Drug therapy for delirium in terminally ill adults

Background

Delirium is common in people with a terminal illness. A person experiencing delirium may be confused, lack concentration, have disturbed patterns of sleep and waking, and experience hallucinations. Delirium can start suddenly and can cause distress to both the person and their family. Delirium may be caused by the underlying disease with which the person is affected, or as a side effect of drugs or other symptoms. Often it is not clear why a person has delirium. The multifaceted nature of delirium makes its management challenging. When it is not possible to identify the underlying cause, drug treatments are sometimes used to manage the symptoms.

Study characteristics

The aim of this review was to find out what we know about the effectiveness and side effects of drugs in the management of delirium in adults with a terminal illness. For the purpose of this review, terminally ill adults includes anyone with an advanced progressive illness such as advanced cancer, advanced dementia or organ failure, as well as those receiving hospice and end-of-life care. We compared drug therapy with placebo (a substance with no known active effect), usual care, or any other drug or non-drug treatment.

Key results

Our search to July 2019 found four trials, involving 399 adults in total. Participants had advanced cancer (three studies) or advanced AIDS (one study), and all had symptoms of delirium. The drugs evaluated were antipsychotics (three studies) or benzodiazepines (one study), compared to placebo or each other, on their own or in combination with another drug or placebo.

Most studies reported the outcomes we deemed most important: delirium symptoms, agitation, and adverse events (side effects).

It was not possible to combine the data from different studies due to a lack of similarity between them. We found low-quality evidence that certain drugs (haloperidol and risperidone) may slightly worsen delirium symptoms for terminally ill adults with mild- to moderate-severity delirium. We found moderate-quality evidence that haloperidol probably slightly increases adverse side effects for people with mild- to moderate-severity delirium.

Quality of the evidence

We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. Very low quality evidence means that we are very uncertain about the results. High-quality evidence means that we are very confident in the results. We found no high-quality evidence. This was due to the small number of people taking part, the number of people dropping out of the studies, and the small number of studies.

Conclusion

We found low-quality evidence that, compared to placebo, drug therapy (specifically haloperidol and risperidone) may slightly worsen delirium symptoms in terminally ill people with delirium of mild to moderate severity. We found low- to moderate-quality evidence that these drugs may slightly increase adverse side effects. Given the small numbers of studies and participants on which current evidence is based, further research is essential.

Authors' conclusions: 

We found no high-quality evidence to support or refute the use of drug therapy for delirium symptoms in terminally ill adults. We found low-quality evidence that risperidone or haloperidol may slightly worsen delirium symptoms of mild to moderate severity for terminally ill people compared with placebo. We found moderate- to low-quality evidence that haloperidol and risperidone may slightly increase extrapyramidal adverse events for people with mild- to moderate-severity delirium. Given the small number of studies and participants on which current evidence is based, further research is essential.

Read the full abstract...
Background: 

Delirium is a syndrome characterised by an acute disturbance of attention and awareness which develops over a short time period and fluctuates in severity over the course of the day. It is commonly experienced during inpatient admission in the terminal phase of illness. It can cause symptoms such as agitation and hallucinations and is distressing for terminally ill people, their families and staff. Delirium may arise from any number of causes and treatment should aim to address these causes. When this is not possible, or treatment is unsuccessful, drug therapy to manage the symptoms may become necessary.

This is the second update of the review first published in 2004.

Objectives: 

To evaluate the effectiveness and safety of drug therapies to manage delirium symptoms in terminally ill adults.

Search strategy: 

We searched CENTRAL, MEDLINE, Embase, CINAHL and PsycINFO from inception to July 2019, reference lists of retrieved papers, and online trial registries.

Selection criteria: 

We included randomised controlled trials of drug therapies in any dose by any route, compared to another drug therapy, a non-pharmacological approach, placebo, standard care or wait-list control, for the management of delirium symptoms in terminally ill adults (18 years or older).

Data collection and analysis: 

We independently screened citations, extracted data and assessed risk of bias. Primary outcomes were delirium symptoms; agitation score; adverse events. Secondary outcomes were: use of rescue medication; cognitive status; survival. We applied the GRADE approach to assess the overall quality of the evidence for each outcome and we include eight 'Summary of findings' tables.

