Accounting for the effects of moderately increased pressure on the energetics of melting and solubility in metered dose inhalers.

The purpose of this study is to account for thermodynamic variations due to changes in the physical environment of propellant-based systems, particularly metered dose inhalers (MDIs). Twenty organic compounds were measured via differential scanning calorimetry under ambient pressure, 60 psi, and 90 psi. The increase in pressure did not affect the melting point of any of the compounds. A modest increase (approximately 8%) in enthalpy of fusion was noted. This correlates to a modest increase in entropy of fusion, and thus ideal crystalline solubility, though the magnitude of this change depends primarily on the melting point of the given compound. Because the relationship between melting point and solubility is logarithmic, compounds with higher melting points are affected more by this increased energy of melting. Based on the findings, modest changes can be made to predictive models to estimate solubility in propellant systems to account for changes in the physical environment of MDIs.

Short-term growth and adrenal function in children with asthma treated with inhaled beclomethasone dipropionate hydrofluoroalkane-134a.

Inhaled beclomethasone dipropionate (BDP) with the propellant hydrofluoroalkane-134a (HFA) has been designed to be equivalent in terms of safety to chlorofluorocarbon (CFC)-formulated metered dose inhalers (MDI). The aim was to assess whether BDP HFA MDI 100 microg twice daily was equivalent to BDP CFC MDI 100 microg twice daily in terms of effects on short-term lower leg growth rate (LLGR) and measures of hypothalamic-pituitary-adrenal (HPA) function. The study consisted of a randomized double-blind cross-over trial with three active, a run-in and two wash-out periods each consisting of 2 wk. The place of study was a secondary referral outpatient clinic. The subjects involved were 14 boys and 10 girls with asthma, aged 7-12 yr. They were all administered BDP HFA 100 microg, BDP CFC 100 microg and 200 microg twice daily. The outcome measures included LLGR and 24-h urine-free cortisol (UFC) and total cortisol metabolites (TCM). Mean (SD) LLGR during run-in and BDP HFA 100 microg, BDP CFC 100 microg and 200 microg twice daily periods were 0.43 (0.23), 0.09 (0.29), 0.10 (0.45) and 0.08 (0.27) mm/wk. The one-sided 97.5% confidence interval for the difference in LLGR between BDP HFA 100 microg and BDP CFC 100 microg was 0.24, thus, below the predefined criterion of 0.20 mm/week. Inter-period comparisons of active treatments showed no differences between means of LLGR, UFC or TCM. Though non-inferiority between BDP HFA and CFC 100 microg twice daily in terms of effects on LLGR was not found, equivalence was suggested by comparisons of LLGR during run-in and active treatments and by HPA function measures.

Radial and temporal variations in surface heat transfer during cryogen spray cooling.

Cryogen spray cooling (CSC) is a heat extraction process that protects the epidermis from thermal damage during dermatologic laser surgery. The objective of the present work is to investigate radial and temporal variations in the heat transferred through the surface of a skin phantom during CSC. A fast-response thermal sensor is used to measure surface temperatures every 1 mm across a 16 mm diameter of the sprayed surface of the phantom. An analytical expression based on Fourier's law and Duhamel's theorem is used to compute surface heat fluxes from temperature measurements. Results show that radial and temporal variations of the boundary conditions have a strong influence on the homogeneity of heat extraction from the skin phantom. However, there is a subregion of uniform cooling whose size is time dependent. It is also observed that the surface heat flux undergoes a marked dynamic variation, with a maximum heat flux occurring at the centre of the sprayed surface early in the spurt followed by a quick decrease. The study shows that radial and temporal variations of boundary conditions must be taken into account and ideally controlled to guarantee uniform protection during CSC of human skin.

Dose response to aerosolized perflubron in a neonatal swine model of lung injury.

