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Man and machines: Insights into ventilation strategies May 2006 Dr Geoff Shaw Dept of Man and machines: Insights into ventilation strategies May 2006 Dr Geoff Shaw Dept of Intensive Care Christchurch Hospital Clin Sen Lecturer Dept of Medicine CSM&HS University of Otago, NZ Senior fellow Dept of Mechanical Engineering, University of Canterbury, NZ

The ventilator is our identity The ventilator is our identity

The ventilator is our identity Mechanical ventilation has been used clinically for about 80 The ventilator is our identity Mechanical ventilation has been used clinically for about 80 years…. . First there was

Negative pressure ventilation… Polio in California Negative pressure ventilation… Polio in California

The ventilator is our identity Then there was The ventilator is our identity Then there was

Positive Pressure Ventilation: 90% death rate 90% survival Dr H Lassen at Copenhagen’s Blegdams Positive Pressure Ventilation: 90% death rate 90% survival Dr H Lassen at Copenhagen’s Blegdams Hospital

PEEP 1967 First report of ARDS: Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. PEEP 1967 First report of ARDS: Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress syndrome in adults. Lancet; 1967, (II) 319 -323 1972 First formal investigation of the effect of PEEP Improved Pa. O 2 by applying 0 -15 cm PEEP in 10 patients with ARDS. Putative mechanism prevention of airway closure Falke KJ, Pontoppidan H, Kumar A et al Ventilation with end-expiratory pressure in acute lung disease; J Clin Invest 1972, 51: 2315– 2323

PEEP 1975 “Optimum PEEP” Defined as best O 2 transport (CO X O 2 PEEP 1975 “Optimum PEEP” Defined as best O 2 transport (CO X O 2 content) highest compliance of respiratory system. Suter PM, Fairley B, Isenberg MD. Optimum end-expiratory airway pressure in patients with acute pulmonary failure. N Engl J Med 1975; 292: 284– 289 “Super PEEP” that which produces minimal shunt Kirby RR, Downs JB, Civetta JM et al. High level positive end expiratory pressure (PEEP) in acute respiratory insufficiency. Chest 1975; 67: 156– 163 1981 “Minimal PEEP” 2 cm higher than lower inflection point of inflation limb of the pressure volume curve Lemaire F, Harf A, Simonneau G et al [Gas exchange, static pressure volume curve and positive-pressure ventilation at the end of expiration. Study of 16 cases of acute respiratory insufficiency in adults]. Ann Anesthesiol Fr 1981; 22: 435– 441

PV Curve Upp nfle oin tion p lec inf Lower er i ctio t PV Curve Upp nfle oin tion p lec inf Lower er i ctio t n p oint Radford EP (1957) Recent studies of the mechanical properties of mammalian lungs. In: Remington JW (ed) Tissue elasticity American Physiological Society Washington, pp 177– 190

VILI PIP=14, PEEP=0 PIP= 45, PEEP=10 Webb & Tierney ARRD 1974; 110; 556 PIP= VILI PIP=14, PEEP=0 PIP= 45, PEEP=10 Webb & Tierney ARRD 1974; 110; 556 PIP= 45, PEEP = 0

Otherapies 1979 “ECMO”: NIH trial 90% mortality in both groups. High volumes and pressures Otherapies 1979 “ECMO”: NIH trial 90% mortality in both groups. High volumes and pressures Zapol WM, Snider MT, Hill JD et al. Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA 1979; 242: 2193– 2196 1980’s “ECO 2 R” (Extracorporeal CO 2 removal) Concept of “lung rest” Normal gas exchange targets Unacceptable complications especially bleeding Gattinoni L, Agostoni A, Pesenti A et al. Treatment of acute respiratory failure with low-frequency positive pressure ventilation and extracorporeal removal of CO 2. Lancet 1980; II: 292– 294 Gattinoni L, Pesenti A, Mascheroni D et al. Low-frequency positive-pressure ventilation with extracorporeal CO 2 removal in severe acute respiratory failure. JAMA 1986; 256: 881– 886

