Clinical Trials for Prevention and Treatment of Delirium: - PowerPoint Presentation

1. Clinical Trials for Prevention and Treatment of Delirium: Overview and Novel ApproachesJohn W. Devlin, PharmD, FCCM, FCCP, BCCCPProfessor of Pharmacy, Northeastern UniversityResearch Scientist and Critical Care Pharmacist,Division of Pulmonary and Critical Care Medicine, Brigham and Women’s HospitalBoston, MA

2. DisclosuresResearch Funding:NIANHLBICIHR

3. Key Points – Prevention and TreatmentDaily risk reduction efforts is the foundation for prevention effortsMultimodal protocols using non pharmacologic-based strategies key to delirium prevention and treatmentPharmacologic interventions generally have minimal benefit:Reserve for short-term use for select patients with delirium-related symptoms3

4. Delirium Risk Factors4Predisposing FactorsAge Dementia or pre-existing cognitive impairmentHistory of deliriumFunctional impairmentSensory impairment: Vision impairmentHearing impairmentComorbidity/severity of illnessDepressionHistory of transient ischemia/stroke≥ moderate alcohol use (2 drinks per day)Inouye SK et al. Lancet 2014Generally are not modifiable

5. Delirium Risk FactorsPrecipitating FactorsMedications: Psychoactives – particularly sedative-hypnotics and opioidsAnticholinergicsCorticosteroids – higher dosesMetoclopramideMedication withdrawalPhysical restraintsBladder catheterPhysiologic and metabolic abnormalities:Elevated BUN/creatinine ratio – excessive diuresis?Abnormal sodium, glucose, or potassiumMetabolic acidosisInfectionAny iatrogenic eventMajor surgeryTrauma or urgent admission5Inouye SK et al. Lancet 2014Generallyare more modifiable

6. Dr. DRE: *Important to use a standardized approach to mitigate delirium risk factors on a daily basis during ICU IPT roundsDiseasesSepsis CHFCOPDNew organ dysfunctionHypoxemiaDRug Removal Sedative down-titration e.g. SATsStop/Reduce psychoactive medsEnvironmentImmobilizationSleep (day/night orientation)NoiseHearing aids/glasses

7. Many sources of poatential bias........Systematic deviation in the variable of interestAccounting for Delirium Risk factors in Cohort Studies

8. ICU AdmissionMultivariate, non-time dependent, cohortPatient exposure to drug X Delirium during ICU stayNo delirium during ICU stayICU DischargeRR of developing delirium with exposure to drug X during ICU stay Presence of baselinerisk factors for delirium consideredBaseline risk factors, Y/N exposure to Drug X, And Y/N ≥ 1 ICU day with delirium modelled using multivariate techniquesAccounting for Delirium Risk factors in Cohort Studies

9. ICU AdmissionMultivariate, non-time dependent, cohortICU D#4 Patient first-exposure to drug X Delirium during ICU stayNo delirium during ICU stayICU DischargeRR of developing delirium with exposure to drug X during ICU stay Presence of baselinerisk factors for delirium consideredBaseline risk factors, Y/N exposure to Drug X, And Y/N ≥ 1 ICU day with delirium modelled using multivariate techniquesAccounting for Delirium Risk factors in Cohort Studies ICU D#3 Onset of Delirium

10. Day #5 ICU stayDay # 1 ICU StayDay #2 ICU stayDay #3 ICU stayDay #4 ICU stayBaseline delirium risk factors consideredAwake, no deliriumAwake, no deliriumDeliriumDeliriumAwake, no deliriumNo Drug XDrug XDrug XDrug XNo Drug XNew onset septic shockSituations where a multivariate, non-time dependent, cohort analysis may be problematicLikely ↑ severity of illnessAccounting for Delirium Risk factors in Cohort Studies

11. Attributable mortality of delirium during the ICU admissionDelirium has been shown to be an independent predictor of death during the ICU stay in 9 studiesBut severity of illness can vary over course of ICU stay and not considered at time of delirium occurrenceCompeting events (e.g. ICU discharge, new-onset of coma) may preclude the detection of delirium before ICU death occurs Ouimet S. ICM 2007Ely EW. JAMA 2004Lin SM. CCM 2004Pisani MA AJRCCM 2009Van den Boorgaard M. Int J NS 2012Van den Boorgaard M. Crit Care 2010Lin SM J Crit Care 2008Salluh JI. Crit Care 2010Tomasi CD J Crit Care 2012Accounting for Delirium Risk factors in Cohort Studies

