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Abstract Background The recruitment-to-inflation ratio (R/I) has been recently proposed to bedside assess response to PEEP. The impact of PEEP on ventilator-induced lung injury depends on the extent of dynamic strain reduction. We hypothesized that R/I may reflect the potential for lung recruitment (i.e. recruitability) and, consequently, estimate the impact of PEEP on dynamic lung strain, both assessed through computed tomography scan. Methods Fourteen lung-damaged pigs (lipopolysaccharide infusion) underwent ventilation at low (5 cmH2O) and high PEEP (i.e., PEEP generating a plateau pressure of 28–30 cmH2O). R/I was measured through a one-breath derecruitment maneuver from high to low PEEP. PEEP-induced changes in dynamic lung strain, difference in nonaerated lung tissue weight (tissue recruitment) and amount of gas entering previously nonaerated lung units (gas recruitment) were assessed through computed tomography scan. Tissue and gas recruitment were normalized to the weight and gas volume of previously ventilated lung areas at low PEEP (normalized-tissue recruitment and normalized-gas recruitment, respectively). Results Between high (median [interquartile range] 20 cmH2O [18–21]) and low PEEP, median R/I was 1.08 [0.88–1.82], indicating high lung recruitability. Compared to low PEEP, tissue and gas recruitment at high PEEP were 246 g [182–288] and 385 ml [318–668], respectively. R/I was linearly related to normalized-gas recruitment (r = 0.90; [95% CI 0.71 to 0.97) and normalized-tissue recruitment (r = 0.69; [95% CI 0.25 to 0.89]). Dynamic lung strain was 0.37 [0.29–0.44] at high PEEP and 0.59 [0.46–0.80] at low PEEP (p

Abstract In critically ill patients with acute respiratory failure, thoracic images are essential for evaluating the nature, extent and progression of the disease, and for clinical management decisions. For this purpose, computed tomography (CT) is the gold standard. However, transporting patients to the radiology suite and exposure to ionized radiation limit its use. Furthermore, a CT scan is a static diagnostic exam for the thorax, not allowing, for example, appreciation of "lung sliding". Its use is also unsuitable when it is necessary to adapt or decide to modify mechanical ventilation parameters at the bedside in real-time. Therefore, chest X-ray and lung ultrasound are today's contenders for shared second place on the podium to acquire a thoracic image, with their specific strengths and limitations. Finally, electrical impedance tomography (EIT) could soon have a role, however, its assessment is outside the scope of this review. Thus, we aim to carry out the following points: (1) analyze the advancement in knowledge of lung ultrasound use and the related main protocols adopted in intensive care units (ICUs) over the latest 30 years, reporting the principal publications along the way, (2) discuss how and when lung ultrasound should be used in a modern ICU and (3) illustrate the possible future development of LUS.

Our study investigates the post-mortem findings of the diaphragm's muscular structural changes in mechanically ventilated COVID-19 patients. Diaphragm samples of the right side from 42 COVID-19 critically ill patients were analyzed and correlated with the type and length of mechanical ventilation (MV), ventilatory parameters, prone positioning, and use of sedative drugs. The mean number of fibers was 550±626. The cross-sectional area was 4120±3280 μm2, while the muscular fraction was 0.607±0.126. The overall population was clustered into two distinct populations (clusters 1 and 2). Cluster 1 showed a lower percentage of slow myosin fiber and higher fast fiber content than cluster 2, 68% versus 82%, p

Abstract Background The recent pandemic outbursts, due to SARS-CoV-2, have highlighted once more the central role of the inflammatory process in the propagation of viral infection. The main consequence of COVID-19 is the induction of a diffuse pro-inflammatory state, also defined as a cytokine storm, which affects different organs, but mostly the lungs. We aimed to prove the efficacy of cinnamaldehyde, the active compound of cinnamon, as an anti-inflammatory compound, able to reduce SARS-CoV-2 induced cytokine storm. Results We enrolled 53 COVID-19 patients hospitalized for respiratory failure. The cohort was composed by 39 males and 13 females, aged 65.0 ± 9.8 years. We reported that COVID-19 patients have significantly higher IL-1β and IL-6 plasma levels compared to non-COVID-19 pneumonia patients. In addition, human mononuclear cells (PBMCs) isolated from SARS-CoV-2 infected patients are significantly more prone to release pro-inflammatory cytokines upon stimuli. We demonstrated, using in vitro cell models, that macrophages are responsible for mediating the pro-inflammatory cytokine storm while lung cells support SARS-CoV-2 replication upon viral infection. In this context, cinnamaldehyde administration significantly reduces SARS-CoV-2-related inflammation by inhibiting NLRP3 mediated IL-1β release in both PBMCs and THP-1 macrophages, as well as viral replication in CaLu-3 epithelial cells. Lastly, aerosol-administered cinnamaldehyde was able to significantly reduce IL-1β release in an in vivo lung-inflammatory model. Conclusion The obtained results suggest the possible use of cinnamaldehyde as a co-adjuvant preventive treatment for COVID-19 disease together with vaccination, but also as a promising dietary supplement to reduce, more broadly, viral induced inflammation.

OBJECTIVES:. In patients with COVID-19 respiratory failure, controlled mechanical ventilation (CMV) is often necessary during the acute phases of the disease. Weaning from CMV to pressure support ventilation (PSV) is a key objective when the patient’s respiratory functions improve. Limited evidence exists regarding the factors predicting a successful transition to PSV and its impact on patient outcomes. DESIGN:. Retrospective observational cohort study. SETTING:. Twenty-four Italian ICUs from February 2020 to May 2020. PATIENTS:. Mechanically ventilated ICU patients with COVID-19-induced respiratory failure. INTERVENTION:. The transition period from CMV to PSV was evaluated. We defined it as “failure of assisted breathing” if the patient returned to CMV within the first 72 hours. MEASUREMENTS AND MAIN RESULTS:. Of 1260 ICU patients screened, 514 were included. Three hundred fifty-seven patients successfully made the transition to PSV, while 157 failed. Pao2/Fio2 ratio before the transition emerged as an independent predictor of a successful shift (odds ratio 1.00; 95% CI, 0.99–1.00; p = 0.003). Patients in the success group displayed a better trend in Pao2/Fio2, Paco2, plateau and peak pressure, and pH level. Subjects in the failure group exhibited higher ICU mortality (hazard ratio 2.08; 95% CI, 1.42–3.06; p < 0.001), an extended ICU length of stay (successful vs. failure 21 ± 14 vs. 27 ± 17 d; p < 0.001) and a longer duration of mechanical ventilation (19 ± 18 vs. 24 ± 17 d, p = 0.04). CONCLUSIONS:. Our study emphasizes that the Pao2/Fio2 ratio was the sole independent factor associated with a failed transition from CMV to PSV. The unsuccessful transition was associated with worse outcomes.

Abstract Background This study hypothesized that patients with extubation failure exhibit a loss of lung aeration and heterogeneity in air distribution, which could be monitored by chest EIT and lung ultrasound. Patients at risk of extubation failure were included after a successful spontaneous breathing trial. Lung ultrasound [with calculation of lung ultrasound score (LUS)] and chest EIT [with calculation of the global inhomogeneity index, frontback center of ventilation (CoV), regional ventilation delay (RVD) and surface available for ventilation] were performed before extubation during pressure support ventilation (H0) and two hours after extubation during spontaneous breathing (H2). EIT was then repeated 6 h (H6) after extubation. EIT derived indices and LUS were compared between patients successfully extubated and patients with extubation failure. Results 40 patients were included, of whom 12 (30%) failed extubation. Before extubation, when compared with patients with successful extubation, patients who failed extubation had a higher LUS (19 vs 10, p = 0.003) and a smaller surface available for ventilation (352 vs 406 pixels, p = 0.042). After extubation, GI index and LUS were higher in the extubation failure group, whereas the surface available for ventilation was lower. The RVD and the CoV were not different between groups. Conclusion Before extubation, a loss of lung aeration was observed in patients who developed extubation failure afterwards. After extubation, this loss of lung aeration persisted and was associated with regional lung ventilation heterogeneity. Trial registration Clinical trials, NCT04180410, Registered 27 November 2019—prospectively registered, https://clinicaltrials.gov/ct2/show/NCT04180410 .

