ERS Annual Congress Milan September 2017 Skills workshop SW 7, 9, 11 Cardiopulmonary exercise test interpretation: tips and pitfalls

Transcription

1 ERS Annual Congress Milan September 2017 Skills workshop SW 7, 9, 11 Cardiopulmonary exercise test interpretation: tips and pitfalls Monday, 11 September :00 10:20 10:40 13:00 14:30 16:50 Green 3 (North) MICO

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3 Skills workshop : SW7,9,11 Cardiopulmonary exercise test interpretation: tips and pitfalls Aims : To identify typical patterns of response to cardiopulmonary exercise testing and to show how to discriminate these from anomalous response profiles that can cause misinterpretation of test results. Tracks: Exercise, rehabilitation and physiology Tags: Basic translational science Target audience: Allied health professional - Cardiologist - Fellow - Lung function technician - Physiologist - Physiotherapist - Pulmonologist - Researcher - Respiratory physician - Respiratory therapist - Scientist - Student Chairs : Susan Ward (Crickhowell, United Kingdom), Denis O'Donnell (Kingston, ON, Canada) Introduction Oxygen uptake: relationship between work and uptake rate Richard Casaburi (Rancho Palos Verdes, United States of America), Paolo Palange (Rome, Italy) Anaerobic/lactate threshold Harry Rossiter (Hermosa Beach, United States of America), Susan Ward (Crickhowell, United Kingdom) Breathing pattern and dynamic hyperinflation Denis O'Donnell (Kingston, ON, Canada) Ventilatory efficiency Paolo Onorati (Alghero, Italy), J. Alberto Neder (Kingston, ON, Canada)

4 COMING SOON ERS monograph Clinical Exercise Testing Edited by Paolo Palange, Pierantonio Laveneziana, Alberto Neder and Susan A. Ward ISBN Chapters will include: determinants of physiological system responses; discriminating features of responses; reference values; response patterns; and exercise testing in children, cystic fibrosis, lung and heart disease, COPD and lung transplantation. Clinical Exercise Testing will be published in June 2018 and will be available to order from April 2018 at ersbookshop.com If you re an ERS member, you automatically have full online access to the ERS Monographs. Find out more ERSPUBLICATIONS.COM

5 Thank you for viewing these presentations. We would like to remind you that these materials are the property of the authors. It is provided to you by the ERS for your personal use only, as submitted by the authors by the authors

6 ERS 2017 Cardiopulmonary Exercise Testing Skills Workshop Workstation 2: Anaerobic/Lactate Threshold Harry B. Rossiter, PhD Division of Pulmonary and Critical Care Physiology and Medicine, David Geffen School of Medicine at UCLA, LA BioMed at Harbor-UCLA Medical Center, Torrance, CA Introduction The objective of this workstation is to better understand the method by which the lactate threshold (LT) is identified non-invasively using gas exchange and ventilatory variables during a ramp-incremental cardiopulmonary exercise test (CPET). Principles of ramp-incremental cardiopulmonary exercise testing Clinical cardiopulmonary exercise test (CPET) aims to uncover physiological system failure(s) by placing the system under stress. Stressing organ systems that contribute to exercise intolerance should reveal abnormality from the magnitude and/or profile of physiologic responses. Interpretation is based on two inter-related perspectives: 1. discriminating an abnormal magnitude or pattern of response (compared with the age-, gender- and activity-matched standard subject ) of selected variables, and 2. matching the magnitude or pattern of abnormality with that characteristic of particular impairments of physiological system functions observed in disease states The ramp-incremental exercise test, where the power output is increased as a smooth function of time until the limit of tolerance, aims to optimize the stress profile to make abnormalities easily discriminable, while minimizing the time, effort and strain on the participant and clinical laboratory. An optimal ramp-incremental exercise test (or ramp test) is spans an individual s entire tolerance range within ~ 10 minutes. Concomitant gas exchange, ventilatory and electrocardiographic measurements provide an effective means of assessing the integrative functioning of the physiological systems, including: a) establishing the upper limits (peak) of system function b) defining the effective operating range (the range of aerobic capacity ); c) evaluating exercise responses in comparison to a reference population, or with regard to other physiological functions; d) providing a frame of reference for change with respect to therapeutic interventions or training; e) as a means of "triggering" an abnormality, and typically most importantly; f) identifying the cause(s) of exercise intolerance. Estimation of the lactate (or anaerobic) threshold The lactate threshold (or anaerobic; LT or AT) is the greatest metabolic rate, typically expressed in units of oxygen uptake (V O 2, L/min or ml/min/kg), at which arterial blood [lactate] can be stabilized at, or below, the resting concentration. While the LT can be measured invasively from rapid sampling of the arterial blood, the preferred approach in the clinical setting is to estimate the lactate threshold non-invasively from features present in the combined ventilatory and gas exchanges responses during a 1

7 CPET ramp test. Using this method, not only are demands on patients and technical support minimised, but because sampling of ventilatory and gas exchanges variables can be made more rapidly than arterial blood i.e. on a breath-by-breath basis, better threshold discrimination can also result. The basis of is the close inverse-proportionality that exists between blood [lactate] and [bicarbonate]. Accumulation of lactate and associated hydrogen ion is buffered in the muscle and blood by potassium bicarbonate and sodium bicarbonate respectively. This leads to the formation of carbonic acid which rapidly dissociates to CO 2 and H 2 O. The rate of additional CO 2 flux towards the lung from this source, supplements the rate of CO 2 output (V CO 2 ) produced by aerobic metabolism in the mitochondrial TCA cycle, and can be measured in the pulmonary gas exchange as an increase in V CO 2 in relation to V O 2 (Fig 1). R=1 LT Figure 1. Carbon dioxide output (V CO 2 ) in relation to oxygen uptake (V O 2 ) during ramp-incremental exercise in a patient with heart failure. An abrupt increase in V CO 2 relative to V O 2 indicates the lactate-threshold (LT), where the rate of change of ΔV CO 2 /ΔV O 2 (R) increases above a value of 1. N.B. the rate of change of R is not, by necessity, the same as the absolute value of R. Redrawn from Bowen et al.,

8 The intersection of the S 1 (slope 1, below LT) and S 2 (slope 2, above LT) regions of the V CO 2 - V O 2 relationship (termed, the V-slope plot) is the primary source for estimating the LT. However, this relationship alone is not sufficient to confirm that the additional V CO 2 output does not derive from a source other than bicarbonate buffering of the metabolic acidosis. There are three potential sources of additional V CO 2 during the ramp test: 1. An abrupt increase in the rate of aerobic metabolism of carbohydrates or fatty acids 2. Pulmonary hyperventilation causing a fall in alveolar and arterial PCO 2 3. Buffering of a metabolic acidosis by bicarbonate The third source is the one that identifies the LT, but the other sources must also be ruled out. Source #1 (an abrupt increase in the rate of aerobic metabolism) is ruled out by plotting V CO 2 against V O 2. An increase in aerobic metabolism, such as might occur if additional muscle activity occurred (e.g. onset of excessive body movement or arm work during cycling), is expected to increase both V O 2 and V CO 2 in a proportion between ~0.7 and 1.0. In other words this mechanism would not selectively increase V CO 2 at a rate in excess of that of V O 2. Source #2 (pulmonary hyperventilation) can be ruled out by inspection of both the end-tidal gas tensions (P ET CO 2 and P ET O 2 ) and the ventilatory equivalents (the ratios of ventilation with gas exchange; V E/V CO 2 and V E/V O 2 ). V E has been widely demonstrated to change as a linear function of V CO 2 over a wide range of power output during ramp exercise: V E = mv CO 2 + c where the slope (m) equals ΔV E/ΔV CO 2, and c is the V E intercept. V E can also usefully be normalised with respect to V CO 2 to yield the ventilatory equivalent for CO 2 (V E/V CO 2 ): V E/V CO 2 = m + c/v CO 2 Re-arranging this equation yields: m = V E/V CO 2 - c/v CO 2 That is, V E/V CO 2 declines with increasing power output in a curvilinear (or hyperbolic) fashion, and the minimum asymptote of this V E/V CO 2 ratio is equal to m at very high power output. For convenience, the asymptote is often approximated by the V E/V CO 2 value at the lactate threshold, or at its minimum point during the ramp test (the former is approximately 1 unit greater than the latter). An important feature of the V E response for ramp tests is that the linearity of the V E-V CO 2 relationship is maintained beyond LT. That is, V E changes in proportion to the total CO 2 load, which represents the aerobic metabolic component (source #1) supplemented by additional CO 2 released by the bicarbonate buffering of the metabolic (source #3). The linearity of the V E-V CO 2 relationship extending above LT means that hyperventilation (source #2) can be ruled out as a mechanism of increased V CO 2 at the LT identified from the V- 3

