Neerlandetal.BMCGeriatrics (2015) 15:7 DOI10.1186/s12877-015-0006-3 STUDY PROTOCOL Open Access The protocol of the Oslo Study of Clonidine in Elderly Patients with Delirium; LUCID: a randomised placebo-controlled trial Bjørn Erik Neerland1*†, Karen Roksund Hov1,2†, Vegard Bruun Wyller3,4, Eirik Qvigstad5, Eva Skovlund6, Alasdair MJ MacLullich7 and Torgeir Bruun Wyller1,2 Abstract Background: Deliriumaffects15%ofhospitalisedpatientsandislinkedwithpooroutcomes,yetfewpharmacological treatmentoptionsexist.Onehypothesisisthatdeliriummayinpartresultfromexaggeratedand/orprolongedstress responses.Dexmedetomidine,aparenterally-administeredalpha2-adrenergicreceptoragonistwhichattenuates sympatheticnervoussystemactivity,showspromiseastreatmentinICUdelirium.Clonidineexhibitssimilar pharmacodynamicpropertiesandcanbeadministeredorally.Wethereforewishtoexplorepossibleeffectsof clonidineuponthedurationandseverityofdeliriumingeneralmedicalinpatients. Methods/Design:TheOsloStudyofClonidineinElderlyPatientswithDelirium(LUCID)isarandomised, placebo-controlled,double-blinded,parallelgroupstudywith4-monthprospectivefollow-up.Wewillrecruit 100oldermedicalinpatientswithdeliriumorsubsyndromaldeliriumintheacutegeriatricward.Participantswill berandomisedtooralclonidineorplacebountildeliriumfreefor2days(DiagnosticandStatisticalManualof MentalDisorders(DSM-5)criteria),orafteramaximumof7daystreatment.Assessmentofhaemodynamics(blood pressure,heartrateandelectrocardiogram)anddeliriumwillbeperformeddailyuntildischargeoramaximumof 7daysafterendoftreatment.Theprimaryendpointisthetrajectoryofdeliriumovertime(measuredbyMemorial DeliriumAssessmentScale).Secondaryendpointsincludethedurationofdelirium,useofrescuemedicationfor delirium,pharmacokineticsandpharmacodynamicsofclonidine,cognitivefunctionafter4months,lengthofhospital stayandneedforinstitutionalisation. Discussion:LUCIDwillexploretheefficacyandsafetyofclonidinefordeliriuminoldermedicalinpatients. Trialregistration:ClinicalTrials.govNCT01956604.EudraCTNumber:2013-000815-26 Keywords:Delirium,Treatment,Clonidine,Drugtherapy,Double-blindmethod,Aged,Therapeuticuse,Adrenergic alpha-2ReceptorAgonists Background remains poorly understood and few treatment options Deliriuminhospitalisedmedicalpatients areavailable. Delirium commonly affects older people with acute The prevalence of delirium is at least 15% in hospita- medical illness [1,2]. It is associated with patient dis- lised medical patients [7-9]. In patients with dementia tress, increased length of stay, higher risk of new insti- theprevalenceisevenhigher,beingupto50%inmedical tutionalisation, higher mortality, and an increased risk wards[10].Oldageandpre-existingcognitiveimpairment of future dementia [3-6]. Despite its impact, delirium are the most important predisposing factors for delirium [1,9], but, in principle, any acute medical condition can precipitate delirium in a vulnerable individual [7]. Sub- *Correspondence:bjorn.erik@neerland.net syndromal delirium is a clinical condition thatfalls ona †Equalcontributors 1OsloDeliriumResearchGroup,DepartmentofGeriatricMedicine,University continuum between no symptoms and delirium defined ofOslo,Pb4956,N-0424,Oslo,Norway by the Diagnostic and Statistical Manual of Mental Fulllistofauthorinformationisavailableattheendofthearticle ©2015Neerlandetal.;licenseeBioMedCentral.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/4.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycredited.TheCreativeCommonsPublicDomain Dedicationwaiver(http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthisarticle, unlessotherwisestated. Neerlandetal.BMCGeriatrics (2015) 15:7 Page2of14 Disorders-5 (DSM-5) [11]. Subsyndromal delirium may alpha-2-adrenoreceptors. Clonidine is a partial agonist progresstofull-scaledelirium,andisaclinicallyimportant with an alpha-2a-to-alpha-1 selectivity ratio of 39. For condition associated with poor outcomes. Efforts to dexmedetomidine this ratio is 1300 [28]. They exert a prevent, detect and treat subsyndromal delirium are general inhibitoryinfluence on thesympathetic nervous thusjustified. system, inparticulardue to CNS effects [29].Dexmede- tomidine decreases sympathetic activity and attenuates Pathophysiologyofdelirium the hemodynamic and neuroendocrinal stress responses The pathophysiology of delirium remains poorly under- (including of cortisol), resulting in decreased heart rate stood. Leading hypotheses focus on neurotransmission, (HR) and blood pressure (BP) as well as sedative and inflammation and acute stress as possible mechanisms analgesic effects [30]. In the intensive care setting, both [12]. Decreased cholinergic