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.

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.

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.

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.

Mathematical models for pressure controlled ventilation of oleic acid-injured pigs.

One-compartment, mathematical models for pressure controlled ventilation, incorporating volume dependent compliances, linear and nonlinear resistances, are constructed and compared with data obtained from healthy and (oleic acid) lung-injured pigs. Experimental data are used to find parameters in the mathematical models and were collected in two forms. Firstly, the P(e)-V curves for healthy and lung injured pigs were constructed; these data are used to compute compliance functions for each animal. Secondly, dynamic data from pressure controlled ventilation for a variety of applied pressures are used to estimate resistance parameters in the models. The models were then compared against the collected dynamic data. The best mathematical models are ones with compliance functions of the form C(V) = a + bV where a and b are constants obtained from the P(e)-V curves and the resistive pressures during inspiration change from a linear relation P(r) = RQ to a nonlinear relation P(r) = RQ(epsilon) where Q is the flow into the one-compartment lung and epsilon is a positive number. The form of the resistance terms in the mathematical models indicate the possible presence of gas-liquid foams in the experimental data.

Protective effects of hypercapnic acidosis on ventilator-induced lung injury.

To investigate whether respiratory acidosis modulates ventilator-induced lung injury (VILI), we perfused (constant flow) 21 isolated sets of normal rabbit lungs, ventilated them for 20 min (pressure controlled ventilation [PCV] = 15 cm H(2)O) (Baseline) with an inspired CO(2) fraction adjusted for the partial pressure of CO(2) in the perfusate (PCO(2) approximately equal to 40 mm Hg), and then randomized them into three groups. Group A (control: n = 7) was ventilated with PCV = 15 cm H(2)O for three consecutive 20-min periods (T1, T2, T3). In Group B (high PCV/normocapnia; n = 7), PCV was given at 20 (T1), 25 (T2), and 30 (T3) cm H(2)O. The targeted PCO(2) was 40 mm Hg in Groups A and B. Group C (high PCV/hypercapnia; n = 7) was ventilated in the same way as Group B, but the targeted PCO(2) was approximately equal to 70 to 100 mm Hg. The changes (from Baseline to T3) in weight gain (Delta WG: g) and in the ultrafiltration coefficient (Delta K(f) = gr/min/ cm H(2)O/100g) and the protein and hemoglobin concentrations in bronchoalveolar lavage fluid (BALF) were used to assess injury. Group B experienced a significantly greater Delta WG (14.85 +/- 5.49 [mean +/- SEM] g) and Delta K(f) (1.40 +/- 0.49 g/min/cm H(2)O/100 g) than did either Group A (Delta WG = 0.70 +/- 0.43; Delta K(f) = 0.01 +/- 0.03) or Group C (Delta WG = 5.27 +/- 2.03 g; Delta K(f) = 0.25 +/- 0.12 g/min/cm H(2)O/ 100 g). BALF protein and hemoglobin concentrations (g/L) were higher in Group B (11.98 +/- 3.78 g/L and 1.82 +/- 0.40 g/L, respectively) than in Group A (2.92 +/- 0.75 g/L and 0.38 +/- 0.15 g/L) or Group C (5.71 +/- 1.88 g/L and 1.19 +/- 0.32 g/L). We conclude that respiratory acidosis decreases the severity of VILI in this model.

Relative roles of vascular and airspace pressures in ventilator-induced lung injury.

