RECOVER 2.0 Worksheet

QUESTION ID: ALS-14

PICO Question:
In cats and dogs with CPA (P) does intraosseous administration of drugs (I) compared with intravenous drug administration (C) improve outcome (O)?

Outcomes:
Favorable neurologic outcome, Surrogate marker(s) of perfusion, Survival to Discharge, ROSC

Prioritized Outcomes (1= most critical; final number = least important):

1. Favorable neurological outcome

2. Survival to discharge

3. ROSC

4. Surrogate markers of perfusion

Domain chairs: Gareth Buckley, Elizabeth Rozanski

Evidence evaluators: Debbie Wilson, Eva Larouche-Lebel

Conflicts of interest:

Search strategy: See attached document

Evidence Summary:

Study Design

Reduced Quality Factors 0 = no serious, - = serious, - - = very serious

Positive Quality Factors 0 = none, + = one, ++ = multiple

Dichotomous Outcome Summary

Non-Dichotomous Outcome Summary Brief description

Overall Quality High, moderate, low, very low, none

No of studies

Study Type

RoB

Indirectness

Imprecision

Inconsistency

Large Effect

Dose-Response

Confounder

# Intervention with Outcome

# Control with Outcome

RR (95% CI)

Outcome: Favorable neurological outcome

2	CT	0	- -	-	-								Very low
4	Obs	0	-	0	0								Very low
1	Exp	0	-	0	0								Low

Outcome: Survival to discharge

2	CT	0	- -	-	-								Very low
6	Obs	0	-	0	0								Very low
1	Exp	0	-	0	0								Low

Outcome: ROSC

2	CT	-	- -	0	-								Very low
6	Obs	0	-	0	0								Very low
19	Exp	0	-	0	-								Very low

PICO Question Summary

Introduction

In dogs and cats undergoing CPR, intravenous access is considered ideal for administration of resuscitative medications and fluids/blood products. However, in some cases IV access may be difficult to obtain and alternative methods, such as intraosseous (IO) or intratracheal (IT), have been proposed. In many patients, obtaining IO access may be easier than obtaining IV access. The goal of this PICO was to determine if IO access is as efficacious as IV access for drug delivery during CPR.

