Comparison between high-flow nasal oxygen (HFNO) alternated with non-invasive ventilation (NIV) and HFNO and NIV alone in patients with COVID-19: a retrospective cohort study.

BACKGROUND: Non-invasive respiratory support (conventional oxygen therapy [COT], non-invasive ventilation [NIV], high-flow nasal oxygen [HFNO], and NIV alternated with HFNO [NIV + HFNO] may reduce the need for invasive mechanical ventilation (IMV) in patients with COVID-19. The outcome of patients treated non-invasively depends on clinical severity at admission. We assessed the need for IMV according to NIV, HFNO, and NIV + HFNO in patients with COVID-19 according to disease severity and evaluated in-hospital survival rates and hospital and intensive care unit (ICU) lengths of stay. METHODS: This cohort study was conducted using data collected between March 2020 and July 2021. Patients ≥ 18 years admitted to the ICU with a diagnosis of COVID-19 were included. Patients hospitalized for < 3 days, receiving therapy (COT, NIV, HFNO, or NIV + HFNO) for < 48 h, pregnant, and with no primary outcome data were excluded. The COT group was used as reference for multivariate Cox regression model adjustment. RESULTS: Of 1371 patients screened, 958 were eligible: 692 (72.2%) on COT, 92 (9.6%) on NIV, 31 (3.2%) on HFNO, and 143 (14.9%) on NIV + HFNO. The results for the patients in each group were as follows: median age (interquartile range): NIV (64 [49-79] years), HFNO (62 [55-70] years), NIV + HFNO (62 [48-72] years) (p = 0.615); heart failure: NIV (54.5%), HFNO (36.3%), NIV + HFNO (9%) (p = 0.003); diabetes mellitus: HFNO (17.6%), NIV + HFNO (44.7%) (p = 0.048). > 50% lung damage on chest computed tomography (CT): NIV (13.3%), HFNO (15%), NIV + HFNO (71.6%) (p = 0.038); SpO2/FiO2: NIV (271 [118-365] mmHg), HFNO (317 [254-420] mmHg), NIV + HFNO (229 [102-317] mmHg) (p = 0.001); rate of IMV: NIV (26.1%, p = 0.002), HFNO (22.6%, p = 0.023), NIV + HFNO (46.8%); survival rate: HFNO (83.9%), NIV + HFNO (63.6%) (p = 0.027); ICU length of stay: NIV (8.5 [5-14] days), NIV + HFNO (15 [10-25] days (p < 0.001); hospital length of stay: NIV (13 [10-21] days), NIV + HFNO (20 [15-30] days) (p < 0.001). After adjusting for comorbidities, chest CT score and SpO2/FiO2, the risk of IMV in patients on NIV + HFNO remained high (hazard ratio, 1.88; 95% confidence interval, 1.17-3.04). CONCLUSIONS: In patients with COVID-19, NIV alternating with HFNO was associated with a higher rate of IMV independent of the presence of comorbidities, chest CT score and SpO2/FiO2. Trial registration ClinicalTrials.gov identifier: NCT05579080.

Dyspnoea in acutely ill mechanically ventilated adult patients: an ERS/ESICM statement.

This statement outlines a review of the literature and current practice concerning the prevalence, clinical significance, diagnosis and management of dyspnoea in critically ill, mechanically ventilated adult patients. It covers the definition, pathophysiology, epidemiology, short- and middle-term impact, detection and quantification, and prevention and treatment of dyspnoea. It represents a collaboration of the European Respiratory Society (ERS) and the European Society of Intensive Care Medicine (ESICM). Dyspnoea ranks among the most distressing experiences that human beings can endure. Approximately 40% of patients undergoing invasive mechanical ventilation in the intensive care unit (ICU) report dyspnoea, with an average intensity of 45 mm on a visual analogue scale from 0 to 100 mm. Although it shares many similarities with pain, dyspnoea can be far worse than pain in that it summons a primal fear response. As such, it merits universal and specific consideration. Dyspnoea must be identified, prevented and relieved in every patient. In the ICU, mechanically ventilated patients are at high risk of experiencing breathing difficulties because of their physiological status and, in some instances, because of mechanical ventilation itself. At the same time, mechanically ventilated patients have barriers to signalling their distress. Addressing this major clinical challenge mandates teaching and training, and involves ICU caregivers and patients. This is even more important because, as opposed to pain which has become a universal healthcare concern, very little attention has been paid to the identification and management of respiratory suffering in mechanically ventilated ICU patients.

Dyspnoea in acutely ill mechanically ventilated adult patients: an ERS/ESICM statement.

