Correspondence
With interest, we read Valerie J Page and colleagues’ report1 of the HopeICU trial in which they conclude that haloperidol does not shorten the duration of delirium in critically ill patients. The investigators state that haloperidol should be reserved only for management of acute agitation. These findings are in contrast with other recent studies,2,3 which might be a result of several limitations to Page and colleagues’ study. First, the study was powered to find a treatment difference of 2 days, which we assume that the investigators deemed relevant. However, each day that a patient is delirious results in a 10% higher mortality.4 Therefore the observed difference of 1 day could be clinically relevant, but would need a sample size that was about four times larger than the one used here. Second, although the investigators did not establish the actual delirium risk of patients with the recent developed prediction model,5 they chose to use a surrogate measure—ie, need for mechanical ventilation within 72 h of admission. Therefore, plausibly, patients with a low risk of delirium might have been included, resulting in a diluted efficacy of haloperidol. We previously reported the results of a non-randomised controlled trial, showing that patients with the highest risk of developing delirium seem to benefit the most from prophylactic treatment with haloperidol.3 Third, and most importantly, Page and colleagues enrolled both nondelirious and delirious patients at time of inclusion. This implies that they studied both the prophylactic and therapeutic efficacy of haloperidol, which we think should be reported separately. Based on these three issues, we believe that the absence of a prophylactic and treatment effect of haloperidol has not yet been established, and warrants further study. www.thelancet.com/respiratory Vol 1 October 2013
We declare that we have no conflicts of interest.
*Mark van den Boogaard, Peter Pickkers [email protected] Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, 6500HB Nijmegen, Netherlands 1
2
3
4
5
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. Wang W, Li HL, Wang DX, et al. Haloperidol prophylaxis decreases delirium incidence in elderly patients after noncardiac surgery: a randomized controlled trial. Crit Care Med 2012; 40: 1–9. van den Boogaard M, Schoonhoven L, Van Achterberg T, Van der Hoeven JG, Pickkers P. Haloperidol prophylaxis in critically ill patients with a high risk for delirium. Critical Care 2013; 17: R9. Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness PH. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med 2009; 180: 1092–97. van den Boogaard M, Pickkers P, Slooter AJ, 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.
Prophylactic haloperidol: too early to lose hope Delirium is a very prevalent syndrome and an important independent predictor of negative outcome in patients in the intensive-care unit (ICU), but there is no proven pharmacological intervention to prevent or treat this disorder.1 Therefore, the study by Valerie J Page and colleagues,2 which provided an assessment of the use of haloperidol in the ICU setting, was needed. However, the results of this trial should not be classed as definitive because the study has some limitations. First, haloperidol was used as both a prophylaxis and treatment, and the number of patients with delirium at enrolment was not stated. We would expect that the dose needed to treat a patient with delirium would be higher
than the prophylactic dose. Also, the criteria for stopping the drug should be reconsidered, since although patients might be 2 days free of delirium, they still could be at risk of developing delirium. Second, regarding the statistical analysis, the primary outcome was the number of delirium-free and comafree days in the first 14 days after randomisation, but patients who died before day 14 were recorded as having zero days free of delirium and coma, restricting the analysis to survivors, and correcting the incidence of the main outcome (delirium) according to the competing event (death). When analysing time-to-event data and competing outcomes, a technique known as cumulative incidence analysis can be used to assess the actual incidence of delirium. 3 This type of analysis would have provided more accurate results in Page and colleagues’ study, and should be used in future trials that intend to address delirium incidence. Last, the study authors conclude that their results do not support the use of haloperidol in patients needing mechanical ventilation, irrespective of whether patients screen positive for delirium or are in a coma. They believe that haloperidol should be reserved for short-term management of acute agitation; however, we think it is too soon to come to this conclusion.
Science Photo Library
Hope for haloperidol in delirium
We declare that we have no conflicts of interest.
