TYBD 2016.pptx
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TYBD 2016.pptx
27/04/16 Ağrı Sedasyon DELİRYUM Deliryum YB hastası Stres Anksiyete Perihan Ergin Özcan İstanbul Tıp Fakültesi Anesteziyoloji AD Yoğun Bakım Bilim Dalı Uyku Patofizyoloji Nöroinflamasyon Mental statüde akut değişiklik Mental statüde dalgalanma Dezorganize düşünce Melatonin disregülasyonu Bilinç düzeyinde değişiklik Dikkatsizlik Halüsinasyon Hayal Saplantı, kuruntu Serebral metabolizmada bozulma Nöroendokrin anomaliler Koma Deliryum Hipoksemi, Metabolik düzensizlik Yaşlanma Oksidatif stres Sinyal iletiminde bozulma İlaçlar Sistemik inflammasyon Mikrogila aktivasyonu Hasta özellikleri Yaş Alışkanlıklar Cinsiyet Yanlız yaşama NörotransmiNer disregülasyonu Kronik patoloji Kardiyak hastalık Pulmoner hastalık Kognitif bozukluk deliryum NörotransmiNerlerin sentez ve salınımında azalma Beyinde sitokin seviyesinin artması NörotransmiNer dengesinde ve sinaptik iletişimde bozulma Çevresel faktörler Acilden YB’a kabul Izolasyon Gün ışığı görememe Gürültü Ziyaretçinin olmaması Fiziksel kısıtlama Akut hastalık Kalış süresi Ateş Mortalite yüsek hastalık Normal beslenememe Perfüzyonların sayısı Sedasyon Psikoaktif tedavi Girişimler 1 27/04/16 Diagnostic and Statistical Manual (DSM) of Mental Disorders 5 A-‐‑DikkaNe ve farkındalıkta bozulma Ani başlayan mental statüde değişiklik veya dalgalı seyir. B-‐‑ Kısa sürede gelişmesi ve gün içinde dalgalanmalar göstermesi ve Dikkatsizlik C-‐‑ Kognitif fonksiyonlarda bozulma ve D-‐‑ A ve C’deki durum daha önceki tanımlanmış nörokognitif hastalıkla açıklanmamalı veya Karışık, düzensiz düşünce Bilinç düzeyinde değişiklik Değerlendirme -‐‑tanı • CAM-ICU; Confusion Assessment Method for Intensive Care Medicine • ICDSC; Intensive are Delirium Screening Checklist • Delirium Detection Score • NEECHAM cofusion scale • CTD; Cognitive Test for Delirium • Kısaltılmış CTD E-‐‑ Bu bozulmanın başka bir medikal durum, intoksikasyon, yoksunluk gibi durumları fizyolojik sonucu olduğuna dair kanıtların olması Richmond Sedasyon Ajitasyon Skoru RASS Skor +4 Boğuşma halinde İleri derecede boğuşuyor/şiddet uyguluyor. Personel tehlikede. +3 Çok ajite Tüpleri veya kateterleri çeker/çıkarır. Agresif. +2 Ajite Anlamsız hareket. Ventilatör ile senkronize değil. +1 Huzursuz Endişeli fakat hareketler agresif/şiddetli değil. 0 Uyanık ve sakin -1 Uykulu Sese göz teması ile uyanıklığı sürdürüyor (>10sn). -2 Hafif sedatize Sese göz teması ile kısa süreli uyanıklık (<10sn). -3 Orta derecede sedatize Sese hareket yanıtı fakat göz teması yok. -4 Derin sedatize Sese yanıt yok, fiziksel uyarıya hareket yanıtı. -5 Uyandırılamıyor Sese veya fiziksel uyarıya yanıt yok. 2002;166,1338-44. Özellik 1 Akut başlangıç veya dalgalı seyir Sessler, CN, et al. Am J Respir Crit Care Med Pozi=f Nega=f Evet Hayır Hasta Degerlendirmesi 1B Hastanın son 24 saat içinde bilinç düzeyinde dalgalanma oldu Evet mu? Hayır Bilinc düzeyindeki değişiklik* (A_E) (Hastanın cevabı 1A veya 1B ye evet ise sonuç pozi=fdir). 1A Hastada ani bilinç değişikliği oldu mu? Pozi=f 1.Gun 2.Gun 3.Gun 4.Gun 5.Gun çalisma süresince A ya da B hasta değerlendirmesine uymuyorsa GKS veya Richmond ajitasyon sedasyon skalasında değişlik oldu mu? Özellik 2 Dikkat bozukluğu İCDSC Nega=f Hastanın dikkat ve odaklanmasında güçlük var mı? Hastanın cevabı 2A veya 2B de <8 ise sonuç pozi=fdir. 2A Harfler ile dikkat değerlendirme muayenesi 2B Resimler ile dikkat değerlendirme muayenesi Özellik 3 Düşünce organizasyonunun bozukluğu Dağınık ve anlaşılmaz düşüncelerin kanıX var mı? Dikkatsizlik Dezoryantasyon Halusinasyon, deluzyon, psikoz Psikomotor retardasyon/ ajitasyon Uygunsuz konusma ya da duygudurum Uyku/ uyanıklık sikluslarındaki degişiklik Semptomlarda dalgalanmalar Total skor (0-‐‑8) Dört sorudan üç veya daha fazlasına yanlış cevap vermesi ile, veya komutları izlemedeki yetersizliği ile kanıtlanır. 3A Sorular ile değerlendirme 3B Komutlar ile değerlendirme Özellik 4 Bilinç seviyesi Hastanın RASS Skoru sı[rdan farklıysa sonuç pozi=\ir Genel CAM-‐ ICU Değerlendirmesi evet hayır A : Cevap Yok, skor : Yok B: Siddetli ve tekrar eden uyarilara yanit( sesli ve agrili uyari, skor: Yok C: Hafif ya da orta derecede uyariya yanit, skor: 1 D: Normal uyaniklik, skor: 1 E: Normal uyarana asiri yanit, skor: 1 ( 1. ve 2.özelliğe 3. veya 4. özelliğin eşlik etmesi ) 2 27/04/16 Clinical tools for monitoring delirium in the ICU Journal of Critical Care (2012) delirium patients diagnosed by CAM-‐‑ICU or ICDSC presented similar clinical profile, but outcomes in patients diagnosed only by ICDSC were comparable with nondelirium patients. The findings of our study suggest that CAM-‐‑ICU is a be@er predictor of outcome. • Düşük Sedasyon skorunda deliryum değerlendirmesi ( yani RASS -‐‑2,-‐‑3 daha yüksek deliryum insidansına neden olabilir. • RASS skoruna göre deliryum değerlendirmesi • CAM-‐‑ICU ve ICDSC ile değerlendirme RASS > -‐‑2 RASS , -‐‑2,-‐‑3 Tam uyanık CAM-‐‑ICU %31 %22 %9 ICDSC %29 %22 %9 Deliryum değerlendirmesi sedasyon seviyesine bağlıdır CAM-‐‑ICU ve ICDSC sadece sedasyon etkilerini de ölçebilir Deliryumu olduğundan fazla gösterebilir van den Boogaard et al. Critical Care 2011, 15:R297 http://ccforum.com/content/15/6/R297 RESEARCH The Role of Continuous Electroencephalography in the ICU Open Access Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and noninflamed patients van den Boogaard et al. Critical Care 2011, 15:R297 http://ccforum.com/content/15/6/R297 Page 6 of 9 Table 3 Differences between delirium and nondelirium patients in inflamed and noninflamed patients Inflamed (n = 46) Noninflamed patients (n = 54) 1 4 1,3 Mark van den Boogaard1*, Matthijs , KieranNondelirium L Quinn2(n , Theo , Johannes van der Hoeven Delirium Kox (n = 26) = 20) vanP Achterberg value Delirium (n = 24) G Nondelirium (n = 30) , Proinflammatory4cytokines and Peter Pickkers1,3 Lisette Schoonhoven TNF-a (pg/ml) IL-1b (pg/ml) IL-6 (pg/ml) Abstract IL-8 (pg/ml) 13 [10-16] 11 [5-18] 0.17 8 7 [5-11] 0.18 [3-6] 4 [3-17] 0.67 3 [3-6] 3 [3-6] 0.69 [38-143] 41 [21-90] 0.09 50 [29-90] 34 [22-64] 0.047a 31 [24-44] 17 [9-26] < 0.001a 20 [12-32] 14 [9-22] Introduction: Delirium occurs in critically ill [3-6] patients and 0.22 is associated with and IL-17 (pg/ml) 4 frequently [3-7] 3 3 [3-4]disease severity 3 [3-3] infection. several pathways for delirium been described, associated with in 82 [66-141] 88 delirium [72-120] IL-18 Although (pg/ml) 136 [88-187] 84 have [65-132] 0.03a biomarkers intensive care unit (ICU) patients not well studied. We examined plasma biomarkers in delirious MIF (pg/ml) 438 is[294-796] 257 [157-576] 0.13 334 [214-561] 249 and nondelirious [179-702] patients and the role cytokines of these biomarkers on long-term cognitive function. Antiinflammatory a 24 with [17-51] IL-1ra In (pg/ml) [27-74] study, 32 we included [18-47] 100 ICU 0.04patients Methods: an exploratory 48 observational or without 16 delirium [11-25] and with IL-10 (pg/ml) 23 [13-47] infection/systemic 13 [5-35] inflammatory 0.08 response 28 [12-44] 22 Delirium [9-46] was ("inflamed”) and without ("noninflamed”) syndrome (SIRS). Chemotactic cytokines diagnosed by using the confusion-assessment method-ICU (CAM-ICU). Within 24 hours after the onset of delirium, a 268 [192-398] (pg/ml) 516 [295-822] [199-339] blood MCP-1 was obtained for biomarker analysis. No251 differences in patient0.001 characteristics were found 233 between[175-306] delirious Defensin and nondelirious patients. To determine associations between biomarkers and delirium, univariate and multivariate (μg/ml) analyses were 0.06 performed. [0.03-0.13] Eighteen 0.07 [0.03-0.09]after ICU 0.60 discharge, 0.06 a [0.04-0.10] 0.04 questionnaire [0.03-0.10] logisticHNP regression months cognitive-failure Markers of inflammation was distributed to the ICU survivors. CRPIn (mg/ml) [56-190] 84 patients [43-140] 0.40 41 [27-64] Results: total, 50 delirious84and 50 nondelirious were included. We42found[29-65] that IL-8, MCP-1, procalcitonin a 0.22 patients [0.11-0.55] 0.12 In the [0.06-0.18] (ng/ml) 1.0 significantly [0.23-2.0] 0.28 [0.10-0.64] (PCT), Procalcitonin cortisol, and S100-b were associated with delirium0.003 in inflamed (n = 46). Stress-response hormone noninflamed group of patients (n = 54), IL-8, IL-1ra, IL-10 ratio Ab1-42/40, and ratio AbN-42/40 were significantly Cortisolwith (μmol/L) [0.34-0.98] 0.48 analysis, [0.18-0.61] 0.46 [0.23-0.72] (odds 0.30 ratio, [0.06-0.66] associated delirium. In 0.59 multivariate regression IL-8 was0.06 independently associated 9.0; 95% Brain-specific proteins confidence interval (CI), 1.8 to 44.0) with delirium in inflamed patients and IL-10 (OR 2.6; 95% CI 1.1 to 5.9), and S100-b 172 to[113-409] 0.07 patients. 128 Furthermore, [87-210] 136 of several [92-247] (OR,(pg/ml) 0.03; 95% CI, 0.002 0.50) with 134 delirium [88-163] in noninflamed levels Ab1-42/40 Tau (pg/ml) 42 [26-131] 43 were significantly [24-75] 0.56 40 [21-78] 27 amyloid-b forms, but not human Tau or S100-b, correlated with self-reported cognitive[17-46] [0.62-3.45] 1.12 [0.40-2.21] 0.68 1.17 [0.48-1.26] Ratio tau/Ab1-42 impairment 18 months after1.03 ICU discharge, whereas inflammatory markers were not[0.60-2.52] correlated 0.90 to impaired long41 [31-52] 38 [31-42] 0.36 34 [26-43] 36 [30-42] Ab1-42 (pg/ml) term cognitive function. Ab1-40 (pg/ml) P value [5-13] 3 73 158 [132-229] 155 [137-178] 0.55 148 [109-223] 129 [106-158] Conclusions: In inflamed patients, the proinflammatory cytokine IL-8 was associated with delirium,0.26 whereas[0.23-0.33] in 0.23 [0.20-0.28] 0.24 [0.22-0.26] 0.72 0.22 [0.19-0.26] Ratio Ab1-42/40 were associated with delirium. This suggests that noninflamed patients, antiinflammatory cytokine29IL-10 and Ab AbN-42 (pg/ml) 31 [26-43] [24-39]1-42/40 0.57 28 [20-37] 28 [24-35] the underlying mechanism governing the development of delirium in 0.24 inflamed 225 patients[168-273] differs from178that in [145-220] 200 [167-283] 184 [147-229] AbN-40 (pg/ml) noninflamed patients. Finally,0.16 elevated levels of amyloid-b correlated with long-term subjective cognitive-impairment Ratio Ab N-42/40 [0.13-0.18] 0.18 [0.12-0.19] 0.47 0.13 [0.10-0.17] 0.16 [0.14-0.20] delirium may represent the first sign[1.00-1.39] of a (subclinical) dementia process. Future studies must confirm these results. Ratio Ab1-42/N-42 1.28 1.31 [1.18-1.48] 0.26 1.24 [1.04-1.33] 1.23 [1.05-1.39] The study was registered in 0.82 the Clinical Trial Register (NCT00604773). [0.74-0.89] 0.89 [0.73-0.96] 0.27 0.72 [0.65-0.84] 0.76 [0.70-0.87] Ratio Ab 1-40/N-40 0.001a 0.63 0.54 0.08 0.02a 0.03a 0.15 0.51 0.44 0.01a 0.06 0.60 0.08 0.07 0.55 0.08 0.001a 0.79 0.04a 0.02a 0.90 0.35 Data are expressed as median and IQR. Differences were tested with the Mann-Whitney U test. a * Correspondence: P value <m.vandenboogaard@ic.umcn.nl 0.05. 1 Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, P.O. Box 9101, Nijmegen, 6500HB, the Netherlands subjective cognitive problems Full list of with author long-term information is available at the end of the article in ICU between Alzheimer (AD) and non-Alzheimer dementia patients, illustrating that the underlying mechanism of patients and controls [17,18,32] have yielded conflicting © 2012 van den Boogaard et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative respect levels of forms of Ab. delirium is relevantCommons for Attribution its long-term cognitive results with which License (http://creativecommons.org/licenses/by/2.0), permitstounrestricted use, different distribution, and reproduction in any medium, provided the original work Increased is properly cited. levels of Ab1-42 [17] as well as increased levels of consequences. This is the first study investigating plasma amyloidb Ab1-40 [18] were found in dementia patients [32]. In addi(Ab) levels and human Tau in critically ill patients in rela- tion, increased levels of the Tau/Ab1-42 ratio have been tion to the presence of delirium. In view of the reported found in cerebrospinal fluid (CSF) of patients with cerebral increased incidence of dementia after ICU/hospital admis- amyloid deposition [33], but this has not yet been investision [16], our findings could provide a possible mechanis- gated in plasma. In the present study, the difference in tic link, because noninflamed delirium is associated with levels of total Tau and the Tau/Ab1-42 ratio between nonAb, but this must be confirmed in a longitudinal study inflamed delirious patients and noninflamed nondelirious focusing on these biomarkers combined with more-exten- patients approached statistical significance. It is known sive cognitive testing. Furthermore, Ab is associated with that plasma levels of Ab are age dependent [34]; however, sustained long-term subjective cognitive dysfunction in this could not have confounded our results because no difICU patients. Studies comparing plasma levels of Ab ferences in age existed between delirious and nondelirious DELİRYUM YBKS HKS Maliyet YB Deliryumu Morbidite mortalite Hiperaktif Ajitasyon Aceleci Hırçın Hipoaktif Apati Letarji Azalmış cevap Düz duygulanım Miks Uzun dönem kognitif bozukluk Uzun Süreli Sağlıkla İlgili Yaşam Kalitesi 3 27/04/16 Nöroinflamasyon Serebral perfüzyon anomalileri NörotransmiGer dengesizliği Sepsis hastası Hiperaktif deliryum Sedasyon mon RASS RASS<-‐‑3 RASS≥-‐‑3 Mikst tip Deliryum/ajitasyon Koma Hipoaktif deliryum Deliryum + De Akut Beyin Disfonksiyonu Sepsis associated Deliryum (SAD) Subsendromal deliryum Gerekirse EEG, SEP, CT, MRI NIH Public Access Author Manuscript Crit Care Med. Author manuscript; available in PMC 2013 July 01. NIH-PA Author Manuscript The Association between Brain Volumes, Delirium Duration and Cognitive Outcomes in Intensive Care Unit Survivors: A Prospective Exploratory CohortNIH Magnetic Resonance Imaging Public Access Author Manuscript Study Crit Care Med. Author manuscript; available in PMC 2013 July 01. 