Cellulitis owing to Aeromonas hydrophilia: treatment with hyperbaric oxygen.

Aeromonas hydrophilia, a Gram-negative facultative anaerobe, is a rare cause of cellulitis. We review the literature and report a case of Aeromonas hydrophilia cellulitis which failed to respond to the conventional management of surgical debridement and antibiotics. Hyperbaric oxygen therapy was used successfully to control the infection. As far as we are aware this is the first case in world literature of Aeromonas hydrophilia cellulitis treated with hyperbaric oxygen.

Application of linear and nonlinear time series modeling to heart rate dynamics analysis.

The linear autoregressive (AR) model is often used to investigate the pathophysiologic mechanisms controlling heart rate (HR) dynamics. This study implemented parametric models new to this field to determine if a more appropriate HR dynamics modeling structure exists. The linear AR and autoregressive-moving average (ARMA) models, and the nonlinear polynomial autoregressive (PAR) and bilinear (BL) models were fit to instantaneous HR time series obtained from nine subjects in the supine position. Model orders were determined by the Akaike Information Criteria (AIC). Model residual variance was used as the primary intermodel comparison criterion, with significance evaluated by a chi 2 distributed statistic. The BL model best represented the HR dynamics, as its residual variance was significantly (p < 0.05) smaller than that of the corresponding AR model for nine out of nine data sets. In all cases, the BL model had a smaller residual variance than either the ARMA or PAR models. The bilinear model was ineffective at data forecasting, however, we show that this cannot reflect BL model validity because poor prediction is inherent to the BL model structure. The apparent superiority of the nonlinear bilinear model suggests that future heart rate dynamics studies should put greater emphasis on nonlinear analyses.

Influence of autoregressive model parameter uncertainty on spectral estimates of heart rate dynamics.

Linear autoregressive (AR) model-based heart rate (HR) spectral analysis has been widely used to study HR dynamics. Owing to system and measurement noise, the parameters of an AR model have intrinsic statistical uncertainty. In this study, we evaluate how this AR parameter uncertainty can translate to uncertainty in HR power spectra. HR time series, obtained from seven subjects in supine and standing positions, were fitted to AR models by least squares minimization via singular value decomposition. Spectral uncertainty due to inexact parameter estimation was assessed through a Monte Carlo study in which the AR model parameters were varied randomly according to their Gaussian distributions. Histogram techniques were used to evaluate the distribution of 50,000 AR spectral estimates of each HR time series. These Monte Carlo uncertainties were found to exceed those predicted by previous theoretical approximations. It was determined that the uncertainty of AR HR spectral estimates, particularly the locations and magnitudes of spectral peaks, can often be large. The same Monte Carlo analysis was applied to synthetic AR time series and found levels of spectral uncertainty similar to that of the HR data, thus suggesting that the results of this study are not specific to experimental HR data. Therefore, AR spectra may be unreliable, and one must be careful in assigning pathophysiological origins to specific spectral features of any one spectrum.

Structure and orientation of the pore-forming peptide, melittin, in lipid bilayers.

Ten analogues of the 26-residue, bee venom peptide, melittin (H3N(+)-GIGAVLKVLTTGLPALISWIKRKRQQ-CONH2), were synthesized, each with 13C enrichment of a single peptide carbonyl carbon. These peptides were incorporated into bilayers of the diether lipid, ditetradecylphosphatidylcholine, aligned between stacked glass plates. Solid-state 13C nuclear magnetic resonance spectra were obtained as a function of the angle between the bilayer planes and the magnetic field of the spectrometers, and at temperatures above and below the lipid gel-to-liquid crystalline transition temperature, Tc. For bilayers aligned with the normal along the applied magnetic field there was no shift in the carbonyl resonances of residues Ile2, Ala4, Leu9, Leu13, or Ala15, with minor changes for residues Val8 and Ile20, and small changes at Val5, Leu6 and Ile17 on immobilization of the peptide below Tc. In contrast, the spectra for bilayers aligned at right angles to the field showed greatly increased anisotropy below Tc for all analogues. From these experiments it was evident that the peptide was well-aligned in the bilayers and reoriented about the bilayer normal. The observed reduced chemical shift anisotropies and the chemical shifts were consistent with melittin adopting a helical conformation with a transbilayer orientation in the lipid membranes. With the exception of Ile17, there was no apparent difference between the behaviour of residues in the two segments that form separate helices in the water-soluble form of the peptide, suggesting that in membranes the angle between the helices is greater than the 120 degrees observed in the crystal form.