Abstract Background According to the Surviving Sepsis Campaign (SSC) fluids and vasopressors are the mainstays of early resuscitation of septic shock while inotropes are indicated in case of tissue hypoperfusion refractory to fluids and vasopressors, suggesting severe cardiac dysfunction. However, septic cardiac disfunction encompasses a large spectrum of severities and may remain “subclinical” during early resuscitation. We hypothesized that “subclinical” cardiac dysfunction may nevertheless influence fluid and vasopressor administration during early resuscitation. We retrospectively reviewed prospectically collected data on fluids and vasoconstrictors administered outside the ICU in patients with septic shock resuscitated according to the SSC guidelines that had reached hemodynamic stability without the use of inotropes. All the patients were submitted to transpulmonary thermodilution (TPTD) hemodynamic monitoring at ICU entry. Subclinical cardiac dysfunction was defined as a TPTD-derived cardiac function index (CFI) ≤ 4.5 min−1. Results At ICU admission, subclinical cardiac dysfunction was present in 17/40 patients (42%; CFI 3.6 ± 0.7 min−1 vs 6.6 ± 1.9 min−1; p

Advanced respiratory monitoring encompasses a diverse range of mini- or noninvasive tools used to evaluate various aspects of respiratory function in patients experiencing acute respiratory failure, including those requiring extracorporeal membrane oxygenation (ECMO) support. Among these techniques, key modalities include esophageal pressure measurement (including derived pressures), lung and respiratory muscle ultrasounds, electrical impedance tomography, the monitoring of diaphragm electrical activity, and assessment of flow index. These tools play a critical role in assessing essential parameters such as lung recruitment and overdistention, lung aeration and morphology, ventilation/perfusion distribution, inspiratory effort, respiratory drive, respiratory muscle contraction, and patient–ventilator synchrony. In contrast to conventional methods, advanced respiratory monitoring offers a deeper understanding of pathological changes in lung aeration caused by underlying diseases. Moreover, it allows for meticulous tracking of responses to therapeutic interventions, aiding in the development of personalized respiratory support strategies aimed at preserving lung function and respiratory muscle integrity. The integration of advanced respiratory monitoring represents a significant advancement in the clinical management of acute respiratory failure. It serves as a cornerstone in scenarios where treatment strategies rely on tailored approaches, empowering clinicians to make informed decisions about intervention selection and adjustment. By enabling real-time assessment and modification of respiratory support, advanced monitoring not only optimizes care for patients with acute respiratory distress syndrome but also contributes to improved outcomes and enhanced patient safety.

Abstract Background Long-term outcomes of patients treated with helmet noninvasive ventilation (NIV) are unknown: safety concerns regarding the risk of patient self-inflicted lung injury and delayed intubation exist when NIV is applied in hypoxemic patients. We assessed the 6-month outcome of patients who received helmet NIV or high-flow nasal oxygen for COVID-19 hypoxemic respiratory failure. Methods In this prespecified analysis of a randomized trial of helmet NIV versus high-flow nasal oxygen (HENIVOT), clinical status, physical performance (6-min-walking-test and 30-s chair stand test), respiratory function and quality of life (EuroQoL five dimensions five levels questionnaire, EuroQoL VAS, SF36 and Post-Traumatic Stress Disorder Checklist for the DSM) were evaluated 6 months after the enrollment. Results Among 80 patients who were alive, 71 (89%) completed the follow-up: 35 had received helmet NIV, 36 high-flow oxygen. There was no inter-group difference in any item concerning vital signs (N = 4), physical performance (N = 18), respiratory function (N = 27), quality of life (N = 21) and laboratory tests (N = 15). Arthralgia was significantly lower in the helmet group (16% vs. 55%, p = 0.002). Fifty-two percent of patients in helmet group vs. 63% of patients in high-flow group had diffusing capacity of the lungs for carbon monoxide

Abstract Background Proportional assist ventilation with load-adjustable gain factors (PAV+) is a mechanical ventilation mode that delivers assistance to breathe in proportion to the patient’s effort. The proportional assistance, called the gain, can be adjusted by the clinician to maintain the patient’s respiratory effort or workload within a normal range. Short-term and physiological benefits of this mode compared to pressure support ventilation (PSV) include better patient-ventilator synchrony and a more physiological response to changes in ventilatory demand. Methods The objective of this multi-centre randomized controlled trial (RCT) is to determine if, for patients with acute respiratory failure, ventilation with PAV+ will result in a shorter time to successful extubation than with PSV. This multi-centre open-label clinical trial plans to involve approximately 20 sites in several continents. Once eligibility is determined, patients must tolerate a short-term PSV trial and either (1) not meet general weaning criteria or (2) fail a 2-min Zero Continuous Positive Airway Pressure (CPAP) Trial using the rapid shallow breathing index, or (3) fail a spontaneous breathing trial (SBT), in this sequence. Then, participants in this study will be randomized to either PSV or PAV+ in a 1:1 ratio. PAV+ will be set according to a target of muscular pressure. The weaning process will be identical in the two arms. Time to liberation will be the primary outcome; ventilator-free days and other outcomes will be measured. Discussion Meta-analyses comparing PAV+ to PSV suggest PAV+ may benefit patients and decrease healthcare costs but no powered study to date has targeted the difficult to wean patient population most likely to benefit from the intervention, or used consistent timing for the implementation of PAV+. Our enrolment strategy, primary outcome measure, and liberation approaches may be useful for studying mechanical ventilation and weaning and can offer important results for patients. Trial registration ClinicalTrials.gov NCT02447692 . Prospectively registered on May 19, 2015.

Abstract The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection can be asymptomatic or cause a disease (COVID-19) characterized by different levels of severity. The main cause of severe COVID-19 and death is represented by acute (or acute on chronic) respiratory failure and acute respiratory distress syndrome (ARDS), often requiring hospital admission and ventilator support. The molecular pathogenesis of COVID-19-related ARDS (by now termed c-ARDS) is still poorly understood. In this review we will discuss the genetic susceptibility to COVID-19, the pathogenesis and the local and systemic biomarkers correlated with c-ARDS and the therapeutic options that target the cell signalling pathways of c-ARDS.

Prone positioning (PP) represents a therapeutic intervention with the proven capacity of ameliorating gas exchanges and ventilatory mechanics indicated in acute respiratory distress syndrome (ARDS). When PP is selectively applied to moderate-severe cases of ARDS, it sensitively affects clinical outcomes, including mortality. After the COVID-19 outbreak, clinical application of PP peaked worldwide and was applied in 60% of treated cases, according to large reports. Research on this topic has revealed many physiological underpinnings of PP, focusing on regional ventilation redistribution and the reduction of parenchymal stress and strain. However, there is a lack of evidence on biomarkers behavior in different phases and phenotypes of ARDS. Patients response to PP are, to date, decided on PaO2/FiO2 ratio improvement, whereas scarce data exist on biomarker tracking during PP. The purpose of this review is to explore current evidence on the clinical relevance of biomarkers in the setting of moderate-severe ARDS of different etiologies (i.e., COVID and non-COVID-related ARDS). Moreover, this review focuses on how PP may modulate biomarkers and which biomarkers may have a role in outcome prediction in ARDS patients.