activity and increased dopa- substances reduce the need for opioids and sedatives minergic activity in the central nervous system (CNS) [31]. Dexmedetomidine is increasingly used in intensive are commonly postulated, with these neurotransmitter care patients, and is also used as an adjuvant during deficits resulting from multiple precipitants. A causal regional anaesthesia. Recently conducted studies indi- association between inflammation (pro-inflammatory catethattheincidenceofdeliriumislowerinintensivecare cytokines) and delirium has also been proposed [13,14]. patientsreceivingdexmedetomidinethaninthosereceiving Another hypothesis implies that delirium may be the benzodiazepines [32,33], propofol [34] or morphine [35]. result of aberrant stress responses [13] as delirium com- Currentlyavailableevidencethussuggeststhatdexmedeto- monly follows stress (physical or psychological). And midine may have value in the prevention and treatment whilst stress responses are adaptive in young people, of delirium in the intensive care unit [36,37]. Indeed, it theymightbealteredwithageing,leadingtoexaggerated isnowinclinicaluseintheUSAandEurope[38]. and more prolonged stress responses. This hypothesis Most patients with delirium are however treated out- would also imply alterations of autonomic nervous side of intensive care units, where intravenous use of systemactivityinpatientswithdelirium[15]. dexmedetomidine is not feasible. An alternative agent mightthusbeorallyadministredclonidine,whichhasvery Pharmacologicaltreatmentofdelirium similar pharmacodynamics to that of dexmedetomidine The hyperactive form of delirium is frequently treated [31],eventhoughitsalpha-2selectivityissomewhatlower pharmacologically, but the effect of different treatment [28]. Clonidine additionally has an independent stimula- modalities is poorly studied. The drug treatment of tory effect on the parasympathetic activity and a slight hypoactive delirium has hardly been evaluated at all. anti-inflammatory effect [39,40], further making it an Thus more research on pharmacological treatment interesting candidate for delirium treatment. This does options for delirium is urgently needed. Haloperidol also accord with the hypothesis of delirium as a conse- [16,17] and other antipsychotics (olanzapine [18], ris- quenceofaberrantstressresponses[13]. peridone [19] and quetiapine [20]) are commonly used, andthereissome,althoughweak,evidenceoftheireffi- Clinicalexperiencewithclonidine cacy[21,22].Thereisnoevidenceontheeffectsofanti- Clonidine has been used as an anti-hypertensive drug for psychoticsinpatientswithdeliriumsuperimposedupon decades, as well as for anesthesia-related applications, dementia. For patients with parkinsonism or dementia such as perioperative analgesia [29,41], sedation and with Lewy bodies, antipsychotics are generally avoided, anxiolysis, and for management of both acute postopera- leavingevenfewertreatmentoptionsforthesepatients. tive, chronic and neuropathic pain [41-43]. In one study, Antipsychotics have several drawbacks, including an use of intravenous clonidine after surgical correction of increased risk of death and cardiovascular events, sed- acute type-A aortic dissection reduced the severity of de- ation, falls risk, and cognitive impairment [23]. These lirium, improved the respiratory function and shortened risks increase with age, dementia and disability. This thelengthofstayintheintensivecareunit[44]. calls for special caution for patients with delirium super- The adverse effects of clonidine include orthostatic imposed on dementia [21]. Benzodiazepines and other hypotension, bradycardia and AV-block. Such effects are, sedatives are also frequently used, but the evidence sup- however, dependent on dosage. In a previous report, porting these agents is even weaker [24]. There is no low-dose treatment (75 μg) in healthy adults was associ- clear evidence for the efficacy of cholinesterase inhibi- ated with a reduction in heart rate from 72 beats/min to tors inthetreatmentofdelirium[25-27]. 