Adenosine 5'-monophosphate in asthma: gas exchange and sputum cellular responses.

Adenosine 5'-monophosphate (AMP) bronchoprovocation reproduces the lung function abnormalities that occur spontaneously during acute asthma and detects peripheral airway inflammation better than direct bronchoconstrictive agents. Pulmonary gas exchange disturbances may reflect changes in small airways related to airway inflammation rather than bronchoconstriction alone. The present authors investigated whether AMP induced a greater imbalance in the ventilation/perfusion ratio than methacholine (MCh), at an equivalent degree of bronchoconstriction, with and without salbutamol pre-medication. In total, 36 asthmatics were studied in three randomised, double-blind, crossover studies: 1) before and after AMP or MCh; 2) before and 30 min after salbutamol or placebo, followed by AMP; or 3) MCh challenge. Sputum was collected before and 4 h post-challenge. Compared with MCh, AMP provoked similar pulmonary gas exchange abnormalities at an equivalent degree of intense bronchoconstriction (forced expiratory volume in one second decrease of 28-44%). While salbutamol blocked AMP- or MCh-induced bronchoconstriction, arterial oxygen tension (P(a,O(2))) and alveolar-arterial oxygen tension difference (P(A-a,O(2))) disturbances induced by AMP and MCh were only partially blocked (P(a,O(2)) by 46 and 42%, respectively; P(A-a,O(2)) by 58 and 57%, respectively). Compared with MCh, AMP increased the percentage of neutrophils (mean+/-se increased from 28+/-4% to 38+/-4%), but this increase did not occur after salbutamol pre-treatment. Both adenosine 5'-monophosphate and methacholine induced similar peripheral airway dysfunction. The fully inhibited adenosine 5'-monophosphate-induced neutrophilia with residual hypoxaemia observed after salbutamol treatment is probably related to beta(2)-agonists acting on both bronchial and pulmonary circulation.

Effects of erythropoietin on muscle O2 transport during exercise in patients with chronic renal failure.

Erythropoietin (rHuEPO) has proven to be effective in the treatment of anemia of chronic renal failure (CRF). Despite improving the quality of life, peak oxygen uptake after rHuEPO therapy is not improved as much as the increase in hemoglobin concentration ([Hb)] would predict. We hypothesized that this discrepancy is due to failure of O2 transport rates to rise in a manner proportional to [Hb]. To test this, eight patients with CRF undergoing regular hemodialysis were studied pre- and post-rHuEPO ([Hb] = 7.5 +/- 1.0 vs. 12.5 +/- 1.0 g x dl-1) using a standard incremental cycle exercise protocol. A group of 12 healthy sedentary subjects of similar age and anthropometric characteristics served as controls. Arterial and femoral venous blood gas data were obtained and coupled with simultaneous measurements of femoral venous blood flow (Qleg) by thermodilution to obtain O2 delivery and oxygen uptake (VO2). Despite a 68% increase in [Hb], peak VO2 increased by only 33%. This could be explained largely by reduced peak leg blood flow, limiting the gain in O2 delivery to 37%. At peak VO2, after rHuEPO, O2 supply limitation of maximal VO2 was found to occur, permitting the calculation of a value for muscle O2 conductance from capillary to mitochondria (DO2). While DO2 was slightly improved after rHuEPO, it was only 67% of that of sedentary control subjects. This kept maximal oxygen extraction at only 70%. Two important conclusions can be reached from this study. First, the increase in [Hb] produced by rHuEPO is accompanied by a significant reduction in peak blood flow to exercising muscle, which limits the gain in oxygen transport. Second, even after restoration of [Hb], O2 conductance from the muscle capillary to the mitochondria remains considerably below normal.

Platelet-activating factor causes ventilation-perfusion mismatch in humans.

