Impact of Positive End-Expiratory Pressure and FiO2 on Lung Mechanics and Intrapulmonary Shunt in Mechanically Ventilated Patients with ARDS Due to COVID-19 Pneumonia.

Purpose: This study aimed to investigate the effects of inspired oxygen fraction (FiO2) and positive end-expiratory pressure (PEEP) on gas exchange in mechanically ventilated patients with COVID-19. Methods: Two FiO2 (100%, 40%) were tested at 3 decreasing levels of PEEP (15, 10, and 5 cmH2O). At each FiO2 and PEEP, gas exchange, respiratory mechanics, hemodynamics, and the distribution of ventilation and perfusion were assessed with electrical impedance tomography. The impact of FiO2 on the intrapulmonary shunt (delta shunt) was analyzed as the difference between the calculated shunt at FiO2 100% (shunt) and venous admixture at FiO2 40% (venous admixture). Results: Fourteen patients were studied. Decreasing PEEP from 15 to 10 cmH2O did not change shunt (24 [21-28] vs 27 [24-29]%) or venous admixture (18 [15-26] vs 23 [18-34]%) while partial pressure of arterial oxygen (FiO2 100%) was higher at PEEP 15 (262 [198-338] vs 256 [147-315] mmHg; P < .05). Instead when PEEP was decreased from 10 to 5 cmH2O, shunt increased to 36 [30-39]% (P < .05) and venous admixture increased to 33 [30-43]% (P < .05) and partial pressure of arterial oxygen (100%) decreased to 109 [76-177] mmHg (P < .05). At PEEP 15, administration of 100% FiO2 resulted in a shunt greater than venous admixture at 40% FiO2, ((24 [21-28] vs 18 [15-26]%, P = .005), delta shunt 5.5% (2.3-8.8)). Compared to PEEP 10, PEEP of 5 and 15 cmH2O resulted in decreased global and pixel-level compliance. Cardiac output at FiO2 100% resulted higher at PEEP 5 (5.4 [4.4-6.5]) compared to PEEP 10 (4.8 [4.1-5.5], P < .05) and PEEP 15 cmH2O (4.7 [4.5-5.4], P < .05). Conclusion: In this study, PEEP of 15 cmH2O, despite resulting in the highest oxygenation, was associated with overdistension. PEEP of 5 cmH2O was associated with increased shunt and alveolar collapse. Administration of 100% FiO2 was associated with an increase in intrapulmonary shunt in the setting of high PEEP. Trial registration: NCT05132933.

Incidence of asymptomatic catheter-related thrombosis in intensive care unit patients: a prospective cohort study.

BACKGROUND: Catheter-related thrombosis (CRT) incidence, rate, and risk factors vary in literature due to differences in populations, catheters, diagnostic methods, and statistical approaches. The aim of this single-center, prospective, observational study was to assess incidence, incidence rate (IR), cumulative incidence, and risk factors by means of IR ratio (IRR) of asymptomatic CRT in a non-oncologic Intensive Care Unit (ICU) population. CRT development was assessed daily by means of ultrasound screening. The proportions of patients and catheters developing CRT and CRT incidence rates, expressed as the number of events per catheter-days (cd), were calculated. Kalbfleisch and Prentice's method was used to estimate the cumulative incidence of CRTs. Univariate and multivariable Poisson regression models were fitted to calculate IRR in risk factors analysis. RESULTS: Fifty (25%, 95% CI 19-31) out of 203 included patients, and 52 (14%, 95% CI 11-18) out of 375 catheters inserted developed CRT [IR 17.7 (13.5-23.2) CRTs/1000*cd], after 5 [3-10] days from insertion. Forty-six CRTs (88%) were partial thrombosis. All CRTs remained asymptomatic. Obesity and ECMO support were patient-related protective factors [IRR 0.24 (0.10-0.60), p = 0.002 and 0.05 (0.01-0.50), p = 0.011, respectively]. The internal jugular vein had higher CRT IR than other sites [20.1 vs. 5.9 CRTs/1000*cd, IRR 4.22 (1.22-14.63), p = 0.023]. Pulmonary artery catheter and left-side cannulation were catheter-related risk factors [IRR 4.24 (2.00-9.00), p < 0.001 vs. central venous catheters; IRR 2.69 (1.45-4.98), p = 0.002 vs. right cannulation, respectively]. No statistically significant effect of the number of simultaneously inserted catheters [IRR 1.11 (0.64-1.94), p = 0.708] and of the catheterization length [IRR 1.09 (0.97-1.22), p = 0.155] was detected. The ICU length of stay was longer in CRT patients (20 [15-31] vs. 6 [4-14] days, p < 0.001), while no difference in mortality was observed. CONCLUSIONS: CRTs are frequent but rarely symptomatic. This study suggests that obesity and ECMO are protective factors, while pulmonary artery catheter, internal jugular vein and left-side positioning are risk factors for CRT.

