Academy of Medicine, Singapore clinical guideline on the use of sedation by non-anaesthesiologists during gastrointestinal endoscopy in the hospital setting.

INTRODUCTION: In Singapore, non-anaesthesiologists generally administer sedation during gastrointestinal endoscopy. The drugs used for sedation in hospital endoscopy centres now include propofol in addition to benzodiazepines and opiates. The requirements for peri-procedural monitoring and discharge protocols have also evolved. There is a need to develop an evidence-based clinical guideline on the safe and effective use of sedation by non-anaesthesiologists during gastrointestinal endoscopy in the hospital setting. METHODS: The Academy of Medicine, Singapore appointed an expert workgroup comprising 18 gastroenterologists, general surgeons and anaesthesiologists to develop guidelines on the use of sedation during gastrointestinal endoscopy. The workgroup formulated clinical questions related to different aspects of endoscopic sedation, conducted a relevant literature search, adopted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology and developed recommendations by consensus using a modified Delphi process. RESULTS: The workgroup made 16 recommendations encompassing 7 areas: (1) purpose of sedation, benefits and disadvantages of sedation during gastrointestinal endoscopy; (2) pre-procedural assessment, preparation and consent taking for sedation; (3) Efficacy and safety of drugs used in sedation; (4) the role of anaesthesiologist administered sedation during gastrointestinal endoscopy; (5) performance of sedation; (6) post-sedation care and discharge after sedation; and (7) training in sedation for gastrointestinal endoscopy for non-anaesthesiologists. CONCLUSION: These recommendations serve to guide clinical practice during sedation for gastrointestinal endoscopy by non-anaesthesiologists in the hospital setting.

Application of a standardised protocol for hepatic venous pressure gradient measurement improves quality of readings and facilitates reduction of variceal bleeding in cirrhotics.

INTRODUCTION: Hepatic venous pressure gradient (HVPG) measurement is recommended for prognostic and therapeutic indications in centres with adequate resources and expertise. Our study aimed to evaluate the quality of HVPG measurements at our centre before and after introduction of a standardised protocol, and the clinical relevance of the HVPG to variceal bleeding in cirrhotics. METHODS: HVPG measurements performed at Singapore General Hospital from 2005-2013 were retrospectively reviewed. Criteria for quality HVPG readings were triplicate readings, absence of negative pressure values and variability of ≤ 2 mmHg. The rate of variceal bleeding was compared in cirrhotics who achieved a HVPG response to pharmacotherapy (reduction of the HVPG to < 12 mmHg or by ≥ 20% of baseline) and those who did not. RESULTS: 126 HVPG measurements were performed in 105 patients (mean age 54.7 ± 11.4 years; 55.2% men). 80% had liver cirrhosis and 20% had non-cirrhotic portal hypertension (NCPH). The mean overall HVPG was 13.5 ± 7.2 mmHg, with a significant difference between the cirrhosis and NCPH groups (p < 0.001). The proportion of quality readings significantly improved after the protocol was introduced. HVPG response was achieved in 28 (33.3%, n = 84) cirrhotics. Nine had variceal bleeding over a median follow-up of 29 months. The rate of variceal bleeding was significantly lower in HVPG responders compared to nonresponders (p = 0.025). CONCLUSION: The quality of HVPG measurements in our centre improved after the introduction of a standardised protocol. A HVPG response can prognosticate the risk of variceal bleeding in cirrhotics.

Epidemiology and Clinical Evolution of Liver Cirrhosis in Singapore.

INTRODUCTION: Liver cirrhosis is a common cause of morbidity and mortality and an important burden on the healthcare system. There is limited literature on liver cirrhosis in Singapore. We aimed to describe the epidemiology and clinical characteristics of cirrhotic patients seen in an ambulatory setting in a tertiary referral centre. MATERIALS AND METHODS: This is a retrospective observational cohort study of cirrhotic patients attending the ambulatory clinic of Singapore's largest tertiary hospital over 5 years. Cirrhosis was diagnosed on characteristic radiological features and/or histology. Aetiology of cirrhosis was determined by history, serology, biochemistry and/or histology. Data on decompensation events and death were retrieved from computerised hospital records. RESULTS: The study included 564 patients with median follow-up of 85 months. Mean age was 60.9 ± 12.5 years with 63.8% males. Main aetiologies of cirrhosis were chronic hepatitis B (CHB) (63.3%), alcohol (11.2%), cryptogenic (9%) and chronic hepatitis C (CHC) (6.9%). CHB was the predominant aetiology in Chinese and Malays whereas alcohol was the main aetiology in Indians. CHC cirrhosis was more common in Malays than other races. Majority had compensated cirrhosis with 76.8%/18.3%/5%; Child-Pugh A/B/C respectively. Decompensation events occurred in 155 patients (27.5%) and 106 of them (18.8%) died. Diagnosis of cirrhosis via surveillance ultrasound was associated with improved 10-year survival. Age at diagnosis, portal vein thrombosis, Child-Pugh class and decompensation within 1 year of diagnosis were independent predictors of mortality. CONCLUSION: CHB is the primary cause of liver cirrhosis in Singapore. The major aetiologies of cirrhosis vary amongst the different ethnic groups. Cirrhotics with advanced age, portal vein thrombosis, poorer liver function and early decompensation have a higher mortality risk.

