Bronchodilator reversibility in Australian adults with chronic obstructive pulmonary disease.

BACKGROUND AND AIMS: Bronchodilator reversibility (BDR) and inhaled corticosteroid (ICS) use were assessed for volunteers who responded to an advertisement requesting current or ex-smokers who were experiencing breathlessness to attend for lung function testing. METHODS: One hundred and fifty-four volunteers responded. Forced expiratory volume (FEV1) was measured before and after 400 microg of salbutamol. Significant BDR was assessed according to guidelines of: (i) the American Thoracic Society (> or =12% plus 200 mL of baseline FEV1 or forced vital capacity), (ii) the British-Thoracic Society (BTS) (> or =15% plus 200 mL of baseline FEV1), (iii) the European Thoracic Society (> or =10% predicted FEV1), and (iv) the most commonly used criteria in Australia and New Zealand (> or =15% of baseline FEV1). RESULTS: One hundred and twenty-three subjects (33 female; 40 current smokers; median pack years 48 (range 5-144)) were suitable for analysis (i.e. had no history of asthma, demonstrable airflow limitation and a forced expiratory ratio (FER) of <70%). Twenty (16%) patients had an FEV1 within the normal range but FER of <70%, 24 (20%) patients had mild disease (FEV1 60-80% predicted), 31 (24%) patients had moderate disease (FEV1 40-59% predicted), and 48 (39%) patients had severe disease (FEV1 <40% predicted), according to BTS criteria. Significant BDR was evident in: (i) 58 (47%) subjects by American criteria, (ii) 26 (21%) subjects by British criteria, (iii) 19 (15%) subjects by European criteria and (iv) 36 (29%) subjects by Australasian criteria. ICS use was reported by 71 (58%) subjects overall and was weakly, but significantly, related to poorer FEV1 (r = -0.2; P < 0.01), and greater BDR (r = 0.3; P < 0.005). CONCLUSION: Chronic obstructive pulmonary disease in Australian volunteers with no history of asthma encompasses many individuals with significant BDR. Interestingly, most volunteers reported ICS use and this was related to poorer spirometry and greater BDR. However, until the underlying immuno-pathology has been determined they cannot be assumed to have "asthma" or even an "asthmatic element".

A novel hypothesis to explain the bronchconstrictor effect of deep inspiration in asthma.

BACKGROUND: In healthy subjects deep inspiration transiently dilates the airways, while many asthmatic subjects show bronchoconstriction by a mechanism which is incompletely understood. We hypothesised that the negative intrathoracic pressure associated with deep inspiration occurring in the context of increased leakiness of the airway vasculature may temporarily increase airway oedema and thus reduce luminal diameter in subjects with asthma. METHODS: The effects of non-forced deep inspiration and forced deep inspiration through resistance (generating enhanced negative intrathoracic pressure) on specific airway conductance (sGaw) were compared in 10 asthmatic and 11 healthy subjects. Each performed two respiratory manoeuvres: (1) sGaw was measured immediately after three deep inspirations without added resistance, each performed at a predetermined rate (equal to that when performed maximally through resistance); and (2) sGaw was measured immediately after three forced inspirations through resistance. RESULTS: Compared with deep inspiration without added resistance, sGaw was significantly reduced after deep inspiration through resistance in the asthmatic group by a mean (SD) of -13.5 (11.0)% (p=0.003) but was unchanged in the control group (-0.5 (12.4)%, p=0.67). CONCLUSIONS: Given the similar time-volume relationship in the two manoeuvres, the reduction in sGaw is unlikely to be due to differences in smooth muscle behaviour. It is suggested that the enhanced negative intrathoracic pressure acting across the airway capillaries increases airway wall oedema and reduces airway calibre. Such a mechanism operational during normal rapid deep inspiration might contribute to bronchoconstriction after deep inspiration in subjects with asthma.

The apparent response of airway function to deep inspiration depends on the method of assessment.

