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EBM in GI Emergency Hsiu-Po Wang Department of Emergency Medicine National Taiwan University Hospital EBM in GI emergency • • • • • Non-variceal UGI bleeding Variceal UGI bleeding Stress ulcer Acute pancreatitis Fulminant hepatic failure/ Hepatic coma Consensus Recommendations for Nonvariceal Upper Gastroinestinal Bleeding Ann Intern Med. 2003;139:843-857 Categorizaion of Evidence Quality of Evidence Description I Evidence obtained from at least 1 properly randomized, control led trial II-1 Evidence obtained from well-designed controlled trials without randomization II-2 Evidence obtained from well-designed cohort or case-control s tudies, preferably from more than 1 center or research group II-3 Evidence obtained from comparisons between times or places with or without intervention, or dramatic results in uncontrolled experiments III Opinions of respected authorties, based on clinical experience, descriptive studies, or reports of expert committees Recommendation • Immediate evaluation and appropriate resuscitation are cri tical to proper management – Evidence: III Opinions of respected authorties, based on clinical experience, d escriptive studies, or reports of expert committees Recommendation - NG tube • In selected patients, the placement of a NG tube can be considered because the findings may have prognostic value. – Evidence: II-3 Evidence obtained from comparisons between times or places with or without intervention, or dramatic results in uncontrolled experiments Recommendation - NG tube • The detection of red blood with in-and-out NG: poor outcome and need for emergency endoscopy • RUGBE: the presence of bright blood in the aspirate was an independent predictor of rebleeding • OG or NG lavage may be helpful to clear the blood before endoscopy Recommendation - Clinical stratification • Clinical stratification of patient into low- and high-risk categories is important for proper management. – Evidence: II-2 Evidence obtained from well-designed cohort or case-control studi es, preferably from more than 1 center or research group Recommendation - Clinical stratification • Rebleeding: > 65 years old, shock, poor overall health status, comorbid illnesses, low initial hb level, melena, transfusion requirement. fresh red blood on rectal examination/emesis/NG as pirate • Death: > 60 years old, shock, poor overall health status, comorbid illnesses, low initial Hb level, melena, transfusion requirement. fresh red blood on rectal examination/emesis/NG aspirate, inset of bleeding while hospitalized for another reason, sepsis, ↑ BUN/Cre/GOT • Specialty of attending physician influence the outcome Recommendation - Early stratification based on clinical and endoscopic criteria • Early stratification of patient into low- and high-risk categories for rebleeding or mortality, based on clinical and endoscopic criteria, is important for proper manage ment. – Evidence: I Evidence obtained from at least 1 properly randomized, controlled trial Recommendation - Early stratification based on clinical and endoscopic criteria • Laine et al: clean ulcer base 5%, flat spot 10%, adherent clot 22%, nonbleeding visible vessel 43%, active bleeding 55% • Rockall risk score: age, shock, comorbidity, diagnosis, endoscopic stigmata of recent bleeding Recommendation - disposition • Early endoscopy with risk classification by clinical and endoscopic criteria allows for safe and prompt discharge of patients classified as low risk – Evidence: I • Improves patient outcomes for patients classified as high risk – Evidence: II • And reduces resource utilization for patients classified as either low or high risk – Evidence: I Recommendation – early endoscopy ? • Observation study: low-risk patients have no major complication in those triaged to outpatient care with early endoscopy • Retrospective cohort trial: hospital stay and need for surgery with early endoscopy in unselected patients↓ • Randomized, controlled trial: early endoscopy and endoscopic therapy ↓transfusion, hospital stay in patient with bloody NG aspirate • Patient at low risk, high risk, and unselected patients: ↓hosptial s tay • Two randomized, controlled trial: Patient at low risk with early endoscopy 43%~91% ↓ cost Recommendation • NIH consensus(1989) and meta-analysis: benefits of endoscopic therapy mainly examined patients with high-risk • Meta-analysis(Bordou et al): endoscopic treatment ↓ rebleeding, surgery, and mortality, compared with drug or placebo • Endoscopic therapy for adherent clots ↓ rebleeding ompared with medical therapy alone c Recommendation - second-look endoscopy • Routine second-look endoscopy is not recommended – Evidence: I – Second-look endoscopy may be of statistical benefit in select high-risk patients, but data are conflicting regarding its routine use – A second endoscopy is ultimately needed in patients whose initial endoscopic examination is incomplete Recommendation - rebleeding • In cases of rebleeding, a second attempt at endoscopic therapy is generally recommended – Evidence: I – Randomized comparison: immediate endoscopic retreatment in patients with rebleeding after endoscopic hemostasis ↓need for surgery without increasing the risk for death and was associated with fewer complications Recommendation - Surgical consultation • Surgical consultation should be sought for patients who have failed endoscopic therapy – Evidence: II-2 Evidence obtained from well-designed cohort or case-control studies, preferably from more than 1 center or research group – RUGBE: 14.1% rebleeding, 6.5% required surgery – Lau et al: 27% of high-risk patient with rebleeding after endoscopic treatment required salvage surgery Recommendation - H2-receptor antagonists • H2-receptor antagonists are not recommended in the management of patients with acute UGI bleeding – Evidence: I Evidence obtained from at least 1 properly randomized, controlled trial Recommendation - H2-receptor antagonists • H2-receptor antagonists