The use of benzodiazepines to treat adults with delirium, excluding patients being cared for in intensive care units (ICU)

Background: Delirium is a serious complication of many illnesses, which occurs most commonly in young children and older adults. It usually presents as a sudden change in a patient's behaviour or mental state. Another name for it is ‘acute confusional state.’ Patients with delirium may not know where they are, what time it is, or what is happening to them. They may have frightening experiences, such as vivid hallucinations. They may become either restless or lethargic and inactive. Delirium can be very distressing for patients and for those who are caring for them. Studies show that about a third of patients on general medical wards develop delirium. It is a frequent complication after surgery (e.g. it happens in up to 60% of people who have surgery for a hip fracture). The effects of delirium can last for a long time. For older people, it can lead to longer hospital stays and it has been associated with increased risks of death, disability, loss of independence, and later dementia. It adds significantly to healthcare costs.

Benzodiazepines are medicines that are often used as sedatives. Sometimes, healthcare workers prescribe them to treat delirium when other strategies have not helped. Currently, it is not clear if benzodiazepines are an effective treatment for patients with delirium or whether they can harm them.

Review question: Patients need more and better treatment options for delirium. We wanted to know if benzodiazepines are a helpful treatment option for delirium in any healthcare setting except ICU (patients in ICU are very sick and they may need different kinds of treatment). To find the best answer, we looked for studies where the investigators compared any benzodiazepine to another medicine, or to a dummy medicine that does not contain any active ingredients (placebo). To make the comparison fair, patients in the studies must all have had the same random chance (like the flip of a coin) to receive the benzodiazepine or the other treatment.

Search date: We searched the medical literature up to 10 April 2019.

Study characteristics: We found only two small studies which were suitable to include in our review. In one study, the 58 patients who took part all had advanced cancer. They were treated in a specialist palliative care unit. The study compared lorazepam (a benzodiazepine) to placebo. In the second study, the 30 patients all had AIDS (acquired immune deficiency syndrome). They were treated in general medical wards. This study compared lorazepam to two different drugs that are sometimes used to treat delirium.

Key results: We did not find any important benefits for patients who took lorazepam instead of the other treatment in these two studies. Patients who took it did not have better outcomes. We do not have any definite evidence that lorazepam was more harmful than the other treatment, but, in the study of patients with AIDS, the researchers stopped treating people with lorazepam after the first six people who took it all had serious side effects. Because there were only two suitable studies and both had small numbers of patients in them, we cannot draw any firm conclusions. Currently, there is no good evidence to tell us whether or not benzodiazepines should be used to treat patients with delirium. Clinicians, patients, and carers should be aware of the lack of evidence. We think there is a need for more research, and particularly for studies that involve older patients in general medical and surgical settings, where most delirium is treated.

Authors' conclusions: 

There is no enough evidence to determine whether benzodiazepines are effective when used to treat patients with delirium who are cared for in non-ICU settings. The available evidence does not support their routine use for this indication. Because of the scarcity of data from randomised controlled trials, further research is required to determine whether or not there is a role for benzodiazepines in the treatment of delirium in non-ICU settings.

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Background: 

Delirium is a very common condition associated with significant morbidity, mortality, and costs. Current critical care guidelines recommend first and foremost the use of nonpharmacological strategies in both the prevention and treatment of delirium. Pharmacological interventions may augment these approaches and they are currently used widely in clinical practice to manage the symptoms of delirium. Benzodiazepines are currently used in clinical practice to treat behavioural disturbances associated with delirium but current guidelines do not recommend their use for this indication. The use of these medicines is controversial because there is uncertainty about whether they are effective for patients or have the potential to harm them.

Objectives: 

To assess the effectiveness and safety of benzodiazepines in the treatment of delirium (excluding delirium related to withdrawal from alcohol or benzodiazepines) in any healthcare settings other than intensive care units (ICU).

Search strategy: 

We searched ALOIS: the Cochrane Dementia and Cognitive Improvement Group's Specialized Register up to 10 April 2019. ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (including MEDLINE, Embase, PsycINFO, CINAHL, LILACS), numerous trial registries (including national, international and pharmaceutical registries), and grey literature sources.

Selection criteria: 

We included randomised controlled trials (RCTs) conducted in healthcare settings that ranged from nursing homes and long-term care facilities to any hospital setting except for ICUs, involving adult patients with delirium excluding those with delirium related to alcohol or benzodiazepine withdrawal. Included RCTs had to assess the effect of benzodiazepines, at any dose and given by any route, compared with placebo or another drug intended to treat delirium.

Data collection and analysis: 

Two review authors independently assessed study eligibility, extracted data, and assessed the risk of bias of included studies. We decided whether or not to pool data on the basis of clinical heterogeneity between studies. We used GRADE (Grades of Recommendation, Assessment, Development and Evaluation) methods to assess the quality of evidence.

Main results: 

We identified only two trials that satisfied the selection criteria. We did not pool the data because of the substantial clinical differences between the trials.

In one trial, participants (n = 58) were patients in an acute palliative care unit with advanced cancer who had a mean age of 64 years. All of the participants had delirium, were treated with haloperidol, and were randomised to receive either lorazepam or placebo in combination with it. Due to very serious imprecision, all evidence was of low certainty. We were unable to determine whether there were clinically important differences in the severity of delirium (mean difference (MD) 2.10, 95% CI -0.96 to 5.16; n = 50), length of hospital admission (MD 0.00, 95% CI -3.45 to 3.45; n = 58), mortality from all causes (risk ratio (RR) 0.33, 95% CI 0.04 to 3.02; participants = 58) or any of a number of adverse events. Important effects could not be confirmed or excluded. The study authors did not report the length of the delirium episode.

In the other trial, participants (n = 30) were patients in general medical wards with acquired immune deficiency syndrome (AIDS) who had a mean age of 39.2 years. Investigators compared three drug treatments: all participants had delirium, and were randomised to receive lorazepam, chlorpromazine, or haloperidol. Very low-certainty evidence was identified, and we could not determine whether lorazepam differed from either of the other treatments in the effect on severity of delirium, any adverse event, or mortality from all causes. The study authors did not report the length of the delirium episode or the length of hospital admission.

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