Georg Auzinger

Acute liver failure is a rare disorder with high mortality and resource cost. In the developing world, viral causes predominate, with hepatitis E infection recognised as a common cause in many countries. In the USA and much of western Europe, the incidence of virally induced disease has declined substantially in the past few years, with most cases now arising from drug-induced liver injury, often from paracetamol. However, a large proportion of cases are of unknown origin. Acute liver failure can be associated with rapidly progressive multiorgan failure and devastating complications; however, outcomes have been improved by use of emergency liver transplantation. An evidence base for practice is emerging for supportive care, and a better understanding of the pathophysiology of the disorder, especially in relation to hepatic encephalopathy, will probably soon lead to further improvements in survival rates.

Acute liver failure (ALF) often results in cardiovascular instability, renal failure, brain oedema and death either due to irreversible shock, cerebral herniation or development of multiple organ failure. High-volume plasma exchange (HVP), defined as exchange of 8-12 or 15% of ideal body weight with fresh frozen plasma in case series improves systemic, cerebral and splanchnic parameters.In this prospective, randomised, controlled, multicentre trial we randomly assigned 182 patients with ALF to receive either standard medical therapy (SMT; 90 patients) or SMT plus HVP for three days (92 patients). The baseline characteristics of the groups were similar. The primary endpoint was liver transplantation-free survival during hospital stay. Secondary-endpoints included survival after liver transplantation with or without HVP with intention-to-treat analysis. A proof-of-principle study evaluating the effect of HVP on the immune cell function was also undertaken.For the entire patient population, overall hospital survival was 58.7% for patients treated with HVP vs. 47.8% for the control group (hazard ratio (HR), with stratification for liver transplantation: 0.56; 95% confidence interval (CI), 0.36-0.86; p=0.0083). HVP prior to transplantation did not improve survival compared with patients who received SMT alone (CI 0.37 to 3.98; p=0.75). The incidence of severe adverse events was similar in the two groups. Systemic inflammatory response syndrome (SIRS) and sequential organ failure assessment (SOFA) scores fell in the treated group compared to control group, over the study period (p<0.001).Treatment with HVP improves outcome in patients with ALF by increasing liver transplant-free survival. This is attributable to attenuation of innate immune activation and amelioration of multi-organ dysfunction.

High circulating ammonia concentrations are common in patients with acute liver failure (ALF) and are associated with hepatic encephalopathy (HE) and intracranial hypertension (ICH). Other risk factors are poorly characterized. We evaluated the relation of the admission arterial ammonia concentration and other clinical variables with the development of HE and ICH. Arterial ammonia was measured on admission to the intensive care unit in 257 patients; 165 had ALF and severe HE, and there were 3 control groups: acute hepatic dysfunction without severe HE (n = 50), chronic liver disease (n = 33), and elective surgery (n = 9). Variables associated with ICH and HE were investigated with regression analysis. Ammonia was higher in ALF patients than controls. An independent risk factor for the development of severe HE and ICH, a level greater than 100 mumol/L predicted the onset of severe HE with 70% accuracy. The model for end-stage liver disease (MELD) score was also independently predictive of HE, and its combination with ammonia increased specificity and accuracy. ICH developed in 55% of ALF patients with a level greater than 200 mumol/L, although this threshold failed to identify most cases. After admission, ammonia levels remained high in those developing ICH and fell in those who did not. Youth, a requirement for vasopressors, and renal replacement therapy were additional independent risk factors.Ammonia is an independent risk factor for the development of both HE and ICH. Additional MELD scoring improved the prediction of HE. Factors other than ammonia also appear important in the pathogenesis of ICH. Ammonia measurements could form part of risk stratification for HE and ICH, identifying patients for ammonia-lowering therapies and invasive monitoring.

Acute liver failure (ALF) is a rare condition characterized by the development of encephalopathy in the absence of chronic liver disease. Cerebral edema occurs in up to 80% of patients with Grade IV encephalopathy. In the current prospective randomized controlled clinical trial, we examined the effect of induced hypernatremia on the incidence of intracranial hypertension (IH) in patients with ALF. Thirty patients with ALF and Grade III or IV encephalopathy were randomized. Patients in Group 1 (n = 15) received the normal standard of care. Patients in Group 2 (n = 15) received standard care and hypertonic saline (30%) via infusion to maintain serum sodium levels of 145-155 mmol/L. Intracranial pressure (ICP) was monitored in all patients with a subdural catheter (Camino Systems, San Diego, CA) for up to 72 hours after inclusion. Serum sodium levels became significantly different from the levels observed in the control group at 6 hours (P <.01). Over the first 24 hours, norepinephrine dose increased relative to baseline in the control group (P <.001; 13 patients) but not in the treatment group. ICP decreased significantly relative to baseline over the first 24 hours in the treatment group (P =.003; 13 patients) but not in the control group. The incidence of IH, defined as a sustained increase in ICP to a level of 25 mm Hg or greater, was significantly higher in the control group (P =.04). In conclusion, induction and maintenance of hypernatremia can reduce the incidence and severity of IH in patients presenting with ALF.

<h3>Background & Aims</h3> Acute liver failure (ALF) is a rapidly progressive critical illness with high mortality. Complex intensive care unit (ICU) protocols and emergency liver transplantation (ELT) are now often available, but rarity and severity of illness have limited its study and evidence-base for care. We reviewed patients treated over a 35-year period at a specialist high-volume ICU, quantifying changes in disease aetiology, severity and evolution of ICU support and ELT use and outcome. <h3>Methods</h3> Review of adult patients admitted during the period 1973–2008, with acute liver dysfunction and coagulopathy with overt hepatic encephalopathy (ALF) and those without (acute liver injury; ALI). <h3>Results</h3> 3305 patients fulfilled inclusion criteria, 2095 with ALF. Overall hospital survival increased from 30% in 1973–78 to 76% in 2004–08; in ALF from 17% to 62% (both <i>p</i><0.0001). In ALF patients treated without ELT, survival rose from 17% to 48% (<i>p</i><0.0001); in those undergoing ELT (n=387) from 56% in 1984–88 to 86% in 2004–08 (<i>p</i><0.01). Coincident with drug sales-restriction, paracetamol-related admissions fell significantly. Viral admissions fell from 56% to 17% of non-paracetamol cases (<i>p</i><0.0001). Admission markers of liver injury severity fell significantly and the proportion of patients with intracranial hypertension (ICH) fell from 76% in 1984–88 to 20% in 2004–08 (<i>p</i><0.0001). In those with ICH, mortality fell from 95% to 55% (<i>p</i><0.0001). <h3>Conclusions</h3> The nature and outcome of ALF have transformed over 35years, with major improvements in survival and a fall in prevalence of cerebral oedema and ICH, likely consequent upon earlier illness recognition, improved ICU care, and use of ELT.

Abstract Acetaminophen-induced acute liver failure (AALF) is associated with innate immunity activation, which contributes to the severity of hepatic injury and clinical outcome. A marked increase in hepatic macrophages (h-mϕ) is observed in experimental models of AALF, but controversy exists regarding their role, implicating h-mϕ in both aggravation and resolution of liver injury. The role of h-mϕ in human AALF is virtually unexplored. We sought to investigate the role of chemokine (C-C motif) ligand 2 (CCL2) in the recruitment of circulating monocytes to the inflamed liver and to determine how the h-mϕ infiltrate and liver microenvironment may contribute to tissue repair versus inflammation in AALF. We evaluated circulating monocytes, their chemokine (C-C motif) receptor 2 (CCR2) expression, and serum CCL2 levels in patients with AALF. Cell subsets and numbers of circulation-derived (MAC387+) or resident proliferating (CD68/Ki67+) h-mϕ in hepatic immune infiltrates were determined by immunohistochemistry. Inflammatory cytokine levels were determined in whole and laser microdissected liver tissue by proteome array. In AALF, circulating monocytes were depleted, with the lowest levels observed in patients with adverse outcomes. CCL2 levels were high in AALF serum and hepatic tissue, and circulating monocyte subsets expressed CCR2, suggesting CCL2-dependent hepatic monocyte recruitment. Significant numbers of both MAC387+ and CD68+ h-mϕ were found in AALF compared with control liver tissue with a high proportion expressing the proliferation marker Ki67. Levels of CCL2, CCL3, interleukin (IL)-6, IL-10, and transforming growth factor-β1 were significantly elevated in AALF liver tissue relative to chronic liver disease controls. Conclusion: In AALF, the h-mϕ population is expanded in areas of necrosis, both through proliferation of resident cells and CCL2-dependent recruitment of circulating monocytes. The presence of h-mϕ within an anti-inflammatory/regenerative microenvironment indicates that they are implicated in resolution of inflammation/tissue repair processes during AALF. (HEPATOLOGY 2012)

Background & Aims Patients with cirrhosis are prone to infection which is a frequent precipitant of hepatic encephalopathy (HE). Clinical studies have examined the importance of inflammation and infection in modulating the manifestation of symptoms of HE in acute liver failure and patients with cirrhosis and minimal/low grade HE. It would be logical to presume that this relationship persists in patients who develop severe HE in cirrhosis although this has not been examined to date. Methods We report the findings of a prospective audit of 100 consecutive patients with cirrhosis admitted between Jan 2000 and March 2008 to a liver Intensive Care Unit (ICU) where HE was the primary indication for admission (59% Grade 3; 41% Grade 4). Haematological and microbiological data were collected at ICU admission, and organ scores and outcomes were recorded. Results 46% of patients had positive cultures taken within ±48 h from admission to ICU [25% blood] and a further 22% were culture negative but had evidence of systemic inflammation (SIRS). SIRS score (p = 0.03) and SOFA score (p = 0.006) were significantly higher in those patients with Grade 4 HE, who were also less likely to survive (p <0.001). HE grade/coma score did not correlate with ammonia, biochemistry or MELD score. Fifty-two percent of patients survived their ICU stay while the remainder developed progressive multiorgan failure and died; 38% survived to discharge, and 16% were transplanted. Conclusions These data support an association between infection/SIRS and not ammonia, in patients with cirrhosis that develop severe HE. The presence or absence of infection/SIRS did not determine survival. Patients with cirrhosis are prone to infection which is a frequent precipitant of hepatic encephalopathy (HE). Clinical studies have examined the importance of inflammation and infection in modulating the manifestation of symptoms of HE in acute liver failure and patients with cirrhosis and minimal/low grade HE. It would be logical to presume that this relationship persists in patients who develop severe HE in cirrhosis although this has not been examined to date. We report the findings of a prospective audit of 100 consecutive patients with cirrhosis admitted between Jan 2000 and March 2008 to a liver Intensive Care Unit (ICU) where HE was the primary indication for admission (59% Grade 3; 41% Grade 4). Haematological and microbiological data were collected at ICU admission, and organ scores and outcomes were recorded. 46% of patients had positive cultures taken within ±48 h from admission to ICU [25% blood] and a further 22% were culture negative but had evidence of systemic inflammation (SIRS). SIRS score (p = 0.03) and SOFA score (p = 0.006) were significantly higher in those patients with Grade 4 HE, who were also less likely to survive (p <0.001). HE grade/coma score did not correlate with ammonia, biochemistry or MELD score. Fifty-two percent of patients survived their ICU stay while the remainder developed progressive multiorgan failure and died; 38% survived to discharge, and 16% were transplanted. These data support an association between infection/SIRS and not ammonia, in patients with cirrhosis that develop severe HE. The presence or absence of infection/SIRS did not determine survival.

Characteristics of decompensated cirrhosis and acute-on-chronic liver failure (ACLF) include susceptibility to infection, immuneparesis, and monocyte dysfunction. MER receptor tyrosine kinase (MERTK) is expressed by monocytes and macrophages and contributes to down-regulation of innate immune responses. We investigated whether MERTK expression is altered on monocytes from patients with liver failure.We analyzed blood and liver samples collected from patients admitted to the liver intensive therapy unit at King's College Hospital in London from December 2012 through July 2014. Patients had either ACLF (n = 41), acute decompensation of cirrhosis without ACLF (n = 9), cirrhosis without decompensation (n = 17), or acute liver failure (n = 23). We also analyzed samples from healthy individuals (controls, n = 29). We used flow cytometry to determine the level of innate immune function, and associated the findings with disease severity. We developed an assay to measure recruitment and migration of immune cells from the tissue parenchyma. Immunohistochemistry and confocal microscopy were used to determine levels of MERTK in bone marrow, liver, and lymph node tissues. We performed immunophenotype analyses and measured the production of tumor necrosis factor and interleukin 6 and intracellular killing of Escherichia coli by monocytes and peritoneal macrophages incubated with lipopolysaccharide, with or without an inhibitor of MERTK (UNC569).The number of monocytes and macrophages that expressed MERTK was greatly increased in the circulation, livers, and lymph nodes of patients with ACLF, compared with patients with stable cirrhosis and controls. MERTK expression (mean fluorescence intensity) correlated with the severity of hepatic and extrahepatic disease and systemic inflammatory responses. Based on immunophenotype, migration, and functional analyses, MERTK-expressing monocytes migrate across the endothelia to localize into tissue sites and regional lymph nodes. Expression of MERTK reduced the response of cultured monocytes to lipopolysaccharide; the addition of UNC569 restored production of inflammatory cytokines in response to lipopolysaccharide.Patients with ACLF have increased numbers of immunoregulatory monocytes and macrophages that express MERTK and suppress the innate immune response to microbes. The number of these cells correlates with disease severity and the inflammatory response. MERTK inhibitors restore production of inflammatory cytokines by immune cells from patients with ACLF, and might be developed to increase the innate immune response in these patients.

Abstract Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples ( n = 474) from hospitalized COVID-19 patients ( n = 123), non-COVID-19 ICU sepsis patients ( n = 25) and healthy controls ( n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22–2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified ‘Age, RNAemia’ and ‘Age, PTX3’ as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.

<h3>Importance</h3> In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. <h3>Objective</h3> To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. <h3>Design, Setting, and Participants</h3> This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. <h3>Interventions</h3> Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). <h3>Main Outcomes and Measures</h3> The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. <h3>Results</h3> Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, −7.6% to 11.5%];<i>P</i> = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, −2.1 [95% CI, −3.8 to −0.3];<i>P</i> = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. <h3>Conclusions and Relevance</h3> Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02654327

Acute liver failure and septic shock share many clinical features, including hyperdynamic cardiovascular collapse. Adrenal insufficiency may result in a similar cardiovascular syndrome. In septic shock, adrenal insufficiency, defined using the short synacthen test (SST), is associated with hemodynamic instability and poor outcome. We examined the SST, a dynamic test of adrenal function, in 45 patients with acute hepatic dysfunction (AHD) and determined the association of these results with hemodynamic profile, severity of illness, and outcomes. Abnormal SSTs were common, occurring in 62% of patients. Those who required noradrenaline (NA) for blood pressure support had a significantly lower increment (median, 161 vs. 540 nmol/L; P <.001) following synacthen compared with patients who did not. Increment and peak were lower in patients who required ventilation for the management of encephalopathy (increment, 254 vs. 616 nmol/L, P <.01; peak, 533 vs. 1,002 nmol/L, P <.01). Increment was significantly lower in those who fulfilled liver transplant criteria compared with those who did not (121 vs. 356 nmol/L; P <.01). Patients who died or underwent liver transplantation had a lower increment (148 vs. 419 nmol/L) and peak (438 vs. 764 nmol/L) than those who survived (P <.01). There was an inverse correlation between increment and severity of illness (Sequential Organ Failure Assessment, r = -0.63; P <.01). In conclusion, adrenal dysfunction assessed by the SST is common in AHD and may contribute to hemodynamic instability and mortality. It is more frequent in those with severe liver disease and correlates with severity of illness.

Invasive candidiasis and candidemia are frequently encountered in the nosocomial setting, particularly in the intensive care unit (ICU).To review the current management of invasive candidiasis and candidemia in non-neutropenic adult ICU patients based on a review of the literature and a European expert panel discussion.Candida albicans remains the most frequently isolated fungal species followed by C. glabrata. The diagnosis of invasive candidiasis involves both clinical and laboratory parameters, but neither of these are specific. One of the main features in diagnosis is the evaluation of risk factor for infection which will identify patients in need of pre-emptive or empiric treatment. Clinical scores were built from those risk factors. Among laboratory diagnosis, a positive blood culture from a normally sterile site provides positive evidence. Surrogate markers have also been proposed like 1,3 beta-D: glucan level, mannans, or PCR testing. Invasive candidiasis and candidemia is a growing concern in the ICU, apart from cases with positive blood cultures or fluid/tissue biopsy, diagnosis is neither sensitive nor specific. The diagnosis remains difficult and is usually based on the evaluation of risk factors.

Though emergency liver transplantation (ELT) is an established treatment for severe acute liver failure (ALF), outcomes are inferior to elective surgery. Despite prioritization, many patients deteriorate, becoming unsuitable for ELT.We examined a single-centre experience of 310 adult patients with ALF registered for ELT over a 10-year period to determine factors associated with failure to transplant, and in those patients undergoing ELT, those associated with 90-day mortality.One hundred and thirty-two (43%) patients had ALF resulting from paracetamol and 178 (57%) from non-paracetamol causes. Seventy-four patients (24%) did not undergo surgery; 92% of these died. Failure to transplant was more likely in patients requiring vasopressors at listing (hazard ratio 1.9 (95% CI 1.1-3.6)) paracetamol aetiology (2.5 (1.4-4.6)) but less likely in blood group A (0.5 (0.3-0.9)). Post-ELT survival at 90-days and one-year increased from 66% and 63% in 1994-1999 to 81% and 79% in 2000-2004 (p<0.01). Four variables were associated with post-ELT mortality; age >45 years (3 (1.7-5.3)), vasopressor requirement (2.2 (1.3-3.8), transplantation before 2000 (1.9 (1.1-3.3)) and use of high-risk grafts (2.3 (1.3-4.2).The data indicate improved outcomes in the later era, despite higher level patient dependency and greater use of high-risk grafts, through improved graft/recipient matching.

Ammonia is recognized as a toxin central to complications of liver failure. Hyperammonaemia has important clinical consequences, but optimal means to reduce circulating levels are uncertain. In patients with liver disease, continuous renal replacement therapy (CRRT) with haemofiltration (HF) is often required to treat concurrent kidney injury, but its effects upon ammonia levels are poorly characterized. To evaluate the effect of HF at different treatment intensities on ammonia clearance (AC) and arterial ammonia concentration.Prospective study of adult patients with liver failure and arterial ammonia >100 μmol/L requiring CRRT using veno-venous HF. Arterial ammonia concentration and AC measured at 1 and 24 h after initiation of low (35 ml/kg/h) or high (90 ml/kg/h) filtration volume.Twenty-four patients (10 acute liver failure, 10 chronic liver disease and 4 following liver resection) were studied. Clearance of urea and ammonia solutes correlated closely (r = 0.819, P = 0.007). Ammonia clearance correlated closely with ultrafiltration rate (r = 0.86, P < 0.001). At 1 h, AC was 39 (34-54) ml/min (low volume) vs 85 (62-105) ml/min (high volume) CRRT, (P < 0.001) and at 24 h 44 (34-63) vs 105 (82-109) ml/min, (P = 0.01). Overall, a 22% reduction in median arterial ammonia concentration was observed over 24 h of HF from 156 (137-176) to 122 (85-133) μmol/L, (P ≤ 0.0001).Clinically significant ammonia clearance can be achieved in adult patients with hyperammonaemia utilizing continuous VVHF. Ammonia clearance is closely correlated with ultrafiltration rate. HF was associated with a fall in arterial ammonia concentration.