12. Attributable mortality of delirium during the ICU admissionN=1112 mixed medical-surgical ICU patients: 50.2% developed ≥ 1 delirium episode (median 3 days)Crude ICU mortality: 17% (delirium) vs. 7% (no delirium); p < 0.001Delirium was significantly associated with mortality in multivariate logistic regression (OR 1.77; 1.15, 2.72) and survival analysis (HR 2.08; 1.40, 3.09)After adjustment for time-varying confounders (including daily SOFA, coma and ICU discharge) using a marginal structural model: HR of ICU mortality in patients with delirium = 1.19 ; 0.75, 1.89Only 7.2% of the of the ICU deaths were attributable to deliriumKlein Klouwenberg PMC et al. BMJ 2014: 349:g6652Accounting for Delirium Risk factors in Cohort Studies

13. Time-fixed (at ICU baseline)Time-varying (daily) Admission service (e.g. medical vs surgical)Day of ICU admissionAgeDaily severity of illness (e.g. SOFA)Severity of illness (APACHE-2 score)Severe sepsisCharlson Comorbidity IndexUse of mechanical ventilationHistory of chronic alcohol usePresence of condition(s) that might drive use of the study medication (Agitation, Pain etc)History of hypertensionUse of a medication with a similar indication to the study medication (e.g., propofol if investigating benzodiazepines)History of psychoactive medication useUse of other competing medications known to affect delirium occurrence (e.g. dexmedetomidine if investigating benzodiazepines) Emergent (vs. elective) ICU admissionFactors that could affect the PK/PD response of the medication (e.g., BMI)

14. ICU Day xICU Day x+1 Awake, not deliriousAwake, not deliriousDeliriumDeliriumComaConsiderations when transitioning from one mental state to anotherAccounting for Delirium Risk factors in Cohort Studies

15. Relative Risk for each 5 mg BZ administered in midazolam equivalentsZaal I, Devlin JW, et al. Intensive Care Med 2015Accounting for Delirium Risk factors in Cohort Studies

16. Accounting for Delirium Risk factors in Randomized, Controlled Trials

17. All mechanically ventilated adults admitted to 3 different ICUs (medical n=2; surgical n=1) were evaluated q12h with SAS and the ICDSC for up to 3 days from thetime of ICU admission:Important way to reduce inclusion biasAmong the 481 patients who had SSD only 68 were randomized= 14.1% !!The Tufts MC IRB started off ‘making us” exclude patients>/=80 years from trial- DSMB helped get this upto 85 yearsImportant to carefully considerand define the criteria for stopping study intervention.Anticipated safety concerns vs. Unanticipated safety concerns

18. All mechanically ventilated adults admitted to 3 different ICUs (medical n=2; surgical n=1) were evaluated q12h with SAS and the ICDSC for up to 3 days from thetime of ICU admission:Important way to reduce inclusion biasAmong the 481 patients who had SSD only 68 were randomized= 14.1% !!The Tufts MC IRB started off ‘making us” exclude patients>/=80 years from trial- DSMB helped get this upto 85 yearsImportant to carefully considerand define the criteria for stopping study intervention.Anticipated safety concerns vs. Unanticipated safety concernsIf there is an important subgroup of patients who may respond to intervention differently: Incorporate stratification prior to randomizationIf there is major potential confounding factor that could influence response to the intervention: A priori define a subgroup analysis to evaluate whether the primary outcome differs between the two different patient groups

19. Key Points – Prevention and TreatmentDaily risk reduction efforts is the foundation for prevention effortsMultimodal protocols using non pharmacologic-based strategies key to delirium prevention and treatmentPharmacologic interventions generally have minimal benefit:Reserve for short-term use for select patients with delirium-related symptoms19

20. Nonpharmacologic Strategies – Acutely Hospitalized Medical StrategiesDescriptionOrientation/Therapeutic activitiesProvide lighting, signs, calendars, clocksReorient to time, place, person, your roleCognitively stimulating activities (e.g. reminiscing)Facilitate regular visits from family, friendsFluid repletionEncourage patients to drink; consider parenteral fluids if necessary Seek advice regarding fluid balance in patients with comorbidities (heart failure, renal disease)Early mobilizationEncourage early post-operative mobilization, regular ambulation. Keep walking aides (canes, walkers) nearby at all times Encourage active, range-of-motion exercisesFeeding assistanceFollow general nutrition guidelines and seek advice from dietician as needed Ensure proper fit of denturesVision/HearingResolve reversible causes of impairmentEnsure working hearing and visual aids are available and usedSleep enhancement Avoid medical/nursing procedures during sleep if possible Schedule medications to avoid disturbing sleep Reduce noise at night 20Hshieh T, et al. AJGP 2018