Mechanical Ventilation for COVID-19 Patients.

Non-invasive ventilation (NIV) or invasive mechanical ventilation (MV) is frequently needed in patients with acute hypoxemic respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. While NIV can be delivered in hospital wards and nonintensive care environments, intubated patients require intensive care unit (ICU) admission and support. Thus, the lack of ICU beds generated by the pandemic has often forced the use of NIV in severely hypoxemic patients treated outside the ICU. In this context, awake prone positioning has been widely adopted to ameliorate oxygenation during noninvasive respiratory support. Still, the incidence of NIV failure and the role of patient self-induced lung injury on hospital outcomes of COVID-19 subjects need to be elucidated. On the other hand, endotracheal intubation is indicated when gas exchange deterioration, muscular exhaustion, and/or neurological impairment ensue. Yet, the best timing for intubation in COVID-19 is still widely debated, as it is the safest use of neuromuscular blocking agents. Not differently from other types of acute respiratory distress syndrome, the aim of MV during COVID-19 is to provide adequate gas exchange while avoiding ventilator-induced lung injury. At the same time, the use of rescue therapies is advocated when standard care is unable to guarantee sufficient organ support. Nevertheless, the general shortage of health care resources experienced during SARS-CoV-2 pandemic might affect the utilization of high-cost, highly specialized, and long-term supports. In this article, we describe the state-of-the-art of NIV and MV setting and their usage for acute hypoxemic respiratory failure of COVID-19 patients.

Individualized positive end-expiratory pressure guided by end-expiratory lung volume in early acute respiratory distress syndrome: study protocol for the multicenter, randomized IPERPEEP trial.

BACKGROUND: In acute respiratory distress syndrome (ARDS), response to positive end-expiratory pressure (PEEP) is variable according to different degrees of lung recruitability. The search for a tool to individualize PEEP based on patients' individual response is warranted. End-expiratory lung volume (EELV) assessment by nitrogen washing-washout aids bedside estimation of PEEP-induced alveolar recruitment and may therefore help titrate PEEP on patient's individual recruitability. We designed a randomized trial to test whether an individualized PEEP setting protocol driven by EELV measurement may improve a composite clinical outcome in patients with moderate-to-severe ARDS (IPERPEEP trial). METHODS: IPERPEEP is an open-label, multicenter, randomized trial that will be conducted in 10 intensive care units in Italy and will enroll 132 ARDS patients showing PaO2/FiO2 ratio ≤ 150 mmHg within 24 h from endotracheal intubation while on mechanical ventilation with PEEP 5 cmH2O. To standardize lung volumes at study initiation, all patients will undergo mechanical ventilation with tidal volume of 6 ml/kg of predicted body weight and PEEP set to obtain a plateau pressure within 28 and 30 cmH2O for 30 min (EXPRESS PEEP). Afterwards, a 5-step decremental PEEP trial will be conducted (EXPRESS PEEP to PEEP 5 cmH2O), and EELV will be measured at each step. Recruitment-to-inflation ratio will be calculated for each PEEP range from EELV difference. Patients will be then randomized to receive mechanical ventilation with PEEP set according to the optimal recruitment observed in the PEEP trial (IPERPEEP arm) trial or to achieve a plateau pressure of 28-30 cmH2O (control arm, EXPRESS strategy). In both groups, tidal volume size, use of prone positioning and neuromuscular blocking agents, and weaning from PEEP and from mechanical ventilation will be standardized. The primary endpoint of the study is a composite clinical outcome incorporating in-ICU mortality, 60-day ventilator-free days, and serum interleukin-6 concentration over the course of the initial 72 h of treatment. DISCUSSION: The IPERPEEP study is a randomized trial powered to elucidate whether an individualized PEEP setting protocol based on bedside assessment of lung recruitability can improve a composite clinical outcome during moderate-to-severe ARDS. TRIAL REGISTRATION: ClinicalTrials.gov NCT04012073 . Registered 9 July 2019.

Prone position in intubated, mechanically ventilated patients with COVID-19: a multi-centric study of more than 1000 patients.

