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http://www.bestbets.org/cgi-bin/bets.pl?record=00060 Is haloperidol or a benzodiazepine the safest treatment for acute psychosis in the critically ill patient? Norman Khasati and Jacqueline Thompson - Report by: Search checked by: Joel Dunning - RCS Research Fellow Institution: Department of Cardiac Surgery, Wythenshawe Hospital Date submitted: 18th February 2004 Date completed: 1st June 2004 Last modified: 1st June 2004 Status: Green (complete) Three part question In [patients in a high dependency setting] is [haloperidol or benzodiazepines] the safest treatment in [treating acute psychosis]? Clinical scenario Its 1am and you are the registrar on call. You are asked to see a 70 year old lady 3 days post aortic valve replacement. She is confused and agitated and is trying to pull out her central line. She has already removed her arterial line and is on the side of the bed demanding to see her husband and wanting to get her clothes to go home. Her pulse is 160 and she is in AF, her BP is 100/55 and her oxygen saturation is 92%. She has no past psychiatric history and the nurses are very keen to see her sedated as it is currently taking 3 people to keep her under control. You want to control her agitation but you are anxious that you may oversedate her or cause cardiac side-effects as a result of additional drug administration. You wonder what is the optimal policy for sedation of this agitated lady. Search strategy Medline 1966-Nov 2003 using the OVID interface [exp haloperidol OR haloperidol.mp OR benzodiazepine.mp OR exp lorazepam OR lorazepam.mp or exp diazepam OR diazepam.mp ] AND [exp Critical Care OR exp Critical Illness/ OR critically ill patient.mp. OR exp Intensive Care Units/ OR coronary care unit.mp OR cardiac surg$ unit.mp OR High dependency.mp] Search outcome 294 papers were found of which 5 papers were clinically relevant. One of these papers summarised several case reports that were also found. In addition 4 more papers were found on checking reference lists. All these papers are presented in the table Relevant paper(s) Author, date and country Patient group Study type (level of evidence) 36 patients attending for endoscopy received intravenous diazepam. Respiratory and cardiopulmonary Rao S et al, function was measured Cohort 1973, using indicator-dilution study (2b) Canada technique with CVP and invasive BP monitoring 18 patients has moderate to severe obstructive lung disease Outcomes Cardiac parameters post diazepam in normal patients (Pts with abnormal lung function had similar or less marked findings) Respiratory parameters after diazepam Key results Study weaknesses Heart rate mean inc 13.4%. Blood pressure mean drop 12.5%. Stroke volume mean drop of Non post operative, 31.5% at 15 mins. Cardiac non cardiac patients output mean dec. 14% High doses of pCO2 mean 8% increase. diazepam SaO2 normal pts no change, lung pts mean drop 92%-88% received mean 34mg diazepam 18 patients with normal lung function received mean 58mg Enough diazepam was used to allow endoscopy Mean dose of 100mg per day to control agitation. Patient 1 had 140mg on day 1 then 7.5mg per 4 hours maintenance. Dose of haloperidol Patient 2 had 20mg per 4 Small case series hours and 270mg in one day. Patient 3 had 485mg over 8 hours. Patient 4 had up to 530mg per day No complications reported Complications in these 4 patients Patient suffered a cardiac arrest immediately after haloperidol administration. Single case report Complication A second cardiac arrest Case report occurred 2 hours later (5) Not a patient post immediately after a second cardiac surgery 7.5mg dose of haloperidol Case report of 4 cardiac patients in the Coronary Care Unit requiring high TesarGE et dose Haloperidol for Case al, control of agitation. Series 1985, (5) USA Initial starting dose of 5mg but rapidly increased to single doses of 30-75mg Case report of a single patient on an intensive Huyse F & care unit for legionella van pnumoniae pneumonia Schijndel receiving haloperidol RS, 1988, 7.5mg of iv haloperidol Holland administered for agitation while weaning Retrospective cohort of 2,000 medically ill patients with cancer Adams F, 1988, Canada Protocol used : 5mg of haloperidol and Cohort 0.5mg of lorazepam study and hydromorphone. (4) 20 mins later if no response 10mg haloperidol and 0.52mg lorazepam. Repeat this at 30 min intervals until agitation controlled Review of the literature and presentation of a protocol for tranquilisation of Agitated ICU patients Protocol : Tesar GE & 0.5-2.0mg mild agitation Stern TA, Review 5.0-10mg moderate 1988, (5) agitation USA 10mg or more severe agitation Allow 20 mins before repeat dose If agitation persists double dose and repeat Development of practise parameters on Shapiro AJ behalf of the American Systematic et al, College of Critical Care Review 1995, Medicine (3a) USA Task force of 40 experts from the society Outcome Patient discharged home Protocol has been safely Clinical experience in used in 2 cancer centers 2000 patients for 8 years No clinical data or follow up data given about these 2000 patients No demographics or patient selection given Safety seems to be decided according to authors clinical memory Not cardiac patients Onset of action 10-30mins but is very safe. Haloperidol use and Haloperidol produces complications trivial effects on haemodynamic function Additional use of lorazepam Lorazepam has fewer cardiovascular complications than other benzodiazepines. In severe agitation lorazepam 2-10mg may also be given Presented as level 1 evidence. Usual dose 510mg. Onset of action 3060 min after IV administration Benzodiazepines not Stated that recommended for benzodiazepines may acute delirium cause a paradoxical Haloperidol is the preferred treatment for delirium in the critically ill patient Review is essentially expert opinion rather than systematic review of the literature Not specifically constructed for patients post cardiac surgery Quoted papers in support of recommendations are case series? and convened to construct these guidelines in conjunction with full literature review over the course of 1 year Lorazepam is preferred agent for prolonged treatment of anxiety in the critically ill patient Nondelirious, medically Improvement in hospitalized AIDS delirium score at 24 patients were hours (mean initial prospectively entered score was 20) into the study. Randomization to Breitbart W treatment was Double et al, performed if patient Blind PRCT 1996, subsequently met DSM- (2b) USA IIIR criteria for delirium Adverse effects Treatment: haloperidol (N = 11), chlorpromazine (N = 13), lorazepam (N = 6). 