Toxicology journal club sept 2011

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Toxicology journal club sept 2011

  1. 1. ToxicologyJournal Club<br />Effect of adrenaline on survival in out-of-hospital cardiac arrest:<br />A randomised double-blind placebo-controlled trial<br />Resuscitation. 2011 Sep;82(9):1138-43. Epub 2011 Jul 2.<br />Juan Pablo Peña Diaz, MD<br />Medicina de Urgencias<br />
  2. 2. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Effect of adrenaline on survival in out-of-hospital cardiac arrest:<br />Ian G. Jacobs, Judith C. Finn, George A. Jelinek, Harry F. Oxer, Peter L. Thompson<br />
  3. 3. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Cardiovascular disease caused the dead of 15 million people in 1996 (29 % global mortality)<br />Ischemic Heart Disease: 7 million/people/year<br />Risk for Sudden Death: 5 to 7 times<br />Incidence in USA: 95.7 per 100,000 person years<br />Becker L, Larsen MP, Eisenberg MS. Incidence of cardiac arrest during self-transport for chest pain. Ann EmergMed. 1996 Dec;28(6):612-6<br />Nichol G, Thomas E, Callaway CW, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA 2008;300:1423–31.<br />Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD. Heart Disease and Stroke Statistics 2010 Update: A report from the American Heart Association. Circulation. 2011;123<br />
  4. 4. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />AMI: 295.000 people die before hospital arrival (70%)<br />55% to 60% were attended by EMS<br />Commonest cardiac arrest rhythm:<br />VF / VT (23% a 30%)<br />Survival to hospital discharge: < 7%<br />Becker L, Larsen MP, Eisenberg MS. Incidence of cardiac arrest during self-transport for chest pain. Ann EmergMed. 1996 Dec;28(6):612-6.<br />
  5. 5. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />OnlyClass I Evidence<br />Closed-chest cardiacmassage. JAMA. 1960 Jul 9;173:1064-7.<br />
  6. 6. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Routine use of adrenaline (epinephrine) in treating cardiac arrest has been recommended for over half a century<br />Firstdescribed in 1906:<br />
  7. 7. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />JAMA. 1968 Jan 22;203(4):255-60.<br />
  8. 8. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Ann Emerg Med September 1984 (Part 2);13:840-843<br />
  9. 9. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Weconcludethatepinephrineproduces a significantdose-dependent vasopressor responseduring CPR in humanbeings. Thisfindingsupports work in animal modelsandanecdotalreports in humanbeings, indicatingthat doses ofepinephrinethat are higherthanthosecurrentlyrecommendedmaybeneededduring late CPR in humanbeings.<br />AnnEmergMed , September 1989;18:920-926<br />
  10. 10. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Resus, 1.995<br />EMS setting<br />Observational<br />Prospective<br />417: Adrenaline<br />786: No Adrenaline<br />AuthorizedbyMedicaldispatcher<br />
  11. 11. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Ann EmergMed. 2007;50:635-642<br />Singapore EMS<br />ObservationalProspectiveBefore-after<br />October 2002 to October 2004<br />1.296 pts<br /><ul><li> 615 pre-epinephrine
  12. 12. 681 epinephrine phase</li></ul>AIM: Evaluatethe incremental benefit<br />of introducing intravenous epinephrine in the out-of-hospital<br />setting on the survival outcomes of cardiac arrest patients<br />
  13. 13. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />There was no significant difference in survival to discharge, adjusted for rhythm; return of circulation or survival to<br />admission <br />There was a minimal increase in scene time in the epinephrine phase (10.3 minutes versus 10.7 minutes) <br />Conclusion: We were unable to establish a significant survival benefit with the introduction of IV epinephrine to an EMS system<br />
  14. 14. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Objective: To determine whether removing intravenous drug administration from an ACLS protocol would improve survival to hospital discharge after out-of-hospital cardiacarrest.<br />Prospective<br />Randomized<br />Controlled<br />Non Blinded<br />JAMA. 2009;302(20):2222-2229<br />
  15. 15. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />851 Pts<br /><ul><li> 418 in the ACLS with IV
  16. 16. 433 were in the ACLS with no access to IV drug administration group</li></ul>- Survivalto hospital discharge was 10.5% for the IV vs 9.2% for the no IV drug administration group (P=.61)<br />- Hospital admission with ROSC 32% vs 21%, (P.001)<br />- Survival with favorable neurological outcome 9.8% vs 8.1% (P=.45)<br />- Survival at 1 year 10% vs8%(P=.53)<br />
  17. 17. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Despite adrenaline being universally considered “standard of care” in the treatment of cardiac arrest there has never been a randomized placebo-controlled trial to establish its efficacy.<br />