Aerosolized perfluorocarbon (PFC) improves gas exchange, lung mechanics, and pulmonary artery pressure. The objective of this intervention was to study the dose-response effect to aerosolized perfluorooctylbromide (PFOB; perflubron, LiquiVent, Alliance Pharmaceutical Corp.) in surfactant-depleted piglets. After induction of lung injury by saline lavage, 25 newborn piglets were randomly assigned to receive 0, 1.25, 2.5, 5.0, or 7.5 mL/kg aerosolized PFOB per hour. A 2-h therapy period was followed by a 3-h observation period. In all animals, respiratory support was performed with intermittent mandatory ventilation. After aerosol treatment and 3 h of observation, arterial oxygen pressure was similarly improved in the 2.5-, 5.0-, and 7.5-mL. kg(-1). h(-1) aerosol-PFOB groups and higher compared with the 1.25-mL. kg(-1). h(-1) aerosol-PFOB (P < 0.01) and the control groups (P < 0.001). Compared with the control group, arterial carbon dioxide pressure was significantly reduced with 2.5-, 5.0-, and 7.5-mL. kg(-1). h(-1) aerosol-PFOB (P < 0.001). Treatment with 1.25 mL. kg(-1). h(-1) aerosol-PFOB did not significantly affect arterial carbon dioxide pressure. The 20% terminal dynamic compliance/dynamic compliance was significantly improved in the groups that received 2.5, 5.0, and 7.5 mL. kg(-1). h(-1) aerosol-PFOB compared with control animals. Mean pulmonary artery pressure was lower after therapy with 5.0 and 7.5 mL. kg(-1). h(-1) aerosol-PFOB (P < 0.01) than in the control group. IL-1beta gene expression in lung tissue was significantly reduced with PFOB 1.25 mL. kg(-1). h(-1). In summary, aerosolized PFOB improved terminal dynamic compliance, pulmonary gas exchange, and pulmonary artery pressure in a dose-dependent manner. In terms of oxygenation and lung mechanics, the optimum dose was between 2.5 and 5 mL. kg(-1). h(-1).

Effect of spurt duration on the heat transfer dynamics during cryogen spray cooling.

Although cryogen spray cooling (CSC) is used to minimize the risk of epidermal damage during laser dermatologic surgery, optimization of the current cooling approach is needed to permit the safe use of higher light doses, which should improve the therapeutic outcome in many patients. The objective of this study was to measure the effect of spurt duration (delta t) on the heat transfer dynamics during CSC using a model skin phantom. A fast-response temperature sensor was constructed to record the changes in surface temperature during CSC. Temperature measurements as a function of delta t at two nozzle-to-skin distances (z = 50 and 20 mm) were performed. The average surface heat fluxes (q) and heat transfer coefficients (h) for each delta t were computed using an inverse heat conduction problem algorithm. It was observed that q undergoes a marked dynamic variation during the entire delta t, with a maximum heat flux (qc) occurring early in the spurt (5-15 ms), followed by a quick decrease. The estimated qc vary from 450 to 600 kW m(-2), corresponding to h maxima of 10 and 17-22 kW m(-2) K(-1) for z = 50 and 20 mm, respectively. For z = 50 mm, spurts longer than 40 ms do not increase the total heat removal (Q) within the first 200 ms. However, for z = 20 mm, delta t longer than 100 ms are required to achieve the same Q. It is shown that the heat transfer dynamics and the time it takes to reach qc during CSC can be understood through classic boiling theory as a transition from transient to nucleate boiling. Based on the results of this model skin phantom, it is shown that spurts longer than 40 ms have a negligible impact on both q and Q within clinically relevant cooling times (10-100 ms).

Small airway asthma therapy, challenges, and the future.

