3. Results

#### 3.1 Patient characteristics

Overall, 17, 7, 20, and 19 patients were included in Group 1, 2, 3, and 4, respectively (Figure 1). Characteristics of patients are shown in Table 1.

Variables

77

Group 1

No. pts Mean SD or

Median (range)

 No.

Mean SD or

Median (range)

 No.

Mean SD or

Median (range)

 No.

Mean SD or

Median (range)

pts

n (%)

pts

n (%)

pts

n (%)

n (%)

> Age (years)

Sex

Clinical presentations

Hepatic

n (%) Upper bleeding, n (%)

Ascites, n (%) Laboratory tests

White blood cell (109/L)

Hemoglobin (g/L)

Platelet count (109/L) Total bilirubin (umol/L)

Albumin (g/L)

Alanine

(U/L)

Aspartate

(U/L)

Blood urea nitrogen

17

 10.31 5.54 9.39 (4.11–25.97)

 7 7.44 2.05

 7 107.67 93.20 67.3 (52.65–314)

 8.85 (3.86–9.05)

 20 10.49 6.14 8.79 (3.03–23.27)

 20 77.00 27.05

 67.05 (42–147)

 19 66.02 27.36 73.9 (18.32–129.9)

(mmol/L)

Serum creatinine (umol/L)

Potassium (mmol/L)

Sodium (mmol/L)

Prothrombin

 time (seconds)

 17

 17.13 2.30

 16.5 (15–23.9)

 7 16.76 2.23

 17 (14.7–20.8)

 19 14.90 2.93

 13.8 (12.9–24.9)

 18 14.46 3.26

 13.3 (12–23.4)

 17 67.71 21.71 62.78 (31.85–117.38)

17

17 136.95 4.68 137.4 (126.3–142.9)

 4.09 0.69

 3.84 (3.1–6.03)

 7 4.07 0.50

 7 139.64 3.86 141.2 (132–142.7)

 4.16 (3.33–4.64)

 20 4.06 0.48

 20 138.02 4.08 138.35 (126.6–144)

 3.99 (3.25–4.99)

 19 4.01 0.65

 19 135.96 6.86 137.4 (115.1–142.6)

 4.04 (2.86–5.84)

aminotransferase

17 32.13 18.14 25.05 (17.17–89.1)

aminotransferase

17 22.41 17.96 14.71 (10.13–77.1)

 17

17 71.65 21.14 17 117.65 93.00

 17 28.25 24.39

17

 29.09 5.19

 29.8 (18.7–39.1)

 7 27.67 5.21

 7 19.85 7.34 22.02 (10.57–28.38)

 7 33.00 16.81 29.61 (17.88–65.85)

 25.6 (22–36.3)

 20 34.24 4.70 33.65 (24.8–41.5)

 20 17.93 14.75

 19 21.64 12.29

 15.5 (10.3–58)

 19 83.15 100.04 37.22 (13.79–369.2)

 19 5.72 2.36

 5.29 (2.09–11.21)

 15.05 (4.57–65)

 19 91.44 97.24 49.12 (5.06–311.04)

 17.2 (8.1–92.3)

 7 24.19 14.83

 16.6 (8.3–49.1)

 20 12.29 8.71

 6.08 3.92

 4.9 (1.5–18.5)

 72 (37–124)

 82 (29–387)

 7 115.14 43.97

 118 (59–174)

 20 305.20 274.58

 7 85.00 17.25

 79 (70–119)

 20 93.95 29.40

 7 5.4 2.29

 4.3 (2.2–8.4)

 20 9.66 5.54

 8.65 (4.3–28.9)

 91.5 (48–136)

 238 (98–1287)

 9.15 (3.5–33.7)

 19 50.87 59.56

 18

 37 6.46

 37.4 (25.8–49.3)

 19.6 (10–213.3)

 19 223.89 87.69

 19 138.21 31.10

 19 9.42 4.11

 8.7 (2.1–16.5)

 135 (83–205)

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

 221 (41–434)

17

 12 (70.6%)

—

7 1 (14.3%)

—

20

—

 —

19

—

 —

gastrointestinal

17

 17 (100%)

—

7 7 (100%)

—

20

 17 (85%)

—

19

—

 —

encephalopathy,

17

 1 (5.9%)

—

7

 0 (0)

—

20

—

 —

19

—

 —

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

—male, n (%)

17 58.06 11.04

17

 9 (52.9%)

—

7 6 (85.7%)

 57 (34–75)

 7 54.57 9.54

 52 (42–71)

—

20

 15 (75%)

—

19 14 (73.7%)

 20 59.10 20.24

 57 (20–93)

 19 53.89 20.53

 49 (28–84)

—

Group 2

Group 3

Group 4

#### Figure 1.

Flow chart of patient enrollment. Abbreviations: GIB, gastrointestinal bleeding.


