a b s t r a c t

Objective: The objective of the study is to determine the safety of intravenously administered combination sedatives in the emergency department (ED).

Methods: This was a retrospective study of alcohol-Intoxicated patients in the ED. We examined the incidence of adverse events in Agitated patients who received combination sedatives intravenously and compared the efficacy of combination sedatives and single-agent sedatives.

Results: Of 1300 patient visits, there was a single adverse event, a dystonic reaction, in the combination sedative group, for an Adverse event rate of less than 1%. Patients who received combination sedatives were less likely to require a second dose of sedative medication than patients who received a single-agent sedative (21% vs 44%).

Conclusions: Combination sedatives appear to be safe when administered intravenously in the ED. Combination sedatives may be more effective than single-agent sedatives in agitated Alcohol-intoxicated patients.

(C) 2013

Introduction

Agitated patients are often brought to the emergency department (ED) for the patient’s safety as well as safety to the general public. There are many reasons for patients to be agitated and combative: drug and alcohol use, psychiatric illness, hypoglycemia, and many medical problems. Regardless of the cause, most agitated patients require sedation, largely because it is difficult to provide medical care to a combative patient. Many drugs are used for the sedation of agitated patients in the ED, but benzodiazepines and butyrophenones are among the most commonly used. These medications are generally considered to be safe, but studies have generally examined these medications as single agents, in Psychiatric patients, and given intramuscularly or orally [1-10]. Studies of combination medications have suggested that they are more effective [5,8], but this finding is not universal [6,7]. Thus, the safety of such combination sedatives has not been established, particularly when they are administered intravenously. It is also not known if a particular drug combination is more effective than another drug combination. We sought to answer these questions by examining a subset of our ED patients, the alcohol-intoxicated patient. We reviewed and compared the safety and efficacy of intravenous combination sedatives in agitated alcohol- intoxicated patients in our ED.

* Corresponding author. Tel.: +1 718 918 5827; fax: +1 718 918 7459.

E-mail address: [email protected] (S.F. Li).

Methods

The study was a retrospective, observational cohort. We searched our hospital electronic medical database for patients who presented to the ED with alcohol intoxication. For the purposes of this study, alcohol refers to ethanol. The database was queried using the discharge Diagnosis codes for alcohol dependence and alcohol abuse (International Classification of Diseases, Ninth Revision, codes 303, 305, respectively). Demographic and clinical data were collected using a standardized data collection form, with specific attention to the type of sedative drugs that were administered (if any), how many times the sedatives were administered, and adverse outcomes. Adverse events were defined as death, arrhythmia requiring treatment, hypoxia requiring treatment, airway management for any reason, dystonia, and Allergic reactions. Adverse events that were not predefined were also recorded in the review. Agitation was defined as documentation of patient agitation at ED triage. Efficacy was defined as the need for a second dose of sedative medication.

The primary outcome of the study was the incidence of adverse events in patients who received combination sedatives. Secondary outcomes include comparison of Adverse event rates in combination sedatives and single-agent sedatives and comparison of efficacy in combination sedatives and single-agent sedatives. Data were reported using confidence intervals (CIs). We estimated that 1000 patients would be needed for the study based on the following estimates: 25% of alcohol-intoxicated patients in the ED were sedated with combination sedatives, an adverse event rate of less than 0.01, and

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Table

Most common types of sedatives given to alcohol-intoxicated patients

^a Number of patients given sedative.

^b Number of patients requiring a second dose of sedative.

250 patients were required for an upper limit CI of 0.01 or less. We reviewed 1500 patient visits from the period September 2007 to September 2009 (60 visits from each month) to ensure that we would collect at least 1000 valid patient visits. Sixty patient visits were cross- reviewed to determine Interrater agreement and for quality assur- ance. Data were analyzed using Excel X for Mac. The study was approved by our institutional review board.

Results

Of the 1500 patient visits, 1300 patient visits were included. Two hundred visits were excluded for invalid encounters, duplicate encounters, and psychiatric ED patients. The patients were largely male (77%); the mean age was 44 years old. Blood alcohol levels were tested in 835 patients; the mean level was 239 mg/dL. Two hundred ninety-four patients (23%) were agitated at triage. Twenty patients who received sedation were subsequently admitted to the hospital. One patient each was admitted for pancreatitis, observation after an automobile collision, observation after multiple ingestions, and the remaining patients were admitted for detox. Virtually all medications were administered intravenously (N 99%).

