Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Mar 19.
Published in final edited form as: Crit Care Med. 2014 Jun;42(6):1442–1454. doi: 10.1097/CCM.0000000000000224

Randomized ICU Trials Do Not Demonstrate an Association Between Interventions That Reduce Delirium Duration and Short-Term Mortality: A Systematic Review and Meta-Analysis

Nada S Al-Qadheeb A, Ethan M Balk B, Gilles L Fraser C, Yoanna Skrobik D, Richard R Riker C, John P Kress E, Shawn Whitehead A, John W Devlin A
PMCID: PMC4799649  NIHMSID: NIHMS606026  PMID: 24557420

Abstract

Background

Interventions that reduce delirium duration may also lower short-term mortality. We reviewed randomized trials of adult ICU patients of interventions hypothesized to reduce delirium burden to determine whether interventions that are more effective at reducing delirium duration are associated with a reduction in short-term mortality.

Search Methods

We searched CINHAHL, EMBASE, MEDLINE and the Cochrane databases from 2001 through 2012. Citations were screened for randomized trials that enrolled critically ill adults, evaluated delirium at least daily, compared a drug or non-drug intervention hypothesized to reduce delirium burden with standard care (or control), and reported delirium duration and/or short-term mortality (≤45 days). In duplicate, we abstracted trial characteristics and results and evaluated quality using the Cochrane risk of bias tool. We performed random effects model meta-analyses and meta-regressions.

Results

We included 17 trials enrolling 2,849 patients which evaluated a pharmacologic intervention (n=13) [dexmedetomidine (n=6); an antipsychotic (n=4); rivastigmine (n=2); and clonidine (n=1)], a multimodal intervention (n=2) [spontaneous-awakening (n=2)]; or a non-pharmacologic intervention (n=2) [early mobilization (n=1); increased perfusion (n=1)]. Overall, average delirium duration was lower in the intervention groups [difference = −0.64 days; 95% CI, −1.15 to −0.13; P = 0.01) being reduced by ≥3 days in 3 studies, 0.1 to < 3 days in 6 studies, 0 days in 7 studies and < 0 days in 1. Across interventions, for 13 studies where short-term mortality was reported, short-term mortality was not reduced (risk ratio = 0.90; 95% CI, 0.76 to 1.06; P = 0.19). Across 13 studies that reported mortality, meta-regression revealed that delirium duration was not associated with reduced short-term mortality (P = 0.11).

Conclusions

A review of current evidence fails to support that ICU interventions that reduce delirium duration reduce short-term mortality. Larger controlled studies are needed to establish this relationship.

Keywords: critical illness, delirium, mortality, meta-analysis, systematic review, randomized controlled study, antipsychotic, dexmedetomidine

Delirium is common in the intensive care unit (ICU), is associated with a prolonged mechanical ventilation and hospital stay, and may be linked to cognitive and/or functional impairment (1–4) The ‘burden of delirium’ in the critically ill can be quantified by its duration, severity or intensity, or as various delirium-associated complications. Among markers of delirium burden, delirium duration is the simplest and most reliable measure. Delirium severity scales require patients to communicate verbally (5). Delirium screening tools are limited in their ability to evaluate delirium severity, assessment results may be confounded by concomitant conditions (e.g. level of sedation), and the longer-term complications of delirium of greatest clinical relevance remain. unclear may influence the re delirium assessment tools are limited by the paucity of data as well as confounders for delirium detection and longitudinal outcomes preclude using this association as a measure (6–10).

Mortality in the first month after ICU admission has been commonly used as an outcome to evaluate the efficacy and safety of interventions in the critically ill (11, 12). A number of pharmacological (e.g., antipsychotics, dexmedetomidine) and non-pharmacological (e.g., early mobilization) interventions have been shown to reduce delirium burden in the critically ill (5, 13–15). However, when evaluated in prospective, randomized studies, none of these interventions have been shown to reduce short-term mortality. Many studies were too small to detect a difference in short-term mortality or evaluated an ICU population with a low mortality rate (e.g. cardiac surgery) (14).

While duration of CAM-ICU screened delirium has been associated independently with higher mortality in the critically ill (16–18), it remains unclear if interventions that decrease delirium duration in the critically ill will also reduce short-term mortality (19). Using the increased power of meta-analytic techniques, we sought to review published randomized trials to test the hypothesis that interventions that reduce the duration of delirium are associated with a reduction in short-term mortality.

METHODS

Trial Identification

An experienced medical librarian assisted our search for eligible studies using the following key words: “delirium" OR "brain dysfunction" AND “intensive care” OR “critical care” OR “ICU” AND “random*”. We searched six databases (EMBASE, MEDLINE, CINAHL, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and www.ClinicalTrials.gov) for relevant trials from 2001 to December 2012. We reviewed personal files, reference lists of review articles, and reference lists in eligible studies for additional trials. In addition, we requested advice from experts in the field, searched abstract books from major critical care, surgical and geriatric scientific meetings, and contacted investigators conducting randomized controlled trials in this area. We chose 2001 as the initial search year since two ICU delirium screening instruments with good psychometric strength, and frequently used in clinical practice, were published that year [i.e., CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC)](5, 10, 20). Non-English language and grey literature (unpublished, non-peer reviewed studies) were excluded. The IRB at Northeastern University waived the need for IRB approval.

Eligibility Criteria

We included randomized controlled parallel group or factorial trials of adults (≥19 years or older) admitted to an ICU at the time of study randomization. We included any pharmacological, non-pharmacological or mixed pharmacological/non-pharmacological strategy hypothesized to decrease delirium burden (i.e., delirium duration, delirium severity or delirium-associated complications) with any other strategy. To be included, trials had to measure delirium at least once daily with a validated technique such as the CAM-ICU or ICDSC or have delirium assessed by a psychiatrist or neurologist using Diagnostic and Statistical Methods (DSM –IV) criteria (10, 20, 21). Ideally, trials reported both delirium duration and short-term mortality (i.e., either at hospital discharge or 21, 28, 30, or 45 days after the time of study randomization).

Trial Selection

We screened abstracts and titles in duplicate for potentially relevant studies. These were re-screened in duplicate in full-text form. For articles that did not report either delirium duration or short-term mortality we contacted the corresponding author to provide the missing outcome(s) or to confirm that these data were not collected during the study. Corresponding authors who failed to respond after the first contact were contacted two additional times over a 6-week period.

