This Cochrane Systematic Review by Burry and others was published online during September 2019.
We reviewed the evidence from randomized controlled trials for the benefits and safety of all prescription medicines used to treat critically ill adult patients with delirium in the intensive care units (ICUs) of hospitals.
Delirium is commonly associated with surgery, infection, or critical illness. It is experienced as new‐onset, generally short‐term inability to think clearly. Patients with delirium shift between periods of clear thinking and periods of agitation and/or great sleepiness and confusion. Lack of sleep, pain, a noisy environment, physical restraint, and the use of sedatives and strong analgesics are some of the contributing factors. Delirium affects both immediate and longer‐term health outcomes of critically ill patients as it can increase the length of time a breathing machine is required, time spent in the ICU and in hospital, and the chance of functional weakening and death. The odds of a poor outcome with delirium are increased with frail patients and those of advanced age and already present cognitive difficulties. Frequently, delirious ICU patients are given medicines to help treat symptoms such as agitation.
This review is current to 21 March 2019. We found 14 randomized controlled studies that enrolled a total of 1844 adult participants. Six different classes of medicines were tested. These were antipsychotic drugs used as tranquillizers in ten studies; the sedative alpha2 agonist dexmedetomidine in three studies; statins that reduce cholesterol in two studies; opioids as part of pain management in one study; serotonin antagonists for nausea and vomiting in one study; and cholinesterase inhibitors, which are medicines for Alzheimer’s disease, in one study. Ten studies compared medicine to placebo ‐ an inactive medicine also known as a sugar pill; four studies compared different drugs. Eleven studies with 1153 participants reported on the main outcome of this review ‐ duration of delirium.
When drug classes were directly compared with placebo, only the alpha2 agonist dexmedetomidine was found to reduce the duration of delirium, and the cholinesterase inhibitor rivastigmine was found to prolong the duration of delirium. Each of these results is based on findings from a single small study. The other drugs when compared to placebo did not change delirium duration. The Review authors used the statistical method of network meta‐analysis to compare the six different drug classes. Dexmedetomidine was ranked most effective in reducing delirium duration, followed by atypical antipsychotics. However, network meta‐analysis of delirium duration failed to rule out the possibility of no difference for all six drug classes compared to placebo. Using this method, we did not find that any drug improved the duration of coma, length of stay, long‐term cognitive outcomes, or death. The alpha2 agonist dexmedetomidine shortened time spent on a breathing machine. Adverse events often were not reported in these trials or were rare when reported. An analysis of reported events showed that events were similar to those reported with placebo. We found 10 ongoing studies and six studies awaiting classification that, once published and assessed, may change the conclusions of this review.
Quality of the evidence:
Most of the included studies were small but of good design. Nine of the 14 studies were considered to have low risk of bias.
Implications for practice:
In clinical practice, pharmacological interventions are commonly administered to critically ill patients to manage their symptoms of delirium (Burry 2017). We found evidence that the alpha2 agonist dexmedetomidine may have some role in shortening delirium duration, although this small effect was seen in pairwise analyses based on a single small study compared with placebo, and was not seen in the NMA results. No other pharmacological intervention including antipsychotics, the most commonly prescribed drug for delirium treatment, had any effect on delirium duration nor on any of our a priori selected secondary outcomes. It is also important to note that the cholinesterase inhibitor rivastigmine was associated with harm, and as such, guidelines suggest against its use for treatment of ICU delirium. The 10 ongoing studies and the six studies awaiting classification, once published and assessed, may alter the conclusions of this review; therefore, their results are much anticipated. The frequency of prescribing these drug classes for critically ill adults with delirium and the non‐significant findings of our review should be considered at the bedside and should be incorporated into future pain, agitation, and delirium guidelines.
Implications for research:
We identified 10 ongoing studies, of which seven have a large target enrolment number (100 to 1000 participants), suggesting growing interest in the treatment of ICU delirium. These RCTs should strengthen our results and may potentially alter the direction of our findings. For example, five ongoing trials are examining antipsychotics and three are examining the alpha2 agonist dexmedetomidine ‐ the drug classes found most promising in our analysis ‐ each trial with large target enrolment.
We note the promise of many new treatment trials on the horizon; however, we must acknowledge the need to standardize outcome reporting in ICU delirium trials to permit maximum pooling and interpretation of results. We found far greater variability in the definitions of study outcomes used than we had anticipated, which led us to modify our primary outcome and to limit pooling for some outcomes (e.g. mortality). We found no reporting on some clinically important outcomes such as symptom management (e.g. treating agitation, stopping treatment interferences) and long‐term cognitive outcomes, and we found new outcomes not listed in our protocol (e.g. number of days in coma) in multiple new RCTs and ongoing trials. The Del‐COrS (“Developmnt of core outcome sets for effectiveness trial of interventions to prevent and/or treat delirium”) Group is leading the development of international consensus on outcomes for trials of intervention to prevent and treat delirium in multiple patient populations (Rose 2017). Findings from this group should be used to guide future ICU delirium trials.
We also found that RCTs in this review rarely reported on the use of non‐pharmacological strategies. Among the trials that we identified, all but one showed poor utilization of non‐pharmacological strategies. For example, early mobilization has been shown to reduce the duration of delirium (Barr 2013), and its use in practice is encouraged. Therefore, future trials should clearly describe the use of such strategies in their methods and should report compliance in their results. We also found poor reporting on the use of physical restraints ‐ a non‐pharmacological intervention associated with delirium and prolonged duration of delirium (Rose 2016).
The full details of this Cochrane Systematic Review are available via this link.