Effects of soman (pinacolyl methylphosphonofluoridate) on coronary blood flow and cardiac function in swine.

The effects of soman (pinacolyl methylphosphonofluoridate) on coronary blood flow, the electrocardiogram, and cardiac function were measured in alpha-chloralose-anesthetized swine. Coronary blood flow (CBF), mean arterial blood pressure (MAP), peak systolic left ventricular pressure (IVP), maximum rate of left ventricular pressure development (dP/dtmax), cardiac output, and the ECG were monitored continuously. A dose of 2X LD50 of soman (1 LD50 = 4.6 micrograms/kg) was given at 1 LD50/min in the femoral vein, which produced an increase in coronary sinus plasma acetylcholine (ACh) from a control of 0.7 +/- 0.01 nmol/ml to a maximum 314% of control at 15 min and a decrease in CBF from a control of 99 +/- 13 ml/min/100 g to a minimum 55% of control at 15 min. The increase in ACh in the coronary sinus was significantly correlated with a decrease in CBF (r = -0.87, p < 0.001). The fall in CBF was accompanied by concomitant decreases in IVP, MAP, and dP/dtmax, with S-T segment elevation and ventricular fibrillation. The increase in coronary sinus acetylcholine concentration was significantly correlated with a 10-fold fall in coronary sinus acetylcholinesterase levels from a control of 2.47 +/- 0.97 mol acetylcholine hydrolyzed/ml blood/min and was consistent with the time course for the reduced hemodynamic measurements. These studies support the hypothesis that acetylcholine increases following soman toxicity may decrease coronary blood flow, thereby initiating ischemic electrocardiographic changes and reducing cardiac function.

Regional volume changes in canine lungs suspended in air.

NASA: The purpose of this study was to determine the effect of the absence of a pleural pressure gradient (simulating the presumed condition found in microgravity) upon regional expansion of the lung. We attempted to produce a uniform pressure over the surface of the lung by suspending excised lungs in air. Such studies should help determine whether or not absence of a pleural pressure gradient leads to uniform ventilation. A preparation in which there is no pleural pressure gradient should also be useful in studying non-gravitational effects on ventilation distribution.^ieng

Differential response of dog and pig tracheal smooth muscle to the acetylcholinesterase inhibitor soman.

The effect of the acetylcholinesterase inhibitor soman on tracheal smooth muscle (TSM) from the dog and pig was studied. In response to soman, tracheal ring preparations contract more and the resting tension for TSM preparations is higher for the dog compared with the pig. Tension induced by electrical field stimulation (EFS) and the half-time of EFS-train induced contractions have a similar dependence on soman exposure in both dog and pig TSM. These results suggest that the basal acetylcholine secretion or leakage within the TSM nerve terminal is probably higher for the dog compared with the pig.

Insertion forces and risk of complications during cricothyroid cannulation.

Our purpose was to determine the forces required to insert several different styles of cricothyroid cannulas and to relate the magnitude of these forces and cannula design features to the incidence of complications during insertion. Tests were done on unembalmed cadavers and anesthetized dogs. Samples of 4 different commercial cricothyroid cannulas were tested. Each cannula type was tested in 5 different cadavers and 10 different dogs. A lubricant was applied to the cannulas in half of the dogs tested. Major findings are 1) there is a linear correlation between insertion force and device diameter, 2) higher puncture force is associated with a greater incidence of complications, 3) posterior wall penetration occurs more frequently with a curved penetrating device, 4) using small pilot needles to guide insertion of large cannulas minimizes complications, and 5) lubricant is less effective for cannulas having abrupt diameter changes. These findings provide guidelines for design of safer cricothyroid cannulas.

A simple algorithm for averaging multiple cycles of waveforms having varying cycle periods.

We present a simple method for averaging multiple cycles of a waveform having cycles with varying periods. This averaging process preserves the morphology of the waveform by converting fixed time per point data into fixed fraction of cycle data. The algorithms are implemented using the ASYST system, which provides efficient code for performing the computations and permits straightforward integration of the data acquisition and analysis tasks. An example is given of the results of the program in processing cyclical waveforms obtained in respiratory research.

