This is the first study to demonstrate that dexmedetomidine is more effective than conventional haloperidol therapy for the treatment of combined agitation and delirium in intubated patients in the ICU. Dexmedetomidine, in comparison to haloperidol, safely shortened the time to extubation, reduced ICU length of stay, hastened liberation from mechanical restraint, reduced the need for supplementary sedation, reduced QTc interval prolongation and possibly reduced the need for tracheostomy.
In the primary analysis, we treated tracheostomy as equivalent to extubation. We contend this is reasonable as tracheostomy in this context represents the failure of treatment of agitation and delirium, reflecting the clinician's decision that the patient would be unlikely to be soon extubated. Had the three patients in the haloperidol group not undergone tracheostomy, they could only have remained intubated for longer; hence our analysis biases towards observing less difference between the two groups. We nonetheless also analysed the data by excluding these patients and by treating them as censored in the survival analyses; our conclusion was unchanged.
There is a theoretical concern that given its short half-life, when dexmedetomidine is discontinued a patient might return to a state of agitation so severe as to require reintubation. That none of our patients required reintubation does not discount this possibility, given the small number we studied. We continued dexmedetomidine following extubation for as long as the treating clinician felt the patient was at risk of reintubation due to agitation. Had we not done so, this risk may or may not have been manifest.
Dexmedetomidine shares no common adverse reactions with haloperidol. Transient hypertension during the administration of the loading dose, followed by hypotension and bradycardia, are the only adverse reactions reported . Our study was not powered to observe anything but marked haemodynamic effects, so we can only conclude that dexmedetomidine did not cause a dramatic increase in vasopressor requirement.
Rationale for trial design
Dexmedetomidine has been studied and marketed primarily as a sedative alternative to propofol or benzodiazepines. The sedative, analgesic and anxiolytic effects of dexmedetomidine have been convincingly demonstrated [9, 17–20]. These trials were performed in the initial postoperative period and so the approved product information limits the duration of dexmedetomidine infusion to 24 hours . However, prolonged infusions have been used successfully in case series and published trials [11–13, 21, 22]. We considered allowing clinicians to decide when to terminate the infusion would be safer and more effective than imposing an arbitrary time limit.
Dexmedetomidine might prevent agitation by reducing the use of other sedatives known to cause delirium . In a trial involving 106 patients, dexmedetomidine resulted in more days alive without delirium or coma and more time at the targeted level of sedation than did lorazepam . However, concerns were subsequently raised about the equivalence of dosing , cost-effectiveness  and the validity of the outcome measure . A second trial comparing dexmedetomidine to midazolam as a sedative in 375 patients found dexmedetomidine associated with significantly less delirium and a shorter duration of intubation . However, even if cost-effective in preventing delirium elsewhere , widespread application of dexmedetomidine as a sedative is prohibitively expensive in our current context. We therefore wondered whether dexmedetomidine might be effective in the treatment of established delirium, reasoning that this might be sufficiently cost-effective.
Despite widespread use and incorporation into international guidelines , there is no evidence from placebo-controlled trials supporting the use of haloperidol (or indeed any other medication) in the management of ICU-associated delirium . Our results may therefore reflect comparison with an ineffective agent. Olanzipine and risperidone are the only other agents used in our management of critical illness delirium: both have been compared with haloperidol; neither is more effective [29, 30]. We therefore concluded that, although imperfect, haloperidol represented 'standard care' in our management of delirium in the ICU.
We administered haloperidol by infusion rather than conventional bolus dosing. This approach has been used successfully in case series of ICU patients [31, 32] and is presented as theoretically superior in current guidelines . The relatively long half-life of haloperidol (12 to 36 hours) means that control of agitation when the infusion rate is increased may take longer in comparison to dexmedetomidine. This concern probably does not explain our results, as haloperidol tended to be used at the upper end of the permitted dose in most patients for most of the time it was infused. We chose to use haloperidol by infusion for two main reasons. First, we were concerned that 'on demand' boluses of haloperidol might lead to relative underdosing compared with dexmedetomidine by continuous infusion. Second, we designed our trial as a prelude to a larger double-blind study, in which (to preserve blinding) both study drugs would need to be given by continuous infusion. In the absence of evidence, we selected a dose range of haloperidol that reflected our usual practice. Although this was somewhat less than the 3 to 11.35 mg/hour (in a 75 kg patient) recommended by current guidelines , a dose of 272 mg haloperidol (as per those guidelines) in a 24-hour period substantially exceeds our routine practice. We nonetheless accept that we may have found haloperidol less effective than dexmedetomidine due to an inadequate dose.
