title: Intravenous Lipid Emulsion Therapy for Severe Diphenhydramine Toxicity: A Randomized, Controlled Pilot Study in a Swine Model.
abstract: OBJECTIVE
  Diphenhydramine is a moderately lipophilic antihistamine with sodium channel blockade properties. It is consumed recreationally for mild hallucinogenic and hypnotic effects and causes dysrhythmias, seizures, and death with overdose. Intravenous lipid emulsion is a novel agent used to treat lipophilic drug overdose. Two case reports describe clinical improvement with intravenous lipid emulsion after diphenhydramine toxicity, but no prospective studies have been reported. Our objective is to determine whether intravenous lipid emulsion improved hypotension compared with sodium bicarbonate for severe diphenhydramine toxicity in a model of critically ill swine.
  
  
  METHODS
  Twenty-four swine weighing 45 to 55 kg were infused with diphenhydramine at 1 mg/kg per minute until the mean arterial pressure reached 60% of baseline. Subjects were randomized to receive intravenous lipid emulsion (bolus of 7 mL/kg and then 0.25 mL/kg per minute) or sodium bicarbonate (2 mEq/kg plus an equal volume of normal saline solution). We measured pulse rate, systolic blood pressure, mean arterial pressure, cardiac output, QRS interval, and serum diphenhydramine level. Twelve animals per group provided a power of 0.8 and α of .05 to detect a 50% difference in mean arterial pressure. We assessed differences between groups with a repeated-measures linear model (MIXED) and Kaplan-Meier estimation methods. We compared systolic blood pressure, mean arterial pressure, and cardiac output with repeated measures ANOVA.
  
  
  RESULTS
  Baseline weight, hemodynamic parameters, QRS interval, time to hypotension, and diphenhydramine dose required to achieve hypotension were similar between groups. After hypotension was reached, there was no overall difference between intravenous lipid emulsion and sodium bicarbonate groups for cardiac output or QRS intervals; however, there were transient differences in mean arterial pressure and systolic blood pressure, favoring intravenous lipid emulsion (difference: mean arterial pressure, sodium bicarbonate versus intravenous lipid emulsion -20.7 [95% confidence interval -31.6 to -9.8]; systolic blood pressure, sodium bicarbonate versus intravenous lipid emulsion -24.8 [95% confidence interval -37.6 to -12.1]). Time to death was similar. One intravenous lipid emulsion and 2 sodium bicarbonate pigs survived. End-of-study mean total serum diphenhydramine levels were similar. The mean lipid layer diphenhydramine level was 6.8 μg/mL (SD 3.1 μg/mL) and mean aqueous layer level 8.6 μg/mL (SD 5.5 μg/mL).
  
  
  CONCLUSIONS
  In our study of diphenhydramine-induced hypotensive swine, we found no difference in hypotension, QRS widening, or diphenhydramine levels in aqueous layers between intravenous lipid emulsion and sodium bicarbonate.
authors.affiliation: Department of Emergency Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX. Electronic address: smvarney@gmail.com.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Varney
authors.affiliation: Medical Toxicology, San Antonio Military Medical Center, San Antonio, TX.
authors.forename: Vikhyat S
authors.initials: VS
authors.lastname: Bebarta
authors.affiliation: Department of Emergency Medicine, San Antonio Military Medical Center, San Antonio, TX.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Boudreau
authors.affiliation: Office of the Chief Scientist/59th MDW, Wilford Hall Ambulatory Surgical Center, San Antonio, TX.
authors.forename: Toni E
authors.initials: TE
authors.lastname: Vargas
authors.affiliation: Department of Emergency Medicine, San Antonio Military Medical Center, San Antonio, TX.
authors.forename: Maria
authors.initials: M
authors.lastname: Castaneda
authors.affiliation: Office of the Chief Scientist/59th MDW, Wilford Hall Ambulatory Surgical Center, San Antonio, TX; Medpro Technologies, San Antonio, TX.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Zarzabal
mesh_terms: D000818:Animals; D004155:Diphenhydramine / Q000633:toxicity*; D004195:Disease Models, Animal; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics; D007022:Hypotension / Q000139:chemically induced* / Q000188:drug therapy*; D010865:Pilot Projects; D017693:Sodium Bicarbonate / Q000494:pharmacology; D013552:Swine
chemical_list: D005217:Fat Emulsions, Intravenous; D004155:Diphenhydramine; D017693:Sodium Bicarbonate