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NICE Guideline: Evidence for pharmacological treatment of delirium
Journal of Psychosomatic Research 70 (2011) 197 – 198
Letter to the Editor NICE Guideline: Evidence for pharmacological treatment of delirium To the Editor: In the last decade, there has been a move towards developing national guidelines for management of delirium, like the ones in America [1], Australia [2], and Canada [3]. The limitation of low level of evidence for the pharmacological treatment of delirium remains a common factor among all these guidelines. There are stark similarities in the pharmacological recommendations for treatment of delirium in these guidelines. The American guideline recommended the sole use of low-dose (0.5–1 mg) haloperidol. The newer Australian guideline recommends the use of low-dose haloperidol, olanzapine, or risperidone. The Canadian guideline is specifically aimed at management of delirium in the elderly. It recommends very low dose (0.25–0.5 mg) haloperidol in the first instance. This guideline also recommends using low dose risperidone, olanzapine or quetiapine. In the UK, the National Institute of Clinical Excellence (NICE) guideline, ‘Delirium: Diagnosis, Prevention and Management’ [4], is the most recent, comprehensive, and a major development to guide the clinical management of a complex neuropsychiatric syndrome. This extensive document also highlights the gap in evidence-based pharmacological treatment of delirium. For the pharmacological treatment of delirium, the NICE guideline recommends that: ‘If a person with delirium is distressed or considered a risk to themselves or others and verbal and non-verbal de-escalation techniques are ineffective or inappropriate, consider giving short term (usually for 1 week or less) haloperidol or olanzapine. Start at the lowest clinically appropriate dose and titrate cautiously according to symptoms.’
This recommendation is based on the outcome of two RCTs [5,6] and one quasi randomised study [7]. When looking at the evidence for pharmacological treatment of delirium, only those RCTs which had more than 20 patients in each arm of the study were considered by NICE. A systematic review of literature [8] has shown some other RCTs on this topic comparing various antipsychotics [9–11]. There are only two recent placebo-controlled RCTs on this subject. These two RCTs have treated delirium with quetiapine in intensive care [12] and general hospital [13]. 0022-3999/10/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
Quetiapine is the only medication that has been compared with placebo for this purpose. The NICE guideline has included a randomised trial that initially recruited 20 patients to compare amisulpride with quetiapine. After dropouts, 15 patients in the quetiapine group and 16 in the amisulpride group completed the trial. No intention-to-treat (ITT) analysis was carried out. In all the other studies that have been excluded, the number of patients is less than 20 except one study [11] where the haloperidol group had 24 patients in comparison to the risperidone group with 18 patients. No ITT analysis has been given for missing data in any of the excluded studies. Only recently, the issue of statistics based on ITT has been addressed [13,14]. A meta-analysis of the current evidence from RCTs (Table 1) would not be very meaningful. The combined total number of patients treated with haloperidol, olanzapine, and quetiapine remains 164, 102, and 54, respectively. The total number of patients treated with typical and atypical antipsychotics remains relatively small (177 for haloperidol and chlorpromazine vs. 202 for olanzapine, quetiapine, risperidone, and amisulpride). The evidence from RCTs is further supported by a number of open-label prospective studies that have treated 651 patients with various drugs including haloperidol, risperidone, olanzapine, quetiapine, aripiprazole, perospirone, melatonin, mianserin, and trazadone [8]. Therefore, we feel the guideline's recommendation for pharmacological treatment of delirium is rather oversimplified. Further studies involving larger samples and exploration of response predictors in various delirium populations are needed to clarify the role and safety of antipsychotics in the management of delirium. The issue of sample size can be countered by designing multicenter studies and using appropriate ITT analysis. Multicenter studies have their own limitations of inter-rater reliability and dealing with local procedures. These concerns can be addressed through proper planning and a strict inclusion and treatment protocol. Even though the number of RCTs for treatment of delirium has increased in the last 6 years, many important questions remain unanswered regarding the drug treatment of delirium. The multisymptom nature of delirium (cognitive vs. noncognitive, hyperactive vs. hypoactive vs. mixed) contributes both to the difficulties in identifying the efficacy of specific drug treatment and to the potential for
198
Letter to the Editor / Journal of Psychosomatic Research 70 (2011) 197–198
Table 1 Number of patients treated with an active treatment in eight RCTs for treatment of delirium
Breitbart et al. (1996) [9] Han and Kim (2004) [10] Skrobik et al. (2004) [7] a Kim et al. (2005) [11] Lee et al. (2005) [6] a Hu et al. (2006) [5] a Devlin et al. (2010) [12] b Tahir et al. (2010) [13] c Total a b c
Haloperidol
Chlorpromazine
Lorazepam
11 12 45 24
13
6
Risperidone
Quetiapine
Amisulpride
15
16
18 21 54
16
12 28 18
72
164
Olanzapine
74
13
6
30
102
Trials included in NICE guideline. Placebo-controlled RCT with 18 patients in the placebo group. Placebo-controlled RCT with 21 patients in the placebo group.
