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Critical Care, Trauma, and Resuscitation: Research Reports

Epinephrine Improves 24-Hour Survival in a Swine Model of Prolonged Ventricular Fibrillation Demonstrating that Early Intraosseous Is Superior to Delayed Intravenous Administration

Zuercher, Mathias MD*,†; Kern, Karl B. MD*,‡; Indik, Julia H. MD, PhD*,‡; Loedl, Michael BS§; Hilwig, Ronald W. DVM, PhD*; Ummenhofer, Wolfgang MD; Berg, Robert A. MD*,‖; Ewy, Gordon A. MD*,‡

Author Information
doi: 10.1213/ANE.0b013e31820dc9ec

Cardiac and cerebral perfusion during resuscitation are major determinants of survival with good neurological outcomes after cardiac arrest. Therefore, recent changes to the American Heart Association Guidelines for Cardiopulmonary Resuscitation (CPR)1 have focused on improving such perfusion during CPR. An alternative approach to resuscitation, called cardiocerebral resuscitation, was developed specifically to optimize cardiac and cerebral perfusion,2,3 thereby deemphasizing ventilation.

In experimental settings, coronary perfusion pressure (CPP) has been shown to be the most important determinant of survival during prolonged (>8 minutes) cardiac arrest.35 In animal studies, early administration of epinephrine improves CPP during chest compressions, enhances the potential for successful defibrillation, and improves survival after cardiac arrest. However, many large clinical trials have been unable to show improved outcome after administration of epinephrine in out-of-hospital cardiac arrest.611

One difference between effective animal studies and unsuccessful clinical trials is the time to drug administration. For example, Reynolds et al.12 found the mean time from the onset of cardiac arrest to first drug administration in animal CPR models to be 9.5 minutes in comparison with 19.4 minutes reported in human clinical trials. Placing an IV line in patients during cardiac arrest, especially during continuing CPR, is challenging, time-consuming, and sometimes impossible. The intraosseous (IO) route has been an established technique in pediatric emergency care for more than 3 decades.1317 IV and IO administration are established for both epinephrine and vasopressin.18,19 New devices have also been shown to be feasible and reliable tools for establishing IO access in adult patients. They allow early administration of vasoactive medication without interrupting chest compressions during resuscitation.2026

In a realistic model of prolonged ventricular fibrillation (VF) cardiac arrest in adult swine, we compared IO and IV epinephrine to test the hypotheses that (i) IO epinephrine administration results in an equipotent effect on CPP in comparison with IV application with an inconsequential delay (<1 minute), and (ii) early IO administration of epinephrine (1 minute after start of resuscitation efforts) improves 24-hour survival in comparison with delayed IV application (8 minutes after the start of resuscitation efforts).


Animal Preparation

This study was conducted with approval of the University of Arizona Institutional Animal Care and Use Committee. A pilot pharmacodynamic study included 6 mature domestic male pigs, weighing 34 ± 3 kg; the randomized outcome study included 30 mature domestic pigs (21 female, 9 male), weighing 33 ± 3 kg. Two additional pigs were excluded because of atrial tears occurring during the experiment.

