Stereospecific effects of ketamine enantiomers on canine tracheal smooth muscle.

1. Ketamine is a potent bronchodilator which relaxes airway smooth muscle (ASM). Clinically, ketamine is used as a 1:1 racemic mixture of enantiomers that differ in their analgesic and anaesthetic effects. The aim of this study was to determine whether there was a difference between the enantiomers in their ability to relax isolated ASM and to explore mechanisms responsible for any observed differences. 2. Canine tracheal smooth muscle strips were loaded with fura-2 and mounted in a photometric system to measure simultaneously force and [Ca2+]i. Calcium influx was estimated by use of a manganese quenching technique. 3. In strips stimulated with 0.1 microM ACh (EC50) R(-)-ketamine (1-100 microM) caused a significantly greater concentration-dependent decrease in force (P<0.0001) and [Ca2+]i than S(+)-ketamine (1-100 microM) (P<0.0005). In contrast, there was no significant difference between the enantiomers in their ability to inhibit calcium influx (45% decrease in influx rate for R(-)-ketamine and 44% for S(+)-ketamine, P =0.782). In strips contracted with 24 mM isotonic KCI (which activates voltage-operated calcium channels), the enantiomers modestly decreased force and [Ca2+]i; there was no significant difference between the enantiomers in their effects on force (P=0.425) or [Ca2+]i (P=0.604). 4. The R(-)-enantiomer of ketamine is a more potent relaxant of ACh-induced ASM contraction than the S(+)-enantiomer. This difference appears to be caused by differential actions on receptor-operated calcium channels.

Cemented versus noncemented total hip arthroplasty--embolism, hemodynamics, and intrapulmonary shunting.

Bone cement implantation syndrome is characterized by hypotension, hypoxemia, cardiac arrhythmias, cardiac arrest, or any combination of these complications. It may result from venous embolization that occurs in conjunction with intramedullary hypertension in the femur during insertion of the prosthesis in patients undergoing cemented total hip arthroplasty (THA). Intramedullary hypertension does not occur in patients undergoing noncemented THA. In this study, we sought to compare embolization between patients undergoing cemented and noncemented THA and to determine whether this state resulted in cardiorespiratory deterioration. In this prospective investigation of 35 patients undergoing elective THA, we used transesophageal echocardiography and invasive hemodynamic monitoring, and in 12 of them, we monitored distribution of pulmonary ventilation and perfusion intraoperatively. Embolization was significantly greater after insertion of the prosthesis in patients undergoing cemented than in those undergoing noncemented THA. Cemented THA was also associated with decreased cardiac output and increased pulmonary artery pressure and pulmonary vascular resistance. Increases in ventilation-perfusion mismatching, however, could not be demonstrated 30 minutes after insertion of the femoral prosthesis. Intraoperative monitoring for embolism may help physicians assess patients in whom cardiorespiratory function deteriorates during THA.

Body position and ventilation-perfusion relationships in unilateral pulmonary disease.

The effect of positional change (right vs left lateral decubitus) on the distribution of ventilation and perfusion ratios was determined in four patients with respiratory failure and chest roentgenographic findings of unilateral pulmonary disease. In these patients with a unilateral interstitial pattern, improvement in oxygenation which occurred when the "good" side was dependent (down) was associated with changes in the patterns of ventilation-perfusion distribution; two patients showed a predominant decrease in right-to-left intrapulmonary shunt, and two showed an improvement in ventilation-perfusion equality. Therefore, when unilateral interstitial pulmonary disease was present, positional change resulted in changes in right-to-left intrapulmonary shunt or low ventilation-perfusion ratios or both. Variability between patients can be explained by the nonhomogeneity of pulmonary disease in patients with respiratory failure.

Measurement of ventilatory reserve as an indicator for early extubation after cardiac operation.

The decision to perform tracheal extubation in 44 patients who underwent cardiac operation was based on an assessment of mental alertness, recovery of muscle strength, hemodynamic stability, and adequacy of pulmonary gas exchange. No patients required reintubation. Concomitant measurements of vital capacity (VC) and maximal inspiratory pressure (PImax) were made before a trial of spontaneous ventilation was commenced, after 45 minutes of spontaneous ventilation, and after tracheal extubation. By generally accepted criteria, these measurements suggested the need for continuing mechanical ventilation in 14 patients at the time mechanical ventilatory support was removed and in eight patients at the time of tracheal extubation. In this study, consideration of measurements of VC and PImax would have led to longer trachael intubation, especially in those patients who were extubated within 10 hours of the completion of anesthesia.

