IO v IV drugs: ALS 2046 TF SR

Conflict of Interest Declaration

The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: Keith Couper, Jerry P Nolan, Charles D Deakin, Asger Granfeldt, Mathias Holmberg.

CoSTR Citation

Couper K, Andersen LW, Drennan IR, Grunau BE, Kudenchuk PJ, Lall R, Lavonas, EJ, Perkins GD, Vallentin MF, Granfeldt A

Intravenous and intraosseous drug administration for Cardiac Arrest in Adults. Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2024 October 16. Available from: http://ilcor.org

Methodological Preamble and Link to Published Systematic Review

The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review (PROSPERO 2024 CRD42024577647) conducted by task force members. Evidence for adult cardiac arrest was sought and considered by the Advanced Life Support Task Force. Header -Systematic Review

Webmaster to insert the Systematic Review citation and link to Pubmed using this format when it is available if published

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Adults in cardiac arrest in any setting (in-hospital or out-of-hospital) with an indication for vascular access

Intervention: Initial attempt(s) at vascular access in cardiac arrest made via the intraosseous (IO) route

Comparators: Initial attempt(s) at vascular access in cardiac arrest made via the intravenous (IV) route.

Outcomes: Return of spontaneous circulation, survival (30-days/ discharge; 3-months; 6-months); survival with favorable neurological outcome (30-days/ discharge; 3-months; 6-months); health-related quality of life (3-months/ 6-months).

Study Designs: Randomized controlled trials (RCTs) only.

Timeframe: All years and all languages were included as long as there was an English abstract. Literature search updated to September 4, 2024.

PROSPERO Registration CRD42024577647

In most cases bias was assessed per comparison rather than per outcome, since there were no meaningful differences in bias across outcomes. In cases where differences in risk of bias existed between outcomes this was noted.

Consensus on Science

Grade Tables:ALS 2046 Grade Tables

For the critical outcome of survival at 30-days, we identified moderate-certainty evidence (downgraded for serious imprecision) from 3 randomized controlled trials enrolling 9,272 adults with out-of-hospital cardiac arrest, which showed no benefit from the intraosseous route compared with the intravenous route (odds ratio 0.99, 95% confidence interval 0.84 to 1.17; absolute effect 1 fewer per 1,000, 95% confidence interval 10 fewer to 11 more).

For the critical outcome of survival with favorable neurological outcome at 30-days/ hospital discharge, we identified low-certainty evidence (downgraded for risk of bias and serious imprecision) from 3 randomized controlled trials enrolling 9,186 adults with out-of-hospital cardiac arrest, which showed no benefit from the intraosseous route compared with the intravenous route (odds ratio 1.07, 95% confidence interval 0.88 to 1.30; absolute effect 3 more per 1,000, 95% confidence interval 5 fewer to 13 more).

For the critical outcome of health-related quality of life (measured using EQ-5D-5L) at 3-months, we identified low-certainty evidence (downgraded for very serious imprecision) from 1 randomized controlled trial enrolling 147 adults with out-of-hospital cardiac arrest, which showed no benefit from the intraosseous route compared with the intravenous route (mean difference 4, 95% confidence interval -2.33 to 10.33).

For the important outcome of return of spontaneous circulation at any time, we identified low-certainty evidence (downgraded for serious inconsistency and serious imprecision) from 2 randomized controlled trials enrolling 7,545 adults with out-of-hospital cardiac arrest, which showed no benefit from the intraosseous route compared with the intravenous route (odds ratio 0.91, 95% confidence interval 0.83 to 1.00; absolute effect 22 fewer per 1,000, 95% confidence interval 43 fewer to 0 fewer).

For the important outcome of sustained return of spontaneous circulation, we identified moderate-certainty evidence (downgraded for serious inconsistency) from 2 randomized controlled trials enrolling 7,518 adults with out-of-hospital cardiac arrest, which showed a lower odds of achieving sustained return of spontaneous circulation with intraosseous route compared with the intravenous route (odds ratio 0.89; 95% confidence interval 0.80 to 0.99; absolute effect 21 fewer per 1,000, 95% confidence interval 40 fewer to 2 fewer).

For the critical outcome of survival at hospital discharge, we identified moderate-certainty evidence (downgraded for serious imprecision) from 3 randomized controlled trials enrolling 9,234 adults with out-of-hospital cardiac arrest, which showed no benefit from the intraosseous route compared with the intravenous route (odds ratio 1.04; 95% confidence interval 0.88-1.23; absolute effect 2 more per 1,000, 95% confidence interval 7 fewer to 13 more).

For the critical outcome of survival at 3-months, we identified low-certainty evidence (downgraded for very serious imprecision) from 1 randomized controlled trial enrolling 1,476 adults with out-of-hospital cardiac arrest, which showed no benefit from the intraosseous route compared with the intravenous route (odds ratio 1.21; 95% confidence interval 0.86 to 1.69; absolute effect 18 more per 1,000; 95% confidence interval 12 fewer to 56 more).

