Model of functional restriction in chronic obstructive pulmonary disease, transplantation, and lung reduction surgery.

Mechanical interactions between lung and chest wall are important determinants of respiratory function. When chest wall expansion during maximal inhalation generates insufficiently negative pleural pressures, the lungs remain functionally underinflated; this may be termed functional restriction. To explore mechanisms and effects of functional restriction in patients with emphysema, and to predict effects of single lung transplantation and lung volume reduction surgery (LVRS), we used a computational model based on standard physiology and measurements from individual patients. The model's lungs, separated by a compliant mediastinum, exhibit flow limitation according to the equal pressure point approach of Mead and coworkers. Pulmonary elastic recoil pressure is characterized by an exponential equation modified to reflect airway closure. Simulated respiratory maneuvers can be specified by variations in flow or pressure at the airway opening or in respiratory muscle activation. Model simulations successfully mimic recordings from individual patients. Input parameter values may then be altered to predict effects of surgical interventions in these same patients. The model simulations show the following. Single lung transplantation in emphysema can cause functional restriction of the normal transplanted lungs, and larger transplanted lungs may perform less well than smaller ones. LVRS improves lung and chest wall function in emphysema, but not in normal states. Surgical reduction of the native emphysematous lung after single lung transplantation can reduce functional restriction of the transplant and thereby improve its function.

Human lung volumes and the mechanisms that set them.

Definitions of human lung volumes and the mechanisms that set them are reviewed in the context of pulmonary function testing, with attention to the distinction between functional residual capacity (FRC) and the static relaxation volume of the respiratory system, and to the circumstances in which FRC and residual volume are set by dynamic rather than by static mechanisms. Related terms, conventions, and issues are addressed, including some common semantic and conceptual difficulties, with attention to "gas trapping", "hyperinflation", and "restriction".

Force, speed, and oxygen consumption in thoroughbred and draft horses.

Thoroughbred (TB) and draft horses (DH) have long been selected for tasks of very different intensities and force-speed relationships. To study their adaptations, we measured O2 consumption and related variables in three TB and four DH during progressive exercise tests on a level treadmill. The horses exerted a draft force of 0, 5, 10, 15, or 20% of their body weight at speeds that increased by 2 m/s every 3 min until they could not maintain that speed. We found that TB could exert the same draft forces as DH and, at each force, TB achieved about twice the speed, twice the external power, and twice the O2 consumption as DH; thus the two breeds had the same gross efficiencies. We also found maximal O2 consumption of TB to be about twice that of DH (134 vs. 72 ml . kg-1 . min-1, respectively), suggesting adaptations to high-intensity exercise. Peak efficiency was reached at lower speeds in DH than in TB, suggesting adaptations to high-force, low-speed exercise. These differences between TB and DH in force-speed and aerobic capacities and in speed for peak efficiency likely reflect different contraction velocities in locomotor muscles.

Ventilatory capacities at sea level and high altitude.

Because air is less dense at high altitude (HA), airway resistance is reduced and maximum inspiratory and expiratory flows are greater than at sea level (SL). Despite the reduction in airway resistance, ventilatory muscle endurance may be decreased by hypobaric hypoxia and, thus, may be a factor in limiting exercise at HA. To explore the effects of HA on ventilatory capacities and their relation to ventilatory demands of exercise, we measured 15-s maximum voluntary ventilation (MVV), 15-min maximum sustainable ventilation (MSV), and maximum airway pressures (Plmax and PEmax) in 18 healthy young men at SL and HA (Pikes Peak, 4300 m, or hypobaric chamber, PB approximately 460 mmHg). In eight of these subjects ventilatory capacities were compared with exercise ventilations. We also measured the effects of 36% O2 on the MSV in 12 of the subjects exposed to simulated altitude. Similar results were obtained at either simulated or actual HA. We found that MVV increased (p < 0.001) by 20% and the MSV (p < 0.001) by 15% at HA. Administration of 36% O2 at HA increased MSV further by 5% with no effect on MVV. No effect of HA on maximum inspiratory and expiratory pressures was found. We confirmed previous findings of modest increases in forced 1-s expired volume (FEV1) and slight decreases in forced vital capacity (FVC) at HA. At both SL and HA, the MSV exceeded the ventilatory demands of submaximal cycle exercise that could be sustained for about 30 min. During progressive cycle exercise to exhaustion, however, peak VE was not different from MVV, either at SL or HA. We conclude that the small, but significant, increase in MSV with 36% O2 administration at HA suggests that hypoxia decreases ventilatory endurance for flow loads as determined by the MSV. Thus, the possibility that ventilatory limits have a role in cessation of exercise at high altitude cannot be ruled out.

