Liquid assisted ventilation uses perfluorochemical (PFC) liquids to replace the common gas mixture during mechanical ventilation. These liquids are able to dissolve a sufficient quantity of O2 and CO2 at atmospheric pressure to support gas exchange in the lungs.1 Liquid assisted ventilation can be performed either as partial or total liquid ventilation. During partial liquid ventilation (PLV), a fraction of the functional residual capacity (FRC) is filled with PFC liquid and a conventional mechanical gas ventilator ensures lung ventilation. In contrast, total (or tidal) liquid ventilation (TLV) necessitates a dedicated mechanical system to ventilate completely filled lungs with a tidal volume of PFC.
By eliminating the air-liquid interface, TLV allows recruitment of collapsed lung regions at lower pressure,2,3 hence decreasing the risk of lung injuries and ensuring a more homogeneous alveolar ventilation.4,5 Other potential advantages of TLV include a better washout of inflammatory debris from the lungs and in vivo anti-inflammatory antioxidant and antibacterial effects of PFC.6–11 Many studies involving various experimental models of acute lung injury suggest clear benefits from TLV5,12–16 as compared with all other tested ventilation strategies, including conventional and high-frequency gas ventilation and PLV. Diverse types of tidal liquid ventilators have been developed for conducting animal experiments. 2,6,17–38 Regardless of the technologies used, a liquid ventilator must perform the following essential functions: Insert and withdraw the tidal volume Vt of PFC from the lungs, oxygenate the PFC, and maintain it at a desired temperature (usually the patient’s temperature).
To oxygenate and remove CO2 and to maintain the PFC at the desired temperature, the gas exchanger can be an extracorporeal membrane oxygenator (ECMO)6,17,19–21,24,26,29,32 a hollow-fiber oxygenator,30 or a bubble-type gas exchanger.18,22,27,28 However, with all types of gas exchangers, PFC vapors escape from the outlet port. Hence, a condenser is essential for preventing excessive losses of PFC. Various devices have been used, such as metallic tubes in an ice bath or heat-sink devices.19,27
To insert and withdraw the tidal volume of PFC, some devices exploit gravity by placing reservoirs at different heights to force the PFC liquid in and out of the lungs.20,22,24 However, a pump is necessary to precisely control inspiratory and expiratory flows,32 hence the earlier use of ventilators and peristaltic pumps,19–21,33 bellow pumps,25 gear pumps,22 and piston pumps.27–30 The latter produces steady flows nearly exempted of pulsations, although the main interest of a piston pump is to achieve perfect volume-controlled ventilation. Moreover, it was shown that more PFC is drained from the lungs through the use of a piston pump, compared with a peristaltic or gravimetric system.31
Two main problems must be considered in the control of the pump in TLV: avoid airway closure (chocked flow) during expiration and control FRC in the lungs. Development of airway closure can be avoided by including pressure limits that manage (i.e., stop or slow down) the pump when an important negative pressure is reached.26,27,29,32,39 Measurement of FRC can be obtained by monitoring the patient’s weight,22,25,30 end-expiratory pressure,19 or liquid volume in the ventilator.20,21,26
The main objective of this study was to develop a TLV ventilator for experimental and clinical use. The foremost novelty of the presented ventilator is its independent expiratory and inspiratory piston pumps, which allow an optimized control of the ventilation profile and FRC.
Section II is a description of the overall ventilator, the integrated condenser-heater-oxygenator element, the pump system, and its controller. The calibration tests presented in section III allowed validation of the system design. Finally, results obtained during in vivo testing in an experimental model of healthy newborn lambs are presented in section IV.
Materials and Methods
Description of the Tidal Liquid Ventilator
The prototype tidal liquid ventilator, presented in Figure 1, is designed for infants weighing up to 9 kg, using a Vt of 25 ml/kg body weight. It is controlled by an industrial programmable logic computer (S7-300 series, Siemens Canada Ltd, Pointe-Claire, Canada); a touch panel serves as a human-machine interface.34,35 As presented in Figure 1, this TLV ventilator includes 1) two independent piston pumps to insert and withdraw PFC from the lungs; 2) a gas exchanger to perform complete PFC oxygenation and CO2 removal; it includes a heating system to heat and maintain the desired PFC temperature, a condenser to retrieve PFC vapors, and a filter to remove sputum and any other unwanted materials (e.g., meconium) from the expired liquid; 3) four pneumatic pinch valves to control the inspiratory and expiratory fluid circuit independently; 4) a buffer reservoir to monitor the level of PFC in the ventilator; and 5) a condenser to attenuate PFC losses by evaporation.
