Incidence of acute exertional rhabdomyolysis. Serum myoglobin and enzyme levels as indicators of muscle injury.

This study was conducted to determine, on a prospective basis, the incidence of acute exertional rhabdomyolysis (AER) among recruits at the Marine Corps Recruit Depot, San Diego, Calif. Blood samples were taken from each of 337 volunteer recruits on each of their first six days of regularly scheduled training. Serum myoglobin, serum creatine phosphokinase, lactic dehydrogenase, and serum glutamic oxaloacetic transaminase values were used as indicators of muscle injury. Substantial elevations of serum enzyme activity were observed throughout the study population. Of the study population, 39.2% had serum myoglobin levels that ranged from 0.37 mug/ml to 21.9 mug/ml during the study interval. Six subjects had serum myoglobin levels consistent with those reported in clinical cases of AER. It is concluded that, in a recruit population, large numbers of men may have myoglobinemia but not be seen initially as clinical cases.

Computations for a best match strategy for kidney transplantation.

In some cases success or failure of a proposed innovation in transplantation may be better judged if we consider the average survival time of the graft rather than the actuarial survival at a point in time. It is suggested that HLA matching may be an example of such a case and that the possible clinical benefits of modest improvements in matching may have been underestimated. Calculations are made that show that transplanting to the best match available in a pool of 100 patients might increase the expected graft survival time by more than 1 year.

A proposal for the analysis of kidney graft survival.

A survival analysis using a model provides numerous advantages over other approaches. The effectiveness of concomitant variables in describing the data can be evaluated whether the variables are continuous or dichotomized. We can evaluate the effectiveness of such variables in describing either short- or long-term components of the risk. The expected life span of the graft may be computed with the model and complements the insight obtained from the more commonly displayed survival curves.

Manual differential cell counts help predict bacterial infection. A multivariate analysis.

We developed logistic regression models that combine information from the automated CBC and manual 100-cell differential counts to predict bacterial infection. The logistic models were fitted from a case group of 116 patients with proven bacterial infection and a control group of 930 presumably uninfected outpatients. A 4-variable, 15-parameter model, which includes automated absolute neutrophil, manual band, and manual immature granulocyte counts, performed best with a receiver operating characteristic (ROC) curve area of 89%. A more practical 2-variable model including automated absolute neutrophil and manual band counts performed almost as well with an ROC curve area of 86%. The automated neutrophil count-only model is less informative with an ROC curve area of 78%. The combined information from automated and manual differential cell counts more accurately predicts bacterial infection than automated counting alone. Despite these modest improvements, the high cost of manual differential cell counts dictates careful patient selection. The supplemental information gained from manual differential counts is most useful for patients with low to normal neutrophil counts (8,000/microL [8.0 x 10(9)/L] or less). Further studies are indicated to determine the characteristic patient populations deriving maximal benefit from this information.

How well mixed is inert gas in tissues?

The washout of inert gas from tissues typically follows multiexponential curves rather than monoexponential curves as would be expected from homogeneous, well-mixed compartment. This implies that the ratio for the square root of the variance of the distribution of transit times to the mean (relative dispersion) must be greater than 1. Among the possible explanations offered for multiexponential curves are heterogeneous capillary flow, uneven capillary spacing, and countercurrent exchange in small veins and arteries. By means of computer simulations of the random walk of gas molecules across capillary beds with parameters of skeletal muscle, we find that heterogeneity involving adjacent capillaries does not suffice to give a relative dispersion greater than one. Neither heterogeneous flow, nor variations in spacing, nor countercurrent exchange between capillaries can account for the multiexponential character of experimental tissue washout curves or the large relative dispersions that have been measured. Simple diffusion calculations are used to show that many gas molecules can wander up to several millimeters away from their entry point during an average transit through a tissue bed. Analytical calculations indicate that an inert gas molecule in an arterial vessel will usually make its first vascular exit from a vessel larger than 20 micron and will wander in and out of tissue and microvessels many times before finally returning to the central circulation. The final exit from tissue will nearly always be into a vessel larger than 20 micron. We propose the hypothesis that the multiexponential character of skeletal muscle tissue inert gas washout curves must be almost entirely due to heterogeneity between tissue regions separated by 3 mm or more, or to countercurrent exchanges in vessels larger than 20 micron diam.

A model of extravascular bubble evolution: effect of changes in breathing gas composition.

