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Objective: Angiotensin-converting enzyme (ACE) is considered as a possible marker for endothelial cell damage in serum or bronchoalveolar lavage fluid. This hypothesis was tested during cardiac surgery and during the adult respiratory distress syndrome., Design: We used patients with an expected different degree of endothelial cell damage. ACE levels in serum and bronchoalveolar lavage fluid were compared with indirect markers of alveolo-capillary barrier integrity., Setting: Interdisciplinary team in a university hospital., Methods: 13 Cardiac surgery patients received no glucocorticoids and 13 others received 2 g methylprednisolone before extracorporeal circulation. Thirteen patients were used as controls and 15 patients had nonseptic adult respiratory distress syndrome. All underwent bronchoalveolar lavage for ACE determination., Results: At different times during surgery serum angiotensin-converting enzyme levels were not significantly different between the two groups. In post-operative bronchoalveolar lavage fluid, angiotensin-converting enzyme levels were significantly higher in patients who received corticoids (27.8 +/- 1.7 U/l, mean +/- SEM), compared to patients without corticoids (19.8 +/- 1.4 U/l), control patients (18.2 +/- 1.3 U/l) or patients with full blown non-septic adult respiratory distress syndrome (18.8 +/- 1.1 U/l). There were no correlations between lavage angiotensin-converting enzyme and other parameters for alveolo-capillary membrane integrity in the lavage fluid such as the number of neutrophil cells, albumin or protein concentration, and between lavage angiotensin-converting enzyme and PaO2/FIO2 ratio during lavage., Conclusion: Angiotensin-converting enzyme activity in serum or bronchoalveolar lavage fluid does not reflect damage of endothelial cells or damage of alveolocapillary integrity in acute pulmonary disease.

A sensitive and specific radioimmunoassay was used to measure interleukin 8 (IL-8) in bronchoalveolar lavage fluids from control subjects, patients with the adult respiratory distress syndrome (ARDS) and patients undergoing coronary bypass surgery, a risk factor for developing ARDS. Concentrations of IL-8, albumin, total protein and numbers of neutrophils were higher in both patient groups than in controls. Levels of IL-8 were significantly correlated with the influx of neutrophils, plasma protein extravasation and with the PaO2/FiO2 ratio. These data suggest that IL-8 may mediate the recruitment of neutrophils from the vascular compartment into the alveolar space and may therefore be an important determinant in neutrophil-mediated lung injury. Since increased levels of IL-8 were also found in BAL fluid from patients at risk in whom ARDS did not develop, other factors are likely to be involved and IL-8, as well as other markers of inflammation, are of little prognostic use.

Human alveolar type II cells are thought to play a role in the pathogenesis of lung injury. Patterns of mediator release of arachidonic acid metabolism by type II cells were therefore studied after challenge with calcium ionophore A23187, opsonized zymosan and hydrogen peroxide. A time- and concentration dependent release of cyclooxygenase products was observed, with release of PGE2 greater than 6-keto-PGF1 alpha greater than TxB2. Addition of glutathione or bicarbonate further increased the production of PGE2. N-ethylmaleimide, a sulfhydryl (SH) reactant, induced a dose-dependent increase in the release of TxB2 and 6-keto-PGF1 alpha, but not of PGE2. This relates most likely to the SH-dependency and glutathione requirement of the PGE2 isomerase and SH-independence of thromboxane and prostacyclin isomerase.

Carotid endarterectomy is reported to abolish hypoxic ventilatory responsiveness. This effect is thought to be due to denervation or destruction of the carotid bodies by surgical exposure. The technique of carotid endarterectomy, however, does not require the sacrifice of these structures. Six patients who had bilateral carotid endarterectomy with careful preservation of the carotid bodies and their innervation were studied pre- and postoperatively with respect to hypoxic ventilatory responsiveness and the latter was taken as a measure of chemoreceptor activity. Five patients showed a weak or absent response to hypoxia before surgery. In four of these there was a significant increase in reactivity after the procedure (p less than 0.01 in one case, p less than 0.05 in three others). The fifth patient had a non-significant increase and the sixth had a normal response before and after surgery. Thus, loss of chemoreceptor function after bilateral carotid endarterectomy was not observed in this group of patients with preserved carotid bodies. The low ventilatory hypoxic sensitivity before surgery and its occasional increase after removal of the plaque suggests that atherosclerosis might well impair the microscopic blood supply to the carotid bodies, inducing sensor dysfunction but this hypothesis requires further investigation.

