Gastrointestinal Disorders PDF

Gastrointestinal Disorders 3. 4. is more effective than oral therapy alone (conditional recommendation, low-quality evidence). Oral aminosalicylate therapy should be used for mildly active extensive colitis (strong recommendation, moderate-qua...

Gastrointestinal Disorders 3. 4. is more effective than oral therapy alone (conditional recommendation, low-quality evidence). Oral aminosalicylate therapy should be used for mildly active extensive colitis (strong recommendation, moderate-quality evidence). b. Patients with mildly active UC who are intolerant of or who have responded to aminosalicylate therapy should receive oral budesonide (Uceris) for left-sided disease (strong recommendation, moderate-quality evidence) or systemic corticosteroids for any extent of UC (strong recommendation, low-quality evidence) to induce remission. c. Continued topical and/or oral aminosalicylate therapy, but not corticosteroids, should be used to maintain remission (strong recommendation, moderate-quality evidence). Moderately to severely active UC a. In moderately active UC, oral budesonide is recommended to induce remission (strong recommendation, moderate-quality evidence). b. In moderately to severely active UC, systemic steroids, anti-TNF therapy (adalimumab, golimumab, or infliximab), vedolizumab, tofacitinib, or ustekinumab may be used to induce remission. (strong recommendations, moderate to high quality of evidence). c. Infliximab for induction of remission should be combined with thiopurine therapy (strong recommendation, moderate-quality evidence for azathioprine). d. Patients whose induction with anti-TNF therapy has failed should receive vedolizumab, tofacitinib, or ustekinumab to induce remission (strong recommendation, moderate-quality evidence). e. A patient who achieves remission with a biologic agent should be continued on that agent to maintain remission (strong recommendation, moderate-quality evidence). Patients whose remission is achieved using corticosteroids may receive thiopurine therapy to maintain remission (conditional recommendation, low-quality evidence). f. Newer oral treatment options (ozanimod and upadacitinib) are indicated for induction and maintenance of remission of moderate to severe active UC in patients for whom TNF antagonist therapy has failed. These agents have not yet been incorporated into treatment guidelines, but can be considered for patients who have experienced failure of the initial treatment options. Hospitalized patients with acute severe UC a. Methylprednisolone 40–60 mg/day or the equivalent intravenously is recommended to induce remission (strong recommendation, low-quality evidence). b. If a patient’s UC does not respond after 3–5 days of intravenous corticosteroid therapy, rescue therapy with infliximab or cyclosporine is recommended (strong recommendation, moderate-quality evidence). c. If remission is achieved with infliximab, continue therapy for maintenance. If remission is achieved with cyclosporine, maintain remission with a thiopurine or vedolizumab. F. Medical management of CD 1. Treatment is selected according to disease location and severity. 2. Mild-moderate active disease: First line for ileal, ileocolonic, or colonic disease a. Oral aminosalicylate (mesalamine 3.2–4 g/day or sulfasalazine 6 g/day) is commonly used but considered minimally effective. b. Budesonide 9 mg/day is preferred for terminal ileal or ascending colonic disease. c. Metronidazole 10–20 mg/kg/day may be used in patients not responding to oral aminosalicylates, but it is generally more effective in patients with perianal or colonic disease. d. Ciprofloxacin 1 g/day is considered as effective as mesalamine (generally, second line), but is usually more effective in perianal or colonic disease and is typically used in combination with metronidazole. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-141 Gastrointestinal Disorders 3. Moderate-severe disease a. Corticosteroids (prednisone 40–60 mg/day or budesonide 9 mg/day if terminal ileal involvement) until resolution of symptoms and resumption of weight gain b. Anti-TNFα agents in combination with thiopurines are the preferred therapies for induction of remission for moderate to severe CD. Thiopurine monotherapy or methotrexate is not recommended to induce remission in moderate to severe active CD. i. Infliximab 5 mg/kg is an alternative first-line treatment (improvement in up to 80% of patients). Infliximab can be combined with azathioprine in patients whose therapy with aminosalicylates and corticosteroids has failed and who are naive to biologic agents. This combination is superior to each drug given alone; however, there