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Background & AimsDuring the past decade, survival has increased among patients admitted to general intensive care units, but it is not clear if it has increased for patients admitted with cirrhosis and organ failure. The chronic liver failure–sequential organ failure assessment (CLIF-SOFA) recently was developed as an adaptation to the SOFA to predict outcomes of patients, but requires validation. We investigated changes in outcomes of patients with cirrhosis and organ failure since 2000, compared the abilities of SOFA and CLIF-SOFA to predict patient survival, and validated the CLIF-SOFA system.MethodsIn a retrospective study, we collected data from 971 patients (median age, 52 y; age range, 16–90 y; 62% male) with cirrhosis (54% alcohol associated, 12% viral, and 34% other causes). The patients were admitted under emergency conditions from January 1, 2000, to December 31, 2010, to a liver intensive therapy unit in the United Kingdom. Patient survival while in the hospital was compared with measures of illness severity, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, model for end-stage liver disease (MELD) scores, SOFA scores, and CLIF-SOFA scores.ResultsPatients had a median APACHE II score of 21 (range, 5–50) and a median MELD score of 23 (range, 6–40). The median APACHE II score at admission decreased from 23 to 22 over the study period (P < .001), whereas the median MELD score at admission decreased from 23 to 18 (P < .001). Overall survival until hospital discharge was 51%; this value increased from 40% in 2000 to 63% in 2010 (P < .001). The unadjusted odds ratio for change in mortality/year was 0.87 (95% confidence interval, 0.83–0.91; P < .001). The APACHE II score adjusted odds ratio for mortality was 0.89 (95% confidence interval, 0.84–0.93; P < .001). The etiology of cirrhosis was not associated with a significant difference in survival. CLIF-SOFA and SOFA scores at the time of admission predicted patient survival with area under the receiver operating curve (AUROC) values of 0.813 and 0.799, respectively; the scores at 48 hours after admission predicted survival with AUROC values of 0.853 and 0.840, and scores after 1 week predicted survival with AUROC values of 0.842 and 0.844, respectively. These AUROC values were higher than those obtained from APACHE II or MELD scores.ConclusionsThe proportion of patients with cirrhosis who survived after admission to intensive care increased from 2000 to 2010. SOFA and CLIF-SOFA scores during the first week of critical care appear to have similar abilities to predict patient survival. During the past decade, survival has increased among patients admitted to general intensive care units, but it is not clear if it has increased for patients admitted with cirrhosis and organ failure. The chronic liver failure–sequential organ failure assessment (CLIF-SOFA) recently was developed as an adaptation to the SOFA to predict outcomes of patients, but requires validation. We investigated changes in outcomes of patients with cirrhosis and organ failure since 2000, compared the abilities of SOFA and CLIF-SOFA to predict patient survival, and validated the CLIF-SOFA system. In a retrospective study, we collected data from 971 patients (median age, 52 y; age range, 16–90 y; 62% male) with cirrhosis (54% alcohol associated, 12% viral, and 34% other causes). The patients were admitted under emergency conditions from January 1, 2000, to December 31, 2010, to a liver intensive therapy unit in the United Kingdom. Patient survival while in the hospital was compared with measures of illness severity, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, model for end-stage liver disease (MELD) scores, SOFA scores, and CLIF-SOFA scores. Patients had a median APACHE II score of 21 (range, 5–50) and a median MELD score of 23 (range, 6–40). The median APACHE II score at admission decreased from 23 to 22 over the study period (P < .001), whereas the median MELD score at admission decreased from 23 to 18 (P < .001). Overall survival until hospital discharge was 51%; this value increased from 40% in 2000 to 63% in 2010 (P < .001). The unadjusted odds ratio for change in mortality/year was 0.87 (95% confidence interval, 0.83–0.91; P < .001). The APACHE II score adjusted odds ratio for mortality was 0.89 (95% confidence interval, 0.84–0.93; P < .001). The etiology of cirrhosis was not associated with a significant difference in survival. CLIF-SOFA and SOFA scores at the time of admission predicted patient survival with area under the receiver operating curve (AUROC) values of 0.813 and 0.799, respectively; the scores at 48 hours after admission predicted survival with AUROC values of 0.853 and 0.840, and scores after 1 week predicted survival with AUROC values of 0.842 and 0.844, respectively. These AUROC values were higher than those obtained from APACHE II or MELD scores. The proportion of patients with cirrhosis who survived after admission to intensive care increased from 2000 to 2010. SOFA and CLIF-SOFA scores during the first week of critical care appear to have similar abilities to predict patient survival.

Background & Aims Animal models and human case series of acute liver failure (ALF) suggest moderate hypothermia (MH) to have protective effects against cerebral oedema (CO) development and intracranial hypertension (ICH). However, the optimum temperature for patient management is unknown. In a prospective randomized controlled trial we investigated if maintenance of MH prevented development of ICH in ALF patients at high risk of the complication. Methods Patients with ALF, high-grade encephalopathy and intracranial pressure (ICP) monitoring in specialist intensive care units were randomized by sealed envelope to targeted temperature management (TTM) groups of 34 °C (MH) or 36 °C (control) for a period of 72 h. Investigators were not blinded to group assignment. The primary outcome was a sustained elevation in ICP >25 mmHg, with secondary outcomes the occurrence of predefined serious adverse effects, magnitude of ICP elevations and cerebral and all-cause hospital mortality (with or without transplantation). Results Forty-six patients were randomized, of whom forty-three were studied. There was no significant difference between the TTM groups in the primary outcome during the study period (35% vs. 27%, p = 0.56), for the MH (n = 17) or control (n = 26) groups respectively, relative risk 1.31 (95% CI 0.53–3.2). Groups had similar incidence of adverse events and overall mortality (41% vs. 46%, p = 0.75). Conclusions In patients with ALF at high risk of ICH, MH at 33–34 °C did not confer a benefit above management at 36 °C in prevention of ICH or in overall survival. This study did not confirm advantage of its prophylactic use. (ISRCTN registration number 74268282; no funding.) Lay summary Studies in animals with acute liver failure (ALF) have suggested that cooling (hypothermia) could prevent or limit the development of brain swelling, a dangerous complication of the condition. There is limited data on its effects in humans. In a randomized controlled trial in severely ill patients with ALF we compared the effects of different temperatures and found no benefit on improving survival or preventing brain swelling by controlling temperature at 33–34 °C against 36 °C. Animal models and human case series of acute liver failure (ALF) suggest moderate hypothermia (MH) to have protective effects against cerebral oedema (CO) development and intracranial hypertension (ICH). However, the optimum temperature for patient management is unknown. In a prospective randomized controlled trial we investigated if maintenance of MH prevented development of ICH in ALF patients at high risk of the complication. Patients with ALF, high-grade encephalopathy and intracranial pressure (ICP) monitoring in specialist intensive care units were randomized by sealed envelope to targeted temperature management (TTM) groups of 34 °C (MH) or 36 °C (control) for a period of 72 h. Investigators were not blinded to group assignment. The primary outcome was a sustained elevation in ICP >25 mmHg, with secondary outcomes the occurrence of predefined serious adverse effects, magnitude of ICP elevations and cerebral and all-cause hospital mortality (with or without transplantation). Forty-six patients were randomized, of whom forty-three were studied. There was no significant difference between the TTM groups in the primary outcome during the study period (35% vs. 27%, p = 0.56), for the MH (n = 17) or control (n = 26) groups respectively, relative risk 1.31 (95% CI 0.53–3.2). Groups had similar incidence of adverse events and overall mortality (41% vs. 46%, p = 0.75). In patients with ALF at high risk of ICH, MH at 33–34 °C did not confer a benefit above management at 36 °C in prevention of ICH or in overall survival. This study did not confirm advantage of its prophylactic use. (ISRCTN registration number 74268282; no funding.)

Predicting survival in decompensated cirrhosis (DC) is important in decision making for liver transplantation and resource allocation. We investigated whether high-resolution metabolic profiling can determine a metabolic phenotype associated with 90-day survival.Two hundred and forty-eight subjects underwent plasma metabotyping by (1)H nuclear magnetic resonance (NMR) spectroscopy and reversed-phase ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-TOF-MS; DC: 80-derivation set, 101-validation; stable cirrhosis (CLD) 20 and 47 healthy controls (HC)).(1)H NMR metabotyping accurately discriminated between surviving and non-surviving patients with DC. The NMR plasma profiles of non-survivors were attributed to reduced phosphatidylcholines and lipid resonances, with increased lactate, tyrosine, methionine and phenylalanine signal intensities. This was confirmed on external validation (area under the receiver operating curve [AUROC]=0.96 (95% CI 0.90-1.00, sensitivity 98%, specificity 89%). UPLC-TOF-MS confirmed that lysophosphatidylcholines and phosphatidylcholines [LPC/PC] were downregulated in non-survivors (UPLC-TOF-MS profiles AUROC of 0.94 (95% CI 0.89-0.98, sensitivity 100%, specificity 85% [positive ion detection])). LPC concentrations negatively correlated with circulating markers of cell death (M30 and M65) levels in DC. Histological examination of liver tissue from DC patients confirmed increased hepatocyte cell death compared to controls. Cross liver sampling at time of liver transplantation demonstrated that hepatic endothelial beds are a source of increased circulating total cytokeratin-18 in DC.Plasma metabotyping accurately predicts mortality in DC. LPC and amino acid dysregulation is associated with increased mortality and severity of disease reflecting hepatocyte cell death.

Abstract Aims Coronavirus disease 2019 (COVID-19) can lead to multiorgan damage. MicroRNAs (miRNAs) in blood reflect cell activation and tissue injury. We aimed to determine the association of circulating miRNAs with COVID-19 severity and 28 day intensive care unit (ICU) mortality. Methods and results We performed RNA-Seq in plasma of healthy controls (n = 11), non-severe (n = 18), and severe (n = 18) COVID-19 patients and selected 14 miRNAs according to cell- and tissue origin for measurement by reverse transcription quantitative polymerase chain reaction (RT–qPCR) in a separate cohort of mild (n = 6), moderate (n = 39), and severe (n = 16) patients. Candidates were then measured by RT–qPCR in longitudinal samples of ICU COVID-19 patients (n = 240 samples from n = 65 patients). A total of 60 miRNAs, including platelet-, endothelial-, hepatocyte-, and cardiomyocyte-derived miRNAs, were differentially expressed depending on severity, with increased miR-133a and reduced miR-122 also being associated with 28 day mortality. We leveraged mass spectrometry-based proteomics data for corresponding protein trajectories. Myocyte-derived (myomiR) miR-133a was inversely associated with neutrophil counts and positively with proteins related to neutrophil degranulation, such as myeloperoxidase. In contrast, levels of hepatocyte-derived miR-122 correlated to liver parameters and to liver-derived positive (inverse association) and negative acute phase proteins (positive association). Finally, we compared miRNAs to established markers of COVID-19 severity and outcome, i.e. SARS-CoV-2 RNAemia, age, BMI, D-dimer, and troponin. Whilst RNAemia, age and troponin were better predictors of mortality, miR-133a and miR-122 showed superior classification performance for severity. In binary and triplet combinations, miRNAs improved classification performance of established markers for severity and mortality. Conclusion Circulating miRNAs of different tissue origin, including several known cardiometabolic biomarkers, rise with COVID-19 severity. MyomiR miR-133a and liver-derived miR-122 also relate to 28 day mortality. MiR-133a reflects inflammation-induced myocyte damage, whilst miR-122 reflects the hepatic acute phase response.

A systematic review and meta-analysis of the entire COVID-19 Tracheostomy cohort was conducted to determine the cumulative incidence of complications, mortality, time to decannulation and ventilatory weaning. Outcomes of surgical versus percutaneous and outcomes relative to tracheostomy timing were also analysed. Studies reporting outcome data on patients with COVID-19 undergoing tracheostomy were identified and screened by 2 independent reviewers. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed. Outcome data were analysed using a random-effects model. From 1016 unique studies, 39 articles reporting outcomes for a total of 3929 patients were included for meta-analysis. Weighted mean follow-up time was 42.03±26 days post-tracheostomy. Meta-analysis showed that 61.2% of patients were weaned from mechanical ventilation [95%CI 52.6%-69.5%], 44.2% of patients were decannulated [95%CI 33.96%-54.67%], and cumulative mortality was found to be 19.23% [95%CI 15.2%-23.6%] across the entire tracheostomy cohort. The cumulative incidence of complications was 14.24% [95%CI 9.6%-19.6%], with bleeding accounting for 52% of all complications. No difference was found in incidence of mortality (RR1.96; p=0.34), decannulation (RR1.35, p=0.27), complications (RR0.75, p=0.09) and time to decannulation (SMD 0.46, p=0.68) between percutaneous and surgical tracheostomy. Moreover, no difference was found in mortality (RR1.57, p=0.43) between early and late tracheostomy, and timing of tracheostomy did not predict time to decannulation. Ten confirmed nosocomial staff infections were reported from 1398 tracheostomies. This study provides an overview of outcomes of tracheostomy in COVID-19 patients, and contributes to our understanding of tracheostomy decisions in this patient cohort.

Organ allocation based on Model for End-Stage Liver Disease (MELD) resulted in decreased waiting list mortality in the United States. However, reports suggest an increase in resource utilization as a consequence of this. The aim of this study is to assess the correlation of MELD at transplant with post-liver transplant (LT) intensive care unit (ICU) costs. We assessed clinical and demographic variables of 402 adult patients who underwent LT at King's College Hospital, London, UK, between January 2000 and December 2003. ICU cost calculations were based on the therapeutic intervention scoring system (TISS). Graft quality was assessed using the donor risk index (DRI). Patients with a MELD score > 24 had significantly longer post-LT ICU stay (P < 0.0001) and total post-LT hospital stay (P = 0.008). In addition, they had significantly increased TISS scores, ICU cost, and need for renal replacement therapy (RRT) (P < 0.001). MELD score (by point) and MELD > 24 was associated with prolonged ICU stay (P = 0.004 and P = 0.005, respectively). On univariate analysis, etiology of alcohol-related liver disease (ALD), repeat LT, Budd-Chiari syndrome, and refractory ascites were associated with prolonged ICU stay. Using multivariate analysis, MELD > 24, refractory ascites, ALD and Budd-Chiari syndrome were associated with prolonged ICU stay. There was no association between using grafts with higher DRI and longer ICU stay, need for RRT, increased cost, or hospital survival on univariate analyses (P = not significant). Use of MELD as a method of organ allocation results in significant increase in ICU cost after LT. Using TISS as surrogate marker for ICU costs reveals that the cost implications are related to the need for RRT and prolonged ICU stay.

To determine what physiological and biochemical factors predict development of bacteraemia and mortality in patients with acute liver failure (ALF).Retrospective analysis of 206 ALF patients admitted to a specialist liver intensive therapy unit (LITU) from January 2003 to July 2005 (data collected prospectively).A total of 206 patients were defined with ALF: 72 (35%) suffered bacteraemia (BAClf) and 134 (65%) did not (NBAClf). Gram positive organisms were observed in 44% of isolates, gram negatives in 52% and fungaemia in 4%. Median time to first bacteraemia was 10 (7-16) days. On admission, BAClf patients had higher SIRS scores and degrees of hepatic encephalopathy (HE). During their LITU course, BAClf patients had significantly increased requirements for renal replacement therapy (RRT), mechanical ventilation, and longer median LITU stay. Multivariate analysis (logistical regression) demonstrated significant predictors of bacteraemia on admission were HE grade >2 (Odds Ratio 1.6) and SIRS score >1 (OR 2.7). In all patients, independent predictors of mortality (logistical) were age (OR 1.41), maximum HE grade pre-intubation (1.76), Lactate (1.14) and Acute Physiology and Chronic Health Evaluation II score (APACHEII) (1.09), but not bacteraemia. Transplantation was protective (OR 0.20).In this study, severity of hepatic encephalopathy and SIRS score >1 were predictive of bacteraemia. APACHEII was independently predictive of mortality in all ALF patients but not bacteraemia.

Severe liver disease in pregnancy is generally considered to have a favorable prognosis. The limited data available have not yielded disease-specific prognostic criteria or guidance on who should undergo liver transplantation (LT). We retrospectively evaluated 54 admissions with pregnancy-related liver disease to (1) evaluate if any admission parameters were associated with death and/or transplantation and (2) identify maternal complications. Eighteen had acute fatty liver of pregnancy and 32 had hypertension/eclampsia related disease. Seven patients (13%) died and four (7%) underwent LT. Survival rates were 43/48 if not listed for LT and 4/6 if listed. Of the four transplanted, three survived. Patients who died and/or underwent LT were more likely to have encephalopathy (p = 0.04) and hyperlactaemia (p = 0.03). Serum lactate was the best discriminant (ROC AUC 0.84). An admission lactate greater than 2.8mg/dL had 73% sensitivity and 75% specificity for predicting death or LT. The addition of encephalopathy to this parameter increased sensitivity and specificity to 90% and 86%, respectively. The King's College criteria were not effective in predicting outcome. This study confirms the overall favorable prognosis in pregnancy-related liver failure but indicates that elevated lactate levels in the presence of encephalopathy best identify patients at greatest risk of death or LT.

The care of patients with acute liver failure (ALF) presents unique clinical challenges to the practicing physician. It combines the management of rapidly progressive, severe multiple organ failure, unpredictable and often devastating complications, and a need for urgent decision-making in the application of emergency liver transplantation. However, outcomes for patients with this condition have shown progressive improvement over the last four decades. In this article, practical clinical approaches to the care of critically ill patients with ALF are discussed, taking an organ systems-based perspective and discussing the underlying pathophysiological processes and major areas of uncertainty as to what constitutes best practice.

Chronic liver disease (CLD) is associated with muscle wasting, reduced exercise tolerance and aerobic capacity (AC). Measures of AC determined with cardiopulmonary exercise testing (CPET) may predict survival after liver transplantation (LT), but the relationship with nontransplant outcomes is uncertain. In patients assessed for LT, we examined the relationship of CPET AC parameters with the severity of liver disease, nutritional state, and survival with and without LT. Patients assessed for elective first LT who underwent CPET and an anthropometric assessment at a single center were studied. CPET-derived measures of AC that were evaluated included the peak oxygen consumption (VO2 peak) and the anaerobic threshold (AT). Three hundred ninety-nine patients underwent CPET, and 223 underwent LT; 45% of the patients had a VO2 peak < 50% of the predicted value, and 31% had an AT < 9 mL/kg/minute. The VO2 peak and AT values correlated with the Model for End-Stage Liver Disease score, but they more closely correlated with serum sodium and albumin levels. The handgrip strength correlated strongly with the VO2 peak. Patients with impaired AC had prolonged hospitalization after LT, and nonsurvivors had lower AT values than survivors 1 year after transplantation (P < 0.05); this was significant in a multivariate analysis. One hundred seventy-six patients did not undergo LT; the 1-year mortality rate was 34.6%. The AT (P < 0.05) and VO2 peak values (P < 0.001) were lower for nonsurvivors. In a multivariate analysis, AT was independently associated with nonsurvival. In conclusion, AC was markedly impaired in many patients with CLD. In patients who did not undergo transplantation, impaired AT was predictive of mortality, and in patients undergoing LT, it was related to postoperative hospitalization and survival. AC should be evaluated as a modifiable factor for improving patient survival whether or not LT is anticipated.