Different cycles are available on the TLV ventilator. A preparation cycle allows the clinician to circulate the PFC liquid in a closed loop to warm, oxygenate the liquid, and remove air bubbles. Then, a filling sequence can be used to fill the patient’s lungs by using one pump.34,35 Finally, the respiratory cycle is used to carry out TLV. This cycle is divided into four distinct phases: 1) inspiration phase: valves 2 and 3 are closed, valve 1 is opened, and the inspiratory pump moves up to insert the inspiratory volume of PFC, Vi, into the lungs; 2) end-inspiration pause: valves 1 and 3 are closed; the positive end-inspiratory pressure, PEIP, is measured during this pause with the use of a pressure sensor (SPR524, Millar Instruments Inc., Houston, TX) positioned in the endotracheal tube, 12 mm proximal to its ending; 3) expiration phase: valves 1 and 4 are closed, valve 3 is opened, and the expiratory pump moves down to withdraw the expiratory volume of PFC, Ve, from the lungs; 4) end-expiration pause: valves 1 and 3 are closed; the positive end-expiratory pressure, PEEP, is measured during this pause through the use of the endotracheal pressure sensor.
The expiratory pump and the inspiratory pump are the same but are controlled individually. Pump independence is used to 1) optimize PFC residing time in the gas exchangers by pushing the expired liquid as soon as possible in the oxygenators; this is done at the onset of the inspiration phase by opening valve 4 (valve 3 is closed) and by pushing the liquid present in the expiratory pump as fast as possible; 2) improve pressure measurement in the buffer reservoir by waiting until the latest possible moment to fill the inspiratory pump with oxygenated PFC; at the end of the expiration phase, the PFC is pumped from the buffer reservoir by opening valve 2 (valve 1 is closed); 3) modify FRC during ventilation according to the clinician’s request; the requested correction of FRC, ΔV, is the PFC volume to retrieve from (if negative) or to add into (if positive) the lungs during one cycle; 4) compensate for small pumping errors and to deal with an eventual exceptional stoppage of the cycle, caused when reaching either an upper or lower pressure limit detected by pressure measurement in the endotracheal tube.
The ventilator is designed with an integrated condenser-heater-oxygenator (CHO) unit. This design integrates a bubble gas exchanger for PFC oxygenation and CO2 removal, a heater element to maintain the liquid at the desired temperature, and a condenser to retrieve PFC vapors. In Figures 2 and 3, two heater-oxygenators are linked in series to increase the efficiency of gas exchange.
The pure oxygen bubbles generated at the bottom of each oxygenator by a perforated elastomer membrane constitute the surface for gas exchange. The interior of the oxygenator is divided into two sections, an inner tube and an annular tubular section, which communicate with each other at the bottom. Hence, PFC arriving from or exiting the lungs is not in direct contact with the oxygenated liquid going into or entering the lungs. When a volume pumped from the lungs (Ve) is injected into oxygenator 1, the level is maintained by overflow, so an equivalent amount of PFC travels from oxygenator 1 to oxygenator 2 and finally to the buffer reservoir. This configuration maximizes the contact time between the oxygen bubbles and the PFC.
A heating element, wound around the lower portion of each oxygenator, heats the stainless steel component and hence the PFC it contains. Bubbles generated by the perforated membrane (Figure 3) produce a constant agitation of the liquid, resulting in a uniform temperature distribution throughout the inner and annular sections of the two oxygenators. The PFC temperature, measured by a type E thermocouple probe, is processed by a proportional-integrator controller implemented in the PLC to control the heating element (125 W, Omega, Rope Heater FRG-030 Omega, Laval, Canada).
