Abnormalities of sodium and H2O handling in chronic obstructive lung disease.

The pathogenesis of edema and hyponatremia in chronic obstructive lung disease (COLD), is poorly understood. Previously, in nonedematous patients with hypercapnia, small increases in plasma renin activity occurred, which prompted this study. In 25 hypercapnic, edematous, often hyponatremic patients with COLD, we measured renal hemodynamics, H2O, and sodium (Na+) excretion, plasma levels of renin activity (PRA), plasma levels of aldosterone (PA), and the plasma arginine vasopressin (AVP)-osmolality relationship. A high prevalence of elevated PRA, PA, and AVP levels excessively high for plasma osmolality was observed. Elevated PRA and Pa correlated with the inability to excrete Na+; an elevated AVP level correlated with the inability to excrete H2). These data suggest that, in conjunction with the hypercapnia-hypoxia-mediated disturbance in renal function, stimulation of the renin-aldosterone level and of the AVP systems contributes, respectively, to edema formation and to hyponatremia in advanced COLD.

Ethylene oxide neurotoxicity: a cluster of 12 nurses with peripheral and central nervous system toxicity.

Ethylene oxide (EO) is commonly used to sterilize heat-sensitive products used by hospital patients and personnel. Ethylene chlorohydrin (EC), a by-product, is considered highly toxic. We report a cluster of 12 operating-room nurses and technicians who developed symptoms after a 5-month exposure to high levels of EO and EC in disposable surgical gowns. All patients reported a rash on the wrist where contact was made with the gowns, headaches, and hand numbness with weakness. Ten of 12 patients complained of memory loss. Neurologic evaluation revealed neuropathy on examination in nine of the 12 patients, elevated vibration threshold in four of nine, abnormal pressure threshold in 10 of 11, atrophy on head MRI in three of 10, and neuropathy on conduction studies in four of 10. Neuropsychological testing demonstrated mild cognitive impairment in four of six patients. Sural nerve biopsy in the most severely affected patient showed findings of axonal injury. Several patients in this group display signs of peripheral and CNS dysfunction following exposure to EO. Possible mechanisms of neurotoxicity include direct exposure of peripheral nerves through cutaneous absorption and central involvement through inhalation and vascular dissemination. The frequency of central and peripheral nervous system symptoms, supported by objective testing in these EO-exposed patients, suggests other healthcare personnel may be at similar risk.

Effect of hypoxemia on sodium and water excretion in chronic obstructive lung disease.

To determine the role of hypoxemia in the pathogenesis of impaired sodium and water excretion in advanced chronic obstructive lung disease, 11 clinically stable, hypercapneic patients requiring long-term supplemental oxygen were studied. The renal, hormonal, and cardiovascular responses to sodium and water loading were determined during five-and-a-half-hour studies on a control day (arterial oxygen tension = 80 +/- 6 mm Hg) and on an experimental day under hypoxic conditions (arterial oxygen tension = 39 +/- 2 mm Hg). Hypoxemia produced a significant decrease in urinary sodium excretion but did not affect urinary water excretion. Hypoxemia also resulted in concomitant declines in mean blood pressure, glomerular filtration rate, and filtered sodium load. Renal plasma flow and filtration fraction were unchanged whereas cardiac index rose. On the control day, plasma renin activity and norepinephrine levels were elevated whereas aldosterone and arginine vasopressin levels were normal; none of these four hormones was affected by hypoxemia. Renal tubular function did not appear to be altered by hypoxemia as there was no significant change in fractional reabsorption of sodium. The concurrent decreases in glomerular filtration rate, filtered sodium load, and mean blood pressure at constant renal plasma flow suggest that the reduction in urinary sodium excretion was due to an effect of hypoxemia on glomerular function, possibly related to impaired renovascular autoregulation.

A comparison of two challenge tests for identifying exercise-induced bronchospasm in figure skaters.

