Drug administration in animal studies of cardiac arrest does not reflect human clinical experience.
BACKGROUND
To date, there is no evidence showing a benefit from any advanced cardiac life support (ACLS) medication in out-of-hospital cardiac arrest (OOHCA), despite animal data to the contrary. One explanation may be a difference in the time to first drug administration. Our previous work has shown the mean time to first drug administration in clinical trials is 19.4min. We hypothesized that the average time to drug administration in large animal experiments occurs earlier than in OOHCA clinical trials.


METHODS
We conducted a literature review between 1990 and 2006 in MEDLINE using the following MeSH headings: swine, dogs, resuscitation, heart arrest, EMS, EMT, ambulance, ventricular fibrillation, drug therapy, epinephrine, vasopressin, amiodarone, lidocaine, magnesium, and sodium bicarbonate. We reviewed the abstracts of 331 studies and 197 full manuscripts. Exclusion criteria included: non-peer reviewed, all without primary animal data, and traumatic models. From these, we identified 119 papers that contained unique information on time to medication administration. The data are reported as mean, ranges, and 95% confidence intervals. Mean time to first drug administration in animal laboratory studies and clinical trials was compared with a t-test. Regression analysis was performed to determine if time to drug predicted ROSC.


RESULTS
Mean time to first drug administration in 2378 animals was 9.5min (range 3.0-28.0; 95% CI around mean 2.78, 16.22). This is less than the time reported in clinical trials (19.4min, p<0.001). Time to drug predicted ROSC (odds ratio 0.844; 95% CI 0.738, 0.966).


CONCLUSIONS
Shorter drug delivery time in animal models of cardiac arrest may be one reason for the failure of animal studies to translate successfully into the clinical arena.
Reynolds
Joshua C
JC
School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States.
Rittenberger
Jon C
JC
Menegazzi
James J
JJ
D000638:Amiodarone / Q000008:administration & dosage; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004837:Epinephrine / Q000008:administration & dosage; D006323:Heart Arrest / Q000188:drug therapy*; D006801:Humans; D008012:Lidocaine / Q000008:administration & dosage; D008020:Life Support Care / Q000379:methods*; D008278:Magnesium Sulfate / Q000008:administration & dosage; D012044:Regression Analysis; D017693:Sodium Bicarbonate / Q000008:administration & dosage; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000008:administration & dosage*; D014667:Vasopressins / Q000008:administration & dosage
D000889:Anti-Arrhythmia Agents; D014662:Vasoconstrictor Agents; D014667:Vasopressins; D008278:Magnesium Sulfate; D017693:Sodium Bicarbonate; D008012:Lidocaine; D000638:Amiodarone; D004837:Epinephrine