1. Workup of Dyspnea - Pulmonary Joel A Wirth, MD, FCCP Director, Division of Pulmonary and Critical Care Medicine, Maine Medical Center Staff Physician, Chest Medicine Associates

2. Case 2 48 year old woman with unexplained exertional dyspnea. Age 9: CHD (ASD with endocardial cushion defect) with a late repair at Boston Children’s Hospital Age 10: Mitral Valve replacement ( porcine) Age 13: Mechanical valve. Age 40: MV re-do with a TV ring and pacemaker placement. Worsening DOE for the past 8 years. She is a lifelong nonsmoker, has history of mild asthma. Episodes of daily chest tightness are very severe, aggravated climbing stairs, supine position and humidity. Associated symptoms include dry cough, fatigue, lower extremity edema and occasional wheezing. 48 year old woman with unexplained exertional dyspnea. Age 9: CHD (ASD with endocardial cushion defect) with a late repair at Boston Children’s Hospital Age 10: Mitral Valve replacement ( porcine) Age 13: Mechanical valve. Age 40: MV re-do with a TV ring and pacemaker placement. Worsening DOE for the past 8 years. She is a lifelong nonsmoker, has history of mild asthma. Episodes of daily chest tightness are very severe, aggravated climbing stairs, supine position and humidity. Associated symptoms include dry cough, fatigue, lower extremity edema and occasional wheezing.

3. Case 2 (Continued) Past Medical/Surgical History Congenital heart disease s/p ASD and MV repair, TV ring Secondary pulmonary hypertension Bradycardia s/p pacemaker placement Right hemidiaphragm paralysis (phrenic nerve injury) 2005 Diastolic heart failure Hepatitis C Asthma Medications VITAMIN B COMPLEX, VALIUM, COUMADIN, CITALOPRAM, ATIVAN Social History Education and Employment: Radiation therapist. Never smoker.

4. PHYSICAL EXAMINATION Vital Signs PRRBPSpO2Weight kg/lbBMI 7816104/6897% on RA59.320/130.821.43 Physical Exam Constitutional No apparent distress. Thin and well developed. Head / Face Normocephalic. ENTNormal. No mucosal lesions. Respiratory Normal to inspection and palpation. Lungs CTA. Right hemidiaphragm diminished excursion to percussion. Cardiovascular RRR. Crisp MV Prosthetic HS. No MRG. Abdomen Soft, non-tender without organomegaly or masses. Back / Spine No kyphosis or scoliosis. Musculoskeletal No skeletal tenderness or joint deformity. Extremities No edema or cyanosis, no clubbing. Neurological Alert and oriented. Psychiatric No anxiety or depression. Case 2 (Continued)

5. Our Patient: Resting Echocardiogram

6. Basic Workup of Exertional Dyspnea Lung Disease Airways disease Interstitial Lung Disease Neuromuscular Disease Vocal Cord Dysfunction PFTs Chest Imaging (CXR, CT) Methacholine Challenge Testing Heart Disease Myocardial Disease (Systolic, Diastolic) Valvular Heart Disease Coronary Artery Disease EKG Echocardiography BNP Pulmonary Vascular Disease (Pulmonary Hypertension, PE) Echocardiography, CTPA, V/Q Metabolic Disease Anemia Thyroid Disease CBC, TFTs Deconditioning, AnxietyExclusion

7. Our Differential Diagnosis for her Dyspnea: 1.Lung Disease Airways disease (Asthma) Interstitial Lung Disease Vocal Cord Dysfunction Thoracic Cage Abnormality (Paralyzed right hemidiaphragm) 2.Heart Disease Left ventricular diastolic dysfunction Valvular Heart Disease Pacemaker Malfunction Coronary Artery Disease 3.Pulmonary Vascular Disease (Pulmonary Hypertension, PE) 4.Peripheral (Myopathy/Malnutrition/Neuromuscular dysfunction) 5.Anemia 6.Thyroid Disease 7.Deconditioning 8.Perception/Anxiety

8. Evaluation of Unexplained Dyspnea Balady G J et al. Circulation. 2010;122:191-225

9. Does Anemia cause dyspnea and exercise limitation? Cote et al., Eur Resp J. 2007 29:923-929

10. Thyroid Disease: Mechanisms for Exertional Dyspnea Hyperthyroidism: Reduced Heart Rate Reserve Slower Heart Rate and BP Recovery Hypothyroidism: Impaired oxygen metabolism Reduced maximal Heart Rate Reduced maximal Ventilation