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

2.5 Outcomes

Digestive System - Recent Advances

groups was assessed.

2.6 Statistical analysis

3. Results

Figure 1.

76

terlipressin for portal hypertension.

difference was statistically significant.

3.1 Patient characteristics

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

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

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

Overall, 17, 7, 20, and 19 patients were included in Group 1, 2, 3, and 4, respectively (Figure 1). Characteristics of patients are shown in Table 1.

Flow chart of patient enrollment. Abbreviations: GIB, gastrointestinal bleeding.


Table 1.

Group 4, somatostatin or octreotide in acute pancreatitis.

Characteristicsof

 patients. 3.2 Change in serum sodium concentration

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

4.68 versus 135.52

of somatostatin or octreotide (139.64

of somatostatin or octreotide (138.02

of somatostatin or octreotide (135.96

reduction among groups

(136.95

(Figure 2D).

(Figure 2E).

(Figure 2F).

Figure 2.

79

Group 1. Serum sodium concentration before the infusion of terlipressin was not

p = 0.426) (Figure 2A), the first re-

5.34,

3.11,

3.40,

p = 0.813)

…

p = 0.630)

p = 0.098)

significantly different from the lowest value during the infusion of terlipressin

Serum Sodium Concentration in Patients with Portal Hypertension and Acute Gastrointestinal

examination value during the infusion of terlipressin (136.24 4.97, <sup>p</sup> = 0.989) (Figure 2B), or the value after stopping the infusion of terlipressin (136.29 2.86, <sup>p</sup> = 0.926) (Figure 2C).

Group 2. Serum sodium concentration before the infusion of somatostatin or octreotide was not significantly different from the lowest value during the infusion

Group 3. Serum sodium concentration before the infusion of somatostatin or octreotide was not significantly different from the lowest value during the infusion

Group 4. Serum sodium concentration before the infusion of somatostatin or octreotide was not significantly different from the lowest value during the infusion

The percentage of patients who developed serum sodium concentration reduction in Group 1 (8/17, 47.1%) was not significantly different from Group 2 (3/7,

Change in serum sodium concentration. (A) Serum sodium concentration before the infusion of terlipressin versus the lowest value during the infusion of terlipressin in Group 1. (B) Serum sodium concentration before the infusion of terlipressin versus the first re-examination value during the infusion of terlipressin in Group 1. (C) Serum sodium concentration before the infusion of terlipressin versus the value after stopping the infusion of terlipressin in Group 1. (D) Serum sodium concentration before the infusion of somatostatin or octreotide versus the lowest value during the infusion of somatostatin or octreotide in Group 2. (E) Serum sodium concentration before the infusion of somatostatin or octreotide versus the lowest value during the infusion of somatostatin or octreotide in Group 3. (F) Serum sodium concentration before the infusion of somatostatin or octreotide versus

the lowest value during the infusion of somatostatin or octreotide in Group 4.

3.3 Percentage of patients who developed serum sodium concentration

3.86 versus 138.41

4.08 versus 137.69

6.87 versus 134.60

4.79,

78

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

#### 3.2 Change in serum sodium concentration

Group 1. Serum sodium concentration before the infusion of terlipressin was not significantly different from the lowest value during the infusion of terlipressin (136.95 4.68 versus 135.52 4.79, p = 0.426) (Figure 2A), the first reexamination value during the infusion of terlipressin (136.24 4.97, p = 0.989) (Figure 2B), or the value after stopping the infusion of terlipressin (136.29 2.86, p = 0.926) (Figure 2C).

Group 2. Serum sodium concentration before the infusion of somatostatin or octreotide was not significantly different from the lowest value during the infusion of somatostatin or octreotide (139.64 3.86 versus 138.41 5.34, p = 0.813) (Figure 2D).

