Dexmed Agitated Delirium Pilot

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Carrasco G, Baeza N, Cabré L. "Dexmedetomidine for the Treatment of Hyperactive Delerium Refractory to Haloperidol in Nonintubated ICU Patients: A nonrandomized controlled trial". Crit Care Med. 2016 Jul. 44(7):1295-1306.
PubMedFull 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.
  • 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

Further Reading

  1. Parker RO et al. Dexmedetomidine for the treatment of hyperactive delirium refractory to haloperidol in non-intubated patients. J Thorac Dis 2016. 8:E596-8.
  2. Knauert MP & Pisani MA Dexmedetomidine for hyperactive delirium: worth further study. J Thorac Dis 2016. 8:E999-E1002.