Robert L. Johnson

Reflex cardiovascular depression during unilateral lung hyperinflation in the dog.

We have examined whether lung hyperinflation in the anesthetized dog reflexly depresses cardiac output, stroke volume, heart rate, and blood pressure and whether these changes persist for more than a minute. To eliminate any mechanical restriction to venous return and pulmonary blood flow during lung hyperinflation, a model was developed in which all pulmonary artery blood flow and all ventilation were directed to the right lung in dogs with widely open chest and the left lung was hyperinflated before and after left cervical vagotomy. Heart rate, stroke volume, and blood pressure decreased by 24, 20, and 27%, respectively, within 15 s of left lung inflation to 30 cm H(2)O. Heart rate increased to preinflation levels by 1 min, but stroke volume and blood pressure remained depressed during lung hyperinflation for at least 15 min. Upon deflation, stroke volume and blood pressure returned to control levels within 1 min. Division of the left vagosympathetic trunk at the neck interrupted all autonomic afferent and efferent nerves of the left lung, but left intact the right vagal sympathetic and parasympathetic afferent and efferent nerves of the heart. After left cervical vagotomy the transient fall in heart rate, stroke volume, and blood pressure during left lung hyperinflation was greatly reduced or eliminated. These results suggest that unilateral lung hyperinflation reflexly depresses heart rate and blood pressure, which are partially compensated with time, and reflexly depresses stroke volume, which persists uncompensated until the lung is deflated. These findings may explain the depressed cardiovascular function observed during regional lung overdistention especially when it occurs during positive pressure ventilation.

A Longitudinal Study of Adaptive Changes in Oxygen Transport and Body Composition

The effects of a 20-day period of bed rest followed by a 55-day period of physical training were studied in five male subjects, aged 19 to 21. Three of the subjects had previously been sedentary, and two of them had been physically active. The studies after bed rest and after physical training were both compared with the initial control studies. Effects of Bed Rest All five subjects responded quite similarly to the bed rest period. The total body weight remained constant; however, lean body mass, total body water, intracellular fluid volume, red cell mass, and plasma volume tended to decrease. Electron microscopic studies of quadriceps muscle biopsies showed no significant changes. There was no effect on total lung capacity, forced vital capacity, one-second expiratory volume, alveolar-arterial oxygen tension difference, or membrane diffusing capacity for carbon monoxide. Total diffusing capacity and pulmonary capillary blood volume were slightly lower after bed rest. These changes were related to changes in pulmonary blood flow. Resting total heart volume decreased from 860 to 770 ml. The maximal oxygen uptake fell from 3.3 in the control study to 2.4 L/min after bed rest. Cardiac output, stroke volume, and arterial pressure at rest in supine and sitting positions did not change significantly. The cardiac output during supine exercise at 600 kpm/min decreased from 14.4 to 12.4 L/min, and stroke volume fell from 116 to 88 ml. Heart rate increased from 129 to 154 beats/min. There was no change in arterial pressure. Cardiac output during upright exercise at submaximal loads decreased approximately 15% and stroke volume 30%. Calculated heart rate at an oxygen uptake of 2 L/min increased from 145 to 180 beats/min. Mean arterial pressures were 10 to 20 mm Hg lower, but there was no change in total peripheral resistance. The A-V 02 difference was higher for any given level of oxygen uptake. Cardiac output during maximal work fell from 20.0 to 14.8 L/min and stroke volume from 104 to 74 ml. Total peripheral resistance and A-V 02 difference did not change. The Frank lead electrocardiogram showed reduced T-wave amplitude at rest and during submaximal exercise in both supine and upright position but no change during maximal work. The fall in maximal oxygen uptake was due to a reduction of stroke volume and cardiac output. The decrease cannot exclusively be attributed to an impairment of venous return during upright exercise. Stroke volume and cardiac output were reduced also during supine exercise. A direct effect on myocardial function, therefore, cannot be excluded. Effects of Physical Training In all five subjects physical training had no effect on lung volumes, timed vitalometry, and membrane diffusing capacity as compared with control values obtained before bed rest. Pulmonary capillary blood volume and total diffusing capacity were increased proportional to the increase in blood flow. Alveolar-arterial oxygen tension differences during exercise were smaller after training, suggesting an improved distribution of pulmonary blood flow with respect to ventilation. Red cell mass increased in the previously sedentary subjects from 1.93 to 2.05 L, and the two active subjects showed no change. Maximal oxygen uptake increased from a control value of 2.52 obtained before bed rest to 3.41 L/min after physical training in the three previously sedentary (+33%) and from 4.48 to 4.65 L/min in the two previously active subjects (+4%). Cardiac output and oxygen uptake during submaximal work did not change, but the heart rate was lower and the stroke volume higher for any given oxygen uptake after training in the sedentary group. In the sedentary subjects cardiac output during maximal work increased from 17.2 L/min in the control study before bed rest to 20.0 L/min after training (+16.5%). Arterio-venous oxygen difference increased from 14.6 to 17.0 ml/100 ml (+16.5%). Maximal heart rate remained constant, and stroke volume increased from 90 to 105 (+17%). Resting total heart volumes were 740 ml in the control study before bed rest and 812 ml after training. In the previously active subjects changes in heart volume, maximal cardiac output, stroke volume, and arteriovenous oxygen difference were less marked. Previous studies have shown increases of only 10 to 15% in the maximal oxygen uptake of young sedentary male subjects after training. The greater increase of 33% in maximal oxygen uptake in the present study was due equally to an increase in stroke volume and arteriovenous oxygen difference. These more marked changes may be attributed to a low initial level of maximal oxygen uptake and to an extremely strenuous and closely supervised training program.