The study animals were anesthetized with 5% isoflurane in oxygen, administered via facemask. After endotracheal intubation, a surgical plane of anesthesia was maintained with 1% to 2.5% isoflurane in ambient air. Mechanical ventilation was delivered at a rate of 10 to 12 per minute at an initial tidal volume of 15 mL/kg by a rate- and volume-regulated ventilator/anesthesia machine (Narkomed 2A, North American Drager, Telford, PA) and was subsequently adjusted to maintain end-tidal carbon dioxide (EtCO2) at 40 ± 4 mm Hg, measured by infrared capnometer (47210A, Hewlett-Packard, Palo Alto, CA). The positive end-expiratory pressure was set to 5 cm H2O. Air flow was measured using a pneumotachometer (MP45 to 871, Validyne Engineering Corp., Northridge, CA). Solid-state, micromanometer-tipped catheters (MCP-500, Millar Instruments, Houston, TX) were placed via the internal jugular vein sheath (7F, Cordis Corp., Miami, FL) into the right atrium and into the descending thoracic aorta via a common carotid artery sheath for high-fidelity pressure measurements. A fluid-filled, double-lumen thermodilution catheter (Swan-Ganz Healthcare Corp., Irvine, CA) was placed via the external jugular vein introducer sheath (8F, Cordis Corp., Miami, FL) into the pulmonary artery to measure baseline right atrium pressure, wedge pressure, and cardiac output by thermodilution technique. To avoid mechanical damage to the pulmonary circulation, we withdrew catheters before start of the experiments. The internal jugular introducer sheath was used as a central venous access site for drug administration. Correct placement of all catheters was verified by fluoroscopy. Adhesive multifunction defibrillation electrode pads (DP2/DP6, Philips Medical Systems, Seattle, WA) were placed in anterior–posterior positions. Electrocardiographic (ECG) leads were attached to 3 limbs to monitor heart rate and rhythm. IO access was obtained using the Bone Injection Gun (B.I.G.™, adult size; Waismed, Caesarea, Israel) placed on the proximal medial part of the tibial tuberosity as recommended by the manufacturer. After removal of the trocar, 12 cm of Luer lock stopcock tubing was connected, and the correct IO position was verified by free aspiration of bone marrow and ease of flushing with saline without signs of extravasation of fluids. The animals received 5000 IU of heparin IV.


Aortic pressure (AoP) and right atrial pressure (RAP), ECG, and EtCO2 were acquired using hardware from Gould Instrument Systems, Inc. (LDS, Middleton, WI), continuously displayed on a P3 Plus Ponemah Physiology Platform (Data Sciences International, St. Paul, MN), and recorded on a laptop computer (Gateway, Sioux City, SD) for subsequent data analysis. Data were recorded at a frequency of 200 Hz. CPP was calculated as the difference between AoP and RAP at the mid-relaxation phase. Arterial blood gases and electrolyte and lactate analyses were assessed at baseline using iStat1 (Abbott Laboratory Diagnostics, Abbott Park, IL).

Experimental Protocol

After baseline data were collected (baseline dataset 1), VF was induced using a pacing electrode temporarily placed in the right ventricle. The presence of VF was confirmed by the characteristic ECG waveform and the precipitous decrease in AoP. Anesthesia and ventilation were discontinued, and the animals underwent a 10-minute period of untreated VF before resuscitation efforts were initiated. Study personnel were blinded to the content of the injections delivered into the respective IO or IV ports.

Pilot pharmacodynamic study.

Six animals were studied using a randomized cross-over design for hemodynamic effect of IO- and IV-administered epinephrine. All animals underwent a 10-minute period of untreated VF followed by continuous chest compressions at 100 per minute with a force to attain a peak AoP of 80 to 90 mm Hg. After 1 minute of chest compressions, epinephrine (0.045 mg/kg)27,28 or placebo (0.9% NaCl) was randomly injected simultaneously through the IV and the IO access ports. After 2 minutes, a single biphasic defibrillation shock of 150 J was given. If a perfusing rhythm was achieved, the animal's lungs were ventilated and allowed to stabilize for 15 to 20 minutes before inducing VF a second time for the cross-over design. If a nonperfusing rhythm was present, a second simultaneous injection was given, and chest compressions were continued for 2 minutes, followed by a single shock. The procedure was repeated an additional time, if necessary. The trial was terminated if the animal had not attained return of spontaneous circulation (ROSC) after the third shock. If resuscitated, VF was again induced, and the same procedures as mentioned above were performed, but the injection sites were reversed. At the end of the trial, the animals were humanely euthanized by IV injection of a commercial euthanasia solution (Fatal+, Vortech Pharmaceuticals, Dearborn, MI). A gross postmortem examination was performed to assess any unusual findings of the heart, lungs, and thorax.

Randomized outcome study.