Effects of restraint and isolation stress and epidural blockade on endocrine and blood metabolite status, muscle glycogen metabolism, and incidence of dark-cutting longissimus muscle of sheep.

Crossbred lambs (47.3 kg BW) were used to study the effects of restraint and isolation stress on endocrine status and blood metabolites, antemortem glycogenolysis, and incidence of the dark-cutting condition (DCC) in the longissimus muscle (LM) and to determine the role of muscle contraction in the formation of the DCC in sheep. Lambs were assigned randomly to three treatments: unstressed controls (C); a single 6-h period of restraint and isolation stress (RIS); and a single 6-h period of RIS following epidural blockade (RISEB) with lidocaine. Blood was collected immediately before lambs were subjected to RIS and RISEB and at 12-min intervals during the 6-h period. Serum concentrations of glucose, lactate, and insulin were higher (P < .01) in RIS and RISEB lambs than in C lambs. Serum free fatty acid concentrations were higher (P < .01) in stressed lambs only during the first 4 h of stress. Plasma epinephrine and cortisol concentrations also were higher (P < .01) in RIS and RISEB lambs than in C lambs. Lambs were slaughtered within 30 min after completion of stress. Immediately after stunning and at .75, 3, 6, 12, and 24 h postmortem, samples were removed from the LM in the hindsaddle and foresaddle for glycogen, lactate, and pH determinations. Muscle pH was elevated (P < .01) by RIS and RISEB; ultimate pH exceeded 6.0. The LM from carcasses of RIS and RISEB lambs had lower (P < .01) glycogen and lactate concentrations in both regions than the LM of C lambs. Subjecting sheep to a single 6-h period of RIS was an effective animal model to induce the DCC. Failure of the epidural blockade to inhibit antemortem glycogen metabolism and formation of the DCC indicates that muscle contraction was not requisite to those processes in sheep.

Complications with the use of carfentanil citrate and xylazine hydrochloride to immobilize domestic horses.

Carfentanil citrate, the only opioid approved in the United States for immobilizing large exotic animals, increasingly has been used to chemically restrain exotic horses, such as Prezwalski's horses (Equus przewalskii) and wild horses (E caballus). Because carfentanil's duration of action is long and renarcotization may develop 2 to 24 hours after administration of antagonists, a study was designed to compare the physiologic effects of opioid antagonists, using domestic horses chemically restrained with xylazine hydrochloride and carfentanil. The study was terminated after the initial 3 horses developed severe tachycardia and hypertension, which resulted in the death of 1 horse from pulmonary edema. Although it was possible that the clinical findings in these horses may have resulted from use of an inadequate dosage of carfentanil or xylazine, or both, analysis of the results more likely indicated that domestic and exotic horses may respond differently to carfentanil, and domestic horses may not be a good model for use in studies of carfentanil.

Ventilation and carbon dioxide exchange in exercising horses: effect of inspired oxygen fraction.

