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Drug routes in out-of-hospital cardiac arrest: A summary of current evidence

  • Amy Hooper
    Affiliations
    Critical Care Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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  • Jerry P Nolan
    Affiliations
    Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UK

    Department of Anaesthesia and Intensive Care Medicine, Royal United Hospital, Bath, UK
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  • Nigel Rees
    Affiliations
    Pre-hospital Emergency Response Unit, Welsh Ambulance Services NHS Trust, St Asaph, UK

    Institute of Life Sciences, Swansea University, Swansea, UK
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  • Alison Walker
    Affiliations
    West Midlands Ambulance Service University NHS Foundation Trust, Brierley Hill, UK

    Department of Emergency Medicine, Harrogate and District NHS Foundation Trust, Harrogate, UK
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  • Gavin D Perkins
    Affiliations
    Critical Care Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

    Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UK
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  • Keith Couper
    Correspondence
    Corresponding author at: Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
    Affiliations
    Critical Care Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

    Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UK
    Search for articles by this author
Open AccessPublished:October 26, 2022DOI:https://doi.org/10.1016/j.resuscitation.2022.10.015

      Abstract

      Recent evidence showing the clinical effectiveness of drug therapy in cardiac arrest has led to renewed interest in the optimal route for drug administration in adult out-of-hospital cardiac arrest. Current resuscitation guidelines support use of the intravenous route for intra-arrest drug delivery, with the intraosseous route reserved for patients in whom intravenous access cannot be established.
      We sought to evaluate current evidence on drug route for administration of cardiac arrest drugs, with a specific focus on the intravenous and intraosseous route. We identified relevant animal, manikin, and human studies through targeted searches of MEDLINE in June 2022.
      Across pre-hospital systems, there is wide variation in use of the intraosseous route. Early administration of cardiac arrest drugs is associated with improved patient outcomes. Challenges in obtaining intravenous access mean that the intraosseous access may facilitate earlier drug administration. However, time from administration to the central circulation is unclear with pharmacokinetic data limited mainly to animal studies.
      Observational studies comparing the effect of intravenous and intraosseous drug administration on patient outcomes are challenging to interpret because of resuscitation time bias and other confounders. To date, no randomised controlled trial has directly compared the effect on patient outcomes of intraosseous compared with intravenous drug administration in cardiac arrest.
      The International Liaison Committee on Resuscitation has described the urgent need for randomised controlled trials comparing the intravenous and intraosseous route in adult out-of-hospital cardiac arrest. Ongoing clinical trials will directly address this knowledge gap.

      Keywords

      Out-of-hospital cardiac arrest (OHCA) is a leading cause of death across the world. Internationally, rates of Emergency Medical Service treated OHCA range from 30 to 97 EMS treated OHCA per 100,000 person-years, with a European and North American incidence of 56 and 62 cases per 100,000 person-years respectively.
      • Gräsner J.-T.
      • Wnent J.
      • Herlitz J.
      • et al.
      Survival after out-of-hospital cardiac arrest in Europe - Results of the EuReCa TWO study.
      • Kiguchi T.
      • Okubo M.
      • Nishiyama C.
      • et al.
      Out-of-hospital cardiac arrest across the World: First report from the International Liaison Committee on Resuscitation (ILCOR).
      Despite the development of systems that seek to optimise key aspects of the community response to OHCA, such as bystander cardiopulmonary resuscitation (CPR) and public access defibrillation, only around 8 % of individuals with OHCA will survive to hospital discharge.
      • Gräsner J.-T.
      • Wnent J.
      • Herlitz J.
      • et al.
      Survival after out-of-hospital cardiac arrest in Europe - Results of the EuReCa TWO study.
      • Kiguchi T.
      • Okubo M.
      • Nishiyama C.
      • et al.
      Out-of-hospital cardiac arrest across the World: First report from the International Liaison Committee on Resuscitation (ILCOR).
      • Hawkes C.
      • Booth S.
      • Ji C.
      • et al.
      Epidemiology and outcomes from out-of-hospital cardiac arrests in England.
      • Semeraro F.
      • Greif R.
      • Böttiger B.W.
      • et al.
      European Resuscitation Council Guidelines 2021: Systems saving lives.
      Following the arrival of the emergency medical services (EMS), patient care will transition from basic life support (BLS) to advanced life support (ALS). Key aspects of ALS include optimisation of ventilation, identification and treatment of reversible causes, and administration of drugs.
      • Soar J.
      • Böttiger B.W.
      • Carli P.
      • et al.
      European Resuscitation Council Guidelines 2021: Adult advanced life support.
      Current guidelines support the use of adrenaline and antiarrhythmic drugs for shockable rhythms refractory to defibrillation, and immediate use of adrenaline in non-shockable cardiac arrest.
      • Soar J.
      • Böttiger B.W.
      • Carli P.
      • et al.
      European Resuscitation Council Guidelines 2021: Adult advanced life support.
      • Lott C.
      • Truhlář A.
      • Alfonzo A.
      • et al.
      European Resuscitation Council Guidelines 2021: Cardiac arrest in special circumstances.
      • Soar J.
      • Berg K.M.
      • Andersen L.W.
      • et al.
      Adult Advanced Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations.
      • Panchal A.R.
      • Bartos J.A.
      • Cabañas J.G.
      • et al.
      Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
      Use of other drugs, such as fibrinolytics and fluids, are recommended only to treat an identified or likely reversible cause of the cardiac arrest and in accordance with local scopes of practice.
      Current resuscitation guidelines recommend that the intravenous (IV) route is used for drug administration in OHCA wherever possible, with the intraosseous (IO) route advised only where IV access cannot be achieved.
      • Soar J.
      • Böttiger B.W.
      • Carli P.
      • et al.
      European Resuscitation Council Guidelines 2021: Adult advanced life support.
      This recommendation is underpinned only by very low certainty evidence.
      • Soar J.
      • Berg K.M.
      • Andersen L.W.
      • et al.
      Adult Advanced Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations.
      The objective of this review is to provide a broad summary of current evidence on routes for drug administration in cardiac arrest particularly in the context of the IO route, describe ongoing clinical trials and summarise areas for further research. Box 1.
      summary of search strategy and paper selection.
      We searched MEDLINE from inception to 7th June 2022 using terms to describe cardiac arrest (heart arrest*, out-of-hospital cardiac arrest*, cardiac arrest, cardiopulmonary resuscitation*, advanced cardiac life support*, cardiopulmonary resuscitation) and terms for relevant drug routes (intraosseous infusions*, intraosseous, intracardiac, intramuscular injections*, intramuscular, endobronchial, drug administration routes*). We also searched clinical trial registries for details of ongoing randomised controlled trials. In addition, we reviewed International Liaison Committee on Resuscitation Consensus on Science and Treatment recommendation statements and the reference lists of key papers, such as systematic reviews. We included only papers published in English. *- indicates term searched as a Medical Subject Heading (MeSH term) in MEDLINE.

