CORRESPONDENCE with reduced capacity to form epithelial junctions during ALI differentiation in vitro. Of importance, this cannot merely be attributed to cigarette smoking, but rather appears to be a diseaserelated effect. Disrupted expression of tight junction proteins was also observed in lung sections of the same patients with COPD, indicating that the disruption of epithelial barrier as previously observed on cigarette smoking is persistent on smoking cessation. This may be due to the compromised ability of the bronchial epithelium of patients with COPD to (re)constitute cell–cell contacts and to redifferentiate into a functionally intact epithelium upon damage, for example, by cigarette smoking. Upon epithelial differentiation, efficient tight junction assembly may be crucial for the formation of a polarized epithelial layer (15). Tight junctions regulate paracellular permeability and functionally segregate the basolateral from the apical compartment, which is a requirement for full epithelial polarization and epithelial homeostasis (16). Loss of epithelial integrity may facilitate transepithelial crossing of noxious gases as well as pathogens. This may have important implications, because viral and bacterial infections have been implicated in nearly 50% of COPD exacerbations (17). Therefore, there is a great need to further investigate the mechanisms underlying impaired epithelial barrier function to improve mucosal barrier function in COPD. This may improve insight in strategies to improve barrier function in COPD, a promising novel target in the treatment of COPD. n Author disclosures are available with the text of this letter at www.atsjournals.org. Irene H. Heijink, Ph.D. Jacobien A. Noordhoek, B.Sc. Wim Timens, M.D. Antoon J. M. van Oosterhout, Ph.D. Dirkje S. Postma, M.D. University of Groningen Groningen, The Netherlands
Copyright © 2014 by the American Thoracic Society
Our Enlightened Understanding of the Risks of Persistent Delirium
References 1. Holgate ST. Epithelium dysfunction in asthma. J Allergy Clin Immunol 2007;120:1233–1244, quiz 1245–1246. 2. Shaykhiev R, Otaki F, Bonsu P, Dang DT, Teater M, Strulovici-Barel Y, Salit J, Harvey BG, Crystal RG. Cigarette smoking reprograms apical junctional complex molecular architecture in the human airway epithelium in vivo. Cell Mol Life Sci 2011;68:877–892. 3. Milara J, Peiro´ T, Serrano A, Cortijo J. Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke. Thorax 2013;68:410–420. 4. Hogg JC. Bronchial mucosal permeability and its relationship to airways hyperreactivity. Eur J Respir Dis Suppl 1982;122:17–22. 5. Heijink IH, Brandenburg SM, Postma DS, van Oosterhout AJ. Cigarette smoke impairs airway epithelial barrier function and cell–cell contact recovery. Eur Respir J 2012;39:419–428. 6. van den Berge M, Steiling K, Timens W, Hiemstra PS, Sterk PJ, Heijink IH, Liu G, Alekseyev YO, Lenburg ME, Spira A, et al. Airway gene expression in COPD is dynamic with inhaled corticosteroid treatment and reflects biological pathways associated with disease activity. Thorax 2014;69:14–23. 7. Hackett TL, Shaheen F, Johnson A, Wadsworth S, Pechkovsky DV, Jacoby DB, Kicic A, Stick SM, Knight DA. Characterization of side population cells from human airway epithelium. Stem Cells 2008;26: 2576–2585. 8. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS; GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.
