delİryum)deliryum) mental statüdeakut+ değişiklik) dikkatsizlik) statüde dalgalanma)...

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DELİRYUM Perihan Ergin Özcan İstanbul Tıp Fakültesi

Anesteziyoloji AD Yoğun Bakım Bilim Dalı

YB hastası

Sedasyon

Ağrı

Deliryum

Stres Anksiyete

Uyku

Koma Deliryum

Mental statüde akut değişiklik

Dikkatsizlik

Mental statüde dalgalanma

Dezorganize düşünce

Bilinç düzeyinde değişiklik Halüsinasyon

Hayal Saplantı, kuruntu

Nöroinflamasyon Oksidatif stres

Nöroendokrin anomaliler Melatonin disregülasyonu Yaşlanma

NörotransmiNer disregülasyonu Sinyal iletiminde bozulma

Patofizyoloji

deliryum

Hipoksemi, Metabolik düzensizlik

Serebral metabolizmada bozulma

NörotransmiNerlerin sentez ve salınımında

azalma

İlaçlar

NörotransmiNer dengesinde ve sinaptik iletişimde bozulma

Sistemik inflammasyon

Mikrogila aktivasyonu

Beyinde sitokin seviyesinin artması

Hasta özellikleri Yaş Alışkanlıklar Cinsiyet Yanlız yaşama

Kronik patoloji Kardiyak hastalık Pulmoner hastalık Kognitif bozukluk

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

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Ani başlayan mental statüde değişiklik veya dalgalı seyir.

ve

ve

Karışık, düzensiz düşünce

Bilinç düzeyinde değişiklik

veya

Dikkatsizlik

Diagnostic and Statistical Manual (DSM) of Mental Disorders 5

A-‐‑DikkaNe ve farkındalıkta bozulma

B-‐‑ Kısa sürede gelişmesi ve gün içinde dalgalanmalar göstermesi

C-‐‑ Kognitif fonksiyonlarda bozulma

D-‐‑ A ve C’deki durum daha önceki tanımlanmış nörokognitif hastalıkla açıklanmamalı

E-‐‑ Bu bozulmanın başka bir medikal durum, intoksikasyon, yoksunluk gibi durumları fizyolojik sonucu olduğuna dair kanıtların olması

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

Sessler, CN, et al. Am J Respir Crit Care Med 2002;166,1338-44.

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.

Richmond Sedasyon Ajitasyon Skoru RASS

Özellik 1 Akut başlangıç veya dalgalı seyir

(Hastanın cevabı 1A veya 1B ye evet ise sonuç pozi=fdir). Pozi=f Nega=f

1A Hastada ani bilinç değişikliği oldu mu? Evet Hayır 1B Hastanın son 24 saat içinde bilinç düzeyinde dalgalanma oldu mu?

GKS veya Richmond ajitasyon sedasyon skalasında değişlik oldu mu?

Evet Hayır

Özellik 2 Dikkat bozukluğu

Hastanın dikkat ve odaklanmasında güçlük var mı? Hastanın cevabı 2A veya 2B de <8 ise sonuç pozi=fdir.

Pozi=f

Nega=f

2A Harfler ile dikkat değerlendirme muayenesi 2B Resimler ile dikkat değerlendirme muayenesi Özellik 3 Düşünce organizasyonunun bozukluğu Dağınık ve anlaşılmaz düşüncelerin kanıX var mı?

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

( 1. ve 2.özelliğe 3. veya 4. özelliğin eşlik etmesi ) evet hayır

Hasta Degerlendirmesi 1.Gun 2.Gun 3.Gun 4.Gun 5.Gun

Bilinc düzeyindeki değişiklik* (A_E) çalisma süresince A ya da B hasta değerlendirmesine uymuyorsa Dikkatsizlik Dezoryantasyon Halusinasyon, deluzyon, psikoz Psikomotor retardasyon/ ajitasyon Uygunsuz konusma ya da duygudurum Uyku/ uyanıklık sikluslarındaki degişiklik Semptomlarda dalgalanmalar Total skor (0-‐‑8)

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

İCDSC

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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

CAM-‐‑ICU ICDSC RASS > -‐‑2 %31 %29 RASS , -‐‑2,-‐‑3 %22 %22 Tam uyanık %9 %9

Deliryum değerlendirmesi sedasyon seviyesine bağlıdır CAM-‐‑ICU ve ICDSC sadece sedasyon etkilerini de ölçebilir Deliryumu olduğundan fazla gösterebilir

The Role of Continuous Electroencephalography in the ICU

with long-term subjective cognitive problems in ICUpatients, illustrating that the underlying mechanism ofdelirium is relevant for its long-term cognitiveconsequences.This is the first study investigating plasma amyloidb

(Ab) levels and human Tau in critically ill patients in rela-tion to the presence of delirium. In view of the reportedincreased incidence of dementia after ICU/hospital admis-sion [16], our findings could provide a possible mechanis-tic link, because noninflamed delirium is associated withAb, but this must be confirmed in a longitudinal studyfocusing on these biomarkers combined with more-exten-sive cognitive testing. Furthermore, Ab is associated withsustained long-term subjective cognitive dysfunction inICU patients. Studies comparing plasma levels of Ab

between Alzheimer (AD) and non-Alzheimer dementiapatients and controls [17,18,32] have yielded conflictingresults with respect to levels of different forms of Ab.Increased levels of Ab1-42 [17] as well as increased levels ofAb1-40 [18] were found in dementia patients [32]. In addi-tion, increased levels of the Tau/Ab1-42 ratio have beenfound in cerebrospinal fluid (CSF) of patients with cerebralamyloid deposition [33], but this has not yet been investi-gated in plasma. In the present study, the difference inlevels of total Tau and the Tau/Ab1-42 ratio between non-inflamed delirious patients and noninflamed nondeliriouspatients approached statistical significance. It is knownthat plasma levels of Ab are age dependent [34]; however,this could not have confounded our results because no dif-ferences in age existed between delirious and nondelirious

Table 3 Differences between delirium and nondelirium patients in inflamed and noninflamed patientsInflamed (n = 46) Noninflamed patients (n = 54)

Delirium (n = 26) Nondelirium (n = 20) P value Delirium (n = 24) Nondelirium (n = 30) P value

Proinflammatory cytokines

TNF-a (pg/ml) 13 [10-16] 11 [5-18] 0.17 8 [5-13] 7 [5-11] 0.18

IL-1b (pg/ml) 3 [3-6] 4 [3-17] 0.67 3 [3-6] 3 [3-6] 0.69

IL-6 (pg/ml) 73 [38-143] 41 [21-90] 0.09 50 [29-90] 34 [22-64] 0.047a

IL-8 (pg/ml) 31 [24-44] 17 [9-26] < 0.001a 20 [12-32] 14 [9-22] 0.001a

IL-17 (pg/ml) 4 [3-7] 3 [3-6] 0.22 3 [3-4] 3 [3-3] 0.63

IL-18 (pg/ml) 136 [88-187] 84 [65-132] 0.03a 82 [66-141] 88 [72-120] 0.54

MIF (pg/ml) 438 [294-796] 257 [157-576] 0.13 334 [214-561] 249 [179-702] 0.08

Antiinflammatory cytokines

IL-1ra (pg/ml) 48 [27-74] 32 [18-47] 0.04a 24 [17-51] 16 [11-25] 0.02a

IL-10 (pg/ml) 23 [13-47] 13 [5-35] 0.08 28 [12-44] 22 [9-46] 0.03a

Chemotactic cytokines

MCP-1 (pg/ml) 516 [295-822] 251 [199-339] 0.001a 268 [192-398] 233 [175-306] 0.15

Defensin

HNP (μg/ml) 0.06 [0.03-0.13] 0.07 [0.03-0.09] 0.60 0.06 [0.04-0.10] 0.04 [0.03-0.10] 0.51

Markers of inflammation

CRP (mg/ml) 84 [56-190] 84 [43-140] 0.40 42 [29-65] 41 [27-64] 0.44

Procalcitonin (ng/ml) 1.0 [0.23-2.0] 0.28 [0.10-0.64] 0.003a 0.22 [0.11-0.55] 0.12 [0.06-0.18] 0.01a

Stress-response hormone

Cortisol (μmol/L) 0.59 [0.34-0.98] 0.48 [0.18-0.61] 0.06 0.46 [0.23-0.72] 0.30 [0.06-0.66] 0.06

Brain-specific proteins

S100-b (pg/ml) 172 [113-409] 134 [88-163] 0.07 128 [87-210] 136 [92-247] 0.60

Tau (pg/ml) 42 [26-131] 43 [24-75] 0.56 40 [21-78] 27 [17-46] 0.08

Ratio tau/Ab1-42 1.03 [0.62-3.45] 1.12 [0.40-2.21] 0.68 1.17 [0.60-2.52] 0.90 [0.48-1.26] 0.07

Ab1-42 (pg/ml) 41 [31-52] 38 [31-42] 0.36 34 [26-43] 36 [30-42] 0.55

Ab1-40 (pg/ml) 158 [132-229] 155 [137-178] 0.55 148 [109-223] 129 [106-158] 0.08

Ratio Ab1-42/40 0.23 [0.20-0.28] 0.24 [0.22-0.26] 0.72 0.22 [0.19-0.26] 0.26 [0.23-0.33] 0.001a

AbN-42 (pg/ml) 31 [26-43] 29 [24-39] 0.57 28 [20-37] 28 [24-35] 0.79

AbN-40 (pg/ml) 200 [167-283] 184 [147-229] 0.24 225 [168-273] 178 [145-220] 0.04a

Ratio Ab N-42/40 0.16 [0.13-0.18] 0.18 [0.12-0.19] 0.47 0.13 [0.10-0.17] 0.16 [0.14-0.20] 0.02a

Ratio Ab1-42/N-42 1.28 [1.00-1.39] 1.31 [1.18-1.48] 0.26 1.24 [1.04-1.33] 1.23 [1.05-1.39] 0.90

Ratio Ab1-40/N-40 0.82 [0.74-0.89] 0.89 [0.73-0.96] 0.27 0.72 [0.65-0.84] 0.76 [0.70-0.87] 0.35

Data are expressed as median and IQR. Differences were tested with the Mann-Whitney U test.aP value < 0.05.

van den Boogaard et al. Critical Care 2011, 15:R297http://ccforum.com/content/15/6/R297

Page 6 of 9

RESEARCH Open Access

Biomarkers associated with delirium in critically illpatients and their relation with long-termsubjective cognitive dysfunction; indications fordifferent pathways governing delirium ininflamed and noninflamed patientsMark van den Boogaard1*, Matthijs Kox1, Kieran L Quinn2, Theo van Achterberg4, Johannes G van der Hoeven1,3,Lisette Schoonhoven4 and Peter Pickkers1,3

Abstract

Introduction: Delirium occurs frequently in critically ill patients and is associated with disease severity andinfection. Although several pathways for delirium have been described, biomarkers associated with delirium inintensive care unit (ICU) patients is not well studied. We examined plasma biomarkers in delirious and nondeliriouspatients and the role of these biomarkers on long-term cognitive function.

