EP1117455A1 - Echange de gaz et de chaleur au moyen d'une ventilation mixte par liquide - Google Patents

Echange de gaz et de chaleur au moyen d'une ventilation mixte par liquide

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Publication number
EP1117455A1
EP1117455A1 EP99956513A EP99956513A EP1117455A1 EP 1117455 A1 EP1117455 A1 EP 1117455A1 EP 99956513 A EP99956513 A EP 99956513A EP 99956513 A EP99956513 A EP 99956513A EP 1117455 A1 EP1117455 A1 EP 1117455A1
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EP
European Patent Office
Prior art keywords
pfc
gas
liquid
temperature
ventilation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99956513A
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German (de)
English (en)
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EP1117455A4 (fr
Inventor
Steven Bradley Harris
Michael Gregory Darwin
Sandra Renee Russell
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Critical Care Research Inc
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Critical Care Research Inc
Critical Care Research Inc
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Publication of EP1117455A1 publication Critical patent/EP1117455A1/fr
Publication of EP1117455A4 publication Critical patent/EP1117455A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/0054—Liquid ventilation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/10—Preparation of respiratory gases or vapours
    • A61M16/105—Filters
    • A61M16/106—Filters in a path
    • A61M16/107—Filters in a path in the inspiratory path

Definitions

  • the present invention relates to ventilator and heat exchange systems and, more particularly, to a "mixed-mode" gas-plus-liquid ventilator system using an endotracheal catheter to add and remove liquid ventilation or heat-exchange medium from the lungs continuously and/or cyclically, with delivery of gas to the lungs at a rate and volume independent of addition and removal of liquid.
  • the Lungs As a Gas Exchanger and Heat Exchanger
  • An alternative to invasive temperature modifying techniques would be to use the large surface area of the lungs as a heat exchanger. Nearly all of the cardiac output (i.e., all blood flowing to the body) flows through the lungs, and since the lungs possess a surface area of at least 70 square meters, they form an ideal heat exchanger that would allow for rapid core cooling and re-warming of the patient without the problems associated with the techniques previously discussed.
  • the lungs are accessible via the trachea, the relatively benign maneuver of endotracheal intubation (a skill universally possessed by paramedics) allows for quick field access to this powerful heat exchanger.
  • Heat exchange in the lungs using liquid ventilation is superior to gas ventilation because at standard temperature and pressure, gases such as oxygen and air have only approximately a 2200th of the volumetric specific heat capacity of water. Thus, under ordinary circumstances the lungs serve as a relatively poor heat exchanger if only gaseous media are used. This includes the use of the highly conductive — low viscosity gas mixture of oxygen and helium (Heliox). The high conductivity of Heliox makes it far more efficacious as a heat exchange medium under high pressure conditions where its specific heat capacity is greater that at normal pressures; however these conditions are of little relevance to most clinical situations.
  • the Basics of Liquid Ventilation The Basics of Liquid Ventilation
  • Liquid ventilation involves the breathing of gas-carrying liquid as the medium of gas exchange within the lungs. Since the first liquid ventilation experiments (1950's) in mice using super-oxygenated saline, several liquid media for ventilation have been studied.
  • the class of agents currently optimized to function as liquid breathing media are the fluorocarbons (containing only fluorine and carbon), and the organic perfluorochemicals (PFCs).
  • PFC compounds contain elements other than fluorine and carbon, with fluorine or other halogens comprising the majority of peripheral moieties within the molecule.
  • PFC compounds comprise molecules that are relatively insoluble in either water or lipid, and are more-or-less chemically and pharmacologically inert. PFCs do not dissolve native lung surfactants, and are far less injurious to the lungs than any known silicone or water-based solution.
  • TLV total liquid ventilation
  • each TLV breathing cycle provides a certain volume that can be passed through the lung heat exchanger.
  • TLV (as opposed to gas exchange) for heat exchange, is that liquids such as PFCs have a specific heat capacity several thousand-fold that of gas at normal pressure.
  • total liquid ventilation suffers from a number of drawbacks:
  • TLV During higher than normal CO 2 production rates (e.g. disease), TLV would clearly not be adequate for CO 2 removal.
  • high CO 2 (hypercapnic) states are 1) increased metabolic states (e.g. cancer, infection, burns), 2) states of physiologic stress (e.g. hyperthermia, agitation), and 3) post-ischemic conditions where substantial metabolic debt has been incurred and the need to rapidly unload CO ⁇ and deliver large amounts of O 2 are essential.
  • Such hypercapnic/hypercarbic states are also frequently present in shock due to sepsis or trauma, and thought to be due to both an increased production of CO 2 , and a decreased elimination of CO 2 due to low blood flow or pulmonary edema.
  • TLV In anesthetized, paralyzed, normothermic dogs, TLV is capable of maintaining steady-state gas exchange with adequate O 2 delivery and CO 2 removal. However, TLV is not adequate to steady-state CO 2 removal under basal metabolic conditions in smaller animals with higher specific metabolic rates, such as guinea pigs. As Matthews and co- workers document (1978), the parameters for maintaining normocapnia in anesthetized beagles are narrow, even under basal normothermic metabolic conditions. In this study, as liquid ventilation rates were increased from 2.8 to 5.6 liquid breaths per minute, and alveolar ventilation was increased from 574 to 600 mL/min/animal (increase of 4%), the paCO 2 continued to increase until dangerous hypercapnia occurred.
  • PLV Partial Liquid Ventilation
  • FRC functional residual capacity
  • PFC liquid loading is accompanied by conventional mechanical ventilation using a standard gas ventilator at normal gas rates and tidal volumes. Since the breaths are delivered as gas, PLV allows for the number of breaths per minute, and alveolar ventilation rates, to be set much closer to the physiologically acceptable and desirable rate. PLV can even be used with high frequency gas ventilators, and can accommodate a wide range of metabolic states in which the demand for O2 delivery and CO2 removal is greater than that of basal states. PLV is currently being tested in human clinical trials.
  • One aspect of the present invention is a mixed-mode liquid ventilation (MMLV) method for gas and/or heat exchange in the lungs (human clinical and veterinary applications).
  • MMLV mixed-mode liquid ventilation
  • the MMLV method allows mixing of gas and liquid in the small airways of the lungs, producing small-scale liquid mixing in a convection-like process, rapid return of fluid from the lung periphery, and more rapid and efficient transfer of heat, and dissolved gasses, during the practice of ventilation with liquids.
  • nitric oxide or nitric oxide donors are administered to facilitate gas and heat exchange.
  • the gas is helium.
  • liquid ventilation medium is a perfluorocarbon or perfluorochemical.
  • a further aspect of the present invention is a method of inducing small-scale mixing of liquid heat exchange ventilation media, using other known ventilation methodologies, alone or in combination. These specifically include known types of gas ventilation, including high frequency oscillating ventilation.
