Chest wall loading during supine and prone position in patients with COVID-19 ARDS: effects on respiratory mechanics and gas exchange.

BACKGROUND: Recent reports of patients with severe, late-stage COVID-19 ARDS with reduced respiratory system compliance described paradoxical decreases in plateau pressure and increases in respiratory system compliance in response to anterior chest wall loading. We aimed to assess the effect of chest wall loading during supine and prone position in ill patients with COVID-19-related ARDS and to investigate the effect of a low or normal baseline respiratory system compliance on the findings. METHODS: This is a single-center, prospective, cohort study in the intensive care unit of a COVID-19 referral center. Consecutive mechanically ventilated, critically ill patients with COVID-19-related ARDS were enrolled and classified as higher (≥ 40 ml/cmH2O) or lower respiratory system compliance (< 40 ml/cmH2O). The study included four steps, each lasting 6 h: Step 1, supine position, Step 2, 10-kg continuous chest wall compression (supine + weight), Step 3, prone position, Step 4, 10-kg continuous chest wall compression (prone + weight). The mechanical properties of the respiratory system, gas exchange and alveolar dead space were measured at the end of each step. RESULTS: Totally, 40 patients were enrolled. In the whole cohort, neither oxygenation nor respiratory system compliance changed between supine and supine + weight; both increased during prone positioning and were unaffected by chest wall loading in the prone position. Alveolar dead space was unchanged during all the steps. In 16 patients with reduced compliance, PaO2/FiO2 significantly increased from supine to supine + weight and further with prone and prone + weight (107 ± 15.4 vs. 120 ± 18.5 vs. 146 ± 27.0 vs. 159 ± 30.4, respectively; p < 0.001); alveolar dead space decreased from both supine and prone position after chest wall loading, and respiratory system compliance significantly increased from supine to supine + weight and from prone to prone + weight (23.9 ± 3.5 vs. 30.9 ± 5.7 and 31.1 ± 5.7 vs. 37.8 ± 8.7 ml/cmH2O, p < 0.001). The improvement was higher the lower the baseline compliance. CONCLUSIONS: Unlike prone positioning, chest wall loading had no effects on respiratory system compliance, gas exchange or alveolar dead space in an unselected cohort of critically ill patients with C-ARDS. Only patients with a low respiratory system compliance experienced an improvement, with a higher response the lower the baseline compliance.

EXpert consensus On Diaphragm UltraSonography in the critically ill (EXODUS): a Delphi consensus statement on the measurement of diaphragm ultrasound-derived parameters in a critical care setting.

BACKGROUND: Diaphragm ultrasonography is rapidly evolving in both critical care and research. Nevertheless, methodologically robust guidelines on its methodology and acquiring expertise do not, or only partially, exist. Therefore, we set out to provide consensus-based statements towards a universal measurement protocol for diaphragm ultrasonography and establish key areas for research. METHODS: To formulate a robust expert consensus statement, between November 2020 and May 2021, a two-round, anonymous and online survey-based Delphi study among experts in the field was performed. Based on the literature review, the following domains were chosen: "Anatomy and physiology", "Transducer Settings", "Ventilator Impact", "Learning and expertise", "Daily practice" and "Future directions". Agreement of ≥ 68% (≥ 10 panelists) was needed to reach consensus on a question. RESULTS: Of 18 panelists invited, 14 agreed to participate in the survey. After two rounds, the survey included 117 questions of which 42 questions were designed to collect arguments and opinions and 75 questions aimed at reaching consensus. Of these, 46 (61%) consensus was reached. In both rounds, the response rate was 100%. Among others, there was agreement on measuring thickness between the pleura and peritoneum, using > 10% decrease in thickness as cut-off for atrophy and using 40 examinations as minimum training to use diaphragm ultrasonography in clinical practice. In addition, key areas for research were established. CONCLUSION: This expert consensus statement presents the first set of consensus-based statements on diaphragm ultrasonography methodology. They serve to ensure high-quality and homogenous measurements in daily clinical practice and in research. In addition, important gaps in current knowledge and thereby key areas for research are established. Trial registration The study was pre-registered on the Open Science Framework with registration digital object identifier https://doi.org/10.17605/OSF.IO/HM8UG .