BACKGROUND: Limited data are available on the use of prone position in intubated, invasively ventilated patients with Coronavirus disease-19 (COVID-19). Aim of this study is to investigate the use and effect of prone position in this population during the first 2020 pandemic wave. METHODS: Retrospective, multicentre, national cohort study conducted between February 24 and June 14, 2020, in 24 Italian Intensive Care Units (ICU) on adult patients needing invasive mechanical ventilation for respiratory failure caused by COVID-19. Clinical data were collected on the day of ICU admission. Information regarding the use of prone position was collected daily. Follow-up for patient outcomes was performed on July 15, 2020. The respiratory effects of the first prone position were studied in a subset of 78 patients. Patients were classified as Oxygen Responders if the PaO2/FiO2 ratio increased ≥ 20 mmHg during prone position and as Carbon Dioxide Responders if the ventilatory ratio was reduced during prone position. RESULTS: Of 1057 included patients, mild, moderate and severe ARDS was present in 15, 50 and 35% of patients, respectively, and had a resulting mortality of 25, 33 and 41%. Prone position was applied in 61% of the patients. Patients placed prone had a more severe disease and died significantly more (45% vs. 33%, p < 0.001). Overall, prone position induced a significant increase in PaO2/FiO2 ratio, while no change in respiratory system compliance or ventilatory ratio was observed. Seventy-eight % of the subset of 78 patients were Oxygen Responders. Non-Responders had a more severe respiratory failure and died more often in the ICU (65% vs. 38%, p = 0.047). Forty-seven % of patients were defined as Carbon Dioxide Responders. These patients were older and had more comorbidities; however, no difference in terms of ICU mortality was observed (51% vs. 37%, p = 0.189 for Carbon Dioxide Responders and Non-Responders, respectively). CONCLUSIONS: During the COVID-19 pandemic, prone position has been widely adopted to treat mechanically ventilated patients with respiratory failure. The majority of patients improved their oxygenation during prone position, most likely due to a better ventilation perfusion matching. TRIAL REGISTRATION: clinicaltrials.gov number: NCT04388670.

Viscoelastic Coagulation Monitor as a Novel Device to Assess Coagulation at the Bedside. A Single-Center Experience During the COVID-19 Pandemic.

Viscoelastic coagulation monitor (VCM) is a portable device developed to evaluate the viscoelastic properties of whole blood activated by contact with glass. In this study, VCM was employed to analyze the viscoelastic profiles of 36 COVID-19 intensive care patients. Full anticoagulant dose heparin (unfractionated [UFH]; low molecular weight [LMWH]) was administrated to all patients. The association between VCM and laboratory parameters was retrospectively analyzed. The administration of UFH-influenced VCM parameters prolonging clotting time (CT) and clot formation time (CFT) and reducing angle (alpha) and amplitudes of the VCM tracings (A10, A20, and maximum clot firmness [MCF]) compared with LMWH therapy. A tendency toward hypercoagulation was observed by short CT and CFT in patients receiving LMWH. Clotting time was correlated with UFH dose (Spearman's rho = 0.48, p ≤ 0.001), and no correlation was found between CT and LMWH. All VCM tracings failed to show lysis at 30 and 45 minutes, indicating the absence of fibrinolysis. A10, A20, and MCF exhibited very-good to good diagnostic accuracy for detecting platelet count and fibrinogen above the upper reference limit of the laboratory. In conclusion, VCM provided reliable results in COVID-19 patients and was easy to perform with minimal training at the bedside.

The Medical Emergency Team in Italy: an overview of in-hospital emergencies response.

BACKGROUND AND AIM: Medical Emergency Team (MET), implemented in many hospitals worldwide, aims to improve the safety of in-hospital patients whose condition is deteriorating. This study describes MET presence and organization in the Italian National Healthcare System Hospitals. METHODS: A national survey with an online questionnaire was performed. The questionnaire, created ad hoc, was sent by e-mail to the nursing coordinators and MET referents of the Hospitals affiliated to the Italian National Healthcare System with an Anesthesia and Intensive Care service. RESULTS: One hundred-ninety-seven hospitals were interviewed (36.2% of the whole national network). A dedicated MET, composed at least by an intensivist and a nurse, was present only in 118 cases (59.9%). The team was composed by a non-dedicated staff (67.8% of doctors, 69.5% of nurses) and a minimum shared standard of education for the nurse component was absent. One third of the estimated hospitals did not use a warning score for emergency call activation. DISCUSSION AND CONCLUSION: This survey showed a heterogenous and often lacking organization of in-hospital emergency management in Italy. MET system needs to be implemented in terms of presence in the Italian hospitals, and standardized for personnel structure and training, and equipment availability. A broader study is necessary to compare our data with those of other European Countries to better identify the specific areas which need to be improved more promptly.