  • Another aspect of the invention is the use of MMLV to treat hypothermic pathologies by heating said liquid ventilation medium, and thus increasing body temperature.
  • a further aspect of the invention is the use of MMLV to induce hypothermia for medical purposes, or to treat hyperthermic pathologies, by cooling said liquid ventilation medium, and thus decreasing body temperature.
  • liquid ventilation media may be infused at temperatures as low as -10 C.
  • Another aspect of the invention is a method of preserving biological material, for example beating-heart cadaveric preparations, using the rapid cooling available witth MMLV.
  • a further aspect of the invention is a method for increasing the efficiency of CPR using MMLV.
  • a final aspect of the invention is an automatic apparatus for MMLV, which connects to the lungs via the bronchi and uses a computer to control loading and unloading of said oxygenated liquid and gas so that mixing occurs; and also makes use of the computer to insure that pressure limits are not exceeded, and gas ventilation proceeds in a way which most rapidly induces removal of fluid heat exchange media.
  • the computer controls liquid infusion in such a way as to maximize time integrated arterial/ venous temperature differences, for best cooling rates, subject to ventilatory constraints.
  • said computer controls the liquid ventilatory volume delivered and removed (dV/dt) to be about 10% to 50% that typically necessary for gas ventilation.
  • the apparatus has a cold reservoir where pre-cooled PFC may be stored.
  • the apparatus has a heat exchanger for PFC.
  • the apparatus has an active liquid ventilation system, which may employ a canula able to remove liquid at the same time gas breaths are delivered.
  • Gas and liquid are typically infused and removed through separate concentric tubes in many of the most efficient implimentations of the invention, but may be removed through the same tube.
  • FIG. 1 shows a graph from Example 1 of canine tympanic, central venous blood, aortic arterial blood, and esophageal surface temperatures over time, during mixed gas and liquid ventilation, in which a single loading volume of liquid PFC is delivered into the endotracheal tube.
  • PFC as a single load of 76 mL/kg of PFC at a temperature of 4.4°C is loaded into the lungs over 145 seconds.
  • FIG. la shows a canine instrumented for measurement of temperatures as in Example
  • Indirect brain temperature is measured via a copper/Constantan thermocouple probe placed on the right tympanic membrane.
  • Venous temperature was measured by a thermistor in a thermodilution catheter inserted via the femoral vein into the inferior vena cava.
  • Arterial blood temperature was measured by a thermocouple probe inserted via the femoral artery into the descending aorta. Selected instrumentation modalities from Examples to follow are also illustrated.
  • FIG. 2 illustrates the three major thermal kinetic compartments, and respective fractional heat capacities of such compartments, in an anesthetized canine with normal cardiac output, undergoing heat exchange through PFC lung lavage, as in Example #1.
  • Existence and characteristics of such compartments may be inferred from measurements such as are graphed in FIG. 1, in studies such as Example #1, in the way that is hereafter detailed.
  • FIG. 3 shows canine tympanic, rectal, venous blood, and aortic blood temperature as a function of time from Example 2, showing multiple cycles of loading and unloading of chilled PFC at -1°C from the lungs.
  • This example illustrates PFC removal using a suction reservoir, illustrating the full principle of mixed-mode liquid ventilation (MMLV).
  • MMLV mixed-mode liquid ventilation
  • FIG. 4 is shows a table of PFC liquid infusion volumes, measured temperatures of these volumes, and the calculated difference in their heat contents, from example 2. This table illustrates the qualitative and quantitative heat transfers involved in the MMLV technique.
  • FIG. 5 shows a graph of canine tympanic, central venous, aortic, rectal, and PFC suction temperatures from Example 3 of a 24.5 kg dog when infusion and suction rates are increased to 16.7 mL/kg/min. Temperatures were measured as in FIG. la.
  • FIG. 6A is an illustration of a device for Mixed-mode Liquid Ventilation (MMLV). Its use is in manual mode (manual valve control) is illustrated in Examples 2 through 6. Its use in full computer- valve-control mode is illustrated in figures 10a and 19.
  • MMLV Mixed-mode Liquid Ventilation
  • FIG.6B is an illustration of how the device of FIG.6A attaches to the lungs via the endotracheal tube.
  • FIG.7 shows canine tympanic, rectal, venous, and aortic blood temperature as a function of time from Example 4.
  • a 17.3 kg dog was used with an infusion rate of 45 mL/kg/min. increased by a factor of 2.6 from that shown in FIG. 3.
  • Illustrated is a procedure which cooled the animal by 12 C over 30 minutes, for net cooling of 10 C after thermal equilibration. This animal survived long-term, without evidence of respiratory damage. Temperatures were measured as in FIG. la.
  • FIG.8 shows canine rectal temperature as a function of time from Example 6 of a 30 kg dog (a much larger animal than illustrated in FIG.7), when the infusion rate was maintained at 46 mL/kg/min, and suction rates were increased to accommodate larger absolute volumes. Temperatures were measured as in FIG. la.
  • FIG. 9 shows rectal, tympanic, venous, aortic, and suction temperature as a function of time from Example 6. using a 19.8 kg dog with PFC infusion rate of 46 mL/kg/min. This example illustrates temperature relationships during the fastest manual cooling cycle rates. Temperatures were measured as in FIG. la.
  • FIG. 9a shows the same experiment, but with temperatures graphed without PFC temperatures, for ease of interpretation.
  • FIG. 10 Shows typmanic temperatures of 5 anmals cooled by rapid lavage with
  • FIG. 10a shows tympanic temperatures of 5 animals cooled by rapid lavage (same group as above) vs cooling of dogs by machine cooling at 50% of the lavage load, but twice the lavage rate.
  • FIG.l la shows PO2 results of arterial blood gases drawn every 2 mintues in 4 animals cooled by rapid manually controlled PFC lavage, vs 2 animals given the same manual lavage with body temperature PFC. Temperatures are measured as in FIG la.
  • FIG.l lb shows pO2 results of arterial blood gases drawn every 2 mintues in 3 animals cooled by rapid machine controlled PFC lavage, vs- 2 animals given the same maschine lavage with body temperature PFC. Temperatures are measured as in FIG la.
  • FIG. l ie shows paCO2 results of arterial blood gases drawn every 2 mintues in 5 animals cooled by rapid manually controlled PFC lavage, vs 2 animals given the same manual lavage with body temperature PFC. Temperatures are measured as in FIG la.
  • FIG.l ld shows paCO2 results of arterial blood gases drawn every 2 mintues in 3 animals cooled by rapid machine-controlled PFC lavage, vs 2 animals given the same lavage lavage with body temperature PFC. Temperatures are measured as in FIG la.
  • FIG.13 Shows VCO2 measured by the above method in another dog during another rapid PFC manual MMLV lavage. This graph shows that VCO2 production is stable after PFC lavage stops, and does not rise until shivering begins. The slight increase immediately after lavage is known to be false spectrophotometric reading of PFC vapor.
