Predictive role of hepatic venous pressure gradient in bleeding events among patients with cirrhosis undergoing orthotopic liver transplantation.

Background & Aims: Major bleeding events during orthotopic liver transplantation (OLT) are associated with poor outcomes. The proportion of this risk related to portal hypertension is unclear. Hepatic venous pressure gradient (HVPG) is the gold standard for estimating portal hypertension. The aim of this study was to analyze the ability of HVPG to predict intraoperative major bleeding events during OLT in patients with cirrhosis. Methods: We retrospectively analyzed a prospective database including all patients with cirrhosis who underwent OLT between 2010 and 2020 and had liver and right heart catheterizations as part of their pre-transplant assessment. The primary endpoint was the occurrence of an intraoperative major bleeding event. Results: The 468 included patients had a median HVPG of 17 mmHg [interquartile range, 13-22] and a median MELD on the day of OLT of 16 [11-24]. Intraoperative red blood cell transfusion was required in 72% of the patients (median 2 units transfused), with a median blood loss of 1,000 ml [575-1,500]. Major intraoperative bleeding occurred in 156 patients (33%) and was associated with HVPG, preoperative hemoglobin level, severity of cirrhosis at the time of OLT (MELD score, ascites, encephalopathy), hemostasis impairment (thrombocytopenia, lower fibrinogen levels), and complications of cirrhosis (sepsis, acute-on-chronic liver failure). By multivariable regression analysis with backward elimination, HVPG, preoperative hemoglobin level, MELD score, and tranexamic acid infusion were associated with the primary endpoint. Three categories of patients were identified according to HVPG: low-risk (HVPG <16 mmHg), high-risk (HVGP ≥16 mmHg), and very high-risk (HVPG ≥20 mmHg). Conclusions: HVPG predicted major bleeding events in patients with cirrhosis undergoing OLT. Including HVPG as part of pre-transplant assessment might enable better anticipation of the intraoperative course. Impact and implications: Major bleeding events during orthotopic liver transplantation (OLT) are associated with poor outcomes but the proportion of this risk related to portal hypertension is unclear. Our work shows that hepatic venous pressure gradient (HVPG), the gold standard for estimating portal hypertension, is a strong predictor of major bleeding events and blood loss volume in patients with cirrhosis undergoing OLT. Three groups of patients can be identified according to their risk of major bleeding events: low-risk patients with HVPG <16 mmHg, high-risk patients with HVPG ≥16 mmHg, and very high-risk patients with HVPG ≥20 mmHg. HVPG could be systematically included in the pre-transplant assessment to anticipate intraoperative course and tailor patient management.

Evaluation of transcranial Doppler use in patients with acute liver failure listed for emergency liver transplantation.

PURPOSE: Acute liver failure (ALF) is characterized by hepatic encephalopathy (HE) often due to intracranial hypertension (ICH). The risk/benefit-balance of intraparenchymal pressure catheter monitoring is controversial during ALF. AIMS: Perform an evaluation of transcranial Doppler (TCD) use in patients with ALF listed for emergency liver transplantation. MATERIAL AND METHODS: Single center retrospective cohort study including all patients registered on high emergency LT list between 2012 and 2018. All TCD measurements performed during ICU stay after listing and after LT (when performed) were recorded. TCD was considered abnormal when pulsatility index (PI) was >1.2. RESULTS: Among 106 patients with ALF, forty-seven (44%) had a TCD while on list. They had more severe liver and extrahepatic organ failure. When performed, TCD was abnormal in 51% of patients. These patients more frequently developed ICH events (45% vs. 13%, p = .02) and more frequently required increase in sedative drugs and vasopressors. While 22% of patients with normal TCD spontaneously survived, all of those with abnormal TCD died or were transplanted (p = .02). All transplanted patients who had abnormal exams normalized their TCD within 2 (1-2) days after LT. CONCLUSION: TCD may be a useful non-invasive tool for ICH detection and management, then guide sedation withdrawal.

External ventricular drainage for intracranial hypertension after traumatic brain injury: is it really useful?

