Effects of acetazolamide on pulmonary artery pressure and prevention of high-altitude pulmonary edema after rapid active ascent to 4,559 m.

Acetazolamide prevents acute mountain sickness (AMS) by inhibition of carbonic anhydrase. Since it also reduces acute hypoxic pulmonary vasoconstriction (HPV), it may also prevent high-altitude pulmonary edema (HAPE) by lowering pulmonary artery pressure. We tested this hypothesis in a randomized, placebo-controlled, double-blind study. Thirteen healthy, nonacclimatized lowlanders with a history of HAPE ascended (<22 h) from 1,130 to 4,559 m with one overnight stay at 3,611 m. Medications were started 48 h before ascent (acetazolamide: n = 7, 250 mg 3 times/day; placebo: n = 6, 3 times/day). HAPE was diagnosed by chest radiography and pulmonary artery pressure by measurement of right ventricular to atrial pressure gradient (RVPG) by transthoracic echocardiography. AMS was evaluated with the Lake Louise Score (LLS) and AMS-C score. The incidence of HAPE was 43% versus 67% (acetazolamide vs. placebo, P = 0.39). Ascent to altitude increased RVPG from 20 ± 5 to 43 ± 10 mmHg (P < 0.001) without a group difference (P = 0.68). Arterial Po2 fell to 36 ± 9 mmHg (P < 0.001) and was 8.5 mmHg higher with acetazolamide at high altitude (P = 0.025). At high altitude, the LLS and AMS-C score remained lower in those taking acetazolamide (both P < 0.05). Although acetazolamide reduced HAPE incidence by 35%, this effect was not statistically significant, and was considerably less than reductions of about 70%-100% with prophylactic dexamethasone, tadalafil, and nifedipine performed with the same ascent profile at the same location. We could not demonstrate a reduction in RVPG compared with placebo treatment despite reductions in AMS severity and better arterial oxygenation. Limited by small sample size, our data do not support recommending acetazolamide for the prevention of HAPE in mountaineers ascending rapidly to over 4,500 m.NEW & NOTEWORTHY This randomized, placebo-controlled, double-blind study is the first to investigate whether acetazolamide, which reduces acute mountain sickness (AMS), inhibits short-term hypoxic pulmonary vasoconstriction, and also prevents high-altitude pulmonary edema (HAPE) in a fast-climbing ascent to 4,559 m. We found no statistically significant reduction in HAPE incidence or differences in hypoxic pulmonary artery pressures compared with placebo despite reductions in AMS and greater ventilation-induced arterial oxygenation. Our data do not support recommending acetazolamide for HAPE prevention.

Pretreatment metastatic growth rate determines clinical outcome of advanced melanoma patients treated with anti-PD-1 antibodies: a multicenter cohort study.

BACKGROUND: Checkpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies. METHODS: MGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB-IV melanoma patients (discovery cohort: n=53, confirmation cohort: n=126, independent multicenter validation cohort: n=158). MGR was computed during the pretreatment period before initiation of therapy with anti-PD-1 antibodies nivolumab or pembrolizumab by measuring the increase of the longest diameter of the largest target lesion. Tumor doubling time served as quality control. Kaplan-Meier analysis and univariable as well as multivariable Cox regression were used to examine the prognostic impact of MGR. RESULTS: Pretreatment MGR >3.9 mm/month was associated with impaired OS in the discovery cohort (HR 6.19, 95% CI 2.92 to 13.10, p<0.0001), in the confirmation cohort (HR 3.62, 95% CI 2.19 to 5.98, p<0.0001) and in the independent validation cohort (HR 2.57, 95% CI 1.56 to 4.25, p=0.00023). Prior lines of systemic treatment did not influence the significance of MGR. Importantly, the prognostic impact of MGR was independent of total tumor burden, diameter of the largest metastasis, number of prior lines of systemic treatment, LDH, as well as liver and brain metastasis (discovery and confirmation cohorts: both p<0.0001). Superiority of MGR compared with these variables was confirmed in the independent multicenter validation cohort (HR 2.92, 95% CI 1.62 to 5.26, p=0.00036). CONCLUSIONS: High pretreatment MGR is an independent strong prognostic biomarker associated with unfavorable survival of melanoma patients receiving anti-PD-1 antibodies. Further investigations are warranted to assess the predictive impact of MGR in distinct systemic therapeutic regimens.