  • FIG.14 shows the relationship between aortic temperature and heart rate during cold MMLV lavage in a canine. Temperatures were measured as in Fig 1.
  • FIG.15 shows the central venous pressure and heart rate during MMLV. Central venous pressure was monitored via a fiber optic pulmonary artery (PA) catheter advanced via open cut down of the femoral artery to the level of the right atrium.
  • PA pulmonary artery
  • FIG.16 shows the central venous pressure and mean arterial pressure during
  • FIG 16a shows the same study and variables graphed for a different canine being lavaged in the same way with body temperature PFC, in order to eliminate the temperature variable.
  • FIG.17 shows the central venous pressure and PFC infusion suction temperature during MMLV. This illustrates the relationship between infusion of cold PFC and venous pressure. Central venous pressure was monitored as in FIG. 15.
  • FIG 17a shows the central venous pressure and PFC infusion/suction temperature during MMLV, as in FIG 17, but using infused PFC at body temperature.
  • FIG.18 shows the PFC infusion temperature and ventilator airway pressure during MMLV with cold PFC.
  • FIG.19 shows airway pressure over time with cold machine controlled rapid PFC
  • FIG 20 shows airway pressure over time with cold manual PFC MMLV cycling, in a canine from FIG 10.
  • pressure control by hand is especially good.
  • the technique and apparatus also may be used with liquid ventilation to increase CO2 removal from the body, when liquid media have been introduced to the lungs primarily for heat exchange purposes.
  • the technique and apparatus also take advantage of our discovery that gas ventilation may be used to facilitate recovery of liquid in perfluorocarbon lung lavage, as well as the novel discovery that the non-thermal convection (transport of dissolved gas by liquid mass flow not related to differential density) that occurs with mixing of liquid and gas in the lungs' small airways, allows for faster and more efficient heat and gas exchange.
  • a technique is needed to achieve better and more efficient cooling or re-warming using liquid ventilation.
  • This technique must allow for the continuous addition and removal of PFC (as liquid or aerosol) from the lungs, while also allowing for the delivery of gas breaths via a mechanical ventilator or other means at a rate independent of the input and removal of PFC liquid from the lungs is required.
  • the reason for this is that while liquid ventilation is performed to control addition or removal of heat, gas ventilation must also occur independently to allow for adequate oxygen delivery and carbon dioxide removal.
  • MMLV Mixed-Mode Liquid Ventilation
  • conventional mechanical ventilation is initiated via endotracheal intubation or the use of other means to isolate the airway from the gastrointestinal system, and allow application of positive pressure to the lungs (i.e., the esophageal gastric tube obturator airway (EGTA), the Combitube airway, etc.).
  • EGTA esophageal gastric tube obturator airway
  • Combitube airway i.e., the esophageal gastric tube obturator airway (EGTA), the Combitube airway, etc.).
  • EGTA esophageal gastric tube obturator airway
  • Combitube airway etc.
  • the PFC may be loaded in liquid or aerosol/spray form, and loading may be done continuously or intermittently (timed with inhalations).
  • the technique works best when the PFC is recycled through a gas-exchanger as well as a heat exchanger, but
  • liquid alveolar "minute volumes” liquid alveolar ventilation typically averages 25 to 33% of those for gas.
  • the volume of gas delivered with each mechanical breath is decreased, using a pre-determined peak inspiratory flow pressure as the cut-off point.
  • Current experience with a canine model indicates that the maximum peak airway pressure which is tolerable without inducing significant volu- and baro-trauma to the lungs is ⁇ 40 cm water (29 mmHg or Torr). These pressures occur at the ends of small (10 mL/kg) gas breaths, when the lungs already hold 40 to 50 mL/kg of PFC.
  • the tidal volume of gas delivered to the lungs should be increased as the liquid is progressively removed.
  • the lungs are fully loaded with PFC to 60 to 70% of total lung capacity, mechanical gas breaths must be very small in volume to prevent overpressure.
  • gas ventilation can occur at a maximally effective rate and volume needed for CO2 removal.
  • CO2 is removed by both PFC and gas ventilation.
  • PFC infusion/suction cycle ratios may be adjusted, however, to increase CO2 removal in situations where this is especially needed. Increasing the time during which the lung is unloaded of fluid allows for best time efficiency in CO2 removal, at a given maximal airway pressure.
  • a time of 30 seconds for infusion, and 15 to 20 seconds for liquid removal is typical for experiments at our fastest manually controlled liquid loading and unloading rates (see experiment 7 below).
  • a typical algorithm for manually controlled MMLV for a medium- sized dog (20 kg) is to load PFC at 40 to 50 mL/kg/min and unload PFC at approximately 80 mL/kg/min.
  • machine control of PFC infusion and suction is required.
  • FIG. 10a shows cooling rates for 3 animals cooled with machine infusions of 8 mL/kg (50 ml/kg for 10 seconds) followed by machine-controlled suction of the same PFC volume, for 4 to 7 seconds.
  • FC-75 a proprietary mixture of fluorinated hydrocarbons reported to consist mostly of perfluoro-butyl-tetrahydrofuran (CF3-CF2-CF2-CF2-C4F8O), and which has a volumetric specific heat capacity of 0.45 cal/mL/°C.
  • FC-75 a proprietary mixture of fluorinated hydrocarbons reported to consist mostly of perfluoro-butyl-tetrahydrofuran (CF3-CF2-CF2-CF2-C4F8O), and which has a volumetric specific heat capacity of 0.45 cal/mL/°C.
  • a loading rate of 45 mL/kg/min (30 seconds) followed by an unloading rate of 80-90 mL/kg/min gives a recycled liquid minute volume of 22.5 mL/kg infused and removed, averaged out over 45 seconds (time for liquid entry and removal).
  • Rates of ⁇ 0.5°C/min represent about 1/2 of the cooling rates available on cardiopulmonary bypass (CPB), but are superior to cooling rates achieved with all other techniques, both invasive and noninvasive. They are also, as a matter of practicality, far superior also to "time from intent to treat" CPB rates, since times to achieve machine connection for the average patient must here be realistically added into the equation.
  • CPB cardiopulmonary bypass
  • the liquid loading sequence is typically achieved by pumping the PFC from a reservoir through a circuit consisting of a heat exchanger, a 20 micron pre-filter followed by 0.2 micron absolute filter, and an oxygenator (FIG.6A).
  • the oxygenator if used, must currently be a true membrane oxygenator. as the current generation of hollow fiber capillary oxygenators available in the U.S. are fenestrated at the micro-scale, and depend on the high H2O/gas surface tension to keep gas and liquid in the oxygenator separated, and do not work with the relatively low surface-tension PFCs.