The condenser, presented in Figure 3, recovers the PFC from the mixture of gas and PFC vapors escaping from the oxygenators. By alternating long and short fins, this mixture is forced to zigzag inside the condenser. Thus, the entire cold surface is used to condensate PFC vapors into liquid, which falls by force of gravity into the oxygenator. Thermoelectric modules (DA-025-24-02, Supercool Thermoelectrics, Göteborg, Sweden) used to cool down the fins are controlled by the PLC to maintain their temperature (measured by a type K thermocouple probe) at a constant desired value (typically at 5°C).
Control System of the Piston Pump
A schematic representation of the piston pumps used on the TLV ventilator, with all of its components, is given in Figure 4. Figure 5 presents the complete control system implemented for the control of the two piston pumps. Three hierarchies must be considered: the control of the desired volumes (the controllers), the generation of inspiratory and expiratory volume references (the generators), and the volume supervisor (the Supervisor).
Each pump uses an individual proportional controller that independently commands the pump motor by using a feedback loop control design. The objective of this feedback loop is to follow the volume reference (ye(t) → re(t) for the expiratory pump and yi(t) → ri(t) for the inspiratory pump) delivered by the corresponding (inspiratory or expiratory) generator, based on the volume measured in the pumps by the potentiometers. The references are computed to perform the desired volume profile, Ve[k] and Vi[k], during the specified time Te[k] and Ti[k]. Two volume profiles (illustrated in Figure 6) are considered the ramp for inspiration and the exponential for expiration. The ramp volume profile is generated with a 20% acceleration, 40% constant, and 40% deceleration.27 The exponential volume profile is generated according to the equation
where Re[k] = Ve[k]/(1 – exp(–Te[k]/τ)), τ is the time constant, t the time (equal to zero at the beginning of an expiration), and k the index of the cycle.
The Supervisor Module
The supervisor module computes the inspiratory volume, Vi[k], and the expiratory volume, Ve[k], according to the clinician’s requests with regard to tidal volume, Vt[k], and the FRC correction, ΔV. In addition, the supervisor module compensates for errors in piston movement, when present. The following algorithm is used:
The desired inspiratory volume is computed with Vt[k] and ΔV (if it needs to be decreased):
At the end of inspiration, the effective inspiratory volume is measured, yi[k] = yi(t) for t = Ti[k], to compute the volume error, Ei[k], produced by the inspiratory pump:
The desired expiratory volume, Ve[k], is computed based on the Vt[k], ΔV (if it needs to be increased), Ei[k], and the previous expiratory error, Ee[k−1]:
At the end of expiration, the effective expiratory volume is measured, ye[k] = ye(t) for t = Te[k], to compute the volume error produced by the expiratory pump, Ee[k], which is memorized for the next respiratory cycle:
This error management algorithm (Equations 2 to 5) is stable and converges on a number of cycles, depending on the form of the error.
Finally, lower and upper pressure limits are set to protect the patient’s lung. If the upper pressure, Pmax, is reached during the inspiration phase, P(t) > Pmax, the inspiratory pump is stopped, and the cycle switches to the end-inspiratory pause. In this case, due to Equation 3, only the volume instilled in the lungs will be expired. Also, if the lower pressure limit, Pmin, is reached during the expiration phase with the risk of an airway closure, P(t) < Pmin, the expiratory pump is stopped, and the cycle switches to the end-expiratory pause. In such a case, the desired inspiratory volume for the next inspiration is equal to the volume expired from the lungs during the stopped expiratory cycle, Vi[k] = ye[k – 1], instead of the volume computed according to Equation 2. Hence, every time a pressure limit is reached, the volume inserted or expired from the lungs is adjusted to maintain the same FRC. Hence, each pump is time-limited, volume-controlled, and pressure-limited.
Testing of the Condenser
Before this test, the offsets on each thermocouple probe were previously removed. Throughout their calibration range, they maintained a standard deviation of ±0.3°C. Condenser efficiency was determined by using PFOB (perfluorooctyl-bromide) liquid. The gas and PFC vapor mixture coming from both oxygenators at 39°C was redirected to an external reservoir, where the condenser sits. In this reservoir, the amount of retrieved PFC liquid was measured and compared with the level variation in the buffer reservoir. During this test, the PFC liquid in the ventilator moves in a closed loop, using the preparation cycle.34,35 The bottom of the condenser was maintained at 5°C, and the gas flow was set to 3 l/min in each oxygenator. The measured condenser efficiency was 75% ± 5%, yielding a net PFOB loss of about 21 ml/h.