For the critical outcome at survival with favourable neurological outcome at 3-months, we identified low-certainty evidence (downgraded for downgraded for very serious imprecision) from 1 randomized controlled trial enrolling 1,473 adults with out-of-hospital cardiac arrest, which showed no benefit from the intraosseous route compared with the intravenous route (odds ratio 1.17; 95% confidence interval 0.82-1.65; absolute effect 14 more per 1,000, 95% confidence interval 15 fewer to 50 more).

For the critical outcome of survival at 6-months, we identified no evidence.

For the critical outcome of survival with favorable neurological outcome at 6-months, we identified no evidence.

For the critical outcome of health-related quality of life at 6-months, we identified no evidence.

Treatment Recommendations

We suggest IV access, as compared to IO access, as the first attempt for vascular access during adult cardiac arrest (weak recommendation, low certainty evidence).

If IV access cannot be rapidly achieved within two attempts, it is reasonable to consider IO access as an alternative route for vascular access during adult cardiac arrest (good practice statement).

Justification and Evidence to Decision Framework Highlights

• This topic was prioritized by the ALS Task Force based on the publication (or forthcoming publication) of three large randomised controlled trials evaluating the clinical effectiveness of an intraosseous vascular access strategy compared with an intravenous vascular access strategy in adult out-of-hospital cardiac arrest since the last ILCOR systematic review and CoSTR in 2020.^1-4

• In considering the importance of this topic, the task force noted that several observational studies have reported marked increases in the use of the intraosseous route in adult out-of-hospital cardiac arrest over recent years, despite council guidelines continuing to recommend that the peripheral intravenous route should be the primary route for drug administration in adult cardiac arrest.^5-7

• Given the availability of data from large RCTs and challenges in interpreting observational studies due to confounding and resuscitation time bias, the task force chose to consider only randomized controlled trials.⁸

In making these recommendations, the ALS Task Force considered the following:

• The expected mechanism through which intraosseous drug administration might improve clinical outcomes is by facilitating faster administration of time-critical cardiac arrest drugs. However, whilst this effect was observed in an early randomized controlled trial,⁹ time to drug administration was similar between the intraosseous and intravenous groups in all three recent trials.

• The use of intraosseous access did not result in a statistically significant improvement in survival, survival with favourable neurological outcome, or health-related quality of life at any time-point, in comparison to intravenous access.

• The three trials were all superiority trial aiming to test the superiority of one group compared with the other group, such that the absence of an observed effect should not be interpreted as indicating that an intraosseous vascular access strategy is equivalent to an intravenous vascular access strategy.

• There was moderate-certainty evidence that the use of intraosseous access reduced the odds of achieving sustained return of spontaneous circulation.

• In emergency care throughout the world, the intravenous route is the standard approach for administering drugs and fluid.

• There are important cost implications in relation to intraosseous access, both in terms of training and equipment. Even in settings where intraosseous access is routinely available, the costs of a single intraosseous needle is markedly higher than a peripheral intravenous cannula.

• Animal data provide some evidence that the pharmacokinetics of drugs administered via the intraosseous route may be influenced by insertion site (proximal humerus v proximal tibia).¹⁰ The findings of the systematic review sub-group analyses showed no evidence of an interaction between site and clinical outcome, with point estimates favoring the proximal tibial route, albeit with very wide confidence intervals.

• Previous data suggests that the benefit of amiodarone may be enhanced when given through the intravenous route.¹¹ Experts have expressed concern that absorption of lipophilic drugs, such as amiodarone, may be particularly influenced by intraosseous administration.¹¹ However, this effect has not been observed in animal studies.¹²

• Trial sequential analyses suggest that the optimal information size has been reached for small sized effects (absolute difference of 2%), but not for very small effects.

• The good practice statement reflects the approach taken in two of the included trials, whereby patients in the intravenous group were protocolized to receive two intravenous vascular access attempts, and then the route for subsequent vascular access attempts was at the discretion of the attending clinician.

• There may be patients where IV access is not feasible due to specific patient factors (e.g. the patient is known to be very difficult to secure IV access) or environmental factors (e.g. very poor lighting; space constraints). For this small group of patients, it may be reasonable to attempt IO access first.

• There was an absence of direct evidence for the in-hospital setting, but it was noted that the question is likely of less relevance to the hospital setting as:

• A high proportion of patients will likely have established intravenous access at the time of cardiac arrest,¹³ and,
• For the minority of patients without established intravenous access, environmental conditions (e.g. space/ lighting) and the higher number of staff members would likely lead to a high rate of successful intravenous access attempts.

Knowledge Gaps

Where there is a need for intraosseous access, there are limited data on the optimum anatomical site for insertion.

