title: Factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors.
abstract: 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.
  
  
  OBJECTIVE
  To compare biological and drug treatment characteristics in patients with coma and/or delirium while in the ICU.
  
  
  METHODS
  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: Maisonneuve-Rosemont Hospital and Université de Montréal, Intensive Care Unit, Montréal, Quebec, Canada.
authors: Yoanna
authors: Y
authors: Skrobik
authors: Caroline
authors: C
authors: Leger
authors: Mariève
authors: M
authors: Cossette
authors: Veronique
authors: V
authors: Michaud
authors: Jacques
authors: J
authors: Turgeon
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D003128:Coma / Q000139:chemically induced* / Q000235:genetics*; D016638:Critical Illness; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003693:Delirium / Q000139:chemically induced / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000009:adverse effects; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics; D007362:Intensive Care Units; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000009:adverse effects*; D009363:Neoplasm Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D006993:Hypnotics and Sedatives; D009363:Neoplasm Proteins; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D005283:Fentanyl