2Department University Institute of Imaging Sciences, Nashville, TN 1,2,3,4,5 Max L. Gunther, PHD , Alessandro MD, MPH4,5,6J.L. , Erin Krauskopf, BS7, P.P. Pandharipande, T.D. Girard, Morandi, J.C. Jackson, A. Morandi, Thompson, 4,5,6,10, James C. Jackson, 4Center for Quality of Aging, Vanderbilt University Pratik Pandharipande, MD,Brummel, MSCI8,9, C.G. Timothy D. Girard, MD, MSCI Medical Center B.T. Pun, N.E. Hughes, E.E. Vasilevskis, A.K. Shintani, 11 Sunil Geevarghese, PSYD1,4,5,10, Jennifer Thompson, MPH11,A.Ayumi K. Shintani, PHD K.G. Moons, S.K. Geevarghese, Canonico, R.O. Hopkins, G.R., Bernard, 5Center for Health Services Research in the Department of Medicine 13 Angelo Canonico, MD14, Kristen Merkle, BA3, MD, MSCI12, Russell R Miller MD, R.S. Dittus, andIII, E.W. Ely,MPH for the, BRAIN-ICU Study Investigators* 3, Baxter P. Rogers, PHD2,3,16, J. Chris Gatenby, PHD2,3,16, 6Division of Allergy, Pulmonary, Critical Care Medicine, Christopher J. Cannistraci, MS Center for Health Services Research, 1,2 PHD2,3,16, Ramona O. Hopkins, PHD7,13,15, E. Department of Medicine, Vanderbilt University Stephan School ofHeckers, Medicine MD, MSC , John C.AGore, BS TR AC T Wesley Ely, MD, MPH4,5,6,10, and for the VISIONS Investigation (VISualizing Icu SurvivOrs 7Psychology Department, Brigham Young University, Provo, Utah Neuroradiological Sequelae) 1Department of Psychiatry, Vanderbilt University Medical Center 8Anesthesia Service, Department of Veterans Affairs Medical Center, Tennessee Valley BACKGROUND Healthcare System The authors’ full names, degrees,2Department and affili- Survivors of critical illness oftenVanderbilt have a prolonged and disabling form of cognitive of Radiological Sciences, University Medical Center ations are listed in the Appendix. Address impairment that remains inadequately characterized. of Critical Care reprint in therequests Department of Anesthesiology, Vanderbilt University School of 3Vanderbilt to Dr. Pandharipande at University Institute of Imaging Sciences, Nashville, TN Medicine, Nashville, TN 1211 21st Ave. S, MAB Ste. 526, Nashville, 4Center for METHODS Quality of Aging, Vanderbilt University Medical Center TN 37212, or at pratik.pandharipande@ 10Geriatric Research, Education and Clinical Center (GRECC) Service, Department of Veterans vanderbilt.edu. We enrolled adults with respiratory failure or shock in the medical or surgical intensive 5Center for Health ServicesTN Research in the Department of Medicine Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, care unit (ICU), evaluated them for in-hospital delirium, and assessed global cognition *The Bringing to Light the Risk Factors and 6Division of Allergy, Pulmonary, Critical Care Medicine, Center Services Research, 11Department of Biostatistics, andof executive function 3 and 12 with for the Health use of the Repeatable Incidence of Neuropsychological DysfuncVanderbilt University School Medicine, Nashville, TNmonths after discharge Department of Medicine, VanderbiltofUniversity School ofStatus Medicine tion in ICU Survivors (BRAIN-ICU) Study Battery for the Assessment Neuropsychological (population age-adjusted 12Division of HepatobiliaryInvestigators SupplemenSurgery are & listed Liverin the Transplantation, Vanderbilt School 7Psychology mean [±SD] score,University 100±15, with lowerof values indicating worse global cognition) and the Department, Brigham Young University, Provo, Utah Medicine, Nashville, TN tary Appendix, available at NEJM.org. Trail Making Test, Part B (population age-, sex-, and education-adjusted mean score, N Engl J Med 2013;369:1306-16. 8Anesthesia Service, Department of Veterans Affairs Medical Center, Tennessee Valley 13Department of Medicine, withIntermountain lower scores indicating executive function). Associations of the duand Critical Care 50±10, Division, Medical worse Center, DOI:Pulmonary 10.1056/NEJMoa1301372 Healthcare System ration of delirium and the use of sedative or analgesic agents with the outcomes were Murray Utah Copyright © 2013 Massachusetts Medical Society. 9Division assessed with theand usethe of linear regression, with adjustment for potential confounders. of Critical Care in Department of Anesthesiology, Vanderbilt University School of Figure 3. Representative example of lateral ventricle size in 46-year-old female 42-year-old female ICU survivors with no preexisting cognitiveMedicine, impairmentNashville, TN AllAxial correspondence and reprint requests should sent to: E. Wesley Figure Ely, MD, MPH, Professor of Medicine, 6109 Medical Center T1-weighted brain images in 2beICU survivors. 3a depicts relatively normal RESULTS 10Geriatric Research, Education and Clinical Center (GRECC) Service, Department of Veterans East, Vanderbilt University, Nashville, TNin 37232-8300, phone female 615-936-3395 and fax 615-936-1269, wes.ely@vanderbilt.edu Web: ventricular volume (see arrow) a 46-year-old whoOf did experience delirium in thenot 821 patients enrolled, 6% had cognitive impairment at baseline, and deliriwww.icudelirium.org, www.vuiis.vanderbilt.edu. Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN the ICU. Patient had a history of respiratory and heart failure. She was admitted to a medical um developed in 74% during the hospital stay. At 3 months, 40% of the patients had Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our 11Department ICU due to acute respiratory distress syndrome (ARDS) and was intubated and and ofsubsequently Biostatistics, Vanderbilt University of Medicine, Nashville, global cognition scores that were 1.5review SD below the population means (similarTN to customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, of School through without evercitable developing delirium. Figure 3b depicts enlarged the managed resulting proof before the it is ICU published in its final form.12 Please note that during production process errors may be scores forthe patients with moderate traumatic brain injury), and 26% University had scores 2School SD of Division of Hepatobiliary Surgery & Liver Transplantation, Vanderbilt discovered which could affect the and all legal disclaimers that develop apply to the journal pertain. ventricles (see arrow) in acontent, 42-year-old female who did delirium in the ICU. Patient the population means (similar to scores for patients with mild Alzheimer’s Medicine,below Nashville, TN Thewas authors have notto disclosed any potential of interest admitted the hospital after conflicts reporting fever and dyspnea with aDeficits chest X-ray and other disease). occurred in both older and younger patients and persisted, with 13Department of Medicine, Pulmonary and Critical Care Division, Intermountain Medical Center, laboratory data confirming ARDS. patient wasi with T h e community n e w e acquired ng l apneumonia n d j o34% uand r and na l The o of f m epatients dic n e assessments at 12 months that were similar to 24% all Utah 12 days of delirium and then admitted to the ICU and mechanically ventilated,Murray experiencing scores for patients with moderate traumatic brain injury and scores for patients resolution. There was no preexisting history of neurologicalwith impairment, and surrogate mild Alzheimer’s disease, respectively. A longer duration of delirium was inquestioning for preexisting cognitive impairment was also negative dependently associated with worse global cognition at 3 and 12 months (P = 0.001 9Division NIH-PA Author Manuscript ACO290315 REVIEW Patients prone for postoperative delirium: preoperative assessment, perioperative prophylaxis, postoperative treatment RBANS Global Cognition Score Trails B Executive-Function Score At 12TMo A BS R AC T 75th difference (95% CI) P value difference (95% CI) P value difference (95% CI) P value difference (95% CI) P value 0 5 −6.3 (−10.3 to −2.3) 0.001 −5.6 (−9.5 to −1.8) 0.04 −5.1 (−9.2 to −1.1) 0.004 −6.0 (−10.2 to −1.9) 0.007 Duration of coma (days) 0 4 −1.5 (−7.0 to 4.1) 0.12 1.2 (−3.3 to 5.7) 0.87 −1.6 (−6.1 to 2.9) 0.70 Mean daily dose of sedative At 3 Mo BACKGROUND At 3 Mo At 12 Mo 0.9 (−3.8 to 5.6) Survivors of critical illness often have a prolonged and disabling form of cognitive 0 7.88 0.3 (−2.9remains to 3.5) 0.20 −0.4 (−3.9 tocharacterized. 3.0) 0.17 −2.9 (−6.9 to 1.0) 0.04 −0.5 (−4.4 to 3.5) impairment that inadequately 0.79 0.19 0 804 0.5 (−2.2 to 3.3) 0.83 −0.4 (−3.4 to 2.7) 0.96 −1.4 (−4.6 to 1.7) 0.44 −1.7 (−5.1 to 1.7) 0.61 0 3826 −4.0 (−11.7 to 3.7) 0.31 −5.7 (−14.1 to 2.8) 0.19 −2.5 (−11.2 to 6.1) 0.57 −0.4 (−9.5 to 8.7) 0.93 3.5 (0.1 to 6.9) 0.14 4.6 (0.4 to 8.8) 0.09 METHODS 13.3 1238.8 T h eton e w e ng u (1.4 r na o f m e dic 1.7 (−2.1 5.4) 0.04l a n d j o 5.2 tol9.1) 0.06 i n e We enrolled adults with respiratory failure or shock in the medical or surgical intensive care unit (ICU), evaluated them for in-hospital delirium, and assessed global cognition and executive function 3 and 12 months after discharge with the use of the Repeatable Battery for the Assessment of Neuropsychological Status (population age-adjusted mean [±SD] score, 100±15, with lower values indicating worse global cognition) and the Trail Making Test, Part B (population age-, sex-, and education-adjusted mean score, 50±10, with lower scores indicating worse executive function). Associations of the duration of delirium and the use of sedative or analgesic agents with the outcomes were assessed with the use of linear regression, with adjustment for potential confounders. RESULTS 1313 Correspondence to PD Dr med. Ulf Guenther, DESA, EDIC, Klinik für Anästhesiologie & Operative Intensivmedizin, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Tel:+ 0049 228 287 14114; e-mail: u.guenther@uni-bonn.de Curr Opin Anesthesiol 2016, 29:000–000 DOI:10.1097/ACO.0000000000000327 www.co-anesthesiology.com Copyright © 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. that of patients with mild Alzheimer’s disease, and one out of three had impairment typically associated with moderate traumatic brain injury. 40 0 3 Mo 12 Mo 3 Mo 12 Mo 3 Mo 12 Mo Impairments affected a broader array of neuroOf the 821 patients 6%(N= had at baseline, and deliriN= 89) 138) cognitive 98) (N= 97) (enrolled, (N= 147) (N= 130) (N=impairment psychological domains than is characteristically ≤49 Yr during the 50–64hospital Yr ≥65 Yr um developed in 74% stay. At 3 months, of the patients had seen in 40% Alzheimer’s disease, but the impairments were very similar to those(similar observed after global cognition scores that were 1.5 SD below the population means to moderFigure 1. Global Cognition Scores in Survivors of Critical Illness. ate traumatic brain injury. A validated instrument scores for with moderate traumatic brain injury), and 26% hadcognitive scores status 2 SDshowed The patients box-and-whisker plots show the age-adjusted global cognition scores on that assessed baseline the Repeatable Battery for the Assessment of Neuropsychological Status that only with 6% of patients had evidence of mild-tobelow the population means (similar scores for patients mild Alzheimer’s (RBANS; with a population age-adjusted mean [±SD] to of 100±15, and lower cognitive impairment before ICU adscores indicating worse global cognition) at 3 months (light-gray boxes) and disease).12 Deficits occurred in both older and younger moderate patients and persisted, with months (dark-gray boxes), according to age. For each box-and-whisker mission, indicating that these profound cognitive the horizontal indicates the median, upper and lower limitsat of 12 months 34% andplot,24% of allbarpatients withtheassessments deficits werethat new were in the similar majority oftopatients. the boxes the interquartile range, and the ends of the whiskers 1.5 times the Long-term cognitive impairment affected both scores for patients witharemoderate traumatic brain interquartile range. Outliers shown as black dots. The green dashed line injury and scores for patients old and young patients, regardless of the burden indicates the age-adjusted population mean (100) for healthy adults, and the with mild disease, A expected longer of duration delirium was incoexisting of conditions at baseline. greenAlzheimer’s band indicates the standard deviationrespectively. (15). Also shown are the population means for mild cognitive (MCI), moderate traumatic at 3A and longer12 duration of delirium was associated dependently associated with impairment worse global cognition months (P = 0.001 brain injury (TBI), and mild Alzheimer’s disease on the basis of other cohort with worse long-term global cognition and exstudies. respectively) Expected population means MCI andexecutive Alzheimer’s disease are and P = 0.04, andforworse function at 3 and 12 months (P = 0.004 ecutive function, an association that was indeshown only for patients 65 years of age or older, since RBANS population pendent of sedative or was analgesic and P = 0.007, respectively). Use of sedative analgesic medications notmedication con- use, norms for these disorders have been generated only in that age or group. age, preexisting cognitive impairment, the burden sistently associated with cognitive impairment at 3 and 12 months. of coexisting conditions, and ongoing organ fail- CONCLUSIONS P = 0.007, respectively) (Table 2, and Fig. S4 and ures during ICU care. Although the mechanisms S5 in the Supplementary Appendix). A longer by which delirium may predispose patients to duration of delirium was also a risk factor for long-term cognitive impairment after critical ill- Patients in medical worse and function surgical ICUs individual are at high risk long-term impairin several RBANS do-for ness have not yet cognitive been elucidated, delirium is asmains (see the Supplementary with inflammation and neuronal ment. A longer duration of delirium in theAppendix). hospital wassociated associated with worse globalapoptoWe did not observe an independent associa- sis, which may lead to brain atrophy.32,33 