Exploring potential mortality reductions in 9 European countries by improving diet and lifestyle: A modelling approach.

BACKGROUND: Coronary heart disease (CHD) death rates have fallen across most of Europe in recent decades. However, substantial risk factor reductions have not been achieved across all Europe. Our aim was to quantify the potential impact of future policy scenarios on diet and lifestyle on CHD mortality in 9 European countries. METHODS: We updated the previously validated IMPACT CHD models in 9 European countries and extended them to 2010-11 (the baseline year) to predict reductions in CHD mortality to 2020(ages 25-74years). We compared three scenarios: conservative, intermediate and optimistic on smoking prevalence (absolute decreases of 5%, 10% and 15%); saturated fat intake (1%, 2% and 3% absolute decreases in % energy intake, replaced by unsaturated fats); salt (relative decreases of 10%, 20% and 30%), and physical inactivity (absolute decreases of 5%, 10% and 15%). Probabilistic sensitivity analyses were conducted. RESULTS: Under the conservative, intermediate and optimistic scenarios, we estimated 10.8% (95% CI: 7.3-14.0), 20.7% (95% CI: 15.6-25.2) and 29.1% (95% CI: 22.6-35.0) fewer CHD deaths in 2020. For the optimistic scenario, 15% absolute reductions in smoking could decrease CHD deaths by 8.9%-11.6%, Salt intake relative reductions of 30% by approximately 5.9-8.9%; 3% reductions in saturated fat intake by 6.3-7.5%, and 15% absolute increases in physical activity by 3.7-5.3%. CONCLUSIONS: Modest and feasible policy-based reductions in cardiovascular risk factors (already been achieved in some other countries) could translate into substantial reductions in future CHD deaths across Europe. However, this would require the European Union to more effectively implement powerful evidence-based prevention policies.

Assessment of the respiratory sensitization potential of proteins using an enhanced mouse intranasal test (MINT).

There remains a need for a simple and predictive animal model to identify potential respiratory sensitizers. The mouse intranasal test (MINT) was developed to assess the relative allergic potential of detergent enzymes, however, the experimental endpoints were limited to evaluation of antibody levels. The present study was designed to evaluate additional endpoints (serum and allergic antibody levels, pulmonary inflammation and airway hyperresponsiveness (AHR)) to determine their value in improving the predictive accuracy of the MINT. BDF1 mice were intranasally instilled on days 1, 3, 10, 17 and 24 with subtilisin, ovalbumin, betalactoglobulin, mouse serum albumin or keyhole limpet hemocyanin; challenged with aerosolized methacholine or the sensitizing protein on day 29 to assess AHR, and sacrificed on day 29 or 30. Under the conditions of this study, evaluation of AHR did not improve the predictive power of this experimental model. Allergic antibody responses and IgG isotype characterization proved to be the most sensitive and reliable indicators of the protein allergenic potential with BAL responses providing additional insight. These data highlight that the evaluation of the respiratory sensitization potential of proteins can be best informed when multiple parameters are evaluated and that further improvements and refinements of the assay are necessary.

Studies of styrene, styrene oxide and 4-hydroxystyrene toxicity in CYP2F2 knockout and CYP2F1 humanized mice support lack of human relevance for mouse lung tumors.

Styrene (S) is lung tumorigenic in mice but not in rats. S and its alkene-oxidized metabolite styrene oxide (SO) were not lung toxic in CYP2F2(-/-) [knockout] mice, indicating S-induced mouse lung tumors are mediated through mouse-specific CYP2F2-generated ring-oxidized metabolite(s) in lung bronchioles. The human relevance of the CYP2F MOA was assessed by insertion of a human CYP2F1, 2A13, 2B6 transgene into CYP2F2(-/-) mice; CYP2F1 expression and activity were confirmed in the transgenic (TG) mice. No evidence of cytotoxicity or increased cell proliferation (BrdU labeling) was seen in TG mice treated with either S or SO (200mg/kg/day ip for 5days). In contrast to S and SO, 4HS (105mg/kg/day ip for 5days) increased BrdU labeling 5-10-fold in WT mice, <3-fold increase in KO mice and 2-4-fold in TG mice. The limited response of 4HS in KO and TG mice may result from intrinsic toxicity or from further metabolism; regardless of the MOA, these findings indicate that the CYP2F-mediated tumorigenic MOA in WT mice is not operative for S, SO, or for 4HS putatively derived from metabolism of S by CYP2F1 in humans, and thus S-induced mouse lung tumors are unlikely to be relevant to human risk.

