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Program Information. Critical Care Aspects of Chronic Hepatic Failure. Aditya N. Dubey, MD Peter K. Linden, MD University of Pittsburgh Medical Center Department Critical Care Medicine. Learning Objectives. After reviewing this topic, the learner will be able to:

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  1. Program Information

  2. Critical Care Aspects of Chronic Hepatic Failure Aditya N. Dubey, MD Peter K. Linden, MD University of Pittsburgh Medical Center Department Critical Care Medicine

  3. Learning Objectives • After reviewing this topic, the learner will be able to: • Recognize complications of chronic liver failure requiring critical care support • Verbalize the pathophysiology and clinical sequelae of portal hypertension • Explain the urgent treatments and management for variceal hemorrhage • Demonstrate strategies to treat diuretic refractory ascites • Describe the diagnosis, treatment, and prevention of spontaneous bacterial peritonitis • Identify the indications for referral for liver transplantation

  4. Hepatic Failure Major Reasons for ICU Admission • Variceal hemorrhage • Encephalopathy • Refractory ascites • Spontaneous bacterial peritonitis • Hepatorenal syndrome

  5. Portal Hypertension Terminology • Portal pressure = PV inflow x outflow resistance • The transhepatic gradient (THG) can be measured by the difference between the free hepatic vein pressure and wedge pressure in the hepatic vein (estimated PV pressure) • THG = free HVP – wedged HVP • Normal gradient <5 mm Hg • Increased risk of bleeding >12 mm Hg • Portal hypertension may be elevated without intrinsic liver disease due to pre- and post-sinusoidal pathology (see next slide).

  6. Causes of Portal Hypertension BLOOD FLOW LIVER Pre-sinusoidal PV thrombosis PV extrinsic comp. Schistosomiasis Sarcoidosis PBC Post Sinusoidal Budd – Chiari Veno-occlusive dis. Severe CHF Restrictive heart dis. Sinusoidal Cirrhosis Alcoholic hepatitis

  7. Variceal Hemorrhage Incidence and Outcome • Gastroesophageal varices in 40%-60% cirrhotics • Variceal hemorrhage occurs in 25%-35% cirrhotics • 30% of the initial bleeding episodes are fatal • 70% have recurrent bleeding with a 1-year survival ranging from 30% to 80% • Non-variceal pathology (ulcers, gastritis, mucosal tear) may cause bleeding in patients with known liver disease and portal hypertension. Sharara AI, Rockey DC. N Engl J Med. 2001;345; 669-681.

  8. Variceal Hemorrhage Initial evaluation and stabilization • Assessment of intravascular volume status • Blood pressure is unreliable indicator of volume status • Hematocrit does not reflect acute blood losses • Fluid resuscitation • Place two large bore IVs and/or a central venous catheter • Colloid or crystalloid titrated to parameters of perfusion • Cross-matched or O-negative blood can be used • Endotracheal intubation prior to endoscopy for: • Uncontrolled bleeding • Altered mental status, severe agitation • Respiratory distress or depression

  9. Hierarchical Treatment for Variceal Bleeding Pharmacologic and endoscopic therapy are the usual 1st and 2nd interventions Pharmacologic Endoscopic Radiologic shunt TIPSS Balloon Tamponade Surgical Shunt

  10. Acute Variceal Hemorrhage: Pharmacotherapy • Octreotide • Synthetic analogue of somatostatin • Decreases portal pressure and azygos blood flow • Stops variceal bleeding in 80% of the cases • Efficacy is similar to endoscopic sclerotherapy and better than vasopressin • 5-day course reduces bleeding after endoscopic therapy • Can cause mild hyperglycemia and abdominal cramping • Vasopressin • Reduces portal pressure but causes myocardial and mesenteric ischemia • Terlipressin • Efficacy similar to endoscopic sclerotherapy and as effective as balloon tamponade when used with nitroglycerin • Not approved for use in U.S. Corley DA. Gastroenterology. 2001;120:946-954; Harry R. Curr Opin Crit Care. 2002;8:164-170; Sharara AI, Rockey DC. N Engl J Med. 2001;345:669-681.

