium. Journal of geriatric psychiatry and neurology 1998; 11: 138-145.

Kochunov P, Ramage A, Lancaster JL, Robin DA, Narayana S, Coyle T, et al. Loss of cerebral white matter structural integrity tracks the gray matter metabolic decline in normal aging. Neuroimage 2009; 45: 17-28.

Kelly K, Nadon N, Morrison J, Thibault O, Barnes CA, Blalock E. Epilepsy Res 2006; 68 Suppl 1: S5-20.

Juraska JM, Lowry NC. Neuroanatomical changes associated with cognitive aging. Behavioral Neurobiology of Aging: Springer; 2011.

Chen JJ, Rosas HD, Salat DH. Age-associated reductions in cerebral blood flow are independent from regional atrophy. Neuroimage 2011; 55: 468-478.

Brown WR, Thore CR. Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol 2011; 37: 56-74.

Bertsch K, Hagemann D, Hermes M, Walter C, Khan R, Naumann E. Brain Res 2009; 1267: 77-88.

Beason-Held LL, Kraut MA, Resnick SM. II. Temporal patterns of longitudinal change in aging brain function. Neurobiol Aging 2008; 29: 497–513.

Celsis P, Agniel A, Cardebat D, Demonet J, Ousset P, Puel M. Age related cognitive decline: a clinical entity? A longitudinal study of cerebral blood flow and memory performance. Journal of Neurology, Neurosurgery & Psychiatry 1997; 62: 601-608.

Meier-Ruge W, Iwangoff P, Reichlmeier K, Sandoz P. Neurochemical findings in the aging brain. Advances in biochemical psychopharmacology 1979; 23: 323-338.

Elie M, Cole MG, Primeau FJ, Bellavance F. Delirium risk factors in elderly hospitalized patients. J Gen Intern Med 1998; 13: 204–212.

McAvay GJ, Van Ness PH, Bogardus ST, Zhang Y, Leslie DL, Leo‐Summers LS, et al. Older adults discharged from the hospital with delirium: 1‐year outcomes. J Am Geriatr Soc 2006; 54: 1245-1250.

Kopelman MD. The cholinergic neurotransmitter system in human memory and dementia: a review. Quarterly Journal of Experimental Psychology 1986; 38: 535-573.

Perry E, Walker M, Grace J, Perry R. Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends Neurosci 1999; 22: 273-280.

Flacker JM, Lipsitz LA. Neural mechanisms of delirium: current hypotheses and evolving concepts. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 1999; 54: B239-B246.

Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. J Gerontol A Biol Sci Med Sci 1999; 54: B239-246.

Golinger RC, Tune LE. Association of Elevated Plasma Anticholinergic Activity. Am J Psychiatry 1987; 144: 1218-1220.

Trzepacz P. editor Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Semin Clin Neuropsychiatry 2000; 5: 132-148.

Flacker JM, Wei JY. Endogenous anticholinergic substances may exist during acute illness in elderly medical patients. J Gerontol A Biol Sci Med Sci 2001; 56: M353-355.

Plaschke K, Thomas C, Engelhardt R, Teschendorf P, Hestermann U, Weigand MA, et al. Significant correlation between plasma and CSF anticholinergic activity in presurgical patients. Neurosci Lett 2007; 417: 16-20.

Flacker JM, Cummings V, Mach JR, Bettin K, Kiely DK, Wei J. The association of serum anticholinergic activity with delirium in elderly medical patients. Am J Geriatr Psychiatry 1998; 6: 31-41.

Tune L, Holland A, Folstein M, Damlouji N, Gardner T, Coyle J. Association of postoperative delirium with raised serum levels of anticholinergic drugs. Lancet 1981; 318: 651-653.

Tune L. editor Serum anticholinergic activity levels and delirium in the elderly. Semin Clin Neuropsychiatry 2000; 5: 149-153.