are not recommended in the management of patients with acute UGI bleeding – Meta-analyses(Bardou et al): no significant improvement in outcomes compared with other pharmacotherpy or endoscopic therapy – PPI is more effective than H2-receptor antagonists and in preventing persistent or recurrent bleeding and surgery ( in selective patients ) Recommendation - non-variceal UGI bleeding • Somatostatin and octreotide are not recommended in the routine management of patients with acute non-varoceal UGI bleeding – Evidence: I – Meta-analyses: neither somatostatin nor octreotide improved outcomes compared with other endoscopic therapy or pharmacotherapy. Recommendation - PPI • An iv bolus followed by continuous-infusion PPI is effective in decreasing rebleeding in patients who have undergone successful endoscopic therapy. – Evidence: I – Randomized trials: high dose bolus and continuous-infusion PPI have shown ↓rebleeding, ↓need for surgery compared with H2 blocker or placebo – Meta-analyses: high dose PPI after successful endoscopic therapy ↓rebleeding – RUGBE: PPI ↓rebleeding, mortality in high-risk patient, trend toward ↓rebleeding in patient with low-risk. Recommendation - PPI • In patient awaiting endoscopy, empirical therapy with a high-dose PPI should be considered. – Evidence III Opinions of respected authorties, based on clinical experience, descriptive studies, or reports of expert committees – Oral Losec reduce rebleeding with or without decreased rates of surgery – RUGBE: some efficacy in patients with both low- and high-risk endoscopic lesions Recommendation - feeding • Patients considered at low risk for rebleeding after endoscopy can be fed within 24hours – Evidence: I – Randomized trial has shown that the time of rebleeding does not influence the hospital course of patients at low risk – Patient with major hemorrhage and endoscopic findings of a Mallory-Weiss tear or an ulcer with a clean base, flat spot, or clot may be fed and discharged home immediately after stabilization At Patient Presentation • Immediately evaluate and initiate appropriate resuscitation • Consider placement of a NG tube in selected patients because the findings may have prognostic value • Stratify patients into low- and high-risk categories for rebleeding and death on the basis of clinical criteria. Use available prognostic scales to assist in decision making At Endoscopy - I • Stratify patient into low- and high-risk categories for rebleeding and death on the basis of clinical and endoscopic criteria. Use available prognostic scales to assist in decision making. • Perform early diagnostic endoscopy (<24hrs) with risk classification by clinical and endoscopic criteria to assist in – Safe and prompt discharge of patients at low risk – Improvement of outcomes for patients at high risk – Reduction of resource utilization for patients at either low or high risk At Endoscopy - II • Endoscopic hemostatic therapy is not indicated for patients with low-risk stigmata • Endoscopic hemostatic therapy is indicated for a patient with a clot in an ulcer bed, including targeted irrigation in an attempt at dislodgment, with appropri ate treatment of the underlying lesion • Endoscopic hemostatic therapy is indicated for patients with high-risk stigmata. Follow-up • Routine second-look endoscopy is not recommended • A second attempt at endoscopic therpay is generally recommended in cases of rebleeding • Seek surgical consultation for patients in whom endoscopic therapy has failed • Patients at low risk after endoscopy can be fed within 24 hours Pharmacotherapy • H2-receptor antagonists are not recommended for patients with acute ulcer bleeding • Somatostatin and octreotide are not routinely recommended for patients with acute ulcer bleeding • IV bolus followed by continuous-infusion PPI can effectively decrease rebleeding in patients who have had successful endoscopic therapy • Consider high-dose PPI for patients awaiting endoscopy EBM for treatment of variceal bleeding Treatment of bleeding varices • • • • • • • Conservative treatment Balloon tamponade Somatostatin analogues Terlipressin Endoscopic ligation Endoscopic sclerotherapy Transjugular intrahepatic portosystemic shunt ( TIPS ) Somatostatin analogues for acute bleeding oesophageal varices • Treating bleeding oesophageal varices with somatostatin a nalogues does NOT appear to reduce deaths, but may le ssen the need for blood transfusions The Cochrane Database of Systematic Reviews 2005 Issue 1 Terlipressin for acute esophageal variceal hemorrhage • 20 RCT included • A statistically significant reduction in mortality compared to placebo (relative risk 0.66, 95% confidence interval 0.49 to 0.88) • Terlipressin vs somatostatin or terlipressin vs endoscopic Tx no statistically significant difference • Terlipressin vs balloon tamponade, terlipressin vs o ctreotide, and terlipressin vs vasopressin ( small, low q uality studies ) no difference in any of the major o utcomes The Cochrane Database of Systematic Reviews 2005 Issue 1 (meta-analysis) Terlipressin for acute esophageal variceal hemorrhage - Summary • Terlipressin appears to be as safe as other treatments • Terlipressin may reduce the mortality from variceal leeding as compared to placebo b • No sufficient data to decide whether terlipressin was better or worse than other available treatments such as other drugs (somatostatin, octreotide) or endoscopic Tx The Cochrane Database of Systematic Reviews 2005 Issue 1 (meta-analysis) Endoscopic ligation vs pharmatherapy for acute bleeding oesophageal varices • Ligation is the most effective treatment option. • No significant difference was found between the fficacy of sclerotherapy and treatment with tostatin or octreotide e soma Endoscopy 2001;33(9): 737-46 (meta-analysis) Sclerotherapy vs medical interventions for bleeding oesophageal varices in cirrhotic patients • No convincing evidence to support the use of emergency sclerotherapy for variceal bleeding in cirrhosis as the first, single