Animals were randomly assigned to 1 of 3 groups: epinephrine IO, delayed epinephrine IV, or saline placebo (Fig. 1). The protocol simulated a 10-minute untreated VF period (“no bystander CPR”) before arrival of “emergency medical service (EMS) personnel.” After this period, immediate chest compressions were initiated (“rescuer 1”); defibrillation electrodes were placed; and an IO access within 1 minute or an IV access within 8 minutes was acquired to simulate a “realistic” time needed to establish IV access. Endotracheal intubation was performed within 7 minutes, and the airway was allowed to remain open for the course of the study.

Figure 1:
Timeline of the randomized outcome study. Shaded and unshaded syringes indicate administration of epinephrine and placebo, respectively. EMS = emergency medical services; IO = intraosseous; IV = intravenous; VF = ventricular fibrillation.

The simulated EMS protocol was translated into the animal setting as follows: the animals were fully instrumented as described above. At minute 11 of cardiac arrest, epinephrine or placebo was injected simultaneously into the IO and the IV ports according to the randomization described below. The first biphasic defibrillation shock (150 J) was given 1 minute later, immediately followed by 200 chest compressions. Four minutes after starting resuscitation efforts, a 10-second pause for rhythm analysis was followed by a second shock and 200 chest compressions if a perfusing rhythm had not been achieved. This was repeated for 6 cycles if necessary. Bag ventilation with 100% O2 at a rate of 10 per minute was begun 7 minutes after starting resuscitation efforts. If a perfusing rhythm was not achieved after 7 cycles or after 24 minutes of unsuccessful resuscitation efforts, the trial was terminated.

Epinephrine injections in the IO group were at 1 minute, 4 minutes + 15 seconds, and every 135 seconds (200 compressions plus a 15-second pause for rhythm analysis and injection) thereafter, if required. In the IO group, placebo (0.9% NaCl) was given via the IV access at the corresponding injection time. The epinephrine injections in the IV group did not begin until minute 8 of resuscitation, followed by the same injection sequence as described in the IO procedure. The placebo group was treated with saline injections though the IV and IO access sites at each “injection time.”

ROSC was defined as peak AoP of >50 mm Hg and pulse pressures of >20 mm Hg sustained for 1 minute. Successfully resuscitated animals were deinstrumented and allowed to recover in observation cages. After 24 hours, a neurological examination was performed, as has been previously described.2931 Briefly, a score of 1 is normal (i.e., good neurological outcome), 2 is slightly impaired (e.g., not eating or drinking normally, unsteady gait, or slight resistance to restraint), 3 is severely impaired (i.e., the animal is recumbent, unable to stand, and only partially responsive to stimuli), 4 is comatose, and 5 is dead. After the neurological examination, the animals were humanely euthanized by IV injection.

Statistical Analysis

Sample size and power calculation.

Assuming that 25% of the animals in the placebo group and 75% in the treatment groups survive 24 hours with good neurological outcome, we needed 10 animals in each of the 3 groups to attain a statistical power of 87% with an α error of 0.05. Assuming a 50% increase in CPP at 14 and 16 minutes in the IO group versus the IV group, we needed 10 animals to attain a power of 97%.

Data analysis.

Data were entered into Microsoft Excel for Windows (Microsoft Office; Microsoft Corp., Redmond, WA). Statistics were calculated with SPSS version 15.0 (SPSS, Inc., Chicago, IL). Hemodynamic variables and blood gases were analyzed by Student t test and Mann–Whitney U test. A one-way analysis of variance (ANOVA) was used for comparisons of the 3 groups. Categorical data were analyzed using Fisher exact test. Bonferroni correction was used to account for multiple group comparisons. A P < 0.017 was considered significant for comparisons of the 3 groups.