  • the PFC liquid is then delivered to the subject through a tube which is passed through the suction port down the endotracheal tube, to the level of the carina (FIG.6B).
  • This single-lumen tube may be used to both deliver and suction liquid from the lungs.
  • this tube is a specially constructed flat-wire- reinforced ultra-thin-wall tube with a fenestrated open-end, but many other designs are possible within the claimed type of device. Control of PFC infusion and removal may be done by a computer-controlled valve-driver and pressure-sensor device.
  • Such a device used for the series of illustrative examples herein, was designed by and built by Korr Biomedical Corporation, Salt Lake City, Utah, under direction of the patent claimants.
  • mechanical ventilation with gas proceeds in routine fashion with a pressure-limited or pressure-controlled mechanical gas volume-ventilator. This includes appropriate monitoring and control of peak inspiratory pressure, peak flow, tidal volume, minute volume, Fi ⁇ 2 (inspired oxygen concentration), gas composition, and other relevant ventilatory parameters.
  • the mechanical ventilator in the best implementation of the technique must be able to sense and adjust these parameters appropriately as liquid is loaded and unloaded from the lungs.
  • An additional relief valve must be included in the vacuum circuit also, in order to limit negative airway pressures which occur after liquid suction is completed during each cycle, and the suction circuit pump suddenly becomes exposed to airway gas.
  • the relationship between the volume of liquid in the lungs at any one time during mechanical gas ventilation, and the other variables of peak pressure, peak flow, tidal volume and ventilatory rate, is very important: 1) As a first approximation, peak positive airway pressure should not exceed 40 cm of water at the endotracheal tube external connector, and peak gas flow should decrease from a maximum of 60 L/min (LPM) to a minimum of 20 LPM or less, as the lungs are progressively loaded with PFC.
  • LPM 60 L/min
  • tidal volume of delivered gas will decrease to essentially zero whenever the lungs are loaded with PFC to 50-60% of TLC (ca. 50 mL/kg) and return to normal delivered tidal volumes of gas (i.e., 10 to 20 mL/kg/breath) when the lungs are unloaded of fluid to a volume approximately that of functional residual capacity (30 mL/kg).
  • normal delivered tidal volumes of gas i.e., 10 to 20 mL/kg/breath
  • rapid (4/minute) small infusions of fluid ⁇ 10 mL/kg may be used to keep maximal airway pressures low.
  • gas ventilatory frequency may also decrease during times of high lung liquid content, in order to minimize gas flow pressures.
  • gas ventilation rate and volume will increase in frequency as rapidly as the preselected limiting peak inspiratory pressure (or peak flow pressure) will allow, to a rate of 12 to 15 breaths per minute.
  • This ventilatory rate has thus far been found to be effective for unloading of the lungs with PFC. via active suctioning. However, rates of up to 30 breaths/minute and more have been used, and in some circumstances are effective. High frequency ventilation may also be used.
  • a catheter under the surface of PFC liquid collecting in the bronchi may be involved in liquid removal, and have little or no effect on gas ventilation given around the removal catheter, until the suction tip becomes exposed to gas.
  • MMLV allows PFC to be both pushed and pulled out of the lung, without chest compression. Briefly, PFC can be rapidly suctioned from the lungs when ventilator gas actively replaces it.
  • the liquid Following delivery of a PFC load to the lungs, the liquid must be removed and recycled through the heat exchanger/filter, and often oxygenator assembly.
  • This assembly rids the liquid of CO2, adds oxygen, removes mucus, bacteria and other airway debris, and appropriately heats or cools the fluid.
  • rapid but gentle removal of liquid from the lungs is best achieved by applying suction to the PFC delivery catheter for alternatively the endotracheal tube) while imposing mechanical gas ventilation through a different concentric tube, per the algorithm described above.
  • perfluorothorax when it occurs, is clinically far less problematic with low vapor pressure (e.g., -10 mmHg at body temp) PFCs, such as 3M Company's "FC-40” mixture, or the proprietary pharmaceutical perfluorooctylbromide, or perflubron (LiquiventTM, Alliance Pharmaceuticals).
  • vapor pressure e.g., -10 mmHg at body temp
  • FC-40 3M Company's "FC-40” mixture
  • perfluorooctylbromide or perflubron (LiquiventTM, Alliance Pharmaceuticals).
  • Our invention of MMLV is suitable for use with all of these PFCs, and many others. However, for MMLV combined with manual or mechanical CPR, which greatly increases the risk of perfluorothorax, only low vapor pressures PFCs are suitable for use.
  • Certain PFCs with undesirable low-temperature characteristics such as high viscosity or freezing behavior near 0 C, cannot be used as cooling media in the most extreme cooling applications described herein.
  • low liquid temperatures near 0 C
  • core temperature drops of as much as -12 C. All animals allowed to survive the most rapid cold PFC cycling temperatures and rates described herein, returned to normal A- a gradients (a measure of, lung oxygenation function) within 48 i ours after the procedure.
  • Appropriate ventilating gas composition is also very important for different clinical problems.
  • very high Fi ⁇ 2 will be desirable, while in other situations some gas breaths may contain no oxygen for a short period.
  • An example of the latter would be in cases of re-perfusion after cardiac arrest, where oxygen might be temporarily withheld for a few seconds in order to protect against exacerbation of re-perfusion injury by reintroduction of oxygen while free radical scavenging drugs are delivered to the tissues.
  • nitric oxide (NO) to the ventilating gas, or to the PFC via the oxygenator, in concentrations ranging from 5 to 80 parts per million (or to effect) can overcome cold-induced vasoconstriction of the lung airways, and allow for improved rates of gas exchange.
  • NO nitric oxide
  • Each experimental Example is a single exemplary animal, or a group of similarly treated animals, and will be used to illustrate one or more principles of the invention. They will also illustrate novel physiologic principles necessary to understand the mechanism of the invention. Although other materials and methods similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.
  • Example 1 illustrates the rapid rate of heat transfer which typically occurs in Partial Liquid Ventilation (PLV) when a load of warm or cold fluid is infused as well as the three compartment heat reservoir model.
  • PLV Partial Liquid Ventilation
  • FIG. l Illustrated in FIG. l is a canine model in which one load of non-isothermal PFC is given.
  • one infusion of 1.65 L of cold, (4.4°C) oxygenated PFC (here, the 3M Company PFC product "FC-84") is given rapidly (683 mL/min, over 145 seconds
  • FIG.l shows a graph of canine temperatures in experimental Example 1.
  • the graph shows temperatures over time, as 75.7 mL/kg of PFC at 4.4°C is loaded into the lungs over 145 seconds.
  • Illustrated are animal esophageal temperature and indirect brain temperature as measured via a copper/Constantan thermocouple probe placed in the esophagus, and another on the right tympanic membrane.
  • Also illustrated are venous and arterial blood temperature which were measured, respectively, by a thermistor in a thermodilution catheter inserted via the femoral vein into the inferior vena cava, and by a thermocouple probe inserted via femoral artery into the descending aorta.
