Trials and guidelines in cardiac arrest and resuscitation

This "cardiac arrest and resuscitation" category also ended up with cardiogenic shock because it felt as if there was a considerable area of overlap in the Venn diagram of cardiac arrest, VA ECMO, cardiogenic shock, ECPR and post-arrest prognostication in the comatose survivor.  Cardiology trials concerned with management of non-shocked heart failure and more-or-less-perfusing arrhythmias are therefore relegated to the critical care cardiology section. Most of these have come from Critical Care Reviews and The Bottom Line. Wherever possible, the original paper is linked from the name of the study, and the Bottom Line review is linked from the year of publication.

Cardiogenic shock trials

Which inotropes?

Fang et al - 2018 - meta-analysis of levosimendan in cardiogenic shock. n=648 from 13 papers. No survival benefit (but a trend towards a survival benefit).

Levy et al - 2019 - adrenaline vs noradrenaline; n=57 in France. Higher incidence of refractory shock with adrenaline (37% vs 7%).

DOREMI - 2021 - milrinone vs dobutamine; n=192 in Canada, mostly SCAI C and D. Doesn't matter: no difference in mortality (49% vs 54%) or arrhythmias (48 vs 44%).

Early angio for cardiogenic shock?

CULPRIT-SHOCK - 2017 - culprit lesion vs multi-vessel PCI; n=706 in Europe. Composite of death and RRT was better with single-vessel PCI (45.9% vs 55.4%), but at their (underpowered, exploratory) 1-year follow up there was no difference

Why not IABP?

IABP-SHOCK2 - 2012 - IABP oir just inotropes for MI with cardiogenic shock;  n=600 in Germany. No difference in mortality (39.7% vs. 41.3%).

Why not VA ECMO?

ECMO-CS - 2022 - what if VA ECMO for SCAI stage D or E before complete cardiovascular collapse? n=122 in Czech Republic. No difference in mortality (47% vs 50%) or composite outcome (63.8% vs 71.2%). Try the inotropes first, they reckon.

ECLS-SHOCK - 2023 - what if VA ECMO in shocked MI before the angiogram? n=420. No difference in mortality (47.8% vs 49.0%) but longer ventilation and more bleeding complications.

HYPO-ECMO - 2022 - what if VA ECMO but at 33-34°C? n=374 in France. No mortality difference (42% vs 51%), but underpowered to detect anything under 15%. 

Cardiac arrest resuscitation trials

Gueugniaud et al - 1998 - what if five times more adrenaline? n=3327 in France and Belgium; 5mg vs 1mg adrenaline.  No mortality difference (2.3% vs 2.8%). 

Kudenchuk et al - 1999 - what if amiodarone for refractory VF? n=504 in the US. Survival to hospital admission was better (44% vs 34%). 

Wenzel et al - 2004 - why not 40 units of vasopressin instead of adrenaline? n=1219 in Europe. No difference in survival to hospital for VF (46.2% vs 43.0%); but for asystole, there was some difference (29.0% vs. 20.3%).

Olasveengen et al - 2009 - but what if we don't give any drugs? n=851 in Norway. No difference in survival (10.5% vs. 9.2%) but improved ROSC (40% vs. 25%). The drugs in the control group were amiodarone, adrenaline and atropine.

Jacobs et al - 2011 - forget the adrenaline? n=534 in Western Australia. No difference in survival (4% vs. 1.9%) but improved ROSC with adrenaline (25.3% vs 8.4%) 

Hagihara et al - 2012 - forget the adrenaline, but in a massive prospective cohort? n=417,188, so basically everybody in Japan. OR 3.75 for ROSC, but 0.46 for survival. 

VSE - 2013 - what if 40mg methylprednisolone and 20 units of vasopressin? n=300 in Greece; in-hospital cardiac arrest. More sustained ROSC (83.9% vs. 65.9%) and survival to discharge with good neurology (13.9% vs. 5.1%).

ROC-CCC - 2015 - what if compression only CPR? - n=23,711 in the US or Canada. No difference in survival (9.7% vs 9.0%).

ALPS - 2016 - amiodarone or lignocaine after the third shock? n=4653 in North America. Doesn't matter (18.8% vs 17.5% survival to discharge; ...placebo 16.6%)

Andersen et al - 2017 - the ones that got intubated early: did they do better? Retrospective cohort; n=108,079. Turns out they did worse (survival 33.2% vs. 17%). 

COCA - 2021 - what if you give IV calcium? n=397 in Denmark. No difference in sustained ROSC (19% in calcium group vs 27% in the placebo group)

SNOCAT - 2021 - what if you gave sodium nitrate, for "cytoprotection"? n=1502 in the US. No improvement in survival to admission (43% vs 44%)

VAM-IHCA - 2021 - again, 40mg methylprednisolone and 20 units of vasopressin? n=512 in Denmark. Higher chances of ROSC (42% vs 33%) but no impact on survival.

DOSEVF - 2022 - but what if two defibrillators? n=405 in Canada. Turns out, double sequential shocks were much better - survival to discharge was 30.4% vs. 13.3%.

Mechanical CPR trials

LINC - 2013 - LUCAS vs manual CPR. n=2589 in Europe. No difference in 4-hr survival (23.6% vs 23.7%).

CIRC - 2014 - AutoPulse vs manual CPR. n=4231 in US and Europe. No difference in 24-hour survival  (21.8% vs 25.0%).

PARAMEDIC - LUCAS-2 vs manual CPR. n=4471 in the UK. No difference in 30-day survival (6 vs 7%), but only 60% of those randomised to LUCAS actually got LUCASed.

ECPR trials

CHEER - 2015 - VA ECMO mechanical compressions and cooling for VT/VF: an observational study (not an RCT), n=26 at the best ICU in Australia.  Survival to discharge 54%, for patients with a median downtime of 40 minutes (normally you would expect 16.1%, so this result is very impressive).

2CHEER - 2020 - VA ECMO instead of normal ACLS for VT/VF; also an observational study. n=25 in Sydney, Australia.  Survival to discharge 44% with a median downtime of 57 minutes.

ARREST - 2020 - VA ECMO instead of normal ACLS for VT/VF; n=30 in the US. Huge difference in mortality (43% vs 7%) - stopped early because equipoise was lost. Average downtime was 59 minutes.

Prague OHCA - 2022 - VA ECMO instead of normal ACLS for VT/VF;  n=264, obviously in Prague. 180-day survival with minimal or no neurological impairment much better with ECPR: 31.5% vs 22.0%. Median downtime 61 minutes.

INCEPTION - 2023 - VA ECMO instead of normal ACLS for VT/VF; n=160 in the Netherlands. No difference in favourable outcome (20% vs 16%), but downtime was about 74 minutes on average, and 66% of those randomised to ECPR never received it.

Angiography following cardiac arrest

COACT - 2019 - early angio after cardiac arrest with no ST elevation? n=558, in the Netherlands. No difference in 90-day survival (64.5% vs 67.2%); cardiogenic shock patients were excluded.

TOMAHAWK - 2021 - early angio after cardiac arrest with no ST elevation? n=554 in Germany and Denmark. No difference in mortality (54 vs 46%); cardiogenic shock patients were excluded.

EMERGE - 2022 - early angio after cardiac arrest with no ST elevation? n=279, in France. No difference in survival (34.1% vs 30.7%).

Post-cardiac arrest care

Therapeutic hypothermia

Bernard et al - 2002 - 32–34°C for 24 hrs; n=77 in Australia. Better favourable neurological outcome (49 vs 26)%

HACA - 2002 - 32–34°C for 24 hrs; n=275 in Europe. Better favourable neurological outcome (55% vs 39%).

TTM - 2014 - why not 36ºC? n=950 in Australia and Europe. No difference in mortality (48% vs 50%).

Lilja et al - 2015 - seriously, why not 36ºC? n=342 in Europe. No difference in mortality (46% vs 49%) or cognitive outcome (38 vs 39% normal or mildly impaired) 

TTM48 - 2017 - why not 48 hrs instead of 24? n=335 in Europe. No difference in favourable neurological outcome (69% vs. 64%) or mortality (27% vs. 34%), but Evald et al (2019) found that the 48-hr survivors had better cognitive function.

HYPERION  - 2019 - why not 36.5-37.5ºC? n=584 in France. Slightly better chance of good neuro outcome at 90 days (10.2% vs. 5.7%) but not mortality.

TTM2 - 2021 - why not just 37.5ºC? n=1900, all over the world. No difference in mortality (50% vs 48%) or poor functional outcome (55% vs 55%) at 6 month.

Other supportive strategies

ANTHARTIC - 2019 - what if you give them IV augmentin for 2 days? n=198 in France. Lower rates of VAP (19% v 34%) but no difference in anything else.

BOX (oxygen) - 2022 - what if PaO2 was only 68 -75 mmHg? n=802 in Denmark. No difference in composite outcome (32.0% vs 33.9%)

BOX (blood pressure)2022 - what if MAP was 77 mmHg, instead of 63 mmHg?  n=802 in Denmark. No difference in composite outcome (34.0% vs 32%)

TELSTAR - 2022 - what if you give antiepileptics for the weird EEG? n=179 in Belgium and the Netherlands. No difference in bad neurological outcome (90% vs 92%).

TAME - 2023 - what if the CO2 was 50-55 for 24 hours? n=1700, all over the world. No difference in favourable neurological outcome (43.5% vs 44.6%). 

Prognostication following cardiac arrest

Bouwes et al - 2012 - Can we predict poor outcome with clinical examination, NSE and SSEPs? n=391 in Denmark. The answer is yes. Highly sensitive and specific, especially absence of corneal reflex at 72 hrs and absent SSEPs at 24 hrs.

Guidelines

Undifferentiated shock guidelines

For specific shock states:

Cardiac arrest resuscitation guidelines

Post-resuscitation care

Prognostication following cardiac arrest

Brain death and organ donation

References

Cardiac arrest resuscitation trials

Gueugniaud, Pierre-Yves, et al. "A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital." New England Journal of Medicine 339.22 (1998): 1595-1601.

Kudenchuk, Peter J., et al. "Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation." New England Journal of Medicine 341.12 (1999): 871-878.

Wenzel, Volker, et al. "A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation." New England Journal of Medicine 350.2 (2004): 105-113.

Jacobs, Ian G., et al. "Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo-controlled trial." Resuscitation 82.9 (2011): 1138-1143.

Hagihara, Akihito, et al. "Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest." Jama 307.11 (2012): 1161-1168.

Mentzelopoulos, Spyros D., et al. "Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial." Jama 310.3 (2013): 270-279.

Nichol, Graham, et al. "Trial of continuous or interrupted chest compressions during CPR." New England Journal of Medicine 373.23 (2015): 2203-2214.

Andersen, Lars W., et al. "Association between tracheal intubation during adult in-hospital cardiac arrest and survival." Jama 317.5 (2017): 494-506.

Kudenchuk, Peter J., et al. "Amiodarone, lidocaine, or placebo in out-of-hospital cardiac arrest." New England Journal of Medicine 374.18 (2016): 1711-1722.

Desch, Steffen, et al. "Angiography after out-of-hospital cardiac arrest without ST-segment elevation." New England Journal of Medicine 385.27 (2021): 2544-2553.

Vallentin, Mikael Fink, 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." Jama 326.22 (2021): 2268-2276.

Kim, Francis, et al. "Effect of out-of-hospital sodium nitrite on survival to hospital admission after cardiac arrest: a randomized clinical trial." Jama 325.2 (2021): 138-145.

Andersen, Lars W., et al. "Effect of vasopressin and methylprednisolone vs placebo on return of spontaneous circulation in patients with in-hospital cardiac arrest: a randomized clinical trial." Jama 326.16 (2021): 1586-1594.

Cheskes, Sheldon, et al. "Defibrillation strategies for refractory ventricular fibrillation." New England Journal of Medicine 387.21 (2022): 1947-1956.

Mechanical CPR trials

Rubertsson, Sten, et al. "Mechanical chest compressions and simultaneous defibrillation vs conventional cardiopulmonary resuscitation in out-of-hospital cardiac arrest: the LINC randomized trial." Jama 311.1 (2014): 53-61.

Wik, Lars, et al. "Manual vs. integrated automatic load-distributing band CPR with equal survival after out of hospital cardiac arrest. The randomized CIRC trial." Resuscitation 85.6 (2014): 741-748.

Perkins, Gavin D., et al. "Mechanical versus manual chest compression for out-of-hospital cardiac arrest (PARAMEDIC): a pragmatic, cluster randomised controlled trial." The Lancet 385.9972 (2015): 947-955.

ECPR trials

Stub, Dion, et al. "Refractory cardiac arrest treated with mechanical CPR, hypothermia, ECMO and early reperfusion (the CHEER trial)." Resuscitation 86 (2015): 88-94.

Dennis, Mark, et al. "Prospective observational study of mechanical cardiopulmonary resuscitation, extracorporeal membrane oxygenation and early reperfusion for refractory cardiac arrest in Sydney: the 2CHEER study." Critical Care and Resuscitation 22.1 (2020): 26-34.

Kim, Won Young, et al. "The impact of downtime on neurologic intact survival in patients with targeted temperature management after out-of-hospital cardiac arrest: National multicenter cohort study." Resuscitation 105 (2016): 203-208.

Yannopoulos, Demetris, et al. "Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial." The lancet 396.10265 (2020): 1807-1816.

Belohlavek, Jan, et al. "Effect of intra-arrest transport, extracorporeal cardiopulmonary resuscitation, and immediate invasive assessment and treatment on functional neurologic outcome in refractory out-of-hospital cardiac arrest: a randomized clinical trial." Jama 327.8 (2022): 737-747.

Ruijter, Barry J., et al. "Treating rhythmic and periodic EEG patterns in comatose survivors of cardiac arrest." New England Journal of Medicine 386.8 (2022): 724-734.

Angiography post cardiac arrest

Hauw-Berlemont, Caroline, et al. "Emergency vs delayed coronary angiogram in survivors of out-of-hospital cardiac arrest: results of the randomized, multicentric EMERGE trial." JAMA cardiology 7.7 (2022): 700-707.

Lemkes, Jorrit S., et al. "Coronary angiography after cardiac arrest without ST-segment elevation." New England Journal of Medicine 380.15 (2019): 1397-1407.

Thiele, Holger, et al. "PCI strategies in patients with acute myocardial infarction and cardiogenic shock.New England Journal of Medicine 377.25 (2017): 2419-2432.

Therapeutic hypothermia

Bernard, Stephen A., et al. "Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia." New England journal of medicine 346.8 (2002): 557-563.

Hypothermia after Cardiac Arrest Study Group. "Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest." New England Journal of Medicine 346.8 (2002): 549-556.

Arredondo, Anthony F. "TTM Trial Investigators. Targeted Temperature Management at 33° C versus 36° C after Cardiac Arrest." American Journal of Respiratory and Critical Care Medicine 189.8 (2014): 995.

Lilja, Gisela, et al. "Cognitive function in survivors of out-of-hospital cardiac arrest after target temperature management at 33 C versus 36 C." Circulation 131.15 (2015): 1340-1349.

Lascarrou, Jean Baptiste, et al. "Therapeutic hypothermia after nonshockable cardiac arrest: the HYPERION multicenter, randomized, controlled, assessor-blinded, superiority trial." Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine 23 (2015): 1-12.

Kirkegaard, Hans, et al. "Targeted temperature management for 48 vs 24 hours and neurologic outcome after out-of-hospital cardiac arrest: a randomized clinical trial." Jama 318.4 (2017): 341-350.

Evald, Lars, et al. "Prolonged targeted temperature management reduces memory retrieval deficits six months post-cardiac arrest: a randomised controlled trial." Resuscitation 134 (2019): 1-9.

Dankiewicz, Josef, et al. "Hypothermia versus normothermia after out-of-hospital cardiac arrest." New England Journal of Medicine 384.24 (2021): 2283-2294.

François, Bruno, et al. "Prevention of early ventilator-associated pneumonia after cardiac arrest." New England Journal of Medicine 381.19 (2019): 1831-1842.

Eastwood, Glenn, et al. "Mild Hypercapnia or Normocapnia after Out-of-Hospital Cardiac Arrest." New England Journal of Medicine (2023).

Schmidt, Henrik, et al. "Oxygen targets in comatose survivors of cardiac arrest." New England Journal of Medicine 387.16 (2022): 1467-1476.

Kjaergaard, Jesper, et al. "Blood-pressure targets in comatose survivors of cardiac arrest." New England Journal of Medicine 387.16 (2022): 1456-1466.

Prognostication

Fang, M., H. Cao, and Z. Wang. "Levosimendan in patients with cardiogenic shock complicating myocardial infarction: a meta-analysis." Medicina Intensiva (English Edition) 42.7 (2018): 409-415.

Guidelines

Levy, Bruno, et al. "Epinephrine versus norepinephrine for cardiogenic shock after acute myocardial infarction." Journal of the American College of Cardiology 72.2 (2018): 173-182.

Suverein, Martje M., et al. "Early extracorporeal CPR for refractory out-of-hospital cardiac arrest." New England Journal of Medicine 388.4 (2023): 299-309.

Thiele, Holger, et al. "Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial." The Lancet 382.9905 (2013): 1638-1645.

Thiele. Extracorporeal Life Support in Infarct-Related Cardiogenic Shock. N Engl J Med 2023;epublished August 26th

Ostadal, Petr, et al. "Extracorporeal membrane oxygenation in the therapy of cardiogenic shock: results of the ECMO-CS randomized clinical trial." Circulation 147.6 (2023): 454-464.

Levy, Bruno, et al. "Effect of moderate hypothermia vs normothermia on 30-day mortality in patients with cardiogenic shock receiving venoarterial extracorporeal membrane oxygenation: a randomized clinical trial." JAMA 327.5 (2022): 442-453.

Muraro, Antonella, et al. "EAACI guidelines: Anaphylaxis (2021 update).Allergy 77.2 (2022): 357-377.

Lacey, Jonathan, et al. "A multidisciplinary consensus on dehydration: definitions, diagnostic methods and clinical implications.Annals of medicine 51.3-4 (2019): 232-251.

Rossaint, Rolf, et al. "The European guideline on management of major bleeding and coagulopathy following trauma." Critical Care 27.1 (2023): 80.

Kwon, Brian K., et al. "A clinical practice guideline for the management of patients with acute spinal cord injury: recommendations on hemodynamic management." Global Spine Journal 14.3_suppl (2024): 187S-211S.

Prognostication

Bouwes, Aline, et al. "Prognosis of coma after therapeutic hypothermia: a prospective cohort study." Annals of neurology 71.2 (2012): 206-212.

Guidelines

Cecconi, Maurizio, et al. "Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine." Intensive care medicine 40 (2014): 1795-1815.

Wyckoff, Myra H., et al. "2022 International consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations: Summary from the basic life support; advanced life support; pediatric life support; neonatal life support; education, implementation, and teams; and first aid task forces." Pediatrics 151.2 (2023): e2022060463.

Merchant, Raina M., et al. "Part 1: executive summary: 2020 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care." Circulation 142.16_Suppl_2 (2020): S337-S357.

Rajajee, Venkatakrishna, et al. "Guidelines for Neuroprognostication in Comatose Adult Survivors of Cardiac Arrest." Neurocritical Care 38.3 (2023): 533-563.

Nolan, Jerry P., et al. "European resuscitation council and European society of intensive care medicine guidelines 2021: post-resuscitation care.Resuscitation 161 (2021): 220-269.

Callaway, Clifton W., et al. "Part 8: post–cardiac arrest care: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care." Circulation 132.18_suppl_2 (2015): S465-S482.

Henry, Timothy D., et al. "Invasive management of acute myocardial infarction complicated by cardiogenic shock: a scientific statement from the American Heart Association." Circulation 143.15 (2021): e815-e829.

Sandroni, Claudio, et al. "ERC-ESICM guidelines on temperature control after cardiac arrest in adults." Intensive care medicine 48.3 (2022): 261-269.

Baglia, R. "Management of cardiogenic shock: AHA scientific statement." (2017).

Naidu, Srihari S., et al. "SCSCAI SHOCK Stage Classification Expert Consensus Update: A Review and Incorporation of Validation StudiesJournal of the American College of Cardiology 79.9 (2022): 933-946.

Perman, Sarah M., et al. "Temperature Management for Comatose Adult Survivors of Cardiac Arrest: A Science Advisory From the American Heart Association." Circulation (2023).

Panchal, Ashish R., et al. "2019 American Heart Association focused update on advanced cardiovascular life support: use of advanced airways, vasopressors, and extracorporeal cardiopulmonary resuscitation during cardiac arrest: an update to the American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care." Circulation 140.24 (2019): e881-e894.

Dunning, Joel, et al. "Joint British Societies’ guideline on management of cardiac arrest in the cardiac catheter laboratory.Heart 108.12 (2022): e1-e18.