A Portable Servoregulation Controller to Automate CO2 Removal in Artificial Lungs.

Artificial lung (AL) systems provide respiratory support to patients with severe lung disease, but none can adapt to the changing respiratory needs of the patients. Precisely, none can automatically adjust carbon dioxide (CO2) removal from the blood in response to changes in patient activity or disease status. Because of this, all current systems limit patient comfort, activity level, and rehabilitation. A portable servoregulation controller that automatically modulates CO2 removal in ALs to meet the real-time metabolic demands of the patient is described. The controller is based on a proportional-integral-derivative (PID) based closed-loop feedback control system that modulates sweep gas (air) flow through the AL to maintain a target exhaust gas CO2 partial pressure (target EGCO2 or tEGCO2). The presented work advances previous research by (1) using gas-side sensing that avoids complications and clotting associated with blood-based sensors, (2) incorporating all components into a portable, battery-powered package, and (3) integrating smart moisture removal from the AL to enable long term operation. The performance of the controller was tested in vitro for ∼12 h with anti-coagulated bovine blood and 5 days with distilled water. In tests with blood, the sweep gas flow was automatically adjusted by the controller rapidly (<2 min) meeting the specified tEGCO2 level when confronted with changes in inlet blood partial pressure of CO2 (pCO2) levels at various AL blood flows. Overall, the CO2 removal from the AL showed a strong correlation with blood flow rate and blood pCO2 levels. The controller successfully operated continuously for 5 days when tested with water. This study demonstrates an important step toward ambulatory AL systems that automatically modulate CO2 removal as required by lung disease patients, thereby allowing for physiotherapy, comfort, and activity.

Toward a Servoregulation Controller to Automate CO2 Removal in Wearable Artificial Lungs.

A laptop-driven, benchtop control system that automatically adjusts carbon dioxide (CO2) removal in artificial lungs (ALs) is described. The proportional-integral-derivative (PID) feedback controller modulates pump-driven air sweep gas flow through an AL to achieve a desired exhaust gas CO2 partial pressure (EGCO2). When EGCO2 increases, the servoregulator automatically and rapidly increases sweep flow to remove more CO2. If EGCO2 decreases, the sweep flow decreases to reduce CO2 removal. System operation was tested for 6 hours in vitro using bovine blood and in vivo in three proof-of-concept sheep experiments. In all studies, the controller automatically adjusted the sweep gas flow to rapidly (<1 minute) meet the specified EGCO2 level when challenged with changes in inlet blood or target EGCO2 levels. CO2 removal increased or decreased as a function of arterial pCO2 (PaCO2). Such a system may serve as a controller in wearable AL systems that allow for large changes in patient activity or disease status.

Membrane Lung and Blood Pump Use During Prolonged Extracorporeal Membrane Oxygenation: Trends From 2002 to 2017.

Extracorporeal life support (ECLS) has grown in its application since its first clinical description in the 1970s. The technology has been used to support a wide variety of mechanical support modalities and diseases, including respiratory failure, cardiorespiratory failure, and cardiac failure. Over many decades and safety and efficacy studies, followed by randomized clinical trials and thousands of clinical uses, ECLS is considered as an accepted treatment option for severe pulmonary and selected cardiovascular failure. Extracorporeal life support involves the use of support artificial organs, including a membrane lung and blood pump. Over time, changes in the technology and the management of ECLS support devices have evolved. This manuscript describes the use of membrane lungs and blood pumps used during ECLS support from 2002 to 2017 in over 65,000 patients reported to the Extracorporeal Life Support Organization Registry. Device longevity and complications associated with membrane lungs and blood pump are described and stratified by age group: neonates, pediatrics, and adults.

Evaluation of an Anti-Thrombotic Continuous Lactate and Blood Pressure Monitoring Catheter in an In Vivo Piglet Model undergoing Open-Heart Surgery with Cardiopulmonary Bypass.

