Purpose: Current clinical Extra Corporeal CO2 removal systems rely on human intervention to adjust to changes in patient activity. Previous studies have investigated the use of capnography for measurement of arterial blood carbon dioxide tension (PaCO2) using artificial lungs (AL). The presented work demonstrates an initial implementation of a controller that directly monitors and regulates PaCO2 using exhaust gas CO2 (EGCO2) measurements. Method: The system operates through two cycles, namely measurement and control. First, the sweep gas flow through the AL is temporarily (~60s) reduced to ~400 mL/min to allow the CO2 concentration on the blood and gas phase of the AL to equilibrate. This allows for EGCO2 (measured via a CO2Meter GC-0017) values to be used as an estimate of PaCO2. The control cycle is based on Proportional-Integral-Derivative (PID) principle wherein the system automatically modulates sweep gas flows through the AL to minimize the difference between the desired PaCO2 and the estimated PaCO2 (i.e., measured EGCO2). Blood samples were intermittently collected at the inlet of the AL to monitor actual PaCO2 (measured via a Radiometer ABL800 Flex blood gas analyzer). The in vitro study setup (Fig. 1) consists of a Novalung iLA oxygenator (main AL) and a Capiox RX25 oxygenator (conditioning AL) connected in parallel to model a typical ECMO circuit. The blood reservoir mimics the blood volume (7 L) while the centrifugal pump simulates cardiac output (fixed at ~5 L/min) of a patient. Blood flow through the main AL (AV shunt) was regulated at ~1 L/min using a Hoffman clamp. CO2 concentration in the sweep gas through the conditioning AL was modulated to simulate metabolic activity. The baseline CO2 concentration measured at the outlet of the conditioning AL that projects reservoir PaCO2 level when the main AL is not operational. The baseline blood concentration was varied between 45 and 90 mmHg representing all levels of normocapnia and hypercapnia. Results: Prior to the controller testing, a feasibility study was performed to determine the accuracy of capnography technique in calculating the PaCO2 using the AL. A total of forty-two blood samples were collected at blood flow rates of 0.5, 0.6 and 1.0 L/min. The results show a good correlation between PaCO2 and EGCO2 (r2=0.824, P<0.001). There was a reasonable degree of agreement between the PaCO2 and EGCO2 with accuracy (bias or mean difference between PaCO2 and EGCO2) of 6.04 mmHg with a precision (95% limits of agreement) of ± 9.62 mmHg (Fig. 2). Despite the limitation of the AL in estimating PaCO2 using EGCO2, the PID controller implementation demonstrated that average reservoir CO2 concentration can be maintained at 44.23 ± 8.7 mmHg for a target PaCO2 of 40 mmHg (Fig. 3),against baseline blood reservoir PaCO2 of 60.76 ± 13.81 mmHg.Figure 1. Image showing in vitro test setup. The bovine blood in the test circuit was anticoagulated (ACT > 1200s) with heparin and maintained at 37°C.Figure 2. a) The regression curve generated between PaCO2 samples and measured EGCO2 b) Agreement between PaCO2 samples and measured EGCO2.Figure 3. a) In vitro test results showing changes in all PaCO2 concentrations in the circuit b) Result summary comparing average reservoir PaCO2 level with target PaCO2