63 beats/min, and a reduction in mean arterial pressure (MAP) from 88 mmHg to 75 mmHg. Less than 50% Alpha-2-adrenoreceptoragonists experienced sedation, dry mouth or dizziness, and for Dexmedetomidine and clonidine are both alpha-2- those who reported any of these side-effects, the severity adrenoceptor agonists activating presynaptic inhibitory was mild [45]. Clonidine has been studied in outpatients Neerlandetal.BMCGeriatrics (2015) 15:7 Page3of14 with Alzheimer's dementia [46,47] and in patients with delirium.Inpublicationsontheeffectondeliriumofdex- Parkinson's disease [48,49]. Treatment with daily doses medetomidine, the plasma concentration levels are not of clonidine less than 200 mcg was well tolerated in reported.Additionally,dexmedetomidineisapproximately these patients. Relative contraindications to clonidine 8timesmoreselective(alpha2versusalpha1)thancloni- for its licensed indications include bradyarrhythmias, dine [28,31], and so pharmacokinetic data on dexmedeto- polyneuropathy, renal insufficiency and evidence of midine cannot be used to estimate effective doses of reduced cerebral and/or peripheral circulation due to clonidine. We thus have to extrapolate from pharmacoki- vesseldisease neticdataonclonidineusedforotherpurposes.Weknow thatclonidinehasbothsedativeandanxiolyticeffects,and Pharmacokineticsofclonidine that these centrally mediated effects are closely related to Maximum plasma concentration (Cmax) following oral plasmaconcentrationlevels[53,54]. administration occurs after 1–3 h [45] and reduction in In a study of adolescents with chronic fatigue syn- mean arterial pressure as well as the risk of side effects drome, adosage of50 μgtwice per dayresultediname- is highest at this peak. Cmax and area under the dian trough concentration (C ) at 0.21 μg/L after 14 0 concentration-time-curve (AUC) increase proportionally days of treatment, rising to a median level of 0.41 μg/L with increasing doses. Clonidine traverses the blood– (C ) two hours after administration of one regular max brain-barrier. The half-life during the elimination phase doseof50μg[55,56].Inastudyof healthynormotensive shows great inter-individual variation and is found to be subjects, treatment with oral clonidine 225 μg daily for between 5 and 25.5 hours. The metabolism is hepatic one week resulted in a steady state of 0.3-0.35 ng/ml. and the metabolites are inactive. Clonidine is mainly After intake of one 75 μg tablet, the serum level then excretedrenally (70%). increased to 0.7 ng/ml at 2 h. There was a significant relationship between the plasma level of clonidine and Rationalefordosageplanofclonidine sedation [53]. In subjects receiving oral clonidine 100 μg A dosage plan for clonidine is presented in Table 1. Be- twice per day for 6 weeks, plasma concentration ranged cause we are studying short-term use in anacutesetting, between 0.4 and 0.7 ng/ml (levels 2 hours after intake of we want to achieve steady-state (serum concentration 100 μg) [52]. Another study found that a single dose of levels) more quickly by using loading doses (day 1) 75 μg gave a Cmax of 0.66 ng/ml after achieving steady- under close monitoring of blood pressure. On days 2–7 state withtwo 75μgdoses [57]. we will administer a lower maintenance dose. We will The present patient population (elderly with a glom- thus give 75 μg clonidine every 3rd hour up to a max- erular filtration rate [GFR] limit of>30 ml/min) may imumof4dosesonday1,andthen75μgtwice perday. have a longer half life of clonidine due to a diminished Concentration levels of clonidine known to have renal capacity as compared to younger. Altough the clinical effects range from 0.2 to 2.0 ng/ml [50-52]. We metabolism of clonidine is hepatic, varying amounts are aiming for the lower levels, that is, between0.3 ng/ml of unmetabolised clonidine is secreted renally. Conse- (median trough concentration) and 0.7 ng/ml (maximal quently, patients may also have a higher risk of adverse concentration), because higher plasma concentration events related to the study drug. We therefore choose a levels increases the risk of adverse events, including lowerdosage,consideredsafe,of75μgtwiceper day. hypotension. Nonetheless, lower plasma concentration levels may be insufficient to give a significant effect on Loadingdoses ourprimaryendpoint. The loading dose is based on half-life. Clonidine follows To our knowledge, there are no studies of the rela- first order kinetics for elimination, and thus the mean tionshipbetweenplasmaconcentrationofclonidineand steady state is proportional to the daily dose. Doubling Table1Dosageplanforclonidine Time Safety Dosage Day1 SystolicBPhastobe>120mmHgbeforethefirstloadingdose. 