Observations of bubble evolution in rats after decompression from air dives (O. Hyldegaard and J. Madsen. Undersea Biomed. Res. 16: 185-193, 1989; O. Hyldegaard and J. Madsen. Undersea Hyperbaric Med. 21: 413-424, 1994; O. Hyldegaard, M. Moller, and J. Madsen. Undersea Biomed. Res. 18: 361-371, 1991) suggest that bubbles may resolve more safely when the breathing gas is a heliox mixture than when it is pure O(2). This is due to a transient period of bubble growth seen during switches to O(2) breathing. In an attempt to understand these experimental results, we have developed a multigas-multipressure mathematical model of bubble evolution, which consists of a bubble in a well-stirred liquid. The liquid exchanges gas with the bubble via diffusion, and the exchange between liquid and blood is described by a single-exponential time constant for each inert gas. The model indicates that bubbles resolve most rapidly in spinal tissue, in adipose tissue, and in aqueous tissues when the breathing gas is switched to O(2) after surfacing. In addition, the model suggests that switching to heliox breathing may prolong the existence of the bubble relative to breathing air for bubbles in spinal and adipose tissues. Some possible explanations for the discrepancy between model and experiment are discussed.

How countercurrent blood flow and uneven perfusion affect the motion of inert gas.

Monte Carlo simulations of the passage of inert gas through muscle tissue reveal that countercurrent gas exchange is more important than heterogeneity of flow in determination of the shape of inert gas washout curves. Semilog plots of inert gas washout are usually curved rather than straight. Two explanations often offered are that countercurrent flow may distort the shape and that uneven perfusion of the tissue gives rise to nonuniform washout. The curvature of the semilog plot may be summarized by the relative dispersion (RD), which is the ratio of the standard deviation of transit times to the mean transit time. For straight semilog plots, RD is 1. Semilog plots of data showing xenon washout from dog tissues are curved and have and RD of approximately 2. We have simulated the transit of gas particles through a vascular bed composed of repeating units of 100 mg of tissue perfused by three small vessels 80 microns in diameter and several levels of branching that direct flow through 190,000 capillaries. Geometric distribution of flow is important. Similar degrees of flow heterogeneity affect the curvature of the washout curve more if regions of heterogeneous flow are widely spaced than if they are close together. Diffusion blunts the effects of heterogeneous flow by mixing particles in high-flow regions with particles in low-flow regions. Because of this mixing, alternating regions of high flow and low flow spaced at intervals of less than 0.5 cm are unlikely explanations for the curved semilog plots.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of lipid on inert gas kinetics.

A Monte Carlo simulation of inert gas transit through skeletal muscle has been extended to include regions of increased gas solubility to simulate regions of high lipid content. Position of the regions within the simulation module was varied, as was the muscle-lipid partition coefficient (lambda). The volume percentage of the lipid regions (alpha) was varied from 0 to 25% while lambda covered the range from 1 to 50. The effects of alpha and lambda on mean transit time and on relative dispersion (RD; ratio of SD to the mean) were examined for a single lipid volume and compared with expected values under the assumption that the tissue is composed of two well-stirred compartments. Mean transit times varied from approximately 0.80 to 1.20 times the values predicted by a simple parallel two-compartment model, whereas RD varied from 0.9 to 3.6. For fixed lambda, RD as a function of lipid fraction passes through a maximum that is shifted and was also smaller than expected from a simple two-compartment model. For fixed alpha, RD approaches an asymptotic value for large lambda, but the asymptote is smaller than that expected from the two-compartment model. When lipid is distributed in only two regions, RD decreases with increasing separation of the regions and with increasing surface area of the fat regions. A model of two well-stirred compartments that allows mixing between the compartments yields results similar to those from the simulation.

Decompression outcome following saturation dives with multiple inert gases in rats.

This investigation examined the question of whether gas mixtures containing multiple inert gases provide a decompression advantage over mixtures containing a single inert gas. Unanesthetized male albino rats, Rattus norvegicus, were subjected to 2-h simulated dives at depths ranging from 145 to 220 fsw. At pressure, the rats breathed various He-N2-Ar-O2 mixtures (79.1% inert gas-20.9% O2); they were then decompressed rapidly (within 10 s) to surface pressures. The probability of decompression sickness (DCS), measured either as severe bends symptoms or death, was related to the experimental variables in a Hill equation model incorporating parameters that account for differences in the potencies of the three gases and the weight of the animal. The relative potencies of the three gases, which affect the total dose of decompression stress, were determined as significantly different in the following ascending order of potency: He less than N2 less than Ar; some of these differences were small in magnitude. With mixtures, the degree of decompression stress diminished as either N2 or Ar was replaced by He. No obvious advantage or disadvantage of mixtures over the least potent pure inert gas (He) was evident, although limits to the expectation of possible advantage or disadvantage of mixtures were defined. Also, model analysis did not support the hypothesis that the outcome of decompression with multiple inert gases in rats under these experimental conditions can be explained totally by the volume of gas accumulated in the body during a dive.

