ONLINE DATA SUPPLEMENT
Benzodiazepine-associated delirium in intensive care unit patients
Irene J.Zaal, John W. Devlin, Marijn Hazelbag, Peter M.C. Klein Klouwenberg, Arendina W. van der Kooi, David S.Y. Ong, Olaf L. Cremer, Rolf H. Groenwold, Arjen J.C.Slooter
FIGURE E1: Transition matrix
ICU =Intensive Care Unit,, = transitions of interest, = other possible transitions.
Figure E2: Continuous infusion of benzodiazepines and the risk for delirium the next day.Among patients in coma with mean/median values for all other covariables, the absolute risk is plotted for delirium occurring the next day (y-axis) conditional on the continuously infused IV benzodiazepine (x-axis). The 95% Confidence Interval is plotted in grey.
Medication / Conversion factor
Midazolam / * 1.00
Lorazepam / * 7.14
Oxazepam / * 0.57
Temazepam / * 0.71
Zopiclone / * 1.10
TABLE E2: Covariables considered for use in multivariable analysis
Covariable / Day / Measure / Range / Included
Time-fixed variables
Admission category / 0 / Categorical / Medical / ●
0 / Surgical / ●
0 / Trauma / ●
Age / 0 / Continuous / 18- ∞ / ●
APACHE IV Score(1) / 0 / Continuous / 0 - 220 / ●
Body mass index / 0 / Continuous / 0 - ∞ / ●
Charlson Comorbidity Index(2) / 0 / Continuous / 0-37 / ●
Current alcohol use* / 0 / Binomial / (Y/N)
Dementia† / 0 / Binomial / (Y/N)
Hypertension‡ / 0 / Binomial / (Y/N) / ●
Planned admission / 0 / Binomial / (Y/N) / ●
Psychoactive medication use§ / 0 / Binomial / (Y/N) / ●
Time-varying variables
Metabolic acidosisll / X / Binomial / (Y/N) / ●
Day of ICU admission / X / Continuous / 0 - ∞ / ●
mSOFA (3)** / X / Continuous / 0-20 / ●
Severe sepsis/septic shock†† / X / Binomial / (Y/N) / ●
Use of mechanical ventilation / X / Binomial / (Y/N) / ●
Use of an alpha-2-agonist / X / Binomial / (Y/N) / ●
Use of an opioid / X / Binomial / (Y/N) / ●
Use of propofol / X / Binomial / (Y/N) / ●
APACHE = Acute Physiology and Chronic Health Evaluation, SOFA = Sequential Organ Failure Assessment, Y/N = Yes/No.
*>3 units of alcohol per day, as documented in the medical records or mentioned in the (proxy) history at the time of ICU admission.
†by (proxy) interview at the time of ICU admission or described in the medical records as diagnosed by a geriatrician or neurologist.
‡presence of hypertension or use of an antihypertensive medication(s) documented in the medical record prior hospitaladmission.
§documented use of an antipsychotic (i.e., aripiprazole, bromperidol, chlorpromazine, chlorprothixene, clozapine, flufenazine, flupentixol, fluspirilene, haloperidol, olanzapine, paliperidone, penfluridol, perfenazine, periciazine, pimozide, pipamperon, quetiapine, risperidone, sertindole, sulpiride, tiapride, zuclopentixole); an antiparkinson (ie., apo-morphine, biperidene, bromocriptine, dexetimide, entacapon, levodopa/benserazide, levodopa/carbidopa, levodopa/carbidopa/entacapon, orfenadrine, pergolide, pramipexole, rasagiline, ropinirole, rotigotine, selegiline, tolcapon, trihexyfenidyl) and/or a benzodiazepine (i.e., alprazolam, bromazepam, brotizolam, chlordiazepoxide, chloralhydrate, clobazam, clorazepam, diazepam, flunitrazepam, flurazepam, loprazolam, lorazepam, lormetazepam, midazolam, nitrazepam, oxazepam, prazepam, temazepam, zolpidem, zopiclone) medication before hospital admission. llwith pH in daily arterial bloodgas of ≤ 7.35. **modified Sequential Organ Failure Assessment (without central nervous component). ††according to international sepsis definitions (4-7).