      Cardiac arrest drugs

      The importance of drug route in OHCA is predicated on the concept that the drugs are effective. The clinical effectiveness of drugs in OHCA was challenged by a Norwegian trial of 851 OHCA patients who were randomised to receive ALS with or without IV cannulation and drug administration.
      • Olasveengen T.M.
      • Sunde K.
      • Brunborg C.
      • Thowsen J.
      • Steen P.A.
      • Wik L.
      Intravenous Drug Administration During Out-of-Hospital Cardiac Arrest: A Randomized Trial.
      Whilst administration of IV drugs improved rates of return of spontaneous circulation (ROSC), this did not translate into longer term benefit with no statistically significant difference observed for survival at hospital discharge.
      Recent, larger randomised controlled trials have provided evidence supporting the use of both adrenaline
      • Jacobs I.G.
      • Finn J.C.
      • Jelinek G.A.
      • Oxer H.F.
      • Thompson P.L.
      Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial.
      • Perkins G.D.
      • Ji C.
      • Deakin C.D.
      • et al.
      A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
      • Perkins G.D.
      • Kenna C.
      • Ji C.
      • et al.
      The effects of adrenaline in out of hospital cardiac arrest with shockable and non-shockable rhythms: Findings from the PACA and PARAMEDIC-2 randomised controlled trials.
      and antiarrhythmics
      • Kudenchuk P.J.
      • Brown S.P.
      • Daya M.
      • et al.
      Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest.
      during OHCA. The ALPS placebo controlled trial showed no difference in ROSC, survival to discharge or neurological outcomes in the intention to treat population between either amiodarone or lidocaine and placebo.
      • Kudenchuk P.J.
      • Brown S.P.
      • Daya M.
      • et al.
      Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest.
      However, in the a priori identified sub-group of those with a bystander witnessed cardiac arrest, there was evidence of improved survival to hospital discharge with both amiodarone (difference 5.0 %, 95 % confidence interval (CI) 0.3 % to 9.7 %) and lidocaine (difference 5.2 %, 95 % CI 0.5 % to 9.9). The UK PARAMEDIC-2 randomised controlled trial randomised 8014 OHCA patients to receive either adrenaline or placebo.
      • Perkins G.D.
      • Ji C.
      • Deakin C.D.
      • et al.
      A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
      Adrenaline was found to significantly improve both the rate of ROSC (adjusted odds ratio (aOR) 3.83, 95 % CI 3.30 to 4.43) and survival at 30-days (aOR 1.47, 95 % CI 1.09 to 1.97), with the benefit continuing at one-year following OHCA (aOR 1.38, 95 % CI 1.00 to 1.92).
      • Perkins G.D.
      • Ji C.
      • Deakin C.D.
      • et al.
      A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
      • Haywood K.L.
      • Ji C.
      • Quinn T.
      • et al.
      Long term outcomes of participants in the PARAMEDIC2 randomised trial of adrenaline in out-of-hospital cardiac arrest.
      The point estimate for favourable neurological outcome at hospital discharge favoured the adrenaline group, although this effect was not statistically significant.
      Drug treatment in cardiac arrest is a time-critical intervention, with observational data showing the association between more rapid drug administration and improved patient outcome, although these studies may be influenced by resuscitation time bias.
      • Rahimi M.
      • Dorian P.
      • Cheskes S.
      • Lebovic G.
      • Lin S.
      Effect of Time to Treatment With Antiarrhythmic Drugs on Return of Spontaneous Circulation in Shock-Refractory Out-of-Hospital Cardiac Arrest.
      • Perkins G.D.
      • Kenna C.
      • Ji C.
      • et al.
      The influence of time to adrenaline administration in the Paramedic 2 randomised controlled trial.
      • Okubo M.
      • Komukai S.
      • Callaway C.W.
      • Izawa J.
      Association of Timing of Epinephrine Administration With Outcomes in Adults With Out-of-Hospital Cardiac Arrest.
      • Hansen M.
      • Schmicker R.H.
      • Newgard C.D.
      • et al.
      Time to Epinephrine Administration and Survival From Nonshockable Out-of-Hospital Cardiac Arrest Among Children and Adults.
      • Andersen L.W.
      • Grossestreuer A.V.
      • Donnino M.W.
      “Resuscitation time bias”- A unique challenge for observational cardiac arrest research.
      An observational study of 32,101 OHCA patients found that each one-minute delay in adrenaline administration was associated with a reduced odds of hospital survival (odds ratio (OR) 0.96, 95 % CI 0.95 to 0.98).
      • Hansen M.
      • Schmicker R.H.
      • Newgard C.D.
      • et al.
      Time to Epinephrine Administration and Survival From Nonshockable Out-of-Hospital Cardiac Arrest Among Children and Adults.
      These data reflect evidence from randomised controlled trials that cardiac arrest drugs are effective in achieving ROSC and observational data showing a strong association between time to ROSC and functional outcome.
      • Perkins G.D.
      • Ji C.
      • Deakin C.D.
      • et al.
      A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
      • Kudenchuk P.J.
      • Brown S.P.
      • Daya M.
      • et al.
      Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest.
      • Nagao K.
      • Nonogi H.
      • Yonemoto N.
      • et al.
      Duration of Prehospital Resuscitation Efforts After Out-of-Hospital Cardiac Arrest.
      • Matsuyama T.
      • Kitamura T.
      • Kiyohara K.
      • et al.
      Impact of cardiopulmonary resuscitation duration on neurologically favourable outcome after out-of-hospital cardiac arrest: A population-based study in Japan.
      • Reynolds J.C.
      • Grunau B.E.
      • Rittenberger J.C.
      • Sawyer K.N.
      • Kurz M.C.
      • Callaway C.W.
      Association Between Duration of Resuscitation and Favorable Outcome After Out-of-Hospital Cardiac Arrest.

