Invasive aspergillosis of the lung and pericardium in a nonimmunocompromised 33 year old man.

In a 33 year old man with no discernible immunologic defect, invasive aspergillosis developed in both the pericardium and lung with marked granulomatous reaction. The patient received 2 g of intravenous amphotericin B over eight weeks, with partial regression of the pulmonary infiltrate and disappearance of symptoms. However, five months later, he returned with marked progression of his disease. Evaluation of host defense, including granulocyte and lymphocyte function, was normal. The patient was given an additional 3g of amphotericin B over nine weeks with marked improvement in symptoms and chest roentgenogram. At six-month follow-up, he was asymptomatic with a stable radiographic appearance. A recurrence in symptoms and the pulmonary infiltrate was noted two months later. He was treated with an additional course of amphotericin and currently is receiving ketoconazole in hopes of suppressing the infection. We could find no immune impairment to explain the severe pulmonary and pericardial disease due to Aspergillus flavus in this young man.

An evaluation of the accuracy of Assess and MiniWright peak flowmeters.

With the advent of small inexpensive peak flowmeters, the at-home monitoring of peak flow rates has become an invaluable aid in the treatment of asthmatic patients. In this study, we evaluated the performance of the MiniWright and Assess peak flowmeters for accuracy and reproducibility. Measurements were made at varying peak flow rates and compared with those obtained simultaneously by a calibrated pneumotachograph. When this segment of the study was completed, the peak flow devices were subjected to 200 uses and were then retested. Four MiniWright peak flowmeters that had been extensively used in our clinic were tested as well. The Assess peak flowmeter was more accurate than the MiniWright at low flow rates (less than 300 L/min), while the MiniWright meter was more accurate at high flow rates (greater than 400 L/min). We also found that the accuracy of the MiniWright meter deteriorated after 200 uses and worsened further after extensive use, while the Assess meter retained its accuracy after 200 uses.

Emergency treatment of acute asthma with albuterol metered-dose inhaler plus holding chamber: how often should treatments be administered?

STUDY OBJECTIVE: To determine the optimal treatment interval for administering albuterol metered-dose inhaler (MDI) with a holding chamber to patients presenting to the emergency department (ED) with acute asthma. DESIGN: Prospective, randomized, double-blind study. SETTING: EDs of two affiliated teaching hospitals in the Bronx, NY. PATIENTS: One hundred adult patients with acute asthma and FEV1 <60% predicted of normal. INTERVENTIONS: At entry (T=0 min), eligible patients all openly received inhaled albuterol (six puffs) via MDI with a spacer. Subsequently, in a double-blind fashion, they received six puffs of albuterol or placebo with new MDIs and spacers at 30, 60, and 90 min such that group 1 (n=34) received albuterol every 30 min, group 2 (n=33) every 60 min, and group 3 (n=33) at 120 min only. FEV1 and vital signs were measured at T=0 and at 15, 30, 60, 90, and 120 min following initial treatment. Potassium levels were measured at T=0 and 120 min. Adverse events, the use of additional inhaled beta-agonists or systemic corticosteroids, and hospitalization rates were recorded. MEASUREMENTS AND RESULTS: At T=0, the groups did not differ in age, FEV1, or prescribed asthma medications. All groups showed significant improvement in FEV1 (p<0.05; T=120 vs 0 min). The conditions of groups 1 and 2 improved significantly more than those of group 3, but did not differ compared to each other. The mean+/-SEM change in FEV1 (T=120 vs 0 min) was 0.993+/-0.108, 0.858+/-0.135, and 0.321+/-0.056 L, respectively, for the three groups. Separate analysis for patients with FEV1% <40% or >40% predicted showed similar results. However, patients who initially were low responders to albuterol treatment (<15 percentage point increase at 15 min) improved significantly with 30-min treatments compared to the other two treatment regimens. Patients who initially responded with >15 percentage point increase in FEV1 at 15 min following initial albuterol inhalation benefited equally from 30- or 60-min treatments compared to 120 min. Potassium levels did not change significantly during the study. Adverse events and hospitalization rates were equivalent. After the conclusion of the study, group 3 patients required a greater number of beta-agonist treatments prior to eventual discharge from the ED. CONCLUSIONS: For acute asthma, albuterol MDI with a holding chamber can be given optimally at 60-min intervals with minimal adverse effects for the majority of patients. However, patients who initially demonstrate a low or poor bronchodilator response to albuterol should be given subsequent treatments at 30-min intervals. This will optimize care and conserve resources for patients who will benefit the most.

