Our focus is to develop more efficient and less traumatic extracorporeal gas exchange techniques as support. This technology could improve treatment for Acute Respiratory Distress Syndrome (ARDS), which affects approximately 200,000 Americans per year with a 38.5% mortality,1 and end stage chronic lung diseases, which claims the lives of 123,884 patients per year.2 Extracorporeal membrane oxygenation (ECMO), in both venoarterial (VA) and venovenous (VV) configurations, has been the only practical extracorporeal gas exchange technique for total respiratory support for 30 years, but is limited by bulky size, complicated equipment, labor intensive management, and traumatic blood/surface interactions.3 VV ECMO with a single, double lumen cannula (DLC) was developed over 20 years ago to require just one central venous cannulation either by cutdown or percutaneous access to achieve gas exchange.4 Commercial DLCs made by Kendall, Jostra, and Origen allowed DLC VV ECMO to become widely practiced in neonates and small children. Extracorporeal gas exchange physiologically equivalent to VA ECMO has been consistently reported.5–7 With currently available DLCs, suitable for use in large children, there is significant recirculation and insufficient venous drainage which leads to insufficient gas exchange,8–10 and no DLC exists for adult VV ECMO. Current DLCs either require gravity drainage or a roller pump. If coupled with a centrifugal pump at the higher required flows, the negative pressure generated can cause the septum of the DLC to shift, limiting drainage. Our immediate goal was to develop a high performance DLC to accomplish total gas exchange in an adult.
In the last 15 years, our group has been developing or testing alternative extracorporeal gas exchange techniques to achieve partial or total oxygen or CO2 removal including intravascular oxygenator (IVOX),11 arteriovenous CO2 removal (AVCO2R),12 the paracorporeal artificial lung (PAL),13–16 and OxyRVAD [a pump assisted oxygenator from right atrium (RA) to pulmonary artery],17,18 all of which are limited by either insufficient gas exchange or complex surgical placement limiting clinical applicability. Our ultimate goal is to develop a minimally invasive, ambulatory and percutaneous PAL utilizing our new Wang-Zwische (W-Z) DLC as the key component, coupled with a compact rotary blood pump and durable gas exchanger.
Materials and Methods
Cannula design and fabrication: The W-Z DLC was designed by D. Wang and J.B. Zwischenberger (patent pending, the rights have been purchased by Avalon Laboratories Inc.), to be introduced percutaneously into the right jugular vein traversing the superior vena cava (SVC) and RA into the inferior vena cava (IVC). Design goals included: 1) Minimal recirculation by opening the drainage lumen to the SVC and IVC and positioning the infusion lumen in the RA directed toward the tricuspid valve (Figure 1); 2) Maximal cross-sectional area of each DLC lumen with minimal blood resistance utilizing an ultra thin nondistensible plastic membrane infusion lumen (Figure 2) and thin wire wound kink resistant cannula walls; 3) Percutaneous access utilizing an atraumatic introducer within the drainage lumen (the thin membrane infusion lumen is collapsed upon insertion allowing a tapered introducer within a smooth outer cannula wall for easy insertion) (Figure 2). Prototypes incorporating each of these design features were fabricated by Avalon Laboratories Inc. After several iterations, the design requirements were met.
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Figure 1.:
W-Z DLC is inserted from right jugular vein into superior vena cava (SVC), traversing right atrium (RA) to inferior vena cava (IVC). It drains venous blood from both SVC and IVC and delivers oxygenated blood in RA toward tricuspid valve to achieve minimal to no recirculation and potential total gas exchange.
Figure 2.:
The infusion lumen is a collapsible ultra thin plastic membrane sleeve which allows a tight fit of the introducer in the drainage lumen to maximize the DLC cross sectional area.
The prototypes were sized at 30 Fr for short term recirculation testing and 26 Fr for a 15 day performance test. The outer wall was fabricated out of high silicone content polyurethane copolymer (0.38 mm thick) with wire wound stainless steel reinforcement. The infusion lumen is a silicone-polyurethane nondistensible membrane sleeve (0.15 mm thick). The drainage/infusion lumen cross-section ratio is 2:1.4. With the infusion lumen sleeve collapsed, an introducer shaft with a soft blunt tip fits tightly within the drainage lumen. For the 30 Fr prototypes, an asymmetric balloon was added above the SVC drainage opening to prevent venous wall suction/occlusion and recirculation (Figure 3).
