Pharmacologic Management of Delirium in the Intensive Care Unit; A New Review

I ran across a new review article about pharmacologic management of delirium in the intensive care unit [1]. Firstly, in my opinion, the first and foremost treatment for delirium should be to aggressively search for and eliminate the medical causes of delirium. This fundamental, first-line recommendation is missing from the review. I also think the conclusion is worth putting in bold-face type: “There is a plethora of studies on pharmacologic management strategies in general medical patients with delirium. Findings from these studies are often extrapolated to the ICU population; however, when looking at studies limited to ICU patients with delirium, there are far fewer credible prospective studies.”

That said, the review has interesting summaries about the major classes of drugs so far studied in ICU populations for managing the agitation of delirium and for preventing delirium. The use of antipsychotics, especially Haloperidol, as well as the newer atypical antipsychotics, is common though not FDA-approved in the management of delirium in patients on general medical units as well as the ICU. The authors mention the relative safety of Haloperidol, even when used intravenously (IV) and even when used in high doses. I remember the days when it was used in high doses were used, including by continuous infusion, sometimes with total daily doses in the hundreds of milligrams [2]. I’m not sure how many consulting psychiatrists are still recommending this practice. We don’t.

There is an excellent review of Dexmedetomidine in both the management and prevention of delirium, which is encouraging though there is still a need for further, larger, and better-controlled studies. I would like to underscore what should be an obvious fact: Dexmedetomidine is not a psychiatric drug and should be managed by intensivists. Asking a psychiatrist, especially one who is not also board-certified in internal medicine, to make recommendations about this alpha-2 agonist used only in critical care units is asking for trouble. This issue is outside the scope of practice of most Psychosomatic Medicine specialists.

I don’t think the authors are firm enough about the recommendation regarding cholinesterase inhibitors, especially Rivastigmine which seemed to lead to higher mortality in the Van Eijk and colleagues study before it was stopped prematurely [3]. Don’t use it.

The landmark studies about preventing delirium with antipsychotics, including the placebo-controlled feasibility study comparing Haldoperidol, Ziprasidone, and placebo in preventing delirium in ICU patients, one of which included the University of Iowa Hospitals and Clinics, in fact found no difference between placebo and active drug [4]. We’ll just have to wait and see what happens with the next phase of the MINDS study, which will enroll larger numbers of patients across many centers, of which The University of Iowa Hospitals and Clinics will again be a part, thus raising the power to show a significant difference (see web link University of Iowa Hospitals Will Recruit for Multicenter ICU Delirium MIND Study « The Practical Psychosomaticist: James Amos, M.D.).

And it was good to see the reminder to clinicians about the independent risk factor for delirium in the ICU–Lorazepam [5].

If you want to see more about my opinion about delirium and the psychiatric consultant’s role, see link The Consulting Psychiatrist’s Role in Managing Delirium Revisited « The Practical Psychosomaticist: James Amos, M.D.

1. Bledowski, J. and A. Trutia (2012). “A review of pharmacologic management and prevention strategies for delirium in the intensive care unit.” Psychosomatics 53(3): 203-211.

BACKGROUND: The prevalence of delirium has been estimated at anywhere between 10% and 30% in general medical patients and in upwards of 80% in patients who are admitted to an intensive care unit (ICU). Given the high prevalence of delirium in the ICU population, it should not be surprising that a large percentage of psychiatric consults arise from this setting. While the mainstay of pharmacologic management of delirium centers on neuroleptic medications, such as haloperidol, recent studies using alternate agents have shown varying levels of promise. OBJECTIVE: Our purpose is to outline the major prospective studies looking at the efficacy of pharmacologic management and prevention strategies for delirium exclusively in adult ICU patients. Both conventional and novel pharmacotherapeutic interventions are discussed. METHOD: Articles were obtained using the MEDLINE/PUBMED database looking specifically at pharmacologic interventions for delirium in the intensive care unit. A search was performed using the key words”delirium,” “intensive care unit,” “treatment,” and “prophylaxis.” The authors limited their search to prospective studies, specifically randomized trials (both placebo-controlled and non-controlled) in the adult ICU population, and eliminated retrospective and observational studies. Relevant citations from the previously mentioned articles were also included in the review. CONCLUSION: There is a plethora of studies on pharmacologic management strategies in general medical patients with delirium. Findings from these studies are often extrapolated to the ICU population; however, when looking at studies limited to ICU patients with delirium, there are far fewer credible prospective studies.