Central venous pressure swing outperforms diaphragm ultrasound as a measure of inspiratory effort during pressure support ventilation in COVID-19 patients.

PURPOSE: The COVID-19-related shortage of ICU beds magnified the need of tools to properly titrate the ventilator assistance. We investigated whether bedside-available indices such as the ultrasonographic changes in diaphragm thickening ratio (TR) and the tidal swing in central venous pressure (ΔCVP) are reliable estimates of inspiratory effort, assessed as the tidal swing in esophageal pressure (ΔPes). METHODS: Prospective, observational clinical investigation in the intensive care unit of a tertiary care Hospital. Fourteen critically-ill patients were enrolled (age 64 ± 7 years, BMI 29 ± 4 kg/m2), after 6 [3; 9] days from onset of assisted ventilation. A three-level pressure support trial was performed, at 10 (PS10), 5 (PS5) and 0 cmH2O (PS0). In each step, the esophageal and central venous pressure tidal swing were recorded, as well as diaphragm ultrasound. RESULTS: The reduction of pressure support was associated with an increased respiratory rate and a reduced tidal volume, while minute ventilation was unchanged. ΔPes significantly increased with reducing support (5 [3; 8] vs. 8 [14; 13] vs. 12 [6; 16] cmH2O, p < 0.0001), as did the diaphragm TR (9.2 ± 6.1 vs. 17.6 ± 7.2 vs. 28.0 ± 10.0%, p < 0.0001) and the ΔCVP (4 [3; 7] vs. 8 [5; 9] vs. 10 [7; 11] cmH2O, p < 0.0001). ΔCVP was significantly associated with ΔPes (R2 = 0.810, p < 0.001), as was diaphragm TR, albeit with a lower coefficient of determination (R2 = 0.399, p < 0.001). CONCLUSIONS: In patients with COVID-19-associated respiratory failure undergoing assisted mechanical ventilation, ΔCVP is a better estimate of inspiratory effort than diaphragm ultrasound.

Hysteresis and Lung Recruitment in Acute Respiratory Distress Syndrome Patients: A CT Scan Study.

OBJECTIVES: Hysteresis of the respiratory system pressure-volume curve is related to alveolar surface forces, lung stress relaxation, and tidal reexpansion/collapse. Hysteresis has been suggested as a means of assessing lung recruitment. The objective of this study was to determine the relationship between hysteresis, mechanical characteristics of the respiratory system, and lung recruitment assessed by a CT scan in mechanically ventilated acute respiratory distress syndrome patients. DESIGN: Prospective observational study. SETTING: General ICU of a university hospital. PATIENTS: Twenty-five consecutive sedated and paralyzed patients with acute respiratory distress syndrome (age 64 ± 15 yr, body mass index 26 ± 6 kg/m, PaO2/FIO2 147 ± 42, and positive end-expiratory pressure 9.3 ± 1.4 cm H2O) were enrolled. INTERVENTIONS: A low-flow inflation and deflation pressure-volume curve (5-45 cm H2O) and a sustained inflation recruitment maneuver (45 cm H2O for 30 s) were performed. A lung CT scan was performed during breath-holding pressure at 5 cm H2O and during the recruitment maneuver at 45 cm H2O. MEASUREMENTS AND MAIN RESULTS: Lung recruitment was computed as the difference in noninflated tissue and in gas volume measured at 5 and at 45 cm H2O. Hysteresis was calculated as the ratio of the area enclosed by the pressure-volume curve and expressed as the hysteresis ratio. Hysteresis was correlated with respiratory system compliance computed at 5 cm H2O and the lung gas volume entering the lung during inflation of the pressure-volume curve (R = 0.749, p < 0.001 and R = 0.851, p < 0.001). The hysteresis ratio was related to both lung tissue and gas recruitment (R = 0.266, p = 0.008, R = 0.357, p = 0.002, respectively). Receiver operating characteristic analysis showed that the optimal cutoff value to predict lung tissue recruitment for the hysteresis ratio was 28% (area under the receiver operating characteristic curve, 0.80; 95% CI, 0.62-0.98), with sensitivity and specificity of 0.75 and 0.77, respectively. CONCLUSIONS: Hysteresis of the respiratory system computed by low-flow pressure-volume curve is related to the anatomical lung characteristics and has an acceptable accuracy to predict lung recruitment.