New tests for the detection of obstructive pulmonary disease.

Abnormalities in small airways appear to be important in the evolution of chronic obstructive pulmonary disease. Patients with these pathologic lesions may have normal values for airway resistance and forced expiratory volume in one second. Two new tests, the closing volume (CV) and the dependence of maximal flow on density, are believed to be sensitive to abnormalities in the peripheral airways. The CV test detects an increased nonuniformity of changes in volume of pulmonary units. Reduced dependence of flow on density is believed to result from an increase in the peripheral component of the losses of driving pressure which determine maximal expiratory flow. Both tests differentiate smokers with normal conventional spirometric data from age-matched nonsmokers. Although this evidence suggests that these tests can be used to detect abnormalities in small airways, there is very little pathologic confirmation of this belief. The clinical significance of abnormalities in the results of either of these tests in an otherwise normal person has not yet been determined.

Effect of positional change on ventilation-perfusion distribution in unilateral pleural effusion.

The effect of pleural effusion on lung function and gas exchange has not been adequately defined. We used the multiple "inert" gas technique to study gas exchange and ventilation-perfusion relationships in both the left and the right lateral decubitus positions in a patient with a moderate unilateral (left) pleural effusion. With position change, only a small change in oxygenation (3 mm Hg) and no change in carbon dioxide tension occurred. The ventilation-perfusion relationships were also nearly identical for both body positions. We conclude that a pleural effusion of moderate size has little effect on overall gas exchange and ventilation-perfusion relationships and that complex mechanisms of the respiratory system compensate for the effusion.

Differences in regional vascular conductances in isolated dog lungs.

The distribution of pulmonary blood flow is influenced by gravity, regional lung expansion, and hypoxic pulmonary vasoconstriction. However, these factors cannot completely explain the three-dimensional distribution of blood flow in the lung. The present study was designed to see whether anatomically related factors could contribute. Regional blood pressure vs. flow curves were determined in 100-230 small parenchymal samples (0.3-0.4 ml) from 12 isolated perfused dog lungs held at constant inflation pressure. In each region four blood flows were measured using radioactively labeled microspheres, and the four corresponding regional perfusion pressures were determined by correcting the measured perfusion pressure for hydrostatic effects. There were considerable differences in the slopes of the pressure vs. flow curves among lung regions. Dorso-caudal regions of the lung had higher vascular conductances than ventrocephalad regions, independent of the vertical orientation of the lung or the inflation volume during injections of microspheres. Thus the distributions of regional vascular conductances were related to the anatomic location and were not related to gravity, nor were they caused by nonuniformities in regional lung expansion or by hypoxic vasoconstriction or edema.

Gas exchange and intrapulmonary distribution of ventilation during continuous-flow ventilation.

In 12 anesthetized paralyzed dogs, pulmonary gas exchange and intrapulmonary inspired gas distribution were compared between continuous-flow ventilation (CFV) and conventional mechanical ventilation (CMV). Nine dogs were studied while they were lying supine, and three dogs were studied while they were lying prone. A single-lumen catheter for tracheal insufflation and a double-lumen catheter for bilateral endobronchial insufflation [inspired O2 fraction = 0.4; inspired minute ventilation = 1.7 +/- 0.3 (SD) 1.kg-1.min-1] were evaluated. Intrapulmonary gas distribution was assessed from regional 133Xe clearances. In dogs lying supine, CO2 elimination was more efficient with endobronchial insufflation than with tracheal insufflation, but the alveolar-arterial O2 partial pressure difference was larger during CFV than during CMV, regardless of the type of insufflation. By contrast, endobronchial insufflation maintained both arterial PCO2 and alveolar-arterial O2 partial pressure difference at significantly lower levels in dogs lying prone than in dogs lying supine. In dogs lying supine, the dependent lung was preferentially ventilated during CMV but not during CFV. In dogs lying prone, gas distribution was uniform with both modes of ventilation. The alveolar-arterial O2 partial pressure difference during CFV in dogs lying supine was negatively correlated with the reduced ventilation of the dependent lung, which suggests that increased ventilation-perfusion mismatching was responsible for the increase in alveolar-arterial O2 partial pressure difference. The more efficient oxygenation during CFV in dogs lying prone suggests a more efficient matching of ventilation to perfusion, presumably because the distribution of blood flow is also nearly uniform.

Simulation of the vertical gradient of transpulmonary pressure by stable foams.

