Pharmacological interventions for the treatment of delirium in critically ill adults

This Cochrane Systematic Review by Burry and others was published online during September 2019.

Review question:
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.

Background:
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.

Study characteristics:

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.

Key findings:
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.

Acute kidney injury as a risk factor of hyperactive delirium: A case control study

This article by Wan and others was published online in the Journal of Critical Care during November 2019.
Purpose:  Delirium and acute kidney injury (AKI) are common organ dysfunctions during critical illness. Both conditions are associated with serious short- and long-term complications. We investigated whether AKI is a risk factor for hyperactive delirium.
Methods:  This was a single-centre case control study conducted in a 30 bedded mixed Intensive Care Unit in the UK. Hyperactive delirium cases were identified by antipsychotic initiation and confirmation of delirium diagnosis through validated chart review. Cases were compared with non-delirium controls matched by Acute Physiology and Chronic Health Evaluation II score and gender. AKI was defined by the KDIGO criteria.
Results:  142 cases and 142 matched controls were identified. AKI stage 3 was independently associated with hyperactive delirium [Odds ratio (OR) 5.40 (95% confidence interval (CI) 2.33–12.51]. Other independent risk factors were mechanical ventilation [OR 2.70 (95% CI 1.40–5.21)], alcohol use disorder [OR 5.80 (95% CI 1.90–17.72)], and dementia [OR 9.76 (95% CI 1.09–87.56)]. Hospital length of stay was significantly longer in delirium cases (29 versus 20 days; p = .004) but hospital mortality was not different.
Conclusions:  AKI stage 3 is independently associated with hyperactive delirium. Further research is required to explore the factors that contribute to this association.
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Effect of Flexible Family Visitation on Delirium Among Patients in the Intensive Care Unit: The ICU Visits Randomized Clinical Trial.

This article by the ICU Visits Study Group Investigators and the Brazilian Research in Intensive Care Network (BRICNet) was published in JAMA in July 2019
Importance:  The effects of intensive care unit (ICU) visiting hours remain uncertain.
Objective:  To determine whether a flexible family visitation policy in the ICU reduces the incidence of delirium.
Design, Setting and Participants:  Cluster-crossover randomized clinical trial involving patients, family members, and clinicians from 36 adult ICUs with restricted visiting hours (<4.5 hours per day) in Brazil. Participants were recruited from April 2017 to June 2018, with follow-up until July 2018.InterventionsFlexible visitation (up to 12 hours per day) supported by family education (n = 837 patients, 652 family members, and 435 clinicians) or usual restricted visitation (median, 1.5 hours per day; n = 848 patients, 643 family members, and 391 clinicians). Nineteen ICUs started with flexible visitation, and 17 started with restricted visitation.
Main Outcomes and Measures:  Primary outcome was incidence of delirium during ICU stay, assessed using the CAM-ICU. Secondary outcomes included ICU-acquired infections for patients; symptoms of anxiety and depression assessed using the HADS (range, 0 [best] to 21 [worst]) for family members; and burnout for ICU staff (Maslach Burnout Inventory).
Results:  Among 1685 patients, 1295 family members, and 826 clinicians enrolled, 1685 patients (100%) (mean age, 58.5 years; 47.2% women), 1060 family members (81.8%) (mean age, 45.2 years; 70.3% women), and 737 clinicians (89.2%) (mean age, 35.5 years; 72.9% women) completed the trial. The mean daily duration of visits was significantly higher with flexible visitation (4.8 vs 1.4 hours; adjusted difference, 3.4 hours [95% CI, 2.8 to 3.9]; P < .001). The incidence of delirium during ICU stay was not significantly different between flexible and restricted visitation (18.9% vs 20.1%; adjusted difference, -1.7% [95% CI, -6.1% to 2.7%]; P = .44). Among 9 prespecified secondary outcomes, 6 did not differ significantly between flexible and restricted visitation, including ICU-acquired infections (3.7% vs 4.5%; adjusted difference, -0.8% [95% CI, -2.1% to 1.0%]; P = .38) and staff burnout (22.0% vs 24.8%; adjusted difference, -3.8% [95% CI, -4.8% to 12.5%]; P = .36). For family members, median anxiety (6.0 vs 7.0; adjusted difference, -1.6 [95% CI, -2.3 to -0.9]; P < .001) and depression scores (4.0 vs 5.0; adjusted difference, -1.2 [95% CI, -2.0 to -0.4]; P = .003) were significantly better with flexible visitation.
Conclusions and Relevance:  Among patients in the ICU, a flexible family visitation policy, vs standard restricted visiting hours, did not significantly reduce the incidence of delirium.
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Differences in 90-day mortality of delirium subtypes in the intensive care unit: A retrospective cohort study