The response to deep inspiration (DI) has been reported in terms of specific airway conductance (SGaw) pre- and post-DI, and by comparing forced expiratory flows following both maximal and partial inspiration (M/P ratio). The lung volume at which M/P has been obtained has varied between studies. We have investigated how the method of assessment affects the apparent response to DI. In 16 asthmatic and 16 control subjects both SGaw and M/P were measured, the latter at various lung volumes from 40 to 15% vital capacity (VC) (remaining). In each group M/P increased as lung volume decreased (r=-0.98, P<0.001 for each group). In contradistinction to M/P ratio, the SGaw ratio (post-DI: pre-DI) suggested a bronchoconstrictor asthmatic response (mean 0.938, SEM 0.029) and a bronchodilator control response (mean 1.063, SEM 0.029). SGaw ratio and M/P were correlated strongly in normals but not in asthmatics. These results confirm that the observed response to DI depends on the method used to measure it. The results in normals are explicable by DI-induced smooth muscle stretch increasing unstressed airway calibre, but also increasing compressibility on forced expiration. The results in asthma suggest the existence of an additional DI-related bronchoconstricting mechanism.

Airway hyperresponsiveness in asthma. Not just a problem of smooth muscle relaxation with inspiration.

Airway hyperresponsiveness in asthma has been attributed to impaired ability of deep inspiration (DI) to stretch airway smooth muscle. We have retested this hypothesis by comparing the responses to methacholine of 10 asthmatic and 10 control subjects. After each dose subjects breathed tidally without deep inspiration for 4 min, followed by a forced partial expiration from which flow was measured at a constant volume, 35% baseline VC (Vp 35). This index is independent of both DI and increases in end-inspiratory lung volume (EILV). EILV increased significantly more in the asthmatic group than in the control group (15.0 versus 2.5% of baseline VC, p = 0. 019), a factor that if not taken into account would tend to mask the difference in the two responses. Comparisons were made after a cumulative dose of 50 microg methacholine, which was the highest dose common to all subjects. The asthmatic response was significantly greater than that seen in the control group, with reductions to 25.9 and 72.1% of baseline Vp 35, respectively (p = 0. 0007). We conclude that the sensitivity of asthmatic airways to methacholine is greater than that of normal airways even when DI is prohibited. Therefore, the hyperresponsiveness of asthmatic airways is not attributable simply to an inability of DI to stretch airway smooth muscle.

Comparison of 5-fluorouracil anabolite levels after intravenous bolus and continuous infusion.

The levels of 5-fluorouracil (5FU) and its anabolites in the serum, bile, pancreatic juice, liver, pancreas, and skeletal muscle of dogs were compared after single bolus administration and after continuous infusion. Six dogs had a bolus of 5FU (15 mg/kg) and were studied for 120 min. Five dogs had a continuous infusion of 5FU (30 mg/kg) and were studied for 24 h. After the bolus infusion, serum 5FU levels were initially high and then declined, whereas anabolite levels gradually increased over 45 min. Within 2 h, anabolite levels exceeded 5FU levels in tissues but were undetectable in bile and pancreatic juice. During the continuous infusion, anabolite levels in serum increased more rapidly than 5FU levels and remained significantly higher for 24 h. Anabolite levels also exceeded 5FU levels in bile, pancreatic juice, pancreas, and muscle but not in the liver. Continuous infusion of 5FU produced higher levels of the anabolites than did bolus infusion and maintained constant levels throughout the infusion period.

5-Fluorouracil pharmacokinetics in patients with metastatic colorectal carcinoma after high-dose leucovorin.

The effect of high-dose leucovorin on 5-fluorouracil (5-FU) pharmacokinetics was studied in 5 patients with metastatic colorectal carcinoma. Patients received leucovorin, 500 mg/m2, and 5-FU, 600 mg/m2, on 1 day and 5-FU alone 1 week later. Plasma concentrations of 5-FU and 5-FU anabolites were determined over 2 hr. Levels of 5-FU were highest initially and then fell rapidly. Plasma concentration-time curves suggested a two-compartment kinetic model. Anabolite levels exceeded 5-FU levels after 15 min. When leucovorin was administered, the time of distribution (t1/2 alpha for 5-FU increased from 8.9 +/- 2.4 to 12.8 +/- 2.5 min (p < 0.0005) and the volume of distribution (Vd) increased from 0.129 +/- 0.039 to 0.237 +/- 0.033 L/kg (p < 0.03). Elimination and plasma clearance of 5-FU were unchanged. Anabolite levels were initially lower (p < 0.05) with leucovorin, suggesting increased tissue extraction of 5-FU.