Analysis of heart rate dynamics as a measure of autonomic tone in obstetrical patients undergoing epidural or spinal anesthesia.

BACKGROUND AND OBJECTIVES: The purpose of this study is to determine if spectral analysis of beat-to-beat heart rate variability will provide important data on autonomic nervous system function during either spinal or epidural anesthesia that is not apparent from the monitoring of mean heart rate and blood pressure. METHODS: Twelve ASA I patients presenting for elective cesarean delivery (7 epidural and 5 spinal anesthetics) were prospectively selected for study. Control and postblock 10-minute segments of instantaneous heart rates were analyzed for each patient. The total spectral power (Ps, 0.02-0.5 Hz), low frequency spectral power (PLF, 0.02-0.12 Hz), and high frequency spectral power (PHF, 0.12-0.5 Hz) were calculated for each data segment. The complexity of the heart rate time series was estimated by calculating the approximate entropy. RESULTS: Neither spinal or epidural anesthesia had any effect on heart rate or blood pressure. Both spinal and epidural anesthesia did produce a significant decrease in PS, PLF, and PHF. Although there were significant decreases in both the PLF and PHF, there was no change in the PLF/PHF ratio. There was a significant reduction in approximate entropy with spinal and epidural anesthesia, indicating a decrease in complexity of the heart rate dynamics. CONCLUSIONS: These data suggest that autonomic tone decreased with spinal and epidural anesthesia but the sympathetic-parasympathetic balance (expressed as PLF/PHF) did not change. Spectral measures, as well as approximate entropy, provide an independent evaluation of the integrity of the autonomic nervous system and cardiovascular control mechanisms that cannot be discerned from mean heart rate and blood pressure.

Chronic cough due to gastroesophageal reflux. Clinical, diagnostic, and pathogenetic aspects.

BACKGROUND: Gastroesophageal reflux (GER) is a common cause of chronic cough. Moreover, chronic cough can be the sole presenting manifestation of GER disease (GERD). It has been suggested recently that GER most often causes chronic cough by stimulating the distal esophagus. To gain further diagnostic and pathophysiologic knowledge, we prospectively evaluated a group of patients with chronic cough likely to be due to GER with extensive gastrointestinal and respiratory studies and then observed their response to antireflux therapy. METHODS: We prospectively characterized 12 subjects whose chronic cough was likely to be due to GER by chest radiographs, barium esophagography, 24-h esophageal pH monitoring (EPM) with probes in the distal and proximal esophagus, esophagoscopy, and bronchoscopy. Then, prior to instituting antireflux therapy, we objectively counted coughs during the distal esophageal infusion of 0.1 N HCl or 0.9 percent saline solution administered in a randomized, double-blind, standardized fashion (ie, Bernstein acid-perfusion test). RESULTS: Gastroesophageal reflux was determined to cause cough in all subjects based on disappearance of cough with antireflux therapy. It was clinically "silent" in 75 percent. The EPM was the test most frequently abnormal (sensitivity, 92 percent). Distal esophageal data revealed that 10 of 12 subjects had GER-induced coughs (12 +/- 12) while only 7 of 12 had an abnormal esophageal pH conventional parameter (eg, percent time pH < 4). Compared with the distal esophagus, GER to the proximal esophagus occurred (p = 0.017) and induced cough (p = 0.004) less often. Compared with baseline (9.3 +/- 17.6), there were no differences in coughs induced by the infusion of saline solution (9.2 +/- 15.9) or acid (15.1 +/- 26.7); the number of coughs induced by acid was negatively correlated with distal esophageal acid-GER events during EPM (r = -0.64, p = 0.01). Neither bronchoscopy nor chest radiographs were consistent with aspiration. CONCLUSIONS: There is a clinical profile that prospectively predicts which patients have chronic cough due to GER. The cough was most likely due to stimulation of the distal esophagus, not aspiration. Intraesophageal acid is unlikely to be the sole mediator in gastric juice causing the cough. While EPM is the single most helpful diagnostic test, conventionally utilized diagnostic indices of GERD can be misleadingly normal; observing GER-induced coughs is more frequently helpful.