Flaherty JH. Psychotherapeutic agents in older adults. Commonly prescribed and over-the-counter remedies: causes of confusion. Clin Geriatr Med 1998; 14: 101-127.

Han L, McCusker J, Cole M, Abrahamowicz M, Primeau F, Élie M. Use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients. Arch Intern Med 2001; 161: 1099-1105.

Praticò C, Quattrone D, Lucanto T, Amato A, Penna O, Roscitano C, et al. Drugs of anesthesia acting on central cholinergic system may cause post-operative cognitive dysfunction and delirium. Med Hypotheses 2005; 65: 972-982.

Mach JR, Dysken MW, Kuskowski M, Richelson E, Holden L, Jilk KM. Serum anticholinergic activity in hospitalized older persons with delirium: a preliminary study. J Am Geriatr Soc 1995; 43: 491-495.

Mulsant BH, Pollock BG, Kirshner M, Shen C, Dodge H, Ganguli M. Serum anticholinergic activity in a community-based sample of older adults: relationship with cognitive performance. Arch Gen Psychiatry 2003; 60: 198-203.

Moyer DD. Review article: terminal delirium in geriatric patients with cancer at end of life. Am J Hosp Palliat Care 2011; 28: 44-451.

Gaudreau J-D, Gagnon P. Psychotogenic drugs and delirium pathogenesis: the central role of the thalamus. Med Hypotheses 2005; 64: 471-475.

Trzepacz PT. The neuropathogenesis of delirium: a need to focus our research. Psychosomatics 1994; 35: 374-391.

Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, et al. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc 2013; 14: 877-882.

Cunningham C, Campion S, Lunnon K, Murray CL, Woods JF, Deacon RM, et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry 2009; 65: 304-312.

Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46-56.

MacLullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C. Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J Psychosom Res 2008; 65: 229-238.

Leung JM, Sands LP, Lim E, Tsai TL, Kinjo S. Does preoperative risk for delirium moderate the effects of postoperative pain and opiate use on postoperative delirium? Am J Geriatr Psychiatry 2013; 21: 946-956.

Cerejeira J, Firmino H, Vaz-Serra A, Mukaetova-Ladinska EB. The neuroinflammatory hypothesis of delirium. Acta Neuropathol 2010; 119: 737-754.

Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 2005; 25: 9275-9284.

de Rooij SE, van Munster BC, Korevaar JC, Levi M. Cytokines and acute phase response in delirium. J Psychosom Res 2007; 62: 521-525.

Beloosesky Y, Hendel D, Weiss A, Hershkovitz A, Grinblat J, Pirotsky A, et al. Cytokines and C-reactive protein production in hip-fracture-operated elderly patients. J Gerontol A Biol Sci Med Sci 2007; 62: 420-426.

McGrane S, Girard TD, Thompson JL, Shintani AK, Woodworth A, Ely EW, et al. Procalcitonin and C-reactive protein levels at admission as predictors of duration of acute brain dysfunction in critically ill patients. Crit Care 2011; 15: R78.

Jackson JC, Gordon SM, Hart RP, Hopkins RO, Ely EW. The association between delirium and cognitive decline: a review of the empirical literature. Neuropsychol Rev 2004; 14: 87-98.

Berr C. Cognitive impairment and oxidative stress in the elderly: results of epidemiological studies. Biofactors 2000; 13: 205-209.

Berr C, Balansard B, Arnaud J, Roussel AM, Alpérovitch A. Cognitive decline is associated with systemic oxidative stress: the EVA study. J Am Geriatr Soc 2000; 48: 1285-1291.

Berr C, Richard M, Roussel A, Bonithon-Kopp C, Group ES. Systemic oxidative stress and cognitive performance in the population-based EVA study. Free Radic Biol Med 1998; 24: 1202-1208.

O’Keeffe S, Devlin J. Delirium and the dexamethasone suppression test in the elderly. Neuropsychobiology 1994; 30: 153-156.