PURPOSES: External ventricular drainage (EVD) is frequently used to control raised intracranial pressure after traumatic brain injury. However, the available evidence about its effectiveness in this context is limited. The aim of this study is to evaluate the effectiveness of EVD to control intracranial pressure and to identify the clinical and radiological factors associated with its success. METHODS: For this retrospective cohort study conducted in a Level 1 traumacenter in Paris area between May 2011 and March 2019, all patients with intracranial hypertension and treated with EVD were included. EVD success was defined as an efficient and continuous control of intracranial hypertension avoiding the use of third tier therapies (therapeutic hypothermia, decompressive craniectomy, and barbiturate coma) or avoiding a decision to withdraw life sustaining treatment due to both refractory intracranial hypertension and severity of brain injury lesions. RESULTS: 83 patients with EVD were included. EVD was successful in 33 patients (40%). Thirty-two patients (39%) required a decompressive craniectomy, eight patients (9%) received barbiturate coma. In ten cases (12%) refractory intracranial hypertension prompted a protocolized withdrawal of care. Complications occurred in nine patients (11%) (three cases of ventriculitis, six cases of catheter occlusion). Multivariate analysis identified no independent factors associated with EVD success. CONCLUSION: In a protocol-based management for traumatic brain injury, EVD allowed intracranial pressure control and avoided third tier therapeutic measures in 40% of cases with a favorable risk-benefit ratio.

Long-term outcome following blunt cerebrovascular injuries: occurrence of ischemic complications, treatment, and outcome.

PURPOSE: Blunt cerebrovascular injuries (BCVI) are a rare but serious complication after trauma. Among patients with BCVI, neurological status is altered in 30% of cases and the prognosis seems to be associated with ischemic complications. The aim of this study was to assess the long-term outcome of BCVI-associated ischemic events. METHODS: This retrospective cohort study (2011-2017) included all patients admitted for severe trauma with identified BCVI in two level-1 trauma centers. Patients were considered to have a poor neurological outcome with a GOS-E between 2 and 5 and a good neurological outcome with GOS-E between 6 and 8. A multivariate logistic regression identified risk factors for poor neurological outcome at 1 year. RESULTS: Of the 6,294 patients admitted in both trauma centers between 2011 and 2017, 81 patients presenting BCVI were identified (incidence of 1.3%). The median age was 35 years (24-44) with a median Injury Severity Score of 28 (17-41). 29 patients (50%) had a good neurological prognosis, while 25 patients (43%) had a poor neurological prognosis at 1 year. Ischemic stroke occurred in 11 patients (13.6%) within a median time of 2 days (2-2.5). No ischemic stroke occurred in the first year after ICU discharge in both groups. In our study, good prognosis at 1 year was not associated with ischemic complications [3 (10) vs 3 (12) p = 1]. CONCLUSION: Ischemic complications after BCVI are rare, occur within the first week and do not seem to impact independently the 1-year neurological prognosis.

Prognostic Impact of Early Recovering Acute Kidney Injury Following Liver Transplantation: A Multicenter Retrospective Study.

BACKGROUND: Acute kidney injury (AKI) is a common complication after liver transplantation (LT), but the specific impact of rapidly resolving AKI is not elucidated. This study investigates the factors associated with early recovery from AKI and its association with post-LT outcomes. METHODS: Retrospective analysis of 441 liver transplant recipients with end-stage liver disease without pretransplant renal impairment. AKI was defined according to Kidney Disease Improving Global Outcomes criteria and early renal recovery by its disappearance within 7 d post-LT. RESULTS: One hundred forty-six patients (32%) developed a post-LT AKI, of whom 99 (69%) recovered early and 45 (31%) did not. Factors associated with early recovery were Kidney Disease Improving Global Outcomes stage 1 (odds ratio [OR],14.11; 95% confidence interval [CI], 5.59-40.22; P < 0.0001), minimum prothrombin time >50 % (OR, 4.50; 95% CI, 1.67-13.46; P = 0.003) and aspartate aminotransferase peak value <1000 U/L (OR, 4.07; 95% CI, 1.64-10.75; P = 0.002) within 48 h post-LT. Patients with early recovery had a renal prognosis similar to that of patients without AKI with no difference in estimated glomerular filtration rate between day 7 and 1 y. Their relative risk of developing chronic kidney disease was 0.88 (95% CI, 0.55-1.41; P = 0.6) with survival identical to patients without AKI and better than patients without early recovery (P < 0.0001). CONCLUSIONS: Most patients with post-LT AKI recover early and have a similar renal prognosis and survival to those without post-LT AKI. Factors associated with early renal recovery are related to the stage of AKI, the extent of liver injury, and the early graft function. Patients at risk of not recovering may benefit the most from perioperative protective strategies, particularly those aimed at minimizing the adverse effects of calcineurin inhibitors.