This statement outlines a review of the literature and current practice concerning the prevalence, clinical significance, diagnosis and management of dyspnoea in critically ill, mechanically ventilated adult patients. It covers the definition, pathophysiology, epidemiology, short- and middle-term impact, detection and quantification, and prevention and treatment of dyspnoea. It represents a collaboration of the European Respiratory Society and the European Society of Intensive Care Medicine. Dyspnoea ranks among the most distressing experiences that human beings can endure. Approximately 40% of patients undergoing invasive mechanical ventilation in the intensive care unit (ICU) report dyspnoea, with an average intensity of 45 mm on a visual analogue scale from 0 to 100 mm. Although it shares many similarities with pain, dyspnoea can be far worse than pain in that it summons a primal fear response. As such, it merits universal and specific consideration. Dyspnoea must be identified, prevented and relieved in every patient. In the ICU, mechanically ventilated patients are at high risk of experiencing breathing difficulties because of their physiological status and, in some instances, because of mechanical ventilation itself. At the same time, mechanically ventilated patients have barriers to signalling their distress. Addressing this major clinical challenge mandates teaching and training, and involves ICU caregivers and patients. This is even more important because, as opposed to pain which has become a universal healthcare concern, very little attention has been paid to the identification and management of respiratory suffering in mechanically ventilated ICU patients.

Follow-up short and long-term mortalities of tracheostomized critically ill patients in an Italian multi-center observational study.

The effects of tracheostomy on outcome as well as on intra or post-operative complications is yet to be defined. Admission of patients with tracheostomy to rehabilitation facility is at higher risk of suboptimal care and increased mortality. The aim of the study was to investigate ICU mortality, clinical outcome and quality of life up to 12 months after ICU discharge in tracheostomized critically ill patients. This is a prospective, multi-center, cohort study endorsed by Italian Society of Anesthesia, Analgesia, Reanimation, and Intensive Care (SIAARTI Prot. n° 643/13) registered in Clinicaltrial.gov (NCT01899352). Patients admitted to intensive care unit (ICU) and requiring elective tracheostomy according to physician in charge decision were included in the study. The primary outcome was ICU mortality. Secondary outcomes included risk factors for ICU mortality, prevalence of mortality at follow-up, rate of discharge from the hospital and rehabilitation, quality of life, performance status, and management of tracheostomy cannula at 3-, 6, 12-months from the day of tracheostomy. 694 critically ill patients who were tracheostomized in the ICU were included. ICU mortality was 15.8%. Age, SOFA score at the day of the tracheostomy, and days of endotracheal intubation before tracheostomy were risk factors for ICU mortality. The regression tree analysis showed that SOFA score at the day of tracheostomy and age had a preeminent role for the choice to perform the tracheostomy. Of the 694 ICU patients with tracheostomy, 469 completed the 12-months follow-up. Mortality was 33.51% at 3-months, 45.30% at 6-months, and 55.86% at 12-months. Patients with tracheostomy were less likely discharged at home but at hospital facilities or rehabilitative structures; and quality of life of patients with tracheostomy was severely compromised at 3-6 and 12 months when compared with patients without tracheostomy. In patients admitted to ICU, tracheostomy is associated with high mortality, difficult rehabilitation, and decreased quality of life. The choice to perform a tracheostomy should be carefully weighed on family burden and health-related quality of life.Clinical trial registration: Clinicaltrial.gov (NCT01899352).

Individualized Thresholds of Hypoxemia and Hyperoxemia and their Effect on Outcome in Acute Brain Injured Patients: A Secondary Analysis of the ENIO Study.

BACKGROUND: In acute brain injury (ABI), the effects of hypoxemia as a potential cause of secondary brain damage and poor outcome are well documented, whereas the impact of hyperoxemia is unclear. The primary aim of this study was to assess the episodes of hypoxemia and hyperoxemia in patients with ABI during the intensive care unit (ICU) stay and to determine their association with in-hospital mortality. The secondary aim was to identify the optimal thresholds of arterial partial pressure of oxygen (PaO2) predicting in-hospital mortality. METHODS: We conducted a secondary analysis of a prospective multicenter observational cohort study. Adult patients with ABI (traumatic brain injury, subarachnoid aneurysmal hemorrhage, intracranial hemorrhage, ischemic stroke) with available data on PaO2 during the ICU stay were included. Hypoxemia was defined as PaO2 < 80 mm Hg, normoxemia was defined as PaO2 between 80 and 120 mm Hg, mild/moderate hyperoxemia was defined as PaO2 between 121 and 299 mm Hg, and severe hyperoxemia was defined as PaO2 levels ≥ 300 mm Hg. RESULTS: A total of 1,407 patients were included in this study. The mean age was 52 (±18) years, and 929 (66%) were male. Over the ICU stay, the fractions of patients in the study cohort who had at least one episode of hypoxemia, mild/moderate hyperoxemia, and severe hyperoxemia were 31.3%, 53.0%, and 1.7%, respectively. PaO2 values below 92 mm Hg and above 156 mm Hg were associated with an increased probability of in-hospital mortality. Differences were observed among subgroups of patients with ABI, with consistent effects only seen in patients without traumatic brain injury. CONCLUSIONS: In patients with ABI, hypoxemia and mild/moderate hyperoxemia were relatively frequent. Hypoxemia and hyperoxemia during ICU stay may influence in-hospital mortality. However, the small number of oxygen values collected represents a major limitation of the study.