Methods: In an exploratory observational study, we included 100 ICU patients with or without delirium and with("inflamed”) and without ("noninflamed”) infection/systemic inflammatory response syndrome (SIRS). Delirium wasdiagnosed by using the confusion-assessment method-ICU (CAM-ICU). Within 24 hours after the onset of delirium,blood was obtained for biomarker analysis. No differences in patient characteristics were found between deliriousand nondelirious patients. To determine associations between biomarkers and delirium, univariate and multivariatelogistic regression analyses were performed. Eighteen months after ICU discharge, a cognitive-failure questionnairewas distributed to the ICU survivors.

Results: In total, 50 delirious and 50 nondelirious patients were included. We found that IL-8, MCP-1, procalcitonin(PCT), cortisol, and S100-b were significantly associated with delirium in inflamed patients (n = 46). In thenoninflamed group of patients (n = 54), IL-8, IL-1ra, IL-10 ratio Ab1-42/40, and ratio AbN-42/40 were significantlyassociated with delirium. In multivariate regression analysis, IL-8 was independently associated (odds ratio, 9.0; 95%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), andAb1-42/40 (OR, 0.03; 95% CI, 0.002 to 0.50) with delirium in noninflamed patients. Furthermore, levels of severalamyloid-b forms, but not human Tau or S100-b, were significantly correlated with self-reported cognitiveimpairment 18 months after ICU discharge, whereas inflammatory markers were not correlated to impaired long-term cognitive function.

Conclusions: In inflamed patients, the proinflammatory cytokine IL-8 was associated with delirium, whereas innoninflamed patients, antiinflammatory cytokine IL-10 and Ab1-42/40 were associated with delirium. This suggests thatthe underlying mechanism governing the development of delirium in inflamed patients differs from that innoninflamed patients. Finally, elevated levels of amyloid-b correlated with long-term subjective cognitive-impairmentdelirium may represent the first sign of a (subclinical) dementia process. Future studies must confirm these results.The study was registered in the Clinical Trial Register (NCT00604773).

* Correspondence: [email protected] of Intensive Care Medicine, Radboud University NijmegenMedical Centre, P.O. Box 9101, Nijmegen, 6500HB, the NetherlandsFull list of author information is available at the end of the article

van den Boogaard et al. Critical Care 2011, 15:R297http://ccforum.com/content/15/6/R297

© 2012 van den Boogaard et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.

YBKS HKS

Maliyet Morbidite mortalite

DELİRYUM

Uzun dönem kognitif bozukluk

Uzun Süreli Sağlıkla İlgili Yaşam Kalitesi

YB Deliryumu

Hiperaktif Ajitasyon Aceleci Hırçın

Hipoaktif Apati Letarji Azalmış cevap Düz duygulanım

Miks

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Hiperaktif deliryum

Hipoaktif deliryum

Mikst tip

Sepsis hastası

Sedasyon mon RASS

Deliryum/ajitasyon

RASS≥-‐‑3

De Deliryum +

Subsendromal deliryum

Sepsis associated Deliryum (SAD)

Koma

RASS<-‐‑3

Akut Beyin Disfonksiyonu

Gerekirse EEG, SEP, CT, MRI

Nöroinflamasyon Serebral perfüzyon anomalileri NörotransmiGer dengesizliği

Figure 3. Representative example of lateral ventricle size in 46-year-old female and 42-year-oldfemale ICU survivors with no preexisting cognitive impairmentAxial T1-weighted brain images in 2 ICU survivors. Figure 3a depicts relatively normalventricular volume (see arrow) in a 46-year-old female who did not experience delirium inthe ICU. Patient had a history of respiratory and heart failure. She was admitted to a medicalICU due to acute respiratory distress syndrome (ARDS) and was subsequently intubated andmanaged through the ICU without ever developing delirium. Figure 3b depicts enlargedventricles (see arrow) in a 42-year-old female who did develop delirium in the ICU. Patientwas admitted to the hospital after reporting fever and dyspnea with a chest X-ray and otherlaboratory data confirming community acquired pneumonia and ARDS. The patient wasadmitted to the ICU and mechanically ventilated, experiencing 12 days of delirium and thenresolution. There was no preexisting history of neurological impairment, and surrogatequestioning for preexisting cognitive impairment was also negative

Gunther et al. Page 20

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The Association between Brain Volumes, Delirium Duration andCognitive Outcomes in Intensive Care Unit Survivors: AProspective Exploratory Cohort Magnetic Resonance ImagingStudy

Max L. Gunther, PHD1,2,3,4,5, Alessandro Morandi, MD, MPH4,5,6, Erin Krauskopf, BS7,Pratik Pandharipande, MD, MSCI8,9, Timothy D. Girard, MD, MSCI4,5,6,10, James C. Jackson,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,Christopher J. Cannistraci, MS3, Baxter P. Rogers, PHD2,3,16, J. Chris Gatenby, PHD2,3,16,Stephan Heckers, MD, MSC1,2, John C. Gore, PHD2,3,16, Ramona O. Hopkins, PHD7,13,15, E.Wesley Ely, MD, MPH4,5,6,10, and for the VISIONS Investigation (VISualizing Icu SurvivOrsNeuroradiological Sequelae)1Department of Psychiatry, Vanderbilt University Medical Center2Department of Radiological Sciences, Vanderbilt University Medical Center3Vanderbilt University Institute of Imaging Sciences, Nashville, TN4Center for Quality of Aging, Vanderbilt University Medical Center5Center for Health Services Research in the Department of Medicine6Division of Allergy, Pulmonary, Critical Care Medicine, Center for Health Services Research,Department of Medicine, Vanderbilt University School of Medicine7Psychology Department, Brigham Young University, Provo, Utah8Anesthesia Service, Department of Veterans Affairs Medical Center, Tennessee ValleyHealthcare System9Division of Critical Care in the Department of Anesthesiology, Vanderbilt University School ofMedicine, Nashville, TN10Geriatric Research, Education and Clinical Center (GRECC) Service, Department of VeteransAffairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN11Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN12Division of Hepatobiliary Surgery & Liver Transplantation, Vanderbilt University School ofMedicine, Nashville, TN13Department of Medicine, Pulmonary and Critical Care Division, Intermountain Medical Center,Murray Utah

All correspondence and reprint requests should be sent to: E. Wesley Ely, MD, MPH, Professor of Medicine, 6109 Medical CenterEast, Vanderbilt University, Nashville, TN 37232-8300, phone 615-936-3395 and fax 615-936-1269, [email protected] Web:www.icudelirium.org, www.vuiis.vanderbilt.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to ourcustomers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review ofthe resulting proof before it is published in its final citable form. Please note that during the production process errors may bediscovered which could affect the content, and all legal disclaimers that apply to the journal pertain.The authors have not disclosed any potential conflicts of interest

NIH Public AccessAuthor ManuscriptCrit Care Med. Author manuscript; available in PMC 2013 July 01.

Published in final edited form as:Crit Care Med. 2012 July ; 40(7): 2022–2032. doi:10.1097/CCM.0b013e318250acc0.

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The Association between Brain Volumes, Delirium Duration andCognitive Outcomes in Intensive Care Unit Survivors: AProspective Exploratory Cohort Magnetic Resonance ImagingStudy

Max L. Gunther, PHD1,2,3,4,5, Alessandro Morandi, MD, MPH4,5,6, Erin Krauskopf, BS7,Pratik Pandharipande, MD, MSCI8,9, Timothy D. Girard, MD, MSCI4,5,6,10, James C. Jackson,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,Christopher J. Cannistraci, MS3, Baxter P. Rogers, PHD2,3,16, J. Chris Gatenby, PHD2,3,16,Stephan Heckers, MD, MSC1,2, John C. Gore, PHD2,3,16, Ramona O. Hopkins, PHD7,13,15, E.Wesley Ely, MD, MPH4,5,6,10, and for the VISIONS Investigation (VISualizing Icu SurvivOrsNeuroradiological Sequelae)1Department of Psychiatry, Vanderbilt University Medical Center2Department of Radiological Sciences, Vanderbilt University Medical Center3Vanderbilt University Institute of Imaging Sciences, Nashville, TN4Center for Quality of Aging, Vanderbilt University Medical Center5Center for Health Services Research in the Department of Medicine6Division of Allergy, Pulmonary, Critical Care Medicine, Center for Health Services Research,Department of Medicine, Vanderbilt University School of Medicine7Psychology Department, Brigham Young University, Provo, Utah8Anesthesia Service, Department of Veterans Affairs Medical Center, Tennessee ValleyHealthcare System9Division of Critical Care in the Department of Anesthesiology, Vanderbilt University School ofMedicine, Nashville, TN10Geriatric Research, Education and Clinical Center (GRECC) Service, Department of VeteransAffairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN11Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN12Division of Hepatobiliary Surgery & Liver Transplantation, Vanderbilt University School ofMedicine, Nashville, TN13Department of Medicine, Pulmonary and Critical Care Division, Intermountain Medical Center,Murray Utah

All correspondence and reprint requests should be sent to: E. Wesley Ely, MD, MPH, Professor of Medicine, 6109 Medical CenterEast, Vanderbilt University, Nashville, TN 37232-8300, phone 615-936-3395 and fax 615-936-1269, [email protected] Web:www.icudelirium.org, www.vuiis.vanderbilt.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to ourcustomers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review ofthe resulting proof before it is published in its final citable form. Please note that during the production process errors may bediscovered which could affect the content, and all legal disclaimers that apply to the journal pertain.The authors have not disclosed any potential conflicts of interest

NIH Public AccessAuthor ManuscriptCrit Care Med. Author manuscript; available in PMC 2013 July 01.

Published in final edited form as:Crit Care Med. 2012 July ; 40(7): 2022–2032. doi:10.1097/CCM.0b013e318250acc0.

