Effects on mechanical power of different devices used for inhaled sedation in a bench model of protective ventilation in ICU.

BACKGROUND: Inhaled sedation during invasive mechanical ventilation in patients with acute respiratory distress syndrome (ARDS) has received increasing attention. However, inhaled sedation devices increase dead-space ventilation and an undesirable effect is the increase in minute ventilation needed to maintain CO2 removal. A consequence of raising minute ventilation is an increase in mechanical power (MP) that can promote lung injury. However, the effect of inhaled sedation devices on MP remains unknown. METHODS: We conducted a bench study to assess and compare the effects of three devices delivering inhaled sevoflurane currently available in ICU (AnaConDa-50 mL (ANA-50), AnaConDa-100 mL (ANA-100), and MIRUS) on MP by using a test lung model set with three compliances (20, 40, and 60 mL/cmH2O). We simulated lung-protective ventilation using a low tidal volume and two levels of positive end-expiratory pressure (5 and 15 cmH2O) under ambient temperature and dry conditions. Following the insertion of the devices, either the respiratory rate or tidal volume was increased in 15%-steps until end-tidal CO2 (EtCO2) returned to the baseline value. MP was calculated at baseline and after EtCO2 correction using a simplified equation. RESULTS: Following device insertion, the EtCO2 increase was significantly greater with MIRUS (+ 78 ± 13%) and ANA-100 (+ 100 ± 11%) than with ANA-50 (+ 49 ± 7%). After normalizing EtCO2 by adjusting minute ventilation, MP significantly increased by more than 50% with all inhaled sedation devices compared to controls. The lowest increase in MP was observed with ANA-50 (p < 0.05 versus ANA-100 and MIRUS). The Costa index, another parameter assessing the mechanical energy delivered to the lungs, calculated as driving pressure × 4 + respiratory rate, significantly increased by more than 20% in all experimental conditions. Additional experiments performed under body temperature, ambient pressure, and gas saturated with water vapor conditions, confirmed the main results with an increase in MP > 50% with all devices after normalizing EtCO2 by adjusting minute ventilation. CONCLUSION: Inhaled sedation devices substantially increased MP in this bench model of protective ventilation, which might limit their benefits in ARDS.

Neurological and respiratory effects of lung protective ventilation in acute brain injury patients without lung injury: brain vent, a single centre randomized interventional study.

INTRODUCTION: Lung protective ventilation (LPV) comprising low tidal volume (VT) and high positive end-expiratory pressure (PEEP) may compromise cerebral perfusion in acute brain injury (ABI). In patients with ABI, we investigated whether LPV is associated with increased intracranial pressure (ICP) and/or deranged cerebral autoregulation (CA), brain compensatory reserve and oxygenation. METHODS: In a prospective, crossover study, 30 intubated ABI patients with normal ICP and no lung injury were randomly assigned to receive low VT [6 ml/kg/predicted (pbw)]/at either low (5 cmH2O) or high PEEP (12 cmH2O). Between each intervention, baseline ventilation (VT 9 ml/kg/pbw and PEEP 5 cmH2O) were resumed. The safety limit for interruption of the intervention was ICP above 22 mmHg for more than 5 min. Airway and transpulmonary pressures were continuously monitored to assess respiratory mechanics. We recorded ICP by using external ventricular drainage or a parenchymal probe. CA and brain compensatory reserve were derived from ICP waveform analysis. RESULTS: We included 27 patients (intracerebral haemorrhage, traumatic brain injury, subarachnoid haemorrhage), of whom 6 reached the safety limit, which required interruption of at least one intervention. For those without intervention interruption, the ICP change from baseline to "low VT/low PEEP" and "low VT/high PEEP" were 2.2 mmHg and 2.3 mmHg, respectively, and considered clinically non-relevant. None of the interventions affected CA or oxygenation significantly. Interrupted events were associated with high baseline ICP (p < 0.001), low brain compensatory reserve (p < 0.01) and mechanical power (p < 0.05). The transpulmonary driving pressure was 5 ± 2 cmH2O in both interventions. Partial arterial pressure of carbon dioxide was kept in the range 34-36 mmHg by adjusting the respiratory rate, hence, changes in carbon dioxide were not associated with the increase in ICP. CONCLUSIONS: The present study found that most patients did not experience any adverse effects of LPV, neither on ICP nor CA. However, in almost a quarter of patients, the ICP rose above the safety limit for interrupting the interventions. Baseline ICP, brain compensatory reserve, and mechanical power can predict a potentially deleterious effect of LPV and can be used to personalize ventilator settings. Trial registration NCT03278769 . Registered September 12, 2017.

