504739
research-article2013
AOPXXX10.1177/1060028013504739Annals of PharmacotherapyFlannery and Flynn
Commentary
More Questions Than Answers in ICU Delirium: Pressing Issues for Future Research
Annals of Pharmacotherapy 47(11) 1558–1561 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013504739 aop.sagepub.com
Alexander H. Flannery, PharmD, BCPS1, and Jeremy D. Flynn, PharmD, FCCP, FCCM1,2
Abstract With the release of the updated pain, agitation, and delirium guidelines by the Society of Critical Care Medicine, a number of new and updated recommendations are provided regarding the pharmacological prevention and treatment of ICU delirium. Whereas this is important to understand the limitations of existing literature in interpreting the guideline recommendations, it also provides an opportunity to identify those areas of practice where we need further knowledge. We discuss 5 of the most critical questions in our view regarding pharmacological therapy for ICU delirium in an attempt to highlight areas of this ICU condition that are much deserving of further research, including the deliriogenic potential of dexmedetomidine, optimal sedative choices for the delirious ICU patient, pharmacological prophylaxis for ICU delirium, optimal treatment duration for ICU delirium, and the impact of pharmacotherapy on long-term cognitive outcomes in ICU survivors. A multitude of opportunities for further research exist in the above areas for clinicians and researchers interested in this ICU condition. Keywords delirium, critical care, dexmedetomidine, antipsychotic Received August 5, 2013; revised August 16, 2013; accepted August 16, 2013
The long-awaited pain, agitation, and delirium guidelines sponsored by the Society of Critical Care Medicine and the American Society for Health-System Pharmacists were recently updated from the previous 2002 edition, with a bolstered section on ICU delirium providing over 20 statements and recommendations.1 Now, 10 years of research later, our results provide us with almost as many questions as we have answers regarding the pharmacotherapy of this complex phenomenon in the ICU. As is often the case, the guideline authors had to sift through controversial and imperfect literature to form recommendations to guide practice. Although it is important to understand the limitations of current literature in interpreting the guidelines, it is equally important to identify those questions that need to be answered as we move forward, particularly as they relate to the pharmacotherapy for prevention and treatment of ICU delirium. Opportunities for further research abound, and the gaps of knowledge in the current guidelines offer an important opportunity to identify future research questions.
and the implication of dexmedetomidine in contributing to ICU delirium remains unknown.2,3 The SEDCOM trial, which suggested a lower prevalence of delirium with dexmedetomidine compared with midazolam, allowed midazolam as needed in both arms, which has made some question whether the reduced prevalence of delirium was a result of dexmedetomidine or the fact that less cumulative benzodiazepine was used in the dexmedetomidine arm.2 In the MENDS trial, which used fentanyl and propofol boluses rather than benzodiazepine boluses for additional comfort, the prevalence of delirium or coma was still 87% in the dexmedetomidine group.3 With an increased focus on analgosedation in the guidelines, does the use of analgosedation reduce the prevalence of delirium compared with an analgesic plus sedation with dexmedetomidine?1 In the landmark trial by Strøm et al,4 a protocol of no sedation significantly increased the number of days without mechanical ventilation compared 1
University of Kentucky HealthCare, Lexington, KY, USA University of Kentucky College of Pharmacy, Lexington, KY, USA
2
Does Dexmedetomidine Contribute to ICU Delirium? Despite sedation with dexmedetomidine, ICU delirium was still highly prevalent in both SEDCOM and MENDS trials,
Corresponding Author: Alexander H. Flannery, PharmD, BCPS, Medical Intensive Care Unit/ Pulmonary, University of Kentucky HealthCare, 800 Rose Street, H110, Lexington, KY 40536, USA. Email: [email protected]
Downloaded from aop.sagepub.com at UNIV OF CONNECTICUT on April 12, 2015
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Flannery and Flynn with a sedation protocol utilizing daily interruptions. However, the prevalence of agitated delirium and use of haloperidol was significantly higher in the no sedation group.4 Whether these results are a result of underdiagnosed delirium is not known; also, contribution ofthe specific opioid used (morphine), inadequate pain control, or the recall of unpleasant events remains unknown.