Blood lactate and blood pressure measurements are important predictors of life-threatening complications after infant open-heart surgeries requiring cardiopulmonary bypass (CPB). We have developed an intravascular nitric oxide (NO)-releasing 5-Fr catheter that contains a lactate sensor for continuous in-blood lactate monitoring and a dedicated lumen for third-party pressure sensor attachment. This device has antimicrobial and antithrombotic properties and can be implanted intravascularly. The importance of this design is its ability to inhibit thrombosis, due to the slow release of NO through the surface of the catheter and around the electrochemical lactate sensors, to allow continuous data acquisition for more than 48 h. An in vivo study was performed using six piglets undergoing open-heart surgery with CPB and cardioplegic arrest, in order to mimic intra-operative conditions for infants undergoing cardiac surgery with CPB. In each study of 3 h, two 5-Fr NO-releasing lactate and blood-pressure monitoring catheters were implanted in the femoral vessels (arteries and veins) and the CPB circuitry to monitor changing lactate levels and blood pressures during and immediately after aortic cross-clamp removal and separation from CBP. Electrical signals continuously acquired through the sensors were processed and displayed on the device's display and via Bluetooth to a computer in real-time with the use of a two-point in vivo calibration against blood gas results. The study results show that lactate levels measured from those sensors implanted in the CPB circuit during CPB were comparable to those acquired by arterial blood gas measurements, whereas lactate levels measured from sensors implanted in the femoral artery were closely correlated with those acquired intermittently by blood gas prior to CPB initiation, but not during CPB. Blood pressure sensors attached to one lumen of the device displayed accurate blood pressure readings compared to those measured using an FDA approved pressure sensor already on the market. We recommend that the sensor be implanted in the CPB's circuit to continuously monitor lactate during CPB, and implanted in the femoral arteries or jugular veins to monitor lactate before and after CPB. Blood pressures dramatically drop during CPB due to lower blood flow into the lower body, and we suspect that the femoral arteries are likely collapsing or constricting on the implanted catheter and disrupting the sensor-to-blood contact. This study shows that the device is able to accurately and continuously monitor lactate levels during CPB and potentially prevent post-surgery complications in infants.

Inflammatory Effects of Blood-Air Interface in a Porcine Cardiopulmonary Bypass Model.

Cardiopulmonary bypass (CPB) causes a systemic inflammatory response syndrome (SIRS) associated with multiorgan injury. A model was developed to test whether a blood-air interface (BAI) in the CPB circuit causes blood element activation and inflammation. Ten healthy swine were placed on partial CPB for 2 hours via the cervical vessels and monitored for 96 hours postoperatively. Five pigs (control group) had minimal air exposure in the circuit, while five were exposed to a BAI simulating cardiotomy suction. There were no significant differences in bypass flow or hemodynamics between the groups. In the BAI group, there was an increase in hemolysis after bypass (plasma-free hemoglobin 5.27 ± 1.2 vs. 0.94 ± 0.8 mg/dl; p = 0.01), more aggressive platelet consumption (28% vs. 83% of baseline; p = 0.009), leukocyte consumption (71% vs. 107% of baseline; p = 0.02), and increased granulocyte CD11b expression (409% vs. 106% of baseline; p = 0.009). These data suggest the inflammatory pattern responsible for the CPB-SIRS phenomenon may be driven by blood-air interaction. Future efforts should focus on BAI-associated mechanisms for minimizing blood trauma and inflammation during CPB.

Nitric Oxide Attenuates the Inflammatory Effects of Air During Extracorporeal Circulation.

Cardiopulmonary bypass causes a systemic inflammatory response reaction that may contribute to postoperative complications. One cause relates to the air/blood interface from the extracorporeal circuit. The modulatory effects of blending nitric oxide (NO) gas into the ventilation/sweep gas of the membrane lung was studied in a porcine model of air-induced inflammation in which NO gas was added and compared with controls with or without an air/blood interface. Healthy swine were supported on partial bypass under four different test conditions. Group 1: no air exposure, group 2: air alone, group 3: air plus 50 ppm NO, and group 4: air plus 500 ppm NO. The NO gas was blended into the ventilation/sweep site of the membrane lung. The platelets and leucocytes were activated by air alone. Addition of NO to the sweep gas attenuated the inflammatory response created by the air/blood interface in this model.

Tidal Flow Perfusion for the Artificial Placenta: A Paradigm Shift.

The modalities of vascular access for the extracorporeal artificial placenta (AP) have undergone many iterations over the past decade. We hypothesized that single lumen cannulation (SLC) of the jugular vein using tidal flow extracorporeal life (ECLS) support is a feasible alternative to venovenous (VV) umbilical-jugular cannulation and double lumen cannulation (DLC) and can maintain fetal circulation, stable hemodynamics, and adequate gas exchange for 24 hours. After in vitro evaluation of the tidal flow system, six preterm lambs at estimated gestational age 118-124 days (term 145 days) were delivered and underwent VV-ECLS. Three were supported using DLC and three with SLC utilizing tidal flow AP support. Hemodynamics, circuit flow, and gas exchange were monitored. Target fetal parameters were as follows: mean arterial pressure 40-60 mmHg, heart rate 140-240 beats per minute (bpm), SatO2% 60-80%, PaO2 25-50 mmHg, PaCO2 30-55 mmHg, oxygen delivery >5 ml O2/dl/kg/min, and circuit flow 100 ± 25 ml/kg/min. All animals survived 24 hours and maintained fetal circulation with stable hemodynamics and adequate gas exchange. Parameters of the tidal flow group were comparable with those of DLC. Single lumen jugular cannulation using tidal flow is a promising vascular access strategy for AP support. Successful miniaturization holds great potential for clinical translation to support extremely premature infants.

