Improved daytime spirometric efficacy of tiotropium compared with salmeterol in patients with COPD.

BACKGROUND: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends long-acting bronchodilators as first-line maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). A study was conducted comparing the long-acting anticholinergic tiotropium with the long-acting beta-agonist salmeterol to confirm the significant improvements in daytime bronchodilator efficacy seen with tiotropium in previous studies. METHODS: Randomized, double-blind, double-dummy, parallel-group study, comparing daytime bronchodilator efficacy of tiotropium 18 mcg once daily with salmeterol 50 mcg twice daily in patients with COPD. Serial spirometry was performed over 12 h after 12 weeks of treatment. Co-primary endpoints were average (over 12 h) and peak FEV1 at 12 weeks. RESULTS: 653 patients were randomized (328 tiotropium, 325 salmeterol): mean age 64 years; 66% male; mean baseline FEV1 1.05 l (37.7% predicted). After 12 weeks, the average post-dose FEV1 over 12 h was significantly higher with tiotropium compared with salmeterol (167 vs. 130 mL, respectively, p=0.03), as was peak FEV1 (262 vs. 216 ml, respectively, p=0.01). The average FEV1 responses from 0-6 h and 6-12 h were higher in the tiotropium group compared with salmeterol (p<0.05). Peak and average FVC were significantly higher with tiotropium compared with salmeterol (p<0.01). Morning pre-dose FEV1 responses were not significantly different; however, tiotropium demonstrated a significantly higher pre-dose FVC than salmeterol (p<0.05). CONCLUSION: Tiotropium demonstrated significantly greater post-dose improvements in spirometric parameters compared with salmeterol. These improvements were sustained over 12 h.

The acute and insidious onset of pulmonary metastatic transitional cell carcinoma.

Transitional cell carcinoma is a common urologic neoplasm. Although pulmonary metastases from this tumor are often not appreciated clinically, they are frequently documented in autopsy studies. Therefore, the clinical recognition of this condition can be problematic. To illustrate this point, we present three patients with progressive unexplained dyspnea and histories of transitional cell carcinoma. Since ineffective and possibly detrimental therapeutic approaches may be initiated, a high index of suspicion for pulmonary metastatic embolization must be maintained. Early histologic identification of these metastatic emboli and initiation of effective chemotherapy may prove beneficial for improved quality of life.

Multiple primary neoplasia of the head and neck and lung. The changing histopathology.

The authors reviewed 1373 consecutive cases of patients with oral head and neck cancer or lung cancer and identified 25 patients with multiple primary neoplasia (MPN). All 25 MPN cases had squamous carcinoma of the head and neck; however, only 40% (N = 10) had squamous carcinoma of the lung. The histologic types of non-squamous lung carcinoma were: adenocarcinoma 36% (N = 9), small cell carcinoma 20% (N = 5), and large cell undifferentiated carcinoma 4% (N = 1). Of 927 cases of MPN of the head and neck and lung reported in the English language literature, only 100 cases (10.78%) demonstrated a histologic discrepancy between the primary tumors. Recent reports demonstrate a histologic shift toward non-squamous lung carcinoma in MPN that is similar to our data, and that corresponds to the increase in non-squamous carcinomas recently seen in lung cancer in general. Possible implications of these findings are discussed.

Predisposing factors to apparent theophylline-induced seizures.

Fifteen patients experienced theophylline-related seizures at our institution over the past 3 years. Thirteen of the patients were receiving oral maintenance theophylline therapy while two patients were on IV therapy at the time of their episode. The serum theophylline concentration (STC) obtained 1.8 +/- 1.5 hours after the seizure was 26 +/- 11 micrograms/mL, although this level was not obtained until 5.2 +/- 2 hours after the last oral dose. Factors potentially decreasing theophylline metabolism (URI, abnormal liver functions, cimetidine therapy) were noted in 11/15 (73%) of the patients. This varied significantly from a control group of asymptomatic patients (P less than .01). Ten of thirteen patients on oral therapy were receiving solid-dose theophylline prescriptions over 17 mg/kg/day and differed from the control group (19 +/- 8 v 14 +/- 4, P less than .01). An abnormal neurologic history, brain scan, or head CT was noted in 11/15 (73%); however, there was no acute mortality or neurologic morbidity noted in this series. The clinical features of our patients differed from previously reported cases with respect to a lower STC, higher incidence of underlying CNS problems, higher percentage of patients on oral therapy, and the absence of serious morbidity or mortality.