Inouye SK. The dilemma of delirium: clinical and research controversies regarding diagnosis and evaluation of delirium in hospitalized elderly medical patients. Am J Med 1994; 97: 278-88.

Cammarano WB, Pittet J-F, Weitz S, Schlobohm RM, Marks JD. Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients. Crit Care Med 1998; 26: 676-684.

Moore RD, Bone LR, Geller G, Mamon JA, Stokes EJ, Levine DM. Prevalence, detection, and treatment of alcoholism in hospitalized patients. JAMA 1989; 261: 403-407.

Davis KM, Wu J-Y. Role of glutamatergic and GABAergic systems in alcoholism. J Biomed Sci 2001; 8: 7-19.

Bayard M, Mcintyre J, Hill KR, Woodside Jr J. Alcohol withdrawal syndrome. Am Fam Physician 2004; 69: 1443-1450.

Spies C, Nordmann A, Brummer G, Marks C, Conrad C, Berger G, et al. Intensive care unit stay is prolonged in chronic alcoholic men following tumor resection of the upper digestive tract. Acta Anaesthesiol Scand 1996; 40: 649-656.

Foy A, Kay J. The incidence of alcohol-related problems and the risk of alcohol withdrawal in a general hospital population. Drug Alcohol Rev 1995; 14: 49-54

Spies C, Neuner B, Neumann T, Blum S, Müller C, Rommelspacher H, et al. Intercurrent complications in chronic alcoholic men admitted to the intensive care unit following trauma. Intensive Care Med 1996; 22: 286-293.

Sommer BR, Wise LC, Kraemer HC. Is dopamine administration possibly a risk factor for delirium? Crit Care Med 2002; 30: 1508-1511.

Milbrandt EB, Kersten A, Kong L, Weissfeld LA, Clermont G, Fink MP, et al. Haloperidol use is associated with lower hospital mortality in mechanically ventilated patients. Crit Care Med 2005 ; 33: 226-229.

Rosen HJ. Double-blind comparison of haloperidol and thioridazine in geriatric outpatients. The Journal of Clinical Psychiatry; 40: 24-31.

Smith G, Taylor C, Linkous P. Haloperidol versus thioridazine for the treatment of psychogeriatric patients: a double-blind clinical trial. Psychosomatics 1974; 15: 134-138.

Woods JC, Mion LC, Connor JT, Viray F, Jahan L, Huber C, et al. Severe agitation among ventilated medical intensive care unit patients: frequency, characteristics and outcomes. Intensive Care Med 2004; 30: 1066-1072.

Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry 1997; 9: 105-107.

Ravona-Springer R, Dolberg OT, Hirschmann S, Grunhaus L. Delirium in elderly patients treated with risperidone: a report of three cases. J Clin Psychopharmacol 1998; 18: 171-172.

Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics 1998; 39: 422-430.

Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med 2004; 30: 444-449.

Girard TD, Pandharipande PP, Carson SS, Schmidt GA, Wright PE, Canonico AE, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Crit Care Med 2010; 38: 428-437.

Wang PS, Schneeweiss S, Avorn J, Fischer MA, Mogun H, Solomon DH, et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med 2005; 353: 2335-2341.

Lonergan E, Britton AM, Luxenberg J, Wyller T. Antipsychotics for delirium. Cochrane Database Syst Rev 2007.

Hunt N, Stern TA. The association between intravenous haloperidol and torsades de pointes: three cases and a literature review. Psychosomatics 1995; 36: 541-549.

Sharma ND, Rosman HS, Padhi ID, Tisdale JE. Torsades de pointes associated with intravenous haloperidol in critically ill patients. Am J Cardiol 1998; 81: 238-240.

Metzger E, Friedman R. Prolongation of the Corrected QT and Torsades de Pointes Cardiac Arrhythmia Associated with Intravenous Haloperidol in the Medically III. J Clin Psychopharmacol 1993; 13: 128-132.