treatment when compared with vasoactive drugs. The Cochrane Database of Systematic Reviews 2005 Issue 1 TIPS compared with endoscopic treatment for prevention of variceal rebleeding • Variceal rebleeding more frequent with ET (46.6%) than w ith TIPS (18.9%) • Post-treatment encephalopathy occurred significantly less often after ET (19%) than after TIPS (34%) • TIPS compared with ET reduces the rebleeding rate, but does not improve survival, and increases the incidence of encephalopathy in a period of 1 to 2.5 years Hepatology 1999;30(3):612-622 (meta-analysis ) Summary of Tx of bleeding varices • Treatment modalities are better than placebo • Endoscopic ligation may be the best option of treatment • Endoscopic sclerotherapy is not better than medications • Medications such as somatostatin, octreotide, terlipressin are safe in treatment of bleeding varices • No difference between somatostatin, octreotide, and terlipressin • TIPS ( compare with endoscopic Tx ) reduces rebleeding rate, but increases in the incidence of encephalopathy EBM in GI emergency • • • • • Non-variceal UGI bleeding Variceal UGI bleeding Stress ulcer Acute pancreatitis Fulminant hepatic failure/ Hepatic coma Opinions about stress ulcers • Stress ulcer bleeding is uncommon • Can occur in spite of prophylactic treatment • Should be considered as markers of prolonged sur vival in critically ill patients, rather than untreatable complications Studies of stress ulcers • More than 100 studies of the frequency, risk factors, and prophylaxis. • These subjects continue to generate controversy. • Why? Study methods, bleeding definition, patient population & number, and so on. • Cushing’s ulcer # associated with CNS injury # single deep lesion in the duodenum or stomach • Curling’s ulcer # associated with thermal injury # may appear in the esophagus, stomach, small bowel & colon Frequency of stress ulcer bleeding • Varies ( decrease recent years ) • Adult Before 1978, 5.3% - 33% 1978-1984 1.6% - 39% 1984-1994 0.1% - 39% ( average 6% ) • Pediatric population Clinical important bleeding: 20% in control group 5.7% in treated group Recommendation#1 (Adult ) Prophylaxis for general ICU patients Coagulopathy platelet < 50000 mm3 PT > 2X control Mechanical ventilation > 48 hours History of GI ulcer or bleeding with one year At least 2 following risk factor: Sepsis ICU stay > 1 week Occult bleeding > 6 D High-dose corticsteriod >250mg/D ASHP Therapeutic Guidelines Recommendation#1 (Pediatrics) Prophylaxis for general ICU patients • No definite conclusion : prophylaxis provides protection • Risk factors: respiratory failrue coagulopathy Shock Surgery> 3 hr Trauma Pediatric Risk of Mortality score > or /& = 10 ASHP Therapeutic Guidelines Recommendation#2 (Adult) Prophylaxis for special populations • • • • Glasgow Coma Score < or/&= 10 Thermal injury > 35% of BSA Partial hepatectomy Multiple trauma: Injury Severity Score > or/&=16 • Transplatation patients perioperatively • Hepatic failure • Spinal cord injury ASHP Therapeutic Guidelines Recommendation#2 (Pediatrics) Prophylaxis for special populations • Thermal injury ( what BSA ?) • For other pediatric surgery or trauma, insufficient evidence to recommend prophylaxis. ASHP Therapeutic Guidelines Recommendation#3 (Adult) Medications for prophylaxis • Conflicting results of meta-analyses & recent RCT • Choice among antacid, H2-antagonists, sucralfate: made on an institution-specific basis • Insufficient data on misoprostal or PPI ASHP Therapeutic Guidelines Prophylactic agents for stress ulcer • Inhibition of gastric acid secretion H2 antagonist, PPI, prostaglandin analogue(?) • Neutralization of gastric acid anatacid • Protective mechanism sucralfate, misoprostol • HSP70 inducer (GGA), free-radical scavenger(?) Prophylaxis for overt bleeding (I) Mx 1 Mx 2 Result H2-receptor antagonists VS placebo or no therapy significantly reduced OR 0.58 (95% CI: 0.42, 0.79) H2-receptor antagonists VS antacid significantly reduced OR 0.44 (95% CI: 0.37, 0.84) Sucralfate VS no prophylaxis decreased OR 0.58 (95% CI: 0.34, 0.99) Antacids VS placebo or no therapy Not statistically significant A trend favour of antacids Database of Abstracts of Reviews of Effects 2005 Issue 1 JAMA 1996;275(4):308-314 Sixty-three RCTs Prophylaxis for overt bleeding (II) Mx 1 Mx 2 Result Sucralfate VS antacids No differential effectiveness Sucralfate VS H2-receptor antagonists No differential effectiveness Database of Abstracts of Reviews of Effects 2005 Issue 1 JAMA 1996;275(4):308-314 Sixty-three RCTs Prophylaxis for clinically-important bleeding Mx 1 Mx 2 Result H2-receptor antagonists VS placebo or no therapy significantly reduced OR 0.44 (95% CI: 0.22, 0.88) H2-receptor antagonists VS antacid No statistically-significant although a trend in favour of H2receptor antagonists Database of Abstracts of Reviews of Effects 2005 Issue 1 JAMA 1996;275(4):308-314 Sixty-three RCTs Meta-analyses for Risk of Pneumonia with Medications of SUP Tryba M J Clin Gastroenterol 1991;13(suppl 1):S44-55 Tryba M Crit Care Med 1991;19:942-9 Cook DJ Chest 1991;100:7-13 Cook DJ Infect Control Hosp Epidemiol 1994;15:437-42 Cook DJ JAMA 1996;275:308-14 sucralfate vs H2-antagonist or antacid sucralfate vs H2-antagonist & antacid sucralfate vs H2-antagonist or antacid sucralfate vs H2-antagonist or antacid sucralfate vs control antacid H2-antagonist lower rate with sucralfate lower rate with sucralfate not favored sucralfate lower rate with sucralfate not favored sucralfate Incidence of pneumonia - Prophylaxis for stress ulcer Mx 1 Mx 2 Result Sucralfate VS H2-receptor antagonists a trend toward a lower incidence of pneumonia Sucralfate VS antacid a trend toward a lower incidence of pneumonia H2-receptor antagonists VS no prophylaxis increased incidence of pneumonia not statistically significant Database of Abstracts of Reviews of Effects 2005 Issue 1 JAMA 1996;275(4):308-314 Sixty-three RCTs Mortality - Prophylaxis for stress ulcer Mx 1 Mx 2 Result Sucralfate VS