Data Abstraction and Risk of Bias Assessment

Using a custom-made data collection form, two reviewers independently abstracted data regarding the design, patient population, intervention and comparison, clinical outcomes, and methodological quality using the “risk of bias tool” recommended by the Cochrane Collaboration (22). For each trial, risk of bias was evaluated for six domains [i.e., reporting, attrition, detection, performance, selection and other (ie. potential sources of bias not accounted for in the prior 6 domains)] and an ‘overall’ risk of bias was estimated. For each domain risk of bias was categorized as “low”, “unclear”, or “high”. Disagreement for all methodological steps was resolved by discussion and consensus.

Data Synthesis

We separately analyzed differences in delirium duration (in days) and risk ratios (RR) of short-term mortality across all studies with adequate data using random effects model meta-analyses. For the calculation of the mean difference delirium duration, data on the means and standard errors were required; these were estimated for studies reporting median and interquartile or full ranges if investigators did not report these values or respond to queries (23). To assess the association between effect of intervention on delirium duration and the short-term mortality, we attempted to run a multivariate random effects meta-analysis with the “mvmeta” function in Stata 11.2 (StataCorp, College Station, TX). However, since the algorithm failed to converge, except under infeasible assumptions about the within-study correlation between delirium duration and mortality (r>0.95), we proceeded with a random effects model meta-regression of all studies where both duration of delirium and short-term mortality were reported. Meta-analyses and the meta-regression were conducted using the “metan” and “metareg” function in Stata 11.2. For each meta-analysis, we report the statistical significance of the chi-squared test for heterogeneity and the I2 statistic, which estimates the variation in the outcome attributable to heterogeneity rather than chance)(24, 25).

Sensitivity Analyses

To explore the clinical and statistical heterogeneity across the studies, we conducted six post hoc sensitivity analyses for delirium duration, short term mortality, and the association between these two outcomes, to account for potential factors that we hypothesized could influence one or more of these outcomes/relationships: 1) the method of delirium assessment (i.e. , CAM-ICU vs. ICDSC) given evidence suggesting that the sensitivity and specificity of these two instruments may differ (5, 26, 27); 2) the predominate ICU service that the patient was admitted to (i.e., medical versus surgical); 3) the presence of delirium at the time of enrollment in some or all patients versus the presence of delirium in none; 4) patients at low risk for mortality (≤5%) versus those at high risk for mortality (≥10%); 5) patients administered a pharmacological intervention versus those administered a non-pharmacological intervention; and 6) among patients administered a pharmacological intervention, those administered antipsychotic versus an alpha-2 receptor agonist (e.g. , clonidine or dexmedetomidine) or an acetylcholinesterate inhibitor (e.g., rivastigmine). For each meta-analysis, we conducted meta-regressions including each of the sensitivity analysis factors as covariates evaluating the statistical significance of the interaction between each factor and the outcome; e.g., we tested the interaction between the method of delirium assessment and delirium duration. We also conducted a sensitivity analysis of the meta-regression between delirium duration and death excluding any study where the duration of delirium was longer in the intervention than the control group.

RESULTS

Trial Identification

Our search yielded 145 publications (136 from the electronic database search; 9 from hand searching). (Figure 1) We excluded 122 articles based on a review of the title and abstract; of 23 remaining studies, 6 were excluded during full review: neither delirium or short-term mortality was evaluated or reported (n=4)(28–31); delirium was evaluated only once at the end of the study (n=1)(32) and agitation, rather than delirium, was evaluated (n=1)(33).

Figure 1. Literature flow.

Figure 1

Open in a new tab

Abbreviations: ICU, intensive care unit.

We included 17 randomized trials enrolling 2,849 patients in this systematic review (34–50). Of these, four evaluated antipsychotic therapy (34–37); one evaluated IV clonidine (38); six evaluated dexmedetomidine (39–44); two evaluated rivastigmine (45, 46); two evaluated daily sedative interruption (47, 50); one evaluated early mobilization after daily sedation interruption (48); and one evaluated the maintenance of a high peri-operative perfusion pressure (49).

Trial Characteristics

Table 1 describes the characteristics of the 17 studies (34–50). Eleven of the 17 studies were blinded (34–39, 42–46 . Among the six unblinded studies (40, 41, 47–50), four evaluated a non-pharmacological intervention that would be challenging to apply in a blinded fashion (47–50).

Table I.