An analysis of decrements in vital capacity as an index of pulmonary oxygen toxicity.

Decrements in vital capacity (% delta VC) were proposed by the Pennsylvania group in the early 1970s as an index of O2-induced lung damage. These workers used the combined effects of PO2 and time of exposure to develop recommendations to limit expected % delta VC. Adopting this general approach, we fitted human pulmonary O2 toxicity data to the hyperbolic equation % delta VC = Bs.(PO2 - B1).(time)B3 using a nonlinear least squares analysis. In addition to the data considered in 1970, our analysis included new data available from the literature. The best fit was obtained when 1) an individual slope parameter, Bs, was estimated for each subject instead of an average slope; 2) PO2 asymptote B1 = 0.38 ATA; and 3) exponent B3 = 1.0. Wide individual variation imposed large uncertainty on any % delta VC prediction. A 12-h exposure to a PO2 of 1 ATA would be expected to yield a median VC decrement of 4%. The 80% confidence limits, however, included changes from +1.0 and -12% delta VC. Until an improved index of pulmonary O2 toxicity is developed, a simplified expression % delta VC = -0.011.(PO2 - 0.5).time (PO2 in ATA and time in min) can be used to predict a median response with little loss in predictability. The limitations of changes in VC as an index are discussed.

Nitrogen gas exchange in the human knee.

Human decompression sickness is presumed to result from excess inert gas in the body when ambient pressure is reduced. Although the most common symptom is pain in the skeletal joints, no direct study of nitrogen exchange in this region has been undertaken. For this study, nitrogen tagged with radioactive 13N was prepared in a linear accelerator. Nine human subjects rebreathed this gas from a closed circuit for 30 min, then completed a 40- to 100-min washout period breathing room air. The isotope 13N was monitored continuously in the subject's knee during the entire period using positron detectors. After correction for isotope decay (half-life = 9.96 min), the concentration in most knees continued to rise for at least 30 min into the washout period. Various causes of this unexpected result are discussed, the most likely of which is an extensive redistribution of gas within avascular knee tissues.

Contribution of tissue lipid to long xenon residence times in muscle.

Experiments demonstrate that the mean residence time of an inert gas in tissue is longer than that predicted by a single-compartment model of gas exchange. Also the relative dispersion (RD, the standard deviation of residence times divided by the mean) is 1 according to this model, but RDs in real tissues are closer to 2, suggesting that a multiple-compartment model might be more accurate. The residence time of a gas is proportional to its solubility in the tissue. Although the noble gases in particular are 10 times more soluble in lipid than in nonlipid tissues, models of gas exchange generally do not incorporate measurements of the lipid in tissue, which may lead to error in the predicted gas residence times. Could a multiple-compartment model that accounts for the lipid in tissue more accurately predict the mean and RD of gas residence times? In this study, we determined the mean and RD of Xe residence times in intact and surgically isolated muscles in a canine model. We then determined the lipid content and the perfusion heterogeneity in each tissue, and we used these measurements with a multiple-compartment model of gas exchange to predict the longest physiologically plausible Xe residence times. Even so, we found the observed Xe mean residence times to be twice as long as those predicted by the model. However, the predicted RDs were considerably larger than the observed RDs. We conclude that lipid alone cannot account for the residence times of Xe in tissue and that a multiple-compartment model is not an accurate representation of inert gas exchange in tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantifying the effect of intravascular perfluorocarbon on xenon elimination from canine muscle.

