Fontan Hepatopathy-Managing Unknowns.

BACKGROUND AND AIMS: How to best monitor Fontan-associated liver disease (FALD) remains unclear. We describe results from a prospective liver care pathway in adults (n=84) with a Fontan circulation. METHODS: Routine assessment of the liver, by acoustic radiation force frequency and ultrasound was undertaken. Results, including liver biochemistry, systemic ventricular function (echocardiography), functional class, medication use and clinical endpoints (varices, hepatocellular carcinoma, heart transplantation and death) were collated. RESULTS: Most individuals returned a cirrhotic range acoustic radiation force impulse imaging (ARFI) result. ARFI values were greater in the proportion of individuals with hepatic nodularity (p=0.024). Univariate analysis demonstrated moderate correlation with platelet number (Spearmans rho= -0.376, p=0.049). Patients with clinical endpoints had lower platelets (p=0.012) but only a trend to hepatic nodularity (p=0.057). Clinical endpoints were more common in those with ventricular dysfunction (p=0.011). Multivariate analysis revealed that age at Fontan and being on angiotensin converting enzyme inhibitors (ACEI) predicted ARFI score (ß=0.06 [95% CI 0.01-0.09], p=0.007 and ß=0.53 [95% CI 0.17-0.89], p=0.005, respectively). However, these associations were not significant once adjusted for Fontan type, age at ARFI, systemic ventricle morphology, ventricle function, or Model for End-stage Liver Disease (MELD-XI) excluding international normalised ratio (INR) (p>0.05 for all). CONCLUSIONS: Ideal FALD monitoring remains unclear. ARFI has utility as a binary non-invasive indicator of cirrhosis, highlighting individuals who may need more frequent ongoing monitoring for hepatocellular carcinoma. However, no definite advantage to serial ARFI, once cirrhotic range ARFI results are present, has been identified.

Fourier-Transform Infra-Red Microspectroscopy Can Accurately Diagnose Colitis and Assess Severity of Inflammation.

The diagnosis and management of inflammatory bowel disease relies on histological assessment, which is costly, subjective, and lacks utility for point-of-care diagnosis. Fourier-transform infra-red spectroscopy provides rapid, non-destructive, reproducible, and automatable label-free biochemical imaging of tissue for diagnostic purposes. This study characterises colitis using spectroscopy, discriminates colitis from healthy tissue, and classifies inflammation severity. Hyperspectral images were obtained from fixed intestinal sections of a murine colitis model treated with cell therapy to improve inflammation. Multivariate analyses and classification modelling were performed using supervised and unsupervised machine-learning algorithms. Quantitative analysis of severe colitis showed increased protein, collagen, and nucleic acids, but reduced glycogen when compared with normal tissue. A partial least squares discriminant analysis model, including spectra from all intestinal layers, classified normal colon and severe colitis with a sensitivity of 91.4% and a specificity of 93.3%. Colitis severity was classified by a stacked ensemble model yielding an average area under the receiver operating characteristic curve of 0.95, 0.88, 0.79, and 0.85 for controls, mild, moderate, and severe colitis, respectively. Infra-red spectroscopy can detect unique biochemical features of intestinal inflammation and accurately classify normal and inflamed tissue and quantify the severity of inflammation. This is a promising alternative to histological assessment.

The management of gastro-oesophageal reflux disease.

If there are no features of serious disease, suspected gastro-oesophageal reflux disease can be initially managed with a trial of a proton pump inhibitor for 4-8 weeks. This should be taken 30-60 minutes before food for optimal effect. Once symptoms are controlled, attempt to withdraw acid suppression therapy. If symptoms recur, use the minimum dose that controls symptoms. Patients who have severe erosive oesophagitis, scleroderma oesophagus or Barrett's oesophagus require long-term treatment with a proton pump inhibitor. Lifestyle modification strategies can help gastro-oesophageal reflux disease. Weight loss has the strongest evidence for efficacy. Further investigation and a specialist referral are required if there is no response to proton pump inhibitor therapy. Atypical symptoms or signs of serious disease also need investigation.

Local fistula injection of allogeneic human amnion epithelial cells is safe and well tolerated in patients with refractory complex perianal Crohn's disease: a phase I open label study with long-term follow up.