Monitoring respiratory mechanics during assisted ventilation.

PURPOSE OF REVIEW: Accurate monitoring of the mechanical properties of the respiratory system is crucial to understand the pathophysiological mechanisms of respiratory failure in mechanically ventilated patients, to optimize mechanical ventilation settings and to reduce ventilator-induced lung injury. However, although the assessment of respiratory mechanics is simple in patients undergoing fully controlled ventilation, it becomes quite challenging in the presence of spontaneous breathing activity. Aim of the present review is to describe how the different components of respiratory mechanics [resistance, static compliance, and intrinsic positive end-expiratory pressure (PEEP)] can be measured at the bedside during assisted modes of ventilation. RECENT FINDINGS: Available techniques for bedside measurement of resistance during assisted ventilation are complex and not commonly implemented. On the contrary, an increasing number of reports indicate that measurement of static compliance and intrinsic PEEP can be easily obtained, both with advanced monitoring systems (esophageal and gastric manometry, diaphragm electromyography, electrical impedance tomography) and, with some limitations, with simple airways occlusion maneuvers. SUMMARY: Assessment of respiratory mechanics in spontaneously breathing patients, with some limitations, is feasible and should be included in everyday clinical practice; however, more data are needed to understand the clinical relevance of the measures obtained during assisted ventilation.

Respiratory Mechanics, Lung Recruitability, and Gas Exchange in Pulmonary and Extrapulmonary Acute Respiratory Distress Syndrome.

OBJECTIVES: Acute respiratory distress syndrome is a clinical syndrome characterized by a refractory hypoxemia due to an inflammatory and high permeability pulmonary edema secondary to direct or indirect lung insult (pulmonary and extrapulmonary form). Aim of this study was to evaluate in a large database of acute respiratory distress syndrome patients, the pulmonary versus extrapulmonary form in terms of respiratory mechanics, lung recruitment, gas exchange, and positive end-expiratory pressure response. DESIGN: A secondary analysis of previously published data. PATIENTS: One-hundred eighty-one sedated and paralyzed acute respiratory distress syndrome patients (age 60 yr [46-72 yr], body mass index 25 kg/m [22-28 kg/m], and PaO2/FIO2 184 ± 66). INTERVENTIONS: Lung CT scan performed at 5 and 45 cm H2O. Two levels of positive end-expiratory pressure (5 and 15 cm H2O) were randomly applied. MEASUREMENTS AND MAIN RESULTS: Ninety-seven and 84 patients had a pulmonary and extrapulmonary acute respiratory distress syndrome. The median time from intensive care admission to the CT scan and respiratory mechanics analysis was 4 days (interquartile range, 2-6). At both positive end-expiratory pressure levels, pulmonary acute respiratory distress syndrome presented a significantly lower PaO2/FIO2 and higher physiologic dead space compared with extrapulmonary acute respiratory distress syndrome. The lung and chest wall elastance were similar between groups. The intra-abdominal pressure was significantly higher in extrapulmonary compared with pulmonary acute respiratory distress syndrome (10 mm Hg [7-12 mm Hg] vs 7 mm Hg [5-8 mm Hg]). The lung weight and lung recruitability were significantly higher in pulmonary acute respiratory distress syndrome (1,534 g [1,286-1,835 g] vs 1,342 g [1,090-1,507 g] and 16% [9-25%] vs 9% [5-14%]). CONCLUSIONS: In the early stage, pulmonary acute respiratory distress syndrome is characterized by a greater impairment of gas exchange and higher lung recruitability. The recognition of the origin of acute respiratory distress syndrome is important for a more customized ventilatory management.

Inflammation and primary graft dysfunction after lung transplantation: CT-PET findings.