Spontaneous fibrinolysis in pulmonary embolism

This study correlated levels of activated fibrinolysis with the presence, extent, and rate of resolution of angiographically documented pulmonary emboli. Pulmonary emboli demonstrable by angiography were associated with detectable fibrin split products in the serum of 24 of 25 patients. In the absence of increased fibrin split products, pulmonary emboli large enough to be demonstrated by angiography were found in only 2 of 25 positive pulmonary angiograms. Spontaneous resolution of pulmonary emboli could not be correlated with the the concentration or persistence of fibrin split products but did correlate well with the presence of a reversible precipitating cause. Thrombophlebitis in the absence of clinical evidence of pulmonary embolism was not associated with increased concentrations of fibrin split products in eight of nine patients. The one patient with increased fibrin split product concentration had evidence on lung scan of silent pulmonary embolism.

Maximal Diffusing Capacity of the Lung for Carbon Monoxide

During exercise pulmonary diffusing capacity for carbon monoxide and oxygen increases because the pulmonary capillary bed expands (1). It seems reasonable that there should be an upper limit to this expansion at which the diffusing capacity reaches maximum. The apparent oxygen diffusing capacity (DLO2) has been noted to approach a plateau or upper limit as the work load increases (2, 3), but a similar plateau for COdiffusing capacity has never been clearly demonstrated (1, 4) perhaps because it has not been measured at heavy enough work loads. Thus our purpose was to determine how high CO diffusing capacity can go as exercise work load increases and to see whether it reaches a plateau before the maximal tolerated work load is achieved. To accomplish this we measured apparent CO diffusing capacity (DLco) and pulmonary blood flow simultaneously in five normal adults, five normal children, and in three adult patients with mitral stenosis. Measurements were made at rest and at increasing treadmill work loads up to and beyond that causing maximal oxygen consumption. At rest and at maximal oxygen consumption the true membrane diffusing capacity for CO (DMco) and the pulmonary capillary blood volume (Vc) were estimated by the RoughtonForster method (5).

Functional Significance of a Low Pulmonary Diffusing Capacity for Carbon Monoxide

Diffusing capacity of the lungs imposes a theoretical limit to oxygen consumption, causing oxygen saturation of arterial blood to fall sharply if this limit is approached (1). The diffusing surface of the normal lung is so large, however, that at sea level oxygen capacity of the blood and the cardiac output rather than diffusing capacity create the major bottleneck to oxygen transport (2). Diffusion becomes an important limit only at high altitudes (3) or when diffusing capacity is reduced sufficiently by disease to cause alveolar capillary block (4). Diffusing capacity of the lungs usually is measured with respect to CO (DLco) rather than oxygen (DLO2). Yet little information exists regarding how low DLCOmust be before alveolar capillary block is manifest. Recent work of Roughton and Forster (5) and of Staub, Bishop, and Forster (6) defines the theoretical relationship between DLco and DLO2 allowing translation of CO diffusing capacity into terms of oxygen transport. Thus we should be able to state more explicitly the functional significance of a low CO diffusing capacity. Our purpose has been to predict the restriction in maximal oxygen transport implied by a low DLco and then to check the prediction by experimental measurement.

Further examination of alveolar septal adaptation to left pneumonectomy in the adult lung.

Recent data from our laboratory are presented concerning alveolar septal adaptation following 42-45% lung resection by left pneumonectomy (PNX) in adult foxhounds compared to sham-operated control animals. Results confirm our previous conclusion that compensation in the remaining lung occurs without a net growth of additional alveolar septal tissue. The major ultrastructural responses are (a) alveolar capillary distention, which recruits capillary blood volume and surface area, leading to a 30-50% increase in lung diffusing capacity estimated by morphometry, a magnitude similar to that measured by physiologic methods; (b) a selectively increased volume of type 2 alveolar epithelial cells. These data, taken together with the balanced compensatory growth of alveolar septal cells observed in adult dogs following 55-58% lung resection by right PNX, support a graded alveolar cellular response to chronic mechanical strain with the alveolar epithelial cells being activated first; as strain increases further with greater lung resection other alveolar cells also become activated leading to an overt increase in septal tissue volume. The spatial distribution of lobar mechanical strain and lobar tissue volume assessed by high resolution computed tomography was markedly non-uniform after PNX, suggesting possible non-uniform distribution of alveolar cellular response. The sequential activation of physiologic recruitment and cellular adaptation confer additive functional benefits that optimize long-term exercise performance after PNX.