Positive end-expiratory pressure-induced recruited lung volume measured by volume-pressure curves in acute respiratory distress syndrome: a physiologic systematic review and meta-analysis.

PURPOSE: Recruitment of lung volume is often cited as the reason for using positive end-expiratory pressure (PEEP) in acute respiratory distress syndrome (ARDS) patients. We performed a systematic review on PEEP-induced recruited lung volume measured from inspiratory volume-pressure (VP) curves in ARDS patients to assess the prevalence of patients with PEEP-induced recruited lung volume and the mortality in recruiters and non-recruiters. METHODS: We conducted a systematic search of PubMed to identify studies including ARDS patients in which the intervention of an increase in PEEP was accompanied by measurement of the recruited volume (Vrec increase versus no increase) using the VP curve in order to assess the relation between Vrec and mortality at ICU discharge. We first analysed the pooled data from the papers identified and then analysed individual patient level data received from the authors via personal contact. The risk of bias of the included papers was assessed using the quality in prognosis studies tool and the certainty of the evidence regarding the relationship of mortality to Vrec by the GRADE approach. Recruiters were defined as patients with a Vrec > 150 ml. A random effects model was used for the pooled data. Multivariable logistic regression analysis was used for individual patient data. RESULTS: We identified 16 papers with a total of 308 patients for the pooled data meta-analysis and 14 papers with a total of 384 patients for the individual data analysis. The quality of the articles was moderate. In the pooled data, the prevalence of recruiters was 74% and the mortality was not significantly different between recruiters and non-recruiters (relative risk 1.20 [95% confidence intervals 0.88-1.63]). The certainty of the evidence regarding this association was very low and publication bias evident. In the individual data, the prevalence of recruiters was 70%. In the multivariable logistic regression, Vrec was not associated with mortality but Simplified Acute Physiology Score II and driving pressure at PEEP of 5 cmH2O were. CONCLUSION: After a PEEP increment, most patients are recruiters. Vrec was not associated with ICU mortality. The presence of similar findings in the individual patient level analysis and the driving pressure at PEEP of 5 cmH2O was associated with mortality as previously reported validate our findings. Publication bias and the lack of prospective studies suggest more research is required.

Voxel-wise assessment of lung aeration changes on CT images using image registration: application to acute respiratory distress syndrome (ARDS).

PURPOSE: (1) To improve the accuracy of global and regional alveolar-recruitment quantification in CT scan pairs by accounting for lung-tissue displacements and deformation, (2) To propose a method for local-recruitment calculation. METHODS: Recruitment was calculated by subtracting the quantity of non-aerated lung tissues between expiration and inspiration. To assess global recruitment, lung boundaries were first interactively delineated at inspiration, and then they were warped based on automatic image registration to define the boundaries at expiration. To calculate regional recruitment, the lung mask defined at inspiration was cut into pieces, and these were also warped to encompass the same tissues at expiration. Local-recruitment map was calculated as follows: For each voxel at expiration, the matching location at inspiration was determined by image registration, non-aerated voxels were counted in the neighborhood of the respective locations, and the voxel count difference was normalized by the neighborhood size. The methods were evaluated on 120 image pairs of 12 pigs with experimental acute respiratory distress syndrome. RESULTS: The dispersion of global- and regional-recruitment values decreased when using image registration, compared to the conventional approach neglecting tissue motion. Local-recruitment maps overlaid onto the original images were visually consistent, and the sum of these values over the whole lungs was very close to the global-recruitment estimate, except four outliers. CONCLUSIONS: Image registration can compensate lung-tissue displacements and deformation, thus improving the quantification of alveolar recruitment. Local-recruitment calculation can also benefit from image registration, and its values can be overlaid onto the original image to display a local-recruitment map. They also can be integrated over arbitrarily shaped regions to assess regional or global recruitment.

