Dahlia RCT

8/17/2019 Dahlia RCT

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Copyright 2016 American Medical Association. All rig hts reserved.

EffectofDexmedetomidine Added to StandardCare

onVentilator-Free Time in Patients WithAgitatedDelirium

A Randomized Clinical Trial

Michael C. Reade, DPhil, FCICM; GlennM. Eastwood, RN, PhD;Rinaldo Bellomo,MD, FCICM; Michael Bailey, PhD;Andrew Bersten,MD, FCICM;

Benjamin Cheung, MBBS, FCICM; Andrew Davies, MBBS, FCICM; Anthony Delaney, PhD, FCICM; Angaj Ghosh, MBBS, FCICM;

Frank van Haren, PhD, FCICM; Nerina Harley, MD,FCICM; DavidKnight, MBBS, FCICM; ShayMcGuiness, MBChB, FCICM;

JohnMulder, MBChB, FCICM; Steve O’Donoghue, MBChB, FCICM; Nicholas Simpson, MBBS, FCICM; PaulYoung,MBChB,FCICM;

for the DahLIA Investigatorsand the Australian and New Zealand IntensiveCare Society Clinical Trials Group

IMPORTANCE Effective therapy has not been established for patients with agitated delirium

receiving mechanical ventilation.

OBJECTIVE To determine the effectiveness of dexmedetomidine when added to standard

care in patients with agitated delirium receiving mechanical ventilation.

DESIGN, SETTING, AND PARTICIPANTS The Dexmedetomidine to Lessen ICU Agitation(DahLIA) study was a double-blind, placebo-controlled, parallel-group randomized clinical

trial involving 74 adultpatients in whom extubation was considered inappropriate because of

theseverity of agitationand delirium.The study was conductedat 15 intensivecare units in

Australiaand NewZealand from May 2011 until December 2013. Patientswith advanced

dementia or traumatic braininjury were excluded.

INTERVENTIONS Bedside nursing staff administered dexmedetomidine (or placebo) initially

ata rate of0.5µg/kg/hand thentitrated torates between0 and 1.5 µg/kg/h toachieve

physician-prescribed sedation goals. The study drug or placebo was continued until no longer

required or up to 7 days. Allothercare was at the discretion of thetreatingphysician.

MAIN OUTCOMESAND MEASURES Ventilator-free hoursin the 7 days following randomization.

There were 21 reported secondary outcomes that were defined a priori.

RESULTS Of the74 randomized patients (median age, 57 years; 18 [24%] women), 2 withdrew

consent later and1 wasfound to have beenrandomized incorrectly, leaving 39 patients in the

dexmedetomidine group and32 patients in theplacebo group foranalysis.Dexmedetomidine

increased ventilator-free hours at 7 days compared with placebo(median, 144.8 hours vs 127.5

hours, respectively; mediandifference betweengroups, 17.0hours [95% CI, 4.0 to 33.2 hours];

P = .01). Among the21 a priori secondary outcomes, none were significantlyworse with

dexmedetomidine, and several showed statistically significant benefit, including reduced time

to extubation (median, 21.9 hours vs 44.3 hours withplacebo; mediandifference between

groups,19.5 hours [95% CI,5.3 to 31.1 hours];P < .001)and accelerated resolutionof delirium

(median, 23.3 hours vs 40.0hours;mediandifference between groups,16.0hours [95% CI, 3.0

to 28.0 hours]; P = .01). Using hierarchical Cox modeling to adjustfor imbalanced baseline

characteristics, allocation to dexmedetomidine was significantly associated with earlier

extubation (hazard ratio, 0.47 [95% CI, 0.27-0.82]; P = .007).

CONCLUSIONS AND RELEVANCE Amongpatientswith agitated delirium receiving mechanical

ventilationin theintensive care unit, the addition of dexmedetomidineto standard care

compared with standardcare alone (placebo)resulted in more ventilator-free hours at 7 days.

Thefindingssupport the use of dexmedetomidinein patients such as these.

TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01151865

JAMA. 2016;315(14):1460-1468. doi:10.1001/jama.2016.2707

Published online March15, 2016.

Editorialpage 1455

Supplementalcontent at

jama.com

Author Affiliations: Author

affiliations arelisted at theendof this

article.

Group Information: TheDahLIA

Investigatorsare listedat theendof

this article.

Corresponding Author: Michael C.

Reade, DPhil, FCICM,University of

Queensland,Health Sciences Bldg,

Herston,Queensland, Australia 4029

([email protected]).

Research

Preliminary Communication | CARING FOR THE CRITICALLY ILL PATIENT

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Theincidenceof deliriumin criticallyill patientsis high.,

Delirium is associated with increased mortality

and decreased long-term cognitive function., Agi-

tated delirium is particularly problematic in patients receiv-

ing mechanical ventilation because it increases the risk

of self-extubation and removal of other essential medical

devices. Identification of an agent that shortens the dura-

tion of established delirium would be an important therapeu-

tic advance.

Dexmedetomidine, a sedative α-agonist, is theoretically

an attractive treatment for patients with agitated delirium in

the intensive care unit (ICU) because unlike other sedatives,

it induces a calm yet rousable state with preserved respira-

torydrive,therebyallowing it tobe continuedafter extubation.

However, to our knowledge, no trial has compared dexme-

detomidinewith placebo for the treatment of patientsreceiv-

ing mechanical ventilation who would be candidates for ex-

tubation based on respiratory, cardiovascular, and metabolic

criteria but who remain intubated because of severe agitated

delirium. Accordingly, we tested the hypothesis that dexme-

detomidine,when added toallotherelements of standardcare,

would result in shorter duration of delirium and earlier extu-

bation in such patients.

