Cardiopulmonary exercise test in patients with subacutepulmonary emboli

Yan Topilsky, MD, Courtney L. Hayes, MS, Amber D. Khanna, MD,Thomas G. Allison, PhD*

Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota

a r t i c l e i n f o

Article history:Received 27 February 2011Revised 26 June 2011Accepted 30 June 2011Online 3 September 2011

Keywords:Exercise testPulmonary embolism

Conflict of Interest: noneAuthor contributions: All authors made suinterpretation of data; reviewed and approv* Corresponding author: Thomas G. Allison, P

SW, Rochester, MN 55905.E-mail address: Allison.thomas@mayo.ed

0147-9563/$ - see front matter � 2012 Elsevidoi:10.1016/j.hrtlng.2011.06.009

a b s t r a c t

Objective: Patients presenting with suspected pulmonary embolism (PE) maypresentachallenge,particularly ifdiagnostic testing isnot immediatelyavailableorclinically not indicated (iodine allergy, pregnancy, renal dysfunction). Thesepatients have abnormal regional gas exchange that can be recognized by a cardio-pulmonary exercise test (CPET), which may become helpful in their evaluation.

Methods: A retrospective analysis was performed of outpatients evaluated forsubacuteexertionaldyspneaof 2 to12weeksdurationwitha test for PEandCPET.Atotal of 108patientsmet inclusioncriteria.Thirtypatients (27.8%)hadconfirmedPE.

Results: The patients with PE had increased nadir ventilatory equivalent ratiofor carbon dioxide (VE/VCO2), decreased peak oxygen uptake/predicted, anddecreased end exercise saturation (P < .005 for all). All patients but 1 had normalbreathing reserve (>15%). A normal nadir VE/VCO2 excluded PE with 100%sensitivity. By using a “flow chart strategy,” the exercise test had 92.8% sensi-tivity and 92.1% specificity for PE. Eight patients with PE died during follow-up(3.8 � 4.6 years), 6 of PE-related causes. Peak VO2/kg was the best predictor ofall-cause mortality and nadir VE/VCO2 for PE-related mortality. There were noserious complications from any of the exercise tests.

Conclusion: PE may be excluded by a normal nadir VE/VCO2 in patients pre-senting with subacute dyspnea. A combination of decreased peak VO2/kg,increased nadir VE/VCO2, normal breathing reserve, and exercise-induceddesaturation may be sensitive and specific for PE. CPET may assist in identi-fying subacute PE in patients with contraindications to use of computedtomography angiography or ventilation perfusion scans.

Cite this article: Topilsky, Y., Hayes, C. L., Khanna, A. D., & Allison, T. G. (2012, MARCH/APRIL). Cardiopul-

monary exercise test in patients with subacute pulmonary emboli. Heart & Lung, 41(2), 125-136.

doi:10.1016/j.hrtlng.2011.06.009.

bstantial contributions ted the final manuscript; ahD, Division of Cardiovas

u (T. G. Allison).

er Inc. All rights reserved

o conception and design or acquisition of data, or analysis andnd contributed significantly to this study.cular Diseases and Internal Medicine, Mayo Clinic, 200 First Street

.

h e a r t & l ung 4 1 ( 2 0 1 2 ) 1 2 5e1 3 6126

The annual incidence of pulmonary embolism (PE) isapproximately 600,000 cases in the United Statesalone.1,2 Reductions in the mortality rate with antico-agulants underscore the importance of correct andearly diagnosis of PE.3-5 Patients presenting to theemergency department with acute dyspnea, tachy-cardia, and desaturationmay be readily diagnosedwithPE by appropriate imaging techniques. Diagnosticstudies to evaluate and assess for PE have evolved overseveral decades. They have been divided into labora-tory examinations (D-dimers),3,6 risk stratificationmodels (Wells score7), and imaging (invasive andnoninvasive) modalities. Invasive evaluation withpulmonary angiography led to noninvasive testing,such as lung ventilation-perfusion scintigraphy andmultidetector computed tomography (CT) angiographywith orwithout venous phase imaging. CT angiographyhas limitations, including cost, high radiation doses,and inapplicability in pregnantwomen or patients withreduced renal function or iodine allergy.5 On the otherhand, ventilation-perfusion scintigraphy is flawed byhigh rates of inconclusive results and significant radi-ation by itself.3 Patients with PE are known to haveincreased physiologic dead space, a feature that hasbeen used for exclusion of PE with a high degree ofcertainty.6,8 Furthermore, patientswith PE are expectedto have exercise-induced hypoxemia because of thereduced size of the functional capillary bed, shorteningthe time available for diffusion equilibration of oxygen(O2) at rest, and even further during exercise. In thepast, safety concerns over maximally exercising thispatient group have been raised because of the risk fordesaturation and syncope. We hypothesized thatpatients with subacute PE will have 1) reduced venti-latory efficiency shown by an increase in the nadirventilatory equivalent ratio for carbon dioxide (VE/VCO2) ratio measured immediately after anaerobicthreshold and 2) decreased oxygen saturation duringeffort.We also evaluated the possible adverse effects ofa cardiopulmonary exercise test (CPET) in patients withsubacute PE.