The clinical significance of small airway pathology makes these passages an important therapeutic target in asthma. Conventional chlorofluorocarbon-based formulations of inhaled corticosteroids for asthmatic inflammation produce aerosols with a relatively large particle size, and as such, offer poor access to the small airways. New corticosteroid formulations use hydrofluoroalkane propellants with a smaller average particle size, allowing better access to the distal lung. By extending the delivery of this medication to the peripheral lung and by increasing the efficiency of lung targeting, these new corticosteroid formulations provide more effective treatment at reduced drug doses.

Deaths related to the inhalation of volatile substances in Texas: 1988-1998.

Analysis of death certificates in Texas from 1988 to 1998 showed that the characteristics of 144 Texans for whom inhalants were mentioned as a contributing cause of death are different from those Texans who report use of inhalants in surveys and from persons who died from inhalant abuse in Virginia. While Texas surveys show little difference in prevalence of use between white and Hispanic adolescents or between boys and girls, Texas death data indicate inhalant use is also a problem among adult white males. The mean age of decedents was 25.6 years (SD 9.8 years), and ages ranged from 8 to 62 years. There were 92% males, 81% whites, and 17% Hispanics. Of the death certificates, 35% mentioned Freon, and 25% mentioned chlorinated hydrocarbons. Of those with the mention of Freon, 42% were students (mean age 16.4 years), and 37% were mechanics, installers, and repairers (mean age 27.4 years), occupations in which Freon can be readily available. Of the chlorinated hydrocarbon deaths, 49% were students (mean age 17.5 years), and 51% were from other occupations (mean age 27.4 years). Research on drug use and the workplace is not extensive, and the effects of inhalant intoxication can be a serious problem in the workplace. Prevention campaigns need to inform the public that inhalant abuse is not just a problem among youngsters, and intervention services for adult abusers should be provided within the context of employee assistance programs.

Investigations on the liver toxicity of a blend of HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) and HCFC-124 (2-chloro-1,1,1,2-tetrafluoroethane) in guinea-pigs.

2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) has been developed as a substitute for ozone-depleting chlorofluorocarbons (CFCs). It is a structural analogue of halothane and similarities in the metabolic pathways and liver toxicity of both compounds have been described. The present study was initiated after an accidental outbreak of hepatitis in an industrial setting to examine whether concomitant exposure to 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124), which is not hepatotoxic, could enhance the liver toxicity of HCFC-123. Male Hartley guinea-pigs were exposed for 4 h to 5,000 ppm HCFC-123 alone or blended with 5,000 ppm HCFC-124, either once (single exposure) or on 5 consecutive days (repeated exposure). The animals were killed either 24 or 48 h after the last exposure. A transient cytolytic action of HCFC-123 was evident by increased mean serum levels of alanine aminotransferase at 24 h and isocitrate dehydrogenase at 24 and 48 h, both after a single or repeated exposure. The liver toxicity of HCFC-123 was confirmed by pathological examination of liver tissue, which showed mild (foci of necrotic hepatocytes) to moderate (multifocal random degeneration and necrosis) damage. Steatosis was also observed and was more pronounced after repeated exposure than after single. One animal out of 6 that were repeatedly exposed to the blend and sacrificed at 24 h showed liver lesions similar to halothane hepatitis. Although a few other animals responded markedly in the blend-treated group, on average, no significant difference in the biochemical or pathological lesions was found between the groups treated with HCFC-123 alone or with the blend. Urinary excretion of trifluoroacetic acid and chlorodifluoroacetic acid increased dose-dependently upon exposure to HCFC-123 and indicated accumulation after repeated exposure. No difference in metabolite excretion was found between animals treated with HCFC-123 alone or blended with HCFC-124. Treatment with HCFC-123 depleted hepatic glutathione levels by about 40 and 25% after single and repeated exposure, respectively; the amplitude of this reduction was not modified by co-exposure to HCFC-124. In conclusion, this study confirmed the hepatotoxicity of HCFC-123, based on biochemical, histopathological and metabolite studies, and found only very limited indication of a potentiation by HCFC-124 of this hepatotoxic effect.

