Robust predictive control for respiratory CO2 gas removal in closed-loop mechanical ventilation: an in-silico study

In this study a physiological closed-loop system for arterial CO2 partial pressure control was designed and comprehensively tested using a set of models of the respiratory CO2 gas exchange. The underlying preclinical data were collected from 12 pigs in presence of severe changes in hemodynamic and pulmonary condition. A minimally complex nonlinear state space model of CO2 gas exchange was identified post hoc in different lung conditions. The control variable was measured noninvasively using the endtidal CO2 partial pressure. For the simulation study the output signal of the controller was defined as the alveolar minute volume set value of an underlying adaptive lung protective ventilation mode. A linearisation of the two-compartment CO2 gas exchange model was used for the design of a model predictive controller (MPC). It was augmented by a tube based controller suppressing prediction errors due to model uncertainties. The controller was subject to comparative testing in interaction with each of the CO2 gas exchange models previously identified on the preclinical study data. The performance was evaluated for the system response towards the following five tests in comparison to a PID controller: recruitment maneuver, PEEP titration maneuver, stepwise change in the CO2 production, breath-hold maneuver and a step in the reference signal. A root mean square error of 2.69 mmHg between arterial CO2 partial pressure and the reference signal was achieved throughout the trial. The reference-variable response of the model predictive controller was superior regarding overshoot and settling time

Distribution of transpulmonary pressure during one-lung ventilation in pigs at different body positions

Background: Global and regional transpulmonary pressure (PL) during one-lung ventilation (OLV) is poorly characterized. We hypothesized that global and regional PL and driving PL (ΔPL) increase during protective low tidal volume OLV compared to two-lung ventilation (TLV), and vary with body position. Methods: In sixteen anesthetized juvenile pigs, intra-pleural pressure sensors were placed in ventral, dorsal, and caudal zones of the left hemithorax by video-assisted thoracoscopy. A right thoracotomy was performed and lipopolysaccharide administered intravenously to mimic the inflammatory response due to thoracic surgery. Animals were ventilated in a volume-controlled mode with a tidal volume (VT) of 6 mL kg⁻¹ during TLV and of 5 mL kg⁻¹ during OLV and a positive end-expiratory pressure (PEEP) of 5 cmH₂O. Global and local transpulmonary pressures were calculated. Lung instability was defined as end-expiratory PL<2.9 cmH₂O according to previous investigations. Variables were acquired during TLV (TLVsupine), left lung ventilation in supine (OLVsupine), semilateral (OLVsemilateral), lateral (OLVlateral) and prone (OLVprone) positions randomized according to Latin-square sequence. Effects of position were tested using repeated measures ANOVA. Results: End-expiratory PL and ΔPL were higher during OLVsupine than TLVsupine. During OLV, regional end-inspiratory PL and ΔPL did not differ significantly among body positions. Yet, end-expiratory PL was lower in semilateral (ventral: 4.8 ± 2.9 cmH₂O; caudal: 3.1 ± 2.6 cmH₂O) and lateral (ventral: 1.9 ± 3.3 cmH₂O; caudal: 2.7 ± 1.7 cmH₂O) compared to supine (ventral: 4.8 ± 2.9 cmH₂O; caudal: 3.1 ± 2.6 cmH2O) and prone position (ventral: 1.7 ± 2.5 cmH₂O; caudal: 3.3 ± 1.6 cmH₂O), mainly in ventral (p ≤ 0.001) and caudal (p = 0.007) regions. Lung instability was detected more often in semilateral (26 out of 48 measurements; p = 0.012) and lateral (29 out of 48 measurements, p < 0.001) as compared to supine position (15 out of 48 measurements), and more often in lateral as compared to prone position (19 out of 48 measurements, p = 0.027). Conclusion: Compared to TLV, OLV increased lung stress. Body position did not affect stress of the ventilated lung during OLV, but lung stability was lowest in semilateral and lateral decubitus position

Continuous external negative pressure improves oxygenation and respiratory mechanics in Experimental Lung Injury in Pigs : A pilot proof-of-concept trial