Adiposity has differing associations with incident coronary heart disease and mortality in the Scottish population: cross-sectional surveys with follow-up.

OBJECTIVE: Investigation of the association of excess adiposity with three different outcomes: all-cause mortality, coronary heart disease (CHD) mortality and incident CHD. DESIGN: Cross-sectional surveys linked to hospital admissions and death records. SUBJECTS: 19 329 adults (aged 18-86 years) from a representative sample of the Scottish population. MEASUREMENTS: Gender-stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause mortality, CHD mortality and incident CHD. Separate models incorporating the anthropometric measurements body mass index (BMI), waist circumference (WC) or waist-hip ratio (WHR) were created adjusted for age, year of survey, smoking status and alcohol consumption. RESULTS: For both genders, BMI-defined obesity (30 kg m(-2)) was not associated with either an increased risk of all-cause mortality or CHD mortality. However, there was an increased risk of incident CHD among the obese men (hazard ratio (HR)=1.78; 95% confidence interval=1.37-2.31) and obese women (HR=1.93; 95% confidence interval=1.44-2.59). There was a similar pattern for WC with regard to the three outcomes; for incident CHD, the HR=1.70 (1.35-2.14) for men and 1.71 (1.28-2.29) for women in the highest WC category (men 102 cm, women 88 cm), synonymous with abdominal obesity. For men, the highest category of WHR (1.0) was associated with an increased risk of all-cause mortality (1.29; 1.04-1.60) and incident CHD (1.55; 1.19-2.01). Among women with a high WHR (0.85) there was an increased risk of all outcomes: all-cause mortality (1.56; 1.26-1.94), CHD mortality (2.49; 1.36-4.56) and incident CHD (1.76; 1.31-2.38). CONCLUSIONS: In this study excess adiposity was associated with an increased risk of incident CHD but not necessarily death. One possibility is that modern medical intervention has contributed to improved survival of first CHD events. The future health burden of increased obesity levels may manifest as an increase in the prevalence of individuals living with CHD and its consequences.

CYP2F2-generated metabolites, not styrene oxide, are a key event mediating the mode of action of styrene-induced mouse lung tumors.

Styrene induces lung tumors in mice but not in rats. Although metabolism of styrene to 7,8-styrene oxide (SO) by CYP2E1 has been suggested as a mediator of styrene toxicity, lung toxicity is not attenuated in CYP2E1 knockout mice. However, styrene and/or SO metabolism by mouse lung Clara cell-localized CYP2F2 to ring-oxidized cytotoxic metabolite(s) has been postulated as a key metabolic gateway responsible for both lung toxicity and possible tumorigenicity. To test this hypothesis, the lung toxicity of styrene and SO was evaluated in C57BL/6 (WT) and CYP2F2⁻/⁻ knockout mice treated with styrene (400 mg/kg/day, gavage, or 200 or 400 mg/kg/day, ip) or S- or R-SO (200 mg/kg/day, ip) for 5 days. Styrene treated WT mice displayed significant necrosis and exfoliation of Clara cells, and cumulative BrdU-labeling index of S-phase cells was markedly increased in terminal bronchioles of WT mice exposed to styrene or S- or RSO. In contrast, Clara and terminal bronchiole cell toxicity was not observed in CYP2F2⁻/⁻ mice exposed to either styrene or SO. This study clearly demonstrates that the mouse lung toxicity of both styrene and SO is critically dependent on metabolism by CYP2F2. Importantly, the human isoform of CYP2F, CYP2F1, is expressed at much lower levels and likely does not catalyze significant styrene metabolism, supporting the hypothesis that styrene-induced mouse lung tumors may not quantitatively, or possibly qualitatively, predict lung tumor potential in humans.

Perceived time is spatial frequency dependent.

We investigated whether changes in low-level image characteristics, in this case spatial frequency, were capable of generating a well-known expansion in the perceived duration of an infrequent "oddball" stimulus relative to a repeatedly-presented "standard" stimulus. Our standard and oddball stimuli were Gabor patches that differed from each other in spatial frequency by two octaves. All stimuli were equated for visibility. Rather than the expected "subjective time expansion" found in previous studies, we obtained an equal and opposite expansion or contraction of perceived time dependent upon the spatial frequency relationship of the standard and oddball stimulus. Subsequent experiments using equi-visible stimuli reveal that mid-range spatial frequencies (ca. 2 c/deg) are consistently perceived as having longer durations than low (0.5 c/deg) or high (8 c/deg) spatial frequencies, despite having the same physical duration. Rather than forming a fixed proportion of baseline duration, this bias is constant in additive terms and implicates systematic variations in visual persistence across spatial frequency. Our results have implications for the widely cited finding that auditory stimuli are judged to be longer in duration than visual stimuli.

The relationship between body size and mortality in the linked Scottish Health Surveys: cross-sectional surveys with follow-up.

OBJECTIVE: To investigate the relationship between body mass index (BMI), waist circumference (WC) or waist-hip ratio (WHR) and all-cause mortality or cause-specific mortality. DESIGN: Cross-sectional surveys linked to hospital admissions and death records. SUBJECTS: In total, 20,117 adults (aged 18-86 years) from a nationally representative sample of the Scottish population. MEASUREMENTS: Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause, or cause-specific, mortality. The three anthropometric measurements BMI, WC and WHR were the main variables of interest. The following were adjustment variables: age, gender, smoking status, alcohol consumption, survey year, social class and area of deprivation. RESULTS: BMI-defined obesity (≥ 30 kg m(-2)) was not associated with increased risk of mortality (HR = 0.93; 95% confidence interval = 0.80-1.08), whereas the overweight category (25-<30 kg m(-2)) was associated with a decreased risk (0.80; 0.70-0.91). In contrast, the HR for a high WC (men ≥ 102 cm, women ≥ 88 cm) was 1.17 (1.02-1.34) and a high WHR (men ≥ 1, women ≥ 0.85) was 1.34 (1.16-1.55). There was an increased risk of cardiovascular disease (CVD) mortality associated with BMI-defined obesity, a high WC and a high WHR categories; the HR estimates for these were 1.36 (1.05-1.77), 1.41 (1.11-1.79) and 1.44 (1.12-1.85), respectively. A low BMI (<18.5 kg m(-2)) was associated with elevated HR for all-cause mortality (2.66; 1.97-3.60), for chronic respiratory disease mortality (3.17; 1.39-7.21) and for acute respiratory disease mortality (11.68; 5.01-27.21). This pattern was repeated for WC but not for WHR. CONCLUSIONS: It might be prudent not to use BMI as the sole measure to summarize body size. The alternatives WC and WHR may more clearly define the health risks associated with excess body fat accumulation. The lack of association between elevated BMI and mortality may reflect the secular decline in CVD mortality.

Influenza Transmission in Preschools: Modulation by contact landscapes and interventions.

Epidemiologic data suggest that schools and daycare facilities likely play a major role in the dissemination of influenza. Pathogen transmission within such small, inhomogenously mixed populations is difficult to model using traditional approaches. We developed simulation based mathematical tool to investigate the effects of social contact networks on pathogen dissemination in a setting analogous to a daycare center or grade school. Here we show that interventions that decrease mixing within child care facilities, including limiting the size of social clusters, reducing the contact frequency between social clusters, and eliminating large gatherings, could diminish pathogen dissemination. Moreover, these measures may amplify the effectiveness of vaccination or antiviral prophylaxis, even if the vaccine is not uniformly effective or antiviral compliance is incomplete. Similar considerations should apply to other small, imperfectly mixed populations, such as offices and schools.

Acute toxicologic and neurotoxic effects of inhaled 1,2-dichloroethane in adult Fischer 344 rats.

Acute toxicologic and neurotoxic effects were evaluated in Fischer 344 rats exposed to 0, 50, 200, 600, or 2000 ppm 1,2-dichloroethane (ethylene dichloride; EDC) for 4 h or 0, 50, 100 or 150 ppm for 8 h. Neurobehavioral and neuropathologic effects were assessed using a functional observational battery (FOB; baseline, days 1, 8, and 15), and by light microscopy, respectively. Acute toxicologic effects were assessed by bronchoalveolar lavage (BAL) and histopathology of the respiratory tract and selected target organs. Neurobehavioral effects consistent with central nervous system (CNS) depression were present at concentrations >200 ppm and were restricted to day 1. There were no neuropathologic changes in the CNS, however, olfactory epithelial regeneration 15 days after exposure to > or = 200 ppm was observed. The no-observed-effect concentration (NOEC) for behavioral neurotoxicity was 200 ppm EDC for 4 h. There were no effects on BAL parameters in any exposure group. Exposure to 2000 ppm EDC altered adrenal gland, kidney, and liver weights, and resulted in morphologic alterations in the kidney and liver. Degeneration/necrosis of the olfactory epithelium was observed at > or = 200 ppm for 4 h and > or = 100 ppm for 8 h. Based on olfactory epithelial degeneration/necrosis, the most sensitive indicator of toxicity in this study, the overall NOEC was 50 ppm EDC for up to 8 h in rats.

The Language of Caring: Quantitating Medical Practice Patterns using Symbolic Dynamics.

Real-world medical decisions rarely involve binary sole condition present or absent-patterns of patient pathophysiology. Similarly, provider interventions are rarely unitary in nature: the clinician often undertakes multiple interventions simultaneously. Conventional approaches towards complex physiologic derangements and their associated management focus on the frequencies of joint appearances, treating the individual derangements of physiology or elements of intervention as conceptually isolated. This framework is ill suited to capture either the integrated patterns of derangement displayed by a particular patient or the integrated patterns of provider intervention. Here we illustrate the application of a different approach-that of symbolic dynamics-in which the integrated pattern of each patients derangement, and the associated provider response, are captured by defining words based on the elements of the pattern of failure. We will use as an example provider practices in the context of mechanical ventilation- a common, potentially harmful, and complex life support technology. We also delineate other domains in which symbolic dynamics approaches might aid in quantitating practice patterns, assessing quality of care, and identifying best practices.

Development of a risk-ranking framework to evaluate potential high-threat microorganisms, toxins, and chemicals in food.

Through a cooperative agreement with the U.S. Food and Drug Administration, the Institute of Food Technologists developed a risk-ranking framework prototype to enable comparison of microbiological and chemical hazards in foods and to assist policy makers, risk managers, risk analysts, and others in determining the relative public health impact of specific hazard-food combinations. The prototype is a bottom-up system based on assumptions that incorporate expert opinion/insight with a number of exposure and hazard-related risk criteria variables, which are propagated forward with food intake data to produce risk-ranking determinations. The prototype produces a semi-quantitative comparative assessment of food safety hazards and the impacts of hazard control measures. For a specific hazard-food combination the prototype can produce a single metric: a final risk value expressed as annual pseudo-disability adjusted life years (pDALY). The pDALY is a harmonization of the very different dose-response relationships observed for chemicals and microbes. The prototype was developed on 2 platforms, a web-based user interface and an Analytica(R) model (Lumina Decision Systems, Los Gatos, Calif., U.S.A.). Comprising visual basic language, the web-based platform facilitates data input and allows use concurrently from multiple locations. The Analytica model facilitates visualization of the logic flow, interrelationship of input and output variables, and calculations/algorithms comprising the prototype. A variety of sortable risk-ranking reports and summary information can be generated for hazard-food pairs, showing hazard and dose-response assumptions and data, per capita consumption by population group, and annual p-DALY.

Acute kidney injury and lung dysfunction: a paradigm for remote organ effects of kidney disease?

An increasing body of evidence suggests that the deleterious effects of Acute Kidney Injury (AKI) on remote organ function could, at least in part, be due to loss of the normal balance of immune, inflammatory, and soluble mediator metabolism that attends injury of the tubular epithelium. Such dysregulation, acting at least in part on endothelium, leads to compromise of remote organ function. Kidney-lung interaction in the setting of AKI therefore constitutes not only a pressing clinical problem, but also an illuminating framework in which to consider possible mechanisms by which renal diseases exert such deleterious effects on patient outcomes, even when dialysis is provided.

Rechargeable antimicrobial surface modification of polyethylene.

Polyethylene films were surface modified, to incorporate amine and amide functionalities, and subsequently were evaluated for their ability to recharge the antimicrobial N-halamine structures after contact with sodium hypochlorite, a common food-approved sanitizer. Surfaces were tested for chlorine retention and release, as well as antimicrobial activity against microorganisms relevant to food quality and food safety, including Escherichia coli K-12, Pseudomonas fluorescens, Bacillus cereus, and Listeria monocytogenes. N-Halamine functionalized polyethylene exhibited chlorine rechargeability, maintaining 5 to 7 nmol/cm2 N-halamine structures for six successive charges. The N-halamine functionalized films achieved a 4-log reduction for all organisms tested and maintained a greater than 3-log reduction for four successive uses, suggesting that the modified polyethylene films are capable of providing rechargeable antimicrobial activity. The modified films exhibited antimicrobial activity in aqueous suspensions (P < 0.05) and reduced microbial growth in diluted broth (P < 0.05), suggesting the potential for biocidal action even in the presence of organic matter. Such a rechargeable antimicrobial surface could supplement existing cleaning and sanitation programs in food processing environments to reduce the adhesion, growth, and subsequent cross-contamination of food pathogens, as well as food spoilage organisms.

Release of 1-methylcyclopropene from heat-pressed polymer films.

Gaseous 1-methylcyclopropene (1-MCP) is an inhibitor of ethylene perception that is being used extensively for apples and ornamental products, and under intensive investigation for its potential benefits for other fruits and vegetables. 1-MCP is currently used in closed environments that maintain stable concentrations for several hours in order to be effective. However, food packaging materials that release 1-MCP at a predictable rate into the package headspace might be useful for application in inhibiting the deleterious effects of ethylene in the postharvest packaging and storage of some horticultural products. A 1-MCP/alpha-cyclodextrin (1-MCP-cd) complex was incorporated into several common packaging films by heat-pressing (dry-blend, lamination) and solution-casting methods. The release of 1-MCP from the films was quantified by gas chromatography with respect to time, loading of 1-MCP, temperature, relative humidity (RH), type of film, and film-forming method. Release of 1-MCP was rapid and high in films held at RH >/= 75%. The rate of release was slow during the 1st 12 h and then increased during the next 24 to 36 h. Higher temperatures resulted in higher and faster release. A loading of 8 mg of 1-MCP-cd per 140 mg of polymer was found to be optimal. Pressing 1-MCP-cd containing films above 100 degrees C reduced the amount of 1-MCP remaining in the film. Incorporation into LDPE resulted in a higher and faster release than from PS, PVC, and PP polymers. 1-MCP release from a film matrix appears to be within the acceptable range for produce packaging applications.

Covalent attachment of lactase to low-density polyethylene films.

Polymer films to which bioactive compounds such as enzymes are covalently attached offer potential for in-package processing of food. Beta-galactosidase (lactase) was covalently attached to surface-functionalized low-density polyethylene films. A two-step wet chemical functionalization introduced 15.7 nmol/cm2 primary amines to the film surface. Contact angle, dye assays, X-ray photoelectron spectroscopy, and appropriate protein assays were used to characterize changes in film surface chemistry after each step in the process of attachment. Glutaraldehyde was used to covalently attach lactase to the surface at a density of 6.0 microg protein per cm2 via reductive amination. The bond between the covalently attached lactase and the functionalized polyethylene withstood heat treatment in the presence of an ionic denaturant with 74% enzyme retention, suggesting that migration of the enzyme into the food product would be unlikely. The resulting polyethylene had an enzyme activity of 0.020 lactase units (LU)/cm2 (approximately 4500 LU/g). These data suggest that enzymes that may have applications in foods can be covalently attached to inert polymer surfaces, retain significant activity, and thus have potential as a nonmigratory active packaging materials.

A survey of horse owners in Great Britain regarding horses in their care. Part 1: Horse demographic characteristics and management.

REASONS FOR PERFORMING STUDY: Information is scarce as to how horses are kept and managed in the general horse population of Great Britain. OBJECTIVES: To characterise the demographics of horses in Great Britain and assess their care (with particular reference to the respiratory system). METHODS: Horse owners were surveyed using a self-administered postal questionnaire. These owners were selected randomly, following geographical stratification, using 2-stage cluster sampling of veterinary practices and their clients. RESULTS: The overall response proportion to the survey was 68.2%. An investigation of nonresponse bias detected minimal differences between responders and nonresponders. A summary of the demographic characteristics, feeding and management of horses in a sample of the general population of Great Britain is presented. CONCLUSIONS AND POTENTIAL RELEVANCE: Horses are kept under a great variety of conditions with some potentially exposed to high concentrations of organic dusts associated with stabling. This information is relevant to their health and welfare.

A survey of horse owners in Great Britain regarding horses in their care. Part 2: Risk factors for recurrent airway obstruction.

REASONS FOR PERFORMING STUDY: Recurrent airway obstruction (RAO) is a commonly encountered respiratory condition of horses. Despite this, the epidemiology of this predominately manageable and reversible disease in Great Britain has been largely ignored. OBJECTIVES: To estimate the prevalence of RAO in the general horse population of Great Britain and to investigate possible risk factors for RAO associated with management or early life. METHODS: Horse owners were surveyed using a self-administered postal questionnaire that contained a risk-screening questionnaire (RSQ) designed to identify horses with RAO. These owners were randomly selected, following geographical stratification, using 2-stage cluster sampling of veterinary practices and their clients. Multilevel, multivariable logistic regression models were used to investigate risk factors for RAO in the selected horse population. RESULTS: The estimated true prevalence of RAO in the selected horse population was 14.0% (95%CI 10.7-17.4%). Risk factors for RAO identified in a general horse management logistic regression model included increasing age and exposure to an urbanised environment. Recurrent airway obstruction has long been associated with mature horses while the association with an urbanised environment could be related to different management practices in these areas or possibly air pollution could be involved. The second model associated exposure to hay and respiratory infection in early life with a horse having RAO in later life. Challenges to the respiratory system in early life may be involved in the development of this disease. CONCLUSIONS AND POTENTIAL RELEVANCE: Recurrent airway obstruction is a significant health problem in the horse population of Great Britain. This form of epidemiological investigation highlights potential risk factors for the disease.

Continuous flow nonthermal CO2 processing: the lethal effects of subcritical and supercritical CO2 on total microbial populations and bacterial spores in raw milk.