Bedside calculation of mechanical power during volume- and pressure-controlled mechanical ventilation.

BACKGROUND: Mechanical power (MP) is the energy delivered to the respiratory system over time during mechanical ventilation. Our aim was to compare the currently available methods to calculate MP during volume- and pressure-controlled ventilation, comparing different equations with the geometric reference method, to understand whether the easier to use surrogate formulas were suitable for the everyday clinical practice. This would warrant a more widespread use of mechanical power to promote lung protection. METHODS: Forty respiratory failure patients, sedated and paralyzed for clinical reasons, were ventilated in volume-controlled ventilation, at two inspiratory flows (30 and 60 L/min), and pressure-controlled ventilation with a similar tidal volume. Mechanical power was computed both with the geometric method, as the area between the inspiratory limb of the airway pressure and the volume, and with two algebraic methods, a comprehensive and a surrogate formula. RESULTS: The bias between the MP computed by the geometric method and by the comprehensive algebraic method during volume-controlled ventilation was respectively 0.053 (0.77, - 0.81) J/min and - 0.4 (0.70, - 1.50) J/min at low and high flows (r2 = 0.96 and 0.97, p < 0.01). The MP measured and computed by the two methods were highly correlated (r2 = 0.95 and 0.94, p < 0.01) with a bias of - 0.0074 (0.91, - 0.93) and - 1.0 (0.45, - 2.52) J/min at high-low flows. During pressure-controlled ventilation, the bias between the MP measured and the one calculated with the comprehensive and simplified methods was correlated (r2 = 0.81, 0.94, p < 0.01) with mean differences of - 0.001 (2.05, - 2.05) and - 0.81 (2.11, - 0.48) J/min. CONCLUSIONS: Both for volume-controlled and pressure-controlled ventilation, the surrogate formulas approximate the reference method well enough to warrant their use in the everyday clinical practice. Given that these formulas require nothing more than the variables already displayed by the intensive care ventilator, a more widespread use of mechanical power should be encouraged to promote lung protection against ventilator-induced lung injury.

Oesophageal pressure and respiratory muscle ultrasonographic measurements indicate inspiratory effort during pressure support ventilation.

BACKGROUND: Bedside measures of patient effort are essential to properly titrate the level of pressure support ventilation. We investigated whether the tidal swing in oesophageal (ΔPes) and transdiaphragmatic pressure (ΔPdi), and ultrasonographic changes in diaphragm (TFdi) and parasternal intercostal (TFic) thickening are reliable estimates of respiratory effort. The effect of diaphragm dysfunction was also considered. METHODS: Twenty-one critically ill patients were enrolled: age 73 (14) yr, BMI 27 (7) kg m-2, and Pao2/Fio2 33.3 (9.2) kPa. A three-level pressure support trial was performed: baseline, 25% (PS-medium), and 50% reduction (PS-low). We recorded the oesophageal and transdiaphragmatic pressure-time products (PTPs), work of breathing (WOB), and diaphragm and intercostal ultrasonography. Diaphragm dysfunction was defined by the Gilbert index. RESULTS: Pressure support was 9.0 (1.6) cm H2O at baseline, 6.7 (1.3) (PS-medium), and 4.4 (1.0) (PS-low). ΔPes was significantly associated with the oesophageal PTP (R2=0.868; P<0.001) and the WOB (R2=0.683; P<0.001). ΔPdi was significantly associated with the transdiaphragmatic PTP (R2=0.820; P<0.001). TFdi was only weakly correlated with the oesophageal PTP (R2=0.326; P<0.001), and the correlation improved after excluding patients with diaphragm dysfunction (R2=0.887; P<0.001). TFdi was higher and TFic lower in patients without diaphragm dysfunction: 33.6 (18.2)% vs 13.2 (9.2)% and 2.1 (1.7)% vs 12.7 (9.1)%; P<0.0001. CONCLUSIONS: ΔPes and ΔPdi are adequate estimates of inspiratory effort. Diaphragm ultrasonography is a reliable indicator of inspiratory effort in the absence of diaphragm dysfunction. Additional measurement of parasternal intercostal thickening may discriminate a low inspiratory effort or a high effort in the presence of a dysfunctional diaphragm.