is a risk of hepatosplenic T cell lymphoma. ii. Certolizumab 400 mg subcutaneously and then 400 mg subcutaneously at weeks 2 and 4, or adalimumab 160 mg subcutaneously initially followed by 80 mg subcutaneously 2 weeks later, can also be considered, particularly in patients with C-reactive protein values greater than 10 mg/L. iii. Adalimumab can be used as initial therapy or for patients who no longer respond to infliximab therapy because they developed antibodies to infliximab. c. Vedolizumab 300 mg (or natalizumab) intravenously every 4 weeks can be considered for patients who did not respond to any other conventional medical therapy. d. Ustekinumab 260-520 mg intravenously on the basis of patient weight, followed by 90 mg subcutaneously every 8 weeks can be used for patients whose conventional or inhibitor therapy has failed. e. Methotrexate maintenance therapy (15–25 mg/week intramuscularly or subcutaneously) is effective in patients whose active disease has responded to intramuscular methotrexate and who have steroid-dependent or steroid-refractory disease. 4. Severe disease a. Severe symptoms despite oral corticosteroids or infliximab therapy b. Assess need for surgical intervention (mass, obstruction, and abscess). c. Administer intravenous corticosteroids (40–60 mg of prednisone equivalent). d. Parenteral nutrition may be needed after 5–7 days. e. Possibly use intravenous cyclosporine if steroids fail. 5. Maintenance therapy a. There is no role for long-term corticosteroid use, but budesonide can be used for up to 3 months in patients with mild-moderate disease with ileal involvement. b. Azathioprine/mercaptopurine or infliximab, or the combination, can be used after induction with corticosteroids. c. Azathioprine/mercaptopurine or mesalamine (more than 3 g/day) can also be used after surgical resection to prevent recurrence. d. Infliximab 5 mg/kg at 0, 2, and 6 weeks and then every 8 weeks or adalimumab 40 mg subcutaneously every other week (starting on day 29 of therapy) e. Vedolizumab 300 mg (or natalizumab) intravenously every 4 weeks can be considered for patients who did not respond to conventional medical therapy. f. Ustekinumab 90 mg subcutaneously every 8 weeks can be used for patients whose conventional or TNF inhibitor therapy has failed. g. Methotrexate intramuscularly 25 mg for up to 16 weeks, followed by 15 mg/week intramuscularly, is effective for patients with chronic active disease. 6. Perianal disease a. Simple perianal fistulas (a single tract without abscess and involving less than 30% of the external sphincter; better prognosis; can be treated less aggressively than complex fistulas) i. Antibiotics: metronidazole or ciprofloxacin ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-142 Gastrointestinal Disorders ii. Azathioprine/mercaptopurine iii. Infliximab, adalimumab, certolizumab b. Complex perianal fistulas (involving more than 30% of the external sphincter, multiple tracts, abscess involvement, recurrent fistulas, rectovaginal fistulas; worse prognosis requiring more aggressive therapy than simple fistulas.) i. Infliximab, adalimumab, or certolizumab in combination with surgery ii. Antibiotics: Metronidazole or ciprofloxacin (mainly as adjunctive therapy in this case) iii. Azathioprine/mercaptopurine or methotrexate Patient Cases 4. A 35-year-old man presents with newly diagnosed mildly active UC affecting his descending colon and rectum (left-sided disease). He takes loratadine 10 mg/day for seasonal allergies. He has no known drug allergies. Which drug regimen is best? A. Balsalazide 750 mg twice daily. B. Methotrexate 25 mg intramuscularly once weekly. C. Infliximab 5 mg/kg intravenously. D. Mesalamine enema 4000 mg rectally once daily. 5. A 25-year-old woman (height 62 inches, weight 50 kg) presents to the clinic with a 12-week history of cramping abdominal pain, fever, fatigue, and 3 or 4 bloody stools per day. A colonoscopy reveals patchy inflammation in the colon and terminal ileum consistent with moderately active CD. She has an allergy to penicillin (rash). Vital signs include body temperature 98°F, heart rate 100 beats/minute, respiratory rate 18 breaths/ minute, and blood pressure 118/68 mm Hg. Which therapeutic choice is best? A. Mesalamine (Pentasa) 1000 mg four times daily. B. Infliximab (Remicade) 275 mg intravenously and azathioprine 100 mg daily. C. Budesonide (Entocort) 9 mg orally once daily. D. Adalimumab (Humira) 40 mg subcutaneously every 2 weeks. V. COMPLICATIONS OF LIVER DISEASE A. Severity of liver disease is assessed using scoring tools such as the Chuld-Turcotte-Pugh or model for endstage liver disease (MELD) scores (Tables 12 and 13). Table 12. Child-Turcotte-Pugh Classification of the Severity of Cirrhosis Variable Encephalopathy Ascites Bilirubin (mg/dL) Albumin (g/L) Prothrombin time (seconds above normal) a 1 Point Absent Absent <2 >3.5 1–4 Score 2 Points Mild-moderate Slight 2–3 2.8–3.5 4–6 3 Points Severe to coma Moderate >3 <2.8 >6 Class A = total score of 5 or 6; class B = total score of 7–9; class C = total score of 10 or more. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-143 Gastrointestinal Disorders Table 13. Model for End-Stage Liver Disease (MELD) Version Original Calculation 9.57 × ln(creatinine) + 3.78 × ln(total bilirubin) + 11.2 × ln(INR) + 6.43 MELD-Na MELD − Na − [0.025 × MELD × (140 − Na)] + 140 UNOS modification Original MELD equation with limits set on laboratory values that are entered Comments Score ranges from 6 to 40 Higher number indicates more severe disease Used to predict mortality and prioritize patients for liver transplantation Incorporates sodium May better discriminate risk of death Lower end of laboratory values for SCr, bilirubin, and INR are set at 1 with a maximum of 4 If two or more dialysis treatments within the prior week or within 24 hr of CVVHD within the prior week, SCr concentration automatically set to 4.0 mg/dL CVVHD = continuous venovenous hemodialysis; INR = international normalized ratio; MELD = model for end-stage liver disease; Na = sodium, UNOS = United Network for Organ Sharing. B. Ascites 1. Definition: Free fluid in the abdominal cavity owing to increased resistance within the liver (forces lymphatic drainage into the abdominal cavity) and reduced osmotic pressure within the bloodstream (hypoalbuminemia); develops at a 5-year cumulative rate of 30% in compensated liver disease 2. Clinical features: protuberant abdomen, shifting dullness, fluid wave, bulging flanks, abdominal pain 3. Diagnosis a. Clinical features b. Abdominal ultrasonography c. Paracentesis, use to determine serum-ascites albumin gradient (SAAG), calculated by subtracting the ascites albumin concentration from the serum albumin concentration; a value greater than 1.1 indicates ascites caused by portal hypertension 4. Treatment a. Treat the underlying cause of cirrhosis. Improvement in cirrhosis may result in improved ascites. b. Attainment of negative sodium balance i. Dietary sodium restriction (<2000 mg/day), fluid restriction (<1.5 L/day) if serum sodium is less than 120–125 mmol/L ii. Goal is sodium excretion greater than 78 mmol/day. A random spot urine sodium concentration greater than the potassium concentration (ratio greater than 1) correlates with a 24-hour sodium excretion of greater than 78 mmol/day with 90% accuracy. iii. Diuretics (a) Spironolactone alone may be sufficient for an initial episode of ascites. Combined spironolactone 100 mg and furosemide 40 mg may be necessary for subsequent episodes. Dose titration up to 400 mg of spironolactone and 160 mg of furosemide may be necessary; maintenance of the initial ratio is not required, but the ratio should be adjusted based on potassium, blood pressure, and urine output. Dose increases of spironolactone should be made every 72 hours to account for its onset of action. Patients who develop gynecomastia with spironolactone may respond to eplerenone or amiloride. Spironolactone 100 mg is considered equivalent to eplerenone 50 mg or amiloride 10 mg. Patients who do not achieve adequate diuresis with furosemide may respond to bumetanide or torsemide. (b) If tense ascites is present, large-volume paracentesis (>5 L removed) can be used. Administer albumin at a dose of 6–8 g/L of ascitic fluid removed if more than 5 L is removed at one time. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-144 Gastrointestinal Disorders iv. No upper limit of weight loss if massive edema is present, 0.5 kg/day in patients without edema v. Monitor for electrolyte imbalances, renal impairment, and gynecomastia (spironolactone). c. Discontinue drugs associated with sodium/water retention, such as NSAIDs. Avoid angiotensinconverting enzyme inhibitors and angiotensin receptor blockers to prevent renal failure. C. Hepatic encephalopathy 1. Definition: Hepatic encephalopathy is brain dysfunction caused by liver insufficiency or portosystemic shunting; it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma. a. Thought to be secondary to the accumulation of nitrogenous substances (mainly NH3) arising from the gut. Overall, NH3 serum concentrations do not correlate well with mental status b. Other theories are related to the activation of γ-aminobutyric acid receptors by endogenous benzodiazepine-like substances, possible zinc deficiency, or altered cerebral metabolism. 