  18. 18. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Methods<br />
  19. 19. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Study patients and setting:<br />
  20. 20. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />
  21. 21. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Perth<br />
  22. 22. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />All calls for ambulances throughout WA are received centrally and ambulances dispatched by the ambulance service communication<br />centre located in Perth. <br />All ambulances in Perth and larger<br />regional centres in WA are staffed by career PMDs where their<br />scope of clinical care is governed by specific SJA-WA clinical practice<br />guidelines.<br />
  23. 23. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />The management of cardiac arrest is based on the recommendations of the Australian Resuscitation Council<br />- Defibrillationwith a manual Defibrillator<br />- Securing the airway (TT or LMA)- No drugs were administered<br />
  24. 24. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Studydesign<br />Randomized<br />Double blind<br />Placebo<br />Controlled trial<br />Patients were randomized to receive:<br /><ul><li> IV Adrenaline 1:1000 or
  25. 25. Placebo (sodiumchloride 0.9%)</li></ul>Out-of-hospital cardiac arrest patients attended by SJA-WA EMS<br />
  26. 26. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Studyoutcomes<br />* Primary endpoint: Survival to hospital discharge** Secondary endpoints:- Pre-hospital ROSC (a period of sustained ROSC in the field for greater 30 s)<br /><ul><li> Cerebral Performance Category (CPC) at hospital</li></ul>Discharge<br /> I – normal function<br /> II – mild tomoderatedisability<br /> III – severedisability<br /> IV – vegetativestate,<br /> V – dead<br />
  27. 27. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />The study was approved by the <br />of the<br />and waiver (disclaim) of consent was granted<br />
  28. 28. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Studyprocedures<br />All out-of-hospital cardiac arrests attended between 11th August 2006 and 30th November 2009<br />Cardiac arrest from any cause<br />Up 18 y.o.<br />Resuscitation initiated by PMDs<br />Blinded selection of medication<br />- Initiated after 3 shocks (VF/VT) or<br /><ul><li>After they got a vein access (PEA/Asys)</li></ul>* No other resuscitation drugs<br />* No Tracheal Route permitted<br />
  29. 29. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Afterarrivalto hospital, treatingED clinicians were unaware of drug assignment and managed the patient as per their usual clinical practice (Guidelines)<br />Data collection<br />Manually recorded by the paramedic<br />Clinically reviewed and data manually entered into the<br />SPSS statisticalpackage<br />These form the WA Ambulance Service Cardiac Arrest Registry<br />CPC scores are derived from medical chart, the reviewer was blinded to the study group allocation<br />
  30. 30. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Statisticalanalysis<br />The sample size required for the study was 2213 patients per group<br />This was derived on a baseline survival to hospital discharge of 5% with an absolute improvement in survival of 2%, alpha 0.05 (two tailed) and power of 80%<br />A total patient enrollment of 5.000 was planned to account for losses to follow-up.<br />
  31. 31. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Patient and study characteristics were described using proportions and means, with differences assessed using Pearson’s chi-square and t-test (or Mann–Whitney) for categorical and continuous data respectively<br />Ambulance time intervals were described using means, medians and interquartile ranges (IQR).<br />Odds ratios (OR) and 95% confidence intervals were derived for primary and secondaryoutcomes.<br />
  32. 32. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Logistic regression was used to adjust for potential confounders on the treatment effect of the study<br />Drug<br />It was planned ‘a priori’ to conduct subgroup analysis of primary and secondary outcomes by shockable versus non-shockable initial cardiac arrest rhythm<br />Analysis was performed on an intention to treat basis and per protocol basis using SPSS statistical software version 17<br />All statistical tests were two sided with a significancelevel of 0.05.<br />
  33. 33. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Studyprofile<br />
  34. 34. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />
  35. 35. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Patients administered adrenaline the likelihood of achieving ROSC pre-hospital was 3.4 times greater than for those receiving placebo (23.5% versus 8.4%; OR 3.4; 95% CI 2.0–5.6)<br />