Description of Study Characteristics

Author (year) Double- blind design? (Y/N) Description of study intervention Method by which delirium evaluated Duration of study follow-up Short-term mortality reporting period Overall Cochrane risk of bias score
Intervention group Control group
PHARMACOLOGICAL INTERVENTION
Antipsychotic therapy
Devlin (2010) Y Quetiapine 50mg PO q12h; ↑ by 50 mg q24h to 200mg q12h + PRN IV haloperidol (n=18) Placebo 50mg PO q12h; ↑ by 50 mg q24h to 200mg q12h + PRN IV haloperidol (n=18) ICDSC by the bedside nurse twice daily 14 days Hospital admission L
Girard (2010) Y Ziprasidone PO q6h + PRN haloperidol (n=30) C1: Haloperidol 5mg PO q6h + PRN haloperidol (n=35); C2: Placebo PO q6h + PRN haloperidol (n=36) CAM-ICU by research team member twice daily 21 days 21 days L
Hakim (2012) Y Postoperative 0.5 mg PO risperidone q12h until either ICDSC=0 or ICDSC≥4 (n = 51) Postoperative placebo q12h until either ICDSC=0 or ICDSC ≥ 4 (n=50) ICDSCby bedside MD q shift; psych. confirmation Hospital discharge Hospital admission L
Wang (2012) Y Postoperative haloperidol (0.5 mg IV x 1 then 0.1mg/hr IV x 12 hr) (n=229) Postoperative placebo (0.5 mg IV x 1 then 0.1mg/hr IV x 12 hr) (n=229) CAM-ICU by research team member daily 28 days 28 days L
Clonidine
Rubino (2010) Y Postoperative clonidine (0.5 mg/kg IV x 1 then 1–2 mg/kg/hr) (n=15) Postoperative placebo (0.5 mg/kg IV x 1 then 1–2 mg/kg/hr) (n=15) DSM-IV by research team member daily Extubation NR L
Dexmedetomidine
Pandharipande (2007) Y Dexmedetomidine IV 0.15–1.5 mcg/kg/hr +PRN propofol (n=52) Lorazepam IV 1–10 mg/hr + PRN propofol (n=51) CAM-ICU by a research nurse twice daily 28 days 28 days L
Maldonado (2009) N Postoperative dexmedetomidine IV (load then 0.2–0.7 mcg/kg/hr) (n=40) C1: Postoperative propofol IV 25– 50 mcg/kg/min (n=38)
C2:Postoperative midazolam IV 0.5–2 mg/hr (n=40)		 DSM-IV by a neuropsychiatrist daily Hospital discharge NR H
Reade (2009) N Dexmedetomidine IV (load then 0.2–0.7 mcg/kg/hr (n=10) Haloperidol IV (2.5mg load then 0.5–2mg/hr (n=10) ICDSC by the bedside nurse every 4 hours Hospital discharge Hospital admission H
Riker (2009) Y Dexmedetomidine IV (load then 0.2–1.4 mcg/kg/hr + PRN IV midazolam (n=244) Midazolam IV (0.02–0.1mg/kg/hr) + PRN IV midazolam (n=122) CAM-ICU by the bedside nurse daily 30 days 30 days L
Ruokonen (2009) Y Dexmedetomidine IV 0.8–1.4 mcg/kg/hr (n=41) Standard sedation (midazolam or propofol) protocol (n=44) CAM-ICU by trained research personnel 45 days 45 days U
Shehabi (2009) Y Postoperative dexmedetomidine IV 0.1–0.7 mcg/kg/hr (n=152) Postoperative morphine IV 10–70 mcg/kg/hr (n=147) CAM-ICU by the bedside nurse daily Hospital discharge Hospital admission L
Rivastigmine
Gamberini (2009) Y Rivastigmine 1.5mg PO 3x daily (n=56) Placebo 3x daily (n=57) CAM-ICU by the bedside nurse daily Hospital discharge Hospital admission L
Van Eijk (2010) Y Rivastigmine PO 2.5mg daily up to 6mg twice daily (n=54) Placebo PO 2.5mg daily up to 6mg twice daily (n=50) CAM-ICU by the research nurse daily 30 days 30 days L
NON-PHARMACOLOGICAL INTERVENTION
Girard (2008) N Daily awakening trial -spontaneous breathing trial (n=168) Usual sedation care-spontaneous breathing trial (n=168) CAM-ICU by trained study personnel daily 21 days 21 days L
Schweickert (2009) N Early mobilization after daily sedative interruption (n=49) Usual physiotherapy after daily sedative interruption (n=55) CAM-ICU by a research team member daily 28 days 28 days L
Siepe (2011) N Maintenance of high intraoperative perfusion pressure (n=44) Maintenance of low intraoperative perfusion pressure (n=44) Psychiatric evaluation 30 days 30 days U
Mehta (2012) N Protocolized sedation + daily sedative interruption (n=214) Protocolized sedation alone (n=209) ICDSC by a bedside nurse daily Hospital discharge Hospital admission L
Open in a new tab

Y=yes; N=no; PRN=as needed; PO=by mouth or feeding tube; IV=intravenous; ICDSC=Intensive Care Delirium Screening Checklist; CAM-ICU=Confusion Assessment for the Intensive Care Unit; DSM=Diagnostic and Statistical Manual; NR=not reported; L=low; H= high; U=unclear

Delirium was evaluated either by a member of the study’s research team using the CAM-ICU (35, 37, 39, 43, 46–48); by bedside clinicians using either the CAM-ICU (42, 44, 45) or the ICDSC (34, 41, 50); by a psychiatrist using DSM-IV criteria (38, 40, 47) or the bedside clinician using the ICDSC with confirmation by a psychiatrist using DSM-IV criteria (36). Duration of delirium was either not collected during the study or was not retrievable from two studies (43, 49). Mortality was reported at hospital discharge for six studies (34, 36, 40, 44, 45, 50), and at post-study randomization day 21 in two studies (35, 47), day 28 in three studies (37, 39, 48), day 30 in three studies (42, 46, 49) or day 45 in one study (43). Short-term mortality was not able to be determined from authors for two studies (38, 40). Most of the studies (n=14) had a low Cochrane risk of bias (34–39, 42, 44–50). (Supplemental Figure)

Table 2 highlights the patient characteristics (34–50). The studies enrolled either a mixed-medical-surgical population (n=8) (34, 35, 39, 41–43, 46, 50); a surgical population (n=7) (36–38, 40, 45, 49); or a medical population (n=2) (47, 48). Most (n=13) of the studies enrolled only patients who were intubated (35, 38–45, 47–50) . The average patient age was older than 50 years across all intervention and control groups in all 17 studies. Where reported, the average Acute Physiology and Chronic Health Evaluation (APACHE) II score varied widely across the studies. In eight of the studies, all patients were delirium-free at the time of study randomization (36–38, 40, 44–5, 48, 49), and in two of the studies all patients had delirium at the time of randomization (34, 46).

Table 2.

