Prognostic Value of Spontaneous Hyponatremia in Cirrhosis with Ascites VICENTE ARROYO, MD, JUAN RODI~S, MD, MIGUEL A. GUTII~RREZ-LIZARRAGA, MD, and LUgS REVERT, MD

Spontaneous hyponatremia in cirrhosis with ascites is generally considered to be due to an impaired renal ability to excrete free water, to be a contraindication o f diuretics, and to be a bad prognostic sign. These concepts are reviewed in this paper. 55 cirrhotics with ascites were divided into three groups. Group I consisted o f 13 patients with hyponatremia and very low free-water clearance (CH~o, 0.07 + 0.26 ml/min). These patients also had poor renal function: low inulin clearance (CINu, 40.6 • 25.9 ml/min) and paraaminohippurate clearance (CpAn, 383 • 275 ml/min). Group H consisted o f 8 patients who also had hyponatremia. CH2o, C~NU, and CpAn in these patients were fairly high: 5.85 • 1.53 ml/min, 85.7 • 26.2 ml/min, and 651 +--294 mt/min. These values are similar to those of the 34 patients without hyponatremia who make up Group 11I." (6.37 +- 4.27 ml/min, 94.7 • 33.1 ml/min, and 598 • 199 ml/min). Hyponatremia in Group I could be related to the impaired free-water clearance. The mechanism o f hyponatremia in Group H patients is not clear. Patients with hyponatremia and low C~Nuand CpAHhad a negative response to diuretics and a poor prognosis. Patients with hyponatremia but with relatively good renal function had a good prognosis, similar to Group III patients. They responded to diuretics with no worsening o f their hyponatremia.

Hyponatremia is frequent in cirrhosis with ascites. Of 50 consecutive patients admitted to our Liver Unit in 1970, 20 were found to have a plasmasodium concentration below 130 mEq/liter (I). Hyponatremia in cirrhosis may be due to overvigorous diuretic treatment (2) or paracentesis (3), but very often there seems to be no direct cause. This spontaneous hyponatremia, which has been From the Liver Unit and Renal Department, Hospital Clfnico, University of Barcelona, Barcelona, Spain. Presented in part at the Eighth Meeting of the European Association for the Study of the Liver, September, 1973, Vittel, France. Address for reprint requests: Dr. Vicente Arroyo, Unidad de Hepatologia, Hospital Clfnico y Provincial, Casanova 143, Barcelona 11, Spain. We thank Dr. Stephen Wilkinson and Dr. Jaime Bosch for their valuable criticism and advice. Digestive Diseases, Vol. 21, No. 3 (March 1976)

termed "dilutional" or "paradoxical" because total body sodium is in fact increased (4, 5), is widely considered to be a result of a dilution of body fluids due to an impaired renal capacity to excrete free water (6-8). Water restriction is therefore said to be mandatory in these patients (8, 9) regardless of the blood-urea nitrogen (6). The development of spontaneous hyponatremia is regarded as a poor prognostic sign in cirrhosis with ascites (8), especially when the plasma-sodium concentration drops below 125 mEq/liter (10--12), although there was a report in one paper (13) of the recovery of 9 out of 15 patients. Hyponatremia has also been considered a contraindication to diuretic therapy (14). This paper offers an appraisal of the foregoing concepts.

249

ARROYO ET AL

MATERIALS AND METHODS 55 consecutive patients form the basis of this study. Suffering from cirrhosis of different etiologies, they were admitted to hospital mainly on account of ascites. Of all the patients 27 had never received diuretics and the others had stopped all diuretic treatment more than two weeks before admission. No patient had had gastrointestinal bleeding in the three months prior to admission, and none had a history of respiratory, renal, or cardiac disease. Water intake before admission was recorded in the clinical notes: none of the patients had drunk more than 3.5 liters per day of liquids (including alcohol). There was no difference in water intake between patients with hyponatremia and the others. Hyponatremia was due neither to hyperglycemia, hyperlypemia, nor hyperproteinemia. The diagnosis of cirrhosis was based on clinical and biochemical data, and in 40 cases it was confirmed histologically. For seven days following admission patients were treated by bed rest and low-salt diet (40-60 mEq/day). Water intake was free, the quantity being checked every day. Renal function tests were performed on the eighth day with the informed consent of all the patients. At about 9 AM, after overnight fasting from food, liquids, and cigarettes, a water load of 20 ml per kilogram of body weight (as 5% dextrose) was infused intravenously, 250 ml every 10 minutes. The patient's bladder was catheterized under strict aseptic conditions with a Foley threeway catheter, and the urine collected at intervals of 30 minutes starting 15 minutes after the end of the water load. Halfway through each collection period a blood specimen was taken for measurement of osmolality, and the free-water clearance (Credo) calculated for the period of maximal diuresis (Cmo = urine v o l u m e - o s m o l a r clearance). This maximal diuresis appeared in the first or second period in the majority of the patients; in one case it appeared in the fourth. Glomerular filtration rate (GFR) was evaluated by inulin clearance (C~Nu), and effective renal plasma flow (RPF) by paraaminohippurate clearance (CpArd. Three consecutive 30-minute clearances were made. The arithmetic mean is the value given in the resuits. Inulin was analyzed by the method of Heyrowsky (15), and paraaminohippurate by the method of Brun (16). Results were corrected to a body-surface area of t.73 m z. Plasma urea concentration was determined by the alkaline hypobromite method (17) (normal range in our laboratory 25 +- 4 mg/100 ml), urine and plasma sodium by flame photometry, and osmolalities with a Fiske osmometer. The patients who did not lose ascites and body weight after seven days of bed rest and low-salt diet were started on diuretics immediately after completion of the renalfunction studies. Either triamterene (300 rag/day) or spironolactone (150 mg/day) was given, and furosemide added (80 mg/day) if no satisfactory diuresis was obtained after seven days. Patients who did not lose at least two kg of body weight within two weeks of this treatment were considered to have a negative response to therapy. Liver function was evaluated by standard liver-function tests (total bilirubin, plasma albumin, and prothrombin time.) Data are presented as mean -+ standard devia-