Urine Electrolytes in the Intensive Care Unit: From Pathophysiology to Clinical Practice.

Assessment of urine concentrations of sodium, chloride, and potassium is a widely available, rapid, and low-cost diagnostic option for the management of critically ill patients. Urine electrolytes have long been suggested in the diagnostic workup of hypovolemia, kidney injury, and acid-base and electrolyte disturbances. However, due to the wide range of normal reference values and challenges in interpretation, their use is controversial. To clarify their potential role in managing critical patients, we reviewed existing evidence on the use of urine electrolytes for diagnostic and therapeutic evaluation and assessment in critical illness. This review will describe the normal physiology of water and electrolyte excretion, summarize the use of urine electrolytes in hypovolemia, acute kidney injury, acid-base, and electrolyte disorders, and suggest some practical flowcharts for the potential use of urine electrolytes in daily critical care practice.

Body Position Alters Mechanical Power and Respiratory Mechanics During Thoracic Surgery.

BACKGROUND: During thoracic surgery, patients are usually positioned in lateral decubitus and only the dependent lung ventilated. The ventilated lung is thus exposed to the weight of the contralateral hemithorax and restriction of the dependent chest wall. We hypothesized that mechanical power would increase during one-lung ventilation in the lateral position. METHODS: We performed a prospective, observational, single-center study from December 2016 to May 2017. Thirty consecutive patients undergoing general anesthesia with mechanical ventilation (mean age, 68 ± 11 years; body mass index, 25 ± 5 kg·m) for thoracic surgery were enrolled. Total and partitioned mechanical power, lung and chest wall elastance, and esophageal pressure were compared in supine and lateral position with double- and one-lung ventilation and with closed and open chest both before and after surgery. Mixed factorial ANOVA for repeated measurements was performed, with both step and the period before or after surgery as 2 within-subject factors, and left or right body position during surgery as a fixed, between-subject factor. Appropriate interaction terms were included. RESULTS: The mechanical power was higher in lateral one-lung ventilation compared to both supine and lateral position double-lung ventilation (11.1 ± 3.0 vs 8.2 ± 2.7 vs 8.7 ± 2.6; mean difference, 2.9 J·minute [95% CI, 1.4-4.4 J·minute] and 2.4 J·minute [95% CI, 0.9-3.9 J·minute]; P < .001 and P = .002, respectively). Lung elastance was higher during lateral position one-lung ventilation compared to both lateral and supine double-lung ventilation (24.3 ± 8.7 vs 9.5 ± 3.8 vs 10.0 ± 3.8; mean difference, 14.7 cm H2O·L [95% CI, 11.2-18.2 cm H2O·L] and 14.2 cm H2O·L [95% CI, 10.8-17.7 cm H2O·L], respectively) and was higher compared to predicted values (20.1 ± 7.5 cm H2O·L). Chest wall elastance increased in lateral position double-lung ventilation compared to supine (11.1 ± 3.8 vs 6.6 ± 3.4; mean difference, 4.5 cm H2O·L [95% CI, 2.6-6.3 cm H2O·L]) and was lower in lateral position one-lung ventilation with open chest than with a closed chest (3.5 ± 1.9 vs 7.1 ± 2.8; mean difference, 3.6 cm H2O·L [95% CI, 2.4-4.8 cm H2O·L]). The end-expiratory esophageal pressure decreased moving from supine position to lateral position one-lung ventilation while increased with the opening of the chest wall. CONCLUSIONS: Mechanical power and lung elastance are increased in the lateral position with one-lung ventilation. Esophageal pressure monitoring may be used to follow these changes.