Outpatient theophylline determinations.

The indications and usefulness of outpatient serum theophylline determinations were prospectively evaluated by doing 151 of these studies in 137 consecutive cases of chronic obstructive pulmonary disease. We found that evaluations were done for the following three groups of indications: group A, worsening bronchospasm; group B, stable asymptomatic cases, and group C, symptoms suggesting theophylline toxicity. When the three clinical groups were compared for frequency of nontherapeutic values, only an increased frequency of subtherapeutic values in patients with bronchospasm (group A) was significant (P<.01). Increasing the dosage up to 15 mg per kg of body weight a day while theophylline determinations are pending appears to be safe in this group of patients. Toxic symptoms were rarely associated with concentrations greater than 20 mug per ml (3/13) and infrequently occurred in patients with concentrations greater than 20 mug per ml (3/29). Nontherapeutic theophylline values did not always result in an adjustment of theophylline dosage. This was influenced by a correlation of symptoms, timing of the theophylline determination and the use of other bronchodilators.

Oxygen derived variables in acute respiratory failure.

The clinical course of 33 patients with acute respiratory distress syndrome (ARDS) was monitored by noninvasive oxygen derived variables and compared to data obtained by invasive monitoring. A total of 350 data points were used to compare the physiologic shunt fraction (Qsp/Qt) with the ratio of arterial oxygen to inspired oxygen concentration (PaO2/FIO2), the alveolar-arterial oxygen pressure difference [P(A-a)O2], the respiratory index (RI)-[P(A-a)O2/PaO2], and the ratio of arterial oxygen to alveolar oxygen (a/A). The PaO2/FIO2 ratio, the RI and the aA ratio correlated well with Qsp/Qt (r = 0.87 to 0.94). The P(A-a)O2 correlated less well (r = 0.68). Changes in the cardiac index (CI) and the arteriovenous oxygen content difference C(a-v)O2 had only a minimal effect on the correlation of the oxygen derived variables with Qsp/Qt, although a higher correlation resulted when these extrapulmonary factors were within normal range. We conclude that a number of oxygen derived variables may accurately reflect the degree of Qsp/Qt. The PaO2/FIO2 ratio is the easiest of these variables to calculate, yet accurately predicts the degree of Qsp/Qt throughout a course of acute respiratory failure.

Drug-resistant Mycobacterium tuberculosis in Korean isolates.

Tuberculosis is a common disease in developing countries. An increasing incidence of resistance to isoniazid (INH) and streptomycin in organisms isolated from patients who contracted their disease in these countries, particularly in the Far East, is well recognized. This drug resistance has led to the recommendation of empirically beginning a regimen in patients with tuberculosis from the Far East of INH, ethambutol, and rifampin. This report documents the increasing incidence of resistance in isolates from Korea to ethambutol and rifampin in addition to INH and streptomycin. It suggests that the empiric use of INH, ethambutol, and rifampin in this group of patients could potentially lead to resistance to all of these drugs because of a significant amount of multidrug resistance. A regimen of INH, rifampin, pyrazinamide, and capreomycin is suggested as appropriate initial therapy in these patients based on the in vitro sensitivity data presented and initial clinical experience.

Efficacy of continuous positive airway pressure administered by face mask.