Incidence and Outcomes of Acute Respiratory Distress Syndrome in Brain-Injured Patients Receiving Invasive Ventilation: A Secondary Analysis of the ENIO Study.

Background: Acute respiratory distress syndrome (ARDS) is an important pulmonary complication in brain-injured patients receiving invasive mechanical ventilation (IMV). We aimed to evaluate the incidence and association between ARDS and clinical outcomes in patients with different forms of acute brain injury requiring IMV in the intensive care unit (ICU). Methods: This was a preplanned secondary analysis of a prospective, multicenter, international cohort study (NCT03400904). We included brain-injured patients receiving IMV for ≥ 24 h. ARDS was the main exposure of interest and was identified during index ICU admission using the Berlin definition. We examined the incidence and adjusted association of ARDS with ICU mortality, ICU length of stay, duration of IMV, and extubation failure. Outcomes were evaluated using mixed-effect logistic regression and cause-specific Cox proportional hazards models. Results: 1492 patients from 67 hospitals and 16 countries were included in the analysis, of whom 137 individuals developed ARDS (9.2% of overall cohort). Across countries, the median ARDS incidence was 5.1% (interquartile range [IQR] 0-10; range 0-27.3). ARDS was associated with increased ICU mortality (adjusted odds ratio (OR) 2.66; 95% confidence interval [CI], 1.29-5.48), longer ICU length of stay (adjusted hazard ratio [HR] 0.59; 95% CI, 0.48-0.73), and longer duration of IMV (adjusted HR 0.54; 95% CI, 0.44-0.67). The association between ARDS and extubation failure approached statistical significance (adjusted HR 1.48; 95% CI 0.99-2.21). Higher ARDS severity was associated with incrementally longer ICU length of stay and longer cumulative duration of IMV. Findings remained robust in a sensitivity analysis evaluating the magnitude of unmeasured confounding. Conclusions: In this cohort of acutely brain-injured patients, the incidence of ARDS was similar to that reported in other mixed cohorts of critically ill patients. Development of ARDS was associated with worse outcomes.

Effects of positive end-expiratory pressure on brain oxygenation, systemic oxygen cascade and metabolism in acute brain injured patients: a pilot physiological cross-sectional study.

Patients with acute brain injury (ABI) often require the application of positive end-expiratory pressure (PEEP) to optimize mechanical ventilation and systemic oxygenation. However, the effect of PEEP on cerebral function and metabolism is unclear. The primary aim of this study was to evaluate the effects of PEEP augmentation test (from 5 to 15 cmH2O) on brain oxygenation, systemic oxygen cascade and metabolism in ABI patients. Secondary aims include to determine whether changes in regional cerebral oxygenation are reflected by changes in oxygenation cascade and metabolism, and to assess the correlation between brain oxygenation and mechanical ventilation settings. Single center, pilot cross-sectional observational study in an Academic Hospital. Inclusion criteria were: adult (> 18 y/o) patients with ABI and stable intracranial pressure, available gas exchange and indirect calorimetry (IC) monitoring. Cerebral oxygenation was monitored with near-infrared spectroscopy (NIRS) and different derived parameters were collected: variation (Δ) in oxy (O2)-hemoglobin (Hb) (ΔO2Hbi), deoxy-Hb(ΔHHbi), total-Hb(ΔcHbi), and total regional oxygenation (ΔrSO2). Oxygen cascade and metabolism were monitored with arterial/venous blood gas analysis [arterial partial pressure of oxygen (PaO2), arterial saturation of oxygen (SaO2), oxygen delivery (DO2), and lactate], and IC [energy expenditure (REE), respiratory quotient (RQ), oxygen consumption (VO2), and carbon dioxide production (VCO2)]. Data were measured at PEEP 5 cmH2O and 15 cmH2O and expressed as delta (Δ) values. Ten patients with ABI [median age 70 (IQR 62-75) years, 6 (60%) were male, median Glasgow Coma Scale at ICU admission 5.5 (IQR 3-8)] were included. PEEP augmentation from 5 to 15 cmH2O did not affect cerebral oxygenation, systemic oxygen cascade parameters, and metabolism. The arterial component of cerebral oxygenation was significantly correlated with DO2 (ΔO2HBi, rho = 0.717, p = 0.037). ΔrSO2 (rho = 0.727, p = 0.032), ΔcHbi (rho = 0.797, p = 0.013), and ΔHHBi (rho = 0.816, p = 0.009) were significantly correlated with SaO2, but not ΔO2Hbi. ΔrSO2 was significantly correlated with VCO2 (rho = 0.681, p = 0.049). No correlation between brain oxygenation and ventilatory parameters was found. PEEP augmentation test did not affect cerebral and systemic oxygenation or metabolism. Changes in cerebral oxygenation significantly correlated with DO2, SaO2, and VCO2. Cerebral oxygen monitoring could be considered for individualization of mechanical ventilation setting in ABI patients without high or instable intracranial pressure.

Dexmedetomidine improves pulmonary outcomes in thoracic surgery under one-lung ventilation: A meta-analysis.