2. Riker, R. R., G. L. Fraser, et al. (1994). “Continuous infusion of haloperidol controls agitation in critically ill patients.” Crit Care Med 22(3): 433-440.

OBJECTIVE: To evaluate the safety and efficacy of continuous infusion of haloperidol in treating agitated critically ill adult patients. DESIGN: Case series of patients treated with continuous infusion of haloperidol and followed to hospital discharge, during a 6-month period. SETTING: A 34-bed multidisciplinary intensive care unit (ICU) in a 598-bed nonuniversity, tertiary care teaching hospital. PATIENTS: Consecutive sample of eight patients requiring mechanical ventilation who had severe agitation which was refractory to intermittent bolus treatment with benzodiazepines, narcotics, and haloperidol. INTERVENTIONS: Continuous infusions of haloperidol (range 3 to 25 mg/hr) were supplemented, as required, to maintain adequate sedation. MEASUREMENTS AND MAIN RESULTS: The four men and four women averaged 47 yrs of age, and the average length of hospitalization was 33 days, with 25 days spent in the ICU. On the day continuous infusion of haloperidol was initiated, the average Acute Physiology and Chronic Health Evaluation (APACHE) II and Therapeutic Intervention Scoring System (TISS) scores were 24 and 47, respectively. The Sedation-Agitation Scale score averaged +2.4 (maximum agitation score being +3) before continuous infusion of haloperidol decreasing to +1.8 after 1 day (p = .38) and to +0.8 after 2 days (p = .06) of continuous infusion of haloperidol. The average daily haloperidol dose increased from 68 mg before continuous infusion of haloperidol to 269 mg (p < .008) after 1 day. The daily total of nonhaloperidol sedatives decreased from 18.3 to 10.9 sedation-equivalent units (p = .15) and the daily number of bolus administrations of sedatives decreased from 23 to 7 (p = .01) after 1 day of continuous infusion of haloperidol. Estimated nursing time to prepare, administer, and monitor these bolus medications decreased from 320 to 96 mins per 24 hrs (p = .01). Of the five patients discharged alive (37.5% mortality rate), four were successfully weaned from assisted ventilation during continuous infusion of haloperidol. Two of these four patients were difficult to wean because of agitation and oversedation. Four possible complications were noted: minor tremors (n = 2), atrial dysrhythmias with intermittent third-degree atrioventricular block and QT interval prolongation (n = 1), and ventricular tachycardia (n = 1). CONCLUSIONS: Continuous infusion of haloperidol effectively controls severe agitation in critically ill patients, reduces requirements for bolus administration of sedatives and nursing time lost to that task, and may facilitate ventilator weaning. Parenteral administration of haloperidol was associated with few complications in > 1,340 patient-hours of continuous administration.

3. van Eijk, M. M., K. C. Roes, et al. (2010). “Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial.” Lancet 376(9755): 1829-1837.

