Hyponatraemia – Current Treatment Strategies and Perspectives for the Future
levels of tolvaptan in hyponatraemia 1 (SALT-1) (conducted in the US) and SALT-2 (conducted in the US and Europe) trials.47
included individuals with hyponatraemia due to cardiac failure, liver failure, and SIAD. Both studies were designed as randomised, placebo-controlled trials of tolvaptan versus placebo; patients were not required to maintain fluid restriction. The tolvaptan dose was adjusted from 15–60 mg daily according to clinical need, and continued for 30 days, with patient monitoring continued for seven days after discontinuation of tolvaptan. Mean baseline serum sodium was similar in both groups at 128 mmol/l. Serum sodium underwent a predictable rise to a mean of 136 mmol/l in the tolvaptan group by the end of the study and did not change significantly in the placebo group. The greatest rise in serum sodium concentration was in those patients with the lowest baseline plasma sodium concentration.
The main side effects encountered were thirst and dry mouth due to the aquaretic effect of tolvaptan. A small number of patients had a serum sodium concentration rise of more than 0.5 mmol/l/hour; none suffered any neurological sequela. An open-label extension of the SALT-1 and -2 studies of almost two years duration showed that the serum sodium normalisation was sustained and only five of 111 patients experienced an over-rapid correction of serum sodium levels, with one of 111 developing hypernatraemia.48
None of these patients developed any
neurological complications. The SALT studies also examined the Short Form 12 (SF-12) Mental Component Scores before and after therapy; the mean scores significantly improved in the hyponatraemic cohort, indicating that treatment was symptomatically beneficial.
The mean baseline plasma sodium concentration in SALT-1 and -2 was 128 mmol/l, thus it is not possible to comment on the effect of tolvaptan in those patients with severe hyponatraemia who are at most risk for CPM. This is a particularly important consideration, given the observation that the greatest rise in plasma sodium occurred in those patients with the lowest baseline concentrations. Therefore, there is not yet enough evidence to show that tolvaptan can induce a predictable and controllable rise in plasma sodium concentration in those patients who have severe, acute, symptomatic hyponatraemia and who are currently managed with hypertonic saline. The best data looking at a more severely hyponatraemic cohort is taken from a study on the management of hyponatraemia with either intravenous conivaptan (a compound not yet available in Europe) or placebo.49 Subgroup analysis of those subjects with SIAD, some of whom had plasma sodium concentrations as low as 115 mmol/l, showed that conivaptan therapy led to a safe, effective, and predictable normalisation of plasma sodium concentrations. However, patients requiring emergency treatment with hypertonic saline were excluded.
The most likely role for the vaptans in the immediate future is in the treatment of mild to moderate hyponatraemia due to SIAD. None are yet
1. Baran D, Hutchinson TA, The outcome of hyponatraemia in a general hospital population, Clin Nephrol, 1984;22:72–6.
2. Anderson RJ, Hospital-associated hyponatraemia, Kidney Int, 1986;29:1237–47.
3. Sajadieh A, Binici Z, Mouridsen MR, et al., Mild hyponatraemia carries a poor prognosis in community subjects, Am J Med, 2009;122:679–86.
4. Zilberberg MD, Exuzides A, Spalding J, et al., Hyponatraemia and hospital outcomes among patients with pneumonia: a retrospective cohort study, BMC Pulm Med, 2008;8:16.
5. Sherlock M, O'Sullivan E, Agha A, et al., The incidence and pathophysiology of hyponatraemia after subarachnoid hemorrhage, Clin Endocrinol (Oxf), 2006;64:250–4.
6. Sherlock M, O'Sullivan E, Agha A, et al., Incidence and pathophysiology of severe hyponatraemia in neurosurgical
However, the high cost of the vaptans compared with fluid restriction may limit their usage. This potential stumbling block may be overcome by the fact that a number of recent studies have shown that hyponatraemia increases duration of hospital stay4,5 care stay,4,11
regardless of the cause.