Group 3. Serum sodium concentration before the infusion of somatostatin or octreotide was not significantly different from the lowest value during the infusion of somatostatin or octreotide (138.02 4.08 versus 137.69 3.11, p = 0.630) (Figure 2E).

Group 4. Serum sodium concentration before the infusion of somatostatin or octreotide was not significantly different from the lowest value during the infusion of somatostatin or octreotide (135.96 6.87 versus 134.60 3.40, p = 0.098) (Figure 2F).

#### 3.3 Percentage of patients who developed serum sodium concentration reduction among groups

The percentage of patients who developed serum sodium concentration reduction in Group 1 (8/17, 47.1%) was not significantly different from Group 2 (3/7,

#### Figure 2.

Change in serum sodium concentration. (A) Serum sodium concentration before the infusion of terlipressin versus the lowest value during the infusion of terlipressin in Group 1. (B) Serum sodium concentration before the infusion of terlipressin versus the first re-examination value during the infusion of terlipressin in Group 1. (C) Serum sodium concentration before the infusion of terlipressin versus the value after stopping the infusion of terlipressin in Group 1. (D) Serum sodium concentration before the infusion of somatostatin or octreotide versus the lowest value during the infusion of somatostatin or octreotide in Group 2. (E) Serum sodium concentration before the infusion of somatostatin or octreotide versus the lowest value during the infusion of somatostatin or octreotide in Group 3. (F) Serum sodium concentration before the infusion of somatostatin or octreotide versus the lowest value during the infusion of somatostatin or octreotide in Group 4.

Variables

78

Group 1

No. pts Mean SD or

Median (range)

 No.

Mean SD or

Median (range)

 No.

Mean SD or

Median (range)

 No.

Mean SD or

Median (range)

pts

n (%)

pts

 19 33.56 5.67

 33.1 (25.6–47.9)

 18 35.68 6.20

 34.6 (29.2–50.1)

n (%)

pts

n (%)

n (%)

> Activated partial

17

 38.21 5.11

 37.4 (29–47.8)

 7 39.07 4.25 40.2 (34.6–44.5)

thromboplastin

(seconds)

International

ratio

D-Dimer (mg/L) Model for end-stage liver

disease score

Child-Pugh score

Duration of terlipressin

(days)

Duration of somatostatin or

——

 —

7 6.79 4.58

 6.5 (1.5–14.5)

 20 3.88 2.54

 3 (0.25–12)

 19 10.36 5.14

 10 (2–20)

> octreotide (days)

Blood transfusion, n (%)

Amount of red blood cell

transfused (U) Group 1, terlipressin in portal hypertension; Group 2, somatostatin or octreotide in portal hypertension; Group 3, somatostatin or octreotide in non-variceal gastrointestinal

Group 4, somatostatin or octreotide in acute pancreatitis.

Table 1. Characteristics

 of patients.

 bleeding;

 17 11

 5.06 1.77

 5 (2–8)

 4 3.38 1.38

 3.25 (2–5)

 9 2.39 1.43

 2 (1–5.5)

——

 11 (64.7%)

—

7 4 (57.1%)

—

20

 9 (45.0%)

—

 ——

 —

 —

17

17

 3.15 1.18

 3 (1.25–5)

——

 —

 —

 —

 —

 ——

 7.76 1.92

 7 (5–12)

 7 7.14 1.77

 7 (5–10)

—

 —

 —

 ——

 —

 —

17

17

 8.23 4.68

 8.58 (0.9–16.84)

 7 10.48 5.60 11.05 (3.1–19.72) —

 2.09 2.23

 1.09 (0.15–7.39)

 7 1.85 2.29

 1.02 (0.38–6.86)

 19 2.90 10.40

 —

 —

 ——

 —

 0.33 (0.1–45.81)

 17 2.42 2.70

 1.51 (0.24–9.38)

 normalized

17

 1.45 0.30

 1.34 (1.16–2.08)

 7 1.38 0.25

 1.39 (1.14–1.83)

 19 1.17 0.31

 1.05 (0.95–2.24)

 18 1.32 0.34

 1 (0.88–2.08)

Digestive System - Recent Advances

 time

Group 2

Group 3

Group 4

Variables Sodium decreased Sodium stable or increased P

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

Median (range)

(18.7–39.1)

(10.13–77.1)

(17.17–52.5)

(4.56–25.97)

(31.85–117.38)

(3.72–6.03)

(130–142.9)

(15–20.4)

(30.6–47.8)

(0.37–6.45)

(0.9–16.84)

Child-Pugh score 8 7.75 2.12 7 (6–12) 9 7.78 1.86 8 (5–11) 0.807

(0.5–1.67)

Factors associated with serum sodium concentration reduction in patients treated with terlipressin.