Concepts of ARDS in 1980’s Lungs homogeneous, heavy and stiff Normalise p. CO 2 Concepts of ARDS in 1980’s Lungs homogeneous, heavy and stiff Normalise p. CO 2 by use of high pressures and volumes Use of PEEP to normalise p. O 2 Barotrauma = “complication” Major concerns were haemodynamic impairments caused by PEEP

“Baby Lung” Quantitative assessment of CT images in ARDS. amount of normally aerated tissue “Baby Lung” Quantitative assessment of CT images in ARDS. amount of normally aerated tissue = 5 -6 yr old child Gattinoni L, Pesenti A, The concept of the “baby lung”. Intensive Care Med; 2005: 31: 776 -784

“Baby Lung” Respiratory compliance correlates with amount of normally aerated tissue Gattinoni L, Pesenti “Baby Lung” Respiratory compliance correlates with amount of normally aerated tissue Gattinoni L, Pesenti A, Baglioni S et al. Inflammatory pulmonary edema and positive end-expiratory pressure: correlations between imaging and physiologic studies. 1988; J Thorac Imaging 3: 59– 64

“Sponge Lung” Assumes lung oedema in ARDS is evenly distributed throughout the lung from “Sponge Lung” Assumes lung oedema in ARDS is evenly distributed throughout the lung from sternum to vertebrae. (not gravitationally dependent). Gas in dependent regions is squeezed out by superimposed pressure including the weight of the heart Bone RC The ARDS lung. New insights from computed tomography. JAMA 1993; 269: 2134– 2135 Gattinoni L, Pesenti A, The concept of the “baby lung”. Intensive Care Med; 2005: 31: 776 -784

Superimposed pressure Opening Pressure Inflated 0 Small Airway Collapse 10 -20 cm. H 2 Superimposed pressure Opening Pressure Inflated 0 Small Airway Collapse 10 -20 cm. H 2 O Alveolar Collapse (Reabsorption) 40 -60 cm. H 2 O Consolidation (modified from Gattinoni)

“Permissive hypercapnia” 1990 Low tidal volumes to rest lung; CO 2 levels allowed to “Permissive hypercapnia” 1990 Low tidal volumes to rest lung; CO 2 levels allowed to permissively rise Changed the goals of ventilation Hickling KG, Henderson SJ, Jackson R. Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med 1990; 16: 372– 377

Permissive hypercapnia Late ’ 90’s: clinical trials of low tidal volume ventilation Acute Respiratory Permissive hypercapnia Late ’ 90’s: clinical trials of low tidal volume ventilation Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342: 1301– 1308. 861 patients Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lo-Physirenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338: 347– 354. 63 patients Stewart TE, Meade MO, Cook DJ, Granton JT, Hodder RV, Lapinsky SE, Mazer CD, Mc. Lean RF, Rogovein TS, Schouten BD, et al. Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. N Engl J Med 1998; 338: 355– 361. 120 patients Brochard L, Roudot-Thoraval F, Roupie E, Delclaux C, Chastre J, Fernandez-Mondejar E, Clementi E, Mancebo J, Factor P, Matamis D, et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. Multicenter Trial Group on Tidal Volume Reduction in ARDS. Am J Respir Crit Care Med 1998; 158: 1831– 1838 116 patients Brower RG, Shanholtz CB, Fessler HE, Shade DM, White P Jr, Wiener CM, Teeter JG, Doddo JM, Almog Y, Piantadosi S. Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med 1999; 27: 1492– 1498. 52 patients

Confusion and controversy! Eichacker PQ, . Gerstenberger EP, Banks SM, Cui X, Natanson C. Confusion and controversy! Eichacker PQ, . Gerstenberger EP, Banks SM, Cui X, Natanson C. Meta-analysis of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes. Am J Respir Crit Care Med Vol 166. pp 1510– 1514, 2002

Lung recruitment in ARDS 68 patients with ARDS: Highly variable % potentially recruitable lung Lung recruitment in ARDS 68 patients with ARDS: Highly variable % potentially recruitable lung 13% ± 11% % potentially recruitable correlated with % lung maintained after application of PEEP Higher % potentially recruitable lung correlated with: Lung weight Pa. O 2/FIO 2 ratio Compliance Dead space Mortality Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 2006; 354: 1775 -86.

Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 2006; 354: 1775 -86.

Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 2006; 354: 1775 -86.

Mortality relates to recruitable lung Gattinoni L, Caironi P, Cressoni M, et al. Lung Mortality relates to recruitable lung Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 2006; 354: 1775 -86.

Lung recruitment in ARDS Upp ? er i nfle ctio t oin tion p Lung recruitment in ARDS Upp ? er i nfle ctio t oin tion p nflec i Lower Gattinoni L Am J Respir Crit Care Med 2001; 164: 1701– 1711 n p oint

Over-stretch = “Volutrauma” Ventilation induced lung injury (VILI) Epithelial and endothelial cells are anchored Over-stretch = “Volutrauma” Ventilation induced lung injury (VILI) Epithelial and endothelial cells are anchored to the lung “skeleton” Elastin fibres Bunched up collagen fibres Gattinoni L, Pesenti A, The concept of the “baby lung”. Intensive Care Med; 2005: 31: 776 -784

Stress and strain Stress = K (Youngs module of material) x Strain Stress = Stress and strain Stress = K (Youngs module of material) x Strain Stress = PL (transpulmonary pressure) Strain = Vt (Δ Lung Vol) / “baby lung” (volume at ZEEP) K = E spec (Specific lung elastance) Hence: E spec = PL x Baby Lung / Vt E spec = Transpulmonary Pressure at which the EELV doubles (~12 -13 cm normally)

Gattanoni’s hypothesis. . . If… E spec is constant within narrow limits in ARDS Gattanoni’s hypothesis. . . If… E spec is constant within narrow limits in ARDS Then… An estimate of stress and strain can be made by knowing either size of “baby lung”, or PL (Neither are measured routinely in ICU)

“Volutrauma”: Volume–dependent elastance E 2 Volume Non-linear portion; volume dependent compliance (E 2) Paw “Volutrauma”: Volume–dependent elastance E 2 Volume Non-linear portion; volume dependent compliance (E 2) Paw = Airway pressure E 1 = volumeindependent respiratory elastance Linear portion; constant compliance; independent of volume (E 1) Pressure E 2 = Volume-dependent component of elastance VT = tidal volume Po = static recoil pressure at endexpiration PEEP (tot) Bersten AD. Measurement of overinflation by multiple linear regression analysis in patients with acute lung injury. Eur Respir J 1998; 12: 526– 532.

“Volutrauma”: = safe zone = dangerous overstretched zone VEI = End expiratory volume above “Volutrauma”: = safe zone = dangerous overstretched zone VEI = End expiratory volume above resting volume Bersten AD. Measurement of overinflation by multiple linear regression analysis in patients with acute lung injury. Eur Respir J 1998; 12: 526– 532.

“Volutrauma”: = safe zone = dangerous overstretched zone %E 2 was >30% in 50% “Volutrauma”: = safe zone = dangerous overstretched zone %E 2 was >30% in 50% of data where Pel <30 cm! Pel, dyn =Dynamic elastic airway pressure Bersten AD. Measurement of overinflation by multiple linear regression analysis in patients with acute lung injury. Eur Respir J 1998; 12: 526– 532.