Change in model for end-stage liver disease score at two weeks, as an indicator of mortality or liver transplantation at 60 days in acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is characterised by a sudden deterioration of underlying chronic liver disease, resulting in increased rates of mortality and liver transplantation. Early prognostication can benefit optimal allocation of resources. METHODS: ACLF was defined as per the disease criteria of the Asian Pacific Association for the Study of the Liver. Inpatient discharge summaries from between January 2001 and April 2013 were reviewed. The primary outcome was mortality or liver transplantation within 60 days from onset of ACLF. Absolute 'model for end-stage liver disease' (MELD) score and change in MELD at Weeks 1, 2 and 4 were reviewed in order to identify the earliest point for prediction of mortality or liver transplantation. RESULTS: Clinical data were collected on 53 subjects who fulfilled the inclusion and exclusion criteria. At 60 days from presentation, 20 patients (37.7%) died and 4 (7.5%) underwent liver transplantation. Increased MELD of ≥2 after 2 weeks was 75.0% sensitive and 75.9% specific for predicting mortality or liver transplantation. If the MELD score did not increase at 2 weeks, predictive chance of survival was 93.8% over the next 60 days. MELD change at 1 week showed poor sensitivity and specificity. Change at 4 weeks was too late for intervention. CONCLUSION: Change in MELD score at 2 weeks provides an early opportunity for prognostication in ACLF. A MELD score that does not deteriorate by Week 2 would predict 93.8% chance of survival for the next 60 days. This finding warrants further validation in larger cohort studies.

Epidemiology and prognosis of paraneoplastic syndromes in hepatocellular carcinoma.

Background. Paraneoplastic syndromes (PNS) such as hypercalcaemia, hypercholesterolaemia, and erythrocytosis have been described in hepatocellular carcinoma (HCC). Aims. (1) To examine the prevalence, clinical characteristics, and survival of PNS in HCC patients and (2) to evaluate the extent to which each individual PNS impacts on patient survival. Methods. We prospectively evaluated the prevalence, clinical characteristics, and survival of PNS among 457 consecutive HCC patients seen in our department over a 10-year period and compared them with HCC patients without PNS. Results. PNS were present in 127 patients (27.8%). The prevalence of paraneoplastic hypercholesterolemia, hypercalcemia, and erythrocytosis 24.5%, 5.3%, and 3.9%, respectively. Patients with PNS had significantly higher alpha-fetoprotein levels, more advanced TNM stage, and shorter survival. Among the individual PNS, hypercalcemia and hypercholesterolemia were associated with more advanced disease and reduced survival but not erythrocytosis. On multivariate analysis, the presence of PNS was not found to be an independent prognostic factor for reduced HCC survival. Conclusion. PNS are not uncommon in HCC and are associated with poor prognosis and reduced survival due to their association with increased tumor burden. However, they do not independently predict poor survival. Individual PNS impact differently on HCC outcome; paraneoplastic hypercalcemia in particular is associated with poor outcome.

Screening for hepatocellular carcinoma.

Hepatocellular carcinoma is one of the most serious complications of chronic liver disease and is the third most lethal cancer worldwide. Symptoms emerge very late in the course of its natural history with an attendant poor outcome. Screening is of paramount importance in a successful strategy to treat hepatocellular carcinoma. A successful screening program rests the availability of an at-risk population, reliable diagnostics tests that are able to diagnose a condition at a stage where effective, and relatively simple and acceptable treatments are available. In hepatocellular carcinoma, all patients with liver cirrhosis or chronic hepatitis B virus infection are at risk. Six monthly ultrasound and alpha-foetoprotein determination form the backbone of the screening program. Newer modalities and tests show promise but have not supplanted the standard tests.

Treatment of hepatitis B in decompensated liver cirrhosis.

