CORRESPONDENCE morbidity associated with delirium, because inclusion of patients with RRD has almost certainly “watered down” the impact of this brain organ dysfunction in earlier publications (4). As PD/MxD comprise the vast majority of patients, do the authors believe that these powerful prognostic data call for us as clinicians (and indeed prompt the need to update guidelines [5]) to perform delirium evaluations both before and after an SAT? Second, the authors believed that patients with PD/MxD were sicker than patients with RRD, yet measures of illness severities were similar (Acute Physiology and Chronic Health Evaluation scores, 21–23). However, the sepsis incidence was approximately threefold higher in patients with PD/MxD, which brings up the important possibility that sedative-associated delirium is more dangerous in patients with widespread inflammation and coagulopathy. Can the authors provide analyses to understand PD/MxD in light of concomitant presence of sedation and sepsis? This could be investigated using serum drug levels and also through appropriate interaction analyses. Such data from this investigation would be hypothesis generating and advance the field. Because many patients with PD/MxD surely had sedatives and analgesics floating in their blood (and active in their brain) beyond 2 hours, these data would also illuminate distinctions between benign and ominous forms of sedative-associated delirium. n Author disclosures are available with the text of this letter at www.atsjournals.org. E. Wesley Ely, M.D., M.P.H. Vanderbilt University Medical Center Nashville, Tennessee

References 1. Patel SB, Poston JT, Pohlman A, Hall JB, Kress JP. Rapidly reversible, sedation-related delirium versus persistent delirium in the intensive care unit. Am J Respir Crit Care Med 2014;189:658–665. 2. Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004;291:1753–1762. 3. 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;180:1092–1097. 4. Takala J. Of delirium and sedation [editorial]. Am J Respir Crit Care Med 2014;189:622–624. 5. Barr J, Fraser GL, Puntillo K, Ely EW, Gelinas ´ C, Dasta JF, Davidson JE, Devlin JW, Kress JP, Joffe AM, et al.; American College of Critical Care Medicine. 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.

Copyright © 2014 by the American Thoracic Society

Only a Small Subset of Sedation-related Delirium Is Innocuous: We Cannot Let Our Guard Down To the Editor: Patel and colleagues (1) recently described a subset of intensive care unit (ICU) patients with rapidly reversible, sedation-related Correspondence

delirium that may not portend the poor outcomes associated with more persistent delirium. We write both to commend the authors for advancing the field of delirium research and to warn healthcare providers of the dangers inherent in interpreting these results too broadly by assuming that all sedation-related delirium is innocuous. Although the authors were generally careful to state that their conclusions pertain only to the small proportion (12%) of patients with rapidly reversible delirium, even they occasionally liberalized their terminology and thereby implied that all patients who become delirious when sedated are at low risk for poor outcomes, surmising that “sedative-induced delirium is very different and clearly less dangerous than other types of delirium.” We assert that sedation-related delirium should not be ignored for several reasons. First, only 12% of patients in this study had the rapidly reversible form of sedation-related delirium found to be less dangerous. In sharp contrast, 77% of patients had “persistent delirium,” which remained present after sedative interruption but was in no way proven to be unrelated to sedation. Given that most sedatives remain in the system well after the 2-hour time frame used to delineate rapidly reversible from persistent delirium, sedation was very likely an important contributor to the persistent delirium that was associated with poor outcomes. Second, because benzodiazepine use was sparse in this study, the results may not be generalizable to the large majority of ICUs where benzodiazepine use is still quite prevalent. Not only are benzodiazepines the sedative class most often associated with delirium (2), but they are probably more likely to predispose patients to the persistent type of delirium associated with worse outcomes than shorter-acting sedatives. Third, no tool can predict which patients will develop rapidly reversible rather than persistent sedation-related delirium. ICU clinicians must therefore remain extremely cautious when using deliriogenic sedatives. Not only should such sedatives be used rarely and judiciously, but careful delirium monitoring should also be systemically implemented in all ICUs, as recommended in the recently revised pain, agitation, and delirium guidelines (3), irrespective of whether patients are being managed by light sedation techniques or with sedation interruption. As shown by Patel and colleagues (1), assessing for delirium before interrupting sedatives may overestimate delirium prevalence (by 12% in their study), but failing to conduct these assessments will result in the costly mistake of overlooking delirium in the majority of patients (77% in this study). The authors’ new data clearly inform our use of delirium assessments; future delirium studies will be more informative if investigators collect delirium evaluations both before and after sedative interruption. n Author disclosures are available with the text of this letter at www.atsjournals.org. Pratik P. Pandharipande, M.D., M.S.C.I. Christopher G. Hughes, M.D. Vanderbilt University School of Medicine Nashville, Tennessee Timothy D. Girard, M.D., M.S.C.I. Vanderbilt University School of Medicine Nashville, Tennessee and Tennessee Valley Healthcare System Nashville, Tennessee

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CORRESPONDENCE References 1. Patel SB, Poston JT, Pohlman A, Hall JB, Kress JP. Rapidly reversible, sedation-related delirium versus persistent delirium in the intensive care unit. Am J Respir Crit Care Med 2014;189: 658–665. 2. Pandharipande P, Shintani A, Peterson J, Pun BT, Wilkinson GR, Dittus RS, Bernard GR, Ely EW. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 2006;104:21–26. 3. Barr J, Fraser GL, Puntillo K, Ely EW, Gelinas ´ C, Dasta JF, Davidson JE, Devlin JW, Kress JP, Joffe AM, et al.; American College of Critical Care Medicine. 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.