Regulation of PaCO2 during rest and exercise: a modeling study.

A nonlinear mathematical model of the CO2 control system was used to examine a number of issues concerning the regulation of PaCO2 during rest and exercise. To gain insight to the regulatory properties of the respiratory system, the open loop gain (GL) and closed loop sensitivities SI = delta PaCO2/delta PICO2 and SV = delta PaCO2/delta VCO2 were calculated. GL indicates the ability of a control system to regulate the controlled variable, PaCO2 in the model. SI and SV represent the change in PaCO2 to unit changes in PICO2 and VCO2, respectively. Model predications were obtained for rest and various intensities of exercise for the following challenges to the respiratory system: (a) CO2 inhalation, (b) i.v. CO2 loading, (c) application of an external dead space, and (d) a shift in the resting operating point. Increasing exercise intensity produced a substantial decrease in GL and increase in SI consistent with the hypothesis that exercise degrades the ability of the respiratory system to regulate PaCO2. However, SV decreased indicating that the respiratory system would actually be better able to regulate PaCO2 if there were fluctuations in VCO2. Thus, GL does not completely describe the regulatory characteristics of the respiratory control system. It is demonstrated that the regulatory characteristics of the respiratory system as described by GL, SI, and SV are complex and depend on the nature of the challenge. Techniques for systematically describing the regulatory properties of the CO2 control system are described.

Appropriate use of antitussives and protussives. A practical review.

As a symptom of an underlying condition, cough is one of the most common reasons patients see physicians. To the majority, a cough means that 'something is wrong' and it causes exhaustion and/or self-consciousness. Patients find these reasons as well as effects on lifestyle, fear of cancer and/or AIDS or tuberculosis to be the most troublesome concerns for which they seek medical attention. The treatment of cough can be divided into two main categories: (a) therapy that controls, prevents or eliminates cough (i.e. antitussive); and (b) therapy that makes cough more effective (i.e. protussive). Antitussive therapy can be either specific or nonspecific. Definitive or specific antitussive therapy depends on determining the aetiology or operant pathophysiological mechanism, and then initiating specific treatment. Since the cause of chronic cough can almost always be determined, it is possible to prescribe specific therapy that can be almost uniformly successful. Non-specific antitussive therapy is directed at the symptom; it is indicated when definitive therapy cannot be given. Practically speaking, the efficacy of nonspecific therapy must be evaluated in double-blind, placebo-controlled, randomised studies of pathological cough in humans. Such studies have demonstrated the efficacy of dextromethorphan, codeine and ipratropium bromide aerosol in patients with chronic bronchitis. While the preferred treatment for patients with cough due to angiotensin converting enzyme (ACE) inhibitor therapy is withdrawal of the offending drugs, it may be possible to ameliorate the cough by adding nifedipine, sulindac or indomethacin to the treatment regimen. The efficacy of protussive therapy has not been well documented. Although hypertonic saline aerosol and erdosteine in patients with bronchitis, and amiloride aerosol in patients with cystic fibrosis have been shown to improve mucus clearance, their clinical utility has not been adequately studied.