OBJECTIVES: Studies documenting the increased incidence of exercise-induced bronchospasm (EIB) in figure skaters have employed a method that incorporates on-ice exercise with rink-side spirometry. The literature suggests that bronchial provocation challenge testing is better than exercise testing for identifying EIB. To test this hypothesis in figure skaters, a unique athletic population that trains and competes in cold air, we compared these two methods in the same individuals. PATIENTS/METHODS: Two challenge tests were performed on a group of competitive figure skaters (n = 29, 26 female subjects; mean+/-SD age = 12.3+/-3.5 years): (1) rink-side (temperature = 14 degrees C, humidity = 60%) spirometry before and 1, 5, 10, and 15 min after 5 min of intense skating; and (2) eucapnic voluntary hyperventilation (EVH), breathing 5% CO2, 21% O2, balance N2 at a rate of 60% of maximum voluntary ventilation (not to exceed 70 L/min) for 5 min (temperature = 18 degrees C, humidity = 50%), with an identical pretest and posttest spirometry schedule. EIB was defined as at least one of the following: a > or =10% decline in Fev1; a > or = 20% decline in maximum midexpiratory flow rate; or a > or = 25% decline in peak expiratory flow rate. RESULTS: Sixteen of 29 skaters (55%) developed EIB: 9 were positive by on-ice testing; 12 were positive by EVH testing; 5 were positive on both tests; on-ice testing missed 7 skaters with EIB; EVH testing missed 4 with EIB. CONCLUSION: In the group of figure skaters studied, EVH challenge testing was better at identifying EIB than on-ice exercise testing. However, these data suggest that evaluation for EIB in athletes who train and compete in the cold should include exercise testing in cold air along with a challenge test such as EVH to increase the yield of positive responders.

Elevated O2 cost of ventilation contributes to tissue wasting in COPD.

BACKGROUND AND OBJECTIVES: Thirty to 50% of all COPD patients experience tissue wasting that may be caused by hypermetabolism, but the cause of the perturbed metabolic state is unclear. We hypothesized that the elevated O2 cost of ventilation (O2 COV) may be a contributing factor. All of the data are presented as means (+/-SEM). Ten hypoxemic (a PaO2 of 54+/-3 mm Hg) stable COPD patients (an FEV1/FVC ratio of 42+/-4%) and five healthy control subjects were studied. The patients were divided into two groups based on nutritional status. Group 1 (n = 6) was malnourished (a body mass index [BMI] of 17.6+/-0.7 kg/m2), and group 2 (n = 4) was normally nourished (a BMI of 26.0+/-3 kg/m2). The O2 COV was determined by measuring the change in the oxygen consumption (VO2) and the minute ventilation (VE) caused by CO2-induced hyperventilation. RESULTS AND CONCLUSIONS: Group 1 had an elevated O2 COV when compared to group 2 and the control group, respectively: 16.4+/-1.0 vs 9.7+/-1.0 and 2.4+/-0.2 mL O2/L of VE (p < 0.05). The VO2 at rest was higher for group 1 than for group 2 and the control group, respectively: 4.5+/-0.3 vs 3.1+/-0.5 and 3.4+/-0.2 mL/kg/min (p < 0.05). The resting energy expenditure (REE) % predicted for group 1 was also higher than group 2 and the control group, respectively: 125+/-3% vs 87+/-7% and 97+/-2% (p < 0.05). Significant correlations were observed that implicate the increased O2 COV as a cause of tissue wasting: O2 COV vs BMI (r = -0.79; p = 0.007), O2 COV vs REE % predicted (r = 0.66; p = 0.039), and REE % predicted vs BMI (r = -0.83; p = 0.003). The O2 COV was also correlated with lung function: FEV1/FVC vs O2 COV (r = -0.84; p = 0.002). We conclude that in these COPD patients the O2 COV is associated with an increased metabolic rate which, in turn adversely affects the nutritional status.

Effects of fenoterol on oxygen transport in patients with chronic airflow obstruction.

A rise in cardiac output and a fall in arterial oxygen tension are well known side effects of bronchodilator drugs, particularly beta-adrenergic agonists. In recent years, fenoterol (Berotec), an effective beta-adrenergic agonist, has been used at increasing rates in asthmatic subjects, as well as in patients with chronic obstructive pulmonary disease (COPD). The effects of fenoterol on systemic hemodynamics or arterial oxygenation (or both) in patients with COPD have not been investigated; in these individuals, who often have increased sympathetic tone and hypoxemia even at rest, cardiovascular stimulation and a fall in arterial oxygen tension would be particularly undesirable side effects. In 14 patients with COPD (seven without a reversible component of airflow obstruction [group 1]; and seven with a reversible component of airflow obstruction [group 2]), we studied all of the important parameters of oxygen transport before and 60 minutes after administration of fenoterol. Studies were performed at rest and after exercise. At baseline, group 1 showed a faster heart rate, a lower cardiac output, a lower arterial oxygen flow, a wider arteriovenous oxygen content difference (C[a-v]O2), and a higher fraction of oxygen extracted by the tissues from a given arterial oxygen flow. In both groups, all measured parameters, including cardiac output and arterial oxygen pressure (PaO2) remained statistically unchanged one hour after administration of fenoterol; with exercise, the heart rate, blood pressure, minute ventilation, oxygen consumption, C(a-v)O2, and the percentage of oxygen extracted from arterial oxygen flow, as well as cardiac output and PaO2, increased in all instances; the exercise responses were not affected by the drug. These results suggest that at the time of its maximal effect on the airways (60 minutes), fenoterol has no untoward effect on the oxygen transport system, at rest or during exercise, in patients with COPD with or without a reversible component.

