Serum Sodium Concentration in Patients with Portal Hypertension and Acute Gastrointestinal Bleeding Treated with Terlipressin: A Retrospective Observational Study

Xinmiao Zhou, Lichun Shao,Tingxue Song, Wenchun Bao, Xiaozhong Guo and Xingshun Qi

## Abstract

This retrospective observational study aimed to investigate the risk of serum sodium concentration in patients treated with terlipressin and attempted to explore the factors associated with serum sodium concentration. We included 17 patients with portal hypertension treated with terlipressin (Group 1), 7 with portal hypertension treated with somatostatin/octreotide (Group 2), 20 with acute non-variceal gastrointestinal bleeding treated with somatostatin/octreotide (Group 3), and 19 with acute pancreatitis treated with somatostatin/octreotide (Group 4). In all groups, serum sodium concentration at baseline was not significantly different from the lowest value during the infusion of terlipressin, somatostatin, or octreotide (Group 1: 136.95 4.68 versus 135.52 4.79, p = 0.426; Group 2: 139.64 3.86 versus 138.41 5.34, p = 0.813; Group 3: 138.02 4.08 versus 137.69 3.11, p = 0.630; Group 4: 135.96 6.87 versus 134.60 3.40, p = 0.098). The rate of serum sodium concentration reduction in Group 1 (8/17) was not significantly different from Group 2 (3/7, p = 1.000), Group 3 (11/20, p = 0.746), or Group 4 (14/19, p = 0.171). Age, sex, baseline MELD and Child-Pugh scores, cDDD value and duration of terlipressin, blood transfusion, and diuretics and paracentesis during terlipressin were not significantly associated with serum sodium concentration reduction in Group 1. In conclusion, serum sodium concentration is often reduced in patients treated with terlipressin. However, the association of sodium concentration reduction with terlipressin should be clarified.

Keywords: hyponatremia, terlipressin, sodium, portal hypertension, gastrointestinal bleeding

#### 1. Introduction

Terlipressin is a prodrug of vasopressin, which transforms into vasopressin by enzymatic cleavage of the glycyl residues [1, 2]. It has been approved as the choice of treatment for acute esophagogastric variceal bleeding (EGVB) [3–6]. Such a potent effect is mainly due to the activation of V1 receptors, which are dominantly located in the arterial smooth muscles of splanchnic circulation. The activation of V1 receptors causes the splanchnic vasoconstriction and thereby reduces the splanchnic blood flow and portal pressure [7]. In addition, terlipressin also activates the V2 receptors and increases the number of aquaporin-2 channels in the apical plasma membrane, thereby causing the water reabsorption in the renal collecting ducts [8]. This V2 receptor-mediated antidiuretic effect may result in dilutional hyponatremia. Mild to severe hyponatremia has been reported in a proportion of patients receiving terlipressin [9–12]. More notably, scattered case reports have also shown that patients with hyponatremia related to terlipressin develop the seizure [13–15].

ligation alone (n = 2), gastric tissue glue injection alone (n = 1), and esophageal

Serum Sodium Concentration in Patients with Portal Hypertension and Acute Gastrointestinal…

Twenty patients treated with somatostatin or octreotide for acute non-variceal gastrointestinal bleeding were considered as the second control group (Group 3). Among them, 15 patients underwent endoscopic examinations. The causes of bleeding were peptic ulcer (n = 9), acute gastric mucosal lesions (n = 1), gastric cancer (n = 1), Mallory-Weiss syndrome (n = 1), post-resection of colonic polyps (n = 1), colon cancer (n = 2), gastric occupation (n = 1), or unknown causes (n = 5). Nineteen patients treated with somatostatin or octreotide for acute pancreatitis

Terlipressin (Ferring Pharmaceuticals, Kiel, Germany) was given by continuous intravenous infusion 1 mg every 6 hours in 16 patients and intravenous bolus 1 mg followed by continuous intravenous infusion 1 mg every 6 hours in 1 patient. Terlipressin can be maintained for a maximum of 5 days [16]. Terlipressin was discontinued till bleeding ceased for 72 hours (no hematemesis and melena) or