Abstract Background Dyspnea is common after COVID-19 pneumonia and can be characterized by a defective CO2 diffusion (DLCO) despite normal pulmonary function tests (PFT). Nevertheless, DLCO impairment tends to normalize at 1 year, with no dyspnea regression. The altered regional distribution of ventilation and a dysfunction of the peripheral lung may characterize dyspnea at 1 year after COVID-19 pneumonia. We aimed at assessing the pattern of airway resistance and inflammation and the regional ventilation inhomogeneity in COVID-19 pneumonia survivors at 12-months after hospital discharge. Methods We followed up at 1-year patients previously admitted to the respiratory units (intensive care or sub-intensive care unit) for COVID-19 acute respiratory failure at 1-year after hospital discharge. PFT (spirometry, DLCO), impulse oscillometry (IOS), measurements of the exhaled nitric oxide (FENO) and Electrical Impedance Tomography (EIT) were used to evaluate lung volumes, CO2 diffusion capacity, peripheral lung inflammation/resistances and the regional inhomogeneity of ventilation distribution. A full medical examination was conducted, and symptoms of new onset (not present before COVID-19) were recorded. Patients were therefore divided into two groups based on the presence/absence of dyspnea (defined as mMRC ≥1) compared to evaluate differences in the respiratory function derived parameters. Results Sixty-seven patients were admitted between October and December 2020. Of them, 42/67 (63%) patients were discharged alive and 33 were evaluated during the follow up. Their mean age was 64 ± 11 years and 24/33 (73%) were males. Their maximum respiratory support was in 7/33 (21%) oxygen, in 4/33 (12%) HFNC, in 14/33 (42%) NIV/CPAP and in 8/33 (24%) invasive mechanical ventilation. During the clinical examination, 15/33 (45%) reported dyspnea. When comparing the two groups, no significant differences were found in PFT, in the peripheral airway inflammation (FENO) or mechanical properties (IOS). However, EIT showed a significantly higher regional inhomogeneity in patients with dyspnea both during resting breathing (0.98[0.96–1] vs 1.1[1–1.1], p = 0.012) and during forced expiration (0.96[0.94–1] vs 1 [0.98–1.1], p = 0.045). Conclusions New onset dyspnea characterizes 45% of patients 1 year after COVID-19 pneumonia. In these patients, despite pulmonary function test may be normal, EIT shows a higher regional inhomogeneity both during quiet and forced breathing which may contribute to dyspnea. Clinical trial registration Clinicaltrials.gov NCT04343053, registration date 13/04/2020.

Abstract Monitoring with electrical impedance tomography (EIT) during a decremental PEEP trial has been used to identify the PEEP that yields the optimal balance of pulmonary overdistension and collapse. This method is based on pixel-level changes in respiratory system compliance and depends on fixed or measured airway driving pressure. We developed a novel approach to quantify overdistension and collapse during pressure support ventilation (PSV) by integrating transpulmonary pressure and EIT monitoring and performed pilot tests in three hypoxemic patients. We report that our experimental approach is feasible and capable of identifying a PEEP that balances overdistension and collapse in intubated hypoxemic patients undergoing PSV.

Abstract Background Diaphragmatic dysfunction is a major factor responsible for weaning failure in patients that underwent prolonged invasive mechanical ventilation for acute severe respiratory failure from COVID-19. This study hypothesizes that ultrasound measured diaphragmatic thickening fraction (DTF) could provide corroborating information for weaning COVID-19 patients from mechanical ventilation. Methods This was an observational, pragmatic, cross-section, multicenter study in 6 Italian intensive care units. DTF was assessed in COVID-19 patients undergoing weaning from mechanical ventilation from 1st March 2020 to 30th June 2021. Primary aim was to evaluate whether DTF is a predictive factor for weaning failure. Results Fifty-seven patients were enrolled, 25 patients failed spontaneous breathing trial (44%). Median length of invasive ventilation was 14 days (IQR 7–22). Median DTF within 24 h since the start of weaning was 28% (IQR 22–39%), RASS score (− 2 vs − 2; p = 0.031); Kelly-Matthay score (2 vs 1; p = 0.002); inspiratory oxygen fraction (0.45 vs 0.40; p = 0.033). PaO2/FiO2 ratio was lower (176 vs 241; p = 0.032) and length of intensive care stay was longer (27 vs 16.5 days; p = 0.025) in patients who failed weaning. The generalized linear regression model did not select any variables that could predict weaning failure. DTF was correlated with pH (RR 1.56 × 1027; p = 0.002); Kelly-Matthay score (RR 353; p

Abstract Purpose In the acute respiratory distress syndrome (ARDS), decreasing Ventilation-Perfusion $$\left( {{{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}} \right)$$ V ˙ / Q ˙ mismatch might enhance lung protection. We investigated the regional effects of higher Positive End Expiratory Pressure (PEEP) on $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch and their correlation with recruitability. We aimed to verify whether PEEP improves regional $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch, and to study the underlying mechanisms. Methods In fifteen patients with moderate and severe ARDS, two PEEP levels (5 and 15 cmH2O) were applied in random order. $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch was assessed by Electrical Impedance Tomography at each PEEP. Percentage of ventilation and perfusion reaching different ranges of $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ ratios were analyzed in 3 gravitational lung regions, leading to precise assessment of their distribution throughout different $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch compartments. Recruitability between the two PEEP levels was measured by the recruitment-to-inflation ratio method. Results In the non-dependent region, at higher PEEP, ventilation reaching the normal $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ compartment (p = 0.018) increased, while it decreased in the high $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ one (p = 0.023). In the middle region, at PEEP 15 cmH2O, ventilation and perfusion to the low $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ compartment decreased (p = 0.006 and p = 0.011) and perfusion to normal $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ increased (p = 0.003). In the dependent lung, the percentage of blood flowing through the non-ventilated compartment decreased (p = 0.041). Regional $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch improvement was correlated to lung recruitability and changes in regional tidal volume. Conclusions In patients with ARDS, higher PEEP optimizes the distribution of both ventilation (in the non-dependent areas) and perfusion (in the middle and dependent lung). Bedside measure of recruitability is associated with improved $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch.

Abstract Increased ventilatory work beyond working capacity of the respiratory muscles can induce fatigue, resulting in limited respiratory muscle endurance (Tlim). Previous resistive breathing investigations all applied square wave inspiratory pressure as fatigue‐inducing pattern. Spontaneous breathing pressure pattern more closely approximate a triangle waveform. This study aimed at comparing Tlim, maximal inspiratory pressure (PImax), and metabolism between square and triangle wave breathing. Eight healthy subjects (Wei = 76 ± 10 kg, H = 181 ± 7.9 cm, age = 33.5 ± 4.8 years, sex [F/M] = 1/7) completed the study, comprising two randomized matched load resistive breathing trials with square and triangle wave inspiratory pressure waveform. Tlim decreased with a mean difference of 8 ± 7.2 min (p = 0.01) between square and triangle wave breathing. PImax was reduced following square wave (p = 0.04) but not for triangle wave breathing (p = 0.88). Higher VO2 was observed in the beginning and end for the triangle wave breathing compared with the square wave breathing (p = 0.036 and p = 0.048). Despite higher metabolism, Tlim was significantly longer in triangle wave breathing compared with square wave breathing, showing that the pressure waveform has an impact on the function and endurance of the respiratory muscles.

Background: Both general anesthesia and pneumoperitoneum insufflation during abdominal laparoscopic surgery can lead to atelectasis and impairment in oxygenation. Setting an appropriate level of external PEEP could reduce the occurrence of atelectasis and induce an improvement in gas exchange. However, in clinical practice, it is common to use a fixed PEEP level (i.e., 5 cmH2O), irrespective of the dynamic respiratory mechanics. We hypothesized setting a PEEP level guided by EIT in order to obtain an improvement in oxygenation and respiratory system compliance in lung-healthy patients than can benefit a personalized approach. Methods: Twelve consecutive patients scheduled for abdominal laparoscopic surgery were enrolled in this prospective study. The EIT Timpel Enlight 1800 was applied to each patient and a dedicated pneumotachograph and a spirometer flow sensor, integrated with EIT, constantly recorded respiratory mechanics. Gas exchange, respiratory mechanics and hemodynamics were recorded at five time points: T0, baseline; T1, after induction; T2, after pneumoperitoneum insufflation; T3, after a recruitment maneuver; and T4, at the end of surgery after desufflation. Results: A titrated mean PEEP of 8 cmH2O applied after a recruitment maneuver was successfully associated with the “best” compliance (58.4 ± 5.43 mL/cmH2O), with a low percentage of collapse (10%), an acceptable level of hyperdistention (0.02%). Pneumoperitoneum insufflation worsened respiratory system compliance, plateau pressure, and driving pressure, which significantly improved after the application of the recruitment maneuver and appropriate PEEP. PaO2 increased from 78.1 ± 9.49 mmHg at T0 to 188 ± 66.7 mmHg at T4 (p < 0.01). Other respiratory parameters remained stable after abdominal desufflation. Hemodynamic parameters remained unchanged throughout the study. Conclusions: EIT, used as a non-invasive intra-operative monitor, enables the rapid assessment of lung volume and regional ventilation changes in patients undergoing laparoscopic surgery and helps to identify the “optimal” PEEP level in the operating theatre, improving ventilation strategies.

(1) Background: Acute kidney injury (AKI) is common among critically ill COVID-19 patients, but its temporal association with prone positioning (PP) is still unknown, and no data exist on the possibility of predicting PP-associated AKI from bedside clinical variables. (2) Methods: We analyzed data from 93 COVID-19-related ARDS patients who underwent invasive mechanical ventilation (IMV) and at least one PP cycle. We collected hemodynamic variables, respiratory mechanics, and circulating biomarkers before, during, and after the first PP cycle. PP-associated AKI (PP-AKI) was defined as AKI diagnosed any time from the start of PP to 48 h after returning to the supine position. A t-test for independent samples was used to test for the differences between groups, while binomial logistical regression was performed to assess variables independently associated with PP-associated AKI. (3) Results: A total of 48/93 (52%) patients developed PP-AKI, with a median onset at 24 [13.5–44.5] hours after starting PP. No significant differences in demographic characteristics between groups were found. Before starting the first PP cycle, patients who developed PP-AKI had a significantly lower cumulative fluid balance (CFB), even when normalized for body weight (p = 0.006). Central venous pressure (CVP) values, measured before the first PP (OR 0.803, 95% CI [0.684–0.942], p = 0.007), as well as BMI (OR 1.153, 95% CI = [1.013–1.313], p = 0.031), were independently associated with the development of PP-AKI. In the multivariable regression analysis, a lower CVP before the first PP cycle was independently associated with ventilator-free days (OR 0.271, 95% CI [0.123–0.936], p = 0.011) and with ICU mortality (OR:0.831, 95% CI [0.699–0.989], p = 0.037). (4) Conclusions: Acute kidney injury occurs frequently in invasively ventilated severe COVID-19 ARDS patients undergoing their first prone positioning cycle. Higher BMI and lower CVP before PP are independently associated with the occurrence of AKI during prone positioning.

Abstract Mechanical ventilation is a life-saving technology, but it can also inadvertently induce lung injury and increase morbidity and mortality. Currently, there is no easy method of assessing the impact that ventilator settings have on the degree of lung inssflation. Computed tomography (CT), the gold standard for visually monitoring lung function, can provide detailed regional information of the lung. Unfortunately, it necessitates moving critically ill patients to a special diagnostic room and involves exposure to radiation. A technique introduced in the 1980s, electrical impedance tomography (EIT) can non-invasively provide similar monitoring of lung function. However, while CT provides information on the air content, EIT monitors ventilation-related changes of lung volume and changes of end expiratory lung volume (EELV). Over the past several decades, EIT has moved from the research lab to commercially available devices that are used at the bedside. Being complementary to well-established radiological techniques and conventional pulmonary monitoring, EIT can be used to continuously visualize the lung function at the bedside and to instantly assess the effects of therapeutic maneuvers on regional ventilation distribution. EIT provides a means of visualizing the regional distribution of ventilation and changes of lung volume. This ability is particularly useful when therapy changes are intended to achieve a more homogenous gas distribution in mechanically ventilated patients. Besides the unique information provided by EIT, its convenience and safety contribute to the increasing perception expressed by various authors that EIT has the potential to be used as a valuable tool for optimizing PEEP and other ventilator settings, either in the operative room and in the intensive care unit. The effects of various therapeutic interventions and applications on ventilation distribution have already been assessed with the help of EIT, and this document gives an overview of the literature that has been published in this context.

Introduction Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation.Methods and analysis The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage.Ethics and dissemination The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research.Trial registration number NCT04647396.

Abstract 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.

Abstract Background Systems aiding in selecting the correct settings for mechanical ventilation should visualize patient information at an appropriate level of complexity, so as to reduce information overload and to make reasoning behind advice transparent. Metaphor graphics have been applied to this effect, but these have largely been used to display diagnostic and physiologic information, rather than the clinical decision at hand. This paper describes how the conflicting goals of mechanical ventilation can be visualized and applied in making decisions. Data from previous studies are analyzed to assess whether visual patterns exist which may be of use to the clinical decision maker. Materials and methods The structure and screen visualizations of a commercial clinical decision support system (CDSS) are described, including the visualization of the conflicting goals of mechanical ventilation represented as a hexagon. Retrospective analysis is performed on 95 patients from 2 previous clinical studies applying the CDSS, to identify repeated patterns of hexagon symbols. Results Visual patterns were identified describing optimal ventilation, over and under ventilation and pressure support, and over oxygenation, with these patterns identified for both control and support modes of mechanical ventilation. Numerous clinical examples are presented for these patterns illustrating their potential interpretation at the bedside. Conclusions Visual patterns can be identified which describe the trade-offs required in mechanical ventilation. These may have potential to reduce information overload and help in simple and rapid identification of sub-optimal settings.

Background: Accurate risk stratification of critically ill patients with coronavirus disease 2019 (COVID-19) is essential for optimizing resource allocation, delivering targeted interventions, and maximizing patient survival probability. Machine learning (ML) techniques are attracting increased interest for the development of prediction models as they excel in the analysis of complex signals in data-rich environments such as critical care. Methods: We retrieved data on patients with COVID-19 admitted to an intensive care unit (ICU) between March and October 2020 from the RIsk Stratification in COVID-19 patients in the Intensive Care Unit (RISC-19-ICU) registry. We applied the Extreme Gradient Boosting (XGBoost) algorithm to the data to predict as a binary outcome the increase or decrease in patients’ Sequential Organ Failure Assessment (SOFA) score on day 5 after ICU admission. The model was iteratively cross-validated in different subsets of the study cohort. Results: The final study population consisted of 675 patients. The XGBoost model correctly predicted a decrease in SOFA score in 320/385 (83%) critically ill COVID-19 patients, and an increase in the score in 210/290 (72%) patients. The area under the mean receiver operating characteristic curve for XGBoost was significantly higher than that for the logistic regression model (0.86 vs. 0.69, P