OBJECTIVE: To determine whether elevations in pulmonary vascular pressure induced by mechanical ventilation are more injurious than elevations of pulmonary vascular pressure of similar magnitude occurring in the absence of mechanical ventilation. DESIGN: Prospective comparative laboratory investigation. SETTING: University research laboratory. SUBJECTS: Male New Zealand white rabbits. INTERVENTIONS: Three groups of isolated, perfused rabbit lungs were exposed to cyclic elevation of pulmonary artery pressures arising from either intermittent positive pressure mechanical ventilation or from pulsatile perfusion of lungs held motionless by continuous positive airway pressure. Peak, mean, and nadir pulmonary artery pressures and mean airway pressure were matched between groups (35, 27.4 +/- 0.74, and 20.8 +/- 1.5 mm Hg, and 17.7 +/- 0.22 cm H2O, respectively). MEASUREMENTS AND MAIN RESULTS: Lungs exposed to elevated pulmonary artery pressures attributable to intermittent positive pressure mechanical ventilation formed more edema (6.8 +/- 1.3 vs. 1.1 +/- 0.9 g/g of lung), displayed more perivascular (61 +/- 26 vs. 15 +/- 13 vessels) and alveolar hemorrhage (76 +/- 11% vs. 26 +/- 18% of alveoli), and underwent larger fractional declines in static compliance (88 +/- 4.4% vs. 48 +/- 25.1% decline) than lungs exposed to similar peak and mean pulmonary artery pressures in the absence of tidal positive pressure ventilation. CONCLUSIONS: Isolated phasic elevations of pulmonary artery pressure may cause less damage than those occurring during intermittent positive pressure mechanical ventilation, suggesting that cyclic changes in perivascular pressure surrounding extra-alveolar vessels may be important in the genesis of ventilator-induced lung injury.

Dynamic behavior during noninvasive ventilation: chaotic support?

Acute noninvasive ventilation is generally applied via face mask, with modified pressure support used as the initial mode to assist ventilation. Although an adequate seal can usually be obtained, leaks frequently develop between the mask and the patient's face. This leakage presents a theoretical problem, since the inspiratory phase of pressure support terminates when flow falls to a predetermined fraction of peak inspiratory flow. To explore the issue of mask leakage and machine performance, we used a mathematical model to investigate the dynamic behavior of pressure-supported noninvasive ventilation, and confirmed the predicted behavior through use of a test lung. Our mathematical and laboratory analyses indicate that even when subject effort is unvarying, pressure-support ventilation applied in the presence of an inspiratory leak proximal to the airway opening can be accompanied by marked variations in duration of the inspiratory phase and in autoPEEP. The unstable behavior was observed in the simplest plausible mathematical models, and occurred at impedance values and ventilator settings that are clinically realistic.

Effects of decreased respiratory frequency on ventilator-induced lung injury.

To determine if decreased respiratory frequency (ventilatory rate) improves indices of lung damage, 17 sets of isolated, perfused rabbit lungs were ventilated with a peak static airway pressure of 30 cm H(2)O. All lungs were randomized to one of three frequency/peak pulmonary artery pressure combinations: F20P35 (n = 6): ventilatory frequency, 20 breaths/min, and peak pulmonary artery pressure, 35 mm Hg; F3P35 (n = 6), ventilatory frequency, 3 breaths/min, and peak pulmonary artery pressure of 35 mm Hg; or F20P20 (n = 5), ventilatory frequency, 20 breaths/min, and peak pulmonary artery pressure, 20 mm Hg. Mean airway pressure and tidal volume were matched between groups. Mean pulmonary artery pressure and vascular flow were matched between groups F20P35 and F3P35. The F20P35 group showed at least a 4.5-fold greater mean weight gain and a 3-fold greater mean incidence of perivascular hemorrhage than did the comparison groups, all p

Effects of mean airway pressure and tidal excursion on lung injury induced by mechanical ventilation in an isolated perfused rabbit lung model.

OBJECTIVE: To study the relative contributions of mean airway pressure (mPaw) and tidal excursion (V(T)) to ventilator-induced lung injury under constant perfusion conditions. DESIGN: Prospective, randomized study. SETTING: Experimental animal laboratory. SUBJECTS: Fifteen sets of isolated rabbit lungs. INTERVENTIONS: Rabbit lungs were perfused (constant flow, 500 mL/min; capillary pressure, 10 mm Hg) and randomized to be ventilated at identical peak transpulmonary pressure (pressure control ventilation [30 cm H2O and frequency of 20/min]) with three different ventilatory patterns that differed from each other by either mPaw or V(T): group A (low mPaw [13.4+/-0.2 cm H2O]/large V(T) [55+/-8 mL], n = 5); group B (high mPaw [21.2+/-0.2 cm H2O]/small V(T) [18+/-1 mL], n = 5); and group C (high mPaw [21.8+/-0.5 cm H2O]/large V(T) [53+/-5 mL], n = 5). MEASUREMENTS AND MAIN RESULTS: Continuous weight gain (edema formation), change in ultrafiltration coefficient (deltaKf, vascular permeability index), and histology (lung hemorrhage) were examined. In group A, deltaKf (0.08+/-0.08 g/min/cm H2O/100 g) was less than in group B (0.28+/-0.19 g/min/cm H2O/100 g) or group C (0.41+/-0.29 g/min/cm H2O/100 g) (p = .05). Group A experienced significantly less hemorrhage (histologic score, 5.4+/-2.2) than groups B (10.3+/-2.1) and C (11.1+/-3.0) (p < .05). A similar trend was observed for weight gain. In contrast to tidal excursion, mPaw was found to be a significant factor for lung hemorrhage and increased Kf (two-way analysis of variance; p < .05). Weight gain (r2 = .54, p = .04) and lung hemorrhage (r2 = .65, p = .01) correlated with the mean pulmonary artery pressure changes that resulted from the implementation of the ventilatory strategies. The difference between the changes in mPaw and mean pulmonary artery pressure linearly predicted deltaKf (p = .005 and .05, respectively, r2 = 0.73). CONCLUSIONS: Under these experimental conditions, mPaw contributes more than tidal excursion to lung hemorrhage and permeability alterations induced by mechanical ventilation.

Noninvasive ventilation: an emerging supportive technique for the emergency department.

Noninvasive ventilation (NIV) is the provision of ventilatory support to a spontaneously breathing patient without endotracheal intubation. In this review, we detail concerns related to endotracheal intubation and summarize the physiologic effects and clinical application of NIV. We then address the use of NIV in 5 conditions of particular interest to the practitioner of emergency medicine: exacerbated chronic obstructive lung disease, severe asthma, patients who are not candidates for endotracheal intubation, pneumonia, and pulmonary edema.

Consequences of vascular flow on lung injury induced by mechanical ventilation.

To investigate whether the magnitude of blood flow contributes to ventilator-induced lung injury, 14 sets of isolated rabbit lungs were randomized for perfusion at either 300 (Group A: n = 7) or 900 ml/ min (Group B: n = 7) while ventilated with 30 cm H2O peak static pressure. Control lungs (Group C: n = 7) were ventilated with lower peak static pressure (15 cm H2O) and perfused at 500 ml/min. Weight gain, changes in the ultrafiltration coefficient (DeltaKf) and lung static compliance (CL), and extent of hemorrhage (scored by histology) were compared. Group B had a larger decrease in CL (-13 +/- 11%) than Groups A (2 +/- 6%) and C (5 +/- 5%) (p < 0.05). Group B had more hemorrhage and gained more weight (16.2 +/- 9.5 g) than Groups A (8.7 +/- 3.4 g) and C (1.6 +/- 1.0 g) (p < 0.05 for each pairwise comparison between groups). Finally, Kf (g . min-1 . cm H2O-1 . 100 g-1) increased the most in Group B (DeltaKf = 0.26 +/- 0. 20 versus 0.17 +/- 0.10 in Group A and 0.05 +/- 0.04 in Group C; p < 0.05 for B versus C). We conclude that the intensity of lung perfusion contributes to ventilator- induced lung injury in this model.

Patient-ventilator interaction: a general model for nonpassive mechanical ventilation.

A general mathematical model for the dynamic behaviour of a single-compartment respiratory system in response to an arbitrary applied inspiratory airway pressure and arbitrary respiratory muscle activity is investigated. The model is used to compute explicit expressions for ventilation and pressure variables of clinical interest for clinician-selected and impedance-determined inputs. The outcome variables include tidal volume, end-expiratory pressure, minute ventilation, mean alveolar pressure, average pleural pressure, as well as the work performed by the ventilator and the respiratory muscles. It is also demonstrated that under suitable conditions, there is a flow reversal that can occur during inspiration.

