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two in two days
Christopher Partyka
8th April 2014
Case 1.
74 yo male - collapse.
Batphone.
P 120, SBP 70, SaO2 94% (NRB)
Transient RBBB on ECG
Case 1.
A. patent.
B. RR 32. mild ↑WOB. Bilateral AE.
SaO2 92% [15L NRB]
C. P 124. BP 72/50. cold & clammy. mottled.
D. Ag...
Case 1 - Now what ?!
DDx ?
Immediate treatment ?
Investigations ?
Case 1 - Now what ?!
DDx ?
Immediate treatment ?
Investigations ?
- Myocardial infarction
- AAA
- Ao dissection
- ?Haemorr...
Case 1 - Now what ?!
DDx ?
Immediate treatment ?
Investigations ?
- High flow O2
- IV access + fluid bolus
- then what..?
Case 1 - Now what ?!
DDx ?
Immediate treatment ?
Investigations ?
- CXR
- ECG
- Blood gas
Case 1 - some results...
Case 1 - some results...
Case 1 - some results...
Case 1 - Now what ?!
RUSH protocol...
FAST - negative
No AAA
IVC - full !!
ECHO...
Case 1.
RV
LV
Case 1.
Clot in transit
Case 1 - the conclusion
PEA arrest
Provisional Dx - massive PE
Thrombolysis given under CPR
Case 1 - the conclusion
Prolonged resuscitation
CPR on and off for 3 hours.
ICU admission at 3.5 hours.
Adrenaline infusio...
Thrombolytics for PE
Can we alter outcomes ?!?
Scary statistic
Two thirds of patients who die of PE do so within
an hour of hospital presentation
more scary statistics...
~10% of non-traumatic sudden deaths
1 in 2 arrive in PEA/asystole
MASSIVE
~5% of PEs
58% 90 day
m...
Massive PE
Overt right ventricular failure
Persistent systemic arterial hypotension
SBP < 90mmHg for 15mins or more
Shock
...
Submassive PE
A population at risk
RV dysfunction without hypotension
Dilatation or hypokinesis on ECHO
Dilatation on CT
↑...
Submassive PE
RV:LV > 0.9 predicts mortality
OR 2.53 [95%CI 1.17-5.50]
Persistent RV dysfunction at discharge
4x mortality...
Bust some clots ?!
Pros:
Rapid resolution of symptoms
Stabilise cardiorespiratory function
Reduce RV damage
Improve exerci...
Bust some clots ?!
Cons:
Disabling or fatal haemorrhage (incl. ICH)
Blood transfusions
Unnecessary intervention (incl. sur...
The evidence...
Thrombolytics for PE
What is accepted practice then ?!
Thrombolysis:
first line treatment for massive PE [B]
may be instituted on clinical grounds alone if cardiac
arrest is immi...
Thrombolysis:
first line treatment for massive PE [B]
may be instituted on clinical grounds alone if cardiac
arrest is immi...
Thrombolysis:
reasonable for massive PE w/ acceptable bleeding
risk [B]
considered for submassive PE w/ adverse prognosis
...
Thrombolytics for PE
Blind application doesn’t work !!!
~70% of OHCA result from AMI or PE
Thrombolytics during CPR may improve survival
DB RCT
original article
Thrombolysis duri...
original article
Thrombolysis during Resuscitation
for Out-of-Hospital Cardiac Arrest
Bernd W. Böttiger, M.D., Hans-Richar...
MAPPET-3 Trial
ALTEPLASE IN PULMONARY EMBOLISM
HEPARIN PLUS ALTEPLASE COMPARED WITH HEPARIN ALONE IN PATIENTS
WITH SUBMASS...
MAPPET-3 Trial
DB RCT
Acute PE with RV strain
- ECG
- ECHO
- CT
Heparin plus 100mg alteplase
vs
Heparin plus placebo
MAPPET-3 Trial
DB RCT
Acute PE with RV strain
- ECG
- ECHO
- CT
No difference shown for in-hospital mortality
(3.4% vs 2.2...
MAPPET-3 TrialThe New England Journal of Medicine
*The numbers shown are based on calculations for the intention-to-treat ...
The “MOPPET” trial
Moderate Pulmonary Embolism Treated With Thrombolysis
(from the “MOPETT” Trial)
Mohsen Sharifi, MDa,b,
*...
The “MOPPET” trial
Single-centre, randomised
“half dose” t-PA vs control [no placebo]
Unwell patients w/ moderate PE
Anato...
The “MOPPET” trial
Theory:
PE is exquisitely sensitive to 'lytics
the lungs see 100% of the circulation
Brain ~ 15%
Myocar...
The “MOPPET” trial
Primary endpoints:
Pulmonary HTN
Recurrent PE
The “MOPPET” trial
Primary endpoints:
Pulmonary HTN
Recurrent PE
Pulmonary HTN at 28 months:
16% vs 57%, p<0.001
The “MOPPET” trial
Secondary endpoints:
Total mortality
Hospital LOS
Bleeding
Recurrent PE
The “MOPPET” trial
Secondary endpoints:
Total mortality
Hospital LOS
Bleeding
Recurrent PE
Benefits:
↓ recurrent PE - 0% vs...
PEITHO trial
American Heart Journal, 163(1), 33–38.e1.
PEITHO trial
Prospective, international, MC, DB, RCT
Tenecteplase vs placebo
+ standard anticoagulation
1006 normotensive ...
PEITHO trial
Table I. Inclusion and exclusion criteria
Inclusion criteria Exclusion criteria
(1) Age 18 y (1) Hemodynamic ...
PEITHO trial
hypotheses are as follows: H0: 7-day-death-hemcoltenect =
7-day-death-hemcolplacebo vs H1: 7day-death-hemcolt...
PEITHO trial
Primary outcome
Death or
Haemodynamic collapse =
CPR
SBP < 90 for ≥15mins
End-organ hypo perfusion
Vasopresso...
PEITHO trial
Primary outcome
Death or
Haemodynamic collapse =
CPR
SBP < 90 for ≥15mins
End-organ hypo perfusion
Vasopresso...
PEITHO trial
Safety outcomes
Ischaemic or haemorrhagic stroke in 7 days
Other major bleeding = Fatal bleeding
Blood transf...
PEITHO trial
Safety outcomes
Ischaemic or haemorrhagic stroke in 7 days
Other major bleeding = Fatal bleeding
Blood transf...
