Introduction
Materials and methods
Patients
Study intervention
Intercurrent care
Data collection
Endpoints
Statistical analysis
Results
Dexemedetomidine | Haloperidol |
P
| |
---|---|---|---|
N | 10 | 10 | |
Age, years: median (IQR) | 52 (42 to 69) | 68.5 (43 to 78) | 0.241 |
Males: % | 90 | 80 | 0.531 |
APACHE II score in the 24 hours immediately prior to enrolment: median (IQR) | 13.3 (10 to 18) | 15.5 (11 to 19) | 0.383 |
Physical restraint prior to enrolment: % | 80 | 50 | 0.160 |
Midazolam use: % | 60 | 40 | 0.371 |
Propofol use: % | 70 | 70 | 1.000 |
Haloperidol use: % | 30 | 10 | 0.264 |
Morphine use: % | 80 | 80 | 1.000 |
Other sedative or anti-psychotic use: % | 0 | 0 | |
Time intubated prior to randomisation, hours: median (IQR) | 45.0 (34.5 to 73.3) | 65.2 (28.0 to 87.0) | 0.496 |
RASS -2 to 1 (ie. desired level of sedation and agitation control) at enrolment: % | 30 | 10 | 0.264 |
ICDSC ≥ 4 (ie. delirium present) at enrolment: % | 30 | 40 | 0.405 |
ICDSC ≥ 4 at any stage prior to or during infusion of trial drug: % | 50 | 50 | 1.00 |
ICDSC > 0 (ie. at least subsyndromal delirium present) at enrolment: % | 80 | 100 | 0.136 |
ICDSC > 0 at any stage prior to or during infusion of trial drug: % | 100 | 100 | 1.00 |
Surgical diagnosis: % | 70 | 30 | 0.074 |
Admission diagnosis | 0.493 | ||
Pneumonia, % | 0 | 20 | |
Other sepsis, % | 20 | 20 | |
Post cardiothoracic surgery, % | 30 | 10 | |
Post neurosurgery, % | 30 | 20 | |
Other, % | 20 | 30 |
Dexemedetomidine | Haloperidol |
P
| |
---|---|---|---|
Time receiving study drug infusion while intubated, %: median (IQR) | 100 (99.1 to 100.0) | 94.26 (68.9 to 100.0) | 0.2755 |
Loading dose given, % | 80 | 60 | 0.329 |
Drug rate of infusion during the periods when it was administered: mean (95% CI) | 0.47 (0.33 to 0.62) μg/kg/hour | 1.43 (0.96 to 1.90) mg/hour | N/A |
Study drug continued after extubation, % | 70 | 40 | 0.18 |
Time study drug continued after extubation, hours: median (IQR) | 2.5 (0.0 to 26.0) | 0.0 (0.0 to 2.0) | 0.15 |
Of patients who continued study drug after extubation, time continued, hours: median (IQR) | 15 (1 to 26) | 6.5 (2 to 16.5) | 0.57 |
Primary endpoint
Dexmedetomidine | Haloperidol |
P
| |
---|---|---|---|
Primary
| |||
Time to extubation, hours: median (IQR) | 19.9 (7.3 to 24.0) | 42.2 (23.2 to 117.8) | 0.016 |
Secondary
| |||
Time to ICU discharge after randomisation, days: median (IQR) | 1.5 (1 to 3) | 6.5 (4 to 9) | 0.0039 |
Total ICU length of stay, days: median (IQR) | 4.5 (2 to 7) | 8.0 (7.0 to 11.0) | 0.0093 |
Time taken to achieve a satisfactory RASS agitation score (-2 to 1), hours: median (IQR) | 4 (0 to 7) | 18 (9 to 22) | 0.071 |
Time taken to achieve a satisfactory ICDSC score (< 4), hours: median (IQR) | 0 (0 to 2) | 0 (0 to 2) | 0.509 |
Proportion of time with a satisfactory RASS agitation score (-2 to 1), %: median (IQR) | 50.5 (20 to 78) | 26.5 (13 to 42) | 0.256 |
Proportion of time with a satisfactory ICDSC score (< 4) when assessable, %: median (IQR) | 95.5 (51 to 100) | 31.5 (17 to 97) | 0.122 |
Proportion of time with a desirable ICDSC score (< 1) when assessable, %: median (IQR) | 61.0 (0.0 to 100.0) | 0.0 (0.0 to 0.0) | 0.134 |
