Dimers and Spirals

Dimers and Spirals - Nearly all men can Every gun that is...

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Unformatted text preview: Nearly all men can Every gun that is made, Every gun that is made, withstand adversity; if every warship you want to test a man's launched, every character, give him rocket fired, signifies power. … a theft from those Abraham Lincoln who hunger and are source unknown not fed, from those who are cold and are Never do anything not clothed. against conscience even if the state Dwight D. Eisenhower demands it. April 16, 1953 Albert Einstein quoted in obituary Of Dimers and Spirals Of Dimers and Spirals Joe Lex, MD, FAAEM Temple University Hospital July 29, 2003 The Trouble with PE The Trouble with PE Most common preventable cause of hospital death Most common undiagnosed cause of hospital death Most cases recognized by the true expert – the pathologist (70 – 80% of PE is diagnosed postmortem) The Trouble with PE The Trouble with PE 650,000 cases / year in USA 200,000 deaths Incidence unchanged for 3 decades Frequency in ED: ? ? ? 21% of ED patients with pleuritic chest pain have PE by angiography The Trouble with PE The Trouble with PE What We’ve Tried Before What We’ve Tried Before ABG A­a gradient Chest x­ray EKG FSP / FDP Leg ultrasound Venous plethysmography V/Q scan Chest US TTE TEE MRI MRA Alveolar dead space www.emedhome.com/archives­data.cfm?ID=news032502&Type=news High Probability V/Q Scan High Probability V/Q Scan This means PE, right?? High Probability V/Q Scan High Probability V/Q Scan NOT unless pre­test probability is moderate or high Using angiography as Gold Standard Low pre­test probability + high probability V/Q scan = 45 – 66% false positive Wells P et al. Clin Chest Med. 2003 (Mar);24(1):13 Pulmonary Angiography Pulmonary Angiography “Gold Standard” not used Fear of mortality – Recent study with n=1400 showed 0 deaths, 4 major complications (0.3%) Limited after hours availability Special expertise required Pulmonary Angiography Pulmonary Angiography “Gold Standard” not used Costs a lot of money Side effects: arrhythmias, hypotension, contrast reaction Not 100% sensitive: 1.6% VTE rate at one year follow­up (CI 0.3 – 6.0%) Current Expert Opinion Current Expert Opinion Treat for PE when probability of PE >80% Safely NOT treat for PE when probability ≤ 2% MUST use Bayesian thinking (more on this later) The New Kids The New Kids D­dimer Latex agglutination Standard ELISA Rapid ELISA Erythrocyte agglutination – Turbidimetric – Immunofiltration – – – – Helical (Spiral) Computerized Tomographic Pulmonary Angiography (HCTPA) – – – Single­beam Multiple beam Electron beam D­Dimers D­Dimers Dimer = 2 identical monomers Fibrin breaks into D, E, X, Y (“fibrin split products”) D­dimer = 2 D fragments joined by covalent bond T½ 4 to 6 hours Measurable ~1 week Part of MOCHA­JAVA MOCHA – JAVA MOCHA – JAVA Markers of Cascade and Hemostasis Activation, Juxtaposed Against Vascular Activity Bottom Right­Hand Corner Bottom Right­Hand Corner Coagulation Pathway Lysis Pathway Fibrin Splits Fibrin Splits Some Essential Statistics Some SpPin: with high Specificity, a Positive result tends to rule in SnNout: with high Sensitivity, a Negative result tends to rule out Bayesian Analysis Bayesian Analysis An objective mathematical process in which the estimated pre­test probability of a disease or the strength of a clinician's suspicion of disease is altered by the result of a diagnostic test to create a post­test probability for that particular disease Rt. Rev. Bayes Rt. Rev. Bayes Example Sn=95% Sp=50% PTP=20% Some Essential Statistics Some Pretest Probability (PTP): from clinical model or gestalt Pretest odds = PTP ÷ (1 – PTP) Positive LR = SN ÷ (1 – SP) Negative LR = (1 – SN) ÷ SP LR x pretest odds = post­test odds Post­test odds ÷ (1 + post­test odds) = post­test probability Some Essential Statistics Some Example: SN=95% SP=50% PTP=20% LR+ = 0.95 ÷ (1 – 0.5) = 1.9 LR­ = (1 – 0.95) ÷ 0.5 = 0.1 Pretest odds = 0.2 ÷ (1 – 0.2) = 0.25 = 25% SN=95% SP=50% PTP=20% SN=95% SP=50% PTP=20% LR+=1.9 LR­=0.1 PTO=25% Post test odds with positive test: 0.25 x 1.9 = 0.475 Post­test probability with positive test: 0.475 ÷ 1.475 = 32% Thus we’ve gone from a pretest probability of 20% to a post­test probability of 32% This doesn’t help very much SN=95% SP=50% PTP=20% SN=95% SP=50% PTP=20% LR+=1.9 LR­=0.1 PTO=25% Post test odds with negative test: 0.25 x 0.1 = 0.025 Post test probability with negative test: 0.025 ÷ 1.025 = 0.024 So a negative test in a patient with a 20% pretest probability leaves a 2.4% post­test probability (i.e. ~1 in 40 negatives is false) Or… Or… Pull out your PDA Find