Airway Pressure-time curves During inspiration, if: a =the slope of the P-t relation at Airway Pressure-time curves During inspiration, if: a =the slope of the P-t relation at t = 1 s c = the pressure at t = 0. b = dimensionless number shape of the P-t curve b <1, P-t curve is convex; ↑ compliance b >1 P-t curve is convex; ↓ compliance b =1 P-t curve is straight; ↔compliance Ranieri VM, Zhang H, Mascia L, et al. Pressure–time curve predicts minimally injurious ventilatory strategy in an isolated rat lung model. Anesthesiology 2000; 93: 1320– 8

Airway Pressure-time curves Ranieri VM, Zhang H, Mascia L, et al. Pressure–time curve predicts Airway Pressure-time curves Ranieri VM, Zhang H, Mascia L, et al. Pressure–time curve predicts minimally injurious ventilatory strategy in an isolated rat lung model. Anesthesiology 2000; 93: 1320– 8

Hypothetical model of Pplateau vs Vt ~based on meta analysis of 5 trials of Hypothetical model of Pplateau vs Vt ~based on meta analysis of 5 trials of low volume ventilation Eichacker PQ, . Gerstenberger EP, Banks SM, Cui X, Natanson C. Meta-analysis of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes. Am J Respir Crit Care Med Vol 166. pp 1510– 1514, 2002

Under-stretch = “Atelectrauma” Condom model demonstrating intrapulmonary stresses “Atelectasis” as modelled by applying negative Under-stretch = “Atelectrauma” Condom model demonstrating intrapulmonary stresses “Atelectasis” as modelled by applying negative pressure to a condom surrounded by an “alveolar pressure” of 20 cm. H 2 O Mead J, Takishima T, Leith D. Stress distribution in lungs: a model of pulmonary elasticity. J Appl Physiol 1970; 28: 596 -608

“Atelectrauma” Shear forces in the zone of lung opening, caused by stretching of densely “Atelectrauma” Shear forces in the zone of lung opening, caused by stretching of densely distributed alveolar membranes, obliquely attached to bronchiolar basal membranes Jonson B. Elastic pressure-volume curves in acute lung injury and acute respiratory distress syndrome Intensive Care Med 31: 205– 212, 2005, with permission from: Jonson B (1982) In: Prakash O (ed) Applied physiology in clinical respiratory care. Nijhoff, The Hague, pp 123– 139

Atelectasis = Stress Mead and colleagues have Consider inflating a partially postulated that: collapsed Atelectasis = Stress Mead and colleagues have Consider inflating a partially postulated that: collapsed lung to PL=30 cm. H 2 O. Peff =-PL (V/V 0)2/3 Where PL = Palv - Ppl PL = transpulmonary pressure, Palv = alveolar pressure, Ppl = pleural pressure V = Inflated volume, V 0 = collapsed volume Let the volume of the degassed region be 1/10 of its final inflated volume. PL is therefore amplified by 102/3 Thus the initial pressure tending to expand the atelectatic region is: 30 x 102/3 = 140 cm H 2 O !! Mead J, Takishima T, Leith D. Stress distribution in lungs: a model of pulmonary elasticity. J Appl Physiol 1970; 28: 596 -608

Alveolar wall stress in 2 -D condom model Wall areas stressed next to regions Alveolar wall stress in 2 -D condom model Wall areas stressed next to regions of hyperiflation and collapse Surfactant depletion in pig model Recruitment occurs throughout static inflation Courtesy of Gary Nieman, Syracuse NY

Deflation /re-inflation PV curves Saline-lavaged rabbits Solid lines show re-inflation plots after deflation from Deflation /re-inflation PV curves Saline-lavaged rabbits Solid lines show re-inflation plots after deflation from 30 cm H 2 O airway pressure to different endexpiratory pressures. Little hysteresis with deflation to 15 cm H 2 O, little derecruitment above that pressure. Hickling KG: Reinterpreting the pressure-volume curve in patients with acute respiratory distress syndrome. Curr Opin Crit Care 2002, 8: 32– 38 Published with permission from: Rimensberger PC, Cox PN, Frndova H, et al. : The open lung during small tidal volume ventilation: Concepts of recruitment and “optimal” positive end expiratory pressure. Crit Care Med 1999, 27: 1946– 1952.

