Physicians evaluating patients with acute-on-chronic liver failure (ACLF) and hepatic encephalopathy should focus on one question from the start, according to Ram Subramanian, MD, MBA.
“Far and away, when I see new-onset hepatic encephalopathy and cirrhosis, the first question I ask myself is ‘Where is the infection?’” he said.
Dr. Subramanian offered this and other pearls about ACLF in a session on “Liver Urgencies and Emergencies” at Southern Hospital Medicine 2018, held in Atlanta in October.
“The backbone of therapy for these folks is number one, find and reverse the precipitating factor. Typically it's an infection, so find the SBP [spontaneous bacterial peritonitis], find the UTI [urinary tract infection],” he said.
In addition to infection, precipitants of hepatic encephalopathy in ACLF include dehydration, gastrointestinal (GI) bleeding, electrolyte derangements, and TIPS (transjugular intrahepatic portosystemic shunt), said Dr. Subramanian, who is a hepatologist and intensivist and medical director of liver transplant at Emory University School of Medicine in Atlanta.
If patients have low Model of End-Stage Liver Disease (MELD) scores and profound hepatic encephalopathy, clinicians should give early attention to imaging, he advised.
“[If] you don't get some feel as to why are they having this sort of disconnect between the degree of liver disease and encephalopathy, please look at the imaging and make sure they don't have a spontaneous shunt,” he advised. “When you have somebody who is falling asleep and . . . keep[s] coming into the unit, getting admitted from the ER, for recurrent hepatic encephalopathy in a cirrhotic patient, think about looking at that imaging to make sure you're not missing a vascular reason for that.”
Dr. Subramanian does not recommend using ammonia levels for initial diagnosis but said they can be used serially to gauge response to therapy.
To treat the encephalopathy, eliminate nitrogenous sources from the GI tract with lactulose, rifaximin, or metronidazole, he said. He noted that there is no role for intracranial pressure-lowering agents in these patients. In cases where physicians are concerned about oral dosing due to aspiration, he recommended starting with lactulose enemas. “That's a good way to bridge them, get their mental status a bit better, and then you can start PO lactulose,” he said.
Before giving lactulose orally, Dr. Subramanian checks to be sure that the KUB (kidney, ureter, and bladder) doesn't show an ileus and that the patient doesn't have metabolic acidosis. “Remember that lactulose induces diarrhea, so you can superimpose a nongap metabolic acidosis onto that,” he said.
For patients with refractory hepatic encephalopathy, albumin dialysis with the Molecular Adsorbent Recirculating System (MARS) is appropriate, Dr. Subramanian said. “This is the one indication that actually has [randomized controlled trial]-level evidence of MARS efficacy: albumin dialysis. . . . This has saved us quite a few times, especially as our [patients'] MELDs get higher as they await transplantation.”
Assessment and complications
Assessment of fluid and intravascular status can be challenging in critically ill patients with cirrhosis, Dr. Subramanian said.
“How should hypotension be defined in these patients? I'm not sure,” he said. He noted that for patients with end-organ evidence of perfusion who are making urine and mentating, a mean arterial pressure of 60 mm Hg may be normal. “Resist the urge to fluid-challenge them, because the fluid's just going to convert to ascites.”
Dr. Subramanian also mentioned the need to watch for abdominal compartment syndrome in ACLF. Try to diagnose it early and then provide timely therapeutic paracentesis to improve blood pressure and renal perfusion, he advised. “It's just a word of caution to look below the diaphragm if you have a cirrhotic who's getting hypotensive.”
Hepatopulmonary syndrome is a unique form of hypoxia in patients with cirrhosis that can't be detected on X-ray, Dr. Subramanian said. The syndrome is diagnosed with bubble echocardiography, specifically bubbles in the right heart that find their way into the left heart in a delayed fashion via pulmonary arteriovenous malformations.
“If you see bubbles in the left heart, it is pathologic. Normally when the bubbles get to [the pulmonary artery] they should collapse,” he said. “If you have a cirrhotic [patient] in the inpatient unit who has unexplained hypoxemia by pulse ox, please check a bubble echo to make sure you're not missing hepatopulmonary syndrome.”
Portopulmonary hypertension is a form of pulmonary arterial hypertension that can occur in cirrhosis, Dr. Subramanian said. “Some patients with cirrhosis will present with massive [lower-extremity] edema in the absence of much ascites, so when you start seeing that scenario, you [have] to think about is there cardiac dysfunction and portopulmonary hypertension.”
For diagnosis, transthoracic echocardiography should be performed first, and patients with an estimated right ventricular systolic pressure above 50 mm Hg should undergo right-heart catheterization. On right-heart catheterization, a mean pulmonary artery pressure greater than 25 mm Hg and a pulmonary vascular resistance consistent with pulmonary arterial hypertension confirm the diagnosis, Dr. Subramanian said. He noted that patients with a mean pulmonary artery pressure above 35 mm Hg will not be considered for liver transplant because of a high risk for death during the procedure.
Hepatic hydrothorax is typically right-sided, can be bilateral, and may present in the absence of ascites, Dr. Subramanian said. When treating this condition, combination diuretic therapy should be maximized, with consideration of the kidneys, Dr. Subramanian said. “You want to maintain a ratio of 100 [mg] of [spironolactone] to 40 [mg] of [furosemide] to maintain normal potassium levels, and we can crank it up four times—we can take it up to 400 [mg] to 160 [mg]—as long as it's tolerated by renal function.”
If performing serial thoracentesis to treat hepatic hydrothorax, “Please don't put a large-bore chest tube in and definitely don't hook it up to suction, because then you'll clearly induce shock,” Dr. Subramanian said. He also noted that refractory hydrothorax is one of the indications for TIPS.
For variceal bleeding in ACLF, it's important to immediately reduce splanchnic flow with splanchnic vasoconstrictors, Dr. Subramanian said. The second step is to start antibiotics, as there are “decent data” showing that they can reduce risk of rebleeding and improve mortality, he said.
Endoscopy can be used to determine bleeding location, Dr. Subramanian said. Endoscopic band ligation is indicated for esophageal varices while TIPS is indicated for gastric varices. “If you have a bleeding gastric varix, in most centers in North America, that is an automatic call for TIPS, because it's sitting in the fundus, it's deeper, it's less amenable to endoscopic hemostasis,” Dr. Subramanian said.
He also reminded his audience to question whether the splenic vein is open in a patient with gastric varix. “Remember that if you see an isolated gastric varix, it may not be due to portal hypertension. It may be just splenic vein thrombosis from pancreatitis, for example,” he said. “So if you have splenic vein thrombosis as your trigger for gastric varices, that requires a splenectomy. It's not a portal hypertensive issue.”
While TIPS can be a literal lifesaver in patients with refractory esophageal bleeding that can't be stopped by endoscopy or patients with gastric varices, post-TIPS hepatic dysfunction is a danger in those whose MELD scores are high, Dr. Subramanian cautioned. “If you take a higher-MELD patient and put the TIPS in . . . they can start developing post-TIPS lactic acidosis, hyperammonemia to some degree, [international normalized ratio] elevation, so watch out if you are forced to do a TIPS in someone who's exsanguinating but with a high MELD score,” he said.
SBP and hepatorenal syndrome
In patients with ascites and SBP, Dr. Subramanian recommended diagnostic paracentesis and early antibiotics if new-onset encephalopathy, acute kidney injury, or hypotension is also present. He reminded his audience that this is an indication for albumin, with a target dosage of 1.5 g/kg for three to five days to decrease the risk for hepatorenal syndrome.
Anything that compromises central blood volume can trigger hepatorenal syndrome, Dr. Subramanian said. “I can't emphasize this enough: Please watch your pH and your metabolic parameters,” he said. “When you superimpose [acute kidney injury] on ACLF, it's a perfect storm for severe metabolic acidosis, and then your pressors don't work and then you start going into a vicious spiral. And this is when I call nephrology, especially in the ICU setting.”
Octreotide is the standard of treatment for hepatorenal syndrome in North America, Dr. Subramanian said, noting that while terlipressin is commonly used in Europe, it has not yet been approved by the FDA. Hepatorenal syndrome usually reverses well after liver transplant, he said.
Finally, patients with decompensated cirrhosis should be considered as immunocompromised hosts, and this is central to management, Dr. Subramanian said. He reminded attendees that SBP, urinary tract infections, and pneumonia can all trigger septic physiology in this population, as can cellulitis, “the other big player.”
Empiric antibiotics should be administered early when an infectious insult is suspected, with double coverage as is done for septic shock, Dr. Subramanian advised. He noted that fungal superinfections are “the new kid on the block” and that infection with such organisms as Candida and Aspergillus are becoming much more common.
“I just want to raise your antennae. If you have a cirrhotic [patient] who's exceeding your desired length of stay or they're frequent flyers, just make sure you screen for fungal superinfections as well,” he said.