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Objective: The maintenance of healthy and functional mitochondrial network via mitochondrial quality control (QC) mechanisms, is critical throughout life to respond to physiological adaptations and stress. Due to their role in energy production, mitochondria are exposed to high amounts of reactive oxygen species making their DNA (mtDNA) particularly vulnerable to oxidative damage. Mitochondrial dysfunction causes altered QC mechanisms (i.e. altered biogenesis, dynamics, autophagy/mitophagy) and mtDNA damage and depletion, and in some cases, mtDNA release. When this occurs, mtDNA released from mitochondria into the extracellular and cytosol environment plays a central role in the damage-associated molecular patterns (DAMPs) through the activation of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, acting as an inflammatory trigger. Both 3,5-diiodo-L-thyronine (3,5-T2) and 3,5,3’-triiodo-L-tyronine (T3) have been shown to influence the mitochondrial QC system. However, the underlying mechanisms are poorly understood and likely differentiated when comparing the two iodothyronines. Here, by using a rat model of chemically induced hypothyroidism, we investigated the effect of administration of either 3,5-T2 or T3 on some key factors related to inflammation, mtDNA damage and mitochondrial QC system in the liver. Methods: Hypothyroidism was induced by propylthiouracil and iopanoic acid; 3,5-T2 and T3 were intraperitoneally administered to hypothyroid rats for 1 week at 25 and 15 µg/100 g BW, respectively. Factors linked to hepatic inflammation (i.e. cGAS-STING pathways) were investigated. The status of mtDNA damage/repair and mitochondrial QC mechanisms (biogenesis, dynamics, and mitophagy) were studied. Results: We showed an increase in mtDNA damage in the liver of hypothyroid rats accompanied by a significant reduction of mtDNA copy number, suggesting a reduction in mitochondrial biogenesis. Moreover, in hypothyroid rats, we found increased protein expression of both cGAS and cSTING, indicating activation of DAMPs pathways. The administration of either 3,5-T2 or T3 affected QC mechanisms ameliorating mitochondria fitness. Both iodothyronines enhanced mitochondrial copy number, reduced the mtDNA lesion frequency and oxidative damage, induced mtDNA repair mechanism and mitochondriogenesis, being T3 more effective than 3,5-T2. Also mitochondrial dynamics and autophagy were influenced. Of note, 3,5-T2, but not T3, reverted the activation of inflammatory triggers. Conclusion: The reported data highlight new molecular mechanisms underlying the effect elicited by the administration of naturally occurring iodothyronines to hypothyroid rats on liver pathways related to QC to preserve mitochondrial health.

Thyroid dysfunctions are associated with liver diseases ranging, in severity, from insulin resistance (IR) to hepatocellular carcinoma. The pathogenic mechanisms appear complex and are not attributable, exclusively, to the impaired thyroid hormone (TH) signalling. Using a mouse model of human congenital hypothyroidism, young double heterozygote for both NK2 homeobox 1 (Nkx2-1)- and Paired box 8 (Pax8)-null mutations (DHTP) mice, and single heterozygous Pax8+/− and Nkx2-1+/− mice, we studied the liver pathways, the endocrine and metabolic factors affected in conditions of different dysthyroidisms. Young Nkx2-1+/− females displayed a slight hyperthyroidism and, in liver, increased TH signalling (i.e. increased expression of Dio1 and Trβ1) and lipogenic gene expression, with triglycerides accumulation. Hypothyroid DHTP and euthyroid Pax8+/− females shared liver and skeletal muscle IR and hepatic hypothyroidism (i.e. reduced expression of Mct8, Dio1 and TRβ1), activation of AKT and increased expression of glutathione peroxidase 4. Oxidative stress and reduced mitochondrial COX activity were observed in DHTP mice only. Pax8+/− females, but, unexpectedly, not DHTP ones, displayed transcriptional activation of the hepatic (and renal) gluconeogenic pathway, hypercortisolemia, fasting hyperglycaemia and hyperinsulinemia, reduced serum β-hydroxybutyrate, associated with hepatic AMPK activation. DHTP mice showed hypercholesterolemia and activation of mTOR. Collectively, the data indicate that heterozygote mutations of Pax8 and Nkx2-1 genes may produce multiple dysmetabolisms, even under systemic euthyroidism. Differential liver pathways and multiple hormonal axes are affected with implications for energy and nutrient homeostasis. The identified players may be specific target in the management of thyroid dysfunction-associated dysmetabolisms in terms of prevention/counteraction of IR, type 2 diabetes and related comorbidities.