Stored curves Date & time P/-V Tool 2 Actual Settings P-start Current settings Total Stored curves Date & time P/-V Tool 2 Actual Settings P-start Current settings Total time To open setting window Start/Stop button Cursor buttons To open Plot window To select and view stored curves 5 cm. H 2 O P-top 35 cm. H 2 O end PEEP 10 cm. H 2 O Ramp speed 3 cm. H 2 O/s T-pause 1 s T-total 23 s V 2000 -/12 -12 15: 33: 34 3. 78 Assist lines 1 / 5 30 492 15 Xxxxxxxxx erttrert Xxxxx erttrert Inspiratory limb (green) Expiratory limb (yellow) Settings Start/Stop Cursor 1 Cursor 2 P Plot History Cursor 1 Cursor 2 C cursor Insp. limb 100 / 5 900 / 22 37. 5 Exp. limb 155 / 5 1120 / 22 36. 5 Close Cursor 1 for both limbs Cursor 2 for both limbs Compliances for both red lines Data of insp. limb Data of Exp. limb

Pressure Galileo datalogger: Inflation deflation method Flow Hickling KG. Using the expiratory pressure volume Pressure Galileo datalogger: Inflation deflation method Flow Hickling KG. Using the expiratory pressure volume curve- VILI at the bedside. 25 th Symposium of Intensive Care and Emergency Medicine, March 21 -25, 2005

Volume Galileo datalogger: Inflation deflation method Pressure Hickling KG. Using the expiratory pressure volume Volume Galileo datalogger: Inflation deflation method Pressure Hickling KG. Using the expiratory pressure volume curve- VILI at the bedside. 25 th Symposium of Intensive Care and Emergency Medicine, March 21 -25, 2005

Models of threshold opening and closing pressures Inspiratory tidal PV plots Incremental = black Models of threshold opening and closing pressures Inspiratory tidal PV plots Incremental = black symbols Decremental = open symbols TOP = 0– 40, TCP = 0– 4. At each PEEP level the volume at equivalent pressures and the mean tidal PV slope are greater during decremental PEEP. Hickling KG: Reinterpreting the pressure-volume curve in patients with acute respiratory distress syndrome. Curr Opin Crit Care 2002, 8: 32– 38 Redrawn from: Hickling KG: Best compliance during a decremental, but not incremental, positive end-expiratory pressure trial is related to open-lung positive end expiratory pressure: a mathematical model of acute respiratory distress syndrome lungs. Am J Respir Crit Care Med 2001, 163: 69– 78

Models of threshold opening and closing pressures The mean tidal PV slope plotted against Models of threshold opening and closing pressures The mean tidal PV slope plotted against PEEP Incremental PEEP = black symbols Decremental PEEP = open symbols Max PV slope with: Incremental PEEP is at 20 cm H 2 O Decremental PEEP is at 16 cm H 2 O Hickling KG: Best compliance during a decremental, but not incremental, positive end-expiratory pressure trial is related to open-lung positive end expiratory pressure: a mathematical model of acute respiratory distress syndrome lungs. Am J Respir Crit Care Med 2001, 163: 69– 78

Models of threshold opening and closing pressures Flow pressure curves Simulated data Max change Models of threshold opening and closing pressures Flow pressure curves Simulated data Max change in slope corresponds to beginning of de-recruitment But very difficult to judge slope changes by eye especially when very steep Hence a flow pressure curve can indicate the max rate of de-recruitment Hickling KG. Using the expiratory pressure volume curve- VILI at the bedside. 25 th Symposium of Intensive Care and Emergency Medicine, Brussels, Belgium, March 21 -25, 2005

Derecruitment Pressure Galileo datalogger: Flow-Pressure Flow Hickling KG. Using the expiratory pressure volume curve- Derecruitment Pressure Galileo datalogger: Flow-Pressure Flow Hickling KG. Using the expiratory pressure volume curve- VILI at the bedside. 25 th Symposium of Intensive Care and Emergency Medicine, March 21 -25, 2005

Models of threshold opening and closing pressures (A) Airway pressure vs volume /recruited volume Models of threshold opening and closing pressures (A) Airway pressure vs volume /recruited volume determined from CT (open circles and dotted line; expressed as percent of maximum volume) and recruitment (black circles and solid line; expressed as percent maximum recruitment) (B) Frequency distribution of estimated opening pressures. Note that recruited volume continues throughout inflation, up to 50 cm H 2 O pressure. Hickling KG: Reinterpreting the pressure-volume curve in patients with acute respiratory distress syndrome. Curr Opin Crit Care 2002, 8: 32– 38 Redrawn from: Crotti S, Mascheroni D, Caironi P, et al. : Recruitment and de-recruitment during acute respiratory failure: A clinical study. Am J Respir Crit Care Med 2001, 164: 131– 140.