successful clinical application. Underlying pathology and etiology make the choice and use of antipsychotics even more complex. Overall, the comprehensive NICE delirium guideline is a positive development in the field of delirium management. However, there is still a need to improve the understanding of pathophysiology of delirium and the efficacy of specific drug therapy in delirium subtypes and subgroups by being more inclusive rather than restrictive in approach. Due to the current lack of large, multicenter trials in this field, we feel it would have been prudent for NICE to have relaxed the strict exclusion criteria of any RCT with less than 20 patients in each arm and integrate the results of smaller yet significant studies. Tayyeb A Tahir Emma Morgan Department of Liaison Psychiatry University Hospital of Wales Cardiff and Vale University Health Board Heath Park, Cardiff, UK E-mail address: [email protected] Eamonn Eeles Department of Geriatric Medicine School of Medicine, Cardiff University University Hospital Llandough Cardiff and Vale University Health Board Penarth, UK doi:10.1016/j.jpsychores.2010.10.011
References [1] APA. American Psychiatric Association, Practice guidelines for the treatment of patients with delirium. Am J Psychiatry 1999;156(suppl):1–20. [2] Tropea J, Slee JA, Brand CA, Gray L, Snell T. Clinical practice guidelines for the management of delirium in older people in Australia. Australas J Ageing 2008;27:150–6. [3] Hogan D, Gage L. National guidelines for seniors' mental health: the assessment and treatment of delirium. Can J Geriatr 2006;9:542–51. [4] NICE. Delirium: diagnosis, prevention, and management of delirium. Clin Gudel 2010;103:512–39. [5] Hu H, Deng W. Olanzapine and haloperidol for senile delirium: a randomized controlled observation. Chin J Clin Rehabil 2006;10:188–90. [6] Lee KU, Won WY. Amisulpride versus quetiapine for the treatment of delirium: a randomized, open prospective study. Int Clin Psychopharmacol 2005;20:311–4. [7] Skrobik YK, Bergeron N. Olanzapine vs haloperidol:treating delirium in a critical care setting. Intensive Care Med 2004;30:444–9. [8] Bourne R, Tahir T. Treatment of delirium: past, present and future. J Psychosom Res 2008:22–55. [9] Breitbart W, Marotta R. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996;153:231–7. [10] Han CS, Kim YK. A double-blind trial of respiridone and haloperidol for the treatment of delirium. Psychosomatics 2004:297–301. [11] Kim JY, Jung IK. Antipsychotics and dopamine transporter gene polymorphisms in delirium patients. Psychiatry Clin Neurosci 2005; 59:183–8. [12] Devlin JW, Roberts RJ. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med 2010;38: 419–27. [13] Tahir TA, Eeles E, Karapareddy V, Muthuvelu P, Chapple S, Phillips B, et al. A randomized controlled trial of quetiapine versus placebo in the treatment of delirium. J Psychosom Res 2010;69(5):485–90. [14] Adamis D. Statistical methods for analysing longitudinal data in delirium studies. Int Rev Psychiatry 2009;21:74–85.