9 slope. There is no evidence of a reduction in PaCO 2 at the LT in a ramp test, to provide respiratory compensation for the lactic acidosis: rather, the respiratory compensation for the metabolic acidosis begins at higher power output, when both V E/V CO 2 and m begin to increase. The phase between LT and the respiratory compensation point (RCP) is sometimes termed the phase of isocapnic buffering, and serves to provide corroboration that the identified LT is indeed realted to buffering the metabolic acidosis and is not hyperventilatory in origin. Further corroboration is sought in P ET CO 2 (a surrogate for relative changes in PaCO 2, albeit an index that comes with many caveats), which should be stable or rising at metabolic rates exceeding the LT. Conversely, an abrupt fall in P ET CO 2 and increase in V E/V CO 2 (or m) would indicate that the additional CO 2 output was hyperventilatory in origin and therefore not V E, on the other hand, does not change in a usefully-constant relationship to V O 2 as power output increases. Therefore, the ventilatory equivalent for O 2 (V E/V O 2 ), is used as an index of the additional ventilatory drive that attends the accelerated CO 2 output at power outputs above LT. V E/V O 2 and V E/V CO 2 decline throughout the moderate power output range, however, V E/V O 2 begins to increase (and P ET O 2 begins to fall) at LT reflective of the ventilatory consequences of the increased CO2 output from buffering the acidosis. Therefore, overall, the LT can be identified from combined gas exchange and ventilatory indices of: An increase in V CO 2 relative to V O 2, i.e. a breakpoint in the V-slope plot An increase V E/V O 2 and a decrease in P ET O 2 And that the above occur without an abrupt increase in V E/V CO 2 or decrease in P ET CO 2 Conclusion The lactate threshold occurs at a metabolic rate that engenders a sustained metabolic acidosis. The LT can be reliably estimated non-invasively using ramp-incremental exercise with combined gas exchange and ventilatory measurements. The LT is identified from an increased rate of pulmonary CO 2 output relative to O 2 uptake, and which is verified to be not of hyperventilatory origin. References ATS/ACCP Statement on Cardiopulmonary Exercise Testing. IV. Conceptual and physiologic basis of cardiopulmonary exercise testing measurements. Johnson B, Whipp B., Zeballos J, Weisman IM, Beck K, Mahler D, Cotes J, Sietsema K, Killian K. Am J Respir Crit Care Med 167: , Beaver WL, Wasserman K, Whipp BJ. Bicarbonate buffering of lactic acid generated during exercise. J Appl Physiol 60: , Beaver WL, Wasserman K, Whipp BJ. A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol 60: ,

10 Bowen TS, Cannon DT, Begg G, Baliga V, Witte KK, Rossiter HB. A novel cardiopulmonary exercise test protocol and criterion to determine maximal oxygen uptake in chronic heart failure. J Appl Physiol 113: , Neder JA, Nery LE, Peres C, Whipp BJ. Reference values for dynamic responses to incremental cycle ergometry in males and females aged 20 to 80. Am J Respir Crit Care Med 164: , Ozcelik O, Ward SA, Whipp BJ. Effect of altered body CO2 stores on pulmonary gas exchange dynamics during incremental exercise in humans. Exp Physiol 84: , Palange P, Ward SA, Carlsen K-H, Casaburi R, Gallagher C, Gosselink R, Puente-Maestu L, O Donnell D, Schols A, Singh S, Whipp BJ. Recommendations on the use of exercise testing in clinical practice. Eur Resp J 29: , Reinhard U, Muller PH, Schmulling RM. Determination of anaerobic threshold by the ventilation equivalent in normal individuals. Respiration 38: 36-42, Roca J, Whipp BJ. Eds: Clinical Exercise Testing. European Respiratory Monograph vol 2, No 6. Sheffield: European Respiratory Journals, Sun X-G, Hansen JE, Garatachea N, Storer TW, Wasserman K. Ventilatory efficiency during exercise in healthy subjects. Am J Respir Crit Care Med 166: , Ward SA. Discriminating features of responses in cardiopulmonary exercise testing. European Respiratory Monograph 40:36-68, Ward SA, Whipp BJ. Influence of body CO2 stores on ventilatory-metabolic coupling during exercise. In: Control of Breathing and Its Modeling Perspective. Eds: Honda Y, Miyamoto Y, Konno K, Widdicombe JG. New York: Plenum Press, 1992, pp Wasserman K, Hansen JE, Sue DY, Stringer WW, Sietsema KE, Sun XG, Whipp BJ. Principles of Exercise Testing and Interpretation, 5th edition. Lippincott Williams & Wilkins: Philadelphia, Whipp BJ. The bioenergetic and gas-exchange basis of exercise testing. Clin Chest Med 15: , Whipp BJ. Physiological mechanisms dissociating pulmonary CO 2 and O 2 exchange dynamics during exercise in humans. Exp Physiol 92: , Whipp BJ, Mahler M. Dynamics of gas exchange during exercise. In: Pulmonary Gas Exchange, Vol. II. Ed: West JB. New York: Academic Press, pp 33-96, Whipp BJ., Wagner PD, Agusti A. Determinants of the physiological systems responses to 5

11 muscular exercise in healthy subjects. In: Clinical Exercise Testing Eds: Palange P, Ward SA. European Respiratory Monograph 40, pp 1-35, Whipp BJ, Ward SA. The coupling of ventilation to pulmonary gas exchange during exercise. In: Pulmonary Physiology and Pathophysiology of Exercise. In: Whipp BJ & Wasserman K, eds.), pp , Dekker, New York, Whipp BJ, Ward SA. The physiological basis of the 'anaerobic threshold' and implications for clinical cardiopulmonary exercise testing. Anaesthesia 66(11): , Whipp BJ, Ward SA, Wasserman K. Respiratory markers of the anaerobic threshold. Adv Cardiol 35: 47-64,

12 ERS 2017 Skills workshop Cardiopulmonary exercise test interpretation: tips and pitfalls Workstation 2: Anaerobic/Lactate threshold Harry B Rossiter PhD, FACSM Division of Respiratory & Critical Care Physiology & Medicine David Geffen School of Medicine at UCLA Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center hrossiter@ucla.edu Nothing to Disclose

13 Conflict of interest disclosure I have no real or perceived conflicts of interest that relate to this presentation. I have the following real or perceived conflicts of interest that relate to this presentation: Affiliation / Financial interest Grants/research support: Commercial Company Honoraria or consultation fees: Participation in a company sponsored bureau: Stock shareholder: Spouse / partner: Other support / potential conflict of interest: This event is accredited for CME credits by EBAP and EACCME and speakers are required to disclose their potential conflict of interest. The intent of this disclosure is not to prevent a speaker with a conflict of interest (any significant financial relationship a speaker has with manufacturers or providers of any commercial products or services relevant to the talk) from making a presentation, but rather to provide listeners with information on which they can make their own judgments. It remains for audience members to determine whether the speaker s interests, or relationships may influence the presentation. The ERS does not view the existence of these interests or commitments as necessarily implying bias or decreasing the value ofthe speaker s presentation. Drug or device advertisement is forbidden.

14 Objective To better understand the method by which the lactate threshold is identified non-invasively using gas exchange and ventilatory variables during an incremental cardiopulmonary exercise test

15 Cellular Respiration Drives Gas Exchange after Wasserman et al. J Appl Physiol 22:71-85, 1967

16 Ramp-incremental Exercise Test Ramp-Incremental Exercise Test A smooth increase in work rate, from unloaded exercise, until the limit of tolerance is reached

17 Lactate Threshold Estimation.. * CH 3.CHOH.COO - + H + * * + Na + *.HCO - 3 i.e. Lactate ion & proton + Sodium bicarbonate * Sodium lactate * + * Carbonic acid* the dot CO 2. ΔVCO 2 increases H 2 CO 3 H 2 O Whipp BJ. Unpublished

18 Buffering the Exercise Acidosis

19 Buffering the Metabolic Acidosis Below LT Above LT

20 LT Estimation using Gas Exchange.. V E increases out of proportion to VO 2 (hyperventilation relative. to O 2 ), but matched to VCO 2 (no hyperventilation relative to CO 2 ) supplemental CO 2 load Whipp BJ et al. unpublished

21 LT Estimation using Gas Exchange 1. Supplemental CO 2 load at the lung 2. Hyperventilation relative to O 2 uptake Henson et al. Eur J Appl Physiol 59:21-28, 1989

22 Lactate Threshold Estimation 1. Supplemental CO 2 load 2. Hyperventilation relative to O 2 3. No hyperventilation relative to CO 2 Sue et al. Chest 94: , 1988

23 Lactate Threshold Estimation Sources of excess CO 2 output during ramp exercise 1. Accelerated aerobic substrate catabolism of fatty acids or carbohydrates 2. Pulmonary hyperventilation with a fall in alveolar (endtidal) and arterial PCO 2 3. Bicarbonate buffing: NaHCO 3 in blood, KHCO 3 in muscle Whipp BJ. Unpublished

24 False Positives Normocapnia P ET CO 2 = 40 mm Hg Prior Hyperventilation P ET CO 2 = 20 mm Hg S 1 S 1 Rosi index : R 0 /S 1 > 1.0 suggestive of a pseudothreshold Ozcelik, Ward & Whipp BJ. Exp Physiol. 84: , 1999

25 False Negatives 56yo, male IHD 38.7 kg/m 2 LVEF=30% BB, ACEi, Digoxin Asprin, Furosemide, Spironolactone, Statin Bowen et al. J Appl Physiol 113: , 2012

