Noradrenaline and albumin in paracentesis-induced circulatory dysfunction in cirrhosis: a randomized pilot study

Authors


Virendra Singh MD DM, Department of Hepatology, PGIMER, # 323/21-A, Chandigarh 160 012, India.
(fax: +91 172 2744401; e-mail: virendrasingh100@hotmail.com).

Abstract.

Objective.  Therapeutic paracentesis in patients with cirrhosis is associated with a circulatory dysfunction. Intravenous albumin has been used to prevent the circulatory dysfunction; however, the use of albumin is controversial and costly. Splanchnic vasodilation is mainly responsible for circulatory dysfunction in these patients. There are no reports of use of noradrenaline, a vasoconstrictor, on the prevention of paracentesis-induced circulatory dysfunction in patients with cirrhosis. Therefore, we studied the preventive effect of noradrenaline on paracentesis-induced circulatory dysfunction in patients with cirrhosis after therapeutic paracentesis and compared it with that of intravenous albumin in a randomized pilot study.

Methods.  Forty patients with cirrhosis and tense ascites underwent therapeutic paracentesis with albumin or noradrenaline in a randomized controlled trial at a tertiary centre. Effective arterial blood volume was assessed by measuring plasma renin activity at baseline and at 6 days after treatment.

Results.  Effective arterial blood volume as indicated by plasma renin activity before and 6 days after paracentesis did not differ in the two groups (20.62 ± 10.27–22.02 ± 10.15 ng mL−1 h−1; P = 0.11 in the albumin group and 19.66 ± 8.91–20.78 ± 9.41 ng mL−1 h−1; P = 0.37 in the noradrenaline group). Plasma aldosterone concentration before and 6 days after paracentesis were also similar in both groups (1196.5 ± 434.2–1217.0 ± 405.7 pg mL−1; P = 0.7 in the albumin group and 1206.0 ± 522.5–1273.5 ± 444.8 pg mL−1; P = 0.22 in the noradrenaline group). The cost of noradrenaline treatment was significantly lower when compared with that of albumin (P < 0.001).

Conclusions.  Noradrenaline is as effective as albumin in preventing paracentesis-induced circulatory dysfunction in patients with cirrhosis after therapeutic paracentesis, but at a fraction of the cost.

Introduction

Paracentesis with plasma volume expanders is an effective therapy in patients with cirrhosis and tense ascites [1–4]. Therapeutic paracentesis, if performed without plasma volume expansion, leads to circulatory dysfunction and frequently may be associated with impairment in renal function [5–9]. These changes are prevented by intravenous infusion of albumin [5, 6, 10, 11]. However, albumin being a blood product may have an inherent risk of transmission of diseases and its use is controversial in some countries [3, 12, 13]. Arteriolar vasodilation plays a major role in causing circulatory dysfunction in these patients [8, 9, 11, 14]. Administration of a vasoconstrictor may decrease paracentesis-induced arteriolar vasodilation and prevent these complications. Recently, terlipressin, a vasoconstrictor, has been successfully used to combat this adverse effect of therapeutic paracentesis [15, 16]; however, it is costly and not available in some countries. Noradrenaline is another vasoconstrictor. There are no reports of the use of noradrenaline in these patients for prevention of post-paracentesis circulatory dysfunction. Therefore, we planned a pilot study to compare the effects of noradrenaline and albumin on post-paracentesis circulatory dysfunction in patients with cirrhosis and tense ascites undergoing therapeutic paracentesis.

Patients and methods

A total of 82 patients with cirrhosis and tense ascites attending the hepatology department of a tertiary centre between March 2004 and July 2005 were admitted, and finally 40 patients were prospectively included in the study. The Ethics Committee of the institute approved the study. Written informed consent was obtained. Diagnosis of cirrhosis was based on clinical, laboratory and ultrasonographic findings with or without liver biopsy [11]. Inclusion criteria was the presence of tense ascites requiring therapeutic paracentesis; patients less than 70 years of age; absence of arterial hypertension, a history of coronary heart disease, cardiac failure, symptomatic arteritis, respiratory or renal disease, diabetes mellitus, hepatocellular carcinoma and hepatic encephalopathy; absence of sepsis and gastrointestinal bleeding within 7 days before the study; and the absence of recent use of diuretics, plasma expanders or paracentesis. These patients were randomly assigned to the noradrenaline (20) or the albumin (20) group. These patients were on low sodium diet (34 mmol day−1) for at least 3 days before inclusion in the study. Effective arterial blood volume was assessed by measuring plasma renin activity at baseline and on the day of hospital discharge (6 days later).