Methods

TheDexmedetomidine to LessenICU Agitation(DahLIA) study

was a double-blind, parallel-group, placebo-controlled mul-

ticenter randomized trialin whichintubatedICU patients were

allocated randomly : to receive dexmedetomidine or saline

as a treatment for agitated delirium. No other aspect of pa-

tient care wasconstrained, with theexception that clonidine

was prohibited due to its potential interaction with dexme-

detomidine.Thetrialwas conducted betweenMay ,,and Decem-

ber , , in the ICUs of hosp itals in Austr alia and

New Zealand, of which are mixed medical-surgical units

( tertiary academic and metropolitan) and of which ad-

mitsprimarilypostoperative cardiac surgical patients.The trial

protocol, which contains the statistical analysis plan, ap-

pearsin Supplement . The trialprotocolwas approvedby the

AustinHospital human research ethics committee and,where

required, by individual hospital ethics committees.

Consent was sought from the person responsible for the

patient. In some jurisdictions,if this personcould notbe con-

tacted, the patient could be enrolled in anticipation of retro-

spectiveconsent. In other jurisdictions,eligiblepatients wereenrolled when the treating clinician considered participation

to be in the patient’s bestinterest; however, patients werenot

included if relatives indicatedthat the patientwould notwish

to participate.

Once thepatienthad recovered sufficiently, allhad theop-

portunityto provide fully informed consent tothe use of data

and ongoing study participation.Either the patient or person

responsible could withdraw consent at any stage. A data and

safety monitoring committee reviewed all adverse effects.

There was no interim analysis.

Adult patients (aged ≥years) were eligible forthe study

if, in the opinion of their treating physician, they continued

to requiremechanical ventilationonly because their degree of

agitationwas so severeas to make lesseningtheirsedation and

extubation unsafe. These criteria were quantified objectively

by requiring that the patient should meet all of these addi-

tional criteria during the hours prior to randomization:

() need for mechanical restraint, antipsychotic or sedative

medication, or both restraint and medication; () have Con-

fusionAssessment Method for theICU (CAM-ICU) results that

indicated presence of delirium; and () have a Motor Activity

AssessmentScale (MAAS) scoreof or greater, confirming psy-

chomotor agitation.

Patients were excluded if they () were pregnant or breast-

feeding, () had dementia that required professional nursing

care, () had a head injury as the cause of theiraltered mental

state, ()were already receivingdexmedetomidine or clonidine

for sedation, () had been enrolled previously in the study,

or () there was a known contraindication to haloperidol or

α-agonists.

Patients were randomized, stratified by site and age (


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tomy, with liberation from sedation and mechanical ventila-

tion defined in thesame manner as used forthe primary out-

come), time taken to achieve a satisfactory sedation score

(Richmond Agitation-SedationScalescoreof −to ),time taken

to achieve a satisfactory agitation score (MAAS score of to

), proportion of study time with a satisfactory MAAS score,

perioduntilthe nurse caringfor thepatientthoughtit wastime

to extubate, time to the first CAM-ICU results that indicated

absence of delirium, time spent having CAM-ICU results that

indicated presence of delirium, the requirement for sedative

and antipsychotic medications, the proportion who under-

wenttracheostomy, requirement forreintubation,daily Sepsis-

related Organ Failure Assessment score, andlengthsof stay in

the ICU and hospital. Adverse events wererecordedboth pro-

spectively and by review of each clinical chart.Modified intention-to-treat analyses were performed.

Modification was permitted to account for postrandomiza-

tioncircumstances that prevented useof data fromcertain pa-

tients.Because there were nomissing data forthe primaryout-

comeand lessthan %missingfor all secondaryoutcomes,no

data imputationwas performed. Dueto nonnormality, allcon-

tinuous outcomes were compared using Mann-Whitney tests

withlocationshifts between treatmentgroupscalculatedusing

the Hodges-Lehmannestimateand reportedusing distribution-

free % confidence limits.

The sensitivity analysis accounting for multiple sites was

performed using the van Elteren statistic. Categorical out-

comes were compared using χ

or Fisher exact tests and re-ported as differences in proportion (% confidence inter-

val). Time-to-event data were compared using log-rank tests

and presented as Kaplan-Meier curves. To accountfor any ef-

fect ofsite andfor baseline imbalances,a Cox proportionalhaz-

ards regression model was used with patients nested within

site, andsitetreatedas a randomeffect with the followingco-

variatesincluded in the model: Acute Physiologyand Chronic

Health EvaluationII diagnosis, durationof intubation,and elec-

tivestatus.Proportionalityassumptions weredeterminedusing

log survival plots.

All statisticalanalyses were performed using Stata version

. (StataCorp) or SAS version . (SAS Institute Inc) with a

-sided P value ofless than.consideredsignificant. Noadjust-

mentwas madefor multiplecomparisons, andso thesecondary

outcomes presented (although all prespecified) should be con-

sideredexploratory, yielding hypothesis-generating findings.

Basedon a pilotstudy with a mean control estimateof

ventilator-freehours (SD, ventilator-freehours),a sample

size of patients wasestimatedto provide % powerto de-

tect a -hour difference (ie, half the effectsize observed in a

pilot study) using a -tailed hypothesis at an α level of ..

Thesecalculations include an inflationrate of %to account

for thepossibility that ventilation-freedays would notbe nor-

mally distributed.

However, the sponsoring pharmaceutical company (Ho-spira Australia) decided against extending funding and pro-

visionof study drug beyonda date that hadbeenearlier agreed.