Background: Noninvasive respiratory support (NIRS) has been extensively used during the COVID-19 surge for patients with acute respiratory failure. However, little data are available about barotrauma during NIRS in patients treated outside the intensive care unit (ICU) setting. Methods: COVIMIX-2 was an ancillary analysis of the previous COVIMIX study, a large multicenter observational work investigating the frequencies of barotrauma (i.e., pneumothorax and pneumomediastinum) in adult patients with COVID-19 interstitial pneumonia. Only patients treated with NIRS outside the ICU were considered. Baseline characteristics, clinical and radiological disease severity, type of ventilatory support used, blood tests and mortality were recorded. Results: In all, 179 patients were included, 60 of them with barotrauma. They were older and had lower BMI than controls (p < 0.001 and p = 0.045, respectively). Cases had higher respiratory rates and lower PaO2/FiO2 (p = 0.009 and p < 0.001). The frequency of barotrauma was 0.3% [0.1–1.3%], with older age being a risk factor for barotrauma (OR 1.06, p = 0.015). Alveolar-arterial gradient (A-a) DO2 was protective against barotrauma (OR 0.92 [0.87–0.99], p = 0.026). Barotrauma required active treatment, with drainage, in only a minority of cases. The type of NIRS was not explicitly related to the development of barotrauma. Still, an escalation of respiratory support from conventional oxygen therapy, high flow nasal cannula to noninvasive respiratory mask was predictive for in-hospital death (OR 15.51, p = 0.001). Conclusions: COVIMIX-2 showed a low frequency for barotrauma, around 0.3%. The type of NIRS used seems not to increase this risk. Patients with barotrauma were older, with more severe systemic disease, and showed increased mortality.

Sepsis and septic shock are common in critically ill patients and, as recommended by the Surviving Sepsis Campaign (SSC), early empiric antimicrobial therapy, specifically within the first hour, is crucial for the successful management of these conditions. To be effective, the antimicrobial therapy must also be appropriately administered: the drugs should cover the most probable pathogens and achieve effective concentrations at the site of infection. However, pharmacokinetics are frequently altered in critically ill patients and continuously change since the clinical conditions of these patients quickly and markedly change over time, either improving or deteriorating. Accordingly, optimizing antimicrobial drug dosing is fundamental in intensive care units (ICUs). This Special Issue of Microorganisms examines the epidemiology, diagnostic innovations, and strategies applied in the context of infections in critically ill patients with MDR infections.

Abstract Background Hip fracture is one of the most common orthopedic causes of hospital admission in frail elderly patients. Hip fracture fixation in this class of patients is considered a high-risk procedure. Preoperative physical examination, plasma natriuretic peptide levels (BNP, Pro-BNP), and cardiovascular scoring systems (ASA-PS, RCRI, NSQIP-MICA) have all been demonstrated to underestimate the risk of postoperative complications. We designed a prospective multicenter observational study to assess whether preoperative lung ultrasound examination can predict better postoperative events thanks to the additional information they provide in the form of “indirect” and “direct” cardiac and pulmonary lung ultrasound signs. Methods LUSHIP is an Italian multicenter prospective observational study. Patients will be recruited on a nation-wide scale in the 12 participating centers. Patients aged > 65 years undergoing spinal anesthesia for hip fracture fixation will be enrolled. A lung ultrasound score (LUS) will be generated based on the examination of six areas of each lung and ascribing to each area one of the four recognized aeration patterns—each of which is assigned a subscore of 0, 1, 2, or 3. Thus, the total score will have the potential to range from a minimum of 0 to a maximum of 36. The association between 30-day postoperative complications of cardiac and/or pulmonary origin and the overall mortality will be studied. Considering the fact that cardiac complications in patients undergoing hip surgery occur in approx. 30% of cases, to achieve 80% statistical power, we will need a sample size of 877 patients considering a relative risk of 1.5. Conclusions Lung ultrasound (LU), as a tool within the anesthesiologist’s armamentarium, is becoming increasingly widespread, and its use in the preoperative setting is also starting to become more common. Should the study demonstrate the ability of LU to predict postoperative cardiac and pulmonary complications in hip fracture patients, a randomized clinical trial will be designed with the scope of improving patient outcome. Trial registration ClinicalTrials.gov, NCT04074876. Registered on August 30, 2019.

The aim of this study (NCT04343053) is to investigate the relationship between platelet activation, myocardial injury, and mortality in patients affected by Coronavirus disease 2019 (COVID-19). Fifty-four patients with respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were enrolled as cases. Eleven patients with the same clinical presentation, but negative for SARS-CoV-2 infection, were included as controls. Blood samples were collected at three different time points (inclusion [T1], after 7 ± 2 days [T2] and 14 ± 2 days [T3]). Platelet aggregation by light transmittance aggregometry and the circulating levels of soluble CD40 ligand (sCD40L) and P-selectin were measured. Platelet biomarkers did not differ between cases and controls, except for sCD40L which was higher in COVID-19 patients (p = .003). In COVID-19 patients, P-selectin and sCD40L levels decreased from T1 to T3 and were higher in cases requiring admission to intensive care unit (p = .004 and p = .008, respectively). Patients with myocardial injury (37%), as well as those who died (30%), had higher values of all biomarkers of platelet activation (p

Abstract Background QuickSOFA, a prognostic score proposed for patients with infection, has shown a poor predictive value in the geriatric population, probably because of the inappropriateness of the Glasgow Coma Scale (GCS) in assessing acute alteration of mental status in older patients. Indeed, the GCS might result chronically low in older patient with pre-existing cognitive disorders. The aim of this study was to develop an alternative quickSOFA (geriatric-quickSOFA), using the presence of delirium, assessed according to DSM-5 criteria, instead of GCS assessment, to predict mortality in hospitalized older patients with sepsis. Methods Retrospective observational study in Acute Geriatrics Unit of St. Anna Hospital of Ferrara (Italy). The study enrolled 165 patients hospitalized between 2017 and 2018 with diagnosis of sepsis or septic shock. Demographic, clinical data and 30-day survival were collected for each patient. Based on arterial blood pressure, respiratory rate, and the presence of delirium, geriatric-quickSOFA was calculated at admission. Primary outcome was 30-day mortality. Results One hundred sixty-five patients were enrolled with a median age of 88 years; 60.6% were men. High quickSOFA score was not significantly correlated neither with in-hospital nor 30-day mortality. High geriatric-qSOFA score was significantly related to both in-hospital (13.3%vs 51.5%, p = 0.0003) and 30-day mortality (30.0%vs 84.3%, p

Abstract Background Prone positioning (PP) has been used to improve oxygenation in patients affected by the SARS-CoV-2 disease (COVID-19). Several mechanisms, including lung recruitment and better lung ventilation/perfusion matching, make a relevant rational for using PP. However, not all patients maintain the oxygenation improvement after returning to supine position. Nevertheless, no evidence exists that a sustained oxygenation response after PP is associated to outcome in mechanically ventilated COVID-19 patients. We analyzed data from 191 patients affected by COVID-19-related acute respiratory distress syndrome undergoing PP for clinical reasons. Clinical history, severity scores and respiratory mechanics were analyzed. Patients were classified as responders (≥ median PaO2/FiO2 variation) or non-responders (

Abstract Background Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS. Methods This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS. Results In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p

Background: Investigating the health-related quality of life (HRQoL) after intensive care unit (ICU) discharge is necessary to identify possible modifiable risk factors. The primary aim of this study was to investigate the HRQoL in COVID-19 critically ill patients one year after ICU discharge. Methods: In this multicenter prospective observational study, COVID-19 patients admitted to nine ICUs from 1 March 2020 to 28 February 2021 in Italy were enrolled. One year after ICU discharge, patients were required to fill in short-form health survey 36 (SF-36) and impact of event-revised (IES-R) questionnaire. A multivariate linear or logistic regression analysis to search for factors associated with a lower HRQoL and post-traumatic stress disorded (PTSD) were carried out, respectively. Results: Among 1003 patients screened, 343 (median age 63 years [57–70]) were enrolled. Mechanical ventilation lasted for a median of 10 days [2–20]. Physical functioning (PF 85 [60–95]), physical role (PR 75 [0–100]), emotional role (RE 100 [33–100]), bodily pain (BP 77.5 [45–100]), social functioning (SF 75 [50–100]), general health (GH 55 [35–72]), vitality (VT 55 [40–70]), mental health (MH 68 [52–84]) and health change (HC 50 [25–75]) describe the SF-36 items. A median physical component summary (PCS) and mental component summary (MCS) scores were 45.9 (36.5–53.5) and 51.7 (48.8–54.3), respectively, considering 50 as the normal value of the healthy general population. In all, 109 patients (31.8%) tested positive for post-traumatic stress disorder, also reporting a significantly worse HRQoL in all SF-36 domains. The female gender, history of cardiovascular disease, liver disease and length of hospital stay negatively affected the HRQoL. Weight at follow-up was a risk factor for PTSD (OR 1.02, p = 0.03). Conclusions: The HRQoL in COVID-19 ARDS (C-ARDS) patients was reduced regarding the PCS, while the median MCS value was slightly above normal. Some risk factors for a lower HRQoL have been identified, the presence of PTSD is one of them. Further research is warranted to better identify the possible factors affecting the HRQoL in C-ARDS.

