Effect of bronchoscopic lung volume reduction on dynamic hyperinflation and exercise in emphysema Nicholas S Hopkinson, Tudor P Toma, David M Hansell, Peter Goldstraw, John Moxham, Duncan M Geddes & Michael I Polkey. E1
Methods Subjects studied This paper includes all patients with COPD who had valves inserted at our institution barring one who had severe, exercise limiting osteoarthritis and was a priori excluded from the study. Valves used Endobronchial occlusion was performed using one-way valves (Emphasys Medical, Inc, Redwood City, Ca) made of nitinol and silicone (Figures E1,E2) placed to occlude segmental bronchi leading to the most affected area of lung (1, 2). Initially, valves were inserted on a single occasion under general anesthesia. Subsequently some procedures were carried out with sedation only and some of these were staged with valves being inserted on two separate occasions one to two weeks apart. In the last four patients studied a modified valve was available. The main difference was that the new design allowed it to be compressed in a tube that goes through the working channel of the bronchoscope. Patients 16 and 17 had only new valves inserted whereas 18 and 19 had a combination of classic and new valves. Pulmonary Function Technicians working in the Lung Function Department of the Royal Brompton Hospital performed these tests. Spirometry was obtained using a heated pneumotachograph with flow integration, lung volumes by whole body plethysmography and gas transfer with a single breath technique (Compact Master lab system, Jaeger, Germany). Blood gas tensions were measured in arterialized earlobe E2
capillary samples (Radiometer ABL 30, Denmark.) Predicted values used are those of the European Coal and Steel Community (3). The equipment was regularly calibrated and the tests were performed in accordance with the British Thoracic Society guidelines (4). Exercise testing Subjects exercised on a Jaeger Ergoline 800 cycle ergometer. At baseline an incremental exercise test was performed. This protocol involved a two-minute rest period before subjects started to cycle. The initial workload was set at zero watts and increased by 5 watts every 30 seconds. Patients continued until they experienced intolerable symptoms. The endurance cycle test performed before and after BLVR was set at a workload 80% of that reached on this incremental test. Metabolic data was gathered using an Oxycon device (Jaeger Systems, Germany). Subjects wore nose clips and breathed through a lightweight mouthpiece from which inspired and expired gas was continually sampled to allow assessment of inspired and expired oxygen and CO 2 fractions. The mouthpiece contains a turbine spirometer to measure flow, which is integrated to allow measurement of tidal volume (V T ) and hence minute ventilation (VE). Inspiratory capacity (IC) maneuvers performed every minute allowed assessment of dynamic lung volumes. On the assumption that total lung capacity does not change during exercise (5, 6) end expiratory lung volume (EELV) was calculated as TLC IC. Inspiratory reserve volume (IRV) was calculated as IC-V T. Predicted values for minute ventilation assume a maximum ventilatory capacity 35 times FEV 1 (7). E3