PEITHO
No difference in 30-day
mortality.
Finally; the MOPPET crew
return in 2014...
Prospective, observational study.
98 consecutive patients with moderate to severe PE
“safe-dose” t-PA + heparin followed b...
Address for correspondence:
Mohsen Sharifi, MD,
Arizona Cardiovascular Consultants
and Vein Clinic, 3850 E. Baseline
Road, ...
Address for correspondence:
Mohsen Sharifi, MD,
Arizona Cardiovascular Consultants
and Vein Clinic, 3850 E. Baseline
Road, ...
now we are enlightened...
... back to our tales !!
24 hours later...
47 yo female - “life-threatening asthma”
Batphone.
RR 30, ‘no air entry’, SaO2 92% (NRB)
P 120, SBP 120
...
Case 2.
A. patent. no stridor.
B. RR 44. ↑WOB++. Good AE - no wheeze.
SaO2 92% [15L NRB]
C. P 124. BP 118/70. warm periphe...
Case 2 - Now what ?!
DDx ?
Immediate treatment ?
Investigations ?
Case 2 - Now what ?!
DDx ?
Immediate treatment ?
Investigations ?
- PE
- asthma
- infectious
- metabolic
Case 2 - Now what ?!
DDx ?
Immediate treatment ?
Investigations ?
- BiPAP
- IV access + fluid bolus
- empiric ABx
- heparin...
Case 2 - Now what ?!
DDx ?
Immediate treatment ?
Investigations ?
- CXR
- ECG
- Blood gas
Case 2 - some results...
Case 2 - some results...
Case 2 - some results...
A-gradient of ~580 !!
Case 2 - the conclusion
septal
bowing
RV
LV
RV >> LV
Case 2 - the conclusion
Precipitous desaturation when BiPAP disconnected
Decision to intubate
Diagnostic uncertainty
Marke...
CTPA report
Case 2 - the conclusion
CT → ICU → IR → IVC filter → ICU
Thrombolysed
100mg Alteplase
Heparin + warfarin
DC home on day 5
Discharge ECHO
Conclusion
Consider PE as a DDx for undifferentiated shock
Utilise ECHO [RUSH, ?PE, SOB...]
Consider RV dilatation or hypo...
< 75
References.
Goldhaber SZ, Visani L, De Rosa M, et al. for ICOPER. Acute pulmonary embolism; clinical outcomes in the Inter...
Social Media
LITFL - Thrombolysis for submassive pulmonary
embolus.
RAGE Podcast - Session two
EMNerd.com - The Adventure ...
any questions ??
2 in 2 days
2 in 2 days
2 in 2 days
2 in 2 days
2 in 2 days
2 in 2 days
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2 in 2 days
2 in 2 days
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2 in 2 days

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These are the slides from a presentation I recently gave at work. It demonstrates two fascinating cases [one massive & one submassive PE] & lends itself to a review of the literature assessing the roles and evidence behind thrombolysis for pulmonary embolism.

Covered includes the MAPPET-3, MOPPET & PEITHO trials.

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Transcript of "2 in 2 days"

  1. 1. two in two days Christopher Partyka 8th April 2014
  2. 2. Case 1. 74 yo male - collapse. Batphone. P 120, SBP 70, SaO2 94% (NRB) Transient RBBB on ECG
  3. 3. Case 1. A. patent. B. RR 32. mild ↑WOB. Bilateral AE. SaO2 92% [15L NRB] C. P 124. BP 72/50. cold & clammy. mottled. D. Agitated. GCS 13 [E3, V4, M6]. Nil focal deficit. E. Afebrile. BSL 6.4.
  4. 4. Case 1 - Now what ?! DDx ? Immediate treatment ? Investigations ?
  5. 5. Case 1 - Now what ?! DDx ? Immediate treatment ? Investigations ? - Myocardial infarction - AAA - Ao dissection - ?Haemorrhage - ?Septic - ??others...
  6. 6. Case 1 - Now what ?! DDx ? Immediate treatment ? Investigations ? - High flow O2 - IV access + fluid bolus - then what..?
  7. 7. Case 1 - Now what ?! DDx ? Immediate treatment ? Investigations ? - CXR - ECG - Blood gas
  8. 8. Case 1 - some results...
  9. 9. Case 1 - some results...
  10. 10. Case 1 - some results...
  11. 11. Case 1 - Now what ?!
  12. 12. RUSH protocol... FAST - negative No AAA IVC - full !! ECHO...
  13. 13. Case 1. RV LV
  14. 14. Case 1. Clot in transit
  15. 15. Case 1 - the conclusion PEA arrest Provisional Dx - massive PE Thrombolysis given under CPR
  16. 16. Case 1 - the conclusion Prolonged resuscitation CPR on and off for 3 hours. ICU admission at 3.5 hours. Adrenaline infusion ++ PEA again at 7 hours. Could not be resuscitated → RIP.
  17. 17. Thrombolytics for PE Can we alter outcomes ?!?
  18. 18. Scary statistic Two thirds of patients who die of PE do so within an hour of hospital presentation
  19. 19. more scary statistics... ~10% of non-traumatic sudden deaths 1 in 2 arrive in PEA/asystole MASSIVE ~5% of PEs 58% 90 day mortality SUBMASSIVE ~40% of PEs 22% 90 day mortality MINOR ~55% of PEs <1% 90 day mortality
  20. 20. Massive PE Overt right ventricular failure Persistent systemic arterial hypotension SBP < 90mmHg for 15mins or more Shock Pulselessness ~5% of cases High mortality Death within hours...
  21. 21. Submassive PE A population at risk RV dysfunction without hypotension Dilatation or hypokinesis on ECHO Dilatation on CT ↑ Troponin ↑ Pro-BNP Right heart “cripples” Chronic pulmonary HTN Poor functionality upon DC
  22. 22. Submassive PE RV:LV > 0.9 predicts mortality OR 2.53 [95%CI 1.17-5.50] Persistent RV dysfunction at discharge 4x mortality !! 8x recurrent PE 44% have chronic PHT at 1 year Troponin elevation predicts mortality OR 5.90 [95%CI 2.68-12.95] Why we should care !!