30 critically ill patients who received intravenous haloperidol for delusional agitation Tisdale JE et al, 6 patients known to get 2001, torsades de pointes USA after haloperidol therapy QT interval in study pts Casecontrol study (3b) QT interval in control pts Odds of developing torsades 24 control patients Review of papers Dose required to documenting torsades Hassaballa cause torsades de de pointes after iv HA & Balk Review of pointes haloperidol RA, case series 2003, (5) Outcome of torsades 19 individual cases of USA de pointed in these torsades de pointes patients found in the literature worsening of symptoms. reviews and not well No mention made of conducted clinical trials, cardiovascular effects calling level of Presented as level 2 recommendation into evidence. Lorazepam question causes less hypotension than other benzodiazepines Haloperidol: 8 point improvement, Not post operative or chlorpromazine:8 point cardiac surgical improvement, lorazepam: patients 1.5 point improvement. p<0.001 neuroleptics vs 5 patients died within 8 lorazepam days of initiation of Extra-pyramidal side treatment effects were low with haloperidol and Low doses of all drugs chlorpromazine, but ALL used, haloperidol mean patients with lorazepam 2.8mg, chlorpromazime had treatment limiting side 50.0mg, Lorazepam effects including 3.0mg in 1st 24 hours oversedation, disinhibition, ataxia, and increased Small numbers confusion, causing study to be stopped early Prior to haloperidol 501 +/44 ms. After haloperidol 606 +/- 61 ms vs. p = Note a 3 page erratum 0.007 section appears in a Prior to haloperidol 466 +/- subsequent issue of J 44ms. After haloperidol Clin Pharmacol, with 507 +/- 60 ms vs. p = 0.01 several significant changes, compared to 12 fold increased risk in the original article those with QT interval > 521 msec Mean dose 507mg. Lowest Selected collection of dose single dose of 10mg. individual cases from Highest dose 1,000mg in the literature 30 mins None of these patients died as a result of the episode Search strategy for finding papers not given Comment(s) The American College of Critical Care Medicine has provided the highest quality review in this area. They conclude that the first line drug for acute agitation in the critical care environment is haloperidol and that cardiovascular side effects are rare. In addition they state that benzodiazepines may in fact exacerbate symptoms, although lorazepam is a safer second line drug than other benzodiazepines such as diazepam. However this guideline is mainly based on expert consensus in conjunction with case reports. Rao et al demonstrate the unacceptable cardiovascular side-effects with diazepam with an average 14% drop in cardiac output. Breitbart et al in a well conducted randomized controlled trial compared lorazepam and haloperidol in medically unwell AIDS patients. They found that haloperidol produced significantly better resolution of delirium and lorazepam invariably produced treatment limiting side-effects including increased confusion , disinhibition and ataxia. We could find no other papers that documented a poorer performance of lorazepam compared to haloperidol either in terms of side effects or resolution of delirium, and in fact Adams et al described the safe use of a combined policy of both drugs given together. This utilises the fact that the onset of action for lorazepam is faster and allows a lower dose of haloperidol to be used. Tesar et al reported the safe use of haloperidol in doses of 100mg per day or more in agitated patients post cardiac surgery and presents a protocol for its safe use, but the complication of Torsades de pointes is well documented. Hassaballa reported 19 cases of Torsades after haloperidol and Huyse reported a case of cardiac arrest after 7.5mg of haloperidol. Tisdale performed an interesting study that demonstrated that haloperidol always causes a prolonged QT interval and advocates cardiac monitoring and extra caution with a QT interval over 521 msec. Clinical bottom line Haloperidol should be considered the first line drug for agitated patients post cardiac surgery, however lorazepam either alone or in conjunction with haloperidol is an acceptable alternative. References 1. Rao S, Sherbaniuk RW, Prasad K, Lee SJ, Sproule BJ. Cardiopulmonary effects of diazepam. Clin Pharmacol Ther 1973;14(2):182-189. 2. Tesar GE, Murray GB, Cassem NH. Use of high-dose intravenous haloperidol in the treatment of agitated cardiac patients. J Clin Psychopharmacol 1985;5(6):344-347. 3. Huyse F, van Schijndel RS. Haloperidol and cardiac arrest. Lancet 1988;2(8610):568-569. 4. Adams F. Emergency intravenous sedation of the delirious, medically ill patient. J Clin Psychiat 1988;49:(12 SUPPL. DEC);p 22-27. 5. Tesar GE, Stern TA. Rapid Tranquilization of the Agitated Intensive Care Unit Patient. J Intensive Care Med 1988;3(4):195-201. 6. Shapiro BA, Warren J, Egol AB et al. Practice parameters for intravenous analgesia and sedation for adult patients in the intensive care unit: an executive summary. Society of Critical Care Medicine.[comment]. Crit Care Med 1995;23(9):1596-1600. 7. Breitbart W, Marotta R, Platt MM,et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiat 1996;153(2):231-237. 8. Tisdale JE, Rasty S, Padhi ID, et al. 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(12):1310-1318. 9. Hassaballa HA, Balk RA. Torsade de pointes associated with the administration of intravenous haloperidol. Am J Ther 2003;10(1):58-60.