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Complications of cirrhosis: the main issues involving antibiotics, diuretics, and lactulose

for Health Care Providers

3: Complications of cirrhosis: What are the main issues involving antibiotics, diuretics, and lactulose?

Background

A 58-year-old man initially presented with new onset jaundice, ascites, cachexia, edema, and encephalopathy. He has been a heavy alcohol user on and off for approximately 20 years, and 2 years ago he started drinking between a pint and a quart of vodka daily. He required hospitalization 3 times over the course of 3 months for medical management of encephalopathy and ascites, including large-volume paracenteses. He was treated with spironolactone, furosemide, prophylactic ciprofloxacin, lactulose, folic acid, thiamine, and multivitamin. He was noncompliant with his medication regimens between hospitalizations. He then stopped drinking alcohol for 10 months and improved his medication compliance. He was able to increase his albumin and decrease his international normalized ratio (INR) to the normal ranges, increase healthy eating and regain weight, and resolve the edema and ascites. Six months after his last hospitalization, he was able to discontinue all diuretics and lactulose.

Discussion

Questions: What is the role of antibiotics for patients with ascites?

Speaker 1: For patients with documented cirrhosis, and an ascitic albumin measurement of <1 g/dL, do you agree with the use of empiric antibiotics? When they are hospitalized, regardless of their having a history of spontaneous bacterial peritonitis (SBP), should such patients be on antibiotics?

This patient had ascites, but we were not told the protein measurement--so let's assume it is very, very low. Ascitic infection, or SBP, can develop in part because of a low protein content in the ascites fluid. The protein content correlates with complement levels, and complement helps the immune system kill bacteria. Thus, the lower the protein measurement in the ascites, the lower the complement level, and the lower the capacity of the fluid to kill bacteria. If you have a protein content--not albumin content, but total protein content--of >1 g/dL, the chances of developing SBP within 2 years are zero. So, patients with a high content of protein in the fluid do not require antibiotic prophylaxis.

Now, let's discuss patients who have a low ascites protein content--meaning <1 g/dL. These patients are susceptible to developing SBP, but the rate is not incredibly high. In one controlled trial, it was approximately 7% per year. In another study that looked at additional risk factors, researchers followed patients with high bilirubin levels and low platelet counts, finding that 55% of those in this high-risk group developed SBP per year, but no other study has confirmed that result.

For our patient, let's assume that the protein in the ascites was measured and that it was <1 g/dL. I would not treat him with prophylactic antibiotics. The reason I would not is because only one placebo-controlled trial of prophylactic antibiotics has shown a significant reduction in infection, and no differences in survival have been found. So, I do not use primary prophylaxis for SBP. In addition, prophylactic antibiotics have resulted in the development of resistant organisms. In Barcelona, the medical community began to treat every cirrhotic patient with prophylactic norfloxacin, but that led to the development of organisms that are resistant to the quinolone class and Bactrim as well--now in Barcelona, neither class of antibiotics can be used for SBP.

Speaker 2: Let's consider patients who require serial, large-volume paracenteses for refractory ascites.

Speaker 1: In terms of prophylaxis?

Speaker 2: Yes. If you look at the original studies of SBP and rates of SBP, the subjects have all been hospitalized cirrhotic patients. Right? There are currently 4 studies involving outpatients with refractory ascites, and the risk of having SBP in that setting is found to be unbelievably low. The prevalence of SBP at the time of large-volume paracentesis in these studies ranges from zero to 3%. So, given the evolving nature of the recommendations, a cell count or culture probably is not needed when performing routine therapeutic paracentesis.

Speaker 1: For prophylaxis in someone who already has had SBP, norfloxacin is routinely used in the outpatient setting. However, some VA facilities, including ours, do not have norfloxacin in the formulary, so we use ciprofloxacin.

Speaker 2: How does giving Bactrim 5 times a week compare with giving Cipro once weekly?

Speaker 1: I know the Bactrim studies have not yielded good data--they mix primary with secondary prophylaxes. I am a little hesitant to use Bactrim because it occasionally results in hepatotoxicity. But if a patient cannot take norfloxacin for some reason, then I would use Bactrim.

Let's go to issue of the diuretics for ascites. First, the diuretic regimen should be spironolactone based. I usually start with spironolactone alone and then, if the patient has huge ascites, we continue with spironolactone and Lasix. But, the regimen should always be based on spironolactone. For dosing, start with 100 mg of spironolactone daily. If the patient does not respond, add 40 mg of Lasix. If the patient still does not respond, double the dosage to 200 mg of spironolactone, then double the Lasix to 80 mg--and so on, in a progressive way. Remember that ascites is not an emergency condition. Among the complications of cirrhosis, ascites is the one that gives me the least anxiety. So, you have time to carefully adjust diuretic dosages.

The most notable adverse effect of spironolactone is breast pain and gynecomastia, and that is significant because ascitic patients, authentically, are incredibly sensitive. Often, they cannot even wear their clothes comfortably because they have such painful gynecomastia from the spironolactone. It is useful to counteract aldosterone, which is found in increased levels in these patients. The problem with other potassium-sparing diuretics such as triamterene is that they do not counteract aldosterone, so they are not going to be very useful.

The patient in this case arrived with what we think is an acute and chronic disease. He has every complication: jaundice, about which we can do nothing beyond stopping him from drinking alcohol; ascites, for which he was treated very appropriately with diuretics and paracentesis (though I would not have used SBP prophylaxis with Cipro); and encephalopathy, for which he was treated with lactulose.

Lactulose causes severe diarrhea in these patients, so you have to adjust the lactulose intake to dosages that result in only 2-3 bowel movements a day. You do not want these patients to have diarrhea because that leads to more complications, including prerenal azotemia. For dosing, you need to instruct the patient and the patient's family to find a dosage that results in 2-3 bowel movements a day. We usually start with 30 cc twice a day; if that causes diarrhea, the dosage is reduced. If the patient is not having a bowel movement, the dosage is increased. So you work on that, but it is more the patient and the patient's family who make the adjustments. Some patients absolutely cannot tolerate lactulose. Even the minimal dosage of lactulose will give them diarrhea. In such cases, you have to switch to an antibiotic, which would be neomycin.

When encephalopathic patients are improving, even those with hepatitis C cirrhosis, they should be taken off lactulose gradually, not cold turkey. The same idea applies to decreasing dosages of diuretics. The dosage is reduced little by little, and if the patient reaccumulates ascites, it is increased. For patients with alcoholic hepatitis, less diuretic is required as the severity of the condition subsides. As the diuretic dosage is reduced gradually, less lactulose is required, until patients are off these medications completely. Patients can make amazing recoveries from alcoholic hepatitis if they can stop drinking. This case exemplifies what can happen with an acute and chronic liver disease.

Participant: What about magnesium supplements?

Speaker 1: I do not recommend them. Rather, it is important that the patient start eating well. For the patient in this case, even if he has encephalopathy, he needs a good protein diet. Vegetarian sources of protein, such as soybeans, are best for patients with encephalopathy. But they must get a good amount of protein. Good nutrition is of utmost importance for patients with alcoholic hepatitis.

Participant: This patient may go back to drinking.

Speaker 1: Patients with alcoholic cirrhosis who stop drinking can remain compensated for years. So, this patient is not a candidate for liver transplant at present, not by any stretch of the imagination. He needs to be screened for varices and hepatoma, but he should not be referred for transplant, because he can remain compensated as long as he is not drinking.

Speaker 3: It should be pointed out that patients with alcoholic cirrhosis are the only ones who have been put on the transplant list and subsequently been taken off the list because they get too well. And we do not even list people until they have been abstinent for 6 months. The point is that they continue getting better even beyond the first 6 months. Actually, the progressive improvement may not complete until a year or two of abstinence. So, I do not relinquish the notion that they will continue to improve.

In addition, it is my impression that this disease is much less common than it used to be in the VA patient population.

Speaker 1: I agree.

Speaker 3: We are not seeing much alcoholic hepatitis, only a couple of severe cases a year. It seems to have been much more prevalent 10 or 15 years ago. At the same time, the prevalence of variceal bleeding is decreasing, and I wonder whether the two developments are related. I am under the impression that acute alcoholic hepatitis raises portal pressure and may cause bleeding, and that the risk of variceal hemorrhage may be less in nondrinking patients. Also, I wonder whether the trends are similar for inner city hospitals.

Speaker 1: Regarding your first point, it is true that 6 months' abstinence may not be enough to reverse the decompensation. For many patients, that happens after many, many months. We see many patients on the transplant list who, with ongoing abstinence, have the albumin measurement rise to 4.2 g/dL, and no longer need a transplant. I totally agree.

As to the second point, we are not seeing as much alcoholic hepatitis at the VA facility, but there seems to be more acute alcoholic hepatitis and more variceal bleeding at our inner city university hospital.

Speaker 2: As the patient is doing so well while he is not drinking, should we continue to screen him for hepatocellular carcinoma? A similar question comes up for patients who have cirrhosis from hepatitis C but are no longer viremic, with a sustained virologic response after treatment. Do they still need cancer screening?

I think that once patients have reached the level of significant liver disease, we know the risk is there and we want to protect them every way we can.

Speaker 1: The risk may be lower after they stop drinking or clear hepatitis C, but the risk is not reduced enough that we suggest we can stop our screening. We can learn some lessons from our experience with hepatitis B. Hepatitis B patients who are HBsAg and HBeAg positive with a high hepatitis B DNA viral load have the highest risk of hepatocellular carcinoma. If you treat them and achieve HBeAg seroconversion, but the hepatitis B DNA virus is still replicating, the hepatocellular carcinoma risk is lower, though it is still higher than it is for patients who have never been infected with hepatitis B. In other words, once patients have cirrhosis--when it is from alcohol or hepatitis C or hepatitis B--we can lower their risk of hepatocellular carcinoma by reducing the alcohol or seroconverting the hepatitis B or clearing the hepatitis C, but once they have the cirrhosis, the risk is there and you have to continue screening them.

Participant: For patients who live in rural areas, what about the use of home health follow-up for the management of ascites, by tracking their daily weight measurements at home?

Speaker 1: That is a great idea. It would be ideal for management of ascites for people who live in remote areas. Most patients who are compliant are going to resolve the ascites or at least keep it very well controlled. If they are losing weight properly, they can be advised to maintain the current dosage. Or the dosage can be adjusted according to their weight. The only problem that I see is figuring out how to perform the laboratory tests, because you have to periodically measure blood urea nitrogen, creatinine, and electrolytes.

Summary Points

  1. Medical management of ascites should begin with spironolactone. The addition of Lasix and gradual stepwise increases in dosages of spironolactone and Lasix are recommended until the ascites is under optimal control.
  2. The risk of developing SBP is based on the protein content in the ascites. Patients with high ascitic protein (>1 g/dL of protein in the ascitic fluid) are not at risk of SBP. Patients with low ascitic protein (<1 g/dL of protein in the ascitic fluid) are at risk of SBP.
  3. Antibiotic prophylaxis for SBP is controversial. The use of antibiotics as primary prophylaxis for SBP (for patients who have never had an episode of SBP) has not been shown to improve survival, and many experts do not recommend primary prophylaxis with antibiotics. The use of antibiotics as secondary prophylaxis for SBP (for patients who have had SBP in the past) is recommended by many experts, typically with a fluoroquinolone such as norfloxacin, or sulfamethoxazole/trimethoprim (Bactrim) as a second choice.
  4. The most important component of managing a patient with alcoholic hepatitis is the cessation of alcohol use. Patients can significantly improve their clinical status and achieve long-term stability from alcohol cessation alone.
  5. Encephalopathy is managed with lactulose but needs to be titrated carefully in each patient, often with the help of family members. The aim is for the patient to have 2-3 bowel movements a day, without developing diarrhea, which would further complicate the patient's renal and electrolyte balance.
  6. Good nutrition, including adequate protein intake, is critical. Vegetarian sources of protein are best for minimizing encephalopathy.

Related case study: The role of alcohol: What are the acute and chronic effects in alcoholic hepatitis vs hepatitis C?

Facilitators/Speakers

  • Ann Busch, Liver Transplant Clinical Nurse Specialist, Portland VAMC
  • Sue Currie, Associate Director, HCRC, San Francisco VAMC
  • Guadalupe Garcia-Tsao, Director, HCRC, Connecticut VAMC
  • Douglas Heuman, Liver Transplant Program Director, Richmond VAMC
  • Alexander Monto, Director, HCRC, San Francisco VAMC
  • Roberta Ruimy, Manager, Liver/Kidney Transplant Programs, Portland VAMC
  • Brenda Salvas, Health System Specialist, Manager, Liver and Kidney Transplant Program, VA Transplant Program, VA Central Office, Washington, DC
  • Anna Sasaki, Staff Physician, Portland VAMC
  • Kristine Stick, Nurse Practitioner for Hepatology, San Francisco VAMC
  • Suchat Wongcharatrawee, Associate Director HCRC, Connecticut VAMC

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