D-dimer and exhaled CO2/O2 to detect segmental pulmonary embolism in

Transcription

1 On line data supplement D-dimer and exhaled CO2/O2 to detect segmental pulmonary embolism in moderate risk patients Jeffrey A. Kline MD, Melanie M. Hogg BS, D. Mark Courtney MD, Chadwick D. Miller MD, MS, Alan E. Jones MD, Howard A Smithline MD, Nicole Klekowski BA.

2 Overview: The test article is a proprietary device (Breathscreen PE TM, Breathquant Medical LLC, NY, NY).Work was performed at Carolinas Medical Center, Charlotte, NC; Northwestern Memorial Hospital, Chicago, IL; Wake Forest University, Baptist Hospital, Winston-Salem, NC; Baystate Hospital, Springfield, MA. The study protocol was registered on clinicaltrials.gov prior to enrollment (NCT ). 2 Table E1. Inclusion criteria Signs or symptoms for PE (at least one required for inclusion) New onset dyspnea Pulse 90 beats/minute Dyspnea worse than baseline Dizziness Pleuritic chest pain Confusion/Altered mental status Upper abdominal pain Respiratory rate > 20 breaths/minute Upper back pain Cough Syncope Observation of unilateral limb swelling Near Syncope Any pulse oximetry reading < 95% Hemoptysis Risk Factors for PE (at least one required for inclusion) Age >49 years Chronic neuromuscular disease with immobility Surgery (within previous 4 weeks Body mass index > 36 kg/m 2 requiring general endotracheal anesthesia Bed rest of hospitalization > 48 hours Stroke, MI or arterial embolism within previous 30 days Current hospitalization for > 11 hours Congestive heart failure trauma Trauma requiring hospitalization within Active intravenous recreational drug the previous 2 weeks use Personal history of thrombophilia Current DVT within past 3 months without known PE Active malignancy (currently under the Active connective tissue disease care of an oncologist for treatment) (lupus, MCTD, scleroderma) Any exogenous estrogen use Focal infection requiring hospitalization or observation Post-partum status (within past 2 Indwelling deep vein catheter or port weeks) (excludes pacemaker wire) Immobilization of an ankle, knee, hip or Hemodialysis-dependent renal failure shoulder for > 48 hours within the past (within past 2 weeks) 7 days Paralysis of one or more limbs from prior stroke or spinal cord injury

3 Device description: Breathscreen PE TM is approximately the size and weight of a laptop computer. The processing unit contains a rechargeable battery and a display screen attached by an electrical cord to a hair-dryer sized hand-held unit fitted with a disposable mouthpiece. The snorkel style mouthpiece attaches to a chamber that contains a gradient that conforms the exhaled breath wave into laminar flow. An internal barometer adjusts for barometric pressure changes. A thermal-based pneumotach is positioned just distal to the laminar gradient. The sensing chamber contains optics to measure CO 2 and O 2 using infrared absorptiometry and fluorescence emission, respectively. The response time of each sensor was 200 ms, allowing for accurate production of the instantaneous ratio. The internal chamber is heated to prevent condensation. The total deadspace of the sensing chamber was 80 ml. Breath data analysis: Briefly, patients wearing nose clips breathed ambient air in a semi-recumbent position and delivered spontaneous breaths into the hand-held unit until at least seven non-rejected breaths were recorded. A computer algorithm examined each breath in real-time and rejected breaths with an alveolar volume less than 100 ml or <150% of the airway deadspace volume. 25 The protocol specified that if seven acceptable breaths were not obtained within five minutes, the session was to be terminated. The CO 2 /O 2 was reported as the median value obtained from the endpoint of the phase III plateau of between seven and 13 non-rejected breaths. D-dimer collection: Blood was drawn by a qualified phlebotomist into two (blue-top) tubes containing sodium citrate dihydrate (0.11mM). These tubes were drawn and transported on ice and immediately centrifuged at 2500g x 15 minutes and the plasma fraction separated from red cell mass. Plasma was stored at -80ºC.. 26 The plasma D- dimer concentration was measured in batches of single-freeze-thawed aliquots of plasma, (VIDAS ELISA, biomerieux, Durham NC). The fibrinogen level (Dade Thrombin Reagent, Dade Behring, Inc. Newark, DE) was also analyzed with an FDAcleared coagulation analyzer in the hospital laboratory at one of the sites (CMC). Image acquisition: MDCTPA images were obtained at each site as part of standard care, and were done on 64 slice multi-detector equipment with 2.5mm collimation. Intravenous contrast media was given to all patients according to local protocol using a computer-controlled mechanized timing injector in all cases. In most cases, CT venography of the lower extremities was also obtained. Images were obtained using energy, pitch, rotation settings as required for the patient s body habitus. All patients had reconstructions that included transverse, coronal and sagittal views. Images were converted to a digital file using a digital imaging and communications in medicine (DICOM) format, devoid of any annotations or protected health information and transferred to the independent reference reading (IRR) laboratory (Medical Metrics Inc., Houston, TX). Statistical analysis and sample size: The posterior probabilities of PE were compared with 95% confidence intervals for independent proportions. We tested the correlation of both the D-dimer and etco2/o2 as independent variables and the percentage pulmonary vascular obstruction as the dependent variable using first-order regression. We tested the relative predictive value of the D-dimer and the etco2/o2 for the 3

