Antipsychotic prophylaxis in surgical patients modestly decreases delirium incidence — but not duration — in high-incidence samples: A meta-analysis

Abstract

Objective

The objective was to examine whether prophylactic treatment with antipsychotics can decrease the incidence and severity of postsurgical delirium.

Method

A meta-analysis of existing trials comparing delirium incidence between patients given prophylactic antipsychotic and placebo was performed. Secondary outcomes were total hospital days, total days of delirium and severity. Pooled odds ratios (ORs) and mean differences were calculated using a random-effects model.

Results

Five randomized placebo-controlled trials comprising a total of 1491 patients were included. In the pooled analysis, prophylactic antipsychotic administration showed a reduction in delirium incidence (OR: 0.42; 95% confidence interval (CI): 0.24, 0.74). Among the studies reporting other outcomes, patients receiving antipsychotics prophylactically showed no differences in total hospital days (0.1; 95% CI: − 0.73, 0.94), days of delirium (− 1.17; 95% CI: − 5.22, 2.88) or delirium severity (− 1.02; 95% CI: − 6.81, 4.76).

Conclusions

Prophylactic antipsychotic treatment in surgical patients modestly decreases the incidence of delirium, but not the length of hospital stay, duration of delirium or its severity. Given the modest protective effect of antipsychotics and their potential adverse reactions, there is insufficient evidence to support its universal use as a preventive agent, though potential benefit may be seen in populations at high risk of developing delirium.

Introduction

Delirium, an acute change in mental status marked by impairment of attention, remains a common and serious medical complication among hospitalized patients. The full syndrome of delirium often involves hallucinations, agitation, sleep disturbance, affective symptoms and other disruptions in cognition, causing patients risk of injury as well as subjective distress.

In the elderly, the prevalence of delirium in the hospital ranges between 14% and 56% and at least doubles the likelihood of mortality over the subsequent year [1], [2], [3]. One particularly vulnerable period for developing delirium is in the days following surgery, where rates as high as 70% have been reported [4]. Reviews of delirium in patients following orthopedic or cardiac surgeries have found heterogeneous incidence rates ranging from 3.6% to 53.3% and 13.5% to 41.7%, respectively [5], [6].

Differences in the patient population, surgical procedure, anesthesia and method of neuropsychiatric assessment all likely contribute to this variation, though it is clear that delirium remains a significant problem and not solely in the immediate postoperative period. A large prospective study of patients undergoing coronary artery bypass grafting revealed that delirium was a significant, independent predictor of hospitalization for stroke and all-cause mortality over the subsequent 5 years [7]. In patients with dementia at baseline, evidence suggests that episodes of postoperative delirium are even more likely, last longer and accelerate the rate of cognitive decline [7], [8], [9], [10], [11].

With an aging population and an increasing number of elderly patients undergoing surgery, there is a growing need to understand the risk factors associated with delirium as well as potential interventions to prevent it [12]. Multidisciplinary interventions such as the Hospital Elder Life Program (HELP), which involves baseline screening of patients and management of hospital-associated risk factors, led to a reduction in delirium incidence (9.9% versus 15.0%) and duration (105 versus 161 total days), but not severity [13].

Similar reductions were found in other studies employing nonpharmacologic interventions such as staff education, systematic monitoring of mental status, attention to nutrition and other risk factor reduction [14], [15]. A recent study in patients undergoing elective abdominal surgery employed a modified, proactive HELP program consisting of early mobilization, attention to nutritional needs and cognitive activities, which led to a significantly lower rate of delirium (0%) compared to the usual care group (16.7%) [16]. A proactive, structured consultation with a geriatrician reduced delirium incidence by about one third among elderly patients undergoing surgical repair of hip fracture, though this study was not powered to demonstrate which specific recommendations were effective for prevention [17]. Variability in the findings of these studies suggests that patient population and other factors are significantly influencing delirium incidence as well, leading to a limited consensus over which interventions are most preventive in routine practice.

The notion that medications alone can serve as prophylaxis against delirium remains under investigation. Drawing on the observation that decreased acetylcholine was associated with delirium, there was initial hope for the role of cholinesterase inhibitors in prevention [18]. Trials of donepezil and rivastigmine failed to yield significant, positive results in brief perioperative courses, though these studies had relatively low incidence rates and were generally underpowered to demonstrate small treatment effects [19], [20], [21]. In the case of Sampson et al., a trend towards lower incidence and shorter hospital stay was seen with donepezil, though only 33 patients completed the study, and the overall delirium incidence rate (21.2%) was lower than anticipated by the authors. The timing and duration of treatment may also be important, however; over a 24-month study period, standing rivastigmine decreased the incidence and severity of delirium in patients with vascular dementia [22].

A small pilot study of gabapentin 900 mg daily given before and after surgery showed a significant decrease in delirium incidence compared to placebo, with a trend towards lower opiate requirements in the gabapentin arm [23]. Rubino et al. found that a postoperative bolus and subsequent infusion of clonidine reduced delirium severity — though not incidence — in 30 intensive-care patients following aortic dissection repair [24]. A preliminary trial using melatonin to prevent delirium has shown promise, and a larger study has been proposed [25], [26].

While antipsychotics, primarily haloperidol, are routinely used to treat the symptoms of delirium — such as agitation, anxiety, sleep disturbance and hallucinations — there are few studies examining their potential role in actually preventing it [27], [28], [29]. The present meta-analysis reviews the available randomized placebo-controlled trials conducted to date that address this question.