Expiratory muscle recruitment during inspiratory flow-resistive loading and exercise.

Both exercise and inspiratory flow-resistive loading may cause recruitment of expiratory muscles. To evaluate the extent of recruitment in combined exercise and flow-resistive loading, and to estimate the effect on inspiratory muscle work, we studied five men, 26 to 39 yr of age, during mild exercise with different degrees of inspiratory flow-resistive loading. Each subject performed four 1-h exercise runs at 30% of their maximal oxygen consumption on different days while inspiring through an external resistor of either 1.4, 14.5, 19.9, or 30.6 cm H2O/s/L. Mouth and esophageal pressure, inspiratory flow rate, and abdominal and rib cage motion were recorded continuously. Abdominal expansion tended to lead and rib cage expansion tended to lag the start of inspiration as judged from the beginning of negative pressure development at the mouth. These time differences increased as resistive load increased. Plots of abdominal versus rib cage motion also showed increase in phase shift, with the abdomen leading the rib cage on inspiration. For all subjects, the esophageal pressure at the end of expiration became less negative as the resistive load increased, indicating that the end-expiratory volume decreased with increasing resistive load. We conclude that there was increasing use of expiratory muscles as the resistive load increased, and that the initial expansion of the abdomen at high resistive loads represented elastic recoil of structures that had been compressed below the volume at FRC by the expiratory muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary mechanical responses to cholinesterase inhibitor.

Lung static and dynamic compliances, and lung and upper airway resistances were measured in pentobarbital-anesthetized dogs before and after intravenous administration of 2 LD50 of the organophosphate cholinesterase inhibitor pinacolyl methylphosphonofluoridate (GD), followed by 1 mg of atropine 8 min later. Dynamic compliances and resistances were estimated by a linear regression model and by a Fourier analysis technique, with the two methods giving comparable results. GD caused a maximum increase in lung resistance of about 20 times control values, and about an 80% decrease in lung dynamic compliance. Frequency dependence of lung compliance and resistance was increased by GD administration. Following GD administration, upper airway opening pressure increased, indicating the presence of laryngospasm. Upper airway resistance during the latter portion of the breath, when the airway was open, decreased after GD administration, concurrent with the increase in carinal pressure that occurred as the result of increased lung impedance. These results suggest that the GD-induced decrease in upper airway resistance was due to passive distension of the upper airway. Physiological deadspace decreased by a maximum of about 65% following GD administration. Administration of atropine resulted in a prompt and almost complete reversal of all of the GD-induced effects on pulmonary mechanical properties and ventilation. The results of this study suggest that the major pulmonary mechanical effects of GD in the dog are caused by constriction of smooth muscle at different levels of the respiratory tract.

Effects of medroxyprogesterone acetate in obstructive sleep apnea.

We studied the effects of medroxyprogesterone acetate, a respiratory stimulant, on the incidence and duration of episodes of apnea and disordered breathing in 13 nonhypercapnic men with obstructive sleep apnea. Nocturnal polysomnography was done before and after four weeks of treatment with medroxyprogesterone acetate (60 mg/day) and one week after cessation of treatment. There were no significant (p less than 0.05) differences in the mean frequency of apneic episodes per hour of sleep before (31.3 +/- 5.7 [+/- SE]), during (26.8 +/- 6.6), or after (23.6 +/- 7.0) treatment, or in the mean number of disordered breathing episodes per hour of sleep before (19.4 +/- 5.6), during (21.4 +/- 5.8), or after (23.1 +/- 6.3) the period of treatment. Medroxyprogesterone did not alter significantly the total time of apnea or the total time for disordered breathing, expressed as percentages of total sleep time. Arterial oxygen desaturation during apnea and disordered breathing did not change with treatment. Medroxyprogesterone increased the minute ventilation and occlusion pressure responses to hypercapnia measured in the awake state; however, the results of this study demonstrate that medroxyprogesterone does not improve the breathing disorders during sleep in the nonhypercapnic patient with obstructive sleep apnea.

Determinants of alveolar ventilation during high-frequency transtracheal jet ventilation in dogs.