Materials and Methods

Patient Selection

The study population included 152 patients referred toour exercise laboratory between January 1995 andAugust 2009 with subacute exertional dyspnea, definedas exertional dyspnea for more than 2 and less than 12weeks before presentation. All patients included in thestudy had to have diagnostic testing for PE and a CPETon the same index evaluation. A composite referencestandard was used to diagnose or rule out PE as sug-gested by the PIOPED II investigators.9 Briefly, thediagnosis of PE according to the composite referencestandard required either 1) ventilation-perfusion lung

scanning showing a high probability of PE in a patientwith no history of PE or 2) abnormal findings on CTangiography (as defined below). Exclusion of PErequired one of the following conditions: normal find-ings on CT angiography; normal findings onventilation-perfusion scanning; or ventilation-perfusion scanning showing a low or very low proba-bility of PE, a clinical Wells score of <2, and normalfindings on venous ultrasonography. CT angiographyand ventilation perfusion studies were performedusing the protocols previously described.9,10

We excluded 44 patients who did not reach thesedefinitive reference standards, leaving 108 enrolledpatients for further analysis. The study patients weredivided into patients with a final diagnosis of subacutePE (group 1, n ¼ 30) and patients with no PE (group 2,n¼ 78) as defined by the composite reference standard.Demographic data and clinical data were obtained byreview of medical charts. Data were abstracted by thefirst 2 authors (Y.T and C.L.H), and inter-rater reliabilitywas ensured by comparing the abstracted cardiore-spiratory stress test parameters in 10 randomizedpatients by the first author. The review of the data wasapproved by the institutional review board.

Diagnostic Evaluation

Patients were evaluated by their primary physicians forsuspected PE using the Wells model to assign clinicalscores for 7 predefined parameters (Appendix 1) andcalculate their pretest probability for PE. The scoresassignedwere added, and if a patient had< 2 points theprobability of PE was considered to be low (<2.0%).7 Inaddition, all patients underwent diagnostic testing,including at least one of the following: CT angiographyor ventilation-perfusion scanning.

Cardiopulmonary Exercise Test

Symptom-limited treadmill exercise testing withrespiratory gas exchange analysis used an acceleratedNaughton protocol, which consisted of 2-minute stagesbeginning at approximately 2.5 metabolic equivalents(METs) and increasing 2 METs per stage.11 Breath-by-breath minute ventilation (VE), carbon dioxideproduction (VCO2), their ratio (VE/VCO2), and oxygenconsumption (VO2) were measured using a MedicalGraphics metabolic cart (St Paul, MN). Calibration wasdone before each test. Peak VO2 was the highest aver-aged 30-second VO2 during exercise andwas expressedas absolute peakVO2, VO2/kg, and the ratio ofmeasuredpeak VO2/kg to the expected VO2/kg by age and gender.The O2 pulse, an estimate of stroke volume, was calcu-lated as VO2/heart rate.11 VE/VCO2 was the lowestimmediately after anaerobic threshold and before theonset of ventilatory compensation for the exercise-induced lactic acidosis, and was expressed as absolutenadir VE/VCO2 and actual/predicted nadir VE/VCO2

(normalized, as a percent of age, gender, and heightpredicted).12 Anaerobic threshold was determined

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manually using the modified V-slope method. Carbondioxide output (VCO2) was plotted against oxygenuptake (VO2). A line parallel to the line of identity wasdrawn through VCO2 versus VO2 points during theincremental phase of the exercise test. The point atwhich the VCO2 departed from the line (begins toincrease more rapidly than VO2) was taken as theV-slope anaerobic threshold. Arterial blood oxygensaturation was measured using noninvasive pulse oxi-metry. Quality of exercise effort was assessed byrespiratory exchange ratio. Key exercise terms, theirdefinitions, and their clinical importance are listed inAppendix 2.13

Outcomes

Clinical follow-up was obtained by review of medicalrecords. Cause of death was determined by review ofmedical records and death certificates. End points wereall-causemortality and PE-relatedmortality (defined asmortality related to intractable right heart failure, orsudden pulseless electrical activity [PEA]).

Statistical Analysis

The different CPET parameters were not normallydistributed (assessed using the ShapiroeWilk test); thus,because of the low number of patients in the PE group(<30) they were reported as median, first, and thirdquartiles. Comparisons betweengroupswereperformedwith the Wilcoxon rank test. Categoric data werecomparedbetweengroupsusing thechi-squareorFisherexact testwhenever theexpectedvalue inoneof thecellswas less than 5. To analyze independent associationwith PE, univariate analysis based on logistic regressionmodels (with the presence of PE as dependent variableand the different CPET parameters expressed ascontinuous independent variables)was performed.Datawere presented as risk ratio (RR) and 95% confidenceinterval (CI) in brackets. Receiver operating character-istic analysis was used to determine the optimal cutoffvalues of continuous variables for prediction of PE(optimal cutoff valuewas the pointwith thehighest sumof sensitivity and specificity). The area under the curvewas used to quantify the ability of the different variablesto predict PE. Survival distributions were calculatedaccording to the KaplaneMeier method and comparedbymeans of the log-rank test. All testswere 2-sided, andaPvalue< .05wasconsideredstatistically significant.Alldata were analyzed with the JMP System softwareversion 8.0 (SAS Institute, Inc, Cary, NC).

Results

Baseline characteristics for patients with PE (30patients/27.8%) and without PE (78 patients/72.2%) areshown in Table 1. The main differences between thegroups were an increased proportion of men in the PE

group and more tachypnea and crackles on physicalexamination. CPET variables for the overall sample andby PE group are listed in Table 2. An example ofa typical CPET examination in a patient with PE isshown in Figure 1. The patients with PE had signifi-cantly abnormal ventilatory efficiency, suggestingincreased physiologic dead space, and most of them(80%) had a significant decrease in saturation duringexercise, implying shortened time available for diffu-sion equilibration of oxygen. The ratio of measured toexpected peak VO2 predicted also was reduced.

There were no differences in breathing reserve orthe adequacy of exercise effort (Table 2, Figure 2).Forty-three (40%) of the cohort have reached maximalstress (respiratory exchange ratio > 1.15),14,15 and themajority of patients have reached anaerobic threshold(81%). In the remaining patients, the reason for stop-ping the tests was dyspnea (33%), fatigue (18.5%),muscle pain (5.5%), or chest pain (2.7%). There were nodifferences in the causes for stopping the tests bet-ween the groups. We have reanalyzed the cardiopul-monary exercise parameters in the patients whoreached maximal stress (respiratory exchange > 1.15).The results remained unchanged, with the patientswith PE having significantly higher VE/VCO2, lowerVO2 max, and higher prevalence of desaturation.

