Received: 30.04.2021 Revision: 10.05.2021 Accepted: 20.05.2021 Published: 30.05.2021
COL Denise Beaumont, CRNA, DNAP1, LTC Michelle Johnson, CRNA, DNP2, Julie G. Hensler, PhD3, Dawn Blouin, BS4, Joseph O’Sullivan, CRNA, PhD5 and Don Johnson, PhD*6
1Director, United States Army Graduate Program 490 Forage Rd, San Antonio, Texas, 78234-7585
2Former Executive Officer, United States Army Graduate Program in Anesthesia Nursing 3490 Forage Rd, San Antonio, Texas, 78234-7585
3Professor, United States Army Graduate Program in Anesthesia Nursing 3490 Forage Rd, San Antonio, Texas, 78234-7585
4Research Assistant, United States Army Graduate Program in Anesthesia Nursing 3490 Forage Rd, San Antonio, Texas, 78234-7585
5LTC Retired US Army
6Professor and Director of Research, United States Army Graduate Program in Anesthesia Nursing 3490 Forage Rd, San Antonio, Texas, 78234-7585
Abstract: Aim: The aim of this study was to compare area under the curve (AUC), frequency, and odds of return of spontaneous circulation (ROSC) when epinephrine was administered in hypovolemic and normovolemic cardiac arrest models. Methods: 28 adult swine were randomly assigned to 4 groups: HIO Normovolemia Group (HIONG); HIO Hypovolemia Group (HIOHG); IV Normovolemia (IVNG); and IV Hypovolemia Group (IVHG). Swine were anesthetized. The HIOH and IVH subjects were exsanguinated 35% of their blood volume. Each was placed into arrest. After 2 minutes, cardiopulmonary resuscitation was initiated. After another 2 minutes, 1 mg of epinephrine was given by IV or HIO routes; blood samples were collected over 5 minutes and analyzed by high-performance liquid chromatography. Subjects were defibrillated every 2 minutes. Results: The AUC in the HIOHG was significantly less than both the HIONG (p = 0.047) and IVHG (p = 0.021). There were no other significant differences in the groups relative to AUC (p > 0.05). HIONG had a significantly higher occurrence of ROSC compared to HIOHG (p = 0.018) and IVH (p =0.018) but no other significant differences (p > 0.05) The odds of ROSC were 19.2 times greater for HIONG compared to the HIOHG. Conclusion: The study strongly supports the effectiveness of HIO administration of epinephrine and should be considered as a first-line intervention for patients in cardiac arrest related to normovolemic causes. However, our findings do not support using HIO access for epinephrine administration for patients in cardiac arrest related to hypovolemic reasons.
Approximately 550,000 cardiac arrests occur each year just in the United States (Marijon, E. et al., 2016). Cardiac arrest can be classified as either hypovolemic or normovolemic causes (Long, L. R. P et al., 2018). Hemorrhage is the leading cause of cardiac arrest from trauma in both civilian and military sectors (Dowling, M. B. et al., 2016; Eastridge, B. J. et al., 2012; Kelly, J. F. et al., 2008; Lozano, R. et al., 2012; Schauer, S. G. et al., 2018; & Schauer, S. G. et al., 2019). Mortality from hemorrhage approaches 2 million worldwide. Hemorrhage can lead to hypovolemic shock and subsequent cardiac arrest (Marijon, E. et al., 2016). Cardiovascular disease is the leading cause of arrest in a normovolemic scenario. Other normovolemic causes of arrest include myocardial infarct, blunt trauma, drowning, and electrocution (Dobson, A. J. et al., 1991; Katsouyanni, K. et al., 1986; Kloner, R. A. et al., 1997; Leor, J. et al., 1996; Suzuki, S. et al., 1997; & Trichopoulos, D. et al., 1983).
Regardless of the cause, studies have demonstrated that time to epinephrine administration for any patient in arrest is essential for survivability (Anson, J. A. 2014; ames Burgert CRNA, M. S. N. A. et al., 2012;& Neumar, R. W. et al., 2010). For every minute of delay, chances of survival are decreased by nine percent (Hansen, M. et al., 2018). Therefore, vascular access is essential in increasing the chances of survival and can be delayed in attempting intravenous (IV) access. In a cardiac arrest situation, the victim’s veins have collapsed, particularly in hypovolemic shock, making IV access difficult and very time consuming even for the most skilled clinician.
