Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal humans.

The sympathetic response to hypoxia depends on the interaction between chemoreceptor stimulation (CRS) and the associated hyperventilation. We studied this interaction by measuring sympathetic nerve activity (SNA) to muscle in 13 normal subjects, while breathing room air, 14% O2, 10% O2, and 10% O2 with added CO2 to maintain isocapnia. Minute ventilation (VE) and blood pressure (BP) increased significantly more during isocapnic hypoxia (IHO) than hypocapnic hypoxia (HHO). In contrast, SNA increased more during HHO [40 +/- 10% (SE)] than during IHO (25 +/- 19%, P less than 0.05). To determine the reason for the lesser increase in SNA with IHO, 11 subjects underwent voluntary apnea during HHO and IHO. Apnea potentiated the SNA responses to IHO more than to HHO. SNA responses to IHO were 17 +/- 7% during breathing and 173 +/- 47% during apnea whereas SNA responses to HHO were 35 +/- 8% during breathing and 126 +/- 28% during apnea. During ventilation, the sympathoexcitation of IHO (compared with HHO) is suppressed, possibly for two reasons: 1) because of the inhibitory influence of activation of pulmonary afferents as a result of a greater increase in VE, and 2) because of the inhibitory influence of baroreceptor activation due to a greater rise in BP. Thus in humans, the ventilatory response to chemoreceptor stimulation predominates and restrains the sympathetic response. The SNA response to chemoreceptor stimulation represents the net effect of the excitatory influence of the chemoreflex and the inhibitory influence of pulmonary afferents and baroreceptor afferents.

Contrasting effects of hypoxia and hypercapnia on ventilation and sympathetic activity in humans.

We compared the effects of isocapnic hypoxia (IHO) and hyperoxic hypercapnia (HC) on sympathetic nerve activity (SNA) recorded from a peroneal nerve in 13 normal subjects. HC caused greater increases in blood pressure (BP), minute ventilation (VE), and SNA [53 +/- 14% (SE) during HC vs. 21 +/- 7% during IHO; P less than 0.05]. Even at equivalent levels of VE, HC still elicited greater SNA than IHO. However, apnea during HC caused a lesser (P less than 0.05) increase in SNA (91 +/- 26% compared with apnea on room air) than apnea during IHO (173 +/- 50%). Hypercapnic hypoxia resulted in a greater absolute increase in VE (23.6 +/- 2.8 l/min) than the additive increases due to HC alone plus IHO alone (18.0 +/- 1.8 l/min, P less than 0.05). SNA also increased synergistically by 108 +/- 23% with the combined stimulus compared with the additive effect of HC alone plus IHO alone (68 +/- 19%; P less than 0.05). We conclude that 1) HC causes greater increases in VE and SNA than does hypoxia; 2) for the same increase in VE, hypercapnia still causes a greater increase in SNA than hypoxia; however, during apnea, hypoxia causes a much greater increase in SNA than hypercapnia; 3) the inhibitory influence of ventilation on SNA is greater during hypoxia (i.e., predominantly peripheral chemoreceptor stimulation) than hypercapnia (i.e., predominantly central chemoreceptor stimulation); and 4) combined hypoxia and hypercapnia have a synergistic effect on SNA as well as on VE.

Serial exercise testing in pulmonary embolism.

A patient underwent exercise testing during evaluation for unexplained dyspnea. Evidence of ventilation-perfusion mismatch was noted and subsequent testing revealed multiple pulmonary emboli. Ventilation perfusion parameters by serial exercise testing progressively improved during the course of the patient's illness but did not totally normalize. A discussion of the utility of exercise testing in the evaluation of the patient with unexplained dyspnea is provided and the potential value of serial exercise testing in the management of patients with pulmonary emboli is discussed.

Increased bronchovascular permeability after allergen exposure in sensitive asthmatics.