  23. 23. Bust some clots ?! Pros: Rapid resolution of symptoms Stabilise cardiorespiratory function Reduce RV damage Improve exercise tolerance Increase probability of survival Avoid vasopressors Avoid intubation We only need a 33% ↓
  24. 24. Bust some clots ?! Cons: Disabling or fatal haemorrhage (incl. ICH) Blood transfusions Unnecessary intervention (incl. surgery) Increased hospital LOS Risk of ICH ~ 2-3% Risk of major bleeding ~ 22%
  25. 25. The evidence...
  26. 26. Thrombolytics for PE What is accepted practice then ?!
  27. 27. Thrombolysis: first line treatment for massive PE [B] may be instituted on clinical grounds alone if cardiac arrest is imminent [B] a 50 mg bolus of alteplase is recommended [C] not used as first line treatment in non-massive PE [B]
  28. 28. Thrombolysis: first line treatment for massive PE [B] may be instituted on clinical grounds alone if cardiac arrest is imminent [B] a 50 mg bolus of alteplase is recommended [C] not used as first line treatment in non-massive PE [B] “major haemorrhage is twice that of heparin”
  29. 29. Thrombolysis: reasonable for massive PE w/ acceptable bleeding risk [B] considered for submassive PE w/ adverse prognosis & low risk of bleeding [C] NOT for low-risk PE [B] or undifferentiated cardiac arrest [B]
  30. 30. Thrombolytics for PE Blind application doesn’t work !!!
  31. 31. ~70% of OHCA result from AMI or PE Thrombolytics during CPR may improve survival DB RCT original article Thrombolysis during Resuscitation for Out-of-Hospital Cardiac Arrest Bernd W. Böttiger, M.D., Hans-Richard Arntz, M.D., Douglas A. Chamberlain, M.D., Erich Bluhmki, Ph.D., Ann Belmans, M.Sc., Thierry Danays, M.D., Pierre A. Carli, M.D., Jennifer A. Adgey, M.D., Christoph Bode, M.D., and Volker Wenzel, M.D., M.Sc., for the TROICA Trial Investigators and the European Resuscitation Council Study Group* From the University of Cologne, Cologne, and the University of Heidelberg, Heidel- berg — both in Germany (B.W.B.); Charité, Benjamin Franklin Medical Center, Berlin (H.-R.A.); the Prehospital Emergency Re- search Unit, School of Medicine, Cardiff University,Cardiff,UnitedKingdom(D.A.C.); Boehringer Ingelheim, Biberach, Germany (E.B.); the Biostatistical Center, Catholic University of Leuven, Leuven, Belgium (A.B.);BoehringerIngelheim,Reims,France (T.D.);Serviced’AideMédicaled’Urgence de Paris, Hôpital Necker–Enfants Mal- ades, Paris (P.A.C.); the Regional Medical Cardiology Centre, Royal Victoria Hospital, Belfast, United Kingdom (J.A.A.); Albert- Ludwig-University, Freiburg, Germany (C.B.); and Innsbruck Medical University, Innsbruck, Austria (V.W.). Address reprint requests to Dr. Böttiger at the Depart- ment of Anesthesiology and Postopera- tive Intensive Care Medicine, University of Cologne, Kerpener Str. 62, Cologne D-50937, Germany, or at bernd.boettiger@ uk-koeln.de. *The investigators in the Thrombolysis in Cardiac Arrest (TROICA) trial are listed in the Appendix. N Engl J Med 2008;359:2651-62. Copyright © 2008 Massachusetts Medical Society. ABSTR ACT BACKGROUND Approximately 70% of persons who have an out-of-hospital cardiac arrest have under- lying acute myocardial infarction or pulmonary embolism. Therefore, thrombolysis during cardiopulmonary resuscitation may improve survival. METHODS In a double-blind, multicenter trial, we randomly assigned adult patients with wit- nessed out-of-hospital cardiac arrest to receive tenecteplase or placebo during cardio- pulmonary resuscitation. Adjunctive heparin or aspirin was not used. The primary end point was 30-day survival; the secondary end points were hospital admission, return of spontaneous circulation, 24-hour survival, survival to hospital discharge, and neurologic outcome. RESULTS After blinded review of data from the first 443 patients, the data and safety moni- toring board recommended discontinuation of enrollment of asystolic patients be- cause of low survival, and the protocol was amended. Subsequently, the trial was terminated prematurely for futility after enrolling a total of 1050 patients. Tenec- teplase was administered to 525 patients and placebo to 525 patients; the two treat- ment groups had similar clinical profiles. We did not detect any significant differ- ences between tenecteplase and placebo in the primary end point of 30-day survival (14.7% vs. 17.0%; P=0.36; relative risk, 0.87; 95% confidence interval, 0.65 to 1.15) or in the secondary end points of hospital admission (53.5% vs. 55.0%, P=0.67), return of spontaneous circulation (55.0% vs. 54.6%, P=0.96), 24-hour survival (30.6% vs. 33.3%, P=0.39), survival to hospital discharge (15.1% vs. 17.5%, P=0.33), or neuro- logic outcome (P=0.69). There were more intracranial hemorrhages in the tenecte- plase group. CONCLUSIONS When tenecteplase was used without adjunctive antithrombotic therapy during ad- vanced life support for out-of-hospital cardiac arrest, we did not detect an improvement in outcome, in comparison with placebo. (ClinicalTrials.gov number, NCT00157261.) NEJM 2008; 359:2651-62 Tenecteplase vs Placebo during cardiac-arrest
  32. 32. original article Thrombolysis during Resuscitation for Out-of-Hospital Cardiac Arrest Bernd W. Böttiger, M.D., Hans-Richard Arntz, M.D., Douglas A. Chamberlain, M.D., Erich Bluhmki, Ph.D., Ann Belmans, M.Sc., Thierry Danays, M.D., Pierre A. Carli, M.D., Jennifer A. Adgey, M.D., Christoph Bode, M.D., and Volker Wenzel, M.D., M.Sc., for the TROICA Trial Investigators and the European Resuscitation Council Study Group* From the University of Cologne, Cologne, and the University of Heidelberg, Heidel- berg — both in Germany (B.W.B.); Charité, Benjamin Franklin Medical Center, Berlin (H.