BACKGROUND: Local fistula injection of mesenchymal stromal/stem cells (MSC) is effective for complex perianal Crohn's fistulas but is also expensive and requires specialised facilities for cell revival before administration. Human amnion epithelial cells (hAEC) are non-MSC cells with therapeutic properties. The primary aim of this study was safety of hAEC therapy. Secondary aims included hAEC efficacy, feasibility of the protocol and impact on quality of life. METHODS: A phase I open label study of ten adults with active complex Crohn's perianal fistulas refractory to conventional treatment, including anti-tumour necrosis factor alpha therapy, was undertaken. A single dose of hAEC was injected into the fistula tract(s) after surgical closure of the internal opening(s). Study outcomes were assessed at week 24 with follow up for at least 52 weeks. FINDINGS: Local injection of hAEC was safe, well tolerated and the injection procedure was feasible. Complete response occurred in 4 patients, and a partial response in an additional 4 patients. There was a mean reduction in the Perianal Disease Activity Index of 6.5 points (95% CI -9.0 to -4.0, p = 0.0002, paired t-test), modified Van Assche MRI Index of 2.3 points (95% CI -3.9 to -0.6, p = 0.012, paired t-test) and a mean improvement of 15.8 points (95% CI 4.9 to 26.8, p = 0.010, paired t-test) in quality of life using the Short IBD-Questionnaire in complete responders. INTERPRETATION: Local injection of hAEC therapy for refractory complex perianal fistulising Crohn's disease appears safe, well-tolerated, feasible and demonstrated improvement. Quality of life is improved in those who achieve complete fistula healing. FUNDING: This study was funded by competitive research grant funding from the Gastroenterological Society of Australia Seed Grant 2018.

Survival outcomes and predictors of mortality, re-bleeding and complications for acute severe variceal bleeding requiring balloon tamponade.

BACKGROUND: Acute severe variceal bleeding (AVB) refractory to medical and endoscopic therapy is infrequent but associated with high mortality. Historical cohort studies from 1970-1980s no longer represent the current population as balloon tamponade is no longer first-line therapy for variceal bleeding; treatments including vasoactive therapies, intravenous antibiotics, endoscopic variceal band ligation are routinely used, and there is improved access to definitive treatments including transjugular intrahepatic portosystemic shunts. However, only a few studies from the current era exist to describe the practice of balloon tamponade, its outcomes, and predictors with a requirement for further updated information. AIM: To describe current management of AVB requiring balloon tamponade and identify the outcomes and predictors of mortality, re-bleeding and complications. METHODS: A retrospective multi-centre cohort study of 80 adult patients across two large tertiary health networks from 2008 to 2019 in Australia who underwent balloon tamponade using a Sengstaken-Blakemore tube (SBT) were included for analysis. Patients were identified using coding for balloon tamponade. The primary outcome of this study was all-cause mortality at 6 wk after the index AVB. Secondary outcomes included re-bleeding during hospitalisation and complications of balloon tamponade. Predictors of these outcomes were determined using univariate and multivariate binomial regression. RESULTS: The all-cause mortality rates during admission and at 6-, 26- and 52 wk were 48.8%, 51.2% and 53.8%, respectively. Primary haemostasis was achieved in 91.3% and re-bleeding during hospitalisation occurred in 34.2%. Independent predictors of 6 wk mortality on multivariate analysis included the Model for Endstage Liver disease (MELD) score (OR 1.21, 95%CI 1.06-1.41, P = 0.006), advanced hepatocellular carcinoma (OR 11.51, 95%CI 1.61-82.20, P = 0.015) and re-bleeding (OR 13.06, 95%CI 3.06-55.71, P < 0.001). There were no relevant predictors of re-bleeding but a large proportion in which this occurred did not survive 6 wk (76.0% vs 24%). Although mucosal trauma was the most common documented complication after SBT insertion (89.5%), serious complications from SBT insertion were uncommon (6.3%) and included 1 patient who died from oesophageal perforation. CONCLUSION: In refractory AVB, balloon tamponade salvage therapy is associated with high rates of primary haemostasis with low rates of serious complications. Re-bleeding and mortality however, remain high.

Transitioning patients with inflammatory bowel disease from hospital-based to rapid home-based infliximab: A stepwise, safety and patient-orientated process towards sustainability.

