A simplified 4-parameter model of volumetric capnograms improves calculations of airway dead space and slope of Phase III.

To evaluate a compact and easily interpretable 4-parameter model describing the shape of the volumetric capnogram, and the resulting estimates of anatomical dead space (VDAW) and Phase III (alveolar plateau) slope (SIII). Data from of 8 mildly-endotoxemic pre-acute respiratory distress syndrome sheep were fitted to the proposed 4-parameter model (4p) and a previously established 7-parameter model (7p). Root mean square error (RMSE) and Akaike information criterion (AIC), as well as VDAW and SIII derived from each model were compared. Confidence intervals for model's parameters, VDAW and SIII were estimated with a jackknife approach. RMSE values were similar (4p: 1.13 ± 0.01 mmHg vs 7p: 1.14 ± 0.01 mmHg) in the 791 breath cycles tested. However, the 7p overfitted the curve and had worse AIC in more than 50% of the cycles (p < 0.001). The large number of degrees of freedom also resulted in larger between-animal range of confidence intervals for 7p (VDAW: from 6.1 10-12 to 34 ml, SIII: from 9.53 10-7 to 1.80 mmHg/ml) as compared to 4p (VDAW: from 0.019 to 0.15 ml, SIII: from 3.9 10-4 to 0.011 mmHg/ml). Mean differences between VDAW (2.1 ± 0.04 ml) and SIII (0.047 ± 0.004 mmHg/ml) from 7 and 4p were significant (p < 0.001), but within the observed cycle-by-cycle variability. The proposed 4-parameter model of the volumetric capnogram improves data fitting and estimation of VDAW and SIII as compared to the 7-parameter model of reference. These advantages support the use of the 4-parameter model in future research and clinical applications.

Volume-independent elastance: a useful parameter for open-lung positive end-expiratory pressure adjustment.

BACKGROUND: A decremental positive end-expiratory pressure (PEEP) trial after full lung recruitment allows for the adjustment of the lowest PEEP that prevents end-expiratory collapse (open-lung PEEP). For a tidal volume (Vt) approaching zero, the PEEP of minimum respiratory system elastance (PEEP(minErs)) is theoretically equal to the pressure at the mathematical inflection point (MIP) of the pressure-volume curve, and seems to correspond to the open-lung PEEP in a decremental PEEP trial. Nevertheless, the PEEP(minErs) is dependent on Vt and decreases as Vt increases. To circumvent this dependency, we proposed the use of a second-order model in which the volume-independent elastance (E1) is used to set open-lung PEEP. METHODS: Pressure-volume curves and a recruitment maneuver followed by decremental PEEP trials, with a Vt of 6 and 12 mL/kg, were performed in 24 Wistar rats with acute lung injury induced by intraperitoneally injected (n = 8) or intratracheally instilled (n = 8) Escherichia coli lipopolysaccharide. In 8 control animals, the anterior chest wall was surgically removed after PEEP trials, and the protocol was repeated. Airway pressure (Paw) and flow (F) were continuously acquired and fitted by the linear single-compartment model (Paw = Rrs·F + Ers·V + PEEP, where Rrs is the resistance of the respiratory system, and V is volume) and the volume-dependent elastance model (Paw = Rrs·F + E1 + E2·V·V + PEEP, where E2·V is the volume-dependent elastance). From each model, PEEPs of minimum Ers and E1 (PEEP(minE1)) were identified and compared with each respective MIP. The accuracy of PEEPminE1 and PEEPminErs in estimating MIP was assessed by bias and precision plots. Comparisons among groups were performed with the unpaired t test whereas a paired t test was used between the control group before and after chest wall removal and within groups at different Vts. All P values were then corrected for multiple comparisons by the Bonferroni procedure. RESULTS: In all experimental groups, PEEPminErs, but not PEEPminE1, tended to decrease as Vt increased. The difference between MIP and PEEPminE1 exhibited a lower bias compared with the difference between MIP and PEEPminErs (P < 0.001). The PEEPminE1 was always significantly higher than the PEEPminErs (7.7 vs 3.8, P < 0.001) and better approached MIP (7.7 vs 7.3 cm H2O with P = 0.04 at low Vt, and 7.8 vs 7.1 cm H2O with P < 0.001 at high Vt). CONCLUSIONS: PEEPminE1 better identifies the open-lung PEEP independently of the adjusted Vt, and may be a practical, more individualized approach for PEEP titration.