*Marina Verçoza Viana, Rafael B Moraes, Tiago A Tonietto, Marcio M Boniatti [email protected] Hospital de Clinicas de Porto Alegre, Serviço de Medicina Intensiva, Ramiro Barcelos 2350, Porto Alegre, Rio Grande do Sul, Brazil 1
2
Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41: 263–306. 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.
e27
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
With interest, we read Valerie J Page and colleagues’ report1 of the HopeICU trial in which they conclude that haloperidol does not shorten the duration of delirium in critically ill patients. The investigators state that haloperidol should be reserved only for management of acute agitation. These findings are in contrast with other recent studies,2,3 which might be a result of several limitations to Page and colleagues’ study. First, the study was powered to find a treatment difference of 2 days, which we assume that the investigators deemed relevant. However, each day that a patient is delirious results in a 10% higher mortality.4 Therefore the observed difference of 1 day could be clinically relevant, but would need a sample size that was about four times larger than the one used here. Second, although the investigators did not establish the actual delirium risk of patients with the recent developed prediction model,5 they chose to use a surrogate measure—ie, need for mechanical ventilation within 72 h of admission. Therefore, plausibly, patients with a low risk of delirium might have been included, resulting in a diluted efficacy of haloperidol. We previously reported the results of a non-randomised controlled trial, showing that patients with the highest risk of developing delirium seem to benefit the most from prophylactic treatment with haloperidol.3 Third, and most importantly, Page and colleagues enrolled both nondelirious and delirious patients at time of inclusion. This implies that they studied both the prophylactic and therapeutic efficacy of haloperidol, which we think should be reported separately. Based on these three issues, we believe that the absence of a prophylactic and treatment effect of haloperidol has not yet been established, and warrants further study. www.thelancet.com/respiratory Vol 1 October 2013
We declare that we have no conflicts of interest.
*Mark van den Boogaard, Peter Pickkers [email protected] Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, 6500HB Nijmegen, Netherlands 1
2
3
4
5
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. Wang W, Li HL, Wang DX, et al. Haloperidol prophylaxis decreases delirium incidence in elderly patients after noncardiac surgery: a randomized controlled trial. Crit Care Med 2012; 40: 1–9. van den Boogaard M, Schoonhoven L, Van Achterberg T, Van der Hoeven JG, Pickkers P. Haloperidol prophylaxis in critically ill patients with a high risk for delirium. Critical Care 2013; 17: R9. Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness PH. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med 2009; 180: 1092–97. van den Boogaard M, Pickkers P, Slooter AJ, 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.
Prophylactic haloperidol: too early to lose hope Delirium is a very prevalent syndrome and an important independent predictor of negative outcome in patients in the intensive-care unit (ICU), but there is no proven pharmacological intervention to prevent or treat this disorder.1 Therefore, the study by Valerie J Page and colleagues,2 which provided an assessment of the use of haloperidol in the ICU setting, was needed. However, the results of this trial should not be classed as definitive because the study has some limitations. First, haloperidol was used as both a prophylaxis and treatment, and the number of patients with delirium at enrolment was not stated. We would expect that the dose needed to treat a patient with delirium would be higher
than the prophylactic dose. Also, the criteria for stopping the drug should be reconsidered, since although patients might be 2 days free of delirium, they still could be at risk of developing delirium. Second, regarding the statistical analysis, the primary outcome was the number of delirium-free and comafree days in the first 14 days after randomisation, but patients who died before day 14 were recorded as having zero days free of delirium and coma, restricting the analysis to survivors, and correcting the incidence of the main outcome (delirium) according to the competing event (death). When analysing time-to-event data and competing outcomes, a technique known as cumulative incidence analysis can be used to assess the actual incidence of delirium. 3 This type of analysis would have provided more accurate results in Page and colleagues’ study, and should be used in future trials that intend to address delirium incidence. Last, the study authors conclude that their results do not support the use of haloperidol in patients needing mechanical ventilation, irrespective of whether patients screen positive for delirium or are in a coma. They believe that haloperidol should be reserved for short-term management of acute agitation; however, we think it is too soon to come to this conclusion.
Science Photo Library
Hope for haloperidol in delirium
We declare that we have no conflicts of interest.
*Marina Verçoza Viana, Rafael B Moraes, Tiago A Tonietto, Marcio M Boniatti [email protected] Hospital de Clinicas de Porto Alegre, Serviço de Medicina Intensiva, Ramiro Barcelos 2350, Porto Alegre, Rio Grande do Sul, Brazil 1
2
Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41: 263–306. 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.
e27
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
