Prophylaxis of Hepatic Encephalopathy in Cirrhosis Patients
From January 2008 to September 2009, consecutive cirrhotic patients (age 18–70 years) who never had encephalopathy were enrolled. Cirrhosis was diagnosed on a clinical basis involving laboratory tests, endoscopic evidence, sonographic findings and liver histology if available. The exclusion criteria included history of taking lactulose in the past 6 weeks, alcohol intake during the past 6 weeks, hepatocellular carcinoma, previous transjugular intrahepatic shunts (TIPS) or shunt surgery, significant co-morbid illness such as heart, respiratory, or renal failure and any neurologic diseases such as Alzheimer's disease, Parkinson's disease and nonhepatic metabolic encephalopathies. Patients on psychoactive drugs, such as antidepressants or sedatives and those who restarted alcohol during follow up were also excluded. Study was approved by the ethics committee of the institute and informed written consent was taken from every patient before enrolling in the study. The ethical committee of the institute strictly followed the study and data were monitored regularly.
All patients underwent a combination of psychometric tests including number connection test A and B, figure connection tests (FCTs) parts A and B if illiterate; digit symbol test, line tracing test and serial dotting test. The test score is the time required to complete the test, including the time needed to correct any errors. Tests were considered abnormal when the test score was more than mean ± 2 standard deviation (SD) from the age and education matched controls (n = 150) from healthy population.
Critical flicker frequency (CFF) was done by HEPAtonorm analyzer (Hepatonorm Analyzer; R&R Medi-Business Freiburg GmbH, Freiburg, Germany). Flicker frequencies were measured eight times and the mean value was calculated. Critical flicker frequency was considered abnormal when the value was < 38 Hz.
Hepatic encephalopathy was defined according to West-Haven criteria and MHE was diagnosed if two or more psychometric tests were abnormal.
Patients were randomly assigned to receive lactulose (Gp-L group) or not to receive lactulose (Gp-NL group) along with their previous treatment and prophylaxis of variceal bleed if any (endoscopic variceal ligation or beta blockers). The study was not blinded (as it was difficult to remain blind with lactulose therapy) and randomization was performed using tables of random numbers by our statistician who was unaware of patient characteristics. All subjects were followed up every month for treatment compliance and for development of any complications and HE. Instructions were given to patients and their relatives to contact hospital in case of any emergency or change in behavior of the mental state. In the Gp-L group, patients received 30–60 mL of lactulose in two or three divided doses so that patient passed two to three semisoft stools per day. Compliance with the therapy was assured primarily by ensuring increased stool frequency and a change to a softer consistency and by counting the number of bottles of lactulose consumed. Patients who did not turn up were contacted by telephone and instructed for regular check up. All patients were assessed by psychometry and CFF at inclusion into the study and then at month 3 and were followed up until the development of primary endpoint or a maximum of 12 months follow up. Primary endpoint was development of overt HE or 12 months follow up, whichever was earlier. We defined primary prophylaxis as prevention of an episode of overt HE during the follow up period, which was assessed by West Haven criteria. Patients who developed the primary end point in either group were continued with lactulose along with their other medication (Fig. 1).
(Enlarge Image)
Figure 1.
Consort flow chart of the study.
After overnight fasting, patient venous blood was taken and analyzed for routine liver function tests and hematologic parameters by conventional methods at baseline and then at 3-monthly intervals. Repeat relevant investigations were done as and when required. Ultrasound abdomen and Doppler was done to check for large spontaneous shunt and occurrence of any space occupying lesion.
We calculated that a sample size of at least 35 patients in each arm would be required to detect a difference in prophylaxis of HE, that is, with a 5% type 1 error and 90% power for a two-tailed log-rank test. Though there is no study on the prevention of HE in patients with cirrhosis with no past history of HE, on the basis of the results of one previously published study on the prophylaxis of HE, lactulose is effective in 60% of patients in preventing recurrence of HE and we presumed an efficacy of 20% by placebo in the control group. Taking 20% of patients as being lost to follow up, the minimum average number of patients in each arm corresponds to 42 patients. Data processing was performed by using the software packages SPSS. Data were expressed as mean ± SD For a comparison of categorical variables, χ and Fisher's exact tests were used, and for continuous variables, a Mann–Whitney test for unpaired data and a Wilcoxon rank sum test for paired data were used as appropriate. Sensitivity and specificity of CFF to predict HE was calculated using receiver-operating characteristic curves. Correlations between variables were examined with a Pearson correlation. Multiple linear regression analyses were performed to identify independent variables associated with hepatic encephalopathy. Number needed to treat (NTT) and absolute risk reduction (ARR) was calculated by per protocol and intention to treat (ITT). Patients were also categorized according to classification by Garcia-Tsao et al. as compensated and decompensated cirrhosis (which is defined by the development of clinically evident complications of portal hypertension (ascites, variceal hemorrhage, hepatic encephalopathy) or liver insufficiency, i.e. jaundice). The probability level of P < 0.05 was set for statistical significance.