250

tion (M +---SD). The significance of differences between means was determined by the Student's t test. RESULTS

Plasma-Sodium Concentration and Free-water Clearance We define h y p o n a t r e m i a as a plasma-sodium concentration (PNa) below 130 mEq/liter. On the basis of plasma-sodium concentration and free-water clearance, the patients were classified into three groups (Figure 1). Group I includes 13 patients with h y p o n a t r e m i a (eNa 125 • 2 mEq/liter) and very low CH~O (-0.07 • 0.26 ml/min). The highest clearance in this group was 0.27 ml/min, and 6 patients had a negative Cmo. Group II consists of 8 patients, also with hyponatremia (PNa ---- 125.5 • 2.3 mEq/liter) but with relatively high CH~o (5.85 • 1.53 ml/min). The lowest Ca2o in this g r o u p w a s 3.13 m l / m i n , a n d in 2 patients it was nearly 8.0 ml/min. Group III includes 34 patients without hyponatremia (PNa = 136 • 3.9 mEq/liter). All except 2 had a CH~o of o v e r 0.27 mt/min ( 6 . 3 7 - 4.27 ml/min) which was the highest value in Group I. The free-water clearance of G r o u p I patients was significantly lower than that of Group III (P < 0.001). The patients in G r o u p II, in spite of hyponatremia, had a Cn2o similar to that of patients with a normal plasma-sodium concentration. T h e r e was no difference between the plasma-sodium levels of the two groups of patients with hyponatremia. Water intake during the first seven days in hospital was similar in the three groups of patients: 845 • 151 ml/day, 838 --- 159 ml/day, and 820 - 90 ml/day for Groups I, II, and I I I , respectively.

Renal Function The renal function of Group I patients was relatively poor: (CINu = 40.6 --+ 25.9 ml/min, Cear~ = 383.2 • 275 ml/min, plasma urea = 65 • 41 mg/ml. All had a very low urinary-sodium concentration (UNa = 6.3 +---6.5 mEq/liter) (Table 1). Patients in Group II had relatively good renal function: (C~Nu = 85.7 --+ 26.2 ml/min, CpA~ = 651.2 • 294.3 ml/min, plasma urea 29 • 9 mg/ml). The CINU and CPAH were significantly higher and the plasma urea significantly lower than those of G r o u p I. 4 patients had a UN~ over 45 mEq/liter, but in the other 4 cases, UNa was very low. There was no significant difference b e t w e e n the Digestive Diseases, Vol. 21, No. 3 (March 1976)

PROGNOSTIC VALUEOF SPONTANEOUSHYPONATREMIA

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* Individual data of renal and hepatic function are given only for the patients with hyponatremia. t Values obtained in the 7th day of admission. :i: C o m p a r i s o n b e t w e e n G r o u p s I and II. w C o m p a r i s o n b e t w e e n G r o u p s I and III. I[ Comparison b e t w e e n Group II and III. 82 Patients who lost ascites on low-salt diet. # Patients w h o lost ascites on diuretics.

ascites on low-salt diet alone, and all the others except 3 lost ascites after the administration of diuretics. All but one of the hyponatremic patients who did not respond to diuretic treatment had a CINU of about 40 ml/min or less, and a Cpnn of 450 ml/min or less. Those who responded had a CINu and CpAH above these levels (Table 1). Influence of Treatment on Plasma Sodium

The influence of treatment on plasma sodium was analyzed in the 11 hyponatremic patients who lost

252

ascites (3 of Group I and 8 of Group II). 4 of them lost ascites on bed rest and low-salt diet alone, 3 received triamterene, 3 were treated with spironolactone, and 1 with spironolactone and furosemide (Figure 2). In only one patient did PNa fall significantly during diuretic treatment. In 6 there was no significant change. In 4 cases, 2 of Group I and 2 of Group II, plasma sodium increased in spite of diuretics. In the 2 patients of Group I in whom plasma sodium increased during diuretic treatment, a second renal study was made when plasma-sodium concenDigestive Diseases, Vol. 21, No. 3 (March 1976)

P R O G N O S T I C V A L U E OF S P O N T A N E O U S H Y P O N A T R E M I A

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