We describe a simulation of the vertical gradient of transpulmonary pressure (VGTP) using a stable foam, which is suitable for use in studies of the effect of the VGTP on excised lungs. We generated foams that produced linear hydrostatic pressure gradients (HPGs) from 0.18 to 0.44 cmH2O/cm depth, which were stable over time and were reproducible. The HPG was similar under static and dynamic conditions. The foam did not affect lung elastic properties or cause histological changes. We conclude that these stable foams provide a practical, inexpensive simulation of the VGTP and should be useful in studying the effects of the VGTP on regional lung behavior.

Regional ventilation in excised lobes exposed to a transpulmonary pressure gradient.

We performed the quasi-static single-breath oxygen test (SBO2) in 16 excised canine lower lung lobes while the lobes were first suspended in air and then later immersed in stable foams that provided a vertical transpulmonary pressure gradient. In lobes suspended in air, an approximately linear alveolar plateau (AP) was obtained. The AP during foam immersion was markedly curvilinear, with phase IV seen at end expiration. The observed AP during foam immersion could be predicted by a mathematical model that assumed a homogeneous transpulmonary pressure-regional volume relationship equal to the overall pressure-volume (PV) relationship measured with the lobe suspended in air. The accuracy of this model was further confirmed by measuring the washout of nitrogen injected into different lung regions through alveolar capsules. We also used the model to examine the relationship between the onset of dependent airway closure and two of its proposed indicators: the onset of phase IV and the inflection point of the overall PV relationship. In most lobes, the lung volume at the onset of phase IV was less than the modeled lung volume at dependent airway closure. The lung volume at the inflection point was always less than the modeled lung volume at dependent airway closure. We show that the overall PV relationship measured in lobes suspended in air provides an accurate estimate of regional PV relationships during foam immersion.

Gas exchange in dogs in the prone and supine positions.

To determine the cause of the difference in gas exchange between the prone and supine postures in dogs, gas exchange was assessed by the multiple inert gas elimination technique (MIGET) and distribution of pulmonary blood flow was determined using radioactively labeled microspheres in seven anesthetized paralyzed dogs. Each animal was studied in the prone and supine positions in random order while tidal volume and respiratory frequency were kept constant with mechanical ventilation. Mean arterial PO2 was significantly lower (P less than 0.01) in the supine [96 +/- 10 (SD) Torr] than in the prone (107 +/- 6 Torr) position, whereas arterial PCO2 was constant (38 Torr). The distribution of blood flow (Q) vs. ventilation-to-perfusion ratio obtained from MIGET was significantly wider (P less than 0.01) in the supine [ln SD(Q) = 0.75 +/- 0.26] than in the prone position [ln SD (Q) = 0.34 +/- 0.05]. Right-to-left pulmonary shunting was not significantly altered. The distribution of microspheres was more heterogeneous in the supine than in the prone position. The larger heterogeneity was due in part to dorsal-to-ventral gradients in Q in the supine position that were not present in the prone position (P less than 0.01). The decreased efficiency of oxygenation in the supine posture is caused by an increased ventilation-to-perfusion mismatch that accompanies an increase in the heterogeneity of Q distribution.

Electrical activation of expiratory muscles increases with time in pentobarbital-anesthetized dogs.

Although the pentobarbital-anesthetized dog is often used as a model in studies of respiratory muscle activity during spontaneous breathing, there is no information regarding the stability of the pattern of breathing of this model over time. The electromyograms of several inspiratory and expiratory muscle groups were measured in six dogs over a 4-h period by use of chronically implanted electrodes. Anesthesia was induced with pentobarbital sodium (25 mg/kg iv), with supplemental doses to maintain constant plasma pentobarbital concentrations. Phasic electrical activity increased over time in the triangularis sterni, transversus abdominis, and external oblique muscles (expiratory muscles). The electrical activity of the costal diaphragm, crural diaphragm, and parasternal intercostal muscles (inspiratory muscles) was unchanged. These changes in electrical activity occurred despite stable plasma levels of pentobarbital and arterial PCO2. They were associated with changes in chest wall motion and an increased tidal volume with unchanged breathing frequency. We conclude that expiratory muscle groups are selectively activated with time in pentobarbital-anesthetized dogs lying supine. Therefore the duration of anesthesia is an important variable in studies using this model.

Inhomogeneity during deflation of excised canine lungs. I. Alveolar pressures.