Letter to the Editor NICE Guideline: Evidence for pharmacological treatment of delirium To the Editor: In the last decade, there has been a move towards developing national guidelines for management of delirium, like the ones in America [1], Australia [2], and Canada [3]. The limitation of low level of evidence for the pharmacological treatment of delirium remains a common factor among all these guidelines. There are stark similarities in the pharmacological recommendations for treatment of delirium in these guidelines. The American guideline recommended the sole use of low-dose (0.5–1 mg) haloperidol. The newer Australian guideline recommends the use of low-dose haloperidol, olanzapine, or risperidone. The Canadian guideline is specifically aimed at management of delirium in the elderly. It recommends very low dose (0.25–0.5 mg) haloperidol in the first instance. This guideline also recommends using low dose risperidone, olanzapine or quetiapine. In the UK, the National Institute of Clinical Excellence (NICE) guideline, ‘Delirium: Diagnosis, Prevention and Management’ [4], is the most recent, comprehensive, and a major development to guide the clinical management of a complex neuropsychiatric syndrome. This extensive document also highlights the gap in evidence-based pharmacological treatment of delirium. For the pharmacological treatment of delirium, the NICE guideline recommends that: ‘If a person with delirium is distressed or considered a risk to themselves or others and verbal and non-verbal de-escalation techniques are ineffective or inappropriate, consider giving short term (usually for 1 week or less) haloperidol or olanzapine. Start at the lowest clinically appropriate dose and titrate cautiously according to symptoms.’
This recommendation is based on the outcome of two RCTs [5,6] and one quasi randomised study [7]. When looking at the evidence for pharmacological treatment of delirium, only those RCTs which had more than 20 patients in each arm of the study were considered by NICE. A systematic review of literature [8] has shown some other RCTs on this topic comparing various antipsychotics [9–11]. There are only two recent placebo-controlled RCTs on this subject. These two RCTs have treated delirium with quetiapine in intensive care [12] and general hospital [13]. 0022-3999/10/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
Quetiapine is the only medication that has been compared with placebo for this purpose. The NICE guideline has included a randomised trial that initially recruited 20 patients to compare amisulpride with quetiapine. After dropouts, 15 patients in the quetiapine group and 16 in the amisulpride group completed the trial. No intention-to-treat (ITT) analysis was carried out. In all the other studies that have been excluded, the number of patients is less than 20 except one study [11] where the haloperidol group had 24 patients in comparison to the risperidone group with 18 patients. No ITT analysis has been given for missing data in any of the excluded studies. Only recently, the issue of statistics based on ITT has been addressed [13,14]. A meta-analysis of the current evidence from RCTs (Table 1) would not be very meaningful. The combined total number of patients treated with haloperidol, olanzapine, and quetiapine remains 164, 102, and 54, respectively. The total number of patients treated with typical and atypical antipsychotics remains relatively small (177 for haloperidol and chlorpromazine vs. 202 for olanzapine, quetiapine, risperidone, and amisulpride). The evidence from RCTs is further supported by a number of open-label prospective studies that have treated 651 patients with various drugs including haloperidol, risperidone, olanzapine, quetiapine, aripiprazole, perospirone, melatonin, mianserin, and trazadone [8]. Therefore, we feel the guideline's recommendation for pharmacological treatment of delirium is rather oversimplified. Further studies involving larger samples and exploration of response predictors in various delirium populations are needed to clarify the role and safety of antipsychotics in the management of delirium. The issue of sample size can be countered by designing multicenter studies and using appropriate ITT analysis. Multicenter studies have their own limitations of inter-rater reliability and dealing with local procedures. These concerns can be addressed through proper planning and a strict inclusion and treatment protocol. Even though the number of RCTs for treatment of delirium has increased in the last 6 years, many important questions remain unanswered regarding the drug treatment of delirium. The multisymptom nature of delirium (cognitive vs. noncognitive, hyperactive vs. hypoactive vs. mixed) contributes both to the difficulties in identifying the efficacy of specific drug treatment and to the potential for
198
Letter to the Editor / Journal of Psychosomatic Research 70 (2011) 197–198
Table 1 Number of patients treated with an active treatment in eight RCTs for treatment of delirium
Breitbart et al. (1996) [9] Han and Kim (2004) [10] Skrobik et al. (2004) [7] a Kim et al. (2005) [11] Lee et al. (2005) [6] a Hu et al. (2006) [5] a Devlin et al. (2010) [12] b Tahir et al. (2010) [13] c Total a b c
Haloperidol
Chlorpromazine
Lorazepam
11 12 45 24
13
6
Risperidone
Quetiapine
Amisulpride
15
16
18 21 54
16
12 28 18
72
164
Olanzapine
74
13
6
30
102
Trials included in NICE guideline. Placebo-controlled RCT with 18 patients in the placebo group. Placebo-controlled RCT with 21 patients in the placebo group.