The American Heart Association (AHA) states that for victims in arrest that 1 mg epinephrine should be administered with repeated dosing every 3-5 minutes (Link, M. S. et al., 2015). Further, AHA recommends the establishment of intraosseous needle (IO) access if IV access is not rapidly obtained (Link, M. S. et al., 2015). Several studies have demonstrated that the IO and IV have similar efficacy (Beaumont, L. D. et al., 2016; Claessens, A., & Johnson, D. 2015; Cornell, M. et al., 2016; Loughren, M. et al., 2014a; Loughren, M. J. et al., 2014b; Nemeth, M. et al., 2016; Wimmer, M. H. et al., 2016; Von Hoff, D. D. et al., 2008; Burgert, J. M. 2016a; & Burgert, J. M. 2016b). However, most IO studies have investigated drugs used in a normovolemic model. We speculated there may be differences in patients with hypovolemia because of the release of endogenous epinephrine. Both endogenous and the exogenous administered catecholamines may have an additive effect causing vasoconstriction to the bones. Subsequently, there may be less delivery of epinephrine from the bone into the systemic circulation (EEC Committee SaTFotAHA. 2010). In fact, Voelckel found that hemorrhage along with epinephrine administration reduces flow to the bones to almost zero (Voelckel, W. G. et al., 2001). Area under the curve (AUC) reflects the body’s exposure to epinephrine after administration. We reasoned that epinephrine administration in a hypovolemic compared to a normovolemic model may change the volume of distribution. Subsequently, this reduces AUC that may translate into less frequency of return of spontaneous circulation (ROSC). Few studies have investigated the effects of hypovolemia on the efficacy of intraosseous epinephrine administration in a cardiac arrest scenario. In separate studies, Neill and Yauger found that HIO and tibial intraosseous (TIO) were ineffective in achieving ROSC in a pediatric cardiac arrest hypovolemic model (Neill, M. J. et al., 2020; & Yauger, Y. J. et al., 2020). Only one study has compared the effects of IO epinephrine administration using hypovolemia and normovolemia in adult subjects (Long, L. R. P. et al., 2018). In that study, Long found that the humerus intraosseous (HIO) administration of epinephrine was very effective in a normovolemic model but not in a hypovolemic model, but they did not investigate the effects of AUC (Long, L. R. P. et al., 2018).
There are no studies comparing HIO and IV administration of epinephrine relative to AUC in hypovolemic and normovolemic cardiac arrest models. The findings of this study give direction for making decisions regarding vascular access for patients in cardiac arrest, hence, has the potential of saving lives. The aims of this study were to compare AUC, frequency, and odds of ROSC when epinephrine was administered by HIO and IV routes in hypovolemic and normovolemic models of cardiac arrest.
This study was funded by TriService Research Program Grant number (N13-P10) and approved by the Institutional Animal Care and Use Committee (Naval Medical Research Unit, JBSA-FSH protocol 12-01). The study was conducted at the Navy Triservice Medical Research Center in San Antonio, Texas. To avoid as much variability as possible, we purchased swine from the same vendor (Oak Hill Genetics, Ewing, IL). All subjects were cared for according to the Animal Welfare Act and the Guide for the Use of Laboratory Animals (Research CftUotGftCaUoLAIoLA. 2011). This study consisted of four groups (N=28) of adult male Yorkshire-cross, sus scrofa, swine. By using a random number generator (https://www.random.org/integers), we assigned seven swine to each of four groups: HIO Normovolemic Group (HIONG); HIO Hypovolemic Group (HIOHG); IV Normovolemic Group (IVNG) and IV Hypovolemic Group (IVHG). Male pigs were used to avert possible effects from the female hormones. The swine weighed ~70 kg which approximates the average weight of an adult, male human (Gordon, C. C. et al., 2015a; & Gordon, C. C. et al., 2015b). The rationale for using pigs was because the cardiovascular, pulmonary, and bone physiology are very similar to humans (Hannon, J. P. et al., 1990; & Swindle, M. M. et al., 2012). Each of the swine received a thorough health examination to confirm that they were in good health on arrival and before the study. After midnight on the day before the experiment, the subjects were not allowed food but allowed to drink water up until induction of anesthesia. For subjects in the HIO groups, we inserted the EZ-IO device (Teleflex, Philadelphia, Pa). After insertion, we aspirated blood and/or bone marrow to make certain the device was in the humerus.
An intramuscular injection of Telazol (4.4 mg/kg), (Tiletamine/Zolazepam, Fort Dodge Animal Health, Fort Dodge, IA, USA) and then anesthesia (1 to 2 % isoflurane) was administered. The hypovolemic groups were exsanguinated 35% of their blood volume to represent a Class III hemorrhage. For all subjects, an electric current was sent through each of the swine’s heart to produce cardiac arrest, a procedure developed by the investigators (Burgert, J. M. et al., 2015). Anesthesia was discontinued, and each animal was left in arrest for 2 minutes. The rationale for 2 minutes was this was the minimum amount of time to detect cardiac arrest. Mechanical chest compressions at 100 per minute were initiated using the Mechanical Compression Device, Model 1008 (Michigan Instruments, Grand Rapids, MI, USA). The rationale for using the device was to maintain consistency and reproducibility. Ventilation rates of 8 to 10 per minute were used. After another 2 minutes, 1 mg epinephrine was given by IV or HIO routes; blood samples were then collected over 5 minutes.