We hypothesized that platelet-activating factor (PAF), a potent inflammatory mediator, could induce gas exchange abnormalities in normal humans. To this end, the effect of aerosolized PAF (2 mg/ml solution; 24 micrograms) on ventilation-perfusion (VA/Q) relationships, hemodynamics, and resistance of the respiratory system was studied in 14 healthy, nonatopic, and nonsmoking individuals (23 +/- 1 [SEM]yr) before and at 2, 4, 6, 8, 15, and 45 min after inhalation, and compared to that of inhaled lyso-PAF in 10 other healthy individuals (24 +/- 2 yr). PAF induced, compared to lyso-PAF, immediate leukopenia (P < 0.001) followed by a rebound leukocytosis (P < 0.002), increased minute ventilation (P < 0.05) and resistance of the respiratory system (P < 0.01), and decreased systemic arterial pressure (P < 0.05). Similarly, compared to lyso-PAF, PaO2 showed a trend to fall (by 12.2 +/- 4.3 mmHg, mean +/- SEM maximum change from baseline), and arterial-alveolar O2 gradient increased (by 16.7 +/- 4.3 mmHg) (P < 0.02) after PAF, because of VA/Q mismatch: the dispersion of pulmonary blood flow and that of ventilation increased by 0.45 +/- 0.1 (P < 0.01) and 0.29 +/- 0.1 (P < 0.04), respectively. We conclude that in normal subjects, inhaled PAF results in considerable immediate VA/Q inequality and gas exchange impairment. These results reinforce the notion that PAF may play a major role as a mediator of inflammation in the human lung.

Cellular bioenergetics after erythropoietin therapy in chronic renal failure.

After erythropoietin (rHuEPO) therapy, patients with chronic renal failure (CRF) do not improve peak O2 uptake (VO2 peak) as much as expected from the rise in hemoglobin concentration ([Hb]). In a companion study, we explain this phenomenon by the concurrent effects of fall in muscle blood flow after rHuEPO and abnormal capillary O2 conductance observed in CRF patients. The latter is likely associated with a poor muscle microcirculatory network and capillary-myofiber dissociation due to uremic myopathy. Herein, cellular bioenergetics and its relationships with muscle O2 transport, before and after rHuEPO therapy, were examined in eight CRF patients (27 +/- 7.3 [SD] yr) studied pre- and post-rHuEPO ([Hb] = 7.8 +/- 0.7 vs. 11.7 +/- 0.7 g x dl-1) during an incremental cycling exercise protocol. Eight healthy sedentary subjects (26 +/- 3.1 yr) served as controls. We hypothesize that uremic myopathy provokes a cytosolic dysfunction but mitochondrial oxidative capacity is not abnormal. 31P-nuclear magnetic resonance spectra (31P-MRS) from the vastus medialis were obtained throughout the exercise protocol consisting of periods of 2 min exercise (at 1.67 Hz) at increasing work-loads interspersed by resting periods of 2.5 min. On a different day, after an identical exercise protocol, arterial and femoral venous blood gas data were obtained together with simultaneous measurements of femoral venous blood flow (Qleg) to calculate O2 delivery (QO2leg) and O2 uptake (VO2leg). Baseline resting [phosphocreatine] to [inorganic phosphate] ratio ([PCr]/[Pi]) did not change after rHuEPO (8.9 +/- 1.2 vs. 8.8 +/- 1.2, respectively), but it was significantly lower than in controls (10.9 +/- 1.5) (P = 0.01 each). At a given submaximal or peak VO2leg, no effects of rHuEPO were seen on cellular bioenergetics ([PCr]/[Pi] ratio, %[PCr] consumption halftime of [PCr] recovery after exercise), nor in intracellular pH (pHi). The post-rHuEPO bioenergetic status and pHi, at a given VO2leg, were below those observed in the control group. However, at a given pHi, no differences in 31P-MRS data were detected between post-rHuEPO and controls. After rHuEPO, at peak VO2, Qleg fell 20% (P < 0.04), limiting the change in QO2leg to 17%, a value that did not reach statistical significance. The corresponding O2 extraction ratio decreased from 73 +/- 4% to 68 +/- 8.2% (P < 0.03). These changes indicate that maximal O2 flow from microcirculation to mitochondria did not increase despite the 50% increase in [Hb] and explain how peak VO2leg and cellular bioenergetics (31P-MRS) did not change after rHuEPO. Differences in pHi, possibly due to lactate differences, between post-rHeEPO and controls appear to be a key factor in the abnormal muscle cell bioenergetics during exercise observed in CRF patients.