      Out of hospital cardiac arrest drug routes in clinical guidelines

      Since the first resuscitation guidelines were published in 1974, the IV route has been recommended as the primary route for cardiac arrest drug administration.
      • Soar J.
      • Böttiger B.W.
      • Carli P.
      • et al.
      European Resuscitation Council Guidelines 2021: Adult advanced life support.
      • American Heart Association
      National Academy of Sciences- National Research Council. Standards for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiac Care (ECC).
      • Chamberlain D.
      • Bossaert L.
      • Carli P.
      • et al.
      Guidelines for advanced life support: A statement by the Advanced Life Support Working Party of the European Resuscitation Council, 1992.
      • Robertson C.
      • Steen P.
      • Adgey J.
      • et al.
      The 1998 European Resuscitation Council guidelines for adult advanced life support: A statement from the Working Group on Advanced Life Support, and approved by the executive committee of the European Resuscitation Council.
      • de Latorre F.
      • Nolan J.
      • Robertson C.
      • Chamberlain D.
      • Baskett P.
      European Resuscitation Council Guidelines 2000 for Adult Advanced Life Support: A statement from the Advanced Life Support Working Group Members of the ERC ALS Working Group and approved by the Executive Committee of the European Resuscitation Council.
      • Nolan J.P.
      • Deakin C.D.
      • Soar J.
      • Böttiger B.W.
      • Smith G.
      European Resuscitation Council Guidelines for Resuscitation 2005: Section 4.
      • Deakin C.D.
      • Nolan J.P.
      • Soar J.
      • et al.
      European Resuscitation Council Guidelines for Resuscitation 2010 Section 4.
      • Soar J.
      • Nolan J.P.
      • Böttiger B.W.
      • et al.
      European Resuscitation Council Guidelines for Resuscitation 2015: Section 3.
      There has, however, been a move away from guideline support for the intra-arrest insertion of central venous catheters that featured in some early guidelines, because of the risks associated with their insertion.
      • Lee P.M.J.
      • Lee C.
      • Rattner P.
      • Wu X.
      • Gershengorn H.
      • Acquah S.
      Intraosseous Versus Central Venous Catheter Utilization and Performance During Inpatient Medical Emergencies.
      Where the IV drug route cannot be established, guidelines have, over the years, supported a range of other drug routes including the endobronchial, intracardiac, and intraosseous routes. However, guideline support for these alternative routes has changed over time.
      Guideline support for the endobronchial route was withdrawn in 2010 because of unreliable drug bioavailability, even when given at high doses.
      • Deakin C.D.
      • Nolan J.P.
      • Soar J.
      • et al.
      European Resuscitation Council Guidelines for Resuscitation 2010 Section 4.
      The intracardiac route has never been advocated in European resuscitation guidelines, which were first published in 1992.
      • Chamberlain D.
      • Bossaert L.
      • Carli P.
      • et al.
      Guidelines for advanced life support: A statement by the Advanced Life Support Working Party of the European Resuscitation Council, 1992.
      The last North American guidelines to refer to the intracardiac route were published in 1992, with the subsequent withdrawal of the route seemingly driven by concerns about iatrogenic harm, such as cardiac tamponade, pneumothorax and coronary artery puncture.
      • Sabin H.I.
      • Coghill S.B.
      • Khunti K.
      • McNeill G.O.
      Accuracy of intracardiac injections determined by a post-mortem study.
      • American Heart Association
      1992 National Conference on Cardiopulmonary Resuscitation and Emergency Cardiac Care- Adult Advanced Cardiac Life Support.
      The intramuscular route has been referred to in guidelines, but not supported, because of concerns about poor drug absorption during cardiac arrest.
      • American Heart Association
      National Academy of Sciences- National Research Council. Standards for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiac Care (ECC).
      However, over recent years, there has been interest in the clinical use of the intramuscular route during cardiac arrest because it enables rapid injection of cardiac arrest drugs.
      • Pugh A.E.
      • Stoecklein H.H.
      • Tonna J.E.
      • Hoareau G.L.
      • Johnson M.A.
      • Youngquist S.T.
      Intramuscular adrenaline for out-of-hospital cardiac arrest is associated with faster drug delivery: A feasibility study.
      The IO route was first supported by paediatric resuscitation guidelines in 1986 and then adopted in the adult guidelines in 2005.
      • Nolan J.P.
      • Deakin C.D.
      • Soar J.
      • Böttiger B.W.
      • Smith G.
      European Resuscitation Council Guidelines for Resuscitation 2005: Section 4.
      • American Heart Association
      Standards and Guidelines for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiac Care (ECC).
      Current resuscitation guidelines continue to recommend the peripheral IV route as the primary route for drug administration during cardiac arrest, with the IO route advocated only when the IV route cannot be established.
      • Soar J.
      • Böttiger B.W.
      • Carli P.
      • et al.
      European Resuscitation Council Guidelines 2021: Adult advanced life support.
      This guidance is based on an International Liaison Committee on Resuscitation (ILCOR) treatment recommendation, that highlights the evidence underpinning the recommendation is of very low certainty.
      • Soar J.
      • Berg K.M.
      • Andersen L.W.
      • et al.
      Adult Advanced Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations.