2. Clinical features and criteria a. Can result in acute encephalopathy with altered mental status and progress to coma if untreated; asterixis (“hand flap”) is a classic physical finding b. May be precipitated by various factors including constipation, GI bleeding, infection, hypokalemia, dehydration, hypotension, and CNS-active drugs (benzodiazepines and narcotics) c. The West Haven Criteria and the Glasgow Coma Scale are used to classify and grade; see Table 14. Table 14. Common Criteria and Clinical Symptoms for Hepatic Encephalopathy West Haven Criteria Unimpaired Minimal ISHEN Covert Grade I Clinical Description No current or history of encephalopathy Psychometric or neuropsychologic alterations of tests exploring psychomotor speed and executive functions or neurophysiologic alterations without clinical evidence of mental change Trivial lack of awareness Euphoria or anxiety Shortened attention span Impairment of addition or subtraction Grade II Overt Altered sleep rhythm Lethargy or apathy Disorientation for time Obvious personality change Inappropriate behavior Dyspraxia Grade III Asterixis Somnolence to semistupor Responsive to stimuli Confused Gross disorientation Grade IV Bizarre behavior Coma ISHEN = International Society for Hepatic Encephalopathy and Nitrogen Metabolism. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-145 Gastrointestinal Disorders 3. Classifications a. Subtypes according to underlying disease i. Type A: Owing to acute liver failure ii. Type B: Owing to portosystemic bypass or shunting iii. Type C: Owing to cirrhosis b. Duration i. Episodic ii. Recurrent (occurs within a time frame of 6 months or less) iii. Persistent: Denotes a pattern of behavioral alteration that is always present and interspersed with relapses of overt hepatic encephalopathy c. Presence or absence of precipitating factors 4. Treatment a. Assess need for airway support and remove possible precipitating factors. b. Main treatments targeted at reducing the nitrogen load in the gut. c. Treatment recommendations are based on type C (Table 15). Table 15. Treatment of Hepatic Encephalopathy Owing to Cirrhosis (Type C) Type Episodic overt HE (type C) Recommendations Treat episodic overt HE and then use secondary prophylaxis Primary prophylaxis is not indicated unless cirrhosis and high risk for HE Lactulose is first-line treatment for overt HE Rifaximin can be used as add-on therapy with lactulose to prevent recurrence after the second episode of overt HE Oral BCAA can be used as alternative or additional therapy in patients unresponsive to traditional therapies Neomycin or metronidazole can be used as alternative treatment BCAA = branched chain amino acids; HE = hepatic encephalopathy; IV = intravenous. d. Lactulose i. Nonabsorbable disaccharide: Metabolized by colonic bacteria to acetic and lactic acid. NH3 present in the GI lumen is reduced to ammonium ion (NH4+) through the reduction in pH (“ammonia trapping”) and is unable to diffuse into the bloodstream. Lactulose can also alter bacterial metabolism, resulting in increased uptake of NH3. ii. Dose: 45 mL orally every 1–2 hours until the patient has a loose bowel movement and then titrate to two or three loose bowel movements per day (typically, 15 to 45 mL two or three times daily); may also administer as an enema (300 mL plus 700 mL of water retained for 1 hour). Powder formulation (Kristalose) is available in 10- and 20-g packets to be dissolved in 120 mL water (10 g = 15 mL traditional lactulose). This formulation is more palatable than traditional syrup. iii. Can be continued long term to prevent recurrent encephalopathy iv. Flatulence, diarrhea, and abdominal cramping are common adverse effects. e. Antibiotics i. Targeted at reducing the number of intraluminal urease-producing bacteria that can lead to excess NH3 production ii. Neomycin (3–6 g/day in three or four divided doses for 1–2 weeks and then 1–2 g/day maintenance) or metronidazole (250 mg orally twice daily) can be used; neomycin is considered as effective as lactulose. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-146 Gastrointestinal Disorders iii. F  rom 1% to 3% of neomycin is absorbed. Caution is required for with long-term use with renal insufficiency. Long-term metronidazole can result in peripheral neuropathy. iv. Rifaximin is as effective as lactulose and other nonabsorbable antibiotics, and it may be better tolerated. The approved dose for reduction in overt encephalopathy in patients 18 years and older is 550 mg twice daily. Drug cost may be greater, but this may be offset by fewer hospitalizations and shorter lengths of stay. Previous studies in the short-term setting have used 400 mg three times daily. f. Other possible treatments i. Polyethylene glycol 3350 4 L given orally or by nasogastric tube over 4 hours resulted in faster improvement in encephalopathy than lactulose. ii. Benzodiazepine antagonists such as flumazenil can be used in cases of possible benzodiazepine overdose; however, the risk of lowering the seizure threshold often limits their use. iii. Zinc supplementation should be used in patients with documented zinc deficiency. iv. Nutritional interventions include 35–40 kcal/kg/day based on IBW and 1.2–1.5 g/kg/day protein intake D. Gastroesophageal varices 1. Background a. Resistance to blood flow within the liver caused by cirrhosis results in portal hypertension. Collateral blood vessels (e.g., esophageal varices) are formed because of this increased resistance to blood flow. b. Variceal hemorrhage can occur in 25%–35% of patients with cirrhosis and varices; mortality rates are as high as 30%–50% per bleed; recurrence rates are as high as 70% within the first 6 months after an initial bleed. 2. Management of acute variceal bleeding a. Fluid resuscitation and hemodynamic stabilization. Maintain hemoglobin concentration of about 8 g/dL. Administration of fresh frozen plasma or platelets can be considered for patients with considerable coagulopathy. b. Endoscopy to provide assessment and possible intervention i. Sclerotherapy stops bleeding in 80%–90% of patients; it may be associated with complications such as perforation, ulceration, stricture, and bacteremia. Possible sclerosing agents are ethanolamine and sodium tetradecyl sulfate. ii. Endoscopic variceal band ligation can be used as an alternative to sclerotherapy, with fewer complications. c. Medical management of acute variceal bleeding i. Institute after fluid resuscitation (before endoscopy, if possible) ii. Most therapies are targeted at reducing splanchnic blood flow and portal pressure; a combination of endoscopic and vasoactive therapies is most effective. iii. Somatostatin analog: Octreotide (a) Prevents postprandial hyperemia by reducing portal pressure (by reduced splanchnic blood flow) through inhibitory effects on vasoactive peptides such as glucagon, or by a local vasoconstrictor effect (b) Preferred agent in combination with endoscopic interventions because of more favorable adverse effect profiles; main adverse effects include hyperglycemia and abdominal cramping (c) Dosing: 50-mcg intravenous bolus, then 50 mcg/hour intravenously for 3–5 days ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-147 Gastrointestinal Disorders iv. Vasopressin: 0.2–0.4 unit/minute plus nitroglycerin 40–400 mcg/minute for 3–5 days (a) Vasopressin use results in splanchnic vasoconstriction; it is used less often secondary to the need for both drugs and coronary vasoconstriction/ hypertension with vasopressin (nitroglycerin attenuates these effects to some extent). (b) Vasopressin has a worse adverse effect profile than octreotide. Risk of ischemia, hypotension, and skin necrosis limit use. v. Nondrug measures to control bleeding (a) Typically used for medically unresponsive bleeding (b) Minnesota or Blakemore tube: Balloon compression applied directly to bleeding varices (c) Transjugular intrahepatic portosystemic shunt results in shunting of blood from the portal circulation; this may be associated with complications such as bleeding, infection, and increased risk of hepatic encephalopathy (d) Surgery vi. Antibiotic therapy (a) The use of oral or intravenous prophylactic antibiotics in patients with cirrhosis with variceal bleeding reduces short-term mortality; these agents should be prescribed. (b) Typical regimens include ceftriaxone intravenously 1 gram/day for 7 days, especially when quinolone-resistant bacteria are prevalent or the patient has been receiving quinolone prophylaxis. Fluoroquinolone can be considered in patients who do not have a high risk of quinolone resistance. d. Prevention of variceal bleeding i. Primary prophylaxis (a) A screening esophagogastroduodenoscopy is recommended to evaluate for esophageal and gastric varices when the diagnosis of cirrhosis is made. (b) Pharmacologic therapy is not recommended to prevent the development of varices in patients with cirrhosis who have not yet developed varices. (c) Patients who have small varices and no history of bleeding, but meet the criteria for increased risk of bleeding (Child-Pugh class B or C, red wale marks on varices), should receive preventive drug therapy with nonselective β-blockers. (d) Nonselective β-blockers can be considered; however, the long-term benefit is unclear in patients who have small varices and no history of bleeding, but who do not meet the criteria for increased risk of