Respiratory mechanics in late COVID-19 ARDS - a restrictive pattern is strongly associated with death. A cohort study.

INTRODUCTION: COVID-19 is associated with severe respiratory distress and high mortality. We investigated the evolution of the respiratory mechanics in COVID-19 acute respiratory distress syndrome (ARDS) and the occurrence of a restrictive respiratory pattern. MATERIAL AND METHODS: A retrospective, single-centre study including patients admitted to the ICU during the first wave of the pandemic (March-April 2020). RESULTS: A total of 141 consecutive patients were included. Many patients developed a restrictive pattern of respiratory mechanics during the course of the disease. Fifty-two patients died in the hospital (36.8%). In 29 cases (58% of the deceased) death was associated with a pattern of pulmonary mechanics, indicating a restrictive evolution of ARDS. Other diagnoses related to death were pulmonary embolism (n = 7, 14%), septic shock (n = 17, 33%), and other causes (n = 10, 20%), with some patients combining at least 2 of these diagnoses. In a multivariate analysis, age (OR = 1.06; 95% CI: 1.01-1.12; P = 0.029) and the administration of steroid pulses (OR = 2.7; 95% CI: 1.1-6.8; P = 0.03) were associated with the development of a restrictive pulmonary pattern and a higher level of plasmatic interleukin-6. CONCLUSIONS: COVID-19 ARDS is associated with high mortality associated with a specific pattern of respiratory mechanics and sustained activation of innate immunological response. Age and administration of high-dose steroid pulses are associated with this clinical picture.

Progression to lung fibrosis in severe COVID-19 patients: A morphological and transcriptomic study in postmortem samples.

The development of lung fibrosis is a major concern in patients recovered from severe COVID-19 pneumonia. This study aimed to document the evolution of diffuse alveolar damage (DAD) to the fibrosing pattern and define the transcriptional programs involved. Morphological, immunohistochemical and transcriptional analysis were performed in lung samples obtained from autopsy of 33 severe COVID-19 patients (median illness duration: 36 days). Normal lung and idiopathic pulmonary fibrosis (IPF) were used for comparison. Twenty-seven patients with DAD and disease evolution of more than 2 weeks had fibrosis. Pathways and genes related with collagen biosynthesis and extracellular matrix (ECM) biosynthesis and degradation, myofibroblastic differentiation and epithelial to mesenchymal transition (EMT) were overexpressed in COVID-19. This pattern had similarities with that observed in IPF. By immunohistochemistry, pathological fibroblasts (pFBs), with CTHRC1 and SPARC expression, increased in areas of proliferative DAD and decreased in areas of mature fibrosis. Immunohistochemical analysis demonstrated constitutive expression of cadherin-11 in normal epithelial cells and a similar pattern of cadherin and catenin expression in epithelial cells from both normal and COVID-19 samples. Transcriptomic analysis revealed downregulation of the Hippo pathway, concordant with the observation of YAP overexpression in hyperplastic alveolar epithelial cells. Progression to fibrosis in severe COVID-19 is associated with overexpression of fibrogenic pathways and increased in CTHRC1- and SPARC-positive pFBs. Whereas the Hippo pathway seemed to be implicated in the response to epithelial cell damage, EMT was not a major process implicated in COVID-19 mediated lung fibrosis.

Health-related quality of life and stress-related disorders in COVID-19 ICU survivors: Are they worse than with other causes of ARDS?