Consequently, the trialwas terminated prematurelyin Decem-

ber after patients had been randomized. At no stage

did thepharmaceuticalcompanyhave access to thestudy data,

and no data analysis by the study investigators had occurred

prior to this decision.

To account for the possibility that early termination may

exaggerate the effect size, additional analyses were per-

formed post hoc to assess thelikelihood of a null finding had

the study been completedas originallyplanned.These analy-

ses were performed using simulations based first on

theassumption that nonenrolled patients camefrom theorigi-nal projected population and then second based on the as-

sumption that the nonenrolled patients came from the ob-

served population.

Results

From May until December , we randomized pa-

tients (Figure ). However, patient allocated to dexmedeto-

midine had been randomized in error, and patient in each

Figure 1. PatientFlowDiagramof theDahLIATrial

Approximately 21500 admissions ofintubated patients at 15 intensive careunits in 2 countriesa

1 Withdrew consent to use data 1 Withdrew consent to use data

74 Patients randomized

41 Randomized to receivedexmedetomidine

40 Received dexmedetomidineas randomized

1 Study treatment discontinued(met an exclusion criterion andinappropriately randomized)

33 Randomized to receive placebo

33 Received placebo as randomized

39 Included in primary intent-to-treat analysis

32 Included in primary intent-to-treat analysis

Thenumberof patientsnot

randomized dueto notmeetingthe

inclusioncriteriaor havingmet 1 of

the exclusioncriteriawas not

recorded.DahLIA indicates

Dexmedetomidineto Lessen

ICU Agitation.

a Estimatedfrom totaladmission

numbers to eachintensivecare unit

alongwith data from theAustralian

and New Zealand Intensive Care

Society Centre forOutcomesand

Resource Evaluation14 onthe

proportion of theseadmissions that

were intubated.

Research Preliminary Communication DexmedetomidinePlus Standard Carein Patients WithAgitatedDelirium

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group withdrew consent, leaving data from patients in the

dexmedetomidinegroupand inthe placebo groupfor analy-

sis. The baseline characteristics of study participants appear

in Table .

Almost all patients were sedated with propofol. Approxi-

mately one-third of the patients required mechanical re-

straint immediately prior to randomization and % re-

ceived an antipsychotic drug. The median Acute Physiology

and Chronic Health Evaluation II score immediately prior torandomizationwas low, reflecting the inclusioncriterion that

these patients should be ready for extubation except for hav-

ing agitated delirium.

One male patient randomized to receive dexmedetomi-

dine did not receive any study drug because his physician

decided the delirium had resolved almost immediately

after randomization. While blinded to study drug allocation,

the treating physician of patient randomized to placebo

decided, after hours of administering the placebo study

drug, optimal treatment would be dexmedetomidine. There-

fore, open-label dexmedetomidine was commenced, and the

placebo study drug was stopped. Five patients ( allocated to

dexmedetomidine and to placebo) received open-label

dexmedetomidine after administration of the study drug for

days.

Compared with the dexmedetomidine group, patients al-

located to the placebo group received a significantly greater

rateandvolumeof study drugon days and (Table). More

patientsin the placebo group received antipsychotic medica-tions(haloperidol, risperidone, olanzapine, or quetiapine) on

anyday thanwas truefor thedexmedetomidinegroup(.%

vs .%, respectively; mean difference between groups,

−.%[%CI, −.% to −.%; P = .). There wereno sig-

nificant differencesin theuseof individualantipsychotic drugs

(eTablein Supplement). On several days, significantlylower

quantities of intercurrent sedatives (propofol and mid-

azolam)and opioids(morphine andfentanyl)were usedin the

dexmedetomidine group compared with the placebo group

(eTable ).

Table 1. BaselinePatientCharacteristicsa

Dexmedetomidine(n = 39)

Placebo(n = 32)

Tertiary ICU with >18 beds 17 (43.6) 15 (46.9)

Age, median (IQR), y 58 (47-65) 56.5 (46-69.5)

Male sex 28 (71.8) 25 (78.1)

Weight, median (IQR), kg 83 (72-100) 85 (78-105)

Living at home 39 (100) 31 (96.9)

APACHE II score immediately prior to randomization,median (IQR)

Acute physiology 11 (8-16) 11.5 (8.5-16.5)

Total 14 (10-22) 14 (11-20)

APACHE II comorbidity score ≥2 10 (25.6) 6 (18.8)

APACHE II diagnostic category

Nonoperative 17 (43.6) 12 (37.5)

Respiratory 5 (29.4) 5 (41.7)

Cardiovascular 4 (23.5) 0

Neurological 4 (23.5) 2 (16.7)

Other 4 (23.5) 5 (41.7)

Operative 22 (56.4) 20 (62.5)

Multiple trauma 4 (18.2) 2 (10.0)Cardiovascular 10 (45.5) 15 (75.0)

Respiratory 1 (4.5) 0

Neurosurgery including neurotrauma 0 1 (5.0)

Gastrointestinal 5 (22.7) 1 (5.0)

Other 2 (9.1) 1 (5.0)

Emergency ICU admission 29 (74.4) 18 (56.3)

During the 24 h prior to randomization

Mechanical restraint 13 (33.3) 11 (34.4)

Use of pharmacotherapy (n = 38) (n = 32)

Midazolam 4 (10.5) 5 (15.6)

Propofol 38 (100.0) 29 (90.6)

Morphine 9 (23.7) 9 (28.1)

Fentanyl 14 (36.8) 11 (34.4)

Antipsychotic (haloperidol, olanzapine, risperidone,or quetiapine)

9 (23.7) 6 (18.8)

Duration of intubation prior to enrol lment, median (IQR), h 63 (26-96) 43.5 (23-72)

Abbreviations: APACHE II, Acute

Physiologyand Chronic HealthEvaluationII; ICU,intensivecare unit;

IQR, interquartile range.

a Data areexpressed as No. (%)

unlessotherwise indicated.