An amendment to this paper has been published and can be accessed via the original article.

Abstract Introduction Pressure support ventilation (PSV) should allow spontaneous breathing with a “normal” neuro-ventilatory drive. Low neuro-ventilatory drive puts the patient at risk of diaphragmatic atrophy while high neuro-ventilatory drive may causes dyspnea and patient self-inflicted lung injury. We continuously assessed for 12 h the electrical activity of the diaphragm (EAdi), a close surrogate of neuro-ventilatory drive, during PSV. Our aim was to document the EAdi trend and the occurrence of periods of “Low” and/or “High” neuro-ventilatory drive during clinical application of PSV. Method In 16 critically ill patients ventilated in the PSV mode for clinical reasons, inspiratory peak EAdi peak (EAdiPEAK), pressure time product of the trans-diaphragmatic pressure per breath and per minute (PTPDI/b and PTPDI/min, respectively), breathing pattern and major asynchronies were continuously monitored for 12 h (from 8 a.m. to 8 p.m.). We identified breaths with “Normal” (EAdiPEAK 5–15 μV), “Low” (EAdiPEAK 15 μV) neuro-ventilatory drive. Results Within all the analyzed breaths (177.117), the neuro-ventilatory drive, as expressed by the EAdiPEAK, was “Low” in 50.116 breath (28%), “Normal” in 88.419 breaths (50%) and “High” in 38.582 breaths (22%). The average times spent in “Low”, “Normal” and “High” class were 1.37, 3.67 and 0.55 h, respectively (p

Abstract Background A large proportion of patients with coronavirus disease 2019 (COVID-19) develop severe respiratory failure requiring admission to the intensive care unit (ICU) and about 80% of them need mechanical ventilation (MV). These patients show great complexity due to multiple organ involvement and a dynamic evolution over time; moreover, few information is available about the risk factors that may contribute to increase the time course of mechanical ventilation. The primary objective of this study is to investigate the risk factors associated with the inability to liberate COVID-19 patients from mechanical ventilation. Due to the complex evolution of the disease, we analyzed both pulmonary variables and occurrence of non-pulmonary complications during mechanical ventilation. The secondary objective of this study was the evaluation of risk factors for ICU mortality. Methods This multicenter prospective observational study enrolled 391 patients from fifteen COVID-19 dedicated Italian ICUs which underwent invasive mechanical ventilation for COVID-19 pneumonia. Clinical and laboratory data, ventilator parameters, occurrence of organ dysfunction, and outcome were recorded. The primary outcome measure was 28 days ventilator-free days and the liberation from MV at 28 days was studied by performing a competing risks regression model on data, according to the method of Fine and Gray; the event death was considered as a competing risk. Results Liberation from mechanical ventilation was achieved in 53.2% of the patients (208/391). Competing risks analysis, considering death as a competing event, demonstrated a decreased sub-hazard ratio for liberation from mechanical ventilation (MV) with increasing age and SOFA score at ICU admission, low values of PaO2/FiO2 ratio during the first 5 days of MV, respiratory system compliance (CRS) lower than 40 mL/cmH2O during the first 5 days of MV, need for renal replacement therapy (RRT), late-onset ventilator-associated pneumonia (VAP), and cardiovascular complications. ICU mortality during the observation period was 36.1% (141/391). Similar results were obtained by the multivariate logistic regression analysis using mortality as a dependent variable. Conclusions Age, SOFA score at ICU admission, CRS, PaO2/FiO2, renal and cardiovascular complications, and late-onset VAP were all independent risk factors for prolonged mechanical ventilation in patients with COVID-19. Trial registration NCT04411459

Abstract Background The physiological behavior of lungs affected by the acute respiratory distress syndrome (ARDS) differs between inspiration and expiration and presents heterogeneous gravity-dependent distribution. This phenomenon, highlighted by the different distribution of opening/closing pressure and by the hysteresis of the pressure–volume curve, can be studied by CT scan, but the technique expose the patient to radiations, cannot track changes during time and is not feasible at the bedside. Electrical impedance tomography (EIT) could help in assessing at the bedside regional inspiratory and expiratory mechanical properties. We evaluated regional opening/closing pressures, hysteresis and atelectrauma during inspiratory and expiratory low-flow pressure–volume curves in ARDS using electrical impedance tomography. Methods Pixel-level inspiratory and expiratory PV curves (PVpixel) between 5 and 40 cmH2O were constructed integrating EIT images and airway opening pressure signal from 8 ARDS patients. The lower inflection point in the inspiratory and expiratory PVpixel were used to find opening (OPpixel) and closing (CPpixel) pressures. A novel atelectrauma index (AtI) was calculated as the percentage of pixels opening during the inspiratory and closing during the expiratory PV curves. The maximal hysteresis (HysMax) was calculated as the maximal difference between normalized expiratory and inspiratory PV curves. Analyses were conducted in the global, dependent and non-dependent lung regions. Results Gaussian distribution was confirmed for both global OPpixel (r2 = 0.90) and global CPpixel (r2 = 0.94). The two distributions were significantly different with higher values for OPpixel (p

Coagulation disorders and thrombocytopenia are common in patients with septic shock, but only few studies have focused on platelet variables beyond platelet count. The aim of this study was to evaluate whether platelets reactivity predicts sepsis-induced thrombocytopenia in patients with septic shock. We therefore enrolled consecutive patients with septic shock and platelets count >150*103/μL on the day of the diagnosis. Platelets reactivity tests were performed daily from the diagnosis of septic shock until day five; platelet volume distribution and mean platelet volume were also recorded daily. Sepsis-induced thrombocytopenia was defined as a platelet count

Abstract Background Guidelines recommend a restrictive red blood cell transfusion strategy based on hemoglobin (Hb) concentrations in critically ill patients. We hypothesized that the arterial-venous oxygen difference (A-V O2diff), a surrogate for the oxygen delivery to consumption ratio, could provide a more personalized approach to identify patients who may benefit from transfusion. Methods A prospective observational study including 177 non-bleeding adult patients with a Hb concentration of 7.0–10.0 g/dL within 72 h after ICU admission. The A-V O2diff, central venous oxygen saturation (ScvO2), and oxygen extraction ratio (O2ER) were noted when a patient’s Hb was first within this range. Transfusion decisions were made by the treating physician according to institutional policy. We used the median A-V O2diff value in the study cohort (3.7 mL) to classify the transfusion strategy in each patient as “appropriate” (patient transfused when the A-V O2diff > 3.7 mL or not transfused when the A-V O2diff ≤ 3.7 mL) or “inappropriate” (patient transfused when the A-V O2diff ≤ 3.7 mL or not transfused when the A-V O2diff > 3.7 mL). The primary outcome was 90-day mortality. Results Patients managed with an “appropriate” strategy had lower mortality rates (23/96 [24%] vs. 36/81 [44%]; p = 0.004), and an “appropriate” strategy was independently associated with reduced mortality (hazard ratio [HR] 0.51 [95% CI 0.30–0.89], p = 0.01). There was a trend to less acute kidney injury with the “appropriate” than with the “inappropriate” strategy (13% vs. 26%, p = 0.06), and the Sequential Organ Failure Assessment (SOFA) score decreased more rapidly (p = 0.01). The A-V O2diff, but not the ScvO2, predicted 90-day mortality in transfused (AUROC = 0.656) and non-transfused (AUROC = 0.630) patients with moderate accuracy. Using the ROC curve analysis, the best A-V O2diff cutoffs for predicting mortality were 3.6 mL in transfused and 3.5 mL in non-transfused patients. Conclusions In anemic, non-bleeding critically ill patients, transfusion may be associated with lower 90-day mortality and morbidity in patients with higher A-V O2diff. Trial registration ClinicalTrials.gov, NCT03767127 . Retrospectively registered on 6 December 2018.