Predicting the Impact of Diffuse Alveolar Damage through Open Lung Biopsy in Acute Respiratory Distress Syndrome-The PREDATOR Study.

The aim of this retrospective and international study is to identify those clinical variables associated with diffuse alveolar damage (DAD), and to explore the impact of DAD on hospital mortality risk. Inclusion criteria were: adult patients with acute respiratory distress syndrome (ARDS) undergoing open lung biopsy (OLB) during their intensive care unit (ICU) management. The main end-points were: DAD and hospital mortality. In the training (n = 193) and validation cohorts (n = 65), the respiratory rate (odd ratio (OR) 0.956; confidence interval (CI) 95% 0.918; 0.995) and coronary ischemia (OR 5.974; CI95% 1.668; 21.399) on the day of ARDS had an average area under the receiver operating characteristic curve (AUROC) of 0.660 (CI95% 0.585; 0.736) and 0.562 (0.417; 0.706), respectively. PEEP (OR 1.131; CI95% 1.051; 1.218) and coronary ischemia (OR 6.820; CI95% 1.856; 25.061) on the day of OLB had an average AUROC of 0.696 (CI95% 0.621; 0.769) and 0.534 (CI95% 0.391; 0.678), respectively, to predict DAD. DAD (OR 2.296; CI95% 1.228; 4.294), diabetes mellitus requiring insulin (OR 0.081; CI95% 0.009; 0.710) and the respiratory rate (OR 1.045; CI95% 1.001; 1.091) on the day of ARDS had an average AUROC of 0.659 (CI95% 0.583; 0.737) and 0.513 (CI95% 0.361; 0.664) to predict hospital mortality and DAD (OR 2.081; CI95% 1.053; 4.114), diabetes mellitus requiring insulin (OR 0.093; CI95% 0.009; 0.956), PaCO2 (OR 1.051; CI95% 1.019; 1.084), and platelets count (OR 0.999; CI95% 0.999; 0.999) the day of OLB had an average AUROC of 0.778 (CI95% 0.710; 0.843) and 0.634 (CI95%0.481; 0.787) to predict hospital mortalty in the training and validation cohorts, respectively. In conclusion, DAD could not to be predicted clinically and was significantly associated with hospital mortality.

Diagnostic yield and therapeutic impact of open lung biopsy in the critically ill patient.

BACKGROUND: Open lung biopsy (OLB) is a rare procedure in intensive care units (ICUs) for therapeutic management of acute respiratory failure (ARF). The purpose of this study was to analyze the diagnostic yield, therapeutic contribution and complications of OLB in ICU patients with ARF of unclear etiology, including acute respiratory distress syndrome (ARDS) and ARDS mimics. METHODS: Retrospective study conducted in a 10-bed ICU over a 13-year period. Patients undergoing OLB for ARF with undiagnosed infiltrates on CT scan were included. ARDS was defined according to Berlin criteria, and ARDS mimics as a condition looking like ARDS except for the presence of a known cause. OLB was contributive when the OLB findings yielded a specific diagnosis resulting in a change in the patients' treatment or management. RESULTS: Forty six patients were included (sex ratio = 2.5, median and [interquartile range] age = 69 [59-77] years, and admission SAPS II = 42 [33-50]. ARF corresponded to ARDS in 22 patients and to ARDS mimics in 16. OLB yielded 61 diagnoses in 45 patients including diffuse alveolar damage (N = 21), lung fibrosis (N = 18), and organizing pneumonia (N = 11). OLB was contributive in 37 patients (80%), including 13/16 ARDS mimickers. The main contributions of OLB were the introduction or maintenance of steroids (N = 32) and discontinuation of antibiotics (N = 9). In 4 patients OLB resulted directly in the decision to forgo life-sustaining treatment. OLB complications occurred in 16 patients (35%), in one case associated with fatal outcome. CONCLUSION: OLB can play a useful role in the management of ICU patients with ARF of undetermined origin, including ARDS mimickers. Further studies should be done to identify the groups of ICU patients likely to benefit from the procedure with minimum risk.

