- Email: [email protected]
Preventing postoperative delirium: all that glisters is not gold
Comment
Delirium is an important complication of surgery, affecting an estimated 30% of surgical patients in the intensive care unit (ICU).1 Postoperative delirium is distressing for patients and family members, and is associated with increased risk of further negative outcomes, including admission to institutions, dementia, and death.2 Unfortunately, many candidate pharmacological interventions to prevent postoperative delirium have failed.3 The cholinesterase inhibitor rivastigmine exemplifies the failures. Prevention of delirium with rivastigmine seemed mechanistically plausible and was promising in preliminary research, but in a large randomised trial rivastigmine appeared to promote delirium and mortality.4 After a litany of failures, a study in The Lancet provides a glimmer of hope.5 In a 700 patient randomised, double-blind, placebo-controlled trial, Xian Su and colleagues found that prophylactic, low-dose dexmedetomidine (0·1 μg/kg per hr) resulted in an impressive 13% absolute reduction (from 22% to 9%) in the incidence of postoperative delirium in ICU patients. We must, however, temper our enthusiasm and carefully assess the evidence. It is possible that dexmedetomidine will ultimately be found wanting as a prophylactic, like its initially promising predecessors. As a first step, we must highlight some limitations of the study by Su and colleagues, which include questionable biological plausibility, probable presence of the primary outcome prior to institution of the intervention, and imprecision of delirium assessment. Previous studies in ICU patients have used dexmedetomidine in patients requiring sedation with the hypothesis that dexmedetomidine is less likely to cause delirium than drugs such as lorazepam.6,7 When used at night as a sedative in the ICU, dexmedetomidine has preserved day–night sleep cycles, but without evidence of restorative sleep.8 The notion that a sub-sedative, very low dose of a sedative agent could be given to awake, non-delirious patients (assuming that the patients in this study were not delirious at enrolment) to prevent delirium is counter-intuitive and necessitates a conceptual change. Whereas in most clinical trials patients themselves consent to participate, in the study by Su and colleagues, a family member provided consent for 58%
of participants. This occurred because enrolment took place after surgery, when, as explained in the informed consent document for this study, “some patients cannot understand correctly or express their own opinion freely or cannot sign on paper”. In general, we would question the capacity of patients to provide informed consent in the early postoperative period when judgment is impaired by lingering effects of hypnotic, sedative, and potent analgesic agents. The researchers did not formally test for delirium at the time of enrolment. It is therefore likely that some of the patients who consented for themselves were actually delirious, and many of the patients for whom proxies provided consent were probably also delirious. The investigators assert that delirium occurring on the day of surgery is a distinct entity from delirium occurring on subsequent days, and is essentially benign. However, this is a controversial contention. Studies have shown that patients who have early postoperative delirium are also more likely to be delirious on ensuing days.9 In any study, the reliability of the results depends on the accuracy of the metric used to ascertain the primary outcome. The study by Su and colleagues5 used the non-verbal version of the Confusion Assessment Method for the ICU, which was designed for (intubated) patients who are unable to speak. However, the most reliable approaches for delirium detection typically incorporate verbal communication, through which the cardinal feature of disorganised thinking can best be appreciated.10 It is therefore likely that some episodes of delirium went undetected. Despite the study’s limitations, the data speak for themselves, and provide a tantalising prospect for preventing postoperative delirium. The question is whether clinical practice should change, based on this study. A sober appraisal of evidence-based medical practices has revealed that initially positive findings are often not replicated in subsequent trials.11 In general, there is growing concern about lack of reproducibility in science. When the a-priori probability in favour of a particular hypothesis is very low, the posterior probability might remain low, even following a trial with very significant findings.12 From our perspective, the a-priori probability is low that sub-sedative dexmedetomidine, administered on the day of
www.thelancet.com Published online August 16, 2016 http://dx.doi.org/10.1016/S0140-6736(16)31353-8
VCG/Contributor/Getty
Preventing postoperative delirium: all that glisters is not gold
Published Online August 16, 2016 http://dx.doi.org/10.1016/ S0140-6736(16)31353-8 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(16)30580-3
1
Comment
surgery, prevents incident delirium for the next 7 days. Therefore, although exciting and potentially important, the study by Su and colleagues should be viewed as hypothesis generating; clinical implementation without verification of safety and effectiveness would be premature. Given the importance of postoperative delirium and the current lack of any effective pharmacological prophylaxis, this study must be replicated urgently. We must determine whether this glimmer is real, or merely an illusion.
