Extracorporeal life support without systemic anticoagulation: a nitric oxide-based non-thrombogenic circuit for the artificial placenta in an ovine model.

BACKGROUND: Clinical translation of the extracorporeal artificial placenta (AP) is impeded by the high risk for intracranial hemorrhage in extremely premature newborns. The Nitric Oxide Surface Anticoagulation (NOSA) system is a novel non-thrombogenic extracorporeal circuit. This study aims to test the NOSA system in the AP without systemic anticoagulation. METHODS: Ten extremely premature lambs were delivered and connected to the AP. For the NOSA group, the circuit was coated with DBHD-N2O2/argatroban, 100 ppm nitric oxide was blended into the sweep gas, and no systemic anticoagulation was given. For the Heparin control group, a non-coated circuit was used and systemic anticoagulation was administered. RESULTS: Animals survived 6.8 ± 0.6 days with normal hemodynamics and gas exchange. Neither group had any hemorrhagic or thrombotic complications. ACT (194 ± 53 vs. 261 ± 86 s; p < 0.001) and aPTT (39 ± 7 vs. 69 ± 23 s; p < 0.001) were significantly lower in the NOSA group than the Heparin group. Platelet and leukocyte activation did not differ significantly from baseline in the NOSA group. Methemoglobin was 3.2 ± 1.1% in the NOSA group compared to 1.6 ± 0.6% in the Heparin group (p < 0.001). CONCLUSIONS: The AP with the NOSA system successfully supported extremely premature lambs for 7 days without significant bleeding or thrombosis. IMPACT: The Nitric Oxide Surface Anticoagulation (NOSA) system provides effective circuit-based anticoagulation in a fetal sheep model of the extracorporeal artificial placenta (AP) for 7 days. The NOSA system is the first non-thrombogenic circuit to consistently obviate the need for systemic anticoagulation in an extracorporeal circuit for up to 7 days. The NOSA system may allow the AP to be implemented clinically without systemic anticoagulation, thus greatly reducing the intracranial hemorrhage risk for extremely low gestational age newborns. The NOSA system could potentially be applied to any form of extracorporeal life support to reduce or avoid systemic anticoagulation.

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

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.

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.