Chronic hepatitis B infection progresses from an asymptomatic persistently infected state to chronic hepatitis, cirrhosis, decompensated liver disease, and/or hepatocellular carcinoma. About 3% of patients with chronic hepatitis develop cirrhosis yearly, and about 5% of individuals with hepatitis B cirrhosis become decompensated annually. The outcome for patients with decompensated cirrhosis is bleak. Lamivudine, the first oral antiviral agent available for hepatitis B treatment is safe and effective and can improve or stabilize liver disease in patients with advanced cirrhosis and viraemia. Viral resistance restricts its prolonged use. Entecavir and tenofovir are newer agents with excellent resistance profile to date. These and some other antiviral agents are being investigated for optimal use in this rather challenging patient group.

Diagnosis and management of acute variceal bleeding: Asian Pacific Association for Study of the Liver recommendations.

BACKGROUND: Acute variceal bleeding (AVB) is a medical emergency and associated with a mortality of 20% at 6 weeks. Significant advances have occurred in the recent past and hence there is a need to update the existing consensus guidelines. There is also a need to include the literature from the Eastern and Asian countries where majority of patients with portal hypertension (PHT) live. METHODS: The expert working party, predominantly from the Asia-Pacific region, reviewed the existing literature and deliberated to develop consensus guidelines. The working party adopted the Oxford system for developing an evidence-based approach. Only those statements that were unanimously approved by the experts were accepted. RESULTS: AVB is defined as a bleed in a known or suspected case of PHT, with the presence of hematemesis within 24 h of presentation, and/or ongoing melena, with last melanic stool within last 24 h. The time frame for the AVB episode is 48 h. AVB is further classified as active or inactive at the time of endoscopy. Combination therapy with vasoactive drugs (<30 min of hospitalization) and endoscopic variceal ligation (door to scope time <6 h) is accepted as first-line therapy. Rebleeding (48 h of T (0)) is further sub-classified as very early rebleeding (48 to 120 h from T (0)), early rebleeding (6 to 42 days from T (0)) and late rebleeding (after 42 days from T (0)) to maintain uniformity in clinical trials. Emphasis should be to evaluate the role of adjusted blood requirement index (ABRI), assessment of associated comorbid conditions and poor predictors of non-response to combination therapy, and proposed APASL (Asian Pacific Association for Study of the Liver) Severity Score in assessing these patients. Role of hepatic venous pressure gradient in AVB is considered useful. Antibiotic (cephalosporins) prophylaxis is recommended and search for acute ischemic hepatic injury should be done. New guidelines have been developed for management of variceal bleed in patients with non-cirrhotic PHT and variceal bleed in pediatric patients. CONCLUSION: Management of acute variceal bleeding in Asia-Pacific region needs special attention for uniformity of treatment and future clinical trials.

Is the prognosis of young patients with hepatocellular carcinoma poorer than the prognosis of older patients? A comparative analysis of clinical characteristics, prognostic features, and survival outcome.

BACKGROUND: Hepatocellular carcinoma (HCC) is uncommon in young adults. This study examined the clinical characteristics and survival outcome of young HCC patients compared with those in older patients. METHODS: Data were prospectively collected from 638 patients diagnosed with HCC over a 9-year period. Patients aged < or =40 years at diagnosis of HCC were defined as young HCC patients. Their clinical characteristics and survival was compared with those aged >40 years. RESULTS: The prevalence of young HCC was 8.6% (55/638). Young HCC patients had a significantly higher rate of hepatitis B-related disease (HBsAg positivity: 85.5% vs. 59.7%, P = 0.003), better Child-Pugh status (Child-Pugh class A: 69.1% vs. 43.9%, P = 0.002), and lower rates of cirrhosis (12.7% vs. 34.3%, P = 0.001) compared with the older group. They had more advanced disease at diagnosis, with higher alpha-fetoprotein levels (>12 000 microg/l: 45.4% vs. 30.5%, P = 0.026), a higher incidence of portal vein involvement (63.6% vs. 40%, P = 0.003), and a more advanced TNM stage (TNM IV: 83.6% vs. 66.4%, P = 0.018). More young patients were eligible for surgical resection (18.2% vs. 8.2%, P = 0.014). The overall survival between the two groups was similar, but when the patients were stratified for stage of disease, the median survival of young patients with early disease was superior to that of older patients (51.2 vs. 11.6 months, P = 0.025). CONCLUSIONS: HCC in young adults occurs mainly in hepatitis B carriers and is often diagnosed at an advanced stage. Their survival outcome is not different from that of older patients because the advanced disease at presentation offsets the advantages of better liver function and a higher resection rate. However, there is a distinct survival advantage for young patients diagnosed with early disease. These results support the importance of extending HCC surveillance to young hepatitis B carriers.