BACKGROUND: Infliximab and other intravenous biologic infusions are increasingly used for chronic disorders like inflammatory bowel disease (IBD). Rapid infliximab and home-based infusions are attractive solutions to address resource and capacity issues for infusion centres, yet infliximab infusion reactions reportedly occur in up to 25% of patients with IBD, even at the manufacturers' recommended infusion duration of 2 h. AIM: To evaluate the safety, cost and patient satisfaction of transitioning from hospital-based, standard 2 h to rapid home-based, 30-min infliximab infusions. METHODS: All patients receiving rapid infliximab infusions for IBD between 2014 to 2017 (39 mo) were compared with those who received standard two-hour IFX infusions between 2005-2013 (96 mo) at a single IBD centre. Data (per-infusion and per-individual) including adverse drug reactions (ADR), duration (based on needle-departure time) and other clinical data were extracted from electronic medical records. Multivariable logistical regression analysis assessed factors potentially associated with increased risk of ADRs to rapid infusions. The primary outcome was the safety [as per relative risk (RR) of ADR] of (1) rapid 30 m infusions (both hospital- and home-based) vs standard 2 h infliximab infusions. Also, relative cost per infusion and patient satisfaction and productivity were evaluated in rapid infusion recipients who transitioned to home-based infusions. RESULTS: Of 129 patients who received 1461 rapid IFX infusions (2014-2017) were compared with 169 patients who received 2214 standard IFX infusions (2005-2013). Within the rapid cohort, 55 (42.6%) were males, median age 42 years (range 18, 86), 114 (84%) had Crohn's disease (CD) with a median disease duration 5 years (0, 36). Median needle to departure time was higher in the standard than the rapid protocol group, 108 (70, 253) vs 50 (33, 90) min, P < 0.001), with a per infusion cost of $AUD 107.50 vs $49.77, respectively (both P < 0.001). There was no difference in median infusion duration or costs between rapid home vs hospital-based infusions (P = 0.21). 8 patients in the rapid infliximab cohort had an ADR compared with 23 standard infliximab recipients (RR 0.55% vs 1.04% respectively), hence a higher likelihood of ADR with standard compared to rapid infusions [RR 3.0, 95%CI (1.2, 7.7), P = 0.02]. No ADRs were observed in 405 rapid home-based infusions. A lower body mass index (< 22 kg/m2), presence of one or more extra intestinal manifestations, longer disease duration (> 3 years) and previous exposure to another biologic were each independently associated with a higher likelihood of reaction (s) to rapid infusions. All (100%) survey respondents preferred the rapid vs standard infusions, however within rapid infusion recipients, 61.3% found home based infusions more inconvenient than hospital-based infusions despite a median of 0 h per week missed from paid work and no self-reported loss of work productivity. CONCLUSION: Transitioning to rapid infliximab infusions appears very safe with significant cost benefit, patient satisfaction and avails the provision of safe, efficient, home-based infliximab infusions by IBD centres worldwide.

Fontan-associated liver disease: pathophysiology, investigations, predictors of severity and management.

Cardiac hepatopathy is the liver injury resulting from congestion and ischaemia associated with acute or chronic heart failure. The improved longevity of adults with operated congenital heart disease who develop heart failure as an increasingly late event makes this form of liver injury increasingly clinically relevant. Patients with congenital heart disease with a single ventricle anomaly, who require creation of a Fontan circulation, are particularly vulnerable as they have elevated venous filling pressures with chronic liver congestion. Progression to liver fibrosis and eventually cirrhosis may occur, with its associated risks of liver failure and hepatocellular carcinoma. This risk likely increases over the patient's lifetime, related to the duration post-surgical repair and reflects the chronicity of congestion. Liver biopsy is rarely performed due to a higher risk of complications in the setting of elevated venous pressures, and the frequent use of anticoagulation. Non-invasive methods of liver assessment are poorly validated and different factors require consideration compared to other chronic liver diseases. This review discusses the current understanding of cardiac hepatopathy in congenital heart disease patients with a Fontan circulation. This entity has recently been called Fontan Associated Liver Disease in the literature, with the term useful in recognising that the pathophysiology is incompletely understood, and that long-standing venous pressure elevation and hypoxaemia are presumed to play an additional significant role in the pathogenesis of the liver injury.

Vedolizumab for ulcerative colitis: Real world outcomes from a multicenter observational cohort of Australia and Oxford.

