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In this issue, Maggiorini and colleagues explore several aspects of the pathogenesis of high-altitude pulmonary edema. Their study yields important practical answers and serendipitously generates n...

ContextThe pathogenesis of high-altitude pulmonary edema (HAPE) is considered an altered permeability of the alveolar-capillary barrier secondary to intense pulmonary vasoconstriction and high capillary pressure, but previous bronchoalveolar lavage (BAL) findings in well-established HAPE are also consistent with inflammatory etiologic characteristics.ObjectivesTo determine whether inflammation is a primary event in HAPE and to define the temporal sequence of events in HAPE.Design, Setting, and ParticipantsCase study from July through August 1999 of 10 subjects with susceptibility to HAPE and 6 subjects resistant to HAPE, all of whom are nonprofessional alpinists with previous mountaineering experience above 3000 m.Main Outcome MeasuresPulmonary artery pressure measurements and BAL findings at low altitude (490 m) and shortly before or at the onset of HAPE at an altitude of 4559 m.ResultsSubjects who were HAPE susceptible had higher mean (SD) pulmonary artery systolic blood pressures at 4559 m compared with HAPE-resistant subjects (66 vs 37 mm Hg; P = .004). Despite development of HAPE in the majority of HAPE-susceptible subjects, there were no differences in BAL fluid total leukocyte counts between resistant and susceptible subjects or between counts taken at low and high altitudes. Subjects who developed HAPE had BAL fluid with high concentrations of plasma-derived proteins and erythrocytes, but there was no increase in plasma concentrations of surfactant protein A and Clara cell protein. The chest radiograph score was 12.7 for the 3 HAPE-susceptible subjects who developed HAPE before BAL was performed; they were lavaged within 3 to 5 hours. The remainder of the HAPE-susceptible group was lavaged before edema was apparent on radiographs. However, 6 subjects from the HAPE-susceptible group who developed HAPE on the following day had a score on bronchoscopy of 1.5, which increased to 4.6, reflective of mild pulmonary edema. In HAPE cases, there were no elevations in a number of proinflammatory cytokines and eicosanoid and nitric oxide metabolites.ConclusionsEarly HAPE is characterized by high pulmonary artery pressures that lead to a protein-rich and mildly hemorrhagic edema, with normal levels of leukocytes, cytokines, and eicosanoids. HAPE is a form of hydrostatic pulmonary edema with altered alveolar-capillary permeability.

The rates of movement of Na+, Rb+, Cl− and HCO3− from plasma to endolymph were studied in the elasmobranch fish, Squalus acanthias, by use of the appropriate isotopes. Rb+ was used as a marker for K+. The half-times to equilibrium for Na+, Rb+ and Cl− were about 100 hours; for HCO3− it was 6 hours. The equilibrium ratios, endolymph/plasma, are Na+ 0.87, K+ 26, Cl− 1.37, HCO3− 1.47. Carbonic anhydrase inhibition decreased the rate of HCO3− accumulation, suggesting that the process is actually the formation of endolymphatic HCO3− from plasma or tissue CO2. Increase in plasma pCO2 elevates endolymph HCO3− concentration. The secretory tissue contains carbonic anhydrase and Na-K-ATPase. These and other data suggest that a dominant feature of endolymph chemistry may be HCO3− formation linked in some fashion with K+ transport, through rates catalyzed by these two enzymes.

1. 1. Carbonic anhydrase is present as a single isozyme of molecular weight 29000 in the erythrocytes of the teleost, sheepshead (Archosargus probatocephalus). 2. 2. The amino acid composition of this enzyme is generally similar to those of the mammalian isozymes of types I and II, although some notable incongruencies exist. 3. 3. The Michaelis-Menten kinetic constants (Km and kcat) for CO2 hydration by the sheepshead red cell carbonic anhydrase have been determined at pH 7.5–7.6 and at two temperatures, 1 and 25°C. This enzyme is not quite as active as the human red cell carbonic anhydrase isozyme II, although the turnover number is about 3 times that of human isozyme I at both temperatures. 4. 4. The pattern of inhibition of the sheepshead enzyme, by sulfonamides and monovalent anions, is similar to that of the mammalian high activity (type II) isozyme and is different from that exhibited by isozyme I.