Antibiotics for exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Most patients with an exacerbation of chronic obstructive pulmonary disease (COPD) are treated with antibiotics. However the value of their use remains uncertain. Some controlled trials of antibiotics have shown benefit (Berry 1960; Pines 1972) while others have not (Elmes 1965b; Nicotra 1982). OBJECTIVES: To conduct a systematic review of the literature estimating the value of antibiotics in the management of acute COPD exacerbations. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2005); MEDLINE (1966 to December 2005); EMBASE (1974 to December 2005); Web of Science (December 2005), and other electronically available databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) in patients with acute COPD exacerbations comparing antibiotic (for a minimum of five days) and placebo. DATA COLLECTION AND ANALYSIS: Data were analysed using Review Manager software. Continuous data were analysed using weighted mean differences (WMD) and 95% confidence intervals (CI). Relative risks (RR) (and 95% CI) were calculated for all dichotomous data. Where appropriate, number needed to treat to benefit (NNT) and 95% CI were calculated. MAIN RESULTS: Eleven trials with 917 patients were included. Ten trials used increased cough, sputum volume and purulence diagnostic criteria for COPD exacerbation. Eight-hundred and fifty-seven patients provided data for outcomes including mortality, treatment failure, increased sputum volume, sputum purulence, PaCO(2), PaO(2), peak flow and adverse events. Antibiotic therapy regardless of antibiotic choice significantly reduced mortality (RR 0.23; 95% CI 0.10 to 0.52 with NNT of 8; 95% CI 6 to 17), treatment failure (RR 0.47; 95% CI 0.36 to 0.62 with NNT of 3; 95% CI 3 to 5) and sputum purulence (RR 0.56; 95% CI 0.41 to 0.77 with NNT of 8; 95% CI 6 to 17). There was a small increase in risk of diarrhoea with antibiotics (RR 2.86; 95% CI 1.06 to 7.76). Antibiotics did not improve arterial blood gases and peak flow. AUTHORS' CONCLUSIONS: This review shows that in COPD exacerbations with increased cough and sputum purulence antibiotics, regardless of choice, reduce the risk of short-term mortality by 77%, decrease the risk of treatment failure by 53% and the risk of sputum purulence by 44%; with a small increase in the risk of diarrhoea. These results should be interpreted with caution due to the differences in patient selection, antibiotic choice, small number of included trials and lack of control for interventions that influence outcome, such as use of systemic corticosteroids and ventilatory support. Nevertheless, this review supports antibiotics for patients with COPD exacerbations with increased cough and sputum purulence who are moderately or severely ill.

Toward a consensus definition for COPD exacerbations.

In patients with COPD, an acute worsening of respiratory symptoms is often described as an exacerbation. Exacerbations are associated with a significant increase in mortality, hospitalization, and health-care utilization, but there is currently no widely accepted definition of what constitutes an exacerbation of COPD. This paper summarizes the discussions of the workshop, "COPD: Working Towards a Greater Understanding," in which the participants proposed the following working definition of an exacerbation of COPD: a sustained worsening of the patient's condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD.

Nosocomial pneumonia. A multivariate analysis of risk and prognosis.