Respiratory Muscle Blood Flow Distribution during Expiratory Resistance

When work load on the respiratory system is increased the relative increase in blood flow to each of the muscles of breathing provides an index of how the augmented effort of breathing is partitioned among the different muscles. We have used a radio-active microsphere technique to measure blood flow to each of the muscles of respiration in supine dogs during unobstructed respiration and breathing against graded expiratory threshold loads. 79% of the augmented flow went to expiratory muscles; of this increased flow to expiratory muscles 74% went to abdominal wall muscles and 26% to internal intercostals. In our earlier studies of hyperventilation induced by CO(2) rebreathing where expiratory work loads were low, 44% of the increase in flow went to expiratory muscles; of this, only 39% went to abdominal wall muscles and 61% to internal intercostals. During inspiratory resistance which produced small increases in expiratory work, 27% of the increase in blood flow went to expiratory muscles; of this, only 37% went to abdominal wall muscles and 63% to internal intercostals. These results suggest that the internal intercostals are predominantly used for expiration when expiratory work loads are low, whereas the abdominal wall muscles are predominantly used when loads are high. For similar rates of pressure-volume work done on the lung, the total respiratory muscle blood flow is significantly greater during expiratory loads than during unobstructed hyperventilation or inspiratory loads. Thus, the abdominal wall muscles that are utilized for overcoming high pressure expiratory loads are relatively inefficient in converting metabolic energy into pressure-volume work.

Vertical Distributions of Pulmonary Diffusing Capacity and Capillary Blood Flow in Man

In six normal upright subjects, a 100 mol bolus-composed of equal parts of neon, carbon monoxide, and acetylene (Ne, CO, and C(2)H(2))-was inspired from either residual volume (RV) or functional residual capacity (FRC) during a slow inspiration from RV to total lung capacity (TLC). After breath holding and subsequent collection of the exhalate, diffusing capacity and pulmonary capillary blood flow per liter of lung volume (D(L)/V(A) and Q(C)/V(A)) were calculated from the rates of CO and C(2)H(2) disappearances relative to Ne. The means: D(L)/V(A) = 5.26 ml/min x mm Hg per liter (bolus at RV), 6.54 ml/min x mm Hg per liter (at FRC); Q(C)/V(A) 0.537 liters/minute per liter (bolus at RV), 0.992 liters/minute per liter (at FRC). Similar maneuvers using Xenon-133 confirmed that, during inspiration, more of the bolus goes to the upper zone if introduced at RV and more to the lower, if at FRC. A lung model has been constructed which describes how D(L)/V(A) and Q(C)/V(A) must be distributed to satisfy the experimental data. According to this model, there is a steep gradient of Q(C)/V(A), increasing from apex to base, similar to that previously determined by other techniques-and also a gradient in the same direction, although not as steep, for D(L)/V(A). This more uniform distribution of D(L)/V(A) compared with Q(C)/V(A) indicates a vertical unevenness of diffusing capacity with respect to blood flow (D(L)/Q(C)). However, the relative degree of vertical unevenness of D(L)/V(A) compared with Q(C)/V(A) can account only in part for previous observations attributed to the inhomogeneity of D(L)/V(A) and Q(C)/V(A). Thus, a more generalized unevennes of these ratios must exist throughout the lung, independent of gravitation.

Venous-Arterial Admixture in the Lungs in Primary and Secondary Polycythemia

By use of a polarographic technic for measuring arterial oxygen tension, venous-arterial shunting in the lungs was investigated in patients with primary and secondary polycythemia before and after treatment and in nonpolycythemic normal and emphysematous subjects.

A rebreathing method for measuring lung volume, diffusing capacity and cardiac output in conscious small animals

We developed a multiple gas rebreathing technique for measuring lung diffusing capacity (DL(CO)), lung volume (V(L)) and cardiac output simultaneously in conscious spontaneously breathing small animals. Lung volume was measured from the dilution of methane (CH4) or sulfur hexafluoride (SF6) and verified independently by a helium washout technique. Cardiac output and DL(CO) were estimated from the uptake of acetylene and carbon monoxide, respectively. We tested guinea pigs at two levels of alveolar oxygen tension in order to estimate membrane diffusing capacity and pulmonary capillary blood volume by the Roughton-Forster technique. Results show that measured DL(CO) are consistent with reported values in anesthetized guinea pigs as well as with allometric comparison across species. Lung volume estimated from SF6 dilution agreed closely with that estimated independently from helium washout; however, lung volume estimated from CH4 dilution was systematically lower due to the addition of endogenously produced CH4 to the rebreathing system. We conclude that this technique can be used to measure resting lung function in conscious unsedated small animals.