Description of Patient Characteristics and Pertinent Study Outcomes

Author (year) Medical (M) or Surgical (S) (%) Age (years) Male (%) Intubated at study entry (%) Severity of illness at study entryC Prevalence of delirium at time of study entry (%) Duration of delirium (days) Method by which duration of delirium reported
I C I C I C I C I C I C
PHARMACOLOGICAL INTERVENTION
Antipsychotic
Devlin (2010)A M=75 62 64 56 56 72 89 17 16 100 100 1.5 5 Days of delirium
Girard (2010)B M=62 51 C1:54
C2:56		 57 C1:70
C2:61		 100 100 26 C1:26
C2:26		 50 C1:46
C2: 47		 4 4 Days of delirium
Hakim (2012)B S=100 (all cardiac) 67 67 65 72 0 0 61D 64D 0 0 3 3 Days of delirium
Wang (2012)A S=100 (91% abd.) 75 74 63 63 79 78 9 9 0 0 0 0 Days of delirium
Clonidine
Rubino (2010)A S=100 (all aortic) 64 61 67 53 100 100 NR NR 0 0 0.84 2.5 Days of delirium
Dexmedetomidine
Pandharipande (2007)B M=70 60 59 58 45 100 100 29 27 61.5 58.8 2.5 4 Days of delirium
Maldonado (2009)A S=100 (all cardiac) 55 C1:58
C2:60		 65 C1:58
C2: 68		 100 C1:100
C2:1 00		 3.3E C1:3.5E
C2:3.5E 		0 0 2 3 Days of delirium
Reade (2009)B M= 50 52 69 90 80 100 100 13 16 30 40 0 0 Time to delirium resolution
Riker (2009)A M=86 62 63 51 47 100 100 19 18 60 59 1.4 2.7 Days of delirium
Ruokonen (2009)B M=53 64 68 78 77 100 100 100F 100F NR NR NR NR NR
Shehabi (2009)B S=100 (all cardiac) 72 71 75 76 100 100 NR NR 0 0 2 5 Days of delirium
Rivastigmine
Gamberini (2009)B S=100 (all cardiac) 74 74 70 66 100 100 35G 40G 0 0 2.5 3 Days of delirium
Van Eijk (2010)A S=69 68 70 70 58 NR NR 20 20 100 100 5 3 Days of delirium
NON-PHARMACOLOGICAL INTERVENTION
Girard (2008)B M=100 60 64 54 51 100 100 26 27 NR NR 2 2 Days of delirium
Schweickert (2009)B M=100 58 54 41 58 100 100 20 19 0 0 2 4 Days of delirium
Siepe (2011)A S=100 (all cardiac) 69 65 83 77 100 100 5.2H 5.4H 0 0 NR NR NR
Mehta (2012)B M=84 57 60 56 56 100 100 24 23 30 23 1 1 Days of delirium
Open in a new tab
A

Reported as mean

B

Reported as median

C

Acute Physiology and Chronic Health Evaluation (APACHE)-II score unless otherwise indicated

D

Percent of patients with New York Heart Association (NYHA) Class III or IV heart failure

E

American Society of Anesthesiologists (ASA) Physical Status Classification System score

F

Patients having a Sequential Organ Failure Assessment (SOFA) score≥2

G

Simplified Acute Physiology (SAPS)-II score

H

The European System for Cardiac Operative Risk Evaluation (EuroSCORE)

I=intervention; C=control; abd. = abdominal; NR=not reported

Duration of Delirium

All 17 trials reported duration of delirium (Figure 2). The average delirium duration (vs. control) was reduced in the intervention groups (difference = −0.64 days; 95% confidence interval [CI], −1.15 to −0.13; P = 0.014) and was reduced on average ≥3 days for 3 studies, 0.1 to < 3 days for 6 studies, 0 days for 7 studies and < 0 days for one study. Across studies, there was a wide range of net effects on delirium duration, from a significant reduction by 3.4 days to a nonsignificant increase by 2.0 days. Consistent with the range of effects, the studies were significantly heterogeneous (P<0.001); 71% of the differences are attributable to heterogeneity.

Figure 2. Meta-analysis of difference in duration of delirium.

Figure 2

Open in a new tab

The data markers indicate the difference in duration of delirium in days. The size of the grey boxes indicates the weight of each study in the meta-analysis.

Abbreviations: DI, daily interruption; N, number analyzed; OT, occupational therapy; PS, protocolized sedation; PT, physiotherapy; SAT; spontaneous awakening trial; SBT; spontaneous breathing trial.

* These studies reported on second control groups that were not included in this meta-analysis.

Short-Term Mortality

Thirteen trials reported short-term mortality (Figure 3). Across the studies the short-term mortality rate was similar between the intervention (15.6%) and control (16.5%) groups p=0.54). Compared with control, the interventions had no significant effect on death (RR = 0.90; 95% CI 0.76 to 1.06; P = 0.19). The studies were statistically homogeneous (P=0.63, I2 = 0%).

Figure 3. Meta-analysis of risk ratio for short-term mortality.

Figure 3

Open in a new tab

The data markers indicate the risk ratio for mortality. The size of the grey boxes indicates the weight of each study in the meta-analysis.

Abbreviations: DI, daily interruption; n/N, number of deaths/number analyzed; OT, occupational therapy; PS, protocolized sedation; PT, physiotherapy; RR, risk ratio; SAT, spontaneous awakening trial; SBT, spontaneous breathing trial.

* This study reported on a second control group that was not included in this meta-analysis.

Across 13 studies where both duration of delirium and mortality was reported (Figure 4), meta-regression revealed that delirium duration was not associated with a statistically significant reduced short-term mortality; the slope of the ln(RR mortality) = −0.17 (95% CI −0.39, 0.04; P = 0.11). There was no residual heterogeneity for this association (I2 = 0%). Because the study by van Eijk et al. found a relatively large increase in delirium duration with an intervention meant to decrease delirium duration, we ran a sensitivity analysis of the meta-regression without this study (46). The relationship between delirium duration and short-term mortality was not substantially changed and remained non-significant; the slope of the ln(RR mortality) = −0.10 (95% CI −0.34, 0.15); P=0.40).

Figure 4. Scatter plot of difference in duration of delirium versus risk ratio for death.

Figure 4

Open in a new tab

Each circle represents a unique study that reported both the difference between treatments in duration of delirium and the risk ratio (RR) for death. The size of the circles indicates the weight of each study in the random effects model meta-regression. The solid line describes the random effects model meta-regression association across all studies of difference in duration of delirium versus RR death (P=0.11). The dashed line describes the association excluding the study where the intervention resulted in a longer duration of delirium than the control (46)) (P=0.40). The equation for each metaregression line is provided for the logarithm of RR against delirium duration.

Sensitivity Analyses

The results of the six sensitivity analyses are presented in Table 3. There was no evidence that either the outcomes duration of delirium or short-term mortality, nor the association between the two, were different for any of the tested subgroups.

Table 3.