Steroids, hypoxemia, and oxygen transport.

This study investigated the effects of administration of methylprednisolone on oxygen transport in ten stable hypoxemic (mean arterial oxygen pressure, 54 +/- 3 mm Hg) patients with chronic obstructive pulmonary disease (COPD). At 24 hours (after four injections of a bolus of 30 mg of methylprednisolone sodium succinate per kilogram of body weight, given intravenously every six hours), significant differences (P less than 0.05) were an increased cardiac index (3.0 +/- 0.2 to 4.1 +/- 0.2 L/min/sq m), a decreased peripheral vascular resistance (1,186 +/- 100 to 849 +/- 60 dynes/sec/cm-5), an increased flow of oxygen to tissue (0.90 +/- 0.07 to 1.16 +/- 0.09 L/min), a decreased arteriovenous oxygen content difference (49 +/- 3 to 43 +/- 2 ml/L), a decreased concentration of hydrogen ions in the arterial blood (38 +/- 1 to 35 +/- 1 nmol/L) and arterial carbon dioxide tension (39 +/- 2 to 32 +/- 1 mm Hg), and increased levels of lactate (1.1 +/- 0.2 to 3.7 +/- 1.0 mmol/L) and pyruvate (0.14 +/- 0.04 to 0.37 +/- 0.08 mmol/L). Fractional oxygen utilization, oxygen consumption, the partial pressure of oxygen at which hemoglobin was 50 percent saturated, and the level of 2,3-diphosphoglyceric acid remained unchanged. In vitro studies showed that these patients' red blood cells responded with a significant (more than 35 percent) increase in the level of 2.3-diphosphoglyceric acid when incubated for ten hours with concentrations of methylprednisolone that were much higher (1.0 mg/ml) than those attained in vivo (12.5 microgram/ml). These studies demonstrate that repeated infusions of high doses of steroids in a bolus in stable hypoxemic patients with COPD produce significant physiologic changes but no apparent net gain in the oxygenation of tissues.

Exercise-induced asthma in figure skaters.

Many highly trained athletes experience exercise-induced bronchospasm (EIB): studies describing EIB in figure skaters, who may be at increased risk of EIB due to rink temperatures (7 to 10 degrees C), have not been published. We studied professionally coached figure skaters (n = 124) for EIB by spirometry at rinkside immediately before a simulated long program and at 0 to 1, 5, 10, and 15 min postexercise. Postexercise spirometry revealed the presence of EIB (a decrease from baseline in FEV1 of at least 10%) in 43 skaters, while the remainder (n = 81, control group) remained relatively stable. Pre-exercise FEV1, FVC, and FEV1/FVC ratio were not different between groups. The EIB group had significantly lower FEV1 vs baseline at each measurement following exercise: baseline, 3.08 +/- 0.13; 0 to 1 min postexercise, 2.81 +/- 0.13 (p < 0.05); 5 min postexercise, 2.77 +/- 0.14 (p < 0.05); 10 min postexercise, 2.78 +/- 0.13 (p < 0.05); 15 min postexercise, 2.78 +/- 0.13 (p < 0.05). The EIB group also had lower FVC: baseline, 3.48 +/- 0.16; 0 to 1 min postexercise, 3.16 +/- 0.15 (p < 0.05); 5 min postexercise, 3.19 +/- 0.15 (p < 0.05); 10 min postexercise, 3.27 +/- 0.16 (p < 0.05); 15 min postexercise, 3.26 +/- 0.16 (p < 0.05). Control subjects, however, experienced no decline in these variables. In conclusion, the incidence of EIB in the figure skaters measured during this investigation (43 of 124 = 35%) is greater than that of the population at large and other highly trained athletes, signifying that screening for EIB and therapeutic follow-up are reasonable considerations for participants in this sport.

