Preventing Postoperative Delirium After Major Noncardiac Thoracic Surgery

A Randomized Clinical Trial

Babar A. Khan, MD, MS; Anthony J. Perkins, MS; Noll L. Campbell, PharmD; Sujuan Gao, PhD; Sikandar H. Khan, DO; Sophia Wang, MD; Mikita Fuchita, MD; Daniel J. Weber, MD; Ben L. Zarzaur, MD, MPH; Malaz A. Boustani, MD, MPH; Kenneth Kesler, MD

Disclosures

J Am Geriatr Soc. 2018;66(12):2289-2297. 

In This Article

Abstract and Introduction

Abstract

Objectives: To assess the efficacy of haloperidol in reducing postoperative delirium in individuals undergoing thoracic surgery.

Design: Randomized double-blind placebo-controlled trial.

Setting: Surgical intensive care unit (ICU) of tertiary care center.

Participants: Individuals undergoing thoracic surgery (N=135).

Intervention: Low-dose intravenous haloperidol (0.5 mg three times daily for a total of 11 doses) administered postoperatively.

Measurements: The primary outcome was delirium incidence during hospitalization. Secondary outcomes were time to delirium, delirium duration, delirium severity, and ICU and hospital length of stay. Delirium was assessed using the Confusion Assessment Method for the ICU and delirium severity using the Delirium Rating Scale-Revised.

Results: Sixty-eight participants were randomized to receive haloperidol and 67 placebo. No significant differences were observed between those receiving haloperidol and those receiving placebo in incident delirium (n=15 (22.1%) vs n=19 (28.4%); p = .43), time to delirium (p = .43), delirium duration (median 1 day, interquartile range (IQR) 1-2 days vs median 1 day, IQR 1-2 days; p = .71), delirium severity, ICU length of stay (median 2.2 days, IQR 1–3.3 days vs median 2.3 days, IQR 1-4 days; p = .29), or hospital length of stay (median 10 days, IQR 8–11.5 days vs median 10 days, IQR 8-12 days; p = .41). In the esophagectomy subgroup (n = 84), the haloperidol group was less likely to experience incident delirium (n=10 (23.8%) vs n=17 (40.5%); p = .16). There were no differences in time to delirium (p = .14), delirium duration (median 1 day, IQR 1-2 days vs median 1 day, IQR 1-2 days; p = .71), delirium severity, or hospital length of stay (median 11 days, IQR 10-12 days vs median days 11, IQR 10-15 days; p = .26). ICU length of stay was significantly shorter in the haloperidol group (median 2.8 days, IQR 1.1–3.8 days vs median 3.1 days, IQR 2.1–5.1 days; p = .03). Safety events were comparable between the groups.

Conclusion: Low-dose postoperative haloperidol did not reduce delirium in individuals undergoing thoracic surgery but may be efficacious in those undergoing esophagectomy.

Introduction

Delirium is a syndrome of disturbance of attention and awareness that develops quickly and fluctuates over the course of the day.[1] Individuals with delirium are vulnerable to hospital-acquired complications, leading to prolonged intensive care unit (ICU) and hospital stays, new institutionalization, higher healthcare costs, and greater mortality.[2–5] Postoperative delirium is also associated with long-term cognitive decline and dementia.[5,6]

Incidence of postoperative delirium ranges from 15% to 80%.[7–13] For noncardiac thoracic surgery, incidence of delirium could be as high as 50% in individuals undergoing esophagectomies.[14] Current theoretical models of delirium pathophysiology posit that a complex interaction between underlying vulnerabilities such as age and preexisting cognitive impairment coupled with an extensive external stressor such as esophagectomy predisposes to delirium.[15] As a response to surgery, peripheral macrophages produce pro-inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-α),[16,17] leading to blood–brain barrier disruption with infiltration of leukocytes into the central nervous system.[18–20] The resultant microglial activation produces local cytokines (TNF-α, IL-1 β) and reactive oxygen species and promotes cholinergic failure and dopaminergic excess.[21,22]

Haloperidol is a typical antipsychotic that acts primarily by blocking dopamine receptors.[23,24] Haloperidol also inhibits production of pro-inflammatory cytokines IL-1 and TNF-α,[25] and increases levels of the IL-1 receptor antagonist (IL-1RA), an anti-inflammatory cytokine.[26] Haloperidol has been shown to reduce delirium burden in individuals undergoing abdominal surgery[27] and those who have had a hip facture,[28] but its role in reducing delirium in individuals undergoing thoracic surgery is unclear. Using the theoretical pathophysiological framework, we designed this randomized trial to assess the feasibility and efficacy of haloperidol prophylaxis in reducing delirium after major thoracic surgery, specifically esophagectomy.

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