Regular review

Delirium: optimising management

BMJ 2001; 322 doi: http://dx.doi.org/10.1136/bmj.322.7279.144 (Published 20 January 2001)
Cite this as: BMJ 2001;322:144

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2 February 2001

The recent review by Meagher (1) on delirium and its management focuses many interesting points about the diagnosis and treatment of this clinical entity. Surprisingly, however, there is no account to nonconvulsive status epilepticus (NCSE) as a possible cause of altered mental status. NCSE, which was first reported about 25 years ago, accounts for as many as one quarter of all cases of status epilepticus and may occur "de novo" in middle aged or elderly patients with no previous history of epilepsy. Most cases present with alteration of conscious level, and it may therefore mimic delirium. Since NCSE can be identified only by EEG (2,3) many patients are unrecognised and mistaken for behavioral or psychiatric disturbance, which leads to a delay in diagnosis and management. However, prompt commencement of anticonvulsant therapy is necessary, since prolonged NCSE may have a poor outcome (4).

All these arguments underscore the importance of considering NCSE in the differential diagnosis of delirium. Another issue raised by the review involves the role of EEG, as it results from the table on differential diagnosis. Specifically, the Author indicates an identical EEG pattern in both delirium and dementia, represented by abnormalities in 80-90%, and generalised diffuse slowing in 80% of cases. We feel however that the relevance of EEG in delirium and dementia is quite different. EEG changes virtually always accompany delirium, and abnormalities increase with clinical deterioration (5). EEG findings in dementia, on the contrary, are highly dependent on timing. The EEG is initially normal or shows an alpha rhythm just below the lower limits of normal subjects, and generalized slowing appears as the disease progresses. In patients with focal cognitive deficits, there may be accentuation of slow frequency activity over the corresponding brain area. Serial quantitative EEG studies indicate a high correlation between degree of dementia and theta activity, relative power in delta and index of EEG slowing (6).

Despite these data, EEG affects the diagnosis or the treatment only in a minority of patients with dementia (7), while EEG should be performed in all patients with unexplained delirium, particularly in view of the possible occurrence of a NCSE.

References

1. Meagher DJ. Delirium: optimising management. BMJ 2001; 322.144-9

2. Kaplan PW. Nonconvulsive status epilepticus in emergency room. Epilepsia 1996; 37: 643-50.

3. Kaplan PW. Assessing the outcomes in patients with nonconvulsive status epilepticus: nonconvulsive status epilepticus is underdiagnosed, potentially overtreated, and confounded by comorbidity. J Clin Neurophysiol 1999;16:341-52.

4. Young GB, Jordan KG. Do nonconvulsive seizures damage the brain?Yes. Arch Neurol 1998; 55:117-9.

5. Binnie CD, Prior FP.Electroencephalography. J Neurol Neurosurg Psychiatry 1994; 57: 1308-19.

6. Jacobson SA, Leuchter AF, Walter DO. Conventional and quantitative EEG in the diagnosis of delirium among the elderly. J Neurol Neurosurg Psychiatry 1993; 56: 153-8.

7. van Crevel H, van Gool WA, Walstra GJ. Early diagnosis of dementia: which tests are indicated? What are their costs? J Neurol 1999; 246: 73-8.

Competing interests: None declared

Leonardo Cocito, *Associate Professor, **Research Fellow, ***Associate Professor

Daniela Audenino, Alberto Primavera

Department of Neurological Sciences and Vision, University of Genova, Italy

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2 February 2001

Dear Sir

RE: Drug Treatment of Delirium

I was astonished to read that Meagher was recommending high doses (up to 100 mg in 24 hrs), of intravenous haloperidol for severe delirium (1). Although it is sometimes alleged that haloperidol causes less extrapyramidal side effects than oral administration, there is no credable pharmacological rationale for such a view. Similar claims were made for high doses of oral antipsychotics 30 years ago (2) but the alleged "break through" phenomenon was later found to be due to the masking of extrapyramidal symptoms by akinesia (3). Indeed, in a healthy volunteer study recently completed in this department, we found that 75% of those receiving 1 mg of haloperidol intravenously experienced mild to moderate dysphoria/akathisia after 3 hours which persisted to 5 hours (4).