INTRODUCTION: Dexmedetomidine improves intrapulmonary shunt in thoracic surgery and minimizes inflammatory response during one-lung ventilation (OLV). However, it is unclear whether such benefits translate into less postoperative pulmonary complications (PPCs). Our objective was to determine the impact of dexmedetomidine on the incidence of PPCs after thoracic surgery. METHODS: Major databases were used to identify randomized trials that compared dexmedetomidine versus placebo during thoracic surgery in terms of PPCs. Our primary outcome was atelectasis within 7 days after surgery. Other specific PPCs included hypoxemia, pneumonia, and acute respiratory distress syndrome (ARDS). Secondary outcome included intraoperative respiratory mechanics (respiratory compliance [Cdyn]) and postoperative lung function (forced expiratory volume [FEV1]). Random effects models were used to estimate odds ratios (OR). RESULTS: Twelve randomized trials, including 365 patients in the dexmedetomidine group and 359 in the placebo group, were analyzed in this meta-analysis. Patients in the dexmedetomidine group were less likely to develop postoperative atelectasis (2.3% vs 6.8%, OR 0.42, 95%CI 0.18-0.95, P = 0.04; low certainty) and hypoxemia (3.4% vs 11.7%, OR 0.26, 95%CI 0.10-0.68, P = 0.01; moderate certainty) compared to the placebo group. The incidence of postoperative pneumonia (3.2% vs 5.8%, OR 0.57, 95%CI 0.25-1.26, P = 0.17; moderate certainty) or ARDS (0.9% vs 3.5%, OR 0.39, 95%CI 0.07-2.08, P = 0.27; moderate certainty) was comparable between groups. Both intraoperative Cdyn and postoperative FEV1 were higher among patients that received dexmedetomidine with a mean difference of 4.42 mL/cmH2O (95%CI 3.13-5.72) and 0.27 L (95%CI 0.12-0.41), respectively. CONCLUSION: Dexmedetomidine administration during thoracic surgery may potentially reduce the risk of postoperative atelectasis and hypoxemia. However, current evidence is insufficient to demonstrate an effect on pneumonia or ARDS.

Preload Responsiveness in Patients With Acute Respiratory Distress Syndrome Managed With Extracorporeal Membrane Oxygenation.

A restrictive fluid strategy is recommended in patients with acute respiratory distress syndrome (ARDS) managed with venovenous extracorporeal membrane oxygenation (VV ECMO). However, there are no established predictors for preload responsiveness in these patients. In 20 ARDS patients managed with VV ECMO, transesophageal echocardiography was used to repeatedly evaluate dynamic parameters of the left (velocity and stroke volume variation) and right ventricular outflow tract (velocity [respiratory variations of the maximal Doppler velocity in the truncus pulmonalis {ΔV max TP}] and velocity time integral [respiratory variation of the velocity time integral measured in the truncus pulmonalis {ΔVTI_TP}] variation in the truncus pulmonalis), the diameter variation in the superior and inferior vena cava and stroke volume variation measured by pulse contour analysis (SVV_PCA). Patients were categorized as responders and nonresponders according to an increase in stroke volume measured by echocardiography during a Passive Leg Raise Test with a cutoff value ≥10%. The final analysis includes 86 measurements. Predictive values for preload responsiveness were found for ΔV max TP (area under the curve [AUC] of 0.64), ΔVTI_TP (AUC 0.67), and SVV_PCA (AUC 0.74). In conclusion, SVV_PCA and, to a lesser extent, ΔV max TP and ΔVTI_TP are the most accurate parameters to predict preload responsiveness in ARDS patients managed with VV ECMO. Transesophageal echocardiography offers no advantages over pulse contour analysis for predicting preload responsiveness and provides only intermittent monitoring and assessment.

Effects of different positive end-expiratory pressure titration strategies on mechanical power during ultraprotective ventilation in ARDS patients treated with veno-venous extracorporeal membrane oxygenation: A prospective interventional study.

PURPOSE: Ultraprotective ventilation in acute respiratory distress syndrome (ARDS) patients with veno-venous extracorporeal membrane oxygenation (VV ECMO) reduces mechanical power (MP) through changes in positive end-expiratory pressure (PEEP); however, the optimal approach to titrate PEEP is unknown. This study assesses the effects of three PEEP titration strategies on MP, hemodynamic parameters, and oxygen delivery in twenty ARDS patients with VV ECMO. MATERIAL AND METHODS: PEEP was titrated according to: (A) a PEEP of 10 cmH2O representing the lowest recommendation by the Extracorporeal Life Support Organization (PEEPELSO), (B) the highest static compliance of the respiratory system (PEEPCstat,RS), and (C) a target end-expiratory transpulmonary pressure of 0 cmH2O (PEEPPtpexp). RESULTS: PEEPELSO was lower compared to PEEPCstat,RS and PEEPPtpexp (10.0 ± 0.0 vs. 16.2 ± 4.7 cmH2O and 17.3 ± 4.0 cmH2O, p < 0.001 each, respectively). PEEPELSO reduced MP compared to PEEPCstat,RS and PEEPPtpexp (5.3 ± 1.3 vs. 6.8 ± 2.0 and 6.9 ± 2.3 J/min, p < 0.001 each, respectively). PEEPELSO resulted in less lung stress compared to PEEPCstat,RS (p = 0.011) and PEEPPtpexp (p < 0.001) and increased cardiac output and oxygen delivery (p < 0.001 each). CONCLUSIONS: An empirical PEEP of 10 cmH2O minimized MP, provided favorable hemodynamics, and increased oxygen delivery in ARDS patients treated with VV ECMO. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00013967). Registered 02/09/2018https://drks.de/search/en/trial/DRKS00013967.