Pharmacologic elevation of blood inorganic phosphate in hypoxemic patients with COPD.

We have shown that in patients with COPD, myocardial efficiency during exercise is enhanced following acute elevations of plasma phosphate (Pi). A decrease in Hb-O2 affinity (increase in P50) was not responsible for the improvement. We postulated that the physiologic benefit was due to the acute reversal of a subclinical myocardial Pi depletion. To further test this hypothesis in a chronic state, we studied nine stable hypoxemic (PaO2 = 64 +/- 2 mm Hg [+/- SEM]) patients with COPD over five weeks: two weeks at normal plasma Pi; and three weeks at elevated plasma Pi, induced by etidronate disodium (Didronel; 750 mg orally daily). Administration of etidronate disodium increased (p less than 0.05) plasma level of Pi (4.4 +/- 0.2 to 5.8 +/- 0.1 mg/dl), RBC level of Pi (3.1 +/- 0.2 to 4.1 +/- 0.2 mg/dl), RBC level of 2,3-DPG (16.2 +/- 1.1 to 21.3 g+/- 1.3 mumol/g of Hb) and P50 (23.7 +/- 0.5 to 26.0 +/- 0.8 mm Hg). At the end of the treatment, the widening of the C(a-v)O2 with exercise (7.1 +/- 0.8 to 8.9 +/- 0.6 ml/dl) was less pronounced than under control conditions (6.9 +/- 0.4 to 10.1 +/- 0.6 ml/dl; p less than 0.02); concomitantly, the crossover point (COP; the PaO2 below which a rightward-shifted Hb-O2 curve causes the C(a-v)O2 to become narrower rather than wider) increased (37 +/- 2 to 49 +/- 1 mm Hg). Indicators of myocardial work efficiency were not affected by etidronate disodium at rest or during exercise. We postulate that during exercise the potential beneficial effect of the rightward shift of the Hb-O2 curve upon cardiac function was negated by the fall of PaO2 to or below the COP level, a situation which would limit increases in tissue O2 extraction.

The effect of oxygen with exercise on atrial natriuretic peptide in chronic obstructive lung disease.

A recent study on stable, hypoxemic, COLD patients in which ANP was stimulated by LBPP demonstrated that in these individuals elevation of ANP does not exert a "normal" suppressing effect on the PRA-PA axis. Accordingly, we exercised ten comparable COLD patients, another maneuver known to stimulate ANP and to elicit cardiorespiratory responses substantially different from those observed with LBPP. Patients were studied breathing room air and on 40 percent O2 to determine whether the level of oxygenation would modify ANP secretion. Basal levels of ANP on room air were markedly elevated above controls (269 +/- 65 SE vs 70 +/- 20 pg/ml, p less than 0.05); PRA (13.0 +/- 5.4 ng/ml/90 min) and PA (8.6 +/- 3.5 ng/100 ml) were elevated (greater than 2 SD over control levels of 8.1 +/- 1.3 and 2.6 +/- 0.7) in 6/10 and 2/10 patients, respectively. During exercise while breathing O2, only ANP increased; PRA and PA remained unchanged when breathing air and O2. Comprehensive statistical analyses failed to demonstrate a negative relationship between ANP and PRA or ANP and PA. We conclude that in patients with advanced COLD, ANP response to moderate exercise is significantly affected by correction of hypoxemia. This effect may be mediated through changes in airway resistance and consequently cardiac filling pressure.

Oxygen may lower the O2 cost of ventilation in chronic obstructive lung disease.

It is known that the O2 COV in COLD is high; O2 administration to these patients lowers airway resistance, a major determinant of the COV. Thus, O2 should lower the COV. We measured the COV in ten stable COLD patients and five normal control subjects breathing room air and 30 percent O2. Results indicate that the COV of our patients was elevated above that of control subjects, was related to disease severity, and was decreased with 30 percent O2. The COV of control subjects also was lowered by O2. At rest, O2 lowered VE, VEQ O2 and HR. During submaximal exercise O2 lowered VE, reduced VEQ O2 and extended total exercise time. An inverse correlation was noted between COV and maximal O2 uptake. Thus, in stable COLD, the COV is elevated in proportion to the degree of airway obstruction, inversely related to exercise capacity and lowered by O2 administration.