Hepatopancreatic uptake and elimination of 5-fluorouracil after intravenous injection.

The efficacy of 5-fluorouracil (5FU) chemotherapy depends, in part, upon maintaining adequate intracellular levels of active metabolites. The uptake, distribution and elimination of 5FU and 5FU-anabolites were determined after an intravenous bolus infusion of 5FU, 15 mg kg-1, and the relationship between serum and tissue levels were evaluated. In six dogs samples of liver, pancreas, rectus abdominus muscle, blood, bile and pancreatic juice were collected at 0, 15, 45, 90 and 120 min. Bile and pancreatic juice levels of 5FU followed the same pattern as the serum, rising rapidly and falling exponentially, suggesting elimination by simple diffusion. Elimination of anabolites was more complex. Tissue levels of anabolites were highest in the liver and peaked later than in the pancreas and muscle. They were unrelated to serum levels of 5FU. The higher and more sustained levels of 5FU-anabolites in the liver may be responsible for some of the beneficial effects of 5FU chemotherapy on hepatic tumours.

Abdominal surgery in the elderly patient.

The accurate diagnosis of abdominal disease is important in the elderly, both to avoid negative exploration and to plan timely and appropriate operation. Emergency abdominal surgery has a higher mortality than elective surgery and is best avoided. A definitive planned elective procedure in the well-prepared elderly patient will avoid multiple operations and reduce mortality and morbidity.

Measurement of 5-fluorouracil and its active metabolites in tissue.

The 5-fluorouracil content of serum, bile, pancreatic juice, liver, pancreas and muscle was measured by reversed-phase high-performance liquid chromatography using a mobile phase of 5 mM 1-heptanesulfonic acid in 5 mM acetic acid. Free or unmetabolized 5-fluorouracil was extracted from samples with a mixture of light petroleum-n-propanol (40:60). The active metabolites of 5-fluorouracil were hydrolyzed with hot perchloric acid to free 5-fluorouracil and the combined 5-fluorouracil content was extracted. The active metabolite fraction was calculated from the difference between the combined and the free fractions. A straight line plot of the peak areas against concentration was achieved and the detection limit was 50 ng/ml. Five minutes after stopping an intravenous infusion of 15 mg/kg of 5-fluorouracil in a dog, the serum contained only the free form, but other body fluids and tissues contained both free and metabolite fractions. The method may be useful to determine the amount of total drug in patient samples.

Biliary and pancreatic excretion of cefamandole.

After intravenous infusion of secretin and cholecystokinin in six dogs, cefamandole (50 mg/kg of body weight) was given intravenously for 10 min. Samples of serum, bile, pancreatic juice, liver, pancreas, fat, and muscle were collected over a 2-h period. Cefamandole levels were measured by a microbiological assay. The highest levels were as follows: serum, 160 micrograms/ml; bile, 3,071 micrograms/ml; pancreatic juice, 7 micrograms/ml; liver, 101 micrograms/g; pancreas, 44 micrograms/g; muscle, 20 micrograms/g; and fat, 14 micrograms/g. Levels in pancreatic juice were extremely low compared with levels in pancreatic tissue, suggesting the existence of a barrier to excretion at the ductal membrane.

Diagnostic value of liver function tests in bile duct obstruction.

Serological tests may be of value in differentiating acute and chronic bile duct obstruction because the rate of alteration of hepatic cellular integrity and function will affect the rate of cellular product release. In a canine model the common bile duct was obstructed either suddenly (N = 7) or gradually (N = 5). A control group (N = 5) had the common bile duct dissected free from the surrounding tissues. Blood was taken before and 1, 2, 4, 7, 11, 14, 17, 21, and 28 days after initiating obstruction. Serum alkaline phosphatase, bilirubin, aspartate aminotransferase, alanine aminotransferase, ornithine carbamyl transferase, and gamma-glutamyl transferase levels were significantly greater with sudden compared to gradual occlusion, and the values were larger than those in the control. The range of values of alkaline phosphatase, bilirubin, and aspartate aminotransferase did not overlap in the acute and chronic groups at specific times. Serum albumin and total protein were normal in all groups. The magnitude of alkaline phosphatase, aspartate aminotransferase, and bilirubin elevation may help in the differentiation of acute and chronic biliary obstruction.