Delirium cognition and executive function atbenzodiazepines 3 and 12 months. (Funded the National tion between higherscores doses of has previously beenby associated with cerebral atlong-term cognitive scores, except that rophy34 number, and reduced NCT00392795.) white-matter integrity35; both Institutes of Health and andworse others; BRAIN-ICU ClinicalTrials.gov 1306 higher benzodiazepine doses were an indepen- atrophy and white-matter disruption are assocident risk factor for worse executive-function scores ated with cognitive impairment.34,35 It is also at 3 months (P = 0.04) (Table 2). None of the possible that patients who are vulnerable to deother medications examined, including propo- lirium owing to severe critical illness are also fol, dexmedetomidine, and opiates, were con- vulnerable to long-term cognitive impairment and n englsistently j med 369;14 nejm.org october 3, 2013 associated with global cognition or that delirium does not play a causal role in the executive-function outcomes. development of persistent cognitive impairment. The New England Medicine SensitivityJournal analysesof that included only patients After adjustment for delirium, we did not find Downloaded from nejm.org on March 29,for2016. personal use only. uses any without permission. whomFor complete outcome data No wereother available consistent associations between the use of yielded similar resultsSociety. (Table S4All in rights the Supplesedative or analgesic medications and long-term Copyright © 2013 Massachusetts Medical reserved. mentary Appendix). In addition, adjustments for cognitive impairment. The significant association 1312 Long-Term Cognitive Impairment after Critical Illness Percentile† 25th Duration of delirium (days) * Results shown are from linear regression models in which outcome variables were global cognition scores on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS; on a scale from 40 to 160, with lower scores indicating worse performance) or the Trail Making Test, Part B (Trailsan B; with scoreslevel ranging 0 to 100, and lower altered offrom consciousness and scores surgical *The Bringing to Light the Risk Factors and function), the independent variables were duration of delirium, duration of coma, and mean dose of sedative or analgesic medications (all included simultaindicating worse executive versus medical ICU did not qualitatively change neously in theDysfuncmodel), and the covariates were the following potential confounders, which were selected a priori: age, educational level, coexisting conditions, preexisting cognitive Incidence of Neuropsychological our findings. impairment, apolipoprotein E genotype, stroke risk, and ICU variables, including the mean scores for the severity of illness, mean haloperidol dose, duration of severe sepsis, duration tion in ICU Survivors (BRAIN-ICU) of hypoxemia, andStudy an interaction between delirium 120and coma. † Differences (point estimates) in the RBANS and the Trails B scores in the linear regression analyses reflect a comparison between the 25th and the 75th percentile values for each variInvestigators are listed in the Supplemenable among all 821 patients in the original cohort (with the exception of dexmedetomidine dose; because more than 85% of patients received noDISCUSSION dexmedetomidine, we used the minitary Appendix, available at NEJM.org. Normalof delirium, with all other covariates held constant, patients with mum and maximum doses instead). For example, in a comparison of patients with no delirium and those with 5 days 100 5 days of delirium had RBANS global cognition scores that were 5.6 points lower at 12 months than did those with no delirium. Thismulticenter, represents a decrease of approximately 0.5involvSD, In this prospective cohort study N Engl J Med 2013;369:1306-16. which is considered to be a clinically significant decline (see the Supplementary Appendix). A similar comparison of executive-function scores at 3 and 12 of months showed a decrease of ing a diverse population patients in general medMCI 0.5 SD in the scores for patients with 5 days of delirium, which is a clinically significant decline according to the neuropsychology literature. CI denotes confidence interval. 80 DOI: 10.1056/NEJMoa1301372 ical and but surgical ICUs, webeta found that one out of ‡ We used restricted cubic splines for all continuous variables, which allows for a nonlinear relationship between covariates and outcomes requires multiple coefficients to estimate TBI Copyright © 2013 Massachusetts Medical the effect. TheSociety. most appropriate P value is one that takes into consideration all these beta coefficients together. Although valuepatients may indicate is correct),12 themonths comparhadsignificance cognitive (and impairment Alzheimer’s the Pfour disease ison of the 25th and 75th percentiles may yield a point estimate with a confidence interval that crosses zero, or vice versa. after critical illness that was similar in severity to 60 a PD Dr med. Ulf Guenther DESA, EDIC, Linda Riedel, Klinik für Anästhesiologie & Operative Intensivmedizin, Universitätsklinikum Bonn, Bonn, Germany and bPD Dr med. Finn M. Radtke, Anæstesiafdelingen, Næstved Sygehus, Næstved, Denmark 0952-7907 Copyright ! 2016 Wolters Kluwer Health, Inc. All rights reserved. ment. A longer duration of delirium in the hospital was associated with worse global cognition and executive function scores at 3 and 12 months. (Funded by the National Institutes of Health and others; BRAIN-ICU ClinicalTrials.gov number, NCT00392795.) or analgesic agent‡ The authors’ full names, degrees, and affiliations are listed in the Appendix. Address Benzodiazepine (mg) reprint requests to Dr. Pandharipande at Propofol (mg) 1211 21st Ave. S, MAB Ste.Dexmedetomidine 526, Nashville, (µg) TN 37212, or at pratik.pandharipande@ Opiate (mg) vanderbilt.edu. october 3, 2013 ium diagnosis) were independent predictors for POD within the next 7 postoperative days [6]. POD was also a risk factor for post-traumatic stress disorder (PTSD) in elderly patients, as has been confirmed in a large prospective observational study in 1707 patients, in which 12% were identified with PTSD 3 months after surgery [7]. The authors have not disclosed any potential conflictsICUs of interest Patients in medical and surgical are at high risk for long-term cognitive impair- Independent Variable nejm.org & Long-Term Cognitive Impairment after Critical Illness The New England Journal of Medicine Crit Care Med. Author manuscript; available in PMC 2013 July 01. Downloaded from nejm.org on March 29, 2016. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. Table 2. Effect of Duration of Delirium, Duration of Coma, and Exposure to Sedative or Analgesic Agents on Global Cognition and Executive Function.* n engl j med 369;14 cation after major surgery and contributes to increased mortality, prolonged duration of ventilation, longer length of stay in ICU as well as in hospital [1 ], a higher rate of tracheostomy [2], and higher treatment costs [3]. In elderly patients with hip fracture followed up for as long as 13.6 years, univariate analysis demonstrated a strong association between POD and survival, but a multivariate analysis identified only age at the time of surgery, illness severity, and duration of ICU stay after surgery as factors contributing to mortality [4]. As much as prophylaxis and treatment of POD definitely make sense from a cost and even more so from an ethical perspective, it is therefore questionable whether it will improve long-term outcome, and POD is just a marker of the fragile patient. Emergence from anesthesia is often accompanied by signs of delirium, mostly in its hypoactive form. Among 400 patients evaluated for delirium The New England Journal of Medicine Downloaded from nejm.org on March 29, 2016. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. Purpose of review Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our associated impairment at 3 and months. customers wesistently are providing this early with versioncognitive of the manuscript. The manuscript will12 undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. CONCLUSIONS P.P. Pandharipande, T.D. Girard, J.C. Jackson, A. Morandi, J.L. Thompson, 1306 n engl j med 369;14 nejm.org october 3, 2013 B.T. Pun, N.E. Brummel, C.G. Hughes, E.E. Vasilevskis, A.K. Shintani, K.G. Moons, S.K. Geevarghese, A. Canonico, R.O. Hopkins, G.R. Bernard, R.S. Dittus, and E.W. Ely, for the BRAIN-ICU Study Investigators* Ulf Guenther a, Linda Riedel a, and Finn M. Radtke b The aim of this study was to review current literature on identification of patients at risk for postoperative Deliryum bulgularının olması postop ilk hafta deliryum için risk faktörü delirium (POD) and to summarize recent findings on prophylaxis and treatment. Recent findings Age and preoperative cognitive impairment are among the most important risk factors of POD. POD is the Yaşlı popülasyonda PTSD risk faktörü result of a complex interplay of predisposing and precipitating factors. Thus, both prophylaxis and treatment require multicomponent intervention programs. No single medication to prevent or treat POD is available. Avoiding too deep anesthesia, avoiding additional psychoactive substances including benzodiazepines and intravenous opioids, and effective pain management as well as early mobilization Ileri yaş ve kognitif disfonksiyon önemli risk faktörleri are essential. Summary An increase of the proportion of elderly patients undergoing surgery will lead to a higher incidence of Erken tanı yani rutin monitörizasyon POD. Preoperative assessment should facilitate identification of patients at high risk. Perioperative management should include monitoring depth of anesthesia, preference for nonopioid pain therapy, early regular delirium monitoring starting in the recovery room, avoiding ICU-sedation, early mobilization and exercise, and cognitive training. Önleme ve tedavide Keywords cognition, delirium, frailty, mobilization, pain management anestezi derinliğinin takibi opioidlerin az kullanılması erken mobilizasyon signs during PACU stay, delirium signs were present INTRODUCTION in up to 31%, and in 4% at discharge from PACU [5]. Postoperative delirium (POD) is a frequent compli Of note, positive delirium signs (without full delir- All correspondence and reprint requests should be sent to: E. Wesley Ely, MD, MPH, Professor of Medicine, 6109 Medical Center East, Vanderbilt TN 37232-8300, 615-936-3395 andat fax wes.ely@vanderbilt.edu Web: andUniversity, P = 0.04, Nashville, respectively) and worsephone executive function 3 615-936-1269, and 12 months (P = 0.004 original article www.icudelirium.org, www.vuiis.vanderbilt.edu. and P = 0.007, respectively). Use of sedative or analgesic medications was not con- RBANS Global Cognition Score URRENT C OPINION NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript ACO290315; Total nos of Pages: 7; Long-Term Cognitive Impairment after Critical Illness Study of Radiological Sciences, Vanderbilt University Medical Center 3Vanderbilt NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 4,5,6, Erin Krauskopf, BS7, Max L. Gunther, PHD1,2,3,4,5, Alessandro Morandi, MD, MPHedited Published in final form as: T h e n e w e ng l a nd j o u r na l o f m e dic i n e 4,5,6,10 Pratik Pandharipande, MD, MSCI8,9, Timothy Crit D. Girard, MD, MSCI , James C. Jackson, Care Med . 2012 July ; 40(7): 2022–2032. doi:10.1097/CCM.0b013e318250acc0. PSYD1,4,5,10, Jennifer Thompson, MPH11, Ayumi K. Shintani, PHD11, Sunil Geevarghese, MD, MSCI12, Russell R Miller III, MD, MPH13, Angelo Canonico, MD14, Kristen Merkle, BA3, Page 20 Christopher J. Cannistraci, MS3, Baxter P. Rogers, PHD2,3,16, J. Chris Gatenby, PHD2,3,16,article original The Brain Delirium Duration and 2,3,16, Ramona O.between 7,13,15, Volumes, Stephan Heckers, MD, MSC1,2, John C. Gore, PHDAssociation Hopkins, PHD E. Wesley Ely, MD, MPH4,5,6,10, and for the VISIONS Investigation (VISualizing SurvivOrs Care Unit Survivors: A Cognitive Outcomes inIcu Intensive Neuroradiological Sequelae) Prospective 1Department of Psychiatry, Vanderbilt University Medical Center Exploratory Cohort Magnetic Resonance Imaging NIH-PA Author Manuscript Gunther et al. Published in final edited form as: Crit Care Med. 2012 July ; 40(7): 2022–2032. doi:10.1097/CCM.0b013e318250acc0. n engl j med 369;14 nejm.org october 3, 2013 4 Wolters et al. Critical Care 2014, 18:R125 http://ccforum.com/content/18/3/R125 Page 4 of 7 Wolters et al. Critical Care 2014, 18:R125 http://ccforum.com/content/18/3/R125 Page 4 of 7 27/04/16 Table 1 ICU characteristics of the study population Table 1 ICU characteristics of the study population Variables All patientsVariables (n = 1,101) No delirium (n = 689) All patients Delirium (n = 412) (n = 1,101) 59.8 Age (16.5)(mean years, SD) 59.4 (16.6) 60.5 (16.7) 59.8 (16.5) 677 Male (61.5)(number, %) 406 (58.9) 271 (65.8) 677 (61.5) Age (mean years, SD) Male (number, %) APACHE IV score (mean, SD) CumSOFA score (median, IQR) ICU length of stay (median days, IQR) NoP-value delirium (n = 689) 0.29 59.4 (16.6) Delirium (n = 412) 60.5 (16.7) P-value 0.29 0.03 73.7 (28.3) 61.3 (29.2) 99.0 (47.0 to 207.0) 40.0 (19.0 to 99.0) 0.03 406 (58.9) <0.001 53.9 (22.4) <0.001 27.0 (13.0 to 50.5) 271 (65.8) 61.3 APACHE (29.2) IV score (mean, SD) 53.9 (22.4) 40.0 (19.0 to 99.0) score (median,27.0 CumSOFA IQR)(13.0 to 50.5) 73.7 (28.3) <0.001 99.0 (47.0 to 207.0) <0.001 4.0 (3.0ICU to length 8.0) (2.0IQR) to 5.0) of stay (median3.0 days, 8.0 to (5.08.0) to 15.0) 4.0 (3.0 <0.001 3.0 (2.0 to 5.0) 8.0 (5.0 to 15.0) <0.001 Type of admission Type of admission 430 (39.1) 208 (30.2) 222 (53.9) <0.001 Medical (number, %) 430 (39.1) 208 (30.2) 222 (53.9) <0.001 447 (40.6) 351 (50.9) 96 (23.3) Elective surgical (number, %) 447 (40.6) 351 (50.9) 96 (23.3) Acute surgical (number, %) 224 (20.3) 130 (18.9) 94 (22.8) Acute surgical (number, %) 224 (20.3) 130 (18.9) 94 (22.8) Wolters et al. Critical Care 2014, 18:R125 APACHE IV: Acute Physiology and Chronic Health Evaluation IV; CumSOFA: cumulative Sequential Organ Failure Assessment without the central nervous system http://ccforum.com/content/18/3/R125 APACHE IV: Acute Physiology and Chronic Health Evaluation IV; CumSOFA: cumulative Sequential Organ Failure Assessment without the central nervous system Medical (number, %) Elective surgical (number, %) component; IQR: interquartile range; SD: standard deviation. component; IQR: interquartile range; SD: standard deviation. follow-up than patients who did notregard have delirium. Afterthan patients who did not have delirium. After data did not differ from the study population with regard follow-up data did not differ from the study population with adjustment confounders, again difference between for confounders, again the difference between to delirium frequency, age, gender, APACHE to IVdelirium or type frequency, adjustment age,forgender, APACHE IV the or type the two groups was no longer statistically significant of admission. The R length E S EofAstay R CofH the study ofpopulation Open was Access no longer statistically significant admission. The length of stay of the study population the two groups was longer than that of the subjects excluded due to (Table 3). The assumption of homoscedasticity was veriwas longer than that of the subjects excluded due to (Table 3). The assumption of homoscedasticity was verified by plotting the residuals against the fitted values. missing data (median 4.0, IQR 3.0 to 7.0, P = 0.01). fied by plotting the residuals against the fitted values. missing data (median 4.0, IQR 3.0 to 7.0, P = 0.01). Persons who were delirious during their ICU stay dif- Compared to the general Dutch population, both paPersons who were delirious during their ICU stay dif- Compared to the general Dutch population, both pafered from subjects who did not have delirium during tient groups scored lower on the EQ-5DTM. Persons fered from subjects who did not have delirium during tient groups scored lower on the EQ-5DTM. Persons their ICU stay in gender, severity of illness scores, ICU without delirium in the ICU scored 0.85 (IQR 0.72 to their ICU stay in gender, severity of illness scores, ICU without delirium in the ICU scored 0.85 (IQR 0.72 to length of stay and type of admission (Table 1). One year 1.00) and subjects with ICU delirium scored 0.75 (IQR length of stay and type of admission (Table 1). One year 1.00) and subjects with ICU delirium scored 0.75 (IQR after ICU admission, of the subjects (82%) 0.69 to 1.00). In comparison, the estimated average Wolters et 903 al. Critical Care 1,101 2014, 18:R125 Pagecomparison, 4 of 7 after ICU admission, 903 of the 1,101 subjects (82%) 0.69 to 1.00). In the estimated average were known tohttp://ccforum.com/content/18/3/R125 have survived. Because of an administra- EQ-5DTM index for the general Dutch populationTMis were known to have survived. Because of an administra- EQ-5D index for the general Dutch population is tive error, 16 individuals who appeared* still alive did not 0.87 (IQR 0.82 to 1.00) [24]. tivevan error, 16Wietze individuals who appeared stillMarjolein alive did Fnot 0.87 (IQRW0.82 to 1.00) [24]. Annemiek E Wolters , Diederik Dijk, Pasma, Olaf receive a questionnaire, and, therefore, 887 surveys were Persons who hadL Cremer, been delirious duringLooije, their Dylan ICU stay de Lange, a questionnaire, and, therefore, 887 surveys were had 18:R125 been delirious during their ICU stay Wolters etPersons al. Critical who Care 2014, Dieuwke S Veldhuijzen and receive Arjen Slooter sent. The response rate was 64% (571/887). After JC ICU experienced significantly more mild and more severe http://ccforum.com/content/18/3/R125 sent. The response rate was 64% (571/887). After ICU experienced significantly more mild and more severe 1 ICU characteristics of the were studysent population admission, theTable median time until the surveys self-reported problems in cognitive functioning comadmission, the median time until the surveys were sent self-reported problems in cognitive functioning comVariables patientspared (n = 1,101) delirium (n = have 689) delirium Delirium = 412) P-value back was 420 days after discharge (IQR 402 to 444 All days). to subjects No who did not in the(n ICU. back was 420 days after discharge (IQR 402 to 444 days). pared to subjects who did not have delirium in the ICU. In total, 198Agepatients died The strength of this 59.4 association did not weaken (mean years, SD)during follow-up, with a59.8 (16.5) (16.6) 60.5 (16.7)and 0.29 Abstract In total, 198 patients died during follow-up, with a The strength of this association did not weaken and median duration 62 days%)after ICU admission (IQR 25677 (61.5) remained statistically significant when adjustments were Maleof(number, 406 (58.9) 271 (65.8) 0.03 median duration of 62 days after ICU admission (IQR 25 remained statistically significant when adjustments were R E S Erelationship ARCH Introduction: Delirium is associated with impaired outcome, but it is unclear whether this is limited to to 181 days). Univariate survival analysis showed that made for confounding variables (Table 4). APACHE IV score (mean, SD) 61.3 (29.2) 53.9of (22.4) 73.7 (28.3) <0.001 to 181 this days). Univariateis independent survival analysis showed that made for confounding variables (Table 4). in-hospital outcomes and whether relationship the severity of underlying conditions. The aim delirious patients had a significantly increased risk of To verify whether the effect measure for mortality was delirious patients had a significantly increased risk care of 99.0 To whether the effect measure for mortality was CumSOFA score (median, IQR) 40.0 (19.0 to 99.0) 27.0 (13.0 to 50.5) (47.0 toverify 207.0) <0.001 of this study was to investigate the association between delirium in the intensive unit (ICU) and long-term death in the year following ICU admission. However, robust when using the cumulative SOFA, we conducted death in 4.0 the(3.0year ICU 3.0 admission. when using the cumulative SOFA, we conducted mortality, self-reported health-related of following life (HRQoL), self-reported problems with functioning ICU length (median days, confounders IQR) to 8.0) (2.0 5.0) However, 8.0robust (5.0 tocognitive 15.0) <0.001 when adjustments wereof stay made for the de-quality sensitivity analyse and where weto made Cox proportional hazwere made for the de- staysensitivity analyse where we made Cox proportional hazinadmission survivors criticalindependently illness,when takingadjustments severity of models illness atwith baseline andconfounders throughout ICU intoSOFA account. of scribed above, Type delirium was nooflonger as- ard the mean SOFA and the maximal scribed above, delirium wasWe noincluded longer independently as- ardanmodels with theleast mean SOFA and the maximal SOFA Methods: prospective cohort study was(39.1) conducted. patients ICU stay of at sociated with mortality (Table%)A2). scores. Furthermore, we evaluatedwho thesurvived effect 222 of (53.9) adding Medical (number, 430 208 (30.2) <0.001a sociatedcare with mortality (Table 2).who sustained scores. Furthermore, day; exclusions were patients deep variables sedation during the entire ICUwe evaluated the effect of adding In univariateElective analysis, with neurocritical delirium during lengthand of patients stay to these models. Other left surgicalpatients (number, %) 447 (40.6) 351 (50.9) 96were (23.3)of Inscore univariate analysis, patients with delirium during length stayand to these models. Other variables were left Delirium was assessed twice daily the Confusion Assessment Method formodels the ICU (CAM-ICU) their ICU stay had stay. a significantly lower HRQoL at with unchanged. The HRs for death in these remained Acute surgical (number, %) 224 (20.3) 130 (18.9) 94 (22.8) their ICU stay had a significantly lower HRQoL score at unchanged. The HRs foron death in these models remained additionally, patients who received haloperidol were considered delirious. Twelve months after ICU admission, data Long-term outcome of delirium during intensive care unit stay in survivors of critical illness: a prospective cohort study Deliryumda profilaksi Open Access Long-term outcome of delirium during intensive care unit stay in survivors of critical illness: a prospective cohort study * APACHE IV: Acute Physiology and Chronic Health Evaluation IV; CumSOFA: cumulative Sequential Organ Failure Assessment the nervous system van E central Wolters , Diederik mortality were obtained and HRQoL and cognitive functioning were measured with Annemiek the without European Quality of Life – Six component; IQR: interquartile range; SD: standard deviation. ✔ Nonfarmakolojik yöntemler Dijk, Wietze Pasma, Olaf L Cremer, Marjolein F Looije, Dylan W de Lange, dimensions (EQ-6D). analyses were usedinto assess the associations between delirium and Dieuwke S Veldhuijzen andthe Arjen JC Slooter Table 2 Risk of death associatedself-classifier with delirium in Regression Table 3 Differences health-related quality of life between Table 2 Risk type ofwith death associated delirium in And 3 Differences measures adjusted for gender, of regard admission, thewith Acute Physiology Chronic Health Evaluation IVhealth-related quality of life between follow-up than who didTable not have delirium.inAfter data outcome did not within differ from the study population survivors of critical illness, one year after ICU delirious and non-delirious ICU patients survivors, within one year survivors ofSequential critical illness, within one year ICU scoreagain delirious and (APACHEfrequency, IV) score, and cumulative Organ Failure Assessment (SOFA) throughout ICUnon-delirious stay. admission after ICU admission adjustment forafter confounders, the difference between ICU survivors, within one year to delirium age,the gender, APACHE IV or type admission after ICU admission the had twobeen groups was during no Abstract longer statistically significant of admission. The length ofratio, stay of the study Model population Hazard P-value Difference, 95% P-value Results: Of 1101 survivors of critical illness, 412 persons (37%) delirious ICUCIstay, and 198 (18%) died Model Hazard ratio, P-valueof homoscedasticity Model Difference, 95% CI P-value 95% CI subjects (Table 3). The assumption was veriwas within longer twelve than that of the excluded due to no months. When correcting for Crude confounders, significant association between delirium and long-term −0.06 (−0.10 to −0.01) 0.01 Delirium 95% CI Introduction: is associated −0.06 with (−0.10 impaired outcome, but it is unclear whether this relationship is limited to Crude to −0.01) 0.01 1.91 4.0, (1.44 to 2.52) fied by the In residuals against the fitted values. missing data (median IQR 3.0 to <0.001 7.0, = 0.01). mortality was found (hazard ratio: 1.26;P95% confidence interval (CI)plotting 0.93 to 1.71). multivariable analysis, delirium wasPage this Adjusted for gender, APACHE IV, type (−0.10 to 0.01) 0.09 in-hospital outcomes and whether is independent of the severity of underlying conditions. The aim Wolters et al. Critical Care 2014, 5 of relationship 7 Crude18:R125 1.91 (1.44 to 2.52)−0.04 <0.001 Adjusted for gender, both APACHE IV, type −0.04 (−0.10 to 0.01) 0.09 Compared the togeneral Dutch population, pawho delirious during their ICU stay dif-and−0.04; Adjusted for gender, Persons APACHE IV, type were 1.26 (0.93 to 1.71) 0.14 of admission CumSOFA not associated with HRQoL either (regression coefficient: 95% CIto −0.10 0.01). Yet, delirium associated http://ccforum.com/content/18/3/R125 of this studyremained was to investigate the association between delirium in the intensive care unit (ICU) and long-term TM Adjusted for gender, APACHE IV, type 1.26 (0.93 to 1.71) 0.14 of admission and CumSOFA of admission and CumSOFA tient groups scored on the EQ-5D feredwith from subjects who problems did not with have cognitive delirium during Persons mild and severe inquality multivariable analysislower ratios: 2.41; 95% CI. 1.57 to Data functioning on health-related of life was available for(odds 546mortality, patients. Delirious: self-reported health-related quality of life (HRQoL), and self-reported problems with cognitive functioning of admission and CumSOFA Data on health-related quality of life was available for 546 patients. Delirious: 198 patients died within one year. Delirious: n = 102, not delirious: n = 96. n = 182, not delirious: n = 364. APACHE IV: Acute Physiology and Chronic their3.69 ICUand stay3.10; in 95% gender, severity of respectively). illness scores, ICU without delirium in the ICU scored 0.85 (IQRillness, 0.72 to CI 1.10 to 8.74, in survivors ofdelirious: critical takingIV: severity of illness at baseline and throughout ICU stay into account. patients died within one year. Delirious: n = 102, notinterval; delirious: n = 96. cumulative n = 182, not n = 364. APACHE Acute Physiology and Chronic APACHE IV: Acute Physiology and Chronic Health Evaluation IV; 198 CI: confidence Health Evaluation IV; CI: confidence CumSOFA: Sequential length ofSequential stay and ofgroup admission (Table OneFailure yearChronic 1.00) and subjects with ICU delirium scored 0.75 (IQR interval; CumSOFA: cumulative Organ Failure Assessment without Organ Assessment without central system component; ICU: APACHE IV: Acute Physiology and Health Evaluation IV;nervous CI: confidence Health Evaluation CI: confidence cumulative Sequential Conclusions: Intype this of survivors of1). critical illness, delirium during ICU stay was not associated withIV;long-term Methods: A prospective cohortinterval; studyCumSOFA: was conducted. We included patients who survived an ICU stay of at least a central nervous system component; ICU: intensive unit.of the intensive care unit. 