How Do We Sedate Patients With ICU Delirium? In patients with ICU delirium requiring sedation, the guidelines suggest sedation with dexmedetomidine over benzodiazepines.1 The PRODEX trial published last year, which of note was not included in the guideline authors’ review because of the timing of publication, compared dexmedetomidine and propofol for ICU sedation.5 With regard to prevalence of delirium, PRODEX suggested an increased prevalence of neurocognitive disorders, including delirium with propofol when compared with dexmedetomidine. These results must be taken in light of the fact that this was one of many secondary outcomes, baseline prevalence of delirium was not reported, and patients were only screened for delirium once at the 48-hour mark of the study.5 Possibly due to the above confounding reasons, the authors found no difference in the prevalence of delirium between dexmedetomidine and benzodiazepines in the “twin” MIDEX study—data that conflict with the SEDCOM and MENDS studies.2,3,5 Although the prevalence of ICU delirium/coma was reduced with dexmedetomidine in the SEDCOM and MENDS trials, the study of sedation in the delirious patient population specifically remains limited. Approximately 60% of patients in the SEDCOM study were delirious at baseline, whereas the baseline rate of delirium in the MENDS study could not be determined.2,3 It is noteworthy that while propofol or dexmedetomidine are suggested as first-line therapies for sedation, only dexmedetomidine carries the suggestion as the recommended sedative in delirious ICU patients.1 This likely stems from the fact that SEDCOM and MENDS have suggested a reduced prevalence of delirium with dexmedetomidine compared with benzodiazepines, but the risk of developing delirium with propofol compared with benzodiazepines when used for ICU sedation is less well described.2,3 Propofol and benzodiazepines have been compared head to head, but delirium was not assessed reliably or at all.6[sup],7 If propofol and dexmedetomidine are recommended for sedation in nondelirious patients, are they also interchangeable when used for sedating delirious patients? A well-designed comparison of propofol and dexmedetomidine with regard to their outcomes on ICU delirium is needed, which will hopefully be completed with the MENDS II study.8 Future investigations that not only stratify patients by risk for ICU delirium but
also study sedation practices in delirious patients specifically should be encouraged.
Can We Prevent Delirium With Pharmacological Prophylaxis? Although limited studies exist, the guidelines offer no recommendation for pharmacological prophylaxis of delirium in the ICU.1 Low-dose haloperidol prophylaxis in older patients following noncardiac surgery appeared to reduce the incidence of delirium within the first 7 postoperative days, although this study is difficult to generalize to all ICU patients because of the low acuity of the patient population studied.9 A recently published study found that low-dose haloperidol prophylaxis reduced the incidence of delirium as well as reduced the duration of mechanical ventilation and ICU length of stay in mechanically ventilated patients at high risk of developing delirium.10 Using the complex PRE-DELIRIC model to risk stratify patients with regard to their risk of developing delirium, the authors showed that haloperidol was associated with improved outcomes only in the highest-risk patient population.10 This is an important step because it represents the most severely ill patient population studied to date for prophylaxis, suggesting that pharmacological prophylaxis may have a benefit in those patients with a high risk of developing delirium. The development of a valid, bedside predictive model (ie, delirium score) for delirium may not only have great prognostic value but also great value in stratifying patients who may benefit the most from targeted interventions, which may include pharmacological prophylaxis. No studies have been published to date regarding prolonged pharmacological prophylaxis outside of the perioperative period with atypical antipsychotics.