On the day of admission, baseline workup including body weight, blood pressure, heart rate, electrocardiogram, liver function tests and renal function tests were obtained. In addition, arterial blood sample was collected for plasma renin activity and plasma aldosterone concentration. Blood samples were taken from the radial artery, put into chilled ethylenediaminetetraacetic acid tubes, centrifuged at 1013 g for 10 min at −3 °C and stored at −20 °C. Total paracentesis was performed under local anaesthesia and strict aseptic condition. Noradrenaline was started in a continuous infusion at an initial dose of 0.5 mg h−1. The infusion rate was titrated hourly in steps of 0.125 mg h−1 to increase the mean arterial pressure by 10 mmHg above the baseline (max. dose 3 mg h−1) and maintained at that level for the next 72 h with close monitoring . Albumin was given in a dose of 8 g L−1 of ascitic fluid removed. Fifty per cent of the dose was given within 2 h and the remainder 6 h after the procedure. The cost of treatment was calculated taking into consideration the cost of 1-day hospital stay for albumin and 3 days for that of noradrenaline. After paracentesis, diuretics and plasma expanders were withheld until hospital discharge.

On the day of hospital discharge, blood pressure, heart rate and weight were recorded, and electrocardiogram, renal and liver function tests were performed and blood was collected for renin and aldosterone. Plasma renin activity was measured by radioimmunoassay using Gamma Coat 125I RIA plasma renin activity kit (Diasorin, Stillwater, MN, USA). Plasma aldosterone concentration was measured by radioimmunoassay using RIA aldosterone kit (Immunotech SA, Marseille, France).

Outcome measures

Development of paracentesis-induced circulatory dysfunction was taken as the primary end-point. Paracentesis-induced circulatory dysfunction was defined as an increase in plasma renin activity of >50% of the pretreatment value [11]. Development of renal impairment or hyponatraemia were taken as secondary end-points. Renal impairment was defined as an increase in serum creatinine by more than 50% from baseline values to a level >1.5 mg dL−1 [5]. Hyponatraemia was defined as a decrease in serum sodium by more than 5 mEq L−1 to a level below 130 mEq L−1 in patients with serum sodium concentration <130 mEq L−1 before treatment who showed a decrease in serum sodium >5 mEq L−1 after treatment [5].

Statistical analysis

Data were analysed using SPSS (version 13) for Windows. Baseline patient characteristics (demographic, clinical feature and laboratory results) were compared between the two groups by using unpaired t-test. Intragroup comparisons were made using paired t-test. Two-factor repeated-measures anova was used for analysis. The first factor analysed the nature of treatment (noradrenaline or albumin) and the second factor analysed the repetition of measures (i.e. at baseline and on day 6). The effect of age on the outcome measures was analysed using multivariate logistic regression analysis. Results are presented as mean ± SD. P < 0.05 was considered significant.

Results

There were no significant differences between the two groups (albumin and noradrenaline) in various clinical and laboratory parameters except for age (Tables 1 and 2). In the multivariate regression model, there were no differences in the various parameters between the two groups (albumin versus noradrenaline) even after adjusting for age. Baseline values for plasma renin activity were similar in both treatment groups (20.62 ± 10.27 ng mL−1 h−1 in the albumin group versus 19.66 ± 8.91 ng mL−1 h−1 in the noradrenaline group; P = 0.7; Table 2). Two patients in the noradrenaline group and one in the albumin group had an increase in plasma renin activity of more than 50% from baseline (Fig. 1). Baseline mean plasma renin activity did not differ from value at hospital discharge irrespective of the treatment group (20.62 ± 10.27–22.02 ± 10.15 ng mL−1 h−1; P = 0.11 in the albumin group; and 19.66 ± 8.91–20.78 ± 9.41; P = 0.37 in the noradrenaline group) (Table 3). The change in plasma renin activity also did not differ significantly between the two groups (P = 0.85).

Table 1.   Baseline variables of patients in the two study groups
 Albumin group (n = 20) Noradrenaline group (n = 20) P-value
  1. Data are n (%) and mean ± SD. aCost includes cost of hospital stay.

Age (years)52.5 ± 9.943.9 ± 9.50.009
Sex (%)
 Male16 (75)16 (75)0.10
 Female4 (25)4 (25)0.10
Aetiology (%)
 Alcoholic14 (70)12 (60)0.51
 Others6 (30)8 (40)0.51
  HCV related3 (15)2 (10) 
  HBV related0 (0)1 (5) 
  Autoimmune0 (0)1 (5) 
  Idiopathic3 (15)4 (20) 
Mean arterial pressure (mmHg)86.8 ± 5.086.0 ± 6.20.66
Pulse rate (per minute)89.1 ± 6.889.8 ± 6.10.74
Pugh score9.5 ± 1.58.9 ± 1.30.23
Weight (kg)69.3 ± 11.266.8 ± 12.20.51
Volume of ascitic fluid removed (L)6.8 ± 0.87.1 ± 1.10.49
Cost of albumin/noradrenaline (Rs)a3368 ± 3691629 ± 343<0.001
Table 2.   Baseline biochemical and hormonal variables between the two groups
VariablesAlbumin group (n = 20) Noradrenaline group (n = 20) P-value
  1. Data are mean ± SD.

Serum bilirubin (mg dL−1)6.2 ± 7.73.0 ± 3.30.09
Aspartate aminotransferase (U L−1)54 ± 4545 ± 250.4
Alanine aminotransferase (U L−1)37 ± 2532 ± 180.4
Serum albumin (g dL−1)2.8 ± 0.52.6 ± 0.50.2
Prothrombin time index (%)68 ± 1879 ± 170.052
Serum ascite albumin gradient2.1 ± 0.62.3 ± 0.40.3
Serum sodium (mEq L−1)137.6 ± 5.7135.9 ± 2.60.2
Serum creatinine (mg dL−1)0.9 ± 0.20.8 ± 0.20.08
Plasma renin activity (ng mL−1 h−1)20.62 ± 10.2719.66 ± 8.910.7
Plasma aldosterone (pg mL−1)1196.5 ± 434.21206.0 ± 522.50.9
Figure 1.

 Individual changes in plasma renin activity before and after paracentesis in the noradrenaline and albumin groups.

Table 3.   Changes in clinical and laboratory parameters before and on day 6 after paracentesis
VariablesAlbumin group (n = 20)Noradrenaline group (n = 20)
BeforeAfterP-valueBeforeAfterP-value
  1. Data are mean ± SD.

Weight (kg)69.3 ± 11.263.6 ± 10.5<0.00166.8 ± 12.261.7 ± 11.4<0.001
Mean arterial pressure (mmHg)86.8 ± 5.084.8 ± 7.30.2786.0 ± 6.284.2 ± 7.50.42
Serum sodium (mEq L−1)137.6 ± 5.7136.9 ± 4.90.67135.9 ± 2.6135.6 ± 5.40.81
Serum creatinine (mg dL−1)0.9 ± 0.21.06 ± 0.30.160.8 ± 0.20.8 ± 0.20.51
Serum albumin (mg dL−1)2.8 ± 0.53.0 ± 0.70.102.6 ± 0.52.6 ± 0.50.64
Plasma renin activity (ng mL−1 h−1)20.62 ± 10.2722.02 ± 10.150.1119.66 ± 8.9120.78 ± 9.410.37
Plasma aldosterone (pg mL−1)1196.5 ± 434.21217.0 ± 405.70.71206.0 ± 522.51273.5 ± 444.80.22

Baseline plasma aldosterone concentrations did not differ between the albumin and the noradrenaline group (1196.5 ± 434.2 pg mL−1 in the albumin group versus 1206.0 ± 522.5 pg mL−1 in the noradrenaline group; P = 0.9; Table 2). No patient in either group had an increase in plasma aldosterone concentration of more than 50% from baseline (Fig. 2). Mean plasma aldosterone concentrations after 6 days of paracentesis did not differ significantly from the baseline value in both treatment groups (1196.5 ± 434.2–1217.0 ± 405.7 pg mL−1; P =0.7 in the albumin group; and 1206.0 ± 522.5–1273.5 ± 444.8 pg mL−1; P = 0.22 in the noradrenaline group; Table 3). The changes in plasma aldosterone concentration did not differ significantly between the two groups (P = 0.53).

Figure 2.

 Individual changes in plasma aldosterone concentration before and after paracentesis in the noradrenaline and albumin groups.

Baseline serum creatinine did not differ between albumin and noradrenaline groups (P = 0.08; Table 2). The serum creatinine values were not significantly different in both groups after treatment (Table 3). Renal impairment, in the form of rise in serum creatinine to more than 50% of baseline to a level ≥ 1.5 mg dL−1, did not occur in any of the patients in either group. Baseline serum sodium values were similar in both groups (P = 0.2; Table 2). There was no significant difference in either group after treatment (Table 3). The change in serum sodium values after treatment in both groups was also similar (P = 0.85).

Baseline body weight did not differ significantly between two groups (P = 0.51; Table 1). In the both treatment groups, body weight was lower at day 6 than baseline (P < 0.001; Table 3). The changes in the body weight did not differ between groups (P = 0.57).