26 False Negatives R=1 Bowen et al. J Appl Physiol 113: , 2012

27 Conclusion The lactate threshold occurs at a metabolic rate that engenders a sustained metabolic acidosis and is estimated non-invasively from an increased rate of pulmonary CO 2 output relative to O 2 uptake, and which is not of hyperventilatory origin

28 Workstation 2: Anaerobic/lactate threshold Susan A Ward Human Bio-Energetics Research Centre Crickhowell, Powys, NP8 1AT, UK UNITED KINGDOM saward@dsl.pipex.com The principle underlying strategies of cardiopulmonary exercise testing (CPET) is that physiological system failure typically occurs while the system is under exertional stress. The goal of CPET is, therefore to stress those systems contributing to the exercise intolerance to a level at which abnormality becomes discernible, from the response magnitude and/or its profile. The interpretation of the overall test results can then be based on two inter-related perspectives: a) discriminating an abnormal magnitude and/or pattern of response (compared with the age-, gender- and activity-matched standard individual) of appropriately selected variables, and b) matching the magnitude and/or pattern of abnormality with that characteristic of specific impairments of physiological system function. EXERCISE TEST DESIGN The challenge is to select an exercise-test format that optimizes the exertional stress profile. A wide variety of tests are available, each being more or less suitable as a stressor of a particular component of the patient's pathophysiology. However, the appropriateness of the integrated systemic responses to exercise is best studied (at least, for the initial CPET evaluation) by means of an incremental or ramp test of relatively short duration (i.e. rapid ), as this provides a smooth and rapid gradational stress which spans an individual s entire tolerance range. An incremental ramp test which brings the patient to the limit of tolerance in ~ 10 minutes has been shown to provide an optimal ramp duration for assessing the integrative functioning of the involved physiological systems intolerance (Buchfuhrer et al 1983), including: a) establishing the limits of physiological system function; b) defining the effective operating range; c) evaluating the normalcy of exercise responses with regard to a reference population and/or with regard to other physiological functions; d) providing a frame of reference for change with respect to therapeutic interventions (e.g. training); e) as a means of "triggering" an abnormality, and typically most importantly; f) identifying the cause(s) of exercise (American Thoracic Society/American College of Chest Physicians 2003; Wasserman et al 2011). THE ANAEROBIC OR LACTATE THRESHOLD The anaerobic or lactate threshold (θ L) is the highest O 2 uptake ( V O2 ) at which arterial [lactate] does not show a systematic and sustained rise above resting levels. It is often the case that the low θ L values typical of chronic sedentarity and cardiac and pulmonary diseases are ascribed to compromised O 2-dependent processes, although intramuscular enzymatic rate limitation and fibretype recruitment may also be putative candidates (discussed in Gladden 2006; Wasserman et al 2011; Whipp 1994). The preferred approach in the clinical setting is to estimate θ L non-invasively using a symptomlimited rapid incremental or preferably ramp exercise test. Not only are the demands on patients and technical support minimised, but better L discrimination typically also results. The recommended criteria for L identification comprise the intersection point of the S 1 and S 2 regions of the relationship between CO 2 output ( V CO2 ) and V O2, coupled with indices to establish the presence of hyperventilation relative to O 2 but not CO 2, i.e. increases in the ventilatory equivalent for O 2 ( V / V O2 ) and end-tidal PO 2 (P ETO 2), with no increase in the ventilatory equivalent for CO 2 E

29 ( V E / V CO2 ) and no decrease in end-tidal PCO 2 (P ETCO 2) (American Thoracic Society/American College of Chest Physicians 2003; Reinhard et al 1979; Wasserman et al 2011; Whipp et al 1986). V CO2 - V O2 relationship The typical form of the V CO2 - V O2 relationship (also referred to as the V-slope relationship) during rapid ramp exercise is one in which the V CO2 response lags that of V O2 early in the transient (reflecting the slower response kinetics of the former) and then starts to increases reasonably linearly with respect to V O2 (reviewed in American Thoracic Society/American College of Chest Physicians 2003; Wasserman et al 2011). The slope of the V CO2 - V O2 relationship ( V CO2 / V O2 ) in this region has been termed S 1, with a value typically close somewhat less than unity in subjects on a typical western diet, reflecting the influence of the metabolic respiratory quotient (RQ) (reviewed in American Thoracic Society/American College of Chest Physicians 2003; Wasserman et al 2011). More important are changes in CO 2 storage in muscle and blood (i.e. factors that cause the respiratory exchange ratio (R = V CO2 / V O2 ) to differ from RQ) which can be influential, for example, when work rate (WR) is incremented rapidly, such that the increased trapping of metabolically-produced CO 2 resulting in a lower S 1 value (e.g. Ward & Whipp 1992). Above L, the V CO2 - V O2 relationship becomes steeper as aerobically-produced CO 2 is supplemented by additional CO 2 released from bicarbonate (HCO 3- ) buffering of protons associated with lactate accumulation; the V CO2 - V O2 slope in this higher WR region being termed S 2 (reviewed in American Thoracic Society/American College of Chest Physicians 2003; Wasserman et al 2011). The S 1-S 2 break-point has been demonstrated to coincide with the first point of increase in arterial [lactate] and the arterial [lactate]/[pyruvate] ratio and decrease in arterial [HCO 3- ] (reviewed in American Thoracic Society/American College of Chest Physicians 2003; Wasserman et al 2011); thus, it does not originate in either an acceleration of aerobic metabolism or in acute hyperventilation. And as the amount of CO 2 released in the proton buffering process is a function not of the magnitude of [HCO 3- ] decrease but of the rate of [HCO 3- ] decrease, the S 2 slope will be steeper with more rapid WR incrementation rates (e.g. Whipp & Mahler 1980; Ward & Whipp 1992; Whipp 2007). At some point above the S 1-S 2 break-point, delayed compensatory hyperventilation for the metabolic acidosis develops with consequent lowering of P ETCO 2 and arterial PCO 2 (PaCO 2) ( respiratory compensation ), the additional CO 2 released from stores supplementing V CO2 to further steepen the V CO2 - V O2 relationship (reviewed in American Thoracic Society/American College of Chest Physicians 2003; Wasserman et al 2011). Why respiratory compensation does not occur immediately at the L during rapid ramp exercise, i.e. when the acidosis first develops, is unclear but may reflect the existence of some time- or amplituderelated threshold for [H + ] detection by carotid body chemoreceptors (Whipp & Ward 1991; Ward 2014), possibly involving slow intracellular expression of the metabolic acidosis (Buckler et al 1991) and/or slow signal transduction at the level of an H + -sensitive type I voltage-sensitive tandem-p-domain K + channel (Buckler et al 2000). When the V CO2 - V O2 relationship cannot be partitioned into two clearly-linear segments, the V O2 point at which a unit tangent (i.e. Δ V CO2 /Δ V O2 = 1; the tangent occurring at 45 when V CO2 and V O2 axes have the same scale) impacts on the curve may be used as an alternative estimate of θ L (Sue et al 1988; Wasserman et al 2011). This is termed the modified V-slope relationship. Ventilatory equivalents The control of V E during exercise has been widely demonstrated to be more closely linked to CO 2 status than to O 2 status (reviewed in Whipp & Ward 1991). Thus, it is conventional practice to use V CO 2 rather than V O2 as the frame of reference for ventilation considerations. Thus, regulation of 2

30 3 PaCO 2 (and ph) during moderate exercise (i.e. below θ L) is the result of alveolar ventilation ( V ) increasing in proportion to V CO2 as WR increases: V A = 863 V CO2 /PaCO 2 However, a complexity is introduced with respect to total ventilation (i.e. V E ) by the requirement to ventilate the physiological dead space or the dead-space fraction of the breath (V D/V T): V E = 863 V CO2 /PaCO 2(1 - V D/V T) The requirements for PaCO 2 regulation become evident when the above equation is re-arranged, i.e. V E / V CO2 and V D/V T, which therefore must respond in exact proportion: PaCO 2 = 863/{( V / V )(1 - V D/V T)} E For example, higher than normal values of V E / V CO2 at any particular WR can reflect a low PaCO 2, a high V D/V T or both. However, a high V D/V T does not necessarily reflect abnormal pulmonary function, as it is highly dependent on the pattern of breathing: rapid, shallow breathing yielding a high V D/V T even in subjects with normal pulmonary function. The V E - CO2 E V relationship is well described as linear over a wide range of WRs, with a slope m and a small positive V E -intercept c: V E = m CO2 V + c Because of this intercept, V E / V CO2 will decline as WR and V CO2 increase (reflecting an improving efficiency of pulmonary gas exchange), specifically in a curvilinear (hyperbolic) fashion (Whipp & Ward 1982). Re-arrangement of the above equation into: m = V E / V CO2 - c/ V CO2 shows that V E / V CO2 will decline to a theoretical minimum of m at very high WRs and therefore V CO 2 values (Whipp & Ward 1982). On a practical note, this accounts for V E / V CO2 at θ L approximating m (reviewed in Wasserman et al 2011). For rapid ramp tests, the linearity of the V E - CO2 V relationship is maintained beyond θ L, reflecting the delayed onset of respiratory compensation, with the further increase in V CO2 - V O 2 slope being accompanied by V E / V CO2 and m starting to increase and P ETCO 2 starting to fall. In contrast, while V E / V O2 also declines in the moderate WR range, it starts to increase at θ L, reflective of the influence of the augmented V CO2 response on V E. That is, as respond in proportion to the increased CO2 V E continues to V demands, it must therefore increase out of proportion to V O2 (reviewed in American Thoracic Society/American College of Chest Physicians 2003; Wasserman et al 2011). Thus, θ L is characterized by hyperventilation relative to O 2 ( V E / V O2 and P ETO 2 starting to increase) but not relative to CO 2 ( V E / V CO2 not yet increasing and P ETCO 2 not yet falling) (American Thoracic Society/American College of Chest Physicians 2003; Reinhard et al 1979; Wasserman et al 2011; Whipp et al 1986). End-tidal gas tensions End-tidal gas tensions during exercise, i.e. the values determined at the end of an exhalation, are easy to measure and extremely difficult to interpret (reviewed in American Thoracic Society/American College of Chest Physicians 2003; Whipp 1994; Wasserman et al 2011). During exhalation, the instantaneous alveolar PCO 2 (P ACO 2) continues to increase at a rate that is dependent on the mixed venous PCO 2 value (by diffusion) and to a level that depends on the duration of the exhalation. Thus, at the end of the exhalation P ETCO 2 will be higher than the mean P ACO 2 (and the mean PaCO 2). During the subsequent inspiration, the instantaneous P ACO 2 will decline back consequent to the diluting effects of the inspired air. This creates an intra-breath A

