Peter H. Abbrecht

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.

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.

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 warfarins 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 warfarins metabolites, which did not show saturation over this dosage range. These results were used to develop a multicompartmental model of warfarins 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 Kdand maximum capacity estimated at 1.49E-3μg/ml and 2.72 μg/ml, respectively. The second class exhibited linear exchange kinetics with free plasma warfarin. Warfarins 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 nonlinearity was necessary and sufficient to account for the apparent dose dependency in plasma warfarins 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 warfarins metabolic enzymes, which do not show saturation in the dosage range studied.

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.

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.

Regulation of extracellular fluid volume and osmolality

In health, both the total amount and the distribution of water and electrolytes in the body are controlled within narrow limits. While intercompartmental water fluxes depend solely on physical driving forces, the latter are determined by complex circulatory feedback mechanisms that manipulate capillary pressure, and by active transport mechanisms that affect intracellular osmotic pressure. Fluid and electrolyte intake are determined by central neural mechanisms. However, the fine tuning of body fluid and elctrolyte contact is accomplished by alterations in renal excretion controlled by a variety of local (intrarenal) mechanical and endocrine processes, as well as external neural endocrine feedback systems that include the antidiuretic hormone and the renin-angiotensin-aldosterone systems. Analysis of renal control is complicated by multiple interactions among the different control systems.

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 pento-barbital, 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.

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.

An analysis of respiratory drive components during flow-resistive respiratory loading

Inspiratory flow-resistive loading normally causes an additional respiratory drive that limits the resistance-induced decrease in minute ventilation (load compensation). Occlusion pressures (P100) were measured during CO2 rebreathing with and without added inspiratory loads in normal persons and persons with obstructive sleep apnea (OSA). At each point obtained during loaded breathing, the additional drive due to resistive loading was determined by subtracting CO2-dependent drive (estimated from the nonloaded run) from total drive. In normal subjects, the additional drive correlated with each of four different estimates of load magnitude. In OSA subjects, there was no significant increase in drive due to loading and ventilation decreased markedly during loading. The relationships among ventilation rate, load, and drive, with and without load compensation, were analyzed using a 4-quadrant feedback control diagram. The diagram enables the prediction of ventilation rate for any end-tidal CO2 in the loaded and nonloaded cases, and the flow decrement that will occur as a result of added inspiratory resistance.

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.