One hundred and twenty consecutive episodes of nosocomial pneumonia (NP) in 118 nonneutropenic adults admitted to a 1,000-bed teaching hospital were studied in order to investigate the prognosis and risk factors. The overall fatality rate was 36.6 percent. The identification of a "high-risk" microorganism (Pseudomonas aeruginosa, Enterobacteriaceae, and other Gram-negative bacilli, Streptococcus faecalis, Staphylococcus aureus, Candida sp, Aspergillus sp, and episodes of polymicrobial pneumonia), bilateral involvement on chest x-ray examination, the presence of respiratory failure, inappropriate antibiotic therapy, and age older than 60 years or an underlying condition ultimately or rapidly fatal were those factors selected by a stepforward logistic regression analysis as independently worsening the prognosis. A series of variables frequently quoted as predisposing to NP was determined to be either present or absent in the same 120 cases of NP and in an equal number of randomly selected control subjects. After adjusting for confounding, factors significantly predisposing to NP were tracheal intubation, depressed level of consciousness, underlying chronic lung disease, thoracic or upper abdominal surgery, prior episode of a large volume aspiration, and age older than 70 years. Since some of the factors influencing the risk or the prognosis of NP are amenable to medical intervention, a percentage of NP might be prevented and its prognosis can be improved.

Effect of acetylsalicylic acid on pulmonary gas exchange in patients with severe pneumonia: a pilot study.

BACKGROUND: It has been hypothesized that local release of prostacyclin in acute pneumonia may ablate hypoxic pulmonary vasoconstriction, thus contributing to the impairment of pulmonary gas exchange in these patients. Inhibition of cyclooxygenase pathway could prevent this phenomenon by reducing the release of these metabolites. METHODS: A study was designed to assess the effect of I.V. acetylsalicylic acid (ASA) (2 g) on pulmonary gas exchange in seven patients (age, 64+/-11 [mean+/-SD] years) with unilateral severe pneumonia (PaO2/fraction of inspired oxygen, 168+/-67) needing mechanical ventilation. Respiratory gases, pulmonary and systemic hemodynamics, and ventilation-perfusion (VA/Q) distributions were studied before and 15 and 60 min after the infusion of ASA. RESULTS: At baseline, the amount of shunt (VA/Q ratios <0.005) was 28+/-17% of cardiac output, blood flow to areas with low VA/Q ratios (<0.1, excluding shunt) was 8+/-7%, and the dispersion of pulmonary blood flow distribution (second moment, log SD Q) was 1.45+/-0.49 (normal range, 0.3 to 0.6). Sixty minutes after the infusion of ASA, we observed a mild reduction of the amount of shunt, from 28+/-17% to 23.5+/-13% (p<0.05) without changes in arterial oxygenation. This was associated with a significant increase in mean pulmonary artery pressure (from 21.9+/-3.6 to 24.4+/-5.1 and 23.9+/-5.3 mm Hg, p<0.025 and p=0.1) and pulmonary vascular resistance (from 1.4+/-0.9 to 1.8+/-0.8 and 1.8+/-1.3 mm Hg x min x L(-1) , p<0.002 and p=0.11) 15 and 60 min after ASA, respectively. The ASA plasma levels were within the normal therapeutic range (120+/-7 microg/mL, 15 min, and 113+/-11 microg/mL, 60 min after ASA infusion). CONCLUSIONS: Although there was a modest improvement in intrapulmonary shunt, our results suggest that perfusion of ASA in this small sample of patients with severe pneumonia appears to be of little benefit as complementary treatment for severe hypoxemia.

Ventilation-perfusion response after fenoterol in hypoxemic patients with stable COPD.

BACKGROUND: The effects of vasoactive drugs, including bronchodilators, on vascular and pulmonary dynamics are interrelated, complex and difficult to measure, but important because of potential deleterious effects on gas exchange. METHODS: To assess the effects of fenoterol at both high and low dose on pulmonary gas exchange in 24 hypoxemic patients with stable COPD: fenoterol, 5 mg; fenoterol, 1 mg and ipratropium bromide, 0.5 mg; ipratropium bromide, 0.5 mg; or matched placebo were nebulized in a double-blind, placebo-controlled fashion. Spirometry, ventilation, systemic hemodynamics, and respiratory and inert gases were measured before and 15, 60, and 120 min after each treatment. RESULTS: Compared with placebo, heart rate (p < 0.002) and cardiac output (p = 0.05) increased after high-dose fenoterol therapy to return to baseline values by 120 min. Following fenoterol at high dose, mean maximum PaO2 change from baseline decreased by 6.3 +/- 1.1 mm Hg (SD) and both alveolararterial oxygen pressure difference (P[A-a]O2), by 8.3 +/- 4.0 mm Hg, and ventilation-perfusion (VA/Q) mismatching increased, as evidenced by increments of the dispersion of pulmonary blood flow, without reaching significance; likewise, low-dose fenoterol therapy increased VA/Q inequalities while both PaO2 and P(A-a)O2 remained unchanged. CONCLUSIONS: In this population of COPD patients, high-dose fenoterol therapy [corrected] significantly increased heart rate and cardiac output resulting in minor adverse consequences on arterial oxygenation and VA/Q relationships.