      The intraosseous route in cardiac arrest

      Drugs delivered by the IO route enter the medullary cavity within the bone and are absorbed into the non-collapsible vein structure within the cavity. Seminal early research, published in 1922, used animal models to demonstrate absorption of drugs given via the IO route into the central circulation.
      • Drinker C.K.
      • Drinker K.R.
      • Lund C.C.
      The circulation in the mammalian bone-marrow.
      The modern IO cannula is usually inserted using a medical bone drill or other medical mechanical device. In adult cardiac arrest, the proximal humerus and proximal tibia are the most commonly described anatomical sites for IO placement, although insertion in the distal femur has also been described.
      • Rayas E.G.
      • Winckler C.
      • Bolleter S.
      • et al.
      Distal femur versus humeral or tibial IO, access in adult out of hospital cardiac resuscitation.
      The sternal site is well-established in military practice as it enables rapidly infusion of large volumes of fluid.
      • Laney J.A.
      • Friedman J.
      • Fisher A.D.
      Sternal Intraosseous Devices: Review of the Literature.
      Its use is less common in the civilian cardiac arrest setting because of both the need for specialist insertion equipment and the potential challenge of delivering chest compressions with a sternal IO cannula in-situ.
      Data from randomised controlled trials of drug therapies in OHCA and observational studies highlight wide variation in IO use across EMS systems, and an increase in use over time.
      • Perkins G.D.
      • Ji C.
      • Deakin C.D.
      • et al.
      A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
      • Kudenchuk P.J.
      • Brown S.P.
      • Daya M.
      • et al.
      Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest.
      • Nolan J.P.
      • Deakin C.D.
      • Ji C.
      • et al.
      Intraosseous versus intravenous administration of adrenaline in patients with out-of-hospital cardiac arrest: a secondary analysis of the PARAMEDIC2 placebo-controlled trial.
      • Daya M.R.
      • Leroux B.G.
      • Dorian P.
      • et al.
      Survival After Intravenous Versus Intraosseous Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Shock-Refractory Cardiac Arrest.
      • Vallentin M.F.
      • Granfeldt A.
      • Meilandt C.
      • et al.
      Effect of Intravenous or Intraosseous Calcium vs Saline on Return of Spontaneous Circulation in Adults With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.
      • Vadeyar S.
      • Buckle A.
      • Hooper A.
      • et al.
      P117 Increasing use of intraosseous access at out-of-hospital cardiac arrest: a registry-based cohort study.
      The Amiodarone, Lidocaine, or Placebo in OHCA (ALPS) trial, which recruited participants between 2012 and 2015, reported that 22 % of participants received the trial drug by the IO route, although use ac-ross EMS systems ranged from 1 % to 53 %.
      • Kudenchuk P.J.
      • Brown S.P.
      • Daya M.
      • et al.
      Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest.
      • Daya M.R.
      • Leroux B.G.
      • Dorian P.
      • et al.
      Survival After Intravenous Versus Intraosseous Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Shock-Refractory Cardiac Arrest.
      The more recent Calcium for OHCA (COCA) trial, which recruited participants between 2020 and 2021, reported that 60 % received the trial drug by the IO route.
      • Vallentin M.F.
      • Granfeldt A.
      • Meilandt C.
      • et al.
      Effect of Intravenous or Intraosseous Calcium vs Saline on Return of Spontaneous Circulation in Adults With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.
      The proximal humerus site is used less commonly than the proximal tibial site in some OHCA systems. Use of the proximal humerus site accounted for only 2 % and 12 % of IO attempts in the ALPS and COCA trials respectively.
      • Daya M.R.
      • Leroux B.G.
      • Dorian P.
      • et al.
      Survival After Intravenous Versus Intraosseous Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Shock-Refractory Cardiac Arrest.
      • Vallentin M.F.
      • Granfeldt A.
      • Meilandt C.
      • et al.
      Effect of Intravenous or Intraosseous Calcium vs Saline on Return of Spontaneous Circulation in Adults With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.
      The apparent preference by EMS providers for the proximal tibial over the proximal humeral site for IO placement likely reflects a number of factors including easier access to the leg during cardiac arrest, reduced risk of dislodgement particularly during patient transfer, practitioner confidence, and perceived easier landmarking of point of insertion.
      • Reades R.
      • Studnek J.R.
      • Vandeventer S.
      • Garrett J.
      Intraosseous versus intravenous vascular access during out-of-hospital cardiac arrest: a randomized controlled trial.
      There are important risks associated with IO insertion. Potential complications include malposition of the IO cannula, extravasation, fracture, soft tissue infection, fat emboli, growth plate injury, compartment syndrome and osteomyelitis.
      • Kristiansen S.
      • Storm B.
      • Dahle D.
      • et al.
      Intraosseous fluid resuscitation causes systemic fat emboli in a porcine hemorrhagic shock model.
      • Maxien D.
      • Wirth S.
      • Peschel O.
      • et al.
      Intraosseous needles in pediatric cadavers: Rate of malposition.
      • Hallas P.
      • Brabrand M.
      • Folkestad L.
      Complication with intraosseous access: scandinavian users' experience.
      • Greenstein Y.Y.
      • Koenig S.J.
      • Mayo P.H.
      • Narasimhan M.
      A Serious Adult Intraosseous Catheter Complication and Review of the Literature.
      • Rosetti V.A.
      • Thompson B.M.
      • Miller J.
      • Mateer J.R.
      • Aprahamian C.
      Intraosseous infusion: An alternative route of pediatric intravascular access.
      • Kibrik P.
      • Alsheekh A.
      • Rajaee S.
      • Marks N.
      • Hingorani A.
      • Ascher E.
      Compartment Syndrome of the Leg after Intraosseous (IO) Needle Insertion.
      • Petitpas F.
      • Guenezan J.
      • Vendeuvre T.
      • Scepi M.
      • Oriot D.
      • Mimoz O.
      Use of intra-osseous access in adults: a systematic review.
      Reported incidence rates of key complications is typically low. However, an important challenge in interpreting the overall safety profile of IO access is that detailed follow-up of patients to assess for complications may be limited to individuals that survive. Furthermore, even in survivors, complications, such as fat emboli, may not be identified.

      Comparison of the intravenous and intraosseous route- time to drug administration

      Intravenous access is often challenging to secure in OHCA. In some EMS systems, success rates have been reported to be as low as 50 %.
      • Reades R.
      • Studnek J.R.
      • Vandeventer S.
      • Garrett J.
      Intraosseous versus intravenous vascular access during out-of-hospital cardiac arrest: a randomized controlled trial.
      • Tan B.K.K.
      • Chin Y.X.
      • Koh Z.X.
      • et al.
      Clinical evaluation of intravenous alone versus intravenous or intraosseous access for treatment of out-of-hospital cardiac arrest.
      This likely reflects both patient factors, such as collapsed veins, cold peripheries, and environmental factors such as poor lighting and difficult patient position. These challenges likely contribute to delayed drug administration. In the PARAMEDIC-2 trial, median time from emergency call to first drug administration was over 20 minutes.
      • Perkins G.D.
      • Ji C.
      • Deakin C.D.
      • et al.
      A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
      The IO route potentially presents an opportunity for more rapid drug delivery, as insertion relies only on the landmarks of bony structures, rather than identification of a vein.
      The most robust data on speed and success rates of different routes in OHCA comes from a three-armed randomised controlled trial in which 182 adults with non-traumatic OHCA were assigned to receive either tibial IO, humeral IO, or peripheral IV access.
      • Reades R.
      • Studnek J.R.
      • Vandeventer S.
      • Garrett J.
      Intraosseous versus intravenous vascular access during out-of-hospital cardiac arrest: a randomized controlled trial.
      The success rate was highest with the proximal tibial route, which also facilitated the shortest time to drug administration (Table 1). Success rates were higher with proximal humerus than peripheral IV, but time to initial success was longer, potentially reflecting the higher risk of cannula displacement in proximal humeral IO group.
      Table 1Drug route data from randomised controlled trial by Reades et al.
      • Reades R.
      • Studnek J.R.
      • Vandeventer S.
      • Garrett J.
      Intraosseous versus intravenous vascular access during out-of-hospital cardiac arrest: a randomized controlled trial.
      Tibial IO

