Antimicrobial Exposure and the Risk of Delirium in Critically Ill Patients

Jessica J. Grahl; Joanna L. Stollings; Shayan Rakhit; Anna K. Person; Li Wang; Jennifer L. Thompson; Pratik P. Pandharipande; E. Wesley Ely; Mayur B. Patel


Crit Care. 2018;22(337) 

In This Article


We found that first-, second-, and third-generation cephalosporins doubled the odds of delirium after adjusting for baseline co-morbidities, the course of critical care, and other competing antimicrobials and psychotropic medications risks. However, we did not find an association between total days of exposure and delirium in our proportional odds logistic regression model. We also did not find an association between delirium and cefepime. This is the first and largest nested cohort examining the association of antimicrobials and a rigorous longitudinally measured outcome for delirium.

Beta-lactam–induced neurotoxicity is widely recognized, specifically related to penicillins and cephalosporins.[2–5,11,12,31–36] In addition to delirium (often termed encephalopathy[2]), reports of beta-lactam–induced neurotoxicity identify a variety of specific clinical features, including convulsive seizures, non-convulsive status epilepticus, aphasia, and myoclonus. Neurotoxicity may also be more pronounced in elderly patients, patients with renal insufficiency, and patients with prior neurologic disease who are more prone to neurotoxic effects; however, many of these studies were improperly powered or structured to examine these associations and without comparisons to those exposed to other antimicrobials or no antimicrobials. Our study focused specifically on delirium while addressing and adjusting for age, fluctuation in renal function as indicated by the daily modified SOFA score, pre-existing cognitive impairment, and a control sample of nearly 25% of subjects unexposed to any antimicrobial. Although other neurotoxicity features were beyond the scope of our work, we would remark that seizures occurred infrequently in our cohort (12 patients or 3%), where delirium was observed much more commonly (308 patients or 74%).

Available data previously suggested that, among the beta-lactam antibiotics, cefepime, which is commonly initiated in critically ill patients, might carry the highest risk of mental status change and encephalopathy.[2,3] A previous retrospective study of 100 patients identified that cefepime neurotoxicity occurred in 15%, and likelihood of causality was ascribed via a modified Delphi method.[3] In the same study, the clinical dose of cefepime was appropriately adjusted for renal clearance in 64 patients (75.3%) without cefepime neurotoxicity and four patients (28.6%) with neurotoxicity (P = 0.001). Based on findings of retrospective studies like this, cefepime has been clinically identified as a reversible and potentially under-recognized cause of delirium in the ICU, particularly in those patients with renal failure. Clinicians have used this data to justify discontinuation of cefepime after encountering non-seizure mental status change.[37]

In comparison with previous studies, we used a reliable and validated tool for acute brain dysfunction monitoring that is employed worldwide and translated in over 30 languages: the CAM-ICU.[26] All patients in our study, again in contrast to prior investigations, were under the co-management of an ICU pharmacist dedicated to renal dose adjustments daily. In order to control for time-varying elements of critical illness and organ failure (that is, renal impairment), our regression analysis used a daily modified SOFA score. Daily modified SOFA score was not a consistent risk factor for delirium identified in this study; therefore, other factors of critical illness may have had a more significant impact on risk of delirium in this population rather than the presence of organ dysfunction alone. Our nested cohort data demonstrate that isolated delirium in the setting of cefepime exposure does not necessarily imply causation or require discontinuation (in the absence of other neurotoxicity) given its lack of association with next-day delirium in any of our regression models, including restricting observation to the sickest patients.[22]

Our study has several strengths. There is a limited body of literature regarding the association between various antimicrobial classes and delirium in critically ill patients. The current body of literature lacks utilization of a validated monitoring tool such as the CAM-ICU[38] to assess for presence of delirium in critically ill patients in accordance with the 2018 Society of Critical Care Medicine's Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU.[39] Our nested cohort study is the first to assess the association between antimicrobial administration and risk of delirium through longitudinal assessments of the CAM-ICU. Additionally, our study included both medical and surgical ICU patients who received any antimicrobial agent, which improves real-world generalizability, and sought to identify a specific class of agents associated with delirium. Post-operative critically ill adults may be at a particularly high risk for delirium.[40] After we adjusted for ICU type, our findings remained consistent in our main statistical model and sensitivity analysis. Furthermore, this study used a longitudinal statistical model in order to adjust for ICU-related risk and confounders for delirium on a daily basis as well as the temporal change in both exposure and outcome. Even in our most restrictive model isolated to critical illness, where time-varying covariates of sepsis and mechanical ventilation were known daily, our findings remained consistent. Lastly, our study employed a proportional odds logistic regression model in order to measure the association between total antimicrobial exposure and delirium. Pharmacokinetic and pharmacodynamic properties vary among different classes of antimicrobial agents, and total antimicrobial exposure and accumulation may have an impact on the outcome of delirium. Although this model did not identify an association between total exposure of first-, second-, and third-generation cephalosporins and total days of delirium, this model is limited by onset and duration of delirium. Delirium is a fluctuation in mental status that can change over time and may have occurred prior to or after antimicrobial therapy.

