Removal of extensive fluid overload is one of the most difficult challenges in the management of severe congestive heart failure (CHF), particularly in patients who do not respond to diuretic therapy. Peritoneal ultrafiltration (UF) is a simple choice for daily fluid removal. Today, peritoneal dialysis (PD) is increasingly used to treat hypervolemic CHF patients who are resistant to conventional therapies, in particular when complicated by renal insufficiency (reviewed in Refs. 1, 2). Icodextrin was proposed to be a good option for UF in refractory CHF patients.3–6 Icodextrin solution is a long-acting osmotic agent that allows the patient's UF volume to gradually increase for up to 12h.1,3 In a recently published systematic review7 it was found that mortality in CHF patients treated with peritoneal UF was associated with less use of icodextrin.

Icodextrin is generally well tolerated. A small, although statistically significant reduction in serum sodium (∼2mmol/l) consistently observed in multiple trials, is likely not clinically relevant.8 Two female diabetic patients treated by icodextrin-based PD developed severe hyponatraemia with plasma Na<121mmol/l and neurological complications.9 The mechanism by which icodextrin causes hyponatremia is unclear. It was proposed that icodextrin solution leads to accumulation of maltose in the extracellular volume and this gradient induces osmotic flow by a mechanism similar to isosmolar colloid osmosis. The resultant shift in water from the intracellular to the extracellular space can result in dilutional hyponatremia.8 It was demonstrated that icodextrin increased peritoneal Na removal.10

Five refractory CHF patients treated with peritoneal ultrafiltration in our unit, developed significant symptomatic hyponatremia with Na<130mmol/l after icodextrin was added to their program (Table 1).

To find out which patients were more susceptible to severe hyponatremia after icodextrin addition we compared the characteristics of the above 5 patients as a group (median serum sodium was 129meq/l, range 126.3–130meq/l) with the data of 12 refractory CHF patients who were treated with icodextrin during the same period but their median serum sodium was 134.5meq/l (range 132.3–136.7meq/l). Higher SPAP was more likely connected to significant hyponatremia: median SPAP measured 78mmHg (range 43–92mmHg) in severe hyponatremia group compared to 49mmHg (range 37–67mmHg) in mild hyponatremia group (p=0.0225). Patients who developed significant hyponatremia died earlier compared to patients with insignificant hyponatremia. Median survival was 5 months (range 2–7 months) in severe hyponatremia group compared to 15.5 months (range 6–50 months) in mild hyponatremia group (p=0.0318). There was a tendency for significant sodium drop in women compared to men: in significant hyponatremia group 60% were women compared to 8% women in mild hyponatremia group (p=0.0525). Patients with lower baseline sodium showed a tendency for a more significant sodium drop compared to those with higher baseline sodium. Baseline serum sodium was 136.3meq/l (range 133.7–137.3meq/l) in the severe hyponatremia group compared to 138meq/l (range 134.3–141meq/l) in mild hyponatremia group (p=0.0854).

There was no difference between the groups in NYHA functional class, diabetes mellitus rate, serum creatinine and albumin levels, baseline urinary sodium or diuretics use.

We presented the group of patients who developed clinically relevant hyponatremia following icodextrin addition to the program. Five refractory CHF patients showed serum sodium drop by median of 8meq/l during the first month of icodextrin treatment, more profound decrease than previously reported (Table 1).11–13

It have been proposed that several mechanisms could explain the development of hyponatremia in PD, including net water gain due to excessive water intake or low ultrafiltration rate of free-water, negative Na+/K+ balance caused by low Na+/K+ intake or high Na+/K+ removal, and shift of intracellular water to extracellular space induced by the use of icodextrin or hypercatabolism and malnutrition.14

CHF patients had a tendency to low serum sodium level due to neurohumoral activation. The neurohumoral changes limit both sodium and water excretion in an attempt to return perfusion pressure to normal. ADH release directly enhances water reabsorption in the collecting tubules, whereas angiotensin II and norepinephrine limit distal water delivery by reduction in renal perfusion and by increasing proximal sodium and water reabsorption.15 In addition, both the low cardiac output and high angiotensin II levels are potent stimuli to thirst, leading to enhanced water intake. While significant hyponatremia was temporarily related to icodextrin start, we could not exclude the possibility that hyponatremia in these patients is multifactorial. Probably some our patients were non-adherent to free water restriction, while others demonstrated hyperglycemia (although corrected serum sodium was also low). Other possible contributors to hyponatremia in those patients are dietary restriction and chronic use of diuretics. The risk factors for hyponatremia were female sex, low initial sodium level and increased SPAP. All patients except one had hypertonic glucose 4.25% in their program which could increase thirst and as a result free water consumption. Perhaps, icodextrin metabolites accumulation rises serum osmolality, stimulates thirst and free water consumption which further contribute to hyponatremia in those severe CHF patients.

In our cases patients with severe hyponatremia had lower survival compared to mild hyponatremia group. The studies demonstrated that severe underlying disease worsens hyponatremia and clinical outcome.14 Hyponatremia itself may be a surrogate marker for the severity of underlying disease.14 Hyponatremia is known to be an important marker and prognostic factor of left-sided heart failure.16 Recently, it was demonstrated that hyponatremia was an indicator of poor prognosis in patients with echocardiographic evidence of pulmonary hypertension and preserved left ventricular systolic function.17 Perhaps, patients with certain heart failure etiologies and severe heart disease (as represented by lower survival rate compared to mild hyponatremia group) are more susceptible to this complication.

Two CHF patients who developed significant hyponatremia following icodextrin treatment suffered from hip fracture. There is an emerging literature that suggests that hyponatremia increases the adjusted odds ratio for both falls and fractures in the elderly.18 Hyponatremia appears to contribute to falls and fractures by two mechanisms: it produces mild cognitive impairment resulting in unsteady gait and falls and it directly contributes to bone impairment through osteoporosis due to increased bone resorption in order to mobilize sodium from the bone or altered bone quality through decreased bone microfracture repair.18

Hyponatremia in refractory CHF patients is multifactorial. In rare cases, icodextrin may contribute to clinically relevant hyponatremia if the hyponatremia is compounded by other factors. Severe hyponatremia in icodextrin users was associated with poorer survival and is most likely a marker of advanced heart disease. This could be a signal to physician to consider alternative and probably more aggressive interventions.

The authors declare they have no conflict of interest.