MedCalc Scroll down to “Post­test probability (sens/spec)” and you’re in business If you don’t have it but you’ve got your PDA, see me after the talk and I’ll beam it to you In an ideal world… In an ideal world… …we would have PTP for all patients with suspected disease …we would have LRs for each test …low PTP plus a negative test would safely rule out …high PTP plus a positive test would accurately rule in Summary Summary If the probability of disease is low, a negative test is likely to rule out the disease BUT a positive test does not rule it in If the probability of disease is high, a negative test does not rule out the disease BUT a positive test is likely to rule it in Decision Rules Decision Rules Miniati et al (a.k.a. PISA­PED): ‘low’ group, prevalence 10% Am J Respir Crit Care Med 1996;154:1387­1393 Wicki et al (a.k.a. Geneva Rules): lots of rules; hard to memorize; external validation? Arch Intern Med 2001;161:92­97 Decision Rules Decision Rules Wells et al. 3 points if PE most likely 3 points if signs/symptoms DVT 1.5 points for immobilization or surgery, HR >100, prior VTE 1 point for cancer, hemoptysis 0 – 1: low prevalence Clin Chest Med;24(1):March, 2003 Wells Criteria Wells Criteria Advantage No need for ABG Demonstrated reliability and accuracy Tested in ED patients Disadvantage Hard to memorize Must consider alternative diagnosis and decide whether more likely than PE Clin Chest Med;24(1):March, 2003 Wicki vs. Wells Wicki vs. Wells When Wells model is compared to Wicki model using a fixed set of patients, there is a 30% chance that a patient labeled "low probability" by one model would be labeled "moderate probability" by the other model (and vice versa) Chagnon I. Am J Med. 2002; 113(4): 269­75 Kline’s Decision Rules Kline’s Decision Rules Kline et al. If age ≤ 50 years If heart rate ≤ systolic BP Eligible for D­dimer testing Kline et al. Ann Emerg Med 2002;39:144­152 Kline’s Decision Rules Kline’s Decision Rules If age >50 or SBP > HR, ask: 1. Hypoxemia? (SaO2 <95%) 2. Unilateral leg swelling? 3. General anesthesia within 4 weeks? 4. Hemoptysis? If “No” to all, then PTP = 13.3% and negative D­dimer <1% New Five ‘n Dimers New Five ‘n Dimers Latex agglutination ELISA / Rapid ELISA Erythrocyte agglutination Turbidimetric Immunofiltration (“silk screen”) Latex Agglutination Latex Agglutination INACCURATE TEST: DON’T USE IT TO RULE IN OR OUT 15/30 patients with PE proven by angiography had a negative (Accuclot®) study Kutinsky et al: Arch Int Med 1999;159:1569­1572 Kline et al. Ann Emerg Med 2000;35:168­180 ELISA ELISA Enzyme Linked ImmunoSorbent Assay *Meta­analysis n=2,069 Sn=97% Sp=42% LR­ = 0.07 If Pre­test probability= 10% Post­test probability= 0.8% BUT it takes at least 4 hours ELISA by Bayes ELISA by Bayes Sn=97% Sp=42% PTP=10% Screening: use high sensitivity… …but you’ll do a lot more imaging Kline et al. Ann Emerg Med 2000;35:168­180 Rapid ELISA Rapid ELISA Vidas D­Dimer, Instant IA Sn=93% Sp=30% LR­ = 0.23 If pre­test probability = 10% Post­test probability = 2.3% Missing one in 40 Rapid ELISA by Bayes Rapid ELISA by Bayes Sn=93% Sp=30% PTP=10% Erythrocyte Agglutination Erythrocyte Agglutination SimpliRED® (n = 2,297) Sn=95% Sp=35% LR­ = 0.14 If pre­test probability = 10% Post­test probability = 1.4% Miss ~1 in 70 (i.e. <2%) Turbidimetric D­Dimer Turbidimetric D­Dimer Turbiquant, Liatest (n = 654) Sn=98% Sp=43% LR­ = 0.046 If pretest probability = 10% Post­test probability = 0.4% About as good as we can get, but you’ll do a lot of imaging based on false­negative studies Highest Sensitivity Highest Sensitivity Disadvantage: fewer negatives (i.e. more false positives) more imaging If possible, use high specificity combined with clinical suspicion D­dimers NOT specific by nature 1000 Suspected PE Patients 1000 Suspected PE Patients Prevalence of PE = 10% TP FP TN FN Rapid ELISA Sn = 97% Sp = 42% 97 522 ! ! 378 3 !!! BUT… 1000 Suspected PE Patients 1000 Suspected PE Patients Each imaging study also has limited sensitivity, specificity, predictive values, etc. At each step you will miss some patients with true VTE / PE Conclusion on D­Dimers Conclusion on D­Dimers IF your patient has low pretest probability for venous thromboembolic disease, and… IF you use an ELISA, rapid ELISA, turbidimetric, or erythrocyte agglutination D­dimer test… Conclusion on D­Dimers Conclusion on D­Dimers …THEN you can drive your false negative rate to below 2% and safely rule out pulmonary embolism PTP + D­Dimer with small LR­ Conclusion on D­Dimers Conclusion on D­Dimers IF pretest probability is high, then NO D­dimer can safely rule out VTE D­dimer is NOT a “screening test.” It is a diagnostic test to “Rule out” in