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Extracorporeal Carbon Dioxide Removal (ECCO2R) systems support patients with severe respiratory failure. Concurrent ambulation and physical therapy improve patient outcomes, but these procedures are limited by the complexity and size of the extracorporeal systems and rapid changes in patient metabolism and the acid–base balance. Here, we present the first prototype of a wearable ECCO2R system capable of adjusting to a patient's changing metabolic needs. Exhaust gas CO2 (EGCO2) partial pressure is used as an analog for blood CO2 partial pressure (pCO2). Twin blowers modulate sweep gas through the AL to achieve a desired target EGCO2. The integrated system was tested in vitro for 24 h with water, under varying simulated metabolic conditions and target EGCO2 values, and in a single test with whole blood. When challenged with changing inlet water pCO2 levels in in vitro tests, the system adjusted the sweep gas to achieve target EGCO2 within 1 min. Control runs with a fixed sweep gas (without negative feedback) demonstrated higher EGCO2 levels when challenged with higher water flow rates. A single in vitro test with whole ovine blood confirmed functionality in blood. This is the first step toward wearable ECCO2R systems that automatically respond to changing metabolism. Such devices would facilitate physical therapy and grant greater autonomy to patients. [ABSTRACT FROM AUTHOR]