Melissa Whitehouse, PharmD Candidate 10/16/13

TITLE AND BACKGROUND

Title Long-term cognitive impairment after critical illness The bringing to light the risk factors and incidence of neuropsychological dysfunction in ICU survivors (The BRAIN-ICU) study. Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, Brummel NE, Hughes CG, Vasilevskis EE, Shintani AK, Moons KG, Geevarghese SK, Canonico A, Hopkins RO, Bernard GR, Dittus RS, Ely EW Most authors are physicians with work in critical illness, delirium, sedation or infectious disease New England Journal of Medicine: Impact factor of ~51.65 Background Delirium is common in critically ill patients and associated with death. 3 The recognition of the effects of delirium has expanded. Currently ~500 clinical trials in progress regarding delirium. ~40 of them concerning critically ill patients.4

Authors/ Journal

Rationale behind this study?

Delirium in the ICU Long-term cognitive decline Institutionalization/hospitalization $$$ $31.4 billion was spent by Medicare on skilled nursing facilities in 2011. 5 Little is known about epidemiology of long term cognitive impairment after critical illness Delirium has been associated with death and possibly long term cognitive impairment. What exactly is the relationship? Hypothesis: longer duration of delirium in the hospital and higher doses of sedative and analgesic agents are independently associated with more severe cognitive impairment.

GENERAL STUDY OVERVIEW

Funding Study Design National Institute of Health Multicenter, prospective cohort study - 2 centers: Vanderbilt University Medical Center and Saint Thomas Hospital To estimate the prevalence of long-term cognitive impairment after critical illness and to test the hypothesis that a longer duration of delirium in the hospital and higher doses of sedative and analgesic agents are independently associated with more severe cognitive impairment up to one year after hospital discharge.1

Objectives

METHODS
Enrollment Population Size Duration Inclusion/ Exclusion Criteria See enrollment appendix N= 821 March 2007- May 2010 Patients were only followed for 12 months, then released from the study. Adults admitted to a medical or surgical ICU with Excluded patients with recent ICU exposure respiratory failure, cardiogenic shock or septic that was considered substantial shock. Patients who could not be assessed for delirium (blind, deaf, inability to speak English) Patients that would be difficult to follow up with Patients unlikely to survive for 24 hours Could not get informed consent High risk for cognitive defects due to

neurodegenerative disease, cardiac surgery in last 3 months, suspected anoxic brain injury, or severe dementia Patients who had a score of 3.3 or more on Informant Questionnaire on Cognitive Decline in the Elderly test (IQCODE)

Patient Groups

There was a single cohort. Daily assessments of the patients for delirium performed using the Confusion Assessment Method for the ICU (CAM-ICU), with the Richmond Agitation-Sedation Scale (RASS) used to assess the level of consciousness aspect to the CAM-ICU method. Delirium assessments were performed on all patients daily until discharge, death, or day 30. Doses of medications were collected from patient medication record. Benzodiazepine doses were converted to midazolam for comparison and opiate doses were converted to fentanyl dose equivalents. Global cognition and executive function assessed at 3 month and 12 month follow-up using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) test and the Trail Making Test Part B (Trails B).

Endpoints

RBANS global cognition scores and Trail Making Test Part B test (Trails B) executive function scores at 3 month follow-up and 12 month follow-up. Independent risk factors: - Duration of delirium - Use of sedative/analgesic medications

Statistical Analyses

Multiple linear regression with adjustments for covariates using statistical software For missing risk factors or outcomes, they did multiple imputation. Analysis between 25th percentile and 75th percentile.

RESULTS
Baseline characteristics Mostly white Wide variety of diagnoses Median age 60 Patient characteristics are similar among cohort when assessed in the hospital and at follow-up. See table 1

Outcomes

AUTHORS CONCLUSIONS
A longer duration of delirium was an independent risk factor for worse executive function at 3 months and 12 months. The authors briefly mention an important point It is also possible that patients who are vulnerable to delirium owing to severe critical illness are also vulnerable to long-term cognitive impairment and that delirium does not play a causal role in the development of persistent cognitive impairment.

GENERALIZABILITY/CRITIQUE/DISCUSSION
Endpoints This study has shown an important correlation between the duration of delirium and long-term cognitive impairment. Surprisingly, for the majority of the sedatives and analgesics, the dose did not have a consistent correlation with long-term cognitive impairment. The authors point out that although there was no consistent correlation, does not mean that high doses are safe. Separate studies show adverse outcomes with over-sedation. This study may affect the way we treat patients in the future.

MY CONCLUSIONS
Strengths Limitations Converted all benzodiazepine doses to midazolam and all opioid doses to fentanyl so they could be combined and compared. Tried to adjust for confounding variables. Although tests used were subjective, they have been well validated. Blinded the experts evaluating the patients cognitive function. Excluded patients who had been in the ICU recently. Real picture? Additive? Patients were compared to normal values, not their baseline. Was the observation for the correlation between days of delirium and cognitive function based on looking at the graph? Didnt list a correlation coefficient. The study did not take into consideration the type of care they received in the time until follow-up assessments.

Clinical Relevance

With a longer duration of delirium, patients may be at increased risk for long-term cognitive impairment after a stay in the ICU, regardless of their age or indication. This cognitive impairment may have many negative impacts on the patients quality of life and societal finances.

Works Cited 1- Pandharipande PP, et. al. Long-term cognitive impairment after critical illness. N Engl J Med. 2013 Oct 3;369(14):1306-1316. 2- Pandharipande PP, et. al. Supplementary appendix to: Long-term cognitive impairment after critical illness. N Engl J Med. 2013 Oct 3;369(14):S1-35. 3- Ely EW, et. al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004 Apr 14;291(14):1753-62. 4- Clinicaltrials.gov: A service of the U.S. National Institutes of Health [Internet]. Accessed 10/13/2013. Available from: www.clinicaltrials.gov 5- Congressional Budget Office Medicare budget. [Internet]. 2012 Mar 13. Available from: http://www.cbo.gov/sites/default/files/cbofiles/attachments/43060_Medicare.pdf 6- Brown SE, Ratcliffe SJ, Kahn JM, Halpern SD. The epidemiology of intensive care unit readmissions in the United States. Am J Respir Crit Care Med. 2012 May 1;185(9):955-64 7- Confusion Assessment Method for the ICU (CAM-ICU) Flowsheet. Icudelirium.org [Internet]. Accessed 2013 Oct 14. Available from: http://www.icudelirium.org/docs/CAM_ICU_flowsheet.pdf 8- Richmond Agitation Sedation Scale (RASS). Icudelirium.org [Internet]. Accessed 2013 Oct 14. Available from: http://www.icudelirium.org/docs/RASS.pdf