Intro

Date: November 10, 2024 Reference: Couper et al. The Paramedic 3 Trial: A randomized clinical trial of drug route in out-of-hospital cardiac arrest. October 31, 2024 NEJM Access to the SGEM Podcast episode at this LINK. Guest Skeptic: Missy Carter is a PA currently practicing in critical care after having attended the University of Washington's MEDEX program. An alumnus of Tacoma Community College's paramedic program Missy served as a paramedic for the Bremerton Fire Department for nearly 12 years and has been involved in paramedic education since 2004. Missy has been teaching airway management for over a decade and is the creator of the Prehospital Emergency Airway Course which is taught throughout Washington State. Case: You’re doing a ride along with your local emergency medical service (EMS) crews and responding to an out-of-hospital cardiac arrest (OHCA). After starting cardiopulmonary resuscitation (CPR), you note pulseless electrical activity (PEA) on the monitor.  The paramedic is trying to get intravenous (IV) access to give epinephrine per the protocol. She is struggling to find a good vein and she asks you what you think about going straight to intraosseous (IO) access. Background: OHCA remains one of the most challenging and time-sensitive emergencies faced by prehospital and emergency medicine teams. With a survival rate to discharge often below 10% globally, rapid, effective interventions are needed to improve patient outcomes.  Epinephrine has long been a cornerstone in the management of OHCA. Multiple studies have demonstrated how the administration of epinephrine can improve short-term outcomes, such as return of spontaneous circulation (ROSC). However, the evidence regarding its impact on long-term survival and neurological outcomes is mixed​​. Studies like PARAMEDIC-2 have raised questions about whether epinephrine's benefits in achieving ROSC are offset by potential adverse effects on neurological recovery (SGEM#238).  One critical consideration in prehospital epinephrine administration is the method of vascular access. IV administration has been preferred the preferred route, but securing IV access can be challenging in the field and in patients with compromised vascular systems. Intraosseous (IO) access provides an alternative in challenging clinical scenarios. However, there has been limited research comparing the efficacy of IO versus IV administration of epinephrine in terms of both survival and neurological outcomes in OHCA patients​​. Given these complexities, ongoing research continues to explore the most effective methods of delivering epinephrine to optimize outcomes. Recent randomized trials are now evaluating whether the speed and reliability of IO access provide significant benefits over the traditional IV route. Most EMS providers are choosing the proximal tibial as their go-to IO access. The current evidence has not given a definitive answer as to which type of access is best for OHCAs.  Clinical Question: Should we use an IV first or an IO first approach to deliver epinephrine to adult patients with an OHCA? Reference: Couper et al. The Paramedic 3 Trial: A randomized clinical trial of drug route in out-of-hospital cardiac arrest. October 31, 2024 NEJM Population: Adult patients (≥18 years old) who experienced an OHCA and required vascular access for drug administration during cardiopulmonary resuscitation (CPR).  Intervention: IO first approach Comparison: IV first approach  Outcome:  Primary Outcome: Survival at 30 days Secondary Outcomes: ROSC at any time, sustained ROSC, length of stay (LOS) in hospital, survival at discharge, three and six months, neurologic function measured on the modified Rankin Scale (mRS) at discharge, three and six months, and health-related quality of life (assessed using the EQ-5D-5L questionnaire). Trial: Multi-center, non-masked, randomized trial  Authors’ Conclusions: “Among adults with out-of-hospital cardiac arrest requiring drug therapy, the use of an intraosseous-first vascular access strategy did not result in higher 30-day survival than an intravenous-first strategy.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. No  The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). Yes The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No All groups were treated equally except for the intervention. Yes Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. Unsure Funding and financial conflicts of interest. The National Institute for Health and Care Research funded the trial. No fCOIs were disclosed by the authors.  Results: Data were available for analysis in 6,082 OHCA patients (3,040 IO and 3,042 IV). The mean age was 68 years, 64% male and 79% of events happened at home. Twenty percent of patients had an initial shockable rhythm, and 37% were witness arrests with bystander CPR performed in 70% of cases.  Key Result: No statistical difference in 30-day survival rates between the IO and IV groups. Primary Outcome: 30-day survival IO vs IV 4.5% vs 5.1% adjusted risk or mean difference −0.2 (95% CI: −1.1 to 0.8) with an adjusted treatment difference of 0.94 (0.68 to 1.32)  Secondary Outcomes:  ROSC: 36% vs 39.1%, adjusted risk or mean difference −3.2 (95% CI; −5.9 to −0.6) with an adjusted treatment difference of 0.86 (0.76 to 0.97)  No statistical difference in survival to hospital discharge, favourable outcome or length of hospital stay 1. Exclusions: Almost four thousand patients were excluded from the trial because they already had vascular access. The authors suspect it was because paramedics who were not trained in the protocol arrived first. This could have introduced a few potential biases [1]. Selection Bias: Excluding patients with preexisting vascular access may have inadvertently selected patients who had longer response times or were in areas where trial-trained paramedics could arrive first. This could mean the sample is less representative of typical OHCA cases, affecting the trial's external validity and limiting its applicability across diverse emergency settings​​. Survival Bias: If preexisting vascular access correlated with faster intervention times, excluding these patients, might remove a subset who could have had better outcomes due to quicker initial treatment. This exclusion could underestimate the benefits of the tested interventions if such patients typically have higher survival rates Spectrum Bias: By excluding patients who already had vascular access established, the trial may have skewed the participant spectrum, impacting the intervention’s observed effectiveness. Spectrum bias can distort study outcomes if a portion of the patient population with a specific characteristic (like early vascular access) is systematically excluded​. 2. Lack of Masking: The outcome assessors in this trial were aware of group allocation. This introduces the potential for outcome assessor bias impacting the evaluation of neurological status. We have previously discussed how there are concerns about the inter-rater reliability of the mRS score even if done by a neurologist. Quinn et al (2009) reviewed 10 studies and reported the overall reliability of the mRS had a kappa of 0.46 (moderate) and concluded: “There remains uncertainty regarding modified Rankin Scale reliability.” [2] 3. External Validity: The study was conducted in the UK, which may limit generalizability to other emergency medical systems with different protocols or equipment availability. Hinting at a different patient population was the 5% survival rate. This is lower compared to US survival of 11% but on par with the OPALS study done in Canada. The survival rate is like what was reported in the PARAMEDIC 2 trial. The low survival rate is a little odd considering the high rates of bystander CPR in both groups (~69%). Of note, it took them 24 minutes from the time of the call to the delivery of the epinephrine.  Higher rates of ROSC in the IV group, even though the time to drug admission was the same, the time to peak drug concentration may be different between routes.  In the IO group, 17% were humoral head and 73% proximal tibia. If this were reversed, would there be a difference? Animal studies suggest that proximal tibia IO and peripheral IV have a slower time to peak drug concentration than proximal humerus. If these were all humeral heads, would the outcome change? A recent Taiwan trial (VECTOR) compared IV to humeral head IO in OOHCA, and they saw no statistical difference.  4. Stopping Early: The trial was stopped early due to a lower-than-anticipated enrollment rate. The researchers planned to recruit 15,000 patients to achieve sufficient power for detecting a difference of 1% for the primary outcome (30-day survival) between IO and IV access groups. However, due to challenges in patient recruitment and the expiration of the funding period, the trial was concluded with approximately 6,082 patients instead​​. Stopping a trial early can have multiple effects including reduced statistical power, wider confidence intervals, decreased robustness for secondary outcomes, and missing adverse events.  5. Does Epinephrine Work? It would have been a better trial if they included a placebo.