In 292 of 1300 patient encounters (22%), the patient was given a sedative. Patients were sedated with combination drugs in 173 visits and single-agent drugs in 119 visits. The choice of sedatives is summarized in Table. Of combination sedatives, most patients (155) received a combination of haloperidol and lorazepam; 18 patients received a combination of lorazepam and midazolam. Of single-agent sedatives, 113 patients received a benzodiazepine; 6 patients received haloperidol. Most patients who received a sedative (273/292, 93%) were agitated.

There was a single adverse event in the study period, a dystonic reaction, which occurred in a patient who received a haloperidol- lorazepam combination sedative. Thus, the adverse event rate of combination sedatives is 0.0058 (b 1%; 95% CI, 0-0.03). There were no adverse events among patients who received single-agent sedatives. The difference of 0.0058 was not statistically significant (95% CI of difference, -0.0056 to 0.017). No other adverse event (that was not predefined) occurred.

Patients who received combination sedatives were less likely to receive a second dose of sedative. Thirty-six patients (21%) who received a combination drug received a second sedative compared with 52 patients (44%) who received a single-agent sedative. The difference of 0.23 was statistically different (95% CI of difference, 0.12- 0.34). The percentage of patients who required a second dose of medication in sedative subgroups was 19% in haloperidol-benzodiaz- epine, 39% for lorazepam-midazolam, 44% in single-agent benzodiaz- epine, and 33% in single-agent haloperidol.

Discussion

In our study, intravenous combination sedatives and single-agent sedatives appeared to be safe in their use in sedating agitated alcohol- intoxicated patients. The incidence of an adverse event was less than 1%. There were no serious adverse events in the use of these drugs in the ED. The sole adverse drug event was a dystonic reaction that was

reversed by diphenhydramine. The patient had an otherwise uneventful ED course.

Combination sedatives may be more efficacious than single-agent sedatives in the sedation of alcohol-intoxicated patients. In the study, patients were less likely to require a second dose of sedative medication after receiving a combination sedative. Although we compared the efficacy of combination sedatives to single-agent sedatives, the major difference in efficacy was between haloperidol- benzodiazepine and all other sedatives (benzodiazepine-benzodi- azepine, single-agent benzodiazepine, single-agent haloperidol). Only 19% of patients receiving the haloperidol-benzodiazepine combination sedative required a second medication compared with 33% to 44% who received other medications. The addition of a second type of medication may increase the success of sedation.

Our single adverse event was a dystonic reaction, which occurred in a patient who received haloperidol and lorazepam. Dystonic reactions are generally unpredictable, and it is unlikely that the addition of lorazepam increased the incidence of dystonic reaction in our patients. Thus, we believed that it was chance that the adverse event occurred in the combination sedative group, especially since haloperidol was administered far more frequently in the combination sedative group than the single-agent group (155 vs 6 patients).

There were several limitations to our study. The study was a retrospective study, and as noted previously, we cannot state anything definitive about the relative efficacy of drug regimens because patients were not randomized. Furthermore, documenta- tion of adverse events may not be complete because of the retrospective nature of the study. For example, cases of transient hypoxia may not be recorded. Second, there is likely heterogeneity in our patients at baseline. We did not measure blood alcohol levels and urine toxicologic screens on every patient. The present study was targeted toward alcohol-intoxicated patients; thus, we cannot be certain that combination sedatives would be safe in patients with other causes of agitation, such as cocaine, halluci- nogens, or psychiatric illness. Our sample size analysis also underestimated the sample size requirement. A combination sedative was used in only 13% of patient visits (our estimate was 25%); thus, our study may be underpowered to detect small statistical differences. Finally, there was a patient included in our study that was not part of our target population. A patient arrived in the ED after a mixed overdose and was intubated in the field. The patient ingested alcohol as well as other drugs. She was very agitated in the ED and had to be sedated. We did not have the forethought to make field intubation an exclusion criterion, and thus, we included the patient in the study. The patient had an uneventful hospital course.

Conclusion

Intravenous combination sedatives appear to be safe for use in the ED. The risk of adverse events is very low. Combinations of haloperidol and a benzodiazepine may be more effective than other sedatives in agitated alcohol-intoxicated patients.

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