31 4 P ACO 2 oscillation (DuBois et al 1952) whose magnitude in the moderate-intensity domain (i.e. V below θ L) becomes more marked as WR increases, because of the demands of increasing CO2 (reviewed in Whipp 1994). The scenario for P ETO 2 is essentially similar, but the mirror-image of PCO 2; i.e. with P ETO 2 declining with increasing WR despite a reasonably stable arterial PO 2. Thus, the profile of P ETCO 2 with increasing WR is normally such that it increases progressively up to the θ L, with a subsequent period of stability (isocapnic buffering) above θ L before falling at the point of respiratory compensation (reviewed in American Thoracic Society/American College of Chest Physicians 2003; Whipp 1994; Wasserman et al 2011). In contrast, P ETO 2 progressively decreases up to the θ L, at which it starts to increase systematically, accelerating further with the onset of compensatory hyperventilation. Final issues: Some Be Carefuls What is the optimal criterion for θ L discrimination? It is most appropriate that the V-slope approach is used in conjunction with the ventilatory equivalent and end-tidal gas tensions to establish a cluster of variables which cohere with each other to provide the best possible confidence in the estimation (American Thoracic Society/American College of Chest Physicians 2003; Reinhard et al 1979; Wasserman et al 2011; Whipp et al 1986). That is, it is important to emphasise that the demonstration of a break-point in the V CO2 - V O2 relationship cannot, on its own, be confidently ascribed to the onset of a metabolic (lactic) acidosis, as non-specific hyperventilation due to factors such as anxiety, pain or hypoxaemia cannot be ruled out. This requires additional ventilatory-based criteria to demonstrate the onset of hyperventilation relative to O 2 at L, but not to CO 2 - despite a falling arterial ph. What is the optimal work-rate incrementation rate for θ L discrimination? It is conventional practice that the incremental phase duration of a ramp test should be of the order of minutes; i.e. normally ~15-20 Watts/min, but less in poorly-fit individuals and most patients (American Thoracic Society/American College of Chest Physicians 2003; Wasserman et al 2011). Importantly, while θ L is largely independent of the WR incrementation rate (being measured as a V O2 ), the corresponding WR at which θ L is achieved becomes progressively greater the more rapid the WR incrementation rate (as is also the case for V O2 peak) (e.g. Whipp 1994). Slow WR incrementation rates are not recommended as they not only induce boredom and seat discomfort because of the prolonged test duration, but may also compromise the ability to convincingly discriminate θ L. This is the consequence of a slower rate of arterial [lactate] increase above θ L, a slower rate of arterial [HCO 3- ] decrease and a smaller contribution to V CO2 (the increase in V CO2 from these buffering reactions being a function of the rate at which arterial [HCO 3- ] is falling), R and therefore V E (e.g. Whipp & Mahler 1980; Ward & Whipp 1992; Whipp 2007). The change of slope between the S 1 and S 2 segments of the V-slope plot will therefore be smaller and harder to discern with confidence ( false negative ). Also, the onset of respiratory compensation will be far less delayed relative to θ L, constraining the range of isocapnic buffering and impairing the ability to conclusively rule out non-specific hyperventilation as the cause of threshold behaviour V (e.g. Whipp & Mahler 1980; Ward & Whipp 1992; Whipp 2007). E Does hyperventilation matter? A period of acute hyperventilation, either just prior to the ramp test or in its early stages, washes CO 2 out of body stores. This, at the least, can challenge discrimination of the S 1-S 2 break-point. But there can be a far more serious consequence: a false positive (Ward & Whipp 1992; Ozcelik et al 1999; Whipp 2007). That is, a greater-than-normal proportion of the metabolic CO 2 produced once the exercise starts will be diverted into the depleted body stores to recharge them back to normal levels, and therefore less will reach the lungs. Over this period the V CO2 - V O2 slope and R will therefore become abnormally low. Only when the stores have been recharged will the V CO2 - V O2 slope and R recover. This relative acceleration of V CO2 relative to

32 5 V O2 will, in turn, result in increases in V E and V E / V O2, but no change in V E / V CO2. This creates threshold-like behaviour at a time when arterial [lactate] is still unchanged from resting levels. This is a false positive or pseudo-threshold, as all the standard non-invasive criteria for θ L are met, but there is no associated metabolic acidosis. The clue to pseudo-threshold behaviour is that R is typically falling (or even just reaches an abnormally low nadir) consequent to the abnormally high CO 2 storage coincidentally with the supposed threshold. This means that the profile of R should be included in the cluster of variables used to discriminate θ L - but as a supporting index and not as one of primary discrimination. REFERENCES 1. American Thoracic Society/American College of Chest Physicians, ATS/ACCP Statement on Cardiopulmonary Exercise Testing. Am J Respir Crit Care Med 167: , Buchfuhrer MJ, Hansen JE, Robinson TE, Sue DY, Wasserman K, Whipp BJ. Optimizing the exercise protocol for cardiopulmonary assessment. J Appl Physiol 55: , Buckler KJ, Vaughan-Jones RD, Peers C, Lagadicgossmann D, Nye PCG. Effects of extracellular ph, PCO 2 and HCO 3 - on intracellular ph in isolated type-i cells of the neonatal rat carotid body. J Physiol 444: , Buckler KJ, Williams BA, Honore E. An oxygen, acid and anaesthetic sensitive TASK-like background potassium channel in rat arterial chemoreceptor cells. J Physiol 525: , DuBois AB, Britt AG, Fenn WO. Alveolar CO 2 during the respiratory cycle. J Appl Physiol 4: , Gladden LB. Lactate metabolism: a new paradigm for the third millennium. J Physiol 558: 5-30, Ozcelik O, Ward SA, Whipp BJ. Effect of altered body CO 2 stores on pulmonary gas exchange dynamics during incremental exercise in humans. Exp Physiol 84: , Reinhard U, Muller PH, Schmulling RM. Determination of anaerobic threshold by the ventilation equivalent in normal individuals. Respiration 38: 36-42, Sue DY, Wasserman K, Moricca RB, Casaburi R. Metabolic acidosis during exercise in patients with chronic obstructive pulmonary disease. Use of the V-slope method for anaerobic threshold determination. Chest 94: , Ward SA. Regulation of breathing during exercise. In: Colloquium Series on Integrated Systems Physiology: The Respiratory System. Eds: Granger DN, Granger JP. Morgan & Claypool Life Sciences Publishers: Princeton, Ward SA, Whipp BJ. Influence of body CO 2 stores on ventilatory-metabolic coupling during exercise. In: Control of Breathing and Its Modeling Perspective. Eds: Honda Y, Miyamoto Y, Konno K, Widdicombe JG. New York: Plenum Press, 1992, pp Wasserman K, Hansen JE, Sue DY, Stringer WW, Sietsema KE, Sun XG, Whipp BJ. Principles of Exercise Testing and Interpretation, 5th edition. Lippincott Williams & Wilkins: Philadelphia, Whipp BJ. The bioenergetic and gas-exchange basis of exercise testing. Clin Chest Med 15: , Whipp BJ. Physiological mechanisms dissociating pulmonary CO 2 and O 2 exchange dynamics during exercise in humans. Exp Physiol 92: , Whipp BJ, Mahler M. Dynamics of gas exchange during exercise. In: Pulmonary Gas Exchange, Vol. II. Ed: West JB. New York: Academic Press, pp 33-96, Whipp BJ, Ward SA. Cardiopulmonary coupling during exercise. J Exp Biol 100: , Whipp BJ, Ward SA. The coupling of ventilation to pulmonary gas exchange during exercise. In: Pulmonary Physiology and Pathophysiology of Exercise. Eds: Whipp BJ, Wasserman K. Dekker, New York, pp , Whipp BJ, Ward SA, Wasserman K. Respiratory markers of the anaerobic threshold. Adv Cardiol 35: 47-64, ADDITIONAL READING 1. Puente-Maestu L, Palange P, Casaburi R, Laveneziana P, Maltais F, Neder JA, O Donnell D,