Figure 3.:
The first prototype (30 Fr) and performance chart. An asymmetric balloon was added below inferior vena cava (IVC) opening for prevention of venous wall suction-collapse and recirculation.
The DLCs are made by a proprietary dip molding process resulting in flexible yet kink resistant one piece construction because of the “molded in” (0.1 mm) flat wire stainless steel spring. Thin (0.1 mm) custom formed stainless steel reinforcements are used at the cannula tip and around all inlet and outlet holes to provide structural integrity and maintain conformation in these areas. The drainage lumen inlets are sized to provide appropriate flow balance between the SVC and IVC inlet regions.
W-Z DLC prototypes were tested in three sheep (free range ewes, 3–4 years old, 35–45 kg), in a VV circuit using a commercially available DeBakey VAD (MicroMed Cardiovascular Inc., Houston, TX) and affinity gas exchanger (Medtronic Inc., Minneapolis, MN). All animals received care according to the “Guide for the Care and Use of Laboratory Animals (1985)” prepared by the U.S. Department of Health and Human Services and published by NIH. The study was approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Texas Medical Branch, Galveston with strict adherence to the IACUC guidelines regarding humane use of animals.
To assess feasibility of our design concepts, two 30 Fr W-Z DLC prototypes were tested for recirculation in one day acute studies, then one 26 Fr DLC prototype was tested for 15 day performance and gas exchange in an awake sheep. All sheep were intubated with an endotracheal tube (10 mm OD) after initial sedation with 12.5 mg/kg intramuscular ketamine and inhalation with 4% Halothane. General anesthesia was maintained with 1%–2.5% isoflurane delivered by an anesthesia machine (Ohmeda 7,000, BOC Health Care, Liberty Corner, NJ), titrated to a heart rate of 75–120 beats per minute during surgery. The sheep’s neck and groin underwent a sterile prep and drape in the supine position. Two 16-gauge catheters (Intracath, Becton-Dickinson, Sandy, UT) were inserted into the right femoral artery and right femoral vein through a small right groin cut-down for arterial blood pressure monitoring, intravenous infusion and blood gas analysis. Mean arterial pressure (MAP) was continuously monitored using a HP 78534B monitor. The right jugular vein was identified and exposed through a small right neck cut-down (2 cm). After systemic heparinization with bolus intravenous heparin (120 IU/kg), the W-Z DLC was inserted through a small incision on the jugular vein into the SVC, traversing the RA, with the tip positioned in the IVC. The pump-gas exchanger circuit, primed with a heparin/Ringer’s solution (3 unit heparin/ml), was then connected to the inserted W-Z DLC. The pump was turned on to initiate blood flow and 100% oxygen (6 L/min), as sweep gas, was connected to the gas exchanger. The venous blood was drained from both the IVC and SVC drainage holes out the W-Z DLC drainage lumen to the pump-gas exchanger. Oxygenated blood was pumped back through the W-Z DLC infusion membrane sleeve into the RA toward the tricuspid valve, then into the pulmonary circulation.
The pump-gas exchanger circuit blood flow was continuously monitored by a Transonic 9XL tubing flowsensor and HT110 flowmeter (Transonic System Inc., Ithaca, NY). Femoral venous blood, pre and post gas exchanger blood were sampled simultaneously for blood gas analysis to calculate the recirculation rate by the formula19:
where SpreO2: pre device O2 saturation; SpostO2: post device O2 saturation; SvO2: venous O2 saturation.
The survival animal was transferred to the investigational ICU, recovered from anesthesia, extubated, and allowed to stand with free access to food and water. A continuous heparin venous infusion was titrated to ACT of 180–300 seconds.
MAP and heart rate were continuously monitored by a cage-side HP 78534B monitor. The circuit blood flow was continuously monitored by a Transonic 9XL tubing flowsensor and HT110 flowmeter. Blood gases (arterial, venous, pre, and postgas exchange device) were analyzed by Synthesis 15 (Instrumentation Laboratory, Lexington, MA). The outlet sweep gas was collected for measurement of exhaust CO2 concentration (percentage). Pre and postgas exchange device pressures were measured and documented. Sweep gas flow (pure oxygen) was regulated by an oxygen flowmeter (Datex-Omeda Inc., Madison, WI). The following standard formulae were used to calculate gas exchange:
Upon study completion, a large bolus of heparin (300 IU/kg) was given intravenously to prevent postmortem thrombosis formation within the animal and the pump-gas exchanger circuit before autopsy. The acute study animals were euthanized with saturated potassium chloride while still under general anesthesia. The survival animal was euthanized at day 15 when the gas exchange device failed. Autopsy was performed to assess cannula position, thrombosis formation and lung embolization.