DexmedetomidinePlus Standard Carein Patients WithAgitatedDelirium Preliminary Communication Research

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During the days after randomization, propofol use was

commonin both groups(.%of thedexmedetomidine group

and.%of theplacebo group). The mediandosage wassig-

nificantly higher in the placebo group ( mg [interquar-

tile range {IQR}, to mg]) compared with the dex-

medetomidinegroup(mg [IQR, to mg]) (median

difference between groups, −. mg [% CI, − to

−mg]; P < .). Patientsin theplacebogroupweremore

likely to receivemorphine (.%vs .% of thedexmedeto-

midine group; meandifference betweengroups,−.% [%

CI, −.% to −.%]; P = .), and received a significantly

higher median dosage of fentanyl ( µg [IQR, to

µg] vs µg [IQR, to µg], respectively; me-

dian difference between groups, µg [% CI, to

µg]; P = .) (eTable in Supplement ).

Patients randomized to dexmedetomidine had signifi-

cantly more ventilator-free hours at days (median, .

hours vs . hours in the placebo group; median difference

between groups, . hours [% CI, .-. hours]; P = .;

van Elteren site-adjusted P = .) (Table ). There were no

Table2.Quantificationof StudyDrugUseandAdministrationof Intercurrentand SubsequentMedications


Placebo(n = 32)

Difference BetweenGroups (95% CI) P Value

Bolus at start of study drug infusion, No./total No. ofobservations (%)

2/37 (5.4) 2/32 (6.3) −0.8 (−12.0 to 10.3) >.99

Time until peak infusion rate of study drug reached,median (IQR), h

8.3 (5.0 to 17.0) 8.3 (4.0 to 15.3) 0 (−3.0 to 2.0) .68

Total duration of study drug infusion, median (IQR), h 23.5 (19.5 to 35.0) 35.0 (24.8 to 71.5) −10.0 (−262.8 to −2.8) .004

Study drug continued after extubation, No. (%) 4 (10.3) 4 (12.5) −2.2 (−17.1 to 12.7) >.99

Day 1

Study drug rate, median (IQR), mL/ha 12.8 (8.3 to 22.2) 25.4 (21.3 to 30.4) −12.2 (−16.2 to −7.7)


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differences between groups in the proportion of patients

who required tracheostomy (Table ). A sensitivity analysis

examining only patients who did not receive a tracheostomy

showed the same qualitative difference in ventilator-free

hours (median, . hours [IQR, - hours] in the dex-

medetomidine group vs hours [IQR, - hours] in the

placebo group; median difference between groups, .

hours [% CI, .-. hours]; P = .).

In the time to event analysis, dexmedetomidine was as-

sociated withearlier extubation (hazardratio [HR], . [%

CI, .-.]; P = .) (Figure ).In thehierarchical Cox pro-

portionalhazardsregressionmodel adjustingfor baseline char-

acteristics (eTable in Supplement ), allocation to dexme-

detomidineremainedassociated withearlier extubation (HR,

. [%CI, .-.]; P = .). Ina sensitivity analysisthat

usedright censoringfor patientswith tracheostomy at thetime

Table3.PrimaryandSecondary StudyOutcomes


Placebo(n = 32)

Difference BetweenGroups (95% CI) P Value

Primary Outcome

Time ventilator-free during the first 7 d after randomization,median (IQR), h

144.8 (114.0 to 156.0) 127.5 (92.0 to 142.8) 17.0 (4.0 to 33.2) .01

Secondary Outcomes

Time taken to achieve a satisfactory sedation score,median (IQR), da

1 (1 to 1) 1 (1 to 1) 0 (0 to 0) .90

Time until bedside nurse thought patient was readyfor extubation (not tracheostomy), median (IQR), h

19.1 (16.7 to 25.8)b 40.5 (21.1 to 90.7)c −21.1 (−34.5 to −6.0)


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of the procedure, there was no difference in qualitative out-

come (HR, . [% CI, .-.]; P = .).

Themediantime to extubationwas . hours forthe dex-

medetomidinegroupvs . hours forthe placebogroup (me-

diandifferencebetweengroups, . hours [% CI,. to .

hours]; P < .; vanElteren site-adjusted P = .). Bedside

nurses thought their patients were ready to extubate signifi-

cantly earlier ( P < .) if they were receiving dexmedetomi-

dine (median,.hours [IQR,.to . hours]) than if they

were receivingplacebo(median,.hours [IQR, . to .

hours]) (median difference between groups,−. hours [%

CI, −. to −. hours]). The median ICU length of stay was

. days (IQR, . to . days) with dexmedetomidine vs .

days (IQR, . to .days) with placebo ( P = .).

An additional posthoc simulation analysis calculating the

probability of finding no difference in themedian durationof

ventilator-free hours during the first days after randomiza-tionif thetrial includedthe plannednumberof patients (using

boththe original designeffectsand theobserved effects) found

a chanceof less than %of producinga null result( P > .)(cal-

culated using either approach). This lack of likely qualitative

difference occurred because the observed treatment effect in

this study was very similar to that projected.