Melatonin for prevention of postoperative delirium after lower limb fracture surgery in elderly patients (DELIRLESS): study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Postoperative delirium (POD) is one of the most frequent complication after surgery in elderly patients, and is associated with increased morbidity and mortality, prolonged length of stay, cognitive and functional decline leading to loss of autonomy, and important additional healthcare costs. Perioperative inflammatory stress is a key element in POD genesis. Melatonin exhibits antioxidative and immune-modulatory proprieties that are promising concerning delirium prevention, but in perioperative context literature are scarce and conflicting. We hypothesise that perioperative melatonin can reduce the incidence of POD. METHODS AND ANALYSIS: The DELIRLESS trial is a prospective, national multicentric, phase III, superiority, comparative randomised (1:1) double-blind clinical trial. Among patients aged 70 or older, hospitalised and scheduled for surgery of a severe fracture of a lower limb, 718 will be randomly allocated to receive either melatonin 4 mg per os or placebo, every night from anaesthesiologist preoperative consultation and up to 5 days after surgery. The primary outcome is POD incidence measured by either the French validated translation of the Confusion Assessment Method (CAM) score for patients hospitalised in surgery, or CAM-ICU score for patients hospitalised in ICU (Intensive Care Unit). Daily delirium assessment will take place during 10 days after surgery, or until the end of hospital stay if it is shorter. POD cumulative incidence function will be compared at day 10 between the two randomised arms in a competing risks framework, using the Fine and Grey model with death as a competing risk of delirium. ETHICS AND DISSEMINATION: The DELIRLESS trial has been approved by an independent ethics committee the Comité de Protection des Personnes (CPP) Sud-Est (ref CPP2020-18-99 2019-003210-14) for all study centres. Participant recruitment begins in December 2020. Results will be published in international peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT04335968, first posted 7 April 2020. PROTOCOL VERSION IDENTIFIER: N°3-0, 3 May 2021.

SARS-CoV-2 vaccination efficacy on hospitalisation and variants.

We report data regarding three countries with similar healthcare systems which had three different vaccinal strategies between 1st of January and 10th of April 2021: rapid full vaccination (Israel), rapid first-dose vaccination (United Kingdom) and a delayed vaccination strategy (France).

Balanced Opioid-free Anesthesia with Dexmedetomidine versus Balanced Anesthesia with Remifentanil for Major or Intermediate Noncardiac Surgery.

BACKGROUND: It is speculated that opioid-free anesthesia may provide adequate pain control while reducing postoperative opioid consumption. However, there is currently no evidence to support the speculation. The authors hypothesized that opioid-free balanced anesthetic with dexmedetomidine reduces postoperative opioid-related adverse events compared with balanced anesthetic with remifentanil. METHODS: Patients were randomized to receive a standard balanced anesthetic with either intraoperative remifentanil plus morphine (remifentanil group) or dexmedetomidine (opioid-free group). All patients received intraoperative propofol, desflurane, dexamethasone, lidocaine infusion, ketamine infusion, neuromuscular blockade, and postoperative lidocaine infusion, paracetamol, nefopam, and patient-controlled morphine. The primary outcome was a composite of postoperative opioid-related adverse events (hypoxemia, ileus, or cognitive dysfunction) within the first 48 h after extubation. The main secondary outcomes were episodes of postoperative pain, opioid consumption, and postoperative nausea and vomiting. RESULTS: The study was stopped prematurely because of five cases of severe bradycardia in the dexmedetomidine group. The primary composite outcome occurred in 122 of 156 (78%) dexmedetomidine group patients compared with 105 of 156 (67%) in the remifentanil group (relative risk, 1.16; 95% CI, 1.01 to 1.33; P = 0.031). Hypoxemia occurred 110 of 152 (72%) of dexmedetomidine group and 94 of 155 (61%) of remifentanil group patients (relative risk, 1.19; 95% CI, 1.02 to 1.40; P = 0.030). There were no differences in ileus or cognitive dysfunction. Cumulative 0 to 48 h postoperative morphine consumption (11 mg [5 to 21] versus 6 mg [0 to 17]) and postoperative nausea and vomiting (58 of 157 [37%] versus 37 of 157 [24%]; relative risk, 0.64; 95% CI, 0.45 to 0.90) were both less in the dexmedetomidine group, whereas measures of analgesia were similar in both groups. Dexmedetomidine patients had more delayed extubation and prolonged postanesthesia care unit stay. CONCLUSIONS: This trial refuted the hypothesis that balanced opioid-free anesthesia with dexmedetomidine, compared with remifentanil, would result in fewer postoperative opioid-related adverse events. Conversely, it did result in a greater incidence of serious adverse events, especially hypoxemia and bradycardia.