BACKGROUND: Vedolizumab (VDZ), a humanised monoclonal antibody that selectively inhibits alpha4-beta7 integrins is approved for use in adult moderate to severe ulcerative colitis (UC) patients. AIM: To assess the efficacy and safety of VDZ in the real-world management of UC in a large multicenter cohort involving two countries and to identify predictors of achieving remission. METHODS: A retrospective review of Australian and Oxford, United Kingdom data for UC patients. Clinical response at 3 mo, endoscopic remission at 6 mo and clinical remission at 3, 6 and 12 mo were assessed. Cox regression models and Kaplan Meier curves were performed to assess the time to remission, time to failure and the covariates influencing them. Safety outcomes were recorded. RESULTS: Three hundred and three UC patients from 14 centres in Australia and United Kingdom, [60% n = 182, anti-TNF naïve] were included. The clinical response was 79% at 3 mo with more Australian patients achieving clinical response compared to Oxford (83% vs 70% P = 0.01). Clinical remission for all patients was 56%, 62% and 60% at 3, 6 and 12 mo respectively. Anti-TNF naive patients were more likely to achieve remission than exposed patients at all the time points (3 mo 66% vs 40% P < 0.001, 6 mo 73% vs 46% P < 0.001, 12 mo 66% vs 51% P = 0.03). More Australian patients achieved endoscopic remission at 6 mo compared to Oxford (69% vs 43% P = 0.01). On multi-variate analysis, anti-TNF naïve patients were 1.8 (95%CI: 1.3-2.3) times more likely to achieve remission than anti-TNF exposed (P < 0.001). 32 patients (11%) had colectomy by 12 mo. CONCLUSION: VDZ was safe and effective with 60% of UC patients achieving clinical remission at 12 mo and prior anti-TNF exposure influenced this outcome.

An audit of transfusion of red blood cell units in pediatric anesthesia.

BACKGROUND: Patients undergoing surgery are an important user of red blood cells (RBC). Increasingly, medical staff and patients wish to know the likelihood of RBC transfusion for appropriate resource allocation and to inform preoperative discussions regarding risk. Although some adult data are available, little is known about RBC use in children. AIM: The aim of this study was to describe RBC use in the perioperative period in a large pediatric hospital. METHODS: Over a 2-year period the hospital operating theatre database and trauma registry was merged with the blood bank database to identify episodes where RBC units were transfused in association with anesthesia. Incidence of transfusion of RBC units associated with particular procedures was then calculated. RESULTS: A total of 21 441 patients underwent 32 511 anesthetics from January 1, 2006 to December 31, 2007, and 9838 units of RBC were released from the hospital blood bank of which 4070 (41%) were transfused in the perioperative period. Cardiac surgery was the greatest user of RBC units (2359 units). Acute major trauma accounted for only 159 units. Overall 6.3% of anesthetics were associated with a RBC transfusion. The procedures with the greatest frequency of RBC transfusion were cardiac surgery on bypass (79%), cardiac off bypass (55%), liver transplant (87%) and cranioplasty (61%). CONCLUSION: In a tertiary pediatric hospital surgery accounts for a substantial proportion of total RBC use, with particular procedures accounting for the majority of transfusions.

Endocuff Vision is safe to use for dysplasia surveillance in patients with ulcerative colitis: a feasibility study.

Background and study aims Endocuff Vision improves adenoma detection rates in patients without inflammatory bowel disease. This study aimed to investigate the safety and feasibility of Endocuff Vision-assisted high-definition white light endoscopy (HDWLE) with dye-spray chromoendoscopy for detection of dysplasia in patients with ulcerative colitis. Patients and methods Patients with clinically inactive ulcerative colitis due for dysplasia surveillance were recruited. Procedural endpoints included safety, cecal intubation rate (CIR), terminal ileum intubation rate (TIR), withdrawal time, polyp detection rate, dysplasia detection rate (DDR), and sessile serrated lesion detection rate. Results Twenty-five patients (9 female, median age 57 [range 28 - 82] years) were studied. Endocuff Vision-assisted HDWLE was completed in all participants, with a CIR of 100 %, in a median 4 minutes (range 2 - 16), and a TIR of 88% in a median of 6.5 minutes (range 3 - 19). Median withdrawal time was 18 minutes (range 10 - 55), including application of dye-spray, biopsies and polypectomy. The Mayo Endoscopic subscore was 0 in 11, 1 in 9, and 2 in 5 patients. The DDR was 24 % (6 patients had a total of 12 dysplastic lesions) and sessile serrated lesion detection rate was 12 % (3 patients had a total of 4 sessile serrated polyps). No serious adverse events occurred, with one patient developing clinically insignificant minor mucosal bleeding. Conclusion Endocuff Vision-assisted HDWLE is feasible and safe in patients with ulcerative colitis undergoing dysplasia surveillance. Further studies are required to assess superiority of this technique compared with standard high-definition white light endoscopy with chromoendoscopy.