bleeding. (e) Nonselective β-blockers are indicated in all patients with medium or large varices and no history of bleeding. An endoscopic variceal ligation (EVL) can be used if nonselective β-blockers are contraindicated. (f) Mechanism of nonselective β-blockers: Blockade of β1-receptors reduces cardiac output, whereas blockade of β2-receptors prevents splanchnic vasodilation; unopposed α1-mediated constriction of the splanchnic circulation also leads to reductions in portal pressure. (g) Therapy should aim for a resting heart rate of 55–60 beats/minute or a 25% reduction from baseline. Based on available data, a reduction in hepatic-vein pressure gradient (HVPG) of at least 10% for primary prophylaxis and at least 20% for secondary prophylaxis constitutes β-blocker response. (h) Nonselective β-blockers (propranolol, nadolol, carvedilol) are associated with a significant reduction in the incidence of first bleed. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-148 Gastrointestinal Disorders (i) Long-acting nitrates (isosorbide mononitrate or dinitrate) should not be used for primary prophylaxis. These agents are believed to decrease intrahepatic resistance and are considered as effective as propranolol; however, there is an increased incidence of mortality in some studies when they are used as monotherapy. (j) Shunt surgery or endoscopic sclerotherapy should not be used for primary prophylaxis. ii. Secondary prophylaxis (a) All patients with a history of variceal bleeding should receive secondary prophylaxis to prevent recurrent bleeding. (b) A combination of endoscopic variceal band ligation and nonselective β-blockers is considered the most effective regimen. (c) Nonselective β-blockers are associated with approximately a 20% reduction in the incidence of variceal rebleeding; reductions in mortality are minimal and inconsistent between trials. Most studies are of patients with Child-Turcotte-Pugh class A or B cirrhosis; class C patients may be unable to tolerate β-blockers. (d) Combining nonselective β-blockers with nitrates leads to slightly higher reductions in rebleeding rates; no added mortality benefit is observed, and there is a higher incidence of adverse effects with the combination. (e) Sclerotherapy is no longer recommended for secondary prophylaxis because EVL has been shown to be better, with fewer complications. (f) The transjugular intrahepatic portosystemic shunt is highly effective at preventing recurrent bleeding; however, it is associated with a 30%–40% incidence of encephalopathy and is reserved for medically unresponsive patients. (g) Contraindications to nonselective β-blockers: asthma, insulin-dependent diabetes with frequent hypoglycemia, peripheral vascular disease (h) Adverse effects of nonselective β-blockers: light-headedness, fatigue, shortness of breath, sexual dysfunction, bradycardia (i) Adverse effects of EVL: transient dysphagia, chest discomfort E. Spontaneous bacterial peritonitis (SBP) 1. Background a. Definition: SBP is the infection of previously sterile ascitic fluid without an apparent intraabdominal source; it is considered primary, as opposed to secondary, peritonitis. b. May be present in 10%–30% of hospitalized patients with cirrhosis and ascites c. Associated with 20%–40% of in-hospital mortality; poor prognosis after recovery, with 2-year survival after initial episode reported at about 30% 2. Pathophysiology a. Principal theory is seeding of the ascitic fluid from an episode of bacteremia. b. The bacteria present are usually enteric pathogens; thus, they may enter the blood because of increases in gut permeability secondary to portal hypertension, suppression of hepatic reticuloendothelial cells, or translocation of the gut wall and dissemination through the mesenteric lymph system. c. Reduced opsonic activity of the ascitic fluid and alterations in neutrophil function may also be contributing factors. d. Most SBP infections are monobacterial. About 60% are caused by gram-negative bacteria such as Escherichia coli or Klebsiella spp. Recently, there has been an increase in gram-positive organisms (e.g., Staphylococcus spp., Enterococcus spp., Streptococcus spp.) and multidrug-resistant organisms, especially in the setting of nosocomial or health-care associated SBP. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-149 Gastrointestinal Disorders Table 16. Recommended Empiric Antiobiotic Regimens for SBP Community-Acquired SBP Third-generation cephalosporin: cefotaxime or ceftriaxone Nosocomial SBP or Risk Factors for MDRO Piperacillin-Tazobactam +/– Vancomycin (if prior infection or MRSA-positive surveillance swab) —OR— Daptomycin if prior infection or VRE-positive surveillance swab —OR— Meropenem (if current or recent exposure to piperacillin-tazobactam or known MDRO) +/– Glycopeptide (vancomycin or teicoplanin) if MRSA risk MDRO = multidrug-resistant organism; MRSA = methicillin-resistant Staphylococcus aureus; SBP = spontaneous bacterial peritonitis; VRE = vancomycin-resistant enterococcus. 