Results of Sensitivity Analyses

Decrease in duration of delirium [net difference (days), 95% confidence interval; P value for comparison] Short term mortality [risk ratio (RR), 95% confidence interval; P value for comparison] Change in short-term mortality by delirium duration (P –value from meta- regression)
Overall 0.64 (0.13, 1.15) 0.90 (0.76, 1.06) P=0.11
Method of delirium assessment
CAM-ICU 0.11 (−0.34, 0.57) 0.97 ( 0.73, 1.29) P=0.80
ICDSC 0.74 (−0.08, 1.57) 0.87 (0.70, 1.08)
P=0.46 P=0.51
Predominate ICU admitting service
Medical 1.06 (0.09, 2.04) 0.89 (0.75, 1.05) P=0.24
Surgical 0.40 (−0.32, 1.12) 0.97 (0.40, 2.34)
P=0.34 P=0.51
Presence of delirium in some or all patients at baseline
Yes 0.36 (−0.27, 0.98) 0.92 (0.77, 1.09) P=0.61
No 1.02 (0.25, 1.79) 0.67 (0.37, 1.21)
P=0.30 P=0.34
Mortality risk
Low (≤ 5%) 0.13 (−0.26, 0.51) 0.90 (0.77, 1.06) P=0.43
High (≥ 10%) 0.88 (−0.008, 1.76) 0.91 (0.77, 1.08)
P=0.48 P=0.34
Use of a pharmacological intervention
Yes 0.71 (0.02, 1.41) 0.92 (0.70, 1.20) P=0.50
No 0.59 (−0.75, 1.94) 0.67 (0.37, 1.21)
P=0.87 P=0.83
Class of pharmacological intervention
Antipsychotic 0.82 (−0.86, 2.50) 0.79 (0.35, 1.76) P=0.75
Alpha-2 agonist 0.59 (−0.75, 1.94) 0.86 (0.64, 1.16)
Cholinesterase inhibitor −0.57 (−3.00, 1.85) 2.44 (0.91, 6.59)
P=0.54 P=0.31
Open in a new tab

DISCUSSION

This systematic review and meta-analysis is the first to summarize published randomized trials evaluating an intervention in critically ill adults hypothesized to reduce delirium burden. Our analyses confirm that pharmacological and non-pharmacological interventions in the ICU can reduce delirium duration. However, current randomized controlled trial data fail to support that a treatment that reduces delirium duration is associated with a reduction in short-term mortality. Analyses within large trials or patient-level meta-analysis across studies are needed to establish this association.

Our findings appear to differ with the results of a recently published meta-analysis and three published cohort studies (16–18, 51). The meta-analysis of 14 ICU observational studies involving 5891 patients, found that patients who developed delirium had a higher mortality rate than patients who did not (odds ratio: 3.22; 95% confidence interval: 2.30–4.52) (51). However, this meta-analysis did not consider delirium duration and thus conclusions about the association between delirium duration and mortality cannot be made. The three cohort analyses used regression techniques to demonstrate that a significant relationship between delirium duration and mortality exists at 28-days (18), 6 months (16) and 1 year (17). The first analysis of 275 mechanically ventilated ICU patients, found that each additional day spent in delirium was associated with a 10% increased risk of death at six months [hazard ratio (HR), 1.1; 95% confidence interval (CI), 1.0–1.3; p=0.03] (16). The second analysis of 304 medical ICU patients aged ≥60 years revealed that the number of days spent in delirium was significantly associated with greater 1-year mortality [HR, 1.10; 95% CI, 1.02–1.18] (17). A third analysis of 354 patients enrolled in the SEDCOM study found that delirium duration was the strongest predictor of 30-day mortality (p < 0.001) among eight different covariates that were modeled and that a dose-response increase in mortality was seen with increasing durations of delirium (18).

Our results, and their contrast with the above meta-analysis and cohort analyses, raise a number of important questions. Delirium duration may not be a direct cause of death in the ICU; other factors such as severity of illness may influence delirium incidence, delirium duration and short-term mortality (52, 53). The relationship between delirium duration and mortality may vary by the specific delirium-reducing intervention evaluated. Current clinical trials may be too small to identify a relationship between delirium duration and short-term mortality.

Delirium may not always have been accurately recognized in the studies included (54). Only one screening method, the CAM-ICU, has been used in studies showing an association between delirium duration and mortality (16–18). Recent data have suggested that sedation may confound CAM-ICU assessments, and delirium screening with CAM-ICU or ICDSC may not be similar (55–58). This is important given that the method of delirium assessment was found to account for the heterogeneity between studies in the meta-analysis by Zhang et al that associated delirium presence with great mortality (51).

Sedation-induced coma is an independent predictor of ICU and hospital mortality in several studies (59–61). It is possible that confounding factors within and between studies, including the wide variability in the baseline incidence of delirium and the nature of different interventions that also influence coma incidence may have influenced our results (62). Future studies evaluating the association between delirium duration and mortality, should incorporate coma as an independent outcome.

There are important limitations to the data included in the review. We restricted our search to English language studies, did not search the gray literature, and were not able to obtain duration of delirium data from two authors. Although 13 published randomized trials have evaluated the effect of interventions to reduce delirium in the ICU on duration of delirium and death, these studies were highly clinically heterogeneous. Specific statistical techniques (e.g., sensitivity analysis) were thus required. This heterogeneity among the included studies we included may have masked different effects of specific interventions on the duration of delirium and its relationship with mortality. Furthermore, since each intervention was evaluated only within one or two trials, we could not assess whether differences across studies were due to chance or real differences. Thus, our main analyses evaluated the effect of the category of “delirium-reducing interventions” rather than any specific intervention.

Since our primary question of interest was whether interventions that are more effective at reducing delirium duration are also more effective at reducing mortality, not the effect on delirium duration per se on mortality, we believe the meta-regression of the association is informative in its suggestion of a lack of association between reduction in delirium duration and short-term mortality. Multivariate meta-analysis would have been a preferable analysis to explore the simultaneous treatment effects on the two outcomes. Since this algorithm failed to converge, the meta-regression constituted a reasonable alternative analysis. The individual studies included in our systematic review were generally underpowered to assess short-term mortality, resulting in rare events in many studies and wide confidence intervals for the RR of death. This lack of heterogeneity in treatment effect on mortality may also largely explain the lack of heterogeneity in the meta-regression of delirium duration and death and thus reduced the likelihood of our finding a relationship between these two outcomes.

Another concern is the possibility of publication or reporting bias, wherein unpublished studies (or results) are systematically different than available evidence. We aimed to minimize the reporting bias by contacting authors of studies with missing data. We successfully retrieved both delirium duration and mortality data for 13 of 17 trials (2 missing duration data, 2 missing mortality data). We found no reason to suspect that data were omitted in a biased manner. We also found no reason to suspect that unpublished studies would indicate a different association between delirium duration and mortality.

While our analysis suggests that treatments effective at reducing delirium duration may also not reduce short-term mortality, appropriate analyses within (existing or new) RCTs that are adequately powered to test for mortality are needed to further evaluate this relationship. The meta-regression across studies can only be hypothesis-generating and speak only to an association, not causation, between the outcomes. While multivariate meta-analysis would have been a preferable meta-analysis tool, results from such an analysis would still be only hypothesis-generating. Within-study (or patient-level meta-analyses) are needed for more definitive conclusions.