Theoretical interactions between ventilator settings and proximal deadspace ventilation during tracheal gas insufflation.

OBJECTIVE: To investigate the theoretical interactions between ventilator settings, tracheal gas insufflation (TGI), and alveolar ventilation. DESIGN: We derived differential equations governing compartmental volume changes in a one-compartment model of TGI-assisted ventilation and equations governing gas dilution in the airway proximal to the TGI catheter and the additional CO2 clearing ventilation arising from this dilution. This additional ventilation was called proximal ventilation. Validation was conducted in a mechanical lung analog. Model predictions for proximal ventilation were then generated over wide ranges of frequency, duty cycle, and tidal volume. RESULTS: Significant interactions were identified between ventilator settings and proximal ventilation. The persistence of end-expiratory flow from the lung decreased proximal dilution by fresh gas and thereby reduced TGI-aided proximal ventilation. Changes in end-expiratory lung flow resulting from alterations in ventilator settings were correlated inversely with proximal ventilation. CONCLUSIONS: During TGI with constant catheter flow, ventilator settings that promote end-expiratory flow of gas from the lung diminish proximal ventilation. When frequency increases, the decrease in dilution efficiency of the individual breath is partially offset by the increase in cycle number, an effect which is magnified by any concomitant decrease in inspired tidal volume. Prolongation of the duty cycle tends to decrease proximal ventilation. Increases in expiratory resistance, including those arising from the external ventilator circuit or the endotracheal tube, also impair proximal ventilation.

Implications of a biphasic two-compartment model of constant flow ventilation for the clinical setting.

PURPOSE: To investigate the theoretical effects of changing frequency (f), duty cycle (D), or end-inspiratory pause length on the distribution of ventilation and compartmental pressure in a heterogeneous, two compartment pulmonary model inflated by constant flow. METHODS: Differential equations governing compartmental volume changes were derived and solved. Validation was conducted in a mechanical lung analogue with two mechanically independent compartments. Model predictions were then generated over wide ranges of f, D, or end-inspiratory pause. RESULTS: Disparity of compartmental end-expiratory pressure was identified as the primary mechanism by which changes in f, D, or pause alter the distribution of ventilation. Distribution of peak pressures was less sensitive to such changes. Compartmental ventilation was much less uniform than compartmental peak pressure. Ventilation could not be made entirely uniform by changes of f, D, or pause within the usual clinical range. CONCLUSIONS: In a linear, two compartment model of the respiratory system, disparity of compartmental end-expiratory pressures is the primary mechanism by which changes of f, D, or pause alter the distribution of ventilation during inflation with constant flow. Ventilation is less evenly distributed than peak alveolar pressure, and there are limits to the beneficial effects on the distribution of ventilation to be gained from manipulations of machine settings.

Proliferative and neoplastic lesions in the rodent nasal cavity.

Proliferative lesions in the rodent nasal cavity are reviewed; attempt was made to compare species affected, sex differences, strain differences, route of administration and tumor types occurring both spontaneously and after induction by different chemicals. This review is not meant to be all inclusive but to be representative of observed trends. Our general conclusions in this paper are that: 1) spontaneous nasal tumors in rodents are very rare; 2) spontaneous nasal tumors in rats are most often squamous cell tumors, whereas hemangiomas or respiratory adenomas predominate in mice and squamous cell tumors are rare; 3) rats are usually more susceptible to the induction of epithelial tumors of the nasal cavity than mice; 4) chemically-induced hemangiomas and hemangiosarcomas of the nasal cavity have only been reported in mice; 5) tumors of the olfactory epithelium are almost uniformly malignant and invasive, while nonsquamous tumors of the respiratory epithelium are typically less invasive; 6) chemically-induced tumors of the olfactory region, either mesenchymal or epithelial, do not always require an inhalation route of exposure but may occur by systemic targeting of this region; and 7) chemicals inducing tumors in the olfactory region often produce a variety of tumor morphologies in this location as well as squamous and polypoid tumors of the transitional region. More work will be needed to illucidate the mechanisms of nasal carcinogenesis and to further refine the current tumor classification system.