Pharmacologic Management of Intensive Care Unit Delirium: Clinical Prescribing Practices and Outcomes in More Than 8500 Patient Encounters

Abstract

Background: Pharmacologic agents are frequently utilized for management of intensive care unit (ICU) delirium, yet prescribing patterns and impact of medication choices on patient outcomes are poorly described. We sought to describe prescribing practices for management of ICU delirium and investigate the independent association of medication choice on key in-hospital outcomes including delirium resolution, in-hospital mortality, and days alive and free of the ICU or hospital.

Methods: A retrospective study of delirious adult ICU patients at a tertiary academic medical center. Data were obtained regarding daily mental status (normal, delirious, and comatose), pharmacologic treatment, hospital course, and survival via electronic health record. Daily transition models were constructed to assess the independent association of previous day mental status and medication administration on mental status the following day and in-hospital mortality, after adjusting for prespecified covariates. Linear regression models investigated the association of medication administration on days alive and free of the ICU or the hospital during the first 30 days after ICU admission.

Results: We identified 8591 encounters of ICU delirium. Half (45.6%) of patients received pharmacologic treatment for delirium, including 45.4% receiving antipsychotics, 2.2% guanfacine, and 0.84% valproic acid. Median highest Richmond Agitation-Sedation Scale (RASS) score was 1 (0, 1) in patients initiated on medications and 0 (-1, 0) for nonrecipients. Haloperidol, olanzapine, and quetiapine comprised >97% of antipsychotics utilized with 48% receiving 2 or more and 20.6% continued on antipsychotic medications at hospital discharge. Haloperidol and olanzapine were associated with greater odds of continued delirium (odds ratio [OR], 1.48; 95% confidence interval [95% CI], 1.30-1.65; P < .001 and OR, 1.37; 95% CI, 1.20-1.56; P = .003, respectively) and increased hazard of in-hospital mortality (hazard ratio [HR], 1.46; 95% CI, 1.10-1.93; P = .01 and HR, 1.67; 95% CI, 1.14-2.45; P = .01, respectively) while quetiapine showed a decreased hazard of in-hospital mortality (HR, 0.58; 95% CI, 0.40-0.84; P = .01). Haloperidol, olanzapine, and quetiapine were associated with fewer days alive and free of hospitalization (all P < .001). There was no significant association of any antipsychotic medication with days alive and free of the ICU. Neither guanfacine nor valproic acid were associated with in-hospital outcomes examined.

Conclusions: Pharmacologic interventions for management of ICU delirium are common, most often with antipsychotics, and frequently continued at hospital discharge. These medications may not portend benefit, may introduce additional harm, and should be used with caution for delirium management. Continuation of these medications through hospitalization and discharge draws into question their safety and role in patient recovery.

Figure 1:

Prescribing Patterns for Management of Intensive Care Unit Delirium. Illustration of prescribing practices within our cohort. Of the 24,884 ICU admissions, 9,682 were diagnosed with delirium as defined by a positive assessment on the Confusion Assessment Method for the ICU (CAM-ICU). All excluded patients were excluded for home antipsychotic use as obtained from the electronic health record to obtain the final study sample cohort of 8591. Of delirious patients who received pharmacologic treatment, 3898 received antipsychotic medications, 187 received guanfacine, and 72 received valproic acid. Combinations of antipsychotic medications were also frequent with 1192 (30.6%) of antipsychotic recipients receiving a combination of two antipsychotic medications and 664 (17.0%) receiving three or more different antipsychotic medications. Definition of abbreviations: ICU = Intensive Care Unit

Figure 2:

Associations of Pharmacologic Treatment Choice on Delirium Continuation and Mortality the Following Day. Each Figure is the result of a single model performed, after adjusting for described confounders. A: Delirium Continuation Assessed using Daily Transition Model; Odds ratio of transition to delirium by medications received the day prior. Haloperidol and olanzapine were both associated with increased odds of delirium the following day (OR 1.48, 95% CI [1.30, 1.65] and OR 1.37, 95% CI [1.20, 1.56], respectively). Quetiapine, valproic acid, and guanfacine were not associated with continued delirium (OR 1.06, 95% CI [0.97, 1.17], OR 1.26, 95% CI [0.74, 2.15], and OR 1.12, 95% CI [0.72, 1.70], respectively). B: In-Hospital Mortality; Hazard of in-hospital mortality by medication received during ICU stay Haloperidol and olanzapine were associated with an increased hazard of in- hospital mortality (HR 1.46, 95% CI [1.10, 1.93] and HR 1.67, 95% CI [1.14, 2.45], respectively) while quetiapine was associated with a decreased hazard of mortality (HR 0.58, 95% CI [0.40, 0.84]). Guanfacine and valproic acid were not significantly associated with in-hospital mortality. Definition of abbreviations: ICU = Intensive Care Unit, Cl = Confidence Interval

Figure 3:

Association of Pharmacologic Management on ICU- and Hospital-Free Days. Each Figure is the result of a single model performed, after adjusting for described confounders. A: ICU-Free Days over the first 30-days following ICU admission using multivariable linear regression. There was no association of any medication administration on ICU-free days. B: Hospital-Free Days over the first 30-days following ICU admission using multivariable linear regression. Antipsychotic medications haloperidol (Difference in Mean −1.00 days, 95% CI [−1.51, −0.49]), olanzapine (Difference in Mean −1.55 days, 95% CI [−2.26, −0.84]), and quetiapine (Effect size −1.22 days, 95% CI [−1.79, −0.65]) were all associated with fewer hospital free days. Guanfacine and valproic acid had no association with hospital-free days. Definition of abbreviations: ICU = Intensive Care Unit