3. Clinical and laboratory features a. Clinical presentation can vary. About one-third of patients present without symptoms. Common symptoms include fever, abdominal pain, nausea, vomiting, diarrhea, rebound tenderness, and exacerbation of encephalopathy. About 33% of patients present with renal failure, which is associated with significant increases in mortality. GI bleeding and septic shock or hypotension rarely occur. b. Laboratory i. May see systemic leucocytosis or increases in SCr ii. Abdominal paracentesis must be performed. Paracentesis and ascitic fluid cultures must be taken before the first dose of empiric antibiotics is administered. (a) The presence of more than 250 polymorphonuclear cells/mm3 is diagnostic for SBP. (b) Lactate dehydrogenase, glucose, and protein values may help to distinguish it from secondary peritonitis. 4. Treatment of acute SBP a. Because of the high associated mortality, treatment should be initiated promptly in patients with clinical and laboratory features consistent with SBP. b. Predictors of poor outcomes include bilirubin greater than 8 mg/dL, albumin less than 2.5 g/dL, creatinine greater than 2.1 mg/dL, hepatic encephalopathy, hepatorenal syndrome, and upper GI bleeding. c. Antibiotic therapy plus albumin if patient meets criteria for albumin use (see below) i. Empiric therapy targeting likely organisms should be instituted as soon as possible after paracentesis and culture. ii. Empiric antibiotic recommendations are listed in Table 16. iii. Treatment duration: 5–7 days; d. Albumin i. Rationale: The hemodynamics of patients with cirrhosis reflect a state of intravascular hypovolemia and organ hypoperfusion; SBP is thought to exacerbate this effect, resulting in progressive renal hypoperfusion and precipitation of renal failure or hepatorenal syndrome. ii. Albumin infusion improves survival in patients with cirrhosis and SBP. Patients with jaundice and/or acute kidney injury at the time of SBP diagnosis benefit most from albumin infusion. iii. Albumin dosing: 1.5 g/kg on admission; 1 g/kg on hospital day 3 iv. Guidelines suggest using this albumin regimen with antibiotics if SCr > 1 mg/dL, BUN > 30 mg/dL, or total bilirubin > 5 mg/dL. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-150 Gastrointestinal Disorders 5. Prevention a. Prophylactic oral antibiotics are used to reduce the number of enteric organisms in the GI tract (GI decontamination), with the hope of reducing the chance of bacterial translocation to prevent SBP in high-risk patients. b. Antibiotic regimens are similar for both primary and secondary prevention: i. Fluoroquinolones: ciprofloxacin ii. Trimethoprim/sulfamethoxazole c. Primary prevention i. During acute upper GI bleeding, give 7-day course of ceftriaxone during hospitalization. ii. Can also consider indefinite antibiotic prophylaxis in select patients with ascitic fluid protein concentration < 1.5 g/dL and renal dysfunction or liver failure present (SCr > 1.2 mg/dL, BUN > 25 mg/dL, sodium < 130 mg/dL, or Child-Turcotte-Pugh score > 9 with bilirubin > 3 mg/dL). iii. Norfloxacin is the most studied, but is not available in the United States. Use a comparable fluoroquinolone or trimethoprim/sulfamethoxazole for primary prevention. d. Secondary prevention i. All patients recovering from an initial episode of SBP should be treated with oral prophylactic antibiotics indefinitely. ii. Consider patient for liver transplantation because 2-year survival is 25%–30% after recovery. F. Hepatorenal syndrome 1. Criteria in patients with cirrhosis and ascites: SCr > 1.5 mg/dL, no improvement in SCr to less than 1.5 mg/dL after withdrawal of diuretics and administration of albumin, absence of shock, no current nephrotoxins, absence of parenchymal kidney disease and microhematuria, and a normal renal ultrasound 2. Subtypes a. Type 1: Doubling of SCr to greater than 2.5 mg/dL or a 50% reduction in CrCl to less than 20 mL/ minute/1.73 m2 in less than 2 weeks b. Type 2: Nonrapid progression of worsening of renal function. Associated with high mortality. 3. Treatment: Vasoconstrictor therapy along with albumin is recommended. Norepinephrine infusion in the intensive care unit is preferred. Oral midodrine combined with octreotide may be considered in patients who are unable to receive norepinephrine. G. Alcoholic liver disease 1. Subset of chronic liver disease. Patients may develop steatosis and eventually progress to cirrhosis. About 10%–35% of patients may develop severe alcoholic hepatitis. 2. Prognosis of alcoholic hepatitis may be initially evaluated by the Maddrey discriminant function (MDF) score, calculated as 4.6 × (Patient’s PT − Control PT) + Total bilirubin (mg/dL), where PT is prothrombin time. Patients whose score is greater than 32 have a poor prognosis. Patients with a MELD score greater than 20 should also be considered for drug therapy. a. Patients with an MDF greater than 32, with or without encephalopathy, or a MELD score greater than 20 should be considered for a 4-week course of prednisolone 40 mg/day, followed by a 2-week taper. This may lead to a 30% decrease in the risk ratio of short-term death. A Lille score calculation, which is a dynamic measure that considers the change in bilirubin, should be assessed after 7 days of corticosteroid therapy to determine whether improved laboratory findings warrant continuation of the corticosteroid course for the full 28 days. b. Intravenous acetylcysteine in combination with corticosteroids should be considered depending on survival benefit and reduction in early complications (infection, hepatorenal syndrome) compared with corticosteroid therapy alone. c. Pentoxifylline therapy is no longer recommended for alcoholic hepatitis. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-151 Gastrointestinal Disorders Patient Cases 6. A 47-year-old woman with a history of alcoholic cirrhosis (Child-Turcotte-Pugh class C) is admitted to the hospital with nausea, abdominal pain, and fever. Physical examination reveals a distended abdomen with shifting dullness, a positive fluid wave, and the presence of diffuse rebound tenderness. She also has 1+ lower extremity edema. Current medications include furosemide 80 mg twice daily and spironolactone 200 mg once daily. A diagnostic paracentesis reveals turbid ascitic fluid, which was sent for culture. Laboratory analysis of the fluid revealed an albumin concentration of 0.9 g/dL and the presence of 1 × 103 white blood cells (45% polymorphonuclear neutrophils). Serum laboratory studies reveal SCr 1.2 mg/dL, BUN 37 mg/dL, AST 60 IU/ mL, ALT 20 IU/mL, serum albumin 2.5 g/dL, and total bilirubin 3.2 mg/dL. What is the best course of action? A. Initiate intravenous albumin and await culture results. B. Initiate intravenous vancomycin plus tobramycin. C. Initiate intravenous cefotaxime plus albumin therapy. D. Initiate oral trimethoprim/sulfamethoxazole double strength. 7. A 56-year-old man with a history of Child-Turcotte-Pugh class B cirrhosis secondary to alcohol abuse is admitted with a 2-day history of confusion, disorientation, somnolence, and reduced oral intake. On examination, he is afebrile, with abdominal tenderness, reduced reflexes, dry mucous membranes, and asterixis. Paracentesis is negative for infection. He takes propranolol 40 mg three times daily. Which recommendation is best for treating this patient’s hepatic encephalopathy? A. Initiate rifaximin 550 mg orally twice daily. B. Initiate lactulose 30 mL orally every 2 hours. C. Initiate polyethylene glycol 3350 17 g orally twice daily. D. Initiate ceftriaxone 1 g intravenously daily. VI. VIRAL HEPATITIS A. Definitions: For all hepatitis virus infections, acute hepatitis is defined as infection for less than 6 months, whereas chronic infection is infection for more than 6 months. B. HAV 1. Background a. An RNA virus that is associated with the development of self-limited hepatitis b. Transmission occurs mainly through the fecal–oral route. i. Areas of poor sanitation; also flooding leading to increased spread ii. Foodborne: shellfish, water, milk, vegetables iii. Person-to-person contact: sexual, day care, intravenous drug use, household, restaurant workers iv. The Centers for Disease Control and Prevention (CDC) tracks HAV outbreaks. As of November 2021, 22 states report ongoing outbreaks, and 15 states report recently ended outbreaks. The CDC recommends vaccination for prevention of infection (www.cdc.gov/hepatitis/outbreaks/ 2017March-HepatitisA.htm#anchor_1614015686). c. After exposure, incubation for 14–50 days occurs; patients may have general, nonspecific symptoms such as nausea, vomiting, diarrhea, myalgia, fever, abdominal pain, and jaundice. d. Most patients have self-limited disease lasting less than 2 months; death of the hepatocyte results in elimination of the virus. e. HAV is associated with very low mortality (less than 1%) and is not associated with the development of chronic hepatitis. Fulminant hepatitis can occur in some instances. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-152