11. Causes of dyspnea as assessed by Spirometry Echocardiography, & EKG in 129 Danish Subjects Only 69% of patients were diagnosed by these 3 tests * Heart Disease defined as AFib, LV systolic dysfunction or valve disease † Lung Disease defined as FEV1% < 70% ‡ Obesity defined as BMI > 30 kg/m 2 Pedersen et al., Int J Clin Pract, 2007, 61, 9, 1481–1491

12. Why perform exercise testing for exertional dyspnea? Cardiopulmonary measurements obtained at rest may not reliably reflect functional capacity or limitations Determine if dyspnea is physiologic or pathologic Determine cause of limitation: cardiac, pulmonary, or peripheral

13. Types of Exercise Tests 6-min walk test  Submaximal Shuttle walk test  Incremental, maximal, symptom-limited Exercise bronchoprovocation Exertional oximetry Cardiac stress test Exercise echocardiography Cardiopulmonary Exercise Testing (CPET)

14. What can CPET do for YOU? 1.Evaluation of dyspnea Distinguish Cardiac vs Pulmonary vs Peripheral limitation Detection of exercise-induced bronchospasm (EIB) 2.Pulmonary rehabilitation Exercise intensity/prescription Response to participation 3.Pre-op evaluation and risk stratification Lung resection 4.Prognostication of life expectancy Congestive Heart Failure/Cardiomyopathy Pulmonary Arterial Hypertension Cystic Fibrosis 5.Assess response to therapy COPD, Asthma, PAH 6.Disability determination 7.Fitness evaluation

15. Internal and External Respiration

16. What is CPET? Symptom-limited exercise test Measure workload, ventilation, SpO 2, HR, Blood Pressure, EKG, oxygen consumed and carbon dioxide expired, respiratory exchange ratio (RER) Allows calculation of peak oxygen consumption, anaerobic threshold Identifies general cause of exercise limitation and if limit is normal or abnormal

17. Contraindications to CPET Acute MI Unstable angina Unstable arrhythmia Acute endocarditis, myocarditis, pericarditis Syncope Severe, symptomatic AS Uncontrolled CHF Acute PE, DVT Respiratory failure Uncontrolled asthma SpO 2 < 88% on RA Significant non-cardiopulmonary disorder that may affect or be adversely affected by exercise Psychiatric/cognitive impairment limiting cooperation

18. Relative Contraindications to CPET Left main or 3-V CAD Severe arterial HTN (>200/120) Significant pulmonary HTN Tachyarrhythmia, bradyarrhythmia High degree AV block Hypertrophic cardiomyopathy Electrolyte abnormality Moderate stenotic valvular heart disease Advanced or complicated pregnancy Orthopedic impairment

19. General Mechanisms of Exercise Limitation Pulmonary – Ventilatory – Respiratory muscle dysfunction – Impaired gas exchange Cardiovascular – Reduced stroke volume – Abnormal HR response – Circulatory abnormality – Blood abnormality Peripheral – Inactivity/Atrophy/ Malnutrition – Neuromuscular dysfunction – Reduced oxidative capacity of skeletal muscle Perceptual Motivational

20. General Mechanisms of Exercise Limitation Pulmonary – Ventilatory – Respiratory muscle dysfunction – Impaired gas exchange Cardiovascular – Reduced stroke volume – Abnormal HR response – Circulatory abnormality – Blood abnormality Peripheral – Inactivity/Atrophy/ Malnutrition – Neuromuscular dysfunction – Reduced oxidative capacity of skeletal muscle Perceptual Motivational

21. Figure 7. Flow-volume loops. Balady G J et al. Circulation. 2010;122:191-225 Ventilatory Limits to Exercise: Expiratory Flow Rates and MVV

22. Figure 6. V ̇ o2 kinetics. Balady G J et al. Circulation. 2010;122:191-225 Oxygenation Limits to Exercise: Oxygen Deficit and Debt

23. Use of the “V-Slope” Method to detect the Ventilatory (Anaerobic) Threshold, VT (AT) Balady G J et al. Circulation. 2010;122:191-225