BACKGROUND: The leading cause of early mortality after lung transplantation is Primary graft dysfunction (PGD). We assessed the lung inflammation, inflation status and inhomogeneities after lung transplantation. Our purpose was to investigate the possible differences between patients who did or did not develop PGD. METHODS: We designed a prospective observational study enrolling patients who underwent a CT-PET study within 1 week after lung transplantation. Twenty-four patients (10 after double- and 14 after single-lung) were enrolled. Respiratory and hemodynamic data were collected before, during and after lung transplantation. Each patient underwent computed tomography-positron emission tomography (CT-PET) scan early after surgery. Broncho-alveolar lavage (BAL) fluid collection was performed to analyze inflammatory mediators. RESULTS: The grafts showed a [18F]fluoro-2-deoxy-D-glucose ([18F]FDG) uptake rate of 26[18-33]*10-4 mLblood/mLtissue/min (reference values 11[7-15]*10-4). Three double- and six single-lung recipients developed PGD. The grafts of patients who developed PGD had similar [18F]FDG uptake than grafts of patients who did not (28[18-26]*10-4 versus 26[22-31]*10-4, P=0.79). Not-inflated tissue fraction was significantly higher (28[20-38]% versus 14[7-21]%, P=0.01) while well-inflated fraction was significantly lower (29[25-41]% versus 53[39-65]%, P<0.01). Inhomogeneity extent was higher in patients who developed PGD (23[18-26]% versus 14[10-20]%, P=0.01)The lung weight was 650[591-820]g versus 597[480-650]g (P=0.09)). BAL fluid analysis for inflammatory mediators did not detect a difference between the study groups. CONCLUSIONS: Compared to healthy lungs, all the grafts showed increased [18F]FDG uptake rate, but there were no differences between patients who developed PGD and patients who did not. Of note, the PGD patients showed a worse inflation status of lungs and a higher inhomogeneity extent.

Thromboelastography-based anticoagulation management during extracorporeal membrane oxygenation: a safety and feasibility pilot study.

BACKGROUND: There is no consensus on the management of anticoagulation during extracorporeal membrane oxygenation (ECMO). ECMO is currently burdened by a high rate of hemostatic complications, possibly associated with inadequate monitoring of heparin anticoagulation. This study aims to assess the safety and feasibility of an anticoagulation protocol for patients undergoing ECMO based on thromboelastography (TEG) as opposed to an activated partial thromboplastin time (aPTT)-based protocol. METHODS: We performed a multicenter, randomized, controlled trial in two academic tertiary care centers. Adult patients with acute respiratory failure treated with veno-venous ECMO were randomized to manage heparin anticoagulation using a TEG-based protocol (target 16-24 min of the R parameter, TEG group) or a standard of care aPTT-based protocol (target 1.5-2 of aPTT ratio, aPTT group). Primary outcomes were safety and feasibility of the study protocol. RESULTS: Forty-two patients were enrolled: 21 were randomized to the TEG group and 21 to the aPTT group. Duration of ECMO was similar in the two groups (9 (7-16) days in the TEG group and 11 (4-17) days in the aPTT group, p = 0.74). Heparin dosing was lower in the TEG group compared to the aPTT group (11.7 (9.5-15.3) IU/kg/h vs. 15.7 (10.9-21.3) IU/kg/h, respectively, p = 0.03). Safety parameters, assessed as number of hemorrhagic or thrombotic events and transfusions given, were not different between the two study groups. As for the feasibility, the TEG-based protocol triggered heparin infusion rate adjustments more frequently (p < 0.01) and results were less frequently in the target range compared to the aPTT-based protocol (p < 0.001). Number of prescribed TEG or aPTT controls (according to study groups) and protocol violations were not different between the study groups. CONCLUSIONS: TEG seems to be safely used to guide anticoagulation management during ECMO. Its use was associated with the administration of lower heparin doses compared to a standard of care aPTT-based protocol. Trial registration ClinicalTrials.gov, October 22,2014. Identifier: NCT02271126.

Opening pressures and atelectrauma in acute respiratory distress syndrome.