This article by Rood and colleagues was published online in the “Journal of Critical Care” during June 2019
Introduction:  Many intensive care unit (ICU) patients suffer from delirium which is associated with deleterious short-term and long-term effects, including mortality. We determined the association between different delirium subtypes and 90-day mortality.
Materials and methods:  Retrospective cohort study in ICU patients admitted in 2015–2017. Delirium, including its subtypes, was determined using the confusion assessment method-ICU (CAM-ICU) and Richmond agitation sedation scale (RASS). Exclusion criteria were insufficient assessments and persistent coma. Cox-regression analysis was used to determine associations of delirium subtypes with 90-day mortality, including relevant covariates (APACHE-IV, length of ICU stay and mechanical ventilation).
Results:  7362 ICU patients were eligible of whom 6323 (86%) were included. Delirium occurred in 1600 (25%) patients (stratified for delirium subtype: N = 571–36% mixed, N = 485–30% rapidly reversible, N = 433–27% hypoactive, N = 111–7% hyperactive). The crude hazard ratio (HR) for overall prevalent delirium with 90-day mortality was 2.84 (95%CI: 2.32–3.49), and the adjusted HR 1.29 (95%CI: 1.01–1.65). The adjusted HR for 90-day mortality was 1.57 (95%CI: 1.51–2.14) for the mixed subtype, 1.40 (95%CI: 0.71–2.73) for hyperactive, 1.31 (95%CI: 0.93–1.84) for hypoactive and 0.95 (95%CI: 0.64–1.42) for rapidly reversible delirium.
Conclusion:  After adjusting for covariates, including competing risk factors, only the mixed delirium subtype was significantly associated with 90-day mortality.
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Efficacy of music on sedation, analgesia and delirium in critically ill patients. A systematic review of randomized controlled trials

This article by Gonzalo and colleagues was published online in June 2019 in the Journal of Critical Care.
Purpose:  To systematically synthesize randomized controlled trial data on the efficacy of music to provide sedation and analgesia, and reduce incidence of delirium, in critically ill patients.
Material and methods:  Relevant databases (Medline, PubMed, Embase, CINAHL, Cochrane, Alt Healthwatch, LILACS, PsycINFO, CAIRSS, RILM) were searched from inception to April 26, 2018. We also searched the reference lists of included publications and for ongoing trials. The selection of relevant articles was conducted by two researchers at two levels of screening.
Data collection followed the recommendations from the Cochrane Systematic Reviews Handbook. We used the Cochrane Collaboration’s tool for assessing risk of bias. Quality of the evidence was rated according to GRADE.
Results:  The review identified six adult studies and no neonatal or pediatric studies. A descriptive analysis of study results was performed. Meta-analysis was not feasible due to heterogeneity. One study reported a reduction in sedation requirements with the use of music while the other five did not find any significant differences across groups.
Conclusions:  This systematic review revealed limited evidence to support or refute the use of music to reduce sedation/analgesia requirements, or to reduce delirium in critically ill adults, and no evidence in pediatric and neonatal critically ill patients.
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Current practice and perceptions regarding pain, agitation and delirium management in patients receiving venovenous extracorporeal membrane oxygenation