Copyright © 2014 by the American Thoracic Society

Reply: Is the Glass of Delirium Half Full or Half Empty? From the Editorialist*: Pandharipande and colleagues and Ely raise several important issues in their letters in response to Patel and colleagues (1) on rapidly reversible, sedation-related delirium. Both point out that from all patients with positive Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) (indicating “delirium”; 87 of 97 or 89.7%), the proportion of those who became CAM-ICU negative after 2-hour sedation stop was small (12 of 97 or 12.4%), resulting in 75 of 97 (77%) patients with either mixed or persistent delirium. Five patients out of 102 (4.9%) were in a coma and hence not analyzed. The authors warn us not to take sedation-related delirium lightly. So is it good news or bad news that not all “deliriums” are the same? Delirium is certainly a relevant problem in ICU patients, but diagnosing it is controversial. Some experts question the scales based on Diagnostic and Statistical Manual of Mental Disorders categories to diagnose ICU delirium (2), and sedation is a recognized confounder (2, 3). Unfortunately, almost all ICU delirium research has been done without considering the role of sedation at all and therefore appears to be seriously flawed. In fact, Ely and colleagues until recently rejected the concept that sedation-related positive CAM-ICU or “delirium” is any less dangerous than other forms of delirium (4). Now that Patel and colleagues provided the evidence that “delirium” resolving after sedation stop is indeed different from persisting positive CAM-ICU (1), the consequences should be considered. Most of the reported associations of specific drugs or positive CAM-ICU with outcome(s) should be considered in the context of sedation without sedation stops. How common rapidly reversible, sedationrelated delirium was in previous studies is unclear. Haenggi and colleagues (3) found that 20% of patients remained moderately sedated after 2-hour sedation stop, and 19% of ever CAMICU–positive patients were so only when remaining at Richmond Agitation Sedation Scale 22 to 23 despite sedation stop. Patel and colleagues (1) found that 28.9% of CAM-ICU–positive assessments reverted to normal during sedation stop. Prolonging the sedation stops may well have increased CAM-ICU–negative assessments. Such *Dr. Takala wrote an editorial on the article by Patel et al. (Of delirium and sedation. Am J Respir Crit Care Med 2014;189:622–624).

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patients may have had better outcomes than those with more persistent “mixed delirium.” This is the good news. Repeatedly failing to normalize CAM-ICU during the 2-hour sedation stop but not quite fulfilling the criteria of “persistent delirium” may well have a worse outcome. In that case, the consequences of failing to resolve “delirium” were underestimated. This is the bad news. It is clear that persistent delirium is bad for the patient. In Patel and colleagues’ study, CAM-ICU–positive patients had lower Richmond Agitation Sedation Scale than CAM-ICU–negative ones before and after sedation stop; the only way to sort out the role of sedation is to continue the sedation stop. Agitation and poor tolerance to artificial airway and mechanical ventilation are the predominant reasons for restarting sedation. Instead of labeling these patients with “delirium” and restarting sedation, more efforts should be invested in minimizing the use of sedation and giving the brain a chance to clear. n Author disclosures are available with the text of this letter at www.atsjournals.org. Jukka Takala, M.D., Ph.D. Bern University Hospital Bern, Switzerland and University of Bern Bern, Switzerland

References 1. Patel SB, Poston JT, Pohlman A, Hall JB, Kress JP. Rapidly reversible, sedation-related delirium versus persistent delirium in the intensive care unit. Am J Respir Crit Care Med 2014;189:658–665. 2. Devlin JW, Fraser GL, Joffe AM, Riker RR, Skrobik Y; Can delirium Assessments Be Accurately Labelled (CABAL) Investigators group. The accurate recognition of delirium in the ICU: the emperor’s new clothes? Intensive Care Med 2013;39:2196–2199. 3. Haenggi M, Blum S, Brechbuehl R, Brunello A, Jakob SM, Takala J. Effect of sedation level on the prevalence of delirium when assessed with CAM-ICU and ICDSC. Intensive Care Med 2013;39:2171–2179. 4. Brummel NE, Ely EW. Sedation level and the prevalence of delirium. Intensive Care Med 2014;40:135.

Copyright © 2014 by the American Thoracic Society

Reply: The Importance of Determining the Reason for Intensive Care Unit Delirium From the Authors: We thank Pandharipande and colleagues for their interest in our work (1) and agree that the results of this trial must not be interpreted beyond what was reported. Delirium is a constellation of clinical bedside features, rather than a characteristic, discrete “lesion.” It is a syndrome, not a disease. Propofol, the sedative used most frequently in our trial, has a complex pharmacokinetic profile; it certainly is known that propofol remains in the system beyond 2 hours (2) and that there are variable pharmacokinetics of the drug, with age and weight noted to be important contributors (3). Accordingly, measuring serum drug levels, which was not a part of this study, would not likely clarify the question of clinical behavior (i.e., delirium), drug effect, and coexisting illness (e.g., sepsis). It

American Journal of Respiratory and Critical Care Medicine Volume 189 Number 11 | June 1 2014

Only a small subset of sedation-related delirium is innocuous: we cannot let our guard down.

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