The effectiveness of transtracheal jet ventilation is a function of gas delivery pressure (drive pressure), duty cycle (insufflation time/total cycle time), and respiratory frequency. Nine dogs, anesthetized with sodium pentobarbital, were ventilated through a cricothyrotomy cannula using a controller that allowed separate setting of drive pressure, duty cycle, and frequency. PaO2 and PaCO2 were measured after achieving steady-state gas exchange at 15 to 22 different combinations of drive pressure, duty cycle, and frequency in each dog. There were slight increases in PaCO2 and larger decreases in PaO2 as frequency was increased from 10 to 200 cycle/min. Increases in drive pressure and duty cycle resulted in reduced PaCO2 and increased PaO2. Multiple linear regression showed good correlation between PaCO2 and drive pressure, duty cycle, and frequency. The distribution of air flow between alveolar and physiologic dead space, upper airway leakage, and entrainment was determined for each set of conditions. Changes in alveolar ventilation corresponding to the blood gas changes resulted from interaction of dead-space ventilation and upper airway leakage, which varied with breath duration. Decreases in leakage during short breaths tended to compensate for the increased fractional dead-space ventilation at high frequency, thus minimizing the effects of frequency changes on gas exchange.

A control system for high-frequency jet ventilation.

The design of a system for high-frequency jet ventilation is described. Jets of 10-40 psig humidified air were introduced into the trachea through an 8-gauge needle inserted through the cricothyroid membrane. Gas flow to the needle was interrupted by a solenoid valve operated by a controller circuit. The controller allowed the independent setting of duty cycle (ratio of inspiratory time to total cycle time) from 10-50% and respiratory frequency from 10-350/min. When the electrical control signal was set equal to the desired duty cycle, the actual mechanical duty cycle erred from the desired value by as much as 109%. These errors were caused by unequal time delays for solenoid opening and closing. Tests of a commercially available jet-ventilator also demonstrated frequency-dependent errors caused by unequal time delays and changes in wave shape. The controller described here compensates for differences in opening and closing delays and delivers volumes within 3.4% of those calculated from continuous flows.

Pulmonary involvement in mixed connective tissue disease.

To determine the frequency of pulmonary function abnormalities in mixed connective tissue disease (MCTD), we studied 16 consecutive patients. Spirometry, total lung capacity (TLC), diffusing capacity (Dco), static lung compliance (Cst), and tests of respiratory muscle function (peak inspiratory pressure [PIP] and the maximum change in transdiaphragmatic pressure [delta PDI] during a diaphragmatic Müeller maneuver) were obtained. Airway resistance (RAW) and frequency dependence of compliance were also measured. Static lung compliance was less than 0.2 L/cm H2O in four of nine patients. The PIP was less than 75 cm H2O in only one patient and delta PDI was greater than 45 cm H2O in all ten patients evaluated. Frequency dependence of compliance was abnormal in seven of ten patients, whereas RAW was increased in only three of eight patients. The TLC and DCO were less than 80 percent of the predicted values in ten of 16 and 14 of 16 patients respectively. There was no correlation between the level of extractable nuclear antigen and pulmonary function abnormalities. The study did not identify significant abnormalities in respiratory muscle function.

Single motor unit and fiber action potentials during fatigue.

Muscle fatigue is defined as a loss of tension development during constant stimulation. Although the relationship is not well documented, muscle fatigue has been inferred from electromyogram (EMG) signals. The purpose of this study was to determine the relationship between the amplitude and duration of single motor unit action potentials (MUAPs) and the loss of tension development (fatigue) in the medial gastrocnemius muscles of cats. Single motor units were fatigued by continuous stimulation at 10 or 80 Hz or with trains of 40-Hz stimuli. When motor units were stimulated at 10 Hz and with trains at 40 Hz (low frequency), tension declined and remained depressed during recovery. The changes in the MUAP correlated poorly with changes in tension. During and after stimulation at 80 Hz (high frequency), changes in the amplitude and duration of MUAPs correlated highly with changes in tension development. Since the EMG signal is dependent on a summation and cancellation of individual MUAPs, the EMG provides a reasonable estimate of high-frequency fatigue but an unreliable measure of low-frequency fatigue.

Analysis of the pressure-volume relationship of excised lungs.