Consensus on science

Outcome 1: Favorable neurologic outcome For the most critical outcome of favorable neurologic outcome, 2 clinical trials (very low quality of evidence, downgraded for very serious indirectness, serious imprecision and serious inconsistency), 4 observational studies (very low quality of evidence, downgraded for serious indirectness), and 1 experimental study (low quality of evidence, downgraded for serious indirectness) informed the answer to the PICO question. In a prospective clinical trial of 1007 human patients with OOH CPA randomized to either IV access or IV access attempts for 2 minutes and then redirection to IO access (IV+IO), no differences were identified between the groups in survival with good neurologic outcome (IV+IO: 3.4 vs IV: 4%) or survival to discharge (4.9 vs 8.4%), or ROSC (27% vs 27.6%).1 However, patients in the IV+IO arm had a higher percentage of successful vascular access (76.6 vs 61.1%), higher percentage with epinephrine administered pre-hospital (71.3 vs 55.4%), shorter median time between call to emergency services and first epinephrine administration (23 [IQR: 18 – 28] vs 25 [IQR: 20-31] minutes), and shorter time to first dose of epinephrine after EMS arrival at patient side (9 [IQR: 6-14] vs 11 [IQR: 7-18] minutes). In a second clinical trial of 3019 OHCA patients with refractory VF/pVT, patients were randomized to 6 arms (placebo, amiodarone or lidocaine, administered IV or IO).2 The authors reported improvements in survival with good neurologic function in patients treated with IV but not IO amiodarone, and improved survival to hospital discharge for both amiodarone and lidocaine when given IV, but not if given IO, but the study was not designed to test the interaction between the 2 routes. Two retrospective observational studies compared the effects of IV and IO access on outcomes after IHCA. Schwalbach at al. evaluated 1039 patients with CPA, and using a multivariate analysis showed no difference in rate of survival with favorable neurologic status (OR 0.74, 95% CI 0.49-1.13, P=0.16) or survival to discharge (OR 0.71, 95% CI 0.47-1.06, P=0.09).3 However, both the frequency of ROSC and time to ROSC were significantly worse in the IO group. A propensity-matched registry study of 603 pre-pubescent patients with IH CPA had insufficient numbers to statistically evaluate survival with good neurologic function but found no difference in frequency of ROSC or survival to discharge between patients receiving drugs IV vs IO.4 Two additional retrospective studies evaluated outcomes in patients with OHCA receiving drugs IV vs IO. In a study of 1576 people, Baert et al. found no significant differences in favorable neurologic outcome or 30 day survival between the groups, but found lower frequency of ROSC in patients receiving drugs IO.5 In a larger study of 6879 people with OHCA, a propensity adjusted analysis showed lower frequencies of favorable neurologic outcome, survival to discharge, and sustained ROSC in patients receiving drugs IO than in the IV group.6 Finally, in a swine OOH VF model, VF was induced and left untreated for 10 minutes, after which BLS was started.7 The IO group received epinephrine after 1 minute of BLS, and the IV group received epinephrine after 8 minutes. A third group received placebo. There was no difference in survival with good neurologic outcome between the IO and IV groups (6/10 vs 3/10, P>0.05), but 24-hour survival was more common in the IO than the IV group (10/10 vs 4/10, P = 0.001). Frequency of ROSC was similar between the groups (10/10 vs. 9/10, P > 0.05). Outcome 2: Survival to discharge For the next most critical outcome of survival to discharge, 2 observational studies (very low quality of evidence, downgraded for serious indirectness) in addition to the 2 clinical trials (very low quality of evidence, downgraded for very serious indirectness, serious imprecision and serious inconsistency), 4 observational studies (very low quality of evidence, downgraded for serious indirectness), and 1 experimental swine study described above (low quality of evidence, downgraded for serious indirectness) were identified. A registry-based study of 1549 pediatric OHCA showed that although IO attempts were more commonly successful than IV attempts (difference in success of placement 21%, 95% CI 17 to 26%), logistic regression modelling using multiple imputation to address missing data showed that IO catheter patients were less likely to survive to discharge (adjusted OR 0.46; 95% CI 0.21–0.98).8 However, the logistic regression model did not include variables associated with illness severity or type. The second was an OHCA registry study including 1800 patients, which showed in a multivariable adjusted analysis that that IO treated patients had similar frequency of survival to discharge to IV treated patients (OR 0.81 [95% CI 0.55, 1.21], P = 0.31), but lower frequency of ROSC (OR = 0.67 (95% CI 0.50, 0.88), P = 0.004).9 Outcome 3: ROSC For the outcome of ROSC, in addition to the studies described for the 2 higher priority outcomes, 17 additional experimental studies in swine and 1 additional experimental study in lambs were identified that addressed the PICO question (very low quality evidence downgraded for serious indirectness and serious inconsistency). Of these, 2 studies in swine with prolonged, untreated VF (10 minutes) examined immediate tibial intraosseous (TIO) epinephrine vs delayed (8 minutes) epinephrine IV and showed that animals administered epinephrine via either route had higher frequency of ROSC than animals not receiving epinephrine.7,10. However, Mader et al. showed improved odds ratio for ROSC in the immediate TIO group compared to the delayed IV group (3.3 [95%CI = 1.1, 10.2]) while Zuercher et al. showed no difference between the TIO and delayed IV group in ROSC frequency. Four studies compared early IV and TIO or humeral IO (HIO) epinephrine administration in induced VF models (3 in swine and 1 in lambs).11–14 All showed that the frequency of ROSC and time to ROSC were similar between the IV and IO groups. Four studies used hypovolemic swine models of VF. One showed no difference in frequency of ROSC between epinephrine administration IV or HIO15, one showed no difference between sternal IO (SIO), TIO, HIO or IV epinephrine administration16, one showed that IV administration of epinephrine yielded higher ROSC frequency than HIO administration17, and one showed that TIO epinephrine administration was as effective as IV administration in euvolemic animals but IV administration yielded higher frequency of ROSC in hypovolemic animals than TIO administration18. Five swine studies, a mix of hypovolemic and euvolemic induced CPA showed no difference in frequency of ROSC between IV and IO (TIO and/or HIO) administration of vasopressin.19–23 Three additional studies comparing IV vs IO (HIO, SIO, TIO) administration of amiodarone in swine with prolonged shockable rhythms showed no difference in ROSC frequency.24–26 Finally, one study of prolonged VF in swine showed that time to ROSC was shorter when vasopressin, epinephrine and amiodarone were given via the SIO or IV route than via the TIO route, but frequency of ROSC was similar in all 3 groups.27 Outcome 4: Surrogate Markers of Perfusion Given the large amount of evidence for the 3 higher priority outcomes, this outcome was not addressed for this PICO question.