Pilot Pharmacodynamic Study: Effect of Epinephrine on CPP in Relation to Drug Injection Site

Baseline data were not different between the IO and the IV groups. The mean time from injection to onset of increasing CPP was 16 seconds slower with IO than with IV (IO: 38 ± 5 seconds versus IV: 22 ± 2 seconds; P = 0.015), and the time from injection to peak CPP was 17 seconds slower (IO: 60 ± 6 seconds vs. 43 ± 4 seconds; P = 0.045) in the IO group versus the IV group. The peak CPPs were not significantly different (IO: 43 ± 6 mm Hg versus IV: 60 ± 6 mm Hg; P = 0.23). In addition, the ΔCPP, defined as peak CPP minus CPP during the preinjection period, was not significantly different between the IO and IV groups, respectively (IO: 50 ± 6 mm Hg versus IV: 56 ± 6 mm Hg; P = 0.51) (Fig. 2).

Figure 2:
Coronary perfusion pressure (CPP) in relation to intraosseous (IO) vs. intravenous (IV) epinephrine injection. Data are presented as mean ± SEM. The arrow indicates the epinephrine injection. Peak CPP values were not significantly different (values at 50 to 70 seconds for IV in comparison with values at 60 to 80 seconds for IO).

Randomized Outcome Study

Baseline data were, with the exception of the hemoglobin (Hb) value, not different between the IO, IV, and placebo saline groups (Hb-IO: 8.8 g/dL; Hb-IV: 8.0 g/dL; Hb-placebo: 9.2 g/dL; P = 0.015 for IV versus placebo). Without administration of epinephrine, ROSC was uncommon after 10 minutes of untreated VF (1 out of 10 animals in the placebo, in comparison with 10 of 10 animals in the IO group, and 9 of 10 animals in the IV group) (Table 1). Twenty-four-hour survival was substantially more common after IO epinephrine in comparison with the other groups, with 10 of 10 survivors in the IO, 4 of 10 survivors in the IV, and 0 of 10 survivors in the placebo group (P = 0.011, IO versus IV; P < 0.001, IO versus placebo) (Table 2). Good neurological outcome at 24 hours after resuscitation (CPC-1) was more common after IO epinephrine than after placebo (6 of 10 vs. 0 of 10; P = 0.011) (Table 2). Ease of resuscitation was superior in the IO group, as evidenced by fewer shocks needed to achieve ROSC and shorter time to ROSC in the IO group than that in the IV or placebo group (Table 1). The importance of epinephrine in increasing CPP values (>25 to 30 mm Hg) is shown in Figure 3. Without administration of epinephrine, CPP values on average remained below 15 mm Hg. In contrast, after administration of epinephrine, CPP values increased within 1 minute to a range of 35 to 45 mm Hg. The CPP increase after epinephrine administration was comparable between the IO and the IV vascular access sites (Table 3).

Table 1:
Minor Outcome Variables
Table 2:
Major Outcome Variables
Figure 3:
Coronary perfusion pressure (CPP) during a simulated out-of-hospital cardiac arrest treatment protocol. Epinephrine was administered only in the intraosseous (IO) group (at time points 1 minute, 4 minutes, and 6 minutes) and in the intravenous (IV) group (at time points 8 minutes and 10 minutes). CPP during the first and second minutes after administration of epinephrine (A-A′, B-B′, C-C′, and D-D′, respectively) were not statistically different between the 2 access routes..
Table 3:
Coronary Perfusion Pressures After Epinephrine Injection


This study demonstrates that epinephrine administration during resuscitation improves hemodynamics and outcomes. Early epinephrine administration (the IO group) resulted in substantially better outcomes than did delayed epinephrine administration (the IV group). We speculate that timing of epinephrine administration has contributed to the observed lack of benefit of epinephrine in out-of-hospital studies.

