In our cohort of older ICU patients, receipt of benzodiazepines or opioids was significantly associated with prolonged delirium duration even after adjusting for severity of illness, haloperidol use, and dementia. This is the first study to examine use of benzodiazepines and opioids and their association with duration of ICU delirium. Prior studies examining medications and delirium have used varying definitions of medication exposure. Some studies grouped all medications together, others examined only medications with anticholinergic properties, while others reviewed only individual classes of drugs such as antidepressants, benzodiazepines, opioids and steroids (11
). Reported associations between opioid use and delirium are inconsistent. While one study in cancer patients did show a significant impact of opioid use on the risk of delirium (18
), several studies have failed to identify a significant association (41
). Two previous ICU studies to examine opioid use and delirium found no significant association (11
). In a recent review of 11 studies examining medication and the delirium in hospitalized patients (49
), only four studies found a positive association between benzodiazepines and delirium. The magnitude of the association between benzodiazepine use and delirium varied depending on the dosage given and the properties of the medication, with short-acting benzodiazepines having lower risk (12
). In a large ICU cohort the use of sedatives and opiates did not differ in patients with or without delirium and their use increased the risk of delirium only when used to induce coma (11
). Because the majority (77%) of our participants received both benzodiazepines and opioids during their ICU stay, we have grouped them together. In this ICU-based study we demonstrate a positive association between their collective use and duration of delirium among older patients.
Although Kress and colleagues (51
) did not examine delirium, they demonstrated that daily interruption of sedation decreased duration of mechanical ventilation and length of ICU stay, without increasing adverse outcomes (52
). Their study is inconclusive regarding whether the reported improvement in ICU outcomes may be related to a reduction in duration of delirium. Our ICU does not use a sedation interruption protocol so we could not examine the association with duration of delirium.
Thirty-two percent of our patients also received additional medium to high potency anticholinergic medications. We combined these medications into a group as the individual numbers were too small. While these medications were of borderline significance in bivariate analysis (p=0.08), they were not associated with delirium duration in our multivariable model. While there is evidence that anticholinergic medications are linked to delirium in older, non-ICU patients, no studies have evaluated their use in an ICU population (36
). It may be that their contribution to duration of delirium is diminished in critically ill patients receiving benzodiazepines and opioids.
We included haloperidol as a control variable based on the clinical supposition that haloperidol may shorten delirium duration in patients receiving benzodiazepines or opioids. Our results did not support this idea. Haloperidol’s recommended status for treatment of delirium (55
), is based on limited data. There are no randomized placebo controlled studies in critically ill patients demonstrating association between haloperidol and improvement in symptoms or duration of delirium (57
). One study comparing haloperidol to olanzapine found that both medications reduced delirium symptoms (57
We hypothesize that haloperidol may treat symptoms of delirium (such as agitation) without reducing duration of delirium. We reviewed receipt of haloperidol and sedation status in our cohort and found that the majority of patients had delirium and 70% had agitation on the first day they received haloperidol. However, we do not have documentation on what prompted prescription of haloperidol to our study patients. Recent reports from the FDA have highlighted serious adverse effects of haloperidol when used off label in an ICU setting (58
). Given the definition of our outcome, delirium duration, which was designed to establish a temporal relationship with receipt of benzodiazepines and opioids, we cannot draw statistical inferences for haloperidol. This finding for haloperidol, however, raises interesting questions for future research directions, such as randomized controlled trials of delirium treatment in the ICU.
Neither benzodiazepine-opioid use nor haloperidol use was significantly associated with delirium duration among the subgroup of the study sample having dementia. This was likely due to a ceiling effect among patients with dementia who collectively spent close to 80% of their ICU days in a state of delirium.
The major innovation of our study is its examination of duration of delirium rather than occurrence. This is advantageous in an ICU study because so many patients have delirium on the first day of their ICU stay. A second strength is the firm establishment of a temporal ordering between receipt of medications and delirium to ensure their receipt prior to or concomitant with the first episode of delirium. We also examined potential confounders relevant to drug metabolism including liver function and creatinine clearance, allowing us to assess relevant patient factors which may impact the relationship between medications and delirium.
Our study is limited in that we included only older medical ICU patients from a single site. Further studies are needed to determine if these results are generalizable to other settings. We did not examine benzodiazepines and opioids separately because only 28 participants received a benzodiazepine exclusively, 32 received an opioid exclusively, and all 21 receiving propofol also received a benzodiazepine and opioid. Our data reflects the common ICU practice of giving benzodiazepines and opioids together for sedation and pain control. Ideally, these drugs should be investigated separately as there may be a class effect. Our study examined the duration of ICU delirium but did not count delirium days occurring after ICU discharge. Because 27% of our patients had delirium at ICU discharge, implying their episode may have continued post-discharge, our measure of duration of delirium is conservative.
A notable limitation of this study was our inability to separate the effect of these medications from the consequences of intubation. We examined this potential confounder by comparing benzodiazepine or opioid use with delirium duration by intubation status. There was a non-significant trend toward increased delirium duration in the 141 non-intubated patients who received benzodiazepines or opioids (RR-1.18, p=0.26). Although a precise use of dosage was not feasible in our model it is likely that the intubated patients received a higher quantity of medications. Additional comparison revealed that intubated patients had higher APACHE II scores, lower Pa02/Fi02 ratios and more days of medication. While it is conceivable that the baseline differences in disease severity and total dose of medication account for much of the difference in the effect of interest between the intubated and non-intubated subgroups, it is not an issue that can be confirmed in this data set.
Whereas prevention of delirium is an ideal approach and an area of ongoing investigation, many older patients present to the ICU with delirium. Of the 239 delirious patients in our study, the majority were delirious on their day of admission (72%). Although prevention of delirium within the ICU is difficult, it may be possible to reduce delirium duration. In an unadjusted comparison, patients who received benzodiazepines or opioids had an average ICU delirium duration of 5.79 days for each week at risk, compared to 3.08 days for patients who did not receive benzodiazepines or opioids. While there is no evidence that reducing delirium duration will lead to improved outcomes, there is evidence that delirium duration may be linked to adverse neuropsychological outcomes (59
). The impact of reducing delirium duration on outcomes needs to be investigated. Although optimal treatment of the underlying illness is of paramount importance, our data suggest that a reduction in the administration of benzodiazepines and opioids may also be beneficial.
Future studies are needed to determine the optimal medications for sedation, pain and agitation in critically ill patients. Eighty-one percent of patients received benzodiazepines when their RASS score indicated the patient was alert and calm, lethargic or had stupor/coma. This implies that we may be over sedating patients. Until there is further evidence to guide treatment, we recommend regulation of benzodiazepine and opioid use through implementation of sedation protocols, daily interruption of sedation, and frequent reassessment of sedation goals (51
). Studies are needed to determine if lowering dosage of benzodiazepines or opioids reduces duration of delirium and whether shorter duration results in better patient outcomes.