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Copyright © 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

ACO290315; Total nos of Pages: 7;

ACO290315

CURRENTOPINION Patients prone for postoperative delirium:preoperative assessment, perioperative prophylaxis,postoperative treatment

Ulf Guenthera, Linda Riedela, and Finn M. Radtkeb

Purpose of reviewThe aim of this study was to review current literature on identification of patients at risk for postoperativedelirium (POD) and to summarize recent findings on prophylaxis and treatment.

Recent findingsAge and preoperative cognitive impairment are among the most important risk factors of POD. POD is theresult of a complex interplay of predisposing and precipitating factors. Thus, both prophylaxis andtreatment require multicomponent intervention programs. No single medication to prevent or treat POD isavailable. Avoiding too deep anesthesia, avoiding additional psychoactive substances includingbenzodiazepines and intravenous opioids, and effective pain management as well as early mobilizationare essential.

SummaryAn increase of the proportion of elderly patients undergoing surgery will lead to a higher incidence ofPOD. Preoperative assessment should facilitate identification of patients at high risk. Perioperativemanagement should include monitoring depth of anesthesia, preference for nonopioid pain therapy, earlyregular delirium monitoring starting in the recovery room, avoiding ICU-sedation, early mobilization andexercise, and cognitive training.

Keywordscognition, delirium, frailty, mobilization, pain management

INTRODUCTIONPostoperative delirium (POD) is a frequent compli-cation after major surgery and contributes toincreased mortality, prolonged duration of venti-lation, longer length of stay in ICU as well as inhospital [1&], a higher rate of tracheostomy [2], andhigher treatment costs [3]. In elderly patients withhip fracture followed up for as long as 13.6 years,univariate analysis demonstrated a strong associ-ation between POD and survival, but a multivariateanalysis identified only age at the time of surgery,illness severity, and duration of ICU stay aftersurgery as factors contributing to mortality [4]. Asmuch as prophylaxis and treatment of PODdefinitely make sense from a cost and even moreso from an ethical perspective, it is therefore ques-tionable whether it will improve long-term out-come, and POD is just a marker of the fragile patient.

Emergence from anesthesia is often accom-panied by signs of delirium, mostly in its hypoactiveform. Among 400 patients evaluated for delirium

signs during PACU stay, delirium signs were presentin up to 31%, and in 4% at discharge from PACU [5].Of note, positive delirium signs (without full delir-ium diagnosis) were independent predictors forPOD within the next 7 postoperative days [6].POD was also a risk factor for post-traumatic stressdisorder (PTSD) in elderly patients, as has beenconfirmed in a large prospective observational studyin 1707 patients, in which 12% were identified withPTSD 3 months after surgery [7].

aPD Dr med. Ulf Guenther DESA, EDIC, Linda Riedel, Klinik fur Anas-thesiologie & Operative Intensivmedizin, Universitatsklinikum Bonn,Bonn, Germany and bPD Dr med. Finn M. Radtke, Anæstesiafdelingen,Næstved Sygehus, Næstved, Denmark

Correspondence to PD Dr med. Ulf Guenther, DESA, EDIC, Klinik furAnasthesiologie & Operative Intensivmedizin, Universitatsklinikum Bonn,Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Tel:+ 0049 228 28714114; e-mail: [email protected]

Curr Opin Anesthesiol 2016, 29:000–000

DOI:10.1097/ACO.0000000000000327

0952-7907 Copyright ! 2016 Wolters Kluwer Health, Inc. All rights reserved. www.co-anesthesiology.com

REVIEW

Deliryum bulgularının olması postop ilk hafta deliryum için risk faktörü Yaşlı popülasyonda PTSD risk faktörü Ileri yaş ve kognitif disfonksiyon önemli risk faktörleri Erken tanı yani rutin monitörizasyon Önleme ve tedavide

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Table 2. Effect of Duration of Delirium, Duration of Coma, and Exposure to Sedative or Analgesic Agents on Global Cognition and Executive Function.*

Independent Variable Percentile† RBANS Global Cognition Score Trails B Executive-Function Score

25th 75th At 3 Mo At 12 Mo At 3 Mo At 12 Mo

difference (95% CI) P value difference (95% CI) P value difference (95% CI) P value difference (95% CI) P value

Duration of delirium (days) 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 0.9 (−3.8 to 5.6) 0.79

Mean daily dose of sedative or analgesic agent‡

Benzodiazepine (mg) 0 7.88 0.3 (−2.9 to 3.5) 0.20 −0.4 (−3.9 to 3.0) 0.17 −2.9 (−6.9 to 1.0) 0.04 −0.5 (−4.4 to 3.5) 0.19

Propofol (mg) 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

Dexmedetomidine (µg) 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

Opiate (mg) 13.3 1238.8 3.5 (0.1 to 6.9) 0.14 1.7 (−2.1 to 5.4) 0.04 5.2 (1.4 to 9.1) 0.06 4.6 (0.4 to 8.8) 0.09

* 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 (Trails B; with scores ranging from 0 to 100, and lower scores indicating worse executive function), the independent variables were duration of delirium, duration of coma, and mean dose of sedative or analgesic medications (all included simulta-neously in the model), and the covariates were the following potential confounders, which were selected a priori: age, educational level, coexisting conditions, preexisting cognitive 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 of hypoxemia, and an interaction between delirium and 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 vari-able among all 821 patients in the original cohort (with the exception of dexmedetomidine dose; because more than 85% of patients received no dexmedetomidine, we used the mini-mum and maximum doses instead). For example, in a comparison of patients with no delirium and those with 5 days of delirium, with all other covariates held constant, patients with 5 days of delirium had RBANS global cognition scores that were 5.6 points lower at 12 months than did those with no delirium. This represents a decrease of approximately 0.5 SD, which is considered to be a clinically significant decline (see the Supplementary Appendix). A similar comparison of executive-function scores at 3 and 12 months showed a decrease of 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.

‡ We used restricted cubic splines for all continuous variables, which allows for a nonlinear relationship between covariates and outcomes but requires multiple beta coefficients to estimate the effect. The most appropriate P value is one that takes into consideration all these beta coefficients together. Although the P value may indicate significance (and is correct), the compar-ison of the 25th and 75th percentiles may yield a point estimate with a confidence interval that crosses zero, or vice versa.

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n engl j med 369;14 nejm.org october 3, 20131312

P = 0.007, respectively) (Table 2, and Fig. S4 and S5 in the Supplementary Appendix). A longer duration of delirium was also a risk factor for worse function in several individual RBANS do-mains (see the Supplementary Appendix).

We did not observe an independent associa-tion between higher doses of benzodiazepines and worse long-term cognitive scores, except that higher benzodiazepine doses were an indepen-dent risk factor for worse executive-function scores at 3 months (P = 0.04) (Table 2). None of the other medications examined, including propo-fol, dexmedetomidine, and opiates, were con-sistently associated with global cognition or executive-function outcomes.

Sensitivity analyses that included only patients for whom complete outcome data were available yielded similar results (Table S4 in the Supple-mentary Appendix). In addition, adjustments for

an altered level of consciousness and surgical versus medical ICU did not qualitatively change our findings.

DISCUSSION

In this multicenter, prospective cohort study involv-ing a diverse population of patients in general med-ical and surgical ICUs, we found that one out of four patients had cognitive impairment 12 months after critical illness that was similar in severity to that of patients with mild Alzheimer’s disease, and one out of three had impairment typically associated with moderate traumatic brain injury. Impairments affected a broader array of neuro-psychological domains than is characteristically seen in Alzheimer’s disease, but the impairments were very similar to those observed after moder-ate traumatic brain injury. A validated instrument that assessed baseline cognitive status showed that only 6% of patients had evidence of mild-to-moderate cognitive impairment before ICU ad-mission, indicating that these profound cognitive deficits were new in the majority of patients. Long-term cognitive impairment affected both old and young patients, regardless of the burden of coexisting conditions at baseline.

A longer duration of delirium was associated with worse long-term global cognition and ex-ecutive function, an association that was inde-pendent of sedative or analgesic medication use, age, preexisting cognitive impairment, the burden of coexisting conditions, and ongoing organ fail-ures during ICU care. Although the mechanisms by which delirium may predispose patients to long-term cognitive impairment after critical ill-ness have not yet been elucidated, delirium is as-sociated with inflammation and neuronal apopto-sis, which may lead to brain atrophy.32,33 Delirium has previously been associated with cerebral at-rophy34 and reduced white-matter integrity35; both atrophy and white-matter disruption are associ-ated with cognitive impairment.34,35 It is also possible that patients who are vulnerable to de-lirium owing to severe critical illness are also vulnerable to long-term cognitive impairment and that delirium does not play a causal role in the development of persistent cognitive impairment.

After adjustment for delirium, we did not find any consistent associations between the use of sedative or analgesic medications and long-term cognitive impairment. The significant association

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Figure 1. Global Cognition Scores in Survivors of Critical Illness.

The box-and-whisker plots show the age-adjusted global cognition scores on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS; with a population age-adjusted mean [±SD] of 100±15, and lower scores indicating worse global cognition) at 3 months (light-gray boxes) and 12 months (dark-gray boxes), according to age. For each box-and-whisker plot, the horizontal bar indicates the median, the upper and lower limits of the boxes the interquartile range, and the ends of the whiskers 1.5 times the interquartile range. Outliers are shown as black dots. The green dashed line indicates the age-adjusted population mean (100) for healthy adults, and the green band indicates the standard deviation (15). Also shown are the expected population means for mild cognitive impairment (MCI), moderate traumatic brain injury (TBI), and mild Alzheimer’s disease on the basis of other cohort studies. Expected population means for MCI and Alzheimer’s disease are shown only for patients 65 years of age or older, since RBANS population norms for these disorders have been generated only in that age group.

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original article



Long-Term Cognitive Impairment after Critical Illness

P.P. Pandharipande, T.D. Girard, J.C. Jackson, A. Morandi, J.L. Thompson, 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*

The authors’ full names, degrees, and affili-ations are listed in the Appendix. Address reprint requests to Dr. Pandharipande at 1211 21st Ave. S, MAB Ste. 526, Nashville, TN 37212, or at [email protected].

*The Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunc-tion in ICU Survivors (BRAIN-ICU) Study Investigators are listed in the Supplemen-tary Appendix, available at NEJM.org.

N Engl J Med 2013;369:1306-16.DOI: 10.1056/NEJMoa1301372Copyright © 2013 Massachusetts Medical Society.

A BS TR AC T

BACKGROUNDSurvivors of critical illness often have a prolonged and disabling form of cognitive impairment that remains inadequately characterized.

METHODSWe 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 du-ration 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.