Change in cardiac output during Trendelenburg maneuver is a reliable predictor of fluid responsiveness in patients with acute respiratory distress syndrome in the prone position under protective ventilation.

BACKGROUND: Predicting fluid responsiveness may help to avoid unnecessary fluid administration during acute respiratory distress syndrome (ARDS). The aim of this study was to evaluate the diagnostic performance of the following methods to predict fluid responsiveness in ARDS patients under protective ventilation in the prone position: cardiac index variation during a Trendelenburg maneuver, cardiac index variation during an end-expiratory occlusion test, and both pulse pressure variation and change in pulse pressure variation from baseline during a tidal volume challenge by increasing tidal volume (VT) to 8 ml.kg-1. METHODS: This study is a prospective single-center study, performed in a medical intensive care unit, on ARDS patients with acute circulatory failure in the prone position. Patients were studied at baseline, during a 1-min shift to the Trendelenburg position, during a 15-s end-expiratory occlusion, during a 1-min increase in VT to 8 ml.kg-1, and after fluid administration. Fluid responsiveness was deemed present if cardiac index assessed by transpulmonary thermodilution increased by at least 15% after fluid administration. RESULTS: There were 33 patients included, among whom 14 (42%) exhibited cardiac arrhythmia at baseline and 15 (45%) were deemed fluid-responsive. The area under the receiver operating characteristic (ROC) curve of the pulse contour-derived cardiac index change during the Trendelenburg maneuver and the end-expiratory occlusion test were 0.90 (95% CI, 0.80-1.00) and 0.65 (95% CI, 0.46-0.84), respectively. An increase in cardiac index ≥ 8% during the Trendelenburg maneuver enabled diagnosis of fluid responsiveness with sensitivity of 87% (95% CI, 67-100), and specificity of 89% (95% CI, 72-100). The area under the ROC curve of pulse pressure variation and change in pulse pressure variation during the tidal volume challenge were 0.52 (95% CI, 0.24-0.80) and 0.59 (95% CI, 0.31-0.88), respectively. CONCLUSIONS: Change in cardiac index during a Trendelenburg maneuver is a reliable test to predict fluid responsiveness in ARDS patients in the prone position, while neither change in cardiac index during end-expiratory occlusion, nor pulse pressure variation during a VT challenge reached acceptable predictive performance to predict fluid responsiveness in this setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01965574 . Registered on 16 October 2013. The trial was registered 6 days after inclusion of the first patient.

Acute respiratory distress syndrome mimics: the role of lung biopsy.

PURPOSE OF REVIEW: Acute respiratory distress syndrome (ARDS) mimics is a condition looking like ARDS but that does not fulfill every criterion according to the recent Berlin definition. The purpose of this review is to better delineate ARDS mimics, to discuss why the complete diagnosis of ARDS is important, and to make a brief overview on the role of open lung biopsy in this setting. RECENT FINDINGS: Recent autopsy and lung biopsy data from ARDS patients compared lung histologic findings with the new Berlin definition of ARDS. Among them, there are some limited data about two niches, namely open lung biopsy and ARDS mimics suggesting that lung histology is important for making the diagnosis and offering the accurate management. This includes specific new treatments or stopping some medications toxic to the lung. Finally, ARDS with diffuse alveolar damage could be a specific subphenotype of ARDS with poor prognosis. SUMMARY: An ARDS mimic enhances the need of making ARDS diagnosis as comprehensive as possible. In some limited cases, open lung biopsy in skilled hands may have implications for management.