  • the FIG 1. temperature graph illustrates blood temperature (both venocaval and aortic) falling and then rising, as PFC is infused, then allowed to remain in the lungs.
  • Esophageal temperature which is a marker for the temperature of the relatively small amount of PFC in the trachea and large airways, does not come into equilibrium until about 450 seconds after infusion of cold PFC ceases, with a half-time of about 120 seconds.
  • Aortic blood temperature reaches a nadir at essentially the time infusion of cold PFC stops, then rises with a much faster half-time (about 80 seconds), with equilibrium complete at about 210 seconds after infusion ceases.
  • Venous blood follows a similar pattern with a smaller deviation, with the venous temperature nadir offset from that of arterial blood by 30 seconds - roughly the mean blood circulation time of the animal.
  • Example 1 In these experiments involving anesthetized and paralyzed dogs which do not shiver, the heat transfers are too rapid to show any effect from metabolism or surface cooling, and thus only temperature effects from the chilled PFC infused are seen.
  • Example 1 about 2/3 rds of the brain/tympanic temperature change of the animal occurs during the "dwell-time" of the liquid (time between completion of liquid loading and liquid unloading). This indicates that heat is transferred between lungs and blood very rapidly on this time scale (i.e., this system of PFC, lung parenchyma, blood volume, and probably some heart/arterial intima and muscle, comprise a single thermal reservoir or compartment for purposes of analysis, at this time scale).
  • the nadir of aortic blood temperature (occurring at the end of the PFC load) in this experiment is 5.5°C below body temperature, and the temperature for venous blood at this time is 2.6°C below initial body temperature. Tympanic temperature at this time has fallen 0.5°C. From these figures it is possible to make some simple quantitative estimates of heat transfer dynamics between heat compartments in this model, without the use of complex mathematics or computer modeling.
  • the 75.7 mL/kg of PFC given in this experiment represents a heat deficit of (37°C
  • 390 of these "deficit calories" are in blood and PFC.
  • This non-blood "rapid heat equilibrium” visceral mass is thus about the same mass as the blood volume (also usually 7-8% of body mass), and in a 21.8 kg dog would amount to 1.6 kg of tissue.
  • the "rapid equilibrium compartment" or first thermal compartmen t of a dog receiving cold PFC lung lavage is found to consist of about 50% of contribution from less than 2 kg of certain internal viscera (probably mostly lung, with some heart and vessel contribution), and 50% from infused PFC, plus total blood volume.
  • Third Compartment Equilibration Core to Peripheral Tissue Heat Transfer
  • Tympanic cooling reaches a nadir of -1.8°C below the starting body core temperature at this time, reflecting Compartment # and #2 equilibration, then slowly rises toward a point -1.6°C below initial temperature, over an additional 10 minutes (calculated half-time is ⁇ 6 minutes).
  • the delayed rise in body temperature after central cooling (which may be thought of as “after-rise” by analogy to "after-drop” during peripheral re-warming) indicates thermal equilibrium of compartments #1 and #2 is being reached with the third thermal compartment, which is not as well perfused as the brain and central body organs.
  • This third compartment is assumed to represent fatty tissue and some cold-vasoconstricted muscle and skin, and is sometimes referred to in the literature as the "peripheral tissues" (vs. the better-perfused "core tissues. ").
  • the third (or peripheral) compartment may also be expanded to include PFC in large airways (see the esophageal temperature curve in FIG. 1) which also warms with a similar, though slightly faster, half-time.
  • Compartment #1 is PFC, and for smaller loads on top of FRC PFC content, this number will tend to be closer to 17%
  • Example 1 There are several conclusions to be drawn from this example (Example 1), which are important: 1) If gas breaths are used, PFC reaches very rapid thermal equilibrium with blood, even at PFC infusion rates greater than 30 mL/kg/min.
  • heat or "cold” from an infused PFC load is rapidly transferred to a larger mass of lung, vascular tissue, and blood, which acts as a short term storage "heat capacitor” which has an effective heat capacity 3-4 times that of a 60 mL/kg (2/3rds total lung capacity) load of PFC.
  • This combined with some heat transfer from blood to the peripheral tissues during even the fastest PFC lung loading, guarantees that at least 75% of heat or "cold” will be extracted from a significant fraction of a lung load of PFC at infusion rates of " 30 mL/kg/min, even with no deliberate "dwell time.” For example, as seen in FIG.
  • FIGs 3, 4 illustrates heat transfer in a model with multiple cycles of PFC loading and unloading.
  • cold PFC is loaded from FRC (functional residual capacity) to about twice this volume, accompanied by constant gas rate ventilation.
  • This protocol does not represent Total Liquid Ventilation (TLV), because ventilation and CO2 removal are accomplished mostly by gas breaths from a conventional gas ventilator (here at a constant rate of 12 breaths/min).
  • TLV Total Liquid Ventilation
  • gross heat transfer in this experiment is accomplished by unloading the PFC liquid soon (or immediately) after loading, and then repeating the procedure with multiple cycles of freshly chilled liquid. This is similar to a multiple lavage procedure with ice water in the stomach or peritoneum, but has not been described as a technique for PFC infused with air into the lungs or other body compartments, and is novel when used as such.
  • Example 2 illustrates one possible protocol.
  • Example 2 a 25.7 kg anesthetized, intubated, and paralyzed dog was given chilled PFC (temperature -1°C) rapidly into the endotracheal tube, followed by removal by vacuum suctioning.
  • FIG. 3 shows tympanic, rectal, venous, and aortic blood temperatures as a function of time. Also illustrated on the same scale are temperatures of the removed PFC with each cycle, measured in the suction reservoir (which is emptied after each cycle). This experiment illustrates use of multiple loads of chilled fluorocarbon liquid from
  • the rate of PFC liquid loading is 155 mL/min. or 6.0 mL/kg/min. to a total of 24 mL/kg for each 4 minute load, followed by suctioning over 2 minutes to remove fluid at a rate averaging approximately 12 mL/kg/min.
  • the relatively smooth cooling temperature curves are for the entire animal (tympanic and rectal temperatures), whereas the larger, periodic temperature fluctuations (total of 15) are blood temperature swings (as measured with thermocouples in the aorta and inferior vena cava).
  • FIG.3 shows that average temperature of extracted PFC is about 3°C below venous temperature (venous temperature is assumed to be Compartment #1 temperature).
  • venous temperature is assumed to be Compartment #1 temperature.
  • Heat exchange within compartment 1 is seen to be substantially complete. Heat exchange is not complete between compartment 1 and 2 (venous blood and soft tissues) when liquid begins to be removed in this model, and this is a typical feature of heat removal with more rapid rates in MMLV.