Computed tomography vs standard radiology in the evaluation of mediastinal adenopathy.

The value of computed tomography (CT) compared with standard radiology (SR) in the evaluation of mediastinal nodes has not been clearly defined. We compared SR and CT findings with the surgical-pathologic observations in a prospective study of 51 mediastinal nodes in 59 patients, 41 with bronchogenic carcinoma and 18 with benign lung lesions. CT was characterized by a low overall accuracy (true positivity plus true negativity = 60 percent) due to the false positivity (6 percent) and, to a much greater extent, the false negativity (51 percent). The pattern was the same in the malignant and in the benign group. In all instances CT findings were statistically the same as SR findings. We conclude that mediastinal CT provides no advantage over SR. Thus, SR alone is sufficient to select the surgical procedure of choice for evaluating mediastinal nodes, and no radiologic modality should replace surgical exploration in staging mediastinal nodal pathology.

The effect of oxygen on sodium excretion in hypoxemic patients with chronic obstructive lung disease.

In advanced chronic obstructive lung disease (COLD), sodium retention is common, associated with reduction in renal plasma flow (RPF) and stimulation of the renin-aldosterone (PRA-PA) system, two abnormalities due to or influenced by hypercapnia: the independent role of hypoxemia in perturbing sodium homeostasis is unknown. In five stable patients with COLD (FEV1 = 0.9 +/- 0.21, mean +/- SE) with mild edema, during two weeks of a low sodium diet (one week on room air: pH = 7.39 +/- 0.02; PaO2 = 55 +/- 4 mm Hg; PaCO2 = 49 +/- 4 mm Hg; and one week on O2: pH = 7.38 +/- 0.01; PaO2 = 72 +/- 6 mm Hg; PaCO2 = 52 +/- 4 mm Hg) we monitored sodium balance, systemic and renal hemodynamics, plasma sodium and potassium, PRA, PA, and atrial natriuretic hormone (ANH). During air breathing, patients uniformly showed a depression of RPF despite normal cardiac output; plasma hormone levels did not differ from controls but there was elevation (greater than 2 SD above the normal mean) of PRA in four patients, PA in two patients, and ANH in two of five patients. During O2 breathing, urinary sodium increased significantly from 67 +/- 7 to 102 +/- 10 mEq/24 h. Surprisingly, the patients experienced a small but significant weight gain (0.6 +/- 0.1 kg). None of the other variables was affected by O2 therapy. The following conclusions were reached: in advanced COLD, correction of hypoxemia results in sodium diuresis, indicating that hypoxemia (in the presence of hypercapnia) contributes to sodium retention. The mechanism for this beneficial effect of O2 will require further investigation.

Hormonal abnormalities affecting sodium and water balance in acute respiratory failure due to chronic obstructive lung disease.

The pathogenesis of edema and hyponatremia associated with chronic obstructive lung disease (COLD) is poorly understood. In ten edematous COLD patients with acute respiratory failure (ARF), we monitored plasma renin activity (PRA), aldosterone (PA), and antidiuretic hormone (arginine vasopressin, AVP) for six days. Six patients receiving supplemental oxygen and antibiotics had near normal PRA, PA, and AVP, and diuresed Na+ and H2O and lost weight; only one patient was hyponatremic (PNa+ less than 130 mEq/L). On the same therapy, nonresponders (n = 4), with persistently elevated PRA, PA, and AVP, demonstrated no loss of Na+, H2O, or weight; three patients were hyponatremic. The PRA and PA correlated inversely with sodium loss; AVP correlated inversely with free water clearance. These studies suggest that in patients with COLD, edema, and ARF (1) lack of sodium diuresis may be contributed to by secondary hyperaldosteronism; and (2) hyponatremia can be explained by inappropriately elevated plasma AVP.

Modulation of ATP production by oxygen in obstructive lung disease as assessed by 31P-MRS.