How Long Do We Treat ICU Delirium? Although the guidelines provide no definitive answer, a look back at pilot studies of antipsychotics for the treatment of ICU delirium may serve as a starting point. Devlin et al11 in their pilot study of quetiapine demonstrated that quetiapine reduced the time required to first resolution of delirium as compared with placebo. Study treatment was discontinued in the majority of patients either at the intensivist’s discretion or at ICU discharge, per protocol.11 This approach resulted in 20% of patients in the quetiapine group and 56% in the placebo group experiencing ≥1 day of delirium in the 14-day period following study drug discontinuation.11 The MIND trial, although not demonstrating favorable benefits of using antipsychotics for treatment of ICU delirium, tapered the dose as patients remained Confusion Assessment Method for the ICU (CAM-ICU) negative, ultimately
Downloaded from aop.sagepub.com at UNIV OF CONNECTICUT on April 12, 2015
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Annals of Pharmacotherapy 47(11)
discontinuing treatment when patients had been delirium and coma free for >48 hours.12 Perhaps this approach in practice may be a protocolized, efficient, and safe way to ensure that antipsychotics are prescribed for the minimal amount of time necessary. Whether a correlation exists between how long patients are treated for ICU delirium and the use of haloperidol as needed or other antipsychotics after discontinuation of scheduled therapy remains unknown. The answer to this question may help define what a “usual” treatment course for delirium is and may very well depend on the subtype of delirium. It is advisable to treat until CAM-ICU negative, but for how long after and whether rebound effects exist has not been determined. Unlike some infectious disease conditions where duration of treatment is at times defined early in therapy, the treatment duration of ICU delirium should be very much patient specific, and the need for antipsychotics should be frequently reassessed, especially as the patient is discharged from the ICU to the floor. A recent study found that almost 50% of patients were transferred out of the ICU on antipsychotic treatment for delirium, and 33% of patients were discharged home on antipsychotics.13 The alarming results of this study highlight the need to address the issue of ICU delirium treatment length. The inherent assumption in the above question is that antipsychotics help reduce the duration of delirium in the ICU and are valid treatment options. Although the guidelines acknowledge that more evidence exists for using the atypical antipsychotics, confirmatory studies remain under way to evaluate the impact various antipsychotics have in reducing the symptoms and duration of ICU delirium compared with placebo.1 The interplay of the pharmacology of various atypical antipsychotics and the neuropathophysiology of ICU delirium remain largely unknown.
What Is the Impact on Long-term Cognitive Outcomes? An ever-increasing trend in critical care practice is to study not only what happens to patients while in the ICU but theirlong-term outcomes following hospital discharge. As it relates to ICU delirium and cognitive impairment, the impact of our efforts to thwart and treat delirium on longterm cognitive outcomes remains largely unknown. Although a small study demonstrated that dexmedetomidine may impair cognitive function in the ICU to a lesser degree than propofol, this has yet to be replicated in largescale and long-term cognitive outcome trials.14 As we continue to explore dexmedetomidine as a sedative choice for the potential to reduce the prevalence of delirium, is there an impact on long-term cognitive outcomes? As duration of delirium is an independent predictor of long-term cognitive impairment, does the treatment of delirium with atypical antipsychotics offer any long-term cognitive benefit to ICU
survivors?15 An enormous opportunity to contribute to the literature exists in the study of these important, patient-centered outcomes. The MIND-USA study, a multicenter, double-blind, randomized, placebo-controlled trial comparing haloperidol versus ziprasidone versus placebo, is currently recruiting and investigating 3- and 12-month neuropsychological dysfunction as a secondary outcome.16 The above discussion dealt with only a few important areas where we desperately need further knowledge. There is tremendous opportunity for clinicians and researchers to become involved in hypothesis-generating and confirmatory studies. In the interim, an ounce of prevention remains worth a pound of cure when it comes to this underrecognized and arguably life-altering ICU condition. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. 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. 2. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301:489-499. 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;298:2644-2653. 4. Strøm T, Martinussen T, Toft P. A protocol for no sedation of critically ill patients receiving mechanical ventilation: a randomized trial. Lancet. 2010;375:475-480. 5. Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA. 2012;307:1151-1160. 6. Carson SS, Kress JP, Rodgers JE, et al. A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients. Crit Care Med. 2006;34:1326-1332. 7. Hall RI, Sandham D, Cardinal P, et al. Propofol vs midazolam for ICU sedation: a Canadian multicenter randomized trial. Chest. 2001;119:1151-1159. 8. ClinicalTrials.gov. The MENDS II study (Vanderbilt University). http://www.clinicaltrials.gov/ct2/show/NCT01739933. Accessed September 5, 2013. 9. 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;40:731-739.