Respiratory muscle strength In all subjects we measured maximum static inspiratory (PI max ) and expiratory (PE max ) mouth pressures (8) as well as maximum sniff nasal pressure (SNiP) (9). Where patients consented to and were able to tolerate the placement of catheter-mounted balloons, esophageal and gastric pressures were determined and transdiaphragmatic pressure calculated (9). As an additional test of expiratory muscle strength whistle maximum expiratory pressure was also assessed (WMEP) (10). Pressures were recorded using Validyne differential pressure transducers (range +300cmH 2 O; Validyne MP45; Validyne, Northridge, Ca, USA). Signals were amplified and passed to a personal computer running LabView 4 software (National Instruments, Austin, Tx, USA). As a non-volitional test of diaphragm strength the response elicited by bilateral anterolateral magnetic phrenic nerve stimulation (TwPdi) was also determined (11). Stimulations were performed with a 45mm branding iron, figure of eight coil positioned over each phrenic nerve, with its midpoint at the posterior border of the sternomastoid at the level of the cricoid cartilage. Each coil was connected to a Magstim 200 Monopulse magnetic stimulator (Magstim Ltd, Whitland, Wales). Subjects rested for twenty minutes to allow their diaphragm to depotentiate (12). Pressures were visible on screen to allow for visual feedback and also so that magnetic stimuli could be delivered at resting end expiration. Respiratory muscle activity during exercise In patients with pressure catheters in situ we determined the esophageal and diaphragmatic pressure time product (PTPes and PTPdi respectively) to give indices of respiratory muscle activity. These are calculated as the integral of the esophageal or E4
diaphragmatic pressure over time during inspiration multiplied by the respiratory rate to give units of cmh 2 O.sec.min -1. The values were calculated using semi-automated customized LabView software. Onset of inspiratory work was determined as the upward inflection point on the transdiaphragmatic pressure trace. To distinguish intrinsic PEEP from increased expiratory abdominal muscle recruitment during exercise, which can lead to over-estimation of the PTPes (13) the baseline from which esophageal pressure changes were measured was calculated as follows. Mean end expiratory gastric pressure was determined during an initial two-minute period of resting breathing. During the isotime period, the threshold from which PTPes was measured (i.e. calculated intrinsic PEEP (PEEP I )), was taken to be the end expiratory esophageal pressure minus the difference between end expiratory gastric pressure during exercise and that recorded at rest. Static Compliance This was measured using a proprietary system (Compact Master Lab System, Jaeger, Hoechberg, Germany) that employs an interrupter technique to compare changes in transpulmonary pressure with volume change during a relaxed expiration from TLC. Subjects sat comfortably breathing through a mouthpiece. Esophageal pressure, as an index of pleural pressure was recorded using the balloon catheter system described above. Subjects took three tidal breaths and were then asked to breathe slowly up to TLC and then exhale passively. A shutter occluded the mouthpiece for 80ms every 50mls. Change in volume was plotted against transpulmonary pressure (pleural pressure mouth pressure). E5
Subjects performed repeated attempts, usually five or more. For each attempt the slope of the pressure volume curve in the linear portion above FRC was plotted. The value given was the average slope for all technically satisfactory attempts. E6