      (n = 64)
      Humeral IO

      (n = 51)
      Peripheral IV

      (n = 67)
      p-value
      Initial Success- % (95 % CI)95 (90–100)71 (58–83)49 (37–61)<0.001
      Displacement- % (95 % CI)5 (0–10)20 (8–31)6 (0–12)<0.001
      Overall Success- % (95 % CI)91 (83–98)51 (37–65)43 (31–55)<0.001
      Time to initial success, min- median (IQR)4.6 (3.6–6.2)7.0 (3.9–10)5.8 (4.1–8)<0.001
      Key: IO- Intraosseous; IV- intravenous.
      These data contrast with an observational study of 2656 OHCA patients treated in a pre-hospital system in which IO access is routinely used.
      • Ross E.M.
      • Mapp J.
      • Kharod C.
      • Wampler D.A.
      • Velasquez C.
      • Miramontes D.A.
      Time to epinephrine in out-of-hospital cardiac arrest: A retrospective analysis of intraosseous versus intravenous access.
      Overall, 98 % of patients received IO access, of which 86 % of IO cannulae were inserted in the proximal humerus. In this system, with high paramedic exposure to the IO route, IO drug administration, compared with IV drug administration, was associated with a significantly shorter time from arrival to drug delivery (5.0 min, 95 % CI 4.7 to 5.4 v 8.8 min, 95 % CI 6.6 to 10.9, p < 0.001).
      In the context of the COVID-19 pandemic, many systems have implemented protocols that incorporate the need to don personal protective equipment (PPE), such as eye protection, gloves, and face masks, to limit the risk of infection to the rescuer.
      • Couper K.
      • Taylor-Phillips S.
      • Grove A.
      • Freeman K.
      • Osokogu O.
      • Court R.
      • et al.
      COVID-19 in cardiac arrest and infection risk to rescuers: A systematic review.
      • Perkins G.D.
      • Morley P.T.
      • Nolan J.P.
      • et al.
      International Liaison Committee on Resuscitation: COVID-19 consensus on science, treatment recommendations and task force insights.
      • Leong Y.C.
      • Cheskes S.
      • Drennan I.R.
      • Buick J.E.
      • Latchmansingh R.G.
      • Verbeek P.R.
      Clinical considerations for out-of-hospital cardiac arrest management during COVID-19.
      Such PPE might impede the ability of rescuers to undertake procedures requiring manual dexterity, such as intravenous cannulation.
      • Drozd A.
      • Smereka J.
      • Filipiak K.J.
      • et al.
      Intraosseous versus intravenous access while wearing personal protective equipment: a meta-analysis in the era of COVID-19.
      In a randomised controlled manikin crossover study including 65 rescuers wearing a PPE suit, filtering facepiece 3 (FFP3) mask, goggles, and gloves, IO access was quicker and more successful than IV access and was preferred by rescuers.
      • Drozd A.
      • Smereka J.
      • Pruc M.
      • et al.
      Comparison of intravascular access methods applied by nurses wearing personal protective equipment in simulated COVID-19 resuscitation: A randomized crossover simulation trial.

