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

Disclosures

Crit Care. 2018;22(337)

Background

Critically ill patients are commonly initiated on antimicrobial therapy for infection with one or more agents on the basis of physiologic, microbiologic, and pharmacologic factors.^[1] Antimicrobial exposure may represent a risk for antibiotic-associated encephalopathy^[2–5] or the other synonymous and broadly used term for encephalopathy (that is, delirium).^[2,3,6,7] Delirium in hospitalized patients is a strong independent predictor of mortality, increased hospital length of stay, long-term cognitive impairment, cost of care, and subsequent hospitalizations.^[2,8,9]

The associations between antimicrobials and delirium have been limited by cross-sectional approaches and examination of only certain antibiotic classes, such as cephalosporins (for example, cefepime),^{[2,3,5,10–13]} fluoroquinolones,^[14,15] and macrolides,^[2,4] without accounting for confounders related to baseline comorbidities, sepsis, severity of illness, exposure to analgesics, sedatives, and other antimicrobial possibilities (for example, simultaneous exposure or no exposure).^[2] Importantly, there are many risk factors for delirium per intensive care unit (ICU) patient, including ongoing infection, severity of illness, older age, and baseline cognitive impairment.^[16–19] Furthermore, no study of antimicrobials and acute brain dysfunction has used a reliable or validated tool for the outcome of delirium.

The purpose of this study is to determine whether there is an independent association between antimicrobial class exposure in critically ill patients and the daily risk of delirium, measured by using a valid and reliable tool repeatedly over time. Accounting for daily ICU risks, we hypothesized that different classes of antimicrobials would have differential associations with the daily risk of delirium.

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Crit Care. 2018;22(337) © 2018 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Table 1. Baseline demographics of critically ill cohort with medication records
Demographic	N = 418 (100%)^a
Age, years	58 (47–68)
Sex, male	218 (52%)
Race, white	366 (88%)
Education level, years	12 (12–14)
ICU type
SICU	171 (41%)
MICU	247 (59%)
Mechanical ventilation at enrollment	350 (84%)
Sepsis diagnosis at enrollment	116 (28%)
Modified SOFA score at enrollment	7 (5–9)
Charlson Comorbidity Index	2 (1–4)
Pre-existing cognitive impairment, IQCODE category
Mild impairment	51 (12%)
Not impaired	367 (88%)
Delirium
Patients with delirium	308 (74%)
Days of delirium	3 (2–6)
Coma
Patients with coma	234 (56%)
Days of coma	2 (1–4)
Use of antimicrobials in the ICU	318 (76%)
Use of beta-lactams in the ICU	223 (53%)
Use of fluoroquinolones in the ICU	138 (33%)
Use of macrolides in the ICU	29 (7%)
Use of other^b antimicrobials in the ICU	286 (68%)
Use of antimicrobials in the ICU, days^c
First- to third-generation cephalosporins	2 (1–3.8)
Cefepime	4.5 (3–7)
Penicillins	4 (2–6)
Carbapenems	5 (3–8)
Fluoroquinolones	3 (2–5)
Macrolides	2 (1–6)
Other antimicrobials^b	5 (3–9.8)
Use of analgesics and sedatives in the ICU
Benzodiazepine	313 (75%)
Propofol	156 (37%)
Dexmedetomidine	88 (21%)
Opiates	368 (88%)
Use of antipsychotic in the ICU^d
Typical antipsychotic	117 (28%)
Atypical antipsychotic	102 (24%)

Abbreviations: ICU intensive care unit, IQCODE The Informant Questionnaire on Cognitive Decline in the Elderly, MICU medical intensive care unit, SICU surgical intensive care unit, SOFA Sequential Organ Failure Assessment (excluding neurologic component)
^aAll values presented as number (percentage) or median (interquartile range)
^bFor other antimicrobial list, see Additional file 1: Table S1
^c N = 318
^dTypical antipsychotic (for example, haloperidol), atypical antipsychotic (for example, quetiapine and olanzapine)

