Correspondence
3
Moraes RB, Friedman G, Lisboa T, Viana MV, Hirakata V, Czepielewski MA. Comparison of cumulative incidence analysis and Kaplan-Meier for analysis of shock reversal in patients with septic shock. J Crit Care 2012; 27: 317.e7–11.
Author’s reply
If you would like to respond to an article published in The Lancet Respiratory Medicine, please submit your correspondence online at: http:// ees.elsevier.com/thelancetrm
e28
I thank Mark van den Boogaard and Peter Pickkers, and Marina Verçoza Viana and colleagues, for their interest in the Hope-ICU study.1 In response to van den Boogaard and Pickkers, first, I agree that the study was not large enough to exclude a small benefit or harm; however, we noted little difference in delirium duration between groups, suggesting that an effect size in either direction would be small. Second, the risk delirium prediction model PRE-DELIRIC for patients in the intensive-care unit was not available when Hope-ICU was designed.2 We did, however, show in two previous observational studies in a study population similar to that used in the Hope-ICU trial that the incidence of delirium in patients who could be screened was 63–65%.3 These data are consistent with international data from several studies. The high prevalence of delirium in our study supports this rationale. It would be useful to assess the predictive value of the PRE-DELIRIC score in our study cohort to establish whether this score is better at identifying risk of delirium than our assumptions regarding sick ventilated patients or whether patients at higher risk have a beneficial response to haloperidol. Finally, van den Boogaard and Pickkers were correct to say that Hope-ICU did not differentiate between haloperidol as a prophylactic therapy or as a treatment; rather, our pragmatic study was based on how haloperidol would fit into routine
clinical practice if a benefit was established—ie, given early to patients at high risk to prevent delirium and to treat patients with delirium on admission to hospital or as they emerge from coma. In reply to Verçoza Viana and colleagues, it is true that the dose of haloperidol that we used has not been established on the basis of efficacy and, historically, much larger doses have been used to treat delirium.4 However, these larger doses are not supported by the evidence regarding receptor occupancy or by the concern over serious side-effects resulting in the US Food and Drug Association black-box warning for intravenous haloperidol.5–7 With respect to the criteria for stopping the study drug, I agree that we cannot exclude that a small preventative effect was lost. Verçoza Viana and colleagues are correct to suggest that there are competing-risk situations, in which one outcome (eg, death) means another outcome is unrecorded. That situation, however, does not apply to our trial. The outcome measured was the proportion of a specified period that patients were alive and delirium free. As part of that definition, patients who died within this period were assigned a value of zero—ie, incorporating the worse outcome, death, rather than taking into account unrecorded delirium in patients who died. Our study results are a stimulus to pursue more options in delirium research, looking beyond haloperidol to alternative therapies—eg, antiinflammatory interventions—while reinforcing the need to concentrate our efforts on implementation of non-pharmalogical interventions known to help patients—eg, early
mobilisation.8,9 We maintain that the results of our randomised controlled trial do not support the hypothesis that haloperidol reduces delirium in critically ill patients. In view of that conclusion, and until results of ongoing larger trials are available, haloperidol should be reserved for management of agitation in this population of patients. VJP has received honoraria from Orion.
Valerie J Page [email protected] Intensive Care Unit, Watford General Hospital, Watford WD18 0HB, UK 1
2
3
4
5
6
7
8
9
Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo- controlled trial. Lancet Respir Med 2013; 1: 515–23. van den Boogaard M, Pickkers P, Slooter AJC, et al. Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study. BMJ 2012; 344: e420. Page VJ, Navarange S, Gama S, McAuley DF. Routine delirium monitoring in a UK critical care unit. Crit Care 2009; 13: R16. Wang EHZ, Mabasa VH, Loh GW, Ensom MHH. Haloperidol dosing strategies in the treatment of delirium in the critically ill. Neurocrit Care 2012; 16: 170–83. Kapur S, Zipursky R, Roy P. The relationship between D2 receptor occupancy and plasma levels on low dose oral haloperidol: a PET study. Psychopharmacology 1997; 131: 148–52. Lim HS, Kim SJ, Noh YH, et al. Exploration of optimal dosing regimens of haloperidol, a D2 antagonist, via modeling and simulation analysis in a D2 receptor occupancy study. Pharm Res 2013; 30: 683–93. Meyer-Massetti C, Cheng CM, Sharpe BA, et al. The FDA extended warning for intravenous haloperidol and torsades de pointes: how should institutions respond? J Hosp Med 2010; 5: E8–16. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 2009; 373: 1874–82. Morandi A, Hughes CG, Girard TD. Statins and brain dysfunction: a hypothesis to reduce the burden of cognitive impairment in patients who are critically ill. Chest 2011; 140: 580–85.
www.thelancet.com/respiratory Vol 1 October 2013
3
Moraes RB, Friedman G, Lisboa T, Viana MV, Hirakata V, Czepielewski MA. Comparison of cumulative incidence analysis and Kaplan-Meier for analysis of shock reversal in patients with septic shock. J Crit Care 2012; 27: 317.e7–11.
