Gordon R. Neufeld

Paralysis of the awake human: Visual perceptions

Abstract Subparalytic doses ofcurarewere given to three observers. Four major perceptions were reported: (1)displacement or repositioning of the perceived visual world in the direction of a successfully executedeye movement; (2)jumping during a saccade; (3)movement associated with drift of the eye; (4) increasedeffort associated with each eye movement. Paralytic doses ofsuccinylcholinewere administered to a single observer. Three major perceptions were reported: (1)displacement in the direction of the intended eye movement without jumping: (2) a sensation that greateffort was required to move the eye; (3)fading of the visual image due to effective retinal stabilization. Similar visual perceptions were observed when the eye was paralyzed with a local anesthetic; however, nofading or sense ofeffort was reported. No deficits in pattern vision (except for intermittent fading) were reported in any of the studies.

Hemodynamic and Metabolic Effects of Hemorrhage in Man, with Particular Reference to the Splanchnic Circulation

1. Eleven normal subjects were studied before and after removal of 15 to 20% of their blood volume within 35 minutes. 2. This amount of blood loss did not produce conspicuous effects upon any of the usually measured circulatory or metabolic parameters. 3. The results suggest that the splanchnic circulation functions as an important blood reservoir in man, that it can be preferentially depleted of blood by a mechanism which does not automatically increase vascular resistance, and that the ability of our subjects to tolerate blood loss was attributable in large part to this response.

Pulmonary uptake of propofol in cats. Effect of fentanyl and halothane.

Background:Many drugs are removed by the lung. The pulmonary uptake of one drug can be inhibited when a second, highly accumulated drug is administered parenterally or as a chronic oral treatment. The effect of inhalational anesthetics on pulmonary drug uptake has not been extensively studied and may alter pharmacokinetics of intravenously administered drugs. Methods:The uptake of propofol by the lung during a single passage through the pulmonary circulation was studied in four groups of anesthetized cats: spontaneously breathing cats (control group, n = 6), cats whose lungs were mechanically ventilated (n = 6), and cats whose lungs were mechanically ventilated and that were anesthetized with 1% (n = 6) or 1.5% (n = 6) halothane. In an additional group, the single-pass pulmonary uptake of propofol was studied in six spontaneously breathing cats pretreated with fentanyl. The amount of propofol taken up by the lung during the first pass was measured from double indicator-dilution outflow curves using indocyanine green (ICG) as the intravascular reference indicator. Results:The first-pass uptake of propofol (mean ± SEM) was 61.3 ± 4.9% and 60 ± 3.7% of the injected dose in control cats and in cats whose lungs were mechanically ventilated, respectively. Although exposure of the animals to 1% halothane had no significant effect on pulmonary extraction of propofol, the first-pass uptake decreased significantly to 38.8 ± 6.9% in cats exposed to 1.5% halothane compared with control cats and to cats undergoing mechanical ventilation of the lungs without exposure to halothane. Also, in animals pretreated with fentanyl, propofol uptake was reduced to 40 ± 5% compared with the control group. Conclusions:The results demonstrate a substantial extraction of propofol by the lung that is not affected by mechanical ventilation. Inhibition of propofol uptake by 1.5% halothane and by fentanyl provides a potential mechanism of drug-drug interaction that may interfere with the pharmacokinetic profile of propofol, and may alter the amount of propofol needed to achieve or supplement a given depth of anesthesia.

Errors in Measurement of Oxygen Uptake due to Anesthetic Gases

Errors in measurement of exhaled gas volume, mixed expired oxygen and carbon dioxide concentrations, and inspired oxygen concentration and the presence of exhaled anesthetic agents cause errors in on-line calculated oxygen uptake that increase geometrically with increasing inspired oxygen concentration. No one has quantified the decrease in the magnitude of the error that might be realized if directly measured nitrogen concentration were included in the calculation. We used a computer model to evaluate this improvement, assuming an oxygen uptake of 200 ml/min and normal ventilatory parameters. Using a Monte Carlo technique, we generated 100 sets of data points, with random errors averaging 0.5% around the expected gas concentrations, and compared the accuracy of oxygen uptake calculated with and without inclusion of directly measured inspired and expired nitrogen concentrations. When the inspired oxygen fractions were 0.2, 0.5, and 0.8, the calculated oxygen uptakes +/- % standard deviation were 200 +/- 4.3, 200 +/- 12, and 196 +/- 21 when directly measured nitrogen was included versus 200 +/- 3.5, 196 +/- 16, and 205 +/- 71 when it was not. The procedure was repeated, assuming 50 ml/min of anesthetic excretion and the calculated oxygen uptakes were 200 +/- 4.6, 202 +/- 12, and 195 +/- 17 versus 212 +/- 3.8, 251 +/- 17, and 398 +/- 64. Including direct measurement of inhaled and exhaled concentrations of nitrogen or another insoluble inert tracer gas allows accurate measurement of oxygen uptake, even in the presence of exhaled anesthetic gases. It also decreases the error in oxygen uptake determination by a factor of nearly six when the inhaled oxygen fraction is 0.8.

Volumetric capnography in children : influence of growth on the alveolar plateau slope

Background Lung growth in children is associated with dramatic increases in the number and surface area of alveolated airways. Modelling studies have shown the slope of the alveolar plateau (phase III) is sensitive to the total cross‐sectional area of these airways. Therefore, the influence of age and body size on the phase III slope of the volumetric capnogram was investigated. Methods Phase III slope (alveolar dcCO2/dv) and airway deadspace (VDaw) were derived from repeated single‐breath carbon dioxide expirograms collected on 44 healthy mechanically ventilated children (aged 5 months‐18 yr) undergoing minor surgery. Ventilatory support was standardized (VT = 8.5 and 12.5 ml/kg, [florin] = 8–15 breaths/min, inspiratory time = 1 s, end‐tidal partial pressure of carbon dioxide = 30–45 mmHg), and measurements were recorded by computerized integration of output from a heated pneumotachometer and mainstream infrared carbon dioxide analyzer inserted between the endotracheal tube and anesthesia circuit. Experimental data were compared to simulated breath data generated from a numeric pediatric lung model. Results An increased VDaw, a smaller VDaw/VT, and flatter phase III slope were found at the larger tidal volume (P < 0.01). Strong relationships were seen at VT = 12.5 ml/kg between airway deadspace and age (R2 = 0.77), weight (R2 = 0.93), height (R2 = 0.78), and body surface area (R2 = 0.89). The normalized phase III slopes of infants were markedly steeper than that of adolescents and were reduced at both tidal volumes with increasing age, weight, height, and body surface area. Phase III slopes and VDaw generated from modelled carbon dioxide washout simulations closely matched the experimental data collected in children. Conclusions Morphometric increases in the alveolated airway cross‐section with lung growth is associated with a decrease of the phase III slope. During adolescence, normalized phase III slopes approximate those of healthy adults. The change in slope with lung growth may reflect a decrease in diffusional resistance for carbon dioxide transport within the alveolated airway resulting in diminished acinar carbon dioxide gradients.

Sensitivity of CO2 washout to changes in acinar structure in a single-path model of lung airways.

A numerical solution of the convection-diffusion equation with an alveolar source term in a single-path model (SPM) of the lung airways simulates steady state CO2 washout. The SPM is used to examine the effects of independent changes in physiologic and acinar structure parameters on the slope and height of Phase III of the single-breath CO2 washout curve. The parameters investigated include tidal volume, breathing frequency, total cardiac output, pulmonary arterial CO2 tension, functional residual capacity, pulmonary bloodflow distribution, alveolar volume, total acinar airway cross sectional area, and gas-phase molecular diffusivity. Reduced tidal volume causes significant steepening of Phase III, which agrees well with experimental data. Simulations with a fixed frequency and tidal volume show that changes in blood-flow distribution, model airway cross section, and gas diffusivity strongly affect the slope of Phase III while changes in cardiac output and in pulmonary arterial CO2 tension strongly affect the height of Phase III. The paper also discusses differing explanations for the slope of Phase III, including sequential emptying, stratified inhomogeneity, and the issue of asymmetry, in the context of the SPM.

