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This study aimed at investigating the mechanisms underlying the oxygenation response to proning and recruitment maneuvers in coronavirus disease 2019 (COVID-19) pneumonia. Twenty-five patients with COVID-19 pneumonia, at variable times since admission (from 1 to 3 weeks), underwent computed tomography (CT) lung scans, gas-exchange and lung-mechanics measurement in supine and prone positions at 5 cmH2O and during recruiting maneuver (supine, 35 cmH2O). Within the non-aerated tissue, we differentiated the atelectatic and consolidated tissue (recruitable and non-recruitable at 35 cmH2O of airway pressure). Positive/negative response to proning/recruitment was defined as increase/decrease of PaO2/FiO2. Apparent perfusion ratio was computed as venous admixture/non aerated tissue fraction. The average values of venous admixture and PaO2/FiO2 ratio were similar in supine-5 and prone-5. However, the PaO2/FiO2 changes (increasing in 65% of the patients and decreasing in 35%, from supine to prone) correlated with the balance between resolution of dorsal atelectasis and formation of ventral atelectasis (p = 0.002). Dorsal consolidated tissue determined this balance, being inversely related with dorsal recruitment (p = 0.012). From supine-5 to supine-35, the apparent perfusion ratio increased from 1.38 ± 0.71 to 2.15 ± 1.15 (p = 0.004) while PaO2/FiO2 ratio increased in 52% and decreased in 48% of patients. Non-responders had consolidated tissue fraction of 0.27 ± 0.1 vs. 0.18 ± 0.1 in the responding cohort (p = 0.04). Consolidated tissue, PaCO2 and respiratory system elastance were higher in patients assessed late (all p

BackgroundExcessive tidal volume, respiratory rate, and positive end-expiratory pressure (PEEP) are all potential causes of ventilator-induced lung injury, and all contribute to a single variable: the mechanical power. The authors aimed to determine whether high tidal volume or high respiratory rate or high PEEP at iso-mechanical power produce similar or different ventilator-induced lung injury.MethodsThree ventilatory strategies—high tidal volume (twice baseline functional residual capacity), high respiratory rate (40 bpm), and high PEEP (25 cm H2O)—were each applied at two levels of mechanical power (15 and 30 J/min) for 48 h in six groups of seven healthy female piglets (weight: 24.2 ± 2.0 kg, mean ± SD).ResultsAt iso-mechanical power, the high tidal volume groups immediately and sharply increased plateau, driving pressure, stress, and strain, which all further deteriorated with time. In high respiratory rate groups, they changed minimally at the beginning, but steadily increased during the 48 h. In contrast, after a sudden huge increase, they decreased with time in the high PEEP groups. End-experiment specific lung elastance was 6.5 ± 1.7 cm H2O in high tidal volume groups, 10.1 ± 3.9 cm H2O in high respiratory rate groups, and 4.5 ± 0.9 cm H2O in high PEEP groups. Functional residual capacity decreased and extravascular lung water increased similarly in these three categories. Lung weight, wet-to-dry ratio, and histologic scores were similar, regardless of ventilatory strategies and power levels. However, the alveolar edema score was higher in the low power groups. High PEEP had the greatest impact on hemodynamics, leading to increased need for fluids. Adverse events (early mortality and pneumothorax) also occurred more frequently in the high PEEP groups.ConclusionsDifferent ventilatory strategies, delivered at iso-power, led to similar anatomical lung injury. The different systemic consequences of high PEEP underline that ventilator-induced lung injury must be evaluated in the context of the whole body.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

