Are the desirable effects relative to undesirable effects? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Resource use Are the resources required ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Haloperidol is a relatively inexpensive antipsychotic agent. Is the incremental cost small relative to the net benefits? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies
Acceptability Is the option acceptable to key stakeholders? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Feasibility Is the option feasible to implement? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Recommendation Should haloperidol vs. no such strategy be used in critically ill adults WITHOUT delirium? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings ○ ○ ● ○ ○
Benefits & harms of the options What is the overall certainty of this evidence? ○ No included studies ○ Very low ● Low ○ Moderate ○ High The relative importance or values of the Is there important uncertainty about how much people value the main outcomes? ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty or variability ○ No important uncertainty or variability ○ No undesirable outcomes Are the desirable anticipated effects large? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies
Are the undesirable anticipated effects small? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Are the desirable effects large relative to undesirable effects? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Resource use Are the resources required small? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies The price of risperidone is relatively low. However, the long-term consequences of ongoing therapy could be substantive.
to the ICU following surgery. Patients were followed for 7 days and evaluated for delirium with the CAM-ICU. Benefits & harms of the options What is the overall certainty of this evidence? ○ No included studies ○ Very low ○ Low ● Moderate ○ High The relative importance or values of the main The incidence of delirium in the 7 days following intervention group: I = 32 (9%) of 350 vs P = 79 (23%) Time to extubation was statistically significantly Is important uncertainty about how much people value the main outcomes? ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ○ Probably no important uncertainty or variability ● No important uncertainty or variability
Acceptability Is the option acceptable to key stakeholders? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Feasibility Is the option feasible to implement? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Recommendation Should an alpha-2 agonist (e.g., dexmedetomidine) vs. no such strategy be used for patients WITHOUT delirium?
used in 22,292 (7.7%). Cardiac surgery was patients and 2,321 (53.0%) used statins. and 3,478 (1.3%) of the patients in the statin and respectively, with no difference between groups 1.05 [95% CI, 0.85-1.29]; P = .56) or in cardiac 1.03 [95% CI, 0.68-1.56]; P = .89)." value the main outcomes? ○ Possibly important uncertainty or variability ○ Probably no important uncertainty or variability ● No important uncertainty or variability ○ No known undesirable outcomes Are the desirable anticipated effects large? ○ No ● Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies Are the undesirable anticipated effects small? ○ No ○ Probably no ● Uncertain ○ Probably yes
○ Yes ○ Varies Are the desirable effects large relative to undesirable effects? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Resource use Are the resources required small? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Is the incremental cost small relative to the net benefits? ○ No ○ Probably no ● Uncertain ○ Probably yes
○ Yes ○ Varies Acceptability Is the option acceptable to key stakeholders? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Feasibility Is the option feasible to implement? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Recommendation Should statins vs. control be used for delirium prevention?
discharge to a nursing home not estimable - cognitive impairment not estimable - PTSD incidence not estimable - incidence of depression not estimable - functionality not estimable - distress not estimable - Mortality (at any time point) 1 randomised trials not serious not serious not serious very serious a none 9/34 (26.5%) 7/34 (20.6%) RR 1.29 (0.54 to 3.06) 60 more per 1,000 (from 95 fewer to 424 more) LOW CRITICAL Delirium duration 1 randomised trials not serious not serious not serious serious b none 34 34 - MD 0 days (0.56 lower to 0.56 higher) MODERATE IMPORTANT
Problem Is there a problem priority? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies The evidence used to answer this question comes from 1 RCT: Al-Quadheeb 2016 . This evidence revealed no statistically significant effect of haloperidol compared to placebo treatment with regard to incidence, duration, days of mechanical ventilation, ICU length of stay, or delirium duration. Although no open label haloperidol was used in this study, the numbers of participants was small and included 34 in both the haloperidol and placebo arms. Benefits & harms of the options What is the overall certainty of this evidence? ○ No included studies ○ Very low ● Low ○ Moderate ○ High The relative importance or values of of interest: Is there important uncertainty about how much people value the main outcomes? ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty or variability ○ No important uncertainty or variability
Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option ○ ● ○ ○ Recommendation We do not suggest using haloperidol for sub-syndromal delirium in critically ill patients as there is little evidence that it decreases incidence of full syndrome delirium, ICU length of stay, days of mechanical ventilation, delirium duration, or mortality. Justification We are moderately certain that haloperidol use is not associated with decreased duration of delirium or ICU length of stay. We have low certainty about the effect of haloperidol on mortality. Given the lack of clear benefit patients should not be routinely exposed to potential harms associated with this medication. Subgroup considerations Patients who experience significant distress secondary to symptoms of a delirium such as anxiety, fearfulness, hallucinations, or delusions or who may be physically threatening to self or others may benefit from the use of lowest effective of haloperidol for symptomatic relief. Haloperidol should be discontinued following the resolution of the patient's distress. Research possibilities More research is needed on the benefit of haloperidol in treating distress due to delirium symptoms and system innovations to ensure that patients do not remain on antipsychotics indefinitely following symptomatic initiation during a delirium episode. Comments during electronic voting by entire panel Can we say haloperidol should never be used in sub-syndromal delirium? What if pt. is subsyndromal & agitated, belligerent, etc. without enteral access? Author(s): Mark E. Nunnally Question: An atypical antipsychotic compared to no such strategy in critically ill adults WITH subsyndromal delirium Setting: intensive Care Units Bibliography: Hakim 2012 Quality assessment № of patients Effect Quality Importance № of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations an atypical antipsychotic no such strategy Relative (95% CI) Absolute (95% CI) discharge to a nursing home
not estimable - cognitive impairment not estimable - PTSD incidence not estimable - incidence of depression not estimable - functionality not estimable - distress not estimable - Mortality (at any time point) 1 randomised trials not serious not serious serious a very serious b none 2/51 (3.9%) 1/50 (2.0%) RR 1.96 (0.18 to 20.94) 19 more per 1,000 (from 16 fewer to 399 more) VERY LOW CRITICAL Delirium duration 1 randomised trials not serious not serious serious a very serious c none 7 17 - MD 0 days (1.15 lower to 1.15 higher) VERY LOW IMPORTANT delirium severity
incidence with evidence favoring the intervention group and risk ratio of 0.41 (0.02, 0.86 95 % CI). Length of stay in the ICU has high certainty and favors neither intervention or control (mean difference -1.00; 95% CI -0.71) Additionally, patients who are started on an antipsychotic for delirium in the ICU often remain on these medications after discharge from the ICU and even after hospital discharge . These are additional harms that cannot be addressed by this current literature. Are the desirable anticipated effects large? ○ No ○ Probably no ● Uncertain Are the undesirable anticipated effects small? ○ No ○ Probably no ● Uncertain Are the desirable effects large relative to undesirable effects? ○ No ○ Probably no ● Uncertain Resource use Are the resources required small? ○ No ○ Probably no Expense of risperidone is intermediate.
○ Uncertain ● Probably yes Is the incremental cost small relative to the net benefits? ○ No ○ Probably no ● Uncertain Acceptability Is the option acceptable to key stakeholders? ○ No ○ Probably no ● Uncertain Feasibility Is the option feasible to implement? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes
Resource use Are the resources required small? ○ No ○ Probably no ○ Uncertain Probably yes ○ Yes ○ Varies Haloperidol is an inexpensive antipsychotic medication. Is the incremental cost relative to the net benefits? ○ No ○ Probably no Uncertain ○ Probably yes ○ Yes ○ Varies The relative net benefits are uncertain based upon this evidence.
ICU length of stay Setting: Intensive care units Perspective: Criteria Judgements Research evidence Problem Is there a problem priority? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies The evidence for this recommendation comes from 2 RCT's: Devlin 2010 (quetiapine) and Girard 2010 (ziprasidone), including a total of 48 patients in the intervention groups and 54 in the placebo comparator group. Open label haloperidol was used in both of these studies. Benefits & harms of the options What is the overall certainty of this evidence? ○ No included studies ○ Very low ● Low ○ Moderate ○ High The relative importance or values of
Is there important uncertainty about how much people value the main outcomes? ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty or variability ○ No important uncertainty or variability ○ No known undesirable outcomes Are the desirable anticipated effects large? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies
Recommendation Should an atypical antipsychotic vs. no such strategy be used in critically ill adults WITH delirium? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings ○ ○ ● ○ ○ Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option ○ ● ○ ○ Recommendation We do not suggest using atypical antipsychotics for delirium in critically ill patients. Justification We have moderate evidence that atypical antipsychotic use is not associated with a decreased ICU length of stay. We have low certainty about the effect of atypical antipsychotics on delirium duration or duration of ventilation or mortality, but given the lack of demonstrated benefit patients should not routinely be exposed to potential harms associated with these medications. Subgroup considerations Patients who experience significant distress secondary to symptoms of an episode of delirium such as anxiety, fearfulness, hallucinations, or delusions or who may be physically threatening to self or others may benefit from the use of lowest effective doses of atypical antipsychotics for symptomatic relief. Atypical antipsychotics should be discontinued following the resolution of the patient's distress. Research possibilities More research is needed on the benefit of atypical antipsychotics in treating distress due to delirium symptoms, longer term outcomes after critical illness and system innovations to ensure that patients do not remain on antipsychotics indefinitely following symptomatic initiation during a delirium episode. Comments during electronic voting by entire panel Clinically atypicals reduce delirium in some patients, perhaps at the cost of ↑sedation & risk of AEs and complications. perhaps “no recommendation". Maybe part of the problem is that not all delirium is the same. "Routine" use of these drugs may not be indicated but considered if agitation, hallucinations, etc.