The efficacy of administering continuous positive airway pressure (CPAP) by face mask was evaluated in 40 consecutive patients treated with 10 cm of water pressure or greater. Thirty-five patients were treated for progressive hypoxemia with all patients improving their PaO2/FIO2 ratio within the first hour of therapy. Oxygen delivery, when measured, also improved in each patient, although five patients ultimately required endotracheal intubation and higher CPAP levels to further improve their arterial hypoxemia. Five other patients were treated for atelectasis unresponsive to the usual therapeutic measures, with three patients demonstrating roentgenographic improvement. Face mask CPAP proved to be a safe and effective method for treating hypoxemia associated with early progressive respiratory distress in alert, spontaneously breathing patients.

Respiratory failure precipitated by high carbohydrate loads.

Acute respiratory failure developed in three patients needing ventilatory support within hours after total parenteral nutrition was started. We postulate that the high carbohydrate load provided in the parenteral solution resulted in the use of glucose as the primary energy source, with the development of substantial increases in the carbon dioxide production and the respiratory quotient. Because these patients had a relatively fixed ventilatory response, hypercapnia ensued. Excessive carbohydrate loading may precipitate respiratory acidosis in patients unable to adequately improve their alveolar ventilation when compensating for increased carbon dioxide production.

Evaluation of bone pain in carcinoma of the lung. Role of the localized false-negative scan.

False-negative bone scans localized to the vertebral column were detected in ten patients with primary carcinoma of the lung. All patients had macroscopic vertebral metastases at autopsy despite recent normal technetium Tc 99m bone scans and skeletal roentgenograms. Bone scans were 96% accurate in detecting nonvertebral metastases that were grossly visible at postmortem, with seven patients demonstrating multiple skeletal defects. False-negative studies of the vertebral column apparently prevented both the clinician and radiotherapist from treating symptomatic metastases in eight patients despite the administration of radiotherapy to other scan-positive symptomatic areas or to the primary tumor site.

Extraskeletal Ewing's sarcoma: prolonged survival with recurrence after operation.

Unlike the osseous variety, extraskeletal small cell tumors histologically identical to Ewing's sarcoma of bone frequently respond to radical surgical excision. The relative infrequence of this tumor, compounded by the comprehensive eponym "Ewing's sarcoma," may deter surgical intervention in this group of patients. This patient's course demonstrates the value of surgery alone, but emphasizes the role of combined surgery, irradiation, and chemotherapy as the best management for extraskeletal Ewing's sarcoma.

Immunologic and medical considerations in tuberculin-sensitized pregnant patients.

One-hundred and seventy-two pregnant patients were identified as tuberculin sensitive in the first trimester. These patients were followed throughout pregnancy for any signs or symptoms of active tuberculosis which were discovered only in the index case. Post partum, patients were again re-evaluated for tuberculosis and prophylactically treated with isoniazid if they met established criteria. The tuberculous host also represented a model for the study of cell-mediated immunity, which presumably is altered in pregnancy. This investigation revealed a progressive depression of lymphocyte function to a specific antigen, purified protein derivative, obtaining significance at 36 weeks' gestation and continuing through delivery (p is less than 0.001). Nonspecific cell-mediated immunity, however, was not depressed when monitored throughout the gestation by the mitogen, phytohemagglutinin, which would stimulate all lymphocyte clones. This discrepancy in the alteration of specific clones of lymphocytes compared to all noncommitted lymphocytes may account for varying reports of the immune status of the pregnant woman.

Evidence for transmission of lymphocyte responses to tuberculin by breast-feeding.

The possibility that cell-mediated immunity could be acquired by breast-feeding was evaluated in a prospective study of 26 tuberculin positive and 9 negative puerperal mothers and their infants. 13 infants of the positive and all the infants of negative mothers were breast-fed. Tuberculin-reactive T cells were found in colostrum and early milk of most positive but in none of the negative nursing mothers. A significant number (8/13) of infants born to positive mothers had tuberculin-reactive peripheral blood T cells after 4 weeks of breast-feeding compared with bottle-fed infants (1/13) of positive mothers or breast-fed infants (0/9) of negative mothers. Examination of cord blood for tuberculin-reactive T cells provided no significant evidence of transplacental transmission of responsiveness to tuberculin. The results suggest that breast-fed infants may passively acquire T cell responsiveness to a specific antigen by ingestion of breast milk.