H2-receptor antagonists a trend in favour of sucralfate Sucralfate VS antacid statistically-significant reduction in mortality , OR 0.73 (95% CI: 0.54, 0.97) Database of Abstracts of Reviews of Effects 2005 Issue 1 JAMA 1996;275(4):308-314 Sixty-three RCTs Recommendation#3 (Pediatrics & special group) Medications for prophylaxis • Lack of comparative trials of prophylactic agents • The choice of agents should be made on an instit ution-specific basis: administration, adverse effec ts & total cost ASHP Therapeutic Guidelines Recommendation#4 (Adult & Pediatrics) Adverse-effects of prophylaxis • History of serious reactions to prophylactic agents • Sucralfate & antacid: avoid in neonates bezoar formation, accumulation of Al & Mg • Al-contained agents avoided in children with renal impairment • Acid-suppression agent associated with high rate of pneumonia than suvralfate (?) • Adverse effect - part of economic analysis ASHP Therapeutic Guidelines Recommendation#5 (Adult & Pediatrics) Prevention of rebleeding • Lack of available trials prohibits definite recommendations for preventing recurrent bleeding • Consideration could be given to increase dosage, add other medication or switch to a different agent ASHP Therapeutic Guidelines Recommendation#6 (Adult & Pediatrics) When to discontinue prophylaxis • Prophylaxis can be stopped once risk factors have resolved extubation or discharge from ICU ASHP Therapeutic Guidelines Enteral feeding & TPN- risk factor ? • Previous studies have different results due to differences in location of enteral feeding tubes • Enteral feeding: augment mucosa defense & neutralize gastric acid Crit Care Med 1983;11:13-6 • Not related to the use of TPN Armstrong TA, et al. Am J Health-Syst Pharm 1999;56:347-79 Ben-Menachem T, et al. Ann Intern Med 1994;121:568-75 EBM in GI emergency • • • • • Non-variceal UGI bleeding Variceal UGI bleeding Stress ulcer Acute pancreatitis Fulminant hepatic failure/ Hepatic coma EBM in acute pancreatitis • Pharmacotherapy in acute pancreatitis • Anti-acid treatment for acute pancreatitis • Antibiotics prophylaxis for acute pancreatitis • Early ERCP + EST for acute biliary pancreatitis • Early feeding for acute pancreatitis Two mortality peaks of severe acute pancreatitis Mortality infection MOF 1st – 2nd week 3rd – 4rd week Question : Does the patient with acute necrotizing pancreatitis benefit from using specific drugs ? Specific pharmacologic therapy of Acute Pancreatitis • Antiproteolytic agent Aprotinin FFP Gabexate mesilate • Anti-inflammatory agent Lexipafant • Inhibitor of exocrine secretion Glucagon Cacitonin Atropine Somatostatin Octreotide RCTs of Antiproteolytic and Anti-inflammatory Agents in Acute Pancreatitis Trial Agent Effect Trapnell et al., 1974 Aprotinin Morbidity↓, mortality↓ MRC, 1977 Aprotinin No effect Imrie et al., 1978 Aprotinin No effect Leese et al., 1991 Fresh frozen plasma No effect Valderrama et al., 1992 Gabexate mesilate No effect Buchler et al., 1993 Gabexate mesilate No effect McKay et al., 1997 Lexipafant Organ failure score↓ Lexipafant No effect Johnson CD et al., 2001 ( Gut 48:62-9 ) RCTs of Modifiers and Inhibitors of Secretion in Acute Pancreatitis Trial Agnet Effect Olazabal and Fuller, 1978 Glucagon No benefit Debas et al., 1980 Glucagon No benefit Kronborg et al., 1980 Glucagon No benefit Goebell et al., 1979 Calcitonin No benefit Cameron et al., 1979 Atropine No benefit RCTs with Somatostatin and Octreotide (with more than 20 recruited patients) Trial Drug Complication (%) Mortality (%) Choi et al., 1989 Som/C 2.9 5.6 Gjorup et al., 1992 Som/C 42 3 30 3 Mitrovic et al., 1993 Som/C 33 (<0.05) 20 58 40 Luengo et al., 1994 Som/C 2 2 O’Hair et al., 1993 Oct/C 3 1 10 0 Italian Study Group, 1994 Oct/C 6 (=0.05) 2 16 5 Paran et al., 1995 Oct/C 26 (=0.04) 11 74 37 McKay et al., 1997 Oct/C 55 18 37 20 Uhl et al., 1999 Oct 300ug/d 76 15 Oct 600ug/d 72 12 C 71 16 Somatostatin, octreotide and gabexate mesilate in the therapy of acute pancreatitis ? No agent was proven to be of value in the treatment of mild acute pancreatitis. Both SS and OCT beneficial in improving the overall mortality in severe acute pancreatitis no significant effect on complication rate FOY no effect on either early or overall mortality effective in improving the complication rate, and the number of cases submitted to surgery Alimentary Pharmacology and Therapeutics 1998;12(3):237-245 ( Meta-analysis) Somatostatin, octreotide and gabexate mesilate in the therapy of acute pancreatitis ? • 14 and 3 negative studies for somatostatin and octreotide, respectively • Conclusions should therefore be interpreted with caution. Recommendation • In mild, self-limited, acute pancreatitis, no specific pharmacologic treatment is indicated. • Current evidence dose not support the use of specific pharmacologic agents ( antiproteases, anti-inflammatory agents, secretory inhibitiors) in severe acute pancreatitis Combining antisecretory agents with antiproteases would be of great benefit in patients with severe acute pancreatitis ? Conservative Treatment of Acute Pancreatitis • Nasogastric suction & nil per os prospective in morbidity, mortality & length of hospital days # but small number, restricted to alcoholic pancreatitis randomized studies # no significant benefit • H2-receptor antagonists RCTs failed to show clinical benefit Histamine-2 receptor antagonists for acute pancreatitis ? • Five placebo-controlled RCTs (285 patients) • Parenteral cimetidine was evaluated • No statistically-significant difference in complication rates between cimetidine and placebo • No statistically-significant difference in the mean duration of pain between cimetidine and placebo • Rather, the use of cimetidine associated with higher rates of complications and pain Eur J Gastroenterol Hepatol 2002;14(6):679-686 (meta-analysis ) Histamine-2 receptor antagonists for acute pancreatitis ? • Routine use of cimetidine should be abandoned until the safety and efficacy of H2RAs are proven Eur