Global and Regional Diagnostic Accuracy of Lung Ultrasound Compared to CT in Patients With Acute Respiratory Distress Syndrome.

OBJECTIVES: Lung CT is the reference imaging technique for acute respiratory distress syndrome, but requires transportation outside the intensive care and x-ray exposure. Lung ultrasound is a promising, inexpensive, radiation-free, tool for bedside imaging. Aim of the present study was to compare the global and regional diagnostic accuracy of lung ultrasound and CT scan. DESIGN: A prospective, observational study. SETTING: Intensive care and radiology departments of a University hospital. PATIENTS: Thirty-two sedated, paralyzed acute respiratory distress syndrome patients (age 65 ± 14 yr, body mass index 25.9 ± 6.5 kg/m, and PaO2/FIO2 139 ± 47). INTERVENTIONS: Lung CT scan and lung ultrasound were performed at positive end-expiratory pressure 5 cm H2O. A standardized assessment of six regions per hemithorax was used; each region was classified for the presence of normal aeration, alveolar-interstitial syndrome, consolidation, and pleural effusion. Agreement between the two techniques was calculated, and diagnostic variables were assessed for lung ultrasound using lung CT as a reference. MEASUREMENTS AND MAIN RESULTS: Global agreement between lung ultrasound and CT ranged from 0.640 (0.391-0.889) to 0.934 (0.605-1.000) and was on average 0.775 (0.577-0.973). The overall sensitivity and specificity of lung ultrasound ranged from 82.7% to 92.3% and from 90.2% to 98.6%, respectively. Similar results were found with regional analysis. The diagnostic accuracy of lung ultrasound was significantly higher when those patterns not reaching the pleural surface were excluded (area under the receiver operating characteristic curve: alveolar-interstitial syndrome 0.854 [0.821-0.887] vs 0.903 [0.852-0.954]; p = 0.049 and consolidation 0.851 [0.818-0.884] vs 0.896 [0.862-0.929]; p = 0.044). CONCLUSIONS: Lung ultrasound is a reproducible, sensitive, and specific tool, which allows for bedside detections of the morphologic patterns in acute respiratory distress syndrome. The presence of deep lung alterations may impact the diagnostic performance of this technique.

Different routes and formulations of melatonin in critically ill patients. A pharmacokinetic randomized study.

BACKGROUND AND OBJECTIVES: Critically ill patients present reduced endogenous melatonin blood levels, and they might benefit from its exogenous supplementation. The aim of this research was to evaluate the feasibility of different routes of administration and drug formulations of melatonin. The efficiency of absorption was assessed as well as the adequacy in achieving and maintaining the physiological nocturnal blood peak. METHODS: Twenty-one high-risk critically ill patients were randomly assigned to receive melatonin either: (a) per os, as a standard tablet (ST-OS), (b) per os, as a suspension in solid lipid nanoparticles (SLN-OS) or c) transdermal (TD), by applying a jellified melatonin microemulsion (µE) on the skin (µE-TD). SLN-OS and µE-TD were lipid-based colloidal systems. The endogenous melatonin blood values were observed for 24 hours; subsequently, melatonin 3 mg was administered and pharmacokinetics was studied for 24 hours further. RESULTS: In both groups that received ST-OS and SLN-OS, the median time-to-peak blood concentration was 0.5 hours; however, the area under the curve (AUC) after administration of SLN-OS was significantly higher than after ST-OS (157386 [65732-193653] vs 44441 [22319-90705] pg/mL*hours, P = 0.048). µE-TD presented a delayed time-to-peak blood concentration (4 hours), a lower bioavailability (AUC: 3142 [1344-14573] pg/mL*hours) and reached pharmacological peak concentration (388 [132-1583] pg/mL). CONCLUSIONS: SLN-melatonin enterally administered offers favourable pharmacokinetics in critically ill patients, with higher bioavailability with respect to the standard formulation; µE-TD provided effective pharmacological blood levels, with a time-concentration profile more similar to the physiological melatonin pattern.