Allocation to dexmedetomidine was associated with sev-

eral improved indices of delirium (Table ). Withdexmedeto-

midine, delirium resolved more rapidly (median, . hours

vs . hours in the placebo group; median difference be-

tweengroups,. hours[% CI, .-.hours]; P = .; van

Elteren site-adjusted P = .).Compared withthe patientswho

received placebo, the patients who received dexmedetomi-dine had deliriumfor a lower proportion oftheirICU stay, and

had a median of additional delirium-free days during their

ICU stay. There wasno between-group difference in the time

taken to achieve a satisfactory sedation score.

The time taken to achieve a satisfactory MAAS score (or

proportion of timespent witha satisfactory MAAS score) can-

notbe reported becausealmost nopatients had a MAAS score

recorded after that which wasassessed by thestudyresearch

coordinator at the time of study entry. The protocol required

bedside nurses to collect MAAS scores; however, less atten-

tion was provided to educate the nurses regarding collection

of theMAAS score than theCAM-ICU. This absence of data was

missed during interim monitoring,preventing remediation of

the problem during the conduct of the trial.

Adverse events (bradycardia requiring interruption of

study drug, hypotension requiring vasopressor support, and

agitation requiringtemporarily increased sedation)were rare

and not different between study groups. Two of patients

inthe dexmedetomidinegroup and of patients in the pla-

cebo group received a bolus of dexmedetomidine. None of

these patients were among those who experienced a brady-

cardia-related adverse event. A patient with known cardio-

myopathydevelopedventricular tachycardia hoursafter ces-

sation of the study drug; however, the data and safety

monitoring committee ruled that this was not related to the

study, and the protocol continued without modification.

There were no statistically significant differences be-

tween the groups in Sepsis-related Organ FailureAssessment

score on any study day. As expected in this comparatively re-

covered cohortof critically illpatients, ICUand hospital mor-

tality were low and not different between groups. Only pa-

tient requiredreintubation,which occurred hours following

elective extubation. No patient self-extubated.

Discussion

In this double-blind placebo-controlled randomized trial in-

volving patients with agitated delirium receiving mechanical

ventilation, who were primarily receiving propofol-based se-

dation and antipsychotic medications determined by their

treating physicians, dexmedetomidine increased the num-

ber of ventilator-free hours during the days following ran-

domization. Compared with placebo,dexmedetomidine has-

tened theresolution of delirium andextubation in patients byapproximately day. Adverse events were rareand not differ-

ent between the groups.

The results of this study are consistent with earlier large

randomized clinical trials comparingdexmedetomidine with

benzodiazepines or propofol as a sedative, which found dex-

medetomidinewas associatedwithless delirium in theICU,

andreduced time to extubation. However, these were trials

of dexmedetomidine as a sedative rather than as a treatment

fordelirium. Suggestion of a therapeuticeffect of dexmedeto-

midine in established delirium was present in the Safety and

Efficacy of Dexmedetomidine Compared With Midazolam

trial. Inthe post hocanalysisof the%of patients whohad

CAM-ICUresultsindicatingthe presenceof delirium at thetimeof randomization, there was a reduction in the prevalence of

delirium from .% to .%.

Dexmedetomidine had a propofol- and fentanyl-sparing

effect on day . It is possible that deliriogenic sedatives were

replaced with alternatives less prone to cause delirium.

However, propofol and opioids are probably less delirio-

genic than benzodiazepines, and nonbenzodiazepine

alternatives were the overwhelming choice for intercurrent

care. Therefore, a direct antidelirium effect of dexmedeto-

midine remains possible. How an α-agonist might exert this

Figure 2. Kaplan-MeierAnalysisof theProportionof PatientsRemaining

IntubatedDuringtheFirst7 Daysof theStudy

0.80

0.60

0.40

0.20

00

39

32

20 40 120 140 16060 80

2

2

P r o p o r t i o n R e m a i n i n g I n t u b a t e d

o r S e d a t e d W i t h

T r a c h e o s t o m y

Hours After Randomization

No. at riskDexmedetomidine

Dexmedetomidine

Placebo

Placebo

100

4

6

10

13

Hazard ratio, 0.58 (95% CI, 0.360.95);

log-rank P = . 03

1.00





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effect remains speculative. It is possible that the analgesic

effects of dexmedetomidine might have lessened both agi-

tation and delirium.

Our study is the same size as the largest previous trial

of therapy for patients with agitated delirium determined by

the CAM-ICU; that study compared(nonblinded)dexmedeto-

midine with midazolam in patients who had been intu-

batedafterundergoingelective cardiacsurgery.Patientsin the

dexmedetomidine group were extubated earlier (. hours

vs . hours in the midazolam group, P < .), but the be-

tween-group comparisons of agitated delirium were not re-

ported. This study showed the superiority of dexmedetomi-

dine over midazolam as a sedative for patients with agitated

delirium whohad undergone intubation. However,givencon-

sensus recommendations against benzodiazepines in these

circumstances, this is less relevant than the question ad-

dressed by our study.

To our knowledge, the only other published trial target-

ing patients with agitated delirium was a single-center pilot

study of patients, which compared nonblinded infusions

of dexmedetomidine or haloperidol. Dexmedetomidineshort-

ened time toextubation(from.hours to.hours, P = .)

andICU lengthof stay (from . days to .days, P = .). In

our larger trial, only.% of patientsreceivedhaloperidol and

a higher percentage received atypical antipsychotics.