7 49.57 19.44 53 (9–71) 8 50 18.75 56.5 (19–72) 0.772

8 3.25 1.22 3.13 (1.5–5) 9 3.03 1.22 3 (1.25–5) 0.699

8 4 (50%) — 9 7 (77.8%) — 0.335

4 4.5 1.73 5 (2–6) 7 5.39 1.84 5.2 (2–8) 0.331

8 1 (12.5%) — 9 1 (11.1%) — 1.000

8 0 — 9 0 — —

No. pts

Mean SD or n (%)

9 29.11 4.81 29.8

9 21.58 14.73 14.69

9 33.21 22.60 24.64

9 9.60 4.77 9.24

9 65.33 10.31 62.78

9 3.98 0.64 3.8

9 135.98 5.17 137

9 17.29 2.63 16.8

9 37.44 4.26 37.3

9 2.05 2.44 1.07

9 7.87 3.88 7.56

9 1.01 0.41 1

No. pts

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

Alanine aminotransferase

(U/L)

(U/L)

Aspartate aminotransferase

Blood urea nitrogen (mmol/L)

Potassium (mmol/L)

Serum creatinine (umol/L)

Prothrombin time (seconds)

Activated partial thromboplastin time (seconds)

Ammonia (umol/L)

score

Model for End-Stage Liver Disease

cDDD value of terlipressin

Blood transfusion,

Amount of red blood cell transfused (U)

Diuretics during terlipressin, n (%)

Paracentesis during terlipressin,

n (%)

Table 2.

81

Duration of terlipressin (days)

n (%)

Albumin (g/L) 8 29.06 5.92 29.4

Sodium (mmol/L) 8 138.04 4.12 138.9

D-Dimer (mg/L) 8 2.14 2.13 1.3

Mean SD or n (%)

8 23.35 22.08 16.67

8 30.91 12.85 25.51

8 11.1 6.54 9.6

8 70.38 30.66 68.53

8 4.22 0.76 4.01

8 16.95 2.02 16.25

8 39.06 6.12 39.7

8 8.61 5.69 9.49

8 1.15 0.46 1.13

value

0.847

0.923

0.773

0.700

0.847

0.290

0.359

0.629

0.501

0.630

0.847

0.530

Median (range)

(19–35.3)

(11.89–56.9)

(17.22–89.1)

(4.11–18.83)

(50–78.35)

(3.1–5.21)

(126.3–142)

(15.1–23.9)

(29–44.8)

(0.15–7.39)

(1.94–15.06)

(0.42–1.67)

Figure 3.

Percentage of patients who developed serum sodium concentration reduction among groups.

42.9%, p = 1.000), Group 3 (11/20, 55%, p = 0.746), or Group 4 (14/19, 73.7%, p = 0.171) (Figure 3).

#### 3.4 Factors associated with serum sodium concentration reduction in Group 1

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 (Table 2).



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

Table 2.

42.9%, p = 1.000), Group 3 (11/20, 55%, p = 0.746), or Group 4 (14/19, 73.7%,

Percentage of patients who developed serum sodium concentration reduction among groups.

3.4 Factors associated with serum sodium concentration reduction in Group 1

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

Variables Sodium decreased Sodium stable or increased P

Median (range)

Age (years) 8 57.38 10.18 59 (44–73) 9 58.67 12.34 57 (34–75) 0.819 Sex—male, n (%) 8 3 (37.5%) — 9 6 (66.7%) — 0.347

Ascites, n (%) 8 5 (62.5%) — 9 7 (77.8%) — 0.620

Hemoglobin (g/L) 8 74.5 7.45 74 (64–85) 9 69.11 28.80 60 (37–124) 0.360

(12.8–92.3)

8 30.91 25.64 25.5

No. pts

8 0 — 9 1 (11.1%) — 1.000

8 8 (100%) — 9 9 (100%) — —

8 5.38 2.23 4.7 (2.9–8.5) 9 6.72 5.04 5 (1.5–18.5) 0.773

8 113.13 63.75 92.5 (40–237) 9 121.67 117.06 76 (29–387) 0.441

9 25.87 24.52 13.4

(8.1–79.9)

0.248

Mean SD or n (%)

value

Median (range)

p = 0.171) (Figure 3).