To investigate the possibility that an increase in bronchovascular permeability is associated with allergen exposure in sensitive asthmatics we evaluated the amounts of serum proteins in bronchoalveolar lavage (BAL) effluents before and after local challenge with allergen. After exposure of sensitive asthmatic airways (n = 15) to allergen significant increases in total protein compared with controls were observed: 0.08 +/- 0.01 mg/ml in control airways and 0.13 +/- 0.02 mg/ml in challenged airways; P less than 0.05. The greatest changes induced by allergen exposure involved small-molecular-weight proteins (less than 345,000) and an inverse correlation was observed between log molecular weight and percent increase in the concentrations of the specific proteins; r = -0.61. BAL-serum distribution coefficients of serum proteins in airway fluids reflected a greater diffusability of low-molecular-weight proteins immediately after allergen exposure. We also evaluated the movement of serum proteins into lung after local allergen exposure using intravenously administered 99mTc-albumin (n = 10) and found an immediate 3.8-fold increase in amounts of radioactive albumin in allergen exposed airways compared with airways exposed to diluent. Most of the radioactivity was recovered in the first 5 ml of aliquot withdrawn, suggesting a marked increase in the permeability of the bronchial (large airway) vascular-epithelial membrane. An increase in serum proteins was also observed in BAL fluid of asthmatics 2-4 h after aerosol challenge (n = 4), including all proteins in the molecular weight range 45,000-900,000. These studies suggest that allergen exposure in sensitive asthmatics causes an acute increase in bronchovascular permeability to serum proteins.

Blunted peripheral tissue responsiveness to thyroid hormone in uremic patients.

To understand the biologic significance of the low triiodothyronine (T3) syndrome in patients with chronic renal failure (CRF), we examined thyroid hormone profile, basal O2 uptake (VO2), and peripheral blood mononuclear leukocyte (PBL) ouabain binding in these patients and in the control subjects before and after L-triiodothyronine (T3) and sodium ipodate treatment. In the controls (N = 8), T3 administration increased serum total T3 from 136 +/- 15 to 232 +/- 11 ng/dl, and reduced total thyroxine (T4) from 8.14 +/- 0.56 to 6.08 +/- 0.43 micrograms/dl, free T4 from 1.59 +/- 0.12 to 1.03 +/- 0.05 ng/dl and thyroid-stimulating hormone (TSH) from 1.74 +/- 0.24 to 0.41 +/- 0.09 microU/ml. VO2 increased from 2.66 +/- 0.11 to 3.15 +/- 0.09 ml/kg/min. Ipodate treatment, on the other hand, resulted in a reduction of serum total T3 to 102 +/- 21 ng/dl, an increase in total T4 to 9.59 +/- 0.50 micrograms/dl, free T4 to 1.91 +/- 0.13 ng/dl and TSH to 3.64 +/- 1.14 microU/ml. VO2 decreased to 2.43 +/- 0.06 ml/kg/min. P values ranged from less than 0.05 to less than 0.001. In the CRF patients (N = 14), T3 treatment also resulted in a rise in serum total T3 from 75 +/- 5 to 185 +/- 8 ng/dl. Total T4 declined from 6.68 +/- 0.34 to 5.18 +/- 0.48 micrograms/dl, free T4 from 0.85 +/- 0.1 to 0.67 +/- 0.08 ng/dl and TSH from 3.67 +/- 0.86 to 0.94 +/- 0.3 microU/ml. VO2, however, did not change (from 2.91 +/- 0.12 to 2.99 +/- 0.17 ml/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)

A combined surgical approach to non-oat-cell pulmonary carcinoma with single cerebral metastasis.