appropriate patients What About HCTPA? What About HCTPA? Helical (Spiral) Computerized Tomographic Pulmonary Angiography “Slip ring” technology vs. “step and shoot” 3rd, 4th, and 5th generations Single vs. multiple beams HCTPA HCTPA Technique Technique Contrast injection ≥ 3 ml/sec Start at diaphragm, work up 15 – 30 seconds total 1 or 2 breath holds for patient Single beam slices 2 – 3 mm Multi­beam scanners: 1.25 mm Primary Findings Primary Findings MOST IMPORTANT FINDING: intraluminal filling defect (“doughnut” sign) cross­ section Primary Findings Primary Findings MOST IMPORTANT FINDING: intraluminal filling defect (“railroad track” sign) longitudinal Secondary Findings Secondary Findings Normal enhanced lobar artery Secondary Findings Secondary Findings Next inferior slice: same artery completely unopacified Secondary Findings Secondary Findings Eccentric filling defect Secondary Findings Secondary Findings Wedge­shaped opacities representing pulmonary infarcts Secondary Findings Secondary Findings Oligemia: decreased attenuation in periphery, small vessels Accuracy Accuracy “100% sensitive and 100% specific” for large central clots Overall sensitivity ~90% (when compared to angiography) Lower sensitivity for smaller (subsegmental) clots Accuracy Accuracy In several studies, HCTPA done after indeterminate V/Q pre­selected to miss small clots? Up to 2/3 of HCTPA can lead to or support an alternative diagnosis The “Big 4” Questions The “Big 4” Questions 1. What is the frequency of isolated subsegmental clots? 2. How well does HCTPA find them? 3. Are they clinically significant? 4. Can a patient be managed safely based on negative HCTPA alone? Subsegmental Frequency? Subsegmental Frequency? PIOPED showed 6% Other studies: up to 30% ALL PRESELECTED – had earlier normal studies In unselected patients: low Angiography Accuracy? Angiography Accuracy? Pigs: injected w/simulated clot Pulmonary angiography vs. 1­mm HCPTA vs. 3­mm HCTPA No difference in sensitivity No difference in positive predictive value Small Clots Significant? Small Clots Significant? 627 patients with nondiagnostic V/Q and negative leg ultrasound (preselected for small clots) No treatment Long­term follow­up: 6 patients developed significant PE (0.9%) Small Clots Significant? Small Clots Significant? PIOPED: 20 patients with known PE not treated No difference in outcome when grouped according to size of vessel involved Safe If HCTPA Negative? Safe If HCTPA Negative? Small studies using single­beam scanners show NPV ≥ 97% Multi­beam scanners now becoming more common PIOPED II ongoing answer in a few years Safe If HCTPA Negative? Safe If HCTPA Negative? 760 patients 358 low PTP, negative D­dimer STOP! Normal at 3 months 402 had HCTPA & leg US 332 had normal studies, all normal at follow­up Prevalence: 70/760 Swensen SJ et al. Mayo Clin Proc. 2002 Feb;77(2):130­8 www.homestead.com/emguidemaps/files/PE­rationalthinking.html British Thoracic Society British Thoracic Society Clinical Assess and document clinical probability on everyone Consider alternative clinical explanations at presentation and when PE excluded No recommendation as to which decision rule for probability Thorax 2003;58:470­484 D­dimer D­dimer Low probability patient: negative SimpliRED®, Vidas, or MDA reliably excludes PE Intermediate probability patient: negative Vidas or MDA reliably excludes PE No imaging needed in either group Thorax 2003;58:470­484 D­dimer D­dimer Should not be performed on patients with high clinical probability Each hospital should provide information on sensitivity and specificity of its D­dimer test Thorax 2003;58:470­484 Imaging Imaging HCTPA is recommended initial lung imaging modality Patient with good quality HCTPA does not require further investigation or treatment for pulmonary embolism Thorax 2003;58:470­484 Isotope lung scan if… Isotope lung scan 1. 2. 3. Facility is on site Chest x­ray is normal No significant concurrent cardiopulmonary disease 4. Use standardized reporting 5. Non­diagnostic study followed by HCTPA Thorax 2003;58:470­484 Cost Effectiveness Cost Effectiveness No study has yet performed all the relevant comparisons HCTPA replacing V/Q scan at 2/3 the cost D­dimers cost $20 ­ $50 each Algorithms will save money safely Algorithms Work!! Algorithms Work!! Pre­algorithm: 55% of patients with “abnormal” perfusion scans got heparin before final diagnosis With algorithm: 13% Berghout et al. QJM. 2000;93:335­40 Conclusion Conclusion Clinical probability, a high sensitivity D­dimer, and HCTPA decrease the cost of diagnosis, improve safety, and increase convenience for both physicians and patients ...
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