Univariate analysis with PE as the dependent vari-able and the different cardiopulmonary exercise vari-ables as independent variables is presented in Table 3.Peak VO2/kg (mL/kg/min), measured to expected peakVO2/kg percent, peak exercise saturation, nadir VE/VCO2, nadir VE/VCO2/predicted, nadir VE/VO2, andend-tidal PCO2 were the only parameters associatedwith PE.

The best single discriminators (by receiver operatingcharacteristic analysis) between patients with andwithout PE were nadir VE/VCO2 and peak exerciseoxygen saturation (Table 3); areas under the curve(which is a grade of sensitivity vs 1 specificity) were .8and .86, respectively. The optimal cutoff values fordistinguishing patients with subacute PE from patientswith no PE are shown in Table 3. A VE/VCO2/predicted>

100% or a nadir VE/VCO2 ratio > 28 identified all casesof PE; however, such values were also observed in 82%and 81% of patients without PE, respectively.

Flowchart Approach for Identifying PulmonaryEmbolism in Cardiorespiratory Exercise Test

We retrospectively analyzed all our patients usinga flowchart strategy (Figure 3). The branch pointsaddressed were as follows: 1) Is peak VO2/kg > 25.7(mL/min/kg)? 2) Is nadir VE/VO2 < 28? 3) Is breathingreserve < 15%? 4) Did saturation decrease more than4% or to less than 95% during exercise?. Four patientsdid not have saturation data and were excluded fromthe analysis (2 patients with PE and 2 patients withoutPE).

In the remaining 81 patients, after analysis of thefirst 3 branch points, 49 did not have significant

Table 1 e Clinical, demographic, and echocardiographic characteristics in patients with and withoutsubacute pulmonary emboli (data presented as median [first and third quartiles])

Pulmonary emboli (n ¼ 30) No pulmonary emboli (n ¼ 78) P value

Age (y) 63.6 [51.2-74.5] 56.7 [45.8-70.9] .29Male gender n (%) 22 (73.3) 47 (60.2) .002Weight (kg) 85.2 [75.7-94.1] 82.7 [67.7-100.5] .88Height (cm) 172.9 [164.7-180.1] 167.0 [160.0-175.3] .1BSA 1.9 [1.8-2.1] 1.9 [1.7-2.2] .38BMI 28.9 [24.3-31.7] 29.8 [25.0-35.3] .46Baseline laboratory and clinical characteristicsHemoglobin (g/dL) 13.5 [12.2-14.7] 14.1 [12.2-15.3] .39BUN (mg/dL) 21 [13-32] 27 [19.3-37.7] .41Creatinine (mg/dL) 1.1 [1.0-1.6] 1.3 [1.0-1.6] .54Bilirubin (mg/dL) .75 [.5-1.1] .9 [.6-8.4] .72D-dimer units (ng/mL)* 250 [250-950] 250 [200-300] .51CHF n (%) 12 (40) 29 (37.2) .82IHD n (%) 9 (30) 16 (20.5) .6HTN n (%) 9 (30) 31 (40) .69Smoking n (%) 5 (17) 11 (14) .74COPD n (%) 2 (6.6) 8 (10.3) .72Asthma n (%) 2 (7) 6 (8) .85CRF n (%) 6 (20) 22 (28) .37Previous DVT n (%) 21 (70) 54 (69) .94Recent immobilization n (%)y 1 (3) 4 (5) .68Recent pneumonia n (%)y 2 (7) 1 (1) .16Recent surgery n (%)y 1 (3) 3 (4) .89Recent central line placement n (%)y 3 (10) 2 (3) .12Cancer n (%) 2 (6.6) 4 (5.2) .67

Physical examination, hemodynamics and echocardiographyHeart rate (bpm) 70 [62.5-80] 78.0 [64-90.5] .51SBP mm Hg 122 [101-139] 118 [105-145.5] .79DBP mm Hg 68 [61-79] 62 [54-77] .31Physical evidence suggestive of DVT 4 (13) 6 (8) .38Tachypnea > 20 bpm n (%) 7 (23) 4 (5) .008Crackles n (%) 6 (20) 1 (1) .0009Systolic pulmonary pressure mm Hg 36 [29-47.2] 32 [32-44] .55Ejection fraction (%) 60 [45-65] 60 [54-68.5] .46RV dysfunction n (%)z 4 (13.3) 0 (0) .005RV enlarged n (%)z 6 (20) 0 (0) <.0001Wells score > 2 (%)x 1.5 [1.5-4.5] 1.5 [1.37-1.5] .02Reason to stop exercise (%) CP (2.5); DY (33.3); FA (16.7)

MP (7.7); ME (39.8)CP (3.3); DY (33.3); FA (23.4)

MP (.0); ME (40.0)

BSA, body surface area; BMI, body mass index; BUN, blood urea nitrogen; CHF, congestive heart failure; IHD, ischemic heartdisease; HTN, hypertension; COPD, chronic obstructive pulmonary disease; CRF, chronic renal failure; DVT, deep veinthrombosis; SBP, systolic blood pressure; DBP, diastolic blood pressure; CP, chest pain; DY, dyspnea; FA, fatigue; MP, musclepain; ME, maximal effort.* Performed in 66% of patients using different methodologies.y In the last 3 months before the cardiorespiratory stress examination.zVisually estimated in the echocardiographic examination.xAssessed as described in the “Materials and Methods” section. Bold text indicates statistically significant comparisons.

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desaturation during exercise (48 with no PE and 1 withPE) and 32 had significant desaturation during exercise(26 with PE and 6with no PE). The calculated sensitivityand specificity of the flowchart approach for PE were92.8% and 92.1%, respectively.

