Pulmonary Embolism. current concepts. Dr Nick Taylor Visiting Emergency Specialist Teaching Hospital Karapitiya

Transcription

1 Pulmonary Embolism current concepts Dr Nick Taylor Visiting Emergency Specialist Teaching Hospital Karapitiya Senior Specialist and Director ED Training Clinical Lecturer, Australian National University Canberra Hospital, Australia

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4 Pulmonary Embolism: Outline The Problem: Scope The Spectrum: Presentation Investigation: Evaluating the options Pre-test Probability: Improving decisions Risk Stratification: Who to treat Treatment: Acute and long term Case discussions: Bringing it all together

5 Pulmonary Embolism The problem

6 PE: The problem Annual incidence 0.7-1/1000 per year 1/12 eventually die from PE after diagnosis 10% die in the first hour after diagnosis

7 PE: The problem <14% inpatient deaths are from PE Up to 80% deaths from PE are diagnosed at autopsy only Treatment reduces all cause mortality from 15% to <1%

8 PE: The Diagnostic Challenge Difficult clinical diagnosis Experienced ED Physicians are no exception (under and over call!) Radiology tests are not sufficient alone Clinical algorithms are a major improvement on a physician s gut

9 Pulmonary Embolism The Spectrum

10 PE: The Spectrum Risk factors General Medical Age, Immobilization, Pregnancy, Major surgery in last 4 weeks, Long haul plane/car trips Malignancy, previous DVT, sepsis, nephrotic syndrome, ulcerative colitis, CCF, AMI, CVA, Klinefelters Haematologic AT III deficiency, Protein C and S deficiency, Factor V Leiden, Thrombocytosis, Polycythaemia rubra vera, Inherited disorders of coagulation, fibrinolysis, Dysfibrinogenaemias etc. Strong family history of thrombophilia. Connective Tissue Trauma Drugs SLE and lupus anticoagulant, Bechet syndrome, homocysteinuria Multi trauma, CNS/cord injury, Burns, Limb fractures OCP, Oestrogens, Heparin induced thrombocytopaenia, IV drug abuse

11 PE: The Spectrum The classic triad of chest pain, SOB and haemoptysis is found in < 20%. Worryingly, a large percentage of patients are asymptomatic initially

12 PE: The Spectrum Symptoms Chest or back pain (often pleuritic) Upper abdominal pain SOB New wheeze New arrhythmia Haemoptysis Chest wall tenderness Syncope New symptom involving chest that is unexplainable

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14 PE: Signs Massive PE is associated with: SOB (96%), Crackles (56%), Loud second heart sound (53%), Tachycardia (44%), Fever (43%), Sweating (33%), S3 or S4 (33%). Signs of R heart strain on ECG include S1,QIII, T III, RBBB, R axis deviation and R posterior fasicular block but are uncommonly present in non-massive PE.

15 PE: Signs Signs of DVT are very important. Other signs include: pleural rub, hypotension, spontaneous onset of chest wall tenderness

16 A word on DVT Most proximal DVTs have associated PEs Signs and Symptoms Unilateral oedema is the most specific sign Leg pain occurs in 50% but is non specific. Homans sign is not sensitive for DVT. Tenderness occurs in 75% of patients. Warmth and redness can be present but are non specific. Superficial non varicose veins may indicate the presence of venous hypertension.

17 Pulmonary Embolism Pre Test Probability

18 PE: Pre test Probability The calculation of a pre test probabilty to combine with investigations has been repeatedly proven to improve diagnostic accuracy for PE

19 PERC Validated : metanalysis Emerg Med J Sep;30(9): doi: /emermed Epub 2012 Oct 4. Pulmonary embolism rule-out criteria (PERC) in pulmonary embolism--revisited: a systematic review and meta-analysis.singh B1, Mommer SK, Erwin PJ, Mascarenhas SS, Parsaik AK. Because of the high sensitivity and low negative likelihood ratio, PERC rule can be used confidently in clinically low probability population settings. Need low Risk group (<7-15%)