Eighty consecutive patients with pulmonary non-oat-cell carcinoma and a single cerebral metastasis were followed for at least 5 years after therapy. Forty were treated by surgical excision at both sites of disease plus whole-brain irradiation in most cases (group 1). The remaining 40 patients, an observational cohort, were treated either by surgery at only one site of disease (usually craniotomy), whole-brain irradiation, chemotherapy, or some combination of these modalities (group 2). The 1-year survival in group 2 was 15%, and all were dead at 2 years. In group 1, hospital mortality was 1.5%, the 1-year survival rate 35%, the 2-year survival rate 25%, and the 5-year survival rate 12.5%. All the five year survivors were patients with N0 disease. In this subgroup of group 1, the five year survival was 20%. All patients surviving for more than 2 years were in group 1 and had a Karnofsky rating greater than 50 and N0 disease after staging. These data indicate that a combined surgical approach can be accomplished with low morbidity, low mortality, and increased survival rates, especially for patients with N0 disease who are vigorous enough to undergo the combined treatment.

Basal oxygen uptake: a new technique for an old test.

To assess the metabolic effects of T4 and T3, we measured serum total T4 (TT4), free T4 (FT4), total T3 (TT3), TSH, and basal oxygen uptake (VO2) in eight normal subjects in the basal state and after treatment with L-T3 (T3) and sodium ipodate for 2 weeks. T3 treatment resulted in a rise of serum TT3 from a baseline of 137 +/- 16 (+/- SE) to a peak of 239 +/- 15 ng/dl. Serum TT4 declined from 8.14 +/- 0.56 to 6.08 +/- 0.43 micrograms/dl, FT4 from 1.59 +/- 0.13 to 1.03 +/- 0.05 ng/dl, and TSH from 1.74 +/- 0.24 to 0.56 +/- 0.16 microU/ml. Basal VO2 increased from 2.66 +/- 0.11 to 3.15 +/- 0.09 ml/kg X min. Ipodate, on the other hand, led to a lower serum TT3 concentration (102 +/- 21 ng/dl), higher serum TT4 and FT4 (9.59 +/- 0.5 micrograms/dl and 1.91 +/- 0.13 ng/dl, respectively), and elevated TSH (3.64 +/- 0.14 microU/ml). Basal VO2 was reduced to 2.44 +/- 0.06 ml/kg X min. Linear regression analysis revealed an excellent positive correlation between serum TT3 and basal VO2 (n = 25; r = 0.747; P less than 0.001) and a significant negative correlation between serum TT3 and TSH (n = 26; r = -0.526; P less than 0.01). Serum TT4 and FT4 correlated negatively with VO2 and positively with serum TSH. The higher T4 level during ipodate treatment was associated with lower VO2 and higher TSH, and vice versa when T4 was suppressed while receiving T3. When ipodate was given concomitantly with T3 to five subjects, only the effects of T3, characterized by increased VO2 and decreased TSH, were evident. These data indicate that both basal VO2 and serum TSH are sensitive indices of thyroid hormone activities. The latter gives only the directional change (hyper- or hypothyroidism), while the former more accurately quantitates the magnitude of the derangement. Moreover, it appears that in man, T3, and not T4, is the primary hormone that regulates thermogenesis and TSH secretion.

Protective adaptation of low serum triiodothyronine in patients with chronic renal failure.

Low serum triiodothyronine (T3) concentration is frequently found in patients with chronic renal failure (CRF). To test the hypothesis that this may serve to minimize protein catabolism in these patients, we measured nitrogen balance (Nb) in seven CRF and four control subjects in the basal state and when serum T3 concentration was elevated by L-triiodothyronine (LT3) and suppressed by sodium ipodate administration. In the basal state, both the controls and the CRF patients were in positive Nb, 0.02 +/- 0.51 and 0.58 +/- 0.34 g/day, respectively. During LT3 administration, Nb decreased to -0.80 +/- 0.39 g/day in the CRF patients (P less than 0.01), but remained positive, 0.22 +/- 0.67 g/day, in the controls. There was a significant negative correlation between serum T3 concentration and Nb in the CRF patients (r = -0.63, P less than 0.005), but not in the controls. Furthermore, urea nitrogen generation rate, calculated from urea kinetics, increased from a baseline of 4.6 +/- 0.55 to 6.0 +/- 0.50 mg/min during LT3 administration in the CRF patients (P less than 0.01). Sodium ipodate, which significantly lowered serum T3 concentrations, had little effect on nitrogen metabolism in the controls and the CRF patients. These data support the concept that low serum T3 concentrations may confer a protective effect on CRF patients regarding protein-nitrogen conservation and provide a rationale for not correcting such deficiency.