The only previous delirium pharmacotherapy placebo-

controlled trial (in which only .% had a Riker Sedation-

Agitation Scale score of ≥ at the time of enrollment, sug-

gesting agitateddelirium)had a similar designto that of our

study. Patients (notall intubated atthe timeof enrollment) were

randomizedto quetiapine or placebo,with all otherelements

of care as directed by thephysician. Both groupsreceived as-

needed haloperidol. Delirium resolved faster with quetiap-

ine but duration of mechanical ventilation and ICU length of

stay were similar to placebo.This study has several strengths. First, it used a double-

blind, multicenter, randomized, permuted block, placebo-

controlled design. Second, the study had objective enroll-

mentcriteria.Third,the primary endpointwas patientcentered

and with likelyfinancialcost-benefitimplications.Fourth, the

protocol replicated current practice by having bedside nurses

independently titrating the study drug to either a physician-

prescribed sedation goal or a default goal of light sedation.

Fifth, all other therapies wereconsistent withcurrent consen-

sus recommendations.Sixth,thedevelopmentof lack ofphy-

sician equipoise was accommodated by permitting open-

label dexmedetomidine afterpatients had received the study

drug for hours, but this had no effect on the results.

The study also has some limitations. The planned pa-

tients werenot recruited.Unplannedearly termination of clini-

cal trials can exaggerate effect size. However, the probability

of finding a qualitatively different result in the primary out-

come hadthe trial recruitedto thetarget sample size wasless

than %.The relatively small samplesize led to severalchance

imbalancesin baseline characteristics, notably theduration of

ventilation beforerandomization.However, whenadjusted for

this imbalance, dexmedetomidine remained associated with

earlier extubation. Although there was a difference in the pri-

maryoutcome andseveralcongruentsecondary outcomes,the

study was underpowered to detect differences in important

end points including ICU length of stay.

Many patients (n = ) were screened in the effort to

recruit only patients; therefore, the results maynot be gen-

eralizable to patients earlier in the course of their critical ill-

ness, with other forms of delirium,or notintubated.Only pa-

tients whocouldbe extubated (were it notfor agitated delirium)

were recruited. Althoughwe cannotsayif the results apply to

patients with agitated delirium in the ICU earlier in their ill-

nesses,the dexmedetomidine sedative trials provide reassur-

ing evidence of safety and a suggestion of efficacy in this

patient group.

Wecannot comment on whetherdexmedetomidinemight

be effective in patients with traumatic brain injury or demen-

tia. However, there is no evidence that dexmedetomidine

would harm such patients. Resolution of delirium wasone of

the most importantend points, but identification of delirium

in critically ill patientsis problematic, as previouslyargued.

Delirium wasdefined using the CAM-ICU, which hasbeen the

subject of criticism for itsfalse-positive results in thecontext

of recently discontinued sedation., Nonetheless, the

CAM-ICUis recommended by consensus guidelinesand our

study was blinded.

Even though clinicians were blinded to study drug allo-cation, dexmedetomidine often causes bradycardia, which

might have suggestedstudy drug allocation.However, in agi-

tatedpatientsreceivingstrongdosesof sedatingdrugsto avoid

self-injury, changes in heart rate are common.

Conclusions

Among patients with agitated delirium receiving mechanical

ventilation in the ICU, the addition of dexmedetomidine to

standard carecomparedwith standard carealone(placebo)re-

sulted in moreventilator-free hoursat days. Thefindingssup-

port the use of dexmedetomidine in patientssuch as these.

ARTICLE INFORMATION

Published Online: March15, 2016.

doi:10.1001/jama.2016.2707 .

Author Affiliations: Burns,Trauma, and Critical

CareResearchCentre,University of Queensland

and JointHealth Command, Australian Defence

Force, Brisbane,Australia (Reade);Austin Hospital,

Melbourne, Australia (Eastwood); School of

Medicine,University of Melbourneand Austin

Hospital, Melbourne,Australia (Bellomo);

Australian and New Zealand IntensiveCare

ResearchCentre,School of PublicHealth and

Preventive Medicine, Monash University,

Melbourne, Australia (Bailey); Flinders Medical

Centre, Adelaide, Australia (Bersten);Toowoomba

Hospital, Toowoomba, Australia (Cheung);

PeninsulaHealth, Melbourne,Australia(Davies);

Royal North Shore Hospital of Sydney, Sydney,

Australia (Delaney);Northern Hospital, Melbourne,

Australia (Ghosh);CanberraHospital,Canberra,

Australia (vanHaren);Royal MelbourneHospital,

Melbourne, Australia (Harley); Christchurch

Hospital, Christchurch, NewZealand (Knight);

Auckland CityHospital,Auckland, NewZealand

(McGuiness); WesternHospital,Melbourne,

Australia (Mulder);Royal Brisbane and Women’s

Hospital, Brisbane,Australia(O’Donoghue);

Geelong Hospital, Geelong, Australia (Simpson);

WellingtonHospital, Wellington, New Zealand

DexmedetomidinePlus Standard Carein Patients WithAgitatedDelirium Preliminary Communication Research

jama.com (Reprinted) JAMA April 12,2016 Volume 315, Number14 1467



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(Young);Medical ResearchInstituteof

New Zealand, Wellington (Young).

Author Contributions: DrReadehad fullaccess to

allof thedatain thestudy andtakes responsibility

fortheintegrity ofthe data andthe accuracy ofthe

data analysis.

Study concept and design: Reade, Eastwood,

Bellomo.

Acquisition, analysis, or interpretation of data: All

authors.Drafting of themanuscript:Reade, Eastwood,

Bellomo, Young.

Critical revision of themanuscriptfor important

intellectual content: All authors.

Statistical analysis: Reade, Bailey.

Obtained funding:Reade, Bellomo, Young.

Administrative, technical, or material support: All

authors.

Study supervision: Reade, Eastwood.