33 6 Onorati P, Porszasz J, Rabinovich R, Rossiter HB, Singh S, Troosters T, Ward SA. Use of exercise testing in the evaluation of interventional efficacy: an official ERS statement. Eur. Resp. J 47: , Neder JA., Nery LE, Peres C, Whipp BJ.. Reference values for dynamic responses to incremental cycle ergometry in males and females aged 20 to 80. Am J Respir Crit Care Med 164: , Palange P, Ward SA, Carlsen KH, Casaburi R, Gallagher CG, Gosselink R, O'Donnell DE, Puente-Maestu L, Schols AM, Singh S, Whipp BJ. Recommendations on the use of exercise testing in clinical practice. Eur Resp J 29: , Ward SA. Discriminating features of responses in cardiopulmonary exercise testing. European Respiratory Monograph 40: 36-68, Whipp BJ, Wagner PD, Agusti A. Determinants of the physiological systems responses to muscular exercise in healthy subjects. In: Clinical Exercise Testing (Eds: Palange P, Ward SA), European Respiratory Monograph 40, pp. 1-35, Whipp BJ, Ward SA. The physiological basis of the 'anaerobic threshold' and implications for clinical cardiopulmonary exercise testing. Anaesthesia 66(11): , 2011.

34 Skills workshop Cardiopulmonary exercise test interpretation: tips and pitfalls Workstation 2: Anaerobic/Lactate threshold Susan A. Ward DPhil Human Bio-Energetics Research Centre Crickhowell, Powys, United Kingdom bfe

35 Conflict of interest disclosure I have no real or perceived conflicts of interest that relate to this presentation. I have the following real or perceived conflicts of interest that relate to this presentation: Affiliation / Financial interest Grants/research support: Commercial Company Honoraria or consultation fees: Participation in a company sponsored bureau: Stock shareholder: Spouse / partner: Other support / potential conflict of interest: This event is accredited for CME credits by EBAP and EACCME and speakers are required to disclose their potential conflict of interest. The intent of this disclosure is not to prevent a speaker with a conflict of interest (any significant financial relationship a speaker has with manufacturers or providers of any commercial products or services relevant to the talk) from making a presentation, but rather to provide listeners with information on which they can make their own judgments. It remains for audience members to determine whether the speaker s interests, or relationships may influence the presentation. The ERS does not view the existence of these interests or commitments as necessarily implying bias or decreasing the value of the speaker s presentation. Drug or device advertisement is forbidden.

36 Rapid-Incremental (or Ramp) Exercise Test incremental Time (min) ramp bfe Wasserman et al. PETI, 2011

37 * * * * * * bfe Whipp BJ. Unpublished. Susan A. Ward

38 ..... V E increases out of proportion to VO 2 (hyperventilation relative to O 2 ), but matched.. to VCO 2 (no hyperventilation relative to CO 2 ) supplemental CO 2 load Whipp BJ. Unpublished. Susan A. Ward bfe

39 V-slope approach 1: supplemental CO 2 load 2: hyperventilation relative to O 2 bfe Henson et al. Eur J Appl Physiol 59:21-28, 1989.

40 Sources of Excess CO 2 Output during Ramp Exercise 1) Accelerated aerobic substrate catabolism 2) Pulmonary hyperventilation, with a fall in alveolar (end-tidal) and arterial PCO 2? 3) Bicarbonate buffering: (NaHCO 3 in blood and KHCO 3 in muscle) bfe Whipp BJ. Unpublished Susan A. Ward

41 Ventilatory Control Whipp BJ & Ward SA. Unpublished. Susan A. Ward linear hyperbolic At very high WRs, ventilatory equivalent.. for CO 2 approaches V E -VCO 2 slope value bfe Modified from Whipp BJ. Clinics in Chest Med. 15: , 1994.

42 ^ L 1: supplemental CO 2 load 2: hyperventilation relative to O 2 but not CO 2 bfe Whipp BJ Unpublished

43 S=1 Modified V-slope approach Sue et al. Chest 94: , 1988 bfe

44 Lactate threshold bfe Wasserman et al. PETI, 2005 Fig (NL)

45 The Respiratory Compensation Point L RCP ICB RCP L ICB respiratory compensation point lactate threshold isocapnic buffering Why doesn t the respiratory compensation for the metabolic acidosis of exercise occur at the lactate threshold i.e. when arterial ph first starts to fall? bfe Modified from Wasserman et al. PETI, 2005, p 246

46 Some Be Carefuls! Whipp BJ. Unpublished Susan A. Ward bfe

47 V-slope Graph Scaling **Note the Scaling** bfe Wasserman et al. PETI, Fig

48 V-slope Graph Scaling bfe Whipp BJ. Unpublished Susan A. Ward

49 bfe False Positives

50 VO 2 V CO 2 But:.. VCO 2 can begin to increase faster than VO 2 : not just because it begins to be produced faster, but also because its rate of storage begins to slow or stop!! Whipp BJ. Unpublished Susan A. Ward bfe

51 CONTROL PRIOR HYPERVENTILATION bfe Ozcelik et al., 1999

52 3 VCO S 1 = VE/VO VE/VCO PETO 2 (mmhg) PETCO 2 RER bfe VO 2 (L/min)

53 R0 / S1 If R 0 / S 1 << 1.0, then likely a L However, If R 0 / S 1 >> 1.0, then likely a pseudo L bfe Ozcelik et al., 1999

54 bfe False Negatives

55 Rapid Incremental L Slow Incremental? bfe Modified from Whipp BJ, Mahler M. In: Pulmonary Gas Exchange, Vol. II. Ed.: West JB. New York: Academic Press, pp 33-96, 1980.

56 Workstation 2: Anaerobic/lactate threshold Susan A Ward Human Bio-Energetics Research Centre Crickhowell, Powys, NP8 1AT, UK UNITED KINGDOM saward@dsl.pipex.com Harry B Rossiter Division of Respiratory & Critical Care Physiology & Medicine David Geffen School of Medicine at UCLA Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center UNITED STATES OF AMERICA hrossiter@ucla.edu Each question may have more than one correct answer. 1. On a symptom-limited rapid incremental (or ramp) exercise test, the pulmonary CO2 output (V CO2) response normally steepens at the lactate (or anaerobic) threshold. This reflects an additional CO2 load deriving from: a) an accelerated rate of aerobic CO 2 production b) an increase in ventilation (V E) that causes arterial PCO 2 to fall, liberating CO 2 from arterial stores c) bicarbonate-buffering of the associated lactic acidosis d) a decrease in the physiological dead-space fraction of the breath (V D/V T), i.e. pulmonary gas exchange becomes more efficient 2. The following indices are necessary for reliable non-invasive estimation of the lactate (or anaerobic) threshold using a symptom-limited rapid incremental (or ramp) exercise test: a) the respiratory exchange ratio (RER, = V CO 2/ V O 2) equaling a value of 1.0 b) an increase in ventilation (V E) that is out of proportion to pulmonary CO 2 output (V CO 2), i.e. increased ventilatory equivalent for CO2 (V E/V CO 2) c) an abrupt increase in tidal volume d) an increase in ventilation (V E) that is out of proportion to pulmonary O 2 uptake (V O 2), i.e. increased ventilatory equivalent for O2 (V E/V O 2) 3. On a symptom-limited rapid incremental (or ramp) exercise test, a false positive can occur if: a) respiratory compensation for the metabolic acidosis occurs below the lactate (or anaerobic) threshold b) the physiological dead-space fraction of the breath (V D/V T) increases abruptly, i.e. pulmonary gas exchange becomes less efficient c) the patient acutely hyperventilated just prior to starting the exercise test d) the patient acutely hypoventilated just prior to starting the exercise test

57 Workstation 3: Breathing pattern and dynamic hyperinflation Dr. Pierantonio Laveneziana Sorbonne Universités, UPMC Université Paris 06 INSERM UMR_S 1158, Neurophysiologie Respiratoire Expérimentale et Clinique Faculté de Médecine Pierre et Marie Curie (site Pitié-Salpêtrière) 91 Boulevard de l Hôpital 75013, Paris FRANCE Service d Explorations Fonctionnelles de la Respiration, de l'exercice et de la Dyspnée Hôpital Universitaire Pitié-Salpêtrière (AP-HP), Boulevard de l'hôpital 75013, Paris FRANCE pierantonio.laveneziana@aphp.fr AIMS To identify typical patterns of response to cardiopulmonary exercise testing and to show how to discriminate these from anomalous response profiles that can cause misinterpretation of test results. Introduction Through examination and analysis of selected case studies, this Skills Workshop will address key interpretational indices that derive from a Cardiopulmonary Exercise Test in a hands on fashion with experts in the field, to allow participants to (re-)visit the physiological determinants of these indices, their optimal estimation and how they are influenced in commonly-encountered cardiopulmonary diseases characterized by exercise intolerance. Workstation 3: Breathing pattern and dynamic hyperinflation To include considerations of: breathing reserve; flow limitation; volume reserve; how to track dynamic hyperinflation; breathing pattern irregularities. SESSION FORMAT The educational skills workshops are designed to allow participants to gain practical skills in different disciplines of respiratory medicine. The workshops will revolve around workstations and use interactive demonstrations instead of traditional presentations and lectures. The maximum number of participants is 32 per workshop. Each group of 8 people spend 30 minutes per workstation. For the moment, only 2 workshops (10:40-13:00 and 14:30-16:50) are open for registrations. Once they are fully booked we will open up the morning session (08:00-10:20). EQUIPMENT Workstation Workstation 3: Breathing pattern and dynamic hyperinflation Equipment needed Flip chart with pens Laptops (provided by faculty) with set-up for screen projection