E1. Toma TP, Hopkinson NS, Hillier J, Hansell DM, Morgan C, Goldstraw PG, Polkey MI, Geddes DM. Bronchoscopic volume reduction with valve implants in patients with severe emphysema. Lancet 2003;361:931-3. E2. Toma TP, Polkey MI, Goldstraw PG, Morgan C, Geddes DM. Methodological aspects of bronchoscopic lung volume reduction with a proprietary system. Respiration 2003;70:658-64. E3. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl 1993;16:5-40. E4. British Thoracic Society. Guidelines for the measurement of respiratory function. Respir Med 1994;88:165-194. E5. Duranti R, Filippelli M, Bianchi R, Romagnoli I, Pellegrino R, Brusasco V, Scano G. Inspiratory Capacity and Decrease in Lung Hyperinflation With Albuterol in COPD. Chest 2002;122:2009-2014. E6. Stubbing DG, Pengelly LD, Morse JL, Jones NL. Pulmonary mechanics during exercise in subjects with chronic airflow obstruction. J Appl Physiol 1980;49:511-5. E7. Gandevia B, Hugh-Jones P. Terminology for measurements of ventilatory capacity; a report to the thoracic society. Thorax 1957;12:290-3. E8. Wilson SH, Cooke NT, Edwards RH, Spiro SG. Predicted normal values for maximal respiratory pressures in caucasian adults and children. Thorax 1984;39:535-8. E7
E9. Miller JM, Moxham J, Green M. The maximal sniff in the assessment of diaphragm function in man. Clin Sci (Lond) 1985;69:91-6. E10. Chetta A, Harris ML, Lyall RA, Rafferty GF, Polkey MI, Olivieri D, Moxham J. Whistle mouth pressure as test of expiratory muscle strength. Eur Respir J 2001;17:688-95. E11. Mills GH, Kyroussis D, Hamnegard CH, Polkey MI, Green M, Moxham J. Bilateral magnetic stimulation of the phrenic nerves from an anterolateral approach. Am J Respir Crit Care Med 1996;154:1099-105. E12. Wragg SD, Hamnegard C-H, Road J, Kyroussis D, Moran J, Green M, Moxham J. Potentiation of diaphragmatic twitch after voluntary contraction in normal subjects. Thorax 1994;49:1234-37. E13. Ninane V, Rypens F, Yernault JC, De Troyer A. Abdominal muscle use during breathing in patients with chronic airflow obstruction. Am Rev Respir Dis 1992;146:16-21. E8
Table E1 BLVR procedures, complications and development of atelectasis ID Anesthetic Target Atelectasis Complications Baseline Tlim (secs) GTlim secs(%) GRestIC (L) 1 GA RUL N 125 +40 (+32) +0.13 2 GA RUL Y 263 +329 (+125) +0.61 3 GA LUL+Lingula Y Pneumothorax 149 +8 (+5) +0.15 - drained 4 GA LUL+Lingula Y Exacerbation 221 +85 (+38) -0.12 5 GA RUL N Exacerbation 305 +173 (+57) +0.54 6 GA LUL N 226 +114 (+50) +0.25 7 GA RUL N Exacerbation 226-48 (-21) -0.60 8 LA LLL - apical N 115 +320 (+278) +0.50 segment 9 GA LUL+ Y Pneumothorax 143 +559 (+391) +0.82 Lingula - self limiting 10 GA RUL N 321-102 (-32) +0.17 11 LA RLL - apical segment N Exacerbation 55-55 (-100) -0.62 12 LA RUL - 2 stage N Rib fracture 171-81 (-47) -0.18 following fall 13 LA RUL - 2 stage N 195-35 (-18) +0.21 14 LA RUL - 2 Stage N C. Diff 211-34 (-16) -0.02 15 LA RUL - 2 stage Y 100 +143 (+143) +0.46 16 LA RUL - 2 stage N Exacerbation 435 +40 (+9.4) -0.03 17 LA RUL - 2 stage N 606 +9 (+1.5) +0.19 18 LA RUL - 2 stage N 301 +147 (+48.8) +0.26 19 LA RUL - 2 stage N 147 +67(+45.6) +0.02 LA local anesthetic, GA general anesthetic, RUL right upper lobe, LUL left upper lobe (not including lingula), RLL right lower lobe, LLL left lower lobe; C. Diff E9