Exercise to exhaustion in rats and man was studied befor and after administration of acetazolamide. In rats the dose (100 mg/kg) completely inhibited red cell carbonic anhydrase. In man a clinical dose (10 mg/kg) was used, and the degree of inhibition of HCO 3 − dehydration by red cell isoenzymes B and C was measured. These results and relevant data from the literature were used to describe in model form the contributions to pulmonary CO 2 output of the carbonic anhydrase catalyzed reaction HCO 3 − → CO 2 , the uncatalyzed reaction, carbamino hemoglobin, and dissolved CO 2 during rest and exercise. Conclusions are: (1) at rest, 78% of CO 2 exchange in the lung is mediated by carbonic anhydrase catalyzed dehydration of HCO 3 − ; at exercise this rises to 90%; (2) when carbonic anhydrase is totally at rest large P CO 2 gradients are set up in tissue and lung, increasing the uncatalyzed rate and dissolved CO 2 participation, so that CO 2 is evolved at normal rate without enzyme (rat, dog and man); (3) during exercise with complete inhibition (rat), similar or larger gradients are created; nevertheless, exercise tolerance was impaired; (4) in maximal exercise (man), the clinical dose and resulting unbound plasma concentrations of acetazolamide (7.5 μM) yield enzyme inhibition of 98.8%. New gradients of CO 2 are established, which together with increased cardiac output and the residual enzyme, can effect CO 2 evolution 15 times the normal resting value; and (5) the data suggest that in the complete absence of carbonic anhydrase, CO 2 evolution would not proceed at an adequate rate in maximal exercise. In general, this analysis shows that carbonic anhydrase makes carriage and evolution of CO 2 possible across small gradients. The large amount of enzyme serves to keep these gradients narrow; the reserve or ‘excess’ enzyme (above the required for no perturbation in ventilation or blood-gas chemistry) is a 17-fold at rest and 6-fold in excercise. When enzyme is diminished or absent, gradients increase to the in point of physiological effectiveness, except (probably) in the most severe exercise. The increased gradients produced effects such as increased cerebral blood flow, unusual taste for CO 2 and certain clinical signs and symptoms, but the new respiratory steady-state permits quantitative evolution of CO 2 .

Changes in PCO2 and PO2 during expiration have been ascribed to simultaneous gas exchange, but other factors such as ventilation-perfusion inhomogeneity in combination with sequential emptying may also contribute. An experimental and model approach was used to study the relationship between gas exchange and changes in expired PCO2 and PO2 in anesthetized dogs during prolonged high tidal volume expirations. Changes in PCO2 and PO2 were quantified by taking the area bounded by the sloping exhalation curve and a line drawn horizontally from a point where the Fowler dead space plus 250 ml had been expired. This procedure is similar to using the slope of the exhalation curve but it circumvents problems caused by nonlinearity of the PCO2 and PO2 curves. The gas exchange components of the CO2 and O2 areas were calculated using a single-alveolus lung model whose input parameters were measured in connection with each prolonged expiration. The relationship between changes in experimental CO2 areas caused by sudden reductions in mixed venous PCO2 (produced by right atrial infusions of NaOH) and those calculated by the model was also studied. In seven dogs, calculated CO2 and O2 areas were 13% higher and 25% lower than the respective experimental areas, but interindividual variations were large. Changes in experimental CO2 areas caused by step changes in mixed venous PCO2 were almost identical to changes in the calculated areas. We conclude that the changes in PCO2 and PO2 during expiration cannot be explained solely by gas exchange. However, the single-alveolus lung model accurately predicts changes in the CO2 exhalation curve caused by alterations in the alveolar CO2 flow.

Severe hyperkalemia occurred in a patient with radiation pneumonitis and glaucoma shortly after beginning prednisone therapy. There was no evidence of renal failure, diabetes, acidosis, increased potassium intake, or significant tissue trauma. Medications having adverse effects on potassium metabolism were considered, and the patient's use of timolol maleate eyedrops was discontinued. His serum potassium level normalized despite continuation of the prednisone therapy. He became hyperkalemic on rechallenge with timolol and normokalemic following its withdrawal. This case indicates that the potential for beta-blocker-induced hyperkalemia exists even with topical appreciation.