Albumin dialysis in critically ill patients: use versus omission of intradialytic heparin.

Albumin liver dialysis using the Molecular Adsorbent Recirculating System (MARS) (Teraklin AG, Rostock, Germany) is used in severe acute liver failure (ALF). We hypothesized that intradialytic heparin worsens preexisting hemostatic defects without enhancing system longevity or therapeutic efficacy. This was a retrospective, single center study of 10 critically ill patients (M : F = 8:2; mean age 58.5 +/- 16.5 years old; Acute Physiology and Chronic Health Evaluation II 25.0 +/- 3.5) treated with 31 MARS sessions (intradialytically heparinized : nonheparinized = 18:13). Mortality in this cohort was 80%. All MARS circuits were primed with dilute heparinized saline before commencement. However, intradialytic, intermittent, bolus heparin was administered on an ad hoc basis with circuit saline flush where indicated. Acute renal replacement therapy was instituted where indicated. Average total intradialytic heparin used was 757 +/- 389 IU. Circuit pressures were stable with or without intradialytic heparin. Significant reductions in serum urea, creatinine, ammonia, and total bilirubin were achieved using intradialytically heparinized and nonheparinized MARS. Thrombocytopenia and elevated activated partial thromboplastin time (aPTT) were further deranged post-MARS for both circuit types, but significantly so in intradialytically heparinized MARS: pre- versus post-MARS aPTT (s) 57.8 +/- 17.6 versus 88.7 +/- 48.0, P = 0.011, and platelet count (x 10(3)/L) 102.9 +/- 61.1 versus 84.4 +/- 50.5; P = 0.009. The use of low dose, intradialytic heparin during MARS exacerbates preexisting severe coagulopathy and thrombocytopenia in patients with severe ALF without enhancing circuit function and longevity. However, the role and safety of heparinized saline prime need further investigation.

Chronic hepatitis B virus (HBV) infection in pregnancy.

BACKGROUND: Hepatitis B is a considerable disease burden among Asians. Little is known about its disease behaviour in pregnant women. METHODS: Clinical, laboratory and radiological data of pregnant and peri-partum females with chronic hepatitis B virus (HBV) infection who were seen between years 1999 and 2004 were studied. Their progress was documented up to 6 months post-partum. This was compared with the age-matched and HBe status-matched, non-pregnant, female patients with chronic HBV infection, who were consecutively selected from the department's registry as controls (ratio 1 mother: 4 non-pregnant controls), over the corresponding period. RESULTS: A total of 35 mothers and 140 controls were studied. Mean age of patients was 30.7 +/- 3.6 years. Majority of mothers (74.3%) presented during pregnancy itself. 1st:2nd:3rd trimester presentation = 20.0%:48.6%:5.7%. Majority (65.7%) were positive for HBe antigen (HBeAg) at the time of presentation. About 57.1% mothers had a clinical event in the form of alanine transferase (ALT) elevation and/or loss of HBeAg vs 28.8% among controls (P = 0.002). Among HBeAg-positive subjects, more mothers (14.3%) than controls (2.2%) had resultant HBeAg loss (P = 0.02). Among HBeAg negative subjects, more mothers than controls had serum ALT elevations in the post-partum period (P = 0.007). Overall, more mothers had elevated ALT levels than controls, regardless of their HBeAg status. Neither mothers nor control subjects decompensated clinically, neither required liver transplantation nor died during the study period. CONCLUSIONS: Pregnancy is associated with serum ALT elevation and HBeAg loss in patients with chronic HBV infection in the peri-partum period.

A study into the risk of exacerbation of chronic hepatitis B after liver resection for hepatocellular carcinoma.

Liver resection is commonly performed for solitary hepatocellular carcinoma (HCC) in well-compensated cirrhotic and noncirrhotic patients. Data concerning exacerbation of chronic hepatitis B (ECHB) post-liver resection are scant. To determine the incidence, risk factors, and clinical outcomes of ECHB in patients who underwent hepatic resection for HCC. The methods consisted of a retrospective review of consecutive patients with chronic hepatitis B virus (HBV) infection who had undergone liver resection for HCC from January 2002 to December 2004. Seventy-seven patients underwent 82 liver resections; the mean age was 58.0 +/- 12.1 years; 87% male; 20% hepatitis B e-antigen positive. Incidence of all causes of postoperative hepatitis was 25.6% (n = 21), and ECHB was 8.5% (n = 7). Both groups had their peak alanine aminotransferases, 231.0 IU/L (74-1,400) and 312 IU/L (147-1,400), respectively, observed at day 84 postresection. Three patients died as a result of ECHB within 4 months postsurgery. One- and 2-year survival rates were poorest for the ECHB group at 42.9 and 21.4%, compared with those with postoperative hepatitis due to other causes at 60.3 and 45.2% and those without postoperative hepatitis at 87.7 and 73.5% (p < 0.001). Liver resection for HCC in patients with chronic HBV infection carries a risk for ECHB, and affected patients have poorer clinical outcomes. There is a need for close monitoring of these patients preoperatively and in the early postoperative period.

