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.

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.

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.
The full text of this article is available to subscribers via this link to the journal’s homepage The full text of articles from issues older than sixty days is available via this link to an archive of issues of Journal of Critical Care.  A Rotherham NHS Athens password is required.  Eligible staff can register for an Athens password via this link.  Please speak to the library staff for more details.

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.
The full text of the article is available via this link.

Is Admission to the Intensive Care Unit Associated With Chronic Opioid Use? A 4-Year Follow-Up of Intensive Care Unit Survivors

Purpose:  To describe opioid use before and after intensive care unit (ICU) admission and to identify factors associated with chronic opioid use upto 4 years after ICU discharge.

Methods:  Retrospective review of adult patients admitted to the ICU at a tertiary care center between January 1, 2005, to December 31, 2008. We defined “nonuser,” “intermittent,” and “chronic” opioid status by abstinence, use in 70% of days for a given time period, respectively. We assessed opioid use at 3 months prior to ICU admission, at discharge, and annually for upto 4 years following ICU discharge.

Results:  A total of 2595 ICU patients were included for surgical (48.6%), medical (38.4%), and undetermined (13%) indications. The study population included both elective (26.9%) and emergent (73.1%) admissions. Three months prior to ICU admission, 76.9% were nonusers, 16.9% used opioids intermittently, and 6.2% used opioids chronically. We found an increase in nonuser patients from 87.8% in the early post-ICU period to 95.6% at 48-month follow-up. Consequently, intermittent and chronic opioid use dropped to 8.6% and 3.6% at discharge and 2.6% and 1.8% at 48-month follow-up, respectively. Prolonged hospital length of stay was associated with chronic opioid use.

Conclusion:  Admission to ICU and duration of ICU stay were not associated with chronic opioid use.

This research was published in the August 2017 issue of “Journal of Intensive Care Medicine” by Yaffe, Green, Buttler and Witter.  Library members can order the full text of this and other articles via the Rotherham NHS Foundation Trust Library and Knowledge Service website using the article requests online via this link

Progesterone for acute traumatic brain injury

This systematic review by Ma et al was published in the Cochrane Library in December 2016.  The text below is the plain language summary with the full text available via this link.

Review question  To find out whether using the hormone progesterone to treat people who have had an injury to the head that caused brain damage (traumatic brain injury (TBI)) is helpful and safe, if given within 24 hours of the injury.
Background  TBI is one of the main causes of death and disability in people with injuries. Damage to the brain can start at the time of the injury, but can continue for days after the injury too. Progesterone is a hormone that some doctors think could be used as a potential medicine for reducing brain damage if given shortly after TBI. However, as there is uncertainty about the effectiveness of this hormone, it is important that we assess the evidence.
Study characteristics  We searched the medical literature widely for randomised controlled trials that investigated the effects of progesterone in people with TBI up to 30 September 2016. Randomised controlled trials provide the most robust medical evidence. .
Key results:  We included five studies with a total of 2392 participants, and identified three ongoing studies. The studies all compared a group of participants who received progesterone within 24 hours of TBI against a group who received a pretend – or dummy – medicine (known as a placebo) that looked the same as the progesterone.  The results of our review did not find evidence that, when compared to placebo, progesterone could reduce death and disability in people with TBI. There were too few data available on the other outcomes that we were interested in (pressure inside the skull (intracranial pressure), blood pressure, body temperature and adverse events (harms)), for us to be able to analyse these in detail. However, although the information available shows no evidence of a difference in effect between the progesterone and control groups for intracranial pressure, blood pressure or body temperature, one study showed an increased level of an adverse event called phlebitis (inflammation in the vein) in the progesterone group, possibly because the progestreone was given into the vein through an intravascular infusion (‘drip’).
Quality of the evidence  We judged the quality of the evidence to be low for the data on risk of death, and moderate for the data on risk of disability. These judgements resulted from differences across studies, including different doses of progesterone and different time points for assessment of participants in the included studies. This means that we have limited confidence in the conclusions of this review.

Perioperative complications of obese patients

Kiss, T. et al. Current Opinion in Critical Care. August 2016 22(4). pp. 401–405

Purpose of review: The perioperative care of obese patients can often be challenging, as the presence of comorbidities is common in this patient population. In this article, we present recent data on perioperative complications of obese patients and discuss relevant details for daily practice, including drug dosing, airway management, and mechanical ventilation.

Recent findings: The volatile agent desflurane reduces extubation time, without major effects on postoperative anesthesia care unit discharge time, incidence of postoperative nausea and vomiting, or postoperative pain scores compared with other volatile anesthetics. Lean body weight is the most appropriate dosing scalar for most drugs used in anesthesia, including opioids and anesthetic induction agents. Compared with the operational theatre, airway complications occur 20-fold more often in the ICU, with poor outcome. Individual titration of positive end-expiratory pressure (PEEP) after lung recruitment improves gas exchange and lung mechanics intraoperatively, but data on patient outcome are lacking.

Summary: Intensive care physicians who treat obese patients need to be trained in the management of the difficult airway. The application of PEEP and the use of recruitment maneuvers may lead to improved intraoperative oxygenation, but current data do not allow recommending the use of high PEEP combined with lung recruitment maneuvers in this population.

Read the abstract here

Automatic versus manual changeovers of norepinephrine infusion pumps in critically ill adults: a prospective controlled study

Critically ill; Shock; Changeover; Catecholamines; Norepinephrine; Smart infusion pumps


annals of intensive careNorepinephrine is a key drug for treating shock but has a short half-life that requires continuous intravenous administration to maintain the constant plasma concentration needed to obtain a stable blood pressure. The small volume of the syringes used in power infusion pumps requires frequent changeovers, which can lead to norepinephrine flow interruptions responsible for hemodynamic instability. Changeovers from the nearly empty to the full syringe can be performed manually using the quick change technique (QC) or automatically using smart infusion pumps (SIP) that link two syringes. The purpose of our study was to evaluate the hypothesis that, compared to QC, SIP for norepinephrine changeovers was associated with less hemodynamic instability.

After information of the patient or next of kin, patients receiving norepinephrine for shock were allocated to QC or SIP changeovers. QC changeovers were performed by a nurse, who started a new loaded pump when the previous syringe was nearly empty. SIP changeovers were managed automatically by SIP workstations. The primary outcome was the proportion of changeovers followed by a ≥20 % drop in mean arterial pressure (MAP).

411 changeovers were performed, 193 in the 18 patients allocated to QC and 218 in the 32 patients allocated to SIP. Baseline patient characteristics were similar in both groups. The proportion of changeovers followed by an MAP drop ≥20 % was 12.4 % (24/193) with QC and 5.5 % (12/218) with SIP (P = 0.01). By multivariate analysis, two factors were independently associated with a significantly decreased risk of ≥20 % MAP drops during changeovers, namely, SIP (odds ratio, 0.47; 95 % confidence interval, 0.22–0.98) and norepinephrine dosage >0.5 μg/kg/min (odds ratio, 0.39; 95 % confidence interval, 0.19–0.81).

The risk of MAP drops ≥20 % during changeovers can be significantly diminished using SIPs instead of the QC method.