Thoroughbred horses (TB) have no ventilatory response to added CO2 during near-maximal exercise. To see whether that reflects mechanical limits to ventilation or the control of breathing, we examined the effects of varying inspired O2 fraction (0.16, 0.21, or 0.30) in five normal TB standing quietly and galloping at 10 and 14 m/s on a level treadmill. We measured gas exchange (O2 consumption and CO2 production) and ventilation with a flow-through mask system. We also measured PO2, PCO2, and O2 contents in arterial and mixed venous blood and calculated cardiac output by using the Fick equation. Low inspired O2 fraction (0.16 vs. 0.21) had significant effects in TB galloping at 14 m/s. Arterial PO2 then was 38 Torr compared with 56 Torr for horses on air. Tidal volume and minute ventilation were 20% greater than their corresponding values on air, which were 12 liters and 1,475 l/min, respectively, whereas respiratory frequency did not change. O2 consumption and CO2 production were unchanged, but alveolar ventilation was 6% greater, despite increased alveolar and physiological dead spaces, so arterial PCO2 was lower (45 vs. 50 Torr on air). Thus, hypoxia was an effective stimulus to breathing, and minute ventilation was not mechanically limited in TB breathing air at the speeds studied.

Influence of treadmill exercise on pituitary-adrenal secretions, other blood constituents, and meat quality of sheep.

Whether lambs were used to evaluate the influence of treadmill exercise (TME) on physiological responses and meat quality. Lambs were exercised at either 5.6, 7.2, or 8.8 km/h on a 9 degrees incline for 10 min, followed by a 10-min walk at 4.0 km/h and 0 degrees incline, or were unexercised controls (C; n = 3/treatment). Heart rates were determined at -15, 1, 3, 6, 10, and 15 min relative to the onset of exercise. Blood was collected at 2.5-min intervals during and after exercise for determination of plasma concentrations of ACTH, cortisol, and lactate. In addition, blood collected during exercise was evaluated for hematocrit and for concentrations of glucose, hemoglobin, and total protein. Exercised lambs had greater (P < .01) heart rates than C lambs during and after exercise. Blood from TME lambs also had greater (P < .001) hematocrit percentages, total protein, and hemoglobin concentrations. Areas under the ACTH and cortisol response curves were greater (P < .001) for TME than for C lambs. Areas under glucose response curves were greater for all TME treatments (P < .001) than for C and greater (P < .001) for lambs exercised at 8.8 km/h than for lambs exercised at 5.6 km/h. Areas beneath lactate response curves were greater (P < .001) for lambs exercised at 8.8 km/h than for lambs exercised at 7.2 km/h and C lambs. Carcasses from lambs exercised at 5.6 km/h had lesser (P < .05) longissimus muscle (LM) glycogen concentrations at slaughter than carcasses from lambs exercised at either 7.2 or 8.8 km/h and C lambs.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamic moduli of rabbit lung tissue and pigeon ligamentum propatagiale undergoing uniaxial cyclic loading.

In fibrous connective tissue networks, mechanical loads may be transferred from one fiber to the next by friction between slipping fibers (J. Appl. Physiol. 74: 665-681, 1993). Here we tested that hypothesis; it predicts that elastance of fibrous networks increases with increasing frequency, decreases with increasing strain amplitude (delta epsilon), and decreases with tissue swelling by solvent. Similarly, it predicts that hysteresivity (eta) decreases with increasing frequency, increases with increasing delta epsilon, decreases with tissue swelling, and, importantly, exceeds that of isolated fibrous constituents of the matrix. Elastance and eta of two structurally dissimilar connective tissues were measured, the rabbit lung parenchymal strip (a loose collagenous tissue) and the pigeon ligamentum propatagiale (an elastin-rich tissue). Experiments covered the frequency range 0.03125-3.125 Hz. Elastance of lung parenchyma was substantially lower than that of propatagial ligament, increased linearly with the logarithm of frequency, and decreased with delta epsilon; that of ligamentum propatagiale was insensitive to both frequency and delta epsilon. eta of lung parenchyma decreased moderately with increasing frequency and assumed values of approximately 0.1, but eta of ligamentum propatagiale was frequency and delta epsilon invariant and assumed values an order of magnitude smaller. These tissues also showed disparate mechanical responses when exposed to hypertonic bath solutions. Although there were some quantitative differences between predictions and experimental observations, the dynamic behavior of lung parenchyma was generally consistent with that of a network in which load is transferred from one fiber to the next by the agency of friction acting at slipping interface surfaces.