  11. Possible Targets for Therapeutic Intervention in Variceal Hemorrhage • Reduction of cardiac output by beta-1 blockade to prevent bleeding • Reduction of splanchnic blood flow by beta-2 blockade or vasoconstrictors (e.g., alpha-adrenergic agonists or vasopressin analogues) • Reduction of intrahepatic resistance by vasodilators • Reduction of variceal or collateral flow by beta-2 blockade, balloon tamponade, or endoscopic therapy

  12. Esophageal vs. Gastric Varices Esophageal varices • Primary approach is endoscopic banding or sclerotherapy • TIPSS, surgical shunts are alternatives Gastric varices • Diffuse, deep submucosal anatomy • Endoscopic tx difficult, dangerous • Primary approach is TIPSS or surgery

  13. Variceal Hemorrhage: Endoscopic Therapy • Endoscopic Band Ligation (see next slide) • Controls bleeding in 80%-90% of cases • Lower complication rates than sclerotherapy • Endoscopic Sclerotherapy • Intravariceal or paravariceal injection of a sclerosing agent • Stops bleeding in 80%-90% of the cases • Complications include perforation, ulceration, and stricture • Cyanoacrylate Injection • Used to control bleeding from gastric varices • Superior to EBL for treatment of bleeding gastric varices • Not available in U.S. Laine L. Ann Intern Med. 1995;123:280-287; Lo GH. Hepatology. 2001;33:421-427.

  14. Banding of Esophageal Varix

  15. Post-Endoscopy Problems Include… • Abdominal distension: From endoscopic air insufflation, retained luminal blood, and increased ascites from resuscitation. This can even progress to abdominal compartment syndrome with associated respiratory compromise, hypotension, oliguria, and acidosis. Nasogastric decompression may partially alleviate this problem. • Worsening encephalopathy: This may occur due to gastrointestinal passage of blood, hepatic hypoperfusion (“shock liver), and accumulation of sedative medication. • Recurrent bleeding: More likely to recur in advanced cirrhosis. Incidence can be reduced with a 5-day course of octreotide post-banding and long-term use of a non-selective beta-blocker (propranolol, nadolol). • Infection: Spontaneous bacterial peritonitis is 3-5x higher following variceal hemorrhage due to occult bacteremia and ascites seeding. Antimicrobial prophylaxis (quinolone, beta-lactam) reduces the incidence of SBP significantly.

  16. Acute Variceal HemorrhageBalloon Tamponade • Effectively controls bleeding in 90% of patients but is only a temporizing measure in massive uncontrolled variceal hemorrhage when initial endoscopic treatment is delayed or unsuccessful. • Can cause aspiration, esophageal ulceration, perforation with mediastinitis • Balloon-related mortality is 3%-5% • Gastric balloon inflation is usually sufficient • Esophageal balloon inflation should only be used when gastric balloon is unsuccessful as it is associated with higher morbidity.

  17. Sengstaken – Blakemore Tube • Gastric balloon • Esophageal balloon • Gastric aspiration port

  18. Minnesota Tube • Gastric balloon • Esophageal balloon • Gastric aspiration port • Esophageal aspiration port

  19. Tube Positioning and Gastric Balloon Inflation 1.Tube inserted to 50 cm 2.Auscultate in stomach 3.Inflate gastric balloon with 50 cc 4.Stat portable film • Re-confirm proximal position • Inflate GB 300-400 cc air • Pull to insure anchorage • Recheck film • 1-2 lbs of pulley traction

  20. Gastric and Esophageal Balloon Inflation Esophageal Balloon inflated to 30 mm Hg • Last resort • Deflate periodically • Use minimum effective pressure • Complication • ulcer • perforation • stricture

  21. Malposition of the Gastric Balloon

  22. Transjugular Intrahepatic Portosystemic Shunt (TIPSS) Major Indications • Refractory variceal bleeding • Refractory ascites, hydrothorax • Radiologic insertion of a metallic shunt (8-12 mm diameter) that joins the hepatic and portal veins • Target gradient (HV-PV) <12 mm Hg • Restores hepatopedal flow • Decompression of varices

  23. Summary of Trials Comparing TIPSS to Endoscopic Therapy for Variceal Bleeding Generally, higher rates of rebleeding were more common after endoscopy treatment, while encephalopathy rates were higher in the TIPSS groups Stanley AJ, Hayes PC. Lancet. 1997;350:1235-1239.