RESULTSOf the 821 patients enrolled, 6% had cognitive impairment at baseline, and deliri-um developed in 74% during the hospital stay. At 3 months, 40% of the patients had global cognition scores that were 1.5 SD below the population means (similar to scores for patients with moderate traumatic brain injury), and 26% had scores 2 SD below the population means (similar to scores for patients with mild Alzheimer’s disease). Deficits occurred in both older and younger patients and persisted, with 34% and 24% of all patients with assessments at 12 months that were similar to scores for patients with moderate traumatic brain injury and scores for patients with mild Alzheimer’s disease, respectively. A longer duration of delirium was in-dependently associated with worse global cognition at 3 and 12 months (P = 0.001 and P = 0.04, respectively) and worse executive function at 3 and 12 months (P = 0.004 and P = 0.007, respectively). Use of sedative or analgesic medications was not con-sistently associated with cognitive impairment at 3 and 12 months.

CONCLUSIONSPatients in medical and surgical ICUs are at high risk for long-term cognitive impair-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.)



original article



Long-Term Cognitive Impairment after Critical Illness

P.P. Pandharipande, T.D. Girard, J.C. Jackson, A. Morandi, J.L. Thompson, 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*

The authors’ full names, degrees, and affili-ations are listed in the Appendix. Address reprint requests to Dr. Pandharipande at 1211 21st Ave. S, MAB Ste. 526, Nashville, TN 37212, or at [email protected].

*The Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunc-tion in ICU Survivors (BRAIN-ICU) Study Investigators are listed in the Supplemen-tary Appendix, available at NEJM.org.

N Engl J Med 2013;369:1306-16.DOI: 10.1056/NEJMoa1301372Copyright © 2013 Massachusetts Medical Society.

A BS TR AC T

BACKGROUNDSurvivors of critical illness often have a prolonged and disabling form of cognitive impairment that remains inadequately characterized.

METHODSWe 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 du-ration 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.

RESULTSOf the 821 patients enrolled, 6% had cognitive impairment at baseline, and deliri-um developed in 74% during the hospital stay. At 3 months, 40% of the patients had global cognition scores that were 1.5 SD below the population means (similar to scores for patients with moderate traumatic brain injury), and 26% had scores 2 SD below the population means (similar to scores for patients with mild Alzheimer’s disease). Deficits occurred in both older and younger patients and persisted, with 34% and 24% of all patients with assessments at 12 months that were similar to scores for patients with moderate traumatic brain injury and scores for patients with mild Alzheimer’s disease, respectively. A longer duration of delirium was in-dependently associated with worse global cognition at 3 and 12 months (P = 0.001 and P = 0.04, respectively) and worse executive function at 3 and 12 months (P = 0.004 and P = 0.007, respectively). Use of sedative or analgesic medications was not con-sistently associated with cognitive impairment at 3 and 12 months.

CONCLUSIONSPatients in medical and surgical ICUs are at high risk for long-term cognitive impair-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.)



27/04/16

5


Long-term outcome of delirium during intensivecare unit stay in survivors of critical illness: aprospective cohort studyAnnemiek E Wolters*, Diederik van Dijk, Wietze Pasma, Olaf L Cremer, Marjolein F Looije, Dylan W de Lange,Dieuwke S Veldhuijzen and Arjen JC Slooter

Abstract

Introduction: Delirium is associated with impaired outcome, but it is unclear whether this relationship is limited toin-hospital outcomes and whether this relationship is independent of the severity of underlying conditions. The aimof this study was to investigate the association between delirium in the intensive care unit (ICU) and long-termmortality, self-reported health-related quality of life (HRQoL), and self-reported problems with cognitive functioningin survivors of critical illness, taking severity of illness at baseline and throughout ICU stay into account.

Methods: A prospective cohort study was conducted. We included patients who survived an ICU stay of at least aday; exclusions were neurocritical care patients and patients who sustained deep sedation during the entire ICUstay. Delirium was assessed twice daily with the Confusion Assessment Method for the ICU (CAM-ICU) andadditionally, patients who received haloperidol were considered delirious. Twelve months after ICU admission, data onmortality were obtained and HRQoL and cognitive functioning were measured with the European Quality of Life – Sixdimensions self-classifier (EQ-6D). Regression analyses were used to assess the associations between delirium and theoutcome measures adjusted for gender, type of admission, the Acute Physiology And Chronic Health Evaluation IV(APACHE IV) score, and the cumulative Sequential Organ Failure Assessment (SOFA) score throughout ICU stay.

Results: Of 1101 survivors of critical illness, 412 persons (37%) had been delirious during ICU stay, and 198 (18%) diedwithin twelve months. When correcting for confounders, no significant association between delirium and long-termmortality was found (hazard ratio: 1.26; 95% confidence interval (CI) 0.93 to 1.71). In multivariable analysis, delirium wasnot associated with HRQoL either (regression coefficient: −0.04; 95% CI −0.10 to 0.01). Yet, delirium remained associatedwith mild and severe problems with cognitive functioning in multivariable analysis (odds ratios: 2.41; 95% CI 1.57 to3.69 and 3.10; 95% CI 1.10 to 8.74, respectively).

Conclusions: In this group of survivors of critical illness, delirium during ICU stay was not associated with long-termmortality or HRQoL after adjusting for confounding, including severity of illness throughout ICU stay. In contrast,delirium appears to be an independent risk factor for long-term self-reported problems with cognitive functioning.

IntroductionBecause of improved medical care, the number of inten-sive care unit (ICU) survivors has increased consider-ably, but recent studies demonstrate that ICU survivorscan experience substantial long-term morbidity [1-5]. Tofurther improve care for survivors of critical illness, it isimportant to elucidate which factors increase the risk of

long-term morbidity and mortality. Delirium, character-ized by an acute change in attention and cognition, is acommon disorder in ICU patients [6-8]. Previous studieshave consistently found that delirium in the ICU is asso-ciated with long-term mortality and cognitive impair-ment [9-14]. It is, however, unclear whether deliriumalso affects long-term health related quality of life(HRQoL). HRQoL is defined as health, in the medicaldefinition, but also as the importance of independentphysical, social and emotional functioning [15]. Twostudies suggest that delirium is a risk factor for lower

* Correspondence: [email protected] of Intensive Care Medicine, University Medical Center Utrecht,Heidelberglaan 100, 3508 GA Utrecht, The Netherlands

© 2014 Wolters et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.

Wolters et al. Critical Care 2014, 18:R125http://ccforum.com/content/18/3/R125


Long-term outcome of delirium during intensivecare unit stay in survivors of critical illness: aprospective cohort studyAnnemiek E Wolters*, Diederik van Dijk, Wietze Pasma, Olaf L Cremer, Marjolein F Looije, Dylan W de Lange,Dieuwke S Veldhuijzen and Arjen JC Slooter

Abstract

Introduction: Delirium is associated with impaired outcome, but it is unclear whether this relationship is limited toin-hospital outcomes and whether this relationship is independent of the severity of underlying conditions. The aimof this study was to investigate the association between delirium in the intensive care unit (ICU) and long-termmortality, self-reported health-related quality of life (HRQoL), and self-reported problems with cognitive functioningin survivors of critical illness, taking severity of illness at baseline and throughout ICU stay into account.

Methods: A prospective cohort study was conducted. We included patients who survived an ICU stay of at least aday; exclusions were neurocritical care patients and patients who sustained deep sedation during the entire ICUstay. Delirium was assessed twice daily with the Confusion Assessment Method for the ICU (CAM-ICU) andadditionally, patients who received haloperidol were considered delirious. Twelve months after ICU admission, data onmortality were obtained and HRQoL and cognitive functioning were measured with the European Quality of Life – Sixdimensions self-classifier (EQ-6D). Regression analyses were used to assess the associations between delirium and theoutcome measures adjusted for gender, type of admission, the Acute Physiology And Chronic Health Evaluation IV(APACHE IV) score, and the cumulative Sequential Organ Failure Assessment (SOFA) score throughout ICU stay.

Results: Of 1101 survivors of critical illness, 412 persons (37%) had been delirious during ICU stay, and 198 (18%) diedwithin twelve months. When correcting for confounders, no significant association between delirium and long-termmortality was found (hazard ratio: 1.26; 95% confidence interval (CI) 0.93 to 1.71). In multivariable analysis, delirium wasnot associated with HRQoL either (regression coefficient: −0.04; 95% CI −0.10 to 0.01). Yet, delirium remained associatedwith mild and severe problems with cognitive functioning in multivariable analysis (odds ratios: 2.41; 95% CI 1.57 to3.69 and 3.10; 95% CI 1.10 to 8.74, respectively).

Conclusions: In this group of survivors of critical illness, delirium during ICU stay was not associated with long-termmortality or HRQoL after adjusting for confounding, including severity of illness throughout ICU stay. In contrast,delirium appears to be an independent risk factor for long-term self-reported problems with cognitive functioning.

IntroductionBecause of improved medical care, the number of inten-sive care unit (ICU) survivors has increased consider-ably, but recent studies demonstrate that ICU survivorscan experience substantial long-term morbidity [1-5]. Tofurther improve care for survivors of critical illness, it isimportant to elucidate which factors increase the risk of

long-term morbidity and mortality. Delirium, character-ized by an acute change in attention and cognition, is acommon disorder in ICU patients [6-8]. Previous studieshave consistently found that delirium in the ICU is asso-ciated with long-term mortality and cognitive impair-ment [9-14]. It is, however, unclear whether deliriumalso affects long-term health related quality of life(HRQoL). HRQoL is defined as health, in the medicaldefinition, but also as the importance of independentphysical, social and emotional functioning [15]. Twostudies suggest that delirium is a risk factor for lower

* Correspondence: [email protected] of Intensive Care Medicine, University Medical Center Utrecht,Heidelberglaan 100, 3508 GA Utrecht, The Netherlands

© 2014 Wolters et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.