Mechanical connections between elastin and collagen.

The ligament supporting the leading edge of birds' wings is a connective tissue structure with unusual morphologic and elastic features. Its center section is made of a highly extensible composite of elastin and collagen fibers and its two end sections of nearly inextensible pure collagen; these are joined end-to-end in short interdigitating junctions. Substantial forces are transmitted through the junctions showing that collagen and elastin are mechanically connected. The junctions and elastic segment are sufficiently strong that when the intact ligament is maximally strained, the point of failure is commonly in the collagenous segments or their attachments to the tissues of origin or insertion. Here we outline the morphology and describe static force-length properties of this ligament.

Does peak inspiratory flow contribute to setting VO2max? A test of symmorphosis.

Symmorphosis predicts that animal design is optimized in such a way that structure 'statisfies but does not exceed' functional requirements. To provide one test of this hypothesis, we examined peak inspiratory flow and its relation to maximum oxygen uptake in humans. We measured maximal forced (peak) inspiratory flow (VImax) and maximum oxygen uptake (VO2max) via cycle ergometry in well trained (VO2max > 65 ml O2.kg-1.min-1) and untrained (VO2max < 45 ml O2.kg-1.min-1) male subjects. Tests of VImax and peak oxygen uptake (VO2peak) were made while the subjects were breathing through inspiratory orifices differing in area. VImax varied as an identical function of orifice diameter in both groups of subjects. However, VO2peak was more sensitive to decreasing orifice diameter in trained endurance athletes than it was in untrained individuals. The diameter of the largest orifice that caused a reduction in oxygen uptake was over two times larger for trained than for untrained subjects, corresponding to about a four-fold difference in resistance at any flow rate. These results suggest that the structures setting VImax (airway resistance and inspiratory muscle strength) are not matched to oxygen demand (VO2max) in humans. While these structures seem to be 'over-built' and hence do not likely contribute to setting the limits to aerobic performance in most humans, they may be among the primary limiting factors in the most elite endurance athletes.

Stewart's quantitative acid-base chemistry: applications in biology and medicine.

We review P.A. Stewart's quantitative approach to acid-base chemistry, starting with its historical context. We outline its implications for cellular and membrane processes in acid-base physiology; discuss its contributions to the understanding and analysis of acid-base phenomena; show how it can be applied in clinical problems; and propose a classification of clinical acid-base disturbances based on this general approach.

Cardiac output but not high pulmonary artery pressure varies with FIO2 in exercising horses.

Horses have high mean pulmonary artery pressure (Ppa) both at rest and during exercise (approximately 30 and > or = 80 mmHg, respectively). The mechanisms are unknown. To see if hypoxic pulmonary vasoconstriction (HPV) plays a role, we compared pulmonary artery pressure-flow (Ppa-Q) curves when inspired O2 fraction (FIO2) was 0.16, 0.21, and 0.30, in 5 normal Thoroughbred horses standing quietly and while galloping at 10 and 14 m/sec on a level treadmill. We calculated O2 consumption (VO2) from measurements of respired gas composition and flow, and calculated Q from VO2 and measurements of oxygen content in arterial and mixed venous blood (CaO2 and CVO2). VO2 was 3.8, 74 and 128 ml.min-1.kg-1, at rest and at 10 and 14 m/sec, and did not vary with FIO2 at any speed. At 14 m/sec only, when FIO2 was lowered to 0.16, CaO2 fell (to 14.7 from 20 ml/dl on air), Q increased (to 0.86 from 0.66 L.min-1.kg-1 on air), and stroke volume increased (to 4.1 from 3.2 ml.kg-1 on air). Slopes and intercepts of Ppa-Q curves did not vary with FIO2. We conclude that HPV does not contribute to the high Ppa of exercising horses breathing air near sea level.