  24. Complications of TIPSS • Peri-procedure mortality of 1%-2% • Intraperitoneal bleeding due to perforation of the hepatic capsule, hepatic or portal veins • TIPSS embolization • Acute right heart failure due to increased venous return to right heart • Later complications include recurrent bleeding due to TIPSS stenosis or thrombosis, infection, and hepatic encephalopathy.

  25. Conditions That May Contraindicate TIPSS This venogram shows an occlusive thrombus of the portal vein, which may make safe TIPSS placement impossible. This abdominal CT demonstrates a large hypodense hepatic lesion due to hepatocellular carcinoma in a very shrunken cirrhotic liver. Other contraindications include hepatic vein occlusion, heart failure or pulmonary hypertension, biliary obstruction, and poorly controlled systemic infection.

  26. TIPSS Thrombosis/Stenosis • Incidence 12%-74% • Most likely within the first month • Symptoms - recurrent bleeding, ascites • Detection - Doppler ultrasound angiography (shows velocity gradient) • Treatment • Balloon dilatation • Placement of TIPSS

  27. Trans-TIPSS Embolization of Persistent Varices Persistent variceal bleeding due to high-flow collaterals despite a patent TIPSS may be coil-embolized radiologically via the TIPSS itself.

  28. Acute Variceal Hemorrhage: Surgery • The distal splenorenal shunt (Warren shunt) procedure is generally reserved for Child’s A or B cirrhotics. • Consider in patients with bleeding refractory to pharmacologic, endoscopic, and radiologic treatment. • Complications include shunt thrombosis, infection, and worsening encephalopathy. • 30-day mortality is close to 80% in Child’s C patients requiring emergency shunt surgery.

  29. Relative Effectiveness of Available Therapies for the Prevention of Recurrent Variceal Bleeding Beta-blockers are the single most effective and safest strategy to prevent the recurrence of variceal bleeding. More aggressive strategies, such as banding, TIPSS, or shunt surgery, may decrease bleeding but are associated with higher risks and costs. Sharara AI, Rockey DC. N Engl J Med. 2001;345:669-681.

  30. Hepatic Encephalopathy • Hepatic encephalopathy reflects a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other known brain disease.

  31. Grade 1 Trivial lack of awareness Euphoria or anxiety Shortened attention span Impaired performance of addition Grade 2 Lethargy or apathy Minimal disorientation for time or place Subtle personality change Inappropriate behavior Impaired performance of subtraction Asterixis Grade 3 Somnolence to semi-stupor but responsive to verbal stimuli Confusion Gross disorientation Grade 4 Coma, unresponsive to verbal or noxious stimuli Hepatic Encephalopathy – West Haven Criteria for Grading Mental State

  32. Metabolic encephalopathies Hypoglycemia Hypoxia Uremia Electrolyte abnormalities Toxic encephalopathies Alcohol Barbiturates, other CNS depressants Heavy metals Intracranial lesions Subarachnoid, subdural, or intracerebral hemorrhage Stroke Intracranial tumor Intracranial abscess Epilepsy Neuropsychiatric disorders Hepatic Encephalopathy: Differential Diagnosis

  33. Increased ammonia production Gastrointestinal hemorrhage Excess dietary protein Azotemia Infection, including SBP Blood transfusion Hypokalemia Systemic alkalosis Constipation Portosystemic shunts Spontaneous TIPSS Surgical Progressive hepatic parenchymal damage Hepatoma Use of benzodiazepines or other psychoactive drugs Hepatic Encephalopathy: Precipitating Factors Riordan SM, Williams R. N Engl J Med. 1997; 337:473-479.

  34. Why does the ammonia level correlate poorly with encephalopathy? • Venous ammonia levels < arterial • Time lag from ↑NH3 and CNS • Blood-brain permeability is variable • Balance of NH3 / NH4+ • Processing (must be on ice, <20 min)

  35. Management of Hepatic Encephalopathy • First and foremost control the underlying precipitant(s). • Medical therapy - optimal agent is controversial (see meta-analysis) • Lactulose - has multiple actions including cathartic, acidification of the colon to “ion-trap” ammonia as NH4+, and reduction of inoculum of urea-splitting bacteria. Drawbacks include osmotic diarrhea with hypernatremia due to free water loss and gaseous bowel distension. • Neomycin - non-absorbed aminoglycoside that reduces colon bacterial burden. Dosed at 2-6 grams orally per day. Small incidence of ototoxicity and nephrotoxicity with prolonged usage. • Rifaximin - non-absorbed antimicrobial 400 mg q 8 hours orally • Metronidazole - oral dosing at 800 mg/day. No large scale reported experience. Agent is associated with neurotoxicity in hepatic failure due to accumulation. • Flumazenil - benzodiazepine receptor (GABA) antagonist.