3 4
5
6
7 8
Vanessa L Kronzer, *Michael S Avidan Washington University School of Medicine, Department of Anesthesiology, Saint Louis, MO, USA [email protected]
10
We declare no competing interests. 1 2
2
9
Salluh JI, Wang H, Schneider EB, et al. Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ 2015; 350: h2538. McDaniel M, Brudney C. Postoperative delirium: etiology and management. Curr Opin Crit Care 2012; 18: 372–76.
11 12
Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet 2014; 383: 911–22. van Eijk MM, Roes KC, Honing ML, et al. Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial. Lancet 2010; 376: 1829–37. Su X, Meng Z-T, Wu X-H, et al. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet 2016; published online Aug 16. http://dx.doi.org/10.1016/S0140-6736(16)30580-3. Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007; 298: 2644–53. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; 301: 489–99. Oto J, Yamamoto K, Koike S, Onodera M, Imanaka H, Nishimura M. Sleep quality of mechanically ventilated patients sedated with dexmedetomidine. Intensive Care Med 2012; 38: 1982–89. Sharma PT, Sieber FE, Zakriya KJ, et al. Recovery room delirium predicts postoperative delirium after hip-fracture repair. Anesth Analg 2005; 101: 1215–20. Grover S, Kate N. Assessment scales for delirium: a review. World J Psychiatry 2012; 2: 58–70. Prasad V, Vandross A, Toomey C, et al. A decade of reversal: an analysis of 146 contradicted medical practices. Mayo Clin Proc 2013; 88: 790–98. Nuzzo R. Scientific method: statistical errors. Nature 2014; 506: 150–52.
www.thelancet.com Published online August 16, 2016 http://dx.doi.org/10.1016/S0140-6736(16)31353-8
Delirium is an important complication of surgery, affecting an estimated 30% of surgical patients in the intensive care unit (ICU).1 Postoperative delirium is distressing for patients and family members, and is associated with increased risk of further negative outcomes, including admission to institutions, dementia, and death.2 Unfortunately, many candidate pharmacological interventions to prevent postoperative delirium have failed.3 The cholinesterase inhibitor rivastigmine exemplifies the failures. Prevention of delirium with rivastigmine seemed mechanistically plausible and was promising in preliminary research, but in a large randomised trial rivastigmine appeared to promote delirium and mortality.4 After a litany of failures, a study in The Lancet provides a glimmer of hope.5 In a 700 patient randomised, double-blind, placebo-controlled trial, Xian Su and colleagues found that prophylactic, low-dose dexmedetomidine (0·1 μg/kg per hr) resulted in an impressive 13% absolute reduction (from 22% to 9%) in the incidence of postoperative delirium in ICU patients. We must, however, temper our enthusiasm and carefully assess the evidence. It is possible that dexmedetomidine will ultimately be found wanting as a prophylactic, like its initially promising predecessors. As a first step, we must highlight some limitations of the study by Su and colleagues, which include questionable biological plausibility, probable presence of the primary outcome prior to institution of the intervention, and imprecision of delirium assessment. Previous studies in ICU patients have used dexmedetomidine in patients requiring sedation with the hypothesis that dexmedetomidine is less likely to cause delirium than drugs such as lorazepam.6,7 When used at night as a sedative in the ICU, dexmedetomidine has preserved day–night sleep cycles, but without evidence of restorative sleep.8 The notion that a sub-sedative, very low dose of a sedative agent could be given to awake, non-delirious patients (assuming that the patients in this study were not delirious at enrolment) to prevent delirium is counter-intuitive and necessitates a conceptual change. Whereas in most clinical trials patients themselves consent to participate, in the study by Su and colleagues, a family member provided consent for 58%