Real-time acquisition of threshold opening and closing pressures Recruitment is described by Threshold Opening Real-time acquisition of threshold opening and closing pressures Recruitment is described by Threshold Opening Pressure (TOP) Number of Units Derecruitment is described by Threshold Closing Pressure (TCP) Skewed normal distribution Unique to a patient and condition TCP TOP Pressure Chase J, Yuta T, Shaw G, Horn B, Hann C A minimal model of mechanically ventilated lung mechanics to optimise ventilation therapy in the treatment of ARDS in critical care. Proceedings of the 12 th International Conference on Bioengineering, Singapore 2005

PEEP TCP Unique distributions for different levels of PEEP are found TOP Chase J, PEEP TCP Unique distributions for different levels of PEEP are found TOP Chase J, Yuta T, Shaw G, Horn B, Hann C A minimal model of mechanically ventilated lung mechanics to optimise ventilation therapy in the treatment of ARDS in critical care. Proceedings of the 12 th International Conference on Bioengineering, Singapore 2005

Optimisation of ventilation Parameter identification = patient specific model Simulation to determine effect of Optimisation of ventilation Parameter identification = patient specific model Simulation to determine effect of settings on PV curve Optimise ventilator settings as desired Chase J, Yuta T, Shaw G, Horn B, Hann C A minimal model of mechanically ventilated lung mechanics to optimise ventilation therapy in the treatment of ARDS in critical care. Proceedings of the 12 th International Conference on Bioengineering, Singapore 2005

‘Strengths’ in using this approach…. . Real time assessment of recruitment status which is ‘Strengths’ in using this approach…. . Real time assessment of recruitment status which is dependent on PEEP, ventilation strategy, and disease Readily identifies TCP distributions optimization of PEEP Provides opportunity to simulate a ventilation strategy before application. TOP distribution characteristics Prediction of “overstretch”. E. g. Δ recruitment < % max rate ? Correlated with E 2% or CT scan

Limitations… Although flow resistive forces through the endotracheal tube are accounted for, the model Limitations… Although flow resistive forces through the endotracheal tube are accounted for, the model assumes the pressure at the carina will reflect what is happening to alveolar units. Unforeseen resistive changes (eg major bronchial airway obstruction) could therefore lead to incorrect inferences about recruitment status Needs to be clinically validated

A model for teaching and research Mechanical lung model with 6 units of variable A model for teaching and research Mechanical lung model with 6 units of variable compliance (weighted) bellows and variable insp /exp resistances (taps)

Mimicking nature 5 cm PEEP 15 cm PEEP Sponsored by NZ$8000 grant from Hamilton Mimicking nature 5 cm PEEP 15 cm PEEP Sponsored by NZ$8000 grant from Hamilton Medical, Switzerland

Mimicking nature Normal PV loop of “Asthma” PV loops at different levels of PEEP Mimicking nature Normal PV loop of “Asthma” PV loops at different levels of PEEP (Note tidal volume is referenced to zero volume) Chase JG, Yuta T, Shaw GM, Mulligan K, Hann CE. A novel mechanical lung model of pulmonary diseases to assist with teaching and research (in review )

Mind what you have learned. Save you it can. Mind what you have learned. Save you it can.

Acknowledgements Toshi Yuta Kerry Mulligan Assoc. Prof. Geoff Chase Dr Chris Hann Beverley Horn Acknowledgements Toshi Yuta Kerry Mulligan Assoc. Prof. Geoff Chase Dr Chris Hann Beverley Horn