      Comparison of the intravenous and intraosseous route- pharmacokinetic outcomes

      Early intra-arrest drug administration will provide no clinical benefit if the selected route does not facilitate rapid drug delivery to the central circulation. In the context of cardiac arrest, the optimum drug route will maximise drug concentration in the central circulation (high CMAX) and minimise time to maximum drug concentration (low TMAX).
      Human intra-arrest pharmacokinetic studies are extremely challenging to deliver. Our review search identified only two studies.
      • Cho Y.
      • You Y.
      • Park J.S.
      • et al.
      Comparison of right and left ventricular enhancement times using a microbubble contrast agent between proximal humeral intraosseous access and brachial intravenous access during cardiopulmonary resuscitation in adults.
      • Andersen L.W.
      • Holmberg M.J.
      • Granfeldt A.
      • Vallentin M.F.
      Calcium administration and post-cardiac arrest ionized calcium values according to intraosseous or intravenous administration - A post hoc analysis of a randomized trial.
      One study enrolled 10 OHCA who, following emergency department arrival, received a contrast agent given by the humeral IO and brachial IV routes during cardiac arrest.
      • Cho Y.
      • You Y.
      • Park J.S.
      • et al.
      Comparison of right and left ventricular enhancement times using a microbubble contrast agent between proximal humeral intraosseous access and brachial intravenous access during cardiopulmonary resuscitation in adults.
      The humeral IO route was associated with decreased mean time, measured in seconds, to contrast agent detection in both the right (5.6 (standard deviation (SD) 1.71) v 15.4 (SD 3.24), p < 0.001) and left (120.2 (SD 4.18) v 132.0 (SD 3.09), p < 0.001) ventricle, although the clinical importance of these small differences is uncertain.
      In a post-hoc analysis of the COCA randomised controlled trial, post-arrest ionised calcium values were analysed across 84 survivors.
      • Andersen L.W.
      • Holmberg M.J.
      • Granfeldt A.
      • Vallentin M.F.
      Calcium administration and post-cardiac arrest ionized calcium values according to intraosseous or intravenous administration - A post hoc analysis of a randomized trial.
      Patients who received the trial intervention (calcium chloride) had higher ionised calcium values than those who received placebo, whether delivered by the IO or IV route. The difference in values between the intervention and placebo groups did not differ by route of administration (difference −0.02 mmol/L, 95 % CI − 0.12 to 0.08).
      Given the few data from human pharmacokinetic studies, animal studies provide an opportunity to better explore the effect of drug route on pharmacokinetic outcomes in cardiac arrest. Our review search identified 16 swine randomised controlled trials which compared the effect of the peripheral IV with the tibial or humeral IO route on pharmacokinetic outcomes.
      • Burgert J.
      • Gegel B.
      • Loughren M.
      • et al.
      Comparison of tibial intraosseous, sternal intraosseous, and intravenous routes of administration on pharmacokinetics of epinephrine during cardiac arrest: a pilot study.
      • 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.
      • Adams T.S.
      • Blouin D.
      • Johnson D.
      Effects of tibial and humerus intraosseous and intravenous vasopressin in porcine cardiac arrest model.
      • Beaumont L.D.
      • Baragchizadeh A.
      • Johnson C.
      • Johnson D.
      Effects of tibial and humerus intraosseous administration of epinephrine in a cardiac arrest swine model.
      • Fulkerson J.
      • Lowe R.
      • Anderson T.
      • Moore H.
      • Craig W.
      • Johnson D.
      Effects of Intraosseous Tibial vs. Intravenous Vasopressin in a Hypovolemic Cardiac Arrest Model.
      • Hampton K.
      • Wang E.
      • Argame J.I.
      • Bateman T.
      • Craig W.
      • Johnson D.
      The effects of tibial intraosseous versus intravenous amiodarone administration in a hypovolemic cardiac arrest procine model.
      • Holloway M.M.
      • Jurina S.L.
      • Orszag J.D.
      • et al.
      Effects of humerus intraosseous versus intravenous amiodarone administration in a hypovolemic porcine model.
      • Johnson D.
      • Giles K.
      • Acuna A.
      • Saenz C.
      • Bentley M.
      • Budinich C.
      Effects of tibial intraosseous and IV administration of vasopressin on kinetics and survivability in cardiac arrest.
      • Wimmer M.H.
      • 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.
      • Wong M.R.
      • Reggio M.J.
      • Morocho F.R.
      • et al.
      Effects of intraosseous epinephrine in a cardiac arrest swine model.
      • Burgert J.M.
      • Johnson A.D.
      • Garcia-Blanco J.
      • Fulton L.V.
      • Loughren M.J.
      The Resuscitative and Pharmacokinetic Effects of Humeral Intraosseous Vasopressin in a Swine Model of Ventricular Fibrillation.
      • Burgert J.M.
      • Martinez A.
      • O'Sullivan M.
      • Blouin D.
      • Long A.
      • Johnson A.D.
      Sternal Route More Effective than Tibial Route for Intraosseous Amiodarone Administration in a Swine Model of Ventricular Fibrillation.
      • Long R.P.
      • Gardner S.M.
      • Burgert J.
      • et al.
      Humerus intraosseous administration of epinephrine in normovolemic and hypovolemic porcine model.
      • Burgert J.M.
      • Johnson A.D.
      • O'Sullivan J.C.
      • et al.
      Pharmacokinetic effects of endotracheal, intraosseous, and intravenous epinephrine in a swine model of traumatic cardiac arrest.
      • Neill M.J.
      • Burgert J.M.
      • Blouin D.
      • et al.
      Effects of humeral intraosseous epinephrine in a pediatric hypovolemic cardiac arrest porcine model.
      • Yauger Y.J.
      • Johnson M.D.
      • 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.
      Across studies, we identified substantial heterogeneity in relation to type of cardiac arrest model (hypovolaemia/ normovolaemia), drug type (adrenaline/ vasopressin/amiodarone), and anatomical location of IO access (swine equivalent of proximal humerus/ proximal tibia). This heterogeneity precluded pooling of data in a meta-analysis. Findings are summarised in Fig. 1, Fig. 2.
      Figure thumbnail gr1
      Fig. 1Maximum Concentration (CMAX)- peripheral IV v IO: animal studies Figure footer: Data presented as ng/ml for studies reporting adrenaline, pg/ml for studies reporting vasopressin, and ng/ml for studies reporting amiodarone (except
      • Burgert J.M.
      • Johnson A.D.
      • Garcia-Blanco J.
      • Fulton L.V.
      • Loughren M.J.
      The Resuscitative and Pharmacokinetic Effects of Humeral Intraosseous Vasopressin in a Swine Model of Ventricular Fibrillation.
      which reports as pg/dl). Where needed, data were extracted from figures using computer software. For some studies, the standard error was converted to standard deviation to facilitate plotting of the data.
      Figure thumbnail gr2
      Fig. 2Time to maximum concentration (TMAX)- peripheral IV v IO: animal studies Figure footer: Data presented as seconds, except
      • Johnson D.
      • Giles K.
      • Acuna A.
      • Saenz C.
      • Bentley M.
      • Budinich C.
      Effects of tibial intraosseous and IV administration of vasopressin on kinetics and survivability in cardiac arrest.
      which reports as minutes. Where needed, data were extracted from figures using computer software. For some studies, the standard error was converted to standard deviation to facilitate plotting of the data.
      For the comparison of tibial IO and peripheral IV, visual inspection of forest plots shows that studies favour peripheral IV for both TMAX and CMAX. This finding is consistent across both normovolaemic and hypovolaemic models. For the humeral IO and peripheral IV comparison, studies typically favoured the IO route for CMAX and TMAX outcomes in normovolaemic models, although confidence intervals typically transect zero. In contrast, for hypovolaemic models, findings were mixed with differences between humeral IO and peripheral IV appearing to be small. Two studies, which could not be included in figures because of the way in which data were reported, produced similar results to those in the forest plots.
      • 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.
      • Wimmer M.H.
      • 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.
      These pharmacokinetic data should be interpreted with caution. The two human studies are small, and prone to both selection bias and confounding. The animal studies, in line with other cardiac arrest animal research, had important limitations in arrest model heterogeneity, methodology and reporting.
      • Fabian-Jessing B.K.
      • Vallentin M.F.
      • Secher N.
      • et al.
      Animal models of cardiac arrest: A systematic review of bias and reporting.
      • Vognsen M.
      • Fabian-Jessing B.K.
      • Secher N.
      • et al.
      Contemporary animal models of cardiac arrest: A systematic review.
      Furthermore, the applicability of animal cardiac arrest models to human cardiac arrest has been shown to be limited.
      • Lind P.C.
      • Johannsen C.M.
      • Vammen L.
      • Magnussen A.
      • Andersen L.W.
      • Granfeldt A.
      Translation from animal studies of novel pharmacological therapies to clinical trials in cardiac arrest: A systematic review.