The incidence, prevalence, and severity of sarcoidosis in New York City firefighters.

OBJECTIVE: The etiology of sarcoidosis is unknown, but epidemiology suggests that environmental agents are a factor. Because firefighters are exposed to numerous toxins, we questioned whether sarcoidosis was increased in this cohort. SETTING: The New York City Fire Department (FDNY), employing > 11,000 firefighters and nearly 3,000 emergency medical services (EMS) health-care workers (HCWs). DESIGN: In 1985, FDNY initiated a surveillance program to determine the incidence, prevalence, and severity of biopsy-proven sarcoidosis in firefighters. In 1995, EMS HCWs were added as control subjects. RESULTS: Between 1985 and 1998, 4 prior cases and 21 new cases of sarcoidosis were found in FDNY firefighters. Annual incidence proportions ranged from 0 to 43.6/100,000, and averaged 12.9/100,000. On July 1, 1998, the point prevalence was 222/100,000. For EMS HCWs, annual incidence proportions were zero. Radiographic stage 0 or stage 1 sarcoidosis was found in 19 firefighters (76%), and stage 3 was found in 1 firefighter (4%). Pulmonary function (FVC, FEV(1), and diffusing capacity for carbon monoxide) was normal in 17 firefighters (68%), and reduced to

Diaphragm fatigue induced by inspiratory resistive loading in spontaneously breathing rabbits.

Diaphragmatic contractility was assessed in spontaneously breathing ketamine-anesthetized rabbits by measuring the strength of diaphragmatic contraction in response to bilateral supramaximal phrenic nerve stimulation at frequencies between 10 and 100 Hz. During 10-180 min of inspiratory resistive loading, contractility decreased by approximately 40%, and hypoxemia and both respiratory and lactic acidosis developed. After 10 min of recovery, both the response to high-frequency stimulation (100 Hz) and the arterial PO2 and PCO2 returned to base-line levels, whereas metabolic acidosis and reduced response to low-frequency stimulation (10-20 Hz) persisted. Similar levels of hypoxemia and respiratory acidosis in the absence of inspiratory resistive loading did not alter diaphragmatic contractility. We conclude that in anesthetized rabbits excessive inspiratory resistive loading results in partially reversible diaphragm fatigue of the high- and low-frequency types, accompanied by hypoventilation and lactic acidosis.

Fatigue of isolated rat diaphragm: role of impaired neuromuscular transmission.

We compared the contributions of impaired neuromuscular transmission (transmission fatigue) and impaired muscle contractility (contractile fatigue) to fatigue of the isolated rat diaphragm. To make this comparison, we measured the differences in active tension elicited by direct muscle stimulation and by indirect (phrenic nerve) stimulation before and after fatigue induced by indirect supramaximal stimulation at varying frequencies and durations. Transmission fatigue was observed after all experimental protocols. Although significant contractile fatigue was not demonstrated after brief periods of low-frequency stimulation (6 min, 15 Hz, 25% duty cycle), it was present after longer or higher frequency stimulation. We repeated the direct stimulation in the presence of neuromuscular blockade with 6 microM d-tubocurarine to demonstrate that a reduced response to stimulation of intramuscular branches of the phrenic nerve during direct stimulation was not responsible for the apparent contractile fatigue. Since we found significant decreases in the response to direct stimulation even after neuromuscular blockade, we could verify the presence of contractile fatigue. We conclude that both contractile and transmission fatigue can occur in the isolated rat diaphragm and that transmission fatigue is a much more important factor after brief periods of fatiguing contractions.