Respiratory mechanics and mechanical power during low vs. high positive end-expiratory pressure in obese surgical patients - A sub-study of the PROBESE randomized controlled trial.

STUDY OBJECTIVE: We aimed to characterize intra-operative mechanical ventilation with low or high positive end-expiratory pressure (PEEP) and recruitment manoeuvres (RM) regarding intra-tidal recruitment/derecruitment and overdistension using non-linear respiratory mechanics, and mechanical power in obese surgical patients enrolled in the PROBESE trial. DESIGN: Prospective, two-centre substudy of the international, multicentre, two-arm, randomized-controlled PROBESE trial. SETTING: Operating rooms of two European University Hospitals. PATIENTS: Forty-eight adult obese patients undergoing abdominal surgery. INTERVENTIONS: Intra-operative protective ventilation with either PEEP of 12 cmH2O and repeated RM (HighPEEP+RM) or 4 cmH2O without RM (LowPEEP). MEASUREMENTS: The index of intra-tidal recruitment/de-recruitment and overdistension (%E2) as well as airway pressure, tidal volume (VT), respiratory rate (RR), resistance, elastance, and mechanical power (MP) were calculated from respiratory signals recorded after anesthesia induction, 1 h thereafter, and end of surgery (EOS). MAIN RESULTS: Twenty-four patients were analyzed in each group. PEEP was higher (mean ± SD, 11.7 ± 0.4 vs. 3.7 ± 0.6 cmH2O, P < 0.001) and driving pressure lower (12.8 ± 3.5 vs. 21.7 ± 6.8 cmH2O, P < 0.001) during HighPEEP+RM than LowPEEP, while VT and RR did not differ significantly (7.3 ± 0.6 vs. 7.4 ± 0.8 ml∙kg-1, P = 0.835; and 14.6 ± 2.5 vs. 15.7 ± 2.0 min-1, P = 0.150, respectively). %E2 was higher in HighPEEP+RM than in LowPEEP following induction (-3.1 ± 7.2 vs. -12.4 ± 10.2%; P < 0.001) and subsequent timepoints. Total resistance and elastance (13.3 ± 3.8 vs. 17.7 ± 6.8 cmH2O∙l∙s-2, P = 0.009; and 15.7 ± 5.5 vs. 28.5 ± 8.4 cmH2O∙l, P < 0.001, respectively) were lower during HighPEEP+RM than LowPEEP. Additionally, MP was lower in HighPEEP+RM than LowPEEP group (5.0 ± 2.2 vs. 10.4 ± 4.7 J∙min-1, P < 0.001). CONCLUSIONS: In this sub-cohort of PROBESE, intra-operative ventilation with high PEEP and RM reduced intra-tidal recruitment/de-recruitment as well as driving pressure, elastance, resistance, and mechanical power, as compared with low PEEP. TRIAL REGISTRATION: The PROBESE study was registered at www. CLINICALTRIALS: gov, identifier: NCT02148692 (submission for registration on May 23, 2014).

Hypothermia vs Normothermia in Patients With Cardiac Arrest and Nonshockable Rhythm: A Meta-Analysis.