Safety of Cardiopulmonary Exercise Test

Exercise tests were stopped for general fatigue (40.7%),dyspnea (40.7%), dizziness (14.8%), or chest pain(3.7%). There were no serious complications during

any of the exercise tests. No hemodynamically seriousarrhythmia was found, but 3 patients experiencedshort runs of nonsustained ventricular tachycardiawith no change in symptoms or blood pressure. Mildarrhythmia, primarily isolated premature atrial orventricular contractions, was documented in 44.1% ofpatients. Of the 30 exercise tests performed in patientswith confirmed subacute PE, 2 patients (6.6 %) hada decrease in SAO2 to < 85%, or a 10% absolute decreasefrom baseline. There were no significant adverseevents, including syncope, significant arrhythmia,pulmonary congestion, or death.

Table 2 e Cardiopulmonary exercise variables in patients with and without subacute pulmonary embolismand in patients performing maximal effort tests (data presented as median [first and third quartiles])

All patients (n ¼ 108) PE (n ¼ 30) No PE (n ¼ 78) P RR 95% CI P

Exercise time (min) 6.5 [5.0-8.7] 6.0 [5.3-8.1] 6.7 [5.0-9.0] .55Naughton level 4.0 [3.6-5.0] 4.4 [3.5-5.5] .5Peak VO2/kg (mL/kg/min) 15.6 [12.7-20.1] 15.0 [10.8-18.7] 16.2 [12.9-20.4] .20 .9 .82-.98 .007O2 pulse (mL/beat) 10 [7.8-13.4] 9.5 [7.6-12.8] 10.3 [7.8-13.9] .30VO2 expected (%) 64 [52.5-82.5] 54 [46-68.5] 67 [54.2-86] .005 .97 .94-.99 .002VO2 expected < 85 (%) 76 100 67 .001Breathing reserve (%) 46 [37.2-57] 51 [40-61] 45 [37-55.5] .36Breathing reserve < 15 (%) 3 0 4 .56Saturation baseline (%) 99 [97-100] 99 [96.5-100] 99 [97-100] .15Peak exercise saturation (%) 97 [93.5-98] 92 [91-96] 98 [95-99] <.0001 .64 .5-.78 <.0001Saturation decrease (%)* 29.6 80 10.2 <.0001Peak VCO2 (mL/min) 14.8 [10.5-20.1] 12.6 [9.2-15.4] 16.0 [11.3-21.1] .01RER 1.11 [1.02-1.20] 1.10 [1.0-1.19] 1.11 [1.03-1.21] .51Peak EtCO2 (Torr) 33 [29-37] 30 [23.5-34] 34 [30.5-38] .0002 .87 .79-.93 <.0001Peak Vd/Vt (%) 11.1 [5.6-17.1] 12.8 [5.5-22.9] 10.8 [5.6-15.1] .17Nadir VE/VCO2 35.3 [30.8-41.5] 42.5 [35.9-47.2] 33.7 [29.1-37.9] <.0001 1.03 1.02-1.05 <.0001Nadir VE/VO2 38.5 [32.6-45.5] 44.8 [39.2-52.1] 36.4 [31.9-43.6] .0002 2.43 1.54-4.1 .0001VE/VCO2 predicted (%) 124 [109-143] 140 [128-169] 117 [106-128] <.0001

EtCO2, end-tidal CO2; Vd/Vt, dead space in percent; RER, respiratory exchange ratio.* Significant saturation decrease defined as > 4% from baseline or < 95% anytime during exercise. Bold text indicates statis-tically significant comparisons.

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Determinants of Pulmonary Embolism-Related Mortality

The mean follow-up duration after PE was 3.8 � 4.7years. Eight of the 30 patients (26.6%) with documentedPEdied during follow-up. The causes of deaths includedPEA in 3 patients, intractable right ventricular (RV)failure in 2 patients (secondary to chronic thrombo-embolic disease), cardiogenic shock in 1 patient, end-stage amyloidosis in 1 patient, and unknown in 1patient.WedefinedPE-related death asdeath fromPEA,RV failure, or cardiogenic shock. The association of thedifferent cardiopulmonary stress variables with all-cause mortality and PE-related mortality is shown inTable 4. The only parameters associated with all-causemortality were exercise time (RR .6; 95% CI, .37-.88;P¼ .007), peakVO2/kg (RR .9; 95%CI, .78-.99; P¼ .04), andVE/VCO2/predicted (RR 1.02; 95% CI, 1.0-1.03; P ¼ .05).The only parameters associated with PE-related deathwere VE/VCO2 (RR 1.14; 95% CI, 1.04-1.27; P ¼ .003) andVE/VCO2/predicted (RR 1.02; 95% CI, 1.01-1.05; P ¼ .005).

The patientswere classified according to themediannadir VE/VCO2 as VE/VCO2 > 42 and VE/VCO2 � 42. The1- and 2-year survivals were 84.2% � 6.5% and 68.4% �9.8% overall, 100% and 88.9%� 10.5% among thosewithVE/VCO2 � 42, and 68.8% � 11.6% and 49.1% � 14.4%among those with VE/VCO2 > 42 (P ¼ .03), respectively.

Discussion

To our knowledge, this study is the first to analyze theutility and safety of CPET in patients with suspected

subacute PE. We show that patients with PE havesignificant changes in CPETs and that a specificcombination of CPET parameters should raise thepossibility of PE. Furthermore, subacute PE may beexcluded by a normal nadir VE/VCO2 ratio, and a veryhigh nadir VE/VCO2 ratio in patients diagnosed to havePE is a predictor of adverse outcome, especially in thefirst 2 years after diagnosis. Prospective studies, usinga less selected group of patients, looking at the utility ofCPET would be useful in validating these single-centerresults.

Sensitivity of Cardiopulmonary Exercise Testfor Pulmonary Embolism

There weremoremen in the PE group than in the groupwith no PE. Although use of oral contraceptives andpostmenopausal hormone replacement has beenassociated with PE in women, most published datasuggest no consistent differences in the incidence of PEamong men and women.16,17 In previous reports sug-gesting ahigher incidence rate of PE amongwomen,18,19

the difference was attributed largely to a higher inci-dence ofwomen agedmore than 80 years or other typesof bias. A possible explanation for the increased inci-dence ofmen in the PE groupwas ahigher prevalence ofheart failure in men (50.9% vs 25.5%; P ¼ .006), which isa known risk factor for PE.