Effect of long-term undernutrition on male and female rat diaphragm contractility, fatigue, and fiber types.

The effects of long-term undernutrition (10 wk) on diaphragm contractility, fatigue, and fiber type proportions were studied in male and female rats. Contractility and fatigue resistance indexes were measured in an in vitro diaphragm costal strip preparation by using direct stimulation at 37 degrees C. Undernutrition allowed for continued growth in males and females but with substantial reductions in weight gain. Relative to control rats of the same sex, final weights were significantly lower in undernourished males (74 +/- 3%) than females (90 +/- 5%), but weight gain was not significantly different between undernourished males (58 +/- 5%) and females (60 +/- 3%). Only in males did undernutrition significantly reduce costal diaphragm weight (to 77 +/- 5% of control). Diaphragm forces, normalized for cross-sectional area, were not significantly different from male or female control values. Fatigue resistance indexes (fatigue/baseline force) were increased at all stimulation frequencies in undernourished males but not in undernourished females. Costal diaphragm atrophy, involving types I and II fibers, occurred in undernourished males but not in undernourished females. In conclusion, despite long-term undernutrition reducing weight gain to similar levels in males and females (relative to control), there was excellent preservation of diaphragm weight, function, and structure in females but, although diaphragm atrophy occurred, there was preserved contractility and increased fatigue resistance in males.

Pulmonary entrapment of sickle cells: the role of regional alveolar hypoxia.

Pulmonary microvascular occlusion by abnormally adherent and/or nondeformable sickle red blood cells (SS cells) may contribute to the pathogenesis of acute chest syndrome of sickle cell disease. We hypothesized that regional alveolar hypoxia reduces SS cell deformability and, by causing regional vasoconstriction, slows regional perfusion, facilitating endothelial adhesion and mechanical entrapment of cells. In isolated rat lungs perfused at constant average flow with physiological salt solution, we separately ventilated the two lungs: one with 95% O2 and the other with 0, 2.5, 5, or 21% O2. We infused a bolus of 99mTc-labeled SS cells or normal human AA cells along with 113Sn-labeled 15-mu m microspheres as a perfusion marker, then sliced the lungs and counted 99mTc and 113Sn. Weight-normalized perfusion decreased with hypoxia (P < 0.02). Retention of AA cells (perfusion-normalized) averaged approximately 1% in lungs ventilated with 95% O2 and increased only twofold with 0% O2. In contrast, retention of SS cells averaged 3-fold higher than that of AA cells at 95 and 5% O2, 15-fold higher at 2.5% O2, and 25-fold higher at 0% O2 (P < 0.01). Histological examination demonstrated entrapment of individual SS cells in alveolar capillaries of hypoxic but not well-oxygenated lungs. Relief of hypoxia, but not increased perfusate flow, caused prompt efflux of most entrapped cells, which were primarily high-density (high mean corpuscular hemoglobin concentration) cells. Thus substantial retention of SS cells does not occur without hypoxia, but regional hypoxia and/or the resulting vasoconstriction causes extraordinary regional retention of dense SS cells, a phenomenon that appears to be due more to mechanical entrapment of nondeformable cells in capillaries than to endothelial adhesion.

Temperature dependence of rat diaphragm muscle contractility and fatigue.

The diaphragm is a skeletal muscle of mixed fiber type that is unique in its requirement to maintain contractile function and fatigue resistance across a wide range of temperatures to sustain alveolar ventilation under conditions of hypo- or hyperthermia. The direct effect of temperature (15-41 degrees C) on rat diaphragm isometric contractility and fatigue was determined in vitro. As temperature decreased from 37 to 15 degrees C, contraction and relaxation times increased, and there was a left shift of the diaphragm's force-frequency curve, with decreased contractility at 41 and 15 degrees C. Fatigue was induced by 10 min of stimulation with 30 trains/min of 5 Hz at a train duration of 900 ms. Compared with 37 degrees C, fatigue resistance was enhanced at 25 degrees C, but no difference in fatigue indexes was evident at extreme hypothermia (15 degrees C) or hyperthermia (41 degrees C). Only when the fatigue program was adjusted to account for hypothermia-induced increases in tension-time indexes was fatigue resistance evident at 15 degrees C. These findings indicate that despite the diaphragm's unique location as a core structure, necessitating exposure to in vivo temperatures higher than found in limb muscle, the temperature dependence of rat diaphragm muscle contractility and fatigue is similar to that reported for limb muscle of mixed fiber type.