J Gastroenterol Hepatol 2002;14(6):679-686 (meta-analysis ) Question : Does the patient with acute necrotizing pancreatitis benefit from the administration of antibiotic prophylaxis ? Two mortality peaks of severe acute pancreatitis Mortality infection MOF 1st – 2nd week 3rd – 4rd week Why antibiotics ? INFECTION • Develop in 40 to 70 % of patients during the course of necrotizing pancreatitis • One of the principal complications of acute pancreatitis • Combination of sepsis or sepsis-related MOF --- mortality up to 50 % Prophylactic antibiotic reduces sepsis and mortality in acute necrotizing pancreatitis ? • Three RCTs (n=160) were included • Relative risk reduction (RRR), absolute risk reduction (ARR) and number-needed-to-treat (NNT) Pancreas 2001;22(1):28-31 meta-analysis Prophylactic antibiotic reduces sepsis and mortality in acute necrotizing pancreatitis ? • Local pancreatic infection: the RRR was 31% (95% CI: -14, 60), the ARR was 12% (95% CI: -2.4, 26.4), and the NNT was 8 (95% CI: number- needed-to-harm 41, NNT 4) • Sepsis: the RRR was 46% (95% CI: 15, 70), the ARR was 21.1% (95% CI: 6.5, 35.6), and the NNT was 5 (95% CI: 3, 15) • Mortality: the RRR was 72% (95% CI: 40, 100), the ARR was 12.3% (95% CI: 2.7, 22), and the NNT was 8 (95% CI: 5, 37) Pancreas 2001;22(1):28-31 meta-analysis Prophylactic antibiotic reduces sepsis and mortality in acute necrotizing pancreatitis ? • Severe pancreatitis should be evaluated with a rapid bolus, contrast-enhanced computed tomography scan to look for pancreatic necrosis • Patients with pancreatic necrosis should be started on prophylactic antibiotics to prevent infection in ANP • This should reduce the morbidity Pancreas 2001;22(1):28-31 meta-analysis Prophylactic antibiotic reduces sepsis and mortality in acute necrotizing pancreatitis ? • Imipenem (500 mg, three times daily) • Cefuroxime (1.5 g, three times daily) • Combination of loxacin (200 mg, twice daily) metronidazole (500 mg, twice daily) Pancreas 2001;22(1):28-31 meta-analysis Prospective RCTs of Prophylactic Antibiotic Treatment in Severe Acute Pancreatitis NonPancreatic pancreatic Infection Infection MOF Mortality Trial Drug (%) (%) (%) (%) Pederzoli et al., 1993 Imipenem 12* 15* 29 7 Control 30 49 39 12 Sainio et al., 1995 Cefuroxime Control 30 40 Mean 1.0† Mean 1.8 Delcenserie et al., 1996 Ceftazidime/ Amikacine/ 0† 9 Control 58 25 Ofloxacin/ 61 0 3† 23 Metronidazole Schwarz et al., 1997 Metronidazole Luiten et al., 1995 Control 53 15 Oral and rectal SDD/ 18 22 38† 35 IV cefotaxime Control *p < 0.1 †P = 0.03 Prophylactic antibiotic in acute necrotizing pancreatitis ? • Conclusions should be treated with some caution owing to limitations in the search (Pancreas 2001;22(1):28-31) • Large multicentre RCT, seems warranted to confirm the findings of this meta-analysis study (Pancreas 2001;22(1):28-31) Prophylactic antibiotics for severe acute pancreatitis • Study designs of evaluations included: prospective randomised and non-randomised controlled trials (RCTs), retrospective cohort studies; prospective case series with historical control; case control; and retrospective review with historical control. ranged from 1973 to 1997 • To determine the effectiveness of prophylactic antibiotics in preventing the infectious complications of acute pancreatitis Pharmacotherapy 1999;19(5):592-602 Prophylactic antibiotics for severe acute pancreatitis • Earliest four studies were published in the 1970s and none reported any difference in rates of development of infection between treatment groups • Four most recently completed studies (including 3 RCTs and one retrospective review) in the 1990s all reported a decrease in overall infectious complications in patients with moderate to severe disease Pharmacotherapy 1999;19(5):592-602 Early Studies of Antibiotic Prophylaxis • Craig RM et al., Ann Intern Med 1975 Howes R et al., J Surg Res 1975 Finch WTR et al. Ann Surg 1976 • Result: prophylaxis not beneficial over placebo BUT : 1. small sample size 2. with mild disease 3. wrong antibiotics -- ampicillin Prophylactic antibiotics for severe acute pancreatitis • Alone or in combination: – Amino glycosides – Ampicillin – Imipenen – Cefuroxime – Ceftazidime, Amikacin, Metronidazole Pharmacotherapy 1999;19(5):592-602 Prophylactic antibiotics for severe acute pancreatitis • Antibiotics should be administered to patients with severe disease (based on Ranson criteria and CT findings) – Ranson score of 3 or more – two or more acute fluid collections – necrosis involving one third or more of the pancreas Pharmacotherapy 1999;19(5):592-602 Recommendation • Antibiotic prophylaxis is justified in patients with pancreatic necrosis • Antibiotic prophylaxis should be given early in the disease ( within 96 hours after onset ) • Duration: at least 14 days, preferably continued for 3-4 weeks Recommendation • Imipenem is the one with the highest efficacy factors of all available agents • SDD : Effective in combination with intravenous antibiotics. But dosage, choice & duration unclear Early ERCP + EST in gallstoneassociated acute pancreatitis ? Early ERCP + EST is known to have complications such as procedure-related pancreatitis RCTs of early ERCP for acute pancreatitis Study Period Case No. Study design Study results •Safe procedure •Mortality significantly in severe AP ( 24% vs. 61% ) UK 1983-7 121 Single center Hong Kong 198891 195 •Single center •Significantly biliary sepsis •Some with non- •Mortality significantly in ABP biliary etiology ( 0%vs. 12% ) Germany 198994 238 •Multicenter •ABP patients •Bil. > 5 mg/dl excluded •Mortality similar •Early ERCP group with severe complications Early •ERCP group non-significantly increased in Mortality Poland 198495 280 •Single center •ERCP+EST for stone impaction Early ERCP significantly both morbidity ( 17% vs. 36% )and mortality ( 2% vs. 13% ) ERCP in gallstone-associated acute pancreatitis • Cochrane Library (Issue 4 2003), Medline (1966-2004), EMBASE (1980-2004) and LILACS. 