This is the largest evaluation thus far to examine the association between antimicrobial administration and risk of delirium in a critically ill patient population; however, limitations include the single-center population because of the inability to obtain antimicrobial data from the second institution, lack of adjustment for more subtle indicators of hepatic or renal dysfunction (or both), unknown microbial confounding, antimicrobial indication and susceptibility patterns, and unknown reason for admission to the ICU. Additionally, the effects of combination therapy and antimicrobial intensity therapy were not evaluated. Specifically, although the BRAIN-ICU study had only seven subjects with a primary neurologic diagnosis and none of these had sepsis on admission, we cannot confirm whether later infectious diagnoses included encephalitis or meningitis (or both) in any aspect of the cohort. It is unknown whether any providers prescribing antimicrobials shifted agents when encountering delirium. Also, when delirium occurs, reversible causes like seizures are considered part of our differential diagnosis,[41] but electroencephalography is not applied to every patient.

Although this study fills an important void in the literature, antibiotics used in the time frame in which it was conducted (between March 2007 and May 2010) may have have been different from those of the present day. We are limited by the different toxicity profiles of each antimicrobial agent and clearance mechanisms that may be better assessed by using a continuous delirium metric. However, none currently exists, so we were constrained by our observations of outcome (that is, delirium measured twice daily in the ICU). There are many other antimicrobials used worldwide within the classes and subclasses that we studied; therefore, our patients were not exposed to every antimicrobial available and they were not exposed in similar distributions to every class.

This study adjusted for many ICU-related risks and confounders for delirium on a daily basis, however the presence of hypertension, all potentially deliriogenic medications such as steroids, and blood transfusions both which have been associated with delirium were not accounted for. The number of patients who received an electroencephalogram and the results of these was not collected. The incidence of delirium in the study population was high but appropriate for the study time frame. This study was conducted prior to the 2013 Pain, Agitation, and Delirium Guidelines that recommend non-benzodiazepine sedation and prior to the launch of the ICU Liberation ABCDEF Bundle Improvement Collaborative aiming to foster the bedside application of the PAD guidelines.[42] Our sample excluded patients with suspected severe baseline neurologic disease or admission for serious neurologic disease (for example, stroke and traumatic brain injury); thus, findings may not be extrapolated to this patient population in the setting of overt blood–brain barrier damage, although our multinomial models did adjust for the possibility of coma.

Further studies are now needed to examine mechanisms underlying the association between first-, second-, and third-generation cephalosporins and risk of delirium. This research could include pharmacokinetic and pharmacodynamic studies, accounting for differential blood–brain barrier penetration, utilization of antimicrobial monitoring when available, the role of gamma-aminobutyric acid (GABA) receptor agonism/antagonism,[37] and current definitions of sepsis.[43] Patients with neurological injuries were excluded from this study. Given that many patients in a neurology ICU receive high-dose ceftriaxone for central nervous system infections, future studies need to be conducted within this patient population. Additionally, other antimicrobial agents and some analgesics, sedatives, and antipsychotics are associated with risk of delirium in the primary analysis only and not in the sensitivity analysis restricted to time in the ICU. There are multicenter randomized trials studying delirium in critically ill patients and the roles of antipsychotics (; typical versus atypical)[44] and sedatives (; propofol versus dexmedetomidine in sepsis). These trials may shed further light on these complex issues in critically ill patients, who are concomitantly exposed to antimicrobial agents. Our data may suggest that ICU-related risks, such as mechanical ventilation and the previous day's mental status, may have a more profound impact on current mental status and delirium than simply antimicrobial exposure alone.