Respiratory dead space estimation has been sug-gested to diagnose PE and can be calculated usingseveral equations.6,8,20 The ventilatory equivalent forCO2 (VE/VCO2) is a noninvasive method for estimatingincreased dead space. During rest or very mild exer-cise, the relationship between VE and VCO2 can varywidely, predominantly because of psychogenic factors

Figure 1 e A, Cardiopulmonary exercise and CT results of a patient presenting with effort dyspnea of 10 weeksduration. Markedly impaired gas exchange was evident, with low exercise capacity (13.4 mL/kg/min; 27% ofexpected for age and gender), high nadir VE/VCO2 after anaerobic threshold (60 when normal is < 30 for age,height, and gender), normal-high breathing reserve (43%), and significant desaturation during exercise (from99% to 90%), all raising concern for possible subacute PE. B, Contrast-enhanced chest CT demonstrateda dilated right ventricle (**) consistent with pulmonary artery hypertension. Extensive bilateral PE were shown(arrows). Virtually all the segmental and subsegmental pulmonary arteries in both lungs were at leastpartially occluded by PE.

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resulting in hyperventilation and differences in theanatomic dead spaceetidal volume ratio (VD/VT).12

During exercise, after onset of anaerobic threshold,and before the onset of ventilatory compensation forlactic acidosis, the relationship of VE to VCO2 reachesits nadir, and is relatively stable and thus morereproducible.

The best variables to exclude PE in our cohort werenadir VE/VCO2 > 28 or VE/VCO2 higher than predictedthat had 100% sensitivity for PE. In other words, PE wasunlikely with normal nadir VE/VCO2 (<28 or <100%expected) reflecting the universal presence of at least

minimal dead space ventilation in all patients with PEpresenting with dyspnea. Estimated dead space andend-tidal PCO2 were less effective, probably because ofthe unpredictable and variable relationship betweenend-tidal and arterial PCO2 during exercise.21

Patients with PE had the same total exercisecapacity as those who did not have PE (measured bypeak VO2/kg or O2- pulse), but a significantly lower ratioof measured to expected peak VO2 predicted. This doesnot imply that PE does not affect exercise capacity, butreflects the differences in gender between the 2 groupswith a significantly higher proportion of male patients

Table 3 e Cutoff values for distinguishing cases with and without pulmonary emboli from patientspresenting for evaluation of subacute dyspnea (>14 days, <6 weeks)

AUC P 100%sensitivity

100%specificity

Optimal cutoff Cutoffsensitivity

Cutoffspecificity

Peak VO2/kg (mL/min/kg) .65 .007 25.7 5.3 18.5 90 44Peak exercise saturation (%) .86 <.0001 98 88 96 95 82Peak VCO2 (mL/min) .79 <.0001 2281 469 1455 73 61Peak VE/VO2 .73 .0001 27.6 65.2 38.9 80 62EtCO2 mm Hg .73 <.0001 36 19 28 48 85Nadir VE/VCO2 .8 <.0001 28 59 37 73 73VE/VCO2/predicted (%) .77 <.0001 100 237 128 77 75

AUC, area under the curve; EtCO2, end-tidal CO2; Vd/Vt, dead to total ventilation ratio.Values derived from receiver operating characteristic curves. Bold text indicates statistically significant comparisons.

Figure 2 e Cardiopulmonary exercise stress test parameters in patients with and without PE. Patients with PEhave lower exercise capacity (VO2/expected), significant desaturation during effort, abnormal ventilatoryefficiency, and normal breathing reserve. The parameters are represented by box plots (middle hash of thebox indicates the median; 25th to 75th percentiles are represented by end caps of the box; whiskers extend tothe last observed value still within 1.5 times the interquartile range (difference between the 25th and 75thpercentiles) above or below the 25th and 75th percentiles; values are represented by dots. VO2 expected,oxygen consumption expressed as a percent of an appropriate normal response; VE/VCO2, nadir minuteventilation/carbon dioxide production relationship.

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in the PE group. Furthermore, the exercise capacity wasimpaired in the “control group” as well, merelyreflecting the significant morbidity of both the“control” and PE patients.

Flowchart Approach for Identifying PulmonaryEmbolism in Cardiorespiratory Exercise Test

The specificity of each one of the cardiorespiratoryexercise test parameters for PE is low and cannotbe relied on as a confirmatory test. Our primaryhypothesis was that patients with PE will have reducedeffort capacity secondary to the increased RV afterload,

impaired ventilatory efficiency due to increased phys-iologic dead space, exercise-induced arterial hypox-emia due to the shortened time available for diffusionequilibration of O2, and a normal breathing reserve(because they are limited by their cardiac output andventilatory capacity and not by breathing mechanics).By using the flowchart approach, we were able toincrease the sensitivity of the test, and even moreimportant to increase the specificity for PE. We by nomeans suggest that CPET should be used as a primarydiagnostic tool for PE. We believe that other diagnostictools (eg, ventilation-perfusion scintigraphy or multi-detector CT angiography with or without venous phase

Figure 3 e A flowchart analysis of cardiorespiratory stress parameters in patients with suspected PE. The flowchart has 4 branch points. The first is whether the peak VO2/kg is normal or decreased (>25.7 mL/min/kg), thesecond is to determine if the patients had abnormal ventilatory efficiency defined as nadir VE/VO2 > 28, thethird determines whether the limitation is due to obstructive lung disease (breathing reserve < 15%), and thelast is to assess for significant desaturation during exercise (defined > 4% from baseline or < 95% anytimeduring exercise). Four patients did not have saturation data and were excluded from the analysis (2 patientswith PE and 2 without PE). The calculated sensitivity and specificity of the flowchart approach for PE were92.8% and 92.1%, respectively. VO2/kg, oxygen consumption in mL/kg/min; VCO2, carbon dioxide output inmL/kg/min; VE, expiratory ventilation in mL/min; VE/VCO2, nadir minute ventilation/carbon dioxideproduction relationship.