Hypoxic pulmonary vasoconstriction and gas exchange during exercise in chronic obstructive pulmonary disease.

In patients with chronic obstructive pulmonary disease (COPD) studied at rest, nifedipine releases hypoxic pulmonary vasoconstriction (HPV) and worsens gas exchange. During exercise, this drug lowers pulmonary hypertension, but the effects of this lower pulmonary vascular tone on ventilation-perfusion (VA/Q) relationships are still poorly understood. To analyze them, we determined the VA/Q distributions in eight patients with stable COPD (FEV1, 36 percent of predicted) at rest and during exercise (60 percent VO2 max), before and after nifedipine (20 mg sublingually). Nifedipine shifted to the right the pulmonary pressure-flow relationship (p less than 0.01) and increased the dispersion of the blood flow distribution at rest and during exercise (p less than 0.005). These observations strongly suggest that nifedipine released HPV under both conditions. However, even after releasing HPV by nifedipine, exercise distributed blood flow more homogeneously than at rest (p less than 0.05). Besides, exercise greatly decreased the overall degree of VA/Q mismatching (p less than 0.001) not only before but also after nifedipine. Thus, we postulate that most of the VA/Q improvement that exercise may induce in patients with COPD, as it is shown here, is due to improvement in the ventilation distribution. Interestingly, this VA/Q improvement was not paralleled by a significant decrease of P(A-a)O2. This apparent paradox could be explained by 20 percent of the actual P(A-a)O2 during exercise due to diffusion limitation, as assessed through the inert gas approach. Taken all together, these results help to better understand the mechanisms that govern pulmonary gas exchange during exercise in COPD.

Gas exchange and pulmonary hemodynamics during lung resection in patients at increased risk: relationship with preoperative exercise testing.

STUDY OBJECTIVES: To evaluate the intraoperative evolution of patients with COPD during lung resection and to test whether exercise testing could be helpful in the prediction of the intraoperative course. DESIGN: Prospective study. SETTING: University teaching hospital. PATIENTS: Forty patients (mean [+/- SD] age, 65 +/- 9 years) with COPD (ie, FEV(1), 55 +/- 11% of predicted) and resectable lung neoplasms. INTERVENTIONS: Preoperatively, pulmonary function testing, quantitative lung perfusion scanning, and exercise performance testing were administered. Intraoperatively, pulmonary, hemodynamic, and blood gas measurements were performed at five stages, including periods of two-lung ventilation (TLV) and periods of one-lung ventilation (OLV). RESULTS: During OLV, compared with TLV, the PaO(2)/fraction of inspired oxygen (FIO(2)) ratio decreased from 458 +/- 120 to 248 +/- 131 mm Hg (p < 0.05), whereas pulmonary artery pressure (PAP) increased from 18 +/- 5 to 23 +/- 5 mm Hg (p < 0.05). Cardiac output (t) also increased from 4.0 +/- 1.2 to 5.1 +/- 1.9 L/min (p < 0.05), yielding to a higher mixed venous PO(2). Both PaO(2) and t during OLV were significantly lower in patients who had undergone right thoracotomies compared with those who had undergone left thoracotomies. The PaO(2)/FIO(2) ratio during OLV correlated with the PaO(2) during exercise (r = 0.39; p = 0.01) and with the perfusion of the non-neoplastic lung (r = 0.44; p = 0.005). CONCLUSIONS: In COPD patients, OLV leads to a significant derangement of gas exchange, which is more pronounced in right thoracotomies. Preoperative measurement of PaO(2) during exercise and the distribution of perfusion by lung scan might be useful to identify those patients who are at the greatest risk of abnormal gas exchange during lung resections.