Conflict of Interest Disclosures: Theauthorshave

completedand submitted theICMJE Form for

Disclosureof PotentialConflicts of Interest.

DrReadereported receivingsingle feeof A$1000in

2009to contributeto a Hospira clinician advisory

boardpreparing guidelines fortheuse of

dexmedetomidine. Dr Young reportedreceiving

grants and personal feesfrom Baxter HealthcareCorporation. No other disclosureswere reported.

Funding/Support: This studywas partlyfunded by

Hospira Australia through an unrestricted grantof

A$25000plus freestudy drugsupply.Individual

site funding wassupplemented bygrants from the

WellingtonHospitalResearchOffice and theAustin

Hospital IntensiveCare SpecialistsTrustFund.

Roleof the Funder/Sponsor:Thefundershad no

role inthe designand conductof thestudy;

collection,management, analysis, and

interpretationof the data;preparation or approval

of themanuscript; ordecisionto submitthe

manuscript forpublication.

Group Information: TheDahLIA Investigators were

Vic Bennett, JasminBoard, Andrew Davies, Vinodh

Nanjayya,and Shirley Vallance(Alfred Hospital,Melbourne, Australia);Rinaldo Bellomo,Glenn M.

Eastwood,Leah Peck, and HelenYoung(Austin

Hospital, Melbourne, Australia);Charlotte Firth,

EileenGilder, MikeGillham, Lianne McCarthy, Shay

McGuiness, and Rachael Parke (Auckland City

Hospital, Auckland, NewZealand);Natalie Brook,

ElishaFulton,Amy Harney,Frankvan Haren, Katie

Milburn, and HelenRogers(Canberra Hospital,

Canberra,Australia); SetonHenderson,David

Knight, Jan Mehrtens,PatrickSeigne,and Duncan

Sugden (ChristchurchHospital,Christchurch,New

Zealand);Andrew Bersten, AlanaSt John, Kate

Schwartz,and Amy Waters (FlindersMedical

Centre, Adelaide, Australia);Allison Bone,Tania

Elderkin, Melissa Fraser, Tania Salerno,and Nicholas

Simpson (GeelongHospital,Geelong,Australia);

JohnDurning,RobertFrengley, AlexKazemi, Laura

Rust,Rima Song, and AnnaTilsley (Middlemore

Hospital, Auckland, New Zealand);Angaj Ghosh,

MaryPark, and Yasmin Sungkar (NorthernHospital,

Melbourne,Australia); Benjamin Cheung, Indranil

Chatterjee, and JudySmith (ToowoombaHospital,

Toowoomba,Australia); Rachel Dunlop, Steve

O’Donoghue,Michael C. Reade, and JasonRoberts

(Royal Brisbane and Women’s Hospital, Brisbane,

Australia);AnthonyDelaney, Naomi Hammond,

AnneO’Connor, and Melissa Passer (Royal North

Shore Hospital of Sydney, Sydney, Australia);

DeborahBarge, Nerina Harley, Andrea Jordan, and

Elizabeth Moore (Royal MelbourneHospital,

Parkville,Australia); Lynn Andrews, DickDinsdale,

Kristy Whitelaw, and PaulYoung(Wellington

Hospital, Wellington, NewZealand);and Samantha

Bates, AnnaTippett, Forbes McGain, and John

Mulder (WesternHospital,Melbourne, Australia).

Thedata and safety monitoring committee

comprisedPaul Myles, MD,FANZCA,Enjarn Lin,

MBBS, FANZCA, and DavidDaly,MBBS, FANZCA

(all 3 at theAlfred Hospital, Melbourne, Australia).

Thecommittee was not compensated forits work.