PURPOSE: Open lung strategy during ARDS aims to decrease the ventilator-induced lung injury by minimizing the atelectrauma and stress/strain maldistribution. We aim to assess how much of the lung is opened and kept open within the limits of mechanical ventilation considered safe (i.e., plateau pressure 30 cmH2O, PEEP 15 cmH2O). METHODS: Prospective study from two university hospitals. Thirty-three ARDS patients (5 mild, 10 moderate, 9 severe without extracorporeal support, ECMO, and 9 severe with it) underwent two low-dose end-expiratory CT scans at PEEP 5 and 15 cmH2O and four end-inspiratory CT scans (from 19 to 40 cmH2O). Recruitment was defined as the fraction of lung tissue which regained inflation. The atelectrauma was estimated as the difference between the intratidal tissue collapse at 5 and 15 cmH2O PEEP. Lung ventilation inhomogeneities were estimated as the ratio of inflation between neighboring lung units. RESULTS: The lung tissue which is opened between 30 and 45 cmH2O (i.e., always closed at plateau 30 cmH2O) was 10 ± 29, 54 ± 86, 162 ± 92, and 185 ± 134 g in mild, moderate, and severe ARDS without and with ECMO, respectively (p < 0.05 mild versus severe without or with ECMO). The intratidal collapses were similar at PEEP 5 and 15 cmH2O (63 ± 26 vs 39 ± 32 g in mild ARDS, p = 0.23; 92 ± 53 vs 78 ± 142 g in moderate ARDS, p = 0.76; 110 ± 91 vs 89 ± 93, p = 0.57 in severe ARDS without ECMO; 135 ± 100 vs 104 ± 80, p = 0.32 in severe ARDS with ECMO). Increasing the applied airway pressure up to 45 cmH2O decreased the lung inhomogeneity slightly (but significantly) in mild and moderate ARDS, but not in severe ARDS. CONCLUSIONS: Data show that the prerequisites of the open lung strategy are not satisfied using PEEP up to 15 cmH2O and plateau pressure up to 30 cmH2O. For an effective open lung strategy, higher pressures are required. Therefore, risks of atelectrauma must be weighted versus risks of volutrauma. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01670747 ( www.clinicaltrials.gov ).

Airway driving pressure and lung stress in ARDS patients.

BACKGROUND: Lung-protective ventilation strategy suggests the use of low tidal volume, depending on ideal body weight, and adequate levels of PEEP. However, reducing tidal volume according to ideal body weight does not always prevent overstress and overstrain. On the contrary, titrating mechanical ventilation on airway driving pressure, computed as airway pressure changes from PEEP to end-inspiratory plateau pressure, equivalent to the ratio between the tidal volume and compliance of respiratory system, should better reflect lung injury. However, possible changes in chest wall elastance could affect the reliability of airway driving pressure. The aim of this study was to evaluate if airway driving pressure could accurately predict lung stress (the pressure generated into the lung due to PEEP and tidal volume). METHODS: One hundred and fifty ARDS patients were enrolled. At 5 and 15 cmH2O of PEEP, lung stress, driving pressure, lung and chest wall elastance were measured. RESULTS: The applied tidal volume (mL/kg of ideal body weight) was not related to lung gas volume (r (2) = 0.0005 p = 0.772). Patients were divided according to an airway driving pressure lower and equal/higher than 15 cmH2O (the lower and higher airway driving pressure groups). At both PEEP levels, the higher airway driving pressure group had a significantly higher lung stress, respiratory system and lung elastance compared to the lower airway driving pressure group. Airway driving pressure was significantly related to lung stress (r (2) = 0.581 p < 0.0001 and r (2) = 0.353 p < 0.0001 at 5 and 15 cmH2O of PEEP). For a lung stress of 24 and 26 cmH2O, the optimal cutoff value for the airway driving pressure were 15.0 cmH2O (ROC AUC 0.85, 95 % CI = 0.782-0.922); and 16.7 (ROC AUC 0.84, 95 % CI = 0.742-0.936). CONCLUSIONS: Airway driving pressure can detect lung overstress with an acceptable accuracy. However, further studies are needed to establish if these limits could be used for ventilator settings.

Severe hypoxemia: which strategy to choose.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is characterized by a noncardiogenic pulmonary edema with bilateral chest X-ray opacities and reduction in lung compliance, and the hallmark of the syndrome is hypoxemia refractory to oxygen therapy. Severe hypoxemia (PaO2/FiO2 < 100 mmHg), which defines severe ARDS, can be found in 20-30 % of the patients and is associated with the highest mortality rate. Although the standard supportive treatment remains mechanical ventilation (noninvasive and invasive), possible adjuvant therapies can be considered. We performed an up-to-date clinical review of the possible available strategies for ARDS patients with severe hypoxemia. MAIN RESULTS: In summary, in moderate-to-severe ARDS or in the presence of other organ failure, noninvasive ventilatory support presents a high risk of failure: in those cases the risk/benefit of delayed mechanical ventilation should be evaluated carefully. Tailoring mechanical ventilation to the individual patient is fundamental to reduce the risk of ventilation-induced lung injury (VILI): it is mandatory to apply a low tidal volume, while the optimal level of positive end-expiratory pressure should be selected after a stratification of the severity of the disease, also taking into account lung recruitability; monitoring transpulmonary pressure or airway driving pressure can help to avoid lung overstress. Targeting oxygenation of 88-92 % and tolerating a moderate level of hypercapnia are a safe choice. Neuromuscular blocking agents (NMBAs) are useful to maintain patient-ventilation synchrony in the first hours; prone positioning improves oxygenation in most cases and promotes a more homogeneous distribution of ventilation, reducing the risk of VILI; both treatments, also in combination, are associated with an improvement in outcome if applied in the acute phase in the most severe cases. The use of extracorporeal membrane oxygenation (ECMO) in severe ARDS is increasing worldwide, but because of a lack of randomized trials is still considered a rescue therapy. CONCLUSION: Severe ARDS patients should receive a holistic framework of respiratory and hemodynamic support aimed to ensure adequate gas exchange while minimizing the risk of VILI, by promoting lung recruitment and setting protective mechanical ventilation. In the most severe cases, NMBAs, prone positioning, and ECMO should be considered.