Importance: International guidelines recommend body temperature control below 37.8 °C in unconscious patients with out-of-hospital cardiac arrest (OHCA); however, a target temperature of 33 °C might lead to better outcomes when the initial rhythm is nonshockable. Objective: To assess whether hypothermia at 33 °C increases survival and improves function when compared with controlled normothermia in unconscious adults resuscitated from OHCA with initial nonshockable rhythm. Data Sources: Individual patient data meta-analysis of 2 multicenter, randomized clinical trials (Targeted Normothermia after Out-of-Hospital Cardiac Arrest [TTM2; NCT02908308] and HYPERION [NCT01994772]) with blinded outcome assessors. Unconscious patients with OHCA and an initial nonshockable rhythm were eligible for the final analysis. Study Selection: The study cohorts had similar inclusion and exclusion criteria. Patients were randomized to hypothermia (target temperature 33 °C) or normothermia (target temperature 36.5 to 37.7 °C), according to different study protocols, for at least 24 hours. Additional analyses of mortality and unfavorable functional outcome were performed according to age, sex, initial rhythm, presence or absence of shock on admission, time to return of spontaneous circulation, lactate levels on admission, and the cardiac arrest hospital prognosis score. Data Extraction and Synthesis: Only patients who experienced OHCA and had a nonshockable rhythm with all causes of cardiac arrest were included. Variables from the 2 studies were available from the original data sets and pooled into a unique database and analyzed. Clinical outcomes were harmonized into a single file, which was checked for accuracy of numbers, distributions, and categories. The last day of follow-up from arrest was recorded for each patient. Adjustment for primary outcome and functional outcome was performed using age, gender, time to return of spontaneous circulation, and bystander cardiopulmonary resuscitation. Main Outcomes and Measures: The primary outcome was mortality at 3 months; secondary outcomes included unfavorable functional outcome at 3 to 6 months, defined as a Cerebral Performance Category score of 3 to 5. Results: A total of 912 patients were included, 490 from the TTM2 trial and 422 from the HYPERION trial. Of those, 442 had been assigned to hypothermia (48.4%; mean age, 65.5 years; 287 males [64.9%]) and 470 to normothermia (51.6%; mean age, 65.6 years; 327 males [69.6%]); 571 patients had a first monitored rhythm of asystole (62.6%) and 503 a presumed noncardiac cause of arrest (55.2%). At 3 months, 354 of 442 patients in the hypothermia group (80.1%) and 386 of 470 patients in the normothermia group (82.1%) had died (relative risk [RR] with hypothermia, 1.04; 95% CI, 0.89-1.20; P = .63). On the last day of follow-up, 386 of 429 in the hypothermia group (90.0%) and 413 of 463 in the normothermia group (89.2%) had an unfavorable functional outcome (RR with hypothermia, 0.99; 95% CI, 0.87-1.15; P = .97). The association of hypothermia with death and functional outcome was consistent across the prespecified subgroups. Conclusions and Relevance: In this individual patient data meta-analysis, including unconscious survivors from OHCA with an initial nonshockable rhythm, hypothermia at 33 °C did not significantly improve survival or functional outcome.

Pressure-support compared with pressure-controlled ventilation mitigates lung and brain injury in experimental acute ischemic stroke in rats.

BACKGROUND: We aimed to evaluate the pulmonary and cerebral effects of low-tidal volume ventilation in pressure-support (PSV) and pressure-controlled (PCV) modes at two PEEP levels in acute ischemic stroke (AIS). METHODS: In this randomized experimental study, AIS was induced by thermocoagulation in 30 healthy male Wistar rats. After 24 h, AIS animals were randomly assigned to PSV or PCV with VT = 6 mL/kg and PEEP = 2 cmH2O (PSV-PEEP2 and PCV-PEEP2) or PEEP = 5 cmH2O (PSV-PEEP5 and PCV-PEEP5) for 2 h. Lung mechanics, arterial blood gases, and echocardiography were evaluated before and after the experiment. Lungs and brain tissue were removed for histologic and molecular biology analysis. The primary endpoint was diffuse alveolar damage (DAD) score; secondary endpoints included brain histology and brain and lung molecular biology markers. RESULTS: In lungs, DAD was lower with PSV-PEEP5 than PCV-PEEP5 (p < 0.001); interleukin (IL)-1ß was lower with PSV-PEEP2 than PCV-PEEP2 (p = 0.016) and PSV-PEEP5 than PCV-PEEP5 (p = 0.046); zonula occludens-1 (ZO-1) was lower in PCV-PEEP5 than PCV-PEEP2 (p = 0.042). In brain, necrosis, hemorrhage, neuropil edema, and CD45 + microglia were lower in PSV than PCV animals at PEEP = 2 cmH2O (p = 0.036, p = 0.025, p = 0.018, p = 0.011, respectively) and PEEP = 5 cmH2O (p = 0.003, p = 0.003, p = 0.007, p = 0.003, respectively); IL-1ß was lower while ZO-1 was higher in PSV-PEEP2 than PCV-PEEP2 (p = 0.009, p = 0.007, respectively), suggesting blood-brain barrier integrity. Claudin-5 was higher in PSV-PEEP2 than PSV-PEEP5 (p = 0.036). CONCLUSION: In experimental AIS, PSV compared with PCV reduced lung and brain injury. Lung ZO-1 reduced in PCV with PEEP = 2 versus PEEP = 5 cmH2O, while brain claudin-5 increased in PSV with PEEP = 2 versus PEEP = 5 cmH2O.

Application of anti-inflammatory treatment in two different ovine Acute Respiratory Distress Syndrome injury models: a preclinical randomized intervention study.

Whilst the presence of 2 subphenotypes among the heterogenous Acute Respiratory Distress Syndrome (ARDS) population is becoming clinically accepted, subphenotype-specific treatment efficacy has yet to be prospectively tested. We investigated anti-inflammatory treatment in different ARDS models in sheep, previously shown similarities to human ARDS subphenotypes, in a preclinical, randomized, blinded study. Thirty anesthetized sheep were studied up to 48 h and randomized into: (a) OA: oleic acid (n = 15) and (b) OA-LPS: oleic acid and subsequent lipopolysaccharide (n = 15) to achieve a PaO2/FiO2 ratio of < 150 mmHg. Then, animals were randomly allocated to receive treatment with methylprednisolone or erythromycin or none. Assessed outcomes were oxygenation, pulmonary mechanics, hemodynamics and survival. All animals reached ARDS. Treatment with methylprednisolone, but not erythromycin, provided the highest therapeutic benefit in Ph2 animals, leading to a significant increase in PaO2/FiO2 ratio by reducing pulmonary edema, dead space ventilation and shunt fraction. Animals treated with methylprednisolone displayed a higher survival up to 48 h than all others. In animals treated with erythromycin, there was no treatment benefit regarding assessed physiological parameters and survival in both phenotypes. Treatment with methylprednisolone improves oxygenation and survival, more so in ovine phenotype 2 which resembles the human hyperinflammatory subphenotype.

