Dexmed Agitated Delirium Pilot
PubMed • Full text
Clinical Question
In critically ill, non-intubated patients with agitated delirium who are refractory to treatment with haloperidol, is dexmeditomidine a viable rescue agent in terms of cost, safety, and cost.
Bottom Line
In non-intubated ICU patients with agitated delirium, the addition dexmedetomidine to intravenous haloperidol may be a safe and cost effective treatment but more studies are required.
Major Points
The unfortunately common ICU related adverse event is delirium. Often multifactorial, delirium is associated with worse outcomes for patients including increased ICU length of stay, increase ventilator time, and ultimately mortality. Agitation associated with delirium is also dangerous for both the patient care staff. Unfortunately delirium is often refractory to medical management and antipsychotics are the agents of choice. Dexmeditomidne, when used as a sedative is associated with a lower rate of delirium in the intubated patient but little evidence is available in the non-intubated patient or in treating active delirium. With the anxiolytic effects of dexmeditomidine, this trial was conducted to investigate if patients refractory to haloperidol would obtain better control. After prospectively enrolling 132 patients in a non-randomized, non-blinded, observational study, the findings suggest the dexmeditomidine may be an effective and and cost effective choice and more study is required.
Guidelines
As of November 2016, no guidelines reflect the findings of this trial
Design
- Prospective, Single Centre, non-randomized, observational trial
- N=132
- Dexmeditomidine (haloperidol non-responders) (n=46)
- Haloperidol (haloperidol responders) (n=86)
- Setting: 13 bed medical-surgical intensive care unit
- Enrollment: December 31, 2013-December 31, 2014
- Primary Outcome:
- Quality of sedation - % time patient maintained satisfactory level of sedation
Population
Inclusion Criteria
- Between 18-95 years old
- Richmond Agitation Sedation Score of +1 to +4
- Acute onset and fluctuating course of mental disturbance characterized by inattention and either disorganized thinking or altered LOC (evaluated by CAM ICU)
- Intensive Care Delirium Screening Checklist (ICDSC)
Exclusion Criteria
- Intubation, non-invasive ventilation previous to or throughout study
- Pregnancy (Category C)
- Previous diagnosis of psychopathic disorder or history of substance abuse
- Administration of antipsychotic medication in 10 days previous to enrollment
- Any contraindication to haloperidol or dexmedetomidine.
- Neurologic condition that did not allow appropriate neuropsychiatric evaluation (stupor/coma equivalent to a RASS < -3)
Baseline Characteristics
‘’Dexmedetomidine Group Presented
- Age: 73 ± 12
- Male: 80%
- APACHE II Score: 15.3 ± 6.0
- RASS: 3.9 ± 1.8
- Physical Restraints: 34%
- Delirium Assessment
- PRE-DELIRIC Score: 76.8 ± 12.2
- CAM-ICU: 100
- MICDSC: 7.8 ± 3.2
Interventions
- Non-Pharmacologic Prevention of Delirium
- All patients with PRE-DELIRIC ≥50% or older than 65 received:
- repeated reorientation by trained volunteer/nurse
- provision of cognitively stimulating activities three times/day
- non-pharmacologic sleep protocol to enhance normalization of sleep/wake cycles
- early mobilization activities and range of motion exercises
- timely removal of catheters and physical restraints
- institution of the use of eyeglasses and magnifying lenses
- hearing aids and earwax disimpaction, and
- early correction of dehydration.
- All patients with PRE-DELIRIC ≥50% or older than 65 received:
- Initial Haloperidol Titration
- Haloperidol IV 2.5-5mg every 10-30min until RASS 0 to -2 or 30mg TDD
- Then stratified as responders or non-responders
- Haloperidol Responders:
- Haloperidol infusion of 0.5-1mg/h, titrate to maintain RASS 0
- Haloperidol non-responders:
- Haloperidol infusion of 0.5-1mg/h plus dexmedetomidine at 0.2-0.7mcg/kg/h to maintain RASS 0. Once at a RASS of 0, haloperidol was gradually tapered and discontinued. Adjustments to dexmedetomidine infusion were made if necessary.
Outcomes
Comparisons are Dexmedetomidine vs Haloperidol.
Primary Outcomes
- % of time patient maintained at the satisfactory level of sedation (RASS 0-2) / total sedation time x 100.
- 92.7 vs., P=0.0001
Secondary Outcomes
- Percentage of time under satisfactory ICDSCa scores (< 4 points)
- 52.0 vs. 29.5, P= 0.005
- % Removal of physical restraint during treatment
- 87.8 vs. 93.1, P=NS
- Need for supplement analgesics. Mean doses (mg/kg/day)
- Acetaminophen
- 20.8 ± 5.3 vs. 21.7 ± 7.8, P=NS
- Metamizol
- 28.5 ± 7.1 vs. 80.3 ± 8.3, P<0.001
- Morphine
- 0.10 ± 0.005 vs 0.60 ± 0.21, P<0.0001
- Sedation time (hours)
- 33 ± 11 vs. 36 ± 15, P=NS
- Mean doses of drug
- 0.47 ± 0.12mcg/kg/h vs. 1.63 ± 0.11mg/h
- Treatment Failure
- 0 vs. 14%, P=0.03
Cost Comparisons
- Mean cost of Drugs, $
- 86.2±12.6 vs. 4.9±3.1, P<0.0001
- Secondary costs of ICU Care from ICU Admission until end of infusion, $
- 4066±412 vs. 3916±399, P=NS
- Recovery Care Costs until ICU Discharge, $
- 6836±382 vs. 11356±983, P<0.01
- Total costs, $
- 10902±794 vs. 15272±1385, P<0.0001
Adverse Events
‘’Primary Safety Outcome
- Oversedation (RASS -3 to -5) requiring discontinuation of treatment
- 0 vs. 11%, P=0.01
‘’Secondary Safety Outcomes
- ICDSC between 0-1 prior to discharge
- 100% vs 100%
- QTc prolongation
- 0 vs. 2.3% P=NS
- Supraventricular Arrhythmia
- 26% vs. 27% P=NS
- Bradycardia Requiring Treatment
- 10.8% vs 4.6%, P=NS
- Maintained MAP <70 mmHg (hypotensive)
- 13% vs 21%, P=NS
- Newly initiated Norepinepherine infusion
- 8.6% vs. 12.7%, P=NS
- Patients requiring non-invasive ventilation
- 0 vs. 9.3%, P=0.016
- ICU Mortality
- 0 vs. 2.3% P=NS
- Hospital Mortality
- 8.6% vs. 8.1%, P=0.09
Criticisms
- Non-randomized, no blinding
- increased risk of observer and selection bias[1]
- Only evaluated agitated (hyperactive) delirium
- Did not report Haloperidol dose in Dexmedetomidine arm
- Doses of Haloperidol above 10mg may be unnecessary and only lead to adverse events and be an unfair comparator[2]
- Including ICU LOS in the cost effective may be a red herring
Funding
Internal ICU Funding