Downloaded from aop.sagepub.com at UNIV OF CONNECTICUT on April 12, 2015
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Flannery and Flynn 10. van den Boogaard M, Schoonhoven L, van Achterberg T, et al. Haloperidol prophylaxis in critically ill patients with a high risk of delirium. Crit Care. 2013;17:R9. 11. Devlin JW, Roberts RJ, Fong JJ, et al. 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;38:419-427. 12. Girard TD, Pandharipande PP, Carson SS, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Crit Care Med. 2010;38:428-437. 13. Jasiak KD, Middleton EA, Camamo JM, et al. Evaluation of discontinuation of atypical antipsychotics prescribed for ICU delirium. J Pharm Pract. 2013;26: 254-256.
14. Mirski MA, Lewin JJ III, Ledroux S, et al. Cognitive improvement during continuous sedation in critically ill, awake and responsive patients: the Acute Neurological ICU Sedation Trial (ANIST). Intensive Care Med. 2010;36:1505-1513. 15. Girard TD, Jackson JC, Pandharipande PP, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med. 2010;38:1513-1520. 16. ClinicalTrials.gov. The Modifying the Impact of ICU Associated Neurological Dysfunction-USA (MIND-USA) Study (Vanderbilt University). http://www.clinicaltrials.gov/ ct2/show/NCT01211522. Accessed September 5, 2013.
Downloaded from aop.sagepub.com at UNIV OF CONNECTICUT on April 12, 2015
research-article2013
AOPXXX10.1177/1060028013504739Annals of PharmacotherapyFlannery and Flynn
Commentary
More Questions Than Answers in ICU Delirium: Pressing Issues for Future Research
Annals of Pharmacotherapy 47(11) 1558–1561 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013504739 aop.sagepub.com
Alexander H. Flannery, PharmD, BCPS1, and Jeremy D. Flynn, PharmD, FCCP, FCCM1,2
Abstract With the release of the updated pain, agitation, and delirium guidelines by the Society of Critical Care Medicine, a number of new and updated recommendations are provided regarding the pharmacological prevention and treatment of ICU delirium. Whereas this is important to understand the limitations of existing literature in interpreting the guideline recommendations, it also provides an opportunity to identify those areas of practice where we need further knowledge. We discuss 5 of the most critical questions in our view regarding pharmacological therapy for ICU delirium in an attempt to highlight areas of this ICU condition that are much deserving of further research, including the deliriogenic potential of dexmedetomidine, optimal sedative choices for the delirious ICU patient, pharmacological prophylaxis for ICU delirium, optimal treatment duration for ICU delirium, and the impact of pharmacotherapy on long-term cognitive outcomes in ICU survivors. A multitude of opportunities for further research exist in the above areas for clinicians and researchers interested in this ICU condition. Keywords delirium, critical care, dexmedetomidine, antipsychotic Received August 5, 2013; revised August 16, 2013; accepted August 16, 2013
The long-awaited pain, agitation, and delirium guidelines sponsored by the Society of Critical Care Medicine and the American Society for Health-System Pharmacists were recently updated from the previous 2002 edition, with a bolstered section on ICU delirium providing over 20 statements and recommendations.1 Now, 10 years of research later, our results provide us with almost as many questions as we have answers regarding the pharmacotherapy of this complex phenomenon in the ICU. As is often the case, the guideline authors had to sift through controversial and imperfect literature to form recommendations to guide practice. Although it is important to understand the limitations of current literature in interpreting the guidelines, it is equally important to identify those questions that need to be answered as we move forward, particularly as they relate to the pharmacotherapy for prevention and treatment of ICU delirium. Opportunities for further research abound, and the gaps of knowledge in the current guidelines offer an important opportunity to identify future research questions.