  • the amount of heat removed from the animal by the PFC may be easily assessed by measuring the temperature of the PFC infused, and the temperature of the mixed load of removed PFC.
  • mixing (30 seconds of mechanical stirring) was performed on the volume of suctioned PFC to alleviate temperature gradients in PFC as it is removed. Mixing allows for mass-averaged temperature and heat content to be assessed.
  • FIG.4 (table of suction volumes and heat contents) shows temperatures of PFC inspired and removed in this example, their temperatures, and the heat removed with each load of PFC infused and removed. Because some PFC remains in the animal at the end of the experiment, and because suction volumes do not always match infusion volumes, heats can be calculated in two ways.
  • heat infused and removed is calculated for all volumes of PFC, and then a correction is added for the volume difference between infused and removed PFC.
  • heat can be estimated by the difference in mean infusion and suction line temperatures during the middle of infusion and suction, and using infusion volumes only (on the assumption that suction volumes will be similar over the long run).
  • Example 2 shows the results when infusion and suction rates are increased.
  • total PFC volume infused and recycled was 16,469 mL over 85 min, for an average cycle rate of 7.9 mL/kg/min.
  • loading and unloading rates of 2.5 times this rate would in theory be required. Unloading at these rates would need to be facilitated by ventilations during unloading, according to a gas ventilation algorithm, such as that previously discussed.
  • Example 4 is a similar experiment using a 17.3 kg dog and different infusion rates.
  • EXAMPLE 4 Full Mixed-Mode Liquid Ventilation with very rapid PFC loading and variation in ventilatory rate during unloading. .
  • This experiment (FIG.6) using a 17.3 kg dog illustrates the result when infusion rates are increased by a factor of 2.6, from 16.7 to 44 mL/kg/min.
  • PFC liquid loading to 1.5 x FRC is accomplished in approximately 60 seconds (to 44 mL/kg) for the first load, and 30-40 seconds per load, once an equilibrium distribution of PFC in the lungs has been reached (beginning at cycle 4).
  • This results in average infusion volumes of about 30 mL/kg, on top of FRC. Infusions were cut off when pressures reached 40 cm H2O 29 mmHg.
  • infusion rates generally will need to be increased at a more than linear rate per animal mass. This is because average PFC fluid removal rates do not scale well with animal size, due to a maximum removal rate set by the removal catheter and suction system. Larger animals are expected to show slightly faster gross PFC removal rates due to longer times in which pure PFC, rather than a mixture of PFC and gas, is available for removal during suctioning. However, these effects may be partly offset by better system design. For example, in the 17.3 kg animal infused at 45 mL/kg/sec, removal times were 55% to 78% of infusion time. For a 30 kg animal with comparable infusion rates and the same system, total liquid removal time had increased to 145 % of infusion time.
  • Example 6 a 19.8 kg animal infused at 46 mL/kg/min, improvements in the suction system allowed removal rates of 80 mL/kg/min (-1600 mL/min), and suction times had decreased again to less than 70% of infusion times. Similar increases in the ratio of infusion to removal are expected for even larger animals, and in humans. Some of these effects are expected to be ameliorated by the use of larger diameter suction canulae in humans, and by improvements in the liquid circuit which minimize flow resistance.
  • EXAMPLE 6 MMLV with increased suction rates
  • PFC infusion rate was maintained at 46 mL/kg/min (910 mL/min in a 19.8 kg animal), but infusion volumes were cut to 20 mL/kg (with an infusion time of 25 seconds).
  • Suction rates were increased by engineering modifications which decreased resistance in the suction path.
  • Effective PFC turnover in this model reached 27 mL/kg/min, and rates of cooling for the "core tissues" of the animals (Compartment #1 plus Compartment #2) reached 30°C/hr. This is the brain cooling rate.
  • FIGs 3-6 it can be seen by examining venous and arterial temperature curves that at slower infusion rates the venous/arterial temperatre difference has a chance to go to zero, or nearly zero, before new PFC is infused, indicating an unused or inefficient length of time in which heat is still being transferred from blood to body, but no longer from lungs to blood. This happens even at the fastest inspiratory infusion rates of 50 mL/kg/min, if infusion cycles are too long due to overlong suction, or deliberate induction of dwell time (see temperature FIGs. 7 vs. 9 and 9a from Examples 4 vs. 6).
  • FIG. 10 shows body temperatures of a group of 5 animals (mean wt 20.6 kg) subjected to MMLV with chilled PFC, under reasonably identical conditions. These conditions were chosen on the basis previous experiments to result in a rapid core body temperature drop of about 7 C, resulting in a final equilibrium temperature drop of 5 C. This was chosen to be indicative of an emergency hyperthermia situation, in which emergent cooling by more than 5 C would not be expected to be necessary.
  • an infusion volume was set at 50 mL/kg/min for all animals for 20 seconds (16.6 mL/kg), with suctioning controlled by pressure, and averaging about 15-17 seconds (average cycle length was 37 seconds).
  • Animals began at normal body temperature, and were cooled with rapid cycling of PFC for exactly 18 minutes, with results shown. Average amount of PFC cycled was a total of 11.3 L per animal, or 550 mL/ kg.
  • Body core temperature dropped by 7.3 +/- 0.4 (S.D.) C over 20 minutes, with final equilibrium temperature reached, after thermal compartment equilibration, of -6.0 +/- 0.13 (S.D.) C.
  • FIG. 10 the curve of typanic temperatures over time for this group of animals is compared with anaesthetized controls cooled by packing them in ice. Cooling rates with MMLV were not only 4 to 8 times as fast, but were also uniform and predictable.
  • FIG. 6 is an illustration of a device for administration of Mixed-Mode Liquid Ventilation (MMLV).
  • MMLV Mixed-Mode Liquid Ventilation
  • the computer-controlled valve assembly allows infusions of cooled or warmed PFC into a catheter which is positioned in an endotracheal tube connected to a gas ventilator.
  • PFC is also conditioned by being passed through a silicone membrane oxygenator and filters to remove respiratory tract secretions and bacteria.
  • the computer monitors airway infusion, and has a cut off for high pressures on infusion and suction cycles.
  • the ventilator is also controlled by the same computer, which monitors airway pressures and adjusts both PFC infusion and gas ventilation rate and tidal volume to insure that airway pressures do not exceed critical values.
  • PFC infusion can be continuous, or it may be timed and pulsed with each inspiration. In the following examples, PFC is infused continuously.
  • FIG. 10a shows the result of using this method with 3 animals, as compared with the 5 in the FIG. 10 discussed above.