Abstract This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2020. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2020. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.

Abstract Background Expiratory flow limitation (EFL) is characterised by a markedly reduced expiratory flow insensitive to the expiratory driving pressure. The presence of EFL can influence the respiratory and cardiovascular function and damage the small airways; its occurrence has been demonstrated in different diseases, such as COPD, asthma, obesity, cardiac failure, ARDS, and cystic fibrosis. Our aim was to evaluate the prevalence of EFL in patients requiring mechanical ventilation for acute respiratory failure and to determine the main clinical characteristics, the risk factors and clinical outcome associated with the presence of EFL. Methods Patients admitted to the intensive care unit (ICU) with an expected length of mechanical ventilation of 72 h were enrolled in this prospective, observational study. Patients were evaluated, within 24 h from ICU admission and for at least 72 h, in terms of respiratory mechanics, presence of EFL through the PEEP test, daily fluid balance and followed for outcome measurements. Results Among the 121 patients enrolled, 37 (31%) exhibited EFL upon admission. Flow-limited patients had higher BMI, history of pulmonary or heart disease, worse respiratory dyspnoea score, higher intrinsic positive end-expiratory pressure, flow and additional resistance. Over the course of the initial 72 h of mechanical ventilation, additional 21 patients (17%) developed EFL. New onset EFL was associated with a more positive cumulative fluid balance at day 3 (103.3 ml/kg) compared to that of patients without EFL (65.8 ml/kg). Flow-limited patients had longer duration of mechanical ventilation, longer ICU length of stay and higher in-ICU mortality. Conclusions EFL is common among ICU patients and correlates with adverse outcomes. The major determinant for developing EFL in patients during the first 3 days of their ICU stay is a positive fluid balance. Further studies are needed to assess if a restrictive fluid therapy might be associated with a lower incidence of EFL.

Background: Patients with acute respiratory failure (ARF) may need mechanical ventilation (MV), which can lead to diaphragmatic dysfunction and muscle wasting, thus making difficult the weaning from the ventilator. Currently, there are no biomarkers specific for respiratory muscle and their function can only be assessed trough ultrasound or other invasive methods. Previously, the fast and slow isoform of the skeletal troponin I (fsTnI and ssTnI, respectively) have shown to be specific markers of muscle damage in healthy volunteers. We aimed therefore at describing the trend of skeletal troponin in mixed population of ICU patients undergoing weaning from mechanical ventilation and compared the value of fsTnI and ssTnI with diaphragmatic ultrasound derived parameters.Methods: In this prospective observational study we enrolled consecutive patients recovering from acute hypoxemic respiratory failure (AHRF) within 24 h from the start of weaning. Every day an arterial blood sample was collected to measure fsTnI, ssTnI, and global markers of muscle damage, such as ALT, AST, and CPK. Moreover, thickening fraction (TF) and diaphragmatic displacement (DE) were assessed by diaphragmatic ultrasound. The trend of fsTnI and ssTnI was evaluated during the first 3 days of weaning.Results: We enrolled 62 consecutive patients in the study, with a mean age of 67 ± 13 years and 43 of them (69%) were male. We did not find significant variations in the ssTnI trend (p = 0.623), but fsTnI significantly decreased over time by 30% from Day 1 to Day 2 and by 20% from Day 2 to Day 3 (p < 0.05). There was a significant interaction effect between baseline ssTnI and DE [F(2) = 4.396, p = 0.015], with high basal levels of ssTnI being associated to a higher decrease in DE. On the contrary, the high basal levels of fsTnI at day 1 were characterized by significant higher DE at each time point.Conclusions: Skeletal muscle proteins have a distinctive pattern of variation during weaning from mechanical ventilation. At day 1, a high basal value of ssTnI were associated to a higher decrease over time of diaphragmatic function while high values of fsTnI were associated to a higher displacement at each time point.

Background: The COVID-19 pandemic had a relevant impact on the organization of intensive care units (ICU) and may have reduced the overall compliance with healthcare-associated infections (HAIs) prevention programs. Invasively ventilated patients are at high risk of ICU-associated infection, but there is little evidence regarding the impact of the pandemic on their occurrence in non-COVID-19 patients. Moreover, little is known of antibiotic prescription trends in the ICU during the first wave of the pandemic. The purpose of this investigation is to assess the incidence, characteristics, and risk factors for ICU-associated HAIs in a population of invasively ventilated patients affected by non-COVID-19 acute respiratory failure (ARF) admitted to the ICU in the first wave of the COVID-19 pandemic, and to evaluate the ICU antimicrobial prescription strategies. Moreover, we compared HAIs and antibiotic use to a cohort of ARF patients admitted to the ICU the year before the pandemic during the same period. Methods: this is a retrospective, single-centered cohort study conducted at S. Anna University Hospital (Ferrara, Italy). We enrolled patients admitted to the ICU for acute respiratory failure requiring invasive mechanical ventilation (MV) between February and April 2020 (intra-pandemic group, IP) and February and April 2019 (before the pandemic group, PP). We excluded patients admitted to the ICU for COVID-19 pneumonia. We recorded patients’ baseline characteristics, ICU-associated procedures and devices. Moreover, we evaluated antimicrobial therapy and classified it as prophylactic, empirical or target therapy, according to the evidence of infection at the time of prescription and to the presence of a positive culture sample. We compared the results of the two groups (PP and IP) to assess differences between the two years. Results: One hundred and twenty-eight patients were screened for inclusion and 83 patients were analyzed, 45 and 38 in the PP and I group, respectively. We found a comparable incidence of HAIs (62.2% vs. 65.8%, p = 0.74) and multidrug-resistant (MDR) isolations (44.4% vs. 36.8% p= 0.48) in the two groups. The year of ICU admission was not independently associated with an increased risk of developing HAIs (OR = 0.35, 95% CI 0.16–1.92, p = 0.55). The approach to antimicrobial therapy was characterized by a significant reduction in total antimicrobial use (21.4 ± 18.7 vs. 11.6 ± 9.4 days, p = 0.003), especially of target therapy, in the IP group. Conclusions: ICU admission for non-COVID-19 ARF during the first wave of the SARS-CoV-2 pandemic was not associated with an increased risk of ICU-associated HAIs. Nevertheless, ICU prescription of antimicrobial therapy changed and significantly decreased during the pandemic.