and the implication of dexmedetomidine in contributing to ICU delirium remains unknown.2,3 The SEDCOM trial, which suggested a lower prevalence of delirium with dexmedetomidine compared with midazolam, allowed midazolam as needed in both arms, which has made some question whether the reduced prevalence of delirium was a result of dexmedetomidine or the fact that less cumulative benzodiazepine was used in the dexmedetomidine arm.2 In the MENDS trial, which used fentanyl and propofol boluses rather than benzodiazepine boluses for additional comfort, the prevalence of delirium or coma was still 87% in the dexmedetomidine group.3 With an increased focus on analgosedation in the guidelines, does the use of analgosedation reduce the prevalence of delirium compared with an analgesic plus sedation with dexmedetomidine?1 In the landmark trial by Strøm et al,4 a protocol of no sedation significantly increased the number of days without mechanical ventilation compared 1
University of Kentucky HealthCare, Lexington, KY, USA University of Kentucky College of Pharmacy, Lexington, KY, USA
2
Does Dexmedetomidine Contribute to ICU Delirium? Despite sedation with dexmedetomidine, ICU delirium was still highly prevalent in both SEDCOM and MENDS trials,
Corresponding Author: Alexander H. Flannery, PharmD, BCPS, Medical Intensive Care Unit/ Pulmonary, University of Kentucky HealthCare, 800 Rose Street, H110, Lexington, KY 40536, USA. Email: [email protected]
Downloaded from aop.sagepub.com at UNIV OF CONNECTICUT on April 12, 2015
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Flannery and Flynn with a sedation protocol utilizing daily interruptions. However, the prevalence of agitated delirium and use of haloperidol was significantly higher in the no sedation group.4 Whether these results are a result of underdiagnosed delirium is not known; also, contribution ofthe specific opioid used (morphine), inadequate pain control, or the recall of unpleasant events remains unknown.
How Do We Sedate Patients With ICU Delirium? In patients with ICU delirium requiring sedation, the guidelines suggest sedation with dexmedetomidine over benzodiazepines.1 The PRODEX trial published last year, which of note was not included in the guideline authors’ review because of the timing of publication, compared dexmedetomidine and propofol for ICU sedation.5 With regard to prevalence of delirium, PRODEX suggested an increased prevalence of neurocognitive disorders, including delirium with propofol when compared with dexmedetomidine. These results must be taken in light of the fact that this was one of many secondary outcomes, baseline prevalence of delirium was not reported, and patients were only screened for delirium once at the 48-hour mark of the study.5 Possibly due to the above confounding reasons, the authors found no difference in the prevalence of delirium between dexmedetomidine and benzodiazepines in the “twin” MIDEX study—data that conflict with the SEDCOM and MENDS studies.2,3,5 Although the prevalence of ICU delirium/coma was reduced with dexmedetomidine in the SEDCOM and MENDS trials, the study of sedation in the delirious patient population specifically remains limited. Approximately 60% of patients in the SEDCOM study were delirious at baseline, whereas the baseline rate of delirium in the MENDS study could not be determined.2,3 It is noteworthy that while propofol or dexmedetomidine are suggested as first-line therapies for sedation, only dexmedetomidine carries the suggestion as the recommended sedative in delirious ICU patients.1 This likely stems from the fact that SEDCOM and MENDS have suggested a reduced prevalence of delirium with dexmedetomidine compared with benzodiazepines, but the risk of developing delirium with propofol compared with benzodiazepines when used for ICU sedation is less well described.2,3 Propofol and benzodiazepines have been compared head to head, but delirium was not assessed reliably or at all.6[sup],7 If propofol and dexmedetomidine are recommended for sedation in nondelirious patients, are they also interchangeable when used for sedating delirious patients? A well-designed comparison of propofol and dexmedetomidine with regard to their outcomes on ICU delirium is needed, which will hopefully be completed with the MENDS II study.8 Future investigations that not only stratify patients by risk for ICU delirium but
also study sedation practices in delirious patients specifically should be encouraged.