Pilot Pharmacodynamic Study

Although emergency IO access has been used for drug and fluid administration for more than 3 decades, pharmacodynamic data addressing the time to drug effect are scarce in the medical literature, especially for low-flow state situations. In the pilot swine model of prolonged VF cardiac arrest, we found a delayed drug effect of only 17 seconds when epinephrine was administered via the IO route in comparison with a central venous route. Maximum effect on the CPP occurred at 60 ± 6 seconds after IO in comparison with 43 ± 4 seconds after IV administration. We observed nearly equipotent responses of CPP with peak CPP values well above 40 mm Hg after either IO or IV administration. Additionally, the duration of the effect of epinephrine was similar with both routes of administration (Fig. 2). Data from EMS settings indicate that functional IO access can on average be established within 1 minute.20,32 Shoor et al.33 investigated IO pharmacodynamics of epinephrine and ephedrine in a bovine model with a perfusing rhythm and found a mean time of 17 ± 3 seconds from injection to onset of hemodynamic effects and 45 ± 5 seconds from injection to 90% of maximal effect. It may well be that the higher baseline flow during normal sinus rhythm and the longer vascular distances in this bovine model affected these times. Previous work compared central venous, peripheral venous, and IO injection of epinephrine in dogs during sinus rhythm.34 The hemodynamic response, onset of action, time to peak effect, and height and duration of effect were not different among the 3 routes of administration. This was also true in a hemorrhagic shock model.34 Catecholamine plasma levels during cardiac arrest and after IO epinephrine administration in dogs and piglets were highly variable at baseline as well as during cardiac arrest and with regard to endogenous secretion during resuscitation efforts.18,35 There were no simple relationships between catecholamine plasma levels per se and CPP or successful resuscitation. On the other hand, there was a clear relationship between CPP and successful defibrillation as well as for ROSC and survival.5,35,36 Wenzel et al.19 reported similar results for vasopressin (peak within 60 seconds) in a swine model.

Randomized Outcome Study

On the basis of the analysis of pilot data, a randomized outcome trial was designed to simulate a novel approach for the out-of-hospital treatment of prolonged VF. Three groups were compared: (i) early administration of epinephrine through an IO access; (ii) IV administration of epinephrine at a delayed but realistic time point for securing a functional venous access in the field; and (iii) placebo control. Our results demonstrate a significant impact of early epinephrine upon ROSC, 24-hour survival, and 24-hour survival with good neurological outcome. All 10 animals in the IO group and 4 of 10 animals in the IV group survived 24 hours, whereas none of the 10 animals in the placebo group survived. The first administration of vasopressors is typically much more delayed than in our IV group. Rittenberger et al.37 reported that the mean time intervals from dispatch to first medication administration was 17.74 minutes (range 10 to 25 minutes). This could be a major factor explaining why several large out-of-hospital clinical trials of epinephrine administration failed to show any outcome benefits in the treatment of human cardiac arrest victims.611

The current study demonstrates the benefits of epinephrine on increasing CPP during resuscitation. Administration of placebo did not increase CPP to levels associated with successful resuscitation despite high-quality chest compressions. Early IO epinephrine as well as delayed IV epinephrine induced a similar increase in CPP and similar peak effects. The short delay in onset of action noted with the IO route (17 seconds in comparison with IV administration) is more than offset by the marked time advantage when establishing IO access in comparison with an IV route during resuscitation efforts. In our protocol with a 7-minute difference between the establishment of the respective vascular access routes, IO administration of epinephrine resulted in the need for fewer defibrillation shocks and an earlier return of ROSC, thereby resulting in substantially greater rates of ROSC and 24-hour survival. Our study supports the recently published results of Mader et al.,38 which used a different anesthesia technique (propofol IV and paralysis of the animals with pancuronium) and compared 2 different simulated EMS protocols: (a) a continuous chest compression group with early epinephrine IO versus (b) a “standard-CPR” group (30 compressions: 2 ventilations) with delayed epinephrine IV. They found an early increase in CPP after IO epinephrine administration and increased rates in ROSC and 20-minute survival. In contrast, we used the same resuscitation protocol for the IO and IV groups and observed 24-hour neurological outcome as the relevant end point. Furthermore, our study was blinded to personnel with regard to “drug administration (IO, IV, and placebo),” which minimizes potential bias.

