الفهرس 
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Abstract
Hepatic encephalopathy (HE) is a frequent and severe complication of liver disease with poor patient outcomes and reduced survival. It has a huge impact on patients ’ quality of life. Recurrent episodes of HE are associated with increased health care burden, poor prognosis and risk of death. The high morbidity and mortality combined with the costs underline the importance of early prevention of HE. Lactulose is considered the first line for secondary prophylaxis of overt hepatic encephalopathy while rifaximin is add-on therapy. However, side effects of lactulose therapy including excessively sweet taste and gastrointestinal side effects such as abdominal pain, bloating, flatulence, diarrhea and self- titration requirement result in frequent non adherence which increase the patient’s risk of HE. Colistin sulfate is a polymyxin antibiotic which is active against gram negative bacteria. It is poorly absorbed from gastrointestinal tract. Oral colistin sulfate being not systemically absorbed is used for bowel decontamination and treatment of intestinal infections. To our knowledge, this is the first study on the efficacy of oral colistin in the secondary prophylaxis of hepatic encephalopathy. This was a prospective, open-label, parallel, randomized controlled trial carried out on 316 patients who were enrolled from Tropical Medicine and Infectious Diseases Department, Tanta University Hospital, Egypt. The duration of the study was 24 months (recruitment and follow up). It began in November 2020 and ended November 2022. The included patients were randomized into lactulose group (158 patients) or colistin group (158 patients). Finally, 139 patients were considered for analysis in the lactulose group versus 138 patients in the colistin group. Inclusion criteria: • Age >18 years. • Patients with liver cirrhosis and previous history of recovery from hepatic encephalopathy. Exclusion criteria: • History of taking lactulose in past 7 days. • Patients on secondary prophylaxis for spontaneous bacterial peritonitis. • Patients on psychoactive drugs, such as antidepressants or sedatives. • Previous transjugular intrahepatic portosystemic shunts or shunt surgery. • Significant comorbid illness such as heart, respiratory, or neurological disease such as Alzheimer’s disease and Parkinson’s disease. • Hepatocellular carcinoma or other neoplasias that could shorten life expectancy. • Recent infection or antibiotic use within last 6 weeks. • Recent gastrointestinal bleeding in the past 6 weeks. • Renal insufficiency, myasthenia gravis. • Hypersensitivity to colistin sulfate. • Pregnancy or lactation. • Alcohol intake. Outcomes • Primary outcome: - Development of overt hepatic encephalopathy. • Secondary outcomes - Health related quality of life. - Time to first HE-related hospitalization. - Overall mortality. - Side effects of treatment. Cirrhosis was diagnosed on a clinical basis involving laboratory tests, endoscopic evidence, sonographic findings, and liver histology if available. Overt hepatic encephalopathy was diagnosed clinically based on the West Haven criteria grade 2 or higher (Vilstrup, 2014). Secondary prophylaxis was defined as the prevention of recurrence of HE during the follow-up period in patients who had recovered from a previous episode of HE. Previous episodes of HE were documented by examining the patients’ medical records. All the patients in the study were subjected to the following: 1- Full history taking. 2- Clinical examination. 3- Laboratory investigations. 4- Modified Child–Turcotte–Pugh score. 5- Model for end-stage liver disease score. 6- Abdominal ultrasonography. 7- Health related quality of life (HRQOL) assessment using chronic liver disease questionnaire (CLDQ). Follow-up The patients were followed up monthly for 6 months to assess treatment compliance, record side effect of the drugs, recurrence of overt hepatic encephalopathy according to West Haven criteria, and precipitating factor for overt HE in each group. Admission for any reason was also recorded during the study period. Baseline investigations were repeated after 3 months of follow-up evaluation and at the end of study period. Compliance with therapy was assured primarily through direct questioning, by recovery of empty medication envelopes, and counting the number of bottles of lactulose consumed. The patients and their relatives were instructed to contact the medical staff immediately in the event of any alteration in the patient’s mental state. Patients who did not report for follow-up were contacted by telephone and instructed to return for a regular checkup. The following results were obtained: - As regards basic demographic data, baseline clinical and abdominal ultrasonographic data, baseline laboratory investigations and baseline CLDQ score of the studied groups , no significant differences were found between lactulose and colistin groups (P> 0.05). - In the lactulose group, the frequency of development of HE was comparable with that of the colistin group (15.83 versus 18.12%) (P= 0.612). There were no significant differences in the grades of HE between the studied groups (P=0.786). - In patients receiving lactulose, there was no significant difference in the mean duration of hospitalization due to HE when compared with the colistin group (6.647 ± 2.149 versus 6.450 ± 2.665 days) (P=0.808). - There was no significant difference in the mean time to first HErelated hospitalization in the lactulose group versus the colistin group ((110.546 ± 40.001versus 115.917 ± 31.653 days)(P=0.615). - The frequency of patients who developed OHE due to SBP in the colistin group was significantly lower than that in the lactulose group (0.72 versus 7.19%) (P=0.006*). - In the colistin group, four patients out of 138 (2.9%) developed OHE due to constipation (P=0.043*). - No significant differences were detected between the studied groups as regards the frequency and causes of mortality (P> 0.05). - There was no significant difference in the number of hospitalization due to causes other than HE between the studied groups (P> 0.05). - In the colistin group, there was a significant decrease in the number of hospitalization due to SBP when compared with the lactulose group (P= 0.025*). - The percentage of patients with diarrhoea, bloating, distaste to lactulose, flatulence, nausea and abdominal pain were significantly higher in the lactulose group than the colistin group (P<0.05).Side effects were managed by decreasing the dose of lactulose.No serious adverse events were reported in the studied groups. - There were no significant differences between baseline and follow up laboratory investigations, Child-Pugh score and MELD score at 3 and 6 months in the lactulose group (P>0.05). - In the colistin group, no significant differences were detected between baseline and follow up laboratory investigations, Child-Pugh score and MELD score at 3 and 6 months (P> 0.05). - At the end of the study, the overall CLDQ score, abdominal symptoms and activity domain scores were significantly lower when compared with baseline in the lactulose group (P<0.001*). - At the end of the study, there was a significant improvement in abdominal symptoms score (P= 0.001*) and significantly lower scores were obtained for activity and fatigue domains when compared with baseline in the colistin group (P=0.001* and 0.003*respectively). - No significant difference was detected in overall CLDQ score when compared with baseline in the colistin group (P> 0.05). - At the end of the study, a significantly higher CLDQ score was obtained for abdominal symptoms in the colistin group versus the lactulose group (P<0.001*).