Cocaine effects on neonatal heart rate dynamics: preliminary findings and methodological problems.

Cocaine use by pregnant women has been reported to cause fetal and neonatal morbidity and mortality. We hypothesized that human neonates exposed to cocaine via maternal use during pregnancy might manifest changes in beat-to-beat heart rate variability, similar to those described in experimental animals. In this preliminary report, we present findings from the first systematic analysis of heart rate dynamics in a small group of (n = 5) neonates exposed in utero to cocaine compared to gestationally age matched controls (n = 6) without known drug exposure. Overall heart rate spectral power during ten minute periods of quiescent sleep was significantly reduced (p < 0.01) in the cocaine-exposed group, reminiscent of the changes recently reported in an animal model. In two other cocaine-exposed newborns, a quiescent sleep period could not be found. We discuss the special methodological problems associated with collection and interpretation of such data.

Limitations of the open loop gain concept in studies of respiratory control.

A steady state mathematical model was used to study the limitations of applying the open loop gain concept to the ventilatory control system. Open loop gain is a term used in the study of linear control systems and is an indicator of how well the controlled variable is regulated. The model contained descriptions of the O2 and CO2 control systems as well as their interactions. Disturbances to the system were modelled as occurring via inspired air, metabolic rate and ventilation. The ventilatory response to hypoxia was simulated for (a) hypocapnic hypoxia, (b) normocapnic hypoxia (PaCO2 = 40 torr) and (c) hypercapnic hypoxia (PaCO2 = 45 torr). The open loop gains of the O2 and CO2 loops were calculated at each operating point. In addition, the sensitivity of the controlled variable to disturbances to the loop were also compared. It was observed that open loop gain did not completely describe the characteristics of the ventilatory control system. This was due to the fact that the ventilatory system is nonlinear and the regulatory ability of the ventilatory system depends on the route of the disturbance, and (2) open loop gain ignores the interactions of the CO2 and O2 loops, which can be substantial.

Gain of the ventilatory exercise stimulus: definition and meaning.

The ratio G = delta VE/delta VCO2 where delta VA is change in ventilation and delta VCO2 is change in CO2 production, is often used to quantitate the ventilatory response to exercise and is the overall system gain (G). However, the actual variable of interest often is the gain for the exercise stimulus (GEX). Exercise stimulus refers to a stimulus or group of stimuli other than the mean levels of arterial PO2 (PaCO2), PCO2 (PaCO2), and pH (pHa) that act to increase ventilation during exercise. GEX will be equal to G only if the response to exercise is precisely isocapnic, normoxic, and without metabolic acidosis. A mathematical model was used to examine the relationship between G and GEX when 1) the response to exercise is not strictly isocapnic and 2) when the resting PaCO2 is shifted away from its normal value. It was found that 1) when the exercise response was not strictly isocapnic, G was a poor estimate of GEX and 2) when resting PaCO2 was changed while GEX wa assumed to remain constant, G was a function of the resting PaCO2. However, this dependence of G on resting PaCO2 is a system property that was caused by the nonlinear properties of the gas exchange processes and was not a fundamental property of the controller. It is concluded that G may not always be a good estimate of GEX and may lead to incorrect conclusions concerning the nature of the exercise stimulus.

Function in ventilatory control of respiratory neurons at the pontomedullary junction.

Previous studies have demonstrated that electrolytic lesions placed in the midline at the pontomedullary junction result in increased respiratory frequency. The increase in frequency is greater during hypercapnia. The present study sought to determine whether the effects of the lesions were mediated, at least in part, by destruction of neurons. Alternatively, the lesions may have interrupted fiber tracts. Both destruction by kainic acid and inhibition by selective cooling of neurons on the midline at the pontomedullary junction in decerebrate, vagotomized, paralyzed and artificially ventilated cats produced results similar to those engendered by the lesions; i.e., an increased respiratory frequency. Microinjections of glutamate produced a slowing of respiration. In additional cats, extracellular single unit recordings were obtained from 48 neurons located in the medial areas (0-1 mm lateral to midline) at the pontomedullary junction. Of these, 41 neurons were tonically active and 38 were judged to be respiratory-modulated by both the F-test and the Friedman test. The activity of these neurons was sensitive to changes in CO2. Therefore, neurons located at the pontomedullary junction may play a primary role in the integration of central chemoreceptor afferent stimuli.