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imaging) are preferable in most patients and possiblysafer. On the other hand, some patients may havecontraindications to such tests, and for themCPETmaybe helpful in the diagnostic process.

Safety of Cardiopulmonary Exercise Test

Safety concerns over maximally exercising patientswith suspected subacute PE have been raised becauseof the risk for desaturation, syncope, or suddendeath.22,23 As a result, exercise testing is consideredcontraindicated in patients with acute PE. Our retro-spective analysis was reassuring in terms of thesepossible safety concerns in patients presenting morethan 2 weeks after initiation of symptoms. Weemphasize that maximal CPET should not be per-formed in patients with acute onset of dyspnea or withconfirmed or high probability of PE.

Predictive Value for Long-Term Outcome inPulmonary Embolism

Decreased exercise capacity (measured by exercisetime or peak VO2/kg) predicted all-cause mortality butdid not predict PE-related mortality. This is notsurprising because exercise capacity is related to

comorbidity, and not exclusively to PE. On the otherhand, increased nadir VE/VCO2 was the best CPETvariable to predicted death from PE-related causes. Ofnote, all the excess mortality predicted by VE/VCO2

occurred during the first 2 years after diagnosis. It isreasonable to believe that a very high nadir VE/VCO2 isa surrogate marker for extensive thrombosis involvinglarger areas of the lungs, resulting in more dead spaceventilation.

D-Dimers

D-dimers are the products of endogenous fibrinolysis.Depending on the degree of lysis of cross-linked fibrin,a mixture of fibrin-degradation products containingthe D-dimer moiety will be formed. D-dimers areusually detectable 1 hour after thrombus formation,and continued fibrinolysis in an acute pulmonaryembolus results in increased plasma D-dimer for atleast 1 week. Many factors affect the level of D-dimerdetected, and they increase with age, pregnancy, andsmoking. The diagnostic utility of D-dimers is stronglydependent on which assay is used and the acuity ofsymptoms. All our patients had symptoms for morethan 2 weeks; thus, D-dimer testing was not routinelyperformed as part of their evaluation. Furthermore,

Table 4 e Cardiopulmonary exercise variables and their predictive value for total mortality and pulmonaryembolism-related mortality in Cox hazard model (data presented as risk ratio and 95% confidence interval)

Variable PE-related mortality Total mortality

RR P RR P

Exercise time (min) .7 (.4-1.04) .08 .6 (.37-.88) .007Peak VO2 (mL/kg/min)y .89 (.76-1.01) .1 .9 (.78-.99) .04O2 pulse (mL/beat)y .85 (.67-1.08) .2 .95 (.78-1.14) .6Breathing reserve (%) 1.0 (.96-1.08) .6 1.02 (.97-1.07) .4Peak exercise saturation (%) .89 (.438-1.7) .6 .88 (.39-1.63) .7Saturation decrease (%)z .74 (.18-2.2) .6 .74 (.16-2.1) .6RERy 1.24 (.6-2.7) .5 1.5 (.8-2.9) .2EtCO2 (torr)

y .96 (.89-1.04) .3 .98 (.92-1.07) .6Peak Vd/Vt (%)y 1.0 (.93-1.08) .8 1.0 (.94-1.06) .9Nadir VE/VCO2* 1.14 (1.04-1.27) .003 1.06 (.99-1.14) .08VE/VCO2/predicted (%)* 1.02 (1.01-1.05) .005 1.02 (1.0-1.03) .05

EtCO2, end-tidal CO2; Vd/Vt, ratio of dead to total ventilation; RER, respiratory exchange ratio.maximal value after anaerobicthreshold.* Lowest value during exercise.yAt peak exercise.zSignificant saturation decrease defined as > 4% from baseline or < 95% anytime during excerise. Bold text indicates statis-tically significant comparisons.

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because of the changes in the methodology of D-dimertests during the study period, we did not use them forthe assessment or exclusion of PE.

Clinical Implications

A patient presenting to the emergency departmentwith acute onset of severe dyspnea andhigh probabilityof PE would rather be evaluated with specific imagingtests, such as CT or a ventilation perfusion scan, toexclude PE. On the other hand, patients may presentwith subacute dyspnea, which has been present overweeks, and although PE is part of the differential diag-nosis, it is not at the top of the list. These patients maybe sent for a more general diagnostic evaluation,including a chest x-ray, pulmonary function test,echocardiography, and CPET, and not chest CT, venti-lation perfusion scintigraphy, or D-dimers. We showthat a CPET examination, which is recommended forthe evaluation of unexplained dyspnea,24 may allow usto identify patients with a high probability of PE forwhom additional specific evaluation would prove to bebeneficial and have a high yield.

Furthermore, diagnostic imaging studies to evaluateand assess for PE, such as lung ventilation-perfusionscintigraphy and multidetector CT angiography, havelimitations, including cost, high radiation doses, andinapplicability in pregnant women and patients withreduced renal function or iodine allergy.5 Althoughseveral recent studies have suggested that the combi-nation of D-dimer assays together with clinical infor-mation can exclude the diagnosis of PE,6-9 elevatedD-dimer levels are also associated with many othercircumstances, including advancing age, pregnancy,trauma, the postoperative period, inflammatory states,and cancer. CPET may be useful in excluding PE inpatients with contraindications to CT or ventilation

perfusion scans and low pretest probability. A possibleexample may be pregnant young women presentingwith recent dyspnea, who may have elevated D-dimers,25 and in whom chest CT and ventilation/perfu-sion scans, with their significant radiation exposure,may increase the risk of embryonic malformations. Itshouldbenoted thatnoneofourpatientswerepregnant;thus the applicability of CETP in pregnant patients isspeculative.