0.69 interval; CumSOFA: cumulative Sequential Organto Failure Assessment withoutin survivors Organ Failure Assessment without central one nervous system component; ICU: after ICUTable admission, 1,101 subjects (82%) 1.00). comparison, the estimated average Risk care of903 problems with functioning associated with delirium of critical illness, within mortality or4HRQoL after adjusting forcognitive confounding, including severity of In illness throughout ICU stay. In contrast, day; intensive exclusions central nervous system component; ICU: intensive TM unit. care were unit. neurocritical care patients and patients who sustained deep sedation during the entire ICU weredelirium known haveICU survived. of an risk administraEQ-5D care index forproblems the general Dutch population is yearto after appears toadmission be anBecause independent factor for long-term self-reported cognitive stay.with Delirium was functioning. assessed twice daily with the Confusion Assessment Method for the ICU (CAM-ICU) and tive error,Model 16 individuals who appeared stillORalive did problems not 0.87 to 1.00) [24].OR for severe problems with for mild with(IQR 0.82P-value additionally, patients who received P-value haloperidol were considered delirious. Twelve months after ICU admission, data on 95% CI who had been delirious cognitive functioning, CI receive a questionnaire, and, therefore, 887cognitive surveysfunctioning, were Persons their 95% ICU mortalityduring were obtained andstay HRQoL and cognitive functioning were measured with the European Quality of Life – Six long-term significantly morbidity and mortality. Delirium, Introduction sent. TheCrude response rate was 64% (571/887). experienced more mild and more charactersevere Regression 2.02 After (1.39 to ICU 2.94) <0.001 2.93 (1.16 to 7.42) 0.02 dimensions self-classifier (EQ-6D). analyses were used to assess the associations between delirium and the ized by an problems acute in attention and cognition, is a 0.03 Because of improved medical care, number ofsent inten- self-reported admission, the median time untilIV, the the surveys wereto inoutcome cognitive functioning comAdjusted for gender, APACHE 2.41 (1.57 3.69) <0.001 change 3.10 (1.10 measures to 8.74) adjusted for gender, type of admission, the Acute Physiology And Chronic Health Evaluation IV common disorder ICU [6-8]. studies sive (ICU) survivors has 402 increased type of admission, and CumSOFA back wascare 420unit days after discharge (IQR to 444 considerdays). pared to subjects whoindid notpatients have IV) delirium in the (APACHE score,Previous and theICU. cumulative Sequential Organ Failure Assessment (SOFA) score throughout ICU stay. consistently found delirium in the ICU isand assobut recent studies demonstrate that ICU survivors Inably, total, 198 patients died during follow-up, with a delirium Thehave strength association did(n =not weaken Data on cognitive functioning were available for 561 patients. The group (n = 188)of was this divided into:that No problems 99), mild problems (n = 79) and Of 1101 survivors of critical severe problems = 10). after Forlong-term theICU group admission without delirium (n = 373): no remained problems (n =statistically 261), mild problems (nResults: = 103) and severe problems (n = 9).were APACHE IV: illness, Acute 412 persons (37%) had been delirious during ICU stay, and 198 (18%) died ciated with long-term mortality and cognitive impaircan experience morbidity [1-5]. median duration ofsubstantial 62(ndays (IQR 25 To significant when adjustments Physiology and Chronic Health Evaluation IV; CI: confidence interval; CumSOFA: cumulative Sequential Organwithin Failure twelve Assessment without central system for confounders, no significant association between delirium and long-term months. Whennervous correcting ment It is, variables however,(Table unclear improve care forsurvival survivors critical illness, to further 181 days). Univariate showed thatit is made for [9-14]. confounding 4). whether delirium component; ICU: intensive care unit;analysis OR:of odds ratio. mortality was found (hazard ratio: 1.26; 95% confidence interval (CI) 0.93 to 1.71). In multivariable analysis, delirium was also affects long-term health related quality was of life important to elucidate which factorsincreased increase the delirious patients had a significantly riskrisk of of To verify whether the effect mortality not measure associatedfor with HRQoL either (regression coefficient: −0.04; 95% CI −0.10 to 0.01). Yet, delirium remained associated (HRQoL). HRQoL defined as health, inconducted the medical death in similar, the yearwhich following However, is robust, robust when using the is cumulative wein is consistent with a recent study, which adjustments showsICU that admission. our effect measure with mildSOFA, and severe problems with cognitive functioning in multivariable analysis (odds ratios: 2.41; 95% CI 1.57 to definition, but where also the importance of independent when adjustments were made for athe confounders analyse we3.69 made Cox hazfor severity of as illness throughout course of the ICU and length of stay is not mediator in the decausalsensitivity pathand 3.10;proportional 95%the CI 1.10 to 8.74, respectively). * Correspondence: a.e.wolters@umcutrecht.nl social [15]. Two that scribed above, delirium was no longer independently as- ardphysical, models with the and meanemotional SOFA andfunctioning themanner maximal SOFA stay were made in a similar [10]. Factors wayof between delirium and mortality. Department Intensive Care Medicine, University Medical Center Utrecht, Conclusions: In this group survivors of critical illness, delirium during ICU stay was not associated with long-term studies suggest that a risk factor foroflower Heidelberglaan 100, 3508 GA(Table Utrecht,2). The Netherlands sociated with mortality scores. Furthermore, wedelirium evaluated the effect of adding precipitate delirium mayisthus provoke thatforconmortality or HRQoL afterevents adjusting confounding, including severity of illness throughout ICU stay. In contrast, In univariate analysis, patients© 2014 withWolters delirium during length of stay to to these models. Other variables were left the or acceleration of cognitive risk factor for long-term self-reported problems with cognitive functioning. Discussion et al.; licensee BioMed Central Ltd. This istribute an Open Access articledevelopment distributed under the terms of the delirium appears to beCreative an independent Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and their ICUWe staystudied had a significantly lower HRQoL score at unchanged. The HRs for death in these models remained the association between delirium in the ICU impairment, even when delirium is no longer present. It reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain tomade seeavailable whether and long-term mortality,Dedication HRQoL, and problems with cog- would be interesting waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data in this this article, holds only for long-term morbidity and mortality. Delirium, characterIntroduction unless otherwise stated. illness. We found persistent delirium or also for rapidly reversible, sedationnitive functioning in survivors of critical ized by an acute change in attention and cognition, is a Because ofquality improved medical the to number of intenTable 2 Risk death associated delirium in in health-related of life between related delirium [25]. Unfortunately, we were care, not able thatof delirium was notwith associated with mortalityTable and3 Differences common disorder in ICU patients [6-8]. Previous studies sive care unit within (ICU) survivors survivors HRQoL of criticalwhen illness, within one were year after delirious and non-delirious ICUthese survivors, one year has increased considerdistinguish between types of delirium. adjustments madeICU for confounding. have consistently found that delirium in the ICU is assorecent studies demonstrate that ICU survivors admissionBy contrast, subjects who had delirium during their after The evidence ably, of nobut association between delirium and ICUICU admission ciated with long-term mortality and cognitive impaircan experience substantial long-term morbidity [1-5]. To Model Hazard ratio, P-value functionModel Difference, CI P-value long-term mortality and HRQoL95% should not be used as stay experienced more problems with cognitive further improve care for survivors of critical illness, it is ment [9-14]. It is, however, unclear whether delirium 95% CI an excuse to neglect−0.06 delirium the ICU. ing at follow-up than persons who did not have delirium Crude (−0.10 toin−0.01) 0.01 With our also affects long-term health related quality of life important to elucidate which factors increase the risk of Crude 1.91 (1.44 to 2.52) <0.001 show again −0.04 that(−0.10 delirium with in the ICU. The latter finding remained statistically signifiAdjusted for study gender, we APACHE IV, type to 0.01)is associated 0.09 (HRQoL). HRQoL is defined as health, in the medical Adjusted forcant gender, APACHE type 1.26 to 1.71) 0.14 of estiadmissionprolonged and CumSOFA cognitive problems [9-11]. Interventions aimed when weIV,adjusted for(0.93 confounders, including definition, but also as the importance of independent of admission and CumSOFA * Correspondence: a.e.wolters@umcutrecht.nl at reducing incidence may eventually lead to mates of severity of illness throughout the course Data of the on health-related quality ofdelirium life was available for 546 patients. Delirious: physical, social and emotional functioning [15]. Two Department Intensive CareChronic Medicine, University Medical Center Utrecht, 198 patients died n = 182, not delirious: n = 364. APACHE IV:effects AcuteofPhysiology and long-term beneficial on cognitive outcome. ICUwithin stay.one year. Delirious: n = 102, not delirious: n = 96. studies suggest that delirium is a risk factor for lower 100, cumulative 3508 GA Utrecht, The Netherlands APACHE IV: Acute Physiology and Chronic Health Evaluation IV; CI: confidence Health Evaluation IV; CI: confidenceHeidelberglaan interval; CumSOFA: Sequential It is remarkable that thesystem self-reported probTocumulative the bestSequential of our Organ knowledge, our study is the first interval; CumSOFA: Failure Assessment without Organto Failure Assessment without central nervous component;cognitive ICU: © 2014 Wolters central nervous systemfor component; unit. unit. do not seem to have an impact on patients’ self-et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative adjust severityICU:ofintensive illnesscare throughout the course intensive of the carelems Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and association ICU stay, in analyzing the association between delirium reported quality of life in this population. An reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, HRQoL with long-term mortality and HRQoL. Previous studies between more cognitive problems and a lower unless otherwise stated. on these issues adjusted for severity of illness at baseline would be expected. It might be due to a rather limited only [11-14,16]. Next to correction for severity of illness, HRQoL survey. However, our findings are consistent differences with previous studies could be the result of with previous studies in which more extensive tools were Uyandırma ve spontan differences in case mix, as we included ICU survivors used to assess HRQoL and cognitive functioning, namely soluma çalışmaları only. Nevertheless, our study findings emphasize that the ShortForm 36 and the Cognitive Failure Questionthe burden of illness during ICU stay should be taken naire [11]. Perhaps the expectation to find a lower HRQoL into account. For example, a patient after elective sur- in subjects with more cognitive problems is not always gery may have a low predicted mortality. However, when applicable. No a priori sample size calculation was performed. such a patient develops septic shock during their ICU stay, the risk of mortality may change but this is not in- However, this is one of the largest studies so far to adcorporated in the APACHE IV score. Therefore, severity dress this problem. We believe that our study population of illness at admission should not be considered the sole was large enough to study this issue. Nevertheless, our predictor of long-term outcome. To adjust for severity study has several limitations. Due to missing data a relaof illness throughout the course of the ICU stay, we used tively large group had to be excluded, which may have the cumulative SOFA score, which is dependent on both introduced bias. Excluded subjects had a shorter length the duration and the extent of multi-organ failure, and of ICU stay than the study population and did not differ which is strongly associated with long-term mortality in other measured characteristics. Therefore, if selection [18]. We conducted sensitivity analyse with the mean bias would have occurred, we have analyzed a more seSOFA and maximal SOFA, which showed that our effect vere group of subjects. Secondly, the sensitivity of the CAM-ICU in daily practice may be low [7]. Yet, in conmeasure was robust. The association that we found between delirium in the trast to studies where sensitivity of the CAM-ICU was ICU and long-term problems with cognitive functioning studied at one point in time, we used all CAM-ICU Model Crude Konuşma engelleri İşitme Görme Dil Kültürel X Farmakolojik yöntemler “ABCDE bundle” Çevresel düzenleme Sedatif ve analjezik seçimi Yoğun bakım Gürültü Işık Uyku/uyanıklık Duyusal uyarı Reoryantasyon Aile varlığı Girişimleri azalt Erken fizyoterapi Hidrasyon Metabolik denge Hastanın katılımı Ventilatörden ayrılma YB ve hastaneden çıkış Normal beyin fonksiyonlarına dönüş Bağımsız fonksiyonel kapasite Sağkalım Günlük deliryum monitörizasyonu F Aile anlaşması aaaA Erken mobilizasyon Farmakolojik tedavi q Tipik antipsikotikler Haloperidol q Atipik antipsikotikler Olanzepine, risperidone, quetiapine q Sedasyon modifikasyonu; Dexmetedomidine Magnesium 5 Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients A Randomized Trial Richard R. Riker, MD Yahya Shehabi, MD Paula M. Bokesch, MD Daniel Ceraso, MD Wayne Wisemandle, MA Firas Koura, MD Patrick Whitten, MD Benjamin D. Margolis, MD Daniel W. Byrne, MS E. Wesley Ely, MD, MPH Marcelo G. Rocha, MD for the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group P ROVIDING SEDATION FOR PA - Context !