Background: Kinetics of the uptake of inhaled anesthetics have been well studied, but the kinetics of elimination might be of more practical importance. The objective of the authors' study was to assess the effect of the overall ventilation/perfusion ratio (V-A/Q), for normal lungs, on elimination kinetics of desflurane and sevoflurane. Methods: The authors developed a mathematical model of inhaled anesthetic elimination that explicitly relates the terminal washout time constant to the global lung V-A/Q ratio. Assumptions and results of the model were tested with experimental data from a recent study, where desflurane and sevoflurane elimination were observed for three different V-A/Q conditions: normal, low, and high. Results: The mathematical model predicts that the global V-A/Q ratio, for normal lungs, modifies the time constant for tissue anesthetic washout throughout the entire elimination. For all three V-A/Q conditions, the ratio of arterial to mixed venous anesthetic partial pressure P-art/P-mv reached a constant value after 5 min of elimination, as predicted by the retention equation. The time constant corrected for incomplete lung clearance was a better predictor of late-stage kinetics than the intrinsic tissue time constant. Conclusions: In addition to the well-known role of the lungs in the early phases of inhaled anesthetic washout, the lungs play a long-overlooked role in modulating the kinetics of tissue washout during the later stages of inhaled anesthetic elimination. The V-A/Q ratio influences the kinetics of desflurane and sevoflurane elimination throughout the entire elimination, with more pronounced slowing of tissue washout at lower V-A/Q ratios.

Background Previous studies have established the role of various tissue compartments in the kinetics of inhaled anesthetic uptake and elimination. The role of normal lungs in inhaled anesthetic kinetics is less understood. In juvenile pigs with normal lungs, the authors measured desflurane and sevoflurane washin and washout kinetics at three different ratios of alveolar minute ventilation to cardiac output value. The main hypothesis was that the ventilation/perfusion ratio (VA/Q) of normal lungs influences the kinetics of inhaled anesthetics. Methods Seven healthy pigs were anesthetized with intravenous anesthetics and mechanically ventilated. Each animal was studied under three different VA/Q conditions: normal, low, and high. For each VA/Q condition, desflurane and sevoflurane were administered at a constant, subanesthetic inspired partial pressure (0.15 volume% for sevoflurane and 0.5 volume% for desflurane) for 45 min. Pulmonary arterial and systemic arterial blood samples were collected at eight time points during uptake, and then at these same times during elimination, for measurement of desflurane and sevoflurane partial pressures. The authors also assessed the effect of VA/Q on paired differences in arterial and mixed venous partial pressures. Results For desflurane washin, the scaled arterial partial pressure differences between 5 and 0 min were 0.70 ± 0.10, 0.93 ± 0.08, and 0.82 ± 0.07 for the low, normal, and high VA/Q conditions (means, 95% CI). Equivalent measurements for sevoflurane were 0.55 ± 0.06, 0.77 ± 0.04, and 0.75 ± 0.08. For desflurane washout, the scaled arterial partial pressure differences between 0 and 5 min were 0.76 ± 0.04, 0.88 ± 0.02, and 0.92 ± 0.01 for the low, normal, and high VA/Q conditions. Equivalent measurements for sevoflurane were 0.79 ± 0.05, 0.85 ± 0.03, and 0.90 ± 0.03. Conclusions Kinetics of inhaled anesthetic washin and washout are substantially altered by changes in the global VA/Q ratio for normal lungs. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Mechanical ventilation can lead to ventilator-induced lung injury (VILI). In addition to the well-known mechanical forces of volutrauma, barotrauma, and atelectrauma, non-mechanical mechanisms have recently been discussed as contributing to the pathogenesis of VILI. One such mechanism is oscillations in partial pressure of oxygen (PO2) which originate in lung tissue in the presence of within-breath recruitment and derecruitment of alveoli. The purpose of this study was to investigate this mechanism’s possible independent effects on lung tissue and inflammation in a porcine model. To separately study the impact of PO2 oscillations on the lungs, an in vivo model was set up that allowed for generating mixed-venous PO2 oscillations by the use of veno-venous extracorporeal membrane oxygenation (vvECMO) in a state of minimal mechanical stress. While applying the identical minimal-invasive ventilator settings, 16 healthy female piglets (weight 50 ± 4 kg) were either exposed for 6 h to a constant mixed-venous hemoglobin saturation (SmvO2) of 65% (which equals a PmvO2 of 41 Torr) (control group), or an oscillating SmvO2 (intervention group) of 40–90% (which equals PmvO2 oscillations of 30–68 Torr)—while systemic normoxia in both groups was maintained. The primary endpoint of histologic lung damage was assessed by ex vivo histologic lung injury scoring (LIS), the secondary endpoint of pulmonary inflammation by qRT-PCR of lung tissue. Cytokine concentration of plasma was carried out by ELISA. A bioinformatic microarray analysis of lung samples was performed to generate hypotheses about underlying pathomechanisms. The LIS showed significantly more severe damage of lung tissue after exposure to PO2 oscillations compared to controls (0.53 [0.51; 0.58] vs. 0.27 [0.23; 0.28]; P = 0.0025). Likewise, a higher expression of TNF-α (P = 0.0127), IL-1β (P = 0.0013), IL-6 (P = 0.0007), and iNOS (P = 0.0013) in lung tissue was determined after exposure to PO2 oscillations. Cytokines in plasma showed a similar trend between the groups, however, without significant differences. Results of the microarray analysis suggest that inflammatory (IL-6) and oxidative stress (NO/ROS) signaling pathways are involved in the pathology linked to PO2 oscillations. Artificial mixed-venous PO2 oscillations induced lung damage and pulmonary inflammation in healthy animals during lung protective ventilation. These findings suggest that PO2 oscillations represent an independent mechanism of VILI.