Dexmedetomidine compared to low-dose ketamine better protected not only the brain but also the lungs in acute ischemic stroke.

BACKGROUND: Dexmedetomidine (DEX) and low-dose ketamine (KET) present neuroprotective effects in acute ischemic stroke (AIS); however, to date, no studies have evaluated which has better protective effects not only on the brain but also lungs in AIS. METHODS: AIS-induced Wistar rats (390 ± 30 g) were randomized after 24-h, receiving dexmedetomidine (STROKE-DEX, n = 10) or low-dose S(+)-ketamine (STROKE-KET, n = 10). After 1-h protective ventilation, perilesional brain tissue and lungs were removed for histologic and molecular biology analysis. STROKE animals (n = 5), receiving sodium thiopental but not ventilated, had brain and lungs removed for molecular biology analysis. Effects of DEX and KET mean plasma concentrations on alveolar macrophages, neutrophils, and lung endothelial cells, extracted primarily 24-h after AIS, were evaluated. RESULTS: In perilesional brain tissue, apoptosis did not differ between groups. In STROKE-DEX, compared to STROKE-KET, tumor necrosis factor (TNF)-α and vascular cell adhesion molecule-1 (VCAM-1) expressions were reduced, but no changes in nuclear factor erythroid 2-related factor-2 (Nrf2) and super oxide dismutase (SOD)-1 were observed. In lungs, TNF-α and VCAM-1 were reduced, whereas Nrf2 and SOD-1 were increased in STROKE-DEX. In alveolar macrophages, TNF-α and inducible nitric oxide synthase (M1 macrophage phenotype) were lower and arginase and transforming growth factor-ß (M2 macrophage phenotype) higher in STROKE-DEX. In lung neutrophils, CXC chemokine receptors (CXCR2 and CXCR4) were higher in STROKE-DEX. In lung endothelial cells, E-selectin and VCAM-1 were lower in STROKE-DEX. CONCLUSIONS: In the current AIS model, dexmedetomidine compared to low-dose ketamine reduced inflammation and endothelial cell damage in both brain and lung, suggesting greater protection.

Differences in directives to limit treatment and discontinue mechanical ventilation between elderly and very elderly patients: a substudy of a multinational observational study.

PURPOSE: The aim of this study was to characterize differences in directives to limit treatments and discontinue invasive mechanical ventilation (IMV) in elderly (65-80 years) and very elderly (> 80 years) intensive care unit (ICU) patients. METHODS: We prospectively described new written orders to limit treatments, IMV discontinuation strategies [direct extubation, direct tracheostomy, spontaneous breathing trial (SBT), noninvasive ventilation (NIV) use], and associations between initial failed SBT and outcomes in 142 ICUs from 6 regions (Canada, India, United Kingdom, Europe, Australia/New Zealand, United States). RESULTS: We evaluated 788 (586 elderly; 202 very elderly) patients. Very elderly (vs. elderly) patients had similar withdrawal orders but significantly more withholding orders, especially cardiopulmonary resuscitation and dialysis, after ICU admission [67 (33.2%) vs. 128 (21.9%); p = 0.002]. Orders to withhold reintubation were written sooner in very elderly (vs. elderly) patients [4 (2-8) vs. 7 (4-13) days, p = 0.02]. Very elderly and elderly patients had similar rates of direct extubation [39 (19.3%) vs. 113 (19.3%)], direct tracheostomy [10 (5%) vs. 40 (6.8%)], initial SBT [105 (52%) vs. 302 (51.5%)] and initial successful SBT [84 (80%) vs. 245 (81.1%)]. Very elderly patients experienced similar ICU outcomes (mortality, length of stay, duration of ventilation) but higher hospital mortality [26 (12.9%) vs. 38 (6.5%)]. Direct tracheostomy and initial failed SBT were associated with worse outcomes. Regional differences existed in withholding orders at ICU admission and in withholding and withdrawal orders after ICU admission. CONCLUSIONS: Very elderly (vs. elderly) patients had more orders to withhold treatments after ICU admission and higher hospital mortality, but similar ICU outcomes and IMV discontinuation. Significant regional differences existed in withholding and withdrawal practices.

Chemosensory proteins as putative semiochemical carriers in the desert isopod Hemilepistus reaumurii.