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21 PE: Pre test Probability Wells score is probably the best pre-test scoring tool A Wells score 2 has an incidence of PE of about 3%. (40% of patients) Wells score of 3-6 has an incidence of PE up to 20%. ( 53% of patients) Wells score > 6 carries a PE incidence of 35-66%. (7% of patients)

22 PE: Pre test Probability Well s score

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26 PE: Further decisions High risk patients for PE may need multiple imaging modalities for safe exclusion The combination of negative CTPA and bilateral lower limb USS confers a risk of PE of < 1.2 % Low risk patients with a negative XDP can have PE safely excluded (risk %)

27 Pulmonary Embolism Investigation

28 PE: Investigation Pathology: D-dimer ABG Radiology CXR USS V/Q scan Angiography CTPA Echo

29 PE: Investigation ABG: po2 is so non specific that it has a zero or even negative predictive value

30 PE: Investigation XDP: High false positive rate Low specificity but high sensitivity Pre test probability of <5-7% for an XDP result to be applied. Rule out test post stratification Remains elevated in DVT for about 7 days.

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32 XDP Normal ranges for elderly have been proposed and now validated XDP at usual values only excludes 5% at ages>80

33 ECG ECG is neither sensitive nor specific. A normal ECG can be seen in 30% of patients with PE S1Q3T3 occurs in only 20% of patients and has a sensitivity and specificity of 54% and 62%

34 ECG The most common ECG change is T-wave inversion in the precordial leads, found in 68% of patients with PE. These T-wave inversions may mimic an ischemic event, which is seen in 11% of patients without prior history of cardiopulmonary disease Sinus tachycardia is the most frequent rhythm seen in patients with PE, occurring in 36%. Other ECG findings include electrocardiographic manifestations of acute cor pulmonale: right bundle branch block, P-wave pulmonale, right axis deviation, and new-onset atrial fibrillation.

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37 PE Investigation: CXR PIOPED : 12% of 400 CXR in PE were normal Cardiomegaly most common (29%) Pleural effusion, raised hemidiaphragm, prominent PAs, consolidation Focal subpleural density (Hampton s hump) and regional oligaemia (Westermark s). Poor sens/spec

38 CXR: PA dilation and vessel cutoff

39 CXR : Hamptons Hump

40 Westermark s sign

41 PE Investigation: Echo Useful in unstable patient but of limited use in standard work up Specific but not very sensitive - size of PE impt Ann Emerg Med Jan;63(1): doi: /j.annemergmed Epub 2013 Sep 27.Right ventricular dilatation on bedside echocardiography performed by emergency physicians aids in the diagnosis of pulmonary embolism.dresden S1, Mitchell P2, Rahimi L2, Leo M2, Rubin-Smith J2, Bibi S2, White L3, Langlois B2, Sullivan A4, Carmody K

42 RV dysfunction on echo RV wall hypokinesis Moderate or severe McConnell s sign (not as good as once thought RV mid wall hypokinesis, apex preserved) RV dilatation End-diastolic diameter >30 mm in parastemal view RV larger than LV in sobcostal or apical view Increased tricuspid velocity >26 m/sec Paradoxical RV septal systolic motion Pulmonary artery hypertension Pulmonary artery systolic pressure >30 mmhg Dilated IVC with lack of respiratory collapse

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46 PE Investigation: Lower Limb USS Sensitivity of duplex ultrasonography for proximal vein DVT is 97% (95% confidence interval [CI] = 96-98%) but as low as 73% for calf vein DVT (95% CI = 54-93%) in some studies. Less sensitive if asymptomatic Only 50% of known PE have Lower limb DVT found

47 DVT in proximal femoral vein RFV RFA

48 PE Investigation: V/Q Scan Normal ( low percentage but excellent NPV for PE) Low probability: If High PE risk or significant cardiopulmonary disease, need further Ix High probability: Treat for PE Same overall radiation but much less to breasts

49 PE Investigation: V/Q Scan SPECT VQ has all but removed the intermediate group Intermediate probability is a problem without it PIOPED: 40 % of scans, PE present in 1/3 of these. Thus further Ix mandated British Thoracic Society: VQ suitable if: Normal CXR No cardiopulmonary disease Readers stick to predefined criteria Further Ix if indeterminate