Acid-base changes in the running greyhound: contributing variables.

To determine the factors responsible for changes in [H+] during and after sprint exercise in the racing greyhound, Stewart's quantitative acid-base analysis was applied to arterial blood plasma samples taken at rest, at 8-s intervals during exercise, and at various intervals up to 30 min after a 402-m spring (approximately 30 s) on the track. [Na+], [K+], [Cl-], [total Ca], [lactate], [albumin], [Pi], PCO2, and pH were measured, and the [H+] was calculated from Stewart's equations. This short sprint caused all measured variables to change significantly. Maximal changes were strong ion difference decreased from 36.7 meq/l at rest to 16.1 meq/l; [albumin] increased from 3.1 g/dl at rest to 3.7 g/dl; PCO2, after decreasing from 39.6 Torr at rest to 27.9 Torr immediately prerace, increased during exercise to 42.8 Torr and then again decreased to near 20 Torr during most of recovery; and [H+] rose from 36.6 neq/l at rest to a peak of 76.6 neq/l. The [H+] calculated using Stewart's analysis was not significantly different from that directly measured. In addition to the increase in lactate and the change in PCO2, changes in [albumin], [Na+], and [Cl-] also influenced [H+] during and after sprint exercise in the running greyhound.

Ventilatory and P0.1 response to hypercapnia in quadriplegia.

Unlike individuals with comparable degrees of respiratory muscle weakness from other causes, quadriplegic patients have a blunted ventilatory and P0.1 response to hypercapnia. This suggests that the diminished response in quadriplegia is due, in part, to an alteration in respiratory drive. We measured the hypercapnic response in 9 subjects with chronic quadriplegia (Q) and 8 normal controls (N). Ventilatory muscle strength, maximum voluntary ventilation (MVV), and lung volumes were measured in all subjects. The ventilatory response (HCVR) in Q was significantly less than in N (0.73 +/- 0.37 vs 2.95 +/- 0.4 L.min-1.mmHg-1; P less than 0.001), even when normalized for indices of respiratory muscle performance (e.g., vital capacity, MVV). There was no significant change in the HCVR in Q after the administration of naloxone. We also serially studied 2 subjects with acute quadriplegia, and found that despite progressive improvement in respiratory muscle performance, there was no accompanying increase in the response to hypercapnia. These data suggest that muscle weakness alone cannot explain the blunted hypercapnic response in quadriplegia, and are consistent with the hypothesis that these subjects have a reduced ventilatory drive.

Effect of fatigue on maximal inspiratory pressure-flow capacity.

The inspiratory muscles can be fatigued by repetitive contractions characterized by high force (inspiratory resistive loads) or high velocities of shortening (hyperpnea). The effects of fatigue induced by inspiratory resistive loaded breathing (pressure tasks) or by eucapnic hyperpnea (flow tasks) on maximal inspiratory pressure-flow capacity and rib cage and diaphragm strength were examined in five healthy adult subjects. Tasks consisted of sustaining an assigned breathing frequency, duty cycle, and either a "pressure-time product" of esophageal pressure (for the pressure tasks) or peak inspiratory flow rate (for the flow tasks). Esophageal pressure was measured during maximal inspiratory efforts against a closed glottis (Pesmax), maximal transdiaphragmatic pressure was measured during open-glottis expulsive maneuvers (Pdimax), and maximal inspiratory flow (VImax) was measured during maximal inspiratory efforts with no added external resistance before and after fatiguing pressure and flow tasks. The reduction in Pesmax) with pressure fatigue (-25 +/- 7%) was significantly greater than the change in Pesmax with flow fatigue (-8 +/- 8%, P less than 0.01). In contrast, the reductions in Pdimax (-11 +/- 8%) and VImax (-16 +/- 3%) with flow fatigue were greater than the changes in Pdimax (-0.6 +/- 4%, P less than 0.05) or VImax (-3 +/- 4%, P less than 0.05) with pressure fatigue. We conclude that respiratory muscle performance is dependent not only on the presence of fatigue but whether fatigue was induced by pressure tasks or flow tasks. The specific impairment of Pesmax and not of Pdimax or flow with pressure fatigue may reflect selective fatigue of the rib cage muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Restraining hamsters alters their breathing pattern.