Characteristics of the ventilatory exercise stimulus.

Simple mathematical models were used to quantitatively examine a number of hypotheses concerning the nature of the exercise stimulus. The modelling demonstrated the following for an exercise intensity of 5 times the resting metabolic rate. (1) During the steady state, a deviation in the coupling between VE and metabolic rate by +/- 25% of the value necessary for isocapnia, results in a deviation of PaCO2 of +/- 2 torr from isocapnia. (2) In the transient phase, a mismatch between VE and Q (and thus CO2 flow) of 50% results in a change of PaCO2 of only 1 torr. (3) When resting PaCO2 is changed by 10 torr and it is assumed that the coupling between VE and VCO2 does not change, PaCO2 deviates from isocapnia by less than 2 torr. It is concluded that (1) to experimentally test hypotheses of the exercise stimulus requires resolution of small changes in PaCO2; (2) good regulation of PaCO2 does not necessarily imply precise coupling between VE and VCO2; (3) the ventilatory exercise stimulus need not be a precise function of metabolic rate; (4) in the steady state, the normal CO2 controller will be very effective in minimizing changes in PaCO2 due to a mismatch between ventilation and metabolic rate.

Anesthesia selectively reduces hypoglossal nerve activity by actions upon the brain stem.

Alcohol as well as anesthetic and sedative agents depress the respiratory activity of the hypoglossal-genioglossal system more than that of the phrenic-diaphragmatic system. The mechanisms for this selective depression remain unclear. To evaluate the contribution of pathways traversing the spinal cord, the response of phrenic and hypoglossal nerve activities to 0.5% halothane was obtained in decerebrate cats before and after transection of the spinal cord at T1 and again following transection at C1. Halothane produced a much greater decrease in hypoglossal than phrenic activity before and after spinal cord section at T1. Following cord section at C1, which eliminates phrenic activity, 0.5% halothane still produced a marked depression of hypoglossal activity. Therefore, the selective depression of the hypoglossal-genioglossal system does not depend on spinal mechanisms and appears to be mediated in the brain stem.

A role for neural pathways in exercise hyperpnea.

The ventilatory response to exercise induced by stimulation of the peripheral ends of severed sciatic nerves was studied in seven anesthetized dogs. In response to exercise (n = 23) there were increases in expired minute ventilation (delta VE = 4.09 l/min), arterial CO2 partial pressure (delta PaCO2 = 3.06 Torr), and carotid artery temperature (delta Tca = 0.26 degrees C). There was also a concomitant decrease in mean arterial blood pressure (delta MAP = -6.28 Torr). Since the neural pathways from the exercising limbs to the central nervous system had been eliminated by nerve section, the significant increase in PaCO2 during exercise indicates that humoral factors alone cannot produce the normal exercise response, i.e., an isocapnic hyperpnea. Therefore, neural pathways may play a fundamental role in the ventilatory response to exercise in intact animals.

Role of VCO2 in control of breathing of awake exercising dogs.