Duration of delirium may be related to other factors such as changing severity of illness, the use (or avoidance) of ICU interventions that may influence mortality or practice misalignment between intervention and controls groups (1)(63–4). If an intervention reduces delirium but not the underlying severity of illness, that intervention may not improve mortality. Moreover, while the APACHE II score was used to define severity of illness in each study, it is a poor predictor of mortality in current ICU practice (65). Severity of illness may influence both delirium incidence and mortality; once delirium has occurred, use of interventions to decrease delirium duration may not influence short-term mortality. Lastly, given that a number of recent studies have demonstrated that an association exists between delirium duration and longer-term brain dysfunction, and generated substantial debate and discussion, future studies evaluating an intervention that may reduce delirium duration should incorporate an assessment of longer-term cognitive outcomes (2–4, 10, 66–70).

CONCLUSION

Among RCTs evaluating interventions hypothesized to reduce delirium burden in the ICU, delirium duration is reduced, but our analysis suggests that these treatments may not be associated with reduced short-term mortality. To better answer this question, adequately powered randomized trials testing individual delirium-reducing interventions are needed.

Supplementary Material

SDC. Supplemental Figure.

Characterization of methodological quality for the n=17 studies based on a risk of bias (RoB) evaluation using the Cochrane Collaboration tool. (22) For each risk of bias domain, methodologic quality was deemed good of the RoB was low, fair if the RoB was deemed unclear, and poor if the RoB was high.

Acknowledgments

We appreciate the help of Drs. Girard, Gambieri, Hakim, Mehta, Mallick, Pandharipande, Rubino, Ruokonen, Shehabi, Siepe, Van Eijk and Wang who kindly provided us with additional study data. We thank Amy E. LaVertu, MSL, for her help in designing our search strategy. We also thank Norma Terrin, PhD, for her invaluable statistical assistance. Through Dr. Terrin’s assistance, this work was supported in part by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), Grant Number UL1 TR000073 through Tufts Clinical and Translational Science Institute (CTSI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Footnotes

Copyright Form Disclosures: Dr. Devlin received support for the development of educational presentations from Hospira Pharmaceuticals. His institution received grant support from Hospira Pharmaceuticals. The remaining authors have disclosed that they do not have any potential conflicts of interest.