Wolters et al. Critical Care 2014, 18:R125http://ccforum.com/content/18/3/R125

data did not differ from the study population with regardto delirium frequency, age, gender, APACHE IV or typeof admission. The length of stay of the study populationwas longer than that of the subjects excluded due tomissing data (median 4.0, IQR 3.0 to 7.0, P = 0.01).Persons who were delirious during their ICU stay dif-

fered from subjects who did not have delirium duringtheir ICU stay in gender, severity of illness scores, ICUlength of stay and type of admission (Table 1). One yearafter ICU admission, 903 of the 1,101 subjects (82%)were known to have survived. Because of an administra-tive error, 16 individuals who appeared still alive did notreceive a questionnaire, and, therefore, 887 surveys weresent. The response rate was 64% (571/887). After ICUadmission, the median time until the surveys were sentback was 420 days after discharge (IQR 402 to 444 days).In total, 198 patients died during follow-up, with a

median duration of 62 days after ICU admission (IQR 25to 181 days). Univariate survival analysis showed thatdelirious patients had a significantly increased risk ofdeath in the year following ICU admission. However,when adjustments were made for the confounders de-scribed above, delirium was no longer independently as-sociated with mortality (Table 2).In univariate analysis, patients with delirium during

their ICU stay had a significantly lower HRQoL score at

follow-up than patients who did not have delirium. Afteradjustment for confounders, again the difference betweenthe two groups was no longer statistically significant(Table 3). The assumption of homoscedasticity was veri-fied by plotting the residuals against the fitted values.Compared to the general Dutch population, both pa-tient groups scored lower on the EQ-5DTM. Personswithout delirium in the ICU scored 0.85 (IQR 0.72 to1.00) and subjects with ICU delirium scored 0.75 (IQR0.69 to 1.00). In comparison, the estimated averageEQ-5DTM index for the general Dutch population is0.87 (IQR 0.82 to 1.00) [24].Persons who had been delirious during their ICU stay

experienced significantly more mild and more severeself-reported problems in cognitive functioning com-pared to subjects who did not have delirium in the ICU.The strength of this association did not weaken andremained statistically significant when adjustments weremade for confounding variables (Table 4).To verify whether the effect measure for mortality was

robust when using the cumulative SOFA, we conductedsensitivity analyse where we made Cox proportional haz-ard models with the mean SOFA and the maximal SOFAscores. Furthermore, we evaluated the effect of addinglength of stay to these models. Other variables were leftunchanged. The HRs for death in these models remained

Table 1 ICU characteristics of the study populationVariables All patients (n = 1,101) No delirium (n = 689) Delirium (n = 412) P-value

Age (mean years, SD) 59.8 (16.5) 59.4 (16.6) 60.5 (16.7) 0.29

Male (number, %) 677 (61.5) 406 (58.9) 271 (65.8) 0.03

APACHE IV score (mean, SD) 61.3 (29.2) 53.9 (22.4) 73.7 (28.3) <0.001

CumSOFA score (median, IQR) 40.0 (19.0 to 99.0) 27.0 (13.0 to 50.5) 99.0 (47.0 to 207.0) <0.001

ICU length of stay (median days, IQR) 4.0 (3.0 to 8.0) 3.0 (2.0 to 5.0) 8.0 (5.0 to 15.0) <0.001

Type of admission

Medical (number, %) 430 (39.1) 208 (30.2) 222 (53.9) <0.001

Elective surgical (number, %) 447 (40.6) 351 (50.9) 96 (23.3)

Acute surgical (number, %) 224 (20.3) 130 (18.9) 94 (22.8)

APACHE IV: Acute Physiology and Chronic Health Evaluation IV; CumSOFA: cumulative Sequential Organ Failure Assessment without the central nervous systemcomponent; IQR: interquartile range; SD: standard deviation.

Table 2 Risk of death associated with delirium insurvivors of critical illness, within one year after ICUadmissionModel Hazard ratio,

95% CIP-value

Crude 1.91 (1.44 to 2.52) <0.001

Adjusted for gender, APACHE IV, typeof admission and CumSOFA

1.26 (0.93 to 1.71) 0.14

198 patients died within one year. Delirious: n = 102, not delirious: n = 96.APACHE IV: Acute Physiology and Chronic Health Evaluation IV; CI: confidenceinterval; CumSOFA: cumulative Sequential Organ Failure Assessment withoutcentral nervous system component; ICU: intensive care unit.

Table 3 Differences in health-related quality of life betweendelirious and non-delirious ICU survivors, within one yearafter ICU admissionModel Difference, 95% CI P-value

Crude −0.06 (−0.10 to −0.01) 0.01


−0.04 (−0.10 to 0.01) 0.09

Data on health-related quality of life was available for 546 patients. Delirious:n = 182, not delirious: n = 364. APACHE IV: Acute Physiology and ChronicHealth Evaluation IV; CI: confidence interval; CumSOFA: cumulative SequentialOrgan Failure Assessment without central nervous system component; ICU:intensive care unit.

Wolters et al. Critical Care 2014, 18:R125 Page 4 of 7http://ccforum.com/content/18/3/R125









Age (mean years, SD) 59.8 (16.5) 59.4 (16.6) 60.5 (16.7) 0.29

Male (number, %) 677 (61.5) 406 (58.9) 271 (65.8) 0.03




Type of admission

Medical (number, %) 430 (39.1) 208 (30.2) 222 (53.9) <0.001





95% CIP-value

Crude 1.91 (1.44 to 2.52) <0.001


1.26 (0.93 to 1.71) 0.14



Crude −0.06 (−0.10 to −0.01) 0.01


−0.04 (−0.10 to 0.01) 0.09











Age (mean years, SD) 59.8 (16.5) 59.4 (16.6) 60.5 (16.7) 0.29

Male (number, %) 677 (61.5) 406 (58.9) 271 (65.8) 0.03




Type of admission

Medical (number, %) 430 (39.1) 208 (30.2) 222 (53.9) <0.001





95% CIP-value

Crude 1.91 (1.44 to 2.52) <0.001


1.26 (0.93 to 1.71) 0.14



Crude −0.06 (−0.10 to −0.01) 0.01


−0.04 (−0.10 to 0.01) 0.09



similar, which shows that our effect measure is robust,and length of stay is not a mediator in the causal path-way between delirium and mortality.

DiscussionWe studied the association between delirium in the ICUand long-term mortality, HRQoL, and problems with cog-nitive functioning in survivors of critical illness. We foundthat delirium was not associated with mortality andHRQoL when adjustments were made for confounding.By contrast, subjects who had delirium during their ICUstay experienced more problems with cognitive function-ing at follow-up than persons who did not have deliriumin the ICU. The latter finding remained statistically signifi-cant when we adjusted for confounders, including esti-mates of severity of illness throughout the course of theICU stay.To the best of our knowledge, our study is the first to

adjust for severity of illness throughout the course of theICU stay, in analyzing the association between deliriumwith long-term mortality and HRQoL. Previous studieson these issues adjusted for severity of illness at baselineonly [11-14,16]. Next to correction for severity of illness,differences with previous studies could be the result ofdifferences in case mix, as we included ICU survivorsonly. Nevertheless, our study findings emphasize thatthe burden of illness during ICU stay should be takeninto account. For example, a patient after elective sur-gery may have a low predicted mortality. However, whensuch a patient develops septic shock during their ICUstay, the risk of mortality may change but this is not in-corporated in the APACHE IV score. Therefore, severityof illness at admission should not be considered the solepredictor of long-term outcome. To adjust for severityof illness throughout the course of the ICU stay, we usedthe cumulative SOFA score, which is dependent on boththe duration and the extent of multi-organ failure, andwhich is strongly associated with long-term mortality[18]. We conducted sensitivity analyse with the meanSOFA and maximal SOFA, which showed that our effectmeasure was robust.The association that we found between delirium in the

ICU and long-term problems with cognitive functioning

is consistent with a recent study, in which adjustmentsfor severity of illness throughout the course of the ICUstay were made in a similar manner [10]. Factors thatprecipitate delirium may thus provoke events that con-tribute to the development or acceleration of cognitiveimpairment, even when delirium is no longer present. Itwould be interesting to see whether this holds only forpersistent delirium or also for rapidly reversible, sedation-related delirium [25]. Unfortunately, we were not able todistinguish between these types of delirium.The evidence of no association between delirium and

long-term mortality and HRQoL should not be used asan excuse to neglect delirium in the ICU. With ourstudy we show again that delirium is associated withprolonged cognitive problems [9-11]. Interventions aimedat reducing delirium incidence may eventually lead tolong-term beneficial effects on cognitive outcome.It is remarkable that the self-reported cognitive prob-

lems do not seem to have an impact on patients’ self-reported quality of life in this population. An associationbetween more cognitive problems and a lower HRQoLwould be expected. It might be due to a rather limitedHRQoL survey. However, our findings are consistentwith previous studies in which more extensive tools wereused to assess HRQoL and cognitive functioning, namelythe ShortForm 36 and the Cognitive Failure Question-naire [11]. Perhaps the expectation to find a lower HRQoLin subjects with more cognitive problems is not alwaysapplicable.No a priori sample size calculation was performed.

However, this is one of the largest studies so far to ad-dress this problem. We believe that our study populationwas large enough to study this issue. Nevertheless, ourstudy has several limitations. Due to missing data a rela-tively large group had to be excluded, which may haveintroduced bias. Excluded subjects had a shorter lengthof ICU stay than the study population and did not differin other measured characteristics. Therefore, if selectionbias would have occurred, we have analyzed a more se-vere group of subjects. Secondly, the sensitivity of theCAM-ICU in daily practice may be low [7]. Yet, in con-trast to studies where sensitivity of the CAM-ICU wasstudied at one point in time, we used all CAM-ICU

Table 4 Risk of problems with cognitive functioning associated with delirium in survivors of critical illness, within oneyear after ICU admissionModel OR for mild problems with

cognitive functioning, 95% CIP-value OR for severe problems with

cognitive functioning, 95% CIP-value

Crude 2.02 (1.39 to 2.94) <0.001 2.93 (1.16 to 7.42) 0.02

Adjusted for gender, APACHE IV,type of admission, and CumSOFA

2.41 (1.57 to 3.69) <0.001 3.10 (1.10 to 8.74) 0.03

Data on cognitive functioning were available for 561 patients. The delirium group (n = 188) was divided into: No problems (n = 99), mild problems (n = 79) andsevere problems (n = 10). For the group without delirium (n = 373): no problems (n = 261), mild problems (n = 103) and severe problems (n = 9). APACHE IV: AcutePhysiology and Chronic Health Evaluation IV; CI: confidence interval; CumSOFA: cumulative Sequential Organ Failure Assessment without central nervous systemcomponent; ICU: intensive care unit; OR: odds ratio.