Enteral versus intravenous approach for the sedation of critically ill patients: a randomized and controlled trial.

BACKGROUND: ICU patients must be kept conscious, calm, and cooperative even during the critical phases of illness. Enteral administration of sedative drugs might avoid over sedation, and would be as adequate as intravenous administration in patients who are awake, with fewer side effects and lower costs. This study compares two sedation strategies, for early achievement and maintenance of the target light sedation. METHODS: This was a multicenter, single-blind, randomized and controlled trial carried out in 12 Italian ICUs, involving patients with expected mechanical ventilation duration > 72 h at ICU admission and predicted mortality > 12% (Simplified Acute Physiology Score II > 32 points) during the first 24 h on ICU. Patients were randomly assigned to receive intravenous (midazolam, propofol) or enteral (hydroxyzine, lorazepam, and melatonin) sedation. The primary outcome was percentage of work shifts with the patient having an observed Richmond Agitation-Sedation Scale (RASS) = target RASS ±1. Secondary outcomes were feasibility, delirium-free and coma-free days, costs of drugs, length of ICU and hospital stay, and ICU, hospital, and one-year mortality. RESULTS: There were 348 patients enrolled. There were no differences in the primary outcome: enteral 89.8% (74.1-100), intravenous 94.4% (78-100), p = 0.20. Enteral-treated patients had more protocol violations: n = 81 (46.6%) vs 7 (4.2%), p < 0.01; more self-extubations: n = 14 (8.1%) vs 4 (2.4%), p = 0.03; a lighter sedative target (RASS = 0): 93% (71-100) vs 83% (61-100), p < 0.01; and lower total drug costs: 2.39 (0.75-9.78) vs 4.15 (1.20-20.19) €/day with mechanical ventilation (p = 0.01). CONCLUSIONS: Although enteral sedation of critically ill patients is cheaper and permits a lighter sedation target, it is not superior to intravenous sedation for reaching the RASS target. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01360346 . Registered on 25 March 2011.

Pathophysiology and Management of Acute Respiratory Distress Syndrome in Obese Patients.

A rising prevalence of obesity is reported over time and throughout the world. At the same time, the acute respiratory distress syndrome (ARDS) remains an important public health problem, accounting for approximately 10% of intensive care unit admissions and leading to significant hospital mortality. Even in the absence of acute illnesses, obesity affects respiratory mechanics and gas exchange in the setting of a restrictive disease. In the presence of ARDS, obesity adds various challenges to a safe and effective management of respiratory support. Difficult airway management, altered lung and chest wall physiology, and positional gas trapping are routinely encountered. The management of such difficult cases is generally empiric, as it is based on small-sized, physiologic studies or on suggestions from the general anesthesia literature. The present review focuses on those cases in which ARDS is coincident with obesity, with the aim of presenting treatment options based on the current evidence. The first part summarizes the epidemiology of obesity and ARDS. Then the diagnostic challenges due to obesity-related artifacts of the different imaging techniques will be presented. A subsequent, detailed description of the altered respiratory anatomy and physiology of obesity will provide help in selecting an optimal, individually tailored strategy of support. Furthermore, we will discuss how esophageal manometry should be used to adjust the settings of positive end-expiratory pressure and tidal volume; the challenges of prone positioning and extracorporeal support; and the optimal strategies for weaning from mechanical ventilation, including when and how to perform a tracheostomy.

Improved Survival in a Long-Term Rat Model of Sepsis Is Associated With Reduced Mitochondrial Calcium Uptake Despite Increased Energetic Demand.

