Association between opioid and benzodiazepine use and clinical deterioration in ward patients

RESULTS

Patient Characteristics

A total of 144,895 admissions, from 75,369 patients, had ward vital signs or laboratory values documented during the study period. Ward segments from 634 admissions were excluded due to comfort care status, which resulted in exclusion of 479 complete patient admissions. Additionally, 139 patients with tracheostomies were excluded. Furthermore, 2934 patient admissions with a sickle-cell diagnosis were excluded, of which 95% (n = 2791) received an opioid and 11% (n = 310) received a benzodiazepine. Another 14,029 admissions associated with seizures, 6134 admissions involving alcohol withdrawal, and 1332 with both were excluded, of which 66% (n = 14,174) received an opioid and 35% (n = 7504) received a benzodiazepine. After exclusions, 120,518 admissions were included in the final analysis, with 67% (n = 80,463) associated with at least 1 administration of an opioid and 21% (n = 25,279) associated with at least 1 benzodiazepine administration.

In total, there were 672,851 intervals when an opioid was administered during the study, with a median dose of 12 mg oral morphine equivalents (interquartile range, 8-30). Of these, 21,634 doses were replaced due to outlier status outside the 99^th percentile. Patients receiving opioids were younger (median age 56 vs 61 years), less likely to be African American (48% vs 59%), more likely to have undergone surgery (18% vs 6%), and less likely to have most noncancer medical comorbidities than those who never received an opioid (all P < 0.001) (Table 1).

Additionally, there were a total of 98,286 6-hour intervals in which a benzodiazepine was administered in the study, with a median dose of 1 mg oral lorazepam (interquartile range, 0.5-1). A total of 790 doses of benzodiazepines (less than 1%) were replaced due to outlier status. Patients who received benzodiazepines were more likely to be male (49% vs. 41%), less likely to be African-American, less likely to be obese or morbidly obese (33% vs. 39%), and more likely to have medical comorbidities compared to patients who never received a benzodiazepine (all P < 0.001) (Table 1).

The eCART scores were similar between all patient groups. The frequency of missing variables differed by data type, with vital signs rarely missing (all less than 1.1% except AVPU [10%]), followed by hematology labs (8%-9%), electrolytes and renal function results (12%-15%), and hepatic function tests (40%-45%). In addition to imputed data for missing vital signs and laboratory values, our model omitted human immunodeficiency virus/acquired immune deficiency syndrome and peptic ulcer disease from the adjusted models on the basis of fewer than 1000 admissions with these diagnoses listed.

Patient Outcomes

The incidence of the composite outcome was higher in admissions with at least 1 opioid medication than those without an opioid (7% vs. 4%, P < 0.001), and in admissions with at least 1 dose of benzodiazepines compared to those without a benzodiazepine (11% vs. 4%, P < 0.001) (Table 2).

Within 6-hour segments, increasing doses of opioids were associated with an initial decrease in the frequency of the composite outcome followed by a dose-related increase in the frequency of the composite outcome with morphine equivalents greater than 45 mg. By contrast, the frequency of the composite outcome increased with additional benzodiazepine equivalents (Figure).

In the adjusted model, opioid administration was associated with increased risk for the composite outcome (Table 3) in a dose-dependent fashion, with each 15 mg oral morphine equivalent associated with a 1.9% increase in the odds of ICU transfer or cardiac arrest within the subsequent 6-hour time interval (odds ratio [OR], 1.019; 95% confidence interval [CI], 1.013-1.026; P < 0.001).

Similarly, benzodiazepine administration was also associated with increased adjusted risk for the composite outcome within 6 hours in a dose-dependent manner. Each 1 mg oral lorazepam equivalent was associated with a 29% increase in the odds of ward cardiac arrest or ICU transfer (OR, 1.29; 95% CI, 1.16-1.44; P < 0.001) (Table 3).

Sensitivity Analyses

A sensitivity analysis including 1 randomly selected hospitalization per patient involved 67,097 admissions and found results similar to the primary analysis, with each 15 mg oral morphine equivalent associated with a 1.9% increase in the odds of the composite outcome (OR, 1.019; 95% CI, 1.011-1.028; P < 0.001) and each 1 mg oral lorazepam equivalent associated with a 41% increase in the odds of the composite outcome (OR, 1.41; 95% CI, 1.21-1.65; P < 0.001). Inclusion of both opioids and benzodiazepines in the adjusted model again yielded results similar to the main analysis for both opioids (OR, 1.020; 95% CI, 1.013-1.026; P < 0.001) and benzodiazepines (OR, 1.35; 95% CI, 1.18-1.54; P < 0.001), without a significant interaction detected (P = 0.09). These results were unchanged with the addition of zolpidem to the model as an additional potential confounder, and zolpidem did not increase the risk of the study outcomes (P = 0.2).