Drug administration in animal studies of cardiac arrest does not reflect human clinical experience

Abstract

Introduction-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 19.4 minutes. 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 9.5 minutes (range 3.0-28.0; 95% CI around mean 2. 78, 16.22). This is less than the time reported in clinical trials (19.4 min, p<0.001). Time to drug predicted ROSC (Odds Ratio 0.844; 95% CI 0.738, 0.966).Conclusion-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.

Cerebral protection in experimental cardiopulmonary resuscitation (with special reference to the effects of methylene blue)

“…It was demonstrated in our group that chest compressions with the LUCAS device during experimental resuscitation resulted in higher cerebral blood flow and cardiac output than standard manual external chest compressions [165]. In animal studies, superior survival rates with drugs have been demonstrated in comparison with humans, probably due to the fact that drug administration occurs some 10 min earlier in humans than in animal studies [166]. Shorter drug delivery time in animal models of CA may thus be one reason for the failure of animal studies to translate successfully into the clinical arena [16,166].…”

“…In animal studies, superior survival rates with drugs have been demonstrated in comparison with humans, probably due to the fact that drug administration occurs some 10 min earlier in humans than in animal studies [166]. Shorter drug delivery time in animal models of CA may thus be one reason for the failure of animal studies to translate successfully into the clinical arena [16,166]. Using a swine model, it was demonstrated that the duration of resuscitation may be extended throughout the use of a vasoactive drug prior to rescue countershock [167].…”

Terlipressin/adrenaline is better than adrenaline alone in a porcine model of prolonged ventricular fibrillationA randomized controlled study

“…(27,28) Based on available literature, the mean time to first drug administration was only 9.5 min in experiments while in the out-ofhospital setting, the first drug is usually given 19.4 minutes after suspected onset of VF. (27) Thus, the flowchart of our study was designed to respect realistic timing of OHCA. (27) …”

Epinephrine in Resuscitation: Curse or Cure?

“…This is significantly longer than administration times in animal studies where drugs are frequently given in under 10 min [77][78][79]. Reynolds et al found a mean time of 9.5 min to first drug administration in animal CPR models compared with the 19.4 min reported in human clinical trials [80].…”