Required restraint at any time while on study drug, % | 90 | 80 | 0.53 |
Of patients requiring restraint at any time while on study drug, time to first not requiring restraint for > 4 hours, hours: median (IQR) | 18 (7.3 to 38.5) | 38 (26.3 to 49.8) | 0.03 |
Need for supplemental sedative or analgesic medication, % | |||
Propofol | 60 | 80 | 0.33 |
Midazolam | 20 | 10 | 0.53 |
Morphine | 30 | 40 | 0.64 |
Of patients requiring supplemental sedative or analgesic medication, dose rate: mean (95% CI) | |||
Propofol, mg/hour | 87.7 (15.5 to 160.0) | 123.4 (30.4 to 216.3) | 0.504 |
Midazolam, mg/hour | 1.0 (1.0 to 1.0) | 2.4 (N/A) | N/A |
Morphine, mg/hour | 1.0 (0.5 to 1.5) | 1.6 (0.3 to 2.8) | 0.28 |
Of patients requiring supplemental sedative or analgesic medication, % time this was required: mean (95% CI) | |||
Propofol | 41.2 (0 to 88.2) | 79.5 (61.8 to 97.2) | 0.05 |
Midazolam | 0 (0 to 0) | 0 (N/A) | N/A |
Morphine | 0 (0 to 0) | 32.9 (0 to 100) | 0.29 |
Required tracheostomy | 0 | 3 | 0.06 |
Secondary endpoints: efficacy
Secondary endpoints: safety
Dexmedetomidine | Haloperidol | P | |
---|---|---|---|
ICU mortality, n | 0 | 0 | 1.00 |
Hospital mortality, n | 0 | 1 | 0.31 |
QTc interval prior to study drug, sec: mean (95% CI) | 0.411 (0.384 to 0.438) | 0.426 (0.395 to 0.457) | 0.41 |
QTc interval while on study drug, sec: mean (95% CI) | 0.395 (0.365 to 0.425) | 0.446 (0.423 to 0.457) | 0.0061 |
Patients with abnormal QTc interval (> 0.440 sec) while on study drug: % | 40 | 40 | 1.00 |
Patients with longer QTc interval than baseline while on study drug: % | 30 | 70 | 0.07 |
Arrhythmia while on study drug: % | 20 | 20 | 1.00 |
Patients requiring norepinephrine* infusion while on study drug: % | 80 | 50 | 0.16 |
Patients newly requiring norepinephrine or a 20% increase in norepinephrine* infusion in the 8 hours after commencement of study drug: % | 20 | 20 | 1.00 |
Of patients requiring norepinephrine, proportion of the time while on study drug receiving norepinephrine: mean (95%CI) | 59.8 (17.9 to 100.0) | 34.4 (0.0 to 87.1) | 0.37 |
Of patients requiring norepinephrine, level of infusion (μg/min) while on study drug: mean (95%CI) | 2.51 (0.07 to 4.90) | 3.97 (0.00 to 11.07) | 0.55 |
Any adverse event attributed to the study drug: % | 0 | 10** | 0.31 |
Patients requiring reintubation: n, % | 0 | 0 | 1.00 |
Discussion
Efficacy
Safety
Rationale for trial design
Strengths and limitations
Conclusions
Key messages
-
Haloperidol is the drug recommended and most commonly used for the treatment of ICU-associated delirious agitation, but there is little evidence to support this practice.
-
Dexmedetomidine is a selective α 2-agonist licensed for use as a postoperative sedative that may have advantages over haloperidol in this context.
-
In this pilot study, we randomised 20 patients who remained intubated only because of agitated delirium to receive infusions of either haloperidol or dexmedetomidine in addition to usual care.
-
Dexmedetomidine significantly shortened time to extubation and decreased ICU length of stay.
-
We suggest dexmedetomidine is a promising agent for this indication, and warrants testing in a multicentre effectiveness trial.