I. CIRRHOSIS. Annually, more than 26,000 patients with cirrhosis are admitted to an ICU in the United States. Their in-hospital mortality is more than 50%. The most common reasons for ICU admission are variceal hemorrhage, sepsis, and encephalopathy.
A. Pathophysiology. Chronic hepatic fibrosis leads to distortion of the hepatic vasculature, increased vascular resistance, and elevated portal venous pressures. Impaired hepatic function, coupled with elevated portal venous pressures, lead to end-stage liver disease and the systemic effects of cirrhosis: encephalopathy, hyperdynamic circulation, renal dysfunction, ascites, and variceal hemorrhage.
B. MELD (Model for End-Stage Liver Disease) is a prognostic scoring system initially developed to predict survival in cirrhotic patients undergoing elective TIPS (transjugular intrahepatic portosystemic shunt) placement. It has been validated as a predictor for survival in patients with liver disease and is the basis for ranking patients on the liver transplantation wait list. MELD = 9.57*In[Cr] + 3.78*In[total bilirubin] + 11.2* In[INR] + 6.43. The Child-Turcotte-Pugh (CTP) score was originally developed to predict surgical risk in cirrhotic patients. It is based on the concentrations of total bilirubin and serum albumin as well as the INR, degree of ascites, and degree of hepatic encephalopathy. The subjective components of the score limit its predictive capacity. General ICU prognostic scores such as the SOFA (Sequential Organ Failure Assessment) and APACHE (Acute Physiology and Chronic Health Evaluation) scores have been shown to have greater discriminatory power for predicting mortality in cirrhotic patients who are admitted to the ICU.
C. Variceal Hemorrhage. Endotracheal intubation for airway protection, volume resuscitation, and the administration of blood component therapy should be carried out as needed on the basis of the patient’s condition and laboratory values. Standard therapy for acute variceal hemorrhage consists of the administration of a splanchnic vasoconstrictor and prophylactic antibiotic along with endoscopic intervention.
1. Splanchnic vasoconstrictors reduce portal venous pressure and have been shown to be a useful adjunct to endoscopic therapy.
a. Octreotide: 50-mcg IV bolus followed by 50 mcg/h infusion. Administered for 2 to 5 days. Bolus can be repeated in first hour if the hemorrhage remains uncontrolled. Vasopressin, terlipressin, somatostatin, and octreotide have been shown to be effective.
b. Terlipressin: 2 mg IV every 4 hours for the first 48 hours, followed by 1 mg IV every 4 hours. Administered for 2 to 5 days.
c. Somatostatin: 250-mcg bolus followed by infusion of 250 to 500 mcg/h. Administered for 2 to 5 days.
d. Vasopressin: infusion of 0.2 to 0.4 units/min. Its efficacy is limited by side effects including cardiac and peripheral ischemia. It can only be used continuously at the highest effective dose for 24 hours. It should be accompanied by nitroglycerin administration to minimize the potential harmful effects of vasopressin.
2. Prophylactic antibiotic administration reduces the rate of bacterial peritonitis and increases survival in patients with cirrhosis and variceal hemorrhage.
a. Norfloxacin 400 mg PO BID should be administered for 5 to 7 days. If oral administration is not possible, ciprofloxacin may be administered instead.
b. Ceftriaxone 1 g/day IV for 5 to 7 days is recommended in patients with severe cirrhosis or high probability of quinolone-resistant organisms.
3. Endoscopic variceal ligation. Esophagogastroduodenoscopy (EGD) should be performed within 12 hours of admission. Variceal ligation is preferred to sclerotherapy.
4. TIPS (transjugular intrahepatic portosystemic shunt) is indicated for patients who have uncontrollable or recurrent variceal hemorrhage despite pharmacologic and endoscopic therapy.
D. Spontaneous Bacterial Peritonitis (SBP) is an infection of the ascites in the absence of a primary intra-abdominal focus. SBP accounts for 10% to 30% of bacterial infections in hospitalized cirrhotic patients. The in-hospital mortality for the first episode ranges from 10% to 50%.
1. Diagnosis. As signs and symptoms may be absent, diagnostic paracentesis should be performed for cirrhotic patients with ascites admitted to the hospital. The diagnosis is made on the basis of the presence of >250 polymorphonuclear cells (PMN)/mm3 in ascites, in the absence of an intra-abdominal source of infection.
2. Pathogenesis. SBP is caused by the pathologic translocation of intestinal bacteria due to increased intestinal permeability, impaired immunity, and intestinal bacterial overgrowth in cirrhotic patients. Patients may also develop SBP following gastrointestinal hemorrhage or endoscopic procedures. In the majority of cases, enteric gram-negative bacteria are isolated from the ascites. Less frequently gram-positive cocci or anaerobes may be isolated. Polymicrobial SBP is rare and the presence of multiple bacteria in ascites may indicate bowel perforation.