In patients found to have PE by other imagingstudies, reduced exercise capacity and especially anunexpectedly high nadir VE/VCO2 should raise concernfor possible short and midterm (up to 2 years) adverseoutcome and suggest the possible need of prolongedanticoagulation. Chronic thromboembolic disease, thecause of death in 2 of the patients with PE, is potentiallycurable and should be aggressively diagnosed andtreated. The patients with chronic thromboembolicdisease had markedly increased VE/VCO2 (>47). Webelieve that whenever such values are encounteredduring cardiopulmonary stress examinations, chronicthromboembolic disease should be suspected anda focused evaluation for its exclusion should beperformed.

Study Limitations

The major limitation of the investigation is its retro-spective nature. Prospective studies looking at theutility of CPET would be useful in validating theseresults. A second major limitation is selection biasreflected by the high proportion of positive PE results(30/108) and low exercise capacity in all patients in thestudy. This source of bias most greatly affects testsensitivity. The third limitation is the use of

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noninvasive diagnostic tests as part of the referencestandard. Although pulmonary angiography remainsthe gold standard for the diagnosis of pulmonaryembolus, the use of noninvasive diagnostic tests fordiagnosis or exclusion of PE has become the clinicalstandard since the PIOPED II trial. The first 6 CPETsperformed during the study (1995-1998) used a differentsoftware package for assessing gas exchange but thesame modified Naughton protocol for treadmill testing.Finally, patients who died of right heart failure or PEAwere presumed to have had long-term effects from PE,which may not have been the case.

Conclusions

Patients with PE have significant changes in CPET.Subacute PE may be excluded by a normal nadir VE/VCO2 ratio. A combination of decreased peak VO2/kg,increased nadir VE/VCO2, normal breathing reserve,and decreased saturation during exercise should raisethe possibility of PE. A very high nadir VE/VCO2 ratio inpatients found to have PE is a predictor of adverseoutcome, especially in the first 2 years after diagnosis.Prospective studies, using a less selected group ofpatients, looking at the utility of CPET would be usefulin validating these single-center results.

References

1. Dalen JE, Alpert JS. Natural history of pulmonaryembolism. Prog Cardiovasc Dis 1975;17:259-70.

2. Goldhaber SZ. Thrombolysis for pulmonaryembolism. N Engl J Med 2002;347:1131-2.

3. Bounameaux H, Cirafici P, de Moerloose P,Schneider PA, Slosman D, Reber G, et al.Measurement of D-dimer in plasma as diagnostic aidin suspected pulmonary embolism. Lancet 1991;337:196-200.

4. Carson JL, Kelley MA, Duff A, Weg JG, Fulkerson WJ,Palevsky HI, et al. The clinical course of pulmonaryembolism. N Engl J Med 1992;326:1240-5.

5. Sostman HD, Stein PD, Gottschalk A, Matta F,Hull R, Goodman L. Acute pulmonary embolism:sensitivity and specificity of ventilation-perfusionscintigraphy in PIOPED II study. Radiology 2008;246:941-6.

6. Kline JA, Israel EG, Michelson EA, O’Neil BJ, Plewa MC,Portelli DC. Diagnostic accuracy of a bedside D-dimerassay and alveolar dead-space measurement for rapidexclusion of pulmonary embolism: a multicenterstudy. JAMA 2001;285:761-8.

7. Wells PS, Anderson DR, Rodger M, Forgie M, Kearon C,Dreyer J, et al. Evaluation of D-dimer in the diagnosisof suspected deep-vein thrombosis. N Engl J Med 2003;349:1227-35.

8. Kline JA, Meek S, Boudrow D, Warner D, Colucciello S.Use of the alveolar dead space fraction (Vd/Vt) andplasma D-dimers to exclude acute pulmonaryembolism in ambulatory patients. Acad Emerg Med1997;4:856-63.

9. Stein PD, Fowler SE, Goodman LR, Gottschalk A,Hales CA, Hull RD, et al. Multidetector computedtomography for acute pulmonary embolism. N Engl JMed 2006;354:2317-27.

10. Value of the ventilation/perfusion scan in acutepulmonary embolism. Results of the prospectiveinvestigation of pulmonary embolism diagnosis(PIOPED). The PIOPED Investigators. JAMA 1990;263:2753-9.

11. Hansen JE, Sue DY, Wasserman K. Predicted valuesfor clinical exercise testing. Am Rev Respir Dis 1984;129(2 Pt 2):S49-55.

12. Sun XG, Hansen JE, Garatachea N, Storer TW,Wasserman K. Ventilatory efficiency during exercisein healthy subjects. Am J Respir Crit Care Med 2002;166:1443-8.

13. Arena R, Sietsema KE. Cardiopulmonary exercisetesting in the clinical evaluation of patients withheart and lung disease. Circulation 2011;123:668-80.

14. Messika-Zeitoun D, Johnson BD, Nkomo V,Avierinos JF, Allison TG, Scott C, et al.Cardiopulmonary exercise testing determination offunctional capacity in mitral regurgitation:physiologic and outcome implications. J Am CollCardiol 2006;47:2521-7.

15. ATS/ACCP Statement on cardiopulmonary exercisetesting. Am J Respir Crit Care Med 2003;167:211-277.

16. Anderson FA Jr, Hirsh J, White K, Fitzgerald RH Jr.Temporal trends in prevention of venousthromboembolism following primary total hip or kneearthroplasty 1996-2001: findings from the Hip and KneeRegistry. Chest 2003;124(6 Suppl). 349S-56S.

17. Anderson FA Jr,WheelerHB, Goldberg RJ, HosmerDW,Forcier A, Patwardhan NA. Physician practices in theprevention of venous thromboembolism. Ann InternMed 1991;115:591-5.

18. Silverstein MD, Heit JA, Mohr DN, Petterson TM,O’Fallon WM, Melton LJ 3rd. Trends in the incidenceof deep vein thrombosis and pulmonary embolism:a 25-year population-based study. Arch Intern Med1998;158:585-93.

19. Kniffin WD Jr, Baron JA, Barrett J, Birkmeyer JD,Anderson FA Jr. The epidemiology of diagnosedpulmonary embolism and deep venous thrombosis inthe elderly. Arch Intern Med 1994;154:861-6.

20. Rodger MA, Jones G, Rasuli P, Raymond F,Djunaedi H, Bredeson CN, et al. Steady-state end-tidal alveolar dead space fraction and D-dimer:bedside tests to exclude pulmonary embolism. Chest2001;120:115-9.

21. Zimmerman MI, Miller A, Brown LK, Bhuptani A,Sloane MF, Teirstein AS. Estimated vs actual valuesfor dead space/tidal volume ratios during incrementalexercise in patients evaluated for dyspnea. Chest1994;106:131-6.

22. Bhagat R, Schreiber G. Abnormalities oncardiopulmonary exercise test in a dyspneic patient.A case report of unsuspected pulmonary embolism.Respiration 2002;69:543-6.

23. Helmers RA, Zavala DC. Serial exercise testing inpulmonary embolism. Chest 1988;94:517-20.

24. Balady GJ, Arena R, Sietsema K, Myers J, Coke L,Fletcher GF, et al. Clinician’s Guide tocardiopulmonary exercise testing in adults:a scientific statement from the American HeartAssociation. Circulation 2010;122:191-225.

25. Eichinger S. D-dimer testing in pregnancy. SeminVasc Med 2005;5:375-8.

Appendix 1 e Commonly measured variables from cardiopulmonary stress tests24

Variable Definition Physiologic significance Normal response Clinical relevance

Peak VO2/kg(mL/kg/min) Highest demonstrable oxygenconsumption expressedin mL/kg/min

Reflection of integrated functionof pulmonary, cardiac, andskeletal muscle systems

Depends on age, sex, andexercise habits

Expression of aerobic exercisecapacity, indicator of diseaseseverity and degree ofimpairment

VO2 expected (%) Highest demonstrable oxygenconsumption expressed asa percent of an appropriatenormal response

Reflection of integrated functionof pulmonary, cardiac, andskeletal muscle systems

Anaerobic threshold (VT) VO2 above which there is anaccelerated increase in VE andVCO2 relative to VO2

Reflecting exhalation of CO2

derived from the buffering oflactic acid

Defines the upper end of the rangeof moderate-intensity exerciseand related to lactate threshold

Normally averages w50%-65%of maximal/peak VO2

In patients with prematurecessation of exercise, the AT asan effort-independentmeasurement and mayrepresent a submaximalvariable that may assist inclinical decision making

Peak RER The ratio of VCO2 over VO2 atmaximal exercise

As exercise is continued aboveVT, acceleration of VCO2 resultsin increasing RER

Peak RER > 1.15 commonly usedas indication of good effort

Good indicator of subjective effort

Breathing reserve, % Relationship between peakexercise VE and maximalbreathing capacity as estimatedby the resting maximalvoluntary ventilation (MVV):[(MVV-VE peak)/MVV]

Low breathing reserve is typical ofchronic obstructive lungdisease or healthy subjects withhigh cardiovascular capacity

Normal non-athletes havereserves > 15%, but can belower in athletes.

When low may be indicator oflung limitation to effort(obstructive lung disease)

Nadir VE/VCO2 Describes efficiency of pulmonaryclearance of CO2 duringexercise

Expressed as a ratio(at nadir near VT)

Reflects matching of pulmonaryventilation to perfusion

Nadir VE/VCO2 is typically < 30;values increase slightlywith aging

Abnormalities may indicatepulmonary vascular disease

Peak EtCO2 , mm Hg Partial pressure of CO2 at theend of a tidal breath exhalation

Reflects both ventilation-perfusion matching in the lungand the level of arterial PCO2

Rest: 36-42 mm HgIncreases 3-8 mm Hg by VTDecreases from VT to maximal

exercise

Abnormalities may indicatepulmonary vascular diseaseLow values can also reflectacute or chronichyperventilation

O2 pulse (mL/beat) VO2 divided by heart rate Equals the product of strokevolume and arterial and venousoxygen content difference

Peak exercise values vary by thesame factors that affect normalmaximal VO2 and heart rate

Plateau at lower than expectedvalue or decrease withincreasing work rate suggestslow or falling stroke volume andcardiac limitation to exercise

SaO2 Estimated arterial hemoglobinsaturation by noninvasivepulse oximetry

Exercise hypoxemia is common inmany lung diseases and right-to-left shunt

Decrease by > 4% suggestsabnormal oxygenation

VO2, oxygen consumption in mL/kg/min; VCO2, carbon dioxide output in mL/kg/min; VE, expiratory ventilation in mL/min; VT, anaerobic (ventilatory) threshold; VE/VCO2,minute ventilation/carbon dioxide production relationship; peakEtCO2, mm Hg, partial pressure of end-tidal carbon dioxide; SAO2, oxyhemoglobin saturation; RER, respiratoryexchange ratio.

heart

&lung

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Appendix 2 e Calculation of Wells score

Clinical characteristic Score

Clinical signs and symptoms ofdeep vein thrombosis (entire legswelling or calf swelling at least3 cm larger than that on theasymptomatic side measured10 cm below the tibialtuberosity)

3

PE as or more likely than analternative diagnosis

3

Heart rate > 100/min 1.5Immobilization or surgery in theprevious 4 wk

1.5

Hemoptysis 1Active cancer (patients receivingtreatment for cancer within theprevious 6 mo or currentlyreceiving palliative treatment)

1

Previous deep vein thrombosis orPE

1.5

PE was deemed unlikely if the score was < 2.0.

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