JOURNAL CLUB

LONG-TERM COGNITIVE IMPAIRMENT AFTER CRITICAL ILLNESS

JOÃO MELO ALVES, MDLISBOA, PORTUGAL

--INTERNAL MEDICINE ICU

DIRECTOR: PROF. VAN-HEERDEN VERNON, MD

HADASSAH EIN KEREM UNIVERSITARY HOSPITAL JERUSALEM

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THE STUDY

BRAIN-ICUBringing to Light the Risk Factors and Incidence of Neuropsychological

Dysfunction in ICU survivors

Pratik Pandharipande, MD

American Board of Anesthesiology – Anesthesiology & Critical Care

American College of Critical Care Medicine – Fellow

Professor of Anesthesiology, Vanderbilt University School of Medicine

Multicenter prospective cohortNashville (Tennessee, USA)

Vanderbilt University Medical Center Saint Thomas Hospital

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DEFINITIONS

“use of a correct terminology is a key factor to

spread the knowledge on clinical conditions”

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DEFINITIONS

DELIRIUM

MCIDementia

POCD(…)

A. Morandi, PP Pandharipande et. alBest Pract Res Clin Anaesthesiol 26 (2012) 267-276

LTCI-CI

DELIRIUM

Disturbance of consciousness with inattention

Acute change in cognition(memory, disorientation, language, perception)

Acute onset (hours to days) & fluctuating course

Clinical evidence that it is secondary to a medical condition

TIME COURSE

Prevalent

Incident

Persistent

MOTORIC SUBTYPES

Hyperactive

Hypoactive

Mixed

Subsyndromal

Sumperimposed on dementia

DSM-IV-TRDiagnostic and Statistical Manual 4th ed. American

Psychiatric Association. APA Press, 2013.

DEFINITIONS

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LTCI-CILong-term cognitive impairment after critical illness

RBANSRepeatable Battery for the Assessment of Neuropsychological Status

TWO TESTS < 2 S.D.THREE TESTS < 1.5 S.D.

MCI

AD

(…)

A. Morandi, PP Pandharipande et. alBest Pract Res Clin Anaesthesiol 26 (2012) 267-276

DEFINITIONS

PROLOGUE

JOURNAL CLUB

EPILOGUE

LTCI-CILong-term cognitive impairment after critical illness

RBANSRepeatable Battery for the Assessment of Neuropsychological Status

TWO TESTS < 2 S.D.THREE TESTS < 1.5 S.D.

MCI

AD

(…)

A. Morandi, PP Pandharipande et. alBest Pract Res Clin Anaesthesiol 26 (2012) 267-276

DEFINITIONS

PROLOGUE

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EPILOGUE

Reitan RM. Percept Mot Skills 1958 (8)

LTCI-CILong-term cognitive impairment after critical illness

RBANSRepeatable Battery for the Assessment of Neuropsychological Status

TWO TESTS < 2 S.D.THREE TESTS < 1.5 S.D.

MCI

AD

(…)

A. Morandi, PP Pandharipande et. alBest Pract Res Clin Anaesthesiol 26 (2012) 267-276

DEFINITIONS

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LTCI-CI

Small cohorts

Individual disease processes

Large studies lacking in-hospital

RF assessment

LIMITED

EVIDENCE

Multicenter prospective cohort study of a diverse critically ill population

Prevalence of LTCI-CI

Hypothesis: duration of delirium, doses of sedation/analgesia?

BACKGROUND

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EPILOGUE

ADULTSmedical or surgical ICU

respiratory failurecardiogenic shock

septic shock(…)

DELIRIUMNumber of hospital days

SEDATION / ANALGESIA

3 MONTHS

12 MONTHS

IN-HOSPITAL

POST-DISCHARGE

METHODS

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EPILOGUE

ADULTSmedical or surgical ICU

respiratory failurecardiogenic shock

septic shock(…)

DELIRIUMNumber of hospital days

SEDATION / ANALGESIA

3 MONTHS

12 MONTHS

IN-HOSPITAL

POST-DISCHARGE

METHODS

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Covariates

Age

Years of education

Chronic disease burden (Charlson comorbidity index)

Preexisting cognitive impairment (short IQCODE)

Cerebrovascular disease (Framingham Stroke Risk Profile)

Apolipoprotein E genotype

Daily SOFA

Mean daily dose Haloperidol

Duration of severe sepsis, hypoxemia, coma

Multiple linear regression

adjustament for covariates

separate models for 3 and 12 months

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RESULTS

March 2007 – May 2010821 patients

HOSPITAL

MONTH 3

MONTH 12

74% had delirium

569 survivors

510 survirors

COGNITIVE TESTING

448

382

467 patients underwent follow-upat 3 and/or 12 months

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RESULTS

3m 12m

Median RBANS global cognition score

-1.5 σ

≤ moderate TBI 40% 34%

≤ mild Alzheimer’s (-2 σ) 26% 24%

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RESULTS

3m 12m

Median RBANS global cognition score

-1.5 σ

≤ moderate TBI 40% 34%

≤ mild Alzheimer’s (-2 σ) 26% 24%

Impairment not limited to older patients or those with coexisting conditions at baseline:

<49 yo previously healthy, 12m34% ≤ moderate TBI

20% ≤ mild Alzheimer’s

Mild Alzheimer’s predominantly affects delayed memory, but…

LTCI is multidomain

3 MONTHS

12 MONTHS

IN-HOSPITAL

POST-DISCHARGE

RESULTS – RISK FACTORS

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p=0.001 p=0.004

p=0.04 p=0.007

Global RBANS Executive function

DELIRIUM

SEDATION / ANALGESIA

individual RBANS

domains

3 MONTHS

12 MONTHS

IN-HOSPITAL

POST-DISCHARGE

RESULTS – RISK FACTORS

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p=0.001p=0.004p=0.04

p=0.04 p=0.007

Global RBANS Executive function

DELIRIUM

SEDATION / ANALGESIA

individual RBANS

domains

Benzodiazepines Opiates PPF Dexmedetomidine

3 MONTHS

12 MONTHS

IN-HOSPITAL

POST-DISCHARGE

RESULTS – RISK FACTORS

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EPILOGUE

p=0.001 p=0.004

p=0.04 p=0.007

Global RBANS Executive function

DELIRIUM

SEDATION / ANALGESIA

individual RBANS

domains

Causal role?