It is also remarkable that this clinical review does not refer to the work of McKeith et al (5) which has reported severe and often fatal neuroleptic sensitivity in elderly patients with Lewy body dementia. It is even more surprising that droperidol is being recommended in such patients, particularly since it is shortly due to be withdrawn because of increasing recognition of its potential cardiotoxicity associated with prolonged QT intervals (6).

Recommendations based on best practice will probably vary from centre to centre but we would probably recommend low doses of haloperidol (2 to 10 mg) intramuscularly or intravenously or risperidone (0.5 to 1 mg) augmented with very low doses of lorazepam (0.5 to 2 mg) intramuscularly. Diazepam (2 to 20 mg) intravenously (preferably as Diazemuls emulsion which is substantially less irritant) 4 hourly may be sufficient.

The management of agitated delirious patients is fraught with difficulties, particularly in elderly patients, but it will not be helped by the publication of dangerous advice in such a prestigious journal.

Yours sincerely

DJ KING, MD, FRCPsych, FRCP(I), DPM
Professor of Clinical Psychopharmacology
E-mail: d.king@qub.ac.uk

References

1. Meagher, D J, Delirium: Optimising Management. BMJ 2001; 322: 144 -149 (20 January).

2. Rifkin, A., Quitkin, F., Carrillo, C., Klein, DF., and Oaks, G. Very high fluphenazine for nonchromic treatment-refractory patients. Archives of General Psychiatry, 1971; 25: 398-403.

3. Quitkin, F., Rifkin, A., and Klein, DF. Very high dosage vs standard dosage fluphenazine in schizophrenia. A double-blind study of nonchromic treatment- refractory patients. Archives of General Psychiatry, 1975; 32: 1276- 1281

4. McCartan, D., King, D J., Bell, R., Green, J F., Campbell, C., Trimble, K., Pickering, A. The differential effects of chlorpromazine and haloperidol on latent inhibition in healthy volunteers. Journal of Psychopharmacology (in press).

5. McKeith, I., Fairburn, A., Perry, R., Thompson, P., Perry, E. Neuroleptic sensitivity in patients with senile dementia of Lewy body type. BMJ 1992; 305: 673-678.

6. Pharmaceutical Journal, 2001; 266: 73

Competing interests: None declared

David J King, Professor of Clinical Psychopharmacology

Department of Therapeutics and Pharmacology, Queen's University of Belfast

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In reviewing the management of delirium, Meagher confidently asserts that antipsychotics are effective in delirium.1 Unfortunately there is very little evidence to support this assertion.

There are no placebo-controlled trials of antipsychotics in delirium. One trial compared antipsychotics to benzodiazepines and found that antipsychotics were superior, but given that it is widely acknowledged that benzodiazepines may worsen delirium, this result hardly constitutes evidence of efficacy.2 Most clinicians have gained the impression that antipsychotics speed recovery in delirium, but their anecdotal observations must be doubted. Most episodes of delirium last only several days and will improve with resolution of the patient's underlying medical condition. In practice medical management is always instituted simultaneously with antipsychotic prescription. As a consequence, it would be very difficult for clinicians to isolate the relative effect of an antipsychotic on the resolution of delirium. Uncontrolled trials suggesting efficacy will present the same problems.

Delirium often manifests with hallucinations, delusions or thought disorder. In other psychiatric disorders, such as schizophrenia, these symptoms are improved by antipsychotics, so it reasonable to postulate that antipsychotics may also help in delirium. However this hypothesis may be invalid: treatments for asthma, will not necessarily help pneumonia, although both illnesses cause shortness of breath.

With so little evidence to support the use of antipsychotics in delirium, management strategies invoking them must be extremely cautious. Worryingly, Meagher proposes a strategy for the management of severe behavioural disturbance in delirium that could quickly lead to doses of haloperidol of up to 100mg per day. Doses this high may be associated with anticholinergic toxicity and akathisia - a sense of inner restlessness - that may worsen agitation, rather than quell it. Such doses also entail an increased risk of torsades de pointes and neuroleptic malignant syndrome.3,4 Moreover, if the analogy with schizophrenia is valid, it is unlikely that patients would benefit from more than 12mg of haloperidol per day.5

Antipsychotics should be avoided, prior to the exhaustion of all non-pharmacological management options. If antipsychotics are to be used, haloperidol is the drug of choice, but doses should not exceed 12mg per day. If pharmacological management of behavioural disturbance is required after this, then benzodiazepines should be used, with the understanding that gaining control of the behavioural disturbance may involve an unavoidable perpetuation of the delirium that is driving disturbance. Obviously, there is an urgent need for placebo controlled trials.