Digestive System - Recent Advances

Clinical presentations

Hepatic encephalopathy, n (%)

Upper gastrointestinal bleeding, n (%)

(10<sup>9</sup> /L)

80

Laboratory tests White blood cell

Platelet count (109 /L)

Total bilirubin (umol/L)

No. pts

Mean SD or n (%)

(Table 2).

Figure 3.

Factors associated with serum sodium concentration reduction in patients treated with terlipressin.

### 4. Discussion

In the present study, approximately half of our patients receiving terlipressin developed serum sodium concentration reduction after short-term treatment with terlipressin (3.15 1.18 days). The incidence of hyponatremia or serum sodium concentration reduction was often heterogeneous among studies due to the characteristics of patients enrolled; definitions of hyponatremia or serum sodium concentration reduction; and indications, approaches, durations, and dosages of terlipressin. In randomized controlled trials regarding terlipressin for the treatment of EGVB, the incidence of hyponatremia, which was defined as serum sodium <130 mmol/L, was 0–6% [17–20]. Sola et al. [10] found that the incidence of serum sodium decreased >10 mmol/L from the baseline was 36% (21/58) in patients with EGVB treated by terlipressin for 5 days. Yim et al. [12] found that the incidence of serum sodium decreased >10 mmol/L from the baseline was 26.5% (40/151) in patients with EGVB treated by terlipressin for 5 days. Kang et al. [11] also reported that the incidence of serum sodium decreased >5 mmol/L from the baseline was 35.4% (45/127) during or after terlipressin treatment in patients with EGVB and hepatorenal syndrome (HRS).

effect of terlipressin is compromised. We attempted to explore the baseline factors associated with serum sodium concentration reduction during terlipressin. Unfortunately, the duration of terlipressin, cDDD value of terlipressin, blood transfusion, amount of blood transfusion, and diuretics and paracentesis during terlipressin were not significantly associated with serum sodium concentration reduction. Certainly, this analysis should be performed again in a larger number of patients.

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

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

The duration, dosage, and route of terlipressin may be also associated with the risk of hyponatremia related to terlipressin. Bruha et al. [22] conducted a multicenter randomized double-blind study to compare the efficacy and safety of 10-day versus 5-day terlipressin for the treatment of EGVB, and found that prolonged terlipressin treatment was the only risk factor of hyponatremia. Chang et al. [23] conducted a randomized controlled study to compare the efficacy and safety of high-dose versus low-dose terlipressin for the treatment of EGVB. They did not find any patient with hyponatremia in both groups. Cavallin et al. [24] conducted a randomized controlled

study to compare continuous intravenous infusion versus intravenous bolus terlipressin for type 1 HRS. Similarly, they found that no patient developed

tive cohort study, and the sample size was small. Third, a combination of

among patients.

validate our findings.

Acknowledgements

Conflict of interest

Author contributions

None.

Funding

83

None.

hyponatremia in both groups. By comparison, in the present study, we prescribed a relatively short duration of terlipressin and minimized the dosage of terlipressin. There are several limitations in the present study. First, the patient characteristics were heterogeneous in the Group 1. Second, this was a single-center retrospec-

somatostatin and/or octreotide was also given in some of our patients. Fourth, the time point when we re-checked the serum sodium concentration was defined according to the patients' conditions and disease course. Thus, it was not uniform

In conclusion, serum sodium concentration reduction can be observed in patients with portal hypertension during terlipressin treatment. However, this phenomenon might not be closely associated with the use of terlipressin. The present study failed to identify any factors associated with serum sodium concentration reduction. Future studies with a larger number of patients should be performed to

This work was partially presented as a poster presentation at the 18th Congress of Gastroenterology China that was held in Dalian, China, on September 2018.

