Abstract Rationale Precapillary pulmonary hypertension (PH) is associated with impaired gas exchange and abnormal ventilatory control due to enhanced chemosensitivity and increased physiologic dead space. Acetazolamide, a carbonic anhydrase inhibitor, induces a mild metabolic acidosis that stimulates ventilation and may improve carbon dioxide clearance. Although commonly used in altitude physiology and select sleep-related disorders, its physiologic role in PH remains unclear. To evaluate the treatment-attributable effects of acetazolamide, we conducted a pooled analysis using a difference-in-difference (DiD) approach . Methods We systematically searched PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov for randomized controlled trials evaluating acetazolamide in adults with precapillary PH, including idiopathic pulmonary arterial hypertension and chronic thromboembolic PH. Outcomes of interest included arterial PaCO2, serum bicarbonate (HCO3−), ventilatory efficiency (VE/VCO2 slope), arterial oxygenation (PaO2), six-minute walk distance (6MWD), and World Health Organization (WHO) functional class. A random-effects inverse variance model was used to pool mean difference (MD) estimates. DiD methodology using change-from-baseline values was applied to mitigate baseline variability. Heterogeneity was assessed using the I² statistic. Results Two crossover randomized trials (Ulrich et al., 2015; Lichtblau et al., 2024) enrolling 71 subjects met inclusion criteria. Ulrich reported outcomes after one week while Lichtblau reported after 5 weeks. Short-term acetazolamide therapy (250-500 mg twice daily) resulted in a significant reduction in PaCO2 (MD − 0.59 mmHg; 95% CI − 0.68 to − 0.51; p 0.00001) and a corresponding fall in HCO3− (MD − 5.43 mEq/L; p 0.00001), reflecting enhanced ventilatory drive. VE/VCO2 slope improved (MD − 0.09; 95% CI − 0.12 to − 0.06), indicating reduced ventilatory inefficiency, though heterogeneity was high (I²=93%). A modest increase in PaO2 was observed (MD + 1.20 mmHg; 95% CI 0.66 to 1.74). No significant change was detected in 6MWD (MD − 13.5 m; p = 0.10) or WHO functional class (p = 1.00). No serious adverse effects were reported. Conclusions Acetazolamide favorably modulates respiratory physiology in precapillary PH, improving carbon dioxide elimination and ventilatory efficiency while producing consistent metabolic compensation. However, these short-term physiologic effects did not translate into measurable functional improvement. These findings support a mechanistic role for acetazolamide as a ventilatory adjunct in PH, warranting future trials assessing exercise hemodynamics, right ventricular-pulmonary vascular coupling, and long-term clinical outcomes. This abstract is funded by: none
Umer et al. (Fri,) studied this question.