TYBD 2016.pptx

Transkript

TYBD 2016.pptx

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

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