clostridium difficile infection. Improvement was defined as at least 60 seconds increase in endurance time on a cycle ergometer at 80% of maximum workload pre BLVR. Mean change in Tlim was +88(167) seconds (p=0.3) E10
Table E2 Exercise parameters pre and post BLVR Pre 4 weeks t test Peak values Endurance Tlim (secs) 227.1 + 129.4 315.5 + 195.1 0.033* VO 2 (L.min -1 ) 0.85 + 0.3 0.89 + 0.2 0.36 VCO 2 (L.min -1 ) 0.79 + 0.3 0.86 + 0.2 0.13 VE (L.min -1 ) 29.5 + 8.6 31.8 + 8.8 0.057 RR (min -1 ) 26.9 + 4.6 27.5 + 4.8 0.39 HR (min -1 ) 107.8 + 12.2 111.0 + 16.3 0.17 VT (L) 1.09 + 0.2 1.16 + 0.3 0.20 IC (L) 1.45 + 0.4 1.53 + 0.5 0.34 IRV (L) 0.36 + 0.2 0.37 + 0.2 0.84 EELV (L) 7.60 + 1.6 7.18 + 1.7 0.034* Isotime values IC (L) 1.59 + 0.4 1.78 + 0.6 0.14 VO 2 (L.min -1 ) 0.78 + 0.2 0.82 + 0.2 0.67 VCO 2 (L.min -1 ) 0.72 + 0.3 0.78 + 0.2 0.38 VE (L.min -1 ) 28.0 + 9.1 29.3 + 8.4 0.54 RR (min -1 ) 26.1 + 5.4 25.1 + 4.9 0.24 HR (min -1 ) 105.4 + 12.3 109.9 + 12.4 0.17 Borg leg discomfort 3.5 + 1.9 2.9 + 1.7 0.09 Borg breathlessness 4.0 + 1.4 3.5 + 2.0 0.35 E11
VT (L) 1.07 + 0.3 1.17 + 0.3 0.12 IRV (L) 0.52 + 0.3 0.61 + 0.4 0.29 EELV (L) 7.47 + 1.5 6.97 + 1.7 0.052 PTPes (cmh 2 O.s.min -1 ) 327 + 84 306 + 67 0.20 PTPdi (cmh 2 O.s.min -1 ) 227 +130 231+ 91 0.90 VT/Pes swing (mls.cmh 2 O -1 ) 35.4 + 23.1 44.3 + 24.4 0.08 VE/PTPes (L/ cmh 2 O.s.min -1 ) 0.093 + 0.05 0.104 + 0.06 0.05 O 2 Pulse (mls/min) 7.35 + 1.9 7.46 + 1.3 0.92 IC Inspiratory capacity, EELV end expiratory lung volume, IRV inspiratory reserve volume, VE minute ventilation, RR respiratory rate, VT tidal volume, PTPes esophageal pressure time product, PTPdi diaphragm pressure time product. Pes swing is the difference between the peaks of esophageal pressure in each respiratory cycle, VE/PTPes minute ventilation divided by esophageal pressure time product. Invasive measurements were available in 10 of the 19 patients studied. (Mean + SD) (*p<0.05). E12
Table E3 Quality of life pre and post BLVR Pre BLVR Post BLVR T test SGRQ Symptoms 63.7 + 19.2 68.4 + 18.9 0.28 Activities 78.5 + 16.5 76.9 + 17.5 0.54 Impact 45.1 + 13.5 44.0 + 18.6 0.68 Total 58.3 + 12.8 58.0 + 16.6 0.88 SF-36 Physical function 24.7 + 20.4 26.1 + 21.9 0.67 Role Physical 39.5 + 41.1 28.9 + 38.4 0.18 Role emotional 63.2 + 47.0 61.4 + 48.8 0.87 Social function 44.4 + 27.2 45.0 + 29.3 0.92 Mental health score 62.9 + 23.3 62.1 + 19.5 0.81 Energy vitality 33.4 + 17.3 33.4 + 22.5 1 Pain Score 71.3 + 23.5 74.9 + 24.8 0.52 General health perception 27.6 + 19.7 29.7 + 17.7 0.48 Change Health Score 43.4 + 21.8 44.7 + 29.6 0.85 Physical component summary score 41.4 + 18.7 39.9 + 20.1 0.56 Mental component summary score 50.6 + 21.9 50.5 + 24.7 0.98 In the group as a whole there was no significant change in any dimension of quality of life measured. E13
Table E4 Changes following BLVR in patients with or without radiological atelectasis Radiological atelectasis (n=5) Atelectasis not observed (n=14) Pre Post Pre Post FEV 1 (L) 0.89 (0.30) 1.18 (0.36) * 0.90 (0.42) 0.93 (0.43) VC (L) 3.51 (1.2) 4.03 (0.98) 3.3 (0.89) 3.2 (0.89) TLC (L) 9.2 (2.1) 8.6 (2.2) 9.0 (1.3) 8.8 (1.2)* FRC (L) 7.0 (2.1) 6.2 (2.2) 7.1 (1.4) 6.8 (1.5) RV (L) 5.8 (2.3) 4.7 (2.1) 5.6 (1.4) 5.4 (1.4) TL CO (%) 36.9 (11.0) 47.2 (8.2) * 36.9 (10.6) 38.5 (12.5) Tlim (secs) 175 (65) 400 (235) 246 (143) 285 (179) Isotime EELV (L) 7.7 (2.0) 6.7 (2.4) 7.4 (1.4) 7.1 (1.4) * p<0.05 within group E14
Figure E1 E15
Figure E2 E16