Somatostatin was given by continuous intravenous infusion 3 mg every 12 hours. Octreotide was given by continuous intravenous infusion 0.3 mg every 12 hours or subcutaneous injection 0.1 mg every 8 hours depending upon the severity of diseases. Somatostatin and octreotide can be used for 5 days or even longer [3]. As for patients with acute gastrointestinal bleeding, somatostatin or octreotide was discontinued till bleeding ceased for 72 hours (no hematemesis and melena) or patients received successful endoscopic treatments. As for patients with acute pancreatitis, somatostatin/octreotide was discontinued till abdominal symptoms disappeared, serum amylase and lipase levels returned to the normal range or was close to the normal range, inflammation parameters levels returned to the normal

range, and peri-pancreatic exudation disappeared or remarkably reduced.

Baseline data refer to the data recorded before terlipressin, somatostatin, or octreotide was initiated. They included demographic information; etiology of liver cirrhosis; major clinical presentations, such as hepatic encephalopathy, acute upper gastrointestinal bleeding, and ascites; major laboratory tests, such as white blood cell, hemoglobin, platelet count, total bilirubin, albumin, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, serum creatinine, potassium, serum sodium, prothrombin time, activated partial thromboplastin time, international normalized ratio, D-Dimer, Model for End-Stage Liver Disease (MELD) and Child-Pugh scores, blood transfusion, amount of red blood cell transfused, diuretics

and paracentesis, and duration of terlipressin, somatostatin, and octreotide.

We also recorded the first re-examination value during the infusion of

terlipressin and the value after stopping the infusion of terlipressin.

We screened the hepatic and renal function, blood cell counts, and serum electrolytes during hospitalization depending upon the patients' profiles. The lowest serum sodium concentration was collected when terlipressin, somatostatin, or

variceal ligation plus gastric tissue glue injection (n = 2).

DOI: http://dx.doi.org/10.5772/intechopen.89981

were considered as the third control group (Group 4).

patients received successful endoscopic treatments.

2.2 Terlipressin

2.3 Somatostatin/octreotide

2.4 Data collection

octreotide was being given.

75

Herein, this retrospective observational study aimed to investigate the risk of serum sodium concentration during terlipressin treatment and attempted to explore the factors associated with serum sodium concentration hyponatremia.

#### 2. Materials and methods

Study protocol was reviewed and approved by the institutional review board of the General Hospital of Northern Theater Command (formally General Hospital of Shenyang Military Area).

#### 2.1 Study population

All patients who were consecutively admitted to our department between February 2016 and November 2017 and were treated with terlipressin and/or somatostatin and/or octreotide by an attending physician (XQ) were considered as the study population.

Seventeen patients with portal hypertension who were diagnosed with acute gastrointestinal bleeding and were treated with terlipressin were considered as the experimental group (Group 1). Among them, 14 patients were diagnosed with liver cirrhosis due to hepatitis B virus alone (n = 5), hepatitis C virus plus alcohol abuse (n = 2), alcohol abuse alone (n = 2), autoimmune-related liver diseases alone (n = 2), drug-related liver diseases alone (n = 1), or unknown causes (n = 2); 4 patients had hepatocellular carcinoma; 15 patients underwent endoscopic examinations, of whom 6 and 9 had both esophageal and gastric varices and esophageal varices alone, respectively, but 2 patients refused; 9 patients received a combination of somatostatin (n = 6), octreotide (n = 1), and somatostatin plus octreotide (n = 2); 10 patients underwent endoscopic treatments, including esophageal variceal ligation alone (n = 6), esophageal sclerotherapy alone (n = 1), esophageal variceal ligation plus gastric tissue glue injection (n = 2), and esophageal sclerotherapy plus gastric tissue glue injection (n = 1).