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NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163: 1256–1276. 9. Heijink IH, Postma DS, Noordhoek JA, Broekema M, Kapus A. House dust mite–promoted epithelial-to-mesenchymal transition in human bronchial epithelium. Am J Respir Cell Mol Biol 2010;42:69–79. 10. Heijink IH, Brandenburg SM, Noordhoek JA, Postma DS, Slebos DJ, van Oosterhout AJ. Characterisation of cell adhesion in airway epithelial cell types using electric cell–substrate impedance sensing. Eur Respir J 2010;35:894–903. 11. Wegener J, Keese CR, Giaever I. Electric cell–substrate impedance sensing (ECIS) as a noninvasive means to monitor the kinetics of cell spreading to artificial surfaces. Exp Cell Res 2000;259: 158–166. 12. Xiao C, Puddicombe SM, Field S, Haywood J, Broughton-Head V, Puxeddu I, Haitchi HM, Vernon-Wilson E, Sammut D, Bedke N, et al. Defective epithelial barrier function in asthma. J Allergy Clin Immunol 2011;128:549–556, e1–e12. 13. Heijink I, van Oosterhout A, Kliphuis N, Jonker M, Hoffmann R, Telenga E, Klooster K, Slebos DJ, ten Hacken N, Postma D, et al. Oxidantinduced corticosteroid unresponsiveness in human bronchial epithelial cells. Thorax 2014;69:5–13. 14. Hackett TL, Singhera GK, Shaheen F, Hayden P, Jackson GR, Hegele RG, Van ES, Bai TR, Dorscheid DR, Knight DA. Intrinsic phenotypic differences of asthmatic epithelium and its inflammatory responses to RSV and air pollution. Am J Respir Cell Mol Biol 2011;45: 1090–1100. 15. Kubota H, Chiba H, Takakuwa Y, Osanai M, Tobioka H, Kohama G, Mori M, Sawada N. Retinoid X receptor a and retinoic acid receptor g mediate expression of genes encoding tight-junction proteins and barrier function in F9 cells during visceral endodermal differentiation. Exp Cell Res 2001;263:163–172. 16. Dragsten PR, Handler JS, Blumenthal R. Asymmetry in epithelial cells: is the tight junction a barrier to lateral diffusion in the plasma membrane? Prog Clin Biol Res 1982;91:525–536. 17. Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med 2008;359:2355–2365.
To the Editor: Patel and colleagues (1) add a very important new piece to the delirium literature puzzle, which begs two important questions. First, what is the prognostic distinction between a small but important subgroup of patients manifesting rapidly reversible delirium (RRD, n = 12, 12%), defined as delirium symptoms that resolved within 2 hours after cessation of sedative/analgesic medications (often called spontaneous awakening trials [SATs]) versus the much larger group of patients in whom delirium persisted beyond 2 hours of an SAT (comprising persistent delirium [PD] and mixed delirium [MxD], n = 75, 74%)? Consider how many times every day you have patients whose brains remain delirious (“inattentive”) 2 hours after stopping sedation. This simple finding, which was present in three out of every four patients, portended a threefold higher likelihood of death (1-yr mortality of 66% for PD vs. 20% for RRD). In fact, each additional day of “persistent delirium” (again, delirium just 2 or more hours after SAT) was associated with a 14% increased risk of death at 1 year, a risk 4% higher per day than 10% indicated in previous investigations (2, 3). This strengthens our understanding of the
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 11 | June 1 2014
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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Copyright © 2014 by the American Thoracic Society
Our Enlightened Understanding of the Risks of Persistent Delirium
References 1. Holgate ST. Epithelium dysfunction in asthma. J Allergy Clin Immunol 2007;120:1233–1244, quiz 1245–1246. 2. Shaykhiev R, Otaki F, Bonsu P, Dang DT, Teater M, Strulovici-Barel Y, Salit J, Harvey BG, Crystal RG. Cigarette smoking reprograms apical junctional complex molecular architecture in the human airway epithelium in vivo. Cell Mol Life Sci 2011;68:877–892. 3. Milara J, Peiro´ T, Serrano A, Cortijo J. Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke. Thorax 2013;68:410–420. 4. Hogg JC. Bronchial mucosal permeability and its relationship to airways hyperreactivity. Eur J Respir Dis Suppl 1982;122:17–22. 5. Heijink IH, Brandenburg SM, Postma DS, van Oosterhout AJ. Cigarette smoke impairs airway epithelial barrier function and cell–cell contact recovery. Eur Respir J 2012;39:419–428. 6. van den Berge M, Steiling K, Timens W, Hiemstra PS, Sterk PJ, Heijink IH, Liu G, Alekseyev YO, Lenburg ME, Spira A, et al. Airway gene expression in COPD is dynamic with inhaled corticosteroid treatment and reflects biological pathways associated with disease activity. Thorax 2014;69:14–23. 7. Hackett TL, Shaheen F, Johnson A, Wadsworth S, Pechkovsky DV, Jacoby DB, Kicic A, Stick SM, Knight DA. Characterization of side population cells from human airway epithelium. Stem Cells 2008;26: 2576–2585. 8. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS; GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.