Hemophagocytic Lymphohistiocytosis in Intensive Care Unit: A 71-Case Strobe-Compliant Retrospective Study.

Hemophagocytic lymphohistiocytosis (HLH) is a critical condition that may lead to organ failure and early death. The aim of this retrospective observational study was to describe a cohort of HLH patients admitted to intensive care unit (ICU) and investigate the risk factors of early death.A positive HLH diagnosis was defined by an HScore ≥ 169. Univariate and multivariate analyses were carried out to investigate hospital and 28-day mortality risk factors. Between January 2002 and July 2014, 71 HLH cases were seen at our institution.The overall 28-day mortality (start at ICU admission) and hospital mortality were 38% and 68%, respectively. The factors associated with increased 28-day mortality were the sequential organ failure assessment score at ICU admission (P < .001) and advance in age (P = 0.03). The factors associated with increased hospital mortality were a high sequential organ failure assessment score at ICU admission (P < 0.01), advance in age (P = 0.04), and the presence of lymphoma-related HLH or HLH of unknown origin (P < 0.01).Organ failure overtops the classical early-death risk factors in adult ICU-admitted HLH patients. This failure and the subsequent early death may be prevented by timely specific cytotoxic therapies and the control of the underlying disease.

Open lung biopsy in nonresolving ARDS frequently identifies diffuse alveolar damage regardless of the severity stage and may have implications for patient management.

PURPOSE: The aim of the present study was to assess the rate of diffuse alveolar damage (DAD) on open lung biopsy (OLB) performed in the ICU for nonresolving ARDS. METHODS: A single-center retrospective study of patients meeting the Berlin definition criteria for ARDS who had undergone OLB for nonresolving ARDS. Patients were classified into mild, moderate and severe ARDS categories and according to the presence or absence of DAD on the OLB. The ARDS categories were assessed at baseline and at the time of the OLB. The OLBs were reviewed by two pathologists blinded to the ARDS classification. The primary endpoint was the rate of DAD according to the ARDS stage in the patients with nonresolving ARDS who had OLB. The secondary endpoint was the ability of DAD to predict ARDS among all the patients who had OLB. The same clinico-histopathological confrontation was cross validated in another ICU. RESULTS: From January 1998 to August 2013, 113 patients underwent OLB for acute hypoxemic respiratory failure, 83 of whom met the inclusion criteria for ARDS. At the time the OLB was performed, 11 of these patients had mild, 56 moderate, and 16 severe ARDS, respectively. The median (1st-3rd quartiles) time to OLB was 13 (10-18) and 9 (6-14) days from the onset of respiratory symptoms and from ARDS onset, respectively, with no statistical difference between the three ARDS groups. DAD was found in 48 (58 %) patients with ARDS, 4 (36 %) in the mild, 33 (59 %) in the moderate, and 11 (69 %) in the severe stage (P = 0.23). For the 113 patients who underwent OLB, the sensitivity and specificity of DAD to the Berlin definition was 0.58 (0.46-0.69) and 0.73 (0.54-0.88), respectively. Similar results were found in the other ICU. CONCLUSIONS: DAD is present in the majority of patients with nonresolving ARDs and its frequency is no different across the three ARDS stages. On this basis, the systematic use of steroids in nonresolving ARDS is not recommended.

Interaction of the Coxsackie and adenovirus receptor (CAR) with the cytoskeleton: binding to actin.

The Coxsackie and adenovirus receptor (CAR) is a cell adhesion molecule that is highly expressed in the developing brain. CAR is enriched in growth cone particles (GCP) after subcellular fractionation. In GCP, we identified actin as an interaction partner of the cytoplasmic domain of CAR. In vivo, actin and CAR co-immunoprecipitate and co-localize. In vitro, the binding is direct, with a K(d) of approximately 2.6 microM, and leads to actin bundling. We previously demonstrated that CAR interacts with microtubules. These data suggest a role for CAR in processes requiring dynamic reorganization of the cytoskeleton such as neurite outgrowth and cell migration.