Background A correlation between unsuccessful noninvasive ventilation (NIV) and poor outcome has been suggested in de-novo Acute Respiratory Failure (ARF) patients. Consequently, it is of paramount importance to identify accurate predictors of NIV outcome. The aim of our preliminary study is to evaluate the Diaphragmatic Thickening Fraction (DTF) and the respiratory rate/DTF ratio as predictors of NIV outcome in de-novo ARF patients. Methods Over 36 months, we studied patients admitted to the emergency department with a diagnosis of de-novo ARF and requiring NIV treatment. DTF and respiratory rate/DTF ratio were measured by 2 trained operators at baseline, at 1, 4, 12, 24, 48, 72 and 96 h of NIV treatment and/or until NIV discontinuation or intubation. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the ability of DTF and respiratory rate/DTF ratio to distinguish between patients who were successfully weaned and those who failed. Results Eighteen patients were included. We found overall good repeatability of DTF assessment, with Intra-class Correlation Coefficient (ICC) of 0.82 (95% confidence interval 0.72–0.88). The cut-off values of DTF for prediction of NIV failure were p 0.6 for both operators (p Conclusion DTF and respiratory rate/DTF ratio may both represent valid, feasible and noninvasive tools to predict NIV outcome in patients with de-novo ARF. Trial registration ClinicalTrials.gov Identifier: NCT02976233, registered 26 November 2016.

This article provides additional data on the application of early coagulation support protocol in the management of major trauma patients. Data come from a retrospective analysis reported in the article “Early coagulation support protocol: a valid approach in real-life management of major trauma patients. Results from two Italian centres” [1]. Data contain information about the relationship between differences in resource use and mortality outcomes, and patient demographic and clinical features at presentation. Furthermore, a comparison between resource consumption, the probability of multiple transfusions and the mortality outcomes among propensity-score matched patients is reported. Keywords: Blood coagulation, Critical care, Fibrinogen, Haemorrhage, Italy, Propensity score, Sensitivity analysis, Trauma centres

Rationale: High-flow nasal cannula (HFNC) and helmet noninvasive ventilation (NIV) are used for the management of acute hypoxemic respiratory failure.Objectives: Physiological comparison of HFNC an...

Introduction Early coagulation support (ECS) includes prompt infusion of tranexamic acid, fibrinogen concentrate, and packed red blood cells for initial resuscitation of major trauma patients. The aim of this study was to determine the effects, in terms of blood product consumption, length of stay, and in-hospital mortality, of the ECS protocol, compared to the massive transfusion protocol (MTP) in the treatment of major trauma patients. Patients and methods A retrospective analysis was conducted using the registry data of two Italian trauma centres. Adult major trauma patients with, or at risk of, active bleeding who were managed according to the MTP during the years 2011–2012, or the ECS protocol during the years 2013–2014 and were considered at risk of multiple transfusions, were enrolled. The primary endpoint was to determine whether the ECS protocol reduces the use of blood products in the acute management of trauma patients. Secondary endpoints were the outcome measures of length of stay in ICU, length of stay in hospital, and mortality at 24-hours and 28-days after hospital admission. Results Among the 518 major trauma patients admitted to the trauma centres during the study period, 235 patients (118 in the pre-ECS period and 117 in the ECS period) matched one of the inclusion criteria and were enrolled in the study. Compared with the pre-ECS period, the ECS period showed a reduction in the average consumption of packed red blood cells (−1.87 units, 95% confidence interval [CI], −2.40, −1.34), platelets (−1.28 units; 95% CI, −1.64, −0.91), and fresh frozen plasma (−1.69; 95% CI, −2.14, −1.25) in the first 24-hours. Furthermore, during the ECS period, we recorded a 10-day reduction in the hospital length of stay (−10 days, 95% CI, −11.6, −8.4) and a non-significant 28-day mortality increase. Conclusions The ECS protocol was effective in reducing blood product consumption compared to the MTP and confirmed the importance of early fibrinogen administration as a strategy of rapid coagulation. This novel approach may be adopted in real-life management of major trauma patients.

