Human model of the pathophysiology of chronic obstructive pulmonary disease

In order to determine the effects of expiratory flow limitation (EFL)on the ventilatory pump we studied normal subjects during incremental exercise to the limit of tolerance, with and without limitation of expiratory flow at ∼1 L/s. Flow was limited by a Starling resistor placed in the expiratory line of an exercise breathing circuit while the subjects pedalled on a cycle ergometer. With EFL, the decrease in expiratory flow was accompanied by a >100% increase in inspiratory flow and a reduced duty cycle. Exercise was limited at ∼70% of control maximal exercise workload by intolerable dyspnoea.1 The enforced slowing of expiratory flow, and high inspiratory flows engendered high abdominal (Pab) and pleural (Ppl) pressure swings. Expiratory pressures as reflected by ΔPab accounted for 66% of the variance in Borg scale ratings of difficulty in breathing.1 According to the force–velocity relationships of skeletal muscle, for a given central drive, the abdominal muscles should develop greater pressures when expiratory flow is reduced while inspiratory muscle pressures should be decreased when inspiratory flows are high. Indeed, the velocity of shortening of the abdominal muscles was reduced and the pressures they developed were increased. As predicted the velocity of shortening of the diaphragm and inspiratory rib cage muscles was increased, but contrary to predictions, the pressures were too. The power output of all three muscle groups was increased.2 The reason for the increased power outputs and the greater than predicted pressures developed by the diaphragm and inspiratory rib cage muscles was hypercapnia.1–3 End-tidal partial pressures of CO2 (Pet co2) reached values as high as 60 torr. Arterial partial pressure of CO2 confirmed the CO2 retention. Thus, the chemical drive to all respiratory muscles increased. There was a strong correlation between peak expiratory Ppl and Pet co2 (P < 0.0001) indicating the increased drive to expiratory muscles, but also suggesting that expiratory muscle recruitment played a role in retaining CO2. This would occur if the high expiratory alveolar pressures decreased pulmonary capillary blood volume thereby increasing alveolar dead space. Indeed, we found that physiological dead space/tidal volume ratios were increased over control values during EFL exercise.4 We therefore attribute at least some of the hypercapnia to the high values of Pab. If so a vicious circle is established by which Pab leads to increased PCO2, the hypercapnia increases drive to the abdominal muscles, which further increases Pab and so forth. Using optoelectronic plethysmography, which measures the volume of the trunk by tracking surface body markers in 3D, we found that the tidal volume measured this way was greater than the tidal volume measured at the mouth by spirometry. Gas compression only accounted for one-third of the difference. We attributed the remaining two-thirds to blood shifts from the trunk to the extremities. These averaged 326 mL or 7.2 mL/cm H2O alveolar pressure.3 To determine whether the high expiratory pressures and prolonged expiratory time acted like a Valsalva manoeuvre to decrease cardiac output, we measured breath-by-breath O2 consumption (V’O2).5,6 From the Fick equation: Q’c = V’O2/(CaO2 − CvO2), where Q’c is cardiac output and the denominator is the arterial-mixed venous O2 content difference we calculated changes in Q’c from changes in V’O2 when EFL was suddenly imposed during exercise. Under these circumstances CaO2 − CvO2 stays nearly constant for a few seconds and Q’c becomes directly proportional to V’O2. Immediately upon imposition of EFL there was a sustained drop in Q’c by 10%.6 In conclusion, EFL exercise in healthy normal subjects reproduces most of the important clinical features of COPD including exercise limitation, severe dyspnoea, hypercapnic respiratory failure and a situation where energy supplies are unable to meet demand. These manifestations arise from the chest wall, not the lung and are attributable simply to EFL leading to a reduced velocity of shortening of expiratory muscles. This in turn increases Pab which, combined with the short duty cycle, acts like a Valsalva manoeuvre to decrease Q’c and causes hypercapnia. The pathogenesis of the pathophysiology of ventilatory pump abnormalities in COPD can be safely investigated in healthy subjects by experiments that are difficult if not impossible in patients.

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