Provocation by eucapnic voluntary hyperpnoea to identify exercise induced bronchoconstriction.

The International Olympic Committee Medical Commission (IOC-MC) requires notification for use of a beta(2) agonist at the Winter Olympic Games in Salt Lake City. This notification will be required seven days before the event and must be accompanied by objective evidence that justifies the need to use one. The IOC-MC has expressed the viewpoint that, at present, eucapnic voluntary hyperpnoea (EVH) is the optimal laboratory challenge to confirm that an athlete has exercise induced bronchoconstriction (EIB). The EVH test recommended was specifically designed to identify EIB. EVH has been performed in thousands of subjects in both the laboratory and the field. The test requires the subject to hyperventilate dry air containing 5% carbon dioxide at room temperature for six minutes at a target ventilation of 30 times the subject's forced expiratory volume in one second (FEV(1)). The test conditions can be modified to simulate the conditions that give the athlete their symptoms with exercise. A reduction in FEV(1) of 10% or more of the value before the test is considered positive.

Prevalence of pulmonary disorders in patients with newly diagnosed rheumatoid arthritis.

Our objective was to determine the prevalence of airway hyperreactivity (AHR) in patients with newly diagnosed rheumatoid arthritis (RA) who had received no disease-modifying antirheumatic drugs (DMARDs) and to characterise the spectrum of lung diseases identifiable in these patients at the time of presentation. Eighteen consecutive patients with newly diagnosed RA referred to our medical centre's rheumatology clinic over 2 years underwent pulmonary evaluation with arterial blood gas analysis, chest radiographs, spirometry before and after bronchodilator medication, and body plethysmography. They returned on subsequent days in random order for methacholine inhalation challenge (MIC) and eucapnic voluntary hyperventilation (EVH) as bronchoprovocation techniques. One patient had severe obstructive disease at presentation and therefore did not undergo bronchoprovocation. We found a wide variety of pulmonary abnormalities, including two patients with hypoxia (12%), two with obstruction (12%), three with restriction (18%) and four with AHR (23%). The data also suggest a strong association between pulmonary diseases in RA and cigarette smoking. Although no single characteristic lung disease such as AHR was identified in patients presenting with RA, the association between lung disease and cigarette smoking is striking and underscores the need to emphasise smoking cessation in this patient population.

Nitric oxide protects cardiomyocytes against tert-butyl hydroperoxide-induced formation of alkoxyl and peroxyl radicals and peroxidation of phosphatidylserine.

We studied protective effects of nitric oxide against tert-butyl hydroperoxide-induced oxidative damage to cardiac myocytes. Two distinct free radicals species--alkoxyl radicals associated with non-heme iron catalytic sites and myoglobin protein-centered peroxyl radicals--were found in low-temperature EPR spectra of cardiac myocytes exposed to t-BuOOH. The t-BuOOH-induced radical formation was accompanied by site-specific oxidative stress in membrane phospholipids (peroxidation of phosphatidylserine) assayed by fluorescence HPLC after metabolic labeling of cell phospholipids with oxidation-sensitive cis-parinaric acid. An NO-donor, (Z)-1-[N-(3-ammonio-propyl)-N-(n-propyl) amino]-diazen-1-ium-1,2-diolate], protected cardiac myocytes against tert-butyl hydroperoxide-induced: (i) formation of non-protein- and protein-centered free radical species and (ii) concomitant peroxidation of phosphatidylserine. Thus nitric oxide can act as an effective antioxidant in live cardiomyocytes.

Management of primary blast injury.

Blast waves are produced following the detonation of munitions, the firing of large caliber guns, or from any type of explosion. These blast waves can be powerful enough to injure the individuals exposed to them. This type of injury is called primary blast injury (PBI) and the organs most vulnerable to PBI are the gas-filled organs, namely the ear, the lungs and the gastrointestinal tract. The approach to the casualty with PBI is the same as it would be for any trauma victim, i.e. the initiation of life support measures. Attention should be directed to the common life-threatening manifestation of thoracic and abdominal PBI. Pulmonary manifestations would include hemorrhage, barotrauma and arterial air embolism, while abdominal manifestations would include hemorrhage and hollow organ rupture. Therapy is directed at the specific manifestations as well as avoiding additional iatrogenic injury.

The management of blast injury.

The unique physiologic and medical consequences of blast injuries are often unrecognized and frequently poorly understood. The medical consequences, including pulmonary, gastrointestinal and auditory injury, have a defined and unique set of physiologic sequelae. Understanding the mechanism of injury, treatment issues and the potential long-term morbidity of primary blast injuries will enhance survival.

