title: The 60-day temperature-dependent degradation of midazolam and Lorazepam in the prehospital environment.
abstract: BACKGROUND
  The choice of the optimal benzodiazepine to treat prehospital status epilepticus is unclear. Lorazepam is preferred in the emergency department, but concerns about nonrefrigerated storage limits emergency medical services (EMS) use. Midazolam is increasingly popular, but its heat stability is undocumented.
  
  
  OBJECTIVE
  This study evaluated temperature-dependent degradation of lorazepam and midazolam after 60 days in the EMS environment.
  
  
  METHODS
  Lorazepam or midazolam samples were collected prior to (n = 139) or after (n = 229) 60 days of EMS deployment during spring-summer months in 14 metropolitan areas across the United States. Medications were stored in study boxes that logged temperature every minute and were stored in EMS units per local agency policy. Mean kinetic temperature (MKT) exposure was derived for each sample. Drug concentrations were determined in a central laboratory by high-performance liquid chromatography. Concentration as a function of MKT was analyzed by linear regression.
  
  
  RESULTS
  Prior to deployment, measured concentrations of both benzodiazepines were 1.0 relative to labeled concentration. After 60 days, midazolam showed no degradation (mean relative concentration 1.00, 95% confidence interval [CI] 1.00-1.00) and was stable across temperature exposures (adjusted R(2) -0.008). Lorazepam experienced little degradation (mean relative concentration 0.99, 95% CI 0.98-0.99), but degradation was correlated to increasing MKT (adjusted R(2) 0.278). The difference between the temperature dependence of degradation of midazolam and lorazepam was statistically significant (T = -5.172, p < 0.001).
  
  
  CONCLUSIONS
  Lorazepam experiences small but statistically significant temperature-dependent degradation after 60 days in the EMS environment. Additional study is needed to evaluate whether clinically significant deterioration occurs after 60 days. Midazolam shows no degradation over this duration, even in high-heat conditions.
authors.affiliation: Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH 45267-0769, USA. jason.mcmullan@uc.edu
authors.forename: Jason T
authors.initials: JT
authors.lastname: McMullan
authors.forename: Ashley
authors.initials: A
authors.lastname: Pinnawin
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Jones
authors.forename: Kurt
authors.initials: K
authors.lastname: Denninghoff
authors.forename: Nicholas
authors.initials: N
authors.lastname: Siewart
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Spaite
authors.forename: Erin
authors.initials: E
authors.lastname: Zaleski
authors.forename: Robert
authors.initials: R
authors.lastname: Silbergleit
mesh_terms: D000927:Anticonvulsants / Q000737:chemistry / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D004356:Drug Storage / Q000379:methods / Q000592:standards; D004632:Emergency Medical Services / Q000592:standards*; D006801:Humans; D016014:Linear Models; D008140:Lorazepam / Q000737:chemistry* / Q000627:therapeutic use; D008874:Midazolam / Q000737:chemistry* / Q000627:therapeutic use; D015337:Multicenter Studies as Topic; D056687:Off-Label Use; D016032:Randomized Controlled Trials as Topic; D013226:Status Epilepticus / Q000188:drug therapy*; D013696:Temperature; D014481:United States
chemical_list: D000927:Anticonvulsants; D008140:Lorazepam; D008874:Midazolam