Impact of introduction of a goal directed transfusion strategy in a patient blood management program: A single cardiac surgery centre experience.

BACKGROUND: The aim of this retrospective and observational study was to analyse the impact of the introduction of a goal directed transfusion (GDT) strategy based on a viscoelastic test (ROTEM®) and specific procoagulant products in a patient blood management (PBM) Program on blood product use and perioperative bleeding in a single cardiac surgery centre. STUDY DESIGN AND METHODS: Patient population underwent cardiac surgery from 2011 to 2021 was divided in two groups based on PBM protocol used (G#11-14, years 2011-2014, G#15-21, years 2015-2021) and compared for the following variables: intraoperative and postoperative transfusions of packed red blood cell and any procoagulant products, postoperative drain blood loss volume and rate of re-exploration surgery. The second program was defined after the introduction of a GDT protocol based on viscoelastic tests and specific procoagulant products. RESULTS: After the introduction of a GDT protocol, about 80% less amongst patients were transfused with fresh frozen plasma and any procoagulant product (p < 0.001 for both phases). Moreover, similar results were obtained with PRBC transfusions (p < 0.001) and drain blood loss volume (p = 0.006) in the postoperative phase. The main factors affecting the use of any procoagulant and PBRC transfusion in the multivariate logistic regression analysis was Group (2 versus 1, OR 0.207, p < 0.001) and preoperative haemoglobin (OR 0.728, p < 0.001), respectively. DISCUSSION: In our experience, a GDT strategy for the diagnosis and treatment of the coagulopathy in patients undergone cardiac surgery led to a significant reduction in bleeding and transfusion.

Communication and visiting policies in Italian intensive care units during the first COVID-19 pandemic wave and lockdown: a nationwide survey.

BACKGROUND: During the first coronavirus disease 2019 (COVID-19) pandemic wave, an unprecedented number of patients with respiratory failure due to a new, highly contagious virus needed hospitalization and intensive care unit (ICU) admission. The aim of the present study was to describe the communication and visiting policies of Italian intensive care units (ICUs) during the first COVID-19 pandemic wave and national lockdown and compare these data with prepandemic conditions. METHODS: A national web-based survey was conducted among 290 Italian hospitals. Each ICU (active between February 24 and May 31, 2020) was encouraged to complete an individual questionnaire inquiring the hospital/ICU structure/organization, communication/visiting habits and the role of clinical psychology prior to, and during the first COVID-19 pandemic wave. RESULTS: Two hundred and nine ICUs from 154 hospitals (53% of the contacted hospitals) completed the survey (202 adult and 7 pediatric ICUs). Among adult ICUs, 60% were dedicated to COVID-19 patients, 21% were dedicated to patients without COVID-19 and 19% were dedicated to both categories (Mixed). A total of 11,102 adult patients were admitted to the participating ICUs during the study period and only approximately 6% of patients received at least one visit. Communication with family members was guaranteed daily through an increased use of electronic devices and was preferentially addressed to the same family member. Compared to the prepandemic period, clinical psychologists supported physicians more often regarding communication with family members. Fewer patients received at least one visit from family members in COVID and mixed-ICUs than in non-COVID ICUs, l (0 [0-6]%, 0 [0-4]% and 11 [2-25]%, respectively, p < 0.001). Habits of pediatric ICUs were less affected by the pandemic. CONCLUSIONS: Visiting policies of Italian ICUs dedicated to adult patients were markedly altered during the first COVID-19 wave. Remote communication was widely adopted as a surrogate for family meetings. New strategies to favor a family-centered approach during the current and future pandemics are warranted.

Why and how to open intensive care units to family visits during the pandemic.

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.

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.

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.

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.

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.

Platelet mitochondrial dysfunction in critically ill patients: comparison between sepsis and cardiogenic shock.

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.

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.

The effect of protein administration during critical illness depends on body composition: A secondary analysis of a prospective, observational study.

BACKGROUND & AIMS: The most adequate amount of protein that should be administered to critically ill patients is still debated and diverging findings are recently accumulating. We hypothesized that the effect of protein administration might depend on the amount of muscle mass. METHODS: A secondary analysis of a single-centre prospective observational study of body composition in critically ill patients. Mechanically-ventilated subjects with an expected intensive care unit (ICU) stay >72 h were enrolled. Within 24 h from ICU admission, bioimpedance-derived muscle mass (BIA MM) and rectus femoris cross-sectional area (RF CSA) were measured. The amount of proteins and calories administered on the 7th ICU day was recorded. RESULTS: We enrolled 94 subjects (65 males, actual body weight 72.9 ± 14.4 Kg, BMI 26.0 ± 4.8 kg/m2). Actual body weight was only weakly related to BIA MM (R = 0.478, p < 0.001) and not related to RF CSA (R = 0.114, p = 0.276). A higher protein intake was associated with a reduced mortality in the highest quartile of BIA MM (OR 0.68 [0.46; 0.99] per each 10 g of proteins administered) and in the third (OR 0.74 [0.57; 0.98]) and highest quartile of RF CSA (OR 0.68 [0.48; 0.96]). CONCLUSION: A higher protein intake was associated with lower ICU mortality only in patients admitted with a higher muscle mass, as either assessed by BIA or muscle ultrasound.

Generalized music therapy to reduce neuroactive drug needs in critically ill patients. Study protocol for a randomized trial.

BACKGROUND: Critically ill patients are exposed to several physical and emotional stressors, needing analgesic and sedative drugs to tolerate invasive procedures and the harsh intensive care unit (ICU) environment. However, this pharmacological therapy presents several side effects: guidelines suggest using a light sedation target, keeping critically ill patients calm, conscious, and cooperative. Personalized music therapy (MT) can reduce stress and anxiety, decreasing the need for drugs. The aim of the current investigation is to compare different approaches for MT in the ICU: a personalized approach, with music selected by patients/families and listened through headphones, or a generalized approach, with ambient music chosen by a music therapist and transmitted through speakers. PRIMARY OUTCOME: number of days "free from neuroactive drugs" in the first 28 days after ICU admission. SECONDARY OUTCOMES: total amount of neuroactive drugs (midazolam, propofol, morphine, fentanyl, haloperidol), stress during ICU stay (sleep at night, anxiety and agitation, use of physical restraints, stressors evaluated at discharge), the feasibility of generalized MT (interruptions requested by staff members and patients/families). METHODS: Randomized, controlled trial with three groups of critically ill adults: a control group, without MT; a personalized MT group, with music for at least 2 h per day; a generalized MT group, with music for 12.5 h/day, subdivided into fifteen 50-min periods. DISCUSSION: One hundred fifty-three patients are expected to be enrolled. This publication presents the rationale and the study methods, particularly the strategies used to build the generalized MT playlist. From a preliminary analysis, generalized MT seems feasible in the ICU and is positively received by staff members, critically ill patients, and families. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03280329. September 12, 2017.

Family centeredness of care: a cross-sectional study in intensive care units part of the European society of intensive care medicine.

PURPOSE: To identify key components and variations in family-centered care practices. METHODS: A cross-sectional study, conducted across ESICM members. Participating ICUs completed a questionnaire covering general ICU characteristics, visitation policies, team-family interactions, and end-of-life decision-making. The primary outcome, self-rated family-centeredness, was assessed using a visual analog scale. Additionally, respondents completed the Maslach Burnout Inventory and the Ethical Decision Making Climate Questionnaire to capture burnout dimensions and assess the ethical decision-making climate. RESULTS: The response rate was 53% (respondents from 359/683 invited ICUs who actually open the email); participating healthcare professionals (HCPs) were from Europe (62%), Asia (9%), South America (6%), North America (5%), Middle East (4%), and Australia/New Zealand (4%). The importance of family-centeredness was ranked high, median 7 (IQR 6-8) of 10 on VAS. Significant differences were observed across quartiles of family centeredness, including in visitation policies availability of a waiting rooms, family rooms, family information leaflet, visiting hours, night visits, sleep in the ICU, and in team-family interactions, including daily information, routine day-3 conference, and willingness to empower nurses and relatives. Higher family centeredness correlated with family involvement in rounds, participation in patient care and end-of-life practices. Burnout symptoms (41% of respondents) were negatively associated with family-centeredness. Ethical climate and willingness to empower nurses were independent predictors of family centeredness. CONCLUSIONS: This study emphasizes the need to prioritize healthcare providers' mental health for enhanced family-centered care. Further research is warranted to assess the impact of improving the ethical climate on family-centeredness.