To determine what physiological and biochemical factors predict development of bacteremia in nontransplanted patients with acute on chronic liver failure and, on diagnosis of bacteremia, what is the natural history of bacteremic patients versus control subjects (acute on chronic liver failure).None.Retrospective analysis of data collected prospectively and entered into a dedicated physiology database.Specialist liver intensive therapy unit.Critically ill non-transplanted patients with acute on chronic liver failure admitted between January 2003 and July 2005.One hundred eighty-four patients were defined with acute on chronic liver failure; 67 (36%) had bacteremia. One hundred seventeen (64%) patients did not (acute on chronic liver failure). Fifty-eight percent of isolates were Gram-negative organisms, 36% were Gram-positives, and 6% fungemia. Median time to first bacteremia was 8 days (range, 3-12 days). On admission (univariate), bacteremic patients had significantly higher Modified End Stage Liver Disease scores (27 vs. 24, p = .037), Acute Physiology and Chronic Health Evaluation II scores (23 vs. 21, p = .049), and greater degrees of encephalopathy (Glasgow Coma Scale score 10 vs. 12, p = .001). During their liver intensive therapy unit course, bacteremic patients had significantly greater requirements for renal replacement therapy (64% vs. 49%, p = .043), mechanical ventilation (88% vs. 68%, p = .002), and a longer median liver intensive therapy unit stay (16 vs. 5 days, p < .001). Survival to hospital discharge was worse in the bacteremic group (25% vs. 56%, p < .001). Multivariate analysis (logistic regression) was performed separately modeling with Acute Physiology and Chronic Health Evaluation II and Modified End Stage Liver Disease. In the first model, Acute Physiology and Chronic Health Evaluation II (odds ratio 1.24) and bacteremia (2.24) were independent predictors of mortality. In the later model, Modified End Stage Liver Disease (odds ratio, 1.06), requirement for renal replacement therapy (3.08), Glasgow Coma Scale (0.72), and bacteremia (2.30) were significant. Both models performed similarly (Modified End Stage Liver Disease area under the receiver operating characteristic curve, 0.864; Acute Physiology and Chronic Health Evaluation II, 0.862).In nontransplanted patients with acute on chronic liver failure, bacteremia was associated with increased severity of illness on admission, greater requirements for organ support, and independently adversely impacted on survival. Higher Acute Physiology and Chronic Health Evaluation II and Modified End Stage Liver Disease scores were also independently predictive of mortality.

Systemic inflammation and susceptibility to developing sepsis is common in acute liver failure (ALF) resulting in tissue damage and organ failure. This study characterized the function of circulating neutrophils in 25 patients with ALF and subacute liver failure (SALF). ALF (n = 15) / SALF (n = 10) patients were prospectively studied and compared with 11 healthy (HC) and 6 septic controls (SC). Neutrophils were isolated on admission to intensive care and every 3-4 days until death / liver transplantation / recovery. Neutrophil phenotype was determined using fluorochrome-labeled antibodies to CD16 and CD11b and assessed by flow cytometry. Neutrophil phagocytic activity (NPA) was determined using fluorescein isothiocyanate-labeled opsonized Escherichia coli and oxidative burst (OB) was determined by the percentage of neutrophils producing reactive oxygen species (ROS) at rest and after stimulation with opsonized E. coli. Physiological variables, biochemistry, arterial ammonia, microbiology, and outcomes were collected. Plasma pro- and antiinflammatory cytokine profiles were performed by enzyme-linked immunosorbent assay. Neutrophil expression of CD16 which recognizes the FcγRIII region of immunoglobulin G was significantly reduced in the ALF cohort (P < 0.001) on day 1 compared to HC. NPA was significantly impaired in the SALF cohort compared to HC (P < 0.01). Impaired NPA in the ALF and SALF cohorts on admission predicted nonsurvival without liver transplantation (P = 0.01). Spontaneous neutrophil production of ROS was not significantly increased in any of the cohorts. E. coli-stimulated OB was preserved in ALF/SALF cohorts but was significantly impaired in the SC group (P < 0.05). Conclusion: Circulating neutrophils in ALF/SALF have impaired bacteriocidal function similar to that seen in severe sepsis. Neutrophil function indices are important biomarkers in ALF and may be implicated in the development of organ dysfunction and the increased susceptibility to developing sepsis. (HEPATOLOGY 2013)

Non-alcoholic steatohepatitis (NASH) is an increasing cause of liver disease necessitating liver transplantation.In patients with advanced NASH, there are often coexistent clinical issues that impact on the outcome of liver transplantation.There are no guidelines for the assessment and management of patients with NASH undergoing liver transplantation.A group was therefore invited by the Council of the British Transplant Society (BTS) to prepare guidelines for the management of NASH before and after liver transplantation.

Summary Background Patients with cirrhosis are susceptible to sepsis, pre‐disposing to the development of encephalopathy, bleeding and organ dysfunction with associated high mortality. Aim To characterise circulating neutrophil function in a cirrhotic cohort as a determinant of 90‐day and 1‐year mortality. Methods Sixty‐two patients with cirrhosis [49 stable (Child–Pugh A/B/C = 24%/39%/37%); 13 acute‐on‐chronic liver failure] were prospectively studied and compared with 11 healthy controls. Neutrophil function was evaluated at baseline and repeated at critical points during the course of the patient's illness until death/transplantation. Neutrophil phenotype was determined using fluorochrome‐labelled antibodies to CD 16/ CD 11b and assessed by flow cytometry. Neutrophil phagocytic activity ( NPA ) and capacity ( NPC ) were determined using FITC ‐labelled opsonised Escherichia coli . Oxidative burst ( OB ) was quantified by the percentage of neutrophils producing reactive oxygen species ( ROS ) and mean fluorescence intensity at rest, and after stimulation with E. coli . Physiological variables, biochemistry, microbiology and outcomes were collected. Plasma pro‐ and anti‐inflammatory cytokine profiles were performed by ELISA . Results NPA / NPC was impaired in cirrhosis with the most significant dysfunction being observed in those with advanced disease and in those treated with propranolol. NPC predicted survival in stable cirrhosis [ AUROC 0.83 (95% CI 0.68–0.97); P = 0.021] and differentiated survivors from nonsurvivors (90‐day P = 0.01; 1 year P &lt; 0.001). Resting OB ≥12% predicted 90‐day mortality with 80% sensitivity and 71% specificity [ AUROC 0.81 (95% CI 0.64–0.97); P = 0.026 and differentiated survivors from nonsurvivors; P = 0.015]. Conclusion Circulating neutrophils in patients with cirrhosis are dysfunctional and predict the development of infection, organ dysfunction and survival at 90 days and 1 year.

Background: Extracorporeal membrane oxygenation (ECMO) is a complex treatment. Despite this, there are a lack of training programs designed to develop relevant clinical and nonclinical skills required for ECMO specialists. The aim of the current study was to describe the design, implementation and evaluation of a 1-day simulation course for delivering training in ECMO. Methods: A 1-day simulation course was developed with educational and intensive care experts. First, the delegates received a lecture on the principles of simulation training and the importance of human factors. This was, followed by a practical demonstration and discussion of the ECMO circuit, console components, circuit interactions effects and potential complications. There were then five ECMO simulation scenarios with debriefing that covered technical and nontechnical issues. The course culminated in a knowledge-based assessment. Course outcomes were assessed using purpose-designed questionnaires. Results: We held 3 courses with a total of 14 delegates (9 intensive care nurses, 3 adult intensive care consultants and 2 ECMO technicians). Following the course, 8 (57%) gained familiarity in troubleshooting an ECMO circuit, 6 (43%) increased their familiarity with the ECMO pump and circuit, 8 (57%) perceived an improvement in their communication skills and 7 (50%) perceived an improvement in their leadership skills. At the end of the course, 13 (93%) delegates agreed that they felt more confident in dealing with ECMO. Conclusions: Simulation-training courses may increase knowledge and confidence in dealing with ECMO emergencies. Further studies are indicated to determine whether simulation training improves clinical outcomes and translates to reduced complication rates in patients receiving ECMO.

Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation, monocyte dysfunction, and susceptibility to infection. Lysophosphatidylcholines (LPCs) are immune-active lipids whose metabolic regulation and effect on monocyte function in ACLF is open for study.Three hundred forty-two subjects were recruited and characterized for blood lipid, cytokines, phospholipase (PLA), and autotaxin (ATX) concentration. Peripheral blood mononuclear cells and CD14+ monocytes were cultured with LPC, or its autotaxin (ATX)-derived product, lysophosphatidic acid (LPA), with or without lipopolysaccharide stimulation and assessed for surface marker phenotype, cytokines production, ATX and LPA-receptor expression, and phagocytosis. Hepatic ATX expression was determined by immunohistochemistry. Healthy volunteers and patients with sepsis or acute liver failure served as controls. ACLF serum was depleted in LPCs with up-regulated LPA levels. Patients who died had lower LPC levels than survivors (area under the receiver operating characteristic curve, 0.94; P < 0.001). Patients with high-grade ACLF had the lowest LPC concentrations and these rose over the first 3 days of admission. ATX concentrations were higher in patients with AD and ACLF and correlated with Model for End-Stage Liver Disease, Consortium on Chronic Liver Failure-Sequential Organ Failure Assessment, and LPC/LPA concentrations. Reduction in LPC correlated with higher monocyte Mer-tyrosine-kinase (MerTK) and CD163 expression. Plasma ATX concentrations rose dynamically during ACLF evolution, correlating with IL-6 and TNF-α, and were associated with increased hepatocyte ATX expression. ACLF patients had lower human leukocyte antigen-DR isotype and higher CD163/MerTK monocyte expression than controls; both CD163/MerTK expression levels were reduced in ACLF ex vivo following LPA, but not LPC, treatment. LPA induced up-regulation of proinflammatory cytokines by CD14+ cells without increasing phagocytic capacity.ATX up-regulation in ACLF promotes LPA production from LPC. LPA suppresses MerTK/CD163 expression and increases monocyte proinflammatory cytokine production. This metabolic pathway could be investigated to therapeutically reprogram monocytes in ACLF.

In septic shock, supraphysiological doses of corticosteroids reduce norepinephrine requirements. We reviewed our experience of this treatment in hypotensive liver failure.We retrospectively analysed 20 patients with liver failure who were treated with supraphysiological doses of hydrocortisone because of norepinephrine dependence. We compared their norepinephrine requirements, outcome, microbiology and incidence of gastrointestinal bleeding to an historical control group treated with norepinephrine but not corticosteroids.After 48 h of steroid treatment, the median norepinephrine dose was reduced (0.14 microg/kg/min to 0.08 microg/kg/min; P < 0.05) while the blood pressure over the same period of time did not change significantly (67.3 mm Hg to 70 mm Hg). Duration of ITU stay was longer in the steroid treated group (13.5 days vs 3 days; P < 0.05) but survival was similar in both groups. There were 23 episodes of positive bacterial cultures after norepinephrine was started in the steroid treated group, compared with 18 episodes in the control group. More of the positive cultures were due to resistant organisms in the steroid treated group (65% vs 17% in the control group; P < 0.002). There was no significant bleeding due to gastrointestinal inflammation in either group.Supraphysiological doses of corticosteroids reduce norepinephrine requirements in hypotensive liver failure. They do not improve survival but may extend time to find a suitable donor in those awaiting urgent liver transplantation.

Invasive candidiasis and candidemia are frequently encountered in the nosocomial setting particularly in the intensive care unit (ICU).To review the current management of invasive candidiasis and candidemia in non-neutropenic adult ICU patients based on a review of the literature and an European expert panel discussion.Empiric and directed treatment for invasive candidiasis are predicated on the hemodynamic status of the patient. Unstable patients may benefit from broad-spectrum antifungal agents, which can be narrowed once the patient has stabilized and the identity of the infecting species is established. In stable patients, a more classical approach using fluconazole may be satisfactory provided that the patient is not colonized with fluconazole resistant strains or there has been recent past exposure to an azole (<30 days). In contrast, pre-emptive therapy is based on the presence of surrogate markers.

Background & Aims The incidence of cirrhosis and subsequent development of organ dysfunction (OD) requiring intensive care unit (ICU) support is rising. Historically, critically ill cirrhotics are perceived as having poor prognosis and substantial cost of care. Methods The aim was to prospectively analyse resource utilisation and cost of a large cohort of patients (n = 660) admitted to a Liver ICU from 2000 to 2007 with cirrhosis and OD. Child Pugh, MELD, SOFA, APACHE II, and organ support requirements were collected. The Therapeutic Intervention Scoring System (TISS) score, a validated tool for estimating cost in ICU, was calculated daily. Logistic regression was used to determine independent predictors of increased cost. Results Alcohol was the most common etiology (47%) and variceal bleeding (VB) the most common reason for admission (35%). Invasive ventilatory support was required in 74% of cases, vasopressors in 49%, and 50% required renal replacement therapy. Forty-nine per cent of non-transplanted patients survived to ICU discharge. Median TISS score and ICU cost per patient were 261 and €14,139, respectively. VB patients had the highest survival rates (53% vs. 24%; p<0.001) and lower associated cost. A combination of VB (OR 0.48), need for ventilation (OR 2.81), low PO2/FiO2 on admission (OR 0.97), and lactate (OR 0.93) improved cost prediction on multivariate analysis (AUROC 0.7; p<0.001) but organ failure scores per se were poor predictors of cost. Conclusions Patients with cirrhosis and OD result in considerable resource expenditure but have acceptable hospital survival. Further health economic assessment and outcome prediction tools are required to appropriately target resource utilisation. The incidence of cirrhosis and subsequent development of organ dysfunction (OD) requiring intensive care unit (ICU) support is rising. Historically, critically ill cirrhotics are perceived as having poor prognosis and substantial cost of care. The aim was to prospectively analyse resource utilisation and cost of a large cohort of patients (n = 660) admitted to a Liver ICU from 2000 to 2007 with cirrhosis and OD. Child Pugh, MELD, SOFA, APACHE II, and organ support requirements were collected. The Therapeutic Intervention Scoring System (TISS) score, a validated tool for estimating cost in ICU, was calculated daily. Logistic regression was used to determine independent predictors of increased cost. Alcohol was the most common etiology (47%) and variceal bleeding (VB) the most common reason for admission (35%). Invasive ventilatory support was required in 74% of cases, vasopressors in 49%, and 50% required renal replacement therapy. Forty-nine per cent of non-transplanted patients survived to ICU discharge. Median TISS score and ICU cost per patient were 261 and €14,139, respectively. VB patients had the highest survival rates (53% vs. 24%; p<0.001) and lower associated cost. A combination of VB (OR 0.48), need for ventilation (OR 2.81), low PO2/FiO2 on admission (OR 0.97), and lactate (OR 0.93) improved cost prediction on multivariate analysis (AUROC 0.7; p<0.001) but organ failure scores per se were poor predictors of cost. Patients with cirrhosis and OD result in considerable resource expenditure but have acceptable hospital survival. Further health economic assessment and outcome prediction tools are required to appropriately target resource utilisation.

Paracetamol overdose can cause acute kidney injury (AKI) independent of its hepatotoxic effects. We aimed to determine the prevalence of AKI (AKI Network definition) in those with paracetamol-induced hepatotoxicity, identify factors associated with development, assess impact on the outcomes of patient survival and length of stay and determine the proportion of patients recovering renal function (estimated glomerular filtration rate > 60 mL/min) by the time of hospital discharge or transfer out.Between 2000 and 2007, patients admitted to a tertiary referral liver intensive therapy unit (LITU) with paracetamol-induced hepatotoxicity were identified from a prospectively maintained database and evaluated.Those receiving a liver transplant were excluded (n = 54), leaving 302 patients. Renal function remained normal in 21%, the remainder developing AKI (Stages 1-8%, 2-6% and 3-65%). Vasopressor requirement, mechanical ventilation, higher admission phosphate and lower sodium levels along with a higher Day 3 lactate and lower haematocrit were associated with AKI. In survivors with AKI, 51% had recovery of renal function, while 7% remained dialysis dependant although none required it chronically. Overall, there was 25% mortality, all having Stage 3 AKI but AKI was only a univariate not multivariate predictor of reduced patient survival. AKI independently predicted longer length of stay.AKI is very common in critically ill patients with paracetamol-induced hepatotoxicity requiring LITU admission. Although outcomes are poorer with AKI than with normal renal function, they are better than those found in other intensive therapy unit populations. Gradual recovery of renal function is seen in all patients.

Abstract Background &amp; Aims Acute‐on‐chronic liver failure ( ACLF ) has a rapidly progressive disease course associated with significant mortality. The prevalence of clinically significant cerebral oedema in ACLF is unknown. Methods We aimed to describe the prevalence of cerebral oedema in a cohort of ACLF adult (&gt;18 years). We identified patients admitted to a single, specialist intensive care unit between January 2005 and January 2011 with high‐grade hepatic encephalopathy (≥3) and a clinical picture of either ACLF or chronic liver disease ( CLD ). Patients who had undergone cranial CT imaging were identified and their imaging reviewed. The ACLF and CLD groups were compared. Results One thousand and eight patients with CLD were admitted. One hundred and seventy‐three patients (110 male) underwent neuroimaging. Eighty‐one (48 male) fulfilled criteria for ACLF . Variceal bleeding (30%) and sepsis (31%) were the most frequent precipitants of ACLF . Of those with neuroimaging from the total cohort, 30% of CT scans were normal, 30% demonstrated increased cerebral atrophy for age, 17% small vessel disease and 16% intracranial haemorrhage ( ICH ). Cerebral oedema was seen in three patients with ACLF only. An increased prevalence of ICH was observed in the ACLF group (23% vs. 9%, P = 0.008). Conclusion The prevalence of clinically relevant cerebral oedema was low (4%) but fatal. Death was attributable to tonsillar herniation. An increased prevalence of ICH was seen in ACLF patients and remains an important differential.

Objective: Hypoxemia is a feared complication of acute liver failure, and high oxygen requirements will frequently lead to removal of patients from the transplant list. As data regarding the prevalence and outcome of acute respiratory distress syndrome in acute liver failure are scant and hypoxemia being a commonly encountered systemic complication, we analyzed radiological, gas exchange, and ventilator data in consecutive patients admitted with acute liver failure. Patients: Acute liver failure patients receiving mechanical ventilation admitted between January 2007 and February 2011 were included. Interventions: Patients were categorized according to the Berlin definition as: no acute respiratory distress syndrome, acute respiratory distress syndrome (PaO2/FIO2 < 300 mm Hg), and subdivisions of mild, moderate, and severe acute respiratory distress syndrome (200–300 mm Hg, 100–200 mm Hg, and < 100 mm Hg, respectively). Chest radiographs were independently assessed by two observers for the presence or absence of acute respiratory distress syndrome. Absence of left atrial pressure elevation was based on combined hemodynamic and echocardiographic assessment. Measurements and Main Results: Two hundred acute liver failure patients were admitted during the study period of whom 148, median age 39 years (16–74 yr), were included. Thirty-one (21%) had acute respiratory distress syndrome (17 mild acute respiratory distress syndrome [12%], 9 moderate acute respiratory distress syndrome [12%], and 5 severe acute respiratory distress syndrome) within the first 72 hours following admission. Acute respiratory distress syndrome patients required higher positive end-expiratory pressure (7 vs 6 vs 10 vs 15 cm H2O for no, mild, moderate, or severe acute respiratory distress syndrome, p = 0.014), had reduced respiratory system compliance (34 vs 29 vs 30 vs 23 L/cm H2O, p = 0.028), and an increased number of ventilator days (no acute respiratory distress syndrome, 10 d; mild acute respiratory distress syndrome acute lung injury, 12 d; moderate acute respiratory distress syndrome, 23 d; severe acute respiratory distress syndrome, 22 d; p = 0.097). Duration of liver intensive therapy unit stay (p = 0.175), survival (p = 0.877), inotrope requirements (p = 0.495), need for extracorporeal renal support (p = 0.565), and severity of organ failure scores were not affected. Extravascular lung water index had a moderate sensitivity of 65% and specificity of 77% for the prediction of acute respiratory distress syndrome. Conclusion: The prevalence of lung injury is relatively low in acute liver failure, where 21% fulfilled acute respiratory distress syndrome criteria. Overall presence of acute respiratory distress syndrome appeared to have a limited impact on outcome.

Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immune paresis) and are susceptible to sepsis. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), which interacts with the membrane receptor B7 (also called CD80 and CD86), is a negative regulator of T-cell activation. We collected T cells from patients with ALF and investigated whether inhibitory signals down-regulate adaptive immune responses in patients with ALF.We collected peripheral blood mononuclear cells from patients with ALF and controls from September 2013 through September 2015 (45 patients with ALF, 20 patients with acute-on-chronic liver failure, 15 patients with cirrhosis with no evidence of acute decompensation, 20 patients with septic shock but no cirrhosis or liver disease, and 20 healthy individuals). Circulating CD4+ T cells were isolated and analyzed by flow cytometry. CD4+ T cells were incubated with antigen, or agonist to CD3 and dendritic cells, with or without antibody against CTLA4; T-cell proliferation and protein expression were quantified. We measured levels of soluble B7 molecules in supernatants of isolated primary hepatocytes, hepatic sinusoidal endothelial cells, and biliary epithelial cells from healthy or diseased liver tissues. We also measured levels of soluble B7 serum samples from patients and controls, and mice with acetaminophen-induced liver injury using enzyme-linked immunosorbent assays.Peripheral blood samples from patients with ALF had a higher proportion of CD4+ CTLA4+ T cells than controls; patients with infections had the highest proportions. CD4+ T cells from patients with ALF had a reduced proliferative response to antigen or CD3 stimulation compared to cells from controls; incubation of CD4+ T cells from patients with ALF with an antibody against CTLA4 increased their proliferative response to antigen and to CD3 stimulation, to the same levels as cells from controls. CD4+ T cells from controls up-regulated expression of CTLA4 after 24-48 hours culture with sera from patients with ALF; these sera were found to have increased concentrations of soluble B7 compared to sera from controls. Necrotic human primary hepatocytes exposed to acetaminophen, but not hepatic sinusoidal endothelial cells and biliary epithelial cells from patients with ALF, secreted high levels of soluble B7. Sera from mice with acetaminophen-induced liver injury contained high levels of soluble B7 compared to sera from mice without liver injury. Plasma exchange reduced circulating levels of soluble B7 in patients with ALF and expression of CTLA4 on T cells.Peripheral CD4+ T cells from patients with ALF have increased expression of CTLA4 compared to individuals without ALF; these cells have a reduced response to antigen and CD3 stimulation. We found sera of patients with ALF and from mice with liver injury to have high concentrations of soluble B7, which up-regulates CTLA4 expression by T cells and reduces their response to antigen. Plasma exchange reduces levels of B7 in sera from patients with ALF and might be used to restore antimicrobial responses to patients.

Abstract Background With recent advances in technology, patients with acute respiratory distress syndrome (ARDS) and severe acute exacerbations of chronic obstructive pulmonary disease (ae-COPD) could benefit from extracorporeal CO 2 removal (ECCO 2 R). However, current evidence in these indications is limited. A European ECCO 2 R Expert Round Table Meeting was convened to further explore the potential for this treatment approach. Methods A modified Delphi-based method was used to collate European experts’ views to better understand how ECCO 2 R therapy is applied, identify how patients are selected and how treatment decisions are made, as well as to identify any points of consensus. Results Fourteen participants were selected based on known clinical expertise in critical care and in providing respiratory support with ECCO 2 R or extracorporeal membrane oxygenation. ARDS was considered the primary indication for ECCO 2 R therapy ( n = 7), while 3 participants considered ae-COPD the primary indication. The group agreed that the primary treatment goal of ECCO 2 R therapy in patients with ARDS was to apply ultra-protective lung ventilation via managing CO 2 levels. Driving pressure (≥ 14 cmH 2 O) followed by plateau pressure ( P plat ; ≥ 25 cmH 2 O) was considered the most important criteria for ECCO 2 R initiation. Key treatment targets for patients with ARDS undergoing ECCO 2 R included pH (&gt; 7.30), respiratory rate (&lt; 25 or &lt; 20 breaths/min), driving pressure (&lt; 14 cmH 2 O) and P plat (&lt; 25 cmH 2 O). In ae-COPD, there was consensus that, in patients at risk of non-invasive ventilation (NIV) failure, no decrease in PaCO 2 and no decrease in respiratory rate were key criteria for initiating ECCO 2 R therapy. Key treatment targets in ae-COPD were patient comfort, pH (&gt; 7.30–7.35), respiratory rate (&lt; 20–25 breaths/min), decrease of PaCO 2 (by 10–20%), weaning from NIV, decrease in HCO 3 − and maintaining haemodynamic stability. Consensus was reached on weaning protocols for both indications. Anticoagulation with intravenous unfractionated heparin was the strategy preferred by the group. Conclusions Insights from this group of experienced physicians suggest that ECCO 2 R therapy may be an effective supportive treatment for adults with ARDS or ae-COPD. Further evidence from randomised clinical trials and/or high-quality prospective studies is needed to better guide decision making.

To assess the safety of percutaneous dilational tracheostomy (PDT) performed by experienced operators in critically ill patients with liver disease and coagulopathy.Prospective cohort study in a ten bed specialist liver intensive care unit of a tertiary university teaching hospital. Sixty consecutive patients in need of tracheostomy insertion. Patients were categorized as having refractory coagulopathy if their platelet count was < or = 50 x 10(9) cells/L or the INR > 1.5 on the day of and the subsequent 72 hours following PDT despite clotting support.Twenty five patients fulfilled the definition criteria of refractory coagulopathy. There was no significant difference in the number of adverse incidents between groups. Only 1 patient in the coagulopathy group had a severe bleeding complication, however this did not require open surgical intervention. The rate of clinically relevant early complications in all patients was not higher than expected (n = 7, 12%). Resource utilisation was higher for patients with coagulopathy, who received significantly more platelet transfusions over the 3 day period (80 vs 49 units, p = 0.009) and demonstrated a trend towards increased fresh frozen plasma requirements (p = 0.059). The number of patients requiring platelet transfusion was higher in the coagulopathy group (21/25 versus 20/35 p = 0.029). Hospital survival did not differ between groups.PDT is safe and not contraindicated in patients with severe liver disease and refractory coagulopathy.

Purpose of review The mortality of acute liver failure remains unacceptably high and liver transplantation is the only effective treatment available to date. This review focuses on new research developments in the field and aims to provide a pragmatic organ-based treatment approach for liver failure patients requiring intensive care support. Recent findings The pathophysiological basis for cerebral edema formation in acute liver failure continued to be the focus of various investigations. In-vivo observations confirmed the link between ammonia, cerebral glutamine content and intracranial hypertension. The role of arterial ammonia as an important prognostic indicator formed the basis of prospective, observational studies. Reduced monocytic HLA-DR expression linked acute liver failure with poor prognosis, and the cerebral effects and side effects of vasoactive therapy with terlipressin were investigated with two studies showing contradictory results. Summary Despite increased knowledge of the pathophysiological events leading to organ dysfunction in acute liver failure, supportive treatment options remain limited in their efficacy and largely noncurative.

High density lipoprotein (HDL) plays an important role in the transport of cholesterol to the adrenal gland for steroidogenesis and may have actions that modulate response to infection and critical illness. The clinical relevance of HDL level in patients with liver failure remains poorly characterised.In 164 critically-ill patients with acute (ALF) and acute on chronic liver failure (AOCLF) we evaluated the relationship between HDL levels measured on admission to intensive care unit (ICU) and survival, predisposition to sepsis and adrenocortical function assessed through the cortisol response to short synacthen testing (SST).In acute liver failure and acute on chronic liver failure, high density lipoprotein levels were significantly lower in non-survivors (P < 0.01). Levels correlated closely with biochemical markers of liver function and the duration of liver failure. However, predictive accuracy was not superior to conventional markers and on multi-variate analysis did not show independent association with survival. Low HDL concentration was not associated with an increased incidence of sepsis either precipitating or complicating ICU admission. Evidence of adrenocortical insufficiency was present in more than half of patients undergoing SST and HDL level but not other lipid parameters correlated closely with cortisol increment after SST (r = 0.364, P < 0.0001).High density lipoprotein levels are low in patients with liver failure and reflect its severity. Levels are lower in non-survivors but do not offer an advantage as early indicators of prognosis over conventional markers. No evidence of a major predisposing role for infection was found, but findings suggest a close link to adrenal function.

A prospective, multicentre, phase IIIb study with an exploratory, open-label design was conducted to evaluate efficacy and safety of anidulafungin for the treatment of candidaemia/invasive candidiasis (C/IC) in specific ICU patient populations. Adult ICU patients with confirmed C/IC meeting ≥ 1 of the following criteria were enrolled: post-abdominal surgery, solid tumour, renal/hepatic insufficiency, solid organ transplant, neutropaenia, and age ≥ 65 years. Patients received anidulafungin (200 mg on day 1, 100 mg/day thereafter) for 10-42 days, optionally followed by oral voriconazole/fluconazole. The primary efficacy endpoint was global (clinical and microbiological) response at the end of all therapy (EOT). Secondary endpoints included global response at the end of intravenous therapy (EOIVT) and at 2 and 6 weeks post-EOT, survival at day 90, and incidence of adverse events (AEs). The primary efficacy analysis was performed in the modified intent-to-treat (MITT) population, excluding unknown/missing responses. The safety and MITT populations consisted of 216 and 170 patients, respectively. The most common pathogens were Candida albicans (55.9%), C. glabrata (14.7%) and C. parapsilosis (10.0%). Global success was 69.5% (107/154; 95% CI, 61.6-76.6) at EOT, 70.7% (111/157) at EOIVT, 60.2% (77/128) at 2 weeks post-EOT, and 50.5% (55/109) at 6 weeks post-EOT. When unknown/missing responses were included as failures, the respective success rates were 62.9%, 65.3%, 45.3% and 32.4%. Survival at day 90 was 53.8%. Treatment-related AEs occurred in 33/216 (15.3%) patients, four (1.9%) of whom had serious AEs. Anidulafungin was effective, safe and well tolerated for the treatment of C/IC in selected groups of ICU patients.

According to a recent publication by Nayyar et al.,1 severe hypoxemia after liver transplantation (LT) in patients with hepatopulmonary syndrome (HPS) is not uncommon. According to a review of the literature and the authors' local institutional experience, the prevalence could be as high as 12% with a mortality rate of 45%. Very severe preoperative hypoxemia, defined as a partial pressure of oxygen ≤ 50 mm Hg, and the presence of anatomical shunts were identified as predictors of this complication. Among the possible treatment strategies, the authors reported the use of inhaled vasodilator agents and systemic vasoconstrictors such as methylene blue to improve ventilation perfusion matching. The effectiveness of specific rescue ventilation strategies such as high-frequency oscillatory techniques and ventilation in the prone position remains unproven. We would like to propose another potentially beneficial treatment and bridging strategy: venovenous (V-V) extracorporeal membrane oxygenation (ECMO). Long-term ECMO support in this population after transplantation, solely for treating refractory shunt, has thus far not been reported in adults. Cannulation for ECMO after LT can also pose a significant challenge that depends on the configuration used. We have used ECMO in 6 patients (5 adults and 1 child) before and after LT since December 2012. Three patients required extracorporeal cardiac support, whereas the other 3 patients underwent V-V ECMO for hypoxemic respiratory failure. Ethical approval for the reporting of anonymous data was given by the South East London Research Ethics Committee. A 44-year-old patient with alcoholic cirrhosis and very severe HPS (partial pressure of oxygen on home oxygen = 35-40 mm Hg) underwent LT via the piggyback technique. He remained profoundly hypoxemic with severe intrapulmonary shunting for the first 13 days after transplantation. He underwent extensive investigations, including high-resolution and computed tomography pulmonary angiography, but no alternative cause of hypoxemia was identified apart from trivial pleural effusions and some dependent lung collapse. On a bubble echocardiogram, a severe right-to-left shunt persisted. All efforts to ameliorate the shunt flow—positioning maneuvers (including prone ventilation for up to 20 hours/day), the use of flow-modifying medication, nebulized vasodilator therapy, diuresis, and adjustments in ventilator settings—proved unsuccessful. The patient underwent early percutaneous tracheostomy to facilitate weaning; however, all attempts to wean the patient from sedation resulted in profound desaturation (PaO2/FiO2 - 40–60 mmHg) because of increasing cardiac output and shunt flow and increasing peripheral oxygen consumption. Because of concerns about secondary lung injury, infections, and ischemic (hypoxemic) biliary complications, the decision to use V-V ECMO support was made. A double-lumen bicaval cannula (27-Fr) was placed via the right internal jugular vein under fluoroscopic and echocardiographic guidance, and pump flows of 3-4 L/minute were achieved (Fig. 1). According to our institutional practice, low-level circuit anticoagulation with heparin was performed with an early activated clotting time target of 180 seconds followed by an activated partial thromboplastin time ratio of 1.8 to 2. Sketch of a double-lumen cannula traversing the superior vena cava and the right atrium with the tip positioned in the inferior vena cava. The access lumina are in the superior vena cava and inferior vena cava (blue arrows); the return lumen is in the right atrium with the flow directed toward the tricuspid valve (red arrow). A sudden rise in venous access pressures and a drop in the pump flow some 24 hours after ECMO initiation were attributed to cannula migration/malpositioning into the blind end of the donor's inferior vena cava cuff. This was confirmed via transesophageal echocardiography, abdominal sonography, and eventually fluoroscopy when the cannula was repositioned and advanced into the retrohepatic portion of the recipient's inferior vena cava (Fig. 2B). A possible complication arising from this was hemorrhagic venous infarction and hematoma formation of the left lobe of the graft with an aspartate aminotransferase elevation to 2400 U/L without evidence of graft dysfunction/failure (Fig. 3). On computed tomography imaging on the day before ECMO cannulation, the graft appearance was normal with patent vasculature; urgent abdominal sonography at the time of the venous access pressure rise showed normal right and left hepatic artery Doppler signaling and a patent portal vein. It was not possible to reliably identify the left hepatic vein at that stage. (A) High cannula tip position after cannulation. (B) Fluoroscopy image after the advancement of the cannula into the recipient's retrohepatic inferior vena cava. Left lobe graft infarction. The ECMO cannula is positioned in the retrohepatic inferior vena cava. The patient was later successfully weaned off sedation and tolerated minimal respiratory and oxygenation support. The graft function remained well preserved, and the pulmonary shunt flow decreased according to a semiquantitative echocardiographic and clinical assessment. He was weaned off ECMO after 21 days of support and was discharged into ward care a week later. He was subsequently transferred to his referring hospital for further rehabilitation and was later discharged home without the need for supplemental oxygen and with excellent graft function. Although the use of V-V ECMO has previously been reported for the treatment of severe respiratory failure after LT,2 we are aware of only 1 publication on its use in the context of HPS in an adult3; in that particular instance, the patient was primarily supported for the treatment of acute respiratory distress syndrome in order to facilitate transplantation and was taken off ECMO upon the completion of surgery. Another report described the successful use of ECMO in a pediatric patient with autoimmune liver disease and HPS complicated by refractory hypoxemia after LT.4 This was attributed to an increase in the shunt flow in the context of bacteremia. We believe that V-V ECMO should be considered as an early rescue strategy for this small group of patients with severe HPS and persistent posttransplant intrapulmonary shunting. To the best of our knowledge, this is also the first description of the use of the bicaval Wang-Zwische double-lumen cannula for V-V ECMO after LT. The use of this particular type of cannula is in our view preferable because it allows early mobilization and ventilator weaning due to its single access and return site (commonly via the right internal jugular vein). The latest generation of ECMO circuits with their compact design, biocompatible polymethylpentene membrane oxygenators, and heparin-bonded circuits also reduce the risk of bleeding and circuit-related complications significantly. In our own institutional experience, we have managed patients on ECMO without systemic anticoagulation for up to 3 weeks and with no circuit clotting. In this particular instance, low-level anticoagulation was continued because there was no evidence of active bleeding after repositioning of the cannula or when the hematoma was diagnosed on repeat computed tomography imaging 2 days later. Despite this, ECMO remains a highly invasive procedure and requires dedicated specialist nursing and medical care, which in our view can be provided only through an established ECMO service. The durability and less complex setup of modern ECMO circuits keep disposable costs low, with the major expenditures related to personnel costs. Recent calculations5 have estimated that the cost of V-V ECMO for patients is on average double the expenditures for conventional advanced respiratory support; this is based on data from a dedicated ECMO unit. We believe that it is possible to contain costs significantly through the incorporation of an ECMO program within a multidisciplinary intensive care unit staffed by the existing nursing and medical workforce, as is the case at our institution. Adequate training according to recognized standards also obviates the 24-hour presence of a perfusionist. Theoretical concerns about ECMO in this particular setting are related to the potential reversal of hypoxic pulmonary vasoconstrictive responses through the return of highly oxygenated blood to the right heart and subsequently pulmonary circulation. Whether this could delay the reversal of shunting is currently unknown. The use of bicaval cannulae after LT may also be challenging. According to the type of caval anastomosis used, great care should be taken during cannula placement. We strongly recommend both transesophageal echocardiography and fluoroscopic guidance because potentially fatal malpositioning of bicaval cannulae in the right ventricle or hepatic veins has been reported. This applies not only to the cannula tip position but also to the direction of the return flow, which needs to be aimed toward the tricuspid valve rather than the right atrial free wall to minimize the risk of atrial perforation. Despite cannulation of the patient under the guidance of both imaging modalities, the cannula in this case was initially probably not inserted far enough and appeared to be placed with its tip at the level of the piggyback anastomosis (Fig. 2A); it may have subsequently slipped into the donor's inferior vena cava cuff. We think that this ultimately resulted in the venous infarction of the left liver lobe and hematoma formation, although no definitive sonographic diagnosis of an outflow obstruction was made at the time. In conclusion, we advocate the use of ECMO for severe refractory hypoxemia after LT for HPS. It may facilitate early ventilator weaning and, therefore, prevent the need for the prolonged use of sedation and reduce complications associated with these interventions. Early mobilization is feasible, especially with double-lumen cannulae, although great care needs to be taken during the positioning of these devices in the context of LT. Ultimate proof of the effectiveness of this intervention warrants future multicenter trials. Georg Auzinger, M.D., AFICM1,2 Christopher Willars, MBBS, FRCA, FFICM1,2 Robert Loveridge, MBBS, FRCA, FFICM2 Thomas Best, MBBS, FRCA, FFICM2 Andre Vercueil, MBBS, FRCA, FFICM2 Andreas Prachalias, MBBS, M.D., FRCS1 Michael A. Heneghan, M.D., FRCPI1 Julia Wendon, Prof, FRCP, FFICM1,2 1Institute of Liver Studies and 2Critical Care/ECMO Service King's College Hospital London, United Kingdom

Early, accurate prediction of survival is central to management of patients with paracetamol-induced acute liver failure to identify those needing emergency liver transplantation. Current prognostic tools are confounded by recent improvements in outcome independent of emergency liver transplantation, and constrained by static binary outcome prediction. We aimed to develop a simple prognostic tool to reflect current outcomes and generate a dynamic updated estimation of risk of death.Patients with paracetamol-induced acute liver failure managed at intensive care units in the UK (London, Birmingham, and Edinburgh) and Denmark (Copenhagen) were studied. We developed prognostic models, excluding patients who underwent transplantation, using Cox proportional hazards in a derivation dataset, and tested in initial and recent external validation datasets. Mortality was estimated in patients who had emergency liver transplantation. Model discrimination was assessed using area under receiver operating characteristic curve (AUROC) and calibration by root mean square error (RMSE). Admission (day 1) variables of age, Glasgow coma scale, arterial pH and lactate, creatinine, international normalised ratio (INR), and cardiovascular failure were used to derive an initial predictive model, with a second (day 2) model including additional changes in INR and lactate.We developed and validated new high-performance statistical models to support decision making in patients with paracetamol-induced acute liver failure. Applied to the derivation dataset (n=350), the AUROC for 30-day survival was 0·92 (95% CI 0·88-0·96) using the day 1 model and 0·93 (0·88-0·97) using the day 2 model. In the initial validation dataset (n=150), the AUROC for 30-day survival was 0·89 (0·84-0·95) using the day 1 model and 0·90 (0·85-0·95) using the day 2 model. Assessment of calibration using RMSE in prediction of 30-day survival gave values of 0·1642 for the day 1 model and 0·0626 for the day 2 model. In the external validation dataset (n=412), the AUROC for 30-day survival was 0·91 (0·87-0·94) using the day 1 model and 0·91 (0·88-0·95) using the day 2 model, and assessment of calibration using RMSE gave values of 0·079 for the day 1 model and 0·107 for the day 2 model. Applied to patients who underwent emergency liver transplantation (n=116), median predicted 30-day survival was 51% (95% CI 33-85).The models developed here show very good discrimination and calibration, confirmed in independent datasets, and suggest that many patients undergoing transplantation based on existing criteria might have survived with medical management alone. The role and indications for emergency liver transplantation in paracetamol-induced acute liver failure require re-evaluation.Foundation for Liver Research.

