Feasibility of lung cancer hyperthermia using breathable perfluorochemical (PFC) liquids. Part I: Convective hyperthermia.

Clinical studies have shown that hyperthermia in combination with radiotherapy and/or chemotherapy may be effective in the treatment of advanced cancer. No method of lung hyperthermia, however, has been accepted as standard or superior. This investigation sought to demonstrate in animals the thermal and physiologic feasibility of lung hyperthermia induced using heated breathable perfluorochemical (PFC) liquids, a method termed liquid-filled lung convective hyperthermia (LCHT). The ability to use LCHT is rooted in the development of both PFC liquid ventilation, now in clinical development with the PFC perflubron (LiquiVent), and a PFC blood substitute also in late Phase III trials (Oxygent). As LCHT background, the PFC technologies and biology are first reviewed. The physical properties of a variety of PFCs were evaluated for LCHT and it was concluded that more than one liquid is suitable based on such properties. Using total liquid ventilation type devices, LCHT was shown to deliver successfully localized (lobar) lung heating in sheep, and bilateral whole lung heating and whole-body hyperthermia in rabbits, cats and lambs. During LCHT, lung parenchymal temperatures were uniform (<1 degree C) across heated regions. In addition, based on patterns relating lung tissue temperatures to inspiratory and expiratory PFC liquid temperatures in the endotracheal tube, LCHT may minimize invasive thermometry requirements in the lung. Based on acute experiments, it was concluded that LCHT appears feasible and may simplify lung hyperthermia. It was recommended that potentially synergistic combinations of LCHT with other whole-body hyperthermia or local heating modalities, and with chemotherapeutic lung drug delivery, also be explored in the future.

Feasibility of lung cancer hyperthermia using breathable perfluorochemical (PFC) liquids. Part II: Ultrasound hyperthermia.

Enhanced local control of disease in lung cancer has been shown to improve survival, and controlled clinical trials of hyperthermia adjunctive to radiotherapy in other cancers have shown improved disease control and survival over radiotherapy alone. The challenge of lung hyperthermia, however, persists. This investigation sought to demonstrate the feasibility of localized lung hyperthermia at depth via therapeutic ultrasound. The method is based on using breathable perfluorochemical liquids as acoustic coupling media in the lung, liquids that have also been shown to enable controlled liquid-filled lung convective hyperthermia (LCHT). The ability to use both lung convective hyperthermia and liquid-filled lung ultrasound hyperthermia (LUHT) provides potential flexibility in heating patterns for the hyperthermic treatment of lung cancer with concurrent radiotherapy and/or chemotherapy. Using custom ultrasound transducers designed and built for these studies, the acoustic properties of three candidate perfluorochemicals were characterized over a range of temperatures, gas contents and ultrasound frequencies and acoustic intensities. Both sound speed and attenuation were measured in the neat liquids and in isolated lungs filled with the perfluorochemicals. Successful ultrasound hyperthermia at depth was demonstrated in vivo in sheep lung lobes in intraoperative conditions. In addition, the use of ultrasound diagnostic imaging was explored as a tool for use in conjunction with lung ultrasound hyperthermia.

Dose maintenance for Partial Liquid Ventilation: passive heat-and-moisture exchangers.

Partial Liquid Ventilation (PLV), a promising method for the treatment of acute lung failure, has been evaluated in many animal studies. It has recently progressed to the point of controlled clinical trials in which patients of all ages on conventional mechanical ventilation (CMV) have their lungs substantially filled with a perfluorochemical (PFC) liquid, perflubron (PFB). During PLV, it is desirable to both maintain humidification and minimize the evaporation of PFB in order to maintain a desired dose in the lung and to reduce dose consumption and redosing effort. Heat-and-moisture exchangers (HMEs) have been used for years as a passive means of minimizing water vapor loss from the respiratory tract during CMV support of intensive care and surgical patients. In the current study, research was undertaken to leverage the operating principles of existing HMEs such that specialized "fluorophilic" HMEs (FHMEs), devices optimized for both water and PFB conservation, could be realized. A patient simulator (involving both water vapor and PFB vapor sources) was constructed and used in the in-vitro evaluation of various FHME concepts. Dose-retention efficiencies were determined with the aid of an infrared instrument and a digital thermohygrometer. Although no larger than commercial HMEs in terms of dead space (gas-occupying volume), efficient FHMEs resulted, offering less flow resistance (delta P) than their commercial counterparts. Additionally, the presence of PFB vapor did not appear to compromise the water-exchange efficiency of certain HME configurations. One promising FHME design was also tested in swine undergoing 12-hour PLV treatments. A mean conservation efficiency of 63% at an average tidal volume of 550 mL was shown, although somewhat lower efficiencies may result in adult patients because efficiency was found to trend downward with increasing tidal volume. The use of an FHME is expected to sustain dose levels in patients for longer periods with less frequent dosing and reduced dose consumption, saving treatment labor and cost.