Xinmiao Zhou wrote the protocol, collected the data, performed the statistical analysis, interpreted the data, and drafted the manuscript. Tingxue Song wrote the

Theoretically, terlipressin can induce the reduction of serum sodium concentration, because it activates the V2 receptors, thereby increasing the number of aquaporin-2 water channels in the apical plasma membrane and causing the water reabsorption in the renal collecting ducts [8]. However, there is little effect of terlipressin on V2 receptors, which is equal to only 3% of antidiuretic effect of vasopressin [13]. Indeed, the present study did not find any severe hyponatremia in our patients receiving terlipressin. Additionally, serum sodium concentration change (i.e., the baseline value versus the lowest value or the first re-examination value) was not statistically significant in all patients receiving terlipressin.

Somatostatin and its analogues cause the splanchnic vasoconstriction mainly by inhibiting the production and release of vasodilators, such as glucagon and vasoactive intestinal peptide, to reduce the portal pressure [6, 21]. They do not cause the change of serum sodium concentration. Thus, in order to further explore the effect of terlipressin on serum sodium concentration, the present study also compared the risk of serum sodium concentration reduction between patients receiving terlipressin and those receiving somatostatin or octreotide. We found that serum sodium concentration change in patients receiving terlipressin was not different from those receiving somatostatin or octreotide. These findings also suggested little effect of terlipressin on serum sodium concentration.

Several previous studies reported the risk factors for hyponatremia due to terlipressin. In 2010, Sola et al. [10] found that high baseline serum sodium level and low MELD score were independent risk factors for decreased serum sodium level. In 2013, Kang et al. [11] found that high baseline serum sodium level was an independent risk factor for hyponatremia. In 2015, Yim et al. [12] found that younger age, lower Child-Pugh score, higher baseline serum sodium, and long-term use of terlipressin (>5 days) were independent risk factors for hyponatremia and that lower body mass index and Child-Pugh score and higher baseline serum sodium were independent risk factors for rapid and severe hyponatremia. In 2017, Kim et al. [9] found that hepatitis B, diabetes mellitus, baseline serum sodium and creatinine levels, and shock at admission were independent risk factors for hyponatremia. Taken together, higher baseline serum sodium level and better liver function (low MELD or Child-Pugh score) are risk factors for hyponatremia during the treatment with terlipressin. In patients with more severe liver dysfunction, the portal pressure might be higher and the release of endogenous vasopressin was increased, thereby occupying the V2 vasopressin receptor. Thus, the antidiuretic

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

effect of terlipressin is compromised. We attempted to explore the baseline factors associated with serum sodium concentration reduction during terlipressin. Unfortunately, the duration of terlipressin, cDDD value of terlipressin, blood transfusion, amount of blood transfusion, and diuretics and paracentesis during terlipressin were not significantly associated with serum sodium concentration reduction. Certainly, this analysis should be performed again in a larger number of patients.

The duration, dosage, and route of terlipressin may be also associated with the risk of hyponatremia related to terlipressin. Bruha et al. [22] conducted a multicenter randomized double-blind study to compare the efficacy and safety of 10-day versus 5-day terlipressin for the treatment of EGVB, and found that prolonged terlipressin treatment was the only risk factor of hyponatremia. Chang et al. [23] conducted a randomized controlled study to compare the efficacy and safety of high-dose versus low-dose terlipressin for the treatment of EGVB. They did not find any patient with hyponatremia in both groups. Cavallin et al. [24] conducted a randomized controlled study to compare continuous intravenous infusion versus intravenous bolus terlipressin for type 1 HRS. Similarly, they found that no patient developed hyponatremia in both groups. By comparison, in the present study, we prescribed a relatively short duration of terlipressin and minimized the dosage of terlipressin.

There are several limitations in the present study. First, the patient characteristics were heterogeneous in the Group 1. Second, this was a single-center retrospective cohort study, and the sample size was small. Third, a combination of somatostatin and/or octreotide was also given in some of our patients. Fourth, the time point when we re-checked the serum sodium concentration was defined according to the patients' conditions and disease course. Thus, it was not uniform among patients.

In conclusion, serum sodium concentration reduction can be observed in patients with portal hypertension during terlipressin treatment. However, this phenomenon might not be closely associated with the use of terlipressin. The present study failed to identify any factors associated with serum sodium concentration reduction. Future studies with a larger number of patients should be performed to validate our findings.