1. Meagher DJ. Delirium: optimising management. BMJ 2001;322:144–9.

2. Breitbart W, Marotta R, Platt MM, Weisman H, Derevenco M, Grau C, et al. A double blind trial of haloperidol, chlorpromazine and lorazepam in the treatment of delirium in hospitalised AIDS patients. Am J Psychiatry 1996;153:231-7.

3. Hunt N, Stern TA. The association between intravenous haloperidol and torsades de pointes. Three cases and a literature review. Psychosomatics 1995;36:541-9

4. Carnoff SN, Mann SC. Neuroleptic malignant syndrome. Medical Clinics of North America 1993;77(1):185-201.

5. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. Washington, DC: American Psychiatric Association, 1997.

Competing interests: None declared

Christopher James Ryan, Consultation-Liaison Psychiatrist

Westmead Hospital, Sydney, Australia

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Sir,

Junaid and Junaid, in their comments on the review of delirium management (1), point out recent developments regarding droperidol use. News of the apparent demise of droperidol has not yet filtered through to New Zealand where the author is currently on sabbatical. Hopefully, this should not detract from the usefulness of the article since haloperidol is the principal therapeuric agent discussed.

The comments also draw attention to some of the potential risks of haloperidol use. Due to the inactivity that has characterised the field of delirium, drug treatment of delirious patients typically involves non- licensed use of psychotropics. The article provides guidance on routine management but also addresses the difficult area of management options in the small, but clinically compelling, number of patients that do not respond to ordinary measures. The article highlights non-pharmacological approaches to treatment and advocates low-dose haloperidol as appropriate treatment for the vast majority of cases.

There is a paucity of information regarding the management of severely behaviourally disturbed patients with delirium that do not respond to routine measures. An algorithm is presented outlining a stepwise approach to drug doses and monitoring that can be applied in such circumstances. It is expected that all responsible clinicians would carefully consider the relative benefits and risks of high dose haloperidol treatment versus the not inconsiderable risks of uncontrolled disturbance in severely ill delirious patients, which include death. The available literature indicates that very high doses of haloperidol have been used with therapeutic success in such situations. It is hoped that the management of this small number of extremely challenging cases will not be confused with the routine management of patients with delirium.

David Meagher.
Wellington, New Zealand.

(1) Meagher DJ. (2001). Delirium: optimising management. BMJ 322:144- 9.

Competing interests: None declared

David Meagher, Consultant Psychiatrist

Wellington, New Zealand

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25 January 2001

Dear Editor,

In Meagher's(1) otherwise-comprehensive review of delirium, he omits to mention two other useful diagnostic tools that may clarify the situation.

He correctly points out that making the distinction from depression is especially important to avoid the introduction of yet more medication to an unstable situation.Clock drawings may well be abnormal in delirium(2).

Writing disturbances too have been found to be present in delirium(3). Both of these tests are highly sensitive,easily-administered at the bedside and extremely cheap. In cases where the situation is less clear obtaining an EEG may be helpful since generalized slowing may be typically found in a delirium caused by a toxic-metabolic abnormality(2).

References:

1) Regular Review: Delirium:opitimising management, D Meagher, BMJ 2001;322:144-149

2)Consultation Psychiatry 2nd Ed, Rundell and Wise,1994, pp33-4 American Psychiatric Press

3)Writing disturbances in acute confusional states; Chedru F and Geschwind N Neuropsychologia 10:343-353, 1972

Competing interests: None declared

Richard A Rosin, Consultant Geriatric Psychiatrist

Highline Community Hospital, Seattle, WA, USA

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To The Editor:

In his otherwise comprehensive review, Meagher (1) failed to point out benzodiazepine withdrawal as a risk factor of delirium. Of course, he correctly stated that most drugs including benzodiazepine can cause delirium, whereas benzodiazepine can be also useful for delirium that is associated with seizures or withdrawal from alcohol or sedatives (1). So, he said that benzodiazepine can both protect against delirium and be a risk factor for it (1). None the less, he should have mentioned a possibility of benzodiazepine withdrawal symptoms including delirium after abrupt discontinuation of benzodiazepine because these symptoms can be prevented if benzodiazepine is decreased gradually.