Effect of increasing inspired oxygen concentration on hemodynamics and regional blood flows.

Previous reports suggest that in response to increasing FIO2, peripheral resistance increases, cardiac output falls, and regional blood flow decreases. This study examined the influence of varying FIO2 on pulmonary and systemic vascular resistances (PVR, SVR), cardiac output, ventricular work, and regional blood flows in ten anesthetized Yorkshire white pigs. Each animal served as its own control, and was exposed to varying FIO2 in random order. PCO2 was maintained at 40 +/- 5 torr and body temperature at 38.5 degrees C. Heart rate, systemic arterial pressure, pulmonary artery pressure (PAP), pulmonary capillary wedge pressure, thermodilution cardiac output, and blood flows in the femoral, carotid, renal and superior mesenteric arteries were measured at each FIO2. SVR, PVR, left and right ventricular stroke work (LVSW, RVSW) were calculated. One-way analysis of variance-randomized block design (F-test) showed significant decreases in PAP, PVR, and RVSW with increased FIO2. No change was noted in regional flows, cardiac output, SVR, or LVSW. We conclude that in this animal model administration of oxygen up to an FIO2 of 1.0 had no adverse effect on hemodynamic performance.

Acute abdominal disease in the aged.

The elderly patient with acute abdominal disease may present with a classical clinical picture. However, the presentation often is atypical and perplexes the physician. The factors involved include altered anatomical features, fear of being placed in an institution, difficulty in communicating with the physician and family members, diminished response to infection, and multiple coexisting diseases. Awareness of the atypical clinical presentations and the judicious use of special investigations will enable the clinician to make earlier and more accurate diagnoses and, thus, reduce morbidity and mortality.

Pancreatic enzyme secretion during intravenous fat infusion.

The nutritional support of patients with pancreatic and high gastrointestinal fistulas and severe pancreatitis frequently involves intravenous fat infusion. There are conflicting reports on the effect of intravenous fat on pancreatic exocrine secretion. In 10 dogs with chronic pancreatic fistulas, pancreatic juice was collected during secretin (n = 10) or secretin + cholecystokinin (n = 4) stimulation, with and without intravenous fat infusion (5 g/hr). The hormonal-stimulated secretion of lipase, amylase, trypsin, total protein, bicarbonate, and water was unchanged during fat infusion. This study supports the use of intravenous fat as a nutritional source when it is desirable to avoid stimulation of the pancreas.

The effect of verapamil on pancreatic exocrine secretion.

This study set out to examine the effects of a Ca++ channel blocker, verapamil, on pancreatic exocrine secretion because of the known relationship between amylase secretion and intracellular Ca++. Pancreatic secretion was stimulated in dogs by infusing secretin and cholecystokinin. Verapamil was found to inhibit the secretion of amylase but to have no effect on lipase, trypsin, or total protein. There was no effect on the secretion of water and bicarbonate. To determine the possible physiologic significance of these findings, the pancreas was stimulated by a meat meal, and verapamil was found to inhibit amylase secretion again and in addition to inhibit the secretion of water and bicarbonate. The results suggest that verapamil has an inhibitory effect on amylase secretion by blocking the influx of Ca++ into the acinar cell and has an indirect effect leading to inhibition of water and bicarbonate secretion from the duct cells.

Blood-pancreatic juice barrier to antibiotic excretion.

Antibiotics were given intravenously to dogs with chronic pancreatic fistulas, and serum and pancreatic juice levels were measured. Despite adequate serum values, gentamicin, tetracycline, clindamycin, and moxalactam did not appear in the pancreatic juice, which suggested a barrier to their excretion. In contrast, chloramphenicol reached a peak concentration in the pancreatic juice that amounted to 36 percent of the peak serum value. In the pancreatic juice, ampicillin, cefoxitin, and cefamandole reached only 5 percent of the peak serum values but were still within the therapeutic range. We have concluded that there is a blood-pancreatic juice barrier to some antibiotics, which leads to selective excretion.