-Aminobutyric acid receptor agonist medications are the most commonly used sedatives for intensive care unit (ICU) patients, yet preliminary evidence indicates that the "2 agonist dexmedetomidine may have distinct advantages. Objective To compare the efficacy and safety of prolonged sedation with dexmedetomidine vs midazolam for mechanically ventilated patients. Design, Setting, and Patients Prospective, double-blind, randomized trial conducted in 68 centers in 5 countries between March 2005 and August 2007 among 375 medical/surgical ICU patients with expected mechanical ventilation for more than 24 hours. Sedation level and delirium were assessed using the Richmond AgitationSedation Scale (RASS) and the Confusion Assessment Method for the ICU. Interventions Dexmedetomidine (0.2-1.4 µg/kg per hour [n=244]) or midazolam (0.02-0.1 mg/kg per hour [n=122]) titrated to achieve light sedation (RASS scores between −2 and #1) from enrollment until extubation or 30 days. 27/04/16 Main Outcome Measures Percentage of time within target RASS range. Secondary end points included prevalence and duration of delirium, use of fentanyl and openlabel midazolam, and nursing assessments. Additional outcomes included duration of mechanical ventilation, ICU length of stay, and adverse events. Results There was no difference in percentage of time within the target RASS tient comfort is an integral range (77.3% for dexmedetomidine group vs 75.1% for midazolam group; differcomponent of bedside care for ence, 2.2% [95% confidence interval {CI}, −3.2% to 7.5%]; P = .18). The prevalence of delirium during treatment was 54% (n = 132/244) in dexmedetomidinenearly every patient in the in- treated patients vs 76.6% (n = 93/122) in midazolam-treated patients (difference, tensive care unit (ICU). For decades, 22.6% [95% CI, 14% to 33%]; P$.001). Median time to extubation was 1.9 days !-aminobutyric acid (GABA) receptor shorter in dexmedetomidine-treated patients (3.7 days [95% CI, 3.1 to 4.0] vs 5.6 agonists (including propofol and ben- days [95% CI, 4.6 to 5.9]; P = .01), and ICU length of stay was similar (5.9 days zodiazepines such as midazolam) have [95% CI, 5.7 to 7.0] vs 7.6 days [95% CI, 6.7 to 8.6]; P=.24). Dexmedetomidinetreated been the most commonly adminisCARING FOR THEpatients were more likely to develop bradycardia (42.2% [103/244] vs 18.9% THE[23/122]; P$.001), with a nonsignificant increase in the proportion requirtered sedative drugs for ICUCARING patients FOR CRITICALLY ILL PATIENT treatment (4.9% [12/244] vs 0.8% [1/122]; P=.07), but had a lower likelihood guidelines forILLingPATIENT worldwide.1-5 PracticeCRITICALLY providing sedation in the ICU have of tachycardia (25.4% [62/244] vs 44.3% [54/122]; P $ .001) or hypertension requiring treatment (18.9% [46/244] vs 29.5% [36/122]; P=.02). identified the need for well-designed randomized trials comparing the effec- Conclusions There was no difference between dexmedetomidine and midazolam tiveness of different sedative agents for in time at targeted sedation level in mechanically ventilated ICU patients. At comparable sedation levels, dexmedetomidine-treated patients spent less time on the venimportant clinical outcomes.1 Despite tilator, experienced less delirium, and developed less tachycardia and hypertension. the well-known hazards associated with The most notable adverse effect of dexmedetomidine was bradycardia. prolonged use of GABA agonists,6-12 few Trial Registration clinicaltrials.gov Identifier: NCT00216190 investigations of ICU sedation have DEXMEDETOMIDINE VS MIDAZOLAM FOR SEDATION OF CRITICALLY JAMA. 2009;301(5):489-499 www.jama.com compared these agents to other drug classes.12-14 Instead, the recent focus in Author Affiliations and Members of the SEDCOM St, Portland, ME 04102 (rikerr@mmc.org). Dexmedetomidine vs vs Midazolam Midazolam ILL PATIENTS Dexmedetomidine for Sedation Sedation of of Critically Critically Ill for Ill Patients Patients 14.8% (18/122) ofTrial midazolam-treated operation, and tolerance of the venti- tiveness (6.6 [SD, 3.0] vs 5.5 [SD, 3.1]; A Randomized For editorial comment see p 542. Study Group are listed at the end of this article. Corresponding Author: Richard R. Riker, MD, Neu- patients during the double-blind treatA Randomized Trial Caring for the Critically Ill Patient Section Editor: Derek C. Angus, MD, MPH, Contributing Editor, JAMA roscience Institute, Maine Medical Center, 22 Bramhall (angusdc@upmc.edu). lator was higher for dexmedetomidine- P!.001) and cooperation (7.0 [SD, 2.9] (Reprinted) JAMA, February 4, 2009—Vol 301, No. 5 489 ment period. treated patients (21.2 [SD, 7.4] 19.0 vs 6.1 [SD, 3.0]; P = .002), while the Context !-Aminobutyric acid receptor agonist medications are thevs most commonly Richard R. Riker,MD MD Yahya Shehabi, used sedatives for intensive care unit P (ICU) patients, preliminary evidence indi!-Aminobutyric acid receptor medications arethe the most commonly The composite nursingContext assessment [SD, 6.9]; =agonist .001), asyetwere indimean tolerance of ventilator score was dexmedetomidine have yet distinct advantages. cates sedatives that the "foragonist Yahya Shehabi, MDMD used intensive care unit (ICU)may patients, preliminary evidence indiPaula M. Bokesch, score for patient communication, covidual scores formay communication effecnot significantly different (7.6 [SD, 2.2] agonist have distinct advantages. cates that the " 2 Objective To compare dexmedetomidine the efficacy and safety of prolonged sedation with dexmePaula Bokesch, MD DanielM. Ceraso, vs 7.4 [SD, 1.8]; P=.09). Downloaded fromMD jama.ama-assn.org at Istanbul Ãœniversitesi on March 28, 2011 detomidine vs midazolam for efficacy mechanically ventilated patients. sedation with dexmeObjective To compare the and safety of prolonged Daniel MD MA Wayne Ceraso, Wisemandle, detomidine vs midazolam for mechanically ventilated patients.randomized trial con-Ventilator Time and ICU Length of Design, Setting, and Patients Prospective, double-blind, Wayne Wisemandle, MA Outcomes inducted Firas Koura, TableMD 2. Efficacy Patients With Dexmedetomidine vs2005 Midazolam inSetting, 68Treated centers in 5Patients countries between March and randomized August 2007trial among Design, and Prospective, double-blind, conStay. More patients treated with dexmeFiras Koura, MD MD 375 medical/surgical with expected mechanical ventilation more than ducted in 68 centers ICU in 5patients countries between March 2005 and Augustfor 2007 among Patrick Whitten, No. (%) detomidine had study drug stopped be24 hours. Sedation level delirium assessed using the Richmond 375 medical/surgical ICU and patients with were expected mechanical ventilation for Agitationmore than Patrick Whitten, MD MD Benjamin D. Margolis, Sedation (RASS) and thedelirium Confusion Assessment Method the ICU.Agitation24 hours.Scale Sedation level and were assessed using the for Richmond cause the patient was extubated (59% Dexmedetomidine Midazolam P Benjamin Margolis, Daniel W. D. Byrne, MS MD Sedation Scale (RASS) and the Confusion Assessment Method for the ICU. Interventions Dexmedetomidine (0.2-1.4 µg/kg per hour [n = 244]) or midazolam Outcome (n = 244) (n = 122) Value [144/244] vs 45% [55/122]; P = .01). Daniel W. Ely, Byrne, MSMPH (0.02-0.1 mg/kgDexmedetomidine per hour [n = 122])(0.2-1.4 titrated µg/kg to achieve light[n=244]) sedation or (RASS scores E. Wesley MD, hour midazolam 77.3 75.1 per or .18 Time in target sedation range Interventions The Kaplan-Meier estimated median between −2 and #1) from enrollment until extubation 30 days. (0.02-0.1 E. WesleyG.Ely, MD,score MPH −2 to #1), mean, Marcelo Rocha, MD (RASS % a mg/kg per hour [n=122]) titrated to achieve light sedation (RASS scores between −2 and #1) from enrollment untilofextubation 30 days. Main Outcome Measures Percentage time withinortarget RASS range. Secondtime to extubation was 1.9 days shorter Marcelo G. Rocha, MD and all for the SEDCOM (Safety Efficacy Patients completing daily arousal 225 (92) 103 (84.3) .09 ary endOutcome points included prevalence and duration of delirium, use of fentanyl and openMeasures Percentage of time within target RASS range. Secondof Dexmedetomidine Compared With Main for assessments for the SEDCOM (Safety and Efficacy label midazolam, and nursing assessments. Additional outcomes included duration of dexmedetomidine-treated patients ary end points included prevalence and duration of delirium, use of fentanyl and openMidazolam) Study Group of Dexmedetomidine Compared mechanical ventilation, ICU of stay, Additional and adverse events. included Patients requiring study With drug label 222 (91)length 112 (91.8) .85 midazolam, and nursing assessments. outcomes duration(3.7 of days [95% CI, 3.1 to 4.0] vs 5.6 interruption score There Midazolam) Study Groupto maintain RASS Results was noICU difference percentage of time within the target RASS mechanical ventilation, length ofinstay, and adverse events. ROVIDING SEDATION FOR PA days [95% CI, 4.6 to 5.9]; P = .01 by −2 to #1 range (77.3% dexmedetomidine vs 75.1% for midazolam tient comfort is an integral Results Thereforwas no difference ingroup percentage of time within thegroup; targetdifferRASS ROVIDING SEDATION FOR PA log-rank) (Table 2, FIGURE 3). The ence, 2.2% [95% confidence interval {CI}, −3.2% to 7.5%]; P = .18)..01 The prevaDuration of study drugcare treatment, 3.5 (2.0-5.2) (2.8-6.1) component of bedside for range (77.3% for dexmedetomidine group vs4.1 75.1% for midazolam group; differtient comfort is an integral lence of delirium during treatment was 54% (n = 132/244) in dexmedetomidinemedian d in the in- ence, 2.2% [95% confidence interval {CI}, −3.2% to 7.5%]; P = .18). The prevaKaplan-Meier estimated median length nearly every(IQR), component ofpatient bedside care for treated patients vs 76.6% (n = 93/122) in midazolam-treated patients (difference, lence treatment was 54%5.6 (n =(4.6-5.9) 132/244) in dexmedetomidine3.7 (3.1-4.0) .01 to extubation, (95% CI), of d bdelirium during tensive Time care unit (ICU). Formedian of ICU stay was similar (5.9 days [95% 22.6% [95% CI, 14% to 33%]; P $ .001). Median time to extubation was 1.9 days nearly every patient indecades, the in- treated patients vs 5.9 76.6% (n = 93/122) in midazolam-treated patients (difference, !-aminobutyric receptor (5.7-7.0) 7.6 days (6.7-8.6) ICU of(GABA) stay, (95%shorter CI), d bin dexmedetomidine-treated patients (3.7 [95% CI, 3.1 to.24 4.0] vs CI, 5.6 5.7 to 7.0] vs 7.6 days [95% CI, 6.7 tensive care length unitacid (ICU). Formedian decades, [95% CI, 14% to 33%]; P$.001). Median time to extubation was 1.9 days agonistsDelirium (including ben- 22.6% days [95% CI, 4.6 to 5.9]; P = .01), and ICU length of stay was similar (5.9 days !-aminobutyric acidpropofol (GABA) and receptor shorter in dexmedetomidine-treated patients (3.7 days [95% CI, 3.1 to 4.0] vs to 5.6 8.6]; P = .24 by log-rank) (Table 2, [95% CI, 5.7 to 7.0] vs (54) 7.6 days [95% CI, 6.793 to 8.6]; P = .24). Dexmedetomidinezodiazepines such aspropofol midazolam) Prevalence 132 (76.6) !.001 agonists (including and have ben- days [95% CI, 4.6 to 5.9]; = .01),toand ICU length of stay(42.2% was similar (5.9 days treated patients were morePlikely develop bradycardia [103/244] vs been the most commonly adminisc Figure 3). Mean delirium-free days 2.5 1.7 .002 [95% CI, 5.7 to 7.0] vs 7.6 days [95% CI, 6.7 to 8.6]; P=.24). Dexmedetomidinezodiazepines such as midazolam) have 18.9% [23/122]; P $ .001), with a nonsignificant increase in the proportion requirORIGINAL ARTICLE tered sedative drugs for ICU patients treated patients were more likely to develop bradycardia (42.2% [103/244] vsLong-term Use and Subpopulations. been the most commonly adminisOpen-label midazolam use ing treatment (4.9% [12/244] vs 0.8% [1/122]; P = .07), but had a lower likelihood 1-5 worldwide. Practice guidelines for 18.9% [23/122]; P$.001), with a nonsignificant increase in the proportion requirtered sedative for ICU patients of tachycardia (25.4% No.drugs treated 153 (63) 60 (49) P $ .001) or hypertension .02 [62/244] vs 44.3% [54/122]; Results for the intent-to-treat populaproviding sedation in the ICU have treatment (4.9%(18.9% [12/244] vs 0.8% P=.07), but likelihood 1-5 requiring treatment [46/244] vs[1/122]; 29.5% [36/122]; P =had .02).a lower Practice guidelines for ding worldwide.Dose, median (IQR), mg/kg 0.09 (0.03-0.23) (0.03-0.28) .65 identified the need for well-designed of tachycardia (25.4% [62/244] vs 44.3%0.11 [54/122]; P $ .001) or hypertension tion with assigned values (all 375 ranStatin Use and Risk of Delirium in the Critically Ill no[46/244] providing sedation in the ICU have Conclusions There(18.9% was difference dexmedetomidine Fentanyl treatment vsbetween 29.5% [36/122]; P=.02). and midazolam randomized trialsuse comparing the effec- requiring identified3,4the need for well-designed domized patients) were similar to those in time sedation At compa5 at targeted 180 1level in mechanically 6 ventilated No. treated (73.8) 97 (79.5) ICU patients. tiveness for Norton Valerie J. Page1,2, Daniel Davisof different ,trials Xiao B.sedative Zhao1,agents Samuel , Annalisa Casarin Thomas Brown , dexmedetomidine Conclusions There was no, difference between and.25 midazolam rable sedation levels, dexmedetomidine-treated patients spent less time on the venrandomized comparing the effec1 9,10 from the primary analysis for time in Despite important clinical outcomes. Dose, median (IQR), µg/kg d in 6.4 9.6ventilated (2.9-28.6) .27 time experienced at targeted sedation level in mechanically ICU patients. At compaE. Wesley Ely7,8, and Daniel F.ofMcAuley tilator, less (1.8-26.3) delirium, and developed less tachycardia and hypertension. tiveness different sedative agents for the well-known hazards associated with rable sedation levels, dexmedetomidine-treated patients less time on target range (75.4% for dexmedetomi1 The notable adverse effect of dexmedetomidine wasspent bradycardia. 