Background: Continuous external negative pressure (CENP) during positive pressure ventilation can recruit dependent lung regions. We hypothesised that CENP applied regionally to the thorax or the abdomen only, increases the caudal end-expiratory transpulmonary pressure depending on positive end-expiratory pressure (PEEP) in lung-injured pigs. Eight pigs were anesthetised and mechanically ventilated in the supine position. Pressure sensors were placed in the left pleural space, and a lung injury was induced by saline lung lavages. A CENP shell was placed at the abdomen and thorax (randomised order), and animals were ventilated with PEEP 15, 7 and zero cmH(2)O (15 min each). On each PEEP level, CENP of - 40, - 30, - 20, - 10 and 0 cmH(2)O was applied (3 min each). Respiratory and haemodynamic variables were recorded. Electrical impedance tomography allowed assessment of centre of ventilation.Results: Compared to positive pressure ventilation alone, the caudal transpulmonary pressure was significantly increased by CENP of &lt;= 20 cmH(2)O at all PEEP levels. CENP of - 20 cmH(2)O reduced the mean airway pressure at zero PEEP (P = 0.025). The driving pressure decreased at CENP of &lt;= 10 at PEEP of 0 and 7 cmH(2)O (P &lt; 0.001 each) but increased at CENP of - 30 cmH(2)O during the highest PEEP (P = 0.001). CENP of - 30 cmH(2)O reduced the mechanical power during zero PEEP (P &lt; 0.001). Both elastance (P &lt; 0.001) and resistance (P &lt; 0.001) were decreased at CENP &lt;= 30 at PEEP of 0 and 7 cmH(2)O. Oxygenation increased at CENP of &lt;= 20 at PEEP of 0 and 7 cmH(2)O (P &lt; 0.001 each). Applying external negative pressure significantly shifted the centre of aeration towards dorsal lung regions irrespectively of the PEEP level. Cardiac output decreased significantly at CENP -20 cmH(2)O at all PEEP levels (P &lt; 0.001). Effects on caudal transpulmonary pressure, elastance and cardiac output were more pronounced when CENP was applied to the abdomen compared with the thorax.Conclusions: In this lung injury model in pigs, CENP increased the end-expiratory caudal transpulmonary pressure. This lead to a shift of lung aeration towards dependent zones as well as improved respiratory mechanics and oxygenation, especially when CENP was applied to the abdomen as compared to the thorax. CENP values &lt;= 20 cmH(2)O impaired the haemodynamics

Periodic Fluctuation of Tidal Volumes Further Improves Variable Ventilation in Experimental Acute Respiratory Distress Syndrome

In experimental acute respiratory distress syndrome (ARDS), random variation of tidal volumes (VT ) during volume controlled ventilation improves gas exchange and respiratory system mechanics (so-called stochastic resonance hypothesis). It is unknown whether those positive effects may be further enhanced by periodic VT fluctuation at distinct frequencies, also known as deterministic frequency resonance.We hypothesized that the positive effects of variable ventilation on lung functionmay be further amplified by periodic VT fluctuation at specific frequencies. In anesthetized and mechanically ventilated pigs, severe ARDS was induced by saline lung lavage and injurious VT (double-hit model). Animals were then randomly assigned to 6 h of protective ventilation with one of four VT patterns: (1) random variation of VT (WN); (2) P04, main VT frequency of 0.13Hz; (3) P10, main VT frequency of 0.05Hz; (4) VCV, conventional non-variable volume controlled ventilation. In groups with variable VT , the coefficient of variation was identical (30%). We assessed lung mechanics and gas exchange, and determined lung histology and inflammation. Compared to VCV, WN, P04, and P10 resulted in lower respiratory system elastance (63 ± 13 cm H2O/L vs. 50 ± 14 cm H2O/L, 48.4 ± 21 cm H2O/L, and 45.1 ± 5.9 cm H2O/L respectively, P < 0.05 all), but only P10 improved PaO2/FIO2 after 6 h of ventilation (318 ± 96 vs. 445 ± 110mm Hg, P < 0.05). Cycle-by-cycle analysis of lung mechanics suggested intertidal recruitment/de-recruitment in P10. Lung histologic damage and inflammation did not differ among groups. In this experimental model of severe ARDS, periodic VT fluctuation at a frequency of 0.05Hz improved oxygenation during variable ventilation, suggesting that deterministic resonance adds further benefit to variable ventilation

Distribution of transpulmonary pressure during one-lung ventilation in pigs at different body positions