-R.A.); the Prehospital Emergency Re- search Unit, School of Medicine, Cardiff University,Cardiff,UnitedKingdom(D.A.C.); Boehringer Ingelheim, Biberach, Germany (E.B.); the Biostatistical Center, Catholic University of Leuven, Leuven, Belgium (A.B.);BoehringerIngelheim,Reims,France (T.D.);Serviced’AideMédicaled’Urgence de Paris, Hôpital Necker–Enfants Mal- ades, Paris (P.A.C.); the Regional Medical Cardiology Centre, Royal Victoria Hospital, Belfast, United Kingdom (J.A.A.); Albert- Ludwig-University, Freiburg, Germany (C.B.); and Innsbruck Medical University, Innsbruck, Austria (V.W.). Address reprint requests to Dr. Böttiger at the Depart- ment of Anesthesiology and Postopera- tive Intensive Care Medicine, University of Cologne, Kerpener Str. 62, Cologne D-50937, Germany, or at bernd.boettiger@ uk-koeln.de. *The investigators in the Thrombolysis in Cardiac Arrest (TROICA) trial are listed in the Appendix. N Engl J Med 2008;359:2651-62. Copyright © 2008 Massachusetts Medical Society. ABSTR ACT BACKGROUND Approximately 70% of persons who have an out-of-hospital cardiac arrest have under- lying acute myocardial infarction or pulmonary embolism. Therefore, thrombolysis during cardiopulmonary resuscitation may improve survival. METHODS In a double-blind, multicenter trial, we randomly assigned adult patients with wit- nessed out-of-hospital cardiac arrest to receive tenecteplase or placebo during cardio- pulmonary resuscitation. Adjunctive heparin or aspirin was not used. The primary end point was 30-day survival; the secondary end points were hospital admission, return of spontaneous circulation, 24-hour survival, survival to hospital discharge, and neurologic outcome. RESULTS After blinded review of data from the first 443 patients, the data and safety moni- toring board recommended discontinuation of enrollment of asystolic patients be- cause of low survival, and the protocol was amended. Subsequently, the trial was terminated prematurely for futility after enrolling a total of 1050 patients. Tenec- teplase was administered to 525 patients and placebo to 525 patients; the two treat- ment groups had similar clinical profiles. We did not detect any significant differ- ences between tenecteplase and placebo in the primary end point of 30-day survival (14.7% vs. 17.0%; P=0.36; relative risk, 0.87; 95% confidence interval, 0.65 to 1.15) or in the secondary end points of hospital admission (53.5% vs. 55.0%, P=0.67), return of spontaneous circulation (55.0% vs. 54.6%, P=0.96), 24-hour survival (30.6% vs. 33.3%, P=0.39), survival to hospital discharge (15.1% vs. 17.5%, P=0.33), or neuro- logic outcome (P=0.69). There were more intracranial hemorrhages in the tenecte- plase group. CONCLUSIONS When tenecteplase was used without adjunctive antithrombotic therapy during ad- vanced life support for out-of-hospital cardiac arrest, we did not detect an improvement in outcome, in comparison with placebo. (ClinicalTrials.gov number, NCT00157261.) NEJM 2008; 359:2651-62The new engl and jour nal o f medicine Table 4. Outcomes. Outcome Tenecteplase Group (N=525) Placebo Group (N=525) Relative Risk (95% CI) P Value no./total no. (%) Primary end point 30-Day survival 77/525 (14.7) 89/525 (17.0) 0.87 (0.65–1.15) 0.36 Secondary end points Return of spontaneous circulation 283/515 (55.0) 279/511 (54.6) 1.01 (0.90–1.13) 0.96 Hospital admission 281/525 (53.5) 289/525 (55.0) 0.97 (0.87–1.09) 0.67 24-Hr survival 158/517 (30.6) 171/514 (33.3) 0.92 (0.77–1.10) 0.39 Survival to hospital discharge 78/517 (15.1) 90/514 (17.5) 0.86 (0.65 –1.14) 0.33 Neurologic outcome* 0.69 Good cerebral performance 41/86 (47.7) 45/96 (46.9) 1.02 (0.75–1.38) Moderate cerebral disability 13/86 (15.1) 9/96 (9.4) 1.12 (0.88–1.42) Severe cerebral disability 10/86 (11.6) 16/96 (16.7) 1.02 (0.86–1.21) Coma 14/86 (16.3) 18/96 (18.8) 0.99 (0.90–1.08) Brain death 8/86 (9.3) 8/96 (8.3) 1.00 Safety end points Symptomatic intracranial hemorrhage 4/518 (0.8) 0/514 8.93 (0.48–165.45) 0.13 Any intracranial hemorrhage 14/518 (2.7) 2/514 (0.4) 6.95 (1.59–30.41) 0.006 Major nonintracranial hemorrhage 40/517 (7.7) 33/514 (6.4) 1.21 (0.77–1.88) 0.48 Ischemic stroke 4/518 (0.8) 3/514 (0.6) 1.32 (0.30–5.88) 1.00 * Neurologic outcome is measured by cerebral performance category; categories range from 1 to 5, with 1 indicating good cerebral perfor- No survival benefit No increase in ROSC Increased rates of ICH in those who survived
  33. 33. MAPPET-3 Trial ALTEPLASE IN PULMONARY EMBOLISM HEPARIN PLUS ALTEPLASE COMPARED WITH HEPARIN ALONE IN PATIENTS WITH SUBMASSIVE PULMONARY EMBOLISM STAVROS KONSTANTINIDES, M.D., ANNETTE GEIBEL, M.D., GERHARD HEUSEL, PH.D., FRITZ HEINRICH, M.D., AND WOLFGANG KASPER, M.D., FOR THE MANAGEMENT STRATEGIES AND PROGNOSIS OF PULMONARY EMBOLISM-3 TRIAL INVESTIGATORS* ABSTRACT Background The use of thrombolytic agents in the treatment of hemodynamically stable patients with acute submassive pulmonary embolism remains con- troversial. Methods We conducted a study of patients with acute pulmonary embolism and pulmonary hyper- tension or right ventricular dysfunction but without arterial hypotension or shock. The patients were ran- domly assigned in double-blind fashion to receive heparin plus 100 mg of alteplase or heparin plus pla- cebo over a period of two hours. The primary end point was in-hospital death or clinical deterioration requiring an escalation of treatment, which was de- fined as catecholamine infusion, secondary throm- bolysis, endotracheal intubation, cardiopulmonary re- suscitation, or emergency surgical embolectomy or thrombus fragmentation by catheter. Results Of 256 patients enrolled, 118 were random- ly assigned to receive heparin plus alteplase and 138 to receive heparin plus placebo. The incidence of the primary end point was significantly higher in the hep- HROMBOLYSIS is an established treatment for patients with acute massive pulmonary embolism and hemodynamic instability or cardiogenic shock.1 In contrast, the effect of thrombolytic agents on the outcome of hemodynam- ically stable patients who have submassive pulmonary embolism has been debated for decades.2,3 Several fac- tors have contributed to the ongoing controversy: the lack of a large, randomized study assessing clinical end points,4 the risk of serious hemorrhage associated with thrombolytic therapy,1,5-7 and the fact that patients’ hemodynamic status may gradually improve with hep- arin therapy alone.8,9 The clinical data currently available underscore the need to identify patients in whom thrombolysis may have a favorable risk–benefit ratio. Studies based on two large, multicenter registries reported that patients with right ventricular dysfunction due to pulmonary embolism had increased rates of in-hospital death, even in the absence of arterial hypotension or shock.5,10 These findings are in accord with the results of early T NEJM 2002;347:1143-50
  34. 34. MAPPET-3 Trial DB RCT Acute PE with RV strain - ECG - ECHO - CT Heparin plus 100mg alteplase vs Heparin plus placebo
  35. 35. MAPPET-3 Trial DB RCT Acute PE with RV strain - ECG - ECHO - CT No difference shown for in-hospital mortality (3.4% vs 2.2%; p=0.71) More cases of clinical deterioration requiring therapy escalation in heparin-alone group (24.6% vs 10.2%; p=0.004) Only 31% had ECHO confirmation of RV strain !!