Inadequate O2 supply may impair intramuscular oxidative metabolism and O2 availability may modulate ATP production within exercising muscle. Therefore, we studied ATP flux from anaerobic glycolysis, the creatine kinase reaction, and oxidative phosphorylation using 31P-magnetic resonance spectroscopy kinetic data collected during exercise. We examined six chronic obstructive pulmonary disease (COPD) patients with severe hypoxemia (group 1), seven COPD patients with mild hypoxemia (group 2), and seven healthy control subjects. Exercise (90-s isometric contraction of the gastrocnemius-soleus muscle group, 40% of max) was performed on room air for all subjects; for COPD patients, it was repeated during supplemental O2 at identical power outputs, with 60-min rest between the two sets. In group 1 (air vs. O2), oxidative phosphorylation ATP production was lower (P < 0.05), anaerobic glycolysis ATP production was higher (P < 0.05), and anaerobic glycolysis plus creatine kinase ATP production tended to be higher (P = 0.06). In group 2, no differences were observed across conditions. Assuming that mitochondrial size, density, function, and redox state were not affected by acute changes in the inspired O2 fraction, reduced O2 availability is the remaining factor that could have limited oxidative ATP production during hypoxemia. In conclusion, in severely hypoxemic COPD patients, O2 availability apparently limits intramuscular oxidative metabolism because acute hypoxemia increases anaerobic and decreases aerobic ATP production.

Oxygen effect on O2 deficit and VO2 kinetics during exercise in obstructive pulmonary disease.

We evaluated the effect of supplemental O2 on energy metabolism of hypoxemic humans by measuring O2 uptake (VO2) kinetics and other cardiorespiratory parameters in nine male chronic obstructive pulmonary disease (COPD) patients and seven age-matched control subjects (on air and on 30% O2) at rest and during moderate cycle ergometer exercise. Heart rate, ventilation, VO2, CO2 output, respiratory exchange ratio, O2 cost of work, and work efficiency were measured with a computerized metabolic cart; O2 deficit and VO2 time courses were calculated. In COPD patients, 30% O2 breathing resulted in 1) reduction of O2 deficit (from 488 +/- 34 ml in air to 398 +/- 27 ml in O2; P < 0.05) and phase 2 VO2 time constant (from 116 +/- 13 s in air to 74 +/- 12 s in O2; P < 0.05); 2) a smaller steady-state increment in CO2 output than in room air (315 +/- 17 ml/min in O2 vs. 358 +/- 27 ml/min in air; P < 0.02), which resulted in a lower exercise respiratory exchange ratio (0.75 +/- 0.02 in O2 vs. 0.80 +/- 0.02 in air; P < 0.02); and 3) reduced steady-state ventilation (22.6 +/- 1.0 l/min in O2 vs. 25.4 +/- 1.1 l/min in air; P < 0.05). In conclusion, 30% O2 breathing accelerated exercise VO2 kinetics in mildly hypoxemic COPD patients. The observed VO2 kinetics improvement with O2 supplementation is consistent with an enhancement of aerobic metabolism in skeletal muscles during moderate exercise.

Phosphate supplementation, cardiovascular function, and exercise performance in humans.

The use of oral phosphate (Pi) supplements to improve muscular work performance has long been proposed without substantiating data. In a double-blind, crossover experiment 11 male runners ingested calcium Pi (176 mmol/day) or placebo for 4 days. On the 3rd treatment day, subjects ran an incremental maximal aerobic capacity test (VO2 max) on a treadmill, and on the 4th day a treadmill run to exhaustion at approximately 70% VO2max. By the 4th day of Pi loading, plasma Pi was significantly higher than control (P less than 0.05); however, erythrocyte Pi, 2,3-diphosphoglycerate, and O2 half-saturation pressure of hemoglobin (P50) were not elevated. VO2 max was not changed by the treatments (mean 62.9, 64.2, 64.9 ml.kg-1.min-1 for control, Pi, and placebo bouts, respectively) nor was submaximal run time to exhaustion (61.6 min for Pi, 65.5 min for placebo). Stroke volume at steady-state VO2 was decreased with Pi (P less than 0.05), whereas cardiac output tended (P = 0.07) to be lower. Greater arteriovenous O2 difference (P less than 0.05) with Pi suggested a peripheral effect that increased O2 extraction. We concluded that in healthy individuals Pi loading produced no improvement in work tolerance or aerobic capacity but did alter some aspects of cardiovascular function.

Regulation of atrial natriuretic peptide release in normal humans.