Detection of tidal recruitment/overdistension in lung-healthy mechanically ventilated patients under general anesthesia.

BACKGROUND: The volume-dependent single compartment model (VDSCM) has been applied for identification of overdistension in mechanically ventilated patients with acute lung injury. In this observational study we evaluated the use of the VDSCM to identify tidal recruitment/overdistension induced by tidal volume (Vt) and positive end-expiratory pressure (PEEP) in lung-healthy anesthetized subjects. METHODS: Fifteen patients (ASA physical status I-II) undergoing general anesthesia for elective plastic breast reconstruction surgery were mechanically ventilated in volume-controlled ventilation (VCV), with Vt of 8 mL•kg(-1) and PEEP of 0 cm H(2)O. With these settings, ventilatory mode was randomly adjusted in VCV or pressure-controlled ventilation (PCV) and PEEP was sequentially increased from 0 to 5 and 10 cm H(2)O, 5 min per step. Thereafter, PEEP was decreased to 0 cm H(2)O, Vt increased to 10 mL•kg(-1) and, keeping minute ventilation constant, PEEP was similarly increased to 5 and 10 cm H(2)O. Airway pressure and flow were continuously recorded and fitted to the VDSCM with or without considering flow-dependencies. A "distension index" (%E(2)) derived from the VDSCM was used to assess Vt and PEEP-induced recruitment/overdistension. Positive and negative values of %E(2) suggest tidal overdistension or tidal recruitment, respectively. In addition, the linear respiratory system elastance was calculated. Comparisons among variables at each PEEP value, Vt setting, ventilatory mode, and regression model considering or not considering flow-dependencies were performed with the Wilcoxon-sign rank test for paired samples (P < 0.05). Multiple comparisons were corrected with the Bonferroni method. The relative change in the estimated noisy variance was used as an index of the goodness of fit of the models. RESULTS: VDSCM including the flow-dependent parameter significantly improved estimated noisy variance in almost all experimental conditions (11.2 to 71.4, smallest of the lower and highest of the upper 95% confidence intervals). No differences in %E(2) were observed between VCV and PCV, at comparable Vt and PEEP levels, when flow-dependencies were included in the regression model. The negligence of the flow-dependent parameter systematically led to an underestimation of %E(2) in PCV compared to VCV mode (all P < 0.02). At a given Vt, %E(2) was negative at a PEEP of 0 cm H(2)O and significantly increased with PEEP, being almost 0 at a PEEP of 5 cm H(2)O. At a given level of PEEP, %E(2) significantly increased with Vt. CONCLUSIONS: The distension index %E(2), derived from the VDSCM considering flow-dependencies, seems able to identify tidal recruitment/overdistension induced by Vt and PEEP independent of flow waveform in healthy lung-anesthetized patients.

Cardiovascular and Gas Exchange Effects of Individualized Positive End-Expiratory Pressures in Cats Anesthetized With Isoflurane.