Background: There are insufficient data regarding the impact of acute respiratory distress syndrome related to coronavirus disease 2019 (C-ARDS) - caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - on health-related quality of life (HRQoL) and the occurrence of stress-related disorders in coronavirus disease 2019 (COVID-19) intensive care unit (ICU) survivors. The aim of this study is to assess HRQoL and the occurrence of stress-related disorders (acute stress disorder [ASD] and post-traumatic stress disorder [PTSD]) in C-ARDS ICU survivors at 1 and 6 months following hospital discharge. Methods: This prospective observational study included 90 patients treated for C-ARDS between March and May 2020 in the ICU and discharged alive from the hospital. All patients included in the study were contacted by telephone 1 month and 6 months post-hospital discharge to assess the presence of symptoms of stress-related disorders and HRQoL using the 8-item Treatment Outcome Post-traumatic Stress Disorder scale (TOP-8) and 36-item Short Form survey (SF-36). We performed univariate analyses to evaluate differences between patients who developed stress and those who did not. We also compared SF-36 scores in our sample with data from the general Spanish population and from cohorts of non-C-ARDS and severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) survivors. Results: There are 24.1% of patients showed symptoms of ASD; in 13.5% of cases the symptoms persisted 6 months later. Risk factors for the development of symptoms of ASD and PTSD are younger age, female sex, obesity, a previously diagnosed psychiatric disease and disease severity at ICU admission (P < 0.05). HRQoL was greatly affected by C-ARDS; however, there was improvement on all scales of the SF-36 at the 6-month follow-up (P < 0.05). The mean SF-36 score of our sample was higher than those previously reported in non-C-ARDS survivors (P < 0.05) for physical functioning (78.0 vs. 52.0), role functioning/physical (51.0 vs. 31.0), bodily pain (76.1 vs. 57.0), vitality (58.6 vs. 48.0), social function (72.6 vs. 63.0) and role emotional (77.4 vs. 55.0), except on the general health scale. C-ARDS survivors also scored better than SARS-CoV-1 survivors on all scales except for body pain (P < 0.05). Conclusions: The impact of C-ARDS on HRQoL is substantial, with frequent occurrence of PTSD symptoms. Patients are heavily affected in all areas of health in the first month of post-hospital discharge but show a dramatic improvement within 6 months, especially in terms of physical health.

Long-term survival of mechanically ventilated patients with severe COVID-19: an observational cohort study.

BACKGROUND: Information is lacking regarding long-term survival and predictive factors for mortality in patients with acute hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19) and undergoing invasive mechanical ventilation. We aimed to estimate 180-day mortality of patients with COVID-19 requiring invasive ventilation, and to develop a predictive model for long-term mortality. METHODS: Retrospective, multicentre, national cohort study between March 8 and April 30, 2020 in 16 intensive care units (ICU) in Spain. Participants were consecutive adults who received invasive mechanical ventilation for COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection detected in positive testing of a nasopharyngeal sample and confirmed by real time reverse-transcriptase polymerase chain reaction (rt-PCR). The primary outcomes was 180-day survival after hospital admission. Secondary outcomes were length of ICU and hospital stay, and ICU and in-hospital mortality. A predictive model was developed to estimate the probability of 180-day mortality. RESULTS: 868 patients were included (median age, 64 years [interquartile range [IQR], 56-71 years]; 72% male). Severity at ICU admission, estimated by SAPS3, was 56 points [IQR 50-63]. Prior to intubation, 26% received some type of noninvasive respiratory support. The unadjusted overall 180-day survival rates was 59% (95% CI 56-62%). The predictive factors measured during ICU stay, and associated with 180-day mortality were: age [Odds Ratio [OR] per 1-year increase 1.051, 95% CI 1.033-1.068)), SAPS3 (OR per 1-point increase 1.027, 95% CI 1.011-1.044), diabetes (OR 1.546, 95% CI 1.085-2.204), neutrophils to lymphocytes ratio (OR per 1-unit increase 1.008, 95% CI 1.001-1.016), failed attempt of noninvasive positive pressure ventilation prior to orotracheal intubation (OR 1.878 (95% CI 1.124-3.140), use of selective digestive decontamination strategy during ICU stay (OR 0.590 (95% CI 0.358-0.972) and administration of low dosage of corticosteroids (methylprednisolone 1 mg/kg) (OR 2.042 (95% CI 1.205-3.460). CONCLUSION: The long-term survival of mechanically ventilated patients with severe COVID-19 reaches more than 50% and may help to provide individualized risk stratification and potential treatments. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04379258. Registered 10 April 2020 (retrospectively registered).

Pulmonary vascular proliferation in patients with severe COVID-19: an autopsy study.

Diffuse alveolar damage and thrombi are the most common lung histopathological lesions reported in patients with severe COVID-19. Although some studies have suggested increased pulmonary angiogenesis, the presence of vascular proliferation in COVID-19 lungs has not been well characterised. Glomeruloid-like microscopic foci and/or coalescent vascular proliferations measuring up to 2 cm were present in the lung of 14 out of 16 autopsied patients. These lesions expressed CD31, CD34 and vascular endothelial cadherin. Platelet-derived growth factor receptor-ß immunohistochemistry and dual immunostaining for CD34/smooth muscle actin demonstrated the presence of pericytes. These vascular alterations may contribute to the severe and refractory hypoxaemia that is common in patients with severe COVID-19.