This article by Dzierba and colleagues was first published in the Journal of Critical Care during May 2019.
Purpose:  To characterize monitoring of pain, agitation, and delirium; investigate opioid and sedative choices; and describe prevention and treatment of delirium in adults receiving venovenous extracorporeal membrane oxygenation (vv-ECMO) for respiratory failure.
Materials and methods:  International, cross-sectional survey distributed January 2018 to members of the Society of Critical Care Medicine.
Results:  Respondents were predominately physicians (58%) from North America (89%). Fentanyl (77%) and hydromorphone (48%) were the most common intravenous opioids used to manage pain. A deep level of sedation was targeted in the first 24-h after initiation of vv-ECMO 64% of the time. When deep sedation was targeted, propofol (70%) and benzodiazepines (41%) were the most common sedatives. The most common sedatives for light sedation were dexmedetomidine (45%) and propofol (39%). Delirium prevention included avoidance of benzodiazepines (73%), whereas the most common treatment strategy was scheduled atypical antipsychotics (83%). Centers that extubated patients during vv-ECMO used dexmedetomidine as the second preferred sedative as compared to benzodiazepines at non-extubating centers (p = 0.04).
Conclusions:  Most respondents use validated scales and protocols to assess and manage pain, agitation/sedation, and delirium. The majority of respondents reported targeting a deep level of sedation with propofol being used for both deep and light levels of sedation.
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Do health care professionals worry about delirium? Relatives’ experience of delirium in the intensive care unit: A qualitative interview study

This research by Bohart and colleagues was published online in “Intensive and Critical Care Nursing” during May 2019.
Objectives:  In intensive care units, there is a high incidence of delirium, which relates to the risk of complications. Engagement of relatives is an acknowledged part of handling delirium, but knowledge of relatives’ perspectives is lacking.
Aim:  To explore relatives’ experiences of delirium in the critically ill patient admitted to an intensive care unit.Research design:  A qualitative design with a phenomenological approach. Semi-structured interviews with eleven relatives of critically ill patients who had delirium during admission to the intensive care unit.Setting:  An intensive care unit in Denmark.
Findings:  Three categories emerged: ‘Delirium is not the main concern’, ‘Communication with health-care professionals is crucial’, and ‘Delirium impacts on relatives’. Relatives had a lack of knowledge of delirium. Symptoms of delirium were thought of as a natural consequence of critical illness and seemed to be a secondary problem. Health-care professionals did not talk about delirium and information was requested. Delirium and the manifestation of it was experienced in different ways and brought different ways of coping.
Conclusion:  Findings give a new insight into relatives’ experience of delirium in the intensive care unit. Relatives need more information to better understand delirium. Future research must investigate the potential in helping relatives to cope with delirium, to the benefit of both patient and relatives.
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Haloperidol for the management of delirium in adult intensive care unit patients: A systematic review and meta-analysis of randomized controlled trials

This article by Zayed et al was published online in the Journal of Critical Care during January 2019.
Purpose:  Delirium commonly presents as a complication in critically ill patients. Our aim is to perform a meta-analysis investigating the role of haloperidol versus placebo in management (treatment and prophylaxis), of delirium in intensive care unit (ICU).
Materials and methods:  Our study is a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing haloperidol versus placebo for treatment and/or prophylaxis of ICU-related delirium.
Results:  Six RCTs representing 2552 patients. There was no significant difference between haloperidol and placebo-treated patients in short-term all-cause mortality (risk ratio [RR] 0.96; 95% confidence interval [CI] 0.81–1.14; P = 0.67), incidence of delirium (RR 0.93; 95% CI 0.65–1.34; P = 0.70), ICU length of stay (Mean difference [MD] 0.00 days; 95% CI -0.82-0.83; P = 0.99), or delirium/coma-free days (MD 0.09; 95% CI -0.05-0.24; P = 0.21). Haloperidol was not associated with increased risk for serious adverse events (RR 0.65; 95% CI 0.23–1.88; P = 0.43), QTc prolongation (RR 0.87; 95% CI 0.63–1.19; P = 0.38), or extrapyramidal symptoms (RR 0.84; 95% CI 0.57–1.23; P = 0.37).
Conclusion:  Among critically ill patients, haloperidol administration compared with placebo does not significantly affect short-term mortality, incidence of delirium, ICU length of stay, or delirium or coma-free days. Additionally, there was no increased risk of adverse events.
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Dexmedetomidine in prevention and treatment of postoperative and intensive care unit delirium: a systematic review and meta-analysis

