Document Detail


Factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors.
MedLine Citation:
PMID:  23385102     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Delirium and sedative-induced coma are described as incremental manifestations of cerebral dysfunction. Both may be associated with sedative or opiate doses and pharmacokinetic or pharmacogenetic variables, such as drug plasma levels (exposure), drug metabolism, and/or their transport across the blood-brain barrier.
OBJECTIVES: To compare biological and drug treatment characteristics in patients with coma and/or delirium while in the ICU.
PATIENTS AND MEASUREMENTS: In 99 patients receiving IV fentanyl, midazolam, or both, we evaluated drug doses, covariates likely to influence drug effects (age, body mass index, and renal and hepatic dysfunction); delirium risk factors; concomitant administration of CYP3A and P-glycoprotein substrates/inhibitors; ABCB1, ABCG2, and CYP3A5 genetic polymorphisms; and fentanyl and midazolam plasma levels. Delirium and coma were evaluated daily. In patients with only coma (n=15), only delirium (n=7), and neither ever (n=14), we measured plasma levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-1RA, IL-6, IL-8, IL-10, IL-17,macrophage inflammatory protein-1β, and monocyte chemotactic protein-1.
RESULTS: Time to first coma was associated with fentanyl and midazolam doses (p=0.03 and p=0.01, respectively). The number of days in coma was associated with the number of days of coadministration of CYP3A inhibitors (r=0.30; p=0.006). Plasma levels of fentanyl were higher in patients with clinical coma (3.7±4.7 vs. 2.0±1.8 ng/mL, p=0.0001) as were midazolam plasma levels (1050±2232 vs. 168±249 ng/mL, p=0.0001). Delirium occurrence was unrelated to midazolam administration, cumulative doses, or serum levels. Days with delirium were associated with days of coadministration of P-glycoprotein inhibitor (r=0.35; p=0.0004). Delirious patients had higher levels of the inflammatory mediator IL-6 than comatose patients (129.3 vs. 35.0 pg/mL, p=0.05).
CONCLUSIONS: Coma is associated with fentanyl and midazolam exposure; delirium is unrelated to midazolam and may be linked to inflammatory status. These data suggest that iatrogenic coma and delirium are not mechanistically linked.
Authors:
Yoanna Skrobik; Caroline Leger; Mariève Cossette; Veronique Michaud; Jacques Turgeon
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Critical care medicine     Volume:  41     ISSN:  1530-0293     ISO Abbreviation:  Crit. Care Med.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-26     Completed Date:  2013-05-30     Revised Date:  2013-11-04    
Medline Journal Info:
Nlm Unique ID:  0355501     Medline TA:  Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  999-1008     Citation Subset:  AIM; IM    
Affiliation:
Maisonneuve-Rosemont Hospital and Université de Montréal, Intensive Care Unit, Montréal, Quebec, Canada.
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / genetics*
Coma / chemically induced*,  genetics*
Critical Illness
Cytochrome P-450 CYP3A / genetics*
Delirium / chemically induced,  genetics
Dose-Response Relationship, Drug
Female
Fentanyl / administration & dosage,  adverse effects*
Humans
Hypnotics and Sedatives / administration & dosage,  adverse effects
Inflammation / chemically induced,  genetics
Intensive Care Units
Male
Midazolam / administration & dosage,  adverse effects*
Neoplasm Proteins / genetics*
P-Glycoprotein / genetics*
Polymorphism, Genetic / genetics
Grant Support
ID/Acronym/Agency:
//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/ABCB1 protein, human; 0/ABCG2 protein, human; 0/Hypnotics and Sedatives; 0/Neoplasm Proteins; 0/P-Glycoprotein; 437-38-7/Fentanyl; 59467-70-8/Midazolam; EC 1.14.14.1/CYP3A5 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP3A
Comments/Corrections
Comment In:
Crit Care Med. 2013 Oct;41(10):e295-6   [PMID:  24060798 ]
Crit Care Med. 2013 Apr;41(4):1144-6   [PMID:  23528763 ]

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