Baseline mean arterial pressure did not differ between albumin and noradrenaline groups (P = 0.66; Table 1). No significant decrease in mean arterial pressures was noted in either group at day 6 (Table 3). Changes in arterial pressure did not differ between the two groups (P = 0.95). During hospital stay, no patient from either group developed treatment-related complications, except for mild restlessness in one patient in the noradrenaline group, which settled after a few hours. The cost of noradrenaline treatment was significantly lower when compared with that of albumin (P < 0.001; Table 1).

Discussion

Paracentesis-induced arteriolar vasodilatation plays a major role in the development of circulatory dysfunction in patients with cirrhosis and tense ascites [5, 9, 11, 14]. There is a marked increase in plasma renin and aldosterone levels within 1 week after paracentesis [3, 5, 10]. Baseline plasma renin as well as aldosterone concentrations are higher in these patients with cirrhosis [7, 15]. Various studies have shown that paracentesis-induced circulatory dysfunction can be prevented by plasma expanders [2, 3]. As the circulatory impairment in these patients is predominantly caused by accentuation of the arteriolar vasodilation in the splanchnic circulation, use of an arterial vasoconstrictor may be useful in prevention of this complication. Recently, terlipressin has been used successfully in patients with cirrhosis and tense ascites for prevention of paracentesis-induced circulatory dysfunction [15, 16]. In a pilot study, 10 patients with cirrhosis and tense ascites were randomly assigned to treatment with either paracentesis and terlipressin or paracentesis and albumin [15]. This randomized pilot study suggested that terlipressin might be as effective as intravenous albumin in preventing a decrease in effective arterial blood volume in patients with cirrhosis treated by paracentesis for tense ascites [15]. Recently, we also evaluated the role of terlipressin and albumin in 40 such patients, and found terlipressin and albumin to be equally effective in preventing paracentesis-induced circulatory dysfunction in these patients [16]. However, terlipressin is similar in cost to albumin.

Noradrenaline is an α-adrenergic agonist with powerful vasoconstrictor activity, which has been used in the treatment of type 1 hepatorenal syndrome [17]. Noradrenaline constricts mesenteric vessels and reduces splanchnic vasodilatation and may therefore reduce post-paracentesis circulatory dysfunction. However, there are no studies in the literature of its use in the prevention of post-paracentesis circulatory dysfunction in patients with cirrhosis undergoing therapeutic paracentesis.

The present study was designed to investigate the role of noradrenaline in the prevention of post-paracentesis circulatory dysfunction. In the present study, plasma renin activity did not differ significantly in the noradrenaline and albumin groups (P = 0.110 in the albumin group and P = 0.374 in the noradrenaline group). A decrease in effective arterial blood volume was present on day 6 in only two patients in the noradrenaline group and in one patient in the albumin group (shown by an increase in plasma renin activity by more than 50 % from baseline). Thus, paracentesis-induced decrease in effective arterial blood volume was effectively prevented in most patients in the noradrenaline and albumin groups, indicating comparable efficacy of noradrenaline to that of albumin. An increase in plasma renin activity has been reported after short-term noradrenaline infusion in patients with hepatorenal syndrome, suggesting a vasconstrictive effect on the renal artery [18]. However, in another study including nine cirrhotic patients with ascites but without renal failure, noradrenaline infusion was followed by a decrease in aldosterone secretion in six cases and a significant increase in urinary sodium excretion in three cases [19]. Duvoux et al. [17] also reported improvement in renal function and a marked reduction in plasma active renin and aldosterone concentrations during noradrenaline treatment in patients with hepatorenal syndrome. They suggested that the haemodynamic benefit derived from noradrenaline-induced peripheral vasoconstriction probably predominates over the action of noradrenaline on the renal artery and results in improved renal perfusion [17]. The cost of noradrenaline was also lower when compared with albumin (P < 0.001). Noradrenaline was very well tolerated in patients with hepatorenal syndrome and only two patients developed chest pain [17]. We noticed restlessness in only one patient in the noradrenaline group.

Cirrhotics with tense ascites treated with large-volume paracentesis without intravenous albumin infusion frequently develop renal failure or hyponatraemia, or both [5, 8]. Serum creatinine as well as serum sodium did not change significantly in both groups. Baseline values as well as change in arterial pressure did not differ between groups. On follow-up one patient in the albumin group developed spontaneous bacterial peritonitis and another in the noradrenaline group developed sepsis. In a short follow-up (0.5–3 months) most of the patients in both groups were doing well on diuretic therapy and only three patients (two in the albumin group and one in the noradrenaline group) required repeat paracentesis.

In conclusion, the results of this study suggest that noradrenaline is as effective as albumin in the prevention of the circulatory dysfunction in patients with cirrhosis after therapeutic paracentesis, but at a fraction of the cost; however, a larger randomized study is warranted.

Conflict of interest statement

No conflict of interest was declared.

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