Testing of the Pumps and Their Control System
First, the supervisor module was tested to determine whether the algorithm converges and manages measurable pumping errors. A dSpace acquisition station (DS1003 processor board, DS2201 I/O board, dSpace Inc., Novi, MI) was used to precisely record the analog signals provided by the potentiometers of the expiratory and inspiratory pumps. Four Vt were chosen, from 75 to 150 ml, to reflect the weight range of a term newborn lamb. Over a 2-hour period, the differences between the inspired and expired volumes (ΔFRC) were summed. The results are presented as mean ± SD range in Table 1 Of note, the standard deviation of the inspired volume was close to the quantization error of the analog signal by the PLC to its discrete state, which is 0.14 ml. Thus, the supervisor module, presented with Equations 2 to 5, thereby proved its effectiveness in managing measurable errors.
Second, to test the operating capabilities of the expiratory and inspiratory piston pumps and their overall system control, in vivo TLV was mimicked by replacing the lungs with a fixed reservoir. A pressure sensor (Bentley Trantec 800, Irvine, CA) placed at the bottom of the reservoir was used to determine the volume variations within the reservoir, as a surrogate for Vt, over a 2-hour period. As performed earlier, four Vt were chosen, from 75 to 150 ml, to reflect the weight range of a term newborn infant during the first weeks of life. The results presented in Table 2 confirm that the measured Vt is within ±2% of the reference value.
Testing of the Oxygenator
To characterize the oxygenator, the equivalent gas exchange surface was defined by Seq = 6VO2/Db, with Db the bubble diameter and VO2 the oxygen volume in the PFC. The bubble diameter Db was obtained by taking a digital image of the bubbles in the oxygenator and by averaging a total of 50 images. The oxygen volume in the PFC VO2 was calculated by measuring the change in the level of PFC before and after initiating the flow of gas under the membrane. When using PFOB, the mean bubble diameter was 2.0 ± 0.6 mm and the global volume of gas in the PFC averaged 280 ± 10 ml at a total flow rate of 6 l/min. Thus, the Seq was 0.84 ± 0.1 m2. With two oxygenators in series, the equivalent gas exchange area is greater than an ECMO for children weighing less than 10 kg (based on a Medtronic ECMO model 0600, Minneapolis, MN).
In Vivo Testing
The experimental protocol was approved by our institutional Ethics Committee for Animal Care and Experimentation. Five healthy newborn lambs (<5 days) were placed in a supine position under a radiant heater to maintain a central temperature of 39 ± 0.5°C. Heart rate was recorded using a Hewlett-Packard cardiorespiratory monitor (model HP 78342A, Palo Alto, CA). Oxygen saturation (SpO2) was monitored with the use of a pulse oximeter probe placed on the base of the tail (8000R reflectance sensor, Nonin medical, Plymouth, MN). The analog signals generated from the TLV ventilator were recorded by using Signal Ranger I/O boards (SoftdB, Quebec, Canada). Lambs were sedated with atropine (0.1 mg/kg) subcutaneously, ketamine (10 mg/kg), and midazolam (0.1 mg/kg) intramuscularly and orally intubated with a cuffed endotracheal tube (ETT). Gas ventilation (Servo 300, Siemens-Elema AB, Solna, Sweden) was then initiated at a rate of 40 breaths/min, a peak inspiratory pressure of 15 cm H2O, and a positive end-expiratory pressure of 5 cm H2O. The fraction of inspired oxygen (FIO2) was adjusted to maintain an SpO2 of 100%. After cannulation of the right jugular vein, animals were anesthetized with an intravenous bolus of 20 mg/kg thiopental followed by a continuous intravenous infusion of 2 mg/kg per hour. Sedation was obtained with a continuous intravenous infusion of alfentanyl (2 μg/kg per hour) and intermittent intravenous administration of 1 μg/kg as needed. Curarization was obtained with intermittent intravenous administration of vecuronium bromide (0.1 mg/kg). Antibiotics (0.05 mg/kg duplocillin and 5 mg/kg gentamicin) were also injected intramuscularly. A 4F catheter was placed into the femoral artery for monitoring hemodynamic parameters and central temperature by the thermodilution method, using a PC 8000 PICCO monitor (Pulsion Medical System AG, München, Germany). Arterial blood gases were monitored with the use of a blood gas analyzer (model 1306, Coulter Electronic, Ltd, Hialeah, FL). A second catheter, 4F Swan-Ganz (Edwards LifeSciences, Irvine, CA), was placed into the right jugular vein for monitoring pulmonary artery and central venous pressures and for continuous infusion of 4 ml/kg per hour of 5% dextrose. A tracheotomy was then performed, and a 6.0-gauge, cuffed ETT was placed into the trachea.