successful clinical application. Underlying pathology and etiology make the choice and use of antipsychotics even more complex. Overall, the comprehensive NICE delirium guideline is a positive development in the field of delirium management. However, there is still a need to improve the understanding of pathophysiology of delirium and the efficacy of specific drug therapy in delirium subtypes and subgroups by being more inclusive rather than restrictive in approach. Due to the current lack of large, multicenter trials in this field, we feel it would have been prudent for NICE to have relaxed the strict exclusion criteria of any RCT with less than 20 patients in each arm and integrate the results of smaller yet significant studies. Tayyeb A Tahir Emma Morgan Department of Liaison Psychiatry University Hospital of Wales Cardiff and Vale University Health Board Heath Park, Cardiff, UK E-mail address: [email protected] Eamonn Eeles Department of Geriatric Medicine School of Medicine, Cardiff University University Hospital Llandough Cardiff and Vale University Health Board Penarth, UK doi:10.1016/j.jpsychores.2010.10.011
References [1] APA. American Psychiatric Association, Practice guidelines for the treatment of patients with delirium. Am J Psychiatry 1999;156(suppl):1–20. [2] Tropea J, Slee JA, Brand CA, Gray L, Snell T. Clinical practice guidelines for the management of delirium in older people in Australia. Australas J Ageing 2008;27:150–6. [3] Hogan D, Gage L. National guidelines for seniors' mental health: the assessment and treatment of delirium. Can J Geriatr 2006;9:542–51. [4] NICE. Delirium: diagnosis, prevention, and management of delirium. Clin Gudel 2010;103:512–39. [5] Hu H, Deng W. Olanzapine and haloperidol for senile delirium: a randomized controlled observation. Chin J Clin Rehabil 2006;10:188–90. [6] Lee KU, Won WY. Amisulpride versus quetiapine for the treatment of delirium: a randomized, open prospective study. Int Clin Psychopharmacol 2005;20:311–4. [7] Skrobik YK, Bergeron N. Olanzapine vs haloperidol:treating delirium in a critical care setting. Intensive Care Med 2004;30:444–9. [8] Bourne R, Tahir T. Treatment of delirium: past, present and future. J Psychosom Res 2008:22–55. [9] Breitbart W, Marotta R. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996;153:231–7. [10] Han CS, Kim YK. A double-blind trial of respiridone and haloperidol for the treatment of delirium. Psychosomatics 2004:297–301. [11] Kim JY, Jung IK. Antipsychotics and dopamine transporter gene polymorphisms in delirium patients. Psychiatry Clin Neurosci 2005; 59:183–8. [12] Devlin JW, Roberts RJ. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med 2010;38: 419–27. [13] Tahir TA, Eeles E, Karapareddy V, Muthuvelu P, Chapple S, Phillips B, et al. A randomized controlled trial of quetiapine versus placebo in the treatment of delirium. J Psychosom Res 2010;69(5):485–90. [14] Adamis D. Statistical methods for analysing longitudinal data in delirium studies. Int Rev Psychiatry 2009;21:74–85.