Does gas exchange response to prone position predict mortality in hypoxemic acute respiratory failure?

OBJECTIVE: To determine whether gas exchange response to a first prone position session can predict patient outcome in hypoxemic acute respiratory failure. METHODS: Data from a previous multicenter randomized controlled trial were retrospectively analyzed for relationship between PaO(2)/FIO(2) ratio and PaCO(2) changes during the first 8-h prone position session to day 28 mortality rate; 370 prone position sessions were analyzed. Arterial blood gas was measured in supine position before proning and in prone position at the end of the session. Gas exchange improvement was defined as increase in the PaO(2)/FIO(2) ratio of more than 20% (PaO(2)R) or decrease in PaCO(2) of more than 1 mmHg (PaCO(2)R). MAIN RESULTS: The 28-day mortality rate was 26.5% in PaO(2)R-PaCO(2)R, 31.7% in PaO(2)R-PaCO(2)NR, 38.9% in PaO(2)NR-PaCO(2)R, and 43% in PaO(2)NR-PaCO(2)NR (log-rank 14.02, p = 0.003). In a Cox proportional hazards model the gas exchange response was a significant predictor to patient outcome with a 82.5% increase in risk of death in the case of PaO(2)NR-PaCO(2)R or PaO(2)NR-PaCO(2)NR, relative to the gas exchange improvement response (odds ratio 1.825). However, after adjusting for the difference in oxygenation between day 2 and day 1 the gas exchange response does no longer reach significance. CONCLUSION: In patients with hypoxemic acute respiratory failure initial improvement in gas exchange in the first PP session was associated with a better outcome, but this association disappeared when the change in oxygenation from day 1 to day 2 was taken into account, suggesting that underlying illness was the most important predictor of mortality in this patient population.

Quantitative assessment of regional alveolar ventilation and gas volume using 13N-N2 washout and PET.

UNLABELLED: Measurement of alveolar volume (Va) and regional ventilation (a) is crucial to understanding the pathophysiology of acute lung injury and ventilator-induced lung injury. PET has previously been used as a noninvasive, quantitative method to assess a, but formal validation of this technique in experimental lung injury is lacking. This study aims to validate Va and a regional assessment with PET, using inhaled (13)N-N(2) in pigs. METHODS: Two normal and 2 oleic acid-injured pigs were tracheotomized, mechanically ventilated, and studied in 5 different levels of ventilation by changing respiratory rate. In each experimental condition, lungs were washed-in and then washed-out with (13)N-N(2) through an open circuit in the ventilator. Using this method, multiframe images were acquired with a dedicated PET camera. Regions of interest (ROIs) were drawn on each lung. Regional time-activity curves during washout were generated for each ROI and fitted to a mono- and a bicompartmental model. Validation of this method was performed in 2 ways. First, regional values of predicted Va (Va(emission)) were compared with regional volume obtained independently from density analysis on a transmission scan (Va(trans)). Second, regional values of predicted a were summed in each animal during each experimental condition and compared with minute-ventilation values set on the ventilator. RESULTS: The bicompartmental model best fitted the experimental values in normal (94.7% [62.2%-100.0%] (median [interquartile range]) of the ROIs) as well as in injured animals (90.7% [81.6%-97.4%] of the ROIs) (P = 0.49). Va(emission) significantly correlated with Va(trans) (R(2) = 0.89, P < 0.001) but exceeded Va(trans) by 10%. Finally, a strongly and positively correlated with minute-ventilation in both normal (R(2) = 0.96, P < 0.001) and injured (R(2) = 0.96, P < 0.001) animals. CONCLUSION: Measurement of (13)N-N(2) washout using PET is accurate to assess regional alveolar volume and ventilation during experimental acute lung injury.