  36. 36. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Adrenaline was associated with a significant increase in the proportion of patients admitted from the ED to hospital (25.4% versus 13.0%; OR 2.3; 95% CI 1.4–3.6).<br />
  37. 37. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />More thantwicethenumber of patients who received adrenaline survived to hospital discharge, but this failed to reach statistical significance (4.0% versus 1.9%; OR 2.2; 95% CI 0.7–6.3)<br />
  38. 38. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Good neurological outcome (CPC 1 or 2) was achieved in 14 out of the 16 survivors. The two unfavourable<br />neurological outcomes (one CPC = 3 and one CPC = 4) occurred in theadrenalinegroup.<br />
  39. 39. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Treatment effect of adrenaline on prehospital<br />ROSC was more marked in non-shockable rhythms (OR 6.9; 95% CI 2.6–18.4) than shockable rhythms (OR 2.4; 95% CI 1.2–4.5)<br />
  40. 40. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Adjusted models<br />Little change in the effect of adrenaline on ROSC or survival to hospital discharge<br />The presence of an initial shockable rhythm was the only other factor associated with the likelihood of pre-hospital ROSC <br />A younger age and an initial shockable rhythm was also associated with improved survival to hospital discharge<br />
  41. 41. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Discussion<br />This is the 1st Placebo-RCT of Adrenaline in cardiac arrest<br /><ul><li> Adrenaline resulted in a statistically significant increase in ROSC but not in the primary outcome of survival to hospital discharge
  42. 42. For both shockable and non-shockable initial cardiac</li></ul>arrest rhythms we observed significantly better outcomes interms of ROSC and hospital admission with the use of adrenaline.<br />
  43. 43. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Whatthisstudydemonstrates is that the administration of resuscitation drugs during out of hospital cardiac arrest is associated with improvements in short termsurvival.<br />Thisstudy“clearlydemonstrates the superiority of adrenaline over placebo in achieving ROSC”<br />All the studies published to date have employed less robust study designs, used adrenaline doses much lower than recommended for cardiac arrest or compared larger doses of adrenaline againstunprovenstandarddoseadrenalineregimes.<br />
  44. 44. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Thisisanout-of-hospital study, theinfluence of post resuscitation care interventions (therapeutic hypothermia, managing underlying cause, organ perfusion and oxygenation) on survival to hospital discharge are recognised<br />
  45. 45. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Limitations<br />Failure to achieve an adequatesample size<br />Despite having obtained approvals for the study, the concerns of being involved in a trial in which the unproven “standard of care” was being withheld prevented four of the five ambulance services<br />from participating<br />Adverse press reports questioning the ethics of conducting this trial, which subsequently led to<br />the involvement of politicians, further heightened these concerns.<br />
  46. 46. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Theextensivebarriersassociated with trialling interventions deemed “standard of care” where clinical equipoise clearly exists serves only to ensure such interventions remain unproven<br />The findings of this study are clinically important in that it establishes efficacy for the continued use of adrenaline in cardiac arrest as currently recommended, however numerous questions remain unanswered …<br />
  47. 47. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />What is the optimal dose ?<br />When is the moment for adrenaline during<br />cardiacarrest ?<br />
  48. 48. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Robert R Attaran & Gordon A Ewy<br />Future Cardiology. July 2010, Vol. 6, No. 4, Pages 473-482<br />Vasopressor drugs will be more effective with wider adoption of strategies that delay the inevitable deterioration that accompanies untreated or suboptimally treated cardiac arrest.<br />
  49. 49. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />Cardiac arrest survival rates are mutable<br />Michael R. Sayre<br />Resuscitation 82 (2011) 1257– 1258<br />Measurement of survival to hospital discharge following out of-hospital cardiac arrest should be expected of all EMS systems.<br />EMS systems should publicly report their hospital discharge survival rates to their political leaders and the citizens they serve as well as the EMS professionals and hospital staffs caring for those<br />patients.<br />
  50. 50. Effect of adrenaline on survival in out-of-hospital cardiac arrest<br />ToxicologyJournal Club<br />Juan Pablo Peña Diaz, MD / Medicina de Urgencias<br />ThankYou !<br />

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