3. Management. Empiric antibiotic therapy should be initiated immediately following the establishment of the diagnosis. Treatment consists of Cefotaxime 2 g every 8 hours. Alternatively, patients with SBP can be treated with Ofloxacin 400 mg twice per day in the absence of (a) prior exposure to quinolones, (b) shock, (c) grade II or more severe hepatic encephalopathy, and (d) serum creatinine >3 mg/dL. Vancomycin should be added if MRSA is suspected. Antibiotic therapy should be continued for 5 days. If PMN count doesn’t decrease by 25% within 48 hours of initiating therapy, the antibiotic should be changed. Patients with a history of SBP or with esophageal hemorrhage should be treated prophylactically with Norfloxacin. Adjuvant therapy with albumin (1.5 g/kg on day 1 and 1 g/kg on day 3) may prevent worsening of renal function and improve survival in patients with cirrhosis and SBP.
E. Hepatic Encephalopathy develops in up to 50% of patients with cirrhosis and is associated with increased mortality. Up to 80% of episodes are precipitated by infection or gastrointestinal bleeding. The pathophysiology is thought to be due to the impairment of the hepatic clearance of cerebral toxins by the cirrhotic liver.
1. Diagnosis is made on the basis of the patient’s symptoms and signs. The severity of symptoms determines the grade of encephalopathy (see Table 24.1). Serum ammonia levels are elevated but do not correlate with the severity of the disease. Intracranial hypertension (ICH) is rare in patients with hepatic encephalopathy secondary to chronic liver disease unlike in the setting of ALF.
Grades of Encephalopathy
2. Management consists of identifying and treating precipitating causes and lowering serum ammonia levels. Patients who are at risk of aspiration will require intubation.
a. Precipitating causes include GI hemorrhage, infection (SBP, UTI), hypovolemia, renal failure, hypoxia, sedative use, and hypoglycemia.
b. Lactulose (β-galactosidofructose) and Iactitol (β-galactosidosorbitol) are first-line therapeutic agents for hepatic encephalopathy. They are nonabsorbable disaccharides that decrease the absorption of ammonia from the GI tract. Lactulose should be administered at a dose of 20 to 30 g, 2 to 4 times each day, and titrated to achieve 2 to 3 soft stools daily. It can also be administered as an enema. Side effects include dehydration, hypokalemia, and hypernatremia. It is effective in 70% to 80% of patients.
c. Rifaximin 400 mg po tid is added if there is no improvement after 48 hours.
d. Neomycin has been associated with ototoxicity and nephrotoxicity. It is used in patients who are unresponsive to lactulose and intolerant of rifaximin. Oral vancomycin and oral metronidazole have also been used.
F. Ascites is the most common complication of cirrhosis leading to hospitalization. The presence of ascites is suspected on the basis of history and physical exam and confirmed by abdominal ultrasound (US) and paracentesis. Physical exam findings include bulging abdomen and dullness to percussion along the flanks. Approximately 1,500 mL of fluid must be present before flank dullness is detected.
1. Differential diagnosis. The most common etiology of ascites is cirrhosis and portal hypertension. Other potential causes include heart failure, cancer, nephrotic syndrome, and pancreatitis.
2. Diagnostic paracentesis should be performed on all patients presenting with ascites. The fluid should be analyzed for cell count, differential, total protein, and albumin concentration. Serum ascites albumin gradient (SAAG) is the difference between the serum albumin concentration and the ascites albumin concentration. Patients with SAAG ≥1.1 g/dL have ascites secondary to portal hypertension.
3. Initial treatment consists of sodium restriction (<2,000 mg/day) and diuretic administration. Spironolactone is started at 100 mg daily. Furosemide may be added, starting at 40 mg per day. The doses of both diuretics can be increased every 3 to 5 days if weight loss is inadequate. Daily weight loss of 0.5 kg should be targeted. Plasma and urine electrolytes should be monitored frequently.
4. Large-volume paracentesis (>5 L) may be required in patients with tense ascites. The administration of albumin at a dose of 6 to 8 g/L is recommended following drainage of greater than 5 L of ascites.
5. Refractory ascites is defined as ascites that is unresponsive to a sodium-restricted diet and high-dose diuretic treatment (400 mg/day spironolactone and 160 mg/day furosemide) or which recurs rapidly following therapeutic paracentesis. Midodrine 7.5 mg tid may be added to the patient’s diuretic regimen. It has been shown to increase urine sodium, mean arterial pressure, and survival. If possible, B-blockers may be discontinued. Serial paracenteses, TIPS, and liver transplantation are options for patients who remain refractory.
G. Hepatorenal Syndrome (HRS)
1. Diagnostic criteria are cirrhosis with ascites, serum creatinine >1.5 mg/dL, no improvement of serum creatinine after at least 2 days with diuretic withdrawal and volume expansion with albumin, absence of shock, no recent exposure to nephrotoxins, and absence of parenchymal renal disease. Type I HRS is rapidly progressive with a 50% reduction of renal function in 2 weeks. Type II has a slower course.
2. Treatment consists of the infusion of albumin (10–20 g/day) along with the administration of octreotide (200 mcg subcutaneously tid) and midodrine (titrated up to a maximum of 12.5 mg orally tid). Albumin infusion combined with norepinephrine infusion may also be used. Hemodialysis (HD) or continuous venovenous hemoconcentration (CVVH) can be used to maintain volume and electrolyte balance. Ultimately, patients with Type I or Type II HRS will require liver transplantation. Patients with HRS who have been dialyzed for greater than 6 to 8 weeks, may require a combined liver–kidney transplantation.