The effect of pressurized (<50 MPa) CO2 as a nonthermal process for bacterial reduction in raw skim milk was examined using a unique pressurized continuous flow system. The lethal effects of subcritical and super-critical CO2 applied at different temperatures and pressures toward total native psychrotrophic microbial populations, total inoculated Pseudomonas fluorescens, and total inoculated spore populations were studied and compared. Pressures between 10.3 and 48.3 MPa; temperatures of 15, 30, 35, and 40 degrees C; and CO2 concentrations of 0, 3, 66, and 132 g/kg of milk were studied. For both native populations and inoculated P. fluorescens, greater total microbial lethality was observed under supercritical CO2 conditions than under subcritical CO2 conditions. At 30 degrees C, there was no effect on total microbial lethality of increasing pressure up to 20.7 MPa with either 66 or 132 g/kg of CO2; at 35 degrees C, there was a positive relationship between pressure and lethality at CO2 levels of 132 g/kg, but no relationship at 66 g/kg of CO2. For total microbial populations and P. fluorescens, CO2 applied at 132 g/kg at 30 degrees C and pressures of 10.3 to 20.7 MPa resulted in an average standard plate count reduction of 3.81 and 2.93 log, respectively; at 35 degrees C and 20.7 MPa, maximum reductions achieved were 5.36 and 5.02 log, respectively. For both total microbial populations and inoculated P. fluorescens, CO2 exhibited a greater overall lethal effect at 132 g/kg than at 66 g/kg and a greater effect at 35 degrees C than at 30 degrees C. At 24.1 and 48.3 MPa and 40 degrees C, microbial lethality in raw aged milk treated with 3 g/kg of CO2 was not significantly different than that observed for uncarbonated milk; lethality achieved in milk treated with 132 g/kg of CO2 was significantly higher than that achieved in these 2 low-level CO2 treatments. No treatment studied had any significant impact on spore populations. Our work shows that, using the studied system, pressurized CO2 results in greater microbial lethality in milk above critical temperatures than below and suggests that a critical concentration threshold level of CO2 is required for lethal effects. Our work also suggests that supercritical CO2 processing in a continuous flow system can achieve reductions in some microbial populations equal to or better than that typically achieved during high-temperature, short-time pasteurization.

Optimal phasic tracheal gas insufflation timing: an experimental and mathematical analysis.

OBJECTIVE: To investigate the modulation of CO2 clearance by changes in the duration of tracheal gas flow application during tracheal gas insufflation (TGI). DESIGN: Combination of bench studies using a commercial test lung and a commercially available intensive care ventilator and mathematical analysis using a clearance model derived from first principles. SETTING: University pulmonary research laboratory. PATIENTS: None. INTERVENTIONS: Experiments using TGI were performed on a test lung at two combinations of tidal volume and frequency. TGI was limited to part of the expiratory phase (the terminal 10-100% of expiration), and two different TGI catheter flow rates were studied. Permutations over a range of compliances, dead-space volumes, catheter flows, and TGI durations were collected. A mathematical model incorporating key ventilatory and TGI-related variables was developed to provide a first-principles theoretical foundation for interpreting the experimental results. MEASUREMENTS AND MAIN RESULTS: In the physical model, alveolar Pco2 attained a minimum value with TGI flow applied during the terminal 40-60% of the expiratory phase, a finding that was consistent over an almost eight-fold range of expiratory time constants. The mathematical model shows the same qualitative pattern as the experimental model, indicating that the observed behaviors are not an experimental artifact. CONCLUSION: The optimal duration of expiratory TGI flow application is stable over a wide range of impedance characteristics. Such stability suggests that near maximal effect of expiratory TGI could be obtained by applying TGI flow solely within the final 50% of the expiratory phase. Such uniform restriction of the application profile might both simplify technique implementation and decrease adverse consequences.