In patients with cirrhosis, progression to acute decompensation (AD) and acute-on-chronic liver failure (ACLF) has been associated with poor prognosis. Differential leucocyte ratios might predict mortality in systemic inflammatory conditions.To evaluate differential leucocyte ratios as prognostic biomarkers in patients with cirrhosis.Patients with AD and ACLF were recruited from four centres in three countries. Peripheral blood differential leucocytes were measured (three centres using flow cytometry) on hospital admission and at 48 hours. Ratios were correlated to model for end-stage liver disease (MELD), chronic liver failure-sequential organ failure (CLIF-SOFA), suspected/culture-positive bacterial infection and survival.Nine hundred twenty-six patients (562 (61%) male, median age 55 (25-94) years) were studied. Overall, 350 (37%) did not survive to hospital discharge. Neutrophil-lymphocyte ratio (NLR) and monocyte-lymphocyte ratio (MLR) were elevated in patients with AD and ACLF who died during their hospital stay. On multivariate analysis NLR retained statistical significance independently of CLIF-SOFA or MELD. NLR >30 was associated with an 80% 90-day mortality in patients with ACLF but not AD. On sensitivity analysis for subgroups (alcohol-related liver disease and suspected sepsis), NLR and MLR retained statistically robust accuracy for the prediction of mortality. Significant predictive accuracy was only observed in centres using flow cytometry.Leucocyte ratios are simple and robust biomarkers of outcome in ACLF, which are comparable to CLIF-SOFA score but dependent on leucocyte quantification method. NLR and MLR may be used as screening tools for mortality prediction in patients with acutely deteriorating cirrhosis.

The rapid global spread of SARS-CoV-2, the causative agent of COVID-19, has dominated healthcare services, with exponential numbers requiring mechanical ventilation in the intensive care unit (ICU). Tracheostomy facilitates respiratory and sedative weaning but risks potential viral transmission. This study reviewed the tracheostomy provision, techniques, and outcomes for a single-centre prospective cohort during the resource-pressured COVID-19 period. Seventy-two of 176 patients underwent tracheostomy at a median 17 days: 44 surgical (open), 28 percutaneous. Their median age was 58 years, the male to female ratio was 2.4:1, 75.1% were of BAME backgrounds, 76% had a BMI≥25kg/m2, and 65% had ≥2 major co-morbidities. Seventy-nine percent of patients were weaned from sedation at a median 2 days, 61% were weaned from mechanical ventilation at a median 10 days, 39% were discharged from the ICU at a median 11.5 days, and 19.4% were discharged home at a median 24 days. All patients survived the procedure. The mortality rate was 9.7% at a median 12 days. No clinician reported COVID-19 symptoms within 14 days of the procedure. The role of tracheostomy in COVID-19 is currently unclear. Delivery of tracheostomy by maxillofacial surgeons relieved the workload pressure from ICU clinicians. The choice of technique was influenced by the patient and resource factors, resulting in a mixed cohort of open and percutaneous tracheostomy in COVID-19 patients. Preliminary data suggest that open tracheostomy is as favourable as percutaneous tracheostomy for COVID-19 patients, and is safe for clinicians.

Abstract Extracorporeal life support (ECLS) is a means to support patients with acute respiratory failure. Initially, recommendations to treat severe cases of pandemic coronavirus disease 2019 (COVID‐19) with ECLS have been restrained. In the meantime, ECLS has been shown to produce similar outcomes in patients with severe COVID‐19 compared to existing data on ARDS mortality. We performed an international email survey to assess how ECLS providers worldwide have previously used ECLS during the treatment of critically ill patients with COVID‐19. A questionnaire with 45 questions (covering, e.g., indication, technical aspects, benefit, and reasons for treatment discontinuation), mostly multiple choice, was distributed by email to ECLS centers. The survey was approved by the European branch of the Extracorporeal Life Support Organization (ELSO); 276 ECMO professionals from 98 centers in 30 different countries on four continents reported that they employed ECMO for very severe COVID‐19 cases, mostly in veno‐venous configuration (87%). The most common reason to establish ECLS was isolated hypoxemic respiratory failure (50%), followed by a combination of hypoxemia and hypercapnia (39%). Only a small fraction of patients required veno‐arterial cannulation due to heart failure (3%). Time on ECLS varied between less than 2 and more than 4 weeks. The main reason to discontinue ECLS treatment prior to patient’s recovery was lack of clinical improvement (53%), followed by major bleeding, mostly intracranially (13%). Only 4% of respondents reported that triage situations, lack of staff or lack of oxygenators, were responsible for discontinuation of ECLS support. Most ECLS physicians (51%, IQR 30%) agreed that patients with COVID‐19‐induced ARDS (CARDS) benefitted from ECLS. Overall mortality of COVID‐19 patients on ECLS was estimated to be about 55%. ECLS has been utilized successfully during the COVID‐19 pandemic to stabilize CARDS patients in hypoxemic or hypercapnic lung failure. Age and multimorbidity limited the use of ECLS. Triage situations were rarely a concern. ECLS providers stated that patients with severe COVID‐19 benefitted from ECLS.

Objective To show the effectiveness of emergency extracorporeal membrane oxygenation (ECMO) in treating severe, life-threatening flecainide intoxication. Design Case report. Setting Intensive care unit in a quaternary care center. Patient A patient with electromechanical dissociation after severe flecainide acetate overdose. Intervention ECMO. Case Report A 30-yr-old male with a history of depression presented after a severe flecainide overdose with plasma concentrations exceeding 20 times the upper boundary of the therapeutic range. At presentation, the patient was in refractory cardiocirculatory collapse and was successfully resuscitated with ECMO. Twenty-six hours later, extracorporeal support could be discontinued and the patient made a full recovery. Conclusion In patients with severe but potentially reversible cardiac dysfunction attributable to flecainide intoxication, ECMO can maintain cardiac output and vital organ perfusion while allowing time for drug redistribution, metabolism, and clearance.

Acetaminophen-induced hepatotoxicity is the most common cause of acute liver failure (ALF) in the UK. Patients often consume the drug with suicidal intent or with a background of substance dependence.We compared the severity of pretransplant illness, psychiatric co-morbidity, medical and psychosocial outcomes of all patients who had undergone liver transplantation (LT) emergently between 1999-2004 for acetaminophen-induced ALF (n=36) with age- and sex-matched patients undergoing emergent LT for non-acetaminophen-induced ALF (n=35) and elective LT for chronic liver disease (CLD, n=34).Acetaminophen-induced ALF patients undergoing LT had a greater severity of pre-LT illness reflected by higher Acute Physiology and Chronic Health Evaluation II scores and requirement for organ support compared with the other two groups. Twenty (56%) acetaminophen-induced ALF patients had a formal psychiatric diagnosis before LT (non-acetaminophen-induced ALF=0/35, CLD=2/34; P<0.01 for all) and nine (25%) had a previous suicide attempt. During follow-up (median 5 years), there were no significant differences in rejection (acute and chronic), graft failure or survival between the groups (acetaminophen-induced ALF 1 year 87%, 5 years 75%; non-acetaminophen-induced ALF 88%, 78%; CLD 93%, 82%: P>0.6 log rank). Two acetaminophen-induced ALF patients reattempted suicide post-LT (one died 8 years post-LT).Despite a high prevalence of psychiatric disturbance, outcomes for patients transplanted emergently for acetaminophen-induced ALF were comparable to those transplanted for non-acetaminophen-induced ALF and electively for CLD. Multidisciplinary approaches with long-term psychiatric follow-up may contribute to low post-transplant suicide rates seen and low rates of graft loss because of non-compliance.

The timely diagnosis of acute kidney injury (AKI) in liver cirrhosis is challenging.To evaluate whether quantification of glomerular filtration rate (GFR), proteinuria and kidney injury biomarkers can accurately predict the development of AKI.A prospective cohort analysis of patients with cirrhosis was performed. Measures of baseline kidney function included serum creatinine, iohexol clearance and urine protein:creatinine ratio. Blood and urine samples were collected daily. A retrospective analysis of cystatin C GFR and neutrophil gelatinase-associated lipocalin (NGAL) measured 48 h prior to the diagnosis of AKI was undertaken to evaluate their ability to predict the development of AKI.Eighteen of the 34 cirrhosis patients studied developed AKI. A GFR <60 mL/min/1.73 m(2) was identified in 56% with Iohexol clearance compared to 8% using the four-variable modified diet in renal disease formula (P < 0.0001). Prediction of AKI, 48 h prior to the development of AKI with cystatin C GFR and serum NGAL concentration were similar; area under the receiver operating curve (AUROC) values 0.74 (0.51-0.97), P = 0.04 and 0.72 (0.52-0.92), P = 0.02 respectively. The development of AKI was strongly predicted by urine protein:creatinine ratio above the cut-off of >30 (equivalent to 300 mg/day of proteinuria) sensitivity 82% (57-96) and specificity 80% (52-96), AUROC 0.86 (0.73-0.98), P ≤ 0.0001. [OR 21 (3-133), P ≤ 0.002].In patients with liver cirrhosis a urine protein:creatinine ratio >30 predicts AKI. Iohexol clearance and cystatin C formulae identify a greater proportion of patients with a GFR <60 mL/min/1.73 m(2), which also predicts the development of AKI.

There are no studies regarding to these effects in patients with severe liver dysfunction. Objectives The aims of this study were to characterize voriconazole hepatotoxicity in patients with severe liver dysfunction and to compare it with a matched cohort treated with liposomal amphotericin B. Methods This is an observational study, in which adults patients treated with at least 4 doses of voriconazole were included. Patients treated with liposomal amphotericin B were used as control group. Results Sixty nine percent of patients treated with voriconazole showed changes in liver function tests (LFTs) during therapy. They showed elevated transaminases in 35%, cholestasis in 15% or a combination of both in 45%. According to the CTC classification, all patients with hepatotoxicity had a severe reaction. The Roussel Uclaf Causality Assessment Method score in all patients with hepatotoxicity was greater than 8. There was a correlation between initial loading dose greater than 300 mg (4.5 mg/kg) and the risk of hepatotoxicity (p < 0.001). The control group developed alterations in the LFTs in only 10.3% of patients. Conclusion Voriconazole should be used with caution in patients with severe liver dysfunction and following liver transplantation, with frequent monitoring of LFTs or using liposomal amphotericin B instead.

Hyperpyrexia is a well-documented adverse effect of 3,4-methylenedioxymethamphetamine (MDMA) and is associated with a poor prognosis. There are currently limited published records of patients surviving a pyrexia of or greater than 43°C after MDMA intake. Rapid cooling and multiorgan support in an intensive care setting may offer patients the best chance of recovery. We present the case of a 16-year-old male who was admitted to our tertiary, adult intensive care unit (ICU) for unrecordable pyrexia (>43°C) after reported ecstasy intake. The patient went on to develop severe multiorgan failure and profound disseminated intravascular coagulopathy. Initial patient management focused on rapid cooling using an endovascular cooling catheter and rigorous monitoring and treatment of autonomic symptoms, followed by subsequent surgical therapy (fasciotomy) and multiorgan support. The patient eventually achieved a good clinical outcome after 4 weeks of management in the ICU, and was discharged well to his local hospital. Despite multiple end-organ dysfunctions and often severely poor prognosis, survival after severe hyperpyrexia induced by MDMA intake is possible with proper management and organ support in an appropriate intensive care environment.

Acute variceal haemorrhage (AVH) is associated with significant mortality.To determine outcome and factors associated with hospital mortality (HM) in patients with AVH admitted to intensive care unit (ICU) and to compare outcomes of patients requiring transfer to a tertiary ICU (transfer group, TG) to a local in-patient group (LG).A retrospective study of all adult patients (N = 177) admitted to ICU with AVH from 2000-2008 was performed.Median age was 48 years (16-80). Male represented 58%. Median MELD score was 16 (6-39), SOFA score was 8 (6-11). HM was higher in patients who had severe liver disease or critical illness measured by MELD, SOFA, APACHE II scores and number of failed organs (NFO), P < 0.05. Patients with day-1 lactate ≥ 2 mmol/L had increased HM (P < 0.001). MELD score performed as well as APACHE II, SOFA and NFO (P < 0.001) in predicting HM (AUROC = 0.84, 0.81, 0.79 and 0.82, respectively P > 0.05 for pair wise comparisons). Re-bleeding was associated with increased HM (56.9% vs. 31.6%, P = 0.002). The TG (n = 124) had less severe liver disease and critical illness and consequently had lower HM than local patients (32% vs. 57%, P = 0.002). TG patients with ≥2 endoscopies prior to transfer had increased 6-week mortality (P = 0.03). Time from bleeding to transfer ≥3 days was associated with re-bleeding (OR = 2.290, P = 0.043).MELD score was comparable to ICU prognostic models in predicting mortality. Blood lactate was also predictive of hospital mortality. Delays in referrals and repeated endoscopy were associated with increased re-bleeding and mortality in this group.

Nandhabalan, Prashanth M.B.B.S., F.R.C.A., F.F.I.C.M.; Loveridge, Robert M.B.B.S., F.R.C.A., F.F.I.C.M.; Patel, Sameer M.B.B.S., F.R.C.A., F.F.I.C.M.; Willars, Christopher M.B.B.S., F.R.C.A., F.F.I.C.M.; Best, Thomas M.B.B.S., F.R.C.A., F.F.I.C.M.; Vercueil, Andre M.B.B.S., F.R.C.A., F.F.I.C.M.; Vilca‐Melendez, Hector M.D., Ph.D.; Deep, Akash M.D., F.R.C.P.C.H.; Heaton, Nigel M.B.B.S., F.R.C.S.; Auzinger, Georg M.D., A.F.I.C.M. Author Information

Abstract Background Liver volume ( LV ) can be non‐invasively determined from the analysis of computed tomography ( CT ) images, and in patients with acute liver injury ( ALI ) or failure ( ALF ), it can reflect the balance of structural collapse with hepatic regeneration. We examined its relation to cause of liver injury, measures of liver function and histopathological findings, and utility in prediction of complications and mortality. Methods Two hundred and seventy‐three patients with ALF / ALI admitted to a specialist intensive care unit were studied. One hundred and ninety‐nine patients (73%) had non‐acetaminophen ( NA ) aetiologies and 74 (27%) had acetaminophen‐induced disease. LV and proportion of predicted LV ( PLV %) were determined from admission CT imaging. Results LV and PLV % showed marked variation when aetiologic groups were compared ( P &lt; .0001), including loss in cases with indeterminate cause ( LV 939 cm 3 [ IQR 680‐1259], PLV % 56% [42‐84]) and increase in Budd‐Chiari syndrome (1891 cm 3 [1601‐2094], 121% [111‐131]). Progression to high‐grade encephalopathy was more common with smaller LV and PLV . A &lt; 1000 cm 3 threshold identified NA patients who later developed it with 93% (95% CI 83‐98) specificity and odds ratio 10.6 (3.3‐34.5) at median 5 days prior to onset, and risk of death in those with NA ‐drug‐induced ( DILI ) or indeterminate disease with 91% (71‐99) specificity and 63% (50‐75) sensitivity. Conclusion In patients with ALF / ALI , LV shows marked variation by the cause of disease, and in prognostic importance. In indeterminate and DILI cases, loss of volume to &lt;1000 cm 3 may indicate irreversible liver injury and regenerative failure and serve as an early clinical predictor for the development of high‐grade encephalopathy and death.

Objectives: There is a marked propensity for patients with acetaminophen-induced acute liver failure to develop sepsis, which may culminate in multiple organ failure and death. Toll-like receptors sense pathogens and induce inflammatory responses, but whether this is protective or detrimental in acetaminophen-induced acute liver failure remains unknown. Design, Setting, and Patients: We assessed Toll-like receptor expression on circulating neutrophils and their function in 24 patients with acetaminophen-induced acute liver failure and compared with 10 healthy controls. Interventions: Neutrophil Toll-like receptor 2, -4, and -9 expression and cytokine production and function were studied ex vivo at baseline and following stimulation with lipopolysaccharide, oligodeoxynucleotides, ammonium chloride, and interleukin-8. To examine the influence of acetaminophen-induced acute liver failure plasma and endogenous DNA on Toll-like receptors-9 expression, healthy neutrophils were incubated with acetaminophen-induced acute liver failure plasma with and without deoxyribonuclease-I. Measurements and Main Results: Circulating neutrophil Toll-like receptor 9 expression was increased in acetaminophen-induced acute liver failure on day 1 compared with healthy controls (p = 0.0002), whereas Toll-like receptor 4 expression was decreased compared with healthy controls (p < 0.0001). Toll-like receptor 2 expression was unchanged. Neutrophil phagocytic activity was decreased, and spontaneous oxidative burst increased in all patients with acetaminophen-induced acute liver failure compared with healthy controls (p < 0.0001). Neutrophil Toll-like receptor 9 expression correlated with plasma interleukin-8 and peak ammonia concentration (r = 0.6; p < 0.05) and increased with severity of hepatic encephalopathy (grade 0–2 vs 3/4) and systemic inflammatory response syndrome score (0–1 vs 2–4) (p < 0.05). Those patients with advanced hepatic encephalopathy (grade 3/4) or high systemic inflammatory response syndrome score (2–4) on day 1 had higher neutrophil Toll-like receptor 9 expression, arterial ammonia concentration, and plasma interleukin-8 associated with neutrophil exhaustion. Healthy neutrophil Toll-like receptor 9 expression increased upon stimulation with acetaminophen-induced acute liver failure plasma, which was abrogated by preincubation with deoxyribonuclease-I. Intracellular Toll-like receptor 9 was induced by costimulation with interleukin-8 and ammonia. Conclusion: These data point to neutrophil Toll-like receptor 9 expression in acetaminophen-induced acute liver failure being mediated both by circulating endogenous DNA as well as ammonia and interleukin-8 in a synergistic manner inducing systemic inflammation, neutrophil exhaustion, and exacerbating hepatic encephalopathy.