#### Acknowledgements

This work was partially presented as a poster presentation at the 18th Congress of Gastroenterology China that was held in Dalian, China, on September 2018.

#### Conflict of interest

None.

4. Discussion

Digestive System - Recent Advances

hepatorenal syndrome (HRS).

82

In the present study, approximately half of our patients receiving terlipressin developed serum sodium concentration reduction after short-term treatment with terlipressin (3.15 1.18 days). The incidence of hyponatremia or serum sodium concentration reduction was often heterogeneous among studies due to the characteristics of patients enrolled; definitions of hyponatremia or serum sodium concen-

terlipressin. In randomized controlled trials regarding terlipressin for the treatment of EGVB, the incidence of hyponatremia, which was defined as serum sodium <130 mmol/L, was 0–6% [17–20]. Sola et al. [10] found that the incidence of serum sodium decreased >10 mmol/L from the baseline was 36% (21/58) in patients with EGVB treated by terlipressin for 5 days. Yim et al. [12] found that the incidence of serum sodium decreased >10 mmol/L from the baseline was 26.5% (40/151) in patients with EGVB treated by terlipressin for 5 days. Kang et al. [11] also reported that the incidence of serum sodium decreased >5 mmol/L from the baseline was 35.4% (45/127) during or after terlipressin treatment in patients with EGVB and

Theoretically, terlipressin can induce the reduction of serum sodium concentra-

Somatostatin and its analogues cause the splanchnic vasoconstriction mainly by inhibiting the production and release of vasodilators, such as glucagon and vasoactive intestinal peptide, to reduce the portal pressure [6, 21]. They do not cause the change of serum sodium concentration. Thus, in order to further explore the effect of terlipressin on serum sodium concentration, the present study also compared the

tion, because it activates the V2 receptors, thereby increasing the number of aquaporin-2 water channels in the apical plasma membrane and causing the water reabsorption in the renal collecting ducts [8]. However, there is little effect of terlipressin on V2 receptors, which is equal to only 3% of antidiuretic effect of vasopressin [13]. Indeed, the present study did not find any severe hyponatremia in our patients receiving terlipressin. Additionally, serum sodium concentration change (i.e., the baseline value versus the lowest value or the first re-examination

value) was not statistically significant in all patients receiving terlipressin.

risk of serum sodium concentration reduction between patients receiving terlipressin and those receiving somatostatin or octreotide. We found that serum sodium concentration change in patients receiving terlipressin was not different from those receiving somatostatin or octreotide. These findings also suggested little

Several previous studies reported the risk factors for hyponatremia due to terlipressin. In 2010, Sola et al. [10] found that high baseline serum sodium level and low MELD score were independent risk factors for decreased serum sodium level. In 2013, Kang et al. [11] found that high baseline serum sodium level was an independent risk factor for hyponatremia. In 2015, Yim et al. [12] found that younger age, lower Child-Pugh score, higher baseline serum sodium, and long-term use of terlipressin (>5 days) were independent risk factors for hyponatremia and that lower body mass index and Child-Pugh score and higher baseline serum sodium were independent risk factors for rapid and severe hyponatremia. In 2017, Kim et al. [9] found that hepatitis B, diabetes mellitus, baseline serum sodium and

creatinine levels, and shock at admission were independent risk factors for

hyponatremia. Taken together, higher baseline serum sodium level and better liver function (low MELD or Child-Pugh score) are risk factors for hyponatremia during the treatment with terlipressin. In patients with more severe liver dysfunction, the portal pressure might be higher and the release of endogenous vasopressin was increased, thereby occupying the V2 vasopressin receptor. Thus, the antidiuretic

effect of terlipressin on serum sodium concentration.

tration reduction; and indications, approaches, durations, and dosages of

#### Funding

None.

#### Author contributions

Xinmiao Zhou wrote the protocol, collected the data, performed the statistical analysis, interpreted the data, and drafted the manuscript. Tingxue Song wrote the protocol, collected the data, and performed the statistical analysis. Wenchun Bao wrote the protocol, collected the data, and checked the data. Lichun Shao and Xiaozhong Guo checked the data and gave critical comments Xingshun Qi conceived the work, wrote the protocol, performed the statistical analysis, interpreted the data, and revised the manuscript.

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