Tidal Liquid Ventilation Protocol
After a brief period of stabilization, a liquid FRC of 30 ml/kg of warmed, preoxygenated PFC (PFOB from F2 Chemicals, Lancashire, UK) was rapidly instilled into the trachea through the ETT, using a syringe with an 8F gastric feeding tube. Tidal liquid ventilation was then initiated at a rate of 3 to 4 breaths/min, a Vt of 25 ml/kg, and an inspiratory/expiratory (I/E) ratio of 1/3, with a FIO2 of 1.0. An exponential profile was used during expiration and a ramp profile during inspiration. Arterial blood specimens were drawn at 30-minute intervals for determination of PaO2, PaCO2, pH, BE (Base-Excess), and glucose. The ventilator settings were then adjusted to maintain PaO2 >100 mm Hg and PaCO2 at 30 to 50 mm Hg. Sodium bicarbonate or tromethamine (THAM) was used to maintain pH >7.25. The rate of dextrose intravenous infusion was adjusted to maintain glucose blood level at 40 to 100 mg/dl. Normal saline was used as needed to maintain a mean arterial pressure of 65 mm Hg. Hemodynamic parameters were continuously monitored and recorded at 30-minute intervals. Dynamic compliance Cdyn was also recorded at 30-minute intervals, using quasi-static end-inspiration and end-expiration pauses to monitor airway pressures measured at the distal end of the ETT, using a Mikro-Tip catheter 2.3F (SPR524, Millar Instruments Inc., Houston, TX).40,41 After 120 minutes, the animals were given a lethal dose of pentobarbital (100 mg/kg), and the lungs were carefully examined for the presence of perfluorothorax.
Table 3 presents the main results obtained in 5 healthy newborn lambs (<5 days old) with a mean weight of 4.40 ± 1.39 kg. All results are presented as mean ± SD. No perfluorothorax was observed after examination of the lungs. Figure 6 presents typical tracheal pressure and volume profiles during a TLV.
The Condenser-Heater-Oxygenator Unit
The majority of liquid ventilators developed to date use an ECMO with an integrated water heater.6,19–21,24,26,29,30,32 However, to design an optimal integrated CHO and avoid the use of an expensive ECMO, the bubble gas exchanger was selected. On the basis of the characterization results, we were able to demonstrate that the latter compares favorably with an ECMO designed for children weighing <10 kg (Medtronic ECMO model 0600, Minneapolis, MN). Moreover, it can easily be sterilized, and the membrane can be changed between patients.
The major novelty of the presented CHO is its modularity. To reach a specified gas exchange surface, it is possible to add several CHO in parallel or in series, whereas oxygenator sections can be modified to increase the gas exchange area. Hence, the presented prototype can be easily extended from an infant to an adult version. This feature could prove important for future clinical use of the TLV.
The condenser mounted on the top of the gas exchanger limits PFC losses at 21 ml/hr (using PFOB). Based on the data of Wolfson et al.,42 PFC losses from the CHO are lower than that with an Ultrox III (Avecor Cardiovascular Inc., Plymouth, MN) ECMO membrane. However, when comparing PFC losses per square meter of gas exchange area, the CHO and the Ultrox III ECMO membrane are equivalent.