Author(s): Mark E. Nunnally, Karin Neufeld Date: Question: An an alpha-2 agonist (e.g., dexmedetomidine) compared to no such strategy in critically ill adults WITH delirium Setting: Intensive care unit Bibliography: Reade MC, et. al. JAMA 2016, PMID: 26975647 Quality assessment № of patients Effect Quality Importance № of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations an an alpha-2 agonist (e.g., dexmedetomidine) no such strategy Relative (95% CI) Absolute (95% CI) In-hospital mortality 1 randomised trials serious a not serious serious b very serious none 2/39 (5.1%) 0/32 (0.0%) % Difference 5.1 (-1.8 to 12.1) -- per 1,000 (from -- to --) VERY LOW CRITICAL Hospital length of stay 1 randomised trials serious a not serious serious b serious c none 39 32 - median 0 days (3 lower to 3 higher) VERY LOW IMPORTANT ICU length of stay 1 randomised trials serious a not serious serious b serious c none 39 32 - median 1 days fewer (2.1 fewer to 0.1 more) VERY LOW IMPORTANT Duration of CAM positive delirium 1 randomised trials serious a not serious serious b not serious none 39 32 - median 24 hours lower (41 lower to 6 lower) LOW IMPORTANT Ventilator-free days (follow up: 7 days)
○ No known undesirable outcomes Are the desirable anticipated effects ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Are the undesirable anticipated effects small? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies
Acceptability Is the option acceptable to key stakeholders? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Feasibility Is the option feasible to implement? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Recommendation Should an an alpha-2 agonist (e.g., dexmedetomidine) vs. no such strategy be used in critically ill adults WITH delirium? Balance of consequences Undesirable consequences clearly outweigh desirable Undesirable consequences probably outweigh The balance between desirable and undesirable Desirable consequences probably outweigh Desirable consequences clearly outweigh
Problem Is there a problem priority? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes The evidence for this recommendation comes from one study (Needham et al 2016) : a randomized double blind, placebo controlled of 272 patients in Medical ICUs at 35 US hospitals randomized to rosuvastatin (40 mg loading dose and 20 mg daily until 3 days after discharge from the ICU) or placebo -Inclusion CRITERIA: patients with ARDS; receiving Mechanical Ventilation through an endotracheal tube; meeting SIRS criteria with a known or suspected infection; EXCLUSION CRITERIA: ARDS > 48 hours, Pre-Existing condition adversely affecting survival or weaning from Mech Vent; receiving statins within 48 hours of randomization; > 5X's CK, AST, ALT; SPECIFIC to COGNITIVE OUTCOMES ADDITIONAL EXCLUSIONS WERE< 18 years of age; non-English speakers; Homeless; pre-existing cognitive impairment. Benefits & harms of the options What is the overall certainty of this evidence? ○ No included studies ○ Very low ○ Low ● Moderate ○ High The relative Is there important uncertainty about how much people ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty or variability
value the main outcomes? ○ No important uncertainty or variability ○ No known undesirable outcomes Are the desirable anticipated effects ● No ○ Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies Are the undesirable anticipated effects small? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations a single-component non-pharmacologic strategy that is not focused on sleep improvement or early mobilization, reduce delirium (incidence/prevalence, LOS-ICU, hospital mortality or other outcomes) no such intervention Relative (95% CI) Absolute (95% CI) Delirium incidence/prevalence (Taguchi 2007) 1 randomised trials serious a not serious not serious very serious b none 2/5 (40.0%) 1/6 (16.7%) RR 0.31 (-- to --) 115 per 1,000 (from -- to --) VERY LOW IMPORTANT Delirium incidence/prevalence (Lee, 2013) 1 observational studies serious not serious serious very serious c none 6/49 (12.2%) 16/46 (34.8%) RR 0.35 (0.15 to 0.82) 226 fewer per 1,000 (from 63 fewer to 296 fewer) VERY LOW IMPORTANT Delirium incidence/prevalence (Black, 2011) 1 observational studies serious not serious serious serious d none 23/79 (29.1%) 54/70 (77.1%) RR 0.38 (0.26 to 0.54) 478 per 1,000 (from 355 fewer to 571 fewer) VERY LOW IMPORTANT Delirium incidence (Simons, 2016) 1 randomised trials not serious not serious not serious not serious e none 137/361 (38.0%) 123/373 (33.0%) RR 1.15 (0.95 to 1.40) 49 more per 1,000 (from 16 to 132 more) ⨁⨁⨁⨁ HIGH IMPORTANT Delirium incidence/prevalence (Ono, 2011) 1 randomised trials very serious serious serious very serious none 1/10 (10.0%) 5/12 (41.7%) not estimable VERY LOW
Summary of findings: variability ● Probably no important uncertainty or variability ○ No important uncertainty or variability ○ No undesirable outcomes Are the desirable anticipated effects large? ● No ○ Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies Are the undesirable anticipated effects small? ● No ○ Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies