Therapy of Liver Failure
Jennifer L. Davis
Antibiotic Therapy
Antibiotic therapy is indicated in cases of cholelithiasis, cholangitis, and cholangiohepatitis, as well as liver dysfunction secondary to systemic diseases causing sepsis in horses.
Initial treatment should include broad-spectrum IV antibiotics, such as potassium penicillin plus either gentamicin or enrofloxacin, and oral metronidazole to cover B. fragilis. This is followed by long-term oral antibiotics based on culture and sensitivity (if available).1 If no culture is available, the clinician should suspect gram-negative enteric bacteria with or without concurrent anaerobic infection. Trimethoprim sulfonamide combinations or enrofloxacin plus metronidazole are good choices. Chloramphenicol has a good spectrum against most cultured bacteria, but since it is highly metabolized by the liver, it should not be used if hepatic function is severely compromised. High levels of IV penicillin and an aminoglycoside should be administered to foals with suspected Tyzzer's disease.2Cattle with single or multiple liver abscesses often respond to penicillin therapy, but long-term therapy is required, and there is a significant rate of recurrence of clinical signs after therapy is withdrawn. Echolucent abscesses of small to medium size have the best prognosis. Abscesses with an echodense appearance are difficult to treat. Single large abscesses are best treated by surgical drainage, especially those interfering with vagal nerve function.
Treatment of Hepatic Encephalopathy
Treatment of hepatic encephalopathy (HE) involves treatment of the underlying hepatic disease combined with supportive and palliative care. This includes IV fluids, broad-spectrum antibiotics, and gastroprotectants. Padding and wraps should be provided to help prevent self-trauma. Sedation may be necessary to control behavior or aid in treatments, but many of these drugs are metabolized in the liver, so care should be taken during dosing.
Small doses of α2-adrenergic agonists like xylazine or detomidine are recommended. However, these drugs can cause respiratory depression at higher doses, and hypoventilation may aggravate signs of HE. Doses should also be low enough to cause sedation without resulting in prolonged lowering of the head below the level of the shoulder, which may result in worsening cerebral edema. Diazepam and other benzodiazepines should not be used; they may enhance the effects of GABA on inhibitory neurons, worsening HE.3 Based on this, use of the benzodiazepine receptor antagonists has been recommended to lessen HE signs in humans.4 The overall success of flumazenil in treating HE in humans and dogs has been low, and it has rarely been used in the horse. Sarmazenil, a partial inverse agonist at the benzodiazepine receptor, appears to be more promising for reversing signs of HE in dogs5 and has been used for treating moxidectin intoxication in a foal.6Dietary management of HE is very important. Liver failure results in increased serum glucagon, and muscle catabolism releases amino acids. At the same time, hepatic metabolism of aromatic amino acids (AAAs) is reduced and accumulation occurs, whereas muscle and adipose tissue can metabolize branched-chain amino acids (BCAAs), resulting in less accumulation. AAAs cross the blood-brain barrier and can act as false neurotransmitters, aggravating signs of HE, so a low-protein diet with a high BCAA/AAA ratio is recommended.7,8 Low- protein, high-starch feeds include grass or oat hays, beet pulp, cracked corn, milo, sorghum, barley, and oats. Feed small amounts frequently (q2-4h). If affected horses are anorexic, forced enteral or partial parenteral nutrition may be used. Special formulations of amino acids that consist mainly of BCAAs should be used, and lipids should not be added if there is any possibility that lipidosis is present.
Other treatments for HE are designed to reduce intestinal ammonia absorption.
Neomycin is an aminoglycoside antibiotic that suppresses enteric ammonia production. Because it is more nephrotoxic than gentamicin and can be irritating to intestinal mucosa (causing diarrhea), treatment duration is often limited to 3 days or less. Reported doses also vary widely, with some reports recommending higher and more frequent dosing (10 to 20 mg/kg PO q6-12h)9 and others recommending lower doses to decrease the risk of adverse effects (4 to 8 mg/kg PO q8h day 1, followed by 2-4 mg/kg PO q12h for 2 additional days).10 Oral metronidazole (10 to 15 mg/kg twice daily) may be used as an alternative in cases that do not tolerate neomycin. Metronidazole should be used with caution because it is metabolized by the liver, and signs of toxicity may mimic HE. Lactulose (0.2 to 0.5 mL/kg PO q6-8h; equivalent to up to 333 mg/kg) is poorly absorbed by the small intestine and therefore reaches the ileum and large intestine intact. Once in the distal GI tract, it is metabolized to organic acids, acidifying the intestinal contents causing a pH gradient to occur and ammonia to migrate from the blood into the colon, where it is trapped as ammonium and expelled. Acetic acid (vinegar, 0.5 mL/kg PO q12h), mineral oil, and magnesium sulfate administered by nasogastric tube have also been used to decrease ammonia absorption. However, induction of hemorrhage during the procedure may result in swallowing of blood and worsening of enteric ammonia production.Treatments aimed at reducing cerebral edema may also be necessary. Drugs frequently used include furosemide (1 mg/kg IV/IM q8-12h), mannitol (0.5 to 1 g/kg as a 20% solution IV over 20 to 30 minutes q12-24h), and hypertonic saline (2 to 4 mL/kg IV). The prognosis for HE is poor unless the underlying disease can be treated quickly.
Fluid and Colloid Therapy metabolized to bicarbonate in the liver and has an alkalizing effect. However, in horses with severe hepatic dysfunction, lactate may build up in the system and cause a worsening of acidosis.
Acetate buffer solutions can be used as an alternative since acetate is mainly metabolized in the muscle. Sodium chloride (0.9%) with added calcium, dextrose (2.5% to 5%), and supplemental potassium (20 to 40 mEq/L) also can be used. Additional potassium can be given orally (5 to 20 g twice daily) to prevent or treat hypokalemia, since low potassium increases production and absorption of ammonia from the kidney.11 Acidosis may be severe in many horses with hepatic failure, but attempts at correction must be made slowly.12 Too rapid an increase in pH may exacerbate HE. Bicarbonate therapy should be carefully instituted only when the venous pH remains less than 7.1 after appropriate fluid therapy. The prognosis is poor in horses that remain persistently acidotic.Glucose decreases ammonia concentration, reduces the reliance on catabolic gluconeogenesis, decreases protein catabolism, and spares hepatic energy consumed in hepatic gluconeogenesis, so it should be supplemented in cases of hepatic disease. The goal is to maintain blood glucose concentrations in the range of 90 to 120 mg/dL. In the case of hypertriglyceridemia with concurrent insulin resistance, supplemental insulin can be administered, as described in the Hepatic Lipidosis section earlier.
Polycythemia may be relatively unresponsive in some cases of hepatic failure and should not be used as the primary guide for judging adequate fluid therapy. Fresh or fresh frozen plasma can be used to increase colloidal oncotic pressure, clotting-factor transport proteins, and antiproteases. Stored whole blood should not be used because ammonia levels may be high. Hetastarch should also not be used in hepatic failure, owing to its potential effects on coagulation.
Treatment of Inflammation and Fibrosis
Corticosteroids may be beneficial in treating lymphocytic and plasmacytic variants of chronic active hepatitis. Dexamethasone (0.05 to 0.1 mg/kg/day IM or IV decreased over 2 to 3 weeks) or prednisolone (1 mg/kg/day PO for several weeks) are recommended.
Other recommended therapies for resolving inflammation and preventing progression of fibrosis include NSAIDs. Flunixin meglumine (0.5 to 1 mg/kg PO q12h to q24h) or low-dose phenylbutazone (0.5 g/day PO q24h) can be used for anti-inflammatory effects. Vitamin E (10,000 U PO q24h) is recommended as an antioxidant and anti-inflammatory agent. Pentoxifylline (8 to 10 mg/kg PO q12h) is a methylxanthine derivative and works as a nonselective phosphodiesterase inhibitor, resulting in weak inhibition of the inflammatory cytokines TNF-α and IL-6. It also acts to increase RBC deformability, perhaps preventing microthrombosis. In horses, results with pentoxifylline are variable, possibly because of the variable bioavailability with extended dosing.13 Colchicine (0.03 mg/kg PO q24h) can be used to inhibit production of collagen and macrophage- or cytokine-induced inflammation, potentially resulting in decreased fibrosis. Numerous side effects are reported in humans, including nervous system, renal, and dermatologic problems; therefore its use in horses is not currently recommended.Miscellaneous Treatments
Supplemental S-adenosylmethionine (SAMe) (20 mg/kg PO q24h) is used for treatment of liver diseases; endogenous production is reduced secondary to reductions in methionine adenosyltransferase.14 Presumed beneficial effects of SAMe in liver disease include augmentation of glutathione synthase levels in the hepatocyte, stabilization of membrane function, modification of cytokine expression, and inhibition of apoptosis in normal cells. N-acetylcysteine (NAC; 70 mg/kg IV q6h ? 8 treatments) is a cysteine donor thought to be cytoprotective. It may improve hepatic microcirculation and oxygen delivery, enhance hepatic metabolic functions by restoring glutathione levels, block TNF-α release, and act as a free radical scavenger.14 DMSO (0.5 to 1 g/kg IV as experimentally induced acute pancreatitis was monitored in cattle. Twenty-four hours after induction of pancreatitis, an increased echogenicity was noted, but within 3 days, hypoechogenicity was noted secondary to necrosis, hemorrhage, and inflammatory exudates, as confirmed at necropsy.20
Medical management of acute pancreatitis is symptomatic.
Prevention of gastric rupture by continuous gastric decompression and control of abdominal pain are crucial in the treatment of pancreatitis.4 Large volumes of balanced polyionic electrolyte solutions are necessary to maintain the circulating volume and prevent shock. Because hypocalcemia may be a problem, serum calcium concentration should be monitored. Broad-spectrum antibiotics are warranted because of the potential for secondary bacterial infection. NSAIDs and analgesics are used to control inflammation and pain.Chronic interstitial pancreatitis (CIP) in horses and cattle seldom has clinical significance. In horses, Strongylus equinus and Stronglyus edentatus are most often identified as the etiologic agent of CIP; however, Parascaris equorum has been identified in one case report.4,23,24 In cattle, CIP has been primarily associated with the trematodes Eurytrema pancreaticum and Eurytrema coelomacticum; these parasites have not been isolated in the United States.18
Pancreatic disease in adult cattle is related to endocrine dysfunction.25-27 The most frequently reported disorder is type 1 diabetes mellitus, but the etiology in most cases is not determined.25-27 Histopathologic examination generally reveals an absence of beta cells in the islet tissue. Foot-and-mouth disease virus has been associated with diabetes mellitus in cattle after convalescence.18 Hypoplasia of the acinar pancreatic tissue has been described in calves.18 Clinical signs include steatorrhea and diarrhea. Insulin-dependent diabetes mellitus with pancreatic beta cell dysfunction has been documented rarely in horses.28,29 Transient type 1 diabetes has also been diagnosed in the foal,30 and recent work shows that method of delivery (spontaneous versus induced foaling) may have a significant effect on pancreatic function.31 Induced parturition was associated with two- to threefold higher cortisol levels and with differences in the absolute and age-related changes in basal concentrations of glucose, α-amino nitrogen, and insulin.31 Adenocarcinoma of the exocrine pancreas is reported in rare equine cases and should be considered in horses exhibiting the clinical signs of pyrexia, depression, weight loss, and icterus.3,32,33
Pancreatic calculi found in older cattle (>5 years) during necropsy are considered incidental findings.18 The calculi are composed primarily of calcium carbonate and calcium phosphate. Their presence may be associated with grazing on silica-rich soil, vitamin A deficiency, or chronic inflammation of the pancreatic ducts.18 In two reported cases of pancreatic calculi in cattle, the cause for euthaniasia was fracture of the lumbar vertebrae.34,35 The correlation between pancreatic disease and bone pathology in cattle is unknown, but osteoporosis is a known consequence of chronic pancreatitis in humans.