75μgevery3rdhouruntilmaximum 4doses,(e.g.:at2,5,8and11p.m) Loadingdoses IfsystolicBPis<100mmHg,HR<50beats/min,orifRASSis−3orless beforeanyofthesubsequentloadingdoses,nomorestudymedication willbegivenuntiltheplannedmaintenancedosethenextmorning. IfRASSis−2,thetreatingphysicianhastoassessifIMPwillbegivenornot Day2-7 IfsystolicBPis<100mmHg,HR<50beats/min,orifRASSis−3orless 75μgBID,at8–9a.mand8–9p.m justbeforeaplanneddose,nostudymedicationwillbegivenuntilthe Maintenancedoses nextplanneddose12hourslater. IfRASSis−2,thetreatingphysicianhastoassessifIMPwillbegivenornot Neerlandetal.BMCGeriatrics (2015) 15:7 Page4of14 the total daily dose should double the mean plasma con- response) in these initial 20 patients. These data will centration level. A study showed that a single oral dose then guide further dosage for the subsequent 80 pa- of 75ug clonidine gave Cmax 0.29 ng/ml, 150ug gave tients. We are aiming for serum concentration levels be- Cmax 0.61 ng/ml and 250ug gave 1.2 ng/ml [45]. We tween0.3and0.7ng/ml, but mayaccepta smallnumber will administer up to 300 μg the first day, but as 75 ug of single measures above this range. Blood samples for every three hours. Thus, the theoretical Cmax at day serum concentration measurement will be taken 3 hours one would be significantly lower than 1.2 ng/ml, due to after the patient has taken the study drug (each time) on elimination of the drug. How much lower is difficult to day 1 and just before administration of study drug be- estimate, given the large variability in half-life (5 to tween 0800 and 0900 on day 2. The serum concentra- 25hours). tion levels and pharmacodynamic responses will be The expected maximum hypotensive effect correlates assessed by an independent Data Monitoring Commit- well with the Cmax time-point occurring after 2 hours. tee. The determination of the further dosage plan will There is an interindividual difference in the pharmaco- thus be based on both pharmacokinetics/serum concen- dynamic response to clonidine. Our loading dose is trationlevels andthe individualpatients´haemodynamic dependent on and monitored by the individual patients' responses. The further dosage plan will be approved by haemodynamicresponse(bloodpressureandheart rate). TheNorwegianMedicinesAgency. Safetyreview Study objectives A safety review will be done after we have recruited 20 Primaryendpoint patients (10 placebo and 10 clonidine). Recruitment of The endpoints and measurements for efficacy assess- the additional 80 patients will be halted until we have ment are listed in Table 2. Our primary objective is to made an assessment of the serum concentration levels, explore the potential superiority of clonidine vs placebo pharmacokinetics and -dynamics (the haemodynamic in decreasing delirium duration and severity, measured Table2Listofendpointsandmeasurementsforefficacyassessment Endpoint Measurementsforefficacyassessment Primary Deliriumtrajectory MDAS Secondary(alsowithsubanalysesforsubsyndromaldelirium andhypoactive/hyperactive/mixeddelirium) Time-to-firstdeliriumresolution DSM-5 Incidenceof“full-scale”delirium DSM-5 Severityofdelirium MDAS,OSLA Deliriumsubtype MDAS,OSLA,DelApp Useof“rescuemedication”/additionaldrugs(asothersedatives, Registrationofuseofallmedication analgeticsandantipsychotics) Lengthofhospitalstay Registrations Patientdistress ChecklistofNonverbalPainIndicators Cognitivefunctioninfollow-upafter4months MMSE-NR,Clockdrawingtest,Ten-wordsmemorytest, TrialmakingtestAandB,IQCODE,CDR Independenceinfollow-upafter4months BarthelADL,NEADL Pharmacokineticresponsetoclonidine Serumdrugconcentrations Pharmacodynamicresponsetoclonidine BP,HR,ECG,RASS,OSLA,symptomsofbradycardia, orthostatichypotensionorotherside-effects Biomarkers Bloodsamples Institutionalisation Registrations Survival Registrations Safety Sideeffectsofclonidine/in-hospitalcomplications BP,HR,ECG,sedation(RASS,OSLA),andanysymptomsof bradycardia,orthostatichypotensionorotherside-effects Neerlandetal.BMCGeriatrics (2015) 15:7 Page5of14 byMemorial DeliriumAssessmentScale(MDAS)[58]in more definite study later. We will do per protocol ana- patients diagnosed with delirium or subsyndromal delir- lyses and exposure-response analyses based on plasma- ium (according to Diagnostic and Statistical Manual of concentration. Mental Disorders, DSM-5 [59]). The primary endpoint, the trajectory of delirium, is the severity of delirium Methods and design (measured byMDAS)overtime. Studydesign The Oslo Study of Clonidine in Elderly Patients with Secondaryendpoints Delirium (LUCID) is a randomised, placebo-controlled, We will compare the actively treated group with the pla- double-blinded, parallel group study with 4 month pro- cebo group with respect to secondary endpoints shown spective follow-up (Figure 1). We aim to include 100 in Table 2. The main secondary endpoint is the duration inpatients with delirium (or subsyndromal delirium) in of delirium monitored daily by the DSM-5 diagnostic an acute geriatric ward. Patients will be randomised to criteria. We will also study the feasibility of oral cloni- orally administrated clonidine or placebo until delirium dine in a geriatric ward and effects of clonidine upon