Hazel A. Jones

Detection of intrapulmonary hemorrhage with carbon monoxide uptake. Application in goodpasture's syndrome.

We devised a noninvasive measure of pulmonary hemorrhage of value in the management of Goodpastures syndrome. We reasoned that alveolar uptake of inhaled carbon monoxide during breath holding would increase in the presence of extravascular blood, but clearance of its radioisotope (C15O) from a lung field would be delayed. Thus, the ratio of uptake to clearance would indicate lung hemorrhage. In 15 controls and six patients with renal failure without hemorrhage, this ratio ranged from 0.73 to 1.5. In eight patients with Goodpastures syndrome the ratio ranged from 1.5 to 16.5, returning to normal between episodes of bleeding. Measurements of carbon monoxide uptake alone in 10 patients with Goodpastures syndrome were at times well above that predicted for their hemoglobin level, whereas in renal failure with acute pulmonary edema increased carbon monoxide uptake was rarely found. Thus, monitoring of the single-breath carbon monoxide uptake alone can detect episodes of lung hemorrhage.

Effect of posture on inter-regional distribution of pulmonary ventilation in man

Regional ventilation per unit alveolar volume (V/VA) and regional lung expansion (FRCR/TLCR) were measured in twelve normal male human subjects in seated, supine, lateral decubitus and prone postures using a gamma camera and inhalation of the radioactive gases 81Krm (half-life 13 sec) and 85Krm (half-life 4.4 h). FRCR/TLCR decreased from superior to inferior in all postures except prone where it was uniform; V/VA increased from superior to inferior except in the prone position where it was uniform. In the horizontal axis FRCR/TLCR and V/VA were uniformly distributed except for cranial to caudal gradients (with lower values caudally) in supine and lateral decubitus postures. In the prone posture V/VA tended to be higher in caudal lung zones.

Effect of posture on inter-regional distribution of pulmonary perfusion and V̇aQ̇ ratios in man

Using a gamma camera regional pulmonary perfusion per unit alveolar volume (Q/VA) and ventilation-perfusion ratios (VA/Q) were measured in fourteen normal male volunteers in upright, supine, lateral decubitus, prone and prone suspended postures with inhalation and intravenous infusion of radioactive 81Krm (half-life 13 sec) and inhalation of radioactive 85Krm (half-life 4.4 h). In the vertical axis, Q/VA increased from upper to lower lung regions in upright, lateral decubitus, prone and prone suspended postures but was uniform in supine and within the dependent lung in decubitus postures. Horizontally, Q/VA decreased from cranial to caudal in lateral decubitus, prone suspended, and near the diaphragm in supine. Vertically, VA/Q decreased from upper to lower in all postures except in supine and within the dependent decubitus lung where it increased. VA/Q tended to increase from cranial to caudal in horizontal postures. The effects of gravity on Q/VA and VA/Q vertical distributions are modified when FRC is low (supine, lower decubitus lung) because perfusion is more uniformly distributed. Horizontal gradients of Q/VA and VA/Q are more pronounced under conditions of high local lung volume but also occur in postures where FRC is low.

DlCO/Q̇ and diffusion limitation at rest and on exercise in patients with interstitial fibrosis

Pulmonary diffusing capacity for carbon monoxide (DLCO) and pulmonary capillary blood flow (Qp) were measured on exercise in patients with a low DLCO with the aim of predicting, from the overall DL/Qp ratio, diffusion limitation for oxygen and relating it to the fall in arterial oxygen saturation actually observed. Five patients with cryptogenic fibrosing alveolitis (DLCO ranging from 20-54% predicted normal) exercised for 5 min at a work load equal to 60% of their maximum (45 to 90 watts). At 5 min (and previously at rest) they rebreathed rapidly for 15 sec from a 1.0 L bag containing helium (He), sulphur hexafluoride (SF6) and freon-22, 30% oxygen in argon and less than 1 ppm 11C-labelled carbon monoxide. Pulmonary capillary blood flow (Qp) and diffusing capacity (DLCO) were measured from flow-weighted breath-by-breath concentrations of freon-22 and 11CO, after correction for gas mixing delays (using He and SF6). Oxygen saturation (SaO2) (ear oximetry), MO2 and MCO2 and cardiac frequency were measured. PAO2 (ideal) was derived and mixed venous O2 saturation and content were calculated (Fick); PaO2 and PVO2 were derived from standard dissociation curves. For comparison, DLCO and Qp were measured in a similar fashion in five normal subjects exercising at 60 watts. Mean DLCO in patients with fibrosis was 9.62 (SD 2.88) ml.min-1, mm Hg-1 on exercise and mean Qp was 10.48 (SD 1.79) L.min-1 giving mean DLCO/Q ratios of 0.92 (SD 0.28). At 60 watts mean DLCO/Qp in normal subjects was 2.54 (SD 0.3), 2.76-times greater than in patients. SaO2% fell in patients by 3-15% on exercise. Predictions of alveolar-end capillary PO2 gradients from these overall DL/Q gradients showed that diffusion limitation accounted for 99% of the alveolar-arterial PO2 gradient on exercise in fibrosing alveolitis. Hughes (1991 Respir. Physiol. 83:167-178) [corrected] suggests that this simple approach overestimates the contribution of diffusion limitation by about 30%.