Results
All three W-Z DLCs were inserted and advanced smoothly into the desired position in the SVC-RA-IVC within 30 seconds. Placement was confirmed directly by visualization at autopsy in the chronic survival study animal. In the acute study, the cannula placements were presumed because of the minimal recirculation rate measured (3.3 ± 0.2% at 2.0 L/min blood flow). In one animal, recirculation rate increased to 51.3% as the DLC tip was pulled back from the IVC to the RA from 2.1% when properly positioned (Figure 4). The maximal blood flow in the 30 Fr prototypes was 2.3 L/min. Inlet pressure from the cannula was 23 mm Hg and outlet pressure was 89 mm Hg. At 2 L/min blood flow, the recirculation rate was as low as 2.2% with the catheter properly positioned.
Figure 4.:
W-Z DLC showed only 2% recirculation at a flow of 2 L/min. DLC tip dislodgement from inferior vena cava (IVC) to right atrium (RA) made recirculation jump to 50%.
In the survival animal, the sheep stood and ate/drank freely during the 15 day study. The dark desaturated venous drainage blood was in sharp contrast visually to the bright red blood in the infusion channel (Figure 5). The gas exchanger foamed and failed on day 15, and the experiment was terminated.
Figure 5.: A: The experimental sheep stood/seated freely and ate/drank normally with dark black blood out of drainage lumen in clear contrast against the vivid red blood in the infusion lumen. B: Plasma leakage and gas exchanger failure on day 15 with less contrasted blood colors in the drainage/infusion tubing.
The heart rate and MAP remained stable during the 15 day experiment. Arterial blood gas analysis showed a normal PaO2. As expected, the PaCO2 trended low (<25 mm Hg during the first week) (Table 1).
Table 1: The HR, MBP, Hb, and PaO2, PaCO2 During 15 d Paracorporeal Artificial Lung Study
Device Function and Recirculation
Blood flow throughout the 15 day experiment was 2 L/min (Figure 6). The pre pump drainage pressure was 19 ± 4 mm Hg, whereas the pump infusion pressure was 86 ± 4 mm Hg. The pump ΔP was 104 ± 7 mm Hg. With 2 L/min blood flow, up to 140 mL/min (102 ± 32.5) O2 transfer and 230 ml/min (151.7 ± 41.1) CO2 removal was achieved. On day 12, the gas exchanger began to fail as evidenced by plasma leakage (foaming in sweep gas outlet) which compromised performance (Figure 7) for the remainder of the experiment.
Figure 6.:
Steady 2 L/min blood pumping flow over the 15 day experiment.
Figure 7.:
Gas exchange through the circuit over the 15 day experiment.
There was more recirculation intermittently during the 15 day study (20 ± 10%) than was seen in the acute studies (Figure 8), but the O2 saturation difference between drainage and infusion channels was still as high as 41 ± 13%. Hemoglobin remained above 9 g/dl with no blood transfusion throughout the 15 days of respiratory support. The plasma free hemoglobin averaged 35 ± 20 mg/dl.
Figure 8.:
Fluctuations in the recirculation rate (average 20%) and good O2 saturation difference across the gas exchanger.
Autopsy Study
For both the acute and chronic animals, the sheep lungs grossly appeared normal. No atelectasis, emboli or thrombi were found in the lungs by gross and cross-sectional examination. In the two acute studies, catheter position was optimal. The cannula tip (IVC opening of drainage lumen) was positioned in the IVC, with the SVC opening in the mid SVC in both animals. For the chronic sheep, the infusion lumen opening was located just inside the RA-SVC conjunction (Figure 9). This location appeared more cephalad from the tricuspid valve than expected, given the lack of recirculation. No thrombosis was found on the inner or outer cannula body or the three drainage/infusion ports (Figure 10).
Figure 9.:
An autopsy with the right atrium (RA) opened showed that the cannula tip was located in inferior vena cava (IVC) and the infusion lumen opening in conjunction of superior vena cava (SVC) and RA.
Figure 10.:
The cannula taken out after experiment, showed no thrombosis.