Treatment recommendation

We recommend that CPR drugs be administered preferentially via an IV catheter rather than via an IO catheter (strong recommendation, very low quality of evidence). If attempts at IV access are not successful within 2 minutes, we suggest that rescuers pursue IO catheter placement and to concurrently attempt to secure IV and IO access if adequate personnel are available (weak recommendation, very low quality of evidence).

Justification of treatment recommendation

Although there are several clinical trials in people and a large number of experimental studies addressing this PICO question, the results are mixed, suggesting that IV access is likely superior to IO access for resuscitation drug administration during CPR. Given the evidence that early administration of resuscitation drugs is preferred, it is reasonable to pursue IO catheter placement if attempts at IV access are not immediately successful and to concurrently attempt to secure IV and IO access if adequate personnel are available. If both IV and IO access are available, the evidence suggests that preference be given to IV administration of resuscitation drugs.

Knowledge gaps

There are very limited experimental data in dogs and no data in cats on the efficacy of IV vs IO administration of resuscitation drugs. Additionally, there is no evidence to inform choice of the optimal location for IO catheter placement in dogs or cats.

References:

1. Tan BKK, Chin YX, Koh ZX, et al. Clinical evaluation of intravenous alone versus intravenous or intraosseous access for treatment of out-of-hospital cardiac arrest. Resuscitation. 2021;159:129-136.

2. Daya MR, Leroux BG, Dorian P, et al. Survival After Intravenous Versus Intraosseous Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Shock-Refractory Cardiac Arrest. Circulation. 2020;141(3):188-198.

3. Schwalbach KT, Yong SS, Chad Wade R, Barney J. Impact of intraosseous versus intravenous resuscitation during in-hospital cardiac arrest: A retrospective study. Resuscitation. 2021;166:7-13.

4. Recher M, Baert V, Escutnaire J, et al. Intraosseous or Peripheral IV Access in Pediatric Cardiac Arrest? Results From the French National Cardiac Arrest Registry. Pediatr Crit Care Med. 2021;22(3):286-296.

5. Baert V, Vilhelm C, Escutnaire J, et al. Intraosseous Versus Peripheral Intravenous Access During Out-of-Hospital Cardiac Arrest: a Comparison of 30-Day Survival and Neurological Outcome in the French National Registry. Cardiovasc Drugs Ther. 2020;34(2):189-197.

6. Hamam MS, Klausner HA, France J, et al. Prehospital Tibial Intraosseous Drug Administration is Associated with Reduced Survival Following Out of Hospital Cardiac Arrest: A study for the CARES Surveillance Group. Resuscitation. 2021;167:261-266.

7. Zuercher M, Kern KB, Indik JH, et al. Epinephrine improves 24-hour survival in a swine model of prolonged ventricular fibrillation demonstrating that early intraosseous is superior to delayed intravenous administration. Anesth Analg. 2011;112(4):884-890.