1442
NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163: 1256–1276. 9. Heijink IH, Postma DS, Noordhoek JA, Broekema M, Kapus A. House dust mite–promoted epithelial-to-mesenchymal transition in human bronchial epithelium. Am J Respir Cell Mol Biol 2010;42:69–79. 10. Heijink IH, Brandenburg SM, Noordhoek JA, Postma DS, Slebos DJ, van Oosterhout AJ. Characterisation of cell adhesion in airway epithelial cell types using electric cell–substrate impedance sensing. Eur Respir J 2010;35:894–903. 11. Wegener J, Keese CR, Giaever I. Electric cell–substrate impedance sensing (ECIS) as a noninvasive means to monitor the kinetics of cell spreading to artificial surfaces. Exp Cell Res 2000;259: 158–166. 12. Xiao C, Puddicombe SM, Field S, Haywood J, Broughton-Head V, Puxeddu I, Haitchi HM, Vernon-Wilson E, Sammut D, Bedke N, et al. Defective epithelial barrier function in asthma. J Allergy Clin Immunol 2011;128:549–556, e1–e12. 13. Heijink I, van Oosterhout A, Kliphuis N, Jonker M, Hoffmann R, Telenga E, Klooster K, Slebos DJ, ten Hacken N, Postma D, et al. Oxidantinduced corticosteroid unresponsiveness in human bronchial epithelial cells. Thorax 2014;69:5–13. 14. Hackett TL, Singhera GK, Shaheen F, Hayden P, Jackson GR, Hegele RG, Van ES, Bai TR, Dorscheid DR, Knight DA. Intrinsic phenotypic differences of asthmatic epithelium and its inflammatory responses to RSV and air pollution. Am J Respir Cell Mol Biol 2011;45: 1090–1100. 15. Kubota H, Chiba H, Takakuwa Y, Osanai M, Tobioka H, Kohama G, Mori M, Sawada N. Retinoid X receptor a and retinoic acid receptor g mediate expression of genes encoding tight-junction proteins and barrier function in F9 cells during visceral endodermal differentiation. Exp Cell Res 2001;263:163–172. 16. Dragsten PR, Handler JS, Blumenthal R. Asymmetry in epithelial cells: is the tight junction a barrier to lateral diffusion in the plasma membrane? Prog Clin Biol Res 1982;91:525–536. 17. Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med 2008;359:2355–2365.
To the Editor: Patel and colleagues (1) add a very important new piece to the delirium literature puzzle, which begs two important questions. First, what is the prognostic distinction between a small but important subgroup of patients manifesting rapidly reversible delirium (RRD, n = 12, 12%), defined as delirium symptoms that resolved within 2 hours after cessation of sedative/analgesic medications (often called spontaneous awakening trials [SATs]) versus the much larger group of patients in whom delirium persisted beyond 2 hours of an SAT (comprising persistent delirium [PD] and mixed delirium [MxD], n = 75, 74%)? Consider how many times every day you have patients whose brains remain delirious (“inattentive”) 2 hours after stopping sedation. This simple finding, which was present in three out of every four patients, portended a threefold higher likelihood of death (1-yr mortality of 66% for PD vs. 20% for RRD). In fact, each additional day of “persistent delirium” (again, delirium just 2 or more hours after SAT) was associated with a 14% increased risk of death at 1 year, a risk 4% higher per day than 10% indicated in previous investigations (2, 3). This strengthens our understanding of the
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 11 | June 1 2014
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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