Wolters et al. Critical Care 2014, 18:R125 of 7http://ccforum.com/content/18/3/R125

Deliryumda profilaksi

Nonfarmakolojik yöntemler

Farmakolojik yöntemler X

✔

Konuşma engelleri

Çevresel düzenleme

Gürültü Işık Uyku/uyanıklık Duyusal uyarı Reoryantasyon Aile varlığı

Yoğun bakım

İşitme Görme Dil Kültürel

Girişimleri azalt Erken fizyoterapi Hidrasyon Metabolik denge Hastanın katılımı

Uyandırma ve spontan soluma çalışmaları

Sedatif ve analjezik seçimi

Günlük deliryum monitörizasyonu

Erken mobilizasyon

Ventilatörden ayrılma YB ve hastaneden çıkış Normal beyin fonksiyonlarına dönüş Bağımsız fonksiyonel kapasite Sağkalım

aaaA Aile anlaşması

“ABCDE bundle”

F

q Tipik antipsikotikler Haloperidol

q Atipik antipsikotikler Olanzepine, risperidone, quetiapine

q Sedasyon modifikasyonu; Dexmetedomidine Magnesium

Farmakolojik tedavi

27/04/16

6

CARING FOR THECRITICALLY ILL PATIENT

Dexmedetomidine vs Midazolamfor Sedation of Critically Ill PatientsA Randomized TrialRichard R. Riker, MDYahya Shehabi, MDPaula M. Bokesch, MDDaniel Ceraso, MDWayne Wisemandle, MAFiras Koura, MDPatrick Whitten, MDBenjamin D. Margolis, MDDaniel W. Byrne, MSE. Wesley Ely, MD, MPHMarcelo G. Rocha, MDfor the SEDCOM (Safety and Efficacyof Dexmedetomidine Compared WithMidazolam) Study Group

PROVIDING SEDATION FOR PA-tient comfort is an integralcomponent of bedside care fornearly every patient in the in-

tensive care unit (ICU). For decades,!-aminobutyric acid (GABA) receptoragonists (including propofol and ben-zodiazepines such as midazolam) havebeen the most commonly adminis-tered sedative drugs for ICU patientsworldwide.1-5 Practice guidelines forproviding sedation in the ICU haveidentified the need for well-designedrandomized trials comparing the effec-tiveness of different sedative agents forimportant clinical outcomes.1 Despitethe well-known hazards associated withprolonged use of GABA agonists,6-12 fewinvestigations of ICU sedation havecompared these agents to other drugclasses.12-14 Instead, the recent focus in

For editorial comment see p 542.

Author Affiliations and Members of the SEDCOMStudy Group are listed at the end of this article.Corresponding Author: Richard R. Riker, MD, Neu-roscience Institute, Maine Medical Center, 22 Bramhall

St, Portland, ME 04102 ([email protected]).Caring for the Critically Ill Patient Section Editor: DerekC. Angus, MD, MPH, Contributing Editor, JAMA([email protected]).

Context !-Aminobutyric acid receptor agonist medications are the most commonlyused sedatives for intensive care unit (ICU) patients, yet preliminary evidence indi-cates that the "2 agonist dexmedetomidine may have distinct advantages.

Objective To compare the efficacy and safety of prolonged sedation with dexme-detomidine vs midazolam for mechanically ventilated patients.

Design, Setting, and Patients Prospective, double-blind, randomized trial con-ducted in 68 centers in 5 countries between March 2005 and August 2007 among375 medical/surgical ICU patients with expected mechanical ventilation for more than24 hours. Sedation level and delirium were assessed using the Richmond Agitation-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(0.02-0.1 mg/kg per hour [n=122]) titrated to achieve light sedation (RASS scoresbetween −2 and #1) from enrollment until extubation or 30 days.

Main Outcome Measures Percentage of time within target RASS range. Second-ary end points included prevalence and duration of delirium, use of fentanyl and open-label midazolam, and nursing assessments. Additional outcomes included duration ofmechanical ventilation, ICU length of stay, and adverse events.

Results There was no difference in percentage of time within the target RASSrange (77.3% for dexmedetomidine group vs 75.1% for midazolam group; differ-ence, 2.2% [95% confidence interval {CI}, −3.2% to 7.5%]; P=.18). The preva-lence of delirium during treatment was 54% (n=132/244) in dexmedetomidine-treated patients vs 76.6% (n=93/122) in midazolam-treated patients (difference,22.6% [95% CI, 14% to 33%]; P$ .001). Median time to extubation was 1.9 daysshorter in dexmedetomidine-treated patients (3.7 days [95% CI, 3.1 to 4.0] vs 5.6days [95% CI, 4.6 to 5.9]; P=.01), and ICU length of stay was similar (5.9 days[95% CI, 5.7 to 7.0] vs 7.6 days [95% CI, 6.7 to 8.6]; P=.24). Dexmedetomidine-treated patients were more likely to develop bradycardia (42.2% [103/244] vs18.9% [23/122]; P$ .001), with a nonsignificant increase in the proportion requir-ing treatment (4.9% [12/244] vs 0.8% [1/122]; P=.07), but had a lower likelihoodof tachycardia (25.4% [62/244] vs 44.3% [54/122]; P$ .001) or hypertensionrequiring treatment (18.9% [46/244] vs 29.5% [36/122]; P=.02).

Conclusions There was no difference between dexmedetomidine and midazolamin time at targeted sedation level in mechanically ventilated ICU patients. At compa-rable sedation levels, dexmedetomidine-treated patients spent less time on the ven-tilator, experienced less delirium, and developed less tachycardia and hypertension.The most notable adverse effect of dexmedetomidine was bradycardia.

Trial Registration clinicaltrials.gov Identifier: NCT00216190JAMA. 2009;301(5):489-499 www.jama.com

©2009 American Medical Association. All rights reserved. (Reprinted) JAMA, February 4, 2009—Vol 301, No. 5 489

at Istanbul Ãœniversitesi on March 28, 2011jama.ama-assn.orgDownloaded from



































14.8% (18/122) of midazolam-treatedpatients during the double-blind treat-ment period.

The composite nursing assessmentscore for patient communication, co-

operation, and tolerance of the venti-lator was higher for dexmedetomidine-treated patients (21.2 [SD, 7.4] vs 19.0[SD, 6.9]; P=.001), as were the indi-vidual scores for communication effec-

tiveness (6.6 [SD, 3.0] vs 5.5 [SD, 3.1];P! .001) and cooperation (7.0 [SD, 2.9]vs 6.1 [SD, 3.0]; P=.002), while themean tolerance of ventilator score wasnot significantly different (7.6 [SD, 2.2]vs 7.4 [SD, 1.8]; P=.09).

Ventilator Time and ICU Length ofStay. More patients treated with dexme-detomidine had study drug stopped be-cause the patient was extubated (59%[144/244] vs 45% [55/122]; P=.01).The Kaplan-Meier estimated mediantime to extubation was 1.9 days shorterfor dexmedetomidine-treated patients(3.7 days [95% CI, 3.1 to 4.0] vs 5.6days [95% CI, 4.6 to 5.9]; P=.01 bylog-rank) (Table 2, FIGURE 3). TheKaplan-Meier estimated median lengthof ICU stay was similar (5.9 days [95%CI, 5.7 to 7.0] vs 7.6 days [95% CI, 6.7to 8.6]; P=.24 by log-rank) (Table 2,Figure 3).

Long-term Use and Subpopulations.Results for the intent-to-treat popula-tion with assigned values (all 375 ran-domized patients) were similar to thosefrom the primary analysis for time intarget range (75.4% for dexmedetomi-dine-treated patients vs 73.3% formidazolam-treated patients), reduc-tion of delirium in dexmedetomidine-treated patients (24.9% reduction com-pared with midazolam), time toextubation (3.8 days [95% CI, 3.5 to 4.0]vs 5.7 days [95% CI, 4.6 to 6.0]), andICU length of stay (5.9 days [95% CI,5.7 to 7.1] vs 7.7 [95% CI, 6.7 to 10.1]).

For the “long-term use” population(receiving study drug "24 hours), thepercentage of time within the targetRASS range was similar (80.8% fordexmedetomidine and 81% for mid-azolam; mean difference, −0.2% [95%CI, −5.0 to 4.7%]; P=.54), while thedexmedetomidine group experiencedless delirium (treatment effect by GEEshowed a 24% reduction; 95% CI,14%to 34%; P! .001), a shorter time to ex-tubation (3.9 days [95% CI, 3.8 to 4.8]vs 5.8 days [95% CI, 4.7 to 6.2]; P=.03),and a similar ICU length of stay (6.4days [95% CI, 5.8 to 7.5] vs 8.0 days[95% CI, 6.7 to 10.1; P=.46).

When data from low-enrolling cen-ters (!5 patients) were excluded, 298

Table 2. Efficacy Outcomes in Patients Treated With Dexmedetomidine vs Midazolam

Outcome

No. (%)

PValue

Dexmedetomidine(n = 244)

Midazolam(n = 122)

Time in target sedation range(RASS score −2 to #1), mean, %a

77.3 75.1 .18

Patients completing all daily arousalassessments

225 (92) 103 (84.3) .09

Patients requiring study druginterruption to maintain RASS score−2 to #1

222 (91) 112 (91.8) .85

Duration of study drug treatment,median (IQR), d

3.5 (2.0-5.2) 4.1 (2.8-6.1) .01

Time to extubation, median (95% CI), db 3.7 (3.1-4.0) 5.6 (4.6-5.9) .01ICU length of stay, median (95% CI), db 5.9 (5.7-7.0) 7.6 (6.7-8.6) .24Delirium

Prevalence 132 (54) 93 (76.6) !.001Mean delirium-free daysc 2.5 1.7 .002

Open-label midazolam useNo. treated 153 (63) 60 (49) .02Dose, median (IQR), mg/kgd 0.09 (0.03-0.23) 0.11 (0.03-0.28) .65

Fentanyl useNo. treated 180 (73.8) 97 (79.5) .25Dose, median (IQR), µg/kgd 6.4 (1.8-26.3) 9.6 (2.9-28.6) .27

Abbreviations: CI, confidence interval; ICU, intensive care unit; IQR, interquartile range; RASS, Richmond Agitation andSedation Scale.23

aThe mean difference in percentage of time within target sedation range between the dexmedetomidine and mid-azolam treatment groups was calculated using the Mann-Whitney test.

bCalculated using Kaplan-Meier survival analysis, with differences between treatment groups assessed by the log-rank test. Log-rank P values were adjusted for multiple comparisons using the Bonferroni method.

cNumber of days alive without delirium during study drug treatment.dCalculated as the total dose during study treatment divided by body mass.