8. Besserer F, Kawano T, Dirk J, et al. The association of intraosseous vascular access and survival among pediatric patients with out-of-hospital cardiac arrest. Resuscitation. 2021;167:49-57.

9. Feinstein BA, Stubbs BA, Rea T, Kudenchuk PJ. Intraosseous compared to intravenous drug resuscitation in out-of-hospital cardiac arrest. Resuscitation. 2017;117:91-96.

10. Mader TJ, Kellogg AR, Walterscheid JK, Lodding CC, Sherman LD. A randomized comparison of cardiocerebral and cardiopulmonary resuscitation using a swine model of prolonged ventricular fibrillation. Resuscitation. 2010;81(5):596-602.

11. Roberts CT, Klink S, Schmölzer GM, et al. Comparison of intraosseous and intravenous epinephrine administration during resuscitation of asphyxiated newborn lambs. Arch Child Fetal Neonatal Ed. Published online 2021.

12. Johnson D, Garcia-Blanco J, Burgert J, et al. Effects of humeral intraosseous versus intravenous epinephrine on pharmacokinetics and return of spontaneous circulation in a porcine cardiac arrest model: A randomized control trial. Ann Med Surg Lond. 2015;4(3):306-310.

13. Wong MR, Reggio MJ, Morocho FR, et al. Effects of intraosseous epinephrine in a cardiac arrest swine model. J Surg Res. 2016;201(2):327-333.

14. Beaumont LD, Baragchizadeh A, Johnson C, Johnson D. Effects of tibial and humerus intraosseous administration of epinephrine in a cardiac arrest swine model. Am J Disaster Med. 2016;11(4):243-251.

15. Long LRP, Gardner LSM, Burgert J, et al. Humerus intraosseous administration of epinephrine in normovolemic and hypovolemic porcine model. Am J Disaster Med. 2018;13(2):97-106.

16. Burgert JM, Johnson AD, O’Sullivan JC, et al. Pharmacokinetic effects of endotracheal, intraosseous, and intravenous epinephrine in a swine model of traumatic cardiac arrest. Am J Emerg Med. 2019;37(11):2043-2050.

17. Neill MJ, Burgert JM, Blouin D, et al. Effects of humeral intraosseous epinephrine in a pediatric hypovolemic cardiac arrest porcine model. Trauma Surg Acute Care Open. 2020;5(1):e000372.

18. Yauger YJ, Johnson MD, Mark J, et al. Tibial Intraosseous Administration of Epinephrine Is Effective in Restoring Return of Spontaneous Circulation in a Pediatric Normovolemic But Not Hypovolemic Cardiac Arrest Model. Pediatr Emerg Care. Published online 2020.

19. Fulkerson J, Lowe R, Anderson T, et al. Effects of Intraosseous Tibial vs. Intravenous Vasopressin in a Hypovolemic Cardiac Arrest Model. West J Emerg Med. 2016;17(2):222-228.

20. Adams TS, Blouin D, Johnson D. Effects of tibial and humerus intraosseous and intravenous vasopressin in porcine cardiac arrest model. Am J Disaster Med. 2016;11(3):211-218.

21. Johnson D, Giles K, Acuna A, et al. Effects of tibial intraosseous and IV administration of vasopressin on kinetics and survivability in cardiac arrest. Am J Emerg Med. 2016;34(3):429-432.

22. Wimmer MH, Heffner K, Smithers M, et al. The comparison of humeral intraosseous and intravenous administration of vasopressin on return of spontaneous circulation and pharmacokinetics in a hypovolemic cardiac arrest swine model. Am J Disaster Med. 2016;11(4):237-242.

23. Burgert JM, Johnson AD, Garcia-Blanco J, Fulton LV, Loughren MJ. The Resuscitative and Pharmacokinetic Effects of Humeral Intraosseous Vasopressin in a Swine Model of Ventricular Fibrillation. Prehosp Disaster Med. 2017;32(3):305-310.

