Biomedical subjects

T L Clanton

Publications and source records attributed to T L Clanton.

At least 37 records · Page 2Linked to original sources

PubMed1996

High-dose furosemide alters gas exchange in a model of acute lung injury.

PURPOSE: Furosemide is often used to reduce edema in patients with acute respiratory distress syndrome (ARDS). It was hypothesized that furosemide would reduce lung water and improve gas exchange in a phorbol-myristate acetate (PMA) model of acute lung injury. METHODS: Two groups of mongrel dogs received PMA (25 to 30 micrograms/kg) and continuous saline at 10 mL/kg/h; one group received PMA plus two 1-mg/kg doses of furosemide at 1 and 2 hours after PMA. Arterial blood gases on F1O2 = 1.0 and double-dilution lung water were measured at intervals over 7 hours. RESULTS: In dogs receiving PMA+furosemide, AaDO2 and shunt fraction increased compared with dogs receiving PMA only (AaDO2, P = .014; shunt, P = .017). There were no significant differences between the groups in lung water (P = .34) during the experiment or in wet/dry weight postmortem. Urine flow was markedly reduced in both groups; the kidneys appeared unresponsive to the diuretic effects of furosemide. Significant elevations in hematocrit and pulmonary vascular resistance were seen in furosemide-treated compared with PMA-only dogs. CONCLUSIONS: In this model of ARDS, which results in the absence of effective kidney function and multiple organ failure, furosemide compromises alveolar-capillary gas exchange and fails to influence the time course of lung water accumulation. The results suggest that the nondiuretic affects of furosemide cannot explain its purported clinical utility in ARDS.

Animals↗

PubMed1996

N-tert-butyl-alpha-phenylnitrone: a free radical trap with unanticipated effects on diaphragm function.

The spin trap N-tert-butyl-alpha-phenylnitrone (PBN) has a high avidity for free radical species and hence functions as an antioxidant in many biological systems. As such, we hypothesized that PBN would have powerful antioxidant effects on muscle function. We examined the effects of PBN on directly stimulated in vitro (37 degrees C) rat diaphragm. First, a dose-response curve for the effects of PBN on force frequency (n = 8) was established by comparing PBN-treated muscle strips (0.01-10 mM) with time- and stimulus-matched control strips. Second, the effect of 1.0 mM PBN on muscle endurance (n = 8) was established. Our findings were as follows. 1) Compared with baseline, peak twitch and low-frequency muscle tensions increased in a dose-dependent fashion, with peak effects at 1.0 mM PBN. 2) Muscle function at all stimulation frequencies was depressed at doses above 1.0 mM PBN. 3) Complete inhibition at 10 mM PBN was reversed with caffeine administration or washout. 4) During early fatigue, 1.0 mM PBN facilitated force. However, endurance time decreased in the PBN-treated group. We conclude that PBN has direct reversible dose-dependent effects on diaphragm function. However, facilitation of low-frequency forces and the lack of fatigue-attenuating properties suggest that PBN has atypical antioxidant effects on muscle function.

Animals↗

PubMed1995

Clinical assessment of the respiratory muscles.

This review examines approaches to evaluation of the respiratory muscles and describes new techniques that may be more quantitative, less effort dependent, and less invasive than conventional methods. To evaluate strength of the respiratory muscles, maximum inspiratory and expiratory pressures remain useful measures. Potential methodologic errors, however, necessitate careful technique. Evaluation of the twitch response to direct phrenic nerve stimulation may ultimately prove more quantitative and less effort dependent than measurements of maximum pressure. Many techniques are also available to measure endurance of respiratory muscles, but most are less than satisfactory outside the research environment because of poor reproducibility and other procedural difficulties. The maximum incremental resistive loading test, however, has proven to be practical and well tolerated. There is little substitute for careful clinical observation of respiratory muscle coordination and movement, particularly in the patient with suspected respiratory muscle weakness or chest wall distortion. In conclusion, though the respiratory muscles are difficult to evaluate, techniques are available that can be quite helpful for assessment, particularly in response to interventions such as rehabilitation.