Current diagnostic criteria for primary nonfunction (PNF) of liver grafts are based on clinical experience rather than statistical methods. A retrospective, single-center study was conducted of all adults (n = 1286) who underwent primary liver transplant (LT) 2000-2008 in our center. Laboratory variables during the first post LT week were analyzed. Forty-two patients (3.7%) had 2-week graft failure. Transplant albumin, day-1 aspartate aminotransferase (AST), day-1 lactate, day-3 bilirubin, day-3 international normalized ratio (INR), and day-7 AST were independently associated with PNF on multivariate logistic regression. PNF score =(0.000280*D1AST)+ (0.361*D1 Lactate)+(0.00884*D3 Bilirubin)+(0.940*D3 INR)+(0.00153*D7 AST)-(0.0972*TxAlbumin)-4.5503. Receiver operating curve analysis showed the model area under receiver operating curve (AUROC) of 0.912 (0.889-0.932) was superior to the current United Kingdom (UK) PNF criteria of 0.669 (0.634-0.704, p < 0.0001). When applied to a validation cohort (n = 386, 34.4% patients), the model had AUROC of 0.831 (0.789-0.867) compared to the UK early graft dysfunction criteria of 0.674 (0.624-0.721). The new model performed well after exclusion of patients with marginal grafts and when modified to include variables from the first three post-LT days only (AUROC of 0.818, 0.776-0.856, p = 0.001). This model is superior to the current UK PNF criteria and is based on statistical methods. The model is also applicable to recipients of all types of grafts (marginal and nonmarginal).

Bent silicon crystals mounted on high-accuracy angular actuators were installed in the CERN Super Proton Synchrotron (SPS) and extensively tested to assess the feasibility of crystal-assisted collimation in circular hadron colliders. The adopted layout was exploited and regularly upgraded for about a decade by the UA9 Collaboration. The investigations provided the compelling evidence of a strong reduction of beam losses induced by nuclear inelastic interactions in the aligned crystals in comparison with amorphous orientation. A conceptually similar device, installed in the betatron cleaning insertion of CERN Large Hadron Collider (LHC), was operated through the complete acceleration and storage cycle and demonstrated a large reduction of the background leaking from the collimation region and radiated into the cold sections of the accelerator and the experimental detectors. The implemented layout and the relevant results of the beam tests performed in the SPS and in the LHC with stored proton and ion beams are extensively discussed.

The MIRACLE2 score is the only risk score that does not incorporate and can be used for selection of therapies after out-of-hospital cardiac arrest (OHCA). This study sought to compare the discrimination performance of the MIRACLE2 score, downtime, and current randomized controlled trial (RCT) recruitment criteria in predicting poor neurologic outcome after out-of-hospital cardiac arrest (OHCA). We used the EUCAR (European Cardiac Arrest Registry), a retrospective cohort from 6 centers (May 2012-September 2022). The primary outcome was poor neurologic outcome on hospital discharge (cerebral performance category 3-5). A total of 1,259 patients (total downtime = 25 minutes; IQR: 15-36 minutes) were included in the study. Poor outcome occurred in 41.8% with downtime <30 minutes and in 79.3% for those with downtime >30 minutes. In a multivariable logistic regression analysis, MIRACLE2 had a stronger association with outcome (OR: 2.23; 95% CI: 1.98-2.51; P < 0.0001) than zero flow (OR: 1.07; 95% CI: 1.01-1.13; P = 0.013), low flow (OR: 1.04; 95% CI: 0.99-1.09; P = 0.054), and total downtime (OR: 0.99; 95% CI: 0.95-1.03; P = 0.52). MIRACLE2 had substantially superior discrimination for the primary endpoint (AUC: 0.877; 95% CI: 0.854-0.897) than zero flow (AUC: 0.610; 95% CI: 0.577-0.642), low flow (AUC: 0.725; 95% CI: 0.695-0.754), and total downtime (AUC: 0.732; 95% CI: 0.701-0.760). For those modeled for exclusion from study recruitment, the positive predictive value of MIRACLE2 ≥5 for poor outcome was significantly higher (0.92) than the CULPRIT-SHOCK (Culprit lesion only PCI Versus Multivessel PCI in Cardiogenic Shock) (0.80), EUROSHOCK (Testing the value of Novel Strategy and Its Cost Efficacy In Order to Improve the Poor Outcomes in Cardiogenic Shock) (0.74) and ECLS-SHOCK (Extra-corporeal life support in Cardiogenic shock) criteria (0.81) (P < 0.001). The MIRACLE2 score has superior prediction of outcome after OHCA than downtime and higher discrimination of poor outcome than the current RCT recruitment criteria. The potential for the MIRACLE2 score to improve the selection of OHCA patients should be evaluated formally in future RCTs.

Abstract Background Current assumptions rely on intra-abdominal pressure (IAP) being uniform across the abdominal cavity. The abdominal contents are, however, a heterogeneous mix of solid, liquid and gas, and pressure transmission may not be uniform. The current study examines the upper and lower IAP following liver transplantation. Methods IAP was measured directly via intra-peritoneal catheters placed at the liver and outside the bladder. Compartmental pressure data were recorded at 10-min intervals for up to 72 h following surgery, and the effect of intermittent posture change on compartmental pressures was also studied. Pelvic intra-peritoneal pressure was compared to intra-bladder pressure measured via a FoleyManometer. Results A significant variation in upper and lower IAP of 18% was observed with a range of differences of 0 to 16 mmHg. A sustained difference in inter-compartmental pressure of 4 mmHg or more was present for 23% of the study time. Head-up positioning at 30° provided a protective effect on upper intra-abdominal pressure, resulting in a significant reduction in all patients. There was excellent agreement between intra-bladder and pelvic pressure. Conclusions A clinically significant variation in inter-compartmental pressure exists following liver transplantation, which can be manipulated by changes to body position. The existence of regional pressure differences suggests that IAP monitoring at the bladder alone may under-diagnose intra-abdominal hypertension and abdominal compartment syndrome in these patients. The upper and lower abdomen may need to be considered as separate entities in certain conditions.

This study aims to investigate what factors predict the development of postoperative bloodstream infection (BSI) in patients transplanted electively for chronic liver disease and compare outcomes in infected transplant recipients (BCLD) with noninfected patients (CLD).A retrospective cohort study of 218 patients who had elective liver transplantation (LT) between January 2003 and July 2005 and admitted to a specialist intensive care unit (ICU) was done.Fifteen patients had BSI post-LT (BCLD, 29 isolates) while in the ICU, and 203 patients did not (CLD). Thirty-eight percent of isolates were gram negatives; 55%, gram positives; and 7%, fungemia. Median time to first BSI post-LT was 11 days (range, 3-16 days). On admission post-LT to the ICU, patients with BCLD had higher Acute Physiology and Chronic Health Evaluation II scores (23 vs 10, P < .001). While in the ICU, patients with BCLD had greater requirements for renal replacement therapy (73% vs 8%) and days on mechanical ventilation (17 vs 2 days) and longer median ICU stay (21 vs 3 days, P < .001 for all). One-year survival was worse in the BCLD group (40% vs 94%, P < .001). On multivariate analysis, Acute Physiology and Chronic Health Evaluation II score (odds ratio, 1.36) post-LT was independently associated with subsequent BSI. Bloodstream infection (hazards ratio, 8.7) was independently associated with mortality.Bloodstream infection post-LT was associated with increased severity of illness on admission, greater requirements for organ support, and increased mortality.

Acute liver failure (ALF) is a life-threatening multisystem illness complicated by multiple organ failure (MOF) and haemodynamic disturbances. Morbidity and mortality remains high and various prognostic and scoring models are in use to predict outcome. A recent observation in a large cohort of ALF patients suggested a prognostic value of troponin I (cTnI) and its role as a marker of subclinical myocardial injury and outcome.Data from consecutive ALF patients over a four-year period from January 2007 to March 2011 were included. The aim of this study was to correlate any relationship that may exist between cTnI, mortality, severity of illness and non-hepatic organ failure.A total of 218 subjects (age 36 (16 to 90) years, M:F 103:115) were studied, of which 136 had an elevated cTnI > 0.05 μg/L. Higher organ failure scores were found with positive cTnI: APACHE II (19.5 (3 to 51) vs 14 (2 to 51), P = 0.001), APACHE III (81 (15 to 148) vs 59 (8 to 172), P = < 0.001) SOFA (15 (4 to 20) vs 13 (2 to 21), P = 0.027) and SAPS (48 (12 to 96) vs 34 (12 to 97), P = 0.001). Patients with positive cTnI had higher serum creatinine (192 μmol/l (38 to 550) vs 117 μmol/l (46 to 929), P < 0.001), arterial lactate (0.25, P < 0.001) and a lower pH (-0.21, P = 0.002). Also a higher proportion required renal replacement therapy (78% vs 60%, P = 0.006). Patients with elevated cTnI more frequently required vasopressors-norepinephrine (73% vs 50%, P = 0.008). Elevated cTnI did not predict outcome as effectively as other models (AUROC 0.61 (95% CI 0.52 to 0.68)).More than 60% of ALF patients in this study demonstrated elevated cTnI. Despite a close correlation with organ failure severity, cTnI was a poor independent predictor of outcome. cTnI may not represent true myocardial injury and may be better viewed as a marker of metabolic stress.

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. To the Editor: We read with interest the article by Gustot et al.1 on prognostication of patients with acute‐on‐chronic liver failure (ACLF). The authors suggest that accelerated assessment for liver transplantation is underused and that futility of further care may be determined using the number of organ failures (OFs) and chronic liver failure (CLIF Consortium [CLIF‐C]) ACLF score after 1 week of medical therapy. We previously reported2 on patients with cirrhosis managed with full organ support in our intensive care unit and sought to validate the findings of Gustot et al. Of 986 (nontransplanted) patients with cirrhosis admitted between 2000 and 2011, 533 (327 [61%] male, median age 51 [range 16‐90]) were still alive and in the intensive care unit at day 7 after admission; 302 (57%) died within 90 days. Of the 533, the median day 7 CLIF Sequential Organ Failure Assessment score was 12 (range 1‐20) and the CLIF‐C ACLF score was 54 (range 6‐87); 244 patients were ACLF grade 3, 192 (78%) of whom died within 90 days; 137 patients had a CLIF‐C ACLF score >64 at day 7, of whom 126 (92%) died (compared with 100% for Gustot et al.). For patients with four or more OFs at day 7, 88% did not survive. The CLIF‐C ACLF score area under the receiver operating characteristic curve was 0.839 (95% confidence interval 0.805‐0.872, sensitivity 68%, and specificity 85%) for predicting mortality. We agree that ACLF‐3 alone is an inappropriate futility marker, but while four or more OFs may be more useful, in our series 10% of patients survived to 90 days without transplantation (0% survived in the Gustot et al. data set with four or more OFs or CLIF‐C ACLF >64). Within the group perceived to have a futile outlook, those who died had higher median CLIF‐C ACLF than the Gustot et al. cutoff (68 [range 30‐84] versus 56 [range 36‐75] in survivors, P < 0.001). Of the patients with five or more OFs, 11% (4/35) survived. In multivariable logistic regression of patients with a futile prognosis only CLIF Sequential Organ Failure Assessment (not CLIF‐C ACLF) retained independent predictive accuracy of mortality (odds ratio = 1.39, 95% confidence interval 1.01‐1.93; P = 0.043). When withdrawing care due to perceived futility it is important to recognize that this decision is irrevocable and small survival probabilities can be perceived differently between caregivers and patient families. Balancing these aspects while maintaining patient life, dignity, and wishes is fraught with statistical and ethical difficulties, and a single score is an unlikely final arbiter. Exceptionally high degrees of confidence in mortality risk are a prerequisite, and our assessment suggests that mortality may not be as reliably predicted as described by Gustot et al. Recent evidence suggests that more complex algorithms may be required in determining the optimal time limitation.3 Withdrawal of care should be decided from knowledge of local and national survival rates, OF reversibility, and qualitative factors such as frailty and patient wishes. We invite other authors to validate Gustot et al.'s findings while providing care for patients with cirrhosis in the intensive care unit beyond 7 days pending further outcome‐related research.

BACKGROUND: The profound hemodynamic changes seen in acute liver failure (ALF) resemble the hyperdynamic state found in the later stages of septic shock. Vasopressor support frequently is required after initial volume therapy. Markers of preload dependency have not been studied in this patient group. Dynamic maneuvers such as passive leg raising or end-expiratory hold, which have shown good predictive accuracy in a general intensive care unit population, cannot be considered safe in this cohort because of the concerns of intracranial hypertension. METHODS: Mechanically ventilated patients with ALF admitted to a tertiary specialist intensive care unit in shock and multiorgan failure were enrolled. Markers of fluid responsiveness derived from transpulmonary thermodilution, pulse contour analysis, and echocardiography were compared between responders (cardiac index ≥15%) and nonresponders to a colloid fluid challenge (5 mL/kg predicted body weight). The ability to predict fluid responsiveness of stroke volume variation, pulse pressure variation (PPV), and respiratory change in peak (delta V peak) left ventricular outflow tract velocity for preload dependency were analyzed. RESULTS: Thirty-five patients (mean ± SD age, 38 [14] years, 13 male, 22 female]) were assessed after a single fluid challenge. Ten patients (29%) were fluid responders. Changes in cardiac index and stroke volume index in the cohort of 35 patients were correlated ( R = 0.726 [99% confidence interval, 0.401–0.910]; P &lt; .001). PPV predicted fluid responsiveness (area under the receiver operating characteristic curve [AUROC], 0.752 [95% confidence interval, 0.565–0.889]; P = .005; cutoff &gt;9%). The AUROC for stroke volume variation was 0.678 ([95% confidence interval, 0.499–0.825]; P = .084; cutoff &gt;11%). The AUROC for [delta] V peak before fluid bolus was 0.637 (95% confidence interval, 0.413–0.825; P = .322). CONCLUSIONS: PPV based on pulse contour analysis predicted fluid responsiveness in ALF.

Liver transplantation (LT) in patients with portopulmonary hypertension (PoPH) has historically resulted in unpredictable and often poor outcomes. The United Kingdom experience for the period 1992-2012 is reported in this article. A retrospective analysis of patients, preoperatively fulfilling the PoPH European Respiratory Society Task Force on Pulmonary-Hepatic Vascular Disorders diagnostic criteria was conducted across all UK LT centers. Data collection included comorbidities, use of preoperative and postoperative pharmacotherapy, patient survival, and cause of death. To enable survival stratification, PoPH was classified as mild, moderate, or severe based on mean pulmonary pressure of <35 mm Hg, 35-49 mm Hg, and ≥50 mm Hg, respectively. Of 127 patients reported to have PoPH, just 28 fulfilled the diagnostic criteria (14 mild, 9 moderate, 5 severe). Twenty (71.4%) patients were male with median age and Model for End-Stage Liver Disease of 50 years (range, 23-62 years) and 18 (range, 6-43), respectively. Twelve (42.9%) patients died within 5 years of LT. The majority of deaths (10 of 12; 83%) occurred within the first 6 months after LT, aetiologies of which included right heart failure (n = 3), progressive PoPH (n = 2), and sepsis (n = 2). Of those receiving preoperative pharmacotherapy (n = 8), 5 are currently alive and were classified as mild to moderate PoPH. Both severe PoPH patients optimized preoperatively with pharmacotherapy died within a year of LT. Development of effective vasodilatory therapies in the setting of pulmonary arterial hypertension has led to a dramatic improvement in patient survival. The available data indicate that in this era of pharmacotherapy, PoPH in isolation no longer represents a valid consideration to transplant. Liver Transplantation 22 1637-1642 2016 AASLD.