a free (by DSM-5 criteria) or no subsyndromal delirium variety of outcomes as a means to design a potentially for 2 days, or after a maximum of 7 days treatment. If Enrollment Assessed for eligibility (n > 100) Ineligible(n=?) (Reasons recorded) Randomised (n=100) Allocation Allocated to intervention(clonidine)(n=50) Allocated to control (placebo) (n=50) Received allocated intervention (n=?) Received allocated intervention (n=?) Did not receive allocated intervention (n=?) Did not receive allocated intervention (n=?) (Reasons recorded) (Reasonsrecorded) Follow-upand analysis Follow-up at discharge(n=?) Follow-up at discharge(n=?) Lost to follow-up in-hospital(n=?) Lost to follow-up in-hospital (n=?) Discontinued intervention (n=?) Discontinued intervention (n=?) (Reasons recorded) (Reasons recorded) Analysed (n=?) Analysed (n=?) Follow-upafter 4 months(n=?) Follow-upafter 4 months Lost to follow-up in-hospital (n=?) Lost to follow-up in-hospital (n=?) Discontinued intervention (n=?) Discontinued intervention (n=?) (Reasons recorded) (Reasons recorded) Analysed (n=?) Analysed (n=?) Figure1CONSORTStudyflowdiagram. Neerlandetal.BMCGeriatrics (2015) 15:7 Page6of14 the treating physician plan to discharge the patient (still backwards).Ifanyofthesetestsarepositive,ifthepatient having delirium/subsyndromal delirium), before 7 days, isdrowsy,orifthenurseand/orthetreatingphysicianfor we will end the treatment 24 hours before discharge. otherreasonssuspectsdelirium,ascertainmentofdelirium Assessmentofhaemodynamics(bloodpressure,heartrate orsubsyndromaldeliriumwillbeperformed. and ECG) and of delirium will be performed daily until discharge,oramaximumof7daysafterendoftreatment. Diagnosisofdeliriumandsubsyndromaldelirium This study will be conducted in compliance with the Thediagnosisofdeliriumwillbemadebythestudyphysi- Declaration of Helsinki and with ICH/Good Clinical ciansaccordingtoDSM-5criteriabyusinga standardised Practice. Registration of patient data will be carried out procedure(Table4).Levelofarousalwillbeassessedusing in accordance with national personal data laws. The the Richmond Agitation and Sedation Scale (RASS) [61] study design, protocol and informed consent procedures and the Observational Scale of Level of Arousal (OSLA) are approved by the Regional Medical Ethics Committee [62]. Attention will be evaluated using objective tests and the Norwegian Medicines Agency (EUDRACT (Table4)andobservationsbytheexaminerofthepatient´ number 2013-000815-26). The study is also registered at s distractibility, comprehension and tendency to lose the www.clinicaltrials.gov (NCT01956604). thread of conversation. We will also use a smartphone (Android) software application, the “DelApp” [63], which Studypopulation incorporatesaninitialtestoflevelofarousalfollowedbya We will recruit patients >65 years of age from the acute testofattention.Acutechangeinthepatient´smentalsta- geriatric ward at Oslo University Hospital. These pa- tus,andfluctuationofanydisturbance,willbeascertained tients are usually acutely admitted, arriving directly from through informant history from nursing staff and carers the emergency department, with considerable multimor- and also derived from clinical notes. Assessment of add- bidity and polypharmacy, with a high prevalence of itional mental status disturbances will be performed by infections, dehydration, acute cardiac problems, general asking the patient a listof pre-defined questions(Table 4) medical problems, functional decline and delirium. They in addition to information derived from nursing staff and might be included at admission (prevalent delirium), or clinical notes. All these assessments will be used in com- duringthestay(incidentdelirium).Patientswithprevalent bination in relation to the DSM-5 criteria. The objective delirium/subsyndromal delirium must be included within indicators(describedaboveandinTable4)willbesupple- approximately 48 hours after admission and patients mented by the assessor´s judgement regarding subjective with incident delirium/subsyndromal delirium must be featuresandafinaldiagnosismade. included within approximately 48 hours of symptom Subsyndromal delirium will be defined as evidence of onset. All patients must have current delirium/subsyn- change,inadditiontoanyoneofthese:(a)alteredarousal, dromaldeliriumatthetimeofinclusion. (b) attentional deficits, (c) other cognitive change, (d) delusions or hallucinations. DSM-5 criteria D and E Screening must be met. The severity of delirium will be assessed Patientsadmittedtothestudywardwillgothroughasim- forallincludedpatientsbyMDAS[58],basedonthetests ple screening process (see Table 3). This screening is a andinformationdescribedabove.Wewillalsoregisterthe combination of the Single Question in Delirium (SQiD) ConfusionAssessmentMethod(CAM)[64]daily. (askingonequestiontothepatient'sfriendorrelative:”Do you think (name) has been more confused in the last two Evaluatingpatienteligibility weeks?”) [60], combined with two simple attention tests According to the inclusion and exclusion criteria, ECG, (reciting the days of the week and months of the year creatinine/eGFR, body weight and blood pressure Table3Screeningfordeliriuminpatientsattheacutegeriatricward Yes No Screening SQiD □ □ Drowsiness □ □ Cannotrecitemonthsbackwards(unabletoreachJuly) □ □ Cannotrecitealltheweekdaysbackwards □ □ Staffsuspectdelirium □ □ Ascertainmentofdeliriumorsubsyndromaldelirium IfYesinanybox,dodiagnosticprocedure(DSM-5),Table4 Inclusion AllDSM-5criteria(delirium)orsubsyndromaldelirium→canbeincluded Ifthepatientmeetsalltheinclusioncriteria,thepatientwillbeincluded N Table4DiagnosticalgorithmforDSM-5delirium e e DSM-5criteria Teststobeperformedorinformationneeded DSM-5criteria rla n fullfilled? d e t YES NO a l. A.Disturbanceinattention(i.e.,reducedabilitytodirect,focus,sustain,andshift Evaluation TEST Cutoff(definitionof BM attention)andawareness(reducedorientationtotheenvironment). inattention) C G Daily Digitspanforward Lessthan5forward eria Daily Digitspanbackward Lessthan3backwards tric s Daily SAVEAHAART 2ormoreerrors (2 0 1 Initialdiagnosisonly Daysoftheweekinreverseorder Anyerror 5 ) 1 Initialdiagnosisonly Monthsoftheyearinreverseorder UnabletoreachJuly 5:7 Initialdiagnosisonly Countbackwardsfrom20to1 Anyerror Observation(bytheexaminer): Distractibility.Comprehension.Tendencytolosethetread ofconversation The“DelApp”[levelofarousaltestfollowedby countingofserially-presentedlights.Cut-off7/8outof10] B.Thedisturbancedevelopsoverashortperiodoftime(usuallyhourstoafewdays), Informanthistoryfrompatient´scarersandnursingstaff representsachangefrombaselineattentionandawareness,andtendstofluctuatein Questionstocarer/nursingstafforderivedfromclinicalnotes: severityduringthecourseofaday. Hastherebeenasuddenchangeinthepatient´smentalstate? Doesthepatientseemtobebetteratanyperiodintheday comparedtoothertimes? Hasthelevelofconsciousnessbeenaltered(drowsy/not interactingoragitated)? Sleep-wakecycledisturbances? C.Anadditionaldisturbanceincognition(e.g.,memorydeficit,disorientation,language, Questionstothepatient: visuospatialability,orperception). Orientationtotime,placeandperson Recall(3words) Whyareyouinhospital?Willastonefloatinwater?Arethere fishinthesea?(anyerror=disorganisedthinking) Questionstocarer/nursingstafforderivedfromclinicalnotes: Hastherebeenany…: Perceptualdisturbances?Sleep-wakecycledisturbances?Memory disturbances?Psychoticsymptoms? Psychomotorabnormalities? P a D.ThedisturbancesincriteriaAandCarenotexplainedbyanotherpreexisting,established, Informationfromhistory/chart/clinicalassessment ge orevolvingneurocognitivedisorderanddonotoccurinthecontextofaseverelyreduced 7 levelofarousal,suchascoma. of 1 4 Table4DiagnosticalgorithmforDSM-5delirium(Continued) N e e E.Thereisevidencefromthehistory,physicalexamination,orlaboratoryfindingsthatthe Informationfromhistory/chart/clinicalassessment rla n disturbanceisadirectphysiologicconsequenceofanothermedicalcondition,substance d intoxicationorwithdrawal(i.e.,becauseofadrugofabuseortoamedication),orexposure et toatoxinorisbecauseofmultipleetiologies. al. B Deliriumbasedonthetestsandinformationabove? AllDSM-5criteriafulfilled Yes□ No□ M C Subsyndromaldeliriumbasedonthetestsandinformationabove? Definedasevidenceofchange,inadditiontoanyoneofthese: Yes□ No□ Ge (a)alteredarousal,(b)attentionaldeficits,(c)othercognitive ria change,(d)delusionsorhallucinations. tric s CriteriaDandEmustbemet. (2 0 1 5 ) 1 5 :7 P a g e 8 o f 1 4 Neerlandetal.BMCGeriatrics (2015) 15:7 Page9of14 measurements are required. The final decision on eli- (cid:1) Adversereactionstoclonidineorexcipients(lactose, gibility will be agreed with the treating physician on saccharose) the ward. Capacity will be assessed and informed con- (cid:1) Not speakingorreadingNorwegian sent (and/or) assent obtained (see below). (cid:1) Anyotherconditionasevaluatedbythe treating physician Inclusionandexclusioncriteria Patients with delirium or subsyndromal delirium will be Informedconsentandenrolment included in this study by the study physicians. We will Informed consent is a well-known challenge in studies include patients with chronic cognitive impairment or of delirium [65,66], both due to the nature of delirium dementiaaswellaspatientsfreefromdementia.Nursing