There are limited data on patient outcome beyond hospital discharge/ 30-days.

ETD summary table: ALS 2046 Drug Route ETD

References

References listed alphabetically by first author last name in this citation format (Circulation)

1. Granfeldt A, Avis SR, Lind PC, Holmberg MJ, Kleinman M, Maconochie I, Hsu CH, Fernanda de Almeida M, Wang T-L, Neumar RW, et al. Intravenous vs. intraosseous administration of drugs during cardiac arrest: A systematic review. Resuscitation. 2020;149:150-157. doi: 10.1016/j.resuscitation.2020.02.025

2. Meilandt C, Fink Vallentin M, Blumensaadt Winther K, Bach A, Dissing TH, Christensen S, Juhl Terkelsen C, Lass Klitgaard T, Mikkelsen S, Folke F, et al. Intravenous vs. intraosseous vascular access during out-of-hospital cardiac arrest – protocol for a randomised clinical trial. Resuscitation Plus. 2023;15:100428. doi: https://doi.org/10.1016/j.resplu.2023.100428

3. Ko Y-C, Lin H-Y, Huang EP-C, Lee A-F, Hsieh M-J, Yang C-W, Lee B-C, Wang Y-C, Yang W-S, Chien Y-C, et al. Intraosseous versus intravenous vascular access in upper extremity among adults with out-of-hospital cardiac arrest: cluster randomised clinical trial (VICTOR trial). BMJ. 2024;386:e079878. doi: 10.1136/bmj-2024-079878

4. Couper K, Ji C, Lall R, Deakin CD, Fothergill R, Long J, Mason J, Michelet F, Nolan JP, Nwankwo H, et al. Route of drug administration in out-of-hospital cardiac arrest: A protocol for a randomised controlled trial (PARAMEDIC-3). Resusc Plus. 2024;17:100544. doi: 10.1016/j.resplu.2023.100544

5. Vadeyar S, Buckle A, Hooper A, Booth S, Deakin CD, Fothergill R, Ji C, Nolan JP, Brown M, Cowley A, et al. Trends in use of intraosseous and intravenous access in out-of-hospital cardiac arrest across English ambulance services: A registry-based, cohort study. Resuscitation. 2023;191:109951. doi: 10.1016/j.resuscitation.2023.109951

6. Agostinucci J-M, Alhéritière A, Metzger J, Nadiras P, Martineau L, Bertrand P, Gentilhomme A, Petrovic T, Adnet F, Lapostolle F. Evolution of the use of intraosseous vascular access in prehospital advanced cardiopulmonary resuscitation: The IOVA-CPR study. International Journal of Nursing Practice. 2024;n/a:e13244. doi: https://doi.org/10.1111/ijn.13244

7. Suleiman B, Chan P, de Lemos J, Kumbhani D, Link M, Idris A, Mody P. TRENDS IN INTRAOSSEOUS ACCESS IN OUT OF HOSPITAL CARDIAC ARREST. Journal of the American College of Cardiology. 2021;77:292-292. doi: 10.1016/S0735-1097(21)01651-X

8. Andersen LW, Grossestreuer AV, Donnino MW. "Resuscitation time bias"- A unique challenge for observational cardiac arrest research. Resuscitation. 2018;125:79-82. doi: 10.1016/j.resuscitation.2018.02.006

9. Reades R, Studnek JR, Vandeventer S, Garrett J. Intraosseous Versus Intravenous Vascular Access During Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial. Annals of Emergency Medicine. 2011;58:509-516. doi: 10.1016/j.annemergmed.2011.07.020

10. Hooper A, Nolan JP, Rees N, Walker A, Perkins GD, Couper K. Drug routes in out-of-hospital cardiac arrest: A summary of current evidence. Resuscitation. 2022;181:70-78. doi: 10.1016/j.resuscitation.2022.10.015

11. Daya MR, Leroux BG, Dorian P, Rea TD, Newgard CD, Morrison LJ, Lupton JR, Menegazzi JJ, Ornato JP, Sopko G, et al. Survival After Intravenous Versus Intraosseous Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Shock-Refractory Cardiac Arrest. Circulation. 2020;141:188-198. doi: 10.1161/CIRCULATIONAHA.119.042240

12. Hampton K, Wang E, Argame JI, Bateman T, Craig W, Johnson D. The effects of tibial intraosseous versus intravenous amiodarone administration in a hypovolemic cardiac arrest procine model. Am J Disaster Med. 2016;11:253-260. doi: 10.5055/ajdm.2016.0247

13. Andersen LW, Isbye D, Kjærgaard J, Kristensen CM, Darling S, Zwisler ST, Fisker S, Schmidt JC, Kirkegaard H, Grejs AM, et al. Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA. 2021;326:1586-1594. doi: 10.1001/jama.2021.16628