Dose monitoring in Partial Liquid Ventilation by infrared measurement of expired perfluorochemicals.

Patients undergoing Partial Liquid Ventilation (PLV) with the perfluorochemical liquid perflubron (PFB) continuously evaporate the drug from the lung during ventilatory expiration. In this study, two infrared (IR) devices, a modified industrial analyzer ("experimental prototype") and a custom-designed device suitable for use in a clinical environment ("clinical prototype"), were calibrated and validated on the bench to measure a range of PFB concentrations (CPFB) in a gas stream. PFB loss from the lung (area under the CPFB-vs-time-curve) could be correlated during PLV simulation with changes in tidal volume, breathing rate, and variable CPFB-vs-time profiles. The two IR devices produced nearly identical measurements for the same CPFB standards (maximum deviation = 1.5%). The experimental IR prototype was tested in 17 anesthetized, paralyzed, and ventilated swine (42-53 kg) to quantify the total amount and rate of evaporate loss of PFB over 12 hours of PLV, both with and without periodic supplemental PFB doses. The residual PFB volumes in the animal lungs at the end of the study, as determined by a gravimetric postmortem lung method, were found to agree on average for all animals to within 10% of the residual PFB volume as predicted by the IR approach. Furthermore, the IR signal of CPFB does not appear to correlate with the absolute amount of PFB in the lungs, but may reflect the relative proportion of PFB-wetted airway and alveolar surface. The authors conclude that IR quantitation of PFB evaporative loss is acceptably accurate for extended periods of PLV and may be a useful tool in the clinic for PFB dose monitoring and maintenance, thereby helping to optimize PLV treatment.

Recent innovations in total liquid ventilation system and component design.

In addition to partial liquid ventilation (PLV), total liquid ventilation (TLV) is being explored as a potential therapy to mitigate ventilator-associated lung injury and acute lung failure. TLV is ventilation of the completely liquid-filled lung using tidal flow of oxygenated perfluorochemical (PFC) liquid delivered by a "liquid ventilator." Most TLV research to date has focused on "small" lung (animals < 20 kg; vast majority < 5 kg), with primary relevance to its use in children. Recent investigations regarding TLV in larger lungs have helped define new design challenges for liquid ventilator systems to succeed as clinical products. Adult TLV requires the delivery of significantly higher liquid tidal volumes, with proportionately greater O2 and CO2 exchange. Although a simple scale-up of liquid ventilator components such as pumps, tubing, fittings, and gas and heat exchangers might be considered the most straightforward way to compensate for the increased demand, there are a number of practical problems with this approach. These include requirements to: 1) minimize priming volume, 2) minimize PFC evaporative loss, 3) suppress flow-induced cavitation in fittings and components, 4) monitor and control ventilation based on pressure signals exhibiting noise, 5) maintain ability and accuracy of delivered breaths in a fluid mechanical environment having higher inertial forces and pressure losses than for small lung systems, 6) use disposable or sterilizable fluid-contacting components, and 7) maintain PFC materials compatibility. TLV system and component innovations implemented on a new large-animal liquid ventilator prototype are presented. The advantages of new pumps, gas exchangers, and temperature-control components are discussed.

Long-term partial liquid ventilation (PLV) with perflubron in the near-term baboon neonate.

