Effects of inspiratory flow on diaphragmatic motor output in normal subjects.

Increasing inspiratory flow (V) has been shown to shorten neural inspiratory time (TI(n)) in normal subjects breathing on a mechanical ventilator, but the effect of V on respiratory motor output before inspiratory termination has not previously been studied in humans. While breathing spontaneously on a mechanical ventilator, eight normal subjects were intermittently exposed to 200-ms-duration positive pressure pulses of different amplitudes at the onset of inspiration. Based on the increase in V above control breaths (DeltaV), trials were grouped into small, medium, and large groups (mean DeltaV: 0.51, 1.11, and 1.65 l/s, respectively). We measured TI(n), transdiaphragmatic pressure (Pdi), and electrical activity (electromyogram) of the diaphragm (EMGdi). Transient increases in V caused shortening of TI(n) from 1.34 to 1.10 (not significant), 1.55 to 1.11 (P < 0.005), and 1.58 to 1.17 s (P < 0. 005) in the small, medium, and large DeltaV groups, respectively. EMGdi measured at end TI(n) of the pulse breaths was 131 (P < 0.05), 142, and 155% (P < 0.05) of the EMGdi of the control breaths at an identical time point in the small, medium, and large trials, respectively. The latency of the excitation was 126 +/- 42 (SD) ms, consistent with a reflex effect. Increasing V had two countervailing effects on Pdi: 1) a depressant mechanical effect due primarily to the force-length (11.2 cmH(2)O/l) relation of the diaphragm, and 2) an increase in diaphragm activation. For the eight subjects, mean peak Pdi did not change significantly, but there was significant intersubject variability, reflecting variability in the strength of the excitation reflex. We conclude that increasing inspiratory V causes a graded facilitation of EMGdi, which serves to counteract the negative effect of the force-length relation on Pdi.

Medullary metastasis causing impairment of respiratory pressure output with intact respiratory rhythm.

We present an unusual case of weaning failure. A 67-yr-old man presented with confusion, hyponatremia, and hypercapnic respiratory failure that necessitated mechanical ventilation. CXR revealed a right hilar mass (non-small-cell carcinoma on biopsy). Level of consciousness improved with treatment of his hyponatremia. However, attempts at weaning were complicated by hypercapnia with no overt distress. Resistance and elastance were only slightly abnormal, excluding mechanics as a cause of respiratory failure. Maximal inspiratory pressure (MIP) and vital capacity (VC) were reduced at -15 cm H2O and 0.97 L, respectively. Limb muscle strength was well preserved, suggesting isolated respiratory muscle weakness. During a weaning trial respiratory rate increased from 7 to 40 breaths/min as PCO2 increased from 56 to 89 mm Hg, confirming an intact respiratory pacemaker and good response to CO2. However, spontaneous Pdi was only 1 to 2 cm H2O (< 20% of Pdimax) despite profound hypercapnia. The fact that the patient did not utilize a greater fraction of his pressure-generating capacity suggested preferential impairment of the automatic respiratory centers. MRI showed a large central metastatic lesion in the rostral medulla with only a thin rim of uninvolved tissue. This case illustrates the utility of relating the magnitude of spontaneous efforts to maximal voluntary efforts as a means of localizing the site of involvement in cases of respiratory muscle weakness. It also demonstrates that a large medullary mass lesion may selectively impair brainstem modulation of respiratory pressure output while sparing other medullary functions, and in particular the pacemaking function of the respiratory centers.

Effect of inspiratory flow rate on respiratory rate in intubated ventilated patients.

It has previously been demonstrated that in normal subjects using a volume-cycled ventilator, increasing inspiratory flow rate increases respiratory rate. We undertook the current study to determine (1) whether this effect is also present in patients with respiratory disease and (2) whether the effect is independent of upper airway receptors. Eight ventilator-dependent patients in the intensive care unit were studied. Patients were ventilated in the assist-control mode with the back-up rate set at 0.5 breaths/min to ensure that all breaths were patient-triggered. While tidal volume was held constant, flow was changed from a baseline flow of 60 L/min. Trials involved changing flow to either 30 or 90 L/min. There was a significant decrease in respiratory rate (-3.4 +/- 0.6 min-1, p < 0.001) when flow was decreased from 60 to 30 L/min. There was a significant increase in respiratory rate (2.3 +/- 0.8 min-1, p < 0.05) when flow was increased from 60 to 90 L/min. As a result of the change in respiratory rate, TE (expiratory time) showed a variable response to changes in flow rate, with some patients actually demonstrating a reduced TE with higher flow rates. No patients experienced the increase in TE that would have been predicted without a change in respiratory rate. We conclude that in intubated ventilated patients, spontaneous respiratory rate is sensitive to inspiratory flow rate. This effect appears to be independent of upper airway receptors, since it was observed with a by-passed upper airway. The increase in respiratory rate seen at higher flow rates undermines attempts to increase TE by increasing flow rates. It may also cause a tendency toward respiratory alkalosis.