58 BREATHING PATTERN AND DYNAMIC HYPERINFLATION Breathing pattern (from [1]) Introduction The ventilatory response to exercise can be evaluated in terms of ventilatory demand, ventilatory efficiency and ventilatory profile. Ventilatory demand can be assessed as the relative contributions of tidal volume (VT) and respiratory frequency (fr) to total ventilation (VE), ventilatory efficiency as the steepness with which VE rises with respect to carbon dioxide production (VCO2) (i.e., the VE/VCO2 slope and ratio) and ventilatory response profile as the inflection points of the VT and VE relationship during exercise which is usually determined by examining individual Hey plots [2]. In healthy subjects, one, and sometimes two inflection points (VT/VE inflection 1 and 2) can be observed [2, 3]. In addition, the VT/VE inflection corresponds to the attainment of critical constraints on VT expansion and it marks the point where both dyspnoea intensity and selection of perceived unsatisfied inspiration sharply escalate in asthma [4] and COPD patients [5, 6]. Breathing pattern The contributions of tidal volume (VT) and (respiratory frequency) fr to the ventilatory response to incremental exercise can be usefully discerned from the ventilation (V E) VT relationship (Figure 1); although it has become more recently usual in clinical practice for VT to be plotted as a function of V E. Figure 1: Schematic representation of the relationship between minute ventilation (V E) and tidal volume (VT). The solid arrow represents the response in a subject who entrains at a constant breathing frequency (fr). 1, 2, 3: ranges 1, 2 and : iso fr isopleths : the maximum voluntary ventilation. : resting inspiratory capacity (IC). The direction of IC change with exercise is shown by the horizontal arrows: increasing in normal young adults (grey arrow); decreasing in patients with chronic obstructive pulmonary disease consequent to dynamic hyperinflation (dashed arrow); and initially increasing and then decreasing in elderly subjects. See text for further details. Two, and sometimes even three, ranges can normally be discerned in the V E VT relationship [2, 3]. In normal subjects who do not entrain their breathing rhythm to some constant unit multiple of their

59 locomotor cadence, V E initially increases linearly with respect to VT (range 1) up to a value corresponding to ~50 60% of vital capacity (VC): V E = m x VT - c where m is the V'E/VT slope (ΔV E/ΔVT) and c is the V E intercept; the modest contribution of fr in this range being evident in the crossing of lower V E VT isopleths (Figure 1). Indeed, because of the positive V E intercept, fr in range 1 will increase in a hyperbolic fashion as long as the V E VT remains linear. When subjects entrain with a constant fr despite increasing WR, however, the V E VT relationship intercepts at the origin (i.e. c = 0), indicating that increases in VT alone contribute to the V E response; the entrained fr value being equal to m (Figure 1). The V E VT relationship then typically becomes markedly steeper (range 2); this increase of VE is achieved largely by progressive increases in fr. As WR peak is approached, especially in highly fit subjects VT may be seen to actually decrease (range 3), the increasing V E being sustained by disproportionately large increases in fr (Figure 1). It should be noted that the wide variability in the normal breathing pattern response to exercise has hampered the formulation of normal values for the subcomponents of the V E VT relationship, and how their features are influenced by disease. In addition, the mechanisms that dictate this behaviour can only be speculated upon, even in normal healthy subjects, but may include: the influence of respiratorymechanical factors related to the disproportionately large increase in the elastic work of breathing as VT encroaches on the flatter region of the pulmonary compliance curve, especially as respiratory compensation for the metabolic acidosis develops above lactic/ventilatory threshold; and volume related activation of vagal pulmonary mechanoreceptors. The disproportionately large contribution of fr to the V E response that is often seen in more severe COPD and in restrictive lung disease is also associated with a disproportionately large increase in fr during exercise and coheres with these suggestions. When VT at or near peak exercise encroaches upon the inspiratory capacity (IC), this is widely taken to reflect a lack of volume reserve [4, 6, 7]. However, it should be noted that the value used in making such judgements is typically the value obtained under resting conditions. This is not a trivial distinction as (unlike total lung capacity) IC can change with WR to degrees and in directions that can differ widely depending on the particular subject being studied. For example, the progressive decline in endexpiratory lung volume (EELV), which is characteristic of normal healthy subjects [6] will cause IC to increase and thus delay the attainment of any volume-related limit. In contrast, in COPD, the occurrence of dynamic hyperinflation [5-7] will lead to a progressive fall in IC and, therefore, predispose to such a limit being attained at lower levels of V E. In the healthy elderly, the age-related loss of lung recoil can reverse the normal decline of EELV with increasing WR to yield dynamic hyperinflation at higher WRs. If account is not taken of this, the significance of volume limitation in such individuals could be substantially under-estimated. However, as VC is unlikely to change appreciably during exercise, account might better be taken of changes in lung size and functional operating ranges by expressing VT as a function of VC when making judgements about volume limitation, although its sensitivity for ILD has been questioned. Inspiratory capacity (from [8] and [9]) The inspiratory capacity (IC), the maximal volume of air that can be inhaled after a spontaneous quiet exhalation, is a relatively simple measurement and it does not require any specialized equipment since all metabolic systems are able to measure lung volume. Despite the simplicity of this measurement, the IC provides valuable information about dynamic respiratory mechanics during exercise. Serial IC measurements are used to track the behaviour of end-expiratory lung volume (EELV) during exercise - a change in IC reflects an inverse change in EELV [10, 11].

60 Dynamic Hyperinflation: physiological rationale EELV typically decreases with increasing work rate (WR) in healthy individuals [12-14]. In conditions such as COPD, expiratory airflow limitation and delayed regional mechanical time constants for lung emptying predispose to an increase in EELV during the increased ventilation of exercise [10]. This temporary and variable increase in EELV above the resting value is termed dynamic hyperinflation (DH) [15]. DH tends to ameliorate expiratory flow limitation but this beneficial effect soon becomes negated when IC and inspiratory reserve volume (IRV) decline to a critical level. At this point, tidal volume (V T) expansion becomes constrained and there is increased mechanical loading and functional weakness of the inspiratory muscles [5, 16, 17]. These mechanical events can be monitored noninvasively by measuring serial IC and breathing pattern throughout exercise. For this reason, IC is increasingly used as a primary or secondary outcome measure in clinical trials. The value of measuring IC is bolstered by the following facts: resting IC correlates well with as peak V'O 2; the IC/total lung capacity (TLC) ratio is an independent risk factor for mortality and acute exacerbation in patients with COPD; progressive reductions in the resting IC with increasing COPD severity have been shown to be associated with progressive, increasing mechanical constraints and respiratory discomfort during exercise. DH can be evaluated as the difference between the IC at rest and during exercise ( IC). The magnitude of DH that is clinically significant is unknown and will vary between patients. In general, changes in IC > 0.14L (or 4.5% of predicted) are beyond the physiological variability of the measurement (beyond the 95% confidence interval) [10, 18, 19] and likely have important mechanical and perceptual implications. One study has shown that there are no major differences in IC values when comparing treadmill versus cycle exercise in patients with COPD [20]. In addition, DH during exercise predicts morbidity and mortality in COPD [21]. Technical aspects For a comprehensively review of this topic please see Guenette et al. [9]. IC manoeuvres are carried out at the end of a steady-state resting baseline period (approximately 3 minutes) until at least 2 reproducible efforts are achieved (i.e., ±100 ml or within approximately 10% of the largest acceptable value) [10, 18, 19, 22, 23]. IC measurements at rest should not be performed closer than approximately 1 minute apart, and measurements should not be repeated until breathing has returned to the premanoeuvre pattern. During exercise, IC manœuvres are generally performed at 2 or 3 min intervals (typically during the final 30 seconds of each exercise stage when ventilation (V E) is assumed to be reasonably stable), and at the end of exercise. When subjects indicate that they cannot exercise any longer, an IC manoeuvre is immediately performed and the subject is allowed to cool-down; or if an acceptable IC has been performed within the preceding 30 sec and breathing pattern has not re-stabilized, then the value for that IC is used as the end-exercise value. Performing the peak exercise IC several breaths into recovery may not be accurate given that the breathing pattern typically changes immediately upon reducing the work rate and IC may quickly return to resting levels after exercise cessation. IC measurement can be challenging if the individual terminates exercise suddenly. Patients should be coached to inform the technician of their intention to stop approximately 10 seconds in advance so that the final IC can be successfully captured. To avoid possible effects of performing IC manoeuvres on dyspnoea intensity, IC manoeuvres are performed after completing ratings of symptom intensity. Unsatisfactory IC manoeuvres during exercise are usually not repeated until the next scheduled measurement interval.

