A pumpless artificial lung without systemic anticoagulation: The Nitric Oxide Surface Anticoagulation system

Abstract

Background: Artificial lungs have the potential to serve as a bridge to transplantation or recovery for children with end-stage lung disease dependent on extracorporeal life support, but such devices currently require systemic anticoagulation. We describe our experience using the novel Nitric Oxide (NO) Surface Anticoagulation (NOSA) system-an NO-releasing circuit with NO in the sweep gas-with the Pediatric MLung-a low-resistance, pumpless artificial lung.

Methods: NO flux testing: MLungs (n = 4) were tested using veno-venous extracorporeal life support in a sheep under anesthesia with blood flow set to 0.5 and 1 L/min and sweep gas blended with 100 ppm NO at 1, 2, and 4 L/min. NO and NO₂ were measured in the sweep and exhaust gas to calculate NO flux across the MLung membrane. Pumpless implants: Sheep (20-100 kg, n = 3) underwent thoracotomy and cannulation via the pulmonary artery (device inflow) and left atrium (device outflow) using cannulae and circuit components coated with an NO donor (diazeniumdiolated dibutylhexanediamine; DBHD-N₂O₂) and argatroban. Animals were connected to the MLung with 100 ppm NO in the sweep gas under anesthesia for 24 h with no systemic anticoagulation after cannulation.

Results: NO flux testing: NO flux averaged 3.4 ± 1.0 flux units (x10^-10 mol/cm²/min) (human vascular endothelium: 0.5-4 flux units). Pumpless implants: 3 sheep survived 24 h with patent circuits. MLung blood flow was 716 ± 227 mL/min. Outlet oxygen saturation was 98.3 ± 2.6%. Activated clotting time was 151±24 s. Platelet count declined from 334,333 ± 112,225 to 123,667 ± 7,637 over 24 h. Plasma free hemoglobin and leukocyte and platelet activation did not significantly change.

Conclusions: The NOSA system provides NO flux across a gas-exchange membrane of a pumpless artificial lung at a similar rate as native vascular endothelium and achieves effective local anticoagulation of an artificial lung circuit for 24 h.

Keywords: Artificial lung; Biocompatibility; Extracorporeal life support; Extracorporeal membrane oxygenation; Non-thrombogenic circuits; Pediatric respiratory failure.

Figure 1.

Pediatric MLung circuit used for the pumpless implant experiments: 1) device inflow from the pulmonary artery, 2) Pediatric MLung, 3) device outflow to the left atrium, 4) gas line delivering sweep gas and NO to the Pediatric MLung, 5) sweep gas exhaust from which exhaust NO samples were taken. Circuit flow is clockwise in this image.

Figure 2.

Level of nitric oxide (NO) release per square centimeter of gas-exchange membrane in the Pediatric MLung as measured during NO flux experiments. Data shown are means of the 4 MLungs tested at each circuit setting (i.e., combination of blood flow and sweep gas rates). Error bars depict the standard error of the mean.

Figure 3.

Pediatric MLung performance in pumpless implant studies. Mean (A) blood flow (in mL/min) through the Pediatric MLung and pressure drop (in mmHg) across the Pediatric MLung, (B) resistance (in mmHg/L/min) across the Pediatric MLung, and (C) blood oxygen saturation pre- and post-MLung over 24 hours. Mean is calculated at each 15-minute time point for 3 sheep. Error envelopes depict standard error of the mean.

Figure 4.

Activated clotting time (ACT) across the 24-hour experiments. Heparinization occurred prior to hour 0. Data are the median ACT, measured every 2 hours, for the 3 sheep that survived 24 hours. Error envelopes indicate standard error of the mean. Shaded area depicts the target ACT range for therapeutic anticoagulation in these sheep: 240–280 seconds.

Figure 5.

A) Serum hemoglobin (in g/dL), B) white blood cell (WBC) count (in thousands/μL), C) platelet count (in thousands/μL), and D) plasma free hemoglobin (in mg/dL) at baseline (hour 0; prior to cannulation) and after 24 hours of support with the MLung and NOSA system. Data are the mean at hour 0 and hour 24 for the 3 sheep that survived 24 hours. Error bars depict the standard error of the mean.

Figure 6.

Flow cytometry (cellular activation) values at baseline (hour 0; prior to cannulation) and after 24 hours of support with the MLung and NOSA system. Data are shown as a percent of the baseline expression level. Data are the mean at hour 0 and hour 24 for the 3 sheep that survived 24 hours. Error bars depict the standard error of the mean.

Figure 7.

A) MLung and B) circuit tubing and cannulae after 24 hours of support without anticoagulation. The circuit tubing and cannulae are coated with diazeniumdiolated dibutylhexanediamine (DBHD-N₂O₂) and argatroban.