Role of single-breath carbon monoxide-diffusing capacity in monitoring the pulmonary effects of bleomycin in germ cell tumor patients.

Serial pulmonary function tests including single-breath carbon monoxide-diffusing capacity (DLCO), forced vital capacity (FVC), and forced expiratory volume in 1 sec were performed in a relatively homogeneous group of male patients with germ cell tumors treated with vinblastine, bleomycin, and cis-diamminedichloroplatinum. Of the pulmonary function tests used, the DLCO was shown to be the most sensitive indicator of subclinical bleomycin pulmonary effects. Decreases in DLCO were both total dose and schedule dependent. Patients receiving their total dose of bleomycin at a rate of 25 +/- 2 (S.D.) units/week developed a linear decrease in DLCO with increasing total doses of bleomycin. Changes in FVC did not correlate with bleomycin total dose. Although both the mean DLCO and FVC decreased after completion of bleomycin therapy, the mean FVC returned to base-line levels rapidly, whereas the decrease in mean DLCO was persistent for several months. When routine volumetric tests (FVC and forced expiratory volume in 1 sec) and DLCO are used in a systematic manner, DLCO is the most sensitive indicator of the subclinical pulmonary effects of bleomycin in germ cell tumor patients treated with vinblastine, bleomycin, and cis-diamminedichloroplatinum.

What is a 'restrictive' defect?

We studied 211 sets of pulmonary function data to evaluate spirographic findings in patients with restrictive defects, and to determine the significance of the spirographic interpretation of restriction. A combination of clinical and body plethysmographic data was used as the standard for the diagnosis of restriction. Restriction was diagnosed spirographically when forced vital capacity (FVC) was low and the ratio of one-second forced expiratory volume (FEV1) to FVC (FEV1/FVC%) was normal. With these criteria, using 70% as the lower limit of normal for FEV1/FVC%, the spirogram had a 93% sensitivity and an 82% specificity for the detection or exclusion of a restrictive defect. Ten percent of patients with pure obstructive defects by clinical and plethysmographic criteria showed a restrictive defect on the spirogram. Combined obstructive and restrictive defects were rare; in these cases the spirogram showed a restrictive defect but missed the obstructive component.

The interpretation of the spirogram. How accurate is it for 'obstruction'?

The accuracy of the spirogram in detecting or excluding airway obstruction based on airflow limitation was assessed prospectively in 200 subjects, 74 with obstruction and 126 without it. The diagnosis of airway obstruction was based on a combination of clinical and body plethysmographic data. The ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC %) had a sensitivity of 0.82 and a specificity of 0.98. A fixed lower limit seemed better than a lower limit based on prediction formulas. Because specificity is so much higher than sensitivity, less precise clinical information is required to confirm the presence of obstruction if FEV1/FVC % is abnormal than is needed to exclude obstruction if FEV1/FVC % is normal. Using a combination of FEV1/FVC % and the ratio of forced expiratory flow (FEF) at 50% of FVC gave a higher sensitivity with a comparable specificity when compared with FEV1/FVC % used alone. A normal value for FEF between 25% and 75% of FVC virtually ruled out obstruction, but low values had poor specificity.

Orthostatic hypertension. Pathogenetic studies.

Among 1800 referred hypertensive patients, 181 had recumbent diastolic blood pressures (DBP) below 90 mm Hg and standing DBP above 90 mm Hg. Orthostatic increments in DBP were greater in these orthostatic hypertensive patients than in 181 persistently hypertensive patients and 134 normotensive subjects. In 12 patients with orthostatic hypertension, the orthostatic fall in cardiac output (27.3 +/- 2.9%, measured by a respiratory method) was double that in 8 normotensive subjects (13.3 +/- 3.7%, p less than 0.01). An inflated pressure suit over the pelvis and lower limbs prevented the excessive fall in cardiac output and significantly reduced (p less than 0.02) the excessive rise in standing DBP in orthostatic hypertensive patients. Gravitational pooling of blood in the legs and reduction of blood in the head was measured by external gamma counting of autologous erythrocytes labeled with sodium pertechnetate Tc 99m through ports in fixed positions over the leg and the temple. Orthostatic intravascular pooling was significantly greater (p less than 0.01) in orthostatic hypertensive subjects than in normotensive subjects, and the magnitudes of orthostatic pooling and orthostatic increases in DBP were closely correlated (r = +0.85). Plasma norepinephrine concentrations were similar in recumbency and after sustained handgrip exercise, but significantly greater (p less than 0.01) after 5 to 60 mins of standing in orthostatic hypertensive subjects than in normotensive subjects. Our results indicate that orthostatic hypertension is common and that its mechanism in representative patients involves excessive orthostatic blood pooling, which results in decreased venous return, decreased cardiac output, increased sympathetic stimulation (presumably through low-pressure cardiopulmonary receptors), and excessive arteriolar, but not venular, constriction.

Dyspnea in patients with hyperbradykininism and excessive venous pooling.