61 From a technical standpoint, the IC manœuvre involves a maximal inspiration from a stable EELV to TLC. Despite the relative simplicity of this technique, prior to testing, careful and consistent instructions on how to appropriately perform the manœuvre should be given to the individual, and subjects should be given sufficient time to familiarise with the technique for performing IC manoeuvres and practise until a satisfactory manoeuvre is completed. Ideally, the investigator should be able to view the volume-time trace and/or the flow-volume loop tracing during and after the manœuvre. Depending upon which verbal cues worked best for each individual, subjects are generally given: a few breaths warning before a manoeuvre or simply reminded to keep breathing normally, a prompt for the manoeuvre (i.e., at the end of the next normal breath out, breathe all the way in ), and then verbal encouragement to make a maximal effort (i.e., in, in, in ) before relaxing back to pre-manoeuvre breathing. It is recommended to have 3-10 stable breaths (a minimum of 4 with a similar EELV) prior to the IC manœuvre in order to accurately establish the baseline EELV. The best approach is to continuously monitor volume so that: 1. all breaths are captured; 2. anticipatory changes in breathing pattern can be identified during the test; 3. accurate assessment of inspiratory effort can be evaluated; 4. the baseline EELV can be accurately established Reproducibility/Reliability Accurate assessment of EELV (calculated as TLC minus IC) is dependent on the stability of TLC throughout exercise and the ability of the individual to maximally inflate their lungs during the IC manœuvre. Thus, if TLC is constant, any change in IC will reflect the inverse change in EELV. Constancy of TLC has been demonstrated during exercise in healthy individuals [24] and in patients with COPD [25, 26]. It also appears that patients with COPD are able to maximally activate their diaphragm during inspiratory efforts to TLC [27, 28], even when dyspnoeic at the limits of tolerance [27]. Yan et al. [29] determined the reliability of IC measurements in individuals with COPD during incremental cycle exercise by comparing oesophageal pressure at peak inspired plateau volume during serial IC efforts. These authors demonstrated consistent peak oesophageal pressures throughout exercise despite changes in IC. They concluded that TLC did not change and that the IC was reliable for assessing changes in EELV during exercise [29]. In a contemporary study, O Donnell and coworkers [23] verified that TLC was attained with each IC manœuvre during cycle exercise in COPD patients by showing that peak negative oesophageal pressures during IC manœuvres were similar to those at rest. This conclusion is supported by other studies which have shown high reproducibility of the IC [19, 30]. O Donnell et al demonstrated reproducibility of the IC at rest, isotime, and at peak exercise (intraclass correlation R 0.87) in a multi-center clinical trial Interpreting changes after interventions The constant work rate cycle endurance tests at 65-75% has been extensively used in clinical trials to evaluate the effect of bronchodilator therapy on IC, dyspnoea and exercise tolerance in patients with COPD. This test allows for approximately 4-8 minutes of measurement of symptom and physiological responses in the vast majority of patients with moderate to severe COPD. Measurement of dyspnoea and leg discomfort (modified Borg scale), ventilation, breathing pattern and operating lung volumes (IC and IC-derived measurements) during constant work rate tests have been shown to have satisfactory repeatability in a large multicentre study [see above]. Peak symptom-limited VO 2 within-subject has been shown to be similar during high intensity cycle endurance and incremental cycle tests, indicating that the former is in fact a maximal test [see elsewhere in the TF document]. Measurement of serial IC and breathing pattern at rest and throughout exercise allows insight into mechanisms of benefit during therapeutic interventions.

62 Lung deflation is achieved by bronchodilator-induced airway smooth muscle relaxation which accelerates mechanical time constants for lung emptying (by reducing airflow resistance) in heterogeneously distributed alveolar units [17, 31-33]. The resting IC indicates the position of V T relative to TLC on the sigmoidal pressure-volume relation of the relaxed respiratory system and the operating limits for V T expansion during exercise. An increase in resting IC following a bronchodilator indicates reduced elastic/inspiratory threshold loading of the inspiratory muscles, an important determinant of dyspnoea [34-36]. IC has proven to be responsive to change during exercise following numerous pharmacological and nonpharmacological interventions [11, 17, 37-45]. However, as with other spirometric indices, no minimal clinically important difference has been clearly established for direct or indirect measurements of lung hyperinflation. From experience to date, a post-intervention change in IC of ~0.2L at iso-time during exercise (or ~15% predicted) could be considered clinically meaningful. More specifically, post-bronchodilator (BD) changes in resting IC of approximately L or % of predicted IC (or 15-17% of baseline value) for long-acting BD and of approximately L or 10-12% of predicted IC (or 12-15% of baseline value) for short-acting BD have been consistently associated with increased exercise endurance time in the order of 20-30% in patients with moderate to severe COPD ( see Figure 2) [17-19, 33, 37, 41, 45-48]. Figure 2: Relationships between the changes in left panel) endurance time (time to the limit of tolerance (tlim)); middle panel) dyspnoea at isotime; and right panel) isotime inspiratory capacity (IC) after the administration of bronchodilators. Mean minimal clinically important difference (MCID) thresholds of a) 105 s; b) 1 point; and c) 0.2 L. # : lower limit of 95% CI 60 s; *: p<0.05 It is noteworthy that the primary effect of bronchodilator therapy is on the resting IC: by increasing the available dynamic inspiratory reserve volume (IRV), bronchodilator therapy delays the critical respiratory mechanical limitation to exercise. Accordingly, the rate of post-bronchodilator dynamic lung hyperinflation is generally not decreased during exercise (or may actually increase), reflecting the increased V E secondary to the release of V T restriction due to less lung hyperinflation The lower operating lung volume and increased IC allow patients to achieve the required V E during rest and exercise at a lower oxygen cost of breathing [17] (see Figure 2). By deflating the lungs, bronchodilators effectively improve ventilatory muscle performance and results in greater V T expansion as V E increases during exercise [17, 18, 33, 37, 45, 46]. Thus, neuromechanical coupling of respiratory

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67 Skills Workshop Cardiopulmonary exercise test interpretation: tips and pitfalls Workstation 3: Breathing pattern and dynamic hyperinflation Dr Pierantonio Laveneziana Milan, 11/09/2017 Service d Explorations Fonctionnelles de la Respiration, de l'exercice et de la Dyspnée (EFRED) Département "R3S" (Respiration, Réanimation, Réhabilitation, Sommeil) Groupe Hospitalier Pitié-Salpêtrière Charles Foix Assistance Publique-Hôpitaux de Paris Sorbonne Universités, UMR_S 1158, INSERM et Université Pierre et Marie Curie (Paris 6) Neurophysiologie Respiratoire Expérimentale et Clinique

68 Conflicts of interest Nothing to disclose

69 COPD Capillary Network Reduction Alveolar Wall Destruction Air Spaces Enlargement Alveolar Attachments Loss Small Airways Narrowing-Distortion airways resistance Expiratory Flow Limitation Lung Compliance V A /Q anomalies Obstruction ( FEV 1 /VC) VD/VT ventilatory demand ventilatory capacity/ceiling (MVV) Static lung hyperinflation Dynamic lung hyperinflation

70 Expiratory flow-limitation Dynamic Hyperinflation Ventilatory muscle mechanical loading Mechanical constraints on tidal volume expansion Metabolic demand V E = 863 * V CO 2 PaCO 2 * (1-V D /V T ) CO 2 set-point Chemoreceptor and Ergoreceptor Reflexes Alveolar-capillary gas diffusion V A /Q inequality Breathing pattern (V T and RR)

71 Ventilation (l/min) Excessive Ventilatory Requirement and Limited Ventilatory Capacity Cardiopulmonary Exercise Testing: Health Disease VO 2 (ml/kg/min) Healthy Physiological dead space Hypoxemia / hypercapnia Early metabolic acidosis Increased CO 2 production Reflex stimulation (neural) Non-metabolic sources Laviolette L and Laveneziana P, Eur Respir J Laveneziana et al, ERS Task Force 2016

72 Excessive Ventilatory Requirement and Limited Ventilatory Capacity Ventilation COPD COPD Normal BR BR Healthy Level of exercise Laviolette L and Laveneziana P, Eur Respir J Laveneziana et al, ERS Task Force 2016

73 % Total Lung Capacity Ventilatory Mechanics: Healthy vs COPD 100 Healthy P cw COPD P L cmh 2 O - 5 cmh 2 O + 2 cmh 2 O + 5 cmh 2 O FRC (or EELV) in COPD FRC (or EELV) in Healthy 25 Healthy P L Pressure (cmh 2 O)

74 Ventilatory Mechanics: Healthy vs COPD Dynamic hyperinflation: a temporary and variable increase in end expiratory lung volume (EELV) beyond its baseline value EELV: volume of gas left in the lung at the end of a quiet breath out