OBJECTIVES: To investigate the relationship between prognosis, changes in mitochondrial calcium uptake, and bioenergetic status in the heart during sepsis. DESIGN: In vivo and ex vivo controlled experimental studies. SETTING: University research laboratory. SUBJECTS: Male adult Wistar rats. INTERVENTIONS: Sepsis was induced by intraperitoneal injection of fecal slurry. Sham-operated animals served as controls. Confocal microscopy was used to study functional and bioenergetic parameters in cardiomyocytes isolated after 24-hour sepsis. Electron microscopy was used to characterize structural changes in mitochondria and sarcoplasmic reticulum. The functional response to dobutamine was assessed in vivo by echocardiography. MEASUREMENTS AND MAIN RESULTS: Peak aortic blood flow velocity measured at 24 hours was a good discriminator for 72-hour survival (area under the receiver operator characteristic, 0.84 ± 0.1; p = 0.03) and was used in ex vivo experiments at 24 hours to identify septic animals with good prognosis. Measurements from animals with good prognostic showed 1) a smaller increase in mitochondrial calcium content and in nicotinamide adenine dinucleotide fluorescence following pacing and 2) increased distance between mitochondria and sarcoplasmic reticulum on electron microscopy, and 3) nicotinamide adenine dinucleotide redox potential and adenosine triphosphate/adenosine diphosphate failed to reach a new steady state following pacing, suggesting impaired matching of energy supply and demand. In vivo, good prognosis animals had a blunted response to dobutamine with respect to stroke volume and kinetic energy. CONCLUSIONS: In situations of higher energetic demand decreased mitochondrial calcium uptake may constitute an adaptive cellular response that confers a survival advantage in response to sepsis at a cost of decreased oxidative capacity.

Melatonin Pharmacological Blood Levels Increase Total Antioxidant Capacity in Critically Ill Patients.

In this study, the aim was to test the biochemical effects of melatonin supplementation in Intensive Care Unit (ICU) patients, since their blood levels are decreased. Sixty-four patients were enrolled in the study. From the evening of the 3rd ICU day, patients were randomized to receive oral melatonin (3 mg, group M) or placebo (group P) twice daily, at 20:00 and 24:00, until discharged. Blood was taken (at 00:00 and 14:00), on the 3rd ICU day to assess basal nocturnal melatonin values, and then during the treatment period on the 4th and 8th ICU days. Melatonin, total antioxidant capacity, and oxidative stress were evaluated in serum. Melatonin circadian rhythm before treatment was similar in the two groups, with a partial preservation of the cycle. Four hours from the 1st administration (4th ICU day, 00:00), melatonin levels increased to 2514 (982.3; 7148) pg·mL-1 in group M vs. 20.3 (14.7; 62.3) pg·mL-1 in group P (p < 0.001). After five treatment days (8th ICU day), melatonin absorption showed a repetitive trend in group M, while in group P nocturnal secretion (00:00) was impaired: 20 (11.5; 34.5) pg·mL-1 vs. 33.8 (25.0; 62.2) on the 3rd day (p = 0.029). Immediately from the beginning of treatment, the total antioxidant capacity was significantly higher in melatonin treated subjects at 00:00; a significant correlation was found between total antioxidant capacity and blood melatonin values (ρ = 0.328; p < 0.001). The proposed enteral administration protocol was adequate, even in the early phase, to enhance melatonin blood levels and to protect the patients from oxidative stress. The antioxidant effect of melatonin could play a meaningful role in the care and well-being of these patients.

Current Concepts of ARDS: A Narrative Review.

Acute respiratory distress syndrome (ARDS) is characterized by the acute onset of pulmonary edema of non-cardiogenic origin, along with bilateral pulmonary infiltrates and reduction in respiratory system compliance. The hallmark of the syndrome is refractory hypoxemia. Despite its first description dates back in the late 1970s, a new definition has recently been proposed. However, the definition remains based on clinical characteristic. In the present review, the diagnostic workup and the pathophysiology of the syndrome will be presented. Therapeutic approaches to ARDS, including lung protective ventilation, prone positioning, neuromuscular blockade, inhaled vasodilators, corticosteroids and recruitment manoeuvres will be reviewed. We will underline how a holistic framework of respiratory and hemodynamic support should be provided to patients with ARDS, aiming to ensure adequate gas exchange by promoting lung recruitment while minimizing the risk of ventilator-induced lung injury. To do so, lung recruitability should be considered, as well as the avoidance of lung overstress by monitoring transpulmonary pressure or airway driving pressure. In the most severe cases, neuromuscular blockade, prone positioning, and extra-corporeal life support (alone or in combination) should be taken into account.