Intravenous infusions of perfluorocarbon (PFC) may improve decompression sickness outcome in animals by accelerating inert gas elimination from tissue, but any such effect has not been quantified experimentally. In this study we used an animal model of tissue Xe kinetics to test this hypothesis and to quantify the effect of PFC. Eight dogs were ventilated with dilute 133Xe in air for 4 h of Xe uptake. Four dogs were then given an infusion (20 ml/kg iv) of a 40% (vol/vol) perfluorodecalin-glycerol emulsion, and four control dogs were given only isotonic glycerol. All were then switched to open-circuit air breathing for 4 h of Xe elimination. During this time Xe radioactivity-time curves were recorded from two intact hind leg muscles, and the Xe mean residence times during elimination were estimated using an analysis by moments and compared by group. Tissue blood flows were measured using microspheres once during Xe uptake and twice during Xe elimination, and cardiac outputs were measured by thermodilution at 30-min intervals. In the PFC group the measured circulating PFC fraction increased the calculated Xe solubility by an average factor of 1.77 and so was expected to increase the Xe elimination rate by 77%. The observed Xe mean residence times on elimination for the PFC group averaged 33.5 min [95% confidence interval (CI) 19.5-47.6] compared with the glycerol control average of 70.1 min (95% CI 56.1-84.2), representing an increase in the rate of Xe elimination by a factor of 2.09 or 109%.(ABSTRACT TRUNCATED AT 250 WORDS)

Predicting the time of occurrence of decompression sickness.

Probabilistic models and maximum likelihood estimation have been used to predict the occurrence of decompression sickness (DCS). We indicate a means of extending the maximum likelihood parameter estimation procedure to make use of knowledge of the time at which DCS occurs. Two models were compared in fitting a data set of nearly 1,000 exposures, in which greater than 50 cases of DCS have known times of symptom onset. The additional information provided by the time at which DCS occurred gave us better estimates of model parameters. It was also possible to discriminate between good models, which predict both the occurrence of DCS and the time at which symptoms occur, and poorer models, which may predict only the overall occurrence. The refined models may be useful in new applications for customizing decompression strategies during complex dives involving various times at several different depths. Conditional probabilities of DCS for such dives may be reckoned as the dive is taking place and the decompression strategy adjusted to circumstance. Some of the mechanistic implications and the assumptions needed for safe application of decompression strategies on the basis of conditional probabilities are discussed.

Radio frequency (13.56 MHz) energy enhances recovery from mild hypothermia.

The rate of warming after hypothermia depends on the method of rewarming. This study compared the effectiveness of radio frequency (RF) energy against hot (41 degrees C) water immersion (HW) and an insulated cocoon (IC) for rewarming hypothermic men. Six men fasted overnight and were rewarmed for 1 h after attaining a 0.5 degree C reduction in rectal temperature (Tre). Tre and esophageal (Tes) temperature were recorded every 5 min with nonmetallic thermal probes. The base-line value for Tre and Tes just before rewarming was subtracted from each 5 min Tre and Tes during rewarming to give delta Tre and delta Tes. The 12 delta Tes values were averaged for each individual and were compared using analysis of variance. The average delta Tes for RF (1.15 +/- 0.22 degrees C/h) was faster (P less than 0.001) than either IC (0.37 +/- 0.16 degrees C/h) or HW (0.18 +/- 0.09 degree C/h). The present study shows the superiority of RF energy for rewarming mildly hypothermic men.

Bubble-induced dysfunction in acute spinal cord decompression sickness.

Five anesthetized dogs undertook a chamber dive, on air, to 300 feet of seawater for 15 min. After the dive, spinal cord decompression sickness was detected by recording a reduced amplitude of the somatosensory evoked potential compared with predive base-line values. After the diagnosis of decompression sickness and rapid perfusion fixation of the animal, the spinal cord was removed and examined histologically. Numerous space-occupying lesions (SOL) that disrupted the tissue architecture were found in each cord, mainly in the white matter. The size and distribution of the SOL were determined using computerized morphometry. Although SOL occupied less than 0.5% of the white matter volume, we tested a number of algorithms to assess whether the SOL may have been directly involved in the loss of spinal cord function that followed the dive. We determined that the loss of somatosensory evoked potential amplitude may be attributed to the SOL if 30-100% of the spinal cord fibers that they displaced were rendered nonconducting. A number of possible mechanisms by which SOL may interfere with spinal nerve conduction are discussed.

Xenon kinetics in muscle are not explained by a model of parallel perfusion-limited compartments.

Experimental tissue gas kinetics do not follow the prediction for a single stirred perfusion-limited compartment. One hypothesis proposes that the kinetics might be explained by considering the tissue as a collection of parallel compartments, each with its own flow, reflecting the tissue microcirculatory flow heterogeneity. In this study, observed tissue gas kinetics were compared with the kinetics predicted by a model of multiple parallel compartments. Gas exchange curves were generated by recording the time course of tissue radioactivity in the intact calf muscles of anesthetized ventilated dogs exposed to step function changes of 133Xe in the inspired air for 5-h periods. Microcirculatory flow heterogeneity in the same tissue was determined by the radioactive microsphere method. Observed mean tissue transit times were on average longer than predicted by a factor of 6.7. Observed means averaged 52.1 min compared with 8.3 min predicted by the perfusion-limited model. Relative dispersions of tissue transit times were also uniformly larger than predicted. We conclude that Xe gas kinetics in intact canine skeletal muscle are not explained by a model of multiple parallel perfusion-limited compartments. Countercurrent exchange of gas between vessels is a possible explanation.