This article by Flukiger et al was published in Annals of intensive care September 2018.
Background:  To determine the preventive and therapeutic effect of dexmedetomidine on intensive care unit (ICU) delirium.
Methods:  The literature search using PubMed and the Cochrane Central Register of Controlled Trials was performed (August 1, 2018) to detect all randomized controlled trials (RCTs) of adult ICU patients receiving dexmedetomidine. Articles were included if they assessed the influence of dexmedetomidine compared to a sedative agent on incidence of ICU delirium or treatment of this syndrome. Accordingly, relevant articles were allocated to the following two groups: (1) articles that assessed the delirium incidence (incidence comparison) or articles that assessed the treatment of delirium (treatment comparison). Incidence of delirium and delirium resolution were the primary outcomes. We combined treatment effects comparing dexmedetomidine versus (1) placebo, (2) standard sedatives, and (3) opioids in random-effects meta-analyses. Risk of bias for each included RCT was assessed following Cochrane standards.
Results:  The literature search resulted in 28 articles (25 articles/4975 patients for the incidence comparison and three articles/166 patients for the treatment comparison). In the incidence comparison, heterogeneity was present in different subgroups. Administration of dexmedetomidine was associated with significantly lower overall incidence of delirium when compared to placebo (RR 0.52; 95% CI 0.39-0.70; I2 = 37%), standard sedatives (RR 0.63; 95% CI 0.46-0.86; I2 = 69%), as well as to opioids (RR 0.61; 95% CI 0.44-0.83; I2 = 0%). Use of dexmedetomidine significantly increased the risks of bradycardia and hypotension. Limited data were available on circulatory insufficiency and mortality. In the treatment comparison, the comparison drugs in the three RCTs were placebo, midazolam, and haloperidol. The resolution of delirium was measured differently in each study. Two out of the three studies indicated clear favorable effects for dexmedetomidine (i.e., compared to placebo and midazolam). The study comparing dexmedetomidine with haloperidol was a pilot study (n = 20) with high variability in the results.
Conclusions:  Findings suggest that dexmedetomidine reduces incidence and duration of ICU delirium. Furthermore, our systematic searches show that there is limited evidence if a delirium shall be treated with dexmedetomidine.
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Delirium prediction in the intensive care unit: comparison of two delirium prediction models

This article by Wassenaar and others was published in the May 2018 issue of Critical Care.
Background:  Accurate prediction of delirium in the intensive care unit (ICU) may facilitate efficient use of early preventive strategies and stratification of ICU patients by delirium risk in clinical research, but the optimal delirium prediction model to use is unclear. We compared the predictive performance and user convenience of the prediction model for delirium (PRE-DELIRIC) and early prediction model for delirium (E-PRE-DELIRIC) in ICU patients and determined the value of a two-stage calculation.
Methods:  This 7-country, 11-hospital, prospective cohort study evaluated consecutive adults admitted to the ICU who could be reliably assessed for delirium using the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist. The predictive performance of the models was measured using the area under the receiver operating characteristic curve. Calibration was assessed graphically. A physician questionnaire evaluated user convenience. For the two-stage calculation we used E-PRE-DELIRIC immediately after ICU admission and updated the prediction using PRE-DELIRIC after 24 h.
Results:  In total 2178 patients were included. The area under the receiver operating characteristic curve was significantly greater for PRE-DELIRIC (0.74 (95% confidence interval 0.71-0.76)) compared to E-PRE-DELIRIC (0.68 (95% confidence interval 0.66-0.71)) (z score of - 2.73 (p < 0.01)). Both models were well-calibrated. The sensitivity improved when using the two-stage calculation in low-risk patients. Compared to PRE-DELIRIC, ICU physicians (n = 68) rated the E-PRE-DELIRIC model more feasible.
Conclusions:  While both ICU delirium prediction models have moderate-to-good performance, the PRE-DELIRIC model predicts delirium better. However, ICU physicians rated the user convenience of E-PRE-DELIRIC superior to PRE-DELIRIC. In low-risk patients the delirium prediction further improves after an update with the PRE-DELIRIC model after 24h.
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