Respiratory symptoms and lung function among workers in swine confinement buildings: a cross-sectional epidemiological study.

To study possible chronic respiratory problems of people working in swine confinement buildings, a cross-sectional epidemiological study was initiated. A cohort of swine confinement workers was matched for age, sex, and smoking history with nonconfinement swine producers. Pulmonary function studies and a survey questionnaire for chronic respiratory disease symptoms (the American Thoracic Society, Epidemiologic Standardization Project Questionnaire) were performed on both groups. Compared to controls, the confinement workers experienced significantly higher prevalence of chronic bronchitis and wheezing, (odds ratio 7 and 4, respectively). There were, however, no significant differences in baseline pulmonary functions. Based on the high prevalence of chronic respiratory disease symptoms, this study emphasizes an emerging occupational concern in agriculture to the estimated 500,000 persons working in swine confinement operations and the estimated 500,000 additional persons who work in poultry, veal, beef, or dairy confinement operations. It is important to study a representative population of these workers prospectively to determine if a progressive loss in lung function is evident.

Basal and exercise tests on morbidly obese patients before and after gastric bypass.

The psysiologic responses of 13 morbidly obese patients (nine women and four men) were studied during basal and exercise conditions before and after gastric bypass. The mean age of the group was 33 +/- 2.3 years, the weight was 157 +/- 11.3 kg, and the body mass index (BMI = weight [kg]/height [m]2) was 54. Initial mean oxygen consumption (VO2) values were extraordinarily elevated, being 453 ml/min at rest and 2084 ml/min during level walking on a treadmill at 2 mph. The mean weight loss 6.9 months after operation was 41.6 +/- 4 kg (0.2 kg/day). Retesting revealed striking improvement in all measured parameters, with some values approaching the values of the matched control group of lean subjects. Spirometric results were normal for the nonsmokers (n = 8), although insignificant improvement occurred after weight loss. The basic requirement to be accepted for operation was that the patient must be able to exercise for 6 minutes on the treadmill at 2 mph, zero elevation, without developing metabolic acidosis and a respiratory quotient above 1.0. Three superobese men (BMI = 69) with hypercarbia failed to meet the exercise requirement. Their poor performance resulted in hospital treatment until they were in suitable condition upon retesting to undergo operation. Their elevated Paco2 values did not correct to normal until several months after operation. In this study, the basal and exercise VO2 values proved to be sensitive indicators for the amount of weight loss after gastric bypass (P = 0.01 and 0.001, respectively).

Acute effects of the work environment on pulmonary functions of swine confinement workers.

A sample population of owner/operators of swine confinement production facilities (21 subjects in 21 different facilities) were tested by spirometry immediately before and after a 4-hr work period. These confinement workers had statistically significant decrements in flow rates ranging from 3.3% (mean FVC) to 11.9% (mean FEF25-75). The air within the work environment was sampled for particulates and gases during the exposure period. There was suggestive evidence for a dose-response association between environmental exposures to carbon dioxide (CO2) and hydrogen sulfide (H2S). There was also some evidence for an additive relationship between smoking and work environment exposure on decline in lung function. The results of this study indicate that those working in swine confinement buildings experience irritation to the respiratory tract which is manifest by decreased flow rates. These findings suggest this exposure represents an emerging occupational health hazard. Further studies are warranted to assess the potential for chronic or irreversible damage to the respiratory tract.

Role of interleukin-2 release by lung T-cells in active pulmonary sarcoidosis.