  • Unrealistic heat capacities calculated from these numbers (1.2 kcal/kg) makes it obvious that the problem is temperature data from the inpiration and expiration fluid which could not be fairly approximated by a rectangular integral. Assuming these animals had much the same heat capacity as the others, suggests that they were cooled only 75% as efficiently, for a total efficiency of
  • MAP mean arterial pressure
  • CVP central venous pressure
  • Sp ⁇ 2 mixed arterial oxygen saturation
  • SVO2 central venous oxygen saturation
  • the following respiratory parameters were monitored and acquired in some animals using a Novametrix Medical System (Wallimgford, CT) CO2SMO Respiratory Profile Monitor inserted into the ventilator circuit above the endotracheal tube. These parameters were: respiratory rate (RR), end-tidal pCO2 (EtCO2), minute CO2 production (VCO2), mean airway pressure (MAP a ), minute volume (MV), inspired tidal volume (VTi), expiratory volume (VTe), peak inspiratory pressure (PIP), positive end expiratory pressure (PEEP), and peak inspiratory flow rate (PIF). Respiratory Mechanics and Gas Exchange Data from Example 6
  • FIG. 11a and l ib show representative pa ⁇ 2 data from the experiments in FIG 10 and 10a, throughout a decrease in core body temperature of ⁇ 5°C, or when being given body temperature PFC.
  • the paO2 at 100% O2 does not undergo significant fluctuations when cold PFC is given, but on room air, the A-a gradient typically falls by 20 Torr for a day after PFC has been used, then recovers over the next day.
  • For warm PFC cycling it is interesting that even with oxygenated PFC, paO2 dropped signifcantly while the dogs breathed normothermic PFC, indicating a signficant shunt and possibly V/Q mismatch. This, interestingly, was temperature dependent (the only variable). It was seen in automated and hand controlled trials. It remains unexplained, but perhaps represents a cold-prevented problem with vascular opening, which was not seen with body- temperature PFC given at the same rates and pressures.
  • FIGs. l ie and lid show pCO2 direct blood gas measurements (NovaStat II machine) during the active phase of cooling in the same groups. Here the same trend is evident, with cooled animals doing much better on gas exchange. Measurements of directly- obtained arterial paCO2 (femoral artery blood draws) show paCO2 to be well-maintained in cold PFC cycling in MMLV. but that many of these protocols were not sufficient to remove CO2 production when identical infusions of body-temperature PFC (38 C) was used as a control for the effects of chilled PFC.
  • FIG.12 shows preliminary data explaining why cold MMLV experiments have less problems with CO2 elimination.
  • FIG.12 shows combined EtCO2 and VCO2 data during cooling (Example 6) by 5°C using MMLV. Preliminary examination of this data reveals a profound decrease in both EtCO2 and VCO2 which would seem to indicate decreased CO2 elimination. However, these data are misleading since they reflect only the CO2 which is present in the expired gas from mechanical ventilations. An additional amount of CO2 is removed in the PFC which is loaded and unloaded from the lungs, and this volume of CO2 is not measured by the capnograph in the gas path since it is dissolved in the PFC liquid and removed with it.
  • FIG. 13 shows VCO2 measurements of another animal given cold PFC, again with
  • Serum lactate was 2.0 mM prior to the start of MMLV, 1.6 mM 3 minutes after MMLV and 1.3 mM 3 hours following the procedure.
  • FIG.14 shows the relationship between aortic temperature and heart rate.
  • the temperature wave form shown in this graph is a surrogate for the volume of liquid in the lung. It should be noted that of the 22 dogs subjected to ultra cold intrapulmonary cooling with PFC, no animal developed any arrhythmia other than bradycardia associated with cooling, and this was transient, even at core drops of -12°C.
  • the peaks in aortic blood temperature indicate the point where most of the liquid is unloaded from the lungs.
  • the nadirs in aortic blood temperature are indicative of the presence of the maximum volume of cold PFC in the lungs.
  • maximal PFC loading and the nadir of aortic blood temperature
  • heart rate rebounds above baseline when liquid is suctioned from the lungs and the venous return to the heart normalizes. This is analogous to the reflexive rebound in heart rate after the release of pressure in the Valsalva maneuver. This phenomenon occurs since intrapleural (intra-thoracic) pressure has a profound effect on venous blood return to the heart and thus on preload.
  • FIG.18 shows the relationship between PFC load in the lungs (as indicated by PFC infusion/ suction temperature curves) and ventilator gas pressure in Example 6.
  • PIP peak inspiratory pressure as indicated by peaks in the ventilator pressure graph
  • MAP rise steeply and nonlinearly as maximal PFC loading is achieved.
  • PIPs are at 40 cm H2O by the time the last gas breath is delivered with the lungs maximally loaded with PFC.
  • Total alveolar minute ventilation decreases proportionally more than total gas minute volume, as computed by the CO2SMO device, during MMLV. This occurs because the CO2SMO computes minute alveolar ventilation by using minute ventilation and VCO2. Since 59% of the VCO2 is being removed in the form of gas bubbles in the PFC liquid, the sensor of the CO2SMO cannot detect this volume of CO2 and thus the values for gaseous CO2 "alveolar minute volume" production (MV alv) total are artificially low. However, calculation of the theoretical maximum amount of CO2 being removed via PFC suction shows close agreement with the estimated VCO2 of the animal during MMLV.
  • the large values for VTi are an artifact of suctioning PFC and gas from the lungs of the animal and the ventilator circuit at the completion of liquid unloading.
  • these values constitute some information about the total volume of gas/liquid removed from the animal and ventilator circuit during a liquid unloading cycle (since all liquid/gas suctioned from the lungs must be replaced by gas flowing through the CO2SMO over multiple cycles of suction) and thus may be of some use.
  • Wetting the capnographic window with PFC results in false high readings of both EtCO2 and VCO2 until the heater in the capnograph vaporizes the PFC.
  • the dual beam infrared technology used in the capnographic sensor does not tolerate contamination with liquid, whether it is PFC or water.
  • the CO2SMO is designed to measure respiratory parameters using only gas ventilation. The system operates by measuring pCO2 and the absolute and differential pressures of the ventilating gas. Liquid contact, including PFC, renders the system inoperative.
  • the CO2SMO provides valuable data on the respiratory mechanics and physiology of MMLV.
  • Recent changes to the CO2SMO software allow for continuous real-time acquisition of data, as opposed to 1 -minute trends. Use of this enhanced capability should allow for considerable progress in optimizing the algorithms used for MMLV. Progress in Preventing Baro-trauma
  • FIGs 19 and 20 show 2 cold PFC lavage trials from 10 and 10a, in terms of maximal airway pressures, measured at the ET cuff. They differ essentially only by infusion volume (not rate) and machine control (machine control of valving, and a newer ventilator which is more sophisticated). While control of pressure is good with practice in hand-controlled mode, it is clear that the machine-controlled mode with infusions of 8 mL vs. 16 mL and better control over pressure parameters, did the best at controlling pressures in both suction and lavage. Histopathological Evaluation
  • FIGs. 3 and 4 The lungs appeared grossly normal. On light microscopy there were occasional small areas of focal edema and hyper-cellularity in the bronchioles. The heart was grossly and microscopically normal. Full MMLV Examples: MMLV1: The lungs looked good overall with normal gross and microscopic appearance. Large airways, smaller airways, bronchioles, alveolar ducts, alveoli and blood vessels appeared normal. The gross and microscopic appearance of the heart was normal.