24. CPET Pulmonary Parameters 1.O 2 consumed = V O2 2.CO 2 produced = V CO2 3.Respiratory Exchange Ratio (RER) = CO 2 produced / O 2 consumed=V CO2 / V O2 4.Maximum Minute Ventilation (Ve max ) = measured exhaled volume (L/min) 5.Maximum Voluntary Ventilation = Peak Ventilation in L/min Normal = 35 to 41 times FEV1 6.Breathing Reserve = (Predicted MVV – Ve max /Predicted MVV) x 100% Normal > 30% 7.Ventilatory equivalent for CO 2 = V e / V CO2 Efficiency of ventilation, normal is < 30 and improves during exercise Liters of ventilation to eliminate 1 L of CO 2 8.Ventilatory equivalent for O 2 = V e / V O2 Liters of ventilation per L of oxygen uptake

25. General Mechanisms of Exercise Limitation Pulmonary – Ventilatory – Respiratory muscle dysfunction – Impaired gas exchange Cardiovascular – Reduced stroke volume – Abnormal HR response – Circulatory abnormality – Blood abnormality Peripheral – Inactivity/Atrophy/ Malnutrition – Neuromuscular dysfunction – Reduced oxidative capacity of skeletal muscle Perceptual Motivational

26. Cardiac Limits to Exercise: Maximum HR by Age

27. Oxygen Consumption: Fick Equation Fick Equation: Q = VO 2 / C(a-v)O 2 VO 2 = Q x 1.34(SaO2 - SvO2)(Hgb) VO 2 = SV x HR x 1.34(SaO2 - SvO2)(Hgb) Heart disease Muscle disease Deconditioning Lung diseaseAnemia

28. CPET Cardiac Parameters 1.Maximum Heart Rate = HR max 2.Heart Rate Reserve = (Predicted HR max – HR max )/Predicted HR max x 100% Normal is < 15% 3.Heart Rate Response (HRR) = Change in HR/Change in V O2 4. Oxygen Pulse = V O2 / HR ≈ SV Fick Equation: V O2 = SV x HR x C(a-v)O 2 V O2 / HR = SV x C(a-v)O 2 Oxygen Pulse: “...the amount of oxygen consumed by the body from the blood of one systolic discharge of the heart.” Henderson and Prince. Am J Physiol 35:106, 1914

29. Abnormal Exercise Responses during CPET Balady G J et al. Circulation. 2010;122:191-225

30. CPET Patterns of Cardiac and Pulmonary Disease during Exercise Adapted from: Balady G J et al. Circulation. 2010;122:191-225 MEASUREMENTSYMBOL CARDIACPULMONARY FINDINGS Maximum Oxygen Consumption VO2 max Reduced Maximum Heart Rate HR max > 85% predicted < 85% predicted Breathing Reserve BR > 30%< 15% Oxygen Saturation SaO2 > 90%< 90% Oxygen Pulse VO2 max /HR < 12 ml/beat > 12 ml/beat Ventilatory Equivalent for CO2 VE/VCO2 < 30> 30 Anaerobic Threshold/VO2 max AT (or VT) < 40%> 40%

31. Our Patient

32. Our Patient: Pulmonary Function Parameter Patient%Predicted FVC 2.66L69% FEV1 2.24L74% FEV1% 84% TLC 4.24L79% FRC 2.91L96% RV 1.57L84% DLCO 15.962%

33. Our Patient: CPET Parameter PatientNormal VO2 max 22.3 ml/min/kg30.2 (74%) RER 1.1>1.0 HR max 98 beats/min168 (58%) VO2 max /HR 13.9 ml/beat10.5 (132%) BR (87-38)/87 = 56%> 30% VE/VCO2 27< 30 SaO2 96%> 92% AT (or VT) 69%> 40%

34. Our Patient: CPET 168 87 12

35. Our Differential Diagnosis for her Dyspnea: 1.Lung Disease Airways disease (Asthma) Interstitial Lung Disease Vocal Cord Dysfunction Thoracic Cage Abnormality (Paralyzed right hemidiaphragm) 2.Heart Disease Left ventricular diastolic dysfunction Valvular Heart Disease Pacemaker Malfunction Coronary Artery Disease 3.Pulmonary Vascular Disease (Pulmonary Hypertension, PE) 4.Peripheral (Myopathy/Malnutrition/Neuromuscular dysfunction) 5.Anemia 6.Thyroid Disease 7.Deconditioning 8.Perception/Anxiety