Critical Care Medicine www.ccmjournal.org 1281 6. Savel RH, Cohen W, Borgia D, et al: The intensive care unit perspective of becoming a level I trauma center: Challenges of strategy, leadership, and operations management. J Emerg Trauma Shock 2018; 11:65–70 7. Savel RH, Munro CL: Moral distress, moral courage. Am J Crit Care 2015; 24:276–278 8. Savel RH, Munro CL: We are a team ... with room for improvement. Am J Crit Care 2016; 25:472–474 9. Savel RH, Munro CL: Emotional intelligence: For the leader in us all. Am J Crit Care 2016; 25:104–106 10. Savel RH, Munro CL: Servant leadership: The primacy of service. Am J Crit Care 2017; 26:97–99 11. Omar AS, Elmaraghi S, Mahmoud MS, et al: Impact of leadership on ICU clinicians’ burnout. Intensive Care Med 2015; 41:2016–2017 12. Robbins SP, Judge TA: Essentials of Organizational Behavior. 14th Edition. Boston, MA, Pearson, 2018

Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA *See also p. 1761. Dr. Baumgardner disclosed that he is the founder and president of Oscillogy LLC, a small business launched to commercialize measurement of V/Q distributions but currently does not generate any revenue.

Cyclic recruitment and de-recruitment of atelectasis (c-R/D) is a contributor to ventilator-induced lung injury (VILI). Bedside detection of this dynamic process could improve ventilator management. This study investigated the potential of automated lung sound analysis to detect c-R/D as compared to four-dimensional computed tomography (4DCT).

Background: Increasing numbers of patients with obstructive lung diseases need anesthesia for surgery. These conditions are associated with pulmonary ventilation/perfusion (<(V) over dot>(A)/Q)mismatch affecting kinetics of volatile anesthetics. Pure shunt might delay uptake of less soluble anesthetic agents but other forms of V-A/Q scatter have not yet been examined. Volatile anesthetics with higher blood solubility would be less affected by <(V) over dot>(A)/Q mismatch. We therefore compared uptake and elimination of higher soluble isoflurane and less soluble desflurane in a piglet model. Methods: Juvenile piglets (26.7 +/- 1.5 kg) received either isoflurane (n = 7) or desflurane (n = 7). Arterial and mixed venous blood samples were obtained during wash-in and wash-out of volatile anesthetics before and during bronchoconstriction by methacholine inhalation (100 mu g/ml). Total uptake and elimination were calculated based on partial pressure measurements by micropore membrane inlet mass spectrometry and literature-derived partition coefficients and assumed end-expired to arterial gradients to be negligible. <(V) over dot>(A)/Q distribution was assessed by the multiple inert gas elimination technique. Results: Before methacholine inhalation, isoflurane arterial partial pressures reached 90% of final plateau within 16 min and decreased to 10% after 28 min. By methacholine nebulization, arterial uptake and elimination delayed to 35 and 44 min. Desflurane needed 4 min during wash-in and 6 min during wash-out, but with bronchoconstriction 90% of both uptake and elimination was reached within 15 min. Conclusions: Inhaled methacholine induced bronchoconstriction and inhomogeneous (V) over dot>(A)/Q distribution. Solubility of inhalational anesthetics significantly influenced pharmacokinetics: higher soluble isoflurane is less affected than fairly insoluble desflurane, indicating different uptake and elimination during bronchoconstriction.

The data of a corresponding animal experiment demonstrates that nebulized methacholine (MCh) induced severe bronchoconstriction and significant inhomogeneous ventilation and pulmonary perfusion (V̇A/Q̇) distribution in pigs, which is similar to findings in human asthma. The inhalation of MCh induced bronchoconstriction and delayed both uptake and elimination of desflurane (Kretzschmar et al., 2015) [1]. The objective of the present data is to determine V̇A/Q̇ matching by Multiple Inert Gas Elimination Technique (MIGET) in piglets before and during methacholine- (MCh-) induced bronchoconstriction, induced by MCh infusion, and to assess the blood concentration profiles for desflurane (DES) by Micropore Membrane Inlet Mass Spectrometry (MMIMS). Healthy piglets (n=4) under general anesthesia were instrumented with arterial, central venous, and pulmonary artery lines. The airway was secured via median tracheostomy with an endotracheal tube, and animals were mechanically ventilated with intermittent positive pressure ventilation (IPPV) with a FiO2 of 0.4, tidal volume (VT)=10 ml/kg and PEEP of 5cmH2O using an open system. The determination of V.A/Q. was done by MIGET: before desflurane application and at plateau in both healthy state and during MCh infusion. Arterial blood was sampled at 0, 1, 2, 5, 10, 20, and 30 min during wash-in and washout, respectively. Bronchoconstriction was established by MCH infusion aiming at doubling the peak airway pressure, after which wash-in and washout of the anesthetic gas was repeated. Anesthesia gas concentrations were measured by MMIMS. Data were analyzed by ANOVA, paired t-test, and by nonparametric Friedman׳s test and Wilcoxon׳s matched pairs test. We measured airway pressures, pulmonary resistance, and mean paO2 as well as hemodynamic variables in all pigs before desflurane application and at plateau in both healthy state and during methacholine administration by infusion. By MIGET, fractional alveolar ventilation and pulmonary perfusion in relation to the V.A/Q. compartments, data of logSDQ̇ and logSDV̇ (the second moments describing global dispersion, i.e. heterogeneity of distribution) were estimated prior to and after MCh infusion. The uptake and elimination of desflurane was determined by MMIMS.

Objective: Cyclic recruitment and derecruitment of atelectasis can occur during mechanical ventilation, especially in injured lungs. Experimentally, cyclic recruitment and derecruitment can be quantified by respiration-dependent changes in Pao(2) (Delta Pao(2)), reflecting the varying intrapulmonary shunt fraction within the respiratory cycle. This study investigated the effect of inspiration to expiration ratio upon Delta Pao(2) and Horowitz index.Design: Prospective randomized study.Setting: Laboratory investigation.Subjects: Piglets, average weight 30 +/- 2 kg.Interventions: At respiratory rate 6 breaths/min, end-inspiratory pressure (P-endinsp) 40 cm H2O, positive end-expiratory pressure 5 cm H2O, and Fio(2) 1.0, measurements were performed at randomly set inspiration to expiration ratios during baseline healthy and mild surfactant depletion injury. Lung damage was titrated by repetitive surfactant washout to induce maximal cyclic recruitment and derecruitment as measured by multifrequency phase fluorimetry. Regional ventilation distribution was evaluated by electrical impedance tomography. Step changes in airway pressure from 5 to 40 cm H2O and vice versa were performed after lavage to calculate Po-2 based recruitment and derecruitment time constants (TAU).Measurements and Main Results: In baseline healthy, cyclic recruitment and derecruitment could not be provoked, whereas in model acute respiratory distress syndrome, the highest.Pao(2) were routinely detected at an inspiration to expiration ratio of 1:4 (range, 52-277 torr [6.9-36.9 kPa]). Shorter expiration time reduced cyclic recruitment and derecruitment significantly (158 +/- 85 torr [21.1 +/- 11.3 kPa] [inspiration to expiration ratio, 1: 4]; 25 +/- 12 torr [3.3 +/- 1.6 kPa] [inspiration to expiration ratio, 4: 1]; p < 0.0001), whereas the Pao(2) /Fio(2) ratio increased (267 +/- 50 [inspiration to expiration ratio, 1: 4]; 424 +/- 53 [inspiration to expiration ratio, 4: 1]; p < 0.0001). Correspondingly, regional ventilation redistributed toward dependent lung regions (p < 0.0001). Recruitment was much faster (TAU: fast 1.6s [78%]; slow 9.2 s) than derecruitment (TAU: fast 3.1 s [87%]; slow 17.7 s) (p = 0.0078).Conclusions: Inverse ratio ventilation minimizes cyclic recruitment and derecruitment of atelectasis in an experimental model of surfactant-depleted pigs. Time constants for recruitment and derecruitment, and regional ventilation distribution, reflect these findings and highlight the time dependency of cyclic recruitment and derecruitment.

Bronchoconstriction is a hallmark of asthma and impairs gas exchange. We hypothesized that pharmacokinetics of volatile anesthetics would be affected by bronchoconstriction. Ventilation/perfusion (VA/Q) ratios and pharmacokinetics of desflurane in both healthy state and during inhalational administration of methacholine (MCh) to double peak airway pressure were studied in a piglet model. In piglets, MCh administration by inhalation (100 μg/ml, n=6) increased respiratory resistance, impaired VA/Q distribution, increased shunt, and decreased paO2 in all animals. The uptake and elimination of desflurane in arterial blood was delayed by nebulization of MCh, as determined by Micropore Membrane Inlet Mass Spectrometry (wash-in time to P50, healthy vs. inhalation: 0.5 min vs. 1.1 min, to P90: 4.0 min vs. 14.8 min). Volatile elimination was accordingly delayed. Inhaled methacholine induced severe bronchoconstriction and marked inhomogeneous VA/Q distribution in pigs, which is similar to findings in human asthma exacerbation. Furthermore, MCh-induced bronchoconstriction delayed both uptake and elimination of desflurane. These findings might be considered when administering inhalational anesthesia to asthmatic patients.

Background: Vibration response imaging (VRI) is a bedside technology to monitor ventilation by detecting lung sound vibrations. It is currently unknown whether VRI is able to accurately monitor the local distribution of ventilation within the lungs. We therefore compared VRI to electrical impedance tomography (EIT), an established technique used for the assessment of regional ventilation.Methodology/Principal Findings: Simultaneous EIT and VRI measurements were performed in the healthy and injured lungs (ALI; induced by saline lavage) at different PEEP levels (0, 5, 10, 15 mbar) in nine piglets. Vibration energy amplitude (VEA) by VRI, and amplitudes of relative impedance changes (rel.Delta Z) by EIT, were evaluated in seven regions of interest (ROIs). To assess the distribution of tidal volume (V-T) by VRI and EIT, absolute values were normalized to the V-T obtained by simultaneous spirometry measurements. Redistribution of ventilation by ALI and PEEP was detected by VRI and EIT. The linear correlation between pooled V-T by VEA and rel.Delta Z was R-2 = 0.96. Bland-Altman analysis showed a bias of -1.07 +/- 24.71 ml and limits of agreement of -49.05 to +47.36 ml. Within the different ROIs, correlations of V-T-distribution by EIT and VRI ranged between R-2 values of 0.29 and 0.96. ALI and PEEP did not alter the agreement of V-T between VRI and EIT.Conclusions/Significance: Measurements of regional ventilation distribution by VRI are comparable to those obtained by EIT.