The authors will present a comprehensive account of the neurological aspects of SARS-CoV-2 infection. The aim is to provide a practical clinical book which will serve as a guide for clinicians from all specialties involved in the management of COVID-19 patients. The authors share the extensive clinical experience gained in major hospitals in Lombardy, the first European region to face the COVID-19 emergency in 2020. All are recognized international experts in their respective fields and have been involved in the management of COVID-19 cases from the very beginning of the Italian SARS-CoV-2 outbreak. The text begins with a description of pathobiological and pathophysiological aspects related to the involvement of the nervous system, moving on to the discussion of the neurological complications observed in COVID-19 patients; these range from central to peripheral symptoms, and can occur in the acute or post-acute phases of the disease. Further topics are: neuropathology, seizures and EEG, neuroimaging, delirium, encephalomyelitis, stroke, psychopathology and psychiatry, neuropsychology and cognitive impairment, neuromuscu-lar disorders, and the impact of COVID-19 on other pre-existing neurological disorders. In addi-tion, the book will discuss the new developments in teleneurology approaches, which have been a direct response to the ongoing pandemic. Finally, the possible neurological complications of the COVID-19 vaccines and the neurological complications in children will be considered.Each chapter will present a critical review of the existing literature concerning the specific subject matter, followed by practical clinical recommendations, as well as personal considerations based on the experience gained by each author during the course of the COVID-19 pandemic.Neurology of COVID-19 will be an original and innovative reference book for clinicians of all the specialties involved in the management of patients with SARS-CoV-2 infection. ________________________________________________ List of chapters ________________________________________________

Inflammation and oxidative stress characterize sepsis and determine its severity. In this study, we investigated the relationship between albumin oxidation and sepsis severity in a selected cohort of patients from the Albumin Italian Outcome Study (ALBIOS). A retrospective analysis was conducted on the oxidation forms of human albumin [human mercapto-albumin (HMA), human non-mercapto-albumin form 1 (HNA1) and human non-mercapto-albumin form 2 (HNA2)] in 60 patients with severe sepsis or septic shock and 21 healthy controls. The sepsis patients were randomized (1:1) to treatment with 20% albumin and crystalloid solution or crystalloid solution alone. The albumin oxidation forms were measured at day 1 and day 7. To assess the albumin oxidation forms as a function of oxidative stress, the 60 sepsis patients, regardless of the treatment, were grouped based on baseline sequential organ failure assessment (SOFA) score as surrogate marker of oxidative stress. At day 1, septic patients had significantly lower levels of HMA and higher levels of HNA1 and HNA2 than healthy controls. HMA and HNA1 concentrations were similar in patients treated with albumin or crystalloids at day 1, while HNA2 concentration was significantly greater in albumin-treated patients (p < 0.001). On day 7, HMA was significantly higher in albumin-treated patients, while HNA2 significantly increased only in the crystalloids-treated group, reaching values comparable with the albumin group. When pooling the septic patients regardless of treatment, albumin oxidation was similar across all SOFA groups at day 1, but at day 7 HMA was lower at higher SOFA scores. Mortality rate was independently associated with albumin oxidation levels measured at day 7 (HMA log-rank = 0.027 and HNA2 log-rank = 0.002), irrespective of treatment group. In adjusted regression analyses for 90-day mortality, this effect remained significant for HMA and HNA2. Our data suggest that the oxidation status of albumin is modified according to the time of exposure to oxidative stress (differences between day 1 and day 7). After 7 days of treatment, lower SOFA scores correlate with higher albumin antioxidant capacity. The trend toward a positive effect of albumin treatment, while not statistically significant, warrants further investigation.

Rationale: Understanding the physiology of CO2 stores mobilization is a prerequisite for intermittent extracorporeal CO2 removal (ECCO2R) in patients with chronic hypercapnia.Objectives: To describ...