Can We Prevent Delirium With Pharmacological Prophylaxis? Although limited studies exist, the guidelines offer no recommendation for pharmacological prophylaxis of delirium in the ICU.1 Low-dose haloperidol prophylaxis in older patients following noncardiac surgery appeared to reduce the incidence of delirium within the first 7 postoperative days, although this study is difficult to generalize to all ICU patients because of the low acuity of the patient population studied.9 A recently published study found that low-dose haloperidol prophylaxis reduced the incidence of delirium as well as reduced the duration of mechanical ventilation and ICU length of stay in mechanically ventilated patients at high risk of developing delirium.10 Using the complex PRE-DELIRIC model to risk stratify patients with regard to their risk of developing delirium, the authors showed that haloperidol was associated with improved outcomes only in the highest-risk patient population.10 This is an important step because it represents the most severely ill patient population studied to date for prophylaxis, suggesting that pharmacological prophylaxis may have a benefit in those patients with a high risk of developing delirium. The development of a valid, bedside predictive model (ie, delirium score) for delirium may not only have great prognostic value but also great value in stratifying patients who may benefit the most from targeted interventions, which may include pharmacological prophylaxis. No studies have been published to date regarding prolonged pharmacological prophylaxis outside of the perioperative period with atypical antipsychotics.
How Long Do We Treat ICU Delirium? Although the guidelines provide no definitive answer, a look back at pilot studies of antipsychotics for the treatment of ICU delirium may serve as a starting point. Devlin et al11 in their pilot study of quetiapine demonstrated that quetiapine reduced the time required to first resolution of delirium as compared with placebo. Study treatment was discontinued in the majority of patients either at the intensivist’s discretion or at ICU discharge, per protocol.11 This approach resulted in 20% of patients in the quetiapine group and 56% in the placebo group experiencing ≥1 day of delirium in the 14-day period following study drug discontinuation.11 The MIND trial, although not demonstrating favorable benefits of using antipsychotics for treatment of ICU delirium, tapered the dose as patients remained Confusion Assessment Method for the ICU (CAM-ICU) negative, ultimately
Downloaded from aop.sagepub.com at UNIV OF CONNECTICUT on April 12, 2015
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Annals of Pharmacotherapy 47(11)
discontinuing treatment when patients had been delirium and coma free for >48 hours.12 Perhaps this approach in practice may be a protocolized, efficient, and safe way to ensure that antipsychotics are prescribed for the minimal amount of time necessary. Whether a correlation exists between how long patients are treated for ICU delirium and the use of haloperidol as needed or other antipsychotics after discontinuation of scheduled therapy remains unknown. The answer to this question may help define what a “usual” treatment course for delirium is and may very well depend on the subtype of delirium. It is advisable to treat until CAM-ICU negative, but for how long after and whether rebound effects exist has not been determined. Unlike some infectious disease conditions where duration of treatment is at times defined early in therapy, the treatment duration of ICU delirium should be very much patient specific, and the need for antipsychotics should be frequently reassessed, especially as the patient is discharged from the ICU to the floor. A recent study found that almost 50% of patients were transferred out of the ICU on antipsychotic treatment for delirium, and 33% of patients were discharged home on antipsychotics.13 The alarming results of this study highlight the need to address the issue of ICU delirium treatment length. The inherent assumption in the above question is that antipsychotics help reduce the duration of delirium in the ICU and are valid treatment options. Although the guidelines acknowledge that more evidence exists for using the atypical antipsychotics, confirmatory studies remain under way to evaluate the impact various antipsychotics have in reducing the symptoms and duration of ICU delirium compared with placebo.1 The interplay of the pharmacology of various atypical antipsychotics and the neuropathophysiology of ICU delirium remain largely unknown.