Eucapnic voluntary hyperventilation as a bronchoprovocation technique: development of a standarized dosing schedule in asthmatics.

A variety of dosing schedules have been reported for the hyperventilation method of broncho-provocation testing. To evaluate the effect of challenge technique on the bronchoconstrictive response, we had 16 subjects perform eucapnic voluntary hyperventilation (EVH) with dry, room temperature gas using four different dosing schedules. The hyperventilation challenge dosages included the following: (1) a target minute ventilation (VE) of 20 x FEV1 for 6 min; (2) a target VE of 15 x FEV1 for 12 min; (3) an interrupted challenge with a target VE of 30 x FEV1 for 2 min repeated 3 times; and (4) a target VE of 30 x FEV1 for 6 min. Challenges 2, 3, and 4 gave identical absolute ventilatory challenges (identical factor FEV1 x minutes) but at different VE dosages or time. Challenges 1 and 4 were of identical length, but different target VE. The mean postchallenge fall in FEV1 was 16.6 +/- 10.9%, 11.0 +/- 8.1%, 19.6 +/- 9.9%, and 26.7 +/- 11.3% for challenges 1, 2, 3, and 4, respectively. The response to an identical EVH challenge (FEV1 x 30 for 6 min) was reproducible when performed on separate days. We conclude that the challenge technique used for hyperventilation testing will have a significant impact on the bronchoconstrictive response and must be taken into account when interpreting study results. Tests may be quantitatively comparable over a narrow range of challenge time and VE. We recommend that a 6-min uninterrupted EVH challenge using dry, room temperature gas at a target VE of 30 x FEV1 be adopted as the "standard" challenge.

Interpretation of eucapnic voluntary hyperventilation in the diagnosis of asthma.

Eucapnic voluntary hyperventilation (EVH) of dry gas is a physiologic bronchoprovocation challenge useful in the diagnosis of asthma. To determine the best parameter and threshold for diagnosis and the proper timing of postchallenge measurements, we reviewed 120 challenges, comparing the decrement from baseline in FVC, FEV1, mean forced expiratory flow during the middle half of the FVC (FEF25-75%), and peak expiratory flow rate (PEFR) each at 0, 5, 10, and 20 min postchallenge. After adjustment to a standard minute ventilation of 30 times the baseline FEV1 for 6 min, the mean response by 90 mild asthmatics differed from 30 normal subjects in all four parameters (p < 0.0001). In asthmatics, maximum decline from baseline (mean +/- SEM) was as follows: FVC, 12.1 +/- 1.2%; FEV1, 19.7 +/- 1.7%; FEF 25-75%, 33.5 +/- 2.5%; and PEFR, 29.0 +/- 1.9%. Normal subjects had a maximum fall as follows: FVC, 2.9 +/- 0.7%; FEV1, 3.8 +/- 0.7%; FEF25-75%, 11.8 +/- 2.0%; and PEFR, 11.5 +/- 1.0%. Based on comparison of receiver operator characteristic curves, FEV1 was more accurate than FEF25-75% and equivalent to FVC and PEFR. A threshold of 10% change or greater in FEV1 had a specificity of 90%, with a sensitivity of 63.3%. A threshold of 15% or greater had a specificity of 100%, with a sensitivity of 53.3%. The FEV1 fell by 10% or more in 55 of 90 asthmatics at 5 or 10 min after hyperventilation. Measurements at 0 or 20 min added two additional positive responses. We conclude that in the proper clinical setting, subjects whose FEV1 declines by 10% or more at 5 or 10 min after EVH should be diagnosed as having asthma.

The refractory period after eucapnic voluntary hyperventilation challenge and its effect on challenge technique.

To evaluate whether there is a refractory period (RP) after hyperventilation challenge, we compared the bronchoconstrictive response to repetitive eucapnic voluntary hyperventilation challenge with dry, room temperature air (EVH). The serial challenges were identical with 11 known asthmatics hyperventilating for 6 min at a target minute ventilation of 30 times their FEV1 measured before either challenge. There was a significant difference between the mean postchallenge fall in FEV1 to the initial EVH challenge (27.4 +/- 9.8%) and the response to the second EVH challenge (16.1 +/- 5.9%) (p = 0.0001), indicating refractoriness. We then evaluated whether 6 min of uninterrupted EVH challenge gives a similar bronchospastic response to that which results from an equivalent (by total minute ventilation) interrupted challenge of 2 min of EVH repeated three times. The mean post-challenge fall in FEV1 in response to this interrupted challenge was 18.9 +/- 10.6%, which was significantly different from the 27.4% fall in response to 6 consecutive minutes of EVH (p = 0.036). This study demonstrates that there is a refractory period after repeated EVH challenges and this refractoriness affects the response to interrupted, or dosed, EVH challenge.