The Bilirubin Lactate and Etiology (BiLE) score proposed for identifying patients with acute liver failure (ALF) who will not survive without emergency liver transplantation (ELT) has attractive features.1Hadem J. Stiefel P. Bahr M.J. et al.Prognostic implications of lactate, bilirubin, and etiology in German patients with acute liver failure.Clin Gastroenterol Hepatol. 2008; 6: 339-345Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Simple to determine and applicable to all etiologies of ALF, in its derivation cohort a cut-off value of 6.9 showed high specificity and sensitivity in identifying patients who died or underwent ELT. In a larger independent patient sample, we calculated admission BiLE scores and examined the performance of this threshold, making a comparison with the established Kings College Criteria (KCC).2O'Grady J.G. Alexander G.J. Hayllar K.M. et al.Early indicators of prognosis in fulminant hepatic failure.Gastroenterology. 1989; 97: 439-445Abstract PubMed Google ScholarA total of 422 consecutive patients with ALF treated between 1999 and 2007 in our institution were studied, managed following standardized protocols, and considered for ELT if KCC were fulfilled.3Bernal W. Auzinger G. Sizer E. et al.Intensive care management of acute liver failure.Semin Liver Dis. 2008; 28: 188-200Crossref PubMed Scopus (76) Google Scholar The median age was 37 years (interquartile range, 27–46 y), 61% were women, and all had encephalopathy of grade 3 or higher. Fifty-seven percent had ALF resulting from acetaminophen-induced hepatotoxicity and 43% from other causes; 143 (34%) died, 156 (37%) underwent ELT, and 123 (29%) survived with medical management alone.The median BiLE score was 7.1 (range, 4–10.7) in those who died, 7.5 (range, 4.7–11.3) in those transplanted, and 1.9 (range, 0.7–3.6) in medical survivors (P < .000001, Kruskal–Wallis test). Performance of scores greater than 6.9 in comparison with the KCC is shown in Table 1. Sixty-nine of 143 (48%) deaths and 67 of 156 (43%) ELT cases had scores of 6.9 or lower.Table 1Assessment of BiLE Score and KCC as Prognostic Indicators in 422 Patients With ALFCriterionSensitivitySpecificityAccuracyPPVNPVExcluding ELT (n = 266) BiLE > 6.953 (48–56)89 (83–93)69 (64–73)0.86 (79–92)0.6 (56–63) KCC69 (65–73)90 (85–94)79 (74–82)0.89 (83–93)0.72 (68–77)Including ELT (n = 422) BiLE > 6.955 (53–57)89 (83–94)65 (61–67)0.93 (89–96)0.43 (4–45) KCC85 (83–87)90 (85–94)87 (84–89)0.96 (93–97)0.72 (67–75)NOTE. Values in parentheses are 95% confidence intervals.PPV, positive predictive value; NPV, negative predictive value. Open table in a new tab Although the BiLE score differed significantly between survivors and nonsurvivors, we found limited sensitivity and accuracy of this threshold. In the absence of further validation studies it appears premature for transplantation decisions to be made on this basis alone. The Bilirubin Lactate and Etiology (BiLE) score proposed for identifying patients with acute liver failure (ALF) who will not survive without emergency liver transplantation (ELT) has attractive features.1Hadem J. Stiefel P. Bahr M.J. et al.Prognostic implications of lactate, bilirubin, and etiology in German patients with acute liver failure.Clin Gastroenterol Hepatol. 2008; 6: 339-345Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Simple to determine and applicable to all etiologies of ALF, in its derivation cohort a cut-off value of 6.9 showed high specificity and sensitivity in identifying patients who died or underwent ELT. In a larger independent patient sample, we calculated admission BiLE scores and examined the performance of this threshold, making a comparison with the established Kings College Criteria (KCC).2O'Grady J.G. Alexander G.J. Hayllar K.M. et al.Early indicators of prognosis in fulminant hepatic failure.Gastroenterology. 1989; 97: 439-445Abstract PubMed Google Scholar A total of 422 consecutive patients with ALF treated between 1999 and 2007 in our institution were studied, managed following standardized protocols, and considered for ELT if KCC were fulfilled.3Bernal W. Auzinger G. Sizer E. et al.Intensive care management of acute liver failure.Semin Liver Dis. 2008; 28: 188-200Crossref PubMed Scopus (76) Google Scholar The median age was 37 years (interquartile range, 27–46 y), 61% were women, and all had encephalopathy of grade 3 or higher. Fifty-seven percent had ALF resulting from acetaminophen-induced hepatotoxicity and 43% from other causes; 143 (34%) died, 156 (37%) underwent ELT, and 123 (29%) survived with medical management alone. The median BiLE score was 7.1 (range, 4–10.7) in those who died, 7.5 (range, 4.7–11.3) in those transplanted, and 1.9 (range, 0.7–3.6) in medical survivors (P < .000001, Kruskal–Wallis test). Performance of scores greater than 6.9 in comparison with the KCC is shown in Table 1. Sixty-nine of 143 (48%) deaths and 67 of 156 (43%) ELT cases had scores of 6.9 or lower. NOTE. Values in parentheses are 95% confidence intervals. PPV, positive predictive value; NPV, negative predictive value. Although the BiLE score differed significantly between survivors and nonsurvivors, we found limited sensitivity and accuracy of this threshold. In the absence of further validation studies it appears premature for transplantation decisions to be made on this basis alone. Prognostic Implications of Lactate, Bilirubin, and Etiology in German Patients With Acute Liver FailureClinical Gastroenterology and HepatologyVol. 6Issue 3PreviewBackground & Aims: Among the potentially helpful indicators of poor prognosis in acute liver failure (ALF) are etiology, encephalopathy grade, blood lactate, and King’s College Criteria (KCC). The accuracy of these parameters in predicting transplantation or death shows significant variation in different countries. Methods: We retrospectively analyzed 102 patients with ALF treated at our institution between 1996 and 2005. Baseline parameters, simplified acute physiology score III (SAPS-III), KCC, Model for End-Stage Liver Disease (MELD) score, and a novel score of bilirubin, lactate, and etiology (BiLE score) were compared between transplant-free survivors and patients who required liver transplantation or died, by using multivariate linear regression analysis and receiver operating characteristics (ROC). Full-Text PDF ReplyClinical Gastroenterology and HepatologyVol. 7Issue 2PreviewWe thank Dr Bernal and colleagues for their valuable comments on the Bilirubin-Lactate-Etiology (BiLE) score. In a large group of 422 patients with acute liver failure they found the BiLE score to be slightly inferior to King's College Criteria (KCC) with regard to sensitivity and accuracy. Acute liver failure (ALF) comprises a heterogeneous group of patients suffering from a number of different etiologies. This, however, means that the geographic diversity of ALF patient populations may lead to differing performances of the available scoring systems. Full-Text PDF

This paper is devoted to an experimental study of focusing and defocusing positively charged particle beams with the help of specially bent single crystals.Four crystals have been fabricated for this purpose.The studies have been performed at the CERN SPS in 400 GeV=c proton and 180 GeV=c pion beams.The results of measurements of beam envelopes are presented.The rms size of the horizontal profile at the focus was 5-8 times smaller than at the exit of the crystals.The measured focal lengths were 4-21 m.The results of measurements are in good agreement with calculations.Possible applications of focusing crystals in present and future high energy accelerators are discussed.

Our understanding of hemodynamics in cirrhotic patients with sepsis remains limited. Our study aims to investigate differences in hemodynamic profiles using echocardiography between septic patients with and without cirrhosis. This is a single-center, retrospective study of septic patients with echocardiogram within 3 days of ICU admission. We compared baseline characteristics, echocardiographic markers of LV systolic function arterial load between patients with and without cirrhosis. A propensity score-matched case-control model was developed to describe the differences in those echocardiography derived parameters between the groups. 3151 patients with sepsis were included of which 422 (13%) had cirrhosis. In the propensity score matched group with 828 patients, cirrhotic patients had significantly higher left ventricular ejection fraction (64 vs.56%, p < 0.001) and stroke volume (72 vs.48 ml, p < 0.001) along with lower arterial elastance (Ea) (1.35 1vs.20.3, p < 0.001) and systemic vascular resistance (SVR) (851 vs.1209 dynes/s/m−5, p = 0.001). The left ventricular elastance (Ees) (2.83 vs 2.45, p = 0.002) was higher and ventricular-arterial coupling (Ea/Ees) (0.48 vs. 0.86, p < 0.001) lower in cirrhotic compared to non-cirrhotic. Septic patients with cirrhosis had higher LVEF with lower Ea and SVR with higher Ees and significantly lower Ea/Ees suggesting vasodilation as the principal driver of the hyperdynamic profile in cirrhosis.

The high-luminosity upgrade of the LHC brings unprecedented requirements for real-time and precision bunch-by-bunch online luminosity measurement and beam-induced background monitoring. A key component of the CMS Beam Radiation, Instrumentation and Luminosity system is a stand-alone luminometer, the Fast Beam Condition Monitor (FBCM), which is fully independent from the CMS central trigger and data acquisition services and able to operate at all times with a triggerless readout. FBCM utilizes a dedicated front-end application-specific integrated circuit (ASIC) to amplify the signals from CO$_2$-cooled silicon-pad sensors with a timing resolution of a few nanoseconds, which enables the measurement of the beam-induced background. FBCM uses a modular design with two half-disks of twelve modules at each end of CMS, with four service modules placed close to the outer edge to reduce radiation-induced aging. The electronics system design adapts several components from the CMS Tracker for power, control and read-out functionalities. The dedicated FBCM23 ASIC contains six channels and adjustable shaping time to optimize the noise with regards to sensor leakage current. Each ASIC channel outputs a single binary high-speed asynchronous signal carrying time-of-arrival and time-over-threshold information. The chip output signal is digitized, encoded and sent via a radiation-hard gigabit transceiver and an optical link to the back-end electronics for analysis. This paper reports on the updated design of the FBCM detector and the ongoing testing program.

Abstract The high-luminosity upgrade of the LHC brings unprecedented requirements for real-time and precision bunch-by-bunch online luminosity measurement and beam-induced background monitoring. A key component of the CMS Beam Radiation, Instrumentation and Luminosity system is a stand-alone luminometer, the Fast Beam Condition Monitor (FBCM), which is fully independent from the CMS central trigger and data acquisition services and able to operate at all times with a triggerless readout. FBCM utilizes a dedicated front-end application-specific integrated circuit (ASIC) to amplify the signals from CO 2 -cooled silicon-pad sensors with a timing resolution of a few nanoseconds, which enables the measurement of the beam-induced background. FBCM uses a modular design with two half-disks of twelve modules at each end of CMS, with four service modules placed close to the outer edge to reduce radiation-induced aging. The electronics system design adapts several components from the CMS Tracker for power, control and read-out functionalities. The dedicated FBCM23 ASIC contains six channels and adjustable shaping time to optimize the noise with regards to sensor leakage current. Each ASIC channel outputs a single binary high-speed asynchronous signal carrying time-of-arrival and time-over-threshold information. The chip output signal is digitized, encoded, and sent via a radiation-hard gigabit transceiver and an optical link to the back-end electronics for analysis. This paper reports on the updated design of the FBCM detector and the ongoing testing program.

To clarify whether the gas exchange response to prone position is associated with lung recruitability in mechanically ventilated patients with acute respiratory failure.In 32 patients, gas exchange response to prone position was investigated as a function of lung recruitability, measured by computed tomography in supine position.No relationship was found between increased oxygenation in prone position and lung recruitability. In contrast, the decrease of PaCO(2) was related with lung recruitability (R(2) 0.19; P = 0.01). Patients who decreased their PaCO(2) more than the median value (-0.9 mmHg) had a greater lung recruitability (19 +/- 16 vs. 8 +/- 6%; P = 0.02), higher baseline PaCO(2) (48 +/- 8 vs. 41 +/- 11 mmHg; P = 0.07), heavier lungs (1,968 +/- 829 vs. 1,521 +/- 342 g; P = 0.06) and more non-aerated tissue (1,009 +/- 704 vs. 536 +/- 188 g; P = 0.02) than those who did not.During prone position, changes in PaCO(2), but not in oxygenation, are associated with lung recruitability which, in turn, is associated with the severity of lung injury.

A charged particle telescope has been deployed for data taking at high rates in a CERN beam line using protons and other particles. The apparatus has a baseline of approximately 10 m in each arm, and achieves an angular resolution of 5.4 μrad using 400 GeV/c protons. The electronic readout and data acquisition system is based on that developed for the CMS Tracker, and provides almost deadtime-free operation at trigger rates of up to about 10 kHz. The telescope was developed to characterize crystals used in channeling experiments with a primary objective to validate them for use in a future LHC beam collimation system. The telescope has also been used for other studies of fundamental phenomena associated with the channeling process. The telescope is described, and its measured performance, referring to results from channeling studies, including recent measurements in heavy ion beams.

Post hoc analysis of a non-comparative, prospective, multicentre, phase IIIb study was performed to compare efficacy and safety of anidulafungin in elderly (≥65 years) versus non-elderly (<65 years) Intensive Care Unit (ICU) patients with candidaemia/invasive candidiasis (C/IC). Adult ICU patients with confirmed C/IC meeting ≥1 of the following criteria were enrolled: post-abdominal surgery; solid tumour; renal/hepatic insufficiency; solid organ transplantation; neutropenia; age ≥65 years. Patients received anidulafungin (200 mg on Day 1, 100 mg/day thereafter) for ≥10 days followed by optional azole step-down therapy for a total treatment duration of 14-56 days. The primary efficacy endpoint was global (clinical and microbiological) response at the end of all therapy (EOT). Primary efficacy analysis was performed in the modified intent-to-treat (mITT) population (n=170), excluding unknown and missing responses. In total, 80 patients (47.1%) were aged ≥65 years and 90 (52.9%) were aged <65 years; the mean age difference between the two groups was 21.9 years. Global success at EOT in mITT patients was similar in elderly (68.1%) and non-elderly (70.7%) patients (P=0.719). However, global success rates were significantly lower in elderly versus non-elderly patients at 2 and 6 weeks after EOT (P=0.045 and P=0.016, respectively). Ninety-day survival was significantly lower (P=0.006) for elderly (42.8%) versus non-elderly patients (63.3%). The incidence and profile of adverse events were similar in elderly and non-elderly patients. Anidulafungin was effective and safe for treatment of C/IC in elderly ICU patients, despite higher baseline severity of illness scores.

Candidaemia and other forms of invasive candidiasis (C/IC) in the intensive care unit are challenging conditions that are associated with high rates of mortality. New guidelines from the European Society for Clinical Microbiology and Infectious Diseases strongly recommend echinocandins for the first-line treatment of C/IC. Here, a cost-effectiveness model was developed from the United Kingdom perspective to examine the costs and outcomes of antifungal treatment for C/IC based on the European Society for Clinical Microbiology and Infectious Diseases guidelines. Costs and treatment outcomes with the echinocandin anidulafungin were compared with those for caspofungin, micafungin and fluconazole. The model included non-neutropenic patients aged ≥16 years with confirmed C/IC who were receiving intravenous first-line treatment. Patients were categorised as either a clinical success or failure (patients with persistent/breakthrough infection); successfully treated patients switched to oral therapy, while patients categorised as clinical failures switched to a different antifungal class. Other inputs were all-cause mortality at 6 weeks, costs of treatment-related adverse events and other medical resource utilisation costs. Resource use was derived from the published literature and from discussion with clinical experts. Drug-acquisition/administration costs were taken from standard United Kingdom costing sources. The model indicated that first-line anidulafungin could be considered cost-effective versus fluconazole (incremental cost-effectiveness ratio £813 per life-year gained) for the treatment of C/IC. Anidulafungin was cost-saving versus caspofungin and micafungin due to lower total costs and a higher rate of survival combined with a higher probability of clinical success. European Society for Clinical Microbiology and Infectious Diseases guidelines recommend echinocandins for the first-line treatment of C/IC; our model indicated that anidulafungin marries clinical effectiveness and cost-effectiveness. From the United Kingdom perspective, anidulafungin was cost-effective compared with fluconazole for the treatment of C/IC and was cost-saving versus the other echinocandins.

VENOARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION (VA–ECMO) is used increasingly as an emergency support tool for patients suffering from refractory cardiogenic shock of varying etiologies. According to the most recent Extracorporeal Life Support Organization (ELSO) statistics, 709 adult patients underwent VA-ECMO support in 2012 (Extracorporeal Life Support Registry Report, International Summary, January, 2013). The exact number of cases treated in a peripheral femoro-femoral configuration is not known. Although the authors assume that a small percentage of these patients underwent CT imaging, there are no reports they could find in the literature discussing the specific appearances of contrast distribution that have to be expected during extracorporeal circulatory support. Previous retrospective studies predominantly highlighted the clinical and diagnostic benefits 1 Lidegran M.K. Ringertz H.G. Frenckner B.P. et al. Chest and abdominal CT during extracorporeal membrane oxygenation: Clinical benefits in diagnosis and treatment. Acad Radiol. 2005; 12: 276-285 Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar , 2 Jepson S.L. Harvey C. Entwisle J.J. et al. Management benefits and safety of computer tomography in patients undergoing extracorporeal membrane oxygenation therapy: Experience of a single centre. Clin Radiol. 2010; 65: 881-886 Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar of CT scanning as well as the safety of transfers in patients primarily supported in a venovenous (VV) configuration for treatment of refractory respiratory failure.

Extracorporeal membrane oxygenation (ECMO) is increasingly used for the treatment of refractory but potentially reversible respiratory and/or cardiac failure. Data on perioperative support with veno-arterial (V-A) and veno-venous (V-V) ECMO for adult liver transplant recipients are scarce [1,2].We report our experience of ECMO support in patients with acute liver failure (ALF) as a bridge to transplant and postoperative ECMO use following complications after surgery.

The objective of this study was to review our clinical experience on the safety and efficacy of anidulafungin, an echinocandin antifungal, in the treatment of invasive fungal infections (IFIs) in patients with moderate to severe abnormal liver function tests or multiorgan failure and IFI, in a large United Kingdom Liver Centre.The clinical records of the first 50 consecutive patients treated for IFI with anidulafungin between January 7, 2009 and March 2, 2011 were analyzed. Data were collected on demographics, underlying disease, disease characteristics, hematological and biochemical parameters, IFI, concomitant bacterial and viral infections, response to anidulafungin, and anidulafungin-related adverse events.The patients' median age was 54.3 years (range, 19.6-75.9); 60% were male. Twenty-two (44%) patients were liver transplant recipients. Others had hepatopancreaticobiliary disease (n = 15, 30%) or chronic liver disease (n = 11, 22%). Invasive fungal infection (predominantly Candida spp) was proven in 36 (72%) patients, probable in 14 (28%). Of 46 evaluable patients, 35 (76%) had a favorable anidulafungin treatment outcome. Forty-nine (98%) had abnormal liver function tests (LFTs) pretreatment; 31 (62%) had ≥1 LFT raised to ≥2× baseline during anidulafungin treatment.In this highly specialized group of patients, anidulafungin treatment was efficacious and well tolerated by those with decompensated liver disease, multiorgan failure, and high-risk liver transplant with proven or probable IFI.

Budd-Chiari syndrome (BCS) is a rare, potentially fatal disease characterized by hepatic venous outflow tract obstruction. Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication of heparin therapy, with mortality approaching 10%. The reported prevalence of HIT in adults is 0.2-5.2%. Expert consensus through case reports is the only existing evidence of HIT in BCS. To our knowledge, this is the first study to formalize this anecdotal evidence.A retrospective analysis was carried out of patients presenting at a tertiary liver centre with acute liver failure because of BCS or BCS as the primary indication for liver transplantation between 2000 and 2013. The prevalence of HIT in the study group was compared with the highest reported prevalence in adult medical patients receiving heparin (5.2%). Mortality, length of stay and liver transplantation rates were also studied.Of 32 BCS patients, 9 (28.1%) developed HIT, significantly higher than the previously reported prevalence of HIT in medical patients (5.2%) (P<0.0001). There was no difference in mortality (P=0.66), length of stay (P=0.58) and liver transplantation rate (P=0.39) between HIT-positive and HIT-negative patients.The prevalence of HIT (28.1%) in our cohort of BCS patients is significantly higher than that in the general population (0.2-5.2%). Although this study was not powered to detect outcome differences, as heparin is the mainstay of acute BCS treatment, this represents a significant risk. We recommend a high index of suspicion for HIT in patients with BCS and thrombocytopenia, an appropriate HIT-testing strategy and consideration of direct thrombin inhibitors.

At large accelerators, bent crystals are employed to deflect weakly divergent proton beams at the stages of extraction and collimation. We demonstrate that a divergent particle beam may be efficiently deflected using a crystal with a focusing entry face. A 180 GeV/c pion beam with divergence near 0.060 mrad, which exceeds the Lindhard angle by a factor of 4, has been experimentally deflected by 0.25 mrad with efficiency near 22%. The proposed focusing crystal may serve as an element of a novel particle optics for secondary-particle beams in the TeV energy region.

Identifying how the prognostic impact of performance status (PS) differs according to indication, era, and time period ("epoch") after liver transplantation (LT) could have implications for selection and treatment of patients on the waitlist. We used national data from the United Kingdom and Ireland to assess impact of PS on mortality separately for HCC and non-HCC recipients.We assessed pre-LT PS using the 5-point modified Eastern Cooperative Oncology Group scale and used Cox regression methods to estimate hazard ratios (HRs) that compared posttransplantation mortality in different epochs of follow-up (0-90 days and 90 days to 1 year) and in different eras of transplantation (1995-2005 and 2006-2016). 2107 HCC and 10,693 non-HCC patients were included. One-year survival decreased with worsening PS in non-HCC recipients where 1-year survival was 91.9% (95% confidence interval [CI], 88.3-94.4) in those able to carry out normal activity (PS1) compared to 78.7% (95% CI, 76.7-80.5) in those completely reliant on care (PS5). For HCC patients, these estimates were 89.9% (95% CI, 85.4-93.2) and 83.1% (95% CI, 61.0-93.3), respectively. Reduction in survival in non-HCC patients with poorer PS was in the first 90 days after transplant, with no major effect observed between 90 days and 1 year. Adjustment for donor and recipient characteristics did not change the findings. Comparing era, post-LT mortality improved for HCC (adjusted HR, 0.55; 95% CI, 0.40-0.74) and non-HCC recipients (0.48; 95% CI, 0.42-0.55), but this did not differ according to PS score (P = 0.39 and 0.61, respectively).Impact on mortality of the recipient's pretransplant PS is principally limited to the first 3 months after LT. Over time, mortality has improved for both HCC and non-HCC recipients and across the full range of PS.

Abstract Background The optimal analgesic strategy for patients undergoing donor hepatectomy is not known and the potential short‐ and long‐term physical and psychological consequences of complications are significant. Objectives To identify whether a multimodal approach to pain of the donor intraoperatively enhances immediate and short‐term outcomes after living liver donation, and to provide international expert panel recommendations. Data sources Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central. Methods Systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel. PROSPERO 2021 CRD42021260699. Results Nine studies assessing multi‐modal analgesia strategies were included in a qualitative assessment. Interventions included local, regional, and neuro‐axial anesthetic techniques, pharmacological intervention (NSAIDs, COX‐2 inhibitors, ketamine, dexmedetomidine, and lidocaine), and acupuncture. Overall, there was a significant (40%) reduction in opioid requirement on day 1 and a significant reduction in pain scores in the intervention vs control groups. Significant reductions in either length of stay or post‐operative complications were demonstrated in four of nine studies. Conclusions Opioid use for patients undergoing donor hepatectomy is likely to impact both their short‐ and long‐term outcomes. To reduce post‐operative pain scores, shorten length of hospital stay, and promote earlier post‐operative return of bowel function, we recommend that multi‐modal analgesia be offered to patients undergoing living donor hepatectomy. Further research is required to confirm which multi‐modal techniques are most associated with enhanced recovery in living liver donors.

The Pixel Luminosity Telescope is a silicon pixel detector dedicated to luminosity measurement at the CMS experiment at the LHC. It is located approximately 1.75 m from the interaction point and arranged into 16 "telescopes", with eight telescopes installed around the beam pipe at either end of the detector and each telescope composed of three individual silicon sensor planes. The per-bunch instantaneous luminosity is measured by counting events where all three planes in the telescope register a hit, using a special readout at the full LHC bunch-crossing rate of 40 MHz. The full pixel information is read out at a lower rate and can be used to determine calibrations, corrections, and systematic uncertainties for the online and offline measurements. This paper details the commissioning, operational history, and performance of the detector during Run 2 (2015-18) of the LHC, as well as preparations for Run 3, which will begin in 2022.

Intracranial hypertension (ICH) complicates around 25% of grade III/IV encephalopathy in acute liver failure. Intracranial pressure (ICP) monitoring is controversial in this coagulopathic population.

Summary Haemophagocytic lymphohistiocytosis secondary to viral infection is an unusual but well recognised cause of bone marrow dysfunction and multiple organ failure in young patients. Two 18 year‐old patients were admitted to a tertiary liver unit with features of acute liver failure, cardio‐respiratory collapse and pancytopenia. Serological tests and bone marrow examination with in‐situ hybridisation revealed severe acquired haemophagocytic lymphohistiocytosis secondary to acute Epstein–Barr virus infection. Both patients died despite full supportive therapy; the first due to pulmonary haemorrhage, the second due to acute respiratory distress syndrome refractory to high frequency oscillatory ventilation. The clinical spectrum, diagnostic features and current evidence based recommendations for treatment of this condition are explored. The diagnosis of haemophagocytic lymphohistiocytosis should be considered in young patients with marked bone marrow dysfunction and multiple organ failure. Further research into appropriate therapy for patients with acute severe forms of the disease who require intensive organ support is required.

Intentional iron overdose in adults is uncommon. Clinical consequences are variable and depend on the quantity of iron ingested and the delay to treatment. Severe iron overdose can lead to multi-organ failure and acute hepatic necrosis. Here, we report three cases of polypharmacy overdose including iron resulting in acute liver failure. Despite maximum supportive care including liver transplantation in two cases, all patients died. Iron poisoning may have an additive toxic effect in drug-induced acute liver failure and worsen outcome.

Liver InternationalVolume 29, Issue 3 p. 374-374 Stroke after injection of gastric varices Deepak Joshi, Deepak Joshi Institute of Liver Studies, King's College Hospital, London, UKSearch for more papers by this authorJulia Wendon, Julia Wendon Institute of Liver Studies, King's College Hospital, London, UKSearch for more papers by this authorGeorg Auzinger, Georg Auzinger Institute of Liver Studies, King's College Hospital, London, UKSearch for more papers by this author Deepak Joshi, Deepak Joshi Institute of Liver Studies, King's College Hospital, London, UKSearch for more papers by this authorJulia Wendon, Julia Wendon Institute of Liver Studies, King's College Hospital, London, UKSearch for more papers by this authorGeorg Auzinger, Georg Auzinger Institute of Liver Studies, King's College Hospital, London, UKSearch for more papers by this author First published: 04 February 2009 https://doi.org/10.1111/j.1478-3231.2008.01961.xCitations: 7Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume29, Issue3March 2009Pages 374-374 RelatedInformation

CMS started a campaign to identify the future silicon sensor technology baseline of the new tracker for the high-luminosity phase of LHC. We ordered a large variety of 6 inch wafers in different thicknesses and technologies at producer Hamamatsu. Thicknesses ranging from 50 microns to 300 microns are explored on Floatzone, Magnetic Czochralski and Epitaxial Silicon both in n-in-p and p-in-n versions. P-stop and p-spray are explored as isolation technologies for the n-in-p type sensors as well as the feasibility of double metal routing on 6 inch wafers. Each wafer contains many different structures to answer different questions, e.g. geometry, Lorentz angle, radiation tolerance, annealing behavior or read-out schemes. Dedicated process test-structures, as well as diodes, mini-sensors, long and very short strip sensors and real pixel sensors have been designed for this evaluation. This contribution provides an overview of the campaign and summarizes interesting measurements performed so far.

Purpose of review The incidence of cirrhosis is growing steadily and this cohort of patients will present in ever-greater numbers to critical care with acute decompensation, usually secondary to an inter-current event or following elective surgery. This review examines the evidence for treatment options and outcomes. Recent findings Outcome of cirrhotics presenting with end-organ dysfunction is steadily improving and their outcomes are not as poor as sometimes suggested. Treatment options for variceal bleeding and renal dysfunction are evolving and outcomes improving. Summary Critical care support should be offered to patients with cirrhosis and in high-risk variceal bleed patients transhepatic portosystemic shunt should be considered.

The Hepatology Committee of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) aims to educate pediatric gastroenterologists, members of ESPGHAN and professionals from other specialties promoting an exchange of clinical expertise in the field of pediatric hepatology. Herewith we have concentrated on detailing the recent advances in acute liver failure in infants and children.The 2020 ESPGHAN monothematic three-day conference on pediatric hepatology disease, entitled "acute liver failure" (ALF), was organized in Athens, Greece. ALF is a devastating disease with high mortality and most cases remain undiagnosed. As knowledge in diagnosis and treatment of ALF in infants and children has increased in the past decades, the objective was to update physicians in the field with the latest research and developments in early recognition, curative therapies and intensive care management, imaging techniques and treatment paradigms in these age groups.In the first session, the definition, epidemiology, various causes of ALF, in neonates and older children and recurrent ALF (RALF) were discussed. The second session was dedicated to new aspects of ALF management including hepatic encephalopathy (HE), coagulopathy, intensive care interventions, acute on chronic liver failure, and the role of imaging in treatment and prognosis. Oral presentations by experts in various fields are summarized highlighting key learning points.The current report summarizes the major learning points from this meeting. It also identifies areas where there is gap of knowledge, thereby identifying the research agenda for the near future.

Single-lung transplantation for chronic obstructive pulmonary disease can cause unique postoperative problems that might require independent lung ventilation. We evaluated preoperative and immediate postoperative factors to predict the need for independent lung ventilation.We retrospectively studied 170 patients who received a single-lung transplant over a 15-year period, 20 (12%) of whom required independent lung ventilation.Patients requiring independent lung ventilation were similar in age, sex, ischemic time, and donor characteristics to those who required conventional ventilation. Patients receiving independent lung ventilation had a greater degree of preoperative airflow limitation, more hyperinflation, lower postoperative PaO2/fraction of inspired oxygen ratios, more radiologic mediastinal shift, and more transplant lung infiltrate on the postoperative chest radiograph. Multivariate logistic regression analysis showed that independent lung ventilation was associated with increasing levels of recipient hyperinflation (percentage total lung capacity compared with predicted value; odds ratio, 1.04; 95% confidence interval, 1.01-1.07; P = .032) and reduced early postoperative PaO2/fraction of inspired oxygen ratio (odds ratio, 0.97; 95% confidence interval, 0.95-0.99; P = .005). Length of ventilation and intensive care unit stay and mortality were higher in the independent lung ventilation group. Among patients who survived to hospital discharge, there were no differences in long-term mortality between the 2 groups.The need for independent lung ventilation in patients undergoing single-lung transplantation for obstructive lung disease is predicted by the combination of increased hyperinflation measured on recipients' preoperative lung function tests and a low PaO2/fraction of inspired oxygen ratio, indicating graft dysfunction in the immediate postoperative period.

The CBC3 is the latest version of the CMS Binary Chip ASIC for readout of the outer radial region of the upgraded CMS Tracker at HL-LHC.This 254-channel, 130nm CMOS ASIC is designed to be bump-bonded to a substrate to which sensors will be wire-bonded.It will instrument double-layer 2S-modules, consisting of two overlaid silicon microstrip sensors with aligned microstrips.On-chip logic identifies first level trigger primitives from high transversemomentum tracks by selecting correlated hits in the two sensors.Delivered in late 2016, the CBC3 has been under test for several months, including X-ray irradiations and SEU testing.Results and performance are reported.

Experimental results on deflection of a 180 GeV/c π+-meson beam by a 23 mm long bent silicon crystal are analyzed to study the dechanneling process of particles due to multiple scattering. A new approach for the determination of contributions from atomic nuclei and electrons to the multiple scattering using the experimental data for random crystal orientations is suggested. The results of simulations performed using this approach, in which the contribution from atomic electrons is considered according to the prescription of Bethe, are in a good agreement with the experiment.

Although improvement in survival from haematological malignancies has been reported, a substantial number of these patients develop life threatening complications. Critical care outreach services (CCOS) aim to avert inappropriate ICU admissions, while ensuring timely patient review.We retrospectively analysed patients with haematological malignancy reviewed by an outreach service between January 2014 and December 2015 at a single institution. The aim of our study was to describe the patient population assessed by a well-established outreach team, identify predictors of ICU admission, as well as ICU and hospital mortality.Sixty of 126 patients reviewed (47.6%) were admitted to ICU. ICU and hospital mortality were 25.3% and 45.2%, respectively. The odds of being admitted to ICU was 13 times higher (p = 0.013) if the patient was referred for hypoxia, 20 times higher (p = 0.006) if they were referred for sepsis or 14 times higher (p = 0.027) if they were referred to CCOS for hypotension, compared to when the team was automatically alerted. The odds of not surviving hospital admission increased 1.27 times for every extra day of CCOS review (p = 0.02). When a patient was referred having a refractory or progressive haematological condition, the odds of not surviving to hospital discharge increased by four or 12 times, respectively, compared to when the referred patient was in remission. Receiving high flow nasal cannula oxygen (HFNCO) was associated with a reduction in ICU admission (p = 0.03), irrespective of the underlying diagnosis, performance status or location of delivery. The CCOS participated in end-of-life discussions in 29% patients.ICU and hospital mortality of patients with haemato-oncological malignancy continue to improve. CCOS are heavily involved in the recognition and management of these patients, as well as in the facilitation of end-of-life discussions. Sepsis was associated with increased risk of ICU admission and mortality. Initiation of HFNCO outside ICU appears to be feasible and safe and was not associated with increasing risk in this single centre study.

Strong reduction of multiple scattering for channeled particles has been observed in an experiment on the deflection of a 180 GeV/c π+-meson beam by bent silicon crystals. The RMS deflections due to multiple scattering for the channeled particles were about six times smaller than for non-channeled ones. It was shown that the approach suggested recently for the description of multiple scattering for channeled particles using the experimental data for random crystal orientations gives fair agreement with the experiment.

We write in response to the letter by Ivan Iniesta (Dec 22, p 2101),1Iniesta I Lamotrigine and the risk of fulminant hepatic failure.Lancet. 2007; 370: 2101Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar written as a rebuttal to our letter2Shawcross D Knighton S Bernal W Sizer E Auzinger G Old versus new antiepileptic drugs: the SANAD study.Lancet. 2007; 370: 314-315Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar in which we cautioned physicians to be aware of the risks of severe hepatic dysfunction when prescribing lamotrigine, after publication of the SANAD study.3Marson AG Al Kharusi AM Alwaidh M et al.The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1000-1015Summary Full Text Full Text PDF PubMed Scopus (705) Google Scholar We were not given the chance to respond to Iniesta's letter, which suggested that we withheld relevant information on one of the cases we reported and detracted from the message we were trying to convey.Although the symptoms that developed 2 weeks after the patient started lamotrigine were typical of a mononucleosis syndrome, idiosyncratic adverse drug reactions to lamotrigine commonly present with hepatotoxicity, often as part of the DRESS (drug reaction with eosinophil and systemic symptoms) syndrome whereby patients typically develop fever, maculopapular rash, eosinophilia, atypical lymphocytosis, arthralgia, lymphadenopathy, and hepatosplenomegaly.4Zaccara G Franciotta D Perucca E Idiosyncratic adverse reactions to antiepileptic drugs.Epilepsia. 2007; 48: 1223-1244Crossref PubMed Scopus (275) Google ScholarWe acknowledge that the IgM was reactive to cytomegalovirus on presentation at the referral hospital, but repeat testing on three occasions at our institution (on admission, before transplantation, and after transplantation) were non-reactive for IgM, and cytomegalovirus DNA was not detectable in the blood, albeit after previous ganciclovir treatment. IgG for cytomegalovirus and Epstein-Barr virus were positive. Anticonvulsant-induced DRESS syndrome can also reactivate cytomegalovirus associated with IgM positivity.5Aihara M Sugita Y Takahashi S et al.Anticonvulsant hypersensitivity syndrome associated with reactivation of cytomegalovirus.Br J Dermatol. 2001; 144: 1231-1234Crossref PubMed Scopus (86) Google ScholarThere was continuous exposure to valproate before liver failure developed, but in our experience fulminant hepatic failure rarely develops in patients treated with anticonvulsants for many years without another precipitant.Lastly, the explant liver showed near-total hepatocyte loss with stromal loss and ductular reaction that were deemed most likely to be secondary to a drug and not cytomegalovirus, since inclusion bodies were not seen within the liver.We declare that we have no conflict of interest. We write in response to the letter by Ivan Iniesta (Dec 22, p 2101),1Iniesta I Lamotrigine and the risk of fulminant hepatic failure.Lancet. 2007; 370: 2101Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar written as a rebuttal to our letter2Shawcross D Knighton S Bernal W Sizer E Auzinger G Old versus new antiepileptic drugs: the SANAD study.Lancet. 2007; 370: 314-315Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar in which we cautioned physicians to be aware of the risks of severe hepatic dysfunction when prescribing lamotrigine, after publication of the SANAD study.3Marson AG Al Kharusi AM Alwaidh M et al.The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1000-1015Summary Full Text Full Text PDF PubMed Scopus (705) Google Scholar We were not given the chance to respond to Iniesta's letter, which suggested that we withheld relevant information on one of the cases we reported and detracted from the message we were trying to convey. Although the symptoms that developed 2 weeks after the patient started lamotrigine were typical of a mononucleosis syndrome, idiosyncratic adverse drug reactions to lamotrigine commonly present with hepatotoxicity, often as part of the DRESS (drug reaction with eosinophil and systemic symptoms) syndrome whereby patients typically develop fever, maculopapular rash, eosinophilia, atypical lymphocytosis, arthralgia, lymphadenopathy, and hepatosplenomegaly.4Zaccara G Franciotta D Perucca E Idiosyncratic adverse reactions to antiepileptic drugs.Epilepsia. 2007; 48: 1223-1244Crossref PubMed Scopus (275) Google Scholar We acknowledge that the IgM was reactive to cytomegalovirus on presentation at the referral hospital, but repeat testing on three occasions at our institution (on admission, before transplantation, and after transplantation) were non-reactive for IgM, and cytomegalovirus DNA was not detectable in the blood, albeit after previous ganciclovir treatment. IgG for cytomegalovirus and Epstein-Barr virus were positive. Anticonvulsant-induced DRESS syndrome can also reactivate cytomegalovirus associated with IgM positivity.5Aihara M Sugita Y Takahashi S et al.Anticonvulsant hypersensitivity syndrome associated with reactivation of cytomegalovirus.Br J Dermatol. 2001; 144: 1231-1234Crossref PubMed Scopus (86) Google Scholar There was continuous exposure to valproate before liver failure developed, but in our experience fulminant hepatic failure rarely develops in patients treated with anticonvulsants for many years without another precipitant. Lastly, the explant liver showed near-total hepatocyte loss with stromal loss and ductular reaction that were deemed most likely to be secondary to a drug and not cytomegalovirus, since inclusion bodies were not seen within the liver. We declare that we have no conflict of interest.

Echocardiography is commonly used during both venoarterial (V-A) and venovenous extracorporeal membrane oxygenation (ECMO). In many circumstances, transoesophageal echocardiography (TOE) is the preferred monitoring tool. It can aid in cannula positioning, especially during double-lumen cannula placement for V-V ECMO, weaning of V-A ECMO and diagnose causes of high-access pressures and circuit flow problems. We use TOE as our preferred monitoring equipment before, during and after establishing ECMO. We sought to investigate how often information gained from TOE imaging had a major impact on management decisions.

The silicon pixel detector of the CMS experiment at CERN will be replaced with an upgraded version at the beginning of 2017 with the new detector featuring an additional barrel- and end-cap layer resulting in an increased number of fully digital read-out links running at 400 Mbps. New versions of the PSI46 Read-Out Chip and Token Bit Manager have been developed to operate at higher rates and reduce data loss. Front-End Controller and Front-End Driver boards, based on the μTCA compatible CMS Tracker AMC, a variant of the FC7 card, are being developed using different mezzanines to host the optical links for the digital read-out and control system. An overview of the system architecture is presented, with details on the implementation, and first results obtained from test systems.

Abstract Background Targeted temperature management is the modern term for therapeutic hypothermia, where cooling is induced by intensive care clinicians to achieve body temperatures below 36°C. Its use in acute liver failure to improve refractory intracranial hypertension and patient outcomes is not supported by strong quality evidence. Aim This systematic review aims to determine if targeted temperature management improves patient outcome as opposed to normothermia in acute liver failure. Methods A computerized and systematic search of six academic and medical databases was conducted using the following keywords: “acute liver failure", “fulminant hepatic injury", “targeted temperature management", “therapeutic hypothermia", and “cooling". Broad criteria were applied to include all types of primary observational studies, from case reports to randomized controlled trials. Standardized tools were used throughout to critically appraise and extract data. Findings Nine studies published between 1999 and 2016 were included. Early observational studies suggest a benefit of targeted temperature management in the treatment of refractory intracranial hypertension and in survival. More recent controlled studies do not show such a benefit in the prevention of intracranial hypertension. All studies revealed that the incidence of coagulopathy is not higher in patients treated with targeted temperature management. There remains some uncertainty regarding the increased risk of infection and dysrhythmias. Heterogeneity was found between study types, design, sample sizes, and quality. Conclusion Although it does not significantly improve survival, targeted temperature management is efficient in treating episodes of intracranial hypertension and stabilizing an unstable critical care patient without increasing the risk of bleeding. It does not, however, prevent intracranial hypertension. Data heterogeneity may explain the contradictory findings. Relevance to Clinical Practice Controlled studies are needed to elucidate the true clinical benefit of targeted temperature management in improving patient outcome.