itself and the fact that people with underlying dementia home patients are eligible. Patients must be > 65 years are most at risk of developing delirium. Cognitively old, though the average age is expected to be more than intact patients are included in this study on the basis 80 years. Further, the patient must be willing and able to ofwritten,informed consent. Wehavedevelopedacom- receivethestudymedication. prehensive information leaflet for cognitively intact Inclusioncriteria patients anda simplified and shortened version for those All of the following conditions must apply to the pro- who are partly or not at all competent to give their spectivepatientatscreeningpriortoreceivingstudyagent: consent. For patients considered to lack capacity (due to severe delirium and/or dementia), but who are willing to (cid:1) Patient >65years oldadmitted totheacute, take part, we will obtain proxy informed consent from a medical, geriatricward close relative. Consent to remain in the research will be (cid:1) Delirium orsubsyndromaldeliriumwithin thelast obtained as soon as possible if capacity returns. Due to 48hours the importance of including patients as soon as possible (cid:1) Signedinformedconsent frompatientorrelatives after the diagnosis of delirium is made, the close rela- andexpectedcooperationofthe patientsforthe tivesmaygive verbalconsent(byphone)beforerandom- treatment andfollow upmustbeobtained and isation and the written consent will be obtained as soon documented as possible after inclusion. We have good experience with this method from previous studies in our research Exclusioncriteria group [67]. Patients will be excluded from the study if they meet any ofthefollowingcriteria: Randomisationandblinding The randomisation is based on computer-generated ran- (cid:1) Symptomaticbradycardia,bradycardia dueto sick- dom numbers, and will be carried out by a statistician. sinus-syndrome, second- orthird- degree AV-block The randomisation schedule will be distributed to the (ifnottreatedwithpacemaker)oranyother reason producer of the study medication, and capsules made causing HR<50 bpmattimeofinclusion[44]. accordingly. The randomisation will be stratified with (cid:1) Symptomatichypotensionor orthostatic respect to whether or not the patient was admitted from hypotension,ora systolic BP<120atthetime of a nursing home, in order to balance the groups with inclusion respect to pre-admission cognitive decline, independ- (cid:1) Ischemic stroke withinthe last3monthsorcritical enceandcomorbidity,allimportant prognosticfactors. peripheralischemia (cid:1) Acutecoronarysyndrome,unstableorseverecoronary Studymedication heartdisease(symptomsatminimalphysicalactivity; Each capsule (CAPSUGEL) will contain either 75 μg NYHA3and4)andmoderatetosevereheartfailure Catapresan (clonidine hydrochloride) or 75 μg placebo, (NYHA3and4).(Acutecoronarysyndromeisdefined and will be produced and labeled by Kragerø tablettpro- accordingtointernationalguidelines) duksjon A/S. The capsules containing active medication (cid:1) Adiagnosisofpolyneuropathy, phaeochromocytoma and placebo will look identical. If other medications are orrenalinsufficiency(estimatedGFR<30ml/min indicated for the treatment of delirium, the treating accordingto theMDRD formula)[44] physicianwillprescribethis as“standard care”. (cid:1) Bodyweight<45 kg (cid:1) Consideredasmoribundonadmission Monitoringandsafety (cid:1) Unable totakeoralmedications BP and HR will be monitored 3 hours after each loading (cid:1) Currentuseoftricyclicantidepressants,monoamine dose (day 1) and then just before every dose. If there are reuptake inhibitorsorciclosporin signsofsignificanthypotension(systolicBP<100mmHg)or (cid:1) Previously includedinthisstudy bradycardia (heart rate <50 beats/min), further monitoring Neerlandetal.BMCGeriatrics (2015) 15:7 Page10of14 or treatment will be considered individually. During the We will also collect data about patient distress, using whole treatment period blood pressure and heart rate items from The Checklist of Nonverbal Pain Indicators will be assessed twice per day. ECG, serum creatinine, (CNPI) [79]. Possible and suggestive causes of delirium blood glucose and a clinical assessment by a physician areregisteredineachcaseatdischarge. (hydration,side-effects,RASS[61]andOSLA[62])willbe performed daily. Orthostatic BPtests will be performed Laboratorytestsandbloodsampleprocedures during the hospital stay at day 5, 6 or 7 at 1100 (approxi- Data from routine blood samples taken at admission will mately3hoursafteradministrationofstudydrug). be recorded (including Erythrocyte Sedimentation Rate, For all