'Grey literature' was sought by looking at cited references and hand searched to identify further relevant trials. Conference proceedings of United European Gastroenterology Week (published in Gut) and Digestive Disease Week (published in Gastroenterology) • Randomized controlled trials (RCT) of adult patients, from 15 years old or greater The Cochrane Database of Systematic Reviews 2005 Issue 1 ERCP in gallstone-associated acbute pancreatitis • Controlled for confounding due to associated acute cholangitis The Cochrane Database of Systematic Reviews 2005 Issue 1 ERCP in gallstone-associated acbute pancreatitis • Early ERCP +/- ES : – Non-significant effect on reduction of mortality in predicted mild (OR = 0.62, 95% CI = 0.27 to 1.41) and severe GAP (OR = 0.62, 95% CI = 0.27 to 1.41) – Reduction in complications was nonsignificant in predicted mild (OR = 0.89, 95% CI = 0.53 to 1.49), but significant in severe GAP (OR = 0.27, 95% CI = 0.14 to 0.53) The Cochrane Database of Systematic Reviews 2005 Issue 1 ERCP in gallstone-associated acute pancreatitis • PATIENTS WITH A PREDICTED SEVERE ATTACK OF GALLSTONE-ASSOCIATED ACUTE PANCREATITIS NEED EARLY ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY The Cochrane Database of Systematic Reviews 2005 Issue 1 Nutrition problem in acute pancreatitis • About 80 % patients with mild course & return to oral diet in within 7 days ( AJG 1999;86:1385-91 ) • 10-20 % patients with severe course liable to prolonged gastroduodenal atony • Initially withdraw from enteral feeding to avoid meal-stimulated pancreatic secretion ---- no evidence-based evaluation Question : Does nutrition support improve the outcome? Should the patient receive enteral or total parental nutrition ? Studies of TPN in Acute Pancreatitis • Most studies were poorly controlled, nonrandomized, & often retrospective. • Lipid components : safe to use in patients with acute pancreatitis ( Case series ) • TPN decreases morbidity, mortality in patients with acute pancreatitis ? Two prospective, non-randomized studies : yes Sitzman JV et al., Surg Gynecol Obstet 1989 Kalfarentzos FE et al., J Am Coll Nutr 1991 RCTs of comparing TPN with no nutrition support Trial Result Commands Koretz RL et al., 1997 No benefit mild cases Gastroenterology; 113:1414-5 Sax HC et al., 1987 Am J Surg 1987;183:117-24 * : longer hospitalization in TPN group No benefit* catheterrelated sepsis Why Enteral Feeding in Acute Pancreatitis? • Significant morbidity and mortality in acute pancreatitis related to sepsis --- arising from bacteria translocation. • Enteral nutrition may maintain bowel wall integrity and reduce bacterial translocation • TPN with NPO increases intestinal mucosal permeability, bacterial translocation, & decreases GI Ig. Alverdy JC et al., Surgery 1988 Li J et al., J Trauma 1995 How Is Enteral Nutrition Given ? • Suggest that nutrition should be delivered below the ligament of Treitz Pisters PW et al., Surg Gynecol Obstet 1992 • Enteral access gained by nasojejunal tube, percutaneous endoscopic gastrostomy/jejunostomy surgical gastrostomy/jejunostomy RCTs of TEN vs. TPN Trials Result McClave SA et al., 1997 No difference in pain scores, days to diet by mouth, nosocomial infection. Mean Ranson scores, APACHEⅢ, MOF scores decreased in TEN group (TEN as safe & effective but less cost 4X) Kalfarentzos F et al., 1997 Few total complications (p<0.05) and septic complications (<0.01) in TEN TEN less cost 3X Windsor AC et al., 1998 Disease severity scores (CRP, APACHEⅡ) improved in TEN but CT score : not. SIRS, sepsis & MOF all improved in TEN. Recommendation • Predicted to return to oral diet within l wk ( Ranson score2 or APACHEⅡ9 ), nutrition support not indicated • TEN is as safe & effective as TPN, and less complications & cost • Suggest gastrojejunal feeding when TEN Recommendations for the Management of Severe Acute Pancreatitis Effect Level of Evidence Antiproteases Not beneficial 1B Anti-inflammatory agent Not beneficial 1B Somatostatin/octreotide Not beneficial 1A Pharmacologic therapy Prophylactic antibiotics Intravenous antibiotics (imipenem) Reduction of complications 1B SDD/intravenous cefotaxime Duration 14 to 28 days Reduction of mortality 1C 2B Recommendations for the Management of Severe Acute Pancreatitis Effect Level of Evidence EN Reduction of mortality 2C TPN Reduction of mortality 2C Safety of EN versus TPN Reduction of complications 1B Reduction of mortality 2A Infected pancreatic necrosis Reduction of mortality 2A Late versus early intervention Reduction of mortality 1B Nutritional support Nonsurgical treatment (intensive care) Sterile pancreatic necrosis Surgical intervention Question : Does the patient benefit from surgical intervention ? Timing of surgery ? Surgical or Non-surgical Intervention for Acute Pancreatitis • First quarter of the 20th centry surgery high mortality & morbidity • Non-surgical approach followed until late 1960s • A small group of patients with severe form profit from surgery ( analysis of disease process ) Surgical or Non-surgical ? • First consideration : Infected or sterile • Infected pancreatic necrosis accepted indication for operation • Sterile pancreatic necrosis a matter of controversy Recommendation - Determination of Pancreatic Necrosis & Infection • For detection of necrosis CT scan indicated within 48 to 96 hours after onset ***** • FU CT scan repeated weekly only if clinical status deteriorates or fails to improve Recommendation - Determination of Pancreatic Necrosis & Infection • For detection of infection FNA of pancreatic necrosis indicated when # deterioration of clinical status: fever # lab. status : leukocytosis, increase of CRP • If clinically not improved repeat FNA, once per week Nonsurgical management for necrotic pancreatitis • Buchler MW et al., Ann Surg 2000 ( level 2 ) N=86 ( infected necrosis=29, noninfected=57 ) Surgical intervention for infected group Nonsurgical approach for noninfected group Result : mortality surgical group 24% non-surgical group 1.8%(<.01) Non-surgical management for sterile necrosis Surgical Intervention for Infected Pancreatic Necrosis ? • Infection of pancreatic necrosis an absolute indication for operation non-surgical mortality may be up to 100% Bradley ELD et al., World J Surg 1985 Beger HG et al., Gastroenterology 1986 Beger HG at al., Br J Surg 1988 Surgical Intervention for Sterile Pancreatic Necrosis ? • Uncontrolled, retrospective studies ( small ) no benefit for surgery Bradley ELD et al., World J Surg 1985 Karimgani I et al., Gastroenterology 1992 • “ non-responsiveness to maximal intensive unit treatment “ - 72 hours -indication for surgery Gebhardt C et al., Chirurgie 1994 Timing of Surgery - Early or Late ? • The only RCT Rau B et al., J Am Coll Surg 1995;181:279-88 N=41 randomly allocated to # early necrosectomy ( 48-72 hrs after onset ) # late necrosectomy ( at least 12 D after onset ) early termination of the study due to high OR ( 3.4 times ) in early surgery group Recommendation • Infected pancreatic necrosis indication for surgery • Sterile pancreatic necrosis undergo conservative treatment surgery necessary in selected cases critical illness for more than 4 weeks • Early surgery ( within 14 days after onset ) is not recommended in sterile necrosis Timing of Surgery - Early or Late ? • Early intensive conservative treatment with late necrosectomy current rational approach in severe acute pancreatitis • Surgical treatment should be postponed as long as response to conservative treatment • Only rare proven early infected necrosis or unusual complicationsurgent early operation EBM in GI emergency • • • • • Non-variceal UGI bleeding Variceal UGI bleeding Stress ulcer Acute pancreatitis Fulminant hepatic failure/ Hepatic coma Fulminant Hepatic Failure • A syndrome of rapid progressing liver failure encephalopathy within 8 weeks. ( Trey & Davidson 1970 ) • Characterized by encephalopathy, vasoparesis, coagulopathy, then cerebral edema, renal failure, infection • Causes of death: two main groups # cerebral edema # sepsis & MOF Ward Management or Intensive Care Management ? • No controlled clinical trials • BUT considering almost 100% mortality before modern intensive care unit available (Lucke B et al., Am J Pathol 1946;22:867-945) better to be cared in ICU Management of FHF • Supportive care - fluid resuscitation & vasopressor - mechanical ventilation - sedation & paralysis - enema, disaccharides, nutrition(BCAA) - antibiotic prophylaxis • Management of cerebral edema • Management of renal failure Question : Which fluid regimens is better for FHF? Fluid Resuscitation for FHF • FHF develops marked hemodynamic change vasodilatation - relative hypovolemia • No controlled clinical trials • Recent reviews : excess mortality associated with colloid & albumin -- been criticized Schierhout G et al., Br Med J 1998;316:961-4 CIGAR Br Med J 1998;317:235-40 Vasopressor good for FHF ? • Dopamine: In high cardiac output hypotension ( FHF ), low dose dopamine dose not renal perfusion but divert blood flow from gastric mucosa • Dobutamine improve splanchnic blood flow • Epinephrine & norepinephrine improve MAP in FHF Question : Is mechanical ventilation needed ? How about sedation & paralysis ? Mechanical ventilation • Not for hypoxemia • For airway compromise -- from grade II to III encephalopathy, at risk for aspiration • Hyperventilation for cerebral edema -- not shown any advantage in long-term control ICP in FHF ( Ede RJ et al., J hepatol 1986;2:43-51) Sedation & paralysis needed ? • Patients with FHF - agitation & aggressive behavior • No clinical controlled studies • Deep sedation – unnecessary ( C ) • Complicated with infection & necrotizing myopathy -- no indication for routine paralysis Interventions for paracetamol (acetaminophen) overdoses • RCTs on interventions for paracetamol overdose. • Activated charcoal seems the best choice to reduce paracetamol absorption. • N-acetylcysteine should be given to patients with paracetamol overdose. • No N-acetylcysteine regime has been shown to be more effective than any other. The Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD003328 Nonabsorbable disaccharides for hepatic encephalopathy • Enema • Oral Enema - nonabsorbable disaccharides for hepatic encephalopathy • Cleaning of colon is rapid and effective procedure to remove ammoniagenic substrates • 2 double-blind RCTs: favorable response ( A ) Gastroenterology 1981;81:101-6 Heaptology 1987;7:639-43 • Interestingly, enema with tap water was ineffective ( acidification works ?! ) Oral nonabsorbable disaccharides for hepatic encephalopathy • Compared with placebo or no intervention, nonabsorbable disaccharides had no statistically significant effect on mortality (RR 0.41, 95% CI 0.02 to 8.68, four trials) • Trials of high methodological quality no significant effect of nonabsorbable disaccharides on the risk of no improvement of hepatic encephalopathy (RR 0.92, 95% CI 0.42 to 2.04, two trials) The Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD003044 Oral nonabsorbable disaccharides for hepatic encephalopathy • Nonabsorbable disaccharides appeared to be inferior to antibiotics on reducing the risk of no improvement of hepatic encephalopathy (RR 1.24, 95% CI 1.02 to 1.50, 10 trials) The Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD003044 Summary - Nonabsorbable disaccharides for hepatic encephalopathy • The efficacy of lactulose or lactose enema is beyond any doubt • There is insufficient evidence to confirm or exclude whether oral nonabsorbable disaccharides have an effect on patients with hepatic encephalopathy • The effect was not seen when only trials of high quality were analysed. • Antibiotics appeared to be superior to nonabsorbable disaccharides in improving hepatic encephalopathy The Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD003044 Neomycin for hepatic encephalopathy • Neomycin as a standard Tx of HE for about 40 years • So far, no evidence that neomycin is effective • The only RCT with placebo