of participants. This occurred because enrolment took place after surgery, when, as explained in the informed consent document for this study, “some patients cannot understand correctly or express their own opinion freely or cannot sign on paper”. In general, we would question the capacity of patients to provide informed consent in the early postoperative period when judgment is impaired by lingering effects of hypnotic, sedative, and potent analgesic agents. The researchers did not formally test for delirium at the time of enrolment. It is therefore likely that some of the patients who consented for themselves were actually delirious, and many of the patients for whom proxies provided consent were probably also delirious. The investigators assert that delirium occurring on the day of surgery is a distinct entity from delirium occurring on subsequent days, and is essentially benign. However, this is a controversial contention. Studies have shown that patients who have early postoperative delirium are also more likely to be delirious on ensuing days.9 In any study, the reliability of the results depends on the accuracy of the metric used to ascertain the primary outcome. The study by Su and colleagues5 used the non-verbal version of the Confusion Assessment Method for the ICU, which was designed for (intubated) patients who are unable to speak. However, the most reliable approaches for delirium detection typically incorporate verbal communication, through which the cardinal feature of disorganised thinking can best be appreciated.10 It is therefore likely that some episodes of delirium went undetected. Despite the study’s limitations, the data speak for themselves, and provide a tantalising prospect for preventing postoperative delirium. The question is whether clinical practice should change, based on this study. A sober appraisal of evidence-based medical practices has revealed that initially positive findings are often not replicated in subsequent trials.11 In general, there is growing concern about lack of reproducibility in science. When the a-priori probability in favour of a particular hypothesis is very low, the posterior probability might remain low, even following a trial with very significant findings.12 From our perspective, the a-priori probability is low that sub-sedative dexmedetomidine, administered on the day of
www.thelancet.com Published online August 16, 2016 http://dx.doi.org/10.1016/S0140-6736(16)31353-8
VCG/Contributor/Getty
Preventing postoperative delirium: all that glisters is not gold
Published Online August 16, 2016 http://dx.doi.org/10.1016/ S0140-6736(16)31353-8 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(16)30580-3
1
Comment
surgery, prevents incident delirium for the next 7 days. Therefore, although exciting and potentially important, the study by Su and colleagues should be viewed as hypothesis generating; clinical implementation without verification of safety and effectiveness would be premature. Given the importance of postoperative delirium and the current lack of any effective pharmacological prophylaxis, this study must be replicated urgently. We must determine whether this glimmer is real, or merely an illusion.
3 4
5
6
7 8
Vanessa L Kronzer, *Michael S Avidan Washington University School of Medicine, Department of Anesthesiology, Saint Louis, MO, USA [email protected]
10
We declare no competing interests. 1 2
2
9
Salluh JI, Wang H, Schneider EB, et al. Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ 2015; 350: h2538. McDaniel M, Brudney C. Postoperative delirium: etiology and management. Curr Opin Crit Care 2012; 18: 372–76.
11 12
Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet 2014; 383: 911–22. van Eijk MM, Roes KC, Honing ML, et al. Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial. Lancet 2010; 376: 1829–37. Su X, Meng Z-T, Wu X-H, et al. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet 2016; published online Aug 16. http://dx.doi.org/10.1016/S0140-6736(16)30580-3. Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007; 298: 2644–53. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; 301: 489–99. Oto J, Yamamoto K, Koike S, Onodera M, Imanaka H, Nishimura M. Sleep quality of mechanically ventilated patients sedated with dexmedetomidine. Intensive Care Med 2012; 38: 1982–89. Sharma PT, Sieber FE, Zakriya KJ, et al. Recovery room delirium predicts postoperative delirium after hip-fracture repair. Anesth Analg 2005; 101: 1215–20. Grover S, Kate N. Assessment scales for delirium: a review. World J Psychiatry 2012; 2: 58–70. Prasad V, Vandross A, Toomey C, et al. A decade of reversal: an analysis of 146 contradicted medical practices. Mayo Clin Proc 2013; 88: 790–98. Nuzzo R. Scientific method: statistical errors. Nature 2014; 506: 150–52.
www.thelancet.com Published online August 16, 2016 http://dx.doi.org/10.1016/S0140-6736(16)31353-8