Transpulmonary driving pressure (DPL) corresponds to the cyclical stress imposed on the lung parenchyma during tidal breathing and, therefore, can be used to assess the risk of ventilator-induced lung injury (VILI). Its measurement at the bedside requires the use of esophageal pressure (Peso), which is sometimes technically challenging. Recently, it has been demonstrated how in an animal model of ARDS, the transpulmonary pressure (PL) measured with Peso calculated with the absolute values method (PL = Paw—Peso) is equivalent to the transpulmonary pressure directly measured using pleural sensors in the central-dependent part of the lung. We hypothesized that, since the PL derived from Peso reflects the regional behavior of the lung, it could exist a relationship between regional parameters measured by electrical impedance tomography (EIT) and driving PL (DPL). Moreover, we explored if, by integrating airways pressure data and EIT data, it could be possible to estimate non-invasively DPL and consequently lung elastance (EL) and elastance-derived inspiratory PL (PI). We analyzed 59 measurements from 20 patients with ARDS. There was a significant intra-patient correlation between EIT derived regional compliance in regions of interest (ROI1) (r = 0.5, p = 0.001), ROI2 (r = −0.68, p < 0.001), and ROI3 (r = −0.4, p = 0.002), and DPL. A multiple linear regression successfully predicted DPL based on respiratory system elastance (Ers), ideal body weight (IBW), roi1%, roi2%, and roi3% (R2 = 0.84, p < 0.001). The corresponding Bland-Altmann analysis showed a bias of −1.4e-007 cmH2O and limits of agreement (LoA) of −2.4–2.4 cmH2O. EL and PI calculated using EIT showed good agreement (R2 = 0.89, p < 0.001 and R2 = 0.75, p < 0.001) with the esophageal derived correspondent variables. In conclusion, DPL has a good correlation with EIT-derived parameters in the central lung. DPL, PI, and EL can be estimated with good accuracy non-invasively combining information coming from EIT and airway pressure.

Abstract Background Electrical impedance tomography (EIT) is a non-invasive radiation-free monitoring technique that provides images based on tissue electrical conductivity of the chest. Several investigations applied EIT in the context of perioperative medicine, which is not confined to the intraoperative period but begins with the preoperative assessment and extends to postoperative follow-up. Main body EIT could provide careful respiratory monitoring in the preoperative assessment to improve preparation for surgery, during anaesthesia to guide optimal ventilation strategies and to monitor the hemodynamic status and in the postoperative period for early detection of respiratory complications. Moreover, EIT could further enhance care of patients undergoing perioperative diagnostic procedures. This narrative review summarizes the latest evidence on the application of this technique to the surgical patient, focusing also on possible future perspectives. Conclusions EIT is a promising technique for the perioperative assessment of surgical patients, providing tailored adaptive respiratory and haemodynamic monitoring. Further studies are needed to address the current technological limitations, confirm the findings and evaluate which patients can benefit more from this technology.

Abstract Background Noninvasive monitoring of maximal inspiratory and expiratory flows (MIF and MEF, respectively) by electrical impedance tomography (EIT) might enable early recognition of changes in the mechanical properties of the respiratory system due to new conditions or in response to treatments. We aimed to validate EIT-based measures of MIF and MEF against spirometry in intubated hypoxemic patients during controlled ventilation and spontaneous breathing. Moreover, regional distribution of maximal airflows might interact with lung pathology and increase the risk of additional ventilation injury. Thus, we also aimed to describe the effects of mechanical ventilation settings on regional MIF and MEF. Methods We performed a new analysis of data from two prospective, randomized, crossover studies. We included intubated patients admitted to the intensive care unit with acute hypoxemic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS) undergoing pressure support ventilation (PSV, n = 10) and volume-controlled ventilation (VCV, n = 20). We measured MIF and MEF by spirometry and EIT during six different combinations of ventilation settings: higher vs. lower support during PSV and higher vs. lower positive end-expiratory pressure (PEEP) during both PSV and VCV. Regional airflows were assessed by EIT in dependent and non-dependent lung regions, too. Results MIF and MEF measured by EIT were tightly correlated with those measured by spirometry during all conditions (range of R 2 0.629–0.776 and R 2 0.606–0.772, respectively, p

Abstract Background The pressure-volume (P-V) curve has been suggested as a bedside tool to set mechanical ventilation; however, it reflects a global behavior of the lung without giving information on the regional mechanical properties. Regional P-V (PVr) curves derived from electrical impedance tomography (EIT) could provide valuable clinical information at bedside, being able to explore the regional mechanics of the lung. In the present study, we hypothesized that regional P-V curves would provide different information from those obtained from global P-V curves, both in terms of upper and lower inflection points. Therefore, we constructed pressure-volume curves for each pixel row from non-dependent to dependent lung regions of patients affected by acute hypoxemic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS). Methods We analyzed slow-inflation P-V maneuvers data from 12 mechanically ventilated patients. During the inflation, the pneumotachograph was used to record flow and airway pressure while the EIT signals were recorded digitally. From each maneuver, global respiratory system P-V curve (PVg) and PVr curves were obtained, each one corresponding to a pixel row within the EIT image. PVg and PVr curves were fitted using a sigmoidal equation, and the upper (UIP) and lower (LIP) inflection points for each curve were mathematically identified; LIP and UIP from PVg were respectively called LIPg and UIPg. From each measurement, the highest regional LIP (LIPrMAX) and the lowest regional UIP (UIPrMIN) were identified and the pressure difference between those two points was defined as linear driving pressure (ΔP LIN). Results A significant difference (p

Abstract Acute lung injury (ALI) affects over 10% of patients hospitalised in critical care, with acute respiratory distress syndrome (ARDS) being the most severe form of ALI and having a mortality rate in the region of 40%. There has been slow but incremental progress in identification of biomarkers that contribute to the pathophysiology of ARDS, have utility in diagnosis and monitoring, and that are potential therapeutic targets (Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA, Thompson T, Ware LB, Matthay MA, Lancet Respir Med 2014, 2:611–-620). However, a major issue is that ARDS is such a heterogeneous, multi-factorial, end-stage condition that the strategies for “lumping and splitting” are critical (Prescott HC, Calfee CS, Thompson BT, Angus DC, Liu VX, Am J Respir Crit Care Med 2016, 194:147–-155). Nevertheless, sequencing of the human genome, the availability of improved methods for analysis of transcription to mRNA (gene expression), and development of sensitive immunoassays has allowed the application of network biology to ARDS, with these biomarkers offering potential for personalised or precision medicine (Sweeney TE, Khatri P, Toward precision medicine Crit Care Med; 2017 45:934-939). Biomarker panels have potential applications in molecular phenotyping for identifying patients at risk of developing ARDS, diagnosis of ARDS, risk stratification and monitoring. Two subphenotypes of ARDS have been identified on the basis of blood biomarkers: hypo-inflammatory and hyper-inflammatory. The hyper-inflammatory subphenotype is associated with shock, metabolic acidosis and worst clinical outcomes. Biomarkers of particular interest have included interleukins (IL-6 and IL-8), interferon gamma (IFN-γ), surfactant proteins (SPD and SPB), von Willebrand factor antigen, angiopoietin 1/2 and plasminogen activator inhibitor-1 (PAI-1). In terms of gene expression (mRNA) in blood there have been found to be increases in neutrophil-related genes in sepsis-induced and influenza-induced ARDS, but whole blood expression does not give a robust diagnostic test for ARDS. Despite improvements in management of ARDS on the critical care unit, this complex disease continues to be a major life-threatening event. Clinical trials of β2-agonists, statins, surfactants and keratinocyte growth factor (KGF) have been disappointing. In addition, monoclonal antibodies (anti-TNF) and TNFR fusion protein have also been unconvincing. However, there have been major advances in methods of mechanical ventilation, a neuromuscular blocker (cisatracurium besilate) has shown some benefit, and stem cell therapy is being developed. In the future, by understanding the role of biomarkers in the pathophysiology of ARDS and lung injury, it is hoped that this will provide rational therapeutic targets and ultimately improve clinical care (Seymour CW, Gomez H, Chang CH, Clermont G, Kellum JA, Kennedy J, Yende S, Angus DC, Crit Care 2017, 21:257).