Effects of long-term continuous respiratory resistive loading on rat diaphragm function and structure.

The effects of long-term (24- to 28-wk) continuous respiratory resistive loading on diaphragm mass, contractility, fatigue, and fiber types were studied in male rats. Increased respiratory resistance was produced by extratracheal banding, and results were compared with sham-operated pair-fed controls. At the time the animals were killed, banded tracheal segment internal diameter was reduced by 57% of control values. Diaphragm surface area and muscle mass (normalized for body mass) increased by 19% of control values. Isometric diaphragm contractility and fatigue resistance indexes were measured using an in vitro diaphragm costal strip preparation at 37 degrees C. Twitch and tetanic stimulations were evoked using direct stimulation. Compared with controls, baseline tensions (normalized for diaphragm cross-sectional area) were significantly decreased at low frequencies. Fatigue resistance (endurance) indexes were significantly increased at all frequencies. These findings were consistent with observed increases in number and cross-sectional area of type I (low-tension high-endurance) fibers. We conclude that the diaphragm adapts to chronic long-term resistive loads by sacrificing peak tensions for an increase in endurance capacity.

Inhibition of capsaicin-induced cough by the gamma-aminobutyric acid agonist baclofen.

Gamma-aminobutyric acid (GABA) is a central inhibitory neurotransmitter that also exists in the lungs. The GABA-agonist baclofen has been shown to have antitussive activity via a central mechanism in animals. Recently it was demonstrated that a 14-day course of baclofen given three times daily significantly inhibits the cough reflex in healthy volunteers. Because of the prolonged antitussive effect of baclofen that has been previously observed, the present study was conducted to evaluate the antitussive effect of low-dose, oral baclofen given once daily. Forty-one healthy volunteers were randomly assigned in a double-blind manner to receive a 28-day course of baclofen, either 10 mg or 20 mg once daily, or placebo. Subjects underwent cough challenge testing with inhaled capsaicin to establish baseline cough reflex sensitivity, and subsequently after 14 and 28 days of therapy. Subjects receiving baclofen 20 mg daily demonstrated significant inhibition of cough sensitivity after 14 days and after 28 days of therapy compared with baseline. Neither placebo nor baclofen 10 mg daily had a significant effect on cough sensitivity. No serious side effects were experienced by any study participant. These results confirm the recent observation that baclofen has significant antitussive activity in humans. Further, once-daily administration of a relatively low dose of baclofen is sufficient to achieve significant cough inhibition, although at least 14 to 28 days of therapy may be required to attain maximal antitussive effect. These results support further investigation of baclofen or other GABA-agonists as potential therapeutic agents for chronic, nonproductive cough.

Respiratory muscle fatigue.

Respiratory muscle fatigue is caused by excessive effort relative to the strength and endurance of the respiratory muscles. It can be manifested by reductions in respiratory drive (central fatigue), by impaired neuromuscular transmission (transmission fatigue), by decreased contractility (contractile fatigue), or by a combination of these factors. Respiratory muscle fatigue probably contributes to the difficulties some patients have with weaning from mechanical ventilation, the symptoms of exercise intolerance and dyspnea in chronic lung disease, and CO2 retention. Therapy depends on a reduction in the required level of respiratory effort and/or an improvement in respiratory muscle strength and endurance.

Adverse effects of drugs on the respiratory muscles.