Uneven perfusion and ventilation within lung regions studied with nitrogen-13

The clearance of nitrogen-13 (13N) from the upper, mid and lower zones was measured with a gamma camera during spontaneous breathing in 10 seated subjects. The clearance was monitored after (a) an intravenous injection of 13N dissolved in saline and (b) equilibration with 13N gas in closed circuit. Subjects breathed air first, and then a 30 or 11% oxygen mixture. For any region, the time for 90% elimination (T90) was related to the volume expired by the whole lung during that time (VE90). For the mid and lower zones, the clearance was faster (VE90 smaller) after intravenous 13N than after equilibration with 13N gas. This difference persisted when 30% or 11% oxygen was inspired. For the lung overall, the physiological dead space for a mean tidal volume of 884 ml was 277 ml for intravenous 13N clearance, and 384 ml for 13N clearance after equilibration. The conclusions drawn for this study are (1) ventilation in relation to volume is uneven within lung regions (2) intraregional perfusion in relation to volume is also uneven (3) at a local level the well-ventilated units are better perfused (4) these inhomogeneities are not affected by raising or lowering the inspired oxygen concentration.

Rapid analysis for metabolites of 11C-labelled drugs: fate of [11C]-S-4-(tert.-butylamino-2-hydroxypropoxy)-benzimidazol-2-one in the dog

Positron emission tomography (PET) requires the use of compounds labelled with short-lived, positron-emitting isotopes (e.g., t1/2 of 11C approximately 120 min). As the concentration of unbound, non-metabolised drug is required as the input function for modeling, this presents particular problems for the study of the kinetics and metabolism of such compounds. We have now developed a rapid extraction procedure, followed by high-performance liquid chromatography using a short analytical column coupled to an on-line gamma-detector to determine the metabolism and kinetics of a non-selective beta-adrenergic antagonist of high affinity, S-4-(tert.-butylamino-2-hydroxypropoxy)benzimidazol-2-one. This antagonist is potentially well suited to the non-invasive localisation of beta-receptors in vivo. The ligand was rapidly taken up into the beta-receptor pool or excreted in urine, with less than 5% of the drug converted to metabolites. Plasma protein binding was only 16%. No significant metabolism of the ligand was observed in the anaesthetised dog, and, therefore, no correction for blood metabolite concentration is required for kinetic analysis of the 11C-labelled ligand during PET studies in this species. The analytical method reported here should be widely applicable: quantification of metabolites enables accurate estimation of the input function and is critical to the interpretation of PET data.

The contribution of heart beat to gas mixing in the lungs of dogs

The mixing efficiency for two gases of different gaseous diffusivity, helium (He) and sulphur hexafluoride (SF6) have been studied in anaesthetised dogs, closed and open chested, with and without the heart beating. Equilibration of He and SF6 was studied during rebreathing at frequency of 0.5 Hz and a tidal volume of either 0.3 or 0.5 L. Circulation and gas exchange were taken over by a complete heart and lung bypass circuit during the periods when the heart was stopped. The number of breaths required to reach 99% equilibration (n99) ranged from 4 to 14 for He and from 6 to 17 for SF6. There was no significant change in mixing efficiency in any situation. Stopping the heart increased the n99 for He by only 0.4 +/- 11% (1 SD) (n = 21). Opening the chest increased n99 by 1.4 +/- 13% with the heart beating and 2.5 +/- 19% with the heart stopped. The n99 for SF6 was 30 +/- 22% higher than that for He with the chest closed with or without the heart beating. This increased to 37% with the chest opened but was not altered by stopping the heart. The findings for the final phase equilibration rate constant were similar. We conclude that the beating action of the heart does not affect gas mixing in the lungs in the tidal breathing range.

Effect of posture on airway length and diameter in the dog

Abstract Postural changes in regional airway length and diameter, before and after atropine, were studied bronchographically in anaesthetized and recently killed dogs at end expiration. FRC was allowed to change with posture in the anaesthetized dog but was held constant in the dead dog. Systematic regional differences in airway length and diameter have been demonstrated; they vary with posture. When compared with the horizontal posture apical airways in the anaesthetized dog were longer and wider when the dog was erect and shorter and narrower when inverted. Changes in basal airways were small or absent. After atropine all airways increased in diameter and apex-base differences on going from the horizontal to upright posture were more marked; airway length was unaffected. Comparable findings were made in exsanguinated dogs turned prone to supine under isovolume conditions. Estimates of regional transpulmonary pressure, bronchial compliance and regional airways resistance have been made in the live dog from airway dimensions in various postures.

Regional Differences in Airway Resistances and Distribution of Common Dead Space Gas in Normal Subjects

Hughes, Greene, Iliff & Milic Emili (1970, Clinical Science, 39, 1 9 ~ ) have previously shown that for fast inspirations of a bolus of marker gas, distribution is more influenced by regional airway resistances than by regional compliances. In those experiments a 5 ml bolus of radioactive xenon-133 gas was injected at the mouth so the bolus had to traverse the dead space common to both lungs before regional distribution was determined; in addition, the larynx may mix the bolus and lengthen the period during which it is delivered to the lung. In these circumstances, elastic properties of the lung may exert some influence on the distribution. In the present studies using a similar experimental technique, boluses were injected at functional residual capacity (FRC), into a catheter passed through the nose into the trachea in four normal seated subjects who then inhaled as rapidly as possible ( > 3 l/s). We found the distribution of the boluses was similar, whether injected into the trachea or at the mouth, showing a slightly reduced basal ventilation relative to the rest of the lung. However, with a tracheal bolus immediately preceded by a maximal inspiration, there was a marked reduction in ventilation to the lower regions. Measurements were also made at lower inspiratory flow rates (0.1 and 0.4 I/s) controlled by a valve. At both these flow rates the regional distribution of boluses injected at the mouth or into the trachea tended to be similar to each other. These results suggest that airway resistances at FRC are slightly greater in the basal regions relative to the rest of the lung and are markedly greater following a maximal inspiration. In addition, during tidal breathing the distribution of common dead space gas is similar to that inspired at the mouth.