  36. 36. MAPPET-3 TrialThe New England Journal of Medicine *The numbers shown are based on calculations for the intention-to-treat population. †P values were calculated with the use of Fisher’s exact test (two-sided). TABLE 2. IN-HOSPITAL CLINICAL EVENTS.* EVENT HEPARIN PLUS ALTEPLASE (N=118) HEPARIN PLUS PLACEBO (N=138) P VALUE† no. (%) Primary end point 13 (11.0) 34 (24.6) 0.006 Death from all causes 4 (3.4) 3 (2.2) 0.71 Escalation of treatment 12 (10.2) 34 (24.6) 0.004 Catecholamine infusion (for persistent hypotension or shock) 3 (2.5) 8 (5.8) 0.33 Secondary thrombolysis 9 (7.6) 32 (23.2) 0.001 Endotracheal intubation 3 (2.5) 3 (2.2) 0.85 Cardiopulmonary resuscitation 0 1 (0.7) 1.0 Embolectomy or thrombus fragmentation 0 1 (0.7) 1.0 Secondary end points Recurrent pulmonary embolism‡ 4 (3.4) 4 (2.9) 0.89 Major bleeding§ 1 (0.8) 5 (3.6) 0.29 Fatal bleeding 0 1 (0.7) 1.0 Hemorrhagic stroke¶ 0 0 — Ischemic stroke¶ 0 1 (0.7) 1.0
  37. 37. The “MOPPET” trial Moderate Pulmonary Embolism Treated With Thrombolysis (from the “MOPETT” Trial) Mohsen Sharifi, MDa,b, *, Curt Bay, PhDb , Laura Skrocki, DOa , Farnoosh Rahimi, MDa , and Mahshid Mehdipour, DMDa,b , “MOPETT” Investigators The role of low-dose thrombolysis in the reduction of pulmonary artery pressure in moderate pulmonary embolism (PE) has not been investigated. Because the lungs are very sensitive to thrombolysis, we postulated that effective and safe thrombolysis might be achieved by a lower dose of tissue plasminogen activator. The purpose of the present study was to evaluate the role of this “safe dose” thrombolysis in the reduction of pulmonary artery pressure in moderate PE. During a 22-month period, 121 patients with moderate PE were randomized to receive a “safe dose” of tissue plasminogen activator plus anti- coagulation (thrombolysis group [TG], n [ 61 patients) or anticoagulation alone (control group [CG], n [ 60). The primary end points consisted of pulmonary hypertension and the composite end point of pulmonary hypertension and recurrent PE at 28 months. Pulmonary hypertension and the composite end point developed in 9 of 58 patients (16%) in the TG and 32 of 56 patients (57%) in the CG (p <0.001) and 9 of 58 patients (16%) in the TG and 35 of 56 patients (63%) in the CG (p <0.001), respectively. The secondary end points were total mortality, the duration of hospital stay, bleeding at the index hospitalization, recurrent PE, and the combination of mortality and recurrent PE. The duration of hospitalization was 2.2 – 0.5 days in the TG and 4.9 – 0.8 days in the CG (p <0.001). The combination of death plus recurrent PE was 1 (1.6%) in TG and 6 (10%) in the CG (p [ 0.0489). No bleeding occurred in any group, and despite a positive trend in favor of a “safe dose” thrombolysis, no significant difference was noted in the rate of individual outcomes of death and recurrent PE when assessed independently. In conclusion, the results from the present prospective randomized trial suggests that “safe dose” thrombolysis is safe and effective in the treat- ment of moderate PE, with a significant immediate reduction in the pulmonary artery pressure that was maintained at 28 months. Ó 2013 Elsevier Inc. All rights reserved. (Am AM J Cardiol 2013;111:273e277 Half dose t-PA for submassive (moderate) PE
  38. 38. The “MOPPET” trial Single-centre, randomised “half dose” t-PA vs control [no placebo] Unwell patients w/ moderate PE Anatomical defn of ‘submassive’ ECHO not required prior to enrolment
  39. 39. The “MOPPET” trial Theory: PE is exquisitely sensitive to 'lytics the lungs see 100% of the circulation Brain ~ 15% Myocardium ~5% lower dose → lower complications
  40. 40. The “MOPPET” trial Primary endpoints: Pulmonary HTN Recurrent PE
  41. 41. The “MOPPET” trial Primary endpoints: Pulmonary HTN Recurrent PE Pulmonary HTN at 28 months: 16% vs 57%, p<0.001
  42. 42. The “MOPPET” trial Secondary endpoints: Total mortality Hospital LOS Bleeding Recurrent PE
  43. 43. The “MOPPET” trial Secondary endpoints: Total mortality Hospital LOS Bleeding Recurrent PE Benefits: ↓ recurrent PE - 0% vs 5%, p=0.08 ↓ hospital LOS - 2.2 vs 4.9 days, p<0.001 Indifferences: Total mortality Bleeding - none in either group
  44. 44. PEITHO trial American Heart Journal, 163(1), 33–38.e1.