Respiratory mechanics and lung stress/strain in children with acute respiratory distress syndrome.

BACKGROUND: In sedated and paralyzed children with acute respiratory failure, the compliance of respiratory system and functional residual capacity were significantly reduced compared with healthy subjects. However, no major studies in children with ARDS have investigated the role of different levels of PEEP and tidal volume on the partitioned respiratory mechanic (lung and chest wall), stress (transpulmonary pressure) and strain (inflated volume above the functional residual capacity). METHODS: The end-expiratory lung volume was measured using a simplified closed circuit helium dilution method. During an inspiratory and expiratory pause, the airway and esophageal pressure were measured. Transpulmonary pressure was computed as the difference between airway and esophageal pressure. RESULTS: Ten intubated sedated paralyzed healthy children and ten children with ARDS underwent a PEEP trial (4 and 12 cmH2O) with a tidal volume of 8, 10 and 12 ml/kgIBW. The two groups were comparable for age and BMI (2.5 [1.0-5.5] vs 3.0 [1.7-7.2] years and 15.1 ± 2.4 vs 15.3 ± 3.0 kg/m(2)). The functional residual capacity in ARDS patients was significantly lower as compared to the control group (10.4 [9.1-14.3] vs 16.6 [11.7-24.6] ml/kg, p = 0.04). The ARDS patients had a significantly lower respiratory system and lung compliance as compared to control subjects (9.9 ± 5.0 vs 17.8 ± 6.5, 9.3 ± 4.9 vs 16.9 ± 4.1 at 4 cmH2O of PEEP and 11.7 ± 5.8 vs 23.7 ± 6.8, 10.0 ± 4.9 vs 23.4 ± 7.5 at 12 cmH2O of PEEP). The compliance of the chest wall was similar in both groups (76.7 ± 30.2 vs 94.4 ± 76.4 and 92.6 ± 65.3 vs 90.0 ± 61.7 at 4 and 12 cmH2O of PEEP). The lung stress and strain were significantly higher in ARDS patients as compared to control subjects and were poorly related to airway pressure and tidal volume normalized for body weight. CONCLUSIONS: Airway pressures and tidal volume normalized to body weight are poor surrogates for lung stress and strain in mild pediatric ARDS. TRIAL REGISTRATION: Clinialtrials.gov NCT02036801. Registered 13 January 2014.

Mechanical Power and Development of Ventilator-induced Lung Injury.

BACKGROUND: The ventilator works mechanically on the lung parenchyma. The authors set out to obtain the proof of concept that ventilator-induced lung injury (VILI) depends on the mechanical power applied to the lung. METHODS: Mechanical power was defined as the function of transpulmonary pressure, tidal volume (TV), and respiratory rate. Three piglets were ventilated with a mechanical power known to be lethal (TV, 38 ml/kg; plateau pressure, 27 cm H2O; and respiratory rate, 15 breaths/min). Other groups (three piglets each) were ventilated with the same TV per kilogram and transpulmonary pressure but at the respiratory rates of 12, 9, 6, and 3 breaths/min. The authors identified a mechanical power threshold for VILI and did nine additional experiments at the respiratory rate of 35 breaths/min and mechanical power below (TV 11 ml/kg) and above (TV 22 ml/kg) the threshold. RESULTS: In the 15 experiments to detect the threshold for VILI, up to a mechanical power of approximately 12 J/min (respiratory rate, 9 breaths/min), the computed tomography scans showed mostly isolated densities, whereas at the mechanical power above approximately 12 J/min, all piglets developed whole-lung edema. In the nine confirmatory experiments, the five piglets ventilated above the power threshold developed VILI, but the four piglets ventilated below did not. By grouping all 24 piglets, the authors found a significant relationship between the mechanical power applied to the lung and the increase in lung weight (r = 0.41, P = 0.001) and lung elastance (r = 0.33, P < 0.01) and decrease in PaO2/FIO2 (r = 0.40, P < 0.001) at the end of the study. CONCLUSION: In piglets, VILI develops if a mechanical power threshold is exceeded.