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http://www.ncbi.nlm.nih.gov/pubmed/11430542http://www.ncbi.nlm.nih.gov/pubmed/11430542http://www.ncbi.nlm.nih.gov/pubmed/11430542http://www.ncbi.nlm.nih.gov/pubmed/17133176http://www.ncbi.nlm.nih.gov/pubmed/17133176http://www.ncbi.nlm.nih.gov/pubmed/17133176http://www.ncbi.nlm.nih.gov/pubmed/15082703http://www.ncbi.nlm.nih.gov/pubmed/15082703http://www.ncbi.nlm.nih.gov/pubmed/15082703http://www.ncbi.nlm.nih.gov/pubmed/15082703http://www.ncbi.nlm.nih.gov/pubmed/24088092http://www.ncbi.nlm.nih.gov/pubmed/24088092http://www.ncbi.nlm.nih.gov/pubmed/24088092http://www.ncbi.nlm.nih.gov/pubmed/21926597http://www.ncbi.nlm.nih.gov/pubmed/21926597http://www.ncbi.nlm.nih.gov/pubmed/21926597http://www.ncbi.nlm.nih.gov/pubmed/21926597http://www.ncbi.nlm.nih.gov/pubmed/11511942http://www.ncbi.nlm.nih.gov/pubmed/11511942http://www.ncbi.nlm.nih.gov/pubmed/11511942http://www.ncbi.nlm.nih.gov/pubmed/11511942http://www.ncbi.nlm.nih.gov/pubmed/21812509http://www.ncbi.nlm.nih.gov/pubmed/21812509http://www.ncbi.nlm.nih.gov/pubmed/21812509http://www.ncbi.nlm.nih.gov/pubmed/21812509http://www.ncbi.nlm.nih.gov/pubmed/11730446http://www.ncbi.nlm.nih.gov/pubmed/11730446http://www.ncbi.nlm.nih.gov/pubmed/11730446http://www.ncbi.nlm.nih.gov/pubmed/11730446http://www.ncbi.nlm.nih.gov/pubmed/10446819http://www.ncbi.nlm.nih.gov/pubmed/10446819http://www.ncbi.nlm.nih.gov/pubmed/10446819http://www.ncbi.nlm.nih.gov/pubmed/10446819http://www.ncbi.nlm.nih.gov/pubmed/12421743http://www.ncbi.nlm.nih.gov/pubmed/12421743http://www.ncbi.nlm.nih.gov/pubmed/12421743http://www.ncbi.nlm.nih.gov/pubmed/12421743http://www.ncbi.nlm.nih.gov/pubmed/19454032http://www.ncbi.nlm.nih.gov/pubmed/19454032http://www.ncbi.nlm.nih.gov/pubmed/19454032http://www.ncbi.nlm.nih.gov/pubmed/19454032http://www.ncbi.nlm.nih.gov/pubmed/18522520http://www.ncbi.nlm.nih.gov/pubmed/18522520http://www.ncbi.nlm.nih.gov/pubmed/18522520http://www.ncbi.nlm.nih.gov/pubmed/18522520http://www.ncbi.nlm.nih.gov/pubmed/18073360http://www.ncbi.nlm.nih.gov/pubmed/18073360http://www.ncbi.nlm.nih.gov/pubmed/18073360http://www.ncbi.nlm.nih.gov/pubmed/19188334http://www.ncbi.nlm.nih.gov/pubmed/19188334http://www.ncbi.nlm.nih.gov/pubmed/19188334http://www.ncbi.nlm.nih.gov/pubmed/22436955http://www.ncbi.nlm.nih.gov/pubmed/22436955http://www.ncbi.nlm.nih.gov/pubmed/22436955http://www.ncbi.nlm.nih.gov/pubmed/23269131http://www.ncbi.nlm.nih.gov/pubmed/23269131http://www.ncbi.nlm.nih.gov/pubmed/23269131http://www.ncbi.nlm.nih.gov/pubmed/23269131http://www.ncbi.nlm.nih.gov/pubmed/23719785http://www.ncbi.nlm.nih.gov/pubmed/23719785http://www.ncbi.nlm.nih.gov/pubmed/23719785http://www.ncbi.nlm.nih.gov/pubmed/21521683http://www.ncbi.nlm.nih.gov/pubmed/21521683http://www.ncbi.nlm.nih.gov/pubmed/21521683http://www.ncbi.nlm.nih.gov/pubmed/10446827http://www.ncbi.nlm.nih.gov/pubmed/10446827http://www.ncbi.nlm.nih.gov/pubmed/10446827http://www.ncbi.nlm.nih.gov/pubmed/10446827http://www.ncbi.nlm.nih.gov/pubmed/19915454http://www.ncbi.nlm.nih.gov/pubmed/19915454http://www.ncbi.nlm.nih.gov/pubmed/19915454http://www.ncbi.nlm.nih.gov/pubmed/22963220http://www.ncbi.nlm.nih.gov/pubmed/22963220http://www.ncbi.nlm.nih.gov/pubmed/22963220http://www.ncbi.nlm.nih.gov/pubmed/22963220http://www.ncbi.nlm.nih.gov/pubmed/23921976http://www.ncbi.nlm.nih.gov/pubmed/23921976http://www.ncbi.nlm.nih.gov/pubmed/23921976http://www.ncbi.nlm.nih.gov/pubmed/23921976http://www.ncbi.nlm.nih.gov/pubmed/24423152http://www.ncbi.nlm.nih.gov/pubmed/24423152http://www.ncbi.nlm.nih.gov/pubmed/24423152http://www.ncbi.nlm.nih.gov/pubmed/24423152http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.2707http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.2707http://www.ncbi.nlm.nih.gov/pubmed/24423152http://www.ncbi.nlm.nih.gov/pubmed/24423152http://www.ncbi.nlm.nih.gov/pubmed/23921976http://www.ncbi.nlm.nih.gov/pubmed/23921976http://www.ncbi.nlm.nih.gov/pubmed/22963220http://www.ncbi.nlm.nih.gov/pubmed/22963220http://www.ncbi.nlm.nih.gov/pubmed/19915454http://www.ncbi.nlm.nih.gov/pubmed/10446827http://www.ncbi.nlm.nih.gov/pubmed/10446827http://www.ncbi.nlm.nih.gov/pubmed/21521683http://www.ncbi.nlm.nih.gov/pubmed/23719785http://www.ncbi.nlm.nih.gov/pubmed/23269131http://www.ncbi.nlm.nih.gov/pubmed/23269131http://www.ncbi.nlm.nih.gov/pubmed/22436955http://www.ncbi.nlm.nih.gov/pubmed/19188334http://www.ncbi.nlm.nih.gov/pubmed/18073360http://www.ncbi.nlm.nih.gov/pubmed/18522520http://www.ncbi.nlm.nih.gov/pubmed/18522520http://www.ncbi.nlm.nih.gov/pubmed/19454032http://www.ncbi.nlm.nih.gov/pubmed/19454032http://www.ncbi.nlm.nih.gov/pubmed/12421743http://www.ncbi.nlm.nih.gov/pubmed/12421743http://www.ncbi.nlm.nih.gov/pubmed/10446819http://www.ncbi.nlm.nih.gov/pubmed/10446819http://www.ncbi.nlm.nih.gov/pubmed/11730446http://www.ncbi.nlm.nih.gov/pubmed/11730446http://www.ncbi.nlm.nih.gov/pubmed/21812509http://www.ncbi.nlm.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Dahlia RCT