  45. 45. PEITHO trial Prospective, international, MC, DB, RCT Tenecteplase vs placebo + standard anticoagulation 1006 normotensive patients w/ confirmed PE + abnormal RV on ECHO or CT and elevated troponin
  46. 46. PEITHO trial Table I. Inclusion and exclusion criteria Inclusion criteria Exclusion criteria (1) Age 18 y (1) Hemodynamic collapse at presentation⁎⁎ (2) Acute PE (first symptoms 15 d or less before randomization) confirmed by lung scan, or a positive computed tomographic pulmonary angiogram, or a positive selective pulmonary angiogram (2) Known significant bleeding risk (3) RV dysfunction confirmed by echocardiography or spiral computed tomography of the chest (3) Administration of a thrombolytic agent in the previous 4 d Echocardiography (≥1 criterion) (4) Vena cava filter insertion or pulmonary thrombectomy in the previous 4 d • RV end-diastolic diameter N30 mm (parasternal long axis or short axis) (5) Uncontrolled hypertension (systolic BP N180 mm Hg and/or diastolic BP N110 mm Hg at randomization) • Right/left ventricular end-diastolic diameter N0.9 (apical or subcostal 4-chamber view) (6) Treatment with an investigational drug under another study protocol in the previous 7 d or longer, according to local requirements • Hypokinesis of RV-free wall (any view) (7) Previous enrollment in this study • Tricuspid regurgitant jet velocity N2.6 m/s (8) Known hypersensitivity to tenecteplase, alteplase, UFH, or any of the excipients Computed tomography (9) Pregnancy, lactation, or parturition within the previous 30 d; women of childbearing age must have a negative pregnancy test or use a medically accepted method of birth control• Right/left short-axis diameter ratio N0.9 (transverse plane) (10) Known coagulation disorder (including use of vitamin K antagonists and platelet count b100,000/mm3 ) (4) Myocardial injury confirmed by a positive troponin I or T test result⁎ (11) Any other condition that the investigator feels would place the patient at increased risk if the investigational therapy were administered BP denotes blood pressure. ⁎ Cutoff levels for defining elevating troponin I or T levels are defined by the Department of Clinical Chemistry at each participating site. ⁎⁎ At least 1 of the following: (i) the need for cardiopulmonary resuscitation; (ii) systolic blood pressure b90 mm Hg for at least 15 minutes, or a drop of systolic blood pressure by at least 40 mm Hg for at least 15 minutes, with signs of end-organ hypoperfusion (cold extremities, urinary output b30 mL/h, or mental confusion); and (iii) the need for catecholamines (except for dopamine at a rate of ≤5 μg kg−1 min−1 ) to maintain adequate organ perfusion and a systolic blood pressure of N90 mm Hg. The Steering Committee 35 American Heart Journal Volume 163, Number 1
  47. 47. PEITHO trial hypotheses are as follows: H0: 7-day-death-hemcoltenect = 7-day-death-hemcolplacebo vs H1: 7day-death-hemcoltenect ≠ 7day-death-hemcol (where hemcol stands for he- Figure 1 Confirmed acute E comes acute symptomatic PE Absence of TNK § DOUBLE omes,SAE daryOutc hemodynamic collapse* UFH infusion ‡ ow-up <2 h UFH, LMWH or Fondaparinux R DOUBLE BLIND VKA nrayOuto me,Secon Confirmed RV dysfunction + myocardial injury** -termFollo Placebo § Seco ryOutcom UFH infusion ‡ UFH, LMWH or Fondaparinux Long- Prima VKAUFH bolus i.v. † Day 2 Day 7 Day 30 Day 180 Flow diagram of the Pulmonary Embolism International Thrombolysis trial. RV indicates right ventricular (dysfunction); TNK, tenecteplase; VKA, vitamin K antagonists. *As defined in Table I; **criteria defined in Table I; † at a dosage of 80 IU/kg of body weight; ‡ initial infusion rate, 18 IU/kg/h; § the dosing regimen for tenecteplase (or placebo) is shown in Table II. Table II. Tenecteplase dosing regimen Weight (kg) Dose (mg) Dose (Units) Volume (mL) 36 The Steering Committee American Heart Journal January 2012
  48. 48. PEITHO trial Primary outcome Death or Haemodynamic collapse = CPR SBP < 90 for ≥15mins End-organ hypo perfusion Vasopressor requirement within 7 days...
  49. 49. PEITHO trial Primary outcome Death or Haemodynamic collapse = CPR SBP < 90 for ≥15mins End-organ hypo perfusion Vasopressor requirement Primary Outcome t-PA 2.6% vs Placebo 5.6%, p=0.015 RRR 54% HD collapse t-PA 1.6% vs Placebo 5.0%, p=0.002 esp. hypotension & vasopressor req. No difference in 7-day mortality.
  50. 50. PEITHO trial Safety outcomes Ischaemic or haemorrhagic stroke in 7 days Other major bleeding = Fatal bleeding Blood transfusion req'd Inotropic support req'd Emergent surgical intervention
  51. 51. PEITHO trial Safety outcomes Ischaemic or haemorrhagic stroke in 7 days Other major bleeding = Fatal bleeding Blood transfusion req'd Inotropic support req'd Emergent surgical intervention Increased risk of major & minor bleeding. MAJOR: 6.3% vs 1.5%, p<0.001 MINOR: 32.6% vs 8.6%, p<0.001 Stroke: 2.4% vs 0.2%, p=0.003
  52. 52. PEITHO No difference in 30-day mortality.
  53. 53. Finally; the MOPPET crew return in 2014...