      Comparison of the intravenous and intraosseous route- patient outcomes

      Our search identified no published randomised controlled trials that directly compare IO with peripheral IV and report patient outcomes.
      One published randomised controlled trial evaluated the effect of implementing IO access in the Singaporean pre-hospital system.
      • Tan B.K.K.
      • Chin Y.X.
      • Koh Z.X.
      • et al.
      Clinical evaluation of intravenous alone versus intravenous or intraosseous access for treatment of out-of-hospital cardiac arrest.
      In a cluster trial design, ambulance clinicians were randomised to continue standard practice of being permitted to attempt IV access only or to be permitted to attempt IO access if IV access failed. Across 1016 analysed patients, the IO group had a higher rate of successful pre-hospital vascular access, were more likely to receive adrenaline, and had shorter median time to adrenaline administration. Despite these improvements in care processes, ROSC rates were not statistically different between groups (11.7 % v 11.7 %, p = 0.998) and there was a statistically significant reduction in hospital survival in the IO group (4.9 % v 8.4 %, p = 0.027). The generalisability of this study is limited as the IO route is already routinely available in many EMS systems in line with current resuscitation guidelines.
      Several observational studies have sought to compare outcomes between IO and peripheral IV drug administration including nine adult OHCA,
      • Nolan J.P.
      • Deakin C.D.
      • Ji C.
      • et al.
      Intraosseous versus intravenous administration of adrenaline in patients with out-of-hospital cardiac arrest: a secondary analysis of the PARAMEDIC2 placebo-controlled trial.
      • Daya M.R.
      • Leroux B.G.
      • Dorian P.
      • et al.
      Survival After Intravenous Versus Intraosseous Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Shock-Refractory Cardiac Arrest.
      • 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.
      • Clemency B.
      • Tanaka K.
      • May P.
      • et al.
      Intravenous vs. intraosseous access and return of spontaneous circulation during out of hospital cardiac arrest.
      • Feinstein B.A.
      • Stubbs B.A.
      • Rea T.
      • Kudenchuk P.J.
      Intraosseous compared to intravenous drug resuscitation in out-of-hospital cardiac arrest.
      • Hamam M.S.
      • Klausner H.A.
      • 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.
      • Mody P.
      • Brown S.P.
      • Kudenchuk P.J.
      • et al.
      Intraosseous versus intravenous access in patients with out-of-hospital cardiac arrest: Insights from the resuscitation outcomes consortium continuous chest compression trial.
      • Nguyen L.
      • Suarez S.
      • Daniels J.
      • Sanchez C.
      • Landry K.
      • Redfield C.
      Effect of Intravenous Versus Intraosseous Access in Prehospital Cardiac Arrest.
      • Zhang Y.
      • Zhu J.
      • Liu Z.
      • et al.
      Intravenous versus intraosseous adrenaline administration in out-of-hospital cardiac arrest: A retrospective cohort study.
      one adult in-hospital cardiac arrest,
      • Schwalbach K.T.
      • Yong S.S.
      • Chad Wade R.
      • Barney J.
      Impact of intraosseous versus intravenous resuscitation during in-hospital cardiac arrest: A retrospective study.
      and three paediatric OHCA studies.
      • 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.
      • Kawano T.
      • Grunau B.
      • Scheuermeyer F.X.
      • et al.
      Intraosseous Vascular Access Is Associated With Lower Survival and Neurologic Recovery Among Patients With Out-of-Hospital Cardiac Arrest.
      • 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.
      Studies vary markedly in sample size (median 1800, interquartile range 795–7317) and complexity of statistical analysis. These studies have documented both no association between IO drug administration and outcome and an association between IO drug administration and worse patient outcome. Importantly, no study has reported a statistically significant association between IO drug administration and improved patient outcome at any time-point in any analysis.
      These studies are challenging to interpret because most studies, in line with current guidelines, IO access will typically be attempted only when IV access has been unsuccessful or when IV access is predicted to be very difficult. As such, these studies are subject to a high risk of resuscitation time bias and bias from other confounders.
      • Andersen L.W.
      • Grossestreuer A.V.
      • Donnino M.W.
      “Resuscitation time bias”- A unique challenge for observational cardiac arrest research.
      Resuscitation time bias occurs when interventions given early (i.e. IV drugs) during a cardiac arrest are compared with those given later (i.e. IO drugs). As the likelihood of return of spontaneous circulation and survival decreases, the longer a patient remains in cardiac arrest, this tends to bias against the intervention which is given later.
      Systematic reviews have summarised these observational studies and highlighted additional important concerns related to both selection bias and confounding.
      • Granfeldt A.
      • Avis S.R.
      • Lind P.C.
      • et al.
      Intravenous vs. intraosseous administration of drugs during cardiac arrest: A systematic review.
      • Hsieh Y.-L.
      • Wu M.-C.
      • Wolfshohl J.
      • et al.
      Intraosseous versus intravenous vascular access during cardiopulmonary resuscitation for out-of-hospital cardiac arrest: a systematic review and meta-analysis of observational studies.
      A recent meta-analysis of nine observational studies (111,746 patients) found no statistically significant association between IO, compared with IV drug administration, and patient outcome (hospital survival: OR 0.66, 95 % CI 0.42 to 1.04; favourable neurological recovery OR 0.60, 95 % CI 0.27 to 1.33), although there was substantial heterogeneity across studies. In a meta-regression, the review found that the time to access was likely to be an important effect moderator across included observational studies, highlighting the need for randomised controlled trials to determine the optimum vascular access route in cardiac arrest.
      There are two potential strategies for attempting to mitigate the effect of resuscitation time bias.
      • Andersen L.W.
      • Grossestreuer A.V.
      • Donnino M.W.
      “Resuscitation time bias”- A unique challenge for observational cardiac arrest research.
      One strategy is to use propensity score analysis with adjustment for time to drug administration. The importance of adjusting for time to intervention was illustrated by two Japanese propensity score analyses exploring the effect of adrenaline, compared with no adrenaline, on outcome following OHCA which, despite using broadly similar datasets, produced conflicting results.
      • Andersen L.W.
      • Grossestreuer A.V.
      • Donnino M.W.
      “Resuscitation time bias”- A unique challenge for observational cardiac arrest research.
      • Couper K.
      • Perkins G.D.
      Improving outcomes from in-hospital cardiac arrest.
      • Nakahara S.
      • Tomio J.
      • Takahashi H.
      • et al.
      Evaluation of pre-hospital administration of adrenaline (epinephrine) by emergency medical services for patients with out of hospital cardiac arrest in Japan: controlled propensity matched retrospective cohort study.
      • Hagihara A.
      • Hasegawa M.
      • Abe T.
      • Nagata T.
      • Wakata Y.
      • Miyazaki S.
      Prehospital Epinephrine Use and Survival Among Patients With Out-of-Hospital Cardiac Arrest.
      Importantly, the findings of the study which adjusted for time to drug administration were markedly similar to those of the PARAMEDIC-2 randomised controlled trial.
      • Perkins G.D.
      • Ji C.
      • Deakin C.D.
      • et al.
      A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
      • Nakahara S.
      • Tomio J.
      • Takahashi H.
      • et al.
      Evaluation of pre-hospital administration of adrenaline (epinephrine) by emergency medical services for patients with out of hospital cardiac arrest in Japan: controlled propensity matched retrospective cohort study.
      In the context of drug route in cardiac arrest, Baert and colleagues’ recent analysis of 28,856 OHCA patients found that, in unadjusted analyses, IO drug administration was associated with reduced 30-day survival (OR 0.41, 95 % CI 0.27 to 0.62).
      • 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.
      However, this statistically significant association was not observed in a propensity score analysis that adjusted for time to adrenaline administration (OR 0.76, 95 % CI 0.47 to 1.23).
      The second potential strategy for minimising the effect of resuscitation time bias is to explore evidence of an interaction between IV and IO drug administration in randomised controlled trials of intra-arrest drug administration. In these trials, differences in time to obtain vascular access will be evenly balanced across those who received drug and those who received placebo. Both the PARAMEDIC-2 (p-value for interaction 0.18) and ALPS (p-value for interaction 0.15) trials found no evidence of an interaction between the IV and IO routes for their primary outcome, although neither trial was powered to detect such interactions.
      • Kudenchuk P.J.
      • Brown S.P.
      • Daya M.
      • et al.
      Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest.
      • Nolan J.P.
      • Deakin C.D.
      • Ji C.
      • et al.
      Intraosseous versus intravenous administration of adrenaline in patients with out-of-hospital cardiac arrest: a secondary analysis of the PARAMEDIC2 placebo-controlled trial.
      In a detailed analysis of the of PARAMEDIC 2 trial, similar rates of ROSC at hospital handover were observed in patients treated with adrenaline, compared with placebo, whether drug was delivered through the IV route (aOR 4.07, 95 % CI 3.42 to 4.85) or the IO route (aOR 3.98, 95 % CI 2.86 to 5.53).
      • Nolan J.P.
      • Deakin C.D.
      • Ji C.
      • et al.
      Intraosseous versus intravenous administration of adrenaline in patients with out-of-hospital cardiac arrest: a secondary analysis of the PARAMEDIC2 placebo-controlled trial.
      A secondary analysis of the ALPS trial does reported similar time in minutes to vascular access (IV 14.2 (SD 5.6) v IO 13.9 (SD 5.8)) and trial drug administration (IV 19.3 (SD 7.4) v IO 19.4 (SD 7.3). Sub-group analysis according to the route of drug administration (IV versus IO) found no significant effect modification for amiodarone or lidocaine in comparison with placebo during out-of-hospital cardiac arrest.
      • Daya M.R.
      • Leroux B.G.
      • Dorian P.
      • et al.
      Survival After Intravenous Versus Intraosseous Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Shock-Refractory Cardiac Arrest.
      However the point estimates for the effects of both amiodarone and lidocaine for hospital admission, survival to hospital discharge and favourable neurological outcomes, were in the direction of favouring the IV route, albeit with confidence intervals which overlapped with the IO route. The authors note that the study was underpowered for these sub-group analyses and highlight the potential importance of the route of drug administration during resuscitation and call for further research.
      The key clinical question is whether IO or peripheral IV should be the first-choice for drug route in cardiac arrest. Current observational studies do not directly answer this question. Given that the design and analysis of observational studies typically biases against the IO route, the finding in most studies that there is no statistically significant association between drug route and outcome is important. This ongoing uncertainty as to the comparative clinical effectiveness of the IO and IV drug routes in OHCA highlights the need for further research in this area.