Figure 2. Daily Prevalence of Delirium Among Intubated Intensive Care Unit Patients TreatedWith Dexmedetomidine vs Midazolam

DexmedetomidineMidazolam

80

30

60

50

40

70

20

10

0

Sample Size

Treatment DayD

eliri

um P

reva

lenc

e, %

Enrollment

229 118

1 2 3 4 5 6

206 109 175 92 134 77 92 57 60 42 44 34

Delirium was diagnosed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU).24 Atbaseline, 60.3% of dexmedetomidine-treated patients and 59.3% of midazolam-treated patients were CAM-ICU–positive (P=.82). The effect of dexmedetomidine treatment was significant in the generalized estimatingequation27 analysis, with a 24.9% decrease (95% confidence interval,16%-34%; P! .001) relative to mid-azolam treatment. Numbers differ from those for primary analysis because patients were extubated, dis-charged from the intensive care unit, or had missing delirium assessments.

DEXMEDETOMIDINE VS MIDAZOLAM FOR SEDATION OF CRITICALLY ILL PATIENTS

494 JAMA, February 4, 2009—Vol 301, No. 5 (Reprinted) ©2009 American Medical Association. All rights reserved.


-‐1

0

1

2

3

4

5

6

Mg+ Mg-‐

Delirium

Day

s

Effect of Magnesium on Sepsis Associated Delirium Esen F et al ESICM 2008

Exogenous Melatonin for Delirium Prevention:a Meta-analysis of Randomized Controlled Trials

Sheng Chen1 & LiGen Shi1 & Feng Liang1 & Liang Xu1 & Doycheva Desislava2 &QunWu1 &

Jianmin Zhang1

Received: 20 April 2015 /Accepted: 7 July 2015# Springer Science+Business Media New York 2015

Abstract Recently, two high-quality clinical randomizedcontrolled trials (RCTs) regarding the preventive effect of ex-ogenous melatonin on delirium drew inconsistent conclu-sions. We therefore performed a systemic review to explorewhether melatonin had a benefit on delirium prevention.MEDLINE, EMBASE, and Cochrane Library were searchedfrom January 1980 to April 2015 for English language stud-ies. After strict selection and evaluation, the data were extract-ed from the included four RCTs. The primary outcome of thismeta-analysis was the incidence of delirium. The secondaryoutcome was the improvement of sleep–wake rhythm. A totalof four RCTs with 669 elderly patients were included in thepresent study.Melatonin group showed a tendency to decreasethe incidence of delirium (relative risk [RR] 0.41, 95 % con-fidence interval [CI] 0.15 to 1.13; P=0.08) compared withcontrol group. In subgroup analysis of the elderly patients inmedical wards, melatonin supplementation decreasedthe incidence of delirium by 75 % (RR 0.25, 95 % CI 0.07to 0.88; P=0.03), but not in sleep–wake disturbance (RR 1.24,95 % CI 0.51 to 3.00; P=0.64). No differences were found inthe incidence of delirium between the two groups in the elder-ly patients that were presented to surgical wards. In conclu-sion, melatonin supplementation had a significant preventiveeffect in decreasing the incidence of delirium in elderly

patients that were presented to medical wards. Further studiesshould provide sufficient evidence about the effect of melato-nin on delirium in a large sample size.

Keywords Delirium .Melatonin . Sleep–wake cycle .

Meta-analysis

Introduction

Delirium is a life-threatening neuropsychiatric syndrome,which ultimately leads to disturbance in consciousness,change in cognition, disturbed psychomotor activity, and ab-normal sleep–wake cycle [1, 2]. It is a major health concern(2.5 times higher costs) with 2.9 times higher mortality rates inpatients with delirium compared to those with none [3, 4].Delirium’s pathogenic pathways are unclear, and up to date,there are no effective therapeutic strategies to treat delirium. Arecent systematic review showed that delirium prevention hadgreater success than treating delirium once it has developed[5]. Haloperidol and second-generation antipsychotics are themost commonly used pharmacological agents with sedativeeffects for delirium prevention [5]. However, these treatmentshave been shown to cause prolonged QT intervals and extra-pyramidal symptoms that increase the risk of fatal cardiovas-cular incidents [6]. Moreover, these pharmacological agentshave no effect on the disturbed circadian rhythm [6].

Melatonin, a pineal gland hormone secreted during thehours of darkness, is regarded as an important molecular me-diator regulating the circadian rhythm, specially the sleep–wake cycle [7–9]. Observational studies have shown that de-layed or lowmelatonin secretion is associated with delirium inintensive care unit in elderly patients [10–13]. Recent studiesmeasured the postoperative plasma concentration of melato-nin and the urinary excretion of 6-sulfatoxymelatonin (6-

Sheng Chen and LiGen Shi contributed equally to this work.

* Qun [email protected]

1 Department of Neurosurgery, Second Affiliated Hospital, School ofMedicine, Zhejiang University, 88 Jiefang Road,Hangzhou 310009, Zhejiang, China

2 Department of Physiology and Pharmacology, Loma LindaUniversity, Loma Linda, CA, USA

Mol NeurobiolDOI 10.1007/s12035-015-9350-8

Exogenous Melatonin for Delirium Prevention:a Meta-analysis of Randomized Controlled Trials

Sheng Chen1 & LiGen Shi1 & Feng Liang1 & Liang Xu1 & Doycheva Desislava2 &QunWu1 &

Jianmin Zhang1

Received: 20 April 2015 /Accepted: 7 July 2015# Springer Science+Business Media New York 2015

Abstract Recently, two high-quality clinical randomizedcontrolled trials (RCTs) regarding the preventive effect of ex-ogenous melatonin on delirium drew inconsistent conclu-sions. We therefore performed a systemic review to explorewhether melatonin had a benefit on delirium prevention.MEDLINE, EMBASE, and Cochrane Library were searchedfrom January 1980 to April 2015 for English language stud-ies. After strict selection and evaluation, the data were extract-ed from the included four RCTs. The primary outcome of thismeta-analysis was the incidence of delirium. The secondaryoutcome was the improvement of sleep–wake rhythm. A totalof four RCTs with 669 elderly patients were included in thepresent study.Melatonin group showed a tendency to decreasethe incidence of delirium (relative risk [RR] 0.41, 95 % con-fidence interval [CI] 0.15 to 1.13; P=0.08) compared withcontrol group. In subgroup analysis of the elderly patients inmedical wards, melatonin supplementation decreasedthe incidence of delirium by 75 % (RR 0.25, 95 % CI 0.07to 0.88; P=0.03), but not in sleep–wake disturbance (RR 1.24,95 % CI 0.51 to 3.00; P=0.64). No differences were found inthe incidence of delirium between the two groups in the elder-ly patients that were presented to surgical wards. In conclu-sion, melatonin supplementation had a significant preventiveeffect in decreasing the incidence of delirium in elderly

patients that were presented to medical wards. Further studiesshould provide sufficient evidence about the effect of melato-nin on delirium in a large sample size.

Keywords Delirium .Melatonin . Sleep–wake cycle .

Meta-analysis

Introduction

Delirium is a life-threatening neuropsychiatric syndrome,which ultimately leads to disturbance in consciousness,change in cognition, disturbed psychomotor activity, and ab-normal sleep–wake cycle [1, 2]. It is a major health concern(2.5 times higher costs) with 2.9 times higher mortality rates inpatients with delirium compared to those with none [3, 4].Delirium’s pathogenic pathways are unclear, and up to date,there are no effective therapeutic strategies to treat delirium. Arecent systematic review showed that delirium prevention hadgreater success than treating delirium once it has developed[5]. Haloperidol and second-generation antipsychotics are themost commonly used pharmacological agents with sedativeeffects for delirium prevention [5]. However, these treatmentshave been shown to cause prolonged QT intervals and extra-pyramidal symptoms that increase the risk of fatal cardiovas-cular incidents [6]. Moreover, these pharmacological agentshave no effect on the disturbed circadian rhythm [6].

Melatonin, a pineal gland hormone secreted during thehours of darkness, is regarded as an important molecular me-diator regulating the circadian rhythm, specially the sleep–wake cycle [7–9]. Observational studies have shown that de-layed or lowmelatonin secretion is associated with delirium inintensive care unit in elderly patients [10–13]. Recent studiesmeasured the postoperative plasma concentration of melato-nin and the urinary excretion of 6-sulfatoxymelatonin (6-

Sheng Chen and LiGen Shi contributed equally to this work.

* Qun [email protected]

1 Department of Neurosurgery, Second Affiliated Hospital, School ofMedicine, Zhejiang University, 88 Jiefang Road,Hangzhou 310009, Zhejiang, China

2 Department of Physiology and Pharmacology, Loma LindaUniversity, Loma Linda, CA, USA

Mol NeurobiolDOI 10.1007/s12035-015-9350-8

Neurologic Critical Care

Critical Care Medicine www.ccmjournal.org 1899

support from the NIH (AG032355). Dr. Jackson received support from the NIH (AG031322). Dr. Laskowitz received support from the NIH. Dr. Bernard received support from the NIH (TR000445). Dr. Ely received support from the NIH (AG027472 and AG035117), the VA Clinical Sci-ence Research and Development Service (VA Merit Review Award), and the Veterans Affairs Tennessee Valley GRECC; received honoraria from Pfizer, Eli Lilly and Company, Hospira, and Abbott Laboratories; and con-sulted for Cumberland and Masimo. Dr. Girard received support from the NIH (AG034257) and the Veterans Affairs Tennessee Valley GRECC and received honoraria from Hospira.For information regarding this article, E-mail: [email protected]

Objective: Since statins have pleiotropic effects on inflamma-tion and coagulation that may interrupt delirium pathogenesis, we tested the hypotheses that statin exposure is associated with reduced delirium during critical illness, whereas discontinuation of statin therapy is associated with increased delirium.Design: Multicenter, prospective cohort study.Setting: Medical and surgical ICUs in two large tertiary care hos-pitals in the United States.Patients: Patients with acute respiratory failure or shock.Interventions: None.Measurements and Main Results: We measured statin expo-sure prior to hospitalization and daily during the ICU stay, and we assessed patients for delirium twice daily using the Confu-sion Assessment Method for the ICU. Of 763 patients included, whose median (interquartile range) age was 61 years (51–70 yr) and Acute Physiology and Chronic Health Evaluation II was 25 (19–31), 257 (34%) were prehospital statin users and 197 (26%) were ICU statin users. Overall, delirium developed in 588 patients (77%). After adjusting for covariates, ICU statin use was associated with reduced delirium (p < 0.01). This association was modified by sepsis and study day; for example, statin use was associated with reduced delirium among patients with sepsis on study day 1 (odds ratio, 0.22; 95% CI, 0.10–0.49) but not among patients without sepsis on day 1 (odds ratio, 0.92; 95% CI, 0.46–1.84) or among those with sepsis later, for example, on day 13 (odds ratio, 0.70; 95% CI, 0.35–1.41). Prehospital statin

Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & WilkinsDOI: 10.1097/CCM.0000000000000398

*See also p. 1955.1Rehabilitation and Aged Care Unit, Hospital Ancelle, Cremona, Italy.2Geriatric Research Group, Brescia, Italy.3Center for Quality Aging, Vanderbilt University School of Medicine, Nash-ville, TN.