Background Measurement of partial pressure of oxygen (PO2) at high temporal resolution remains a technological challenge. This study introduces a novel PO2 sensing technology based on Multi-Frequency Phase Fluorimetry (MFPF). The aim was to validate MFPF against polarographic Clark-type electrode (CTE) PO2 measurements. Methodology/Principal Findings MFPF technology was first investigated in N = 8 anaesthetised pigs at FIO2 of 0.21, 0.4, 0.6, 0.8 and 1.0. At each FIO2 level, blood samples were withdrawn and PO2 was measured in vitro with MFPF using two FOXY-AL300 probes immediately followed by CTE measurement. Secondly, MFPF-PO2 readings were compared to CTE in an artificial circulatory setup (human packed red blood cells, haematocrit of 30%). The impacts of temperature (20, 30, 40°C) and blood flow (0.8, 1.6, 2.4, 3.2, 4.0 L min−1) on MFPF-PO2 measurements were assessed. MFPF response time in the gas- and blood-phase was determined. Porcine MFPF-PO2 ranged from 63 to 749 mmHg; the corresponding CTE samples from 43 to 712 mmHg. Linear regression: CTE = 15.59+1.18*MFPF (R2 = 0.93; P<0.0001). Bland Altman analysis: meandiff 69.2 mmHg, rangediff -50.1/215.6 mmHg, 1.96-SD limits -56.3/194.8 mmHg. In artificial circulatory setup, MFPF-PO2 ranged from 20 to 567 mmHg and CTE samples from 11 to 575 mmHg. Linear regression: CTE = −8.73+1.05*MFPF (R2 = 0.99; P<0.0001). Bland-Altman analysis: meandiff 6.6 mmHg, rangediff -9.7/20.5 mmHg, 1.96-SD limits -12.7/25.8 mmHg. Differences between MFPF and CTE-PO2 due to variations of temperature were less than 6 mmHg (range 0–140 mmHg) and less than 35 mmHg (range 140–750 mmHg); differences due to variations in blood flow were less than 15 mmHg (all P-values>0.05). MFPF response-time (monoexponential) was 1.48±0.26 s for the gas-phase and 1.51±0.20 s for the blood-phase. Conclusions/Significance MFPF-derived PO2 readings were reproducible and showed excellent correlation and good agreement with Clark-type electrode-based PO2 measurements. There was no relevant impact of temperature and blood flow upon MFPF-PO2 measurements. The response time of the MFPF FOXY-AL300 probe was adequate for real-time sensing in the blood phase.

Atelectrauma refers to lung injury due to recruitment of collapsed lung with each inspiration and de-recruitment with each exhalation. Atelectrauma has long been hypothesized to be a mechanism of ventilator-associated lung injury, but only recently have experimental tools become available to study this phenomenon. Cyclical recruitment of atelectasis has now been clearly demonstrated in specific animal models of lung injury. These animal studies have also shown that recruitment and collapse are time-dependent processes and cannot be predicted solely on the basis of end-inspiratory and end-expiratory pressures. To determine if this is a concern in patients, we need to know the incidence of cyclical recruitment, and we need to know if it injures the lung. Definitive answers are not currently available for either question, and will await the application of new high temporal resolution methods for measuring cyclical recruitment in patients. Recent animal studies suggest that cyclical recruitment, when present, can be very damaging to the lung. Avoiding cyclical recruitment may therefore become an important consideration in clinical ventilator management.

Critical Care Medicine www.ccmjournal.org e821 Investigator Award, from various academic grants (e.g., Wellcome Trust, MRC, European Union), and from different companies that are paid to the institution to support research activity (e.g., with Abbott, Deltex, DSTL, Magnus Oxygen, NewB Innovation, Oxford Optronix, Probe Scientific). He has performed consultancy/advisory board work or received speaker fees from Bayer, Biotest, Deltex, Fresenius, Merck, Pfizer, SOBI, and he is Scientific Officer for Magnus Oxygen; he received support for article research from Wellcome Trust/COAF. The remaining authors have disclosed that they do not have any potential conflicts of interest.