  54. 54. Prospective, observational study. 98 consecutive patients with moderate to severe PE “safe-dose” t-PA + heparin followed by rivaroxaban ECHO followed for pulmonary HTN Address for correspondence: Mohsen Sharifi, MD, Arizona Cardiovascular Consultants and Vein Clinic, 3850 E. Baseline Road, Building 1, Suite 102, Mesa, AZ 85206. seyedmohsensharifi@yahoo.com Clinical Investigations Safe-Dose Thrombolysis Plus Rivaroxaban for Moderate and Severe Pulmonary Embolism: Drip, Drug, and Discharge Mohsen Sharifi, MD; Curt Bay, PhD; Frederic Schwartz, DO; Laura Skrocki, DO Arizona Cardiovascular Consultants and Vein Clinic (Sharifi, Skrocki), Mesa, Arizona; A. T. Still University (Sharifi, Bay, Schwartz), Mesa, Arizona Background: Thrombolysis, though very effective, has not been embraced as routine therapy for symptomatic pulmonary embolism (PE) except in very severe cases. Rivaroxaban recently has been approved for the treatment of venous thromboembolism (VTE). There are no data on the combined use of thrombolysis and rivaroxaban in PE. Hypothesis: ‘‘Safe dose’’ thrombolysis (SDT) plus new oral anticoagulants are expected to become an appealing, safe and effective approach in the treatment of moderate and severe PE in the near future, thereby drastically reducing hospitalization time. Methods: Over a 12-month period, 98 consecutive patients with symptomatic PE were treated by a combination of SDT and rivaroxaban. The SDT was started in parallel with unfractionated heparin and given in 2 hours. Heparin was given for a total of 24 hours and rivaroxaban started at 15 or 20 mg daily 2 hours after termination of heparin infusion. Results: There was no bleeding due to SDT. Recurrent VTE occurred in 3 patients who had been switched to warfarin. No patient on rivaroxaban developed VTE. Two patients died of cancer at a mean follow-up of 12 ± 2 months. The pulmonary artery systolic pressure dropped from 52.8 ± 3.9 mm Hg before to 32 ± 4.4 mm Hg within 36 hours of SDT (P < 0.001). The duration of hospitalization for patients presenting primarily for PE was 1.9 ± 0.2 days. Conclusions: ‘‘Safe dose’’ thrombolysis plus rivaroxaban is highly safe and effective in the treatment of moderate and severe PE, leading to favorable early and intermediate-term outcomes and early discharge. Introduction Over the last few years, new oral anticoagulants have been introduced that can replace vitamin K antagonists in patients with pulmonary embolism (PE).1,2 The trials not been previously reported. This study describes our experience with the combination of SDT and rivaroxaban for the treatment of moderate and severe PE. Clin. Cardiol. 37(2) 78–82 (2014)
  55. 55. Address for correspondence: Mohsen Sharifi, MD, Arizona Cardiovascular Consultants and Vein Clinic, 3850 E. Baseline Road, Building 1, Suite 102, Mesa, AZ 85206. seyedmohsensharifi@yahoo.com Clinical Investigations Safe-Dose Thrombolysis Plus Rivaroxaban for Moderate and Severe Pulmonary Embolism: Drip, Drug, and Discharge Mohsen Sharifi, MD; Curt Bay, PhD; Frederic Schwartz, DO; Laura Skrocki, DO Arizona Cardiovascular Consultants and Vein Clinic (Sharifi, Skrocki), Mesa, Arizona; A. T. Still University (Sharifi, Bay, Schwartz), Mesa, Arizona Background: Thrombolysis, though very effective, has not been embraced as routine therapy for symptomatic pulmonary embolism (PE) except in very severe cases. Rivaroxaban recently has been approved for the treatment of venous thromboembolism (VTE). There are no data on the combined use of thrombolysis and rivaroxaban in PE. Hypothesis: ‘‘Safe dose’’ thrombolysis (SDT) plus new oral anticoagulants are expected to become an appealing, safe and effective approach in the treatment of moderate and severe PE in the near future, thereby drastically reducing hospitalization time. Methods: Over a 12-month period, 98 consecutive patients with symptomatic PE were treated by a combination of SDT and rivaroxaban. The SDT was started in parallel with unfractionated heparin and given in 2 hours. Heparin was given for a total of 24 hours and rivaroxaban started at 15 or 20 mg daily 2 hours after termination of heparin infusion. Results: There was no bleeding due to SDT. Recurrent VTE occurred in 3 patients who had been switched to warfarin. No patient on rivaroxaban developed VTE. Two patients died of cancer at a mean follow-up of 12 ± 2 months. The pulmonary artery systolic pressure dropped from 52.8 ± 3.9 mm Hg before to 32 ± 4.4 mm Hg within 36 hours of SDT (P < 0.001). The duration of hospitalization for patients presenting primarily for PE was 1.9 ± 0.2 days. Conclusions: ‘‘Safe dose’’ thrombolysis plus rivaroxaban is highly safe and effective in the treatment of moderate and severe PE, leading to favorable early and intermediate-term outcomes and early discharge. Introduction Over the last few years, new oral anticoagulants have been introduced that can replace vitamin K antagonists in patients with pulmonary embolism (PE).1,2 The trials not been previously reported. This study describes our experience with the combination of SDT and rivaroxaban for the treatment of moderate and severe PE. Clin. Cardiol. 37(2) 78–82 (2014) Patients, N = 98 47 (48) 56 ± 10 81 ± 11 28 ± 3 54 (55) 34 (35) 32 (33) 12 (12) 5 (5) 5 (5)
  56. 56. Address for correspondence: Mohsen Sharifi, MD, Arizona Cardiovascular Consultants and Vein Clinic, 3850 E. Baseline Road, Building 1, Suite 102, Mesa, AZ 85206. seyedmohsensharifi@yahoo.com Clinical Investigations Safe-Dose Thrombolysis Plus Rivaroxaban for Moderate and Severe Pulmonary Embolism: Drip, Drug, and Discharge Mohsen Sharifi, MD; Curt Bay, PhD; Frederic Schwartz, DO; Laura Skrocki, DO Arizona Cardiovascular Consultants and Vein Clinic (Sharifi, Skrocki), Mesa, Arizona; A. T. Still University (Sharifi, Bay, Schwartz), Mesa, Arizona Background: Thrombolysis, though very effective, has not been embraced as routine therapy for symptomatic pulmonary embolism (PE) except in very severe cases. Rivaroxaban recently has been approved for the treatment of venous thromboembolism (VTE). There are no data on the combined use of thrombolysis and rivaroxaban in PE. Hypothesis: ‘‘Safe dose’’ thrombolysis (SDT) plus new oral anticoagulants are expected to become an appealing, safe and effective approach in the treatment of moderate and severe PE in the near future, thereby drastically reducing hospitalization time. Methods: Over a 12-month period, 98 consecutive patients with symptomatic PE were treated by a combination of SDT and rivaroxaban. The SDT was started in parallel with unfractionated heparin and given in 2 hours. Heparin was given for a total of 24 hours and rivaroxaban started at 15 or 20 mg daily 2 hours after termination of heparin infusion. Results: There was no bleeding due to SDT. Recurrent VTE occurred in 3 patients who had been switched to warfarin. No patient on rivaroxaban developed VTE. Two patients died of cancer at a mean follow-up of 12 ± 2 months. The pulmonary artery systolic pressure dropped from 52.8 ± 3.9 mm Hg before to 32 ± 4.4 mm Hg within 36 hours of SDT (P < 0.001). The duration of hospitalization for patients presenting primarily for PE was 1.9 ± 0.2 days. Conclusions: ‘‘Safe dose’’ thrombolysis plus rivaroxaban is highly safe and effective in the treatment of moderate and severe PE, leading to favorable early and intermediate-term outcomes and early discharge. Introduction Over the last few years, new oral anticoagulants have been introduced that can replace vitamin K antagonists in patients with pulmonary embolism (PE).1,2 The trials not been previously reported. This study describes our experience with the combination of SDT and rivaroxaban for the treatment of moderate and severe PE. Clin. Cardiol. 37(2) 78–82 (2014) No significant major or minor bleeding 1x psoas haematoma 1x gross haematuria 3 recurrent VTE [on warfarin] 2 had cancer Hospital LOS 1.9 ± 0.2 days
  57. 57. now we are enlightened... ... back to our tales !!