4Division of Critical Care, Department of Anesthesiology, Vanderbilt Uni-versity School of Medicine, Nashville, TN.

5Anesthesia Service, Department of Veterans Affairs Medical Center, Ten-nessee Valley Healthcare System, Nashville, TN.

6Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN.

7Center for Health Services Research, Vanderbilt University School of Medicine, Nashville, TN.

8Division of General Internal Medicine and Public Health, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.

9Geriatric Research, Education and Clinical Center Service, Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN.

10 Department of Emergency Medicine, Vanderbilt University School of Medicine, Nashville, TN.

11 Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.

12 Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN.

13 Research Service, Department of Veterans Affairs Medical Center, Ten-nessee Valley Healthcare System, Nashville, TN.

14 Division of Neurology, Department of Medicine, Department of Anes-thesiology, and Department of Neurobiology, Duke University Medical Center, Durham, NC.

This investigation was supported, in part, by the National Institutes of Health (NIH) (AG027472). Dr. Morandi received support from the NIH (AG027472). Dr. Hughes received support from the Foundation for Anes-thesia Education and Research (FAER). Ms. Thompson received sup-port from the NIH (AG027472). Dr. Pandharipande received support from the NIH (HL111111) and the VA Clinical Science Research and Development Service (VA Career Development Award) and he received honoraria from Hospira and Orion Pharma. Dr. Shintani received sup-port from the NIH (AG027472). Dr. Vasilevskis received support from the Veterans Affairs Clinical Research Training Center of Excellence, the Veterans Affairs Tennessee Valley Geriatric Research, Education and Clinical Center (GRECC), and the NIH (AG040157). Dr. Han received

Statins and Delirium During Critical Illness: A Multicenter, Prospective Cohort Study*

Alessandro Morandi, MD, MPH1,2,3; Christopher G. Hughes, MD4,5; Jennifer L. Thompson, MPH6; Pratik P. Pandharipande, MD, MSCI4,5; Ayumi K. Shintani, PhD, MPH6; Eduard E. Vasilevskis, MD, MPH7,8,9; Jin H. Han, MD, MSc10; James C. Jackson, PsyD7,11,12,13; Daniel T. Laskowitz, MD, MHS14; Gordon R. Bernard, MD11; E. Wesley Ely, MD, MPH3,7,9,11; Timothy D. Girard, MD, MSCI3,7,9,11ORIGINAL ARTICLE

Statin Use and Risk of Delirium in the Critically IllValerie J. Page1,2, Daniel Davis3,4, Xiao B. Zhao1, Samuel Norton5, Annalisa Casarin1, Thomas Brown6,E. Wesley Ely7,8, and Daniel F. McAuley9,10

1Intensive Care Unit, Watford General Hospital, West Hertfordshire Hospitals NHS Trust, Watford, United Kingdom; 2Faculty of Medicine,Imperial College, London, United Kingdom; 3Institute of Public Health, University of Cambridge, Cambridge, United Kingdom; 4Centrefor Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom; 5Psychology Department,Institute of Psychiatry, King’s College, London, United Kingdom; 6Department of Anaesthesia, Ealing Hospital, Southall, UnitedKingdom; 7Vanderbilt University Medical Center, Nashville, Tennessee; 8Tennessee Valley VA-GRECC, Nashville, Tennessee; 9Centre forInfection and Immunity, Queen’s University of Belfast, Belfast, United Kingdom; and 10Regional Intensive Care Unit, Royal Victoria Hospital,Belfast, United Kingdom

Abstract

Rationale:Delirium is common in intensive care unit (ICU) patientsand is a predictor of worse outcomes and neuroinflammation isa possible mechanism. The antiinflammatory actions of statins mayreduce delirium.

Objectives: To determine whether critically ill patients receivingstatin therapyhad a reduced risk of delirium than those not on statins.

Methods: A prospective cohort analysis of data from consecutiveICU patients admitted to a UK mixed medical and surgical criticalcare unit between August 2011 and February 2012; the ConfusionAssessment Method for ICU was used to determine the days eachpatient was assessed as being free of delirium during ICU admission.

Measurements and Main Results: Delirium-free days, dailyadministration of statins, and serum C-reactive protein (CRP) were

recorded. Four hundred and seventy consecutive critical care patientswere followed, of whom151 patients received statins. Using random-effects multivariable logistic regression, statin administration theprevious evening was associated with the patient being assessed asfree of delirium (odds ratio, 2.28; confidence interval, 1.01–5.13;P, 0.05) and with lower CRP (b =20.52; P, 0.01) the followingday. When the association between statin and being assessed asfree of delirium was controlled for CRP, the effect size becamenonsignificant (odds ratio, 1.56; confidence interval, 0.64–3.79;P = 0.32).

Conclusions:Ongoing statin therapy is associatedwith a lower dailyrisk of delirium in critically ill patients. An ongoing clinical trial,informed by this study, is investigating if statins are a potentialtherapy for delirium in the critically ill.

Keywords: delirium; statin; inflammation; C-reactive protein;critical care

Delirium is a form of acute braindysfunction, with a prevalence of up to 65%in critically ill patients requiring mechanicalventilation in the United Kingdom (1). It isassociated with significantly worse clinical

outcomes. Delirium is independentlyassociated with a threefold increased risk ofmortality at 6 months, and for survivorsa 10-fold increased risk of cognitiveimpairment at 12 months (2, 3). Long-term

cognitive impairment after critical illnessreduces quality of life, increases healthcarecosts, and leads to institutionalization (4, 5).

Although the pathogenesis of deliriumremains poorly understood, there is

(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 andCognitive 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 gratefullyacknowledged.

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 toanalysis 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 tostudy 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 versionto 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 WD180HB, UK. E-mail: [email protected]

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, 2014Copyright © 2014 by the American Thoracic SocietyOriginally Published in Press as DOI: 10.1164/rccm.201306-1150OC on January 13, 2014Internet address: www.atsjournals.org

666 American Journal of Respiratory and Critical Care Medicine Volume 189 Number 6 | March 15 2014

ORIGINAL ARTICLE

Statin Use and Risk of Delirium in the Critically IllValerie J. Page1,2, Daniel Davis3,4, Xiao B. Zhao1, Samuel Norton5, Annalisa Casarin1, Thomas Brown6,E. Wesley Ely7,8, and Daniel F. McAuley9,10

1Intensive Care Unit, Watford General Hospital, West Hertfordshire Hospitals NHS Trust, Watford, United Kingdom; 2Faculty of Medicine,Imperial College, London, United Kingdom; 3Institute of Public Health, University of Cambridge, Cambridge, United Kingdom; 4Centrefor Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom; 5Psychology Department,Institute of Psychiatry, King’s College, London, United Kingdom; 6Department of Anaesthesia, Ealing Hospital, Southall, UnitedKingdom; 7Vanderbilt University Medical Center, Nashville, Tennessee; 8Tennessee Valley VA-GRECC, Nashville, Tennessee; 9Centre forInfection and Immunity, Queen’s University of Belfast, Belfast, United Kingdom; and 10Regional Intensive Care Unit, Royal Victoria Hospital,Belfast, United Kingdom

Abstract

Rationale:Delirium is common in intensive care unit (ICU) patientsand is a predictor of worse outcomes and neuroinflammation isa possible mechanism. The antiinflammatory actions of statins mayreduce delirium.

Objectives: To determine whether critically ill patients receivingstatin therapyhad a reduced risk of delirium than those not on statins.

Methods: A prospective cohort analysis of data from consecutiveICU patients admitted to a UK mixed medical and surgical criticalcare unit between August 2011 and February 2012; the ConfusionAssessment Method for ICU was used to determine the days eachpatient was assessed as being free of delirium during ICU admission.

Measurements and Main Results: Delirium-free days, dailyadministration of statins, and serum C-reactive protein (CRP) were

recorded. Four hundred and seventy consecutive critical care patientswere followed, of whom151 patients received statins. Using random-effects multivariable logistic regression, statin administration theprevious evening was associated with the patient being assessed asfree of delirium (odds ratio, 2.28; confidence interval, 1.01–5.13;P, 0.05) and with lower CRP (b =20.52; P, 0.01) the followingday. When the association between statin and being assessed asfree of delirium was controlled for CRP, the effect size becamenonsignificant (odds ratio, 1.56; confidence interval, 0.64–3.79;P = 0.32).

Conclusions:Ongoing statin therapy is associatedwith a lower dailyrisk of delirium in critically ill patients. An ongoing clinical trial,informed by this study, is investigating if statins are a potentialtherapy for delirium in the critically ill.

Keywords: delirium; statin; inflammation; C-reactive protein;critical care

Delirium is a form of acute braindysfunction, with a prevalence of up to 65%in critically ill patients requiring mechanicalventilation in the United Kingdom (1). It isassociated with significantly worse clinical

outcomes. Delirium is independentlyassociated with a threefold increased risk ofmortality at 6 months, and for survivorsa 10-fold increased risk of cognitiveimpairment at 12 months (2, 3). Long-term

cognitive impairment after critical illnessreduces quality of life, increases healthcarecosts, and leads to institutionalization (4, 5).

Although the pathogenesis of deliriumremains poorly understood, there is

(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 andCognitive 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 gratefullyacknowledged.

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 toanalysis 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 tostudy 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 versionto 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 WD180HB, UK. E-mail: [email protected]

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, 2014Copyright © 2014 by the American Thoracic SocietyOriginally Published in Press as DOI: 10.1164/rccm.201306-1150OC on January 13, 2014Internet address: www.atsjournals.org

666 American Journal of Respiratory and Critical Care Medicine Volume 189 Number 6 | March 15 2014

Sonuç olarak •  YB hastaları rutin olarak deliryum açısından değerlendirilmeli •  CAM-‐‑ICU ve ICDSC kullanılabilecek skorlardır

•  Tanı duyarlılığını arNırmak ve tedaviye cevabı değerlendirmek için tekrarlanmalıdır

•  Tüm yoğun bakım ekibi deliryumun önlemesi konusunda

bilgilendirilmelidir

27/04/16

7

En iyi monitör “uyanık hasta” En iyi sedasyon “hasta ile konuşma”

delİryum)deliryum) mental statüdeakut+ değişiklik) dikkatsizlik) statüde dalgalanma)...

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