PURPOSE: The feasibility and safety of continuous long-term (4-5 day) partial liquid ventilation (PLV) using perflubron was demonstrated in newborn baboons. PLV, a potential therapy for adult and neonatal respiratory distress syndrome (RDS), is conventional mechanical ventilation (CMV) with the lung filled to about functional residual capacity with perfluorochemical liquid. PROTOCOL: As a pilot trial for a larger preclinical study focused on the safety of extended duration PLV, three near term baboons were studied. The animals were delivered by cesarean section, anesthetized, intubated and placed on CMV. The animals were given intratracheal perflubron (30 ml/kg) and maintained on PLV for 96 hours. The transition back to gas ventilation occurred, after draining, over the fifth day (hrs 96-120). RESULTS: Two of the animals were born with normal pulmonary function, while the third developed respiratory distress prior to PLV. All the animals were adequately supported with PLV using moderate ventilator settings and low concentrations of oxygen. Perflubron distribution was enhanced by periodic rotation of the animals. Preliminary histology show vacuolated alveolar macrophages and no evidence of edema or other significant changes in the lungs. Pulmonary function in the RDS animal, after PLV treatment, showed normal gas exchange and lung mechanics. CONCLUSIONS: Three near term baboons, one with clinical RDS, tolerated 4 days of PLV followed by 1 day of CMV without complications using practical clinical management methods.

Utility of a perfluorochemical liquid for pulmonary diagnostic imaging.

The use of neat perfluorochemical liquid (PFC) as an alternative respiratory medium has gained increasing attention for assessment and treatment of the immature or injured lung. In vitro and in vivo plain film and computed tomographic (CT) studies were performed on small and large animals to evaluate the use of perfluorooctylbromide (perflubron) as a bronchographic contrast agent and to quantitate the distribution and elimination of this fluid from the lung following total liquid ventilation or during gas breathing after tracheal instillation of small quantities of this liquid. The results demonstrate the utility of a highly radiopaque PFC liquid in combination with diagnostic imaging techniques to visualize small airways anatomy, identify regional and gravity dependent differences in distribution/elimination of the fluid, ventilation, and track PFC liquid following therapeutic application.

Local muscle blood flow and temperature responses to 915MHz diathermy as simultaneously measured and numerically predicted.

The therapeutic benefits of diathermy are tied to the relationship thought to exist between tissue temperature and augmented blood flow (BF). To further define this relationship, simultaneous measurements of thigh muscle blood flow (MBF) and temperature have been made in 15 human subjects during 915MHz, direct-contact microwave diathermy (MWD) with simultaneous skin cooling. Tissue temperatures were measured invasively by special thermistor probes designed to minimize MW-induced artifacts, and the local rates of MBF were measured by monitoring the radioactive washout of injected Xenon133 (Xe133). The experimental results have shown that the initial MBF response is characterized by a "critical temperature" behavior such that rapid increases in MBF occur for tissues above approximately 42C when diathermy power is sufficient. A proportionality between tissue temperature and MBF has not been found. To provide more useful descriptions of the temperature fields and diathermic BF responses, two-dimensional numerical thermal simulations of six of the subjects' treatments were constructed and recorded. An average peak simulated MBF of 48ml/min-100g was found for these subjects, a level in excess of previous estimates for maximum perfusion during diathermy.

Determination of perfusion field during local hyperthermia with the aid of finite element thermal models.

Two-dimensional transient thermal models of human thighs undergoing microwave diathermy are developed with the aid of experimental data to shed light on the blood flow response occurring during local hyperthermia in muscle. The experimental data were taken from tests on six human subjects treated with a 915-Mz, direct-contact microwave diathermy device which incorporated a system for simultaneously cooling the skin surface with a cold air stream. The numerically calculated perfusion fields were determined by systematically varying a model's blood flow response to the temperature stimulus until good agreement between the experimental and model temperature fields were achieved. The model blood flow values were then checked against those measured in the human experiments via xenon 133 washout and good agreement here was also found. The future use of models of this type in clinical diagnosis and hyperthermic treatment is proposed.