Excessive tidal volume, respiratory rate, and positive end-expiratory pressure (PEEP) are all potential causes of ventilator-induced lung injury, and all contribute to a single variable: the mechanical power. The authors aimed to determine whether high tidal volume or high respiratory rate or high PEEP at iso-mechanical power produce similar or different ventilator-induced lung injury.Three ventilatory strategies-high tidal volume (twice baseline functional residual capacity), high respiratory rate (40 bpm), and high PEEP (25 cm H2O)-were each applied at two levels of mechanical power (15 and 30 J/min) for 48 h in six groups of seven healthy female piglets (weight: 24.2 ± 2.0 kg, mean ± SD).At iso-mechanical power, the high tidal volume groups immediately and sharply increased plateau, driving pressure, stress, and strain, which all further deteriorated with time. In high respiratory rate groups, they changed minimally at the beginning, but steadily increased during the 48 h. In contrast, after a sudden huge increase, they decreased with time in the high PEEP groups. End-experiment specific lung elastance was 6.5 ± 1.7 cm H2O in high tidal volume groups, 10.1 ± 3.9 cm H2O in high respiratory rate groups, and 4.5 ± 0.9 cm H2O in high PEEP groups. Functional residual capacity decreased and extravascular lung water increased similarly in these three categories. Lung weight, wet-to-dry ratio, and histologic scores were similar, regardless of ventilatory strategies and power levels. However, the alveolar edema score was higher in the low power groups. High PEEP had the greatest impact on hemodynamics, leading to increased need for fluids. Adverse events (early mortality and pneumothorax) also occurred more frequently in the high PEEP groups.Different ventilatory strategies, delivered at iso-power, led to similar anatomical lung injury. The different systemic consequences of high PEEP underline that ventilator-induced lung injury must be evaluated in the context of the whole body.

Esophageal pressure has been suggested as adequate surrogate of the pleural pressure. We investigate after lung surgery the determinants of the esophageal and intrathoracic pressures and their differences. The esophageal pressure (through esophageal balloon) and the intrathoracic/pleural pressure (through the chest tube on the surgery side) were measured after surgery in 28 patients immediately after lobectomy or wedge resection. Measurements were made in the nondependent lateral position (without or with ventilation of the operated lung) and in the supine position. In the lateral position with the nondependent lung, collapsed or ventilated, the differences between esophageal and pleural pressure amounted to 4.4 ± 1.6 and 5.1 ± 1.7 cmH2O. In the supine position, the difference amounted to 7.3 ± 2.8 cmH2O. In the supine position, the estimated compressive forces on the mediastinum were 10.5 ± 3.1 cmH2O and on the iso-gravitational pleural plane 3.2 ± 1.8 cmH2O. A simple model describing the roles of chest, lung, and pneumothorax volume matching on the pleural pressure genesis was developed; modeled pleural pressure = 1.0057 × measured pleural pressure + 0.6592 ( r2 = 0.8). Whatever the position and the ventilator settings, the esophageal pressure changed in a 1:1 ratio with the changes in pleural pressure. Consequently, chest wall elastance (Ecw) measured by intrathoracic (Ecw = ΔPpl/tidal volume) or esophageal pressure (Ecw = ΔPes/tidal volume) was identical in all the positions we tested. We conclude that esophageal and pleural pressures may be largely different depending on body position (gravitational forces) and lung-chest wall volume matching. Their changes, however, are identical. NEW & NOTEWORTHY Esophageal and pleural pressure changes occur at a 1:1 ratio, fully justifying the use of esophageal pressure to compute the chest wall elastance and the changes in pleural pressure and in lung stress. The absolute value of esophageal and pleural pressures may be largely different, depending on the body position (gravitational forces) and the lung-chest wall volume matching. Therefore, the absolute value of esophageal pressure should not be used as a surrogate of pleural pressure.