Pulmonary illness associated with exposure to Mycobacterium-avium complex in hot tub water. Hypersensitivity pneumonitis or infection?

BACKGROUND: Mycobacterium avium complex is common in water. When aerosolized, it is frequently inhaled but rarely causes illness in healthy people. Hypersensitivity pneumonitis to inhaled aerosols has been described; these aerosols are from several sources of water. The pneumonitis forms are collectively known as humidifier lung; the responsible agent in the water remains uncertain. PURPOSE: To report five cases of respiratory illness in healthy subjects using hot tubs contaminated with M avium complex. DESIGN: Descriptive case reports. SETTING: Consultations in two teaching hospitals. PATIENTS: Five healthy people developed respiratory illnesses characterized by bronchitis, fever, and "flu-like" symptoms after using a hot tub. Acute exacerbations of their illness developed within hours of heavy use of the hot tubs. INVESTIGATIONS: A chest radiograph and sputum culture in all, BAL in one, CT scan and lung biopsy in another were performed. Culture of the water of the two hot tubs also was done. RESULTS: Chest radiographs showed interstitial infiltrates or a miliary nodular pattern. Cultures of all sputum samples, the lung biopsy specimens, lung lavage and water samples were positive for M avium complex. The lung biopsy specimen revealed noncaseating granulomas. All patients recovered with no treatment for M avium complex. CONCLUSION: We conclude that the M avium complex in the water was responsible for the pulmonary illnesses. The symptoms and the results of investigations are more suggestive of a hypersensitivity pneumonitis than of an infection, but no serologic proof of an immunologic reaction to the M avium complex or water was obtained.

Plasmin regulates the activation of cell-associated latent TGF-beta 1 secreted by rat alveolar macrophages after in vivo bleomycin injury.

Transforming growth factor beta s (TGF-beta s) are 25-kD multifunctional proteins that regulate inflammation and connective tissue synthesis. With rare exception TGF-beta 1 is secreted noncovalently bound to a latency-associated peptide (LAP) that renders the mature TGF-beta 1 biologically inactive. An important mechanism for the control of TGF-beta 1 action is the regulation of the post-translational processing that removes the LAP from the mature peptide and renders it biologically active. In a model of pulmonary inflammation and fibrosis induced by the antineoplastic antibiotic, bleomycin, we have demonstrated that explanted alveolar macrophages secrete progressively increasing quantities of a biologically active form of TGF-beta 1, the secretion of which was maximal 7 days after bleomycin administration. Thereafter, there was a rapid decline in the secretion of the active form of TGF-beta 1, whereas the latent form continued to be secreted in elevated quantities. Plasmin, a serine protease, was transiently generated by the same bleomycin-activated alveolar macrophages and paralleled the rise in active TGF-beta 1. When alpha 2-antiplasmin, an inhibitor of plasmin, was added to cultures of alveolar macrophages, the post-translational activation of L-TGF-beta 1, was totally abrogated. When plasmin was added to alveolar macrophages in culture, there was complete activation of the L-TGF-beta 1 that had been secreted during the culture period. However, there was no effect of plasmin on the same alveolar macrophage-derived L-TGF-beta 1 in cell-free conditioned media. Our findings suggest that the secretion of an active form of TGF-beta 1 by alveolar macrophages is regulated by the generation of plasmin and requires that the alveolar macrophages be present. Because the diminution of active TGF-beta 1 coincides with the resolution of inflammation, this suggests that the availability of plasmin regulates the biologically active form of TGF-beta 1, and thus, the inflammation seen after bleomycin-induced lung injury.

A double-blind comparative study of fluoxetine and dothiepin in the treatment of depression in general practice.

Fluoxetine, a selective inhibitor of 5-HT uptake, was compared to dothiepin in a double-blind study of 6 weeks duration in 100 depressed patients (male and female) drawn from 8 general practices. Only those who scored at least 17 on the first 17 questions of the Hamilton Psychiatric Rating Scale for Depression (HAM-D) were selected. Both groups improved throughout the trial, though the dothiepin treated patients tended to improve quicker. However, by the end of the trial there was no statistically significant difference between the 2 groups. Subset analyses of HAM-D scores associated with anxiety and sleep revealed no statistically significant differences between the 2 treatments though improvement in anxiety scores was marginally greater for those receiving fluoxetine by the end of the trial. Other global assessments by patients and doctors confirmed the changes in HAM-D scores. Statistically significant weight changes occurred between visits 1 and 5. Whereas fluoxetine-treated patients lost weight (p less than 0.05), dothiepin-treated patients gained weight (p = 0.05) over this period. Adverse effects were reported in 27 patients given fluoxetine and 20 dothiepin. Of these, 14 fluoxetine and 7 dothiepin-treated patients withdrew before the end of the trial. The most common adverse effects were nausea, vomiting and diarrhoea in the fluoxetine group and tiredness, drowsiness and diarrhoea in the dothiepin group. There were no haematological or clinical chemistry changes.