1 2 RASS, Richmond Abbreviations: CI, confidence interval; ICU,most intensive care unit; IQR, interquartile range; Agitation andthe venDespite important clinical outcomes. 6-12 Intensive Care Unit, Watford General Hospital, West Hertfordshire Trust, Watford, United Kingdom; Faculty Medicine, fewHospitals prolonged use of GABA agonists, tilator, NHS experienced less delirium, and developed less of tachycardia and hypertension. 3 Scale. 4 Sedation Imperial College, London, the United Kingdom; Institute of Publicwith Health,Trial University of Cambridge, Cambridge, United Kingdom; Centre Registration clinicaltrials.gov Identifier: NCT00216190 well-known hazards associated dine-treated patients vs 73.3% for a The mean 5 dexmedetomidine The most notable adverse effect of was bradycardia. investigations of ICU sedation difference in percentage of time within target sedation range between the dexmedetomidine and midfor Cognitive Ageing and Cognitive Epidemiology, University ofhave Edinburgh, Edinburgh, United Kingdom; Psychology Department, 6-12 JAMA. 2009;301(5):489-499 www.jama.com few prolonged use of GABA agonists, 6 calculated azolam treatment using the Mann-Whitney midazolam-treated patients), reduccompared these agents togroups other was drug Institute of Psychiatry, King’s College, London, United Kingdom; Department of Anaesthesia, Ealing test. Hospital, Southall,NCT00216190 United Trial Registration clinicaltrials.gov Identifier: b Calculated 8 investigations of ICU sedation have using Kaplan-Meier analysis, Valley with differences between treatment groups9Centre assessed 12-14 Kingdom; 7Vanderbilt University Medical Center, Nashville, Tennessee; Tennessee VA-GRECC, Nashville, Tennessee; for by the logInstead, the recent focus insurvival classes. JAMA. 2009;301(5):489-499 www.jama.com 10 and Members of the SEDCOM tion of delirium in dexmedetomidineAuthor Affiliations St, Portland, ME 04102 (rikerr@mmc.org). rank test. Log-rank P values were adjusted for multiple comparisons using the Bonferroni method. Infection and Immunity, Queen’s University of Belfast, Belfast, United Kingdom; and Regional Intensive Care Unit, Royal Victoria Hospital, compared these agents to other drug Study Group are listed at the end of this article. c Number of days alive without delirium Caring for the Critically Ill Patient Section Editor: Derek during study drug treatment. Belfast, United Kingdom classes.12-14 treated patients (24.9% reduction comInstead, the recent focus in Corresponding Author: Richard R. Riker, MD, NeuC. Angus, MD, MPH, Contributing Editor, JAMA d Calculated For editorial comment 542.during Author Affiliations and Members of themass. SEDCOM St, Portland, ME 04102 (rikerr@mmc.org). as thesee totalp dose study treatment divided by body roscience Institute, Maine Medical Center, 22 Bramhall (angusdc@upmc.edu). Study Group are listed at the end of this article. Caring for the Critically Ill Patient Section Editor: Derek pared with midazolam), time to Corresponding Author: Richard R. Riker, MD, NeuC. Angus, MD, MPH, Contributing Editor, JAMA For editorial comment see p 542. ©2009 American Medical Association. All rightsroscience reserved. (Reprinted) JAMA, February 4, 2009—Vol 301, No. 5 489 Institute, Maine Medical Center, 22 Bramhall (angusdc@upmc.edu). extubation (3.8 days [95% CI, 3.5 to 4.0] ©2009 American Association. All rights reserved. Among Intubated Intensive (Reprinted)Care JAMA, Unit February 4, 2009—Vol 301, No. 5 vs 489 5.7 days [95% CI, 4.6 to 6.0]), and FigureMedical 2. Daily Prevalence ofrecorded. Delirium Abstract Four hundred and seventy consecutive critical carePatients patients Treated With Dexmedetomidine vs Midazolam ICU length of stay (5.9 days [95% CI, were followed, of whom 151 patients received statins. Using randomRationale: Delirium is common in intensive care unit (ICU) patients effects multivariableatlogistic regression, statin administration the Downloaded from jama.ama-assn.org Istanbul Ãœniversitesi on March 28, 2011 5.7 to 7.1] vs 7.7 [95% CI, 6.7 to 10.1]). 80 and is a predictor of worse outcomes and neuroinflammation is previous evening was associated with the patient being assessed as For the “long-term use” population Dexmedetomidine a possible mechanism. The antiinflammatory actions of statins may free of delirium (odds ratio, 2.28; confidence interval, 1.01–5.13; Downloaded from jama.ama-assn.org at Istanbul Ãœniversitesi on March 28, 2011 70 Mol Neurobiol Midazolam reduce delirium. P , 0.05) and with lower CRP (b = 20.52; P , 0.01) the following (receiving study drug "24 hours), the DOI 10.1007/s12035-015-9350-8 day. When the association between statin and being assessed as 60 receiving percentage of time within the target Objectives: To determine whether critically ill patients free of delirium was controlled for CRP, the effect size became statin therapy had a reduced risk of delirium than those not on statins. RASS range was similar (80.8% for nonsignificant (odds ratio, 1.56; confidence interval, 0.64–3.79; 50 P = 0.32). dexmedetomidine and 81% for midMethods: A prospective cohort analysis of data from 40 consecutive ICU patients admitted to a UK mixed medical and surgical critical Conclusions: Ongoing statin therapy is associated with a lower daily azolam; mean difference, −0.2% [95% 30 Confusion care unit between August 2011 and February 2012; the risk of delirium in critically ill patients. An ongoing clinical trial, CI, −5.0 to 4.7%]; P = .54), while the Exogenous Melatonin for Delirium Assessment Method for ICU was used to determine the days each informed by this study, isPrevention: investigating if statins are a potential patient was assessed as being free of delirium during 20 ICU admission. therapy for delirium in the critically ill. dexmedetomidine group experienced a Meta-analysis of Randomized Controlled Trials less delirium (treatment effect by GEE Measurements and Main Results: Delirium-free10 days, daily Keywords: delirium; statin; inflammation; C-reactive protein; Mol Neurobiol administration of statins, and serum C-reactive protein critical care 1 showed a 24% reduction; 95% CI,14% 1 1(CRP) were 1 2 1 0 Sheng Chen & LiGen Shi &Enrollment Feng Liang & 1Liang Xu 2& Doycheva 3Desislava 4& Qun Wu 5& DOI 10.1007/s12035-015-9350-8 6 to 34%; P!.001), a shorter time to exJianmin Zhang 1 Treatment Day tubation (3.9 days [95% CI, 3.8 to 4.8] Neurologic 206 109 175 92 134 77 92 57 60 42 44 34 SampleCritical Size 229 118Care vs 5.8 days [95% CI, 4.7 to 6.2]; P=.03), Delirium is a form of acute brain outcomes. Delirium is independently cognitive impairment after critical illness 24 Delirium diagnosed using the Confusion Assessment Methodquality for theof Intensive Care Unit (CAM-ICU). At and a similar ICU length of stay (6.4 dysfunction, with a prevalence of up to 65% was associated with a threefold increased risk of reduces life, increases healthcare baseline, 60.3% of dexmedetomidine-treated patients and 59.3% of midazolam-treated patients were CAMMelatonin in critically ill patients requiring mechanical mortality at 6 months, and for survivors costs, and leads to institutionalization (4, 5). Exogenous days [95% CI, 5.8 tofor 7.5]Delirium vs 8.0 days Prevention: The effect ofof dexmedetomidine treatment was significant in the generalized ventilation in the United KingdomICU–positive (1). It is 27 a (P=.82). 10-fold increased risk cognitive Although the pathogenesis of deliriumestimating [95% CI, 6.7of to Randomized 10.1; P=.46). Controlled Trials 20 April 2015 / Accepted: 7atJuly 2015 decrease analysis, with a1224.9% (95% confidence midassociated with significantlyReceived: worseequation clinical impairment months (2, 3). Long-term remainsinterval,16%-34%; poorly understood,P!.001) there is relativeato Meta-analysis # Springer Science+Business New York 2015 azolam treatment.Media Numbers differ from those for primary analysis because patients were extubated, disWhen data from low-enrolling cencharged from the intensive care unit, or had missing delirium assessments. 1 1 1 Sheng Chenters & LiGen Shipatients) & Feng Liang & Liang Xu 1 & Doycheva (!5 were excluded, 298 Desislava 2 & Qun Wu 1 & patients that were presented to medical wards. Further studies Recently, twoform high-quality clinical ( Received in original form JuneAbstract 25, 2013; accepted in final December 30, 2013 ) randomized ©2009 American Medical Association. rightsMD reserved. Richard R.All Riker, 2 P P Delirium Prevalence, % 23 Effect of Magnesium on Sepsis Associated Delirium Esen F et al ESICM 2008 Statins and Delirium During Critical Illness: A Multicenter, Prospective Cohort Study* Jianmin Zhang 6 Delirium Days 5 1 should Centre provideforsufficient about the effect of melatocontrolled trials (RCTs) regarding the preventive of ex-of Edinburgh Supported by grant funding from the Wellcome Trust (090661/Z/09/Z to D.D.); theeffect University Cognitiveevidence Ageing and 494 JAMA, February 4, and 2009—Vol 301, No. (G0700704/84698 5 (Reprinted) to D.D); the BBSRC, EPSRC, ESRC, ©2009 American Medical Cognitive Epidemiology, partogenous of the cross-council Health Initiative nin on delirium in 4,5 a large sample size. melatonin Lifelong on delirium drewWellbeing inconsistent concluand MRC; and in part by NIHR CLAHRC for Cambridgeshire Peterborough Support of the IntensiveMD Care Foundation gratefully Alessandro Morandi,and MD, MPH1,2,3(S.N.). ; Christopher G. UK Hughes, ; Jenniferis L. Thompson, MPH6; sions. We therefore performed a systemic review to explore acknowledged. 4 Association. All rights reserved. Pratik P. Pandharipande, MD, MSCI4,5; Ayumi K. Shintani, PhD, MPH6; 3 . Melatonin . Sleep–wake whethertomelatonin had a benefit on delirium Keywords Delirium cycle . Author Contributions: V.J.P. contributed the study conception, study design, acquisitionprevention. of data, and drafting of article. D.D., S.N., and D.F.M. contributed to 7,8,9 10 D.D., and D.F.M. contributed to 7,11,12,13 analysis and interpretation of data and draftingEMBASE, ofE. article. X.B.Z., and T.B. contributed tosearched acquisition the data. E.W.E., MEDLINE, and A.C., Cochrane Library were Meta-analysis Eduard Vasilevskis, MD, MPH ; Jin H. Han,ofMD, MSc ; James C. Jackson, PsyD ; study conception and study design. S.N., D.D., X.B.Z., A.C., T.B., E.W.E., and D.F.M. critically revised the article and all authors approved the final version fromDaniel JanuaryT. 1980 to April 2015 English 14 language stud3,7,9,11 to be published. Laskowitz, MD,forMHS ; Gordon R. Bernard, MD11; E. Wesley Ely, MD, MPHReceived: ; 20 April 2015 / Accepted: 7 July 2015 2 This article has an online supplement, which is was accessible from this issue’s table of contents at www.atsjournals.org meta-analysis the incidence of delirium. The secondary Downloaded from jama.ama-assn.org at Istanbul Ãœniversitesi on March 28, 2011 ORIGINAL ARTICLE After strict and to evaluation, the3,7,9,11 data Correspondence and requests ies. for reprints shouldselection be addressed Valerie J. Page, M.B.were Ch.B.,extractIntensive Care Unit, Watford General Hospital, Watford WD18 # Springer Science+Business Media New York 2015 Timothy D. Girard, MD, MSCI 0HB, UK. E-mail: valerie.page@whht.nhs.uk ed from the included four RCTs. The primary outcome of this Introduction Abstract Recently, two high-quality clinical randomized Statin Use and Risk of Delirium in the Critically Ill patients that were presented to medical wa should provide sufficient evidence about t nin on delirium in a large sample size. E. Wesley Ely , and Daniel F. McAuley Center for Quality Aging, Vanderbilt University School of Medicine, Nashfidence interval [CI] 0.15 to 1.13; P=0.08) compared with Keywords Delirium . Melatonin . Sleep–w Meta-analysis Am J Respir Crit Care Med Vol 189, Iss 6, ppwas 666–673, Mar 15, 2014 of sleep–wake rhythm. A total outcome the improvement Delirium is a life-threatening neuropsychiatric syndrome, controlled trials (RCTs) regarding the preventive effect of exCopyright © 2014 by the American Society *See alsoRCTs p. 1955. support ultimately from the NIHleads (AG032355). Dr. Jackson received support from ofThoracic four with 669 elderly patients were included in the which to disturbance inogenous consciousness, melatonin on delirium drew inconsistent concluOriginally Published in Press as 1DOI: 10.1164/rccm.201306-1150OC on January 13, 2014 the NIH (AG031322). Dr. Laskowitz received support from the NIH. Dr. Rehabilitation andMelatonin Aged Unit, Hospital Cremona, 1,2 Caregroup 3,4 Ancelle, 1 Italy. 5 cognition, disturbed 1 psychomotor activity, present J. study. showed a tendency to decrease change and ab- performed a systemic review to explore Internet address: www.atsjournals.org sions.6Dr. therefore Valerie Page , Daniel Davis , Xiao B. Zhao , Samuel Norton , Annalisa Casarin , Thomas Brown ,WeEly Bernard in received support from the NIH (TR000445). received 2 Geriatric Research Brescia, Italy. 