Table 2. Delirium risk after antimicrobial exposure using a logistic regression model with cluster sandwich covariance estimator
Independent variable	OR	95% CI	P value
Antimicrobials on previous day
Beta-lactams
First- to third-generation cephalosporins	2.20	1.28–3.79	0.004
Fourth-generation cephalosporins	0.97	0.68–1.38	0.867
Penicillins	1.26	0.98–1.62	0.067
Carbapenems	1.43	0.97–2.11	0.069
Fluoroquinolones	0.92	0.69–1.23	0.572
Macrolides	0.64	0.29–1.43	0.274
Other antimicrobials^a	1.44	1.15–1.79	< 0.001
Covariates	OR	95% CI	P-value
Age at enrollment	1.50	1.31–1.71	< 0.001
Mechanical ventilation at enrollment	2.03	1.38–3.00	< 0.001
Sepsis at enrollment	1.18	0.93–1.5	0.182
Modified SOFA score, same day	1.04	0.92–1.18	0.494
Charlson Comorbidity Index	1.07	0.91–1.26	0.391
IQCODE score	1.00	0.98–1.03	0.769
Delirium on previous day	11.21	9.41–13.35	< 0.001
ICU type, surgical	1.02	0.82–1.27	0.859
Dose of analgesics and sedativess^b on previous day
Daily dose of benzodiazepines, mg^c	1.16	1.06–1.25	< 0.001
Daily dose of propofol, mg	2.24	1.15–4.37	0.017
Daily dose of dexmedetomidine, μg	3.90	1.32–11.54	0.014
Daily dose of opiates, μg^d	1.19	1.03–1.37	0.015
Use of antipsychotic on previous day^e
Typical antipsychotic	1.62	1.15–2.29	0.006
Atypical antipsychotic	1.35	1.07–1.69	0.012

Abbreviations: CI confidence interval, ICU intensive care unit, IQCODE The Informant Questionnaire on Cognitive Decline in the Elderly, OR odds ratio, SOFA Sequential Organ Failure Assessment (excluding neurologic component)
^aFor other antimicrobial list, see Additional file 1: Table S1
^bAnalgesic and Sedative drug doses were cube root transformed to reduce the influence of extreme outliers
^cMidazolam equivalents, for example, midazolam 2.5 mg = lorazepam; 1 mg = diazepam 5 mg
^dFentanyl equivalents, for example, fentanyl 100 μg = hydromorphone 0.75 mg = morphine 5 mg
^eTypical antipsychotic (for example, haloperidol), atypical antipsychotic (for example, quetiapine and olanzapine)

Table 3. Delirium risk after antimicrobial exposure using a proportional odds logistic regression model
Independent variable	OR	95% CI	P value
Total days of antimicrobial therapy
Beta-lactams
First- to third-generation cephalosporins	4.61	0.78–27.11	0.091
Fourth-generation cephalosporins	1.83	0.28–12.11	0.533
Penicillins	1.08	0.90–1.29	0.404
Carbapenems	2.14	0.51–9.04	0.299
Fluoroquinolones	1.05	0.89–1.24	0.566
Macrolides	0.16	0.03–1.03	0.054
Other antimicrobials^a	3.14	2.27–4.35	< 0.001
Covariates	OR	95% CI	p-value
Age at enrollment	1.79	1.39–2.3	< 0.001
Mechanical ventilation at enrollment	4.75	2.51–9.0	< 0.001
Sepsis at enrollment	0.84	0.55–1.28	0.416
Modified SOFA score, same day	1.16	0.90–1.48	0.255
Charlson Comorbidity Index	0.88	0.69–1.14	0.344
IQCODE score	1.05	0.99–1.12	0.129
ICU type, surgical	0.86	0.57–1.30	0.477
Use of analgesics and sedatives in the ICU
Benzodiazepines	1.03	0.68–1.59	0.875
Propofol	0.86	0.57–1.30	0.472
Dexmedetomidine	0.55	0.21–1.45	0.227
Opiates	1.03	0.6–1.77	0.904
Use of antipsychotics in the ICU^b
Typical antipsychotic	1.28	0.49–3.32	0.613
Atypical antipsychotic	2.03	0.7–5.94	0.194