  58. 58. 24 hours later... 47 yo female - “life-threatening asthma” Batphone. RR 30, ‘no air entry’, SaO2 92% (NRB) P 120, SBP 120 Adrenaline 500mcg IM x2, cont salbutamol
  59. 59. Case 2. A. patent. no stridor. B. RR 44. ↑WOB++. Good AE - no wheeze. SaO2 92% [15L NRB] C. P 124. BP 118/70. warm peripheries. D. GCS 15. Nil focal. E. Afebrile. BSL 8.4. and....
  60. 60. Case 2 - Now what ?! DDx ? Immediate treatment ? Investigations ?
  61. 61. Case 2 - Now what ?! DDx ? Immediate treatment ? Investigations ? - PE - asthma - infectious - metabolic
  62. 62. Case 2 - Now what ?! DDx ? Immediate treatment ? Investigations ? - BiPAP - IV access + fluid bolus - empiric ABx - heparin bolus + infusion
  63. 63. Case 2 - Now what ?! DDx ? Immediate treatment ? Investigations ? - CXR - ECG - Blood gas
  64. 64. Case 2 - some results...
  65. 65. Case 2 - some results...
  66. 66. Case 2 - some results... A-gradient of ~580 !!
  67. 67. Case 2 - the conclusion septal bowing RV LV RV >> LV
  68. 68. Case 2 - the conclusion Precipitous desaturation when BiPAP disconnected Decision to intubate Diagnostic uncertainty Marked oxygen requirement CTPA....
  69. 69. CTPA report
  70. 70. Case 2 - the conclusion CT → ICU → IR → IVC filter → ICU Thrombolysed 100mg Alteplase Heparin + warfarin DC home on day 5
  71. 71. Discharge ECHO
  72. 72. Conclusion Consider PE as a DDx for undifferentiated shock Utilise ECHO [RUSH, ?PE, SOB...] Consider RV dilatation or hypokinesis Thrombolysis for PE ? Do we have something to gain ? Analyse for contraindications / exclusions Other options... Interventional radiology for example.
  73. 73. < 75
  74. 74. References. Goldhaber SZ, Visani L, De Rosa M, et al. for ICOPER. Acute pulmonary embolism; clinical outcomes in the International Cooperative Pulmonary Embolism Registry. Lancet 1999;353:1386-1389 Grifoni, S., Vanni, S., Magazzini, S., Olivotto, I., Conti, A., Zanobetti, M., et al. (2006). Association of persistent right ventricular dysfunction at hospital discharge after acute pulmonary embolism with recurrent thromboembolic events. Archives of internal medicine, 166(19), 2151–2156. doi:10.1001/archinte.166.19.2151 Kline, J. A. (2009). Prospective Evaluation of Right Ventricular Function and Functional Status 6 Months After Acute Submassive Pulmonary Embolism. Chest, 136(5), 1202. doi:10.1378/chest.08-2988 Frémont, B. (2008). Prognostic Value of Echocardiographic Right/Left Ventricular End-Diastolic Diameter Ratio in Patients With Acute Pulmonary Embolism *. Chest, 133(2), 358. doi:10.1378/chest.07-1231 Böttiger, B. W., et al. (2008). Thrombolysis during resuscitation for out-of-hospital cardiac arrest. The New England journal of medicine, 359(25), 2651–2662. British Thoracic Society Standards of Care Committee Pulmonary Embolism Guideline Development Group. (2003, June). British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax. Jaff, M. R., Mcmurtry, M. S., Archer, S. L., Cushman, M., Goldenberg, N., Goldhaber, S. Z., et al. (2011). Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension: A Scientific Statement From the American Heart Association. Circulation, 123(16), 1788–1830. doi:10.1161/CIR.0b013e318214914f Konstantinides, S., et al. Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators. (2002). Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. The New England journal of medicine, 347(15), 1143–1150. MD, M. S., PhD, C. B., DO, L. S., MD, F. R., DMD, M. M., & Investigators, M. (2013). Moderate Pulmonary Embolism Treated With Thrombolysis (from the ``MOPETT“” Trial). The American Journal of Cardiology, 111(2), 273–277. Steering Committee. (2012). Single-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury: rationale and design of the Pulmonary Embolism Thrombolysis (PEITHO) trial. American Heart Journal, 163(1), 33–38.e1. Sharifi, M., Bay, C., Schwartz, F., & Skrocki, L. (2014). Safe-dose thrombolysis plus rivaroxaban for moderate and severe pulmonary embolism: drip, drug, and discharge. Clinical cardiology, 37(2), 78–82. doi:10.1002/clc.22216
  75. 75. Social Media LITFL - Thrombolysis for submassive pulmonary embolus. RAGE Podcast - Session two EMNerd.com - The Adventure of the Greek Interpreter EMCrit.org - Podcast #51 + MOPPET “wee”
  76. 76. any questions ??
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