Factors both intrinsic and extrinsic to the lung may cause inhomogeneity of alveolar pressures during deflation. Wilson et al. (J. Appl. Physiol. 59: 1924-1928, 1985) predicted that any such inhomogeneity would be limited by interdependence of regional expiratory flows. To test this hypothesis and to explore how the pleural pressure gradient might affect inhomogeneity of alveolar pressures, we deflated at submaximal flows excised canine lobes that first were suspended in air and then were immersed in foams that simulated the vertical gradient of pleural pressure. Interregional inhomogeneity of regional transpulmonary pressures was measured with use of an alveolar capsule technique. Flow-dependent inhomogeneity of alveolar pressures was present, with differences in alveolar pressure quickly relaxing to a constant limiting value at each flow. Foam immersion increased inhomogeneity at a given flow. We conclude that factors intrinsic to the lung cause significant inhomogeneity of alveolar pressures at submaximal expiratory flows and that this inhomogeneity is enhanced by the extrinsic gradient of pleural pressure. These observations are consistent with the interdependence of flow proposed by Wilson et al.

Inhomogeneity during deflation of excised canine lungs. II. Alveolar volumes.

We have previously demonstrated appreciable inhomogeneity of alveolar pressures measured by a capsule technique in excised canine lobes deflated at submaximal flows (J. Appl. Physiol. 65: 1757-1765, 1988). We further analyzed the results of these experiments by estimating alveolar volumes (VA) and regional flows from regional transpulmonary pressures, assuming that regional pressure-volume relationships were homogeneous. Deflation at submaximal flows of lungs suspended in air caused significant flow-dependent inhomogeneity of VA that increased as lung volume decreased. Immersion of lungs in stable foams that simulated the gradient of pleural pressure modified the pattern of emptying, but not always to a gravity-dependent sequence. Limitation of regional expiratory flow was often asynchronous during both air suspension and foam immersion. There was no evidence of a common regional flow-volume curve. Submaximal deflation is a complex heterogeneous process, with the interregional pattern of emptying determined by the interaction of factors that are both intrinsic and extrinsic to the lungs.

Inhomogeneity during deflation of excised canine lungs. III. Single-breath O2 tests.

Both interregional and intraregional mechanisms may cause changes in N2 concentration of expired gas during the phases of the single-breath O2 test (SBO2) that follow dead-space washout. To evaluate the possible importance of each mechanism, we performed the SBO2 in excised canine lungs that were first suspended in air and then immersed in stable foams that simulated the vertical gradient of pleural pressure. The lungs were deflated at constant submaximal flows. The slope of phase III diminished with increasing expiratory flow and increased with foam immersion. The onset of phase IV depended on flow, and a terminal decrease in N2 concentration (phase V) was often observed. Simultaneously measured estimates of regional flows and volumes (J. Appl. Physiol. 65: 1764-1774, 1988) were used to further interpret these results. The onset of phase IV at flows greater than quasi-static signified the onset of flow limitation of dependent regions. The onset of phase V corresponded to flow limitation of nondependent regions.

Chest wall motion during epidural anesthesia in dogs.

To determine the relative contribution of rib cage and abdominal muscles to expiratory muscle activity during quiet breathing, we used lumbar epidural anesthesia in six pentobarbital sodium-anesthetized dogs lying supine to paralyze the abdominal muscles while leaving rib cage muscle motor function substantially intact. A high-speed X-ray scanner (Dynamic Spatial Reconstructor) provided three-dimensional images of the thorax. The contribution of expiratory muscle activity to tidal breathing was assessed by a comparison of chest wall configuration during relaxed apnea with that at end expiration. We found that expiratory muscle activity was responsible for approximately half of the changes in thoracic volume during inspiration. Paralysis of the abdominal muscles had little effect on the pattern of breathing, including the contribution of expiratory muscle activity to tidal breathing, in most dogs. We conclude that, although there is consistent phasic expiratory electrical activity in both the rib cage and the abdominal muscles of pentobarbital-anesthetized dogs lying supine, the muscles of the rib cage are mechanically the most important expiratory muscles during quiet breathing.

Volume quantification of chest wall motion in dogs.