Gas exchange and pulmonary haemodynamic responses to fat emulsions in acute respiratory distress syndrome.

OBJECTIVE: To investigate the gas exchange and pulmonary haemodynamic responses to two different intravenous fat emulsions in patients with acute respiratory distress syndrome (ARDS). DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Intensive care unit in a university-affiliated hospital. PATIENTS: 21 patients with ARDS [mean age, 57 +/- 3 (SEM) years; Acute Physiology and Chronic Health Evaluation II, 20 +/- 3; Murray's score, 2.85 +/- 0.12] consecutively admitted. INTERVENTIONS: Patients were assigned to three groups (n = 7 each): group A (LCT) received long-chain triglycerides (20% LCT), group B (MCT/LCT), medium-chain triglycerides/long-chain triglycerides (20% MCT/LCT: 50/50) and group C placebo (0.9% sodium chloride, NaCl). The infusion was always given at the rate of 2 mg/kg min over a total period of 12 h, with a volume infusion of 500 ml in each group. MEASUREMENTS: Data were collected before, immediately after and 12 h after infusion ceased. Pulmonary and systemic haemodynamic and gas exchange variables were measured at each time point. Serum triglyceride cholesterol, and non-esterified fatty acids levels were measured. RESULTS: During LCT infusion, cardiac output, oxygen consumption and oxygen delivery increased (all p < 0.05), whereas pulmonary haemodynamics, arterial oxygen tension, mixed venous partial pressure of oxygen and venous admixture ratio remained essentially unaltered. No changes were observed following MCT/LCT infusion. CONCLUSIONS: The administration of LCT emulsion given at a slow rate did not alter arterial oxygenation because of the beneficial effect of a high cardiac output, hence offsetting the detrimental effect of increased O2 consumption.

Effects of bronchoalveolar lavage volume on arterial oxygenation in mechanically ventilated patients with pneumonia.

OBJECTIVE: To assess the effect of bronchoalveolar lavage (BAL) volume on arterial oxygenation in critically ill patients with pneumonia. DESIGN: Randomized clinical comparison. SETTING: Six-bed respiratory intensive care unit of a 850-bed tertiary care university hospital. PATIENTS: Thirty-seven intubated and mechanically ventilated patients with clinical suspicion of pneumonia. INTERVENTIONS: Bronchoscopically guided protected specimen brush (PSB) followed by either a "high volume" BAL (n = 16, protected catheter, mean volume: 131 +/- 14 ml) or a "low volume" BAL (n = 21, protected double-plugged catheter, 40 ml volume for all patients). MEASUREMENTS: Arterial oxygen tension/fractional inspired oxygen (PaO2/FIO2) and mean arterial pressure (MAP) before and up to 24 h after the intervention. Bacterial growth in quantitative cultures. Analysis of variance for repeated measurements with inter-subject factors. RESULTS: All patients showed a lower PaO2/FIO2 ratio and higher MAP after the diagnostic procedure, without differences between the study arms (p = 0.608 and p = 0.967, respectively). Patients with significant bacterial growth (p = 0.014) and patients without preemptive antibiotic (p = 0.042) therapy showed a more profound and longer decrease in arterial oxygenation after the diagnostic procedure. CONCLUSIONS: A decrease in the PaO2/FIO2 ratio was observed in all patients after a combined diagnostic procedure, independent of the BAL volume used. A significant bacterial burden recovered from the alveoli and no preemptive antibiotic therapy were associated with a larger and longer-lasting decrease in arterial oxygenation.

Effect of sampling site on femoral venous blood gas values.