Mechanisms? Inflammation and neuronal apoptosis brain atrophy and loss of white matter

integrity

Van Gool WA et al. Lancet 2010 (375)Cunningham C. Biochem Soc Trans 2011 (39)

Gunther ML et al. Crit Care Med 2012 (40)Morandi A et al. Crit Care Med 2012 (40)

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DISCUSSION

≤Alzheimer’s ≤ TBI

These profound cognitive deficits were new in the majority of patients,

and affected both old and young patients, regardless of the burden of

coexisting illnesses at baseline

Longer duration of delirium worse long-term global cognition and executive function

Independent of sedation, analgesia, age, preexistent cognitive impairment, coexisting conditions and SOFA score

Groundbreaking study

A role for interventions targeted at reducing delirium duration?

Limitations

Previous cognitive function not assessed

Patients with incomplete data

Unmeasured confounders?

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DISCUSSION

Reliability of delirium assessment

Letter to the editor (NEJM 370;2 p184)

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BEYOND THE JOURNAL CLUB

“sedation confounds delirium assessement, especially with the CAM-ICU”

“patients who are awake in the ICU have a much lower prevalence of

delirium than more sedated patients”

“as sedation decreases and RASS increases, rate of delirium assessed by

CAM-ICU drops precipitously”

“unequivocally establishes”

“ a new standard of longitudinal cognitive-outcome studies”

“herculean efforts to track patients and conduct blinded cognitive assessments”

“prior observations suggesting drug exposures are clear risk factors were not supported”

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BEYOND THE JOURNAL CLUB

Herridge M, Cameron JI. NEJM 369;14

“unequivocally establishes”

“ a new standard of longitudinal cognitive-outcome studies”

“herculean efforts to track patients and conduct blinded cognitive assessments”

“prior observations suggesting drug exposures are clear risk factors were not supported”

PROLOGUE

JOURNAL CLUB

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BEYOND THE JOURNAL CLUB

Herridge M, Cameron JI. NEJM 369;14

“it would be important to gain an appreciation of how the brain-activity interface affects functional independence, quality of life and patient-

centered outcomes (…) job loss, healthcare utilization, family caregivers”

“risk stratification will help distinguish patients who can regain functional independence and those who have exhausted their organ

reserve and rehabilitive potential and who live in the purgatory of critical illness only to have unacceptably poor outcomes”

“should fuel an informed discussion about what it means for our patients to survive and episode of critical illness (…) when the degree of suffering and futility becomes unacceptable from a patient-centered and societal

standpoint”

Duration of ICU delirium vs. disability and physical health status

N=126

CAM-ICU vs. Katz activities of daily living (…)

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BEYOND THE JOURNAL CLUB

Crit Care Med 2014 (42)

worse activities of daily living scores at 12m (p=0.002)worse motor-sensory function (p=0.02)

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BEYOND THE JOURNAL CLUB

Lancet Resp Med 2014 (2)

3 months 12 months

depression 37% 33%

PTSD 7% 7%

basic activities of daily living 32% 27%

instrumental activities of daily living 26% 23%

(no consistent association between delirium and outcomes…)

BEYOND THE JOURNAL CLUB

PREVENT

Orientation protocols

Cognitive stimulation

Physiologic sleep (e.g. lighting, earplugs)

Early mobilization, avoid restraints

Visual/hearing aids

Monitor orders (e.g. bzd)

Pain

BUNDLES!

TREAT THE

CAUSE

MANAGE SYMPTOMS

Hyperactive only!

Nonpharmacological interventions

LOW DOSE, SHORT ACTING, PRN drugs

Neuroleptics

Atypical antipsichotics

BZD

CholE inhib?

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(A FEW) FINAL WORDS

COMPAY SEGUNDO (1907-2003)

MANUEL DE OLIVEIRA (1908-2015)

1. Pandharipande PP et al. Long-term cognitive impairment after critical illness. N Engl J Med 369 (2013);14,

1306-1316

2. Morandi A, Pandharipande PP et al. Understanding terminology of delirium and long-term cognitive

impairment in critically ill patients. Best Pract Res Clin Anaesthesiol 26 (2012) 267-276

3. Herridge M, Cameron JI. Disability after critical illness (editorial). N Engl J Med 2013 (369:14)

4. Fraser GL, Riker RR, Coursin DC. (letter to the editor).N Engl J Med 2014 (370:2)

5. Brummel NE et al. Delirium in the ICU and subsequent long-term disability among survivors of

mechanical ventilation. Crit Care Med 2014 (42:2)

6. Jackson JC et al. Depression, post-traumatic stress disorder and functional disability in survivors of

critical illness in the BRAIN-ICU study: a longitudinal cohort study. Lancet Respir Med 2014 (2)