Fiberoptic bronchoscopy in the evaluation of newly diagnosed esophageal carcinoma.

To determine the diagnostic utility of fiberoptic bronchoscopy (FB) in the evaluation of patients with newly diagnosed esophageal carcinoma (EC) and whether FB findings impact therapy and survival, we retrospectively reviewed 2,832 FB records (1984 through 1992). Twenty-two cases were identified in which FB was performed to evaluate pulmonary involvement in patients with newly diagnosed EC. Two cases were eliminated due to data unavailability. Seventeen of 20 patients had no pulmonary symptoms and most of them (15/17) had normal chest radiographs. All three patients with pulmonary symptoms (cough, hemoptysis, dyspnea) had significant radiographic abnormalities. In the asymptomatic group, FB findings were normal in nine, showed extrinsic compression of the trachea and/or bronchi in seven, and demonstrated a submucosal tumor nodule in one. The pathologic diagnosis of malignant airway involvement was not made in any asymptomatic patient. In the three symptomatic patients, extensive endobronchial abnormalities were present. Therapy with surgery, radiation, and/or chemotherapy did not differ among patients with extrinsic compression compared to patients with normal FB. Average survival in the patients with normal endobronchial anatomy was 20.5 months, in the group with extrinsic compression 12.2 months, and in the group with marked endobronchial abnormalities, less than 1 month. Statistical analysis of our findings suggest that FB is a low-yield procedure in the evaluation of patients with EC unless pulmonary symptoms of cough and/or hemoptysis or chest radiographic abnormalities are present.

Refractory period during provocation with eucapnic hyperventilation and methacholine.

Eucapnic voluntary hyperventilation (EVH) and methacholine inhalation challenge (MIC) both cause bronchoconstriction in asthmatics. A refractory period, or time when the response to bronchoprovocation in a series of challenges is diminished, has been found after hyperventilation or exercise but not after MIC. We investigated whether EVH or MIC blunted the response to the other test. Sixteen asthmatics were studied on 2 d, taking both tests each day. They were randomized to either EVH or MIC first on Day 1, then the opposite order on Day 2, 6 to 14 d apart. After EVH as a first test, the mean decline in FEV1 from baseline was 18.66 +/- 4.76% (mean +/- SEM), but when EVH followed MIC, the response to EVH was reduced by 30%, to a decline in FEV1 of only 13.02 +/- 3.75% (p = 0.0026). During MIC, the mean provocation dose to cause 20% decrease in FEV1 (PD20) given as the initial challenge was 54.77 +/- 21.60 breath units, compared with 46.94 +/- 19.55 breath units when MIC followed EVH (p = 0.54). However, the subset of patients most sensitive to methacholine (PD20 < 0.1 breath unit) had changes suggestive of a refractory period after EVH, with a mean increase in the PD20 from 0.06 +/- 0.01 to 3.35 +/- 1.43 (p = 0.069). Our data show that MIC attenuates the response to subsequent challenge with EVH. Conversely, EVH may only affect subsequent MIC in those most sensitive to methacholine.

Eucapnic voluntary hyperventilation as a bronchoprovocation technique. Comparison with methacholine inhalation in asthmatics.

Methacholine inhalation challenge (MIC) is probably the most widely used and best standardized test for nonspecific bronchoprovocation challenge (BPC). There has been increasing interest in developing "physical" stimuli such as eucapnic voluntary hyperventilation (EVH) with dry gas to assess airway hyperreactivity (AHR), because of inherent problems with using a pharmacologic agent in epidemiologic surveys. To our knowledge, no studies exist that compare MIC with EVH in known asthmatics. We conducted a prospective, randomized, crossover trial with a group of subjects (n = 16) who met the American Thoracic Society definition of asthma with these objectives: (1) to compare the sensitivity of EVH with MIC; (2) to compare the quantitative response of one test with the response to the other challenge; and (3) to correlate the response of both tests with symptoms, serum IgE levels, and serum eosinophil counts. We found that (1) EVH was positive in 75 percent of cases and MIC was positive in 81 percent of cases; one subject reacted to EVH but not to MIC and vice-versa. (2) The quantitative response to one test correlated with the response to the other test (r = -0.60, p = 0.01). (3) There was a correlation between severity of asthma symptoms and the response to EVH (r = 0.62; p = 0.01), but not to MIC. (4) Response to MIC (log PD20), but not EVH, correlated with serum IgE level (r = -0.53, p = 0.04). We suggest that EVH may be used for the initial assessment of AHR in the evaluation of asthma. Eucapnic voluntary hyperventilation is a sensitive measure of AHR and it correlates well with symptoms. Furthermore, though these points were not addressed in our study, it is more physiologic than MIC, and it is easy and less expensive to perform.