To examine whether the tip of the femoral vein catheter used for sampling femoral venous PO2 during cycling exercise is contaminated by skin or saphenous vein blood, we studied 6 healthy volunteers [21.7 +/- 0.7 (SD) yr] during three identical incremental exercise tests while breathing room air on the same day. Femoral venous blood was sampled simultaneously from two catheters inserted into the femoral vein but advanced in opposite directions (7 cm distally and 5 cm proximally). Blood sampling for measurements of PO2, PCO2, pH, hemoglobin concentration, and oxyhemoglobin saturation was done simultaneously from both catheters in duplicate at rest, at 60% of maximum workload (60% W), and at maximum symptom-limited exercise (100% W). Temperature was measured with a thermistor probe placed in the proximal catheter. At rest, distal PO2 was significantly lower than that measured proximally (24.9 +/- 4.3 vs 30.8 +/- 6.1 mmHg, respectively; P < 0.004), but no differences were found during exercise (60% W, 23.6 +/- 3.4 vs. 24.5 +/- 3.6 mmHg; 100% W, 26.0 +/- 3.6 vs. 25.5 +/- 2.8 mmHg, respectively). Comparison of blood temperatures between proximal and distal sites of sampling in two subjects showed negligible differences. Intrasubject coefficient of variation of distal femoral venous PO2 over the three bouts of exercise was 11.5% (2.9 mmHg) at rest, 5.9% (1.4 mmHg) at 60% W, and 5.6% (1.5 mmHg) at 100% W. Mean differences in distal PO2 between duplicate samples were 0.5 +/- 1.4 mmHg at rest, 0.1 +/- 0.8 mmHg at 60% W, and 0.6 +/- 0.9 mmHg at 100% W.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of high-frequency ventilation in presence of extensive ventilation-perfusion mismatch.

Ten anesthetized normal dogs were each given two methacholine inhalational challenges to produce large amounts of low ventilation-perfusion (VA/Q) regions but little shunt. After one challenge, high-frequency ventilation (HFV) was applied, whereas after the other conventional mechanical ventilation (MV) was used, the order being randomized. Levels of both ventilatory modes were selected prior to challenge so as to result in similar and normal mean airway pressures and arterial PCO2 levels during control conditions. Gas exchange was assessed by both respiratory and multiple inert-gas transfer. Comparing the effect of HFV and MV, no statistically significant differences were found for lung resistance, pulmonary hemodynamic indices, arterial and mixed venous PO2, expired-arterial PO2 differences, or inert-gas data expressed as retention-excretion differences. The only variables that were different were mean airway pressure (2 cm higher during HFV, P less than 0.04) and arterial PCO2 (10 Torr higher during HFV, P less than 0.002). These results suggest that in this canine model of lung disease characterized by large amounts of low VA/Q regions, HFV is no more effective in delivering fresh gas to such regions than is MV.

Effects of training on muscle O2 transport at VO2max.

To quantify the relative contributions of convective and peripheral diffusive components of O2 transport to the increase in leg O2 uptake (VO2leg) at maximum O2 uptake (VO2max) after 9 wk of endurance training, 12 sedentary subjects (age 21.8 +/- 3.4 yr, VO2max 36.9 +/- 5.9 ml.min-1.kg-1) were studied. VO2max, leg blood flow (Qleg), and arterial and femoral venous PO2, and thus VO2leg, were measured while the subjects breathed room air, 15% O2, and 12% O2. The sequence of the three inspirates was balanced. After training, VO2max and VO2leg increased at each inspired O2 concentration [FIO2; mean over the 3 FIO2 values 25.2 +/- 17.8 and 36.5 +/- 33% (SD), respectively]. Before training, VO2leg and mean capillary PO2 were linearly related through the origin during hypoxia but not during room air breathing, suggesting that, at 21% O2, VO2max was not limited by O2 supply. After training, VO2leg and mean capillary PO2 at each FIO2 fell along a straight line with zero intercept, just as in athletes (Roca et al. J. Appl. Physiol. 67: 291-299, 1989). Calculated muscle O2 diffusing capacity (DO2) rose 34% while Qleg increased 19%. The relatively greater rise in DO2 increased the DO2/Qleg, which led to 9.9% greater O2 extraction. By numerical analysis, the increase in Qleg alone (constant DO2) would have raised VO2leg by 35 ml/min (mean), but that of DO2 (constant Qleg) would have increased VO2leg by 85 ml/min, more than twice as much. The sum of these individual effects (120 ml/min) was less (P = 0.013) than the observed rise of 164 ml/min (mean). This synergism (explained by the increase in DO2/Qleg) seems to be an important contribution to increases in VO2max with training.