BACKGROUND: Delirium is frequently diagnosed in critically ill patients and is associated with adverse outcome. Impaired cholinergic neurotransmission seems to have an important role in the development of delirium. We aimed to establish the effect of the cholinesterase inhibitor rivastigmine on the duration of delirium in critically ill patients. METHODS: Patients (aged >/=18 years) who were diagnosed with delirium were enrolled from six intensive care units in the Netherlands, and treated between November, 2008, and January, 2010. Patients were randomised (1:1 ratio) to receive an increasing dose of rivastigmine or placebo, starting at 0.75 mL (1.5 mg rivastigmine) twice daily and increasing in increments to 3 mL (6 mg rivastigmine) twice daily from day 10 onwards, as an adjunct to usual care based on haloperidol. The trial pharmacist generated the randomisation sequence by computer, and consecutively numbered bottles of the study drug according to this sequence to conceal allocation. The primary outcome was the duration of delirium during hospital admission. Analysis was by intention to treat. Duration of delirium was censored for patients who died or were discharged from hospital while delirious. Patients, medical staff, and investigators were masked to treatment allocation. Members of the data safety and monitoring board (DSMB) were unmasked and did interim analyses every 3 months. This trial is registered with, number NCT00704301. FINDINGS: Although a sample size of 440 patients was planned, after inclusion of 104 patients with delirium who were eligible for the intention-to-treat analysis (n=54 on rivastigmine, n=50 on placebo), the DSMB recommended that the trial be halted because mortality in the rivastigmine group (n=12, 22%) was higher than in the placebo group (n=4, 8%; p=0.07). Median duration of delirium was longer in the rivastigmine group (5.0 days, IQR 2.7-14.2) than in the placebo group (3.0 days, IQR 1.0-9.3; p=0.06). INTERPRETATION: Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients. FUNDING: ZonMw, the Netherlands Brain Foundation, and Novartis.

4. Girard, T. D., P. P. Pandharipande, et al. (2010). “Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial.” Crit Care Med 38(2): 428-437.

OBJECTIVE: To demonstrate the feasibility of a placebo-controlled trial of antipsychotics for delirium in the intensive care unit and to test the hypothesis that antipsychotics would improve days alive without delirium or coma. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Six tertiary care medical centers in the US. PATIENTS: One hundred one mechanically ventilated medical and surgical intensive care unit patients. INTERVENTION: Patients were randomly assigned to receive haloperidol or ziprasidone or placebo every 6 hrs for up to 14 days. Twice each day, frequency of study drug administration was adjusted according to delirium status, level of sedation, and side effects. MEASUREMENTS AND MAIN OUTCOMES: The primary end point was the number of days patients were alive without delirium or coma. During the 21-day study period, patients in the haloperidol group spent a similar number days alive without delirium or coma (median [interquartile range], 14.0 [6.0-18.0] days) as did patients in the ziprasidone (15.0 [9.1-18.0] days) and placebo groups (12.5 [1.2-17.2] days; p = 0.66). No differences were found in secondary clinical outcomes, including ventilator-free days (p = .25), hospital length of stay (p = .68), and mortality (p = .81). Ten (29%) patients in the haloperidol group reported symptoms consistent with akathisia, compared with six (20%) patients in the ziprasidone group and seven (19%) patients in the placebo group (p = .60), and a global measure of extrapyramidal symptoms was similar between treatment groups (p = .46). CONCLUSIONS: A randomized, placebo-controlled trial of antipsychotics for delirium in mechanically ventilated intensive care unit patients is feasible. Treatment with antipsychotics in this limited pilot trial did not improve the number of days alive without delirium or coma, nor did it increase adverse outcomes. Thus, a large trial is needed to determine whether use of antipsychotics for intensive care unit delirium is appropriate.

5. Pandharipande, P., A. Shintani, et al. (2006). “Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients.” Anesthesiology 104(1): 21-26.

BACKGROUND: Delirium has recently been shown as a predictor of death, increased cost, and longer duration of stay in ventilated patients. Sedative and analgesic medications relieve anxiety and pain but may contribute to patients’ transitioning into delirium. METHODS: In this cohort study, the authors designed a priori an investigation to determine whether sedative and analgesic medications independently increased the probability of daily transition to delirium. Markov regression modeling (adjusting for 11 covariates) was used in the evaluation of 198 mechanically ventilated patients to determine the probability of daily transition to delirium as a function of sedative and analgesic dose administration during the previous 24 h. RESULTS: Lorazepam was an independent risk factor for daily transition to delirium (odds ratio, 1.2 [95% confidence interval, 1.1-1.4]; P = 0.003), whereas fentanyl, morphine, and propofol were associated with higher but not statistically significant odds ratios. Increasing age and Acute Physiology and Chronic Health Evaluation II scores were also independent predictors of transitioning to delirium (multivariable P values < 0.05). CONCLUSIONS: Lorazepam administration is an important and potentially modifiable risk factor for transitioning into delirium even after adjusting for relevant covariates.

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