Liquid Assisted Ventilation (LAV) is a respiratory support method that utilizes perfluorochemical (PFC) liquid to replace nitrogen gas as a carrier for oxygen (O2) and carbon dioxide (CO2). By eliminating the air-liquid interface, LAV for respiratory support of acute lung injuries allows recruitment of collapsed lung regions at lower pressure. It also reduces ventilation/perfusion mismatch by redistributing pulmonary blood flow and more homogenously distributing ventilation in the injured lungs. Other potential advantages of intrapulmonary PFC include its use as a bronchoalveolar lavage medium to facilitate the washout of debris from the lungs. Two principal modes of LAV have been developed: partial liquid ventilation (PLV) and total (or tidal) liquid ventilation (TLV). In PLV, the lungs are partially filled with PFC and then gas ventilated using a conventional gas ventilator. In TLV, the lungs are completely filled with PFC and a dedicated total liquid ventilator delivers and retrieves a tidal volume of liquid into and from the lungs.
Over the last decade, numerous preclinical studies have demonstrated efficacy and safety of LAV in mature and immature lungs. Phase II and III adult and pediatric clinical PLV studies failed to demonstrate that PLV was superior to conventional gas respiratory support. Those results have been extensively discussed in the literature. In brief, as an abbreviated, oversimplified, uncontrolled approach, the method of PLV does not incorporate the fundamental principle of global elimination of the air-liquid interface, thus falls short in fulfilling the potential of LAV. In contrast, full lung liquid ventilation with a dedicated total liquid ventilator is the most logical approach to apply LAV efficiently and reliably in humans. But, what is the clinical readiness level of this new medical device? During the 6th International Symposium on Perfluorocarbon Application and Liquid Ventilation, a round table discussion on bioengineering was held in which different experts shared their opinions and experiences about the use of a total liquid ventilator design for clinical applications. To structure the discussion, all experts were invited to contribute their knowledge within the context of three matrixes related to the liquid ventilators: 1) function and technology (Table 1), 2) ventilation modes (Table 2), and 3) risk analyses (Table 3).
Function and Technology
Table 1 reflects the consensus reached on the nine necessary functions that a total liquid ventilator must fulfill. These functions include: 1) driving liquid to and from the lungs, 2) directing liquid in the fluid circuit, 3) oxygenating the liquid and scrubbing CO2 from the liquid, 4) filtering debris from the liquid, 4) heating liquid to body temperature, 5) limiting losses of liquid due to evaporation, 6) measuring pressure at the mouth, 7) measuring liquid flow, 8) measure liquid volume, and 9) interfacing with the clinician as seamlessly as a conventional gas ventilator.
The discussion elucidated that each function could be realized by different types of components and that individual components could perform multiple and different functions. A consensus was reached for the following function/component relationships: 1) driving liquid with piston pump, 2) directing liquid with pinch valves, 3) filtering liquid with a gross filter, 4) limiting liquid losses with a condenser, 5) measuring pressure with a pressure sensor, and 6) measuring flow with a flowmeter.
However, less agreement was reached concerning the components to perform PFC liquid gas exchange, that is, how to oxygenate the liquid and remove CO2 from the liquid. For such functions, the considered technologies were based on extracorporeal oxygenators (ECOs). The benefits of the most up-to-date membrane oxygenators (i.e., efficiency, minimal PFC evaporative loss, absence of free gas bubbles) were favored by some experts (group 1). However, concerns about PFC-membrane compatibility and relative expense of these exchangers were raised by other experts (group 2) who recommended bubble oxygenators as an alternative.
It is entirely feasible to control each ventilatory parameter via the total liquid ventilator (Table 2). A consensus was reached that only mandatory breaths are performed during TLV, that inspiration and expiration phases must be controlled independently by the total liquid ventilator, and that pressure-regulated, volume control should be recommended. However, two points of view were debated about the volume versus pressure control modes to maintain the lung volume. Group 1 considered that it is fundamental to consider the priming volume of the total liquid ventilator to estimate the lung volume. Using this approach, measurement of PFC volume in the ventilator and the estimation of all PFC losses (in the patient body and in the ventilator) are required to compute the lung volume. The alternate view (group 2) proposed that controlling the volume in the lungs via the priming volume assumption is not practical or reliable. In this regard, it was argued that because liquid evaporation and secretions generation in the lungs randomly change the priming volume, an efficient and safe estimation is consequently not possible over the long-term. For this reason, it was proposed that pressure regulation at a constant positive end expiratory pressure level with volume control is a more practical approach for long-term clinical use. For this approach to be most accurate, careful monitoring and subsequent fluid replenishment must be incorporated if a bubble oxygenator, with greater PFC evaporative losses, is used.
All clinical devices need to be analyzed for potential risks. Hence, whatever the risk probability and severity, just as is necessary with any form of gas ventilator, the risks associated with a liquid ventilator must be considered. Good engineering practices reduce the probability of risk occurrence. A simple risk analysis based on failure mode effect analysis was done (Table 3). This analysis highlights the system failure effect on the total liquid ventilator itself and on the patient. The latter also quantifies the probability of occurrence and the severity of the failure. A consensus was reached regarding the possibility to perform safe TLV. Additionally, the consensus emphasized that because of the low frequency domain of the process of TLV compared with gas ventilation, TLV enables a greater safety margin with respect to intervention time; it does not require a very fast reaction from the clinician. Should intervention be required, the patient can be quickly disconnected from the total liquid ventilator without hazard and be returned to gas ventilation modes without interrupting lung support or gas exchange.
The consensus obtained from the multi-national scientific community, established the current status of technology, ventilation modes, and risks analysis in total liquid ventilator research. The results of the round table discussions give a clear definition of what should be called a total liquid ventilator, what should be controlled, and the possible device safety for practical applications. The main source of debate was related to the primary volume of the system. The total liquid ventilator was viewed as an “artificial organ” like extracorporeal membrane oxygenation by some (group 1), or as an “external medical device” like any conventional gas ventilator by others (group 2). As with the development process of all innovative technologies, the discussion was robust, insightful, and open to novel solutions. Summarily, the outcome of this international conference recommends continued development of a total liquid ventilator toward clinical applications.