The pressure-volume relationship of excised lungs is explicitly defined in the form of a mathematical model. In the model, lung volume (V) is given by the function V = VmaxF(Ptp,T*)H(Ptp). Vmax is maximum lung volume. F, which describes the recruitment of air-filled units, is a function of transpulmonary pressure (Ptp) and surface tension (T*), whereas H, which is also a function of transpulmonary pressure, describes the expansion of recruited units against tissue forces. F is shown to be the integral of the normalized distribution function of the lung units and remains constant so long as the number of air-filled units does not change. H, on the other hand, is shown to be the product of the elastic properties of the tissues and is responsible for the characteristic non-linear sigmoid shape of lung deflation curves. Results obtained with the model are consistent with the hypothesis that tissue elasticity, tissue hysteresis, area dependent surface tension, and recruitment share responsibility for the characteristic hysteresis of excised lungs.

Obstructive sleep apnea in hypothyroidism.

To determine the incidence and frequency of sleep apnea in persons with hypothyroidism, 11 consecutive patients with newly diagnosed disease were studied before and during thyroid hormone replacement therapy. Nine patients had episodes of apnea, with the number of episodes per hour of sleep ranging from 17 to 176 (mean, 71.8). Six of the nine patients were obese and had 99.5 episodes per hour compared with 16.3 episodes per hour in the 3 nonobese patients (p less than 0.02). After 3 to 12 months of thyroxine replacement therapy, mean apnea frequency decreased from 71.8 +/- 18.0 (SE) to 12.7 +/- 6.1 episodes per hour, without reduction in body weight. There were fewer changes in sleep stage per hour during treatment (22.1 +/- 4.9) than pretreatment (57.6 +/- 14.5). Carbon dioxide response tests done under non-loaded and flow-resistive loaded conditions before and during thyroxine replacement therapy showed increases in the loaded respiratory effort and ventilation during thyroxine treatment. Sleep apnea episodes are common in persons with untreated hypothyroidism, even with normal lung function. Thyroxine replacement therapy decreases apnea frequency, even without change in body weight.

Time domain analysis of diaphragmatic electromyogram during fatigue in men.

Diaphragmatic fatigue has been correlated with a change in the electromyogram recorded from the diaphragm (EMGdi), which suggests that the electromyogram is a potential clinical tool to detect respiratory muscle fatigue. Changes in the EMGdi have previously been quantified by using the power spectral parameters high-low ratio or mean frequency. In this study, we developed an autoregressive model of the EMG in an attempt to improve the analysis of the EMGdi. This model was tested on recordings of the EMGdi that were obtained from an esophageal electrode in five normal subjects breathing to fatigue through an inspiratory resistor. The data obtained from the autoregressive model were directly compared with data from the high-low ratio and mean frequency techniques. The autoregressive model showed an excellent correlation with mean frequency. Both techniques were superior to the high-low ratio measurement. Because the autoregressive model requires much less computation than mean frequency and can be easily implemented in real time on a minicomputer, we propose this as a preferable approach.

Computer processing of phrenic neurograms.

Manual processing of large numbers of electrophysiological waveforms is a tedious process prone to subjective errors in judgment. To eliminate these problems, we developed computer algorithms and techniques to analyze cat phrenic neurograms produced in response to step changes in end-tidal PCO2. The computer analyzed the neurogram in terms of a model waveform, which consisted of 1) base-line activity made up primarily of noise, 2) an initial sharp increase from base line, 3) a slower ramplike increase in activity, 4) a peak value, and 5) a rapid decrease in activity back to base line. Parameters describing these model elements as well as inspiratory and expiratory times were calculated by the computer. Computer-produced parameters were compared with manually calculated parameters from chart recordings for over 200 individual neurograms. Repeated manual processing of the neurogram had a variability of +/- 10% in the parameter estimates. The computer-produced parameters fell within this range more than 89% of the time. Although the techniques described are directed specifically toward phrenic neurogram analysis, the methods are general enough to be useful in computer processing of other types of physiological waveforms.

Control of breathing in obstructive sleep apnea.