Does the restraint required for head or nose-only exposure of rodents to inhaled aerosols or gases alter their breathing pattern? And does prior exercise training, which may increase muscle strength, affect this response to restraint? To answer those questions, we measured breathing pattern in 11 adult male hamsters while they were either 1) free to move in small cages or 2) closely restrained in head-out cones. The measurements were repeated after hamsters spent 6 wk either sedentary in standard cages or in cages with exercise wheels. Hamsters were placed in a plethysmograph to measure respiratory frequency (f) and tidal volume (VT). Their product is minute volume (V). When restrained, f and V were 1.9 and 1.7 times, respectively, greater than when hamsters were free, but VT did not change. After 6 wk, the sedentary group responded differently to restraint; f increased 3-fold, VT decreased by one-half, and V increased 1.6-fold. Exercised hamsters increased f 2.3-fold and decreased VT by one-third; V increased by 1.5-fold. In inhalation studies, changes in breathing pattern would significantly influence the amount of material inhaled, the fraction retained, and thus the amount and distribution of material deposited in the lungs.

Pulse oximetry in horses.

The clinical usefulness of two pulse oximeters was evaluated at two probe sites in nine anesthetized horses. The hemoglobin saturation determined by the pulse oximeters (SaOx) was compared with the hemoglobin saturation calculated from the measured arterial oxygen tension (SaO2). The mean and standard deviation (SD) were calculated from the differences in saturation measurements, over the saturation range of 80% to 100%, for each oximeter used at the tongue probe site and for one oximeter used at the ear. The oximeter results tended to underestimate the SaO2 with mean differences of -3.7% on the tongue and -6.0% on the ear. The limits of agreement were defined as the mean difference +/- 2 SD. Each oximeter used at the tongue produced limits of agreement of +1% to -8%, which meant that 95% of the SaOx values were 1 percentage point above or 8 percentage points below the SaO2. The variability of the differences and limits of agreement were larger when the ear was used as the probe site and at saturations less than 80%. Although both oximeters tended to underestimate the SaO2, they appeared to be clinically useful in detecting changes in arterial hemoglobin saturation.

Adaptations to deep breath-hold diving: respiratory and circulatory mechanics.

Respiration and circulation in diving mammals are characterized by interrelated adaptations of structure, function, and behavior that are incompletely described and understood. This speculative survey touches some of them. a) Arterial blood flow can be controlled by vasoconstriction not only in arterioles but also in large arteries. The latter physiology is not well known. b) Mechanisms that might regulate and limit nitrogen uptake are not clear, although Scholander's suggestion that airspaces become gas-free during deep dives is still accepted. c) Systemic arterial retes may be able to store oxygenated blood in some diving mammals. If so, O2 in the lung might be "skimmed off" early in a dive, leaving the N2 behind. d) Variable clusters of interdependent adaptations in diving mammals include compliant chest walls that avoid thoracic squeeze; inspiratory breath holds that maintain high lung volumes; large tidal volumes that nearly empty the lung at end-expiration (so there is near-complete turnover of lung gas with each breath); airways that are "armored" by cartilage rings all the way out to the airspaces (so that they do not close and trap gas in the lung and do permit high expiratory flow rates even at very low lung volumes); submucosal vascular retes that may prevent airway squeeze; a puzzling difference in the cross-sectional areas of trachea and bony nares; and very large lungs in shallow divers (sea otters). Study of mammalian adaptations to deep diving promises to illuminate basic issues in physiology.