  36. Flumazenil in Hepatic Encephalopathy In this double-blind, placebo-controlled, randomized trial, flumazenil showed transient benefit in higher grades of encephalopathy. The role of flumazenil for all degrees of encephalopathy or as a longer term agent in critically ill patients has not been determined. Barbaro G, et al. Hepatology. 1998;28:374-378.

  37. Ascites - Critical Care Aspects • Complicated ascites may be the principal reason for critical care admission but is frequently associated with hemorrhage, renal failure, and/or hepatic encephalopathy. • Common complications of ascites include: • Diuretic-refractory ascites - defined as unresponsiveness to sodium restriction and high-dose diuretics (400 mg/day spironolactone and 160 mg/day furosemide) OR rapid recurrence after therapeutic paracentesis • Tense ascites - this may result in the development of: • Abdominal compartment syndrome with impaired venous return causing hypotension, impaired renal perfusion causing oliguria, and reduced hepatosplanchnic perfusion • Respiratory compromise may occur due to impaired diaphragmatic contractility and/or hydrothorax due to the passage of ascites into the pleural space • Infection - spontaneous bacterial peritonitis Runyon BA. Hepatology. 2004;39:841-856.

  38. Paracentesis • Abdominal paracentesis is the most rapid and cost-effective technique to diagnose the cause of ascites. • An area of percussion dullness in the left lower quadrant (2 cm cephalad and anterior to the anterior superior iliac spine) has a greater likelihood of ascites present than the midline. • Ultrasound guidance should be utilized if ascites is difficult to localize and to avoid venous collaterals, intestine. • Since bleeding is sufficiently uncommon, the prophylactic use of plasma or platelets before paracentesis is not recommended. • An indwelling drainage catheter can be left for 3-5 days if therapeutic drainage is required. Runyon BA. Hepatology. 2004;39:841-856.

  39. High SAAG 1.1 g/dL Cirrhosis (75% cases) Alcoholic hepatitis Portal vein thrombosis Budd-Chiari syndrome Cardiac failure Veno-occlusive disease Ascites - Classification Low SAAG 1.1 g/dL • Peritoneal carcinomatosis • Pancreatic ascites • Biliary ascites • Nephrotic syndrome • Tuberculous peritonitis Krige J, et al. BMJ. 2001;322.

  40. Spontaneous Bacterial Peritonitis • Spontaneous infection of ascitic fluid in the absence of a secondary intra-abdominal source of infection • Translocation of intestinal bacteria or hematogenous seeding of ascites • Mainly a complication of cirrhotic ascites • Incidence is 15%-20% of cirrhotics with the highest incidence in Child’s class C cirrhosis and following upper gastrointestinal bleeding • E. coli, Klebsiella sp., S. pneumoniae most common • Clinical manifestations include fever, abdominal pain, unexplained encephalopathy, although asymptomatic presentations are not uncommon • Mortality per episode = 20%-30% • One year follow-up mortality = 50%

  41. Spontaneous Bacterial PeritonitisDiagnosis • Ascites should be processed for the following: • Total cell count and differential • Bacterial cultures in blood culture bottles • Other tests (protein, albumin, LDH, glucose, special cultures) may be indicated based upon clinical judgment • A diagnosis of SBP is established by any one of the following: • >250 polymorphonuclear cells per cubic mm of ascitic fluid, and a positive ascitic fluid culture is diagnostic. • Patients with 250 PMNs/mm3 but negative cultures (neutrocytic ascites) • Positive ascites cultures and <250 PMNs/mm3 (monomicrobial non-neutrocytic ascites) Runyon BA. Hepatology. 2004;39:841-856.