In the original description of the syndrome of hyperbradykininism, dyspnea on exertion was not described. However, in five women with the syndrome, ages 31 to 58, four of whom had at least one elevated value of blood kinin as determined by radioimmunoassay, dyspnea on exertion was a prominent complaint. During treadmill walking at a constant power requirement against gravity, expired air gas collections and equilibrium carbon dioxide rebreathing were performed. Seventeen apparently healthy women, ages 18 to 48, served as control subjects. Although oxygen uptake was the same in both groups by design (oxygen uptake 0.91 liters per minute, 0.11 standard deviation [SD], in the control subjects; oxygen uptake 0.97 liters per minute, 0.12 [SD] in the patients), cardiac output was significantly reduced in the patients (cardiac output 8.4 liters per minute, 1.3 [SD], in the control subjects; cardiac output 6.3 liters per minute, 0.9 [SD], in the patients, p less than 0.01). End-tidal carbon dioxide tension was significantly lower in the patients (end-tidal carbon dioxide tension 41 torr, 3 [SD], for the control subjects; end-tidal carbon dioxide tension 33 torr, 7 [SD], for the patients). In one patient, repeated studies over a 12-month period demonstrated a positive relationship between end-tidal carbon dioxide tension and the respiratory exchange ratio. (Respiratory exchange ratio = 0.01 + 0.027 X end-tidal carbon dioxide tension, 0.073 standard error of the estimate [SEE], 0.71 regular correlation coefficient, n = 20). This relationship was opposite to that expected with voluntary overbreathing; it was interpreted to mean that reduced cardiac output with exercise occurred to a variable degree and was the cause of hyperpnea and hypocapnia. In the same patient, studies at exercise with and without the Jobst (antigravity) garment and studies at exercise in the supine and erect position were consistent with the hypothesis that dyspnea and exercise intolerance were caused by venous pooling when standing. It is concluded that hyperbradykininism is characterized not only by orthostatic hypotension and tachycardia with light-headedness, as originally described, but also by severe dyspnea on exertion with exercise intolerance. The mechanism remains obscure, and the treatment is unsatisfactory, but temporary improvement in the abnormal physiology can be achieved in some patients with the use of an antigravity garment.

Post-test probability of asthma following methacholine challenge.

Using recently published data, a nomogram was constructed to estimate the likelihood of asthma following methacholine challenge. Based on Bayes' theorem, the nomogram makes use of the sensitivity and specificity of methacholine challenge to calculate the post-test probability of asthma once the physician makes a determination of the pretest probability, that is, the likelihood of asthma before the test results are considered. A family of curves is presented to cover several levels of cumulative breath units at which the test could become positive, and a single curve is presented for a negative test after 224 cumulative breath units. Separate curves are presented for smokers and nonsmokers. The estimate of pretest probability is most crucial in negative tests where likelihood of asthma is considered high, and in positive tests in patients in whom asthma is considered unlikely. Although these curves will not apply precisely to a different data base, the concept of the relationship between pretest and post-test probability helps in the interpretation of the test results and stresses the importance of using all available information in making a diagnosis.

Relationship of rib cage and abdomen motion to diaphragm function during quiet breathing.

Although rib cage (RC) and abdomen (Ab) motion is believed to reflect intercostal and diaphragm contributions to breathing, systematic investigations have failed to confirm this. We measured inspiratory changes in RC and Ab anterior-posterior diameter (delta RC and delta Ab) both corrected for volume equivalence (isovolume) and not corrected (isodistance, observed), and correlated these with simultaneous changes in gastric (delta Pab) and esophageal (delta Ppl) pressure: delta Pab - delta Ppl = delta Pdi, the change in transdiaphragmatic pressure. The delta Pab/delta Pdi was used as an index of the relative contribution of diaphragm motion to the breathing process. Relative abdomen motion was expressed as delta Ab/(delta Ab + delta RC). Isodistance and isovolume delta Ab/(delta Ab + delta RC) correlated, R = 0.69; observed abdomen motion overestimated abdomen-diaphragm contribution to tidal volume. Isodistance delta Ab/(delta Ab + delta RC) was less for women than men; isovolume delta Ab/(delta Ab + delta RC) was similar for the two sexes. Among individuals, isodistance delta Ab/(delta Ab + delta RC) correlated with delta Pab/delta Pdi (R = 0.73, P less than 0.001). Within a given individual, the mean R for seven subjects for delta Pab/delta Pdi vs delta Ab/(delta Ab + delta RC) was 0.90. We conclude that observed rib cage and abdomen motion reflects intercostal and diaphragm contributions to breathing; the correlation is better within a given subject than among individuals.

Prospective study of controlled oxygen therapy. Poor prognosis of patients with asynchronous breathing.

Thirty-two patients were evaluated within 24 hours of admission for 36 episodes of acute respiratory failure (arterial oxygen pressure less than or equal to 50 mm Hg). Clinical data, spirometric determinations, blood gas analysis, and synchronization of chest (rib cage) and abdominal (diaphragmatic) breathing movements were studied. All patients were initially treated with controlled oxygen therapy. In 25 episodes the patients recovered without intubation (successes). In nine episodes the patients required intubation and assisted ventilation; two of these patients died. Two patients died without intubation. The 25 successful episodes were compared with the 11 requiring intubation or associated with death (failures). The breathing pattern proved to be the best single factor for predicting success or failure (77 percent correct prediction). The breathing pattern plus the arterial carbon dioxide tension on admission was the best two-factor guide (86 percent correct prediction). Patients with asynchronous breathing and severe hypercapnia are so unlikely to do well with a program of controlled oxygen therapy that preparations for intubation and assisted ventilation should be made on admission and such measures should be instituted at the first sign of deterioration.