negative result Hepatogastroenterol 1992;29:542-5 • Combination of neomycin with lactulose was not superior to placebo Heaptology 1992;15:222-8 Branched-chain amino acids for hepatic encephalopathy • Hepatic encephalopathy may be caused by a decreased plasma ratio of branched-chain amino acids (BCAA) to aromatic amino acids. • Treatment with BCAA was proposed with a beneficial effect on patients with hepatic encephalopathy The Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD001939 Branched-chain amino acids for hepatic encephalopathy • 7 randomised trials (556 patients) assessing BCAA versus carbohydrates, neomycin / lactulose, or isonitrogenous control • Compared to the control regimens, BCAA significantly increased the number of patients improving from hepatic encephalopathy • No evidence of an effect of BCAA on survival (RR 1.06, 95% CI 0.98 to 1.14, eight trials) or adverse events (RR 0.97, 95% CI 0.41 to 2.31, three trials) The Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD001939 Summary Branched-chain amino acids for hepatic encephalopathy • No convincing evidence that branchedchain amino acids have a beneficial effect on patients with hepatic encephalopathy was identified. The Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD001939 Is prophylactic antibiotics & SDD needed ? • Patients with FHF susceptibility to infections # impaired phagocytic function # reduced complement levels # need for invasive procedures • IV antibiotics : reduce infection 20%, BUT not improve outcome or length of stay (A) • No controlled studies for SDD, BUT Rolando reported no additional benefit (A) Does Lamivudine prevent FHF ? • So far, no RCT support • Bridging therapy for FHF to liver transplantation Benzodiazepine receptor antagonists for hepatic encephalopathy ? Benzodiazepine receptor antagonists for hepatic encephalopathy ? • Hepatic encephalopathy may be caused by an activation of a receptor-complex in the brain. • Flumazenil, which inhibits this receptorcomplex, might ameliorate the symptoms. Benzodiazepine receptor antagonists for hepatic encephalopathy ? • Thirteen randomised trials with 805 patients were included. Eight trials used a crossover design. All trials were double-blind • Favourable prognosis [93%] survived in the flumazenil group versus [92%] in the placebo group • Flumazenil had a significant beneficial effect on improvement of hepatic encephalopathy at the end of treatment (RD 0.28; 95% CI 0.20 to 0.37, eight trials). • Flumazenil had no significant effect on recovery (RD 0.13; 95% CI -0.09 to 0.36, two trials) or mortality RD 0.01; 95% CI -0.05 to 0.07, 10 trials). • Flumazenil may be associated with adverse events Benzodiazepine receptor antagonists for hepatic encephalopathy ? • Flumazenil leads to a short-term improvement of hepatic encephalopathy in some patients with chronic liver disease and a highly favourable prognosis. • No significant effect on recovery or survival • Flumazenil may be considered for patients with chronic liver disease and hepatic encephalopathy, but cannot be recommended for routine clinical use. The Cochrane Database of Systematic Reviews 2005 Issue 1 Cerebral Edema in FHF - Monitoring • ICP monitor # no controlled studies in FHF • CT scan # predicting power is poor • Jugular vein saturation # controlled trials needed Cerebral Edema in FHF - Treatment • Osmotherapy # mannitol 1g/Kg ( 0.5 g/Kg ) effective in FHF ( Canalese 1982 ) • Dexamethasone ineffective • Barbiturate: no RCT • Hyperventilation : no advantage in long term use However, may try when unresponse to osmotics What management for renal failure in FHF ? • Renal protecting agents # So far, no proven protective agents for FHF # Low dose dopamine • Renal replacement therapy # has been a major part of routine management # BUT no RCT proves renal replacement Tx improve outcome Artificial and bioartificial support systems for liver failure • Bridge' patients with acute or acute-on-chronic liver failure to liver transplantation or recovery • Twelve trials on artificial or bioartificial support systems versus standard medical therapy (483 patients) and two trials comparing different artificial support systems (105 patients) were included The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003628 Artificial and bioartificial support systems for liver failure • Compared to standard medical therapy, support systems had no significant effect on mortality (RR 0.86; 95% CI 0.65-1.12) or bridging to liver transplantation (RR 0.87; 95% CI 0.73-1.05) • But a significant beneficial effect on hepatic encephalopathy (RR 0.67; 95% CI 0.52-0.86) The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003628 Artificial and bioartificial support systems for liver failure • Effect of support systems depended on type of liver failure (P = 0.03). In subgroup analyses, artificial support systems appeared to reduce mortality by 33% in acute-on-chronic liver failure (RR 0.67; 95% CI 0.51-0.90), but not in acute liver failure (RR 0.95; 95% CI 0.71-1.29) ) The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003628 Artificial and bioartificial support systems for liver failure • Comparing artificial support systems significant mortality reductions with intermittent versus continuous haemofiltration (RR 0.58; 95% CI 0.36-0.94) no significant difference between five versus ten hours of charcoal haemoperfusion (RR 1.03; 95% CI 0.65-1.62). incidence of adverse events was inconsistently reported The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003628 Summary - Artificial and bioartificial support systems for liver failure • Artificial support systems may reduce mortality in acute-on-chronic liver failure. • Artificial and bioartificial support systems did not appear to affect mortality in acute liver failure. • Strength of the evidence, additional RCTs are needed before any support system can be recommended for routine use. The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003628 Thanks for your attention !