Lung Recruitment Assessed by Respiratory Mechanics and Computed Tomography in Patients with Acute Respiratory Distress Syndrome. What Is the Relationship?

RATIONALE: The assessment of lung recruitability in patients with acute respiratory distress syndrome (ARDS) may be important for planning recruitment maneuvers and setting positive end-expiratory pressure (PEEP). OBJECTIVES: To determine whether lung recruitment measured by respiratory mechanics is comparable with lung recruitment measured by computed tomography (CT). METHODS: In 22 patients with ARDS, lung recruitment was assessed at 5 and 15 cm H2O PEEP by using respiratory mechanics-based methods: (1) increase in gas volume between two pressure-volume curves (P-Vrs curve); (2) increase in gas volume measured and predicted on the basis of expected end-expiratory lung volume and static compliance of the respiratory system (EELV-Cst,rs); as well as by CT scan: (3) decrease in noninflated lung tissue (CT [not inflated]); and (4) decrease in noninflated and poorly inflated tissue (CT [not + poorly inflated]). MEASUREMENTS AND MAIN RESULTS: The P-Vrs curve recruitment was significantly higher than EELV-Cst,rs recruitment (423 ± 223 ml vs. 315 ± 201 ml; P < 0.001), but these measures were significantly related to each other (R(2) = 0.93; P < 0.001). CT (not inflated) recruitment was 77 ± 86 g and CT (not + poorly inflated) was 80 ± 67 g (P = 0.856), and these measures were also significantly related to each other (R(2) = 0.20; P = 0.04). Recruitment measured by respiratory mechanics was 54 ± 28% (P-Vrs curve) and 39 ± 25% (EELV-Cst,rs) of the gas volume at 5 cm H2O PEEP. Recruitment measured by CT scan was 5 ± 5% (CT [not inflated]) and 6 ± 6% (CT [not + poorly inflated]) of lung tissue. CONCLUSIONS: Respiratory mechanics and CT measure-under the same term, "recruitment"-two different entities. The respiratory mechanics-based methods include gas entering in already open pulmonary units that improve their mechanical properties at higher PEEP. Consequently, they can be used to assess the overall improvement of inflation. The CT scan measures the amount of collapsed tissue that regains inflation. Clinical trial registered with www.clinicaltrials.gov (NCT00759590).

Lung inhomogeneities, inflation and [18F]2-fluoro-2-deoxy-D-glucose uptake rate in acute respiratory distress syndrome.

The aim of the study was to determine the size and location of homogeneous inflamed/noninflamed and inhomogeneous inflamed/noninflamed lung compartments and their association with acute respiratory distress syndrome (ARDS) severity.In total, 20 ARDS patients underwent 5 and 45 cmH2O computed tomography (CT) scans to measure lung recruitability. [(18)F]2-fluoro-2-deoxy-d-glucose ([(18)F]FDG) uptake and lung inhomogeneities were quantified with a positron emission tomography-CT scan at 10 cmH2O. We defined four compartments with normal/abnormal [(18)F]FDG uptake and lung homogeneity.The homogeneous compartment with normal [(18)F]FDG uptake was primarily composed of well-inflated tissue (80±16%), double-sized in nondependent lung (32±27% versus 16±17%, p<0.0001) and decreased in size from mild, moderate to severe ARDS (33±14%, 26±20% and 5±9% of the total lung volume, respectively, p=0.05). The homogeneous compartment with high [(18)F]FDG uptake was similarly distributed between the dependent and nondependent lung. The inhomogeneous compartment with normal [(18)F]FDG uptake represented 4% of the lung volume. The inhomogeneous compartment with high [(18)F]FDG uptake was preferentially located in the dependent lung (21±10% versus 12±10%, p<0.0001), mostly at the open/closed interfaces and related to recruitability (r(2)=0.53, p<0.001).The homogeneous lung compartment with normal inflation and [(18)F]FDG uptake decreases with ARDS severity, while the inhomogeneous poorly/not inflated compartment increases. Most of the lung inhomogeneities are inflamed. A minor fraction of healthy tissue remains in severe ARDS.