patients, drug concentration (mean concentra- Haemoglobin, Leukocytes, Creatinine, Electrolytes, C- tion just before intake and Cmax 3 hours after intake) reactive protein, Albumin,Thyroid stimulating hormone will be measured at day 5, 6 or 7. The pharmacokinetics andfreeThyroxinelevels). ofclonidine variesinter-individually,possibly influencing All patients will have blood drawn for drug concentra- individual treatment responses. But due to the short tion levels at day 5, 6 or 7 (just before and 3 hours after treatment period, measurement of drug concentration intake of study medication), to be able to compare pos- forindividualdrug modification isnot feasible. sible effects and side-effects to the actual plasma- concentration atthe endofthetrial. Datacollection Our study population is expected to have significant Demographic data, medical history, information regard- acute and chronic comorbidity. In this aspect, looking ing the acute underlying medical disease(s), drug use for new biomarkers is challenging, as we do not have a and proxy information will be collected during the delirium-free control group. We will however take blood hospital stay. Once included in the study, patients will samples (serum and plasma) for biomarkers at inclusion, be visited daily for efficacy and safety evaluations by the at mid-stay (day 3–5) and at discharge, to explore study physicians (geriatricians) or by the consultant markers already known to be associated with delirium. on-call duringtheweekend. Interesting biomarker candidates include S100B [80,81], We will assess pre-existent functional and cognitive neopterin [82], IGF-1 [83], MMP-9, protein C, sTNFR1 status by asking the patient’s primary caregiver (the [84]. The serum and plasma will be stored in a biobank bestavailablesource)tocompletequestionnairestoas- freezer at Oslo University Hospital together with blood sess the patient´s functional and cognitive state two stored inEDTAtubes forpossible DNA-analyses. weeks prior to hospital admission. Functional status will be assessed using the Barthel ADL Index [69] and Follow-upassessments the Nottingham Extended ADL Index (NEADL) [70]. We will phone the patient or care-taker by phone one To ascertain prior long-term cognitive decline we will week after the end of the treatment to consider possible use the Informant Questionnaire on Cognitive Decline side-effects/ rebound effects or relapse of the delirium. in the Elderly (IQCODE) [71] and the Clinical Demen- No physical examination or psychometric tests will be tia Rating Scale (CDR) [72]. The Mini-Mental State performed. We will register the level of care, and Evaluation – Norwegian version (MMSE-NR) [73,74] whether the patient has been discharged home or to an will be performed at baseline and at discharge for the institution. purposes of general cognitive screening. The Cornell Four months after discharge, a home visit will be done DepressionScale[75,76]isbasedonproxyinformation to perform cognitive tests (see Table 2). Based on proxy and will be used to evaluate the degree of depressive information, we will evaluate each patient´s level of in- symptoms. dependence and functional and cognitive status. We will Grip strength of the dominant hand will be measured assess the presence of persistent delirium (according to using hand-held dynamometry once during the hospital DSM-5criteria) andsubsyndromaldeliriumandperform stay and at follow-up after 4 months. The severity and the MDAS. Grip strength will be measured. Level of numberofcomorbiditieswillbescoredusingtheCumula- care, any readmissions to hospital and cumulative mor- tiveIllnessRatingScale(CIRS)[77].Thelevelofphysio- tality will be registered.. Causes of death will be ascer- logical disturbance will be assessed by using Acute tained fromtheCauseofDeath Register. Physiology and Chronic Health Evaluation II (APACHE II) [78], the version utilising venous bicarbonate rather Criteriaforpatientdiscontinuation than arterial blood gases. Body Mass Index is registered Patients may be discontinued from study treatment and asamarkerofnutritionalstatus. assessmentsforseveralreasons.Theseinclude:omissionof We will use the algorithm described in the section more than 3 following dosages, voluntary discontinuation above and in Table 4 to diagnose delirium (or subsyn- by the patient, safety reasons as judged by the study phys- dromal delirium)according totheDSM-5criteria. ician or treating physician, or significant non-compliance

The protocol of the Oslo Study of Clonidine in Elderly Patients with Delirium

Similar The protocol of the Oslo Study of Clonidine in Elderly Patients with Delirium