Background. Global and regional transpulmonary pressure (PL) during one-lung ventilation (OLV) is poorly characterized. We hypothesized that global and regional PL and driving PL (ΔPL) increase during protective low tidal volume OLV compared to two-lung ventilation (TLV), and vary with body position.Methods. In sixteen anesthetized juvenile pigs, intra-pleural pressure sensors were placed in ventral, dorsal, and caudal zones of the left hemithorax by video-assisted thoracoscopy. A right thoracotomy was performed and lipopolysaccharide administered intravenously to mimic the inflammatory response due to thoracic surgery. Animals were ventilated in a volume-controlled mode with a tidal volume (VT) of 6 mL kg−1 during TLV and of 5 mL kg−1 during OLV and a positive end-expiratory pressure (PEEP) of 5 cmH2O. Global and local transpulmonary pressures were calculated. Lung instability was defined as end-expiratory PL&lt;2.9 cmH2O according to previous investigations. Variables were acquired during TLV (TLVsupine), left lung ventilation in supine (OLVsupine), semilateral (OLVsemilateral), lateral (OLVlateral) and prone (OLVprone) positions randomized according to Latin-square sequence. Effects of position were tested using repeated measures ANOVA.Results. End-expiratory PL and ΔPL were higher during OLVsupine than TLVsupine. During OLV, regional end-inspiratory PL and ΔPL did not differ significantly among body positions. Yet, end-expiratory PL was lower in semilateral (ventral: 4.8 ± 2.9 cmH2O; caudal: 3.1 ± 2.6 cmH2O) and lateral (ventral: 1.9 ± 3.3 cmH2O; caudal: 2.7 ± 1.7 cmH2O) compared to supine (ventral: 4.8 ± 2.9 cmH2O; caudal: 3.1 ± 2.6 cmH2O) and prone position (ventral: 1.7 ± 2.5 cmH2O; caudal: 3.3 ± 1.6 cmH2O), mainly in ventral (p ≤ 0.001) and caudal (p = 0.007) regions. Lung instability was detected more often in semilateral (26 out of 48 measurements; p = 0.012) and lateral (29 out of 48 measurements, p &lt; 0.001) as compared to supine position (15 out of 48 measurements), and more often in lateral as compared to prone position (19 out of 48 measurements, p = 0.027).Conclusion. Compared to TLV, OLV increased lung stress. Body position did not affect stress of the ventilated lung during OLV, but lung stability was lowest in semilateral and lateral decubitus position

Intraoperative ventilator settings and their association with postoperative pulmonary complications in neurosurgical patients : post-hoc analysis of LAS VEGAS study

Background Limited information is available regarding intraoperative ventilator settings and the incidence of postoperative pulmonary complications (PPCs) in patients undergoing neurosurgical procedures. The aim of this post-hoc analysis of the 'Multicentre Local ASsessment of VEntilatory management during General Anaesthesia for Surgery' (LAS VEGAS) study was to examine the ventilator settings of patients undergoing neurosurgical procedures, and to explore the association between perioperative variables and the development of PPCs in neurosurgical patients. Methods Post-hoc analysis of LAS VEGAS study, restricted to patients undergoing neurosurgery. Patients were stratified into groups based on the type of surgery (brain and spine), the occurrence of PPCs and the assess respiratory risk in surgical patients in Catalonia (ARISCAT) score risk for PPCs. Results Seven hundred eighty-four patients were included in the analysis; 408 patients (52%) underwent spine surgery and 376 patients (48%) brain surgery. Median tidal volume (V-T) was 8 ml [Interquartile Range, IQR = 7.3-9] per predicted body weight; median positive end-expiratory pressure (PEEP) was 5 [3 to 5] cmH(2)0. Planned recruitment manoeuvres were used in the 6.9% of patients. No differences in ventilator settings were found among the sub-groups. PPCs occurred in 81 patients (10.3%). Duration of anaesthesia (odds ratio, 1.295 [95% confidence interval 1.067 to 1.572]; p = 0.009) and higher age for the brain group (odds ratio, 0.000 [0.000 to 0.189]; p = 0.031), but not intraoperative ventilator settings were independently associated with development of PPCs. Conclusions Neurosurgical patients are ventilated with low V-T and low PEEP, while recruitment manoeuvres are seldom applied. Intraoperative ventilator settings are not associated with PPCs

Diclofenac Hypersensitivity: Antibody Responses to the Parent Drug and Relevant Metabolites