We employed high-speed multisliced X-ray-computed tomography to determine the relative volume contributions of rib cage (delta Vrc) and diaphragmatic motion (delta Vdi) to tidal volume (VT) during spontaneous breathing in 6 anesthetized dogs lying supine. Mean values were 40 +/- 6% (SE) for delta Vrc and 62 +/- 8% of VT for delta Vdi. The difference between VT and changes in thoracic cavity volume was taken to represent a change in thoracic blood volume (2 +/- 3% of VT). To estimate how much of delta Vrc was caused by diaphragmatic contraction and how much of delta Vdi was caused by rib cage motion, delta Vrc and delta Vdi were determined during bilateral stimulation of the C5-C6 phrenic nerve roots in the apneic dog and again during spontaneous breathing after phrenicotomy. Thoracic cavity volume (Vth) measured during hypocapnic apnea was consistently larger than Vth at end expiration, suggesting that relaxation of expiratory muscles contributed significantly to both delta Vrc and delta Vdi during spontaneous inspiration. Phrenic nerve stimulation did not contribute to delta Vrc, suggesting that diaphragmatic contraction had no net expanding action on the rib cage above the zone of apposition. Spontaneous breathing after phrenicotomy resulted in small and inconsistent diaphragmatic displacement (8 +/- 4% of VT). We conclude that the diaphragm does not drive the rib cage to inflate the lungs and that rib cage motion does not significantly affect diaphragmatic position during spontaneous breathing in anesthetized dogs lying supine.

Resonant amplification of delivered volume during high-frequency ventilation.

The volume of gas delivered from a high-frequency ventilation (HFV) circuit was measured with an ultrasonic flowmeter. The measurements were done in vitro (20-liter air-filled glass bottle) and in vivo (9 anesthetized dogs lying supine) at oscillation frequencies ranging from 4 to 23 Hz and stroke volumes of the pump ranging from 36 to 150 ml. We varied the length and diameter of the tube connecting the pump with the endotracheal tube, the length and diameter of the bias outflow tube, the diameter of the endotracheal tube, and the stroke volume of the pump. Both in vitro and in vivo, there was resonant amplification of the delivered gas volume; i.e., the delivered gas volume exceeded the stroke volume at certain frequencies. Altering the dimensions of connecting tube, endotracheal tube, bias outflow tube, or stroke volume, i.e., changing the resistance to gas flow, gas compliance, and/or gas inertance in these elements, altered the ratio of gas delivered to stroke volume that could be predicted by an electric analog. These data indicate that the delivered gas volume during HFV depends critically on the configuration of the HFV circuit, the size of the endotracheal tube, the oscillation frequency, and the pump stroke volume. Knowledge of the delivered gas volume during HFV and appreciation of the phenomenon of resonant amplification of the delivered gas volume will permit a more accurate description of factors contributing to gas transport during HFV.

Chest wall motion during spontaneous breathing and mechanical ventilation in dogs.

We measured the volume change of the thoracic cavity (delta Vth) and the volumes displaced by the diaphragm (delta Vdi) and rib cage (delta Vrc) in six pentobarbital-anesthetized dogs lying supine. A high-speed X-ray scanner (dynamic spatial reconstructor) provided three-dimensional images of the thorax during spontaneous breathing and during mechanical ventilation with paralysis. Tidal volume (VT) was measured by integrating gas flow. Changes in thoracic liquid volume (delta Vliq, presumably caused by changes in thoracic blood volume) were calculated as delta Vth - VT. Absolute volume displaced by the rib cage was not significantly different during the two modes of ventilation. During spontaneous breathing, thoracic blood volume increased during inspiration; delta Vliq was 12.3 +/- 4.1% of delta Vth. During mechanical ventilation, delta Vliq was nearly zero. Configuration of the relaxed chest wall was similar during muscular relaxation induced by either pharmacological paralysis or hyperventilation. Expiratory muscle activity produced 50 +/- 11% of the delta Vth during spontaneous breathing. We conclude that at constant VT the volume displaced by the rib cage is remarkably similar during the transition from spontaneous breathing to mechanical ventilation, while both diaphragmatic volume displacement and changes in intrathoracic blood volume decrease by a similar amount.

Halothane decreases both tissue and airway resistances in excised canine lungs.

Studies of the anesthetic effects on the airway often use pulmonary resistance (RL) as an index of airway caliber. To determine the effects of the volatile anesthetic, halothane, on tissue and airway components of RL, we measured both components in excised canine lungs before and during halothane administration. Tissue resistance (Rti), airway resistance (Raw), and dynamic lung compliance (CL, dyn) were determined at constant tidal volume and at ventilatory frequencies ranging from 5 to 45 min-1 by an alveolar capsule technique. Halothane decreased RL at each breathing frequency by causing significant decreases in both Raw and Rti but did not change the relative contribution of Rti to RL at any frequency. Halothane increased CL,dyn at each breathing frequency, although there was little change in the static pressure-volume relationship. The administration of isoproterenol both airway and tissue components of RL; it may act by relaxing the contractile elements in the lung. Both components must be considered when the effects of volatile anesthetics on RL are interpreted.