24. Holloway CMM, Jurina CSL, Orszag CJD, et al. Effects of humerus intraosseous versus intravenous amiodarone administration in a hypovolemic porcine model. Am J Disaster Med. 2016;11(4):261-269.

25. Smith S, Borgkvist B, Kist T, et al. The effects of sternal intraosseous and intravenous administration of amiodarone in a hypovolemic swine cardiac arrest model. Am J Disaster Med. 2016;11(4):271-277.

26. Hampton K, Wang E, Argame JI, et al. The effects of tibial intraosseous versus intravenous amiodarone administration in a hypovolemic cardiac arrest procine model. Am J Disaster Med. 2016;11(4):253-260.

27. O’Sullivan M, Martinez A, Long A, et al. Comparison of the effects of sternal and tibial intraosseous administered resuscitative drugs on return of spontaneous circulation in a swine model of cardiac arrest. Am J Disaster Med. 2016;11(3):175-182.

Supplemental:

FNO

Tan, 2021: prospective, parallel-group, cluster-randomised study comparing ‘IV (2 minutes, switch ti IO if IV not successful)+ IO’ and ‘IV only’ protocols in patients with OHCA in 1007 human patients. Patients in IV+IO arm had higher percentage of successful vascular access (76.6 vs 61.1%), higher percent epi administered pre-hospital (71.3 vs 55.4%), shorter median time from emergency call to first epi (23 [18 – 28] vs 25 [20-31] minutes), and shorter time from arrival at patient side to first epi (9 [6-14] vs 11 [7-18] minutes). [IQR]

No difference in ROSC (27% vs 27.6%), survival with poor neurologic function (3.4 vs 4%), or survival to d/c (4.9 vs 8.4%).

Daya 2020: prespecified analysis of a randomized, placebo-controlled clinical trial of 3019 OOH CPA patients with refractory VF/pVT who received amiodarone, lidocaine, or placebo IV or IO

In comparison with placebo, discharge survival was significantly higher in recipients of intravenous amiodarone (adjusted risk ratio, 1.26 [95% CI, 1.06–1.50]; adjusted absolute survival difference, 5.5% [95% CI, 1.5–9.5]) and intravenous lidocaine (adjusted risk ratio, 1.21 [95% CI, 1.02–1.45]; adjusted absolute survival difference, 4.7% [95% CI, 0.7–8.8]); but not in recipients of intraosseous amiodarone (adjusted risk ratio, 0.94 [95% CI, 0.66–1.32]) or intraosseous lidocaine (adjusted risk ratio, 1.03 [95% CI, 0.74–1.44]). Survival to hospital admission also increased significantly when drugs were given intravenously but not intraosseously, and favored improved neurological outcome at discharge. There were no outcome differences between intravenous and intraosseous placebo, indicating that the access route itself did not demarcate patients with poor prognosis.

Observational

Schwalbach 2021: retrospective observational study, IHCA, 1039 patients, IO had lower overall survival to hospital discharge (20.8% vs 28.4% p = 0.03), lower rates of survival with favourable neurologic status (18.4% vs 25.2% p = 0.04), lower ROR (72.2% vs 80.7%) and longer TTR (12:38 min vs 9:01 min). After multivariate adjustment there was no significant differences between IO and PIV in rates of survival to discharge (OR 0.71, 95% CI 0.47–1.06,p = 0.09) or rates of survival with favourable neurologic status (OR 0.74, 95% CI 0.49–1.13, p = 0.16). The rate of ROSC and time to ROSC remained significantly worse in the IO group.