Main results: 

We included four studies (three new to this update), with 399 participants. Most participants had advanced cancer or advanced AIDS, and mild- to moderate-severity delirium. Meta-analysis was not possible because no two studies examined the same comparison. Each study was at high risk of bias for at least one criterion. Most evidence was low to very low quality, downgraded due to very serious study limitations, imprecision or because there were so few data. Most studies reported delirium symptoms; two reported agitation scores; three reported adverse events with data on extrapyramidal effects; and none reported serious adverse events.

1. Haloperidol versus placebo

There may be little to no difference between placebo and haloperidol in delirium symptoms within 24 hours (mean difference (MD) 0.34, 95% confidence interval (CI) −0.07 to 0.75; 133 participants). Haloperidol may slightly worsen delirium symptoms compared with placebo at 48 hours (MD 0.49, 95% CI 0.10 to 0.88; 123 participants with mild- to moderate-severity delirium).

Haloperidol may reduce agitation slightly compared with placebo between 24 and 48 hours (MD −0.14, 95% −0.28 to −0.00; 123 participants with mild- to moderate-severity delirium).

Haloperidol probably increases extrapyramidal adverse effects compared with placebo (MD 0.79, 95% CI 0.17 to 1.41; 123 participants with mild- to moderate-severity delirium).

2. Haloperidol versus risperidone

There may be little to no difference in delirium symptoms with haloperidol compared with risperidone within 24 hours (MD −0.42, 95% CI −0.90 to 0.06; 126 participants) or 48 hours (MD −0.36, 95% CI −0.92 to 0.20; 106 participants with mild- to moderate-severity delirium). Agitation scores and adverse events were not reported for this comparison.

3. Haloperidol versus olanzapine

We are uncertain whether haloperidol reduces delirium symptoms compared with olanzapine within 24 hours (MD 2.36, 95% CI −0.75 to 5.47; 28 participants) or 48 hours (MD 1.90, 95% CI −1.50 to 5.30, 24 participants). Agitation scores and adverse events were not reported for this comparison.

4. Risperidone versus placebo

Risperidone may slightly worsen delirium symptoms compared with placebo within 24 hours (MD 0.76, 95% CI 0.30 to 1.22; 129 participants); and at 48 hours (MD 0.85, 95% CI 0.32 to 1.38; 111 participants with mild- to moderate-severity delirium).

There may be little to no difference in agitation with risperidone compared with placebo between 24 and 48 hours (MD −0.05, 95% CI −0.19 to 0.09; 111 participants with mild- to moderate-severity delirium).

Risperidone may increase extrapyramidal adverse effects compared with placebo (MD 0.73 95% CI 0.09 to 1.37; 111 participants with mild- to moderate-severity delirium).

5. Lorazepam plus haloperidol versus placebo plus haloperidol

We are uncertain whether lorazepam plus haloperidol compared with placebo plus haloperidol improves delirium symptoms within 24 hours (MD 2.10, 95% CI −1.00 to 5.20; 50 participants with moderate to severe delirium), reduces agitation within 24 hours (MD 1.90, 95% CI 0.90 to 2.80; 52 participants), or increases adverse events (RR 0.70, 95% CI −0.19 to 2.63; 31 participants with moderate to severe delirium).

6. Haloperidol versus chlorpromazine

We are uncertain whether haloperidol reduces delirium symptoms compared with chlorpromazine at 48 hours (MD 0.37, 95% CI −4.58 to 5.32; 24 participants). Agitation scores were not reported. We are uncertain whether haloperidol increases adverse events compared with chlorpromazine (MD 0.46, 95% CI −4.22 to 5.14; 24 participants).

7. Haloperidol versus lorazepam

We are uncertain whether haloperidol reduces delirium symptoms compared with lorazepam at 48 hours (MD −4.88, 95% CI −9.70 to 0.06; 17 participants). Agitation scores were not reported. We are uncertain whether haloperidol increases adverse events compared with lorazepam (MD −6.66, 95% CI −14.85 to 1.53; 17 participants).

8. Lorazepam versus chlorpromazine

We are uncertain whether lorazepam reduces delirium symptoms compared with chlorpromazine at 48 hours (MD 5.25, 95% CI 0.38 to 10.12; 19 participants), or increases adverse events (MD 7.12, 95% CI 1.08 to 15.32; 18 participants). Agitation scores were not reported.

Secondary outcomes: use of rescue medication, cognitive impairment, survival

There were insufficient data to draw conclusions or assess GRADE.

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