A Volume-Controlled and Pressure-Limited Ventilator
Treatment of a critical respiratory patient requires that safety measures are in place to limit the pressure and to precisely control the volumes.32 In the event of airway closure43 during the expiratory phase, the expiratory pump is immediately stopped when the lower pressure limit is reached. Thereafter, the inspiratory volume to be inserted into the lungs is automatically adjusted to ensure a constant FRC level with the TLV maintaining these new parameters. Compared with other prototypes presented in the literature that halt the TLV and await new instructions, this new approach gives more time for health care providers to investigate and correct the situation while the patient still undergoes TLV. If an FRC or Vt correction needs to be made, the volume inspired or expired will be adjusted consequently. Hence, the proposed system is volume controlled by adjusting Vt and FRC and is pressure-limited.
Control of Functional Residual Capacity
In TLV, piston pumps have proven their efficiency27–30 when compared with peristaltic or gravimetric systems.31 Such a choice is necessary to implement an accurate volume control system. However, the main concern with pumping systems is the difference that can occur between the expiratory and inspiratory volumes. It can be calculated that a small volume difference repeated at each cycle leads to a dramatic FRC increase (or decrease) after a 2-hour experiment. Such problems may be related to a small mechanical and electronic bias between each pump components.
The novel solution proposed with the presented prototype is to monitor and control FRC by means of the buffer reservoir and to use inherent pump independence for FRC readjustments, when necessary. To maintain a constant FRC, the supervisor module automatically adjusts the volumes to compensate measurable errors made by the pumps. However, it is important to note that only measurable errors are controlled. In other words, mechanical, electrical, and quantization errors cannot be treated by the pump supervisor module but could influence FRC over a long period of time. Hence, FRC monitoring during TLV is essential for future clinical use.
With the proposed prototype, PFC can be added in the ventilator to compensate for PFC losses.44 Thus, the ventilator volume is kept constant and the buffer reservoir can be used directly to monitor FRC changes. In the present case, any variation in volume level measured in the reservoir at the end-expiratory pause implies an opposite variation in FRC volume. Ongoing work is currently aimed at developing an online algorithm able to process data obtained during TLV (based on measured volumes and pressures) and deliver an accurate estimation of FRC.
In Vivo Results
The results obtained in 5 healthy term newborn lambs demonstrate the efficiency and safety of our TLV ventilator in maintaining adequate gas exchange and normal acido-basis equilibrium during a short, 2-hour TLV trial. The relatively low PaO2 obtained herein as compared with gas ventilation in newborn lambs with normal lungs has been previously described as the so-called Kylstra effect.45 In their theoretical model of gas exchange, Kylstra et al. demonstrated that a gradient (from the alveolus center up to its wall) exists between the inspired PiO2 and alveolar PaO2. Because oxygen diffusion in gases is very fast, this gradient is small. However, oxygen diffusion is much slower in liquids (including PFC liquids), creating a larger gradient, which explains the lower values of PaO2 in TLV compared with gas ventilation.
Cardiovascular stability was also maintained and was not different from results obtained in a similar gas-ventilated animal preparation (data not shown). Furthermore, airway pressure, lung volumes, and ventilation scheme were maintained in the targeted range, including the absence of any observed perfluorothorax. Overall, the present results are in accordance with previous studies on TLV with healthy term newborn lambs and support further testing of our TLV ventilator in animal models of lung injury.46
The distinct advantage of our TLV prototype is its ability to control FRC by using a system of independent pumps and the ability to estimate FRC by means of the buffer reservoir. Current developments will enable better control of FRC and reduction in airway collapse. These developments include a more accurate model of the airway system during TLV, thus improving pump control.
The TLV ventilator presented is also shown to be efficient and safe for volume-controlled, pressure-limited tidal liquid ventilation in 5 term newborn lambs with healthy lungs. Further TLV studies will be performed on experimental models of lung injury, especially acute respiratory distress syndrome.
This work was supported in part by the Quebec Foundation for Research into Children’s Diseases and the Fonds de Recherche sur la Nature et les Technologies.
The authors thank Valerie Cardinal, Johann Lebon, Valerie Provost, and Caroline Ouellet for their technical assistance supporting the in vivo experiments. The authors also thank Rémy Oddo, Guillaume Drolet, and Oliver Berbuer for their technical assistance and Pulsion Medical Systems AG, which provided the acquisition software for the PiCCO.
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