Kinetics of CD169, HLA-DR, and CD64 expression as predictive biomarkers of SARS-CoV2 outcome.

INTRODUCTION: Discriminating between virus-induced fever from superimposed bacterial infections is a common challenge in intensive care units. Superimposed bacterial infections can be detected in severe SARS-CoV2-infected patients, suggesting the important role of the bacteria in COVID-19 evolution. However, indicators of patients' immune status may be of help in the management of critically ill subjects. Monocyte CD169 is a type I interferon-inducible receptor that is up-regulated during viral infections, including COVID-19. Monocyte HLA-DR expression is an immunologic status marker, that decreases during immune exhaustion. This condition is an unfavorable prognostic biomarker in septic patients. Neutrophil CD64 upregulation is an established indicator of sepsis. METHODS: In this study, we evaluated by flow cytometry the expression of cellular markers monocyte CD169, neutrophil CD64, and monocyte HLA-DR in 36 hospitalized patients with severe COVID-19, as possible indicators of ongoing progression of disease and of patients' immune status. Blood testings started at ICU admission and were carried on throughout the ICU stay and extended in case of transfer to other units, when applicable. The marker expression in mean fluorescence intensity (MFI) and their kinetics with time were correlated to the clinical outcome. RESULTS: Patients with short hospital stay (≤15 days) and good outcome showed higher values of monocyte HLA-DR (median 17,478 MFI) than long hospital stay patients (>15 days, median 9590 MFI, p= 0.04) and than patients who died (median 5437 MFI, p= 0.05). In most cases, the recovery of the SARS-CoV2 infection-related signs was associated with the downregulation of monocyte CD169 within 17 days from disease onset. However in three surviving long hospital stay patients, a persistent upregulation of monocyte CD169 was observed. An increased neutrophil CD64 expression was found in two cases with a superimposed bacterial sepsis. CONCLUSION: Monocyte CD169, neutrophil CD64, and monocyte HLA-DR expression can be used as predictive biomarkers of SARS-CoV2 outcome in acutely infected patients. The combined analysis of these indicators can offer a real-time evaluation of patients' immune status and of viral disease progression versus superimposed bacterial infections. This approach allows to better define the patients' clinical status and outcome and may be useful to guide clinicians' decisions. Our study focused on the discrimination between the activity of viral and bacterial infections and on the detection of the development of anergic states that may correlate with an unfavorable prognosis.

Mechanical chest compression and extracorporeal life support for out-of-hospital cardiac arrest. A 30-month observational study in the metropolitan area of Milan, Italy.

BACKGROUND: Return of spontaneous circulation (ROSC) is achieved in 25% of out-of-hospital cardiac arrest (OHCA) patients. Mechanical chest compression (mechCPR) may maintain better perfusion during transport, allowing hospital treatments like extracorporeal circulation life support (ECLS). We aim to assess the effectiveness of a pre-hospital protocol introduction. METHODS: Observational, retrospective study assessing all OHCA patients aged 12-75, with no-flow time <20 min in a metropolitan area (Milan, Italy, 2013-2016). PRIMARY OUTCOMES: ROSC and Cerebral Performance Category score (CPC) ≤2 at hospital discharge. Logistic regressions with multiple comparison adjustments balanced with propensity scores calculated with inverse probability of treatment weighting were performed. RESULTS: 1366 OHCA were analysed; 305 received mechCPR, 1061 manual chest compressions (manCPR), and 108 ECLS. ROSC and CPC ≤2 were associated with low-flow minutes (odds ratio [95% confidence interval] 0.90 [0.88-0.91] and 0.90 [0.87-0.93]), shockable rhythm (2.52 [1.71-3.72] and 10.68 [5.63-20.28]), defibrillations number (1.15 [1.07-1.23] and 1.15 [1.04-1.26]), and mechCPR (1.86 [1.17-2.96] and 2.06 [1.11-3.81]). With resuscitation times >13 min, mechCPR achieved more frequently ROSC compared to manCPR. Among ECLS patients, 70% had time exceeding protocol: 8 (7.5%) had CPC ≤2 (half of them with low-flow times between 45 and 90 min), 2 (1.9%) survived with severe neurological disabilities, and 13 brain-dead (12.0%) became organ donors. CONCLUSIONS: MechCPR patients achieved ROSC more frequently than manual CPR patients; mechCPR was a crucial factor in an ECLS protocol for refractory OHCA. ECLS offered a chance of survival to patients who would otherwise die.