50 V/Q with multiple segmental perfusion defects

51 PE Investigation: Angiography Recent studies suggest similar sensitivity for subsegmental PE to CTPA May play a role in critically unwell patients where CTPA less accurate

52 PE Investigation: CTPA Current imaging modality of choice Advantages Available Cost effective Alternate Diagnosis in 25-70% (7% of these in ED patients required immediate action) High sensitivity for significant PE Good interobserver reliability (75%, increasing to 94% for chest specialists)

53 PE Investigation: CTPA Disadvantages Requires contrast Experience (to avoid pitfalls is paramount) Misses subsegmental PE False positive rate of 5-10% Subject to technical problems Radiation dose

54 CT as prognosis marker Across all end points, the RV/LV diameter ratio on transverse CT sections has the strongest predictive value and most robust evidence base for adverse clinical outcomes in patients with acute pulmonary embolism vs other CT findings Am J Med Jul;128(7): e2. doi: /j.amjmed Epub 2015 Feb 11.Predictive Value of Computed Tomography in Acute Pulmonary Embolism: Systematic Review and Meta-analysis.Meinel FG1, Nance JW Jr2, Schoepf UJ3, Hoffmann VS4, Thierfelder KM5, Costello P6, Goldhaber SZ7, Bamberg F8.

55 CTPA large PE

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58 PE Investigation: Pregnancy XDP normal range still being evaluated V/Q half dose has less radiation to breasts, thyroid but CTPA more likely to be a one-stop test

59 Pulmonary Embolism Risk Stratification

60 Massive PE Jaff et al, 2011 Acute PE with: Sustained hypotension (SBP <90 mm Hg for at least 15 min or requiring inotropic support, not due to a cause other than PE, such as arrhythmia, hypovolemia, sepsis, or LV dysfunction) Pulselessness or persistent profound bradycardia (heart rate <40 bpm with signs or symptoms of shock)

61 Submassive PE (Jaff et al, 2011) Acute PE without systemic hypotension (SBP 90 mm Hg) but with either RV dysfunction or myocardial necrosis RV dysfunction means the presence of at least 1 of the following: RV dilation (apical 4-chamber RV diameter divided by LV diameter >0.9) or RV systolic dysfunction on echocardiography RV dilation (4-chamber RV diameter divided by LV diameter >0.9) on CT Elevation of BNP (>90 pg/ml) Elevation of N-terminal pro-bnp (>500 pg/ml); or Electrocardiographic changes (new complete or incomplete right bundle-branch block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion) Myocardial necrosis: Elevation of troponin I (>0.4 ng/ml) or Elevation of troponin T (>0.1 ng/ml)

62 Other PE definitions used Intermediate-risk PE used in the PEITHO trial defined as the presence of RV dysfunction or a positive troponin Moderate PE used in the MOPPET trial was defined as the presence of signs and symptoms of PE plus computed tomographic pulmonary angiographic involvement of >70% involvement of thrombus in 2 lobar or left or right main pulmonary arteries or by V/Q with > 2

63 S-PESI The Simplified Pulmonary Embolism Severity Index (spesi) was designed to remove some of the more complicated elements of the PESI The spesi is equally or more accurate than PESI. The spesi is meant to aid in decision making, not replace it. Clinical judgement should always take precedence. Patients determined to be low risk can be considered for outpatient management if clinical and social factors warrant it (>98% accurate for no mortality risk)

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65 POMPE-C Cancer pt prognosis

66 PROTECT PROTECT study : derived and validated a multimarker prognostication model based on spesi, troponin, brain natriuretic peptide and lower limb ultrasound to arrive at a risk of 30-day mortality and of a complicated clinical course. Combination of these much greater predictive value than each on its own. An online calculator based on this study can be found at

67 Pulmonary Embolism Treatment

68 Pulmonary Embolism: Treatment Current guidelines suggest Heparin/LMW Heparin for stable patients Thrombolysis for MASSIVE PE patients No clear guideline for surgery unless definite contraindication to anticoagulation/thrombolysis Area of controversy is submassive

69 WHY Sub Massive Matters: mortality Accounts for ~20% of all PE (numbers vary as we get better at detecting small PEs) 2-5% in-hospital death rate in RCTs of submassive PE Meta-analysis by Cho et al, 2014 : increased short-term mortality for hemodynamically stable patients with RV dysfunction (OR 2.29; 13.7% vs 6.5% without RV dysfunction) (NB. there may be selection bias, as those patients that get an echo are more likely to be sick) Haemodynamic instability may be masked by normal systemic BP, Cho et al, 2014 found that of hemodynamically stable patients with PE, 37% have evidence of RV dysfunction on echo.