      The need for further research

      In 2020, ILCOR reviewed current evidence on drug administration route in cardiac arrest, informed by its systematic review authored by Granfeldt and colleagues.
      • Soar J.
      • Berg K.M.
      • Andersen L.W.
      • et al.
      Adult Advanced Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations.
      • Granfeldt A.
      • Avis S.R.
      • Lind P.C.
      • et al.
      Intravenous vs. intraosseous administration of drugs during cardiac arrest: A systematic review.
      ILCOR concluded that current evidence was of very low certainty and that there was an urgent need for a randomised controlled trial comparing intravenous with intraosseous drug administration in adult cardiac arrest. The GRADE evidence to decision framework that supported ILCOR’s evidence review noted increasing IO use by EMS systems and the possibility of more rapid drug delivery, alongside concerns about pharmacokinetics, the risk of misplaced IO access, and uncertain clinical effectiveness. ILCOR also acknowledged uncertainty regarding the optimum IO access site, reflecting probable differences in initial success rate, risk of dislodgement, and pharmacokinetics.
      Through our search of ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform, we sought to identify ongoing human randomised controlled trials of drug routes in cardiac arrest with patient-focussed outcomes.
      • Hunter K.E.
      • Webster A.C.
      • Page M.J.
      • et al.
      Searching clinical trials registers: guide for systematic reviewers.
      We identified five ongoing trials (Table 2). Four trials are comparing IO with IV drug administration in adult out-of-hospital cardiac arrest. Sample size ranges from 762 to 15,000, of which the largest is the UK-based PARAMEDIC-3 trial. The primary outcome is ROSC in two trials and survival at 30-days/ hospital discharge in the other two trials. Two trials protocolise the site of IO access. The fifth trial is a stepped wedge randomised controlled trial evaluating the effect of intramuscular adrenaline compared with standard care on time to ROSC among children with OHCA.
      Table 2Summary of ongoing studies.
      Trial identifierDesignPopulation/ settingInterventionComparatorPrimary OutcomeSample sizeStatus
      NCT04135547

      (VICTOR)
      RCT- individual randomisationAdult OHCA (Taiwan)IO- proximal humerusIV (upper limb)Survival- hospital discharge1,440Currently suspended due to COVID-19- planned completion December 2022
      NCT04130984RCT- individual randomisationAdult OHCA (China)IO- proximal tibiaIVROSC2,356Recruiting- planned completion December 2022
      ISRCTN14223494

      (PARAMEDIC-3)
      RCT- individual randomisationAdult OHCA (UK)IO-first strategyIV-first strategy30-day survival15,000Recruiting- scheduled to complete 2023
      NCT05205031

      (IVIO)
      RCT- individual randomisationAdult OHCA (Denmark)IOIVROSC762Recruiting- planned completion February 2024
      NCT05166343

      (PRIME)
      RCT- Stepped-wedgePaediatric OHCA (Canada)IM adrenaline via auto-injectorStandard of care (IV/ IO adrenaline)Time to ROSC76Recruitment to start June 2022
      IO- Intraosseous; IM- Intramuscular; ISRCTN- International Standard Registered Clinical/soCial sTudy Number (ISRCTN.com); IV- intravenous; NCT- National clinical trial number (clinicaltrials.gov); OHCA- out-of-hospital cardiac arrest; RCT- Randomised controlled trial.

      Conclusion

      The optimum route for drug administration in OHCA is uncertain. The most effective drug route will facilitate rapid access, drug delivery and transport to the central circulation accompanied by improved clinical outcome. There are potential advantages to the IO route, including speed and success of insertion, although this may be influenced by anatomical site. Similarly, there are potential advantages to the IV route, such as a low risk of dislodgement and a potentially more favourable pharmacokinetic profile. Ongoing clinical trials will inform clinical practice regarding the role of intraosseous access in adult out-of-hospital cardiac arrest.

      Funding source

      This project is funded by the NIHR Health Technology Assessment programme (NIHR131105). GDP is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) West Midlands. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Project funders had no role in study design, data collection, data analysis, data interpretation, or the decision to submit for publication.

      CRediT authorship contribution statement

      Amy Hooper: Investigation, Writing – original draft, Writing – review & editing. Jerry P Nolan: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. Nigel Rees: Investigation, Writing – review & editing. Alison Walker: Investigation, Writing – review & editing. Gavin D Perkins: Conceptualization, Investigation, Writing – original draft, Writing – review & editing, Supervision, Funding acquisition. Keith Couper: Conceptualization, Investigation, Writing – original draft, Writing – review & editing, Supervision.

      Conflicts of interest:

      GDP is chief investigator of the PARAMEDIC-3 trial. JPN, AW, and KC are funded PARAMEDIC-3 trials co-investigators. NR is principal investigator of PARAMEDIC-3 for the Welsh Ambulance Service. JPN and GDP are editors of Resuscitation. KC is an editorial board member of Resuscitation.

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