References

  • 1.Ouimet S, Kavanagh BP, Gottfried SB, et al. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med. 2007;33:66–73. doi: 10.1007/s00134-006-0399-8. [DOI] [PubMed] [Google Scholar]
  • 2.van Eijk MM, Slooter AJ. Delirium in intensive care unit patients. Semin Cardiothorac Vasc Anesth. 2010;14:141–147. doi: 10.1177/1089253210371495. [DOI] [PubMed] [Google Scholar]
  • 3.Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41:278–280. doi: 10.1097/CCM.0b013e3182783b72. [DOI] [PubMed] [Google Scholar]
  • 4.Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369(14):1306–16. doi: 10.1056/NEJMoa1301372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Trzepacz PT, Baker RW, Greenhouse J. A symptom rating scale for delirium. Psychiatry Res. 1988;23:89–97. doi: 10.1016/0165-1781(88)90037-6. [DOI] [PubMed] [Google Scholar]
  • 6.Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: Validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU) JAMA. 2001;286:2703–2710. doi: 10.1001/jama.286.21.2703. [DOI] [PubMed] [Google Scholar]
  • 7.Ouimet S, Riker R, Bergeron N, et al. Subsyndromal delirium in the ICU: Evidence for a disease spectrum. Intensive Care Med. 2007;33:1007–1013. doi: 10.1007/s00134-007-0618-y. [DOI] [PubMed] [Google Scholar]
  • 8.Wolters AE, Slooter AJ, van der Kooi AW, et al. Cognitive impairment after intensive care unit admission: A systematic review. Intensive Care Med. 2013;39:376–386. doi: 10.1007/s00134-012-2784-9. [DOI] [PubMed] [Google Scholar]
  • 9.Skrobik Y, Hopkins RO. Post-intensive care cognitive impairment: Questions in mind? Intensive Care Med. 2013;39:524–527. doi: 10.1007/s00134-012-2789-4. [DOI] [PubMed] [Google Scholar]
  • 10.Devlin JW, Fraser GL, Joffe AM, et al. The accurate recognition of delirium in the ICU. the emperor's new clothes? Intensive Care Med. 2013;39(12):2196–9. doi: 10.1007/s00134-013-3105-7. [DOI] [PubMed] [Google Scholar]
  • 11.Russell JA, Walley KR, Singer JN, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. Engl J Med. 2008 Feb 28;358(9):877–87. doi: 10.1056/NEJMoa067373. [DOI] [PubMed] [Google Scholar]
  • 12.Young D, Lamb SE, Shah S, et al. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med. 2013;368:806–813. doi: 10.1056/NEJMoa1215716. [DOI] [PubMed] [Google Scholar]
  • 13.Brummel NE, Girard TD. Preventing delirium in the intensive care unit. Crit Care Clin. 2013;29:51–65. doi: 10.1016/j.ccc.2012.10.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Devlin JW, Al-Qadheeb NS, Skrobik Y. Pharmacologic prevention and treatment of delirium in critically ill and non-critically ill hospitalised patients: A review of data from prospective, randomised studies. Best Pract Res Clin Anaesthesiol. 2012;26:289–309. doi: 10.1016/j.bpa.2012.07.005. [DOI] [PubMed] [Google Scholar]
  • 15.Hipp DM, Ely EW. Pharmacological and nonpharmacological management of delirium in critically ill patients. Neurotherapeutics. 2012;9:158–175. doi: 10.1007/s13311-011-0102-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291:1753–1762. doi: 10.1001/jama.291.14.1753. [DOI] [PubMed] [Google Scholar]
  • 17.Pisani MA, Kong SY, Kasl SV, et al. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med. 2009;180:1092–1097. doi: 10.1164/rccm.200904-0537OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Shehabi Y, Riker RR, Bokesch PM, et al. Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients. Crit Care Med. 2010;38:2311–2318. doi: 10.1097/CCM.0b013e3181f85759. [DOI] [PubMed] [Google Scholar]
  • 19.Fleming TR, DeMets DL. Surrogate end points in clinical trials: Are we being misled? Ann Intern Med. 1996;125:605–613. doi: 10.7326/0003-4819-125-7-199610010-00011. [DOI] [PubMed] [Google Scholar]
  • 20.Bergeron N, Dubois MJ, Dumont M, et al. Intensive care delirium screening checklist: Evaluation of a new screening tool. Intensive Care Med. 2001;27:859–864. doi: 10.1007/s001340100909. [DOI] [PubMed] [Google Scholar]
  • 21.American Psychiatric Association. DSM-IV sourcebook. 1. Washington, DC: American Psychiatric Press; 1994. Task Force on DSM-IV. [Google Scholar]
  • 22.Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. doi: 10.1136/bmj.d5928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:13. doi: 10.1186/1471-2288-5-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58. doi: 10.1002/sim.1186. [DOI] [PubMed] [Google Scholar]
  • 25.Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta- analyses. BMJ. 2003;327:557–60. doi: 10.1136/bmj.327.7414.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Pun BT, Devlin JW. Delirium monitoring in the ICU: strategies for initiating and sustaining screening efforts. Semin Respir Crit Care Med. 2013 Apr;34(2):179–88. doi: 10.1055/s-0033-1342972. [DOI] [PubMed] [Google Scholar]
  • 27.Tomasi CD, Grandi C, Salluh J, et al. Comparison of CAM-ICU and ICDSC for the detection of delirium in critically ill patients focusing on relevant clinical outcomes. J Crit Care. 2012 Apr;27(2):212–7. doi: 10.1016/j.jcrc.2011.05.015. [DOI] [PubMed] [Google Scholar]
  • 28.Prakanrattana U, Prapaitrakool S. Efficacy of risperidone for prevention of postoperative delirium in cardiac surgery. Anaesth Intensive Care. 2007;35:714–719. doi: 10.1177/0310057X0703500509. [DOI] [PubMed] [Google Scholar]
  • 29.Hudetz JA, Patterson KM, Iqbal Z, et al. Ketamine attenuates delirium after cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2009;23:651–657. doi: 10.1053/j.jvca.2008.12.021. [DOI] [PubMed] [Google Scholar]
  • 30.Yapici N, Coruh T, Kehlibar T, et al. Dexmedetomidine in cardiac surgery patients who fail extubation and present with a delirium state. Heart Surg Forum. 2011;14:E93–8. doi: 10.1532/HSF98.201011102. [DOI] [PubMed] [Google Scholar]
  • 31.Skrobik YK, Bergeron N, Dumont M, et al. Olanzapine vs haloperidol: Treating delirium in a critical care setting. Intensive Care Med. 2004;30:444–449. doi: 10.1007/s00134-003-2117-0. [DOI] [PubMed] [Google Scholar]
  • 32.Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: Two randomized controlled trials. JAMA. 2012;307:1151–1160. doi: 10.1001/jama.2012.304. [DOI] [PubMed] [Google Scholar]
  • 33.Strom T, Martinussen T, Toft P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: A randomised trial. Lancet. 2010;375:475–480. doi: 10.1016/S0140-6736(09)62072-9. [DOI] [PubMed] [Google Scholar]
  • 34.Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: A prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med. 2010;38:419–427. doi: 10.1097/CCM.0b013e3181b9e302. [DOI] [PubMed] [Google Scholar]
  • 35.Girard TD, Pandharipande PP, Carson SS, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: The MIND randomized, placebo-controlled trial. Crit Care Med. 2010;38:428–437. doi: 10.1097/ccm.0b013e3181c58715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Hakim SM, Othman AI, Naoum DO. Early treatment with risperidone for subsyndromal delirium after on-pump cardiac surgery in the elderly: A randomized trial. Anesthesiology. 2012;116:987–997. doi: 10.1097/ALN.0b013e31825153cc. [DOI] [PubMed] [Google Scholar]
  • 37.Wang W, Li HL, Wang DX, et al. Haloperidol prophylaxis decreases delirium incidence in elderly patients after noncardiac surgery: A randomized controlled trial. Crit Care Med. 2012;40:731–739. doi: 10.1097/CCM.0b013e3182376e4f. [DOI] [PubMed] [Google Scholar]
  • 38.Rubino AS, Onorati F, Caroleo S, et al. Impact of clonidine administration on delirium and related respiratory weaning after surgical correction of acute type-A aortic dissection: Results of a pilot study. Interact Cardiovasc Thorac Surg. 2010;10:58–62. doi: 10.1510/icvts.2009.217562. [DOI] [PubMed] [Google Scholar]