Objectives: To compare the effects of four levels of end-expiratory pressure [zero (ZEEP) and three levels of positive end-expiratory pressure (PEEP)] on the cardiovascular system and gas exchange of cats anesthetized with isoflurane and mechanically ventilated for 3 h with a tidal volume of 10 ml/kg. Study Design: Prospective, randomized, controlled trial. Animals: Six healthy male neutered purpose-bred cats. Methods: Anesthesia was induced with isoflurane and maintained at 1.3 minimum alveolar concentration. PEEP of maximal respiratory compliance (PEEPmaxCrs) was identified in a decremental PEEP titration, and cats were randomly ventilated for 3 h with one of the following end-expiratory pressures: ZEEP, PEEPmaxCrs minus 2 cmH2O (PEEPmaxCrs-2), PEEPmaxCrs, and PEEPmaxCrs plus 2 cmH2O (PEEPmaxCrs+2). Cardiovascular and gas exchange variables were recorded at 5, 30, 60, 120, and 180 min (T5 to T180, respectively) of ventilation and compared between and within ventilation treatments with mixed-model ANOVA followed by Dunnet's and Tukey's tests (normal distribution) or Friedman test followed by the Dunn's test (non-normal distribution). Significance to reject the null hypothesis was considered p < 0.05. Results: Mean arterial pressure (MAP-mmHg) was lower in PEEPmaxCrs+2 [63 (49-69); median (range)] when compared to ZEEP [71 (67-113)] at T5 and stroke index (ml/beat/kg) was lower in PEEPmaxCrs+2 (0.70 ± 0.20; mean ± SD) than in ZEEP (0.90 ± 0.20) at T60. Cardiac index, oxygen delivery index (DO2I), systemic vascular resistance index, and shunt fraction were not significantly different between treatments. The ratio between arterial partial pressure and inspired concentration of oxygen (PaO2/FIO2) was lower in ZEEP than in the PEEP treatments at various time points. At T180, DO2I was higher when compared to T5 in PEEPmaxCrs. Dopamine was required to maintain MAP higher than 60 mmHg in one cat during PEEPmaxCrs and in three cats during PEEPmaxCrs+2. Conclusion: In cats anesthetized with isoflurane and mechanically ventilated for 3 h, all levels of PEEP mildly improved gas exchange with no significant difference in DO2I when compared to ZEEP. The PEEP levels higher than PEEPmaxCrs-2 caused more cardiovascular depression, and dopamine was an effective treatment. A temporal increase in DO2I was observed in the cats ventilated with PEEPmaxCrs. The effects of these levels of PEEP on respiratory mechanics, ventilation-induced lung injury, as well as in obese and critically ill cats deserve future investigation for a better understanding of the clinical use of PEEP in this species.

Control of positive end-expiratory pressure (PEEP) for small animal ventilators.

BACKGROUND: The positive end-expiratory pressure (PEEP) for the mechanical ventilation of small animals is frequently obtained with water seals or by using ventilators developed for human use. An alternative mechanism is the use of an on-off expiratory valve closing at the moment when the alveolar pressure is equal to the target PEEP. In this paper, a novel PEEP controller (PEEP-new) and the PEEP system of a commercial small-animal ventilator, both based on switching an on-off valve, are evaluated. METHODS: The proposed PEEP controller is a discrete integrator monitoring the error between the target PEEP and the airways opening pressure prior to the onset of an inspiratory cycle. In vitro as well as in vivo experiments with rats were carried out and the PEEP accuracy, settling time and under/overshoot were considered as a measure of performance. RESULTS: The commercial PEEP controller did not pass the tests since it ignores the airways resistive pressure drop, resulting in a PEEP 5 cmH2O greater than the target in most conditions. The PEEP-new presented steady-state errors smaller than 0.5 cmH2O, with settling times below 10 s and under/overshoot smaller than 2 cmH2O. CONCLUSION: The PEEP-new presented acceptable performance, considering accuracy and temporal response. This novel PEEP generator may prove useful in many applications for small animal ventilators.

Ability of dynamic airway pressure curve profile and elastance for positive end-expiratory pressure titration.

OBJECTIVE: To evaluate the ability of three indices derived from the airway pressure curve for titrating positive end-expiratory pressure (PEEP) to minimize mechanical stress while improving lung aeration assessed by computed tomography (CT). DESIGN: Prospective, experimental study. SETTING: University research facilities. SUBJECTS: Twelve pigs. INTERVENTIONS: Animals were anesthetized and mechanically ventilated with tidal volume of 7 ml kg(-1). In non-injured lungs (n = 6), PEEP was set at 16 cmH(2)O and stepwise decreased until zero. Acute lung injury was then induced either with oleic acid (n = 6) or surfactant depletion (n = 6). A recruitment maneuver was performed, the PEEP set at 26 cmH(2)O and decreased stepwise until zero. CT scans were obtained at end-expiratory and end-inspiratory pauses. The elastance of the respiratory system (Ers), the stress index and the percentage of volume-dependent elastance (%E (2)) were estimated. MEASUREMENTS AND MAIN RESULTS: In non-injured and injured lungs, the PEEP at which Ers was lowest (8-4 and 16-12 cmH(2)O, respectively) corresponded to the best compromise between recruitment/hyperinflation. In non-injured lungs, stress index and %E (2) correlated with tidal recruitment and hyperinflation. In injured lungs, stress index and %E (2) suggested overdistension at all PEEP levels, whereas the CT scans evidenced tidal recruitment and hyperinflation simultaneously. CONCLUSION: During ventilation with low tidal volumes, Ers seems to be useful for guiding PEEP titration in non-injured and injured lungs, while stress index and %E (2) are useful in non-injured lungs only. Our results suggest that Ers can be superior to the stress index and %E (2) to guide PEEP titration in focal loss of lung aeration.

Lung production of platelet-activating factor acetylhydrolase in oleic acid-induced acute lung injury.

Platelet-activating factor (PAF) is a proinflammatory mediator that plays a central role in acute lung injury (ALI). PAF- acetylhydrolases (PAF-AHs) terminate PAF's signals and regulate inflammation. In this study, we describe the kinetics of plasma and bronchoalveolar lavage (BAL) PAF-AH in the early phase of ALI. Six pigs with oleic acid induced ALI and two healthy controls were studied. Plasma and BAL samples were collected every 2h and immunohistochemical analysis of PAF-AH was performed in lung tissues. PAF-AH activity in BAL was increased at the end of the experiment (BAL PAF-AH Time 0=0.001+/-0.001 nmol/ml/min/g vs Time 6=0.031+/-0.018 nmol/ml/min/g, p=0.04) while plasma activity was not altered. We observed increased PAF-AH staining of macrophages and epithelial cells in the lungs of animals with ALI but not in healthy controls. Our data suggest that increases in PAF-AH levels are, in part, a result of alveolar production. PAF-AH may represent a modulatory strategy to counteract the excessive pro-inflammatory effects of PAF and PAF-like lipids in lung inflammation.

Positive end-expiratory pressure at minimal respiratory elastance represents the best compromise between mechanical stress and lung aeration in oleic acid induced lung injury.

INTRODUCTION: Protective ventilatory strategies have been applied to prevent ventilator-induced lung injury in patients with acute lung injury (ALI). However, adjustment of positive end-expiratory pressure (PEEP) to avoid alveolar de-recruitment and hyperinflation remains difficult. An alternative is to set the PEEP based on minimizing respiratory system elastance (Ers) by titrating PEEP. In the present study we evaluate the distribution of lung aeration (assessed using computed tomography scanning) and the behaviour of Ers in a porcine model of ALI, during a descending PEEP titration manoeuvre with a protective low tidal volume. METHODS: PEEP titration (from 26 to 0 cmH2O, with a tidal volume of 6 to 7 ml/kg) was performed, following a recruitment manoeuvre. At each PEEP, helical computed tomography scans of juxta-diaphragmatic parts of the lower lobes were obtained during end-expiratory and end-inspiratory pauses in six piglets with ALI induced by oleic acid. The distribution of the lung compartments (hyperinflated, normally aerated, poorly aerated and non-aerated areas) was determined and the Ers was estimated on a breath-by-breath basis from the equation of motion of the respiratory system using the least-squares method. RESULTS: Progressive reduction in PEEP from 26 cmH2O to the PEEP at which the minimum Ers was observed improved poorly aerated areas, with a proportional reduction in hyperinflated areas. Also, the distribution of normally aerated areas remained steady over this interval, with no changes in non-aerated areas. The PEEP at which minimal Ers occurred corresponded to the greatest amount of normally aerated areas, with lesser hyperinflated, and poorly and non-aerated areas. Levels of PEEP below that at which minimal Ers was observed increased poorly and non-aerated areas, with concomitant reductions in normally inflated and hyperinflated areas. CONCLUSION: The PEEP at which minimal Ers occurred, obtained by descending PEEP titration with a protective low tidal volume, corresponded to the greatest amount of normally aerated areas, with lesser collapsed and hyperinflated areas. The institution of high levels of PEEP reduced poorly aerated areas but enlarged hyperinflated ones. Reduction in PEEP consistently enhanced poorly or non-aerated areas as well as tidal re-aeration. Hence, monitoring respiratory mechanics during a PEEP titration procedure may be a useful adjunct to optimize lung aeration.

Effects of descending positive end-expiratory pressure on lung mechanics and aeration in healthy anaesthetized piglets.

INTRODUCTION: Atelectasis and distal airway closure are common clinical entities of general anaesthesia. These two phenomena are expected to reduce the ventilation of dependent lung regions and represent major causes of arterial oxygenation impairment in anaesthetic conditions. In the present study, the behavior of the elastance of the respiratory system (Ers), as well as the lung aeration assessed by CT-scan, was evaluated during a descendent positive end-expiratory pressure (PEEP) titration. This work sought to evaluate the potential usefulness of the Ers monitoring to set the PEEP in order to prevent tidal recruitment and hyperinflation of healthy lungs under general anaesthesia. METHODS: PEEP titration (from 16 to 0 cmH2O, with a tidal volume of 8 ml/kg) was performed, and at each PEEP, helical CT-scans were obtained during end-expiratory and end-inspiratory pauses in six healthy, anaesthetized and paralyzed piglets. The distribution of lung compartments (hyperinflated (HA), normally- (NA), poorly- (PA), and non-aerated areas (N)) was determined and the tidal re-aeration was calculated as the difference between end-expiratory and end-inspiratory PA and NA areas. Similarly, the tidal hyperinflation was obtained as the difference between end-inspiratory and end-expiratory HA. The Ers was estimated on a breath-by-breath basis from the equation of motion of the respiratory system during all PEEP titration with the least squares method. RESULTS: HA decreased throughout PEEP descent from PEEP 16 cmH2O to ZEEP (ranges from 24-62% to 1-7% at end-expiratory and from 44-73% to 4-17% at end-inspiratory pauses) whereas NA areas increased (30-66% to 72-83% at end-expiratory and from 19-48% to 73-77% at end-inspiratory pauses). From 16 to 8 cmH2O, Ers decreased with a correspondent reduction in tidal hyperinflation. A flat minimum of Ers was observed from 8 to 4 cmH2O. For PEEP below 4 cmH2O, Ers increased associated with a rise in tidal re-aeration and a flat maximum of the NA areas. CONCLUSION: In healthy piglets under a descending PEEP protocol, the PEEP at minimum Ers presented a compromise between maximizing NA areas and minimizing tidal re-aeration and hyperinflation. High levels of PEEP, greater than 8 cmH2O, reduced tidal re-aeration but enlarged hyperinflation with a concomitant decrease in normally aerated areas.

Effects of filtering and delays on the estimates of a nonlinear respiratory mechanics model.

Estimation of mechanical properties of the respiratory system may be disturbed by instrumentation and physical set-up. The effects of lowpass filtering, filter mismatch and inter-channel delay in the digital converter are assessed on numerically simulated signals from a nonlinear model of the respiratory system. Large biases in model parameter estimates (up to about -300% for some parameters) were caused by these instrumental interferences and were reduced by including an inertance in the retrieved model. The results reinforce the importance of a careful evaluation of the instrumental set-up used in physiological measurements.

A closed-loop mechanical ventilation controller with explicit objective functions.

A closed-loop lung ventilation controller was designed, aiming to: 1) track a desired end-tidal CO2 pressure (Pet CO2), 2) find the positive end-expiratory pressure (PEEP) of minimum estimated respiratory system elastance (Ers,e), and 3) follow objective functions conjectured to reduce lung injury. After numerical simulations, tests were performed in six paralyzed piglets. Respiratory mechanics parameters were estimated by the recursive least squares (RLS) method. The controller incorporated a modified PI controller for Pet CO2 and a gradient descent method for PEEP. In each animal, three automated PEEP control runs were performed, as well as a manual PEEP titration of Ers,e and a multiple PetCO2 step change trial. Overall performance indexes were obtained from PEEP control, such as minimum Ers,e (37.0 +/- 4.5 cmH2O x L(-1)), time to reach the minimum Ers,e (235 +/- 182 s) and associated PEEP (6.5 +/- 1.0 cmH2O), and from Pet CO2 control, such as rise time (53 +/- 22 s), absolute overshoot/undershoot of PetCO2 (3 +/- 1 mmHg), and settling time (145 +/- 72 s). The resulting CO2 controller dynamics approximate physiological responses, and results from PEEP control were similar to those obtained by manual titration. Multiple dependencies linking the involved variables are discussed. The present controller can help to implement and evaluate objective functions that meet clinical goals.

A numerical model of the respiratory modulation of pulmonary shunt and PaO2 oscillations for acute lung injury.

It is an accepted hypothesis that the amplitude of the respiratory-related oscillations of arterial partial pressure of oxygen (DeltaPaO2) is primarily modulated by fluctuations of pulmonary shunt (Deltas), the latter generated mainly by cyclic alveolar collapse/reopening, when present. A better understanding of the relationship between DeltaPaO2, Deltas, and cyclic alveolar collapse/reopening can have clinical relevance for minimizing the severe lung damage that the latter can cause, for example during mechanical ventilation (MV) of patients with acute lung injury (ALI). To this aim, we numerically simulated the effect of such a relationship on an animal model of ALI under MV, using a combination of a model of lung gas exchange during tidal ventilation with a model of time dependence of shunt on alveolar collapse/opening. The results showed that: (a) the model could adequately replicate published experimental results regarding the complex dependence of DeltaPaO2 on respiratory frequency, driving pressure (DeltaP), and positive end-expiratory pressure (PEEP), while simpler models could not; (b) such a replication strongly depends on the value of the model parameters, especially of the speed of alveolar collapse/reopening; (c) the relationship between DeltaPaO2 and Deltas was overall markedly nonlinear, but approximately linear for PEEP>or=6 cmH2O, with very large DeltaPaO2 associated with relatively small Deltas.

The endotracheal tube biases the estimates of pulmonary recruitment and overdistension.

To assess the impact of the endotracheal tube (ETT) and of different flow waveforms on estimates of alveolar cyclic recruitment (CR) and overdistension (AO). Numerical simulation of the respiratory system plus ETT (inertance L plus a flow-dependent resistance, K (1) and K (2)), with the following non-linear equation of motion PAW(t)= ((K1 + K2 x/V(t)/) x V(t) + L x V(t)) + Rrs x V(t) + (E1 + E2 x V(t) x V(t) + P0 (PAW pressure at the airways opening, V volume), under volume-controlled mechanical ventilation. An index %E2 = 100 x (E2 x V(T))/(E1 + E2)x V(T)) can be calculated where %E(2) > 30% represents AO and %E(2) < 0% represents CR. Parameters were estimated by the least-squares method, either with the complete equation or suppressing L, K(2) or both. %E(2) is always underestimated (down to -152 percent points) with incomplete equations of motion. The estimation of %E (2) may be strongly biased in the presence of an ETT excluded from the estimation model.

Heart-rate and blood-pressure variability during psychophysiological tasks involving speech: influence of respiration.

Changes in heart-rate and systolic arterial pressure variability (HRV and SAPV) indexes have been used in psychophysiology to assess autonomic activation, including during tasks involving speech. The current article clearly demonstrates in a sample of 25 adult subjects that the erratic and broadband respiratory patterns during such tasks violate the usual assumption that respiration is limited to the high-frequency band (0.15-0.4 Hz). For these tasks, interindividual differences and rest-task changes in HRV and SAPV in the low-frequency band (0.04-0.15 Hz) can be explained, to a large extent, by variations in the respiratory volume signal. This makes the use of HRV and SAPV as markers of autonomic function during these tasks highly questionable. Furthermore, a number of subjects with long respiratory period at rest were identified, whose presence in the sample can bias the estimation of baseline rest values.