Anticoagulation minimization is safe and effective in albumin liver dialysis using the molecular adsorbent recirculating system.

The molecular adsorbent recirculating system (MARS) is a blood purification device with renal and hepatic dialytic effects. This study examined the use of low-dose unfractionated heparin in MARS. This was a prospective, observational study of 15 MARS treatment sessions (mean duration per treatment cycle = 12.2 +/- 4.5 h) in four patients with severe acute decompensation of chronic liver disease (n = 3) and fulminant hepatic failure (n = 1) treated with intermittent MARS. All patients were critically ill (APACHE II 24.8 +/- 3.3). Renal dialysis was with continuous hemofiltration and/or slow low-efficiency dialysis. One MARS session was terminated because of vascular access occlusion (1/15; 6.7%). Bleeding was noted in two sessions (2/15; 13%). Twelve MARS sessions were heparin-free and three treatments were with mean heparin dose of 833 +/- 382 IU. Serum biochemical parameters pre- and post-MARS were total bilirubin (micromol/L): 409.4 +/- 141.6 versus 282.9 +/- 90, P < 0.05; plasma ammonia (micromol/L): 44.3 +/- 21.2 versus 28.8 +/- 20.2, P = 0.002; urea (mmol/L): 15.9 +/- 11.8 versus 7.9 +/- 6.6, P = 0.002; creatinine (micromol/L): 252.4 +/- 151.9 versus 150.1 +/- 96.6, P = 0.003. Pre-MARS versus post-MARS systolic (SBPs) and diastolic (DBPs) blood pressures (mm Hg) were SBP = 129.2 +/- 27.7 versus 124 +/- 25, P = 0.838; and DBP = 60.7 +/- 15.3 versus 56 +/- 13, P = 0.595. Prothrombin time (PT), activated partial thromboplastin time (aPTT) and platelet count (Plt) pre- and post-MARS were PT(s): 22 +/- 7.9 versus 23.8 +/- 10.2, P = 0.116; aPTT (s): 64.5 +/- 40.9 versus 85.5 +/- 50.6, P = 0.092; and Plt (x10(3)/mm(3)): 87 +/- 67.6 versus 68.8 +/- 39, P = 0.098. MARS priming with heparin saline was safe. Heparin-minimized MARS did not compromise circuit function and longevity in extended intermittent MARS.

Treatment of chronic hepatitis C in patients with end-stage renal disease and hemophilia--the Singapore experience.

OBJECTIVE: The aim of this study was to determine the response to treatment with interferon-alpha (IFN-alpha) in patients with chronic hepatitis C who had end-stage renal disease (ESRD) or hemophilia in Singapore. METHODS: Treatment-naive hepatitis patients with ESRD or hemophilia were given IFN-alpha(2a) 3 million units three times per week for 12 months in an open-label study. Hepatitis C virus RNA was determined before treatment, at the end of treatment and 6 months thereafter. Regular clinical examinations including blood counts and biochemistry were carried out during and after the treatment. RESULTS: Nine consecutive patients with ESRD (8 men and 1 woman) and 6 consecutive male patients with hemophilia, with a mean age of 43 and 40 years, received treatment. Patients in both groups were predominantly infected with hepatitis C virus genotype 1 and had significant cytopenia affecting all three cell lines during the treatment; only 1 patient developed serious neutropenia, temporarily demanding a reduction of his IFN dose. Biochemical and virological responses at the end of treatment were accomplished by 8 of the 9 (89%) patients with ESRD and 4 of the 6 (67%) patients with hemophilia; however, 1 patient with ESRD and 2 with hemophilia relapsed after the treatment. Four of the 7 patients with ESRD who had sustained virological response underwent successful kidney transplantation later on. CONCLUSION: Monotherapy with IFN-alpha for 12 months is safe for treatment of the patients with chronic hepatitis C who had ESRD or those with hemophilia. A higher sustained virological response rate was observed in patients with ESRD than in those with hemophilia (78 vs. 33%).