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

A final sensitivity analysis for the opioid model involved replacing missing pain scores with imputed values ranging from 0 to the median ward score, which was 5. The results of these analyses did not differ from the primary model and were consistent regardless of imputation value (OR, 1.018; 95% CI, 1.012-1.023; P < 0.001).

Subgroup Analyses

Analyses of opioid administration by subgroup (sex, age quartiles, BMI categories, OSA diagnosis, surgical status, daytime/nighttime medication administration, IV/PO administration, and pain severity) yielded similar results to the overall analysis (Supplemental Figure 2). Subgroup analysis of patients receiving benzodiazepines revealed similarly increased adjusted odds of the composite outcome across strata of gender, BMI, surgical status, and medication administration time (Supplemental Figure 3). Notably, patients older than 70 years who received a benzodiazepine were at 64% increased odds of the composite outcome (OR, 1.64; 95% CI, 1.30-2.08), compared to 2% to 38% increased risk for patients under 70 years. Finally, IV doses of benzodiazepines were associated with 48% increased odds for deterioration (OR, 1.48; 95% CI, 1.18-1.84; P = 0.001), compared to a nonsignificant 14% increase in the odds for PO doses (OR, 1.14; 95% CI, 0.99-1.31; P = 0.066).

In a large, single-center, observational study of ward inpatients, we found that opioid use was associated with a small but significant increased risk for clinical deterioration on the wards, with every 15 mg oral morphine equivalent increasing the odds of ICU transfer or cardiac arrest in the next 6 hours by 1.9%. Benzodiazepines were associated with a much higher risk: each equivalent of 1 mg of oral lorazepam increased the odds of ICU transfer or cardiac arrest by almost 30%. These results have important implications for care at the bedside of hospitalized ward patients and suggest the need for closer monitoring after receipt of these medications, particularly benzodiazepines.

Previous work has described negative effects of opioid medications among select inpatient populations. In surgical patients, opioids have been associated with hospital readmission, increased length of stay, and hospital mortality.^26,28 More recently, Herzig et al.¹⁵ found more adverse events in nonsurgical ward patients within the hospitals prescribing opioids the most frequently. These studies may have been limited by the populations studied and the inability to control for confounders such as severity of illness and pain score. Our study expands these findings to a more generalizable population and shows that even after adjustment for potential confounders, such as severity of illness, pain score, and medication dose, opioids are associated with increased short-term risk of clinical deterioration.

By contrast, few studies have characterized the risks associated with benzodiazepine use among ward inpatients. Recently, Overdyk et al.²⁷ found that inpatient use of opioids and sedatives was associated with increased risk for cardiac arrest and hospital death. However, this study included ICU patients, which may confound the results, as ICU patients often receive high doses of opioids or benzodiazepines to facilitate mechanical ventilation or other invasive procedures, while also having a particularly high risk of adverse outcomes like cardiac arrest and inhospital death.

Several mechanisms may explain the magnitude of effect seen with regard to benzodiazepines. First, benzodiazepines may directly produce clinical deterioration by decreased respiratory drive, diminished airway tone, or hemodynamic decompensation. It is possible that the broad spectrum of cardiorespiratory side effects of benzodiazepines—and potential unpredictability of these effects—increases the difficulty of observation and management for patients receiving them. This difficulty may be compounded with intravenous administration of benzodiazepines, which was associated with a higher risk for deterioration than oral doses in our cohort. Alternatively, benzodiazepines may contribute to clinical decompensation by masking signs of deterioration such as encephalopathy or vital sign instability like tachycardia or tachypnea that may be mistaken as anxiety. Notably, while our hospital has a nursing-driven protocol for monitoring patients receiving opioids (in which pain is serially assessed, leading to additional bedside observation), we do not have protocols for ward patients receiving benzodiazepines. Finally, although we found that orders for opioids and benzodiazepines were more common in white patients than African American patients, this finding may be due to differences in the types or number of medical comorbidities experienced by these patients.

Our study has several strengths, including the large number of admissions we included. Additionally, we included a broad range of medical and surgical ward admissions, which should increase the generalizability of our results. Further, our rates of ICU transfer are in line with data reported from other groups,^41,42 which again may add to the generalizability of our findings. We also addressed many potential confounders by including patient characteristics, individual ward units, and (for opioids) pain score in our model, and by controlling for severity of illness with the eCART score, an accurate predictor of ICU transfer and ward cardiac arrest within our population.^32,37 Finally, our robust methodology allowed us to include acute and cumulative medication doses, as well as time, in the model. By performing a discrete-time survival analysis, we were able to evaluate receipt of opioids and benzodiazepines—as well as risk for clinical deterioration—longitudinally, lending strength to our results.

Limitations of our study include its single-center cohort, which may reduce generalizability to other populations. Additionally, because we could not validate the accuracy of—or adherence to—outpatient medication lists, we were unable to identify chronic opioid or benzodiazepine users by these lists. However, patients chronically taking opioids or benzodiazepines would likely receive doses each hospital day; by including 24-hour cumulative doses in our model, we attempted to adjust for some portion of their chronic use. Also, because evaluation of delirium was not objectively recorded in our dataset, we were unable to evaluate the relationship between receipt of these medications and development of delirium, which is an important outcome for hospitalized patients. Finally, neither the diagnoses for which these medications were prescribed, nor the reason for ICU transfer, were present in our dataset, which leaves open the possibility of unmeasured confounding.