Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: The MIND randomized, placebo-controlled trial*

Objective: To demonstrate the feasibility of a placebo-controlled trial of antipsychotics for delirium in the intensive care unit and to test the hypothesis that antipsychotics would improve days alive without delirium or coma. Design: Randomized, double-blind, placebo-controlled trial. Setting: Six tertiary care medical centers in the US. Patients: One hundred one mechanically ventilated medical and surgical intensive care unit patients. Intervention: Patients were randomly assigned to receive haloperidol or ziprasidone or placebo every 6 hrs for up to 14 days. Twice each day, frequency of study drug administration was adjusted according to delirium status, level of sedation, and side effects. Measurements and Main Outcomes: The primary end point was the number of days patients were alive without delirium or coma. During the 21-day study period, patients in the haloperidol group spent a similar number days alive without delirium or coma (median [interquartile range], 14.0 [6.0–18.0] days) as did patients in the ziprasidone (15.0 [9.1–18.0] days) and placebo groups (12.5 [1.2–17.2] days; p = 0.66). No differences were found in secondary clinical outcomes, including ventilator-free days (p = .25), hospital length of stay (p = .68), and mortality (p = .81). Ten (29%) patients in the haloperidol group reported symptoms consistent with akathisia, compared with six (20%) patients in the ziprasidone group and seven (19%) patients in the placebo group (p = .60), and a global measure of extrapyramidal symptoms was similar between treatment groups (p = .46). Conclusions: A randomized, placebo-controlled trial of antipsychotics for delirium in mechanically ventilated intensive care unit patients is feasible. Treatment with antipsychotics in this limited pilot trial did not improve the number of days alive without delirium or coma, nor did it increase adverse outcomes. Thus, a large trial is needed to determine whether use of antipsychotics for intensive care unit delirium is appropriate. Trial Registration: ClinicalTrials.gov, number NCT00096863.

[1]  Anthony F Jorm.  The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): a review , 2004, International Psychogeriatrics.

[2]  C Michael Stein,et al.  Atypical antipsychotic drugs and the risk of sudden cardiac death. , 2009, The New England journal of medicine.

[3]  G. Bernard,et al.  Delirium and sedation in the intensive care unit: Survey of behaviors and attitudes of 1384 healthcare professionals* , 2009, Critical care medicine.

[4]  R. Dittus,et al.  Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients. , 2008, The Journal of trauma.

[5]  Russell R. Miller,et al.  Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. , 2007, JAMA.

[6]  J. Simpkins,et al.  A prototypical Sigma-1 receptor antagonist protects against brain ischemia , 2007, Brain Research.

[7]  G. Bernard,et al.  Lorazepam Is an Independent Risk Factor for Transitioning to Delirium in Intensive Care Unit Patients , 2006, Anesthesiology.

[8]  P. Eikelenboom,et al.  Haloperidol Prophylaxis for Elderly Hip‐Surgery Patients at Risk for Delirium: A Randomized Placebo‐Controlled Study , 2005, Journal of the American Geriatrics Society.

[9]  M. Kollef,et al.  Delirium as detected by the CAM-ICU predicts restraint use among mechanically ventilated medical patients* , 2005, Critical care medicine.

[10]  Yueh-Fu Fang,et al.  The impact of delirium on the survival of mechanically ventilated patients* , 2004, Critical care medicine.

[11]  Theodore Speroff,et al.  Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. , 2004, JAMA.

[12]  G. Bernard,et al.  Costs associated with delirium in mechanically ventilated patients* , 2004, Critical care medicine.

[13]  S. Gottfried,et al.  Olanzapine vs haloperidol: treating delirium in a critical care setting , 2004, Intensive Care Medicine.

[14]  T. Albertson,et al.  Genomic polymorphisms in sepsis , 2004, Critical care medicine.