As is the case for haloperidol, the optimal dose rate of dexmedetomidine is also not well characterised. We used up to the maximum dose of dexmedetomidine licensed for use in Australia (and elsewhere) at the time of the study, which was 0.7 μg/kg/hour. Two large randomised controlled trials have now safely used doses up to 1.4  and 1.5  μg/kg/hour: at higher doses dexmedetomidine might be even more effective for this indication.
Our study was not blinded. We were concerned at the potential for QTc interval prolongation with high doses of haloperidol , particularly as continuous infusion is not our usual practice. We also noted the risk of hypotension associated with dexmedetomidine , which was at the time an unfamiliar drug in our unit. Having not observed significant complications with either drug, we suggest a larger, blinded trial would be sufficiently safe.
Strengths and limitations
This is a pilot study, with significant limitations. The principal concern is the lack of blinding. If our consultant physicians and bedside nurses had more confidence in dexmedetomidine than haloperidol, they may have been more inclined to attempt earlier extubation in dexmedetomidine patients, or proceed to tracheostomy in patients receiving haloperidol. This is especially true given our usual clinical practice of not using objective criteria to make such decisions, although imposing such restrictive criteria would potentially have led to a significant change in intercurrent care. However, the observed magnitude of the differences between the groups is difficult to attribute to factors other than, at least in part, the different effects of the drugs.
We allowed physicians to decide whether or not to use an initial bolus of dexmedetomidine. There is growing evidence that such a bolus may cause adverse cardiovascular effects (hypotension or hypertension) [22, 33] while adding little sedation [21, 34]. Insufficient numbers may have precluded observation of such effects. Similarly, we may have studied too few patients to allow us to observe clinically important rebound hypertension and tachycardia associated with the abrupt cessation of dexmedetomidine. However, others have found this quantitatively insignificant . The small size of our study also raises the possibility that our results are confounded by unobserved imbalances in the baseline characteristics of the two groups. Although this cannot be excluded and is inherent to every pilot study, again the magnitude of the effect observed adds plausibility to our findings.
We did not keep a screening log, but as our ICU admits about 1000 mechanically ventilated patients per year, it is conceivable that approximately 2300 patients were informally screened but only 20 enrolled. At the time of the study, we, like most others [35, 36], did not routinely assess for delirium using a screening tool. Despite its known high incidence, clinical underdiagnosis of delirium in the ICU [37, 38] partly explains our recruiting difficulty. Additionally, we required patients be unsuitable for extubation only because of agitation. Dexmedetomidine may be effective in delirious patients with ongoing physiological instability; indeed in comparison with benzodiazepines others have found this to be the case [11, 13]. However, while there are several well-studied and effective sedatives, we were concerned that this was not true for drugs specifically targeting delirious agitation. Although our study reflects use of dexmedetomidine in the context of our routine practice at the time, we propose that any follow-up trial should actively screen for delirium using objective criteria. Additionally, we only studied patients with agitated delirium. Hypoactive delirium may be eight times more common (61%) than delirium associated with agitation (8%) , but, while no less important, hypoactive delirium is difficult to identify without active screening. The results of our pilot study do not allow us to comment on the management of hypoactive delirium.
We have no reliable data on pre-morbid cognitive impairment in these patients, the presence of intercurrent conditions known to be associated with delirium or any history of substance abuse. Any imbalance in these factors between the two groups may have confounded the results, in particular as dexemedetomidine may be especially useful for managing drug withdrawal [40, 41]. Having identified these potential confounders, we suggest a future definitive trial examine these factors in detail.
By chance, there were more surgical patients in the dexmedetomidine group, although with the small size of the study this difference was not significant. Dexmedetomidine is an analgesic and pain causes agitation, so dexmedetomidine may have appeared more effective because it was a better treatment for pain. However, in multivariate analysis, surgical diagnosis was not a significant predictor of time to extubation, arguing against this hypothesis.
Relatively few (50%) of our patients had delirium, as identified by an ICDSD score of 4 or above. This is surprising, as the impression of their treating clinicians was that each had delirium as the cause of their agitation. However, Ouimet and colleagues  demonstrated that 'subsyndromal' delirium (an ICDSC score > 0) was also associated with poor outcome, and all of our patients has an ICDSC score more than 0 at some point, supporting the clinical impression that they were delirious. Although agitation is commonly caused by delirium, this is not always the case; pain and presence of an endotracheal tube alone can be sufficient to cause agitation. Some patients were too deeply sedated at the time of enrolment to permit proper use of the ICDSC. Presumably this sedation had been administered because of earlier agitation, which we were then unable to objectively record. A significant weakness of this pilot study is therefore the lack of objective evidence of delirium in many patients prior to randomisation, a deficiency which should be rectified in any confirmatory trial by the use of active screening using either the ICDSC or the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) .