Mental status
day t / Mental status
day t+1 / Exposure / Adjusted Odds ratio*
1. Reverse causation (n=1112 patients, n=9867 days)†
Awake without delirium / Awake without delirium / No / reference
Awake without delirium / Delirium / Yes§ / 1.00 / (0.99-1.02)
Awake without delirium / Delirium / Bolus⁰ / 0.82 / (0.74-0.91)
Awake without delirium / Delirium / Continuous⁰ / 1.02 / (1.00-1.03)
2. Possible carry-over effect of sedation (n=885 patients, n=3616 days)‡
Awake without delirium / Awake without delirium / No / reference
Awake without delirium / Delirium / Yes§ / 1.03 / (1.02-1.05)
Awake without delirium / Delirium / Bolus⁰ / 1.04 / (0.92-1.17)
Awake without delirium / Delirium / Continuous⁰ / 1.03 / (1.01-1.05)
*per 5 mg midazolam equivalent administered.
†With mSOFA day t-1 and benzodiazepine exposure day t-1. Adjusted for covariables: admission category (medical, surgical, trauma), age, Acute Physiology and Chronic Health Evaluation (APACHE) IV Score, Body Mass Index, Charlson Comorbidity Index, hypertension, elective admission (vs. emergency admission), use of a psychoactive medication(s) prior to hospital admission, day of ICU admission, metabolic acidosis, presence of severe sepsis or septic shock, use of mechanical ventilation, use of an alpha-2-agonist, use of an opioid, use of propofol.
‡Only days until either delirium, ICU discharge or death on day t+1 (whichever occurred first).Adjusted for covariables: admission category (medical, surgical, trauma), age, Acute Physiology and Chronic Health Evaluation (APACHE) IV Score, Body Mass Index, Charlson Comorbidity Index, hypertension, elective admission (vs. emergency admission), use of a psychoactive medication(s) prior to hospital admission, day of ICU admission, metabolic acidosis, modified Sequential Organ Failure Assessment score (without neurological component), presence of severe sepsis or septic shock, use of mechanical ventilation, use of an alpha-2-agonist, use of an opioid, use of propofol.
§Model 1 with interaction between mental status on day t and benzodiazepine administration per 5 mg midazolam equivalent.
⁰Model 2 with 1) interaction term between mental status on day t and benzodiazepine administration per 5mg midazolam equivalent administered in boluses and 2) interaction term between mental status on day t and benzodiazepine administration per 5mg midazolam equivalent administered by continuous infusion.
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Table E4. Aged stratified analysis on transitions of daily mental status conditional on benzodiazepine exposureMental status / Mental status / Exposure / Adjusted Odds ratio*†‡
day t / day t+1 / <65 years of age / ≥65 years of age
Awake without delirium / Awake without delirium / No / Reference
Awake without delirium / Delirium / Yes§ / 1.04 / (1.02-1.05) / 1.05 / (1.02-1.08)
Awake without delirium / Delirium / Bolus⁰ / 1.01 / (0.90-1.13) / 0.89 / (0.75-1.04)
Awake without delirium / Delirium / Continuous⁰ / 1.04 / (1.02-1.05) / 1.07 / (1.03-1.11)
*per 5 mg midazolam equivalents.
†adjusted for time-fixed covariables: admission category (medical, surgical, trauma), age, Acute Physiology and Chronic Health Evaluation (APACHE) IV Score, Body Mass Index, Charlson Comorbidity Index, hypertension, elective admission (vs. emergency admission), use of a psychoactive medication(s) prior to hospital admission.
‡adjusted for time-varying covariables on day t: day of ICU admission, metabolic acidosis, modified Sequential Organ Failure Assessment score (without neurological component), presence of severe sepsis or septic shock, use of mechanical ventilation, use of an alpha-2-agonist, use of an opioid, use of propofol.
§Model 1 with interaction between mental status on day t and benzodiazepine administration per 5 mg midazolam equivalent.
⁰Model 2 with 1) interaction term between mental status on day t and benzodiazepine administration per 5mg midazolam equivalent administered in boluses and 2) interaction term between mental status on day t and benzodiazepine administration per 5mg midazolam equivalent administered by continuous infusion.
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