Recher 2021: retrospective registry study, 603 pre-pubescent patients After propensity matching, 101 pairs of patients were created. No difference was observed on return of spontaneous circulation or 0-day survival rates (odds ratio = 1.000 [95% CI, 0.518–1.930]; odds ratio = 0.946 [95% CI, 0.492–1.817], respectively) and on 30 days or hospital discharge survival (n = 3 in both groups) (odds ratio = 1.000 [95% CI, 0.197–5.076]). Meaningful statistical evaluation of neurologic status among survivors was precluded by inadequate numbers.

Baert 2020: OHCA, 1576 patients received intraosseous access, and 27,280 received peripheral intravenous access. After propensity score matching, no significant differences in 30-day survival rates (OR = 0.763 [0.473;1.231]) and neurological outcome (OR = 1.296 [0.973;1.726]) were observed. However, intraosseous patients still showed lower likelihood of short-term survival (ROSC and 0-day survival) even after propensity score matching was implemented.

Haman 2021: 6879 OOH CPA, 37.8% had IO drugs administered. After propensity adjustment, IO route remained associated with lower odds of sustained ROSC (OR 0.72, 95% CI 0.630.81, p < 0.001), hospital survival (OR 0.48, 95% CI 0.370.62, p < 0.001), and favorable neurological outcomes (OR 0.42, 95% CI 0.300.57, p < 0.001).

Experimental:

Zuercher 2011: Swine model of prolonged VF. Animals had 10 minutes of untreated VF, then either IO epi after 1 minute and CPR immediately or IV epi after 8 minutes of CPR. ROSC after 10 minutes of untreated VF was uncommon without administration of epinephrine (1 of 10), whereas ROSC was nearly universal with IO epinephrine or delayed IV epinephrine (10 of 10 and 9 of 10, respectively; P 0.001 for either versus placebo). Twenty-four hour survival was substantially more likely after IO epinephrine than after delayed IV epinephrine (10 of 10 vs. 4 of 10, P 0.001). None of the placebo group survived at 24 hours. Survival with good neurological outcome was more likely after IO epinephrine than after placebo (6 of 10 vs. 0 of 10, P 0.011), and only 3 of 10 survived with good neurological outcome in the delayed IV epinephrine group (not significant versus either IO or placebo).

S2D

Besserer, 2021: Observational registry study, pediatric humans < 17, 1549 OHCA. IO attempts were more commonly successful than IV attempts (difference 21%, 95% CI 17 to 26%). Logistic regression modelling showed patients receiving IO catheters were less likely to survive to discharge (adjusted OR 0.46; 95% CI 0.21–0.98).

Feinstein, 2017: OHCA registry study, 1800 patients. IO versus IV-treated patients were less likely to survive to hospital discharge (14.9% vs 22.8%, p = 0.003), achieve ROSC (43.6% vs 55.5%, p < 0.001) or be hospitalized (38.5% vs 50.0% p < 0.001). In multivariable adjusted analyses, IO treatment was not associated with survival to discharge (odds ratio (OR) (95% confidence interval) 0.81 (0.55, 1.21), p = 0.31), but was associated with a lower likelihood of ROSC (OR = 0.67 (0.50, 0.88), p = 0.004) and survival to hospitalization (OR = 0.68 (0.51, 0.91), p = 0.009).

ROSC:

Observational:

Nguyen, 2019: 406 OOH CPA patients. Retrospective chart review from EMS service. Patients with IV access had higher frequency of ROSC (45.1 vs 25.7%, P<0.001). In addition, patients in which the first attempted access was IV had higher frequency of ROSC than patients in which the first attempted access was IO (42.4 vs 26.6%, P < 0.01). No adjustment for patient demographics, severity of illness or cause of arrest.

Clemency, 2017: 1310 OOH CPA patients, non-inferiority study. Retrospective chart review from EMS service. Providers first attempted parenteral access via IV route in 788 (60.15%) subjects. Providers first attempted parenteral access via IO route in 552 (39.85%) subjects. Rates of ROSC at time of ED arrival were 19.67% when IV access was attempted first and 19.92% when IO access was attempted first. An IO first approach was non-inferior to an IV first approach based on the primary end point ROSC at time of emergency department arrival (p = 0.01).