Over 100 drugs can impair muscle function, either by inhibiting neural drive, causing peripheral neuropathy, blocking neuromuscular junctions, precipitating myasthenia gravis, or producing myopathy. Many of these drugs affect respiratory muscles, particularly the diaphragm. Although a great deal is known about the drug effects on central respiratory drive and neuromuscular blockade, little is known about the depressant effects of drugs specifically on phrenic nerve function or diaphragm contractility. This article has reviewed what is known about the effects of drugs on respiratory myoneural function and what can be inferred from studies on other striated muscles. We hope that this review serves to stimulate further investigation; meanwhile, until more is known, continued clinical caution is justified.

Effects of fire fighting uniform (modern, modified modern, and traditional) design changes on exercise duration in New York City Firefighters.

Fire departments have replaced traditional uniforms with modern, more thermal protective gear. Although the new uniforms afford superior burn protection, they may reduce work time. Our purpose was to determine if exercise time was (1) reduced by wearing the modern versus traditional uniform, and (2) increased by a design change to a modified modern uniform (T-shirt and short pants rather than a shirt and long pants under the outer uniform). Male firefighters (n = 23; age 27 to 59) performed a maximum exercise test in gym clothes (maximal oxygen consumption = 46 +/- 9 ml/kg/min) and then returned on separate days to exercise using a moderately high intensity, constant work rate treadmill protocol while wearing fire fighting breathing apparatus and each of three uniforms. Firefighters exceeded anaerobic threshold by 1 minute and eventually reached or exceeded maximum heart rate and maximal oxygen consumption. Exercise time in modern (15 +/- 3 min) was significantly less than in traditional (18 +/- 5 min) uniform. Exercise time in modified modern (17 +/- 5 min) was significantly greater than in modern and not significantly different than in traditional uniforms. The rate of change in oxygen consumption and water loss were significantly affected by uniform type, with faster rates in modern compared with modified modern or traditional uniforms. These findings show the impact that design changes have on energy demands and exercise duration.

Nutritional factors in the pathogenesis and therapy of respiratory insufficiency in neuromuscular diseases.

Malnutrition is a serious threat to patients with neuromuscular disease and marginally-compensated respiratory muscle weakness. It causes atrophy of inspiratory muscles, further weakening them. It reduces respiratory drive, potentially aggravating respiratory failure, either directly or indirectly, by promoting atelectasis and pneumonia, and it contributes strongly to such patients' risk of infection, their most common cause of death. In treating such patients, it must be remembered that abrupt increases in nutritional support, particularly with high percentages of carbohydrates, will increase CO2 production, potentially worsening ventilatory failure. Certain selected neuromuscular disease patients benefit from specific nutritional treatments (carnitine for carnitine deficient patients, high-calorie diets for muscular dystrophy and acid-maltase deficiency). Finally, the amino acid, fat, and nucleic acid content of the diet affects the immune response in beneficial or harmful ways, that are just now being elucidate. The potential for useful nutritional interventions in patients with neuromuscular diseases has never looked better, but is not yet fully realized. The challenges for the future will be to work out the beneficial and harmful effects of the various nutrients in the various diseases, to find ways to rapidly identify patients who will benefit, and to determine the safest, least uncomfortable, and most effective methods of delivery of the required nutrients.

The patient at risk of ventilator dependency.

Respiratory failure may result from inadequate central respiratory drive, excessive respiratory workload, or inadequate respiratory muscle endurance. With the exception of drug overdoses, central causes of respiratory failure are uncommon in the adult, and respiratory failure can be considered an imbalance between workload and endurance. Excessive workload can result from airway obstruction or chest wall or lung restriction. Anything that increases the required minute ventilation will increase the workload proportionately. Inadequate endurance results from neuromuscular disease, malnutrition, and a variety of metabolic factors. In most cases, treatment of the precipitating cause allows weaning from mechanical ventilation. However, when respiratory failure persists, often because the precipitating cause cannot be treated, all possible contributing conditions must be identified and corrected to the greatest possible extent. In that way, many patients with apparently intractable respiratory failure can be weaned. Four new approaches are showing some promise in the treatment of persistent respiratory failure: pharmacologic therapy to strengthen respiratory muscles, periodic respiratory muscle rest, sedation, and inspiratory muscle training.