Steady-state ventilatory responses to CO2 inhalation, intravenous CO2 loading (loading), and intravenous CO2 unloading (unloading) were measured in chronic awake dogs while they exercised on an air-conditioned treadmill at 3 mph and 0% grade. End-tidal PO2 was maintained at control levels by manipulation of inspired gas. Responses obtained in three dogs demonstrated that the response to CO2 loading [average increase in CO2 output (Vco2) of 216 ml/min or 35%] was a hypercapnic hyperpnea in every instance. Also, the response to CO2 unloading [average decrease in Vco2 of 90 ml/min or 15% decrease] was a hypocapnic hypopnea in every case. Also, the analysis of the data by directional statistics indicates that there was no difference in the slopes of the responses (change in expiratory ventilation divided by change in arterial Pco2) for loading, unloading, and inhalation. These results indicate that the increased CO2 flow to the lung that occurs in exercise does not provide a direct signal to the respiratory controller that accounts for the exercise hyperpnea. Therefore, other mechanisms must be important in the regulation of ventilation during exercise.

Effects of small changes in PaO2 on the ventilatory response to CO2 infusion.

The steady-state ventilatory responses to CO2 inhalation and two levels of intravenous CO2 infusion were examined in chronic awake dogs. Responses were obtained for four treatments: 1) air breathing, in which arterial O2 tension (PaO2) increased during infusion; 2) normoxia, PaO2 maintained at control levels; 3) hypoxia, PaO2 = 70 Torr; and 4) hyperoxia, PaO2 = 160 Torr. In three dogs, the ventilatory responses were obtained for treatments 1, 2, and 4 and in an additional three dogs for treatments 2, 3, and 4. Analysis of the data by directional statistics indicates that the response to infusion was hypercapnic for all treatments, and the slope of the response (change in minute ventilation divided by change in arterial CO2 tension) was identical to that of CO2 inhalation. Also, the slopes of the responses for the low infusion rate, CO2 output (VCO2) = 50%, and the high infusion rate, VCO2 = 270%, were identical, which suggests that the CO2 response is not significantly curvilinear near the eucapnic region. Finally, changing PaO2 between 70 and 160 Torr had no significant effect on the response slopes. Thus the ventilatory response to CO2 infusion in the awake dog is a hypercapnic hyperpnea that is not due to ventilatory inhibition arising from an increase in PaO2.

Immediate human breathing pattern responses to loads near the perceptual threshold.

Breathing pattern responses to small mechanical loads added pseudorandomly to the external airway of human subjects were measured using flow-resistive and elastic loads above and below the threshold for detectability of some subjects. The zeroth lag of the computed cross-correlations between the loading sequence and the various aspects of the breathing pattern response was used as an index of the immediate response to loading. All subjects showed an immediate reduction in tidal volume (VT) and expiratory duration (TE) in response to elastic loading, but inspiratory duration (TI) responded variably. Respiratory frequency (f) was increased, and minute ventilation (V) and mean inspiratory flow (VT/TI) decreased immediately in all subjects. Resistance loading, on the other hand, tended to prolong TI and TE immediately such that f fell. VT responses were variable, and both V and VT/TI fell. The responses to imperceptible loads reflect mainly the action of neural reflexes and characteristics intrinsic to the respiratory muscles and configuration of the chest and abdomen. A mathematical simulation was used to show that the TE responses in particular may indicate the action of subconscious neural reflexes.

Comparative mechanics of mammalian respiratory system.

Compliances (C) of lung, thorax and respiratory system as well as resistances (R) of the respiratory system (lower airways + lung + chest wall) and of upper airway (primarily laryngeal and nasal) were measured in 5 species of mammals, spanning a 1000-fold range of body weights (mouse to dog), immediately following sacrifice with an overdose of sodium pentobarbital. The results indicate that compliance is proportional to BW1.0, while respiratory resistance and upper airway resistance have exponents of -0.819 and -0.702, respectively. The reciprocal of the time constant, tau -1 = (RC)-1 is proportional to BW-0.298 for respiratory resistance alone and BW-0.326 when upper airway resistance is included. Since breathing frequency varies as BW-0.28, these results indicate a proportional relationship between breathing frequency and passive emptying time. This suggests that passive respiratory mechanics play a major role in determining TE and therefore TTOT for animals during quiet breathing. Changes in volume history were found not to affect the slope of the relationships between compliance and body weight.