Serum concentration of epinephrine was determined by using high-performance liquid chromatography (HPLC), the industry standard. The individual performing the calculations was blinded to group assignment. Defibrillation was administered every 2 minutes as recommended by AHA (Link, M. S. et al., 2015). The hypovolemic groups received 500 mL of 5% albumin following blood sampling. CPR continued until ROSC. If ROSC were not achieved, the investigators implemented resuscitation efforts for ROSC for 20 minutes. Once ROSC was achieved, we monitored the subject for 30 minutes. ROSC was operationally defined as a mean arterial pressure of at least 60 mmHg and a palpable pulse.
We calculated a large effect size of 0.6 based on previous, similar research (Wong, M. R. et al., 2016; Burgert, J. M. et al., 2016a; & Burgert, J. M. et al., 2016b). Using an α of 0.05, a large effect size of 0.6, and a power of 0.8, we calculated that we needed a sample size of 28 (n = 7 per group). We performed power analysis using G*Power 3.1 for Windows (Heinrich Heine University, Dusseldorf, Germany). Means and standard error of the means were calculated for each group. A multivariate analyses of variance (MANOVA) was used to determine if there were any significant differences in the pretest data including weight, cardiac output, stroke volume, systolic blood pressure, mean arterial blood pressure, temperature, heart rate, total blood volume, and the amount of blood exsanguinated in the hypovolemic groups. A univariate ANOVA was used to determine if there were significant differences in the AUC by group. A Chi-Square was used to determine if there were significant differences in frequency of ROSC by group. All statistics were calculated using SISA (https://www.quantitativeskills.com/sisa/index.htm). Odds of ROSC by group were calculated by using an odds ratio calculator (https://www.medcalc.org/calc/odds_ratio.php).
One of the major limitations of this study was a small sample size. Nevertheless, we had enough power to find significance. Another limitation was that not all the investigators were blinded to group assignment although they rigorously adhered to the procedures of this study. Also, the findings of this study may not be generalizable to humans; however, the cardiovascular, bone, and respiratory systems are very similar to humans (Hannon, J. P. et al., 1990; & Swindle, M. M. et al., 2012).
Figure Image is available at PDF file
Figure 1: Group Comparison of Area Under the Curve
Figure Image is available at PDF file
Figure 2 ROSC by Group
A MANOVA indicated no significant differences in the pretest data indicating the groups were equivalent on these variables (p > 0.05). A univariate ANOVA indicated significant differences in the AUC by group. The AUC in the HIOHG was significantly less than both the HIONG (p = 0.047) and IVHG (p = 0.021). There were no other significant differences in the groups relative to AUC (p > 0.05). (See Figure 1). A Chi-Square indicated that the HIONG had a significantly higher occurrence of ROSC compared to HIOHG (p = 0.018) and IVH (p =0.018) but no other significant differences (p > 0.05) (See Figure 2) The odds of ROSC were 19.2 times greater for HIONG compared to the HIOHG.
We found the AUC in the HIOHG was significantly less compared to both the HIONG and IVHG, and the frequency of ROSC was significantly higher in the HION compared to both the HIOHG and IVHG. The odds of ROSC were greater for the HIONG compared to the HIOHG. Following acute blood loss, activation the sympathetic nervous system and increased release of endogenous catecholamines serve to shunt blood away from peripheral tissues such as bone, which are not necessary for survival (Moraes, J. M. S. D. et al., 2014; & Tsai, M. H. et al., 2014). Thus, humeral bone marrow may be less perfused in hypovolemic subjects than in normovolemic subjects. Consistent with this idea, studies show that maximum plasma concentration (Cmax) is lower and time to maximum plasma concentration (Tmax) is delayed following HIO epinephrine administration in hypovolemic compared to normovolemic subjects (Long, L. R. P. et al., 2018). Our data are in agreement with previous work and suggest that in hypovolemic subjects, plasma concentrations of epinephrine following HIO administration were insufficient for ROSC in the majority of subjects. By contrast, plasma concentration of epinephrine following HIO administration in normovolemic subjects were sufficient for all subjects to achieve ROSC (Long, L. R. P. et al., 2018).
Early administration of epinephrine is essential for ROSC for patients in cardiac arrest. Valuable time can be saved by using the HIO route compared to the IV route. Early administration of epinephrine is associated with a higher probability of ROSC in patients with cardiac arrest and can significantly reduce odds of death by 58% if administered within 5 minutes (Andersen, L. W. et al., 2015; & Andersen, L. W. et al., 2016). In our study, it took less than 10 seconds to insert the EZ-IO device. Major advantages of using the IO device is the rapid vascular access, and CPR does not have to be interrupted compared to IV insertion. Also, IV access can be difficult and very time consuming. Intravenous failure rates have been shown to be from 10 to 40% in patients not in arrest and that the time to obtain IV access is greatly varied from 2.5 to 16 minutes to as long as 55 minutes in critically ill patients and would probably be longer in a patient in cardiac arrest (Andersen, L. W. et al., 2015; & Andersen, L. W. et al., 2016). In summary, the present study strongly supports the effectiveness of HIO administration of epinephrine and should be considered as a first-line intervention for patients in cardiac arrest related to normovolemic causes. However, our findings do not support using HIO access for epinephrine administration for patients in cardiac arrest from related to hypovolemic reasons.
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