ARTICLE: Couper K, Ji C, Deakin CD, et al., for the PARAMEDIC-3 collaborators. A Randomized Trial of Drug Route in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2025;392:336-348.
OBJECTIVE: To determine the clinical effectiveness of an intraosseous-first strategy, as compared with an intravenous-first strategy, in adults with out-of-hospital cardiac arrest
BACKGROUND
The clinical effectiveness of drugs, such as epinephrine, administered during out-of-hospital cardiac arrest (OHCA), is highly time-dependent.1,2 Previously, the majority of existing literature involves small observational studies that suggest conflicting evidence regarding whether the interosseous or intravenous route facilitates more rapid drug administration.3 The recently published VICTOR trial evaluated adults suffering from non-traumatic OHCA in Taiwan and found no difference in survival to hospital discharge in those with a primary IO vs IV access strategy.4
Interestingly, observational studies evaluating this issue have shown similar or worse outcomes in those receiving intraosseous medication administration compared to intravenous. Due to the nature of these studies and standard practice of EMS personnel, those who require intraosseous access have often failed multiple attempts at intravenous access, thereby delaying time to first medication administration.5 Given this uncertainty and prior conflicting evidence, the authors of the present study performed a randomized control trial evaluating clinical effectiveness of an intraosseous-first compared with an intravenous-first strategy for adult out-of-hospital cardiac arrest.
DESIGN
- This was a pragmatic, open-labeled randomized trial across 11 emergency medical systems in the UK
- Patients undergoing resuscitation who required vascular access were randomly assigned to a 1:1 ratio to either: intraosseous-first or intravenous-first access strategy.
- The randomly assigned access route determined the initial strategy for vascular access. If paramedic could not obtain vascular access by means of initially assigned route within two attempts, the subsequent route was determined by the paramedic
- Anatomic location of IO/IV access was determined by paramedic
- Once vascular access was obtained, all cardiac arrest drugs were given via this route
INCLUSION CRITERIA
- Adults > 18 yo
- OHCA
- Required vascular access for ongoing resuscitation
- Resuscitation being carried out by EMS prior to transport to hospital
EXCLUSION CRITERIA
- <18 yo
- Known or apparent pregnancy
PRIMARY OUTCOME
- Survival at 30 days
SECONDARY OUTCOMES
- Return of spontaneous circulation (ROSC)
- Sustained ROSC at the time of transfer to medical staff at the receiving hospital
- Survival at hospital discharge, 3 months and 6 months
- The time to ROSC
- Length of stay in the hospital or ICU
- Neurologic function (measured by modified Rankin scale) at hospital discharge, 3 months and 6 months
- Health-related quality of life at 3 months and 6 months
KEY RESULTS
In this study the intraosseous route for drug administration and vascular access in cardiac arrest did not result in significantly higher rate of 30 day survival when compared to an intravenous strategy. There was also no difference in rate of favorable neurologic outcome between the two study groups. There was no significant difference in the time to drug administration or the time to return of spontaneous circulation between the intravenous group and the intraosseous group.
Primary Outcome
- Survival at 30 days occurred in 137 of 3030 (4.5%) in the IO group and 155 of 3034 (5.1%) in the intravenous group.
Secondary Outcome
- ROSC: 36% in the IO route and 39.1% in the IV route
- Median time in mins to ROSC: 33 (IO) 32 (IV)
- Sustained ROSC at time of hospital handover: 21.7% (IO) 24.6% (IV)
- Survival to hospital discharge: 3.7% (IO), 4.0% (IV)
- MRS 0-3 at hospital discharge: 2.7% (IO), 2.8% (IV)
- MRS 4-6 at hospital discharge: 97.3% (IO), 97.2% (IV)
LIMITATIONS
- Absence of information on remainder of resuscitative process, such as quality of resuscitative measures carried out
- Absence of information on inpatient post-resuscitative care; assumed compliance with pertinent standard UK guidelines
- Hospital teams are not blinded to procedure; but this unlikely has affected the outcome as subsequent hospital-based resuscitation follows standard protocol
- A large number of patients (n = 3914) who initially met inclusion criteria were excluded due to pre-existing vascular access upon arrival of trial-trained paramedics, likely established by non-trial trained paramedics who arrived earlier at the scene. This may have decreased the total sample size and thus power of the study.
- Non-standardization of IO access placement sites. While this reflects the pragmatic nature of the study as site selection is impacted by body habitus, overlying injury, personal preference of performer, prior observational studies have shown that IO demonstrated facilitation of more rapid drug administration compared to intravenous (IV) when placed at proximal tibial site.3 Thus the non-standardized IO placement in this study may have impacted speed at which resuscitative medications reached systemic effect, and thus subsequent survival outcome.
- There was no difference in time to placement of IV vs IO. The major advantage of an intraosseous line is the ease and speed of placement. It should certainly be faster than the placement of an IV line and in this study time to placement between the two groups was equivalent.
EM TAKE-AWAYS
This study is one of the largest planned randomized trials in investigating clinical impact of drug administration route in out-of-hospital cardiac arrest. It shows that, contrary to past observational studies, there is no significant difference noted in the 30-day survival outcome among cardiac arrest patients who received medications via intravenous versus intraosseous routes. In fact, the study demonstrated those with intraosseous access may have lower ROSC rate, suggesting possible increased difficulty to achieve optimal serum drug concentration via intraosseous mode. This is important to emergency medicine providers as we often face unstable patients in the ED who could decompensate rapidly or receive cardiac arrest patients who have no access.
This, in conjunction with the results of the recent VICTOR trial, builds on the evidence showing no improved outcomes with initial IO versus initial IV access. It is important to keep in mind that these studies only included prehospital patients and prehospital emergency personnel which should lead to a cautious interpretation of the results when trying to apply them to our populations in the in-hospital setting. We should also remember that we have no data to suggest that medication administration in OHCA improves survival with favorable neurologic outcome so the question at hand of which location is best for medication administration may be a moot point if neither intervention has a meaningful effect on survival. With that being said, learning about more evidence-based approaches regarding drug administration routes makes us more mindful of access selection during resuscitation and can allow us to provide more nuanced care for the patient in front of us.
REFERENCES
- Perkins GD, Ji C, Deakin CD, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2018;379(8):711–721.
- Kudenchuk PJ, Brown SP, Daya M, et al. Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2016;374(18):1711–1722.
- Reades R, Studnek JR, Vandeventer S, Garrett J. Intraosseous Versus Intravenous Vascular Access During Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial. Ann Emerg Med. 2011;58(6):509–516.
- Ko YC, Lin HY, Huang EP, 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.
- Granfeldt A, Avis SR, Lind PC, et al. Intravenous vs. intraosseous administration of drugs during cardiac arrest: A systematic review. Resuscitation. 2020;149:150–157.
- Ross EM, Mapp J, Kharod C, Wampler DA, Velasquez C, Miramontes DA. Time to epinephrine in out-of-hospital cardiac arrest: A retrospective analysis of intraosseous versus intravenous access. Am J Disaster Med. 2016;11(2):119–123.