Discussion
A large patient population persists that requires complete respiratory support either for recovery from ARDS or as a bridge to lung transplantation. During the last three decades, ECMO, utilizing a modified heart-lung machine with a bulky, relatively high resistance silicone membrane gas exchanger has been used in select circumstances for prolonged respiratory support (weeks). Recently, a PAL has been developed for long term ambulatory respiratory support but currently major surgery is necessary to anastomose the PAL to the heart and main pulmonary artery.17,18,20–22 A DLC was developed two decades ago for infant/pediatric VV ECMO and proved the concept of respiratory support with a less invasive, single cannula venous access. Although commercially available since 1989 for application in newborns and small children, no alternative for adults exists. Recirculation, kinking and insufficient blood flow plague broader application.23,24 Our W-Z DLC is designed to almost eliminate recirculation and enhance performance in a larger patient. When combined with a compact pump-gas exchanger, this system may supply total respiratory support via minimally invasive percutaneous single venous cannulation to adults and large children.
Our current feasibility study demonstrates a very low recirculation rate at only 2 L/min blood flow with proper DLC placement. The asymmetric balloon below the SVC drainage opening also contributes to the minimal recirculation seen in our acute studies. Throughout our 15 day study, the O2 saturation gain across the gas exchanger is significant (up to 50%) at 2 L/min blood flow, but recirculation was relatively higher (20%) than in the acute studies. Positioning may have contributed to suboptimal DLC function evidenced by a more cephalad RA position (conjuction between SVC and RA) of the DLC infusion lumen opening found at autopsy in this animal.
We demonstrated the feasibility of percutaneous insertion and advancement of the W-Z DLC into the SVC-RA-IVC (25 Fr cannula) without fluoroscopic guidance in six consecutive cadaver sheep before the current study. Our 1 day in vivo studies further demonstrated feasibility of safe insertion without fluoroscopic guidance. However, our single chronic study emphasized the need for proper placement. In future studies and for clinical applications, we recommend fluoroscopic guidance during insertion. Similarly, transthoracic echocardiography may prove helpful allowing safe percutaneous insertion, advancement and optimal positioning in SVC-RA-IVC to avoid right heart injury, and minimize recirculation.
Benefiting from our unique cannula construction with an extremely thin membrane sleeve infusion lumen and thin wall stainless steel reinforced polyurethane outer wall, our 26 Fr DLC can achieve 2.0 L/min blood flow with <120 mm Hg ΔP. We have previously shown that for total CO2 removal, only 1 L/min arterial blood flow is needed.25 At 2 L/min venous blood flow, with no recirculation, a gas exchange device can remove the total CO2 production and transfer over 200 ml/min O2 with normal hemoglobin (12 g/l). Therefore, 2 L/min blood flow can meet the gas exchange requirements for most patients. If necessary, a larger DLC (up to 30 Fr) could be used for more blood flow (up to 5 L/min) and more gas exchange allowing total respiratory support under conditions of stress, hypermetabolism or large body surface area.
The W-Z DLC prototype is constructed with a high silicone content polyurethane copolymer with proven biostability characteristics.26 Under mild systemic heparinization (ACT 180–230 seconds), we found the DLC shaft and drainage openings completely thrombosis free at autopsy after the 15 day in vivo animal study. During our 15 day feasibility study, our W-Z DLC system did not require blood transfusion (blood hemoglobin was maintained above 9 g/dl).
In this first study of our W-Z DLC, only one long-term sheep was used; more studies are needed to prove consistent performance. We did not directly verify DLC position until autopsy, which can be very easily accomplished by fluoroscopy or echocardiography in a clinical setting. Our measures of recirculation are clinically sufficient but a computational fluid dynamics (CFD) analysis may better elucidate the in vivo flow characteristics of the catheter.
In conclusion, the W-Z DLC minimizes recirculation rate, maximizes the cross-sectional flow area at a given DLC size, to maximize flow and to enhance the PAL system’s gas exchange performance. The one site percutaneous venous cannulation may allow total gas exchange as an ambulatory PAL circuit. Our design refinements will be further tested in long-term large animal studies and in prospective randomized outcome studies in our sheep model of ARDS.
Acknowledgment
Supported in part by a National Institutes of Health STTR Grant No. 5 R42 HL067523 and Avalon Laboratories, Rancho Dominguez, California. The large animal experiments were conducted at UTMB, Galveston, Texas.
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