The mean extracorporeal blood flow was maintained at 32% ± 6% of cardiac output with a gas to blood flow ratio of 1.2 ± 0.3. The body temperature remained constant (Table 2).
To maintain adequate intravascular volume, 6.2 ± 4.4 ml · kg−1 · h−1 of crystalloid and 1.9 ± 2.0 ml · kg−1 · h−1 of colloid solutions were infused. This caused a mild hemodilution as indicated by reduced hematocrit and hemoglobin values (Table 3). No significant hemolysis could be detected as plasma-hemoglobin levels did not increase over time. However, although ACT was in the target range, increased levels of TAT and a decrease in platelet count suggest significant activation of the coagulation system (Table 3). Some thrombus formation was detected in the outflow tract of the HEXMO after one experiment, although we could not observe a flow limitation during that experiment.
During the extracorporeal flow phase, the oxygen transfer rate by the HEXMO was unchanged, but the pulmonary oxygen transfer decreased (Table 4, Figure 4). A small decrease in PaCO2 was not significant (Figure 3), although the combined carbon dioxide elimination by the lung and the HEXMO increased (Table 4, Figure 5).
For patients with most severe ARDS, ECMO is a rescue therapy with demonstrated benefit in case of refractory hypoxemia, if it is integrated into an advanced treatment concept.2 Despite advances in oxygenator and blood pump design including a reduced filling volume of approximately 300 ml for both components, the application of ECMO is associated with a number of specific complications, such as hemorrhage, thromboembolism, or technical failure of components.3 The more complex a system, the more vulnerable it is to technical and application failure. The logical consequence is to reduce complexity, which is achieved by the HEXMO by integrating oxygenator and blood pump into a single housing with a reduced filling volume of 150 ml. This new design facilitates full ECMO capacity embedded into a device only slightly bigger than a can of pop. We have tested a prototype development mainly to assess performance and biocompatibility in an in vivo setting.
The HEXMO was effective in reversing hypoxemia, and the lungs were unloaded from pulmonary oxygen transfer as the extracorporeal oxygen transfer became effective. We could not demonstrate a significant reduction in the PaCO2, although the extracorporeal carbon dioxide elimination was clearly present. This may be attributed in part to the experimental design, which does not impair the gas exchange capabilities of the lungs. Thus, native lungs and HEXMO were “competing” for carbon dioxide elimination, a situation which would have not occurred in a model with significant ventilation/perfusion mismatch. We speculate that in a situation where carbon dioxide elimination by the lungs is impaired, the effect of the HEXMO on PaCO2 might have been greater.
Blood flow through the oxygenator is crucial for oxygenation. For example, 300 ml/min was sufficient to reverse hypercapnia but was not effective for oxygen transfer.16 In another new development with an integrated paracorporeal rotating oxygenator, the oxygen transfer rate was limited to 52 ml/min despite higher blood flow rates.17 Carbon dioxide transfer was 64 ml/min mean. The HEXMO has similar oxygen transfer efficiency, but with a gas/blood flow ratio of approximately 1.2, carbon dioxide elimination was limited. We speculate that increasing the gas flow higher than 2 L/min might increase efficacy, as it is recommended similarly for a pumpless extracorporeal device with similar blood flow and gas exchange characteristics.18
During experiments, no hemolysis was observed, and hemodilution after connecting the ECMO to the animals was marginal. Activation of plasmatic coagulation occurred as indicated by increasing concentrations of TAT. Of note, this prototype's surfaces were not heparin coated, which has been shown to be a major advantage for hemocompatibility.4 A previous animal study resulted in lower TAT concentration after 4 hours of ECMO, but all surfaces were heparin coated.12 A further problem was significant thrombus formation in a dead water area at the blood outlet part of the housing. For future development of the HEXMO, a redesign of the blood outlet and heparin coating has to be considered.
The first 4 hours of ECMO seem to be sufficient to provide a reliable estimate of hemocompatibility,19 thus it is reasonable to assume that the HEXMO has the potential to provide long-term support. Assembly and handling of the device is greatly simplified, and the technology can be managed by “turning of one knob.” This will increase ease and safety of patients transfer.
This study has several limitations. To allow comparison with previous studies, we used a porcine model for testing of extracorporeal lung assist.6 We chose ventilation with a hypoxic gas mixture to produce stable severe hypoxemic conditions with a SaO2 <85%. Other methods to create hypoxemia, for example, induction of acute lung injury by surfactant depletion or oleic acid application,12,20 may have direct implications on organ function as the inflammatory component of lung injury is missing in the hypoxia model.21
Because the hypoxia model does not reproduce physiological conditions seen in a clinical situation, it allows to study the effects of the ECMO system independently from inflammatory response and multiorgan failure.
In this study, we tested the first hand-made production in vivo, and with the knowledge gained from these preliminary experiments, the HEXMO prototype can be further developed to improve gas exchange capacity and to optimize blood flow characteristics in the device.
Other available miniaturized ECMO systems usually combine individual coupling of components with a small filling volume12 or the fixed combination of conventional centrifugal pump and oxygenator.22 In these closely to the bedside placed systems, the priming volumes are reduced mainly by shortening of the tubing. A downsized extracorporeal circulation system (Emergency Life Support System-ELS, Maquet, Hirrlingen, Germany) demonstrated safe and simple application for the transport of patients on ECMO compared with conventional, not integrated systems.7 In patients with high bleeding risk, a completely heparin-coated, miniaturized system had demonstrated safe application without increased thromboembolism,23 in the absence of systemic heparinization.
Hemocompatibility and sustainability of the used materials will determine the ability to perform long-term support without failure. As there was some clot formation, the flow design has to be improved. We did not subject the components, blood pump and hollow fibers, to additional material testing, as we only used hand-crafted prototypes for proof of concept. However, this study clearly shows the importance of doing early in vivo tests to enable corrections of the design in the early development stage.
These considerations apply to extracorporeal lung support, but efforts to develop intravascular oxygenators (IVOXs) toward the artificial lung have been made. The first clinically applicable IVOX demonstrated significant gas exchange capabilities in an uncontrolled clinical study with 160 patients, but the device did not prevail clinically due to a high complication rate of 29%.24 Newer concepts integrating a miniaturized blood pump11 or a pulsating balloon in the center of the device25 could overcome the limitations and problems of IVOX.
The HEXMO demonstrated constant gas exchange and blood pumping performance over a period of 4 hours, which was sufficient to improve oxygenation in a model of hypoxic lung failure without causing hemodynamic instability or major hemoincompatibility. Prototype-typical problems with rotor-pump coupling and intradevice formation of blood clots were encountered in <20% and will have to lead to improvements in the design. This new device has demonstrated promising results suggesting further development and testing in various scenarios and over longer time periods.
Supported by START of RWTH Aachen University and Novalung Hechingen, Germany. The authors thank late Prof. Helmut Reul, Helmholtz Institute of Biomedical Technology, RWTH Aachen, who had had substantial intellectual input in the development of the device.
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Copyright © 2011 by the American Society for Artificial Internal Organs
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