Platelet-activating factor antagonists: current status in asthma.

Platelet-activating factor (PAF) is a potent lipid-derived mediator of inflammation that is considered to have a potential role in the pathogenesis of asthma. PAF is produced by many cells associated with asthmatic inflammation and has the ability to evoke some of the clinical hallmarks of asthma, such as bronchoconstriction, mucus production and airway hyperresponsiveness (AHR). In addition, PAF has profound chemoattractant properties for eosinophils and neutrophils and it promotes an increase in microvascular permeability and oedema formation within the airways. Nevertheless, the definitive role of PAF in asthma remains elusive. PAF is formed as a result of the action of phospholipase A(2) and acetyltransferase on membrane phospholipids and it is degraded by a PAF-specific acetylhydrolase. The biological effects of PAF are mediated by the activation of specific receptors expressed on effector cell surfaces, although intracellular signalling and paracrine actions have been described. In addition, at least part of the pulmonary effects of PAF could be related to the secondary release of leukotrienes. In the clinical setting, different ways of modifying the activity of PAF have been explored, in particular the inhibitory actions of PAF receptor antagonists. Both natural and synthetic PAF receptor antagonists have shown conflicting results. Although second generation PAF antagonists (apafant, UK-74505, SR-27417A) appear to have a good protective effect against the systemic and pulmonary actions of inhaled PAF, the protective effects of these compounds on allergen-induced responses and AHR are more modest. In the treatment of asthma, PAF receptor antagonists have failed to produce a significant impact in either acute asthma attacks or the maintenance therapy of chronic forms. Other pharmacological interventions of proven efficacy in asthma, such as salbutamol or 5-lipoxygenase antagonists, have shown some anti-PAF effects. Whether the overall negative results with PAF receptor antagonists indicate that extracellular PAF is not a relevant mediator of airway inflammation or that the compounds explored are not capable of blocking the paracrine actions of PAF remains speculative. A PAF synthase inhibitor could be valuable in the elucidation of the role of PAF and it might be a promising and useful complementary therapeutic tool in the future.

Mechanisms of gas exchange impairment in patients with liver cirrhosis.

This article reviews the basic pathophysiologic mechanisms underlying the abnormal pulmonary gas exchange often seen in patients with cirrhosis. To summarize, the following keypoints seem appropriate: (1) Patients with cirrhosis have a low pulmonary vascular tone characterized by a poor or absent hypoxic pressor response. This results in a marked dilation of the pulmonary vasculature. (2) This abnormal pulmonary vascular tone, independently of airway disease, causes VA/Q mismatch and mild to moderate hypoxemia. Yet, as liver disease progresses and hepatocellular function deteriorates, more severe degrees of intrapulmonary shunt emerge and, probably, O2 diffusion limitation ensues, causing severe respiratory failure (see Table 1). (3) At rest, the high cardiac output and minute ventilation of cirrhosis minimize the degree of arterial hypoxemia that otherwise would be expected from the observed degree of both VA/Q inequality and intrapulmonary shunt. During exercise, the relative "normalization' (with respect to metabolic demands) of the hemodynamic and ventilatory status of the patient explains the fall in PaO2. (4) A clear pathogenic mechanism of these pathophysiologic abnormalities is still lacking, although available evidence suggests that both the liver and the endothelial cells may play a pivotal role in the regulation of the pulmonary vascular tone in these patients. (5) To date, no pharmacologic intervention has been effective in treating hypoxemia in these patients. Yet liver transplantation helps in most of them. This observation reinforces the functional nature of the gas exchange abnormalities of cirrhosis.