The order Isopoda contains both aquatic and terrestrial species, among which Hemilepistus reaumurii, which lives in arid environments and is the most adapted to terrestrial life. Olfaction has been deeply investigated in insects while it has received very limited attention in other arthropods, particularly in terrestrial crustaceans. In insects, soluble proteins belonging to two main families, Odorant Binding Proteins (OBPs) and Chemosensory Proteins (CSPs), are contained in the olfactory sensillar lymph and are suggested to act as carriers of hydrophobic semiochemicals to or from membrane-bound olfactory receptors. Other protein families, namely Nieman-Pick type 2 (NPC2) and Lipocalins (LCNs) have been also reported as putative odorant carriers in insects and other arthropod clades. In this study, we have sequenced and analysed the transcriptomes of antennae and of the first pair of legs of H. reaumurii focusing on soluble olfactory proteins. Interestingly, we have found 13 genes encoding CSPs, whose sequences differ from those of the other arthropod clades, including non-isopod crustaceans, for the presence of two additional cysteine residues, besides the four conserved ones. Binding assays on two of these proteins showed strong affinities for fatty acids and long-chain unsaturated esters and aldehydes, putative semiochemicals for this species.

One-Lung Ventilation and Postoperative Pulmonary Complications After Major Lung Resection Surgery. A Multicenter Randomized Controlled Trial.

OBJECTIVES: The effect of one-lung ventilation (OLV) strategy based on low tidal volume (TV), application of positive end-expiratory pressure (PEEP), and alveolar recruitment maneuvers (ARM) to reduce postoperative acute respiratory distress syndrome (ARDS) and pulmonary complications (PPCs) compared with higher TV without PEEP and ARM strategy in adult patients undergoing lobectomy or pneumonectomy has not been well established. DESIGN: Multicenter, randomized, single-blind, controlled trial. SETTING: Sixteen Italian hospitals. PARTICIPANTS: A total of 880 patients undergoing elective major lung resection. INTERVENTIONS: Patients were randomized to receive lower tidal volume (LTV group: 4 mL/kg predicted body weight, PEEP of 5 cmH2O, and ARMs) or higher tidal volume (HTL group: 6 mL/kg predicted body weight, no PEEP, and no ARMs). After OLV, until extubation, both groups were ventilated using a tidal volume of 8 mL/kg and a PEEP value of 5 cmH2O. The primary outcome was the incidence of in-hospital ARDS. Secondary outcomes were the in-hospital rate of PPCs, major cardiovascular events, unplanned intensive care unit (ICU) admission, in-hospital mortality, ICU length of stay, and in-hospital length of stay. MEASUREMENTS AND MAIN RESULTS: ARDS occurred in 3 of 438 patients (0.7%, 95% CI 0.1-2.0) and in 1 of 442 patients (0.2%, 95% CI 0-1.4) in the LTV and HTV group, respectively (Risk ratio: 3.03 95% CI 0.32-29, p = 0.372). Pulmonary complications occurred in 125 of 438 patients (28.5%, 95% CI 24.5-32.9) and in 136 of 442 patients (30.8%, 95% CI 26.6-35.2) in the LTV and HTV group, respectively (risk ratio: 0.93, 95% CI 0.76-1.14, p = 0.507). The incidence of major complications, in-hospital mortality, and unplanned ICU admission, ICU and in-hospital length of stay were comparable in both groups. CONCLUSIONS: In conclusion, among adult patients undergoing elective lung resection, an OLV with lower tidal volume, PEEP 5 cmH2O, and ARMs and a higher tidal volume strategy resulted in low ARDS incidence and comparable postoperative complications, in-hospital length of stay, and mortality.

Postoperative pulmonary complications and mortality after major abdominal surgery. An observational multicenter prospective study.

BACKGROUND: Postoperative pulmonary complications (PPCs) significantly contribute to postoperative morbidity and mortality. We conducted a study to determine the incidence of PPCs after major elective abdominal surgery and their association with early and 1-year mortality in patient without pre-existing respiratory disease. METHODS: We conducted a multicenter observational prospective clinical study in 40 Italian centers. 1542 patients undergoing elective major abdominal surgery were recruited in a time period of 14 days and clinically managed according to local protocol. The primary outcome was to determine the incidence of PPCs. Further, we aimed to identify independent predictors for PPCs and examine the association between PPCs and mortality. RESULTS: PPCs occurred in 12.6% (95% CI 11.1-14.4%) of patients with significant differences among general (18.3%, 95% CI 15.7-21.0%), gynecological (3.7%, 95% CI 2.1-6.0%) and urological surgery (9.0%, 95% CI 6.0-12.8%). PPCs development was associated with known pre- and intraoperative risk factors. Patients who developed PPCs had longer length of hospital stay, higher risk of 30-days hospital readmission, and increased in-hospital and one-year mortality (OR 3.078, 95% CI 1.825-5.191; P<0.001). CONCLUSIONS: The incidence of PPCs in patients without pre-existing respiratory disease undergoing elective abdominal surgery is high and associated with worse clinical outcome at one year after surgery. General surgery is associated with higher incidence of PPCs and mortality compared to gynecological and urological surgery.

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.