75 Normal COPD P L V. P L V. expiratory flow-limitation airways resistance airway tethering Expiratory flow-limitation mechanical time-constant for lung emptying (compliance x resistance) Expiratory time available is insufficient to allow EELV to return to its baseline value Gas retention or air trapping or lung hyperinflation

76 Normal COPD P L V. P L V. expiratory flow-limitation airways resistance airway tethering In other words, lung emptying during expiration becomes incomplete because it is interrupted by the next inspiration and EELV therefore exceeds the natural relaxation volume of the respiratory system (Palv > Patm)

77 Ventilatory Mechanics: COPD IRV TLC IRV TLC EELV Healthy Normal COPD

78 Determinants of Dynamic Hyperinflation during Exercise in COPD Extent of expiratory flow limitation Ventilatory demand Breathing pattern Resting level of hyperinflation

79 Dynamic Lung Hyperinflation

80 Ventilatory Mechanics: COPD and dynamic hyperinflation Gas dilution techniques Exercise body plethysmography Respiratory inductance plethysmography Optoelectronic plethysmography Inspiratory capacity measurements

81 Inspiratory Capacity: definition Inspiratory capacity (IC) is volume change recorded at the mouth when taking a slow full inspiration with no hesitation, from a position of passive end-tidal expiration, i.e. FRC, to a position of maximum inspiration, expressed in liters at BTPS (ERS/ATS Guidelines, Pellegrino et al, ERJ 2005). The IC manoeuvre consists of a full inspiration to TLC taken without hesitation after a tidal expiration.

82 Inspiration Flow (L/s) Expiration 8 6 TLC V T EELV EELV IC Volume (L) IC 2 RV

83 Dynamic Lung Hyperinflation IC IC V T VT

84 Dynamic Lung Hyperinflation IC IC V T V T

85 Ventilatory Mechanics: Healthy vs COPD Laveneziana P, et al. Appl. Physiol. Nutr. Metab. 2007

86 Value of Inspiratory Capacity A measure of the proximity of V T to TLC IC represents the operating limits for V T expansion during exercise Change in IC reflects change in EELV if TLC remains stable and subjects do not suffer from clinically significant inspiratory muscle weakness

87 JAP 1980 JAP 1980

88 JAP 1980

89 IC measurements at rest: acceptability 3-10 tidal breaths with a stable EELV prior to the IC manoeuvre. At least 3 acceptable measurements at rest.

90 Inspiration Flow (L/s) Expiration Inspiratory Capacity measurements: acceptability 8 6 TLC V T EELV EELV IC Volume (L) IC 2 RV

91 IC measurements at rest: reproducibility Currently no universally accepted recommendations Within-subject CV across visits for resting IC in multicentre trials in 463 COPD patients was reported to be 9.5% (O Donnell et al. ERJ 2009) AARC, 2001: Measurements should agree within ±5% or 60 ml of the mean, whichever is larger ERS/ATS Guidelines, Pellegrino et al ERJ 2005: Within-subject CV for resting IC in obstructive lung disease was reported to be 5±3%. The average of at least three manoeuvres should be reported No difficulty for patients to meet ±100 ml criteria

92 IC measurements during exercise: reproducibility A decrease in dynamic IC of > 140mL suggest significant dynamic hyperinflation (O Donnell et al. AJRCCM 2001) At isotime: within-subject CV across visits for IC at isotime in multicentre trials in 463 COPD patients was reported to be 10.8% (O Donnell et al. ERJ 2009) At peak exercise: within-subject CV across visits for IC at isotime in multicentre trials in 463 COPD patients was reported to be 11.6% (O Donnell et al. ERJ 2009)

93 Dynamic Lung Hyperinflation IC IC V T V T MCID IC during exercise: 150 ml Laveneziana et al, ERS Task Force 2016

94 Inspiration Flow (L/s) Expiration Exercise testing: reliable IC measurements 8 6 TLC 4 2 V T EELV IC IC 4 3 Volume (L) 2 RV EELV No anticipatory changes in breathing pattern prior to the IC manoeuvre Stable EELV prior to the IC manoeuvre Good inspiratory effort to TLC No clinically significant inspiratory muscle weakness

95 Exercise testing: reliable IC measurements in COPD EELV TLC IC TLC EELV No anticipatory changes in breathing pattern prior to the IC manoeuvre Stable EELV prior to the IC manoeuvre Good inspiratory effort to TLC No clinically significant inspiratory muscle weakness

96 Exercise testing: reliable Inspiratory Capacity measurements in COPD IC=1.70L IC=1.71L IC=1.69L IC=1.26L EELV at rest EELV during exercise IC IC TLC TLC No anticipatory changes in breathing pattern prior to the IC manoeuvre Stable EELV prior to the IC manoeuvre Good inspiratory effort to TLC No clinically significant inspiratory muscle weakness

97 Exercise testing: how and when to perform Inspiratory Capacity Familiarization session at rest IC every 2 minutes during exercise After the next breath out, take a deep breath all the way in.and relax Post exercise IC may not reflect peak IC

98 Exercise testing: not reliable Inspiratory Capacity measurements Inadequate number of tidal breaths available prior to the IC manoeuvre Unstable EELV due to: Anticipatory changes in breathing pattern Drift in volume signal Leaks at the mouth/nose Poor inspiratory effort Clinically significant inspiratory muscle weakness

99 Exercise testing: not reliable Inspiratory Capacity measurements Inability to correct volume for stable EELV IC? Anticipatory changes in breathing pattern

100 Exercise testing: not reliable Inspiratory Capacity measurements Inability to correct volume for stable EELV IC? Drift in volume signal [incorrect calibration] Leaks at the mouth/nose?

101 an index of change in EELV prior to performing the IC manoeuver Exercise testing: monitoring end-expiratory oesophageal pressure EELV In research setting, end-expiratory oesophageal pressure can also be monitored as

102 Exercise testing: Inspiratory Capacity values adjustment IC? IC adjusted Adjust volumes from which IC is measured (i.e., from stable EELV to TLC)

103 Exercise testing: good and reliable inspiratory effort EELV during exercise EELV at rest Yan S et al, AJRCCM 1997

104 Exercise testing: not reliable Inspiratory Capacity measurements TLC IC IC RV ERV Rest EELV Exercise Change in IC does not reflect change in EELV if: TLC changes during exercise Inspiratory muscle are significantly weak or fatigued

105 Exercise testing: not reliable Inspiratory Capacity measurements TLC IC IC TLC IC RV ERV EELV Rest Exercise Change in IC does not reflect change in EELV if: TLC does not remain stable during exercise

106 Exercise testing: not reliable Inspiratory Capacity measurements TLC IC IC TLC IC RV ERV Rest EELV Exercise Change in IC does not reflect change in EELV if: Inspiratory muscle are weak or fatigued during exercise The respiratory muscles shorten at a particular velocity and develop force shortening change in pulmonary volume velocity of shortening flow force pressure Subjects suffer from an impairment of inspiratory muscle strength that would be sufficient to prevent them to reach TLC during a voluntary IC manoeuvre

107 Pes (cmh 2 O) Volume (L) Pes (cmh 2 O) Volume (L) PAH-H Rest iso-wr Peak 3.0 TLC IC EELV IC EELV IC EELV No resp muscle weakness/fatigue PAH-NH TLC Pes, IC Pes, IC Pes, IC Rest iso-wr Peak IC EELV IC EELV IC EELV No resp muscle weakness/fatigue Pes, IC Pes, IC Pes, IC Laveneziana P et al, ERJ 2015

108 SUMMARY: reliability of Inspiratory Capacity measurements during exercise No anticipatory changes in breathing pattern prior to the IC manoeuvre Stable EELV prior to the IC manoeuvre Good inspiratory effort to TLC No clinically significant inspiratory muscle weakness

109 mechanical constraint on tidal volume expansion Laveneziana P et al, AJRCCM 2011 Laveneziana P et al, RESPNB 2014

110 mechanical constraint on tidal volume expansion Laveneziana P et al, AJRCCM 2011

111 Tidal Volume (L) Operating Lung Volumes (L) IRV TLC IC Ventilation (L/min) Mechanical restriction: Muscle weakness ILD CW restriction COPD Dynamic hyperinflation Asthma (Laveneziana P et al, RPNB 2012) CHF (Laveneziana P et al. JAP 2009) PAH (Laveneziana et al. ERJ 2013 and 2015) Ventilation (L/min)

112 Negative effects of DH during exercise Elastic/threshold loads Inspiratory muscle weakness Reduced V T expansion tachypnoea Pes/PImax effort C L dyn V D /V T PaCO 2 Early ventilatory limitation to exercise Cardiac impairment Exertional dyspnoea

113 Inspiratory Capacity MCID IC during exercise: 150 ml MCID IC at isotime after interventions: 200 ml

114 Improving Exercise Tolerance - Decreasing Hyperinflation in COPD - Pharmacotherapy - Bronchodilators Inhaled Gas Mixtures - Heliox - Oxygen Rehabilitative Therapy

115 Laveneziana et al, ERS Task Force 2016