Cryogen spray cooling: Effects of droplet size and spray density on heat removal.

BACKGROUND AND OBJECTIVE: Cryogen spray cooling (CSC) is an effective method to reduce or eliminate non-specific injury to the epidermis during laser treatment of various dermatological disorders. In previous CSC investigations, fuel injectors have been used to deliver the cryogen onto the skin surface. The objective of this study was to examine cryogen atomization and heat removal characteristics of various cryogen delivery devices. STUDY DESIGN/MATERIALS AND METHODS: Various cryogen delivery device types including fuel injectors, atomizers, and a device currently used in clinical settings were investigated. Cryogen mass was measured at the delivery device output orifice. Cryogen droplet size profiling for various cryogen delivery devices was estimated by optically imaging the droplets in flight. Heat removal for various cryogen delivery devices was estimated over a range of spraying distances by temperature measurements in an skin phantom used in conjunction with an inverse heat conduction model. RESULTS: A substantial range of mass outputs were measured for the cryogen delivery devices while heat removal varied by less than a factor of two. Droplet profiling demonstrated differences in droplet size and spray density. CONCLUSIONS: Results of this study show that variation in heat removal by different cryogen delivery devices is modest despite the relatively large difference in cryogen mass output and droplet size. A non-linear relationship between heat removal by various devices and droplet size and spray density was observed.

PBPK modeling of canine inhalation exposures to halogenated hydrocarbons.

Human exposure guidelines for halogenated hydrocarbons (halons) and halon replacement chemicals have been established using dose-response data obtained from canine cardiac sensitization studies. In order to provide a tool for decision makers and regulators tasked with setting guidelines for egress from exposure to halon replacement chemicals, a quantitative approach, using a physiologically based pharmacokinetic model, was established that allowed exposures to be assessed in terms of the chemical concentrations in blood during the exposure. This model, which includes a respiratory tract compartment containing a dead-space region, a pulmonary exchange area, and a breath-by-breath description of respiratory tract uptake, allows successful simulation of exhaled breath concentrations of humans during the first minute of exposure to the anesthetics halothane, isoflurane, and desflurane. In the current study, the human model was modified with canine parameters and validated with data obtained from dog studies with halothane, isoflurane, desflurane, and CFC-11. With consideration of appropriate values for ventilation and cardiac output, the model successfully simulated data collected under a variety of exposure scenarios. The canine model can be used for simulating blood concentrations associated with the potential for cardiac sensitization. These target blood concentrations can then be used with the human model for establishing safe human exposure duration. Development of the canine model stresses the need for appropriate data collection for model validation.

Vapocoolant spray is equally effective as EMLA cream in reducing immunization pain in school-aged children.