What Is the Impact on Long-term Cognitive Outcomes? An ever-increasing trend in critical care practice is to study not only what happens to patients while in the ICU but theirlong-term outcomes following hospital discharge. As it relates to ICU delirium and cognitive impairment, the impact of our efforts to thwart and treat delirium on longterm cognitive outcomes remains largely unknown. Although a small study demonstrated that dexmedetomidine may impair cognitive function in the ICU to a lesser degree than propofol, this has yet to be replicated in largescale and long-term cognitive outcome trials.14 As we continue to explore dexmedetomidine as a sedative choice for the potential to reduce the prevalence of delirium, is there an impact on long-term cognitive outcomes? As duration of delirium is an independent predictor of long-term cognitive impairment, does the treatment of delirium with atypical antipsychotics offer any long-term cognitive benefit to ICU
survivors?15 An enormous opportunity to contribute to the literature exists in the study of these important, patient-centered outcomes. The MIND-USA study, a multicenter, double-blind, randomized, placebo-controlled trial comparing haloperidol versus ziprasidone versus placebo, is currently recruiting and investigating 3- and 12-month neuropsychological dysfunction as a secondary outcome.16 The above discussion dealt with only a few important areas where we desperately need further knowledge. There is tremendous opportunity for clinicians and researchers to become involved in hypothesis-generating and confirmatory studies. In the interim, an ounce of prevention remains worth a pound of cure when it comes to this underrecognized and arguably life-altering ICU condition. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. 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. 2. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301:489-499. 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;298:2644-2653. 4. Strøm T, Martinussen T, Toft P. A protocol for no sedation of critically ill patients receiving mechanical ventilation: a randomized trial. Lancet. 2010;375:475-480. 5. Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA. 2012;307:1151-1160. 6. Carson SS, Kress JP, Rodgers JE, et al. A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients. Crit Care Med. 2006;34:1326-1332. 7. Hall RI, Sandham D, Cardinal P, et al. Propofol vs midazolam for ICU sedation: a Canadian multicenter randomized trial. Chest. 2001;119:1151-1159. 8. ClinicalTrials.gov. The MENDS II study (Vanderbilt University). http://www.clinicaltrials.gov/ct2/show/NCT01739933. Accessed September 5, 2013. 9. 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;40:731-739.
Downloaded from aop.sagepub.com at UNIV OF CONNECTICUT on April 12, 2015
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Flannery and Flynn 10. van den Boogaard M, Schoonhoven L, van Achterberg T, et al. Haloperidol prophylaxis in critically ill patients with a high risk of delirium. Crit Care. 2013;17:R9. 11. Devlin JW, Roberts RJ, Fong JJ, et al. 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;38:419-427. 12. Girard TD, Pandharipande PP, Carson SS, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Crit Care Med. 2010;38:428-437. 13. Jasiak KD, Middleton EA, Camamo JM, et al. Evaluation of discontinuation of atypical antipsychotics prescribed for ICU delirium. J Pharm Pract. 2013;26: 254-256.
14. Mirski MA, Lewin JJ III, Ledroux S, et al. Cognitive improvement during continuous sedation in critically ill, awake and responsive patients: the Acute Neurological ICU Sedation Trial (ANIST). Intensive Care Med. 2010;36:1505-1513. 15. Girard TD, Jackson JC, Pandharipande PP, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med. 2010;38:1513-1520. 16. ClinicalTrials.gov. The Modifying the Impact of ICU Associated Neurological Dysfunction-USA (MIND-USA) Study (Vanderbilt University). http://www.clinicaltrials.gov/ ct2/show/NCT01211522. Accessed September 5, 2013.
Downloaded from aop.sagepub.com at UNIV OF CONNECTICUT on April 12, 2015
