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Henry Covelli,1 Bonavuth Pek,2 Isabelle Schenkenberger,3 Catherine Scott-Wilson,4 Amanda Emmett,5 Courtney Crim4 1Kootenai Health, Coeur d’Alene, ID, USA; 2Clinique de Pneumologie et de Sommeil de Lanaudière, Quebec, Canada; 3Klinische Forschung, Berlin, Germany; 4GlaxoSmithKline Inc., Research Triangle Park, 5PAREXEL International, Durham, NC, USA Background: Fluticasone furoate/vilanterol (FF/VI) is a novel, once-daily, inhaled corticosteroid/long-acting β2-agonist combination approved for the treatment of COPD and asthma. We compared the safety and efficacy of FF/VI and tiotropium (TIO) in subjects with moderate-to-severe COPD with greater risk for comorbid cardiovascular disease (CVD).Methods: This randomized, blinded, double-dummy, parallel-group study compared a once-daily morning dose of FF/VI 100/25 mcg delivered via ELLIPTA™ with TIO 18 mcg via HandiHaler® for 12 weeks in subjects with diagnosed COPD, forced expiratory volume in 1 second (FEV1) 30%–70% predicted, and CVD or CVD risk. The primary endpoint was change from baseline in 24-hour weighted mean FEV1 on Day 84. Other efficacy endpoints included time to onset of bronchodilation, trough FEV1, other spirometry measures, rescue medication use, symptoms, quality of life (St George’s Respiratory Questionnaire-COPD [SGRQ-C]), and health status (COPD Assessment Tests [CAT]) measures. Safety endpoints included cardiovascular monitoring, cortisol excretion, COPD exacerbations, and adverse events, including prespecified drug effects.Results: Both FF/VI and TIO improved the 24-hour weighted mean FEV1 from baseline after 12 weeks with no significant difference between treatments. Other endpoints favored FF/VI for time to onset of bronchodilation, rescue medication use, dyspnea, SGRQ-C and CAT scores, or favored TIO for change from baseline in forced vital capacity and inspiratory capacity. Pneumonia occurred more frequently in the FF/VI group, and two TIO-treated subjects died following cardiovascular events. Other safety measures were similar between groups, and cardiovascular monitoring did not reveal increased CVD risk.Conclusion: Both FF/VI and TIO were efficacious in improving lung function in subjects with COPD and comorbid CVD or CVD risk factors, with minor differences in efficacy and safety profiles. Keywords: fluticasone furoate/vilanterol, tiotropium, COPD, cardiovascular disease, ICS/LABA, anticholinergic

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. [ABSTRACT FROM AUTHOR]

Study Objectives: To examine electrocardiographic findings after short- and long-term tiotropium therapy in patients with chronic obstructive pulmonary disease (COPD), and to establish previously reported symptomatic efficacy., Design: Randomized, double-blind, placebo-controlled, parallel-group study., Setting: Twelve outpatient investigational centers in the United States., Patients: One hundred ninety-six patients with COPD., Interventions: Patients received either tiotropium 18 mug once/day or placebo, delivered by the HandiHaler device., Measurements and Main Results: Electrocardiography (predose and 5 min postdose) and 24-hour Holter monitoring were performed at baseline and after 8 and 12 weeks of treatment with tiotropium 18 microg once/day or placebo. Efficacy measures (spirometry, global COPD ratings, scores on the EuroQol Health Questionnaire [EQ-5D], albuterol inhaler as needed) were included to demonstrate that the study population exhibited the characteristic improvements observed in previous tiotropium studies. Mean baseline forced expiratory volume in 1 second (FEV1) was 1.03 L. Mean changes in heart rate from baseline were similar in both groups. No differences were noted in the percentage of patients developing rhythm or conduction abnormalities detected with electrocardiography or Holter monitoring. Frequency of premature beats and mean maximal changes in PR, QRS, QT, QTcB, and QTcF intervals were similar in both groups. No patients developed new-onset QT or QTc intervals greater than 500 msec, and no differences were noted in the percentage of patients developing new QT prolongation less than 30 msec, 30-60 msec, or greater than 60 msec. At 12 weeks, predose and postdose improvements in FEV1 were 184 and 265 ml, respectively, with tiotropium versus placebo (p<0.001). Physician and patient global COPD ratings and the EQ-5D visual analog scale scores were improved with tiotropium (p<0.05); as-needed albuterol was reduced by 25% relative to placebo (p<0.05)., Conclusion: Tiotropium provided spirometric and symptomatic benefits in patients with COPD and was not associated with evidence of electrocardiographic changes in heart rate, rhythm, QT intervals, or conduction.

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.

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.

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.

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.

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.

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.

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.

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.

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.