Table S1. Antimicrobial Agents Used in Critically Ill Cohort (Organized by Major Class and Frequency)
Antimicrobial Therapy	N=318 (100%)
Beta-lactams
1st Generation Cephalosporins
Cefazolin	10 (2.4%)
Cephalexin	2 (0.5%)
2nd Generation Cephalosporins
Cefoxitin	1 (0.2%)
3rd Generation Cephalosporins
Ceftriaxone	24 (5.7%)
Cefotaxime	3 (0.7%)
4^th Generation Cephalosporin
Cefepime	64 (15%)
Penicillins
Piperacillin-tazobactam	117 (28%)
Ampicillin-sulbactam	28 (6.7%)
Nafcillin	8 (1.9%)
Penicillin G	5 (1.2%)
Ampicillin	5 (1.2%)
Amoxicillin-clavulanate	4 (1.0%)
Amoxicillin	2 (0.5%)
Ticarcillin-clavulanate	1 (0.2%)
Carbapenems
Imipenem-cilastatin	28 (6.7%)
Meropenem	26 (6.2%)
Ertapenem	22 (5.3%)
Fluoroquinolones
Levofloxacin	117 (28%)
Ciprofloxacin	34 (8.1%)
Moxifloxacin	1 (0.2%)
Macrolides
Azithromycin	23 (5.5%)
Erythromycin	7 (1.7%)
Antimicrobial Therapy	N=318
Other
Vancomycin	228 (54.5%)
Antifungals²	200 (47.9%)
Antivirals³	84 (20.1%)
Metronidazole	81 (19.4%)
Aminoglycosides⁴	76 (18.2%)
Linezolid	54 (12.9%)
Sulfamethoxazole-trimethoprim	43 (10.3%)
Antiretrovirals⁵	23 (5.5%)
Clindamycin	13 (3.1%)
Rifampin	12 (2.9%)
Doxycycline	11 (2.6%)
Tigecycline	7 (1.7%)
Dapsone	8 (1.9%)
Pentamidine	5 (1.2%)
Isoniazid	1 (0.2%)
Pyrazinamide	1 (0.2%)
Ethambutol	1 (0.2%)

¹Data presented as n (%)
²Antifungals: Fluconazole, Amphotericin B, Itraconazole, Micafungin, Posaconazole, Voriconazole
³Antivirals: Acyclovir, Valacyclovir, Ganciclovir
⁴Aminoglycosides: Amikacin, Gentamicin, Tobramycin
⁵Antiretrovirals: Abacavir, Abacavir-Lamivudine-Zidovudine, Atazanavir, Darunavir, Lamivudine, Lamivudine-Zidovudine, Lopinavir-Ritonavir, Raltegravir, Ritonavir, Tenofovir, Zidovudine

Table S2. Delirium Risk after Antimicrobial Exposure using a Logistic Regression Model with Cluster Sandwich Covariance Estimator Restricted to ICU Days
Independent Variable	OR	95% CI	P-value
Antimicrobials on Previous Day
Beta-lactams
1^st-3^rd Generation Cephalosporins	2.13	1.1–4.1	0.024
4^th Generation Cephalosporins	1	0.65–1.53	0.995
Penicillins	1.02	0.79–1.32	0.864
Carbapenems	1.19	0.80–1.78	0.394
Fluoroquinolones	0.89	0.65–1.21	0.447
Macrolides	0.61	0.25–1.52	0.291
Other antimicrobials¹	0.98	0.75–1.29	0.904
Covariates	OR	95% CI	P-value
Age at Enrollment	1.41	1.19–1.67	<0.001
Mechanical ventilation use, Same Day	2.21	1.66–2.93	<0.001
Sepsis occurrence, Same Day	1.79	1.40–2.3	<0.001
Modified daily SOFA score, Same Day	0.87	0.73–1.02	0.090
Charlson Comorbidity Index	1.08	0.95–1.23	0.227
IQCODE score	1.03	0.98–1.08	0.192
Delirium on Previous Day	7.01	5.64–8.71	<0.001
ICU Type, Surgical	1.34	1.02–1.77	0.037
Dose of Analgesics and Sedativess² on Previous Day
Daily dose of benzodiazepines (mg)³	0.97	0.83–1.13	0.707
Daily dose of propofol (mg)	1.41	0.79–2.52	0.241
Daily dose of dexmedetomidine (mcg)	1.6	0.58–4.46	0.365
Daily dose of opiates (mcg)⁴	0.97	0.78–1.22	0.819
Use of Antipsychotic on Previous Day⁵
Typical Antipsychotic	1.47	1.02–2.11	0.036
Atypical Antipsychotic	1.13	0.85–1.51	0.408