Metformin overdose causes platelet mitochondrial dysfunction in humans.

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.

Association of COVID-19 Vaccinations With Intensive Care Unit Admissions and Outcome of Critically Ill Patients With COVID-19 Pneumonia in Lombardy, Italy.

Importance: Data on the association of COVID-19 vaccination with intensive care unit (ICU) admission and outcomes of patients with SARS-CoV-2-related pneumonia are scarce. Objective: To evaluate whether COVID-19 vaccination is associated with preventing ICU admission for COVID-19 pneumonia and to compare baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU. Design, Setting, and Participants: This retrospective cohort study on regional data sets reports: (1) daily number of administered vaccines and (2) data of all consecutive patients admitted to an ICU in Lombardy, Italy, from August 1 to December 15, 2021 (Delta variant predominant). Vaccinated patients received either mRNA vaccines (BNT162b2 or mRNA-1273) or adenoviral vector vaccines (ChAdOx1-S or Ad26.COV2). Incident rate ratios (IRRs) were computed from August 1, 2021, to January 31, 2022; ICU and baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU were analyzed from August 1 to December 15, 2021. Exposures: COVID-19 vaccination status (no vaccination, mRNA vaccine, adenoviral vector vaccine). Main Outcomes and Measures: The incidence IRR of ICU admission was evaluated, comparing vaccinated people with unvaccinated, adjusted for age and sex. The baseline characteristics at ICU admission of vaccinated and unvaccinated patients were investigated. The association between vaccination status at ICU admission and mortality at ICU and hospital discharge were also studied, adjusting for possible confounders. Results: Among the 10 107 674 inhabitants of Lombardy, Italy, at the time of this study, the median [IQR] age was 48 [28-64] years and 5 154 914 (51.0%) were female. Of the 7 863 417 individuals who were vaccinated (median [IQR] age: 53 [33-68] years; 4 010 343 [51.4%] female), 6 251 417 (79.5%) received an mRNA vaccine, 550 439 (7.0%) received an adenoviral vector vaccine, and 1 061 561 (13.5%) received a mix of vaccines and 4 497 875 (57.2%) were boosted. Compared with unvaccinated people, IRR of individuals who received an mRNA vaccine within 120 days from the last dose was 0.03 (95% CI, 0.03-0.04; P < .001), whereas IRR of individuals who received an adenoviral vector vaccine after 120 days was 0.21 (95% CI, 0.19-0.24; P < .001). There were 553 patients admitted to an ICU for COVID-19 pneumonia during the study period: 139 patients (25.1%) were vaccinated and 414 (74.9%) were unvaccinated. Compared with unvaccinated patients, vaccinated patients were older (median [IQR]: 72 [66-76] vs 60 [51-69] years; P < .001), primarily male individuals (110 patients [79.1%] vs 252 patients [60.9%]; P < .001), with more comorbidities (median [IQR]: 2 [1-3] vs 0 [0-1] comorbidities; P < .001) and had higher ratio of arterial partial pressure of oxygen (Pao2) and fraction of inspiratory oxygen (FiO2) at ICU admission (median [IQR]: 138 [100-180] vs 120 [90-158] mm Hg; P = .007). Factors associated with ICU and hospital mortality were higher age, premorbid heart disease, lower Pao2/FiO2 at ICU admission, and female sex (this factor only for ICU mortality). ICU and hospital mortality were similar between vaccinated and unvaccinated patients. Conclusions and Relevance: In this cohort study, mRNA and adenoviral vector vaccines were associated with significantly lower risk of ICU admission for COVID-19 pneumonia. ICU and hospital mortality were not associated with vaccinated status. These findings suggest a substantial reduction of the risk of developing COVID-19-related severe acute respiratory failure requiring ICU admission among vaccinated people.