[15]  T. Cooper,et al.  Determination of plasma ziprasidone using liquid chromatography with fluorescence detection. , 2004, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[16]  G. Bernard,et al.  Current opinions regarding the importance, diagnosis, and management of delirium in the intensive care unit: A survey of 912 healthcare professionals* , 2004, Critical care medicine.

[17]  Theodore Speroff,et al.  Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). , 2003, JAMA.

[18]  C. Sessler,et al.  The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. , 2002, American journal of respiratory and critical care medicine.

[19]  G. Bernard,et al.  Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome , 2002, Critical care medicine.

[20]  R. Tandon,et al.  Extrapyramidal Side Effects of Antipsychotic Treatment: Scope of Problem and Impact on Outcome , 2002, Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists.

[21]  G. Bernard,et al.  Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). , 2001, JAMA.

[22]  L C Mion,et al.  Nurses' recognition of delirium and its symptoms: comparison of nurse and researcher ratings. , 2001, Archives of internal medicine.

[23]  G. Bernard,et al.  The impact of delirium in the intensive care unit on hospital length of stay , 2001, Intensive Care Medicine.

[24]  Y. Skrobik,et al.  Delirium in an intensive care unit: a study of risk factors , 2001, Intensive Care Medicine.

[25]  Theodore Speroff,et al.  Evaluation of delirium in critically ill patients: Validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) , 2001, Critical care medicine.

[26]  D. Moher,et al.  The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. , 2001, Journal of the American Podiatric Medical Association.

[27]  F. Hustey,et al.  The prevalence and documentation of impaired mental status in elderly emergency department patients. , 2000, Annals of emergency medicine.

[28]  P. Sanders,et al.  Cardiovascular Adverse Effects of Antipsychotic Drugs , 2000, Drug safety.

[29]  E. Bosmans,et al.  Immunosuppressive effects of clozapine and haloperidol: enhanced production of the interleukin-1 receptor antagonist , 2000, Schizophrenia Research.

[30]  Trzepacz Pt.  Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. , 2000 .

[31]  T R Holford,et al.  A multicomponent intervention to prevent delirium in hospitalized older patients. , 1999, The New England journal of medicine.

[32]  H. Sackeim,et al.  A randomized, placebo-controlled dose-comparison trial of haloperidol for psychosis and disruptive behaviors in Alzheimer's disease. , 1998, The American journal of psychiatry.

[33]  J. Tisdale,et al.  Torsades de Pointes associated with intravenous haloperidol in critically ill patients. , 1998, The American journal of cardiology.

[34]  Ross Ihaka,et al.  Gentleman R: R: A language for data analysis and graphics , 1996 .

[35]  Anne W. Schmidt,et al.  Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. , 1995, The Journal of pharmacology and experimental therapeutics.

[36]  Anthony F Jorm,et al.  The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): socio-demographic correlates, reliability, validity and some norms , 1989, Psychological Medicine.

[37]  H. Meltzer,et al.  Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. , 1989, The Journal of pharmacology and experimental therapeutics.

[38]  F. Mastaglia,et al.  Neuroleptic malignant syndrome , 1984, The Medical journal of Australia.

[39]  G. Simpson,et al.  A RATING SCALE FOR EXTRAPYRAMIDAL SIDE EFFECTS , 1970, Acta psychiatrica Scandinavica. Supplementum.

[40]  M. Roizen.  Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients: A Randomized Trial , 2010 .

[41]  S. Gottfried,et al.  Incidence, risk factors and consequences of ICU delirium , 2006, Intensive Care Medicine.

[42]  Y. Hui.  A prospective random control study:comparison of olanzapine and haloperidol in senile delirium , 2004 .

[43]  Philip D Lumb,et al.  Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. , 2002, Critical care medicine.

[44]  P. Trzepacz.  Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. , 2000, Seminars in clinical neuropsychiatry.

[45]  K Y Liang,et al.  An overview of methods for the analysis of longitudinal data. , 1992, Statistics in medicine.