Using a human T-cell line sensitive to interleukin-2 (IL-2), we evaluated supernatants of unstimulated, purified lung T-lymphocytes from patients with sarcoidosis and high-intensity alveolitis (active disease), patients with sarcoidosis and low-intensity alveolitis (inactive disease), patients with idiopathic pulmonary fibrosis, and normal volunteers for the presence of IL-2. After 24 h in culture, supernatants of lung T-cells from patients with sarcoidosis and high-intensity alveolitis contained significantly greater amounts of IL-2 than did supernatants of lung T-cells from the other 3 groups, which we used as controls (p less than 0.001 for each comparison). The IL-2 present in supernatants of lung T-cells had a molecular weight of approximately 15,000 daltons and the supernatants that contained IL-2 significantly (p less than 0.01) increased in vitro immunoglobulin production by T-cell-depleted normal mononuclear cell suspensions stimulated with pokeweed mitogen. These studies suggest that the release of IL-2 by lung T-cells may explain in part the local proliferation of T-cells and hypergammaglobulinemia that are characteristic of pulmonary sarcoidosis.

The pathophysiology of acute high-altitude illness.

Complex physiologic responses occur as nonacclimatized lowland dwellers ascend above 10,000 feet, with a resulting partial pressure of arterial oxygen of less than 60 mm Hg. There are marked hemodynamic changes and shifts in body fluids that may result in organ dysfunction. The suspected pathogenesis of these acute hypobaric hypoxic-induced illnesses is discussed. Cerebral dysfunction may present as acute mountain sickness or high-altitude cerebral edema. Usually asymptomatic high-altitude retinal hemorrhage and noncardiogenic high-altitude pulmonary edema also are described. All of these illnesses apparently represent a spectrum of pathologic states initiated by an exaggerated vascular response to hypoxia. With the exception of retinopathy, high-altitude illness can be prevented by slow ascent. Early recognition of cerebral or pulmonary edema and immediate descent will prevent serious consequences of nonacclimatized persons who are acutely exposed to hypobaric environments.

Fiberoptic bronchoscopy. Indications, training, and certification.

To assist hospital committees in maintaining high standards of practice in their facilities, the American College of Physicians has prepared a list of cognitive and procedural objectives which may serve as guidelines in evaluating physicians' performance of fiber-optic bronchoscopy. These are outlined here, along with indications, contraindications, and high-risk situations.

Idiopathic scoliosis: long-term follow-up and prognosis in untreated patients.

Two hundred and nineteen patients with untreated adolescent idiopathic scoliosis who were seen at the University of Iowa between 1932 and 1948 were studied, and recent information was available on 194 of the patients. The mortality rate was 15 per cent. Backache was somewhat more common in these patients than in the general population, although it was never disabling. The backache was unrelated to the presence of osteoarthritic changes on roentgenograms. Many curves continued to progress slightly in adult life, particularly thoracic curves that had reached between 50 and 80 degrees at skeletal maturity. The lumbar components of combined curves between 50 and 74 degrees also tended to progress. Pulmonary function was affected only in patients with thoracic curves.

The response to atropine sulfate given by aerosol and intramuscular routes to patients undergoing fiberoptic bronchoscopy.

Two groups of 11 patients each were studied in their responses to intramuscular (IM) or aerosolized atropine sulfate, given in preparation for fiberoptic bronchoscopy. The patients in group 1 received 1.0 mg of atropine IM, and those in group 2 were given a prepared solution of atropine in saline (5 mg/ml) at a dosage of 0.1 mg/kg by nebulization (IPPB). Statistical analysis of the FVC, FEV1, FEF25-75%, and FEFmax showed excellent protective bronchodilatory effects of both IM and aerosolized atropine. In fact, the beneficial result was more prolonged when the drug was administered by inhalation. One possible factor to consider, however, is that atropine given by the aerosol route did not inhibit the vasovagal response in three of the 11 patients. Another factor to take into account is that atropine by IM injection is quicker to administer, more convenient, and requires less instrumentation than atropine given by aerosol.

Intrabronchial instillation of paraquat in rats: lung morphology and retention study.