Novel Leukocyte Modulator Device Reduces the Inflammatory Response to Cardiopulmonary Bypass.

Leukocyte (LE) activation during cardiopulmonary bypass (CPB) promotes a systemic inflammatory response that contributes to organ injury and postoperative organ dysfunction. A leukocyte modulatory device (L-MOD) for use during (and after) CPB to limit leukocyte-mediated organ injury was tested in a preclinical model. Twenty-two pigs underwent 180 minutes of CPB and 5 hours postoperative observation. Pigs received no intervention (group 1, n = 9), 3 hours of therapy by incorporation of L-MOD into the CPB circuit (group 2, n = 6), or 8 hours of therapy using a femoral venovenous L-MOD circuit during and after CPB (group 3, n = 7). Leukocyte activation was increased at the end of CPB and leukocyte counts, namely neutrophils, increased postoperatively in most animals. These indices trended much lower in group 3. Systemic vascular resistance was not as reduced post-CPB for the L-MOD-treated pigs, and urine output was significantly greater for group 3 (p < 0.01). At 5 hours post-CPB, group 3 had a lower troponin-I (1.59 ± 0.68 ng/ml) than group 1 or group 2 (3.97 ± 2.63 and 3.55 ± 2.04 ng/ml, respectively, p < 0.05) and a lower urine neutrophil gelatinase-associated lipocalin (7.57 ± 3.59 ng/ml) than the average of the other groups (50.71 ± 49.17, p < 0.05). These results demonstrate the therapeutic potential of L-MOD therapy to mitigate the inflammatory response to CPB. Eight hours of venovenous L-MOD resulted in less organ injury and post-op organ dysfunction in this model.

The effect of air exposure on leucocyte and cytokine activation in an in-vitro model of cardiotomy suction.

INTRODUCTION: Cardiopulmonary bypass (CPB) is known to cause a systemic inflammatory and immune response. OBJECTIVE: An in-vitro model of cardiotomy suction was designed to quantify the effects of incrementally increased air-blood exposure on leucocyte marker CD11b and cytokine activation in two common anticoagulants, heparin and citrate. METHODS: Fresh human blood was exposed to increasing amounts of air flow for ten minutes. Leucocyte and cytokine levels were measured prior to and after ten minutes of air flow. Cytokine levels were also measured after air exposure when incubated for 24 hours at 37oC. RESULTS: Leucocyte activation, measured by CD11b, was elevated between baseline and air flow rates up to 50 mL/min. After 10 minutes of air exposure, no measured cytokine levels were elevated. After 24 hours of incubation, cytokine levels of TNFα, IL-10, IL-6, and IL-8 were elevated. However, only IL-8 was significantly elevated in citrated blood, but not in heparinized blood, when compared to baseline samples that were also incubated for 24 hours. CONCLUSION: This study investigates CD11b levels in response to an air stimulus in blood that was anticoagulated with citrate or heparin. Exposure to an air stimulus activates leucocytes. Activation of CD11b was less when using heparin as an anticoagulant compared to citrate. Cytokine activation occurs with air stimulation, but levels do not immediately rise, indicating that time is required to generate free cytokines.

CO2 clearance by membrane lungs.

INTRODUCTION: Commercial membrane lungs are designed to transfer a specific amount of oxygen per unit of venous blood flow. Membrane lungs are much more efficient at removing CO2 than adding oxygen, but the range of CO2 transfer is rarely reported. METHODS: Commercial membrane lungs were studied with the goal of evaluating CO2 removal capacity. CO2 removal was measured in 4 commercial membrane lungs under standardized conditions. CONCLUSION: CO2 clearance can be greater than 4 times that of oxygen at a given blood flow when the gas to blood flow ratio is elevated to 4:1 or 8:1. The CO2 clearance was less dependent on surface area and configuration than oxygen transfer. Any ECMO system can be used for selective CO2 removal.