Hepatic fat accumulation during liver regeneration.

Fat accumulates in the regenerating liver after partial hepatectomy. The role of intracellular acyltransferases in the synthesis of triglycerides was studied in the liver. Two-thirds hepatectomy was performed in 14 rats. An additional 14 rats had laparotomy only (sham group). Animals were sacrificed at 18 or 24 hr after operation. After 18 hr, microsomal sn-glycerol 3-phosphate acyltransferase specific activity was increased from 708 to 956 pmole of glycerol 3-phosphate incorporated X min-1 X mg-1 protein and the triglyceride content was increased from 2.2 to 12.6 mg/g liver. At 24 hr the microsomal enzyme activity was again increased from 742 to 1203 pmole of glycerol 3-phosphate incorporated X min-1 X mg-1 protein and the triglyceride content rose from 1.9 to 13.9 mg/g liver. A correlation existed between the microsomal enzyme activity and the triglyceride level (r = 0.608, P less than 0.05). The mitochondrial enzyme activity was not increased. At 24 hr peroxisomal dihydroxyacetone acyltransferase activity was elevated from 375 to 523 pmole of dihydroxyacetone phosphate incorporated X min-1 X mg-1 protein but showed no correlation with the triglyceride content; the microsomal activity of the enzyme was not increased. Cytoplasmic NAD+-dependent alpha-glycerol 3-phosphate dehydrogenase decreased by 24 and 32% at 18 and 24 hr. These data indicate that the microsomal sn-glycerol 3-phosphate acyltransferase activity has a major role in promoting triglyceride synthesis during liver regeneration.

Changes in bile salt composition after cholecystectomy and ileal resection.

The effect of ileal resection and cholecystectomy on bile salt metabolism was studied in female prairie dogs 4 weeks after either a sham laparotomy, cholecystectomy, ileal resection, or cholecystectomy and ileal resection. Bile was collected from a common bile duct cannula at hourly intervals for 12 hours. Pool sizes and synthetic rates of primary and secondary bile salts were determined from washout curves. Cholate, chenodeoxycholate, deoxycholate, and lithocholate levels were determined by gas chromatography from pooled collections of bile. After cholecystectomy and ileal resection, the pool sizes of primary and secondary bile salts were significantly reduced to amounts that were much less than the pool sizes after either procedure alone. Primary bile salt synthesis was significantly increased after combined cholecystectomy and ileal resection, to the same degree as cholecystectomy alone. After the combined procedures, there was a decrease in the proportion of cholate in hepatic bile associated with an increase in chenodeoxycholate, deoxycholate, and lithocholate levels. The data suggest that after the loss of both ileum and gallbladder the bile salt pool sizes are drastically reduced, the synthesis of primary bile salts is increased, and the proportion of secondary bile salts is increased. Cholecystectomy should be avoided, if possible, in patients with ileal resection in order to conserve the bile salt pool and prevent severe fat malabsorption.

The effects of ileal resection with cholecystectomy on bile salt metabolism in the prairie dog.

The adverse effects of ileal resection on bile salt metabolism may be aggravated by cholecystectomy. Female prairie dogs had either sham laparotomy, cholecystectomy, distal 50% small bowel resection, or cholecystectomy and distal 50% small bowel resection. After 4 weeks the common bile duct was cannulated and bile collected for up to 12 hr. Bile salt pool size and synthetic rate were measured from the washout curve. Bile salt, phospholipid, and cholesterol concentrations were determined. Bile salt pool size was reduced after cholecystectomy and after ileal resection. Cholecystectomy plus ileal resection further lowered the pool size, increased the synthetic rate, and increased the proportion of secondary bile salts. Cholecystectomy increased the synthesis and the concentration of bile salts in hepatic bile and altered the proportions of biliary lipids. Ileal resection decreased the concentration of hepatic bile salts with the formation of noncholesterol stones. The drastic reduction in pool size with the combined operation might be expected to lead to fat malabsorption. The higher concentration of bile salts after the combined operation compared with ileal resection alone reflects a possible beneficial effect of cholecystectomy.