Various amounts of paraquat (10(-5) to 10(-12) g) in 0.1 ml saline were instilled directly into the left bronchus of male adult rats. Gravimetric, macroscopic, and microscopic studies on the left lobe of the lung showed that 10(-5) g of paraquat produced lung oedema and macroscopic lesions two and 14 days after doing. The pathology of the lung was similar to that seen after systemic poisoning. When 10(-6) g of paraquat was instilled, some animals developed lung oedema and macroscopic lesions. Microscopic examination showed subtle changes in the parenchyma of the lung. With amounts of paraquat equal to or less than 10(-7) g (doses as little as 10(-12) g were used), no changes in the lung were seen. This is contrary to published accounts in which amounts as low as 10(-12) g (1 Pg) were reported to cause acute damage to the rabbit lung. When 3H paraquat was instilled into the left lobe (doses of 10(-5) to 10(-10) g were used), the loss of paraquat from the lung was biphasic. The initial half-life was less than one hour. The secondary phase obeyed first-order kinetics, and the half-life was dependent on the dose of paraquat instilled. This half-life was as short as 11 hours when 10(-5) g paraquat was instilled and was 76 hours after the instillation of 10(-10) g paraquat. The decrease in the half-life of the secondary phase with increasing doses of paraquat is possibly associated with the production of oedema or lung cell damage, or both. After the instillation of 10(-8) g 3H paraquat, the initial half-life was less than 15 minutes, and paraquat was detected in the urine and plasma at that time. This suggests that 50% of the instilled paraquat was rapidly absorbed from the lung into the plasma.

Ultrathin needle aspiration of the lung in infectious and malignant disease.

Fifty patients with either malignant (n = 25) or infectious/inflammatory (n = 25) chest lesions had lung aspirations using ultrathin needles, 24 to 25 gauge. The procedure's overall sensitivity was 87%, and the specificity was 100%. The diagnostic yield was 90% (9/10) from peripheral malignant coin lesions, 100% (3/3) from malignant cavities, and 42% (5/12) from infected, nonmalignant cavities. Antimicrobial therapy probably contributed to poor microbiologic results in the latter group. Twenty-two of the patients previously had flexible fiberoptic bronchoscopy with negative results. In this select group, a diagnosis was established in 45% (10/22): 7 had malignant lesions, 2 had anaerobic lung abscesses, and 1 had histoplasmosis. In patients with infectious diseases, a variety of bacterial, mycobacterial, and fungal infections were confirmed including the diagnosis of Legionella pneumophila in 2 patients. A definitive diagnosis was obtained in 6 of 8 immunosuppressed patients who presented with indeterminate infiltrates on chest radiographs. Complications were minimal, although 21 patients (42%) had COPD, and 13 patients (26%) had moderate to severe hypoxemia (PaO2, 40 60 torr). Mild hemoptysis occurred in 2 patients (4%), and pneumothorax occurred in 4 patients (8%) of whom 2 required chest tube insertion. When compared with other studies using large gauge needles (18 to 22 gauge), ultrathin needle aspiration of the lung produced fewer complications, while maintaining an exceptionally good diagnostic yield.

An effect of paraquat on the lungs of rabbits. Its implications in smoking contaminated marihuana.

Thirty-six rabbits received the herbicide, paraquat (1,1'-dimethyl-4,4'-dipyridylium dichloride), by selective intrabronchial instillation in doses ranging from 0.1 gm to 1 pg. Sixteen additional rabbits were given paraquat dichloride (25 mg/kg of body weight) intraperitoneally, subcutaneously, intravenously, or orally. The lung of the rabbit proved to be highly sensitive to paraquat administered by intrabronchial deposition, moderately sensitive to intravenously administered paraquat, and resistant to the chemical when given intraperitoneally or subcutaneously. One picogram of paraquat dichloride delivered by bronchial catheter produced a 1.0-mm pulmonary lesion consisting of focal hemorrhage, congestion of capillaries, intra-alveolar macrophages, and moderate thickening of the alveolar septa. This finding suggests that pulmonary damage could potentially result from smoking marihuana that has been sprayed with paraquat.