Tisdale JE, Rasty S, Padhi ID, Sharma ND, Rosman H. The effect of intravenous haloperidol on QT interval dispersion in critically ill patients: comparison with QT interval prolongation for assessment of risk of torsades de pointes. J Clin Pharmacol 2001; 41: 1310-1318.

Perrault LP, Denault AY, Carrier M, Cartier R, Belisle S. Torsades de pointes secondary to intravenous haloperidol after coronary bypass grafting surgery. Can J Anaesth 2000; 47: 251-254.

Tisdale JE, Kovacs R, Mi D, McCabe GP, Cariera BL, Sharma N, et al. Accuracy of uncorrected versus corrected QT interval for prediction of torsade de pointes associated with intravenous haloperidol. Pharmacotherapy 2007; 27: 175-182.

Jackson T, Ditmanson L, Phibbs B. Torsade de pointes and low-dose oral haloperidol. Arch Intern Med 1997; 157: 2013-2015.

Lawrence KR, Nasraway SA. Conduction disturbances associated with administration of butyrophenone antipsychotics in the critically ill: a review of the literature. Pharmacotherapy 1997; 17: 531-537.

Bellamy CJ, Kane-Gill SL, Falcione BA, Seybert AL. Neuroleptic malignant syndrome in traumatic brain injury patients treated with haloperidol. J Trauma 2009; 66: 954-958.

Frontera JA. Delirium and sedation in the ICU. Neurocritical care 2011; 14: 463-474.

Sanders KM, Murray GB, Cassem NH. High-dose intravenous haloperidol for agitated delirium in a cardiac patient on intra-aortic balloon pump. J Clin Psychopharmacol 1991; 11: 146-147.

Levenson JL. High-Dose Intravenous Halopendol for Agitated Delirium Following Lung Transplantation. Psychosomatics 1995; 36: 66-68.

Seneff MG, Mathews RA. Use of haloperidol infusions to control delirium in critically ill adults. Ann Pharmacother 1995; 29: 690-693.

Riker RR, Fraser GL, Cox PM. Continuous infusion of haloperidol controls agitation in critically ill patients. Crit Care Med 1994; 22: 433-440.

Menza MA, Murray GB, Holmes VF, Rafuls WA. Decreased extrapyramidal symptoms with intravenous haloperidol. J Clin Psychiatry 1987; 48: 278-280.

Marcantonio E, Juarez G, Goldman L, Mangione C, Ludwig L, Lind L, et al. The Relationship of Postoperative Delirium With Psychoactive Medications. JAMA 1994; 272: 1518-1522.

Skrobik Y, Leger C, Cossette M, Michaud V, Turgeon J. Factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors. Crit Care Med 2013; 41: 999-1008.

Aizawa K-i, Kanai T, Saikawa Y, Takabayashi T, Kawano Y, Miyazawa N, et al. A novel approach to the prevention of postoperative delirium in the elderly after gastrointestinal surgery. Surg Today 2002; 32: 310-314.

Adams F, Fernandez F, Andersson BS. Emergency pharmacotherapy of delirium in the critically ill cancer patient. Psychosomatics 1986; 27: 33-38.

Fernandez F, Levy JK, Mansell PW. Management of delirium in terminally ill AIDS patients. Int J Psychiatry Med 1989; 19: 165-172.

Menza M, Murray G, Holmes V, Rafuls W. Controlled study of extrapyramidal reactions in the management of delirious, medically ill patients: intravenous haloperidol versus intravenous haloperidol plus benzodiazepines. Heart Lung 1988; 17: 238-241.

Kosten TR, O'Connor PG. Management of drug and alcohol withdrawal. N Engl J Med 2003; 348: 1786-1795.

Mayo-Smith MF. Pharmacological management of alcohol withdrawal: a meta-analysis and evidence-based practice guideline. JAMA 1997; 278: 144-1451.

Reiter S, Kutcher SP. Disinhibition and anger outbursts in adolescents treated with clonazepam. J Clin Psychopharmacol 1991; 11: 268.