Fiberoptic bronchoscopy in the evaluation of carcinoma metastatic to the lung.

To determine the clinical presentation of patients with malignancies metastatic to the lung, the diagnostic utility of fiberoptic bronchoscopy (FB), and the primary site of malignancies metastasizing endobronchially, we retrospectively reviewed 1,853 FB records (1987 to 1991) and selected 111 cases for review. Cases were divided on the basis of FB findings into abnormal (44 patients) and normal (67 patients). Pulmonary symptoms (cough, hemoptysis, and chest pain) prompted referral significantly more often in the abnormal FB group (34/44) than in the normal FB group (24/67). The finding of atelectasis on chest radiograph occurred more frequently in patients with endobronchial abnormalities. The spectrum of extrapulmonary malignancies that metastasize endobronchially has changed during the AIDS epidemic. Our study shows the most frequent causes of endobronchial mass lesions were Kaposi's sarcoma and the lymphoma group (Hodgkin's disease, nonHodgkin's lymphoma, chronic lymphocytic leukemia) and the most common malignancies causing submucosal metastases were breast and the lymphoma group. In summary, the highest yield from FB can be expected in patients experiencing symptoms of cough or hemoptysis and/or having radiographic evidence of atelectasis. We propose a new mnemonic "KLAS" (Kaposi's sarcoma, Lymphoma, Adenocarcinoma, Sarcoma) to describe the malignancies most likely to metastasize endobronchially in the 1990s.

Water loss without heat flux in exercise-induced bronchospasm.

We identified inspired gas conditions that result in no net respiratory heat loss, an isenthalpic condition, but induce a mucosal loss of water. Inspired gas at 37 degrees C with 47 mm Hg water vapor pressure, 56 degrees C with 38 mm Hg; and 78 degrees C with 27 mm Hg has the same heat content as fully saturated air at body temperature. In four normal subjects hyperventilating at a minute ventilation of 30 times their FEV1 for 6 min, expired temperatures at the mouth averaged 39 degrees, 43 degrees, and 43 degrees C for the three conditions. Retrotracheal esophageal temperatures did not fall in any subject, thereby demonstrating the absence of significant airway cooling. Nine subjects with exercise-induced bronchospasm were tested under the same conditions. Baseline functions showed an FEV1 of 85 +/- 10% of predicted (mean +/- SD), FVC, 98 +/- 13% of predicted, and FEV1/FVC, 79 +/- 4% of predicted. The asthmatic subjects demonstrated postchallenge mean falls in FEV1 of 3.4%, 6.2%, and 10.1% for the three conditions, with bronchospasm increasing as the temperature of the inspired air increased (p = 0.001). The amount of respiratory water lost from the respiratory mucosa significantly correlated with the resultant bronchospastic response as measured by the fall in FEV1 (p = 0.017), but the net respiratory heat lost did not significantly correlate (p = 0.113). This study demonstrates that bronchospasm can be induced without significant respiratory heat loss or airway cooling and suggests that it is proportional to the amount of water lost from mucosal surfaces.

Blood pressure and other risk factors of cardiovascular disease in two communities with different socio-economic statuses: the Athens study.

Blood pressure and other risk factors of cardiovascular diseases were studied in two rural communities of 631 adults (greater than or equal to 18 years old) with different socio-economic statuses, populations A and B. Population A (n = 381) lived in a tourist village on an island, and population B (n = 250) in a remote mountain village. The socio-economic status of population A had improved considerably over the last decade but the physical environment, habits, culture and way of life had been disrupted. Blood pressure, prevalence of hypertension and other risk factors were higher than in population B where socio-economic status was lower but where there had been no disruption of the environment, traditional habits, culture or way of life. These findings might be due to the lack of preventive medicine services in the community.

Serum calcium and blood pressure in Greek girls.

In a random sample of 492 girls 12-15-years-old total serum calcium appeared to be correlated with blood pressure. Adolescents with total serum calcium equal to a greater than the cohort mean (2.5 mmol/l) had higher systolic blood pressures than those with a value below the cohort mean. This was present at all ages.