However, he recommended reducing doses or stop administration of high risk compounds especially during high risk periods, such as the perioperative period. If benzodiazepine is discontinued abruptly just before operation, there is a possibility that delirium as a benzodiazepine withdrawal symptom may occur.

Reference

1. Meagher DJ. Delirium: optimizing management. BMJ 2001;322:144-9.

Competing interests: None declared

Takeshi Terao, Associate Professor

Department of Psychiatry, University of Occupational and Environmental Health, K

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24 January 2001

Dear Sir

Meagher has helpfully summarised the treatment approaches in his clinical review. I think it is essential that clinical reviews are as up to date as possible and avoid any misleading statements. Meagher fails on both counts.

Droperidol has recently been withdrawn by its manufacturers, Janssen - Cilag in recognition of its adverse effect of increasing QT intervals. Droperidol is no longer available for new patients. Furthermore The British National Formulary (september 2000) very clearly states the maximum daily dose of haloperidol orally is up to 30mg and intramuscularly 18mg in 24 hours.

Meaghers advice that "up to 100mg of intravenous haloperidol every 24 hours is generally safe" is clearly wrong and potentially very dangerous.

Ola Junaid and Kehinde Junaid

Nottingham Healthcare NHS Trust

Competing interests: None declared

Ola Junaid, Consultant psychiatrist

Nottingham Healthcare NHS Trust

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There are three issues in Meagher review on the delirium drug treatment (1) which deserves comment.

The first is the side effects of the used medication. The author suggest that haloperidol is the preferred drug when considering pharmacological treatment in a delirious patient. Moreover, intravenous use in unmanageable cases is proposed. He advise that up to 100 mg of intravenous haloperidol every 24 hours is generally safe as is up to 60 mg intravenous haloperidol every 24 hours if benzodiazepines are used concomitantly.

Although haloperidol is usually well tolerated, side effects do occur. Extra-pyramidal reactions take place, independent of high doses and depending of the length of the treatment and on the fluctuations in the serum levels of the drug. If the treatment goes further 24 – 48 hours, the dystonic reactions probability is high and may require anticholinergic treatment, with the consequent toxicity.

More serious and life-threatening, are dose-related, uncommon side effects of haloperidol in the cardiac QT augmentation (2), with possible secondary “torsade de points”. Most sudden deaths that has occurred during haloperidol treatment in particular, and with antipsychotics in general, are the consequence of this type of cardiac arrhythmic events. Clinicians must be aware of this risk when using antipsychotics, specially in patients with cardiac disturbances.

Second, arrhythmic events with the use of the suggested alternative drug may increase. Meagher adheres to the proposal that droperidol is more suitable when a faster onset of action or greater sedation is required. However, the acquired long QT syndrome is more frequent with droperidol than those observed with haloperidol (3). As a matter of fact, the main risk factors for abnormal QT lengthening in psychiatric patients are: age over 65 years, use of tricyclic antidepressants, thioridazine and droperidol (4). Because of delirium co-morbidity, droperidol administration deserves enhanced clinical evaluation especially since the the beginning of the anti-delirium action is almost the same with droperidol and haloperidol.

Third, in the treatment for resistant cases we can consider also the possibility of electroconvulsive treatments (5). This type of management is frequently rejected by the clinician, but it may be a better alternative to prolonged high doses of antipsychotic drugs.

1.- Meagher DJ. Delirium: optimising management. BMJ 2001; 322: 144 – 149

2.- O’Brien JM, Rockwood RP, Suh KI. Haloperidol-induced torsade de points. Ann Pharmacother 1999; 33: 1046 – 1050

3.- Guy JM, Andre-Fouet X, Porte J et al. [Torsade de points and prolongation of the duration of QT interval after injection of droperidol] Annn Cardiol Angeiol 1991; 40: 541 – 545

4.- QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355: 1048 – 1052

6.- Stromgren LS. ECT in acute delirium and related clinical states. Convuls Ther 1997; 13: 10 – 17

Competing interests: None declared

Salvador Vale, Direccion de Posgrado

Facultad de Medicina, Universidad Autónoma de Campeche, México

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