7,8Group, support sleep–wake from the NIH cycle (AG027472 the VA concern Clinical Scithe incidence of delirium (relative risk [RR] 9,10 0.41, 95 % connormal [1, 2].and It AG035117), is a major health 1 0 3 666 whether melatonin had a benefit on delirium prevention. ence Research and Development Service (VA Merit Review Award), and (2.5 times higher costs) with 2.9 times higherMEDLINE, mortality rates in EMBASE, and Cochrane Library were searched 1ville, TN. 2 the Veterans Valley GRECC; honoraria from Intensive Care Unit, Watford General Hospital, West Hertfordshire NHSAffairs Trust,Tennessee Watford, United Kingdom; Faculty of Medicine, American Journal of Respiratory and Critical Care Medicine Hospitals Volume 189 Number 6 | March 15 2014 received 4 con-to April 2015 for English language studcontrolofCollege, group. subgroup analysis of the 3elderly patients in Health, patients delirium compared to those with none [3,and 4]. Pfizer, Eli with Lilly and Company, Hospira, and Abbott Laboratories; from January 1980 Imperial London, United Kingdom; Institute of Public University of Cambridge, Cambridge, United Kingdom; Centre Division CriticalInCare, Department of Anesthesiology, Vanderbilt Uni5 sulted Edinburgh, for Cumberland andpathways Masimo. Dr. received support from the for Cognitive Ageing and Nashville, Cognitive Epidemiology, University of Edinburgh, United Kingdom; Psychology Department, medical wards, melatonin supplementation decreased versity School of Medicine, TN. Delirium’s pathogenic areGirard unclear, up strict to date, ies.and After selection and evaluation, the data were extract6 NIH (AG034257) and the Veterans Affairs Tennessee Valley GRECC and 5Institute of Psychiatry, King’s College, London, United Kingdom; Department of Anaesthesia, Ealing Hospital, Southall, United Anesthesia Veterans Affairs Medical Tenthe incidence of Department delirium byof 75 % (RR 0.25, 95 %Center, CI 0.07 from the included four RCTs. The primary outcome of this there no effective strategies treat delirium. A for 7Service, 8 are honoraria 9 received fromtherapeutic Hospira. Kingdom; Vanderbilt Medical TN. Center, Nashville, Tennessee; Tennessee Valley VA-GRECC, Nashville,toed Tennessee; Centre nessee Valley HealthcareUniversity System, Nashville, 10 to 0.88; and P=0.03), but not in sleep–wake (RR 1.24, was the incidence of delirium. The secondary systematic review that delirium prevention Infection Immunity, Queen’s Universitydisturbance of Belfast, Belfast, United recent Kingdom; and regarding Regional Intensive Care Unit,meta-analysis Royal Victoriahad Hospital, For information thisshowed article, E-mail: timothy.girard@vanderbilt.edu 6 Department of Biostatistics, Vanderbilt University School of Medicine, Belfast, United Kingdom 95 % CI 0.51 to 3.00; P=0.64). No differences were found in was the improvement of sleep–wake rhythm. A total greater success than treating delirium once outcome it has developed 4 -‐1 Mg+ Mg-‐ Nashville, TN. of four RCTs the incidence of Services deliriumResearch, between the two groups in the elder-of [5]. Haloperidol and second-generation antipsychotics are with the 669 elderly patients were included in the Center for Health Vanderbilt University School present Melatonin group showed a tendency to decrease ly patients that were Medicine, Nashville, TN. presented to surgical wards. In conclumost commonly used pharmacological agents withstudy. sedative 8 Objective: Since statins have [5]. pleiotropic on inflammathe incidence of delirium (relative risk [RR] 0.41, 95 % conDivision of Generalsupplementation Internal Medicine and Health, Department sion, melatonin hadPublic a significant preventiveof effects for delirium prevention However,effects these treatments Medicine, Vanderbilt University School of Medicine, Nashville, TN. tion and that prolonged may interrupt fidencepathogenesis, interval effect in decreasing the incidence of delirium in elderly have beencoagulation shown to cause QT delirium intervals and extra-[CI] 0.15 to 1.13; P=0.08) compared with 9Abstract recorded. Fourhypotheses hundred and seventy consecutive critical care patients Geriatric Research, Education and Clinical Center Service, Department we tested the that statin exposure is associated control group. Inwith subgroup analysis of the elderly patients in pyramidal symptoms that151 increase the risk ofstatins. fatal cardiovasof Veterans Affairs Medical Center, Tennessee Valley Healthcare System, were followed, of whom patients received Using randomreduced delirium during critical illness, whereas discontinuation of medical wards, melatonin supplementation decreased incidents [6]. Moreover, these pharmacological agentsthe Nashville, TN. Rationale: Delirium common in intensive (ICU) patients cular effects multivariable logistic regression, statin administration Sheng Chen and LiGenisShi contributed equally tocare thisunit work. statinno therapy is with increasedrhythm delirium. 10 the incidence of delirium by 75 % (RR 0.25, 95 % CI 0.07 Department of Emergency University Schoolis of have effect onassociated the [6]. assessed and is a predictor of worse Medicine, outcomesVanderbilt and neuroinflammation previous evening wasdisturbed associatedcircadian with the patient being as Multicenter, prospective cohort study. Nashville, TN. The antiinflammatory actions of statins may Design: to 0.88; P=0.03), but not in sleep–wake disturbance (RR 1.24, aMedicine, possible mechanism. free of delirium (odds ratio, 2.28; confidence interval, 1.01–5.13; Melatonin, a pineal gland hormone secreted during the * Qun Wu 11 Setting: Medical andlower surgical two large care Division of Allergy, Pulmonary, and Critical Care Medicine, Department 95,molecular %tertiary CI 0.51 to hos3.00; P=0.64). No differences were found in reduce delirium. P , 0.05) and with CRPICUs (ban=inimportant 20.52; P 0.01) the following wuqun30639@sina.com hours of darkness, is regarded as meof Medicine, Vanderbilt University School of Medicine, Nashville, TN. pitals in the United States. between statin and day. When the association assessed as thebeing incidence of delirium between the two groups in the elderdiator regulating the circadian rhythm, specially the sleep– 12 Department of UniversityillSchool of receiving Medicine, Objectives: ToPsychiatry, determineVanderbilt whether critically patients Patients: Patientswas with acute respiratory or shock. free of delirium controlled for CRP, failure thely effect size became patients thatdewere presented to surgical wards. In conclushown that Nashville, TN. had a reduced risk of delirium than those not on statins. wake cycle [7–9]. Observational studies have 1 statin therapy Department of Neurosurgery, Second Affiliated Hospital, School of Interventions: nonsignificantNone. (odds ratio, 1.56; confidence sion, interval, 0.64–3.79; 13 supplementation had a significant preventive Research Service, Department of Veterans Affairs or low melatonin secretion is associated withmelatonin delirium in Medicine, Zhejiang University, 88 Jiefang Road,Medical Center, Ten- layed P = 0.32). Measurements and Main Results: We measured statin exponessee Valley Healthcare System, Nashville, TN.data from consecutive effect in decreasing the incidence of delirium in elderly Methods: A prospective cohortChina analysis of Hangzhou 310009, Zhejiang, intensive care unit in elderly and patients [10–13]. Recent studies sure prior to hospitalization daily during the ICU stay, and 14 Division of Neurology, of Medicine, AnesICU patients admittedDepartment to a UK mixed medical Department and surgicalofcritical Conclusions: Ongoing statin therapy is associated with a lower daily 2 the postoperative plasma concentration of the melatoDepartment Physiologyofand Pharmacology, Loma Linda Medical measured we assessed patients for delirium twice daily using Confuthesiology, and of Department Duke University care unit between August 2011Neurobiology, and February 2012; the Confusion riskand of delirium in critically ill patients. An ongoing clinical trial, Shi contributed equally to this work. University, Sheng Chen and LiGen nin the urinary excretion 6-sulfatoxymelatonin (6Center, Durham,Loma NC. Linda, CA, USA sion Assessment theofICU. Of 763 patients included, Assessment Method for ICU was used to determine the days each informed by this Method study, is for investigating if statins are a potential This investigation was as supported, by theduring National Institutes of whose (interquartile range) age patient was assessed being freeinofpart, delirium ICU admission. therapymedian for delirium in the critically ill. was 61 years (51–70 yr) Health (NIH) (AG027472). Dr. Morandi received support from the NIH * Evaluation Qun Wu II was and Acute Physiology and Chronic Health (AG027472). Dr. Hughes received support from the Foundation for Aneswuqun30639@sina.com Measurements and Main Results: Delirium-free days, daily Keywords: delirium; statin; inflammation; C-reactive protein; 25 (19–31), 257 (34%) were prehospital statin users and 197 thesia Education and Research (FAER). Ms. Thompson received supadministration of statins, and serum C-reactive protein (CRP) were (26%) criticalwere care ICU statin users. Overall, delirium developed in 588 port from the NIH (AG027472). Dr. Pandharipande received support from the NIH (HL111111) and the VA Clinical Science Research and 1 patients (77%). After adjusting for covariates, ICU statin use was Department of Neurosurgery, Second Affiliated Hospital, School of Development Service (VA Career Development Award) and he received Zhejiang University, 88 Jiefang Road, associated with reduced delirium (p < 0.01). Medicine, This association honoraria from Hospira and Orion Pharma. Dr. Shintani received supHangzhou 310009, port from the NIH (AG027472). Dr. Vasilevskis received support from was modified by sepsis and study day; for example, statin useZhejiang, China the Veterans Affairs Clinical Research Training Center of Excellence, the 2 Department Physiology and Pharmacology, Loma Linda was associated with reduced delirium among patients with of sepsis Veterans Tennessee Valley Geriatric Research, Education and is independently DeliriumAffairs is a form of acute brain outcomes. Delirium cognitive impairment after critical illness University, but Lomanot Linda, CA, USA on study day 1 (odds ratio, 0.22; 95% CI, 0.10–0.49) Clinical Centerwith (GRECC), and theofNIH Dr. Han with received dysfunction, a prevalence up (AG040157). to 65% associated a threefold increased risk of reduces quality of life, increases healthcare 7 Introduction Delirium is a life-threatening neuropsyc which ultimately leads to disturbance change in cognition, disturbed psychomot normal sleep–wake cycle [1, 2]. It is a m (2.5 times higher costs) with 2.9 times high patients with delirium compared to those Delirium’s pathogenic pathways are uncle there are no effective therapeutic strategies recent systematic review showed that delir greater success than treating delirium onc [5]. Haloperidol and second-generation an most commonly used pharmacological ag effects for delirium prevention [5]. Howev have been shown to cause prolonged QT pyramidal symptoms that increase the risk cular incidents [6]. Moreover, these phar have no effect on the disturbed circadian r Melatonin, a pineal gland hormone s hours of darkness, is regarded as an impor diator regulating the circadian rhythm, s wake cycle [7–9]. Observational studies h layed or low melatonin secretion is associa intensive care unit in elderly patients [10– measured the postoperative plasma conce nin and the urinary excretion of 6-sulfa without costs, sepsisand on leads day 1to(odds ratio, 0.92; 95% Copyright © 2014 by the requiring Society of Critical Care Medicine and Lippincott in critically ill patients mechanical mortality at 6 months,among and forpatients survivors institutionalization (4, 5). CI,of0.46–1.84) with sepsis later, for example, on Williams & Wilkins ventilation in the United Kingdom (1). It is a 10-fold increased risk cognitive or among those Although the pathogenesis of delirium day (2, 13 3). (odds ratio, 0.70;remains 95% CI, 0.35–1.41). Prehospital DOI: 10.1097/CCM.0000000000000398 associated with significantly worse clinical impairment at 12 months Long-term poorly understood, there isstatin Critical Care Medicine Sonuç olarak www.ccmjournal.org 1899 ( Received in original form June 25, 2013; accepted in final form December 30, 2013 ) Supported by grant funding from the Wellcome Trust (090661/Z/09/Z to D.D.); the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (G0700704/84698 to D.D); the BBSRC, EPSRC, ESRC, and MRC; and in part by NIHR CLAHRC for Cambridgeshire and Peterborough (S.N.). Support of the UK Intensive Care Foundation is gratefully acknowledged. • YB hastaları rutin olarak deliryum açısından değerlendirilmeli • CAM-‐‑ICU ve ICDSC kullanılabilecek skorlardır Author Contributions: V.J.P. contributed to the study conception, study design, acquisition of data, and drafting of article. D.D., S.N., and D.F.M. contributed to analysis and interpretation of data and drafting of article. X.B.Z., A.C., and T.B. contributed to acquisition of the data. E.W.E., D.D., and D.F.M. contributed to study conception and study design. S.N., D.D., X.B.Z., A.C., T.B., E.W.E., and D.F.M. critically revised the article and all authors approved the final version to be published. Correspondence and requests for reprints should be addressed to Valerie J. Page, M.B. Ch.B., Intensive Care Unit, Watford General Hospital, Watford WD18 0HB, UK. E-mail: valerie.page@whht.nhs.uk This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org Am J Respir Crit Care Med Vol 189, Iss 6, pp 666–673, Mar 15, 2014 Copyright © 2014 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.201306-1150OC on January 13, 2014 Internet address: www.atsjournals.org • Tanı duyarlılığını arNırmak ve tedaviye cevabı değerlendirmek için 666 American Journal of Respiratory and Critical Care Medicine Volume 189 Number 6 | March 15 2014 tekrarlanmalıdır • Tüm yoğun bakım ekibi deliryumun önlemesi konusunda bilgilendirilmelidir 6 27/04/16 En iyi monitör “uyanık hasta” En iyi sedasyon “hasta ile konuşma” 7