Abbreviations: CI=Confidence Interval; ICU=Intensive Care Unit; IQCODE: The Informant Questionnaire on Cognitive Decline in the Elderly; OR= Odds Ratio; SOFA=Sequential Organ Failure Assessment (excluding neurologic component)
¹For other antimicrobial list, see Supplementary Table 1
²Analgesic and Sedative drug doses were cube root transformed to reduce the influence of extreme outliers
³Midazolam equivalents, e.g., midazolam 2.5 mg= lorazepam; 1 mg= diazepam 5 mg
⁴Fentanyl equivalents, e.g., fentanyl 100 mcg= hydromorphone 0.75 mg= morphine 5 mg
⁵Typical antipsychotic (e.g. haloperidol), Atypical antipsychotic (e.g., quetiapine, olanzapine)

Authors and Disclosures

Jessica J. Grahl¹, Joanna L. Stollings^1,2*, Shayan Rakhit^2,3, Anna K. Person^3,4, Li Wang^2,5, Jennifer L. Thompson^2,5, Pratik P. Pandharipande^2,3,6,7, E. Wesley Ely^2,3,7,8,9 and Mayur B. Patel^2,3,7,8,10*

¹Department of Pharmaceutical Services, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37212, USA. ²Critical Illness, Brain dysfunction, Survivorship (CIBS) Center, 2525 West End Avenue, Nashville, TN 37232, USA. ³Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37212, USA. ⁴Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue S, Nashville, TN 37232–2650, USA. ⁵Department of Biostatistics, Vanderbilt University School of Medicine, 2525 West End Avenue, Nashville, TN 37232, USA. ⁶Division of Anesthesiology Critical Care Medicine, Department of Anesthesiology, Vanderbilt University Medical Center, 1211 21st Avenue S, Nashville, TN 37212, USA. ⁷Center for Health Services Research, Vanderbilt University Medical Center, 1215 21st Avenue S, Nashville, TN 27232–8300, USA. ⁸Geriatric Research, Education and Clinical Center Service, Department of Veterans Affairs Medical Center, Tennessee Valley Health Care System, 1310 24th Avenue S, Nashville, TN 37212, USA. ⁹Division of Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue S, Nashville, TN 37232–2650, USA. ¹⁰Division of Trauma and Surgical Critical Care, Departments of Surgery, Neurosurgery, and Hearing & Speech Sciences, Section of Surgical Sciences, Vanderbilt Brain Institute, Vanderbilt University Medical Center, 1211 Medical Center Drive, 404 Medical Arts Building, Nashville, TN 37212, USA.

* Correspondence
joanna.stollings@vumc.org; mayur.b.patel@vumc.org

Authors' contributions
All authors contributed to study conception and design. JJG, JLS, and SR acquired the data. LW conducted statistical analysis, and all authors interpreted results. JJG, JLS, SR, and MBP drafted the manuscript, and all authors critically revised it and approved the final revision.

Competing interests
The authors declare that they have no competing interests. This work was presented at the February 2018 Society of Critical Care Medicine's 47th Critical Care Congress in San Antonio, TX. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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