Lipopolysaccharide transport from the peritoneal cavity to the blood: is it controlled by the vagus nerve?

Vagotomy suppresses fever and hyperalgesia caused by intraperitoneal lipopolysaccharide (LPS) but has little effect on the febrile response to intravenous or intramuscular LPS. This suggests that some vagus-mediated mechanisms are recruited only when LPS is administered via the intraperitoneal route. We hypothesized that such mechanisms are associated with LPS transport from the peritoneal cavity to the circulation. Adult Wistar rats underwent total subdiaphragmatic, bilateral selective celiac, or sham vagotomy. On day 28-32 after surgery, they were injected IP with Escherichia coli LPS (5, 20, or 100 microg/kg) or saline and decapitated 90 min thereafter. Their plasma levels of LPS and their plasma interleukin-6, adrenocorticotropin, and corticosterone responses to LPS were measured. Success of intraperitoneal administration of LPS was verified by increased interleukin-1beta and interleukin-6 concentrations in the peritoneal lavage fluid. Effectiveness of vagotomies was confirmed by increased stomach mass (food retention) and pancreas mass (hypertrophy). In the shams, LPS caused a dose-dependent endotoxemia and increased plasma levels of interleukin-6, adrenocorticotropin, and corticosterone. Neither celiac nor total vagotomy affected any of these responses. LPS escapes from the peritoneal cavity by two primary routes, viz., the hematogenous (via the portal vein) and lymphogenous (via the lymphatic system). The design of the present study did not allow for evaluating the rapid, hematogenous transport. The results obtained suggest that the abdominal vagus does not control the slow. lymphogenous escape of LPS from the peritoneal cavity.

Development and interactions of two inert gas bubbles during decompression.

A mathematical model has been developed to simulate the evolution of two inert gas bubbles in tissue. This is useful for understanding the dynamics of bubbles that presumably arise during decompression. It is assumed that they are spherical and that the tissue volume surrounding them is infinite. The total pressure in each bubble is determined by the barometric and metabolic gas pressures as well as the pressure due to surface tension. Bipolar coordinates are employed to determine the inert gas pressure distribution. Two coupled governing equations for bubble radii are then derived and solved numerically. The results demonstrate how bubble evolution is affected by the distance between bubbles and the initial bubble radii. The existence time and bubble surface flux of two equal-sized bubbles are calculated and compared with those of a single gas bubble model. The results indicate that when two bubbles are very close, it takes 20% more time for two bubbles to dissolve than for a single one, and the total surface flux of two bubbles is nearly 20% less than twice of a single bubble. When the center-to-center distance is 10 times of bubble radius, the effect of bubble interaction on bubble existence time and surface flux are about 6 and 9% changes, respectively. We conclude that if bubbles are not too small, the interactions among bubbles should be included in inert gas bubble models predicting bubble evolution.

A test for variations in individual sensitivity to hyperbaric oxygen toxicity.

It has been suggested that some individuals have above-average sensitivity to hyperbaric oxygen toxicity. An extensive human study completed at the Naval Experimental Diving Unit (NEDU) tested human tolerance to HBO and raised the possibility of assessing this hypothesis. In a group of 113 subjects given multiple exposures, some developed no symptoms of O2 toxicity while others developed symptoms on several occasions. The subjects in this study received unequal numbers of exposures of different depths and durations however, and it was not obvious how to determine unusual sensitivity. To assess the influences of chance vs. differences in sensitivity on the outcome of this experimental series, we performed a Monte Carlo simulation in which the experimental design was duplicated and the sensitivity hypothesis was evaluated statistically. The number of subjects giving rise to any symptoms and the distribution of individuals having symptoms on multiple occasions were evaluated. The simulation showed that the NEDU results were not unusual: nearly one quarter of the time the observed pattern of multiple symptoms could have been expected due to chance alone. The power of this simulation would have permitted detection of sensitivity factors 10 times (or greater) normal in 20% of the subjects at least half of the time.