Asynchronous breathing movements in patients with chronic obstructive pulmonary disease.

An electromagnetic ventilation monitor was used to record the separate anterior-posterior movements of the chest and abdomen during the breathing cycle in 30 patients with chronic obstructive pulmonary disease (COPD) and in 10 normal subjects. In all normal subjects and 17 COPD patients, the chest and abdomen movements were syndhronous and in phase with the flow of air as measured with a spirometer. In 13 COPD patients chest movement was synchronous with the flow of air, but the abdomen moved inward suddently near or at end inspiration and then outward during a variable part of expiration. Compared to COPD patients with a normal breathing pattern, those with asynchronous breathing movements had poorer ventilatory mechanics and 10 of the 13 were dependent on assisted ventilation. Nine of the 13 patients with asynchronous breathing have died in a 10 month period, a significantly higher mortality than in those with normal breathing.

A two-bag system for continuous measurement of oxygen uptake.

Collection of mixed expired gas in a bag has been a classic method for the estimation of VO2 during the steady state but has not been employed during unsteady state exercise in part because there is a need for suspending the acquisition of data during the period of gas analysis unless many bags are used. In this study a two-bag system is described in which one bag fills while the other is analyzed. Bag volume is under the control of the operator, and we employed volumes of 30 to 50 L. Thirty-one subjects were studied with this circuit in a progressive treadmill test. Although VO2 could be falsely elevated during periods of overbreathing, this source of error could be identified and its effect reduced if VO2 was plotted against both ventilation and power requirement. Plateau values of VO2 were identified only in six subjects and the ventilatory threshold in 16.

Effect of cardiac, pulmonary, and vascular disease on one-minute oxygen uptake.

A simplified method for estimation of one-minute oxygen uptake (VO2-1) during treadmill grade walking at vertical power requirements of 250, 750, and 1,000 kg-meters/min was devised, where power=weight (kg) X grade (fractional) X walking speed. All subjects were men. There were 29 controls, 34 subjects with coronary arterial disease (of whom 18 had had myocardial infarction), nine subjects with diffuse pulmonary disease, and four subjects with ischemic vascular disease. Abnormally reduced values for VO2-1 were related to these diseases and, more specifically, to a history of myocardial infarction and (in pulmonary subjects) to reduced single-breath diffusing capacity. Lowest values of VO2-1 for a group were found in ischemic vascular disease. Reduced response of VO2-1 may therefore be caused by central defects of oxygen transport.

Functional results of muscle flap closure for sternal infection.

The morbidity and mortality of infection after median sternotomy have been substantially reduced with the advent of treatment by wide sternal resection and muscle flap closure. A study was performed comparing the cardiorespiratory function of 13 such patients before and after operation as well as with a control group of 15 patients who underwent similar procedures without complication. The groups were comparable in preoperative pulmonary function, though more patients in the study group had evidence of chronic lung disease. Patients were studied 2 to 39 months after the original procedure. Late postoperative pulmonary function test results, exercise tolerance, and oxygen uptake were not significantly different between the groups, and pulmonary function test results were unchanged in those patients who were tested preoperatively. We conclude that muscle flap reconstruction for sternal infection can be expected to give good long-term functional results. Exercise tolerance and pulmonary function may not differ from a control group of cardiac surgical patients, despite the altered composition of the chest wall. Patients with chronic lung disease may be more prone to have this complication.

The effect of progressive exercise on the equilibrium rebreathing cardiac output method.

The equilibrium CO2 rebreathing method has been used in the study of exercise cardiac output (Q) in health and disease, but the requirement for a steady state has usually limited its application to step function exercise. This limits testing to only a few levels of exertion in a laboratory session. We have devised a treadmill test where the grade is flat at the beginning and rises continuously at 1%.min-1 after stable measurements are obtained during level walking. The walking speed is determined by the subject's comfort and tolerance for fast walking. In series I seven normal subjects were studied with this protocol, and an automated system was employed for estimation of Q and oxygen uptake (VO2). For comparison of steady state and progressive tests, an interpolation method was devised which furnished a value of Q (progressive) that could exist at the value of VO2 obtained during the steady state. The average difference in Q so estimated between the steady state and the unsteady state was 0.3 l.min-1, SD = 1.7. This difference was less than the difference between averages of duplicate values of Q obtained during the steady state (1.11.min-1, SD = 16), and the difference between the two differences was not significant. Based on 51 determinations of Q and VO2 in eight normal subjects the unsteady state procedure furnished an average value of the relation slope of delta Q/delta VO2(-1) of 4.8 l.l-1. We conclude that the equilibrium CO2 method can be used to depict the Q, VO2 relationship over the range of VO2 at which rebreathing is tolerable.