4 outcome of any PE by entering these two variables into a logistic regression equation together with nine other independent variables previously shown to be important predictors of PE. A sample size of 500 was estimated to demonstrate a significant increase in posterior probability of PE observed in patients with (D-dimer>499 ng/ml and etco2/o2 <0.28) compared with the posterior probability among patients who had a D-dimer >499 ng/ml, as evidenced by the 95% confidence interval for the difference that does not cross zero. Details of MDCTPA findings: Table E1 shows a matrix of all interpretations by radiologists at both sites. In 72 patients, both the site radiologist and the IRR radiologist agreed that their MDCTPA scans were positive for acute PE. All 72 of these patients were anticoagulated with warfarin sodium. In 17 patients, one of the two radiology readers found acute PE that the other did not. The IRR interpreted seven MDCTPA scans positive for acute PE that were read as indeterminate (n=1) or negative (n=6) by the hospital radiologist. Two of these seven patients were taking warfarin previously, (which was continued), three had warfarin initiated, and two patients were not prescribed any type of anticoagulation within 90 days. The site radiologists interpreted 10 MDCTPA scans as positive, that were indeterminate (n=3) or negative (n=7) at the IRR. All 10 were anticoagulated at the site for the diagnosis of PE. Note that four additional patients had an MDCTPA interpreted as positive for chronic PE without evidence of acute PE, and these were considered acute PE- in this table. Table E2. Radiologist interpretations of MDCTPA scans Central (IRR) Radiologist Site Radiologist Total PE+ PE- indet PE PE indet Total

5 Table E3. Result of logistic regression 5 Variable Coefficient P value Intercept P = D-dimer (ng/ml) P = etco2/o2 (units) P < Pulse Rate (beats/min) 0.01 P = SaO2 (%) P = Thrombophilia 0.18 P = Age over 49 years P = Bed confinement >72 hours P = Recent Surgery P = Active Malignancy P = Estrogen use P = Prior venous thromboembolism P = Pearson chi-square goodness of fit = df = 483 P = Deviance goodness of fit = df = 483 P > Hosmer-Lemeshow test = df = 8 P = 0.35

6 Figure E1. First-order regression plots of the D-dimer (A) and etco2/o2 (B) versus the percentage of pulmonary vasculature obstructed on MDCTPA. The curved lines represent the 95% confidence boundaries. 6 % Pulmonary Vascular Obstruction A D-dimer (ng/ml) % Pulmonary Vascular Obstruction B etco2/o2