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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.
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.
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).
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.
Despite numerous clinical trials, survival rates in out-of-hospital cardiac arrest (OOHCA) remain low. To date, there is no evidence that supports the use of ACLS drugs in this setting. [1–3] Animal studies, in contrast, have demonstrated superior survival rates with drug use. [4–13] One reason for failure of animal studies to translate to clinical practice may be the time at which the first drug is delivered. Previous work has demonstrated the average time to first drug administration in clinical trials is 19.4 minutes (range 13.3–25.0; 95% CI around the mean 12.8, 25.9). [14, Appendix] Thus, clinically, these drugs are administered during the late metabolic phase of cardiac arrest. Consequently, it is not surprising they are ineffective. Based on our laboratory and clinical experience, we hypothesized that the average time to drug administration in large animal experiments occurs earlier than in OOHCA clinical trials.
We conducted a comprehensive 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 used no language restriction. We used OVID to search MEDLINE and obtain the abstracts. All abstracts were printed and two reviewers (JCR & JCR) jointly reviewed all abstracts. We eliminated the following from further review: small animal; non-peer reviewed; all without primary animal data (editorials, case reports, review articles, letters, practice guidelines); studies modeling trauma, sepsis, or burns; studies performed in vitro; and those studies were no exogenous medications were given. We then reviewed independently the full manuscripts of all remaining papers for data describing the time to first medication administration. Both reviewers then compared the articles captured.
The type of animal, number of animals, time to first drug administration, route of medication administration, type of medication, method of delivery (bolus vs. infusion), return of spontaneous circulation (ROSC) and short-term survival were abstracted from the articles. Unlike most meta-analyses where we compare the effect size as a function of treatment compared to control across the studies, our analysis compares the mean response time to the ‘minimally acceptable’ time. Consequently, our effect size is the sample mean and our goal is to combine the study results, derive a confidence interval for mean response time and compare that range to what the guidelines define as appropriate. Given that variances were not available for all studies, we used the weighted study sample sizes relative to the entire sample size across the 119 studies to estimate the effect size variance: 
weighti = Ni Where Ni is the sample size for each study
And which is the total sample size across all the studies.
Due to the large differences in sample sizes across the studies (and obvious heterogeneity), we chose to analyze the results using the random effects model as recommended by Hunter and Smith.  This approach accounts for the variability between studies and is a more conservative method to estimate the confidence interval around the mean. We used Microsoft Excel XP 2002 (Redmond, WA) and STATA 9.0 (College Station, TX) to record and analyze the data. We report the mean times, ranges, and the respective 95% confidence intervals around the mean. We next compared the data from this review with that of our previous study in clinical trials to determine if time to drug predicted ROSC. A t-test was completed to determine if the mean time to drug administration was different between the clinical trial data and the animal trial data. Multivariate logistic regression was used to determine predictors of ROSC in the animal studies. Predictor variables included: time to drug, route of delivery (IV or ET), induction of hypothermia, and type of drug. Time to drug was analyzed as a continuous variable in this regression model. The Hosmer-Lemeshow test was used to assess goodness of fit.
Our literature review yielded 332 abstracts. Of these, 197 were selected for review of the full manuscript. The reason for exclusion is presented in Figure 1. Of the 197 manuscripts, 119 contained unique data on time to first drug administration. There was 100% agreement between both reviewers on which studies to include in our analysis. The average time to first medication administration in these 2378 animals was 9.5 minutes (range 3.0–28.0; 95% CI around mean 2.78, 16.22). This was less than our previously reported clinical trial data (19.4 minutes; p < 0.001). In the regression analysis, time to drug was the lone predictor of ROSC (Odds Ratio 0.844; 95% CI 0.738, 0.966). This regression model had acceptable fit (Hosmer-Lemeshow value 0.195).
Drugs are administered approximately 10 minutes earlier in animal studies than in clinical trials. Specifically, animal studies administer drugs during the circulatory phase while clinical trials administer drugs during the metabolic phase. This delay may be one reason animal studies have failed to translate to clinical practice.
Weisfeldt and Becker have proposed a three phase model of cardiac arrest.  The first phase is electrical and lasts from 0–4 minutes. During this initial phase, ventricular fibrillation responds well to countershock. The second phase, from 4–10 minutes, is the circulatory phase. Both animal and human data support the initiation of CPR before attempting defibrillation to ensure adequate tissue oxygenation and perfusion. Data in this phase also supports supplementary administration of vasopressors with CPR. Immediate rescue shock alone has been ineffective during this phase. [13, 18, 19] The third phase of cardiac arrest occurs beyond 10 minutes. Little research has been conducted in this metabolic phase, even though it is usually during this phase that advanced life support is initiated and patients receive their first dose of medication. One study has suggested that cardiopulmonary bypass may be effective and result in neurologically intact survivors.  Using a swine model, we demonstrated recently that these phases may be extended through the use of an optimal resuscitation incorporating CPR and a drug cocktail prior to rescue countershock.  This model would predict a 21% probability of ROSC with drug administration at 19.4 minutes, and an 83% probability of ROSC with drug administration at 9.5 minutes.
The 2005 ILCOR guidelines downplay the import of medication administration.  In light of this literature review and our own experience with animal models, we believe that these drugs are not inert, but only effective when administered during the circulatory phase of cardiac arrest. These data suggest a shift in resuscitation care to improve drug delivery in the out-of-hospital setting. One method employed to decrease time to drug is system-wide changes in dispatch protocols. These changes have been shown to decrease time to medication administration by 3.5 minutes.  A second method to improve drug delivery time is to provide first responders with the ability to establish intraosseus access and provide drugs. We have demonstrated previously that the use of an intraosseus needle by prehospital basic life support providers is feasible and compares favorably with prior studies of advanced life support intravenous catheter placement. [24, 25] If drug delivery continues to occur late during resuscitative efforts, we are unlikely to find a benefit from any drug or cocktail of drugs in the clinical setting.
Our study has several limitations. First, it is limited to a retrospective review of the literature. There is the possibility that studies have been missed, but we believe this to have been minimized by our inclusive search criteria and extensive review. Second, the animals used are young, healthy animals. The cardiovascular physiology of these animals may be different than that of many people who experience OOHCA. Third, time to drug delivery is reliably and consistently recorded in animal studies. However, in clinical settings this data is limited due to being self-reported. The time from collapse to EMS activation is rarely known. Finally, the outcomes assessed are ROSC and short-term survival. Most animal studies do not provide information on neurologically-intact survival, which is the most relevant outcome from the perspective of the patient. We note that previous studies showing short-term benefits have failed to translate to long-term survival. 
Time to first drug delivery in animal resuscitation studies occurs approximately 10 minutes earlier than in clinical trials. In animal trials, time to drug predicts ROSC. These data suggest that one reason for animal studies to translate into clinical practice may be delay to drug delivery. We suggest that an emphasis on gaining vascular access may improve drug effectiveness.
Drs. Rittenberger and Menegazzi are supported by the Clinical Research Skills Development Core of the Resuscitation Outcomes Consortium through the National Heart, Lung and Blood Institute 5U01 HL077871-02. Dr. Menegazzi is also supported by the National Heart, Lung and Blood institute 5R01 HL080483-2.
|Study||Number of Subjects||Time to Medication Administration||Subject Group|
|Nolan J, et al.||309||14.7||Standard CPR|
|Nolan J, et al.||267||15.8||Active compression-decompression CPR|
|Eisenburger P, et al.||114||18.0|
|Allegra J, et al.||58||13.3||Magnesium sulfate|
|Allegra J, et al.||58||14.7||Placebo|
|Mauer D, et al.||83||14.2||Active compression- decompression CPR|
|Mauer D, et al.||90||13.4||Standard CPR|
|Mader TJ, et al.||66||12.5||Aminophylline|
|Mader TJ, et al.||45||12.9||Control|
|Callaham M, et al.||286||16.0||High-dose epinephrine|
|Callaham M, et al.||260||17.0||Standard-dose epinephrine|
|Callaham M, et al.||270||16.0||Norepinephrine|
|Gueugniaud P, et al.||153||20.7||Standard-dose epinephrine|
|Gueugniaud P, et al.||173||20.6||High-dose epinephrine|
|Persse DE, et al.||24||18.8||Uniform response|
|Persse DE, et al.||181||15.2||Targeted response|
|Rudner R, et al.||171||10.0||Resuscitation not successful|
|Rudner R, et al.||17||10.0||Resuscitation successful|
|Martin DR, et al.||16||16.7||Countershock group|
|Martin DR, et al.||31||18.5||No countershock group|
|Schneider T, et al.||72||13.8|
|Van der Hoeven JG, et al.||261||11.8||Before physician supervision|
|Van der Hoeven JG, et al.||218||13.9||After physician supervision|
|Kudenchuk PJ, et al.||123||21.4||Amiodarone|
|Kudenchuk PJ, et al.||179||20.5||Placebo|
|Dorian P, et al.||162||25.0||Amiodarone|
|Dorian P, et al.||148||24.0||Lidocaine|
|Wenzel V, et al.||589||17.5||Vasopressin|
|Wenzel V, et al.||597||18.1||Epinephrine|
|Brown CG, et al.||244||24.8||Standard-dose epinephrine|
|Brown CG, et al.||230||24.0||High-dose epinephrine|
|Bar-Joseph G, et al.||65||18.7||Escalating Dose Epinephrine BRCT III Site 1|
|Bar-Joseph G, et al.||144||18.6||BRCT III Site 2|
|Bar-Joseph G, et al.||114||20.1||BRCT III Site 3|
|Bar-Joseph G, et al.||136||21.6||BRCT III Site 4|
|Bar-Joseph G, et al.||173||17.1||BRCT III Site 5|
|Bar-Joseph G, et al.||156||20.7||BRCT III Site 6|
|Bar-Joseph G, et al.||96||23.2||BRCT III Site 7|
|Bar-Joseph G, et al.||153||20.3||BRCT III Site 8|
|Bar-Joseph G, et al.||60||19.7||BRCT III Site 9|
|Bar-Joseph G, et al.||290||19.4||BRCT III Site 10|
|Bar-Joseph G, et al.||77||20.5||BRCT III Site 11|
|Bar-Joseph G, et al.||275||14.8||BRCT III Site 12|
|Bar-Joseph G, et al.||37||21.2||BRCT III Site 13|
|Bar-Joseph G, et al.||213||10.7||BRCT III Site 14|
|Bar-Joseph G, et al.||77||24.7||BRCT III Site 15|
|Bar-Joseph G, et al.||56||18.3||BRCT III Site 16|
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