Purpose Quantitative and qualitative changes of skeletal muscle are typical and early findings in trauma patients, being possibly associated with functional impairment. Early assessment of muscle changes—as evaluated by muscle ultrasonography—could yield important information about patient’s outcome. Methods In this prospective observational study, we used ultrasonography to evaluate the morphological changes of rectus femoris (RF) and anterior tibialis (AT) muscles in a group of young, previously healthy trauma patients on enteral feeding. Results We studied 38 severely injured patients (median Injury Severity Score = 34; median age = 40 y.o.) over the course of the ICU stay up to 3 weeks after trauma. We found a progressive loss of muscle mass from day 0 to day 20, that was more relevant for the RF (45%) than for the AT (22%); this was accompanied by an increase in echogenicity (up to 2.5 by the Heckmatt Scale, where normal echogenicity = 1), which is an indicator of myofibers depletion. Conclusions Ultrasound evaluation of skeletal muscles is inexpensive, noninvasive, simple and easily repeatable. By this method, we were able to quantify the morphological changes of skeletal muscle in trauma patients. Further studies may rely on this technicque to evaluate the impact of different therapeutic strategies on muscle wasting.

Background: We recently completed a randomized clinical trial on the lateral-Trendelenburg position (LTP) vs. the semi-recumbent position (SRP) for the prevention of ventilator-associated pneumonia. Here we appraise hospital mortality risks associated with both interventions. Methods: We conducted a randomized, single-blind, controlled study in 17 European centers and 1 in North America. Critically ill, mechanically ventilated patients were randomized to be positioned in LTP or in the SRP. We evaluated all-cause hospital mortality. Also, in a post-hoc interaction exploratory analysis, we assessed mortality risks in patients with or without pulmonary infiltrates upon randomization. Results: A total of 2019 adult patients were screened. Three hundred ninety-five patients were randomized, 194 in LTP and 201 in SRP. Hospital Mortality was 31.3% and 37.1% in the SRP and LTP, respectively (RR 1.18, 95%CI 0.90-1.56, p=0.24). Multiple organ failure was the most common cause of death. Hospital mortality was lower in LTP patients without pulmonary infiltrates, in comparison with SRP, but a trend toward higher mortality was found in LTP patients with pulmonary infiltrates vs. SRP patients (RR with pulmonary infiltrates 1.42, 95% CI 1.01-2.00; RR without pulmonary infiltrates 0.83, CI 0.52-1.33, p=0.07 for heterogeneity). Conclusions: We found a trend toward higher hospital mortality rates in LTP patients with baseline pulmonary infiltrates. These results call for a comprehensive analysis of potential risks associated with LTP in this specific population.

Background: Pre-clinical studies confirmed benefits associated with the lateral-Trendelenburg position (LTP) vs. the semi-recumbent position (SRP) in the prevention of ventilator-associated pneumonia. Methods: We conducted a randomized, single-blind, multicenter, controlled study. Critically ill, mechanically ventilated patients were randomized to be positioned in LTP or SRP. Primary outcome was VAP incidence rate, based on quantitative bronchoalveolar lavage fluid culture ≥ 104 colony-forming units/mL. Secondary outcomes were duration of mechanical ventilation, intensive care unit (ICU) and hospital stays, and ICU/hospital/28-day mortality. Results: Three hundred ninety-five patients were randomized, 194 in LTP and 201 in SRP. The data safety monitoring board recommended stopping the study at the second interim analysis for low incidence of VAP in the control group, lack of benefits in any major secondary outcome and adverse events in the LTP group. The incidence of microbiologically confirmed VAP was 0.5% (1/194 patients) in patients positioned in LTP, and 4.0% (8/201 patients) in patients in SRP, risk ratio (RR) between groups 0.13, 95% confidence interval (CI) 0.02–1.03, p=0.04. Microbiologically confirmed VAP per 1000 ventilator days was 0.88 (95%CI 0.12-6.25) and 7.19 (95%CI 3.60-14.37) in the LTP and SRP, respectively, RR 0.12 (95%CI 0.01-0.91), p=0.02. No statistically significant between-group differences were observed in secondary outcomes. Conclusions: LTP potentially reduces risks of VAP, compared with the SRP. Yet, due to study limitations, further studies are mandatory to corroborate these findings in populations at higher risk of VAP.

Purpose It is unclear whether ventilator-associated pneumonia (VAP) is actually a bilateral and multifocal process. In addition, the diagnostic role of chest x-ray is under debate. Assuming a low microbiologic concordance between the left and right lungs, the reliability of a single pulmonary sampling becomes questionable. The purpose of this study was to determine whether the choice of the pulmonary sampling area is clinically relevant in the management of VAP. Methods In 79 patients admitted to a university general intensive care unit with clinically suspected VAP, right- and left-lung bronchoalveolar lavage (BAL) samples were taken with separate bronchoscopes and quantitatively cultured. Primary end-point variable was microbiologic concordance rate between right- and left-lung BAL cultures. Secondary outcomes included predictors of microbiologic concordance, rates of appropriate antibiotic treatment, and diagnostic accuracy of chest x-ray. Results BAL cultures were bilaterally negative in 21 (27%) of 79 patients, bilaterally positive in 36 (46%), and unilaterally positive (right in 12, left in 10) in 22 (28%). Intra-patient concordance was observed in 47 (59.5%) of 79 cases and independently associated with purulent secretions and bilateral infiltrates on chest x-ray. In simulated prescribing experiments, treatments chosen based on right or left cultures alone were as appropriate as those based on bilateral data in >90% of cases. The presence of a radiographic infiltrate in the sampling area predicted BAL culture positivity with a positive predictive value of only 61%. Conclusions In patients with clinically suspected VAP (especially those without purulent secretions or without radiographically documented bilateral infiltrates), quantitative culture of a single BAL sample may provide an incomplete assessment of lung microbiology, without having a relevant impact on the appropriateness of antimicrobial treatment. These findings suggest that single sampling of respiratory secretions, regardless radiographic opacity, seems to be a reliable diagnostic method in the management of VAP.

Severe liver failure causes accumulation of both albumin bound and water soluble substances that exhibit toxic effects on the brain and lead to hepatic encephalopathy. This is a complex neuropsychiatric syndrome determined by a neurotransmission failure rather than from primary energy deficit.1 Transcranial magnetic stimulation represents a non-invasive method that can be used to study the physiology of the human brain.2 Commonly used transcranial magnetic stimulation parameters include motor thresholds, cortical silent period (CSP), central motor conduction time (CMCT), intracortical inhibition (ICI), and intracortical facilitation. The threshold for producing motor evoked potentials reflects the excitability of a central core of neurons, which arises from the membrane excitability and a balance between inhibitory and excitatory input from local circuits. The CMCT provides information on the corticospinal tract anatomical integrity, CSP and ICI reflect the activity of GABAergic inhibitory circuits.2–6 Additional in vivo information on central motor circuits can be obtained using transcranial electrical stimulation of the motor cortex. transcranial electrical stimulation stimulates the motor areas of the human brain deeply in the white matter and is therefore insensitive to changes in cortical excitability.6 Combining the data from transcranial electrical stimulation and transcranial magnetic stimulation it is possible to determine the site, cortical or subcortical, where brain functional changes have taken place. We used transcranial magnetic stimulation to explore function of the cerebral cortex in five patients affected by severe liver failure. Recently, a molecular adsorbent recirculating system (MARS) has been proposed as a new extracorporeal detoxifying treatment.7 We used transcranial magnetic stimulation to evaluate the effects of MARS treatment on functions of the cerebral cortex in these patients and also the effects of orthotopic liver transplantation in one of them. Clinical and neurophysiological examinations were recorded at baseline and 12–18 hours after the …

INTRODUCTION Laparoscopy plays an essential role in the diagnosis of hepatic diseases. During the past few years, minilaparoscopy (ML) has increasingly emerged as an alternative diagnostic method in this field. We hereby present the preliminary results of a randomized trial comparing ML with conventional laparoscopy (CL). PATIENTS AND METHODS 92 with suspected hepatic disease were randomized either to undergo CL (n = 47) or ML (n = 45). For CL, we used a Hopkins-laparoscope (O 11 mm, Storz, Tuttlingen) and ML was performed with a 1.9 mm small-diameter optic (Wolf, Knittlingen). RESULTS Laparoscopy with simultaneous liver biopsy could successfully be performed in 88/92 patients. ML could be performed in a significantly shorter time than CL (25 vs. 28 min, p < 0.05). Liver cirrhosis was diagnosed by laparoscopy in a similar proportion of patients (70% in CL, 56% in ML). In 76% of cases, histology confirmed macroscopic signs of liver cirrhosis. Cirrhosis was found in one patient of each group solely by histologic examination of biopsy specimens. The number of bleeding complications during CL equaled the proportion of hemorrhagias in the ML-group. DISCUSSION In the workup of hepatic disease, ML is a diagnostic tool comparable with CL. The fact that ML can be performed in significantly shorter time and seems subjectively less invasive might be an argument for a better acceptance by patients.

To investigate incidence, risk factors and outcome of Acinetobacter baumanii infection in trauma patients.A retrospective analysis of prospectively collected data of all trauma patients admitted to a general intensive care unit (ICU) of a 1,500-bed university hospital over 3 years.Three hundred thirty trauma patients were included in the study.Thirty-six (10.9%) cases of A. baumanii infection were observed; 29 of them were late onset pneumonia. Patients with A. baumanii infection had a significantly higher Injury Severity Score (ISS) (p = 0.02), a lower Glasgow Coma Scale (GCS) on ICU admission (p = 0.03), stayed longer in the ICU (p = 0.00001), were mechanically ventilated for a longer period of time (p = 0.00001), were more frequently admitted to the emergency department with hypotension (p = 0.02), and had trans-skeletal traction for more than 3 days (p = 0.003) in comparison to the 294 patients who did not develop A. baumanii infection. At multivariate analysis the time spent on mechanical ventilation (p = 0.02) and the presence of long-term trans-skeletal traction (p = 0.04) were the only independent risk factors for A. baumanii infection. Patients with A. baumanii infection had a high mortality rate (9 out of 36; 25.0%). ISS (p = 0.003), GCS (p = 0.001) and older age (p = 0.00001), but not A. baumanii infection (p = 0.15), were independently correlated with mortality.In trauma patients prolonged mechanical ventilation and delayed fracture fixation with the persistence of trans-skeletal traction were major risk factors for A. baumanii infection. The presence of this infection was not correlated with mortality.

Open access to information in medical science and adequate reporting of clinical trials may allow investigators and editors to recognize bias in study designs and avoid unnecessary duplication of efforts. Unfortunately, most of clinical trials are very expensive and are often supported by industries that may have financial reasons to hide or partially disclose results. However, investigators and editors have a greater interest in publishing results that can immediately change clinical practice rather than negative results, thus contributing to facilitate publication biases. Several years ago, legislation in several countries mandated the registration of clinical trials as an effective means of promoting information access and full transparency in medical research. However, comprehensive registers have not been adequately supported by law, particularly in Europe, where legislation has ironically contributed to fragmented research, and dampened its competitiveness and productivity. In this context, appropriate strategies help to protect the independence of academic research and ensure full transparency in medical science.

Noninvasive ventilation (NIV) is the delivery of mechanical ventilation without the need for an invasive artificial airway [1] and is a safe and effective means to improve gas exchange and reduce the work of breathing in patients with acute respiratory failure (ARF) of various origin [2, 3]. In patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) and hypercapnic respiratory failure, the application of NIV to standard therapy decreases the need for endotracheal intubation, and reduces mortality [2, 4–6]. Similarly, NIV is effective in patients with cardiogenic pulmonary oedema, particularly in those with hypercapnia [7–9]. In patients with acute de novo respiratory failure, randomised controlled studies have shown that NIV reduces mortality in selected patients, such as those with immunosuppression [10] or with postoperative complications [11, 12]. However, the success rate of NIV in hypoxaemic ARF is strictly dependent on the ARF aetiology [5, 13], and the application of NIV in these patients is still controversial [14]. Advantages of NIV application include the reduction of the complications associated with endotracheal intubation [15], the improvement of patient comfort and the preservation of airway defence mechanisms, speech and swallowing [16]. NIV, however, is not successful in all patients; due to peculiarities of this ventilatory modality, such as the possibility of leaks and the need for patient compliance, technical aspects are of the utmost importance to improve its efficacy [17]. In order to optimise the success rate, NIV should be used as soon as incipient signs of respiratory failure develop and some technical aspects should be thoroughly taken into account. The correct choice of ventilator type should rely on the patient’s conditions and the global performance of the machine. The use of intensive care unit (ICU) ventilators is generally preferable in the acute setting, since they are more powerful and have more adjustable features compared with home ventilators. Additionally, circuits with dual tubes reduce the risk of CO2-rebreathing in patients with ARF. An important part of recent technical development for NIV application has concerned the interfaces. Nasal masks may be used in cooperative patients, to increase comfort and reduce complications but facial masks are generally preferable for dyspnoeic patients. Recently, an alternative interface, the helmet, has been proposed to decrease complications and improve tolerance. Recent data have also contributed to elucidate the role of gas humidification during NIV. The success rate during NIV will depend on

In spite of advances in critical care, nosocomial infections still have a considerable impact on Intensive Care Unit (ICU) and hospital length of stay, mortality and costs. Several authors suggest that antibiotic therapy should be instituted as soon as sepsis is suspected in critically patients. Over the last two decades the rates of occurrence for pathogens have significantly changed under selective pressure from broad-spectrum antimicrobial therapy. Shifts from predominance of gram-negative to gram-positive organisms and outbreaks of resistant pathogens address the need for appropriate empirical regimens. Agents such as ceftazidime, imipenem and, more recently, meropenem and tazobactam have been used successfully as monotherapy. Two different clinical trials have reported that meropenem monotherapy is significantly more effective than ceftazidime-based therapy. Because of the outbreak of methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, some investigators suggest adding a glycopeptide to beta-lactamase inhibitor and carbapenem as initial empirical therapy. Such a regimen should be administered before definitive proof of infections and until the results of microbial investigation are available (de-escalation antimicrobial chemotherapy). On the other hand, several authors do not recommend glycopeptide administration in an attempt to limit nosocomial outbreaks of vancomycin-resistant enterococci (VRE) and staphylococci (VRS) and to avoid secondary drawbacks, such as nephrotoxicity and ototoxicity. De-escalation antimicrobial chemotherapy should be tailored to critically ill patients according to their clinical status, severity of illness and suspicion of sepsis or nosocomial pneumonia.

Critically ill patients are at high risk of developing nosocomial infections due to their severity of illness, immunosuppression, and prolonged hospitalization. Among nosocomial infections, pneumonia affects from 20 to 30% of intensive care unit (ICU) patients and is the leading cause of death [1]. The use of the endotracheal (ET) tube to deliver ventilatory support is the single most important predisposing factor for developing nosocomial bacterial pneumonia [2]. Fagon et al. [3] have demonstrated that the risk of pneumonia is incremental in ventilated patients and increases by about 1% per day of continuous invasive ventilation.

The aim of this study was to assess if diurnal or nocturnal shifts were independent risk factors for non-invasive ventilation (NIV) failure.This was an observational study carried out on 18 patients of the general Intensive Care Unit in Rome. A total number of 189 consecutive patients needing mechanical ventilation for respiratory failure were prospectively enrolled: 82 were treated with NIV as a first line intervention. Of the 107 patients who were initially intubated, 59 patients were extubated; once extubation failed they were treated with NIV. NIV failure was assessed during both the day (between 7 am and 10 pm) and night shifts (between 10 pm and 7 am).Of the 141 total patients who received NIV, 51 experienced failure during the day shifts and 18 during the night shifts. No difference in the median day and night shift TISS-28 values were observed in any patients who failed NIV during both day and night shifts. Causes of NIV failure were similar during both diurnal and nocturnal shifts. The inability to correct gas exchanges was the main reason for failure.In a center with NIV expertise, notwithstanding nurse understaffing, diurnal and nocturnal shifts did not affect the rate of NIV failure.