  • MMLV2 The lungs appeared grossly normal. The large and small airways were intact, however, the vessels appeared dilated. The bronchioles and gas exchange compartments exhibited some interstitial edema with some RBC extravasation. Vessels were apparently acutely disrupted. There was no evidence of inflammatory infiltrate. NOTE: it is the pathologist 's impression that this is an acute injury probably secondary to excessive perfusion pressure during fixative perfusion due to the lack of inflammatory changes unless this animal was sacrificed acutely. (In fact this animal was clinically well with normal ABGs at the time of sacrifice which was 2 weeks post MMLV). The heart was normal on both gross and microscopic examination.
  • MMLV3 The lungs appeared normal in all respects except for a few scattered focal bronchiolar inflammatory infiltrates. The heart was normal both grossly and on microscopic examination.
  • MMLV4 The lungs and heart appeared completely normal. As is evident from these histopathological findings, MMLV as practiced even in its currently suboptimum form results in only minor histological injury. As the preceding clinical and laboratory data make clear, MMLV is consistent with both good post- procedure gas exchange, ventilatory mechanics, and long term survival with no clinically apparent sequelae. Optimization of the Current Protocol for MMLV
  • optimization of the protocol for certain clinical applications can include one or more of the following: a) Substitute a sophisticated (feedback responsive) pressure cycled ventilator for the volume cycled, pressure limited ventilator (Puritan Bennett MA-1) which was used to do much of the manual work and used for most of these experiments.
  • FIG 31 shows not only machine controlled ventilation, but the ventilator is a Servo-9000.
  • the rate of heat exchange might be further optimized by discontinuing suction at a PIP of +2 to +5 cm H2O at which time almost all of the available PFC would be unloaded from the lung. This would not only avoid any possibility of trauma from negative intrapulmonary pressures, but would optimize heat exchange by increasing the frequency of liquid loading/unloading cycles per unit of time.
  • MMLV gas/PFC -based liquid ventilation
  • HFOV High Frequency [Oscillating] Ventilation
  • MMLV as a technique can include a novel device which controls gas and liquid ventilation separately, but in an interlocked way, in order to maximize CO2 removal, heat removal and oxygen delivery.
  • MMLV is susceptible to improvements in many ways by anyone skilled in the art, without departing from the spirit of the discovery that non-thermal "convective" mixing and mass transport assistance is necessary for efficient central cooling via PFC lung lavage. Cooling rates of 20°C/hr are easily achieved by our methods, but we note that faster cooling rates are in principle easily achievable by maximizing performance of many features of our system of MMLV, and by use of features of systems which we have described above (HFOV, sweep-flow) when used in the novel way described (i.e., in conjunction with PFC for heat exchange and/or gas exchange).
  • HFOV sweep-flow
  • MMLV facilitates gas exchange more efficiently for the treatment of adult and neonatal respiratory distress syndromes, pulmonary edema, and other pulmonary insults (i.e., alveolar proteinosis, chronic bronchiectasis, as well as chemical and thermal insults to the lung) which result in V/Q mismatch as a consequence of sequestration of alveoli from gas exchange by means other than either TLV, as taught by Shaffer, 1994, US Patent 5,335,650, and Vaseen VA, 1980, US Patent # 4,323,665, or PLV as taught by Schutt, EG 1996 in US Patent # 5,540,225.
  • normothermic MMLV in these conditions has the added advantage of acting to vigorously lavage the large and small airways— thus removing mucus, blood (secondary to hemoptysis or trauma), pulmonary transudate, and other harmful respiratory secretions- all far more efficiently than possible with either TLV or PLV-
  • MMLV can also be used for the therapeutic induction or reversal of hypothermia, including but not limited to: heatstroke, malignant hyperthermia, hyperpyrexia, stroke, head injury, post-ischemic insult, and febrile illnesses.
  • MMLV is useful for the companion animal and human cryopreservation patient (cryonic suspension) and for other postmortem cooling or warming of humans for the purposes of organ preservation, organ or tissue recovery, resuscitation, or facilitation of treatment of trauma patients, exsanguinating injuries, or cardiac arrest.
  • MMLV is a therapeutic modality to improve gas exchange, reverse or induce hypothermia, or maintain normothermia. This claim is understood to include but not be limited to shock as a result of sepsis, poisoning, chemical or thermal burns, and trauma.
  • MMLV can be used for the purpose of increasing the efficacy of closed chest CPR by the mechanism of raising intra-thoracic pressure during the down stroke of external cardiac compression by synchronizing liquid loading with chest compression.
  • a corollary of increased thoracic pressure during the downstroke of CPR is increased cardiac output as a result of decreasing lung compliance (due to liquid loading) thus facilitating cardiac output in CPR via the thoracic pump mechanism. It may be quite dangerous to do CPR in lungs fully loaded with liquid, which they need to be in TLV.
  • boluses of oxygenated PFC can allow metabolic supply of oxygen for many minutes without ventilation at all. It may be that coordinated use of small amounts of
  • Nitric oxide and nitric oxide donors administered via the breathing liquid or the breathing gas, or both, can be used to overcome cold-induced pulmonary vasoconstriction and thus facilitate gas and heat exchange. It is possible that pulmonary vasoconstrictors
  • All, or a large fraction of the oxygen or other breathing gases in the gas ventilation component of MMLV can be replaced with helium in order to reduce ventilating gas viscosity, thus allowing for lower peak airway pressures secondary to gas flow in gas ventilation.
  • Helium is anticipated also to have unique properties in gas-liquid foams: it should form smaller gas bubbles, resulting in improved bubble -induced mixing.
  • the use of helium will also facilitate nitrogen out-gassing from body water during re-warming from hypothermia.
  • the use of 100% inspired helium gas is possible when used with fully oxygenated PFC delivered at appropriate infusion rates (> 10 mL/kg/min).

Abstract

L'invention concerne un nouveau procédé de ventilation et d'échange de chaleur appelé ventilation par liquide en mode mixte (MMLV : mixed mode liquid ventilation). Ce procédé comprend l'utilisation d'un cathéter endothrachéal (fig. 1a et 6b) permettant d'ajouter et de retirer du liquide des poumons de manière continue et/ou cyclique, et d'administrer un gaz à un débit indépendant de l'administration de liquide. Ce procédé produit un mélange de gaz et de liquide à petite échelle dans les voies respiratoires, permettant un échange efficace de gaz et de chaleur. L'invention concerne également des applications médicales de ce procédé, parmi lesquelles l'induction et l'inversion de l'hyperthermie et de l'hypothermie.
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