  42. Spontaneous Bacterial Peritonitis • Suspected secondary bacterial peritonitis • PMN count 250 cells/mm3 • Multiple organisms on Gram’s stain and culture • Anaerobes cultured • Two of the following ascites criteria: • Total protein >1g/dL • LDH > upper limit of normal for serum • Glucose <50 mg/dL • Treatment – third-generation cephalosporin, consider CT scan of abdomen and pelvis, and possible laparotomy

  43. Spontaneous Bacterial PeritonitisAASLD Guidelines • Patients with ascitic fluid PMNs 250/mm3 should receive empiric antibiotic therapy, e.g., cefotaxime, 2 g every 8 hours (I). • Patients with ascitic fluid PMNs <250/mm3 with signs or symptoms of infection should receive empiric antibiotics pending culture results (II-B). • Oral ofloxacin can be considered in patients without vomiting, shock, grade 2 hepatic encephalopathy, or serum creatinine >3 mg/dL. • Prevention of SBP: • Short-term (7 days) inpatient norfloxacin or Bactrim prophylaxis in patients with gastrointestinal hemorrhage • Patients with prior SBP should receive long-term prophylaxis with daily norfloxacin or Bactrim (SBP recurs in up to 70% of cases within one year).

  44. Refractory Ascites: Management • Serial paracentesis every 2 to 4 weeks and/or transjugular intrahepatic portosystemic shunts: • Post-paracentesis volume expansion is controversial but may be considered when 5 L or more of fluid is removed. Albumin (6-8 g per liter of fluid removed), dextran 70 or Hemaccel may be used. • A recent meta-analysis comparing TIPSS vs. paracentesis showed: • 30-day mortality - no difference, OR 1.0 (CI 0.1-10.06) • 24-month mortality - no difference, OR 1.17 (CI 0.52-2.66) • 12-month ascitic fluid reaccumulation - less in TIPSS, OR 0.14 (CI 0.06-0.28) • Hepatic encephalopathy - more with TIPSS, OR 2.11 (CI 1.22-3.66) • No difference in the incidence of GI bleed, infections, or acute renal failure. Sheagren JN, et al. J Clin Gastroenterol. 1996;22:207-210; Saab S. Cochrane Hepato-Biliary Group. 2005.

  45. Tc -Labeled Sulfur Colloid Showing Fluid Passage From Peritoneal to Pleural Space 99 Bhattacharya A, et al. J Gastroenterol Hepatol. 2001;16:317-321.

  46. Right Hydrothorax Managed with Pleural Catheter Drainage Before After

  47. Hepatorenal Syndrome • Type 1 HRS: • Acute impairment in renal function defined by doubling of initial serum creatinine above 2.5 mg/dL or a 50% reduction of the initial 24-hour creatinine clearance to a level lower than 20 mL/min in less than 2 weeks. Mortality is as high as 90% after 2-4 weeks • Type 2 HRS: • Stable or slowly progressive impairment in renal function not meeting the above criteria. Associated with better survival than Type 1 HRS.

  48. Hepatorenal Syndrome Ginès P, et al. N Engl J Med. 2004;350:1646-1654.

  49. Hepatorenal Syndrome • Criteria for Diagnosis of HRS: • Serum creatinine >1.5 mg/dL or 24-hr creatinine clearance <40 mL/min • Absence of shock, ongoing bacterial infection or fluid loss, and no current treatment with nephrotoxic drugs • Absence of sustained improvement in renal function (decrease in serum creatinine to 1.5 mg/dL) after discontinuation of diuretics and trial of plasma expansion • Absence of proteinuria (<500 mg/d) or hematuria (<50 RBCs per HPF) • Absence of ultrasonographic evidence of obstructive uropathy or parenchymal renal disease • Urinary sodium concentration <10 mmol/L

  50. Hepatorenal Syndrome: Treatment • Administration of one of the following drugs or drug combinations can be considered: • Norepinephrine 0.5-3.0 mg/h intravenously • Midodrine 7.5 mg three times daily increased to 12.5 mg three times daily if needed in combination with octreotide 100 g subcutaneously three times daily, increased to 200 g three times daily if needed • Concomitant administration of albumin 1 g/kg intravenously on day one, followed by 20-40 g daily • Treatment is given for 5-15 days. • End point of the treatment is reduction of serum creatinine to <1.5 mg/dL

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