Cardiac Arrest Associated with Pulmonary Embolism (ALS): Systematic Review

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This Review is a draft version prepared by ILCOR, with the purpose to allow the public to comment and is labeled “Draft for Public Comment". The comments will be considered by ILCOR. The next version will be labelled “draft" to comply with copyright rules of journals. The final Review will be published on this website once a summary article has been published in a scientific Journal and labeled as “final”.

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. There were no declared conflicts of interest, intellectual or otherwise, by task force members or authors.

CoSTR Citation

Wetsch WA, Böttiger BW, Andersen LW, Berg KM, Callaway CW, Deakin CD, Donnino MW, Drennan I, Hsu C, Morley PT, Nicholson TC, O’Neil BJ, Neumar RW, Nolan JP, Paiva EF, Parr MJ, Reynolds JC, Sandroni C, Wang TL, Welsford M, Soar J. Cardiac arrest associated with pulmonary embolism Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2020 January 5th. Available from: http://ilcor.org

Methodological Preamble

The continuous evidence evaluation process for the production of this updated 2015 Consensus on Science with Treatment Recommendations (CoSTR) started with a focused systematic review: Cardiac arrest associated with pulmonary embolism in publications since 2014 conducted by Wolfgang Wetsch and Bernd Böttiger, with Jasmeet Soar and Jerry Nolan as additional content experts. Evidence for adult literature was sought and considered by the Advanced Life Support Task Force. These data were taken into account when formulating the Treatment Recommendations.

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Among adults who are in cardiac arrest due to PE or suspected PE in any setting

Intervention: Does any specific alteration in treatment algorithm (eg, fibrinolytics, or any other intervention)

Comparators: Standard advanced life support care

Outcomes: Survival with favorable neurological/functional outcome at discharge, 30 days, 60 days, 180 days AND/OR 1 year. Survival at discharge, 30 days, 60 days, 180 days AND/OR 1 year.

Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) are eligible for inclusion. Unpublished studies (e.g., conference abstracts, trial protocols) are excluded.

Timeframe: All years and all languages were included as long as there was an English abstract; unpublished studies (e.g., conference abstracts, trial protocols) were excluded. Literature search updated to September 14th, 2019.

This update was registered with the ILCOR SAC on 6 October 2019

Consensus on Science

Fibrinolysis

For the critical outcome of survival with favorable neurologic status at 30 days, there was very-low certainty evidence (downgraded for serious imprecision, and very serious risk of bias) from a subgroup of 37 patients with confirmed pulmonary embolism from 1 RCT comparing fibrinolytics versus placebo during cardiac arrest [Böttiger 2008; 2651] that showed no difference in between groups [tenecteplase 2/15, (13.3%) vs placebo 0/22 (0%)] [RR, 7.19; 95% CI, 0.37–139.9] and a single observational study that showed no difference (10% fibrinolysis vs 5% control; adjusted RR 1.97; 95% CI, 0.70-5.56) {Javaudin 2019 1167}.

For the critical outcome of survival at 30 days, very-low certainty evidence (downgraded for risk of bias) from one observational study showed improved survival in the intervention group (16% vs 6%; P = 0.005) {Javaudin 2019 1167}.

For the critical outcome of survival to hospital discharge, very-low-certainty evidence (downgraded for very serious risk of bias and imprecision) from 3 retrospective observational studies showed there was no difference in discharge (10.5% fibrinolysis versus 8.7% control {Yousuf 2016 190};

9.5% fibrinolysis versus 4.8% control {Kürkciyan 2000 1529} and 19.4% fibrinolysis versus 6.7% control (RR, 2.9; 95% CI, 0.75–13.8) {Janata 2003 49}.

For the important outcome of ROSC, very-low-certainty evidence from 3 studies (downgraded for very serious risk of bias) showed benefit for the use of fibrinolytic drugs compared with controls in patients with PE: ROSC was reported to be significantly higher in a retrospective analysis (81.0% fibrinolysis versus 42.9% control; P=0.03).{Kürkciyan 2000 1529} Other studies found that the rate of ROSC was not different (66.7% in fibrinolysis group versus 43.3% in control group; RR, 1.5; 95% CI, 0.8–8.6) {Janata 2003 49}; (47.4% fibrinolysis group vs. 47.8% control group, P = 0.98) {Yousuf 2016 190}.

For the outcome of survival at 24 hours, very-low certainty evidence (downgraded for risk of bias) from one observational study showed no differences (66% in the thrombolysis group versus 63% in the control group, P= .76){[Javaudin 2019 1167}, whereas another study showed favorable results for the intervention (52.8% fibrinolysis versus 23.3% control; RR, 2.3; 95% CI, 1.1–4.7) {Janata 2003 49}.

Surgical Embolectomy

We found very-low-certainty evidence (downgraded for very serious risk of publication bias) from 2 case series {Doerge 1996 952}{Konstantinov 2007 41} with no control groups and a total of 21 patients requiring CPR with a 30-day survival rate of 12.5% and 71.4%, respectively.

Percutaneous Mechanical Thrombectomy

For the important outcome of ROSC, very-low-certainty evidence (downgraded for very serious risk of bias and very serious imprecision) from 1 case series of 7 patients with cardiac arrest with no control group,{Fava 2005 119} ROSC was achieved in 6 of 7 patients (85.7%) treated with percutaneous mechanical thrombectomy.

The overall quality of evidence was rated as very low primarily due to a very serious risk of bias and inconsistency. Because of this no meta-analyses were performed.

Treatment Recommendations

We suggest administering fibrinolytic drugs for cardiac arrest when PE is the suspected cause of cardiac arrest (weak recommendation, very low certainty of evidence).

We suggest the use of fibrinolytic drugs or surgical embolectomy or percutaneous mechanical thrombectomy for cardiac arrest when PE is the known cause of cardiac arrest (weak recommendation, very low certainty of evidence).

The role of extracorporeal life support (eCPR) techniques has been addressed in the 2019 ILCOR CoSTR {Soar 2019 145}{ Soar 2019 e82}

We suggest that extracorporeal CPR may be considered as a rescue therapy for selected patients with cardiac arrest when conventional CPR is failing in settings in which it can be implemented (weak recommendation, very low certainty of evidence).

Justification and Evidence to Decision Framework Highlights

This is an update of the 2015 ILCOR CoSTR and systematic review.

The Task force considered that mechanical or surgical thrombectomy would only be used if the patient had a confirmed pulmonary embolism.

No RCTs were identified.

Given the available evidence no meta-analysis was undertaken.

The Task Force considered that 2-7% of all out-of-hsopital cardiac arrests have a PE,{Javaudin 2019 1167}{Böttiger 2008 2651} and that this figure is likely to be higher for the sicker in-hospital cardiac arrest population.

The Task Force acknowledged that eCPR techniques are now commonly used in patients with cardiac arrest from suspected PE in those settings where eCPR is feasible. This role of CPR for advanced life support was addressed by the 2019 CoSTR and the considered studies included patients with PE.{Soar 2019 145}{Soar 2019 e826} eCPR can facilitate the use of fibrinolysis, mechanical or surgical embolectomy.

The Task Force considered the increased risk of bleeding from fibrinolysis in those patients given fibrinolysis when there was no PE. The results from the TROICA study – which is the largest study with thrombolysis during cardiac arrest – suggest that there is a certain risk for bleeding in the thrombolysis group (any intracranial hemorrhage 2.7 vs 0.4 %, RR 6.95 (1.59–30.41) , p=0.006), but major bleeding complications did not occur more often in thrombolysis group (Symptomatic intracranial hemorrhage 0.8% vs 0%, RR 8.93 (0.48– 165.45), p=0.13; major non-intracranial hemorrhage 7.7% vs 6.4; RR 1.21 (0.77–1.88), p=0.48; ischemic stroke 0.8% vs. 0.6%; RR 1.32 (0.30–5.88), p=1.00).{Böttiger 2008 2651}. In the most recent studies, death from hemorrhage did not occur more often in thrombolysis group than in the control group (6% vs 5%; P = .73) {Javaudin 2019 1167}, and major bleeding complications were not more frequent (5.3% tPA vs. 4.3% control; p=1.00) {Yousuf 2016 190}. Patients are far more likely to die from the cardiac arrest than from the treatment.

Knowledge Gaps

Optimal dosing strategy for fibrinolysis during CPR.

Attachments

Evidence-to-Decision Table: ALS-435 Pulmonary Embolism

References

Böttiger BW, Arntz HR, Chamberlain DA, Bluhmki E, Belmans A, Danays T, Carli PA, Adgey JA, Bode C, Wenzel V; TROICA Trial Investigators; European Resuscitation Council Study Group. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. N Engl J Med. 2008;359(25):2651-62.

Doerge HC, Schoendube FA, Loeser H, Walter M, Messmer BJ. Pulmonary embolectomy: review of a 15-year experience and role in the age of thrombolytic therapy. Eur J Cardiothorac Surg. 1996;10(11):952-7.

Fava M, Loyola S, Bertoni H, Dougnac A. Massive pulmonary embolism: percutaneous mechanical thrombectomy during cardiopulmonary resuscitation. J Vasc Interv Radiol. 2005;16(1):119-23.

Janata K, Holzer M, Kürkciyan I, Losert H, Riedmüller E, Pikula B, Laggner AN, Laczika K. Major bleeding complications in cardiopulmonary resuscitation: the place of thrombolytic therapy in cardiac arrest due to massive pulmonary embolism. Resuscitation. 2003;57(1):49-55.

Javaudin F, Lascarrou JB, Le Bastard Q, Bourry Q, Latour C, De Carvalho H, Le Conte P, Escutnaire J, Hubert H, Montassier E, Leclère B; Research Group of the French National Out-of-Hospital Cardiac Arrest Registry (GR-RéAC). Thrombolysis During Resuscitation for Out-of-Hospital Cardiac Arrest Caused by Pulmonary Embolism Increases 30-Day Survival: Findings From the French National Cardiac Arrest Registry. Chest. 2019;156(6):1167-1175.

Konstantinov IE, Saxena P, Koniuszko MD, Alvarez J, Newman MA. Acute massive pulmonary embolism with cardiopulmonary resuscitation: management and results. Tex Heart Inst J. 2007;34(1):41-5.

Kürkciyan I, Meron G, Sterz F, Janata K, Domanovits H, Holzer M, Berzlanovich A, Bankl HC, Laggner AN. Pulmonary embolism as a cause of cardiac arrest: presentation and outcome. Arch Intern Med. 2000;160(10):1529-35.

Soar J, Maconochie I, Wyckoff MH, Olasveengen TM, Singletary EM, Greif R, et al. 2019 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. Circulation. 2019;140(24):e826-e80.

Soar J, Maconochie I, Wyckoff MH, Olasveengen TM, Singletary EM, Greif R, et al. 2019 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Resuscitation. 2019;145:95-150.

Yousuf T, Brinton T, Ahmed K, Iskander J, Woznicka D, Kramer J, Kopiec A, Chadaga AR, Ortiz K. Tissue Plasminogen Activator Use in Cardiac Arrest Secondary to Fulminant Pulmonary Embolism. J Clin Med Res. 2016;8(3):190-5.


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