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Since the lockdown because of the pandemic, family members have been prohibited from visiting their loved ones in hospital. While it is clearly complicated to implement protocols for the admission of family members, we believe precise strategic goals are essential and operational guidance is needed on how to achieve them. Even during the pandemic, we consider it a priority to share strategies adapted to every local setting to allow family members to enter intensive care units and all the other hospital wards.

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 (r 2  = 0.96 and 0.97, p < 0.01). The MP measured and computed by the two methods were highly correlated (r 2  = 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 (r 2  = 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.

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.

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.

Introduction: Platelet mitochondrial respiratory chain enzymes (that produce energy) are variably inhibited during human sepsis. Whether these changes occur even during other acute critical illness or are associated with impaired platelet aggregation and secretion (that consume energy) is not known. The aims of this study were firstly to compare platelet mitochondrial respiratory chain enzymes activity between patients with sepsis and those with cardiogenic shock, and secondly to study the relationship between platelet mitochondrial respiratory chain enzymes activity and platelet responsiveness to (exogenous) agonists in patients with sepsis., Methods: This was a prospective, observational, case-control study. Platelets were isolated from venous blood of 16 patients with severe sepsis or septic shock (free from antiplatelet drugs) and 16 others with cardiogenic shock, within 48 hours from admission to Intensive Care. Platelet mitochondrial respiratory chain enzymes activity was measured with spectrophotometry and expressed relative to citrate synthase activity, a marker of mitochondrial density. Platelet aggregation and secretion in response to adenosine di-phosphate (ADP), collagen, U46619 and thrombin receptor activating peptide were measured with lumiaggregometry only in patients with sepsis. In total, 16 healthy volunteers acted as controls for both spectrophotometry and lumiaggregometry., Results: Platelets of patients with sepsis or cardiogenic shock similarly had lower mitochondrial nicotinamide adenine dinucleotide dehydrogenase (NADH) (P < 0.001), complex I (P = 0.006), complex I and III (P < 0.001) and complex IV (P < 0.001) activity than those of controls. Platelets of patients with sepsis were generally hypo-responsive to exogenous agonists, both in terms of maximal aggregation (P < 0.001) and secretion (P < 0.05). Lower mitochondrial NADH (R (2) 0.36; P < 0.001), complex I (R (2) 0.38; P < 0.001), complex I and III (R (2) 0.27; P = 0.002) and complex IV (R (2) 0.43; P < 0.001) activity was associated with lower first wave of aggregation with ADP., Conclusions: Several platelet mitochondrial respiratory chain enzymes are similarly inhibited during human sepsis and cardiogenic shock. In patients with sepsis, mitochondrial dysfunction is associated with general platelet hypo-responsiveness to exogenous agonists., Trial Registration: ClinicalTrials.gov NCT00541827 . Registered 8 October 2007.

Introduction: We have recently demonstrated that metformin intoxication causes mitochondrial dysfunction in several porcine tissues, including platelets. The aim of the present work was to clarify whether it also causes mitochondrial dysfunction (and secondary lactate overproduction) in human platelets, in vitro and ex vivo., Methods: Human platelets were incubated for 72 hours with saline or increasing doses of metformin (in vitro experiments). Lactate production, respiratory chain complex activities (spectrophotometry), mitochondrial membrane potential (flow-cytometry after staining with JC-1) and oxygen consumption (Clark-type electrode) were then measured. Platelets were also obtained from ten patients with lactic acidosis (arterial pH 6.97 ± 0.18 and lactate 16 ± 7 mmol/L) due to accidental metformin intoxication (serum drug level 32 ± 14 mg/L) and ten healthy volunteers of similar sex and age. Respiratory chain complex activities were measured as above (ex vivo experiments)., Results: In vitro, metformin dose-dependently increased lactate production (P < 0.001), decreased respiratory chain complex I activity (P = 0.009), mitochondrial membrane potential (P = 0.003) and oxygen consumption (P < 0.001) of human platelets. Ex vivo, platelets taken from intoxicated patients had significantly lower complex I (P = 0.045) and complex IV (P < 0.001) activity compared to controls., Conclusions: Depending on dose, metformin can cause mitochondrial dysfunction and lactate overproduction in human platelets in vitro and, possibly, in vivo., Trial Registration: NCT 00942123.

Introduction: Lactic acidosis can develop during biguanide (metformin and phenformin) intoxication, possibly as a consequence of mitochondrial dysfunction. To verify this hypothesis, we investigated whether body oxygen consumption (VO2), that primarily depends on mitochondrial respiration, is depressed in patients with biguanide intoxication., Methods: Multicentre retrospective analysis of data collected from 24 patients with lactic acidosis (pH 6.93 +/- 0.20; lactate 18 +/- 6 mM at hospital admission) due to metformin (n = 23) or phenformin (n = 1) intoxication. In 11 patients, VO2 was computed as the product of simultaneously recorded arterio-venous difference in O2 content [C(a-v)O2] and cardiac index (CI). In 13 additional cases, C(a-v)O2, but not CI, was available., Results: On day 1, VO2 was markedly depressed (67 +/- 28 ml/min/m2) despite a normal CI (3.4 +/- 1.2 L/min/m2). C(a-v)O2 was abnormally low in both patients either with (2.0 +/- 1.0 ml O2/100 ml) or without (2.5 +/- 1.1 ml O2/100 ml) CI (and VO2) monitoring. Clearance of the accumulated drug was associated with the resolution of lactic acidosis and a parallel increase in VO2 (P < 0.001) and C(a-v)O2 (P < 0.05). Plasma lactate and VO2 were inversely correlated (R2 0.43; P < 0.001, n = 32)., Conclusions: VO2 is abnormally low in patients with lactic acidosis due to biguanide intoxication. This finding is in line with the hypothesis of inhibited mitochondrial respiration and consequent hyperlactatemia.