Lineaweaver WC, Anderson K, Hing DN. Massive doses of midazolam infusion for delirium tremens without respiratory depression. Crit Care Med 1988; 16: 294-295.

BaHammam A. Sleep in acute care units. Sleep Breath 2006; 10: 6-15.

Lipowski Z. Delirium (acute confusional states). JAMA 1987; 258: 1789-1792.

Lindesay J. The concept of delirium. Dement Geriatr Cogn Disord 1999; 10: 310-314.

Berger M, Vollmann J, Hohagen F, Konig A. Sleep deprivation combined with consecutive sleep phase advance as a fast-acting therapy in depression: an open pilot trial in medicated and unmedicated patients. Am J Psychiatry 1997; 154: 870-872.

Mistraletti G, Carloni E, Cigada M, Zambrelli E, Taverna M, Sabbatici G, et al. Sleep and delirium in the intensive care unit. Minerva Anestesiol 2008; 74: 329-333.

Olofsson K, Alling C, Lundberg D, Malmros C. Abolished circadian rhythm of melatonin secretion in sedated and artificially ventilated intensive care patients. Acta Anaesthesiol Scand 2004; 48: 679-684.

Helton MC, Gordon SH, Nunnery SL. The correlation between sleep deprivation and the intensive care unit syndrome. Heart Lung 1980; 9: 464-468.

Whittington MA, Lambert JD, Little HJ. Increased nmda receptor and calcium channel activity underlying ethanol withdrawal hyperexcitability. Alcohol Alcohol 1995; 30: 105-114.

Johns MW, Large AA, Masterton JP, Dudley HA. Sleep and delirium after open heart surgery. Br J Surg 1974; 61: 377-381.

Mundigler G, Delle-Karth G, Koreny M, Zehetgruber M, Steindl-Munda P, Marktl W, et al. Impaired circadian rhythm of melatonin secretion in sedated critically ill patients with severe sepsis. Crit Care Med 2002; 30: 536-540.

Bourne RS, Mills GH, Minelli C. Melatonin therapy to improve nocturnal sleep in critically ill patients: Encouraging results from a small randomised controlled trial. Crit Care 2008; 12: R52.

Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth 2010; 4: 169-173.

De Jonghe A, Van Munster BC, Van Oosten HE, Goslings JC, Kloen P, Van Rees C, et al. The effects of melatonin versus placebo on delirium in hip fracture patients: Study protocol of a randomised, placebo-controlled, double blind trial. BMC Geriatr 2011; 11: 34.

De Jonghe A, Korevaar JC, Van Munster BC, De Rooij SE. Effectiveness of melatonin treatment on circadian rhythm disturbances in dementia. Are there implications for delirium? A systematic review. Int J Geriatr Psychiatry 2010; 25: 1201-1208.

Hanania M, Kitain E. Melatonin for treatment and prevention of postoperative delirium. Anesth Analg 2002; 94: 338-339.

Miyazaki T, Kuwano H, Kato H, Ando H, Kimura H, Inose T, et al. Correlation between serum melatonin circadian rhythm and intensive care unit psychosis after thoracic esophagectomy. Surgery 2003; 133: 662-668.

Matthews CD, Guerin MV, Wang X. Human plasma melatonin and urinary 6-sulphatoxy melatonin: Studies in natural annual photoperiod and in extended darkness. Clin Endocrinol (Oxf) 1991; 35: 21-27.

Balan S, Leibovitz A, Zila SO, Ruth M, Chana W, Yassica B, et al. The relation between the clinical subtypes of delirium and the urinary level of 6-smt. J Neuropsychiatry Clin Neurosci 2003; 15: 363-366.

Bourne RS, Mills GH. Melatonin: Possible implications for the postoperative and critically ill patient. Intensive Care Med 2006; 32: 371-379.

Shigeta H, Yasui A, Nimura Y, Machida N, Kageyama M, Miura M, et al. Postoperative delirium and melatonin levels in elderly patients. Am J Surg 2001; 182: 449-454.