Decreased microglial Wnt/ß-catenin signalling drives microglial pro-inflammatory activation in the developing brain.

Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm-born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain across models of neuroinflammation-mediated injury (mouse, zebrafish) and primary human and mouse microglia we found using analysis of genes and proteins that a reduction in Wnt/ß-catenin signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination. We validated in a cohort of preterm-born infants that genomic variation in the Wnt pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a blood-brain barrier penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.

Time trends in the reporting of conflicts of interest, funding and affiliation with industry in intensive care research: a systematic review.

PURPOSE: Conflict of interest (COI) may compromise, or have the appearance of compromising, a researcher's judgment or integrity in conducting or reporting research. We sought to assess time trends of COI and funding statement reporting in the critical care literature. METHODS: PubMed was searched by using Medical Subject Headings and the appropriate corresponding keywords: "INTENSIVE CARE UNIT" or "ICU" as a major topic. Four years in a 15-year time period (2001-2016) were arbitrarily chosen and one study month was randomly selected for each study period. Studies published during the selected months were included in the analysis. RESULTS: Three hundred and seventy-four studies were evaluated, including five reviews (1.3%) and ten randomized clinical trials (RCTs) (2.7%). COI statements were available in 65% of the studies and 8% had declared COI. COI statement rate, declared COI and funding statements increased over time, while the number of authors affiliated with industry and the discordance between the lack of COI statement and affiliation with industry decreased. Declared COI were more frequent in 2011-2016 as compared to 2001-2010 (OR 4.06; 95% CI 1.15-25.79) and in the higher quartile of a journal's impact factor (OR of 16.73; 95% CI 3.28-306.20). Surprisingly, focus of the study, country of the first author and/or endorsement of the study by a trial group were not associated with COI statements. CONCLUSION: Our study suggests COI reporting to have been unintuitive to most investigators and unreliable before ICMJE statements, and that strong incentives are needed to implement adequate reporting of COI.

Role of microglia in a mouse model of paediatric traumatic brain injury.

The cognitive and behavioural deficits caused by traumatic brain injury (TBI) to the immature brain are more severe and persistent than TBI in the mature brain. Understanding this developmental sensitivity is critical as children under four years of age sustain TBI more frequently than any other age group. Microglia (MG), resident immune cells of the brain that mediate neuroinflammation, are activated following TBI in the immature brain. However, the type and temporal profile of this activation and the consequences of altering it are still largely unknown. In a mouse model of closed head weight drop paediatric brain trauma, we characterized i) the temporal course of total cortical neuroinflammation and the phenotype of ex vivo isolated CD11B-positive microglia/macrophage (MG/MΦ) using a battery of 32 markers, and ii) neuropathological outcome 1 and 5days post-injury. We also assessed the effects of targeting MG/MΦ activation directly, using minocycline a prototypical microglial activation antagonist, on these processes and outcome. TBI induced a moderate increase in both pro- and anti-inflammatory cytokines/chemokines in the ipsilateral hemisphere. Isolated cortical MG/MΦ expressed increased levels of markers of endogenous reparatory/regenerative and immunomodulatory phenotypes compared with shams. Blocking MG/MΦ activation with minocycline at the time of injury and 1 and 2days post-injury had only transient protective effects, reducing ventricular dilatation and cell death 1day post-injury but having no effect on injury severity at 5days. This study demonstrates that, unlike in adults, the role of MG/MΦ in injury mechanisms following TBI in the immature brain may not be negative. An improved understanding of MG/MΦ function in paediatric TBI could support translational efforts to design therapeutic interventions.

From preoperative evaluation to stroke center: Management of postoperative acute ischemic stroke.

Perioperative acute ischaemic stroke is a rare complication with potentially catastrophic outcomes. It has been shown that paying attention to perioperative neurological deficits and acute ischaemic stroke prevention proves to be beneficial in avoiding these catastrophic outcomes and may lead to determining early therapeutic interventions. This article reviews the perioperative management (covering diagnosis and treatment), prevention (covering surgery postponement, management with anticoagulant/antiplatelet and the growing interest in statins and beta-blockers) and intraoperative recommendations (covering anaesthetic techniques, ventilation strategies, transfusion and blood pressure management) specifically for the general surgical population. A summary of current treatments is enlightened by recently described evidence for the effectiveness of mechanical thrombectomy.