21. Delirium Prevention: Multicomponent Nonpharmacologic Bundles for Geriatric InpatientsPrior studies have found 40% of delirium is preventableMultiple successful strategies exist:Hospital Elder Life Program (Inouye 1999, 2000; Chen 2012)Cost-effective:Reduces hospital costs by up to $3800Reduces need for long term careFamilies/volunteers can help deliverProactive geriatric consultation (Marcantonio 2001)Exercise and rehabilitation interventions (Caplan 2006)21

22. Hshieh T et al. JAMA IM 2015Use of Multicomponent Non-Pharm Bundles in Geriatric InpatientsDelirium Incidence22

23. ADECFB. Vasilevskis EE, et al. Chest. 2010;138(5):1224-1233.ABCDEF Bundle ElementsAssess, Prevent and manage PainBoth SAT and SBTChoice of Analgesia and SedationDelirium: Assess, Prevent and ManageEarly Mobility and ExerciseFamily Engagement and Empowerment 

24. Pun, B; Balas, M; Barnes-Daly, MA Crit Care Med 2019ICU Liberation Collaborative: SCCM and GBMF

25. Pun, B; Balas, M; Barnes-Daly, MA et al. Crit Care Med 2019

26. 26Results: Symptom-Related OutcomesPun B, et al. Crit Care Med. 2019; 47:3-14 Dose

27. Devlin J et al. Crit Care Med 2010;38(2):419-427.VERY FEW (IF ANY) ABCDEF BUNDLE COMPONENTS WERE USED DURING 2007-2008

28. Girard TD et al. N Engl J Med 2018; 379:2506ABCDEF Protocol Rigorously Used Daily in All Study Patients

29. Girard TD et al. N Engl J Med 2018; 379:2506

30. Girard TD et al. N Engl J Med 2018; 379:2506

31. Key Points – Prevention and TreatmentDaily risk reduction efforts is the foundation for prevention effortsMultimodal protocols using non pharmacologic-based strategies key to delirium prevention and treatmentPharmacologic interventions generally have minimal benefit:Reserve for short-term use for select patients with delirium-related symptoms31

32.

33. Oh ES et al. Ann Intern Med 2019Systematic Review of Haloperidol or Second-generation Antipsychotic for Delirium Prevention in Acutely Hospitalized Adults- Search ended July 2019 - N=14 RCTs - 9 studies ICU/on-pump cardiac surgery (n=3008 patients) - 5 studies elective surgery (1273 patients)HaloperidolSecond-Gen AP

34. Oh ES et al. Ann Intern Med 2019

35. Inconsistent results and methodological limitations preclude any conclusions Delirium SeverityN =12 RCTs (924 pts) primarily non-ICU Hospital Length of Stay N=7 RCTs (1507 patients Neither haloperidol nor second-gen AP use associated with reductions in hospital LOSRoozbeh N et al, Ann Intern Med 2019

36. Roozbeh N et al, Ann Intern Med 2019Delirium Treatment RCTS with Haloperidol

37. Roozbeh N et al, Ann Intern Med 2019Delirium Treatment RCTS with Second Generation Antipsychotics

38. Should Delirium be the Primary Outcome?Prevention of DeliriumIncident deliriumICU days without deliriumTime to first delirium episodeDuration of first delirium episodeTreatment of DeliriumTime to first resolution of deliriumDuration of deliriumICU days without deliriumSeverity of the deliriumNeufeld KJ, et al. Am J Geriatr Psychiatry 2014; 22:1513Yang FM, et al. BMC Med Research Method 2013; 13:8Davis DHJ, et al. Am J Geriatr Psych 2013

39. Delirium DepressionExecutive Function Reduced Functionality Persistent Cognitive DefectsFamily stressICU memoriesQuality of LifeReturn to IndependenceICU Survival ICU Survivorship PTSD

40. Delirium EvaluationValidated screening tool vs DSM evaluation? Which screening tool to use? - CAM: strong phenotype, but potential feasibility concerns - 4AT: easy to apply, but no clear phenotypeResearcher vs bedside clinician?Frequency: Daily vs twice daily?Degree of training for evaluator

41. Key PointsDaily risk reduction efforts is the foundation for prevention effortsMultimodal protocols using non pharmacologic-based strategies key to delirium prevention and treatmentPharmacologic interventions generally have minimal benefit:Reserve for short-term use for select patients with delirium-related symptoms41