Delirium is an acutely disturbed state of mind that occurs in critically ill adults in the intensive care unit (ICU). It is associated with a prolonged time on mechanical ventilation to assist breathing, longer stay in the ICU and hospital, and higher risk of death. ICU delirium is also linked with cognitive problems such as loss of memory and attention, difficulty in concentrating and reduced awareness. The risk factors for delirium include old age, alcoholism, vision/hearing impairment and, for critically ill patients, the use of restraints, prolonged pain and some medications.
Our aim was to assess the existing evidence on the effect of interventions for preventing ICU delirium, reducing in-hospital death, reducing length of coma/delirium, the need for mechanical ventilation to assist breathing, the length of stay in the ICU and mental problems
We included 12 randomized controlled trials (3885 participants) in our review. The studies included adults aged 48 to 70 years from surgical and medical ICUs. The studies compared different drugs (three studies) various approaches to sedation (five studies), physical or cognitive therapy or both (one study), noise and light reduction in the ICU (two studies), and preventive nursing care (one study). The studies had mostly small numbers of participants and did not blind the researchers who assessed effects on outcomes. We report the findings regarding the effect of the two most commonly explored approaches for preventing delirium, drug and non-drug interventions, haloperidol versus a sham drug, and early physical and cognitive therapy versus usual care.
Our findings suggest that there may be little or no difference between haloperidol and placebo for preventing ICU delirium, but further studies are needed to reduce imprecision and increase our confidence in the findings. More studies of physical and cognitive therapy are needed as there is insufficient evidence to determine whether these non-pharmacological approaches can prevent delirium in the ICU. Additional research is required to explore the benefits and harms of other approaches to prevent delirium in the ICU such as sedation and changes in the ICU environment, and nursing care tailored to prevent delirium.
Quality of the evidence
We rated the quality of the evidence as moderate to very low. Several studies had quality shortcomings, including their use of small numbers of participants, and lack of blinding of those assessing effects of interventions for preventing delirium and other outcomes. For the interventions testing sedation approaches, physical and cognitive therapy, and changes in the environment, additional research is required to clarify their effectiveness. The five studies in ‘Studies awaiting classification’ and 15 ongoing studies may alter the conclusions of the review once they are completed and assessed.
There is probably little or no difference between haloperidol and placebo for preventing ICU delirium but further studies are needed to increase our confidence in the findings. There is insufficient evidence to determine the effects of physical and cognitive intervention on delirium. The effects of other pharmacological interventions, sedation, environmental, and preventive nursing interventions are unclear and warrant further investigation in large multicentre studies. Five studies are awaiting classification and we identified 15 ongoing studies, evaluating pharmacological interventions, sedation regimens, physical and occupational therapy combined or separately, and environmental interventions, that may alter the conclusions of the review in future.
Delirium is defined as a disturbance in attention, awareness and cognition with reduced ability to direct, focus, sustain and shift attention, and reduced orientation to the environment. Critically ill patients in the intensive care unit (ICU) frequently develop ICU delirium. It can profoundly affect both them and their families because it is associated with increased mortality, longer duration of mechanical ventilation, longer hospital and ICU stay and long-term cognitive impairment. It also results in increased costs for society.
To assess existing evidence for the effect of preventive interventions on ICU delirium, in-hospital mortality, the number of delirium- and coma-free days, ventilator-free days, length of stay in the ICU and cognitive impairment.
We searched CENTRAL, MEDLINE, Embase, BIOSIS, International Web of Science, Latin American Caribbean Health Sciences Literature, CINAHL from 1980 to 11 April 2018 without any language limits. We adapted the MEDLINE search for searching the other databases. Furthermore, we checked references, searched citations and contacted study authors to identify additional studies. We also checked the following trial registries: Current Controlled Trials; ClinicalTrials.gov; and CenterWatch.com (all on 24 April 2018).
We included randomized controlled trials (RCTs) of adult medical or surgical ICU patients receiving any intervention for preventing ICU delirium. The control could be standard ICU care, placebo or both. We assessed the quality of evidence with GRADE.
We checked titles and abstracts to exclude obviously irrelevant studies and obtained full reports on potentially relevant ones. Two review authors independently extracted data. If possible we conducted meta-analyses, otherwise we synthesized data narratively.
The electronic search yielded 8746 records. We included 12 RCTs (3885 participants) comparing usual care with the following interventions: commonly used drugs (four studies); sedation regimens (four studies); physical therapy or cognitive therapy, or both (one study); environmental interventions (two studies); and preventive nursing care (one study). We found 15 ongoing studies and five studies awaiting classification. The participants were 48 to 70 years old; 48% to 74% were male; the mean acute physiology and chronic health evaluation (APACHE II) score was 14 to 28 (range 0 to 71; higher scores correspond to more severe disease and a higher risk of death). With the exception of one study, all participants were mechanically ventilated in medical or surgical ICUs or mixed. The studies were overall at low risk of bias. Six studies were at high risk of detection bias due to lack of blinding of outcome assessors. We report results for the two most commonly explored approaches to delirium prevention: pharmacologic and a non-pharmacologic intervention.
Haloperidol versus placebo (two RCTs, 1580 participants)
The event rate of ICU delirium was measured in one study including 1439 participants. No difference was identified between groups, (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.87 to 1.17) (moderate-quality evidence). Haloperidol versus placebo neither reduced or increased in-hospital mortality, (RR 0.98, 95% CI 0.80 to 1.22; 2 studies; 1580 participants (moderate-quality evidence)); the number of delirium- and coma-free days, (mean difference (MD) -0.60, 95% CI -1.37 to 0.17; 2 studies, 1580 participants (moderate-quality of evidence)); number of ventilator-free days (mean 23.8 (MD -0.30, 95% CI -0.93 to 0.33) 1 study; 1439 participants, (high-quality evidence)); length of ICU stay, (MD 0.18, 95% CI 0.60 to 0.97); 2 studies, 1580 participants; high-quality evidence). None of the studies measured cognitive impairment. In one study there were three serious adverse events in the intervention group and five in the placebo group; in the other there were five serious adverse events and three patients died, one in each group. None of the serious adverse events were judged to be related to interventions received (moderate-quality evidence).
Physical and cognitive therapy interventions (one study, 65 participants)
The study did not measure the event rate of ICU delirium. A physical and cognitive therapy intervention versus standard care neither reduced nor increased in-hospital mortality, (RR 0.94, 95% CI 0.40 to 2.20, I² = 0; 1 study, 65 participants; very low-quality evidence); the number of delirium- and coma-free days, (MD -2.8, 95% CI -10.1 to 4.6, I² = 0; 1 study, 65 participants; very low-quality evidence); the number of ventilator-free days (within the first 28/30 days) was median 27.4 (IQR 0 to 29.2) and 25 (IQR 0 to 28.9); 1 study, 65 participants; very low-quality evidence, length of ICU stay, (MD 1.23, 95% CI -0.68 to 3.14, I² = 0; 1 study, 65 participants; very low-quality evidence); cognitive impairment measured by the MMSE: Mini-Mental State Examination with higher scores indicating better function, (MD 0.97, 95% CI -0.19 to 2.13, I² = 0; 1 study, 30 participants; very low-quality evidence); or measured by the Dysexecutive questionnaire (DEX) with lower scores indicating better function (MD -8.76, 95% CI -19.06 to 1.54, I² = 0; 1 study, 30 participants; very low-quality evidence). One patient experienced acute back pain accompanied by hypotensive urgency during physical therapy.