Reiter RJ. Oxidative damage in the central nervous system: Protection by melatonin. Prog Neurobiol 1998; 56: 359-384.

Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336: 186-195.

Verster GC. Melatonin and its agonists, circadian rhythms and psychiatry. Afr J Psychiatry (Johannesbg) 2009; 12: 42-46.

Walker MP, Stickgold R. Sleep, memory and plasticity. Neuroscience and Psychoanalysis 2014; 1.

Cervantes M, Moralí G, Letechipía‐Vallejo G. Melatonin and ischemia–reperfusion injury of the brain. Journal of pineal research 2008 ; 45: 1-7.

Sun FY, Lin X, Mao LZ, Ge WH, Zhang LM, Huang YL, et al. Neuroprotection by melatonin against ischemic neuronal injury associated with modulation of DNA damage and repair in the rat following a transient cerebral ischemia. J Pineal Res 2002; 33: 48-56.

Gerlach AT, Dasta JF. Dexmedetomidine: An updated review. Ann Pharmacother 2007; 41: 245-252.

Maze M, Bonnet F. Analgesics: receptor ligands—2 adrenergic receptor agonist. Anesthetic Pharmacology: Physiologic Principles and Clinical Practice Philadelphia, PA: Churchill Livingstone. 2004: 473-90.

Nishina K, Akamatsu H, Mikawa K, Shiga M, Maekawa N, Obara H, et al. The inhibitory effects of thiopental, midazolam, and ketamine on human neutrophil functions. Anesth Analg 1998; 86: 159-165.

Nelson LE, Lu J, Guo T, Saper CB, Franks NP, Maze M. The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects. Anesthesiology 2003; 98: 428-436.

Huupponen E, Maksimow A, Lapinlampi P, Sarkela M, Saastamoinen A, Snapir A, et al. Electroencephalogram spindle activity during dexmedetomidine sedation and physiological sleep. Acta Anaesthesiol Scand 2008; 52: 289-294.

Maldonado JR, van der StarrePJ, Wysong A. Post-operative sedation and the incidence of ICU delirium in cardiac surgery patients. Anesthesiology. 2003;99:A465.

Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. Jama 2009; 301: 489-499.

Pandharipande P, Girard T, Sanders R, Thompson J, Maze M, Ely E. Comparison of sedation with dexmedetomidine versus lorazepam in septic ICU patients. Critical Care. 2008;12(S2):P275.

Jakob SM, Ruokonen E, Grounds RM, Sarapohja T, Garratt C, Pocock SJ, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: Two randomized controlled trials. Jama 2012; 307: 1151-1160.

Bharati S, Pal A, Biswas C, Biswas R. Incidence of cardiac arrest increases with the indiscriminate use of dexmedetomidine: A case series and review of published case reports. Acta Anaesthesiol Taiwan 2011; 49: 165-167.

Gerlach AT, Murphy CV. Dexmedetomidine-associated bradycardia progressing to pulseless electrical activity: Case report and review of the literature. Pharmacotherapy 2009; 29: 1492.

Reade MC, O'sullivan K, Bates S, Goldsmith D, Ainslie WR, Bellomo R. Dexmedetomidine vs. Haloperidol in delirious, agitated, intubated patients: A randomised open-label trial. Crit Care 2009; 13: R75.

Muzyk AJ, Fowler JA, Norwood DK, Chilipko A. Role of alpha2-agonists in the treatment of acute alcohol withdrawal. Ann Pharmacother 2011; 45: 649-657.

Rayner SG, Weinert CR, Peng H, Jepsen S, Broccard AF. Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the icu. Ann Intensive Care 2012; 2: 12.

Favre JB, Gardaz JP, Ravussin P. Effect of clonidine on icp and on the hemodynamic responses to nociceptive stimuli in patients with brain tumors. J Neurosurg Anesthesiol 1995; 7: 159-167.


  • There are currently no refbacks.

Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.