Diaphragm↗

PubMed1994

Detection of free radicals in blood by electron spin resonance in a model of respiratory failure in the rat.

Previous work has suggested that a free radical mechanism is involved in some types of muscle fatigue and that there can be free radicals released extracellularly. Because muscle fatigue may be an important factor in respiratory failure, the authors tested the hypothesis that increased concentrations of free radicals could be detected in the blood of animals undergoing severe resistive loading to respiratory failure. An ex vivo spin trapping technique with alpha-phenyl-N-tert-butylnitrone (PBN) was used to investigate the possible formation of free radicals in systemic blood samples by electron spin resonance (ESR) spectrometry. After 2.5-3 h of severe inspiratory resistive loading with 70% supplemental inspired oxygen, free radical levels in the form of PBN-adducts were found to rise significantly over the control group breathing room air and the control group breathing 70% oxygen (p < 0.05, N = 8). There were no significant differences between control groups breathing room air and control groups breathing 70% oxygen. This study presents direct evidence that free radicals are produced ex vivo and that they can be detected in the systemic circulation due to excessive resistive loading of the respiratory muscles.

Animals↗

PubMed1994

Loss of diaphragm glutathione is associated with respiratory failure induced by resistive breathing.

It has been suggested that oxidant stress may contribute to dysfunction of respiratory muscles undergoing severe work loads. We examined changes in glutathione content and redox status in the diaphragm and intercostal muscles of anesthetized Sprague-Dawley rats exposed to prolonged inspiratory resistive loading while breathing 70% O2. These results were compared with those from control groups breathing air or 70% O2. Changes in liver glutathione were also examined. Freeze-clamping and an enzymatic recycling assay were used. Results show that 1) in controls, glutathione content was higher in the diaphragm than in the intercostals, 2) severe hypercapnic acidosis without hypoxemia was present with loading, 3) total diaphragm glutathione decreased approximately 35% with no increase in glutathione oxidation with resistive breathing, whereas intercostal and liver glutathione remained unchanged, and 4) the drop in diaphragm glutathione correlated significantly with the drop in minute ventilation and the increase in arterial PCO2, whereas it was not directly related to intensity of respiratory muscle activity. In conclusion, although diaphragm susceptibility to oxidant stress may be increased with resistive breathing, it is unlikely that the modest decrease in total glutathione contributed significantly to respiratory failure in this model.

Airway Resistance↗

PubMed1994

Detection of free radicals by electron spin resonance in rat diaphragm after resistive loading.

Indirect evidence supports free radical production in the diaphragm under excessive mechanical loads in both in vitro and in situ preparations. We hypothesized that free radicals are produced in the diaphragm with loads in vivo at a sufficient concentration to be detected by electron spin resonance (ESR) spectroscopy. Anesthetized rats underwent severe inspiratory resistive loading for 2.5-3 h with maintenance of blood oxygenation and arterial blood pressure by breathing 70% oxygen. The ESR spectra of four samples (freeze-clamped at liquid nitrogen temperature) from each experimental animal were compared with the spectra from a control animal breathing air and a control animal breathing 70% oxygen. We observed 1) an approximately 30% increase in intensity of free radical signal in experimental animals (n = 10) compared with control animals breathing oxygen (n = 10; P < 0.01) and control animals breathing air (n = 10; P < 0.05), 2) that oxygen alone had no effect on the ESR spectrum, and 3) the intensity of the ESR signal decreased approximately 25% in the experimental group when samples were taken 10 min postmortem, whereas no difference in signal was observed for control animals. We conclude that the diaphragm shows an increased production of free radicals associated with respiratory failure induced by resistive breathing.

Animals↗

PubMed1994

Effects of N-acetylcysteine on in vitro diaphragm function are temperature dependent.