  • 39.Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized controlled trial. JAMA. 2007;298:2644–2653. doi: 10.1001/jama.298.22.2644. [DOI] [PubMed] [Google Scholar]
  • 40.Maldonado JR, Wysong A, van der Starre PJ, et al. Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery. Psychosomatics. 2009;50:206–217. doi: 10.1176/appi.psy.50.3.206. [DOI] [PubMed] [Google Scholar]
  • 41.Reade MC, O'Sullivan K, Bates S, et al. Dexmedetomidine vs. haloperidol in delirious, agitated, intubated patients: A randomised open-label trial. Crit Care. 2009;13:R75. doi: 10.1186/cc7890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA. 2009;301:489–499. doi: 10.1001/jama.2009.56. [DOI] [PubMed] [Google Scholar]
  • 43.Ruokonen E, Parviainen I, Jakob SM, et al. Dexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation. Intensive Care Med. 2009;35:282–290. doi: 10.1007/s00134-008-1296-0. [DOI] [PubMed] [Google Scholar]
  • 44.Shehabi Y, Grant P, Wolfenden H, et al. Prevalence of delirium with dexmedetomidine compared with morphine based therapy after cardiac surgery: A randomized controlled trial (DEXmedetomidine COmpared to morphine-DEXCOM study) Anesthesiology. 2009;111:1075–1084. doi: 10.1097/ALN.0b013e3181b6a783. [DOI] [PubMed] [Google Scholar]
  • 45.Gamberini M, Bolliger D, Lurati Buse GA, et al. Rivastigmine for the prevention of postoperative delirium in elderly patients undergoing elective cardiac surgery–-a randomized controlled trial. Crit Care Med. 2009;37:1762–1768. doi: 10.1097/CCM.0b013e31819da780. [DOI] [PubMed] [Google Scholar]
  • 46.van Eijk MM, Roes KC, Honing ML, et al. Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: A multicentre, double-blind, placebo-controlled randomised trial. Lancet. 2010;376:1829–1837. doi: 10.1016/S0140-6736(10)61855-7. [DOI] [PubMed] [Google Scholar]
  • 47.Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (awakening and breathing controlled trial): A randomised controlled trial. Lancet. 2008;371:126–134. doi: 10.1016/S0140-6736(08)60105-1. [DOI] [PubMed] [Google Scholar]
  • 48.Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: A randomised controlled trial. Lancet. 2009;373:1874–1882. doi: 10.1016/S0140-6736(09)60658-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Siepe M, Pfeiffer T, Gieringer A, et al. Increased systemic perfusion pressure during cardiopulmonary bypass is associated with less early postoperative cognitive dysfunction and delirium. Eur J Cardiothorac Surg. 2011;40:200–207. doi: 10.1016/j.ejcts.2010.11.024. [DOI] [PubMed] [Google Scholar]
  • 50.Mehta S, Burry L, Cook D, et al. Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: A randomized controlled trial. JAMA. 2012;308:1985–1992. doi: 10.1001/jama.2012.13872. [DOI] [PubMed] [Google Scholar]
  • 51.Zhang Z, Pan L, Ni H. Impact of delirium on clinical outcome in critically ill patients: A meta-analysis. Gen Hosp Psychiatry. 2013;35:105–111. doi: 10.1016/j.genhosppsych.2012.11.003. [DOI] [PubMed] [Google Scholar]
  • 52.van den Boogaard M, Peters SA, van der Hoeven JG, et al. The impact of delirium on the prediction of inhospital mortality in intensive care patients. Crit Care. 2010;14:R146. doi: 10.1186/cc9214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Joffe A, Coursin DB. All this confusion is killin' me. Crit Care Med. 2010;38:2413–2415. doi: 10.1097/CCM.0b013e3181fa0590. [DOI] [PubMed] [Google Scholar]
  • 54.Reade MC, Aitken LM. The problem of definitions in measuring and managing ICU cognitive function. Crit Care Resusc. 2012;14:236–243. [PubMed] [Google Scholar]
  • 55.Svenningsen H, Egerod I, Videbech P, et al. Fluctuations in sedation levels may contribute to delirium in ICU patients. Acta Anaesthesiol Scand. 2013;57:288–293. doi: 10.1111/aas.12048. [DOI] [PubMed] [Google Scholar]
  • 56.Fagundes JA, Tomasi CD, Giombelli VR, et al. CAM-ICU and ICDSC agreement in medical and surgical ICU patients is influenced by disease severity. PLoS One. 2012;7:e51010. doi: 10.1371/journal.pone.0051010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Riker RR. ICU delirium assessment tools often disagree. Crit Care Med. 2006;34:A27. [Google Scholar]
  • 58.Poston JT, Goding MW, Pholman AS, et al. Assessment of delirium relative to daily sedative interruption. Am J Respir Crit Care Med. 2010;181:A6701. [Google Scholar]
  • 59.Shehabi Y, Bellomo R, Reade MC, et al. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med. 2012;186:724–731. doi: 10.1164/rccm.201203-0522OC. [DOI] [PubMed] [Google Scholar]
  • 60.Shehabi Y, Chan L, Kadiman S, et al. Sedation depth and long-term mortality in mechanically ventilated critically ill adults: A prospective longitudinal multicentre cohort study. Intensive Care Med. 2013;39:960–8. doi: 10.1007/s00134-013-2830-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Hughes CG, Patel MB, Pandharipande PP. Pathophysiology of acute brain dysfunction: What's the cause of all this confusion? Curr Opin Crit Care. 2012;18:518–26. doi: 10.1097/MCC.0b013e328357effa. [DOI] [PubMed] [Google Scholar]
  • 62.Hughes CG, Pandharipande PP. Review articles: The effects of perioperative and intensive care unit sedation on brain organ dysfunction. Anesth Analg. 2011;112:1212–1217. doi: 10.1213/ANE.0b013e318215366d. [DOI] [PubMed] [Google Scholar]
  • 63.van Eijk MM, Slooter AJ. Duration of ICU delirium, severity of the underlying disease, and mortality. Am J Respir Crit Care Med. 2010;181:419–20. doi: 10.1164/ajrccm.181.4.419b. author reply 420–421. [DOI] [PubMed] [Google Scholar]
  • 64.Deans KJ, Minneci PC, Danner RL, et al. Practice misalignments in randomized controlled trials: Identification, impact, and potential solutions. Anesth Analg. 2010;111:444–450. doi: 10.1213/ane.0b013e3181aa8903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Breslow MJ, Badawi O. Severity scoring in the critically ill: Part 1--interpretation and accuracy of outcome prediction scoring systems. Chest. 2012;141:245–252. doi: 10.1378/chest.11-0330. [DOI] [PubMed] [Google Scholar]
  • 66.van den Boogaard M, Schoonhoven L, Evers AW, et al. Delirium in critically ill patients: Impact on long-term health-related quality of life and cognitive functioning. Crit Care Med. 2012;40:112–118. doi: 10.1097/CCM.0b013e31822e9fc9. [DOI] [PubMed] [Google Scholar]
  • 67.Girard TD, Jackson JC, Pandharipande PP, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med. 2010;38:1513–1520. doi: 10.1097/CCM.0b013e3181e47be1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Saczynski JS, Marcantonio ER, Quach L, et al. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012;367(1):30–9. doi: 10.1056/NEJMoa1112923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Guerra C, Linde-Zwirble WT, Wunsch H. Risk factors for dementia after critical illness in elderly medicare beneficiaries. Crit Care. 2012;16(6):R233. doi: 10.1186/cc11901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Fraser GL, Riker RR, Coursin DC. Sedation depth confounds delirium assessment and associated outcomes. N Engl J Med. 2014 in press. [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

SDC. Supplemental Figure.

Characterization of methodological quality for the n=17 studies based on a risk of bias (RoB) evaluation using the Cochrane Collaboration tool. (22) For each risk of bias domain, methodologic quality was deemed good of the RoB was low, fair if the RoB was deemed unclear, and poor if the RoB was high.

NIHMS606026-supplement-SDC.tif (92.7KB, tif)

RESOURCES