During haemodialysis (HD), allowing important CO2- unloading, an irregular breathing pattern (BP) is frequently observed. This has been attributed to a decrease in central chemoreceptor firing, with a greater contribution of the peripheral chemoreceptors in the chemical drive to breathe. To provide further evidence for these findings we studied five patients with end-stage renal failure in chronic HD. They underwent HD with a cuprophane membrane and acetate-containing dialysate. Ventilation was measured continuously using respiratory inductance plethysmography. Oxygen was administered for 30 min, using nasal cannulae, at a rate of 6 l.min-1, starting 130 min after the onset of the HD. Blood gases were taken from the arterial line. During the initial air breathing, arterial oxygen tension (PaO2) decreased from 12.3 +/- 1.2 kPa (92.8 +/- 8.9 mmHg) at 0 min to 10.5 +/- 1.8 kPa (79.0 +/- 13.3 mmHg) at 2 h (p less than 0.01) (mean +/- SD). All patients showed irregular breathing with 1.4 +/- 0.6 apnoeas exceeding 10 s per 10 min after 2 h. Minute ventilation decreased from 6.8 +/- 1.9 l.min-1 at 0 min to 5.4 +/- 1.3 l.min-1 at 2 h (p less than 0.05). During the O2 breathing, PaO2 increased to 26.3 +/- 4.0 kPa (197.8 +/- 30.3 mmHg) (p less than 0.001), while arterial carbon dioxide tension (PaCO2) remained unchanged. The irregular BP previously observed vanished completely. The mean number of apnoeas exceeding 10 s per 10 min decreased to 0.08 +/- 0.12 during O2 (p less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

The dialysis patient treated intermittently on a three-times-weekly schedule is exposed during the short dialysis period (4 hours) to abrupt changes in the internal milieu. During the 44 hours of the interdialytic period, H+ ions accumulate slowly, causing respiratory-compensated (hyperventilation) metabolic acidosis in the patient at the start of dialysis. The arterial bicarbonate concentration (HCO3-) is between 17 and 23 mEq/L and a relatively low arterial carbon dioxide tension (PaCO2) of 33-36 mm Hg is observed. Four hours later, after exposure to a biocompatible (polyacrylonitrile) or bioincompatible membrane (cuprophane) and a bicarbonate or acetate dialysis bath, the patient reaches metabolic alkalosis after mild to moderate hypoventilation, with or without breathing irregularities. Defined another way, the dialysis patient is an acid accumulator for 44 hours, after which a 4-hour period of efficient retitration occurs that is accompanied by a variable degree of hypoxemia. The latter phenomenon has been the subject of numerous investigations during the past 10 years. As happens with complex biologic processes, the conclusions reached by the various investigators are conflicting, depending on their viewpoint and the variables they examined. Since Sherlock in 1977 showed that patients dialyzed with an acetate-containing dialysate became hypoxemic and attributed it to hypoventilation after carbon dioxide (CO2) losses through the dialyzer, a number of other mechanisms have been proposed, defended by some and questioned by others. The purpose of this short overview is to evaluate critically the various proposed mechanisms, showing the minor role played by some and defining the respective roles of the two principal mechanisms, i.e., CO2 unloading, and the complement activation-hypoxemia cascade.

Important CO2 unloading occurs during hemodialysis (HD) when acetate-buffered dialysate is used. This is accompanied by alveolar hypoventilation. To gain more insight into the mechanisms of this alveolar hypoventilation, breathing patterns were studied in 5 patients with end-stage renal failure during HD using acetate-buffered dialysate, which induces CO2 unloading, or bicarbonate without CO2 loss. Ventilation was continuously measured with calibrated respiratory inductance plethysmography using techniques of multiple linear regression analysis. At regular intervals, arterial blood gas was sampled and expired air was analyzed. Breathing patterns were analyzed for VE, VT, TI, TE, and VT/TI. All data were compared with the respective starting value and with the respective value in the other setup. A greater decrease in ventilation was seen during HD with an acetate-containing dialysate because of irregular breathing patterns that resulted in a prolongation of expiratory time. Important variations in tidal volumes, striking apnea periods, and occasional periodic breathing were observed. We suggest that these irregularities are due to CO2 unloading leading to the point where ventilation is totally mediated through the output of the peripheral chemoreceptors.

According to a double-blind cross over design 100 mg almitrine bismesylate or placebo was administered orally to eight patients with chronic airflow obstruction having undergone bilateral carotid body resection up to two years earlier to alleviate their extreme dyspnoea. Almitrine bismesylate failed to improve gas exchange in these patients, nor did it affect ventilation, breathing pattern, ventilatory or hypoxic drive. This study confirms that the drug only exerts its effects on carotid bodies and that the previously documented improvement in V/Q matching also results from its action on carotid bodies.

In this preliminary study, the biocompatibility of a new dialysis membrane, polycarbonate, was studied. The bioincompatible effect of this membrane is less pronounced compared to cuprophane.

Using a double-blind cross-over design, a single dose of 100 mg almitrine bismesylate and placebo were administered orally to eight patients with chronic airflow obstruction having undergone bilateral carotid body resection (BCBR) up to two years earlier to alleviate their extreme dyspnoea. In an open study, two other patients have been given almitrine before and three weeks after BCBR. In all patients, arterial blood gases, ventilation and breathing patterns, neuromuscular drive and hypoxic responsiveness have been studied before and three hours after drug administration. Almitrine failed to improve gas exchange in the patients with BCBR, nor did it affect ventilation, ventilatory or hypoxic drive. In the patients studied before and after BCBR, almitrine only improved gas exchange significantly before BCBR. It is concluded that in man almitrine acts solely as a peripheral chemoreceptor agonist and that the well-documented improvement in V/Q relationship is mediated through carotid body stimulation.