Recent evidence has shown that systemic administration of N-acetylcysteine (NAC), a compound structurally similar to the intracellular antioxidant glutathione, inhibits skeletal muscle fatigue. To further elucidate the actions of NAC, we studied its effects on in vitro rat diaphragm contractile function. Rat diaphragm strips were incubated in tissue baths containing physiological salt solution (n = 29) or physiological salt solution containing 4 mg/ml of NAC (n = 29). Strips were stimulated by either indirect or direct means. After determination of baseline contractile characteristics, strips were fatigued for 4 min at 20 Hz (1 train/s, 0.33 ms train duration). Force-frequency relationships were then studied over a 60-min recovery period. We found that 1) NAC had significant effects on the baseline force-frequency relationship; treated strips had increased peak tension but diminished twitch tension and accelerated twitch kinetics; 2) NAC had significant fatigue-sparing effects that were magnified at 37 degrees C; and 3) NAC treatment did not improve postfatigue recovery. The effects of NAC were generally independent of the stimulation method. We conclude that NAC has direct temperature-dependent effects on diaphragm function. These effects are consistent with the properties of NAC as an antioxidant and suggest important but complex effects of oxidant stress on skeletal muscle.

Acetylcysteine↗

PubMed1994

High- vs low-intensity inspiratory muscle interval training in patients with COPD.

This study determined the effect of a high vs low resistive inspiratory muscle interval training protocol on inspiratory muscle strength (PImax), incremental inspiratory threshold loading (Pitl), inspiratory muscle endurance (IE), and 12-minute distance test (12 MD) in severely impaired patients with COPD. We used a double-blind, two-group, repeated-measure design. Group 1 (n = 12) received supervised high resistive loading at approximately 52 percent PImax and group 2 (n = 8) received supervised low resistive loading at approximately 22 percent PImax. All subjects trained three times weekly (progressing from 5 min per session in week 1 to 18 min per session in week 12) for 12 weeks. After three practice sessions, measures of PImax, Pitl, IE, and 12 MD were taken at baseline, at 4-week intervals, and within 72 h of completing the protocol. Group 1 showed significant improvement in all four dependent variables while group 2 improved in Pitl, IE, and 12 MD. The results suggest there is no significant difference between high and low resistive interval training in more severely impaired patients with COPD.

Aged↗

PubMed1993

Hydroxylation of salicylate by the in vitro diaphragm: evidence for hydroxyl radical production during fatigue.

There is increasing evidence that oxygen-derived free radicals produced during strenuous work by the diaphragm may contribute to diaphragm fatigue and/or injury. However, the precise identity of these oxygen radicals remains unknown, inasmuch as oxygen free radicals are extremely short lived and their detection in biologic systems is quite difficult. There is recent evidence that the salicylate-trapping method may be a useful means of monitoring tissue production of hydroxyl radical (.OH). This method is predicated on the fact that salicylate's phenolic ring can be attacked by .OH at the 3 or 5 position to yield 2,3- or 2,5-dihydroxybenzoic acid (DHB). These metabolites are stable and can be identified by high-performance liquid chromatography (HPLC) coupled with electrochemical or ultraviolet detection. To test the hypothesis that hydroxylated salicylates are produced during diaphragm fatigue, we exposed in vitro rat diaphragm strips to a physiological saline solution containing 2.0 mM sodium salicylate for approximately 15 min. The solution was then removed, and the strips were fatigued (20 Hz, 200-ms train duration, 1 train/s) via phrenic nerve stimulation for 30 s-10 min. The diaphragm strips were subsequently homogenized, and the homogenate was analyzed by HPLC coupled with ultraviolet detection. Levels of 2,3-DHB were significantly higher in fatigued than in control nonfatigued strips. There was also a significant correlation between the amount of 2,3-DHB in the fatigued muscle and the accumulated tension-time product developed during fatigue. 2,5-DHB was not consistently identified in control or experimental strips.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Preservation of sustainable inspiratory muscle pressure at increased end-expiratory lung volume.

Previous studies in isolated muscles have shown that decreases in muscle length reduce the loss of force resulting from fatigue in response to repeated maximal stimulations. However, increases in end-expiratory lung volume (EEV), which presumably decrease the length of the inspiratory muscles, appear to make the inspiratory muscles more susceptible to fatigue. To address this paradox, we studied the influence of changes in EEV on inspiratory muscle fatigue resulting from repeated maximal voluntary inspirations for 15 min in normal humans. Tidal volume and breath timing were constant between runs. Fatigue runs were compared with atmospheric, positive or negative pressures applied to the mouth, sufficient to change EEV by approximately +30% or -20% of inspiratory capacity. Although the maximal initial pressure-time product for the inspiratory muscles (PTmus) was reduced by increased EEV, sustainable PTmus was not significantly affected. In contrast, both initial and sustainable pressure-time products for the diaphragm were reduced at elevated EEV. The rate at which the fatigue process developed was also reduced at increased EEV. There were no significant effects of decreased EEV on any measured pressures. We conclude that when EEV is elevated, within a moderate range, sustainable inspiratory muscle pressure is preserved. However, the contribution of the diaphragm to inspiratory pressure development during fatigue may be uniquely compromised by increased EEV.

Adult↗

PubMed1993

Tumor necrosis factor and endotoxin do not directly affect in vitro diaphragm function.

Ventilatory pump failure can occur in the setting of severe infection. Recent in vivo studies have shown a significant decrease in diaphragm force production in rats with pneumococcal sepsis and sepsis secondary to Escherichia coli endotoxin. We hypothesized that diaphragm impairment during sepsis may be mediated by a direct effect of tumor necrosis factor-alpha (TNF) or endotoxin. To test this hypothesis we studied the mechanical characteristics of isolated rat diaphragm strips in tissue baths containing rTNF-alpha or endotoxin and compared the results with control strips. The strips were stimulated to contract isometrically in the tissue baths that were aerated with 95% O2-5% CO2. Baseline force-frequency determinations were made at 60 min. Following this, the strips were fatigued over a 4-min period (20 Hz, 0.33-s trains, 1 train/s) and force-frequency relationships determined 30 s, 10 min, and 60 min post-fatigue. There were no significant differences found between control and experimental strips in any aspect of contractile function tested, including force-frequency characteristics, fatiguability, and recovery from fatigue. Using an isolated cell line assay (L929), we found evidence of attenuated cytotoxicity of TNF at 26 degrees C compared with 37 degrees C. Therefore, we repeated the experiments studying the effects of TNF on in vitro muscle at 37 degrees C. We once again found no effect of TNF on contractile function. We conclude that the impairment of diaphragm function during sepsis is not mediated by a direct effect of TNF or endotoxin.

Animals↗

PubMed1993

Marked pulmonary function abnormalities in a case of HIV-associated pulmonary hypertension.

Recent reports have suggested an association between primary pulmonary hypertension and human immunodeficiency virus (HIV) infection. This appears to be an accelerated syndrome, associated with a relatively brief duration of symptoms, yet prominent right ventricular failure and severe pulmonary hypertension on presentation. We present a case of a primary pulmonary hypertension in a 35-year-old HIV-seropositive hemophiliac. His accelerated clinical course is consistent with previously reported cases of HIV-related pulmonary hypertension. However, this patient's pulmonary function tests revealed marked hyperinflation, a decreased diffusing capacity, and no airflow obstruction. To our knowledge, this very usual constellation of pulmonary function changes has not been described previously in this syndrome.

Adult↗

PubMed1993

Improved pulmonary function and exercise tolerance with inspiratory muscle conditioning in children with cystic fibrosis.

This study documented the effect of inspiratory muscle conditioning in children with cystic fibrosis. Subjects, ages 7 to 14 years, were divided into two groups. The experimental group (n = 10) trained at a high pressure load (> or = 29 cm H2O) and the control group (n = 10) trained at a minimal pressure load (< or = 15 cm H2O), using a threshold loading device. Subjects trained 30 min a day for 10 weeks. Pulmonary function, inspiratory muscle strength, and exercise tolerance were measured at the beginning and end of the training period. Pulmonary function was measured by body plethysmography. Inspiratory muscle strength was determined by standard measures of maximal inspiratory pressure against an occluded airway. Exercise tolerance was measured by the length of time subjects could walk on a treadmill. Findings indicated that the experimental group showed significant increases in inspiratory muscle strength, vital capacity, total lung capacity, and exercise tolerance in comparison to the control group.

Adolescent↗

PubMed1992

Emphysema-like pulmonary disease associated with human immunodeficiency virus infection.

OBJECTIVE: To describe a possible association between prolonged infection with human immunodeficiency virus (HIV) and a pathophysiologic process suggestive of pulmonary emphysema. DESIGN: Case series. SETTING: The Ohio State University Hospital, Columbus, Ohio. MEASUREMENTS AND MAIN RESULTS: We describe four HIV-seropositive individuals ranging in age from 32 to 55 years who presented with dyspnea. Radiographic examination of the chest showed no infiltrates. All patients were presumed to have had prolonged HIV infection (mean CD4 count, 99.8 +/- 43 cells/mm3), but none had a previous history of pneumonia or opportunistic infections. Comprehensive examination of bronchoalveolar lavage fluid showed no pathogens or other complications of HIV infection. All patients had markedly abnormal pulmonary function tests that were suggestive of emphysema with air-trapping, hyperinflation, and a markedly decreased diffusing capacity. However, only minimal evidence of airflow obstruction was noted. Three patients subsequently had high-resolution computed tomographic scans of the chest that revealed emphysema-like bullous changes. Known causes of emphysema were not present in these patients. CONCLUSIONS: Our findings support an association between prolonged HIV infection and an emphysema-like process. This syndrome may occur in the absence of previous pulmonary infections or apparent pulmonary complications and is characterized by unusual pulmonary function test abnormalities.

Adult↗

PubMed1992

Kinetics of CO uptake and diffusing capacity in transition from rest to steady-state exercise.

In the transition from rest to steady-state exercise, O2 uptake from the lungs (VO2) depends on the product of pulmonary blood flow and pulmonary arteriovenous O2 content difference. The kinetics of pulmonary blood flow are believed to be somewhat faster than changes in pulmonary arteriovenous O2 content difference. We hypothesized that during CO breathing, the kinetics of CO uptake (VCO) and diffusing capacity for CO (DLCO) should be faster than VO2 because changes in pulmonary arteriovenous CO content difference should be relatively small. Six subjects went abruptly from rest to constant exercise (inspired CO fraction = 0.0005) at 40, 60, and 80% of their peak VO2, measured with an incremental test (VO2peak). At all exercise levels, DLCO and VCO rose faster than VO2 (P less than 0.001), and DLCO rose faster than VCO (P less than 0.001). For example, at 40% VO2peak, the time constant (tau) for DLCO in phase 2 was 19 +/- 5 (SD), 24 +/- 5 s for VCO, and 33 +/- 5 s for VO2. Both VCO and DLCO increased with exercise intensity but to a lesser degree than VO2 at all exercise intensities (P less than 0.001). In addition, no significant rise in DLCO was observed between 60 and 80% VO2peak. We conclude that the kinetics of VCO and DLCO are faster than VO2, suggesting that VCO and DLCO kinetics reflect, to a greater extent, changes in pulmonary blood flow and thus recruitment of alveolar-capillary surface area. However, other factors, such as the time course of ventilation, may also be involved.(ABSTRACT TRUNCATED AT 250 WORDS)

Carbon Monoxide↗

PubMed1991

Muscle shortening increases sensitivity of fatigue to severe hypoxia in canine diaphragm.

The effects of inspired O2 on diaphragm tension development during fatigue were assessed using isovelocity (n = 6) and isometric (n = 6) muscle contractions performed during a series of exposures to moderate hypoxia [fraction of inspired O2 (FIO2) = 0.13], hyperoxia (FIO2 = 1), and severe hypoxia (FIO2 = 0.09). Muscle strips were created in situ from the canine diaphragm, attached to a linear ergometer, and electrically stimulated (30 Hz) to contract (contraction = 1.5 s/relaxation = 2 s) from optimal muscle length (Lo = 8.9 cm). Isovelocity contractions shortened to 0.70 Lo, resulting in a mean power output of 210 mW/cm2. Fatigue trials of 35 min duration were performed while inspired O2 was sequentially changed between the experimental mixtures and normoxia (FIO2 = 0.21) for 5-min periods. In this series, severe hypoxia consistently decreased isovelocity tension development by an average of 0.1 kg/cm2 (P less than 0.05), which was followed by a recovery of tension (P less than 0.05) on return to normoxia. These responses were not consistently observed in isometric trials. Neither isovelocity nor isometric tension development was influenced by moderate hypoxia or hyperoxia. These results demonstrate that the in situ diaphragm is relatively insensitive to rapid changes in O2 supply over a broad range and that the tension development of the shortening diaphragm appears to be more susceptible to severe hypoxia during fatigue. This may reflect a difference in either the metabolic or blood flow characteristics of shortening contractions of the diaphragm.

Animals↗

PubMed1990

Increased fatigue of isovelocity vs. isometric contractions of canine diaphragm.

A comparison of fatigue as a loss of force with repeated contractions over time was performed in canine respiratory muscle by isometric (nonshortening) and isovelocity (shortening) contractions. In situ diaphragm muscle strips were attached to a linear ergometer and electrically stimulated (30 or 40 Hz) via the left phrenic nerve to produce either isometric (n = 12) or isovelocity (n = 12) contractions (1.5 s) from optimal muscle length (Lo = 8.8 cm). Similar velocities of shortening between isovelocity experiments [0.19 +/- 0.02 (SD) Lo/S] were produced by maximizing the mean power output (Wmax = 210 +/- 27 mW/cm2) that could be developed over 1.5 s when displacement was approximately 0.30 Lo. Initial peak isometric tension was 1.98 kg/cm2, whereas initial peak isovelocity tension was 1.84 kg/mc2 (P less than 0.01) or 93% of initial isometric tension. Fatigue trials of 5 min were conducted on muscles contracting at a constant duty cycle (0.43). At the end of the trials, peak isovelocity tension had fallen to 50% of initial isometric tension (P less than 0.01), whereas peak isometric tension had only fallen by 27%. These results indicate that muscle shortening during force production has a significant influence on diaphragm muscle fatigue. We conclude that the effects of shortening on fatigue must be considered in models of respiratory muscle function, because these muscles typically shorten during breathing.

Animals↗

PubMed1990

Sustainable inspiratory pressures over varying flows, volumes, and duty cycles.

This study identifies the influence of flow (0.5-2.0 l/s), duty cycle (0.29-0.57), and tidal volume (1.08-2.16 liters) on sustainable inspiratory muscle pressure (Pmus) and transdiaphragmatic pressure (Pdi) development. Six normal humans performed endurance tests using an isoflow method, which allowed for measurements of maximum dynamic Pmus and Pdi, with controlled lung inflation. The subjects repeated maximum dynamic voluntary inspirations for 10 min. Pressures dropped exponentially from initial measurements at rest (Pmusi or Pdi) to sustainable values (Pmus or Pdis). As flow and tidal volume increased, maximum initial and sustainable pressures decreased significantly. However, at a constant duty cycle, the sustainable dynamic pressures remained predictable fractions of initial dynamic pressures (i.e., Pmuss/Pmusi or Pdis/Pdii), regardless of changes in flow and tidal volume. In contrast, as duty cycle increased, the sustainable fractions significantly decreased for both Pdi and Pmus. For example, at a duty cycle of 0.29, Pmuss/Pmusi was approximately 0.71, and at a duty cycle of 0.57, Pmuss/Pmusi was approximately 0.62. Calculated sustainable pressure-time indexes varied significantly between 0.16 to 0.32 for Pmus and 0.11 to 0.22 for Pdi over the breathing patterns studied. We conclude that 1) the maximum dynamic pressure that can be sustained at a given duty cycle is a predictable fraction of the maximum dynamic pressure that can be generated at rest when measured under the same conditions of inspiration and 2) the sustainable fraction of initial dynamic pressure significantly decreases with increasing duty cycle.

Abdomen↗