We retrospectively reviewed the medical records of 11 patients supported with a veno-venous low-flow extracorporeal carbon dioxide (CO2) removal (ECCO2R) device featuring a large gas exchange surface membrane lung (ML) (i.e., 1.8 m). Seven patients suffered from exacerbation of a chronic pulmonary disease, while four subjects were affected by acute respiratory distress syndrome (ARDS). Twenty-four hours of ECCO2R treatment reduced arterial PCO2 from 63 ± 12 to 54 ± 11 mm Hg (p < 0.01), increased arterial pH from 7.29 ± 0.07 to 7.39 ± 0.06 (p < 0.01), and decreased respiratory rate from 32 ± 10 to 21 ± 8 bpm (p < 0.05). Extracorporeal blood flow and CO2 removal were 333 ± 37 and 94 ± 18 ml/min, respectively. The median duration of ECCO2R treatment was 7 days (6.5-9.5). All four ARDS patients were invasively ventilated at the time of treatment start, no one was extubated and they all died. Among the seven patients with exacerbation of chronic pulmonary diseases, four were managed with noninvasive ventilation at ECCO2R institution, while three were extubated after starting the extracorporeal treatment. No one of these seven patients was intubated or re-intubated after ECCO2R institution and five (71%) survived to hospital discharge. A low-flow ECCO2R device with a large surface ML removes a relevant amount of CO2 resulting in a decreased arterial PCO2, an increased arterial pH, and in a reduced ventilatory load.

Introduction: Transpulmonary pressure (PL) is the pressure distending the lung. This pressure equals the stress which develops into the parenchyma at each insufflation and it depends, for a given airway pressure, on the relationship between the lung and the chest wall elastance: a given stress is associated to a given strain, therefor PL is strictly related to ventilator-induced lung injury (VILI). Insufficient knowledge and increased workload account for its limited use in the clinical setting: indeed, the current recommendations for protective ventilation still rely only on the pressures applied to the respiratory system in total (Plateau pressure), without a direct measurement of the real lung stress. Areas covered: We reviewed the significance, the assessment, the application and the limits of transpulmonary pressure in the clinical setting. Expert opinion: Transpulmonary pressure represents a physiologically sound safety limit for mechanical ventilation that should be measured and targeted at least in the most severe ARDS patients. Targeting transpulmonary pressure means 'personalizing' the ventilatory settings.

Trauma, surgery, and infection represent a common source of stress in critically ill patients admitted in intensive care units (ICUs). Although the consequences of stress response in critical illness are still debated and not well understood, many neural and hormonal responses have been recognized to activate homeostatic mechanisms aimed at favoring survival and healing. These responses develop toward three different phases: the first immediate and short (24 h) phase, termed ebb, is directed to immediate survival; the second longer phase (6–7 days), termed flow, is characterized by an increase in total body oxygen consumption and carbon dioxide production with hypermetabolism; the third phase, termed chronic, may last some months and identifies the post-stress period of critical illness. Although the effects of sedatives (analgesics and hypnotics) on tissue metabolic demand of critically ill patient remain difficult to be adequately defined, these drugs commonly delivered in intensive care units actually influence the stress response by decreasing neurohumoral reactions, involving the sympathetic system, and affecting the inflammatory mechanisms. After the neuroendocrine activation, uncontrolled metabolic reactions, characterized by catabolism and the resistance to anabolic signals as insulin, develop. Secondary negative effects (infections, muscle atrophy and weakness, respiratory insufficiency, delayed wound healing) can occur as direct consequences of metabolic phenomena that are clearly difficult to monitor. Finally, sedatives administered to control stress response clearly have detrimental effects (hemodynamic alterations, immunosuppression, delirium) that should be carefully evaluated in the context of a balance between benefits and damages.

Over the last 50 years, botulinum toxin (BoNT) has been transformed from a cause of life-threatening disease to an effective therapy, mainly for muscle spasticity, blepharospasm, and bladder overactivity. Certainly the use of intradetrusor BoNT for the treatment of DO has revolutionized the care of patients with neurogenic bladder and iOAB, largely improving their quality of life. A recent growing body of evidence suggests that intradetrusor injection of BoNT may have beneficial effects in patients with refractory detrusor overactivity (DO) for conservative and/or medical treatments, and it is a new minimally invasive alternative to bladder augmentation in patients with severe overactive bladder (OAB) symptoms and/or untreatable neurogenic bladder.