Seven patients with portal hypertension who were diagnosed with acute gastrointestinal bleeding and were treated with somatostatin or octreotide but without terlipressin were considered as the first control group (Group 2). Among them, 6 patients were diagnosed with liver cirrhosis due to hepatitis B virus alone (n = 1), hepatitis B virus plus alcohol abuse (n = 2), alcohol abuse alone (n = 2), or unknown causes (n = 1); 2 patients had hepatocellular carcinoma; 6 patients underwent endoscopic examinations, of whom 3 and 3 had both esophageal and gastric varices and esophageal varices alone, respectively, but 1 patient was hemodynamically unstable and died before endoscopic examination; 4, 1, and 2 patients received somatostatin alone, octreotide alone, and somatostatin plus octreotide, respectively; and 5 patients underwent endoscopic treatments, including esophageal variceal

Serum Sodium Concentration in Patients with Portal Hypertension and Acute Gastrointestinal… DOI: http://dx.doi.org/10.5772/intechopen.89981

ligation alone (n = 2), gastric tissue glue injection alone (n = 1), and esophageal variceal ligation plus gastric tissue glue injection (n = 2).

Twenty patients treated with somatostatin or octreotide for acute non-variceal gastrointestinal bleeding were considered as the second control group (Group 3). Among them, 15 patients underwent endoscopic examinations. The causes of bleeding were peptic ulcer (n = 9), acute gastric mucosal lesions (n = 1), gastric cancer (n = 1), Mallory-Weiss syndrome (n = 1), post-resection of colonic polyps (n = 1), colon cancer (n = 2), gastric occupation (n = 1), or unknown causes (n = 5).

Nineteen patients treated with somatostatin or octreotide for acute pancreatitis were considered as the third control group (Group 4).

#### 2.2 Terlipressin

of treatment for acute esophagogastric variceal bleeding (EGVB) [3–6]. Such a potent effect is mainly due to the activation of V1 receptors, which are dominantly located in the arterial smooth muscles of splanchnic circulation. The activation of V1 receptors causes the splanchnic vasoconstriction and thereby reduces the splanchnic blood flow and portal pressure [7]. In addition, terlipressin also activates the V2 receptors and increases the number of aquaporin-2 channels in the apical plasma membrane, thereby causing the water reabsorption in the renal collecting ducts [8]. This V2 receptor-mediated antidiuretic effect may result in dilutional hyponatremia. Mild to severe hyponatremia has been reported in a proportion of patients receiving terlipressin [9–12]. More notably, scattered case reports have also shown that patients with hyponatremia related to terlipressin develop the

Herein, this retrospective observational study aimed to investigate the risk of serum sodium concentration during terlipressin treatment and attempted to explore

Study protocol was reviewed and approved by the institutional review board of the General Hospital of Northern Theater Command (formally General Hospital

All patients who were consecutively admitted to our department between February 2016 and November 2017 and were treated with terlipressin and/or somatostatin and/or octreotide by an attending physician (XQ) were considered

Seventeen patients with portal hypertension who were diagnosed with acute gastrointestinal bleeding and were treated with terlipressin were considered as the experimental group (Group 1). Among them, 14 patients were diagnosed with liver cirrhosis due to hepatitis B virus alone (n = 5), hepatitis C virus plus alcohol abuse (n = 2), alcohol abuse alone (n = 2), autoimmune-related liver diseases alone (n = 2), drug-related liver diseases alone (n = 1), or unknown causes (n = 2); 4 patients had hepatocellular carcinoma; 15 patients underwent endoscopic examinations, of whom 6 and 9 had both esophageal and gastric varices and esophageal varices alone, respectively, but 2 patients refused; 9 patients received a combination of somatostatin (n = 6), octreotide (n = 1), and somatostatin plus octreotide (n = 2); 10 patients underwent endoscopic treatments, including esophageal variceal ligation alone (n = 6), esophageal sclerotherapy alone (n = 1), esophageal variceal ligation plus gastric tissue glue injection (n = 2), and esophageal sclerotherapy plus gastric

Seven patients with portal hypertension who were diagnosed with acute gastrointestinal bleeding and were treated with somatostatin or octreotide but without terlipressin were considered as the first control group (Group 2). Among them, 6 patients were diagnosed with liver cirrhosis due to hepatitis B virus alone (n = 1), hepatitis B virus plus alcohol abuse (n = 2), alcohol abuse alone (n = 2), or unknown causes (n = 1); 2 patients had hepatocellular carcinoma; 6 patients underwent endoscopic examinations, of whom 3 and 3 had both esophageal and gastric varices and esophageal varices alone, respectively, but 1 patient was hemodynamically unstable and died before endoscopic examination; 4, 1, and 2 patients received somatostatin alone, octreotide alone, and somatostatin plus octreotide, respectively; and 5 patients underwent endoscopic treatments, including esophageal variceal

the factors associated with serum sodium concentration hyponatremia.

seizure [13–15].

2. Materials and methods

Digestive System - Recent Advances

of Shenyang Military Area).

2.1 Study population

as the study population.

tissue glue injection (n = 1).

74

Terlipressin (Ferring Pharmaceuticals, Kiel, Germany) was given by continuous intravenous infusion 1 mg every 6 hours in 16 patients and intravenous bolus 1 mg followed by continuous intravenous infusion 1 mg every 6 hours in 1 patient. Terlipressin can be maintained for a maximum of 5 days [16]. Terlipressin was discontinued till bleeding ceased for 72 hours (no hematemesis and melena) or patients received successful endoscopic treatments.

#### 2.3 Somatostatin/octreotide

Somatostatin was given by continuous intravenous infusion 3 mg every 12 hours. Octreotide was given by continuous intravenous infusion 0.3 mg every 12 hours or subcutaneous injection 0.1 mg every 8 hours depending upon the severity of diseases. Somatostatin and octreotide can be used for 5 days or even longer [3]. As for patients with acute gastrointestinal bleeding, somatostatin or octreotide was discontinued till bleeding ceased for 72 hours (no hematemesis and melena) or patients received successful endoscopic treatments. As for patients with acute pancreatitis, somatostatin/octreotide was discontinued till abdominal symptoms disappeared, serum amylase and lipase levels returned to the normal range or was close to the normal range, inflammation parameters levels returned to the normal range, and peri-pancreatic exudation disappeared or remarkably reduced.

#### 2.4 Data collection

Baseline data refer to the data recorded before terlipressin, somatostatin, or octreotide was initiated. They included demographic information; etiology of liver cirrhosis; major clinical presentations, such as hepatic encephalopathy, acute upper gastrointestinal bleeding, and ascites; major laboratory tests, such as white blood cell, hemoglobin, platelet count, total bilirubin, albumin, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, serum creatinine, potassium, serum sodium, prothrombin time, activated partial thromboplastin time, international normalized ratio, D-Dimer, Model for End-Stage Liver Disease (MELD) and Child-Pugh scores, blood transfusion, amount of red blood cell transfused, diuretics and paracentesis, and duration of terlipressin, somatostatin, and octreotide.

We screened the hepatic and renal function, blood cell counts, and serum electrolytes during hospitalization depending upon the patients' profiles. The lowest serum sodium concentration was collected when terlipressin, somatostatin, or octreotide was being given.

We also recorded the first re-examination value during the infusion of terlipressin and the value after stopping the infusion of terlipressin.

#### 2.5 Outcomes

The primary end point of the study was to investigate the changes of serum sodium concentration during the administration of terlipressin and/or somatostatin and/or octreotide. The changes of serum sodium concentration were compared (i.e., the baseline value versus the lowest value or the value after stopping the pharmacological treatment). The rate of serum sodium concentration reduction among groups was assessed.

In the Group 1, we evaluated the difference between the baseline and lowest value of serum sodium during the treatment and classified as sodium decreased and sodium stable or increased. The secondary end point was to assess the factors associated with serum sodium concentration reduction in patients treated with terlipressin for portal hypertension.

#### 2.6 Statistical analysis

Continuous variables were presented as mean standard deviations and medians with ranges, and categorical variables as frequency (%). Comparison of continuous variables between groups was performed by using Mann-Whitney U-test and paired comparison rank sum test, and that of categorical variables by using Chi-square or Fisher's exact test. The statistical analyses were performed by using SPSS version 24.0 (SPSS Inc., Chicago, IL, USA) and GraphPad Prism version 6.0 (7825 Fay Avenue, Suite 230, La Jolla, CA 92037, USA). p < 0.05 for the difference was statistically significant.