Atrial volume, pressure, and heart rate are considered the most important modulators of atrial natriuretic peptide (ANP) release, although their relative role is unknown. Continuous positive-pressure breathing in normal humans may cause atrial pressure and atrial volume to go in opposite directions (increase and decrease, respectively). We utilized this maneuver to differentially manipulate atrial volume and atrial pressure and evaluate the effect on ANP release. Effective filling pressure (atrial pressure minus pericardial pressure) was also monitored, because this variable has been proposed as another modulator of ANP secretion. We measured right atrial (RA) pressure, RA area, esophageal pressure (reflection of pericardial pressure), and RA and peripheral venous ANP in seven healthy adult males at rest and during continuous positive-pressure breathing (19 mmHg for 15 min). Continuous positive-pressure breathing decreased RA area (mean +/- SE, *P less than 0.05) 13.6 +/- 1.1 to 10.5 +/- 0.8* cm2, increased RA pressure 4 +/- 1 to 16 +/- 1* mmHg, increased esophageal pressure 2 +/- 1 to 12 +/- 1* mmHg, and increased effective filling pressure 2 +/- 0 to 4 +/- 1* mmHg. RA ANP increased from 67 +/- 17 to 91 +/- 18* pmol/l and peripheral venous ANP from 43 +/- 4 to 58 +/- 6* pmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic basis for inspiratory muscle fatigue in normal humans.

Inspiratory muscle fatigue, a common event in patients in the intensive care unit, is under multifactorial control. To test the hypothesis that systemic oxygenation is a factor in this event, we subjected five healthy males (age 42 +/- 3 yr) to continuous inspiratory pressure (75% of maximal inspiratory pressure, -95 +/- 5 cmH2O) with the use of a controlled breathing pattern while they breathed normoxic (21% O2), hyperoxic (30% O2), and hypoxic (13% O2) mixtures. Inspiratory muscle endurance (IME; time that pressure could be maintained) and other cardiorespiratory parameters were monitored. Room air IME (3.3 +/- 0.4 min) was shortened (P < 0.05) during 13% O2 breathing (1.6 +/- 0.4 min) but was unaffected during 30% O2 breathing (4.0 +/- 0.6 min). Inspiratory loading lowered the respiratory exchange ratio (RER) during the 21 and 30% O2 trials (1.02 +/- 0.01 to 0.80 +/- 0.03% and 1.05 +/- 0.05 to 0.69 +/- 0.01%, respectively) but not during the 13% O2 trials (1.03 +/- 0.03 to 1.06 +/- 0.07%). At the point of fatigue during the 13% O2 trials, RER was lower compared with the same time point during the 21 and 30% O2 trials. A significant relationship was observed between IME and RER (r = -0.73, P = 0.002) but not between IME and any of the other measured variables. We conclude that 1) hypoxemia impairs the ability of the inspiratory muscles to sustain a mechanical challenge and 2) substrate utilization of the respiratory muscles shifts toward a greater reliance on lipid metabolism when O2 is readily available; this shift was not observed when the O2 supply was reduced.

Oxygen affinity of hemoglobin and peripheral nerve degeneration in experimental diabetes.

Peripheral neuropathy remains a major complication of diabetes. Numerous etiological theories of metabolic and/or vascular disturbances have been suggested including decreased endoneurial oxygen tension with presumed tissue hypoxia. Increases in the affinity of hemoglobin for oxygen (Hb-O2 affinity) may also produce tissue hypoxia and such Hb-O2 affinity changes have been implicated in the pathogenesis of diabetic microangiopathy. In order to test whether affinity hypoxia might contribute to the development of diabetic peripheral neuropathy, we have utilized a rat model of high and normal Hb-O2 affinity produced by backcrossing animals with increased and decreased levels of 2,3-diphosphoglycerate (DPG). Diabetes was induced in ten high and ten low DPG animals with a tail vein injection of 55 mg/kg streptozotocin (STZ). Five animals in each group were treated with 2.4 U protamine zinc insulin (PZI)/day while the remaining animals were untreated. All rats were killed after 30 days, sections of tibial and sural nerve were rapidly removed and processed for teased fiber analysis. A minimum of 125 axons were assessed per nerve for E degeneration (myelin ovoids) using the classification developed by Dyck et al. Untreated animals, regardless of DPG levels, demonstrated 0% neuropathy. In contrast, all insulin-treated animals showed degeneration (0.4-17%) that inversely correlated with the DPG level (r = -0.59, P less than 0.04). The results of this study suggest that the level of RBC DPG (and presumably the Hb-O2 affinity) with its attendant effect on tissue oxygen release may play a role in the development of peripheral neuropathy in STZ-induced diabetic rats treated with insulin.