70 Why Submassive matters: Morbidity The implication from the low mortality rate is that even if adjunctive fibrinolytic therapy has extremely high efficacy, for example, a 30% RR in mortality, the effect size on mortality due to submassive PE is probably < 1% Secondary adverse outcomes such as persistent RV dysfunction, chronic thromboembolic pulmonary hypertension, and impaired quality of life represent appropriate surrogate goals of treatment Submassive PE accounts for most deaths from PE Leads to longterm morbidity, especially chronic pulmonary hypertension and worse functional outcome In MAPPET-3, most cases of clinical deterioration occurred within the first five days

71 Pulmonary Embolism: THROMBOLYSIS Cochrane 2015 Most of the studies carried a high risk of bias because of high or unclear risk relating to randomisation and blinding. Metaanalysis showed that, compared with heparin alone, or heparin plus placebo, thrombolytics plus heparin can reduce the odds of death (odds ratio (OR) 0.57, 95% confidence interval (CI) 0.37 to 0.87, P = 0.02, low quality evidence) and recurrence of PE (OR 0.51; 95% CI 0.29 to 0.89, P = 0.02, low quality evidence). The effects of death weakened when we excluded four studies at high risk of bias from analysis: OR 0.66, 95% CI 0.42 to 1.06, P = The incidence of major and minor haemorrhagic events was higher in the thrombolytics group than in the control group, and this difference was statistically significant (OR 2.90, 95% CI 1.95 to 4.31, P < 0.001, low quality evidence; OR 3.09, 95% CI 1.58 to 6.06, P = 0.001, very low quality evidence, respectively). Length of hospital stay (mean difference (MD) -1.35, 95% CI to 1.58) and quality of life were similar between the two treatment groups. Stroke was reported in one study and occurred more often in the thrombolytics group than in the control group, although the confidence interval was wide (OR 12.10, 95% CI 1.57 to 93.39). Limited information from a small number of trials indicated that thrombolytics may improve haemodynamic outcomes, perfusion lung scanning, pulmonary angiogram assessment, echocardiograms, pulmonaryhypertension, coagulation parameters, clinical outcomes and survival time to a greater extent than heparin alone. However, the heterogeneity of the studies and small number of participants involved warrant caution when interpreting results. Similarily, fewer patients from the thrombolytics group required escalation of treatment. None of the included studies reported on post-thrombotic syndrome or compared the cost of the different treatments. AUTHORS' CONCLUSIONS: There is low quality evidence that thrombolytics reduce death following acute pulmonary embolism compared with heparin. Furthermore, thrombolytic therapies included in the review were heterogeneous. Thrombolytic therapy may be helpful in reducing the recurrence of pulmonary emboli but may cause more major and minor haemorrhagic events and stroke. More high quality double blind RCTs assessing safety and cost-effectiveness are required.

72 Thrombolysis metaanalyses (thanks to LFTL) Chaterjee et al, 2014 meta-analysis of 16 RCTs comparing thrombolysis with anticoagulant therapy in patients with PE n = trials accounted for 74% of the total patients NNT 59 for all cause mortality benefit, with mortality absolute risk reduction of 1.12% NNH 18 for major bleeding (not significant if <65 years of age) Study heterogeneity due to variations in definitions for haemodynamic instability, major and minor bleeding and RV dysfunction as well as varying doses and types of thrombolysis between studies One study used catheter directed thrombolysis (limited availabiliy), yet even with this study excluded the primary outcome was statistically significant MAPPETT-3 and PEITHO account for one-third of patients for this meta-analysis, and both have flaws

73 Thrombolysis metaanalyses (thanks to LFTL) Nakamura et al, 2014 meta-analysis of 6 RCTs comparing thrombolysis with anticoagulant therapy in patients with PE n = 1510 Actually had a slightly larger absolute risk difference (1.6%) to Chatterjee et al, 2014, but due to a smaller sample size this was not significant Similar to Chaterjee et al a meta-analysis does nothing to replace a well designed RCT.