Experimental:

Epi IV vs IO

Epi delayed IV vs IO

Multiple drugs

Mader, 2010: Swine model of OHCA, 10 minutes untreated VF, immediate TIO vs delayed IV for epinephrine administration. Odds ratio for ROSC was better in IO group compared to IV group (ROSC [3.3 (95%CI = 1.1, 10.2)]).

Zuercher 2011: Swine prolonged (10 minutes untreated) VF model. TIO epi vs delayed (8 min) IV epi vs no epi. ROSC was the same between the epi groups, worse in the no epi group.

Epi IV vs IO Euvolemic

Roberts, 2021: Lamb asphyxia arrest model, IV vs IO epinephrine. Frequency of ROSC, number of doses of epinephrine and time to ROSC were similar between the groups.

Johnson, 2015: Swine VF model, HIO, IV, epi administration vs CPR + defib only. HIO and IV plasma concentrations of epi were similar except at 30 sec, at which time HIO plasma concentration was higher. ROSC frequency was similar between HIO and IV, but was lower in the CPR+defib only group.

Wong, 2016: Swine VF model, TIO vs IV epinephrine, no difference in time to ROSC or frequency of ROSC between TIO and IV. Epi concentrations were higher and time to max concentration was shorter in IV vs TIO.

Beaumont, 2016: Swine CPA model via electrical stimulation, mix of rhythms. Compared epi administration TIO, HIO and IV. No differences in frequency of ROSC between groups.

Epi Hypovolemia

Long 2018: Swine hypovolemic vs normovolemic VF model, HIO epi, IV epi. No statistically significant difference in ROSC rates between HIO and IV or between normo and hypo-volemic.

Yauger 2020: Pediatric swine VF model, TIO vs IV epinephrine. Hypovolemic and normovolemic animals. TIO was as effective for ROSC as IV in euvolemic patients, TIO was less effective for ROSC in hypovolemic animals than IV.

Neill, 2020: Pediatric swine hypovolemic arrest model, CPA induced by electrical stimulation of the heart (mix of arrest rhythms resulted). IV administration of epi more commonly led to ROSC than humeral IO administration and resulted in higher plasma concentrations of epinephrine, and HIO administration was no more effective than CPR + defib without drug administration.

Burgert 2019: ETT, SIO, TIO, HIO, IV, no epi. Hypovolemic induced CA swine model. No difference in ROSC between the epi groups, all were significantly higher than the no epi group.

Fulkerson 2016: Swine hypovolemic VF model, there was no difference in frequency of ROSC or plasma vasopressin concentrations between TIO and IV.

Adams 2016: Swine hypovolemic VF model, HIO vs. TIO for vasopressin, no difference in ROSC or time to ROSC.

Johnson 2016: Swine IHCA model, TIO vs IV for vasopressin, no difference in ROSC, plasma concentrations were lower in TIO.

Wimmer 2016: Swine hypovolemic arrest model, HIO vs IV vasopressin vs no vasopressin, no difference in ROSC between the IV and HIO groups, significantly lower ROSC in no-vasopressin group.

Burgert 2017: Swine VF model, HIO vs IV vasopressin, no difference in ROSC

Holloway, 2016: Resuscitated hypovolemic swine VF model, HIO vs IV amiodarone, no difference in ROSC or plasma concentrations based on route.

Smith 2016: Swine hypovolemic VF model, SIO vs IV amiodarone, no difference in ROSC.

Hampton 2016: Swine hypovolemic VF model, TIO vs IV amiodarone, no difference in ROSC.

O’Sullivan, 2016: Swine VF arrest model, sternal IO vs tibial IO vs IV vs BLS only vs BLS+defib. Vasopressin, epi, amiodarone administered. Frequency of ROSC was similar between SIO, TIO and IV. Time to ROSC was significantly faster in SIO and IV than TIO.