Noninvasive recovery of acinar anatomic information from CO2 expirograms

A numerical single path model of respiratory gas exchange with distributed alveolar gas sources was used to estimate the anatomical changes in small peripheral airways such as occur in chronic obstructive pulmonary diseases (COPD). A previous sensitivity analysis of the single path model showed that decreasing total acinar airway cross-sectional area by an area reduction factor, R, results in computed gas expirograms with Phase III steepening similar to that observed in COPD patients. From experimental steady state CO2 washout data recorded from six healthy subjects and six COPD patients, optimized area reduction factors for the single path model were found that characterize peripheral airway anatomy for each subject. Area reduction factors were then combined with measured functional residual capacity data to calculate the normalized peripheral airspace diameters in a given subject, relative to the airspace diameters in the generations of an idealized standard lung. Mean area reduction factors for the patient subgroup were 63% of those for the healthy subgroup, which is related to the gas transport limitation observed in disease. Mean airspace sizes for the patient subgroup were 235% of the healthy subgroup, which characterizes the increase in size and reduction in number of peripheral airspaces due to tissue erosion in emphysema. From these results, the air-phase diffusive conductance in COPD patients was calculated to be 32% of the mean value in the healthy subjects. These findings correlated well with standard pulmonary function test data for the patients and yield the recovery of acinar airway information from gas washout by combining the single path model with experimental measurements.

Modelling steady state pulmonary elimination of He, SF6 and CO2: effect of morphometry.

We studied the influence of acinar morphometry on the shape of simulated expirograms computed from a single path convection-diffusion model that includes a source term for gas evolution from the blood (Scherer et al., J. Appl. Physiol. 64: 1022-1029, 1988). Acinar structure was obtained from published data of 3 different lung morphometries. The simulations were performed over a range of tidal volumes (VT) and breathing frequencies (f) comparable to those observed in a previously reported human study. Airways dead space (VDaw) increased with VT in all the morphometric models tested and in the experimental data. The increase in VDaw with VT was inversely related to the diffusivity of the evolving gas and to the rate of increase in airway cross-section of the most mouthward (proximal) alveolated generations of the models. Normalized phase III slope for all the gases decreased with increasing VT in all the models as was previously reported for healthy human subjects. In the model simulations, the greatest sensitivity of phase III slope to VT was seen with the least diffusible gas using the airway morphometry with the smallest cross-sectional areas in the proximal alveolated generations. We conclude that both VDaw and phase III slope of an evolving gas are sensitive to the geometry of the proximal acinar airways and that this is manifest by their dependence on tidal volume, breathing frequency, molecular diffusivity and alveolar/blood source emission rate. The model simulations indicate that heterogeneity of gas washout is not required to explain the magnitude of the phase III slope in healthy human subjects.

Microemboli reduce phase III slopes of CO2 and invert phase III slopes of infused SF6

We investigated the effect of increasing doses of intravenously infused glass microspheres (mean diameter 125 microns) on gas exchange in anesthetized, heparinized, mechanically ventilated goats (VT = 16-18 ml/kg). Breath-by-breath CO2 expirograms were collected using a computerized system (Study A) during the infusion of a total of 15 g of microspheres. We found a 50% decrease in extravascular lung water by indicator dilution with a corresponding doubling of alveolar dead space (VDalv). Airways deadspace (VDaw) decreased by 13 ml (10%) and mean normalized phase III slope for CO2 decreased from 0.23 to -0.08 L-1 becoming negative in 3 of 5 animals. In a second study (Study B), simultaneous breath-by-breath CO2 and infused SF6 expirograms were collected using an infrared CO2 analyzer and a mass spectrometer. Under baseline conditions VDaw for CO2 was smaller than for SF6 and the ratio of the phase III slope for SF6 to the phase III slope for CO2 was 1.39. Following embolization there were no differences in VDaw between the two gases, however, the phase III slope for CO2 became either slightly negative or extremely flat, while the phase III slope for SF6 became negative in 73% of the breaths (-0.17 L-1, P < 0.05). Negative phase III slopes have been predicted by a single path model when blood flow is confined to the most mouthward generations of the acinus (Schwardt et al., Ann. Biomed. Engin, 19: 679-697, 1991). The agreement between the numerical model and the experimental data is consistent with a serial distribution of blood flow within the acinus.

Commercial double-indicator-dilution densitometer using heavy water: Evaluation in oleic-acid pulmonary edema

We evaluated a commercially available, double-indicator-dilution densitometric system for the estimation of pulmonary extravascular water volume in oleic acid-induced pulmonary edema. Indocyanine green and heavy water were used as the nondiffusible and diffusible tracers, respectively. Pulmonary extravascular water volume, measured with this system, was 67% of the gravimetric value (r = 0.91), which was consistent with values obtained from the radioisotope methods. The measured volume was not influenced by changes in cardiac index over a range of 1 to 4 L · min · m2. This system is less invasive than the thermal-dye technique and has potential for repeated clinical measurements of pulmonary extravascular lung water and cardiac output.