74 PEITHO 2014 The trial can thus be seen as comparing early tpa given to normotensive patients with intermediate risk pulmonary embolism, vs. observation on heparin, with late tpa reserved for those who deteriorate significantly. Interpreted this way, an early tpa strategy conferred a 0.8% absolute survival advantage at 30 days, or a number needed to treat of 125 to save a life. This came at a cost of causing 2-3 devastating intracranial hemorrhages and 8 serious non-cranial bleeds along the way. (All this at full dose tpa.)

75 PEITHO Major bleeding occurred five times more frequently in the treatment arm Half of the deaths in the placebo arm were "sudden unexplained" or "other" compared with bleeding or stroke complications in the thrombolysis arm Not all placebo patients developing hemodynamic collapse received subsequent thrombolysis; likewise, almost half of those who received open-label thrombolysis had no hemodynamic collapse.

76 PEITHO Meta-analysis shows that patients with PE, including those who were hemodynamically stable with right ventricular dysfunction, thrombolytic therapy was associated with lower rates of all-cause mortality and increased risks of major bleeding and ICH. Second, in a subset of 1331 patients older than 65 years, thrombolysis was associated with a higher rate of major bleeding (12.93% vs 4.10%) Meta-analysis of thrombolytics in PE found NNT=59 for all-cause mortality and NNH=79 for intracranial hemorrhage. Major bleeding was not significantly increased for patients age 65 or younger Odds ratio=1.25

77 MOPPETT 2012 The MOPPETT trial demonstrated that half-dose thrombolytics (50 mg tpa) might safely reduce the rate of recurrent PE and late-onset pulmonary hypertension in intermediate risk pulmonary embolism No increased bleeding Criticised as being open to biases (?not all bleeding reported) Results have been repeated in Safe-Dose Thrombolysis Plus Rivaroxaban for Moderate and Severe Pulmonary Embolism:Drip, Drug, and Discharge Mohsen Sharifi, Clinical Cardiology Volume 37, Issue 2, pages 78 82, February 2014

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80 Pulmonary Embolism: Treatment Recommended duration of anticoagulation for patients with symptomatic DVT or PE Major transient risk factors: 3 months Associated with minor risk factors, no highrisk thrombophilia: 6 months Unprovoked, with or without low-risk thrombophilia: 6 months Unprovoked with high-risk thrombophilia: Indefinite Cancer or persistent risk factor: Indefinite

81 Pulmonary Embolism Case vignettes

82 Case vignettes: Case 1 18 Female SOB 5 days, no chest pain Febrile 38.5, HR 108, SaO2 93% Occas crackle RLL Hirsute, non smoker

83 Case vignettes: Case 1 Normal CXR ECG Q III PO2 69 XDP + CTPA: saddle embolus Echo; RV strain Thrombolysed, good outcome

84 Case vignettes: Case 2 87F SOB 2/52, pulse 109, Sats 92%, Swollen legs PHx IHD CXR : cardiomegaly, pulmonary oedema random XDP + Improved with diuresis Discharged Returned 2 weeks later, Dx multiple PE

85 Case vignettes: Case 3 23 M Presented with URTI symptoms P 110 settled to 85 BP 98/ improved to 125 Sats 91 improved to 98 CXR? Some consolidation ECG had S1, TWI V2

86 Case vignettes: Case 3 Discharged with CAP Rx Returned 2 days later with fatal massive PE

87 Case vignettes: Case 4 51 Male 1/52 cough, pleuritic chest pain, fever P 108, responded to fluids T 39.5 CXR: RLL opacification, WCC 18.6

88 Wife arrived and said he had PHx unprovoked DVT CTPA: massive PE

89 THANKYOU srilankaemergency.wordpress.com