BACKGROUND: Untreated immunization pain causes undue distress and contributes to underimmunization through physician, and possibly parental, resistance to multiple simultaneous injections. OBJECTIVE: To compare the efficacies of two pain management methods in reducing immediate immunization injection pain and distress in school-aged children. DESIGN: A randomized, controlled clinical trial of eutectic mixture of local anesthetics (EMLA) cream and vapocoolant spray. PATIENTS: Children aged 4 to 6 years and scheduled to receive diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) during health supervision visits. INTERVENTIONS: Enrolled children were randomized to one of three treatment groups: 1) EMLA cream + distraction; 2) vapocoolant spray + distraction; or 3) distraction alone (control). The specific pharmacologic pain control interventions consisted of EMLA cream (2.5% lidocaine, 2.5% prilocaine [Astra Pharmaceutical Products, Inc, Westborough, MA] $15. 00/patient; applied 60 minutes before injection) and vapocoolant spray (Fluori-Methane [Gebauer Company, Cleveland, OH] $0. 50/patient; applied via spray-saturated cotton ball for 15 seconds immediately before injection). MAIN OUTCOME MEASURES: The blinded investigator (BI) measured (by edited videotape) cry duration and the number of pain behaviors using the Observational Scale of Behavioral Distress. Pain visual analog scales (linear and faces scales) were completed by the child, parent, nurse, and the BI. RESULTS: Sixty-two children, aged 4.5 +/- 0.4 years (mean +/- SD) were randomized. The three treatment groups had similar subject characteristics. All pain measures and cry duration were similar for EMLA and vapocoolant spray. Both EMLA and spray were significantly better than control. Results for spray vs control: cry duration (seconds): 8.5 +/- 21.0 vs 38.6 +/- 50.5; number of pain behaviors: 1.2 +/- 1.9 vs. 3.1 +/- 2.1; child-scored faces scale: 2.0 +/- 2.4 vs. 4.1 +/- 2.3; parent-scored faces scale: 1.6 +/- 1.6 vs. 3.0 +/- 1.7; nurse-scored faces scale: 1.6 +/- 1.2 vs. 3.1 +/- 1.4; and BI-scored faces scale: 1.0 +/- 1.5 vs. 2.4 +/- 1.4. CONCLUSIONS: When combined with distraction, vapocoolant spray significantly reduces immediate injection pain compared with distraction alone, and is equally effective as, less expensive, and faster-acting than EMLA cream. As an effective, inexpensive, and convenient pain control method, vapocoolant spray may help overcome physician and parent resistance to multiple injections that leads to missed opportunities to immunize.

Severe frostbite caused by Freon gas.

We have reported a case of severe frostbite due to direct exposure to liquid Freon gas (monochlorodifluoromethane), a fluorinated hydrocarbon widely used as refrigerants, propellants, and industrial solvents. The patient was treated for severe third- and fourth-degree frostbite to the hand. The severity of the injury was apparently the result of direct through-and-through injury from exposure to the liquid (boiling point -40.5 degrees C) and a possible systemic vasoconstrictive effect on arterial smooth muscle due to inhalation of Freon gas.

Expirograms of O2, CO2 and intravenously infused C2H2 and Freon-22 during panting in dogs.

To study pulmonary gas transport in panting, expirograms of several inert and respiratory gases were simultaneously measured in panting dogs. The experiments were performed on 5 conscious dogs (mean body weight 34.4 kg) provided with a chronic tracheostomy. Panting at a mean frequency of 312/min (5.2 Hz) was induced by elevated room temperature (mean 28.1 degrees C). Isotonic saline equilibrated with 50% acetylene and 50% Freon-22 was infused intravenously at a constant rate (4 ml/min). Fractional concentrations in the tracheostomy tube were measured by a respiratory mass spectrometer, using a special sampling system designed for quasi-continuous analysis of rapidly changing gas concentrations. Air flow was monitored by an ultrasonic transit-time flowmeter. A tracing of expired gas concentrations versus expired volume showed no alveolar plateau, displaying a steep increase of Freon-22, acetylene and CO2 (decrease of O2) up to the onset of inspiration. The small but statistically highly significant differences between the expirograms of CO2 and O2, and of Freon-22 and acetylene, could be qualitatively explained by ventilation-perfusion inequalities with sequential emptying, by Taylor dispersion and by reversible solution in airway mucosa in the course of the respiratory cycle.

Long-term carcinogenicity bioassays on three chlorofluorocarbons (trichlorofluoromethane, FC11; dichlorodifluoromethane, FC12; chlorodifluoromethane, FC22) administered by inhalation to Sprague-Dawley rats and Swiss mice.

Three propellant chlorofluorocarbons, namely trichlorofluoromethane (FC11), dichlorodifluoromethane (FC12), and chlorodifluoromethane (FC22) were administered by inhalation at a concentration of 5000, 1000 and 0 ppm, 4 hours daily, 5 days weekly, for 104 and 78 weeks, to rats and mice, respectively. The animals were kept under observation until spontaneous death. Under the experimental conditions, all three compounds failed to show any carcinogenic effects.