There is continuing controversy concerning the use of epinephrine in the treatment of cardiac arrest. Some investigators believe that epinephrine should not be used because of its negative effects such as increased myocardial oxygen consumption, worsening of postresuscitation myocardial dysfunction, and potential proarrhythmogenic effects.39,40 In the absence of any clinical trial showing improved outcomes with epinephrine, some even suggest that epinephrine should be withdrawn from advanced cardiac life support recommendations. Our animal study emphasizes that limited doses of epinephrine administered early in the cardiac arrest resuscitation algorithm (using the IO route) can improve hemodynamics during CPR and can thereby improve outcome.


This study was performed in healthy young swine with normal coronary arteries under isoflurane anesthesia with electrically induced VF, whereas adults with VF cardiac arrest are typically older and have coronary artery disease. The intramedullary volume of the swine tibia is smaller than that in adult humans, and the distance from the tibia plateau to the heart is shorter. Therefore, it may take a few seconds longer to achieve similar effects from IO epinephrine in humans. Although the epinephrine dose administered (0.045 mg/kg) is higher per kilogram than is the recommended human dose, we used an established dose for swine cardiac arrest studies.27,28 Importantly, the IO and IV groups each received the same dose, and the differences in outcomes, therefore, demonstrate the time-dependent effects of epinephrine during resuscitation. Postresuscitation intensive care unit care was not provided for any of our animals. Therefore, malignant dysrhythmia, hypotension, and other potentially life-threatening postresuscitation reactions could not be treated. Nevertheless, this lack of posttreatment care was applied to all treatment groups, eliminating bias.


In a swine model of prolonged VF cardiac arrest, the effect of IO epinephrine on CPP during chest compressions was similar to the effect of IV epinephrine. Hemodynamics during CPR and 24-hour survival improved substantially after epinephrine administration than after placebo. Moreover, early IO epinephrine resulted in shorter time to ROSC, reduced total defibrillation energy, and substantially better 24-hour survival rate than did delayed IV epinephrine.


Name: Mathias Zuercher, MD.

Contribution: Study design, data analysis, conduct of study, and manuscript preparation.

Attestation: Approved the final version of the manuscript.

Conflict ofInterest: None.

Name: Karl B. Kern, MD.

Contribution: Study design, data analysis, conduct of study, and manuscript preparation.

Attestation: Approved the final version of the manuscript.

Conflict of Interest: Unrestricted research grant from Laerdal Foundation for Acute Care Medicine.

Name: Julia H. Indik, MD, PhD.

Contribution: Data analysis and manuscript preparation.

Attestation: Approved the final version of the manuscript.

Conflict of Interest: None.

Name: Michael Loedl, BS.

Contribution: Data analysis, conduct of study.

Attestation: Approved the final version of the manuscript.

Conflict of Interest: None.

Name: Ronald W. Hilwig, DVM, PhD.

Contribution: Study design, conduct of study, and manuscript preparation.

Attestation: Approved the final version of the manuscript.

Conflict ofInterest: None.

Name: Wolfgang Ummenhofer, MD.

Contribution: Study design and manuscript preparation.

Attestation: Approved the final version of the manuscript.

Conflict of Interest: None.

Name: Robert A. Berg, MD.

Contribution: Study design and manuscript preparation.

Attestation: Approved the final version of the manuscript.

Conflict of Interest: Unrestricted research grant from Laerdal Foundation for Acute Care Medicine.

Name: Gordon A. Ewy, MD.

Contribution: Study design and manuscript preparation.

Attestation: Approved the final version of the manuscript.

Conflict of Interest: Unrestricted grants from private donations to the University of Arizona Foundation for support of Sarver Heart Center's Resuscitation Research. Co-investigator on an unrestricted grant from the Laerdal Foundation of Stavanger, Norway, both significant.


We would like to acknowledge Nick Hurst and Alice McArthur for their technical assistance and Allison Dwileski for excellent graphical assistance and editorial support.


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