We studied the responses of ventilation and occlusion pressure (P100) to hypercapnia, with and without the application of an inspiratory flow-resistive load (12 cm H2O/L/sec), in eight control subjects and in eight subjects with obstructive sleep apnea who did not retain carbon dioxide while awake. The hypercapnic response was assessed by a modification of the Read rebreathing technique. For a given endtidal carbon dioxide, ventilation in control subjects was the same with or without load, and P100 was increased with loading. In contrast, the subjects with sleep apnea decreased their ventilation during loading and did not increase their P100 in response to loading. Relationships between ventilation and P100 were similar in the two groups both with and without load. We conclude that patients with occlusive sleep apnea do not exhibit the normal increase in neural drive to compensate for inspiratory flow-resistive loading.

Changes in the pharmacology of warfarin during long-term administration in dogs.

Patients receiving an apparently appropriate maintenance dosage of oral anticoagulant may show unexpected changes in clotting status without readily identifiable cause. The object of this study was to determine whether a consistent change in the pharmacology of warfarin could account for the clinical observations during long-term dosing. Eleven healthy adult dogs received constant daily oral doses of warfarin for 4 weeks. Plasma warfarin concentration (W), measured by gas chromatography, and prothrombin time (PT), measured by the one-stage assay of Quick, were determined daily. W and PT decreased significantly (p less than 0.05) during the last 2 weeks of long-term treatment. No pharmacodynamic changes were observed after prolonged warfarin treatment, suggesting that the decreases in PT were due solely to the decreased W. The decrease in W was not due to an increased free warfarin fraction or to a reduction in W absorption from the gut. The reproducibility of these results was demonstrated in a second group of experiments done 1 month after the first set of studies. Over the entire group of dogs there was no consistent change in warfarin clearance during prolonged dosing. We conclude that during constant daily dosing, W and PT reach early peak values, after which they decrease to levels significantly below peak levels. These results suggest that clinical anticoagulation may require multiple dosage adjustments despite the early attainment of apparently therapeutic anticoagulant regulation with a fixed dosage schedule.

The effect of hepatic uptake on the disappearance of warfarin from the plasma of rats: a kinetic analysis.

To quantify the effects of the liver on the dose dependence of plasma warfarin clearance, an equal number of normal and functionally hepatectomized rats received an intravenous bolus of either 0.01, 0.1, or 1.0 mg/kg body weight of radiolabelled sodium warfarin. Serial samples of plasma and bile collected from each rat during the 1 hr experiment and of hepatic tissue collected at the end of the experiment were analyzed for radioactivity. The disappearance of warfarin from the plasma of hepatectomized rats was not dose dependent and suggested that the apparent dose dependency of plasma warfarin clearance is primarily the result of warfarin's interaction with hepatic tissue. The disappearance of warfarin from the plasma of normal rats was dose dependent with higher doses being cleared less rapidly. This dose dependence, however, was not reflected in the rate of biliary excretion of warfarin's metabolites, which did not show saturation over this dosage range. These results were used to develop a multicompartmental model of warfarin's pharmacokinetics. Plasma warfarin data collected from the hepatectomized rats were used to develop the extrahepatic components of the model, which was then expanded to include hepatic tissues based on data collected from normal rats. To simultaneously fit the plasma, biliary, and hepatic data required that at least two classes of hepatic tissue exchange warfarin with plasma. One tissue exhibited Michaelis-Menten saturation kinetics with Kd and maximum capacity estimated at 1.49E - 3 micrograms/ml and 2.72 micrograms/ml, respectively. The second class exhibited linear exchange kinetics with free plasma warfarin. Warfarin's association with the second class of hepatic tissue leads to its metabolic elimination. Consistent with our experimental findings, the rate of warfarin elimination from the plasma into the bile was linearly related to plasma warfarin concentration. Thus the single hepatic exchange nonlinearly was necessary and sufficient to account for the apparent dose dependency in plasma warfarin's pharmacokinetics. These results suggest that over the range of doses studied, the apparent dose dependent differences in the plasma warfarin concentration profile can be accounted for by saturable hepatic uptake. This mechanism, however, is not related to warfarin's metabolic enzymes, which do not show saturation in the dosage range studied.