Methods
Patient Characteristics
From January 2008 to September 2009, consecutive cirrhotic patients (age 18–70 years) who never had encephalopathy were enrolled. Cirrhosis was diagnosed on a clinical basis involving laboratory tests, endoscopic evidence, sonographic findings and liver histology if available. The exclusion criteria included history of taking lactulose in the past 6 weeks, alcohol intake during the past 6 weeks, hepatocellular carcinoma, previous transjugular intrahepatic shunts (TIPS) or shunt surgery, significant co-morbid illness such as heart, respiratory, or renal failure and any neurologic diseases such as Alzheimer's disease, Parkinson's disease and nonhepatic metabolic encephalopathies. Patients on psychoactive drugs, such as antidepressants or sedatives and those who restarted alcohol during follow up were also excluded. Study was approved by the ethics committee of the institute and informed written consent was taken from every patient before enrolling in the study. The ethical committee of the institute strictly followed the study and data were monitored regularly.
Psychometric Testing
All patients underwent a combination of psychometric tests including number connection test A and B, figure connection tests (FCTs) parts A and B if illiterate; digit symbol test, line tracing test and serial dotting test. The test score is the time required to complete the test, including the time needed to correct any errors. Tests were considered abnormal when the test score was more than mean ± 2 standard deviation (SD) from the age and education matched controls (n = 150) from healthy population.
Measurement of Critical Flicker Frequency Threshold
Critical flicker frequency (CFF) was done by HEPAtonorm analyzer (Hepatonorm Analyzer; R&R Medi-Business Freiburg GmbH, Freiburg, Germany). Flicker frequencies were measured eight times and the mean value was calculated. Critical flicker frequency was considered abnormal when the value was < 38 Hz.
Assessment of Hepatic Encephalopathy and Minimal Hepatic Encephalopathy
Hepatic encephalopathy was defined according to West-Haven criteria and MHE was diagnosed if two or more psychometric tests were abnormal.
Study Design
Patients were randomly assigned to receive lactulose (Gp-L group) or not to receive lactulose (Gp-NL group) along with their previous treatment and prophylaxis of variceal bleed if any (endoscopic variceal ligation or beta blockers). The study was not blinded (as it was difficult to remain blind with lactulose therapy) and randomization was performed using tables of random numbers by our statistician who was unaware of patient characteristics. All subjects were followed up every month for treatment compliance and for development of any complications and HE. Instructions were given to patients and their relatives to contact hospital in case of any emergency or change in behavior of the mental state. In the Gp-L group, patients received 30–60 mL of lactulose in two or three divided doses so that patient passed two to three semisoft stools per day. Compliance with the therapy was assured primarily by ensuring increased stool frequency and a change to a softer consistency and by counting the number of bottles of lactulose consumed. Patients who did not turn up were contacted by telephone and instructed for regular check up. All patients were assessed by psychometry and CFF at inclusion into the study and then at month 3 and were followed up until the development of primary endpoint or a maximum of 12 months follow up. Primary endpoint was development of overt HE or 12 months follow up, whichever was earlier. We defined primary prophylaxis as prevention of an episode of overt HE during the follow up period, which was assessed by West Haven criteria. Patients who developed the primary end point in either group were continued with lactulose along with their other medication (Fig. 1).
(Enlarge Image)
Figure 1.
Consort flow chart of the study.
Blood Tests, Imaging and Biochemical Examinations
After overnight fasting, patient venous blood was taken and analyzed for routine liver function tests and hematologic parameters by conventional methods at baseline and then at 3-monthly intervals. Repeat relevant investigations were done as and when required. Ultrasound abdomen and Doppler was done to check for large spontaneous shunt and occurrence of any space occupying lesion.
Statistical Analysis and Data Management
We calculated that a sample size of at least 35 patients in each arm would be required to detect a difference in prophylaxis of HE, that is, with a 5% type 1 error and 90% power for a two-tailed log-rank test. Though there is no study on the prevention of HE in patients with cirrhosis with no past history of HE, on the basis of the results of one previously published study on the prophylaxis of HE, lactulose is effective in 60% of patients in preventing recurrence of HE and we presumed an efficacy of 20% by placebo in the control group. Taking 20% of patients as being lost to follow up, the minimum average number of patients in each arm corresponds to 42 patients. Data processing was performed by using the software packages SPSS. Data were expressed as mean ± SD For a comparison of categorical variables, χ and Fisher's exact tests were used, and for continuous variables, a Mann–Whitney test for unpaired data and a Wilcoxon rank sum test for paired data were used as appropriate. Sensitivity and specificity of CFF to predict HE was calculated using receiver-operating characteristic curves. Correlations between variables were examined with a Pearson correlation. Multiple linear regression analyses were performed to identify independent variables associated with hepatic encephalopathy. Number needed to treat (NTT) and absolute risk reduction (ARR) was calculated by per protocol and intention to treat (ITT). Patients were also categorized according to classification by Garcia-Tsao et al. as compensated and decompensated cirrhosis (which is defined by the development of clinically evident complications of portal hypertension (ascites, variceal hemorrhage, hepatic encephalopathy) or liver insufficiency, i.e. jaundice). The probability level of P < 0.05 was set for statistical significance.
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