Nosocomial infections associated to COVID-19 in the intensive care unit: clinical characteristics and outcome.

Bacterial and fungal co-infection has been reported in patients with COVID-19, but there is limited experience on these infections in critically ill patients. The objective of this study was to assess the characteristics and ouctome of ICU-acquired infections in COVID-19 patients. We conducted a retrospective single-centre, case-control study including 140 patients with severe COVID-19 admitted to the ICU between March and May 2020. We evaluated the epidemiological, clinical, and microbiological features, and outcome of ICU-acquired infections. Fifty-seven patients (40.7%) developed a bacterial or fungal nosocomial infection during ICU stay. Infection occurred after a median of 9 days (IQR 5-11) of admission and was significantly associated with the APACHE II score (p = 0.02). There were 91 episodes of infection: primary (31%) and catheter-related (25%) bloodstream infections were the most frequent, followed by pneumonia (23%), tracheobronchitis (10%), and urinary tract infection (8%) that were produced by a wide spectrum of Gram-positive (55%) and Gram-negative bacteria (30%) as well as fungi (15%). In 60% of cases, infection was associated with septic shock and a significant increase in SOFA score. Overall ICU mortality was 36% (51/140). Infection was significantly associated with death (OR 2.7, 95% CI 1.2-5.9, p = 0.015) and a longer ICU stay (p < 0.001). Bacterial and fungal nosocomial infection is a common complication of ICU admission in patients with COVID-19. It usually presents as a severe form of infection, and it is associated with a high mortality and longer course of ICU stay.

Diagnostic pathways in major trauma patients admitted to Italian hospitals: survey and discussion points from the trauma update 2019.

BACKGROUND: Major trauma is a leading cause of mortality, morbidity, and disability. Severe trauma patients are taken to hospital with multiple suspected injuries and need urgent diagnosis in order to achieve focused and lifesaving interventions. The primary endpoint of this survey was to evaluate the intrahospital diagnostic paths that trauma patients undergo in Italian hospitals. Thus, during the 14th Italian Trauma Network Congress (Trauma UpDate, Bologna, February 2019), we collected and discussed data from Italian hospitals regarding the usual diagnostic pathway for major trauma patients. METHODS: Three sets of multiple closed questions, designed to measure the structure, protocols, and habits of Italian hospitals were sent prior to the congress. The questionnaire was developed on the basis of the available literature and expert opinion, regarding: (1) the role of E-FAST, chest and pelvis radiographs in stable major trauma patients; (2) diagnostic pathways after the first-level imaging in major trauma patients, focused on a number of clinical scenarios; (3) diffusion and knowledge of trauma-specific computed tomography (CT) protocols and fast radiologic reporting. RESULTS: We obtained a total of 232 responses to our survey. A remarkable heterogeneity was found between hub and spoke hospitals regarding the indications to the first- and second-level diagnostics, and their use before centralization to trauma centers of patients admitted to peripheral hospitals. CONCLUSION: Italian hospitals show a high heterogeneity in the diagnostic pathways proposed to major trauma victims, an interdisciplinary revision of local protocols taking into account hospital capabilities, new evidence, and emergency system geographical distribution is strongly recommended.

Prehospital Airway Management in Severe Traumatic Brain Injury.

OBJECTIVE: Traumatic brain injury (TBI) is a leading cause of death and disability among trauma patients. The final outcome of TBI results from a complex interaction between primary and secondary mechanisms of injury that begin immediately after the traumatic event. The aim of this review was to evaluate the latest evidence regarding the impact of prehospital airway management and the outcome after traumatic brain injury. METHODS: PubMed, Embase, and Cochrane searches were conducted using the MeSH database. Airway management, traumatic brain injury, pneumonia, and the subheadings of these Medical Subject Headings were combined. RESULTS: The review is structured into 4 major topics: airway management devices, prehospital pharmacologic management, mortality and neurologic outcomes, and early respiratory infections. The available literature shows a shift toward a more comprehensive view of prehospital airway management, taking into account not only the location where airway management is attempted but also the drugs administered, the airway management devices used, and the skills of the main professional figures attending the scene. CONCLUSIONS: Literature about this topic is still inconclusive; however, new evidence taking into consideration more complex aspects of airway management rather than orotracheal intubation per se shows improved outcomes with aggressive prehospital airway management.

Early-Onset Ventilator-Associated Pneumonia in Severe Traumatic Brain Injury: is There a Relationship with Prehospital Airway Management?

BACKGROUND: Prehospital airway management in severe traumatic brain injury (TBI) is widely recommended by international guidelines for the management of trauma. Early-onset ventilator-associated pneumonia (EOVAP) is a common occurrence in this population and can worsen mortality and functional outcome. OBJECTIVES: In this retrospective observational study, we aimed to evaluate the association between different prehospital airway management variables and the occurrence of EOVAP. Secondarily we evaluated the correlation between EOVAP and mortality and neurological outcome. METHODS: The study retrospectively evaluated 223 patients admitted from 2010 to 2017 in our trauma intensive care unit for severe TBI. The population was divided into three groups on the basis of the airway management technique adopted (bag mask ventilation, laryngeal tube, orotracheal intubation). Uni- and multivariate logistic regression analyses were performed using the occurrence of EOVAP as the dependent variable, to investigate potential associations with prehospital airway management. RESULTS: A total of 131 episodes (58.7%) of EOVAP were registered in the study population (223 patients). Laryngeal tube and orotracheal intubation were used in patients with significantly lower Glasgow Coma Scale score on scene and a higher Face Abbreviated Injury Scale; advanced airway management significantly increased the total rescue time. The prehospital airway management technique adopted, prehospital type of sedation or use of muscle relaxants, type of transport, and rescue times were not associated with the occurrence of EOVAP. CONCLUSIONS: Prehospital airway management does not have a significant impact on the occurrence of EOVAP in severe TBI patients. Similarly, it does not have a significant impact on mortality or long-term neurological outcome despite increasing duration of mechanical ventilation, intensive care unit, and hospital stay.

Early infections in the intensive care unit after liver transplantation-etiology and risk factors: A single-center experience.

BACKGROUND: Infectious complications represent one of the main causes of perioperative morbidity and mortality of liver transplant recipients. The primary objective of this retrospective observational study was to evaluate incidence and etiology of early (within 1 month from surgery and occurring in the intensive care unit [ICU]) postoperative infections as well as donor- and recipient-related risk factors. METHODS: The data of 280 patients undergoing 299 consecutive liver transplant procedures from January 2012 to December 2015 were extracted from the Italian ICU registry database and hospital registries. Perioperative risk factors, etiology of infections, and antibiotic susceptibility of isolated microorganisms were taken into consideration. RESULTS: Global incidence of postoperative infections was 21%. Pneumonia was the most frequent infection and, globally, gram-negative bacteria were the most common agents. Septic shock was present in 22% of infection cases and hospital mortality was higher in patients with postoperative infection. Preoperative chronic obstructive pulmonary disease, malnutrition, preoperative ascites, encephalopathy, and early re-transplantation were significantly associated to post orthotopic LT infections. CONCLUSION: Infections represent a major cause of early postoperative morbidity and mortality. The impact of single risk factors and the results of their preoperative management should be further investigated in order to reduce the incidence and evolution of postoperative infections.

Post-reperfusion syndrome during orthotopic liver transplantation, which definition best predicts postoperative graft failure and recipient mortality?

Post-reperfusion syndrome during orthotopic liver transplantation, which definition best predicts postoperative graft failure and recipient mortality? PURPOSE: Post-reperfusion syndrome (PRS) is a serious complication of liver transplantation, at present two main definitions are in use, and they differ both clinically and temporally. The primary objective of this study was to evaluate these two definitions as risk factors for post-transplantation mortality and primary graft non-function. MATERIALS AND METHODS: We conducted a retrospective observational study on 794 patients undergoing orthotopic liver transplantation at our university hospital. The presence of PRS was evaluated according to both definitions and correlated with the end points: three months mortality, primary graft non-function (PGNF) and the combined outcome of the two. RESULTS: Both definitions proved to be independent risk factors for three months mortality and the combined outcome. The definition according to Aggarwal et al. was also an independent risk factor for PGNF when adjusted for the propensity score. The Hilmi definition, despite being more comprehensive, did not improve the predictivity of the Aggarwal definition for the evaluated outcomes. CONCLUSIONS: PRS proved to be an independent risk factor for post-transplantation mortality and occurrence of PGNF. The pathophysiological mechanisms of this entity are still not fully understood and preventive strategies could help in reducing patients and graft losses.

Role of epidural anesthesia in a fast track liver resection protocol for cirrhotic patients - results after three years of practice.

AIM: To evaluate the potential benefits and risks of the use of epidural anaesthesia within an enhanced recovery protocol in this specific subpopulation. METHODS: A retrospective review was conducted, including all cirrhotic patients who underwent open liver resection between January 2013 and December 2015 at Bologna University Hospital. Patients with an abnormal coagulation profile contraindicating the placement of an epidural catheter were excluded from the analysis. The control group was composed by patients refusing epidural anaesthesia. RESULTS: Of the 183 cirrhotic patients undergoing open liver resections, 57 had contraindications to the placement of an epidural catheter; of the remaining 126, 86 patients received general anaesthesia and 40 combined anaesthesia. The two groups presented homogeneous characteristics. Intraoperatively the metabolic data did not differ between the two groups, whilst the epidural group had a lower mean arterial pressure (P = 0.041) and received more colloid infusions (P = 0.007). Postoperative liver and kidney function did not differ significantly. Length of mechanical ventilation (P = 0.003) and hospital stay (P = 0.032) were significantly lower in the epidural group. No complications related to the epidural catheter placement or removal was recorded. CONCLUSION: The use of Epidural Anaesthesia within a fast track protocol for cirrhotic patients undergoing liver resections had a positive impact on the patient's outcomes and comfort as demonstrated by a significantly lower length of mechanical ventilation and hospital stay in the epidural group. The technique appears to be safely manageable in this fragile population even though these results need confirmation in larger studies.

Post reperfusion syndrome during liver transplantation: From pathophysiology to therapy and preventive strategies.

This review aims at evaluating the existing evidence regarding post reperfusion syndrome, providing a description of the pathophysiologic mechanisms involved and possible management and preventive strategies. A PubMed search was conducted using the MeSH database, "Reperfusion" AND "liver transplantation" were the combined MeSH headings; EMBASE and the Cochrane library were also searched using the same terms. 52 relevant studies and one ongoing trial were found. The concept of post reperfusion syndrome has evolved through years to a multisystemic disorder. The implications of the main organ, recipient and procedure related factors in the genesis of this complex syndrome are discussed in the text as the novel pharmacologic and technical approaches to reduce its incidence. However the available evidence about risk factors, physiopathology and preventive measures is still confusing, the presence of two main definitions and the numerosity of possible confounding factors greatly complicates the interpretation of the studies.

Thoracic epidural anesthesia: Effects on splanchnic circulation and implications in Anesthesia and Intensive care.

AIM: To evaluate the currently available evidence on thoracic epidural anesthesia effects on splanchnic macro and microcirculation, in physiologic and pathologic conditions. METHODS: A PubMed search was conducted using the MeSH database. Anesthesia, Epidural was always the first MeSH heading and was combined by boolean operator AND with the following headings: Circulation, Splanchnic; Intestines; Pancreas and Pancreatitis; Liver Function Tests. EMBASE, Cochrane library, ClinicalTrials.gov and clinicaltrialsregister.eu were also searched using the same terms. RESULTS: Twenty-seven relevant studies and four ongoing trials were found. The data regarding the effects of epidural anesthesia on splanchnic perfusion are conflicting. The studies focusing on regional macro-hemodynamics in healthy animals and humans undergoing elective surgery, demonstrated no influence or worsening of regional perfusion in patients receiving thoracic epidural anesthesia (TEA). On the other hand most of the studies focusing on micro-hemodynamics, especially in pathologic low flow conditions, suggested that TEA could foster microcirculation. CONCLUSION: The available studies in this field are heterogeneous and the results conflicting, thus it is difficult to draw decisive conclusions. However there is increasing evidence deriving from animal studies, that thoracic epidural blockade could have an important role in modifying tissue microperfusion and protecting microcirculatory weak units from ischemic damage, regardless of the effects on macro-hemodynamics.