Diaphragm ultrasound as indicator of respiratory effort in critically ill patients undergoing assisted mechanical ventilation: a pilot clinical study.

INTRODUCTION: Pressure-support ventilation, is widely used in critically ill patients; however, the relative contribution of patient's effort during assisted breathing is difficult to measure in clinical conditions. Aim of the present study was to evaluate the performance of ultrasonographic indices of diaphragm contractile activity (respiratory excursion and thickening) in comparison to traditional indices of inspiratory muscle effort during assisted mechanical ventilation. METHOD: Consecutive patients admitted to the ICU after major elective surgery who met criteria for a spontaneous breathing trial with pressure support ventilation were enrolled. Patients with airflow obstruction or after thoracic/gastric/esophageal surgery were excluded. Variable levels of inspiratory muscle effort were achieved by delivery of different levels of ventilatory assistance by random application of pressure support (0, 5 and 15 cmH2O). The right hemidiaphragm was evaluated by B- and M-mode ultrasonography to record respiratory excursion and thickening. Airway, gastric and oesophageal pressures, and airflow were recorded to calculate indices of respiratory effort (diaphragm and esophageal pressure-time product). RESULTS: 25 patients were enrolled. With increasing levels of pressure support, parallel reductions were found between diaphragm thickening and both diaphragm and esophageal pressure-time product (respectively, R = 0.701, p < 0.001 and R = 0.801, p < 0.001) during tidal breathing. No correlation was found between either diaphragm or esophageal pressure-time product and diaphragm excursion (respectively, R = -0.081, p = 0.506 and R = 0.003, p = 0.981), nor was diaphragm excursion correlated to diaphragm thickening (R = 0.093, p = 0.450) during tidal breathing. CONCLUSIONS: In patients undergoing in assisted mechanical ventilation, diaphragm thickening is a reliable indicator of respiratory effort, whereas diaphragm excursion should not be used to quantitatively assess diaphragm contractile activity.

Short-term hypoxic vasodilation in vivo is mediated by bioactive nitric oxide metabolites, rather than free nitric oxide derived from haemoglobin-mediated nitrite reduction.

Local increases in blood flow--'hypoxic vasodilation'--confer cellular protection in the face of reduced oxygen delivery. The physiological relevance of this response is well established, yet ongoing controversy surrounds its underlying mechanisms. We sought to confirm that early hypoxic vasodilation is a nitric oxide (NO)-mediated phenomenon and to study putative pathways for increased levels of NO, namely production from NO synthases, intravascular nitrite reduction, release from preformed stores and reduced deactivation by cytochrome c oxidase. Experiments were performed on spontaneously breathing, anaesthetized, male Wistar rats undergoing short-term systemic hypoxaemia, who received pharmacological inhibitors and activators of the various NO pathways. Arterial blood pressure, cardiac output, tissue oxygen tension and the circulating pool of NO metabolites (oxidation, nitrosation and nitrosylation products) were measured in plasma and erythrocytes. Hypoxaemia caused a rapid and sustained vasodilation, which was only partially reversed by non-selective NO synthase inhibition. This was associated with significantly lower plasma nitrite, and marginally elevated nitrate levels, suggestive of nitrite bioinactivation. Administration of sodium nitrite had little effect in normoxia, but produced significant vasodilation and increased nitrosylation during hypoxaemia that could not be reversed by NO scavenging. Methodological issues prevented assessment of the contribution, if any, of reduced deactivation of NO by cytochrome c oxidase. In conclusion, acute hypoxic vasodilation is an adaptive NO-mediated response conferred through bioactive metabolites rather than free NO from haemoglobin-mediated reduction of nitrite.