On 2016 Sep 19, Preben Berthelsen commented:

The consequence of the statistical problems in this study must be considered before accepting the authors’ contention that dexmedetomidine is better than saline in ICU patients with agitated delirium.

In the power/sample size calculation and the pre-trial ClinicalTrials registration, a difference of at least 20 hours in ventilator-free time was defined as the minimum difference of clinical interest. The authors found difference of only 17 hours. This finding was statistically significant but not clinically important as the authors - a priori - had defined the 20 hour difference as the minimum difference of interest.

The trial was stopped early when the sponsor – the manufacturer of dexmedetomidine – lost patience due to slow recruitment of patients. As a consequence, only 71 of the 96 stipulated patients could be included in the final statistical analysis – severely limiting the power of the trial. The authors state in the paper that “no data analysis by the study investigators had occurred prior to this decision.” The decision alluded to is the decision taken by the pharmaceutical company sponsoring the trial. But the essential point is when or why the investigators decided not to finish the trial according to the original plan. Was the decision taken before or after the finding of a statistically significant result? The answer cannot be found in the paper.

Additionally, analyses of the “hard” secondary end points (length of ICU stay, hospital stay or mortality) do not support the authors’ view that dexmedetomidine is superior to saline in ICU patients with agitated delirium.

In conclusion, I find that the authors’ hypothesis that dexmedetomidine is effective in ICU patients with agitated delirium not proven. Moreover, I suspect that the chance of reproducing the positive result of this trial to be no better than fifty-fifty.

P.G.Berthelsen. MD, MIA, DCHA. Charlottenlund, Denmark

On 2016 Sep 19, Preben Berthelsen commented:

The consequence of the statistical problems in this study must be considered before accepting the authors’ contention that dexmedetomidine is better than saline in ICU patients with agitated delirium.

In the power/sample size calculation and the pre-trial ClinicalTrials registration, a difference of at least 20 hours in ventilator-free time was defined as the minimum difference of clinical interest. The authors found difference of only 17 hours. This finding was statistically significant but not clinically important as the authors - a priori - had defined the 20 hour difference as the minimum difference of interest.

The trial was stopped early when the sponsor – the manufacturer of dexmedetomidine – lost patience due to slow recruitment of patients. As a consequence, only 71 of the 96 stipulated patients could be included in the final statistical analysis – severely limiting the power of the trial. The authors state in the paper that “no data analysis by the study investigators had occurred prior to this decision.” The decision alluded to is the decision taken by the pharmaceutical company sponsoring the trial. But the essential point is when or why the investigators decided not to finish the trial according to the original plan. Was the decision taken before or after the finding of a statistically significant result? The answer cannot be found in the paper.

Additionally, analyses of the “hard” secondary end points (length of ICU stay, hospital stay or mortality) do not support the authors’ view that dexmedetomidine is superior to saline in ICU patients with agitated delirium.

In conclusion, I find that the authors’ hypothesis that dexmedetomidine is effective in ICU patients with agitated delirium not proven. Moreover, I suspect that the chance of reproducing the positive result of this trial to be no better than fifty-fifty.

P.G.Berthelsen. MD, MIA, DCHA. Charlottenlund, Denmark