Author’s reply
If you would like to respond to an article published in The Lancet Respiratory Medicine, please submit your correspondence online at: http:// ees.elsevier.com/thelancetrm
e28
I thank Mark van den Boogaard and Peter Pickkers, and Marina Verçoza Viana and colleagues, for their interest in the Hope-ICU study.1 In response to van den Boogaard and Pickkers, first, I agree that the study was not large enough to exclude a small benefit or harm; however, we noted little difference in delirium duration between groups, suggesting that an effect size in either direction would be small. Second, the risk delirium prediction model PRE-DELIRIC for patients in the intensive-care unit was not available when Hope-ICU was designed.2 We did, however, show in two previous observational studies in a study population similar to that used in the Hope-ICU trial that the incidence of delirium in patients who could be screened was 63–65%.3 These data are consistent with international data from several studies. The high prevalence of delirium in our study supports this rationale. It would be useful to assess the predictive value of the PRE-DELIRIC score in our study cohort to establish whether this score is better at identifying risk of delirium than our assumptions regarding sick ventilated patients or whether patients at higher risk have a beneficial response to haloperidol. Finally, van den Boogaard and Pickkers were correct to say that Hope-ICU did not differentiate between haloperidol as a prophylactic therapy or as a treatment; rather, our pragmatic study was based on how haloperidol would fit into routine
clinical practice if a benefit was established—ie, given early to patients at high risk to prevent delirium and to treat patients with delirium on admission to hospital or as they emerge from coma. In reply to Verçoza Viana and colleagues, it is true that the dose of haloperidol that we used has not been established on the basis of efficacy and, historically, much larger doses have been used to treat delirium.4 However, these larger doses are not supported by the evidence regarding receptor occupancy or by the concern over serious side-effects resulting in the US Food and Drug Association black-box warning for intravenous haloperidol.5–7 With respect to the criteria for stopping the study drug, I agree that we cannot exclude that a small preventative effect was lost. Verçoza Viana and colleagues are correct to suggest that there are competing-risk situations, in which one outcome (eg, death) means another outcome is unrecorded. That situation, however, does not apply to our trial. The outcome measured was the proportion of a specified period that patients were alive and delirium free. As part of that definition, patients who died within this period were assigned a value of zero—ie, incorporating the worse outcome, death, rather than taking into account unrecorded delirium in patients who died. Our study results are a stimulus to pursue more options in delirium research, looking beyond haloperidol to alternative therapies—eg, antiinflammatory interventions—while reinforcing the need to concentrate our efforts on implementation of non-pharmalogical interventions known to help patients—eg, early
mobilisation.8,9 We maintain that the results of our randomised controlled trial do not support the hypothesis that haloperidol reduces delirium in critically ill patients. In view of that conclusion, and until results of ongoing larger trials are available, haloperidol should be reserved for management of agitation in this population of patients. VJP has received honoraria from Orion.
Valerie J Page [email protected] Intensive Care Unit, Watford General Hospital, Watford WD18 0HB, UK 1
2
3
4
5
6
7
8
9
Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo- controlled trial. Lancet Respir Med 2013; 1: 515–23. van den Boogaard M, Pickkers P, Slooter AJC, et al. Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study. BMJ 2012; 344: e420. Page VJ, Navarange S, Gama S, McAuley DF. Routine delirium monitoring in a UK critical care unit. Crit Care 2009; 13: R16. Wang EHZ, Mabasa VH, Loh GW, Ensom MHH. Haloperidol dosing strategies in the treatment of delirium in the critically ill. Neurocrit Care 2012; 16: 170–83. Kapur S, Zipursky R, Roy P. The relationship between D2 receptor occupancy and plasma levels on low dose oral haloperidol: a PET study. Psychopharmacology 1997; 131: 148–52. Lim HS, Kim SJ, Noh YH, et al. Exploration of optimal dosing regimens of haloperidol, a D2 antagonist, via modeling and simulation analysis in a D2 receptor occupancy study. Pharm Res 2013; 30: 683–93. Meyer-Massetti C, Cheng CM, Sharpe BA, et al. The FDA extended warning for intravenous haloperidol and torsades de pointes: how should institutions respond? J Hosp Med 2010; 5: E8–16. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 2009; 373: 1874–82. Morandi A, Hughes CG, Girard TD. Statins and brain dysfunction: a hypothesis to reduce the burden of cognitive impairment in patients who are critically ill. Chest 2011; 140: 580–85.
www.thelancet.com/respiratory Vol 1 October 2013