H. Hepatic Hydrothorax is a large pleural effusion that occurs in patients with cirrhosis and ascites. It is usually right sided. Treatment consists of sodium restriction and diuretic administration. Therapeutic thoracentesis should be performed for dyspnea. Chest tube insertion is contraindicated in patients with hepatic hydrothorax. TIPS should be considered for refractory hepatic hydrothorax.
I. Hepatopulmonary Syndrome (HPS) can be found in 10% to 30% of patients with cirrhosis. It is due to pulmonary vasodilation and arteriovenous shunting, giving rise to hypoxia.
1. Signs and symptoms may include shortness of breath, cyanosis, clubbing, platypnea, and orthodeoxia.
2. Diagnosis is based on the presence of liver disease, an A-a gradient ≥15 mmHg (≥20 mmHg if age is >64), and the demonstration of intrapulmonary shunting by contrast echocardiography or radiolabeled macroaggregated albumin.
3. Management. In the absence of OLTx, the 5-year survival is 23%. Most patients with PaO2 <60 mmHg die within 6 months. There is no effective medical therapy for HPS. Intra-arterial coil embolization of pulmonary arteriovenous fistulae has been shown to improve hypoxia. OLTx is the only effective treatment for HPS.
J. Portopulmonary Hypertension (PoPH) is found in approximately 6% of candidates for liver transplantation. It is defined as mean pulmonary artery pressure (mPAP) >25 mmHg in the setting of a pulmonary artery occlusion pressure (PAOP) <15 mmHg and pulmonary vascular resistance (PVR) >240 dyn·s·cm–5 in a patient with portal hypertension.
Liver transplantation in a patient with PoPH and an mPAP >35 mmHg is associated with significant mortality. Screening for PoPH is conducted with TTE. In patients with an estimated right ventricular systolic pressure (RVSP) >40 to 50 mmHg, right heart catheterization (RHC) is conducted to confirm the diagnosis of PoPH. Patients with PoPH are treated with pulmonary vasodilators to reduce the mPAP below 35 mmHg. Therapeutic options include sildenafil (phosphodiesterase inhibitor), bosentan (endothelin receptor antagonist), and epoprostenol (intravenous prostacyclin). Nitric oxide may be used in intubated patients. Patients with mPAP <35 mmHg on pulmonary vasodilator therapy are candidates for liver transplantation as long as right ventricular function is preserved and PVR is <400 dyn·s·cm-5.
II. ACUTE LIVER FAILURE (ALF) has an incidence of less than 10 cases per million persons per year. It most commonly occurs in previously healthy adults and presents with hepatic dysfunction, coagulopathy, and encephalopathy. It is associated with a mortality of up to 50%. The condition of ALF patients may deteriorate rapidly; thus, early contact with a transplantation center should be made to evaluate for suitability to transfer.
A. Definition. ALF is defined as an INR ≥1.5 and encephalopathy in a patient with no preexisting history of cirrhosis and an illness duration of <26 weeks. Based on the time interval between the onset of jaundice and encephalopathy, ALF can be categorized as hyperacute (<1 week), acute (1–4 weeks), or subacute (4–12 weeks). Hyperacute cases are typically due to acetaminophen toxicity (in developed countries) or viral infection (in developing countries).
B. Causes. The most common causes are drug-induced hepatotoxicity, viral hepatitis, autoimmune hepatitis, and shock. Approximately, 15% of cases have no identifiable cause.
C. Initial evaluation should include a history focused on potential viral or toxin exposures as well as evidence of prior liver disease. In Western countries, the most common cause is acetaminophen-induced hepatotoxicity. Consumption in excess of 10 g/day or 150 mg/kg is associated with toxicity. Severe liver injury can occur with doses as low as 3 g/day. Physical examination should focus on the determination of the degree of encephalopathy as well as the presence of stigmata of chronic liver disease. Laboratory analysis should include chemistries, complete blood count, coagulation profiles, and arterial blood gas analysis. Serum glucose should be monitored as patients may develop hypoglycemia. Viral serologies as well as screens for acetaminophen and other toxins should be obtained. Laboratory studies should also be obtained for Wilson’s disease and autoantibodies.
D. Management. The condition of a patient with ALF can deteriorate rapidly. It is essential to consult a liver transplantation service as soon as possible to determine the appropriateness of listing the patient for transplantation. For most etiologies of ALF, management is supportive (Table 24.2).
1. Acetaminophen-induced hepatotoxicity
a. Activated charcoal slurry at a dose of 1 mg/kg should be administered orally if ingestion is suspected to have occurred within a few hours of presentation.
b. N-acetylcysteine is the antidote for acetaminophen poisoning. It should be administered at a dose of 150 mg/kg over 15 min, followed by an infusion or 50 mg/kg over 4 hours, and then 6 mg/kg/h for 16 hours.
I. ALF due to acetaminophen toxicity: