Continuous renal replacement therapy and transplant-free survival in acute liver failure: protocol for a systematic review and meta-analysis.

BACKGROUND: Acute liver failure is a rare syndrome with significant morbidity and mortality, particularly in absence of transplantation as a rescue therapy. An important mechanism contributing to mortality is hyperammonemia which drives cerebral edema and raised intracranial pressure. Multiple therapies for managing hyperammonemia have been trialed. Continuous renal replacement therapy is effective in treating hyperammonemia in other disease states (notably inborn errors of metabolism). Its efficacy in acute liver failure has been suggested but further investigation is required to prove this. The objective of this systematic review will be to determine the efficacy of continuous renal replacement therapy in patients with acute liver failure and its effect on mortality and transplant-free survival. METHODS: MEDLINE, EMBASE, Web of Science, and Cochrane Database will be searched. Identified studies will include all patients with acute liver failure in a critical care unit treated with continuous renal replacement therapy. Primary outcome will be effectiveness of ammonia clearance and mortality. Patients treated with any other modality of ammonia lowering therapy (such as plasma exchange or Molecular Adsorbent Recirculating System) will be excluded. Narrative synthesis of the identified studies will occur and if clinical homogeneity is identified, data will be pooled for meta-analysis using a DerSimonian-Laird random effects model. DISCUSSION: We present a protocol for a systematic review seeking to establish a link between transplant-free survival in acute liver failure and the use of continuous renal replacement therapy. Given the anticipated paucity of literature on this subject, both narrative and quantitative syntheses are planned. SYSTEMATIC REVIEW REGISTRATION: (PROSPERO) CRD42019122520, registered April 16, 2019.

The Natural History of Severe Acute Liver Injury.

OBJECTIVES: Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death. METHODS: 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure. RESULTS: Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death. CONCLUSIONS: A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

The impact of delayed biliary decompression and anti-microbial therapy in 260 patients with cholangitis-associated septic shock.

BACKGROUND: Cholangitis-associated septic shock carries significant mortality. There is uncertainty regarding the most appropriate time to achieve biliary decompression. AIM: To determine whether the timing of biliary decompression and anti-microbial therapy affect the survival in cholangitis patients with septic shock. METHODS: Nested retrospective cohort study of all cholangitis-associated septic shock patients (hypotension requiring vasopressors) from an international, multi-centre database between 1996 and 2011. RESULTS: Among 260 patients (mean age 69 years, 57% male), overall mortality was 37%. Compared to nonsurvivors (n = 96), survivors (n = 164) had lower mean admission Acute Physiology And Chronic Health Evaluation (APACHE) II (22 vs. 28, P < 0.001) and lower median serum lactate on admission (3.4 vs. 4.6 mmol/L, P < 0.001). Survivors were more likely to receive appropriate anti-microbial therapy earlier (median 2.6 vs. 6.8 h from shock, P < 0.001). Survivors were also more likely to undergo successful biliary decompression earlier (median 8.8 vs. 22 h, P < 0.001). After adjusting for co-variates, APACHE II (odds ratio, OR 1.21 per increment (1.11-1.32), time delay to appropriate anti-microbial therapy [OR 1.15 per hour (1.07-1.25)] and delayed biliary decompression >12 h [OR 3.40 (1.12-10.31)] were all significantly associated with increased mortality (P < 0.04 for all; c-statistic 0.896). CONCLUSIONS: Patients with septic shock secondary to acute cholangitis have significant mortality. Endoscopic biliary decompression >12 h after the onset of shock and delayed receipt of appropriate anti-microbial therapy were both significantly associated with adverse hospital outcome. This might suggest that early initiation of anti-microbial therapy and urgent biliary decompression (within 12 h) could potentially improve outcomes in this high-risk patient population.

Appropriate and timely antimicrobial therapy in cirrhotic patients with spontaneous bacterial peritonitis-associated septic shock: a retrospective cohort study.

BACKGROUND: Spontaneous bacterial peritonitis (SBP)-associated septic shock carries significant mortality in cirrhosis. AIM: To determine whether practice-related aspects of antimicrobial therapy contribute to high mortality. METHODS: Retrospective cohort study of all (n = 126) cirrhotics with spontaneous bacterial peritonitis (neutrophil count >250 or positive ascitic culture)-associated septic shock (1996-2011) from an international, multicenter database. Appropriate antimicrobial therapy implied either in vitro activity against a subsequently isolated pathogen (culture positive) or empiric management consistent with broadly accepted norms (culture negative). RESULTS: Overall hospital mortality was 81.8%. Comparing survivors (n = 23) with non-survivors (n = 103), survivors had lower Acute Physiology and Chronic Health Evaluation (APACHEII) (mean ± s.d.; 22 ± 7 vs. 32 ± 8) and model for end-stage liver disease (MELD) (24 ± 9 vs. 34 ± 11) scores and serum lactate on admission (4.9 ± 3.1 vs. 8.9  ± 5.3), P < 0.001 for all. Survivors were less likely to receive inappropriate initial antimicrobial therapy (0% vs. 25%, P = 0.013) and received appropriate antimicrobial therapy earlier [median 1.8 (1.1-5.2) vs. 9.5 (3.9-14.3) h, P < 0.001]. After adjusting for covariates, APACHEII [OR, odds ratio 1.45 (1.04-2.02) per 1 unit increment, P = 0.03], lactate [OR 2.34 (1.04-5.29) per unit increment, P = 0.04] and time delay to appropriate antimicrobials [OR 1.86 (1.10-3.14) per hour increment, P = 0.02] were significantly associated with increased mortality. CONCLUSIONS: Cirrhotic patients with septic shock secondary to spontaneous bacterial peritonitis have high mortality (>80%). Each hour of delay in appropriate antimicrobial therapy was associated with a 1.86 times increased hospital mortality. Admission APACHEII and serum lactate also significantly impacted hospital mortality. Earlier initiation of appropriate antimicrobial therapy could substantially improve outcome.

Review article: Renal support in critical illness.

PURPOSE: This review provides a focused and comprehensive update on established and emerging evidence in acute renal replacement therapy (RRT) for critically ill patients with acute kidney injury (AKI). PRINCIPAL FINDINGS: There have been considerable technological innovations in the methods and techniques for provision of extracorporeal RRT in critical illness. These have greatly expanded our capability to provide both renal and non-renal life-sustaining organ support for critically ill patients. Recent data suggest earlier initiation of RRT in AKI may confer an advantage for survival and renal recovery. Two large trials have recently shown no added benefit to augmented RRT dose delivery in AKI. Observational data have also suggested that fluid accumulation in critically ill patients with AKI is associated with worse clinical outcome. However, several fundamental clinical questions remain to be answered, including issues regarding the time to ideally initiate/discontinue RRT, the role of high-volume hemofiltration or other blood purification techniques in sepsis, and extracorporeal support for combined liver-kidney failure. Extracorporeal support with RRT in sepsis, rhabdomyolysis, and liver failure are discussed, along with strategies for drug dosing and management of RRT in sodium disorders. CONCLUSIONS: We anticipate that this field will continue to expand to promote research and innovation, hopefully for the benefit of sick critically ill patients.

[Review article: Acute kidney injury in critical illness].

PURPOSE: This review provides a focused and comprehensive update on emerging evidence related to acute kidney injury (AKI). PRINCIPAL FINDINGS: Acute kidney injury is a significant clinical problem that increasingly complicates the course of hospitalization and portends worse clinical outcome for sick hospitalized patients. The recent introduction of consensus criteria for the diagnosis of AKI (i.e., RIFLE/AKIN classification) have greatly improved our capacity not only to standardize the diagnosis and classification of severity of AKI, but also to facilitate conducting comparative epidemiologic studies in an effort to better understand the burden of adult and pediatric AKI and its syndromes (i.e., septic, cardio-renal, hepato-renal). The characterization of several novel AKI-specific biomarkers (i.e., neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and interleukin-18) is extending our understanding of the pathophysiology of AKI. Moreover, these biomarkers appear to have clinical relevance for early detection and they provide prognostic value. These innovations are aiding in the design of epidemiologic surveys and randomized trials of therapeutic interventions. Strategies for prevention and conservative management of AKI across a range of clinical settings are discussed, including sepsis, hepato-renal syndrome, cardio-renal syndrome, rhabdomyolysis and in the perioperative setting. CONCLUSIONS: Acute kidney injury is an escalating clinical problem in hospitalized patients. Recent advances in AKI have improved knowledge of its pathogenesis, diagnosis, and prognosis; however, considerable research effort is needed. There are still relatively few interventions proven to alter the natural history of established AKI in hospitalized settings, and its development foretells less favourable outcomes.

Acetaminophen-induced acute liver failure treated with single-pass albumin dialysis: report of a case.

BACKGROUND: Acetaminophen (paracetamol) overdose is a leading cause of acute liver failure (ALF). When patients fulfill the King's College criteria for acetaminophen-induced ALF (AALF), they have a poor prognosis for survival without liver transplantation. Recent advances in artificial liver support have used albumin as a binding and scavenging molecule in ALF. One method, single-pass albumin dialysis (SPAD), involves dialyzing blood against an albumin-containing solution across a high-flux membrane to remove albumin-bound toxins. Herein, we describe our protocol for SPAD and report its use in a case of AALF as a bridge to native liver recovery. CASE: A 41-year-old female with no documented history of liver disease presented with acute acetaminophen toxicity and developed hepatic encephalopathy, coagulopathy and lactic acidosis. The patient met King's College criteria for liver transplantation, based on pH and INR, but was deemed not suitable as a candidate due to psychosocial comorbidities. On day 3 of her ICU admission, she received the first of five consecutive daily runs (total ~77 hours) of SPAD. The patient's course was complicated by cerebral edema requiring mannitol. She was extubated on day 11 and transferred to the ward by day 13. At ICU discharge, her liver function (INR 1.9, bilirubin 435 mmol/L) and kidney function were recovering. She did not have any long-term neurological sequelae. By hospital discharge (day 46) her native liver function had recovered with a bilirubin <100mmol/L. CONCLUSION: We describe a case of a patient with acetaminophen-induced acute liver failure who was successfully bridged to spontaneous native liver recovery as a result of SPAD treatment. In patients with ALF, SPAD may be an additional intervention for temporary extracorporeal support. Further investigation in larger prospective studies is warranted.

Beta-lactones as a new class of cysteine proteinase inhibitors: inhibition of hepatitis A virus 3C proteinase by N-Cbz-serine beta-lactone.

[reaction: see text] N-Benzyloxycarbonyl-L-serine beta-lactone (1) is shown to irreversibly inactivate the 3C cysteine proteinase of hepatitis A virus (HAV) with k(inact) = 0.70 min(-1), K(I) = 1.84 x 10(-4) M and k(inact)/K(I) = 3800 M(-1) min(-1) at an enzyme concentration of 0.1 microM. Mass spectrometric and HMQC NMR studies using 13C-labeled 1 show that the active site cysteine (Cys-172) thiol of the HAV 3C proteinase attacks the beta-position (i.e. C-4) of the oxetanone ring, thereby leading to ring opening and alkylation of the sulfur. In contrast, the enantiomer of this beta-lactone, 2, is a reversible competitive inhibitor (Ki = 1.50 x 10(-6) M) at similar enzyme concentrations. The beta-lactone motif represents a new class of inhibitors of cysteine proteinases.