Background: Hypersensitivity reactions against nonsteroidal antiinflammatory drugs (NSAIDs) like diclofenac (DF) can manifest as Type I-like allergic reactions including systemic anaphylaxis. However, except for isolated case studies experimental evidence for an IgE-mediated pathomechanism of DF hypersensitivity is lacking. In this study we aimed to investigate the possible involvement of drug-and/or metabolite-specific antibodies in selective DF hypersensitivity. Methodology/Principal Findings: DF, an organochemically synthesized linkage variant, and five major Phase I metabolites were covalently coupled to carrier proteins. Drug conjugates were analyzed for coupling degree and capacity to crosslink receptor-bound IgE antibodies from drug-sensitized mice. With these conjugates, the presence of hapten-specific IgE antibodies was investigated in patients' samples by ELISA, mediator release assay, and basophil activation test. Production of sulfidoleukotrienes by drug conjugates was determined in PBMCs from DF-hypersensitive patients. All conjugates were shown to carry more than two haptens per carrier molecule. Immunization of mice with drug conjugates induced drug-specific IgE antibodies capable of triggering mediator release. Therefore, the conjugates are suitable tools for detection of drug-specific antibodies and for determination of their anaphylactic activity. Fifty-nine patients were enrolled and categorized as hypersensitive either selectively to DF or to multiple NSAIDs. In none of the patients' samples evidence for drug/metabolite-specific IgE in serum or bound to allergic effector cells was found. In contrast, a small group of patients (8/59, 14%) displayed drug/metabolite-specific IgG. Conclusions/Significance: We found no evidence for an IgE-mediated effector mechanism based on haptenation of protein carriers in DF-hypersensitive patients. Furthermore, a potential involvement of the most relevant metabolites in DF hypersensitivity reactions could be excluded

Continental bedrock and riverine fluxes of strontium and neodymium isotopes to the oceans

Author Posting. © American Geophysical Union, 2010. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 11 (2010): Q03016, doi:10.1029/2009GC002869.Realistic models of past climate and ocean chemistry depend on reconstructions of the Earth's surface environments in the geologic past. Among the critical parameters is the geologic makeup of continental drainage. Here we show, for the present, that the isotope composition of dissolved strontium in rivers increases linearly with the age of bedrock in drainage basins, with the notable exception of the drainage area of Arabia, India, and Southeast Asia that is affected by unusually radiogenic dissolved Sr from the Himalaya. We also demonstrate that the neodymium isotope compositions of suspended matter in rivers as well as clastic sediments deposited along the ocean margins decrease linearly with the bedrock ages of river drainage basins and large-scale continental drainage regions, as determined from digital geologic maps. These correlations are used to calculate the present-day input of dissolved Sr (4.7 × 1010 mol yr−1, 87Sr/86Sr of ∼0.7111) and particulate Nd isotopes (ɛNd of approximately −7.3 ± 2.2) to the oceans. The fact that the regionally averaged ɛNd of the global detrital input to the global coastal ocean is identical to globally averaged seawater (ɛNd of −7.2 ± 0.5) lends credence to the importance of “boundary exchange” for the Nd isotope composition of water masses. Regional biases in source areas of detrital matter and runoff are reflected by the observation that the average age of global bedrock, weighted according to the riverine suspended sediment flux, is significantly younger (∼336 Myr) than the age of global bedrock weighted according to water discharge (394 Myr), which is younger than the average bedrock age of the nonglaciated, exorheic portions of the continents (453 Myr). The observation that the bedrock age weighted according to Sr flux is younger (339 Myr) than that weighted according to water flux reflects the disproportionate contribution from young sedimentary and volcanic rocks to the dissolved Sr load. Neither the isotope composition of the dissolved nor the particulate continental inputs to the ocean provide unbiased perspectives of the lithologic makeup of the Earth's surface. Temporal changes in bedrock geology as well as the shifting focal points of physical erosion and water discharge will undoubtedly have exerted strong controls on temporal and spatial changes in the isotope chemistry of past global runoff and thus seawater.NSF grants EAR‐ 0125873, EAR‐0519387, and OCE‐0851015 to B.P.‐E. and a CNRS‐funded “poste rouge” position for B.P.‐E. at the Observatoire Midi‐Pyrénées in Toulouse supported this work