Data from the Integrated Health Care Information Services National Managed Care Benchmark Database in the US calculated that hyponatraemia was a predictor on cumulative medical costs at six months (41 % increase) and 12 months (46 %) after discharge from hospital.50
licensed for the management of hypervolemic hyponatraemia in Europe, and they are not yet proven in the management of acute, symptomatic, severe hyponatraemia. The vaptans may replace water restriction as first-line treatment for SIAD, given the frequent failure of fluid restriction and the fact that tolvaptan is effective without the need for fluid restriction.47
Therefore, there is a growing acceptance that hyponatraemia significantly increases healthcare costs; if future studies can show that vaptan therapy reduces this cost by safely and effectively correcting hyponatraemia then their current high costs may become more acceptable.
The other potential problem with widespread use of the vaptans is that of inappropriate prescription; specifically their incorrect use in hypovolaemic hyponatraemia that would worsen the clinical situation. It is not always easy to differentiate between euvolaemia and mild hypovolaemia, if the diagnosis is uncertain a careful isotonic saline challenge may be the safest first step. Patients with hypovolaemic hyponatraemia are likely to respond well whereas patients with SIAD are likely to have a modest response, if any. Thus, despite the availability of an exciting new class of therapeutic agents, clinical acumen remains essential to the accurate diagnosis and management of hyponatraemia.51
Hyponatraemia is the most commonly encountered electrolyte abnormality and is associated with significant morbidity and mortality. Effective treatment is therefore necessary for all levels of hyponatraemia. Correct evaluation of the patient’s volume status is essential to accurately diagnose the underlying cause of hyponatraemia. SIAD is the most common pathophysiological process underlying hyponatraemia and current treatment modalities for this syndrome are poorly effective.
The development of the vaspressin-2 receptor antagonist class of medications gives clinicians the ability to target the underlying pathophysiology of SIAD and hypervolemic hyponatraemia. However, use of these agents may be restricted by their cost. Furthermore, more data is required in terms of the use of these agents in acute severe symptomatic hyponatraemia. n
patients, Postgrad Med J, 2009;85:171–5.
7. Gill G, Huda B, Boyd A, et al., Characteristics and mortality of severe hyponatraemia–a hospital-based study, Clin Endocrinol (Oxf), 2006;65:246–9.
8. Clayton JA, Le Jeune IR, Hall IP, Severe hyponatraemia in medical in-patients: etiology, assessment and outcome, QJM, 2006;99:505–11.
9. Hoorn EJ, Lindemans J, Zietse R, Development of severe hyponatraemia in hospitalized patients: treatment-related risk factors and inadequate management, Nephrol Dial Transplant, 2006;21:70–6.
10. Asadollahi K, Hastings IM, Beeching NJ, Gill GV, Laboratory risk factors for hospital mortality in acutely admitted patients, QJM, 2007;100:501–7.
11. Stelfox HT, Ahmed SB, Khandwala F, et al., The epidemiology
of intensive care unit-acquired hyponatraemia and hypernatremia in medical-surgical intensive care units, Crit Care, 2008;12:R162.
12. Waikar SS, Mount DB, Curhan GC, Mortality after hospitalization with mild, moderate, and severe hyponatraemia, Am J Med, 2009;122:857–65.
13. Verbalis JG, Barsony J, Sugimura Y, et al., Hyponatraemia- induced Osteoporosis, J Bone Miner Res, 2010;25(3):554–63.
14. Gill G, Leese G, Hyponatraemia: biochemical and clinical perspectives, Postgrad Med J, 1998;74:516–23.
15. Musch W, Decaux G, Treating the syndrome of inappropriate ADH secretion with isotonic saline, QJM, 1998;91:749–53.
16. Hahn RG, Fluid absorption in endoscopic surgery, Br J Anesth, 2006;96:8–20.
17. Osborn DE, Rao PN, Greene MJ, Barnard RJ, Fluid absorption
| Page 2
| Page 3
| Page 4
| Page 5
| Page 6
| Page 7
| Page 8
| Page 9
| Page 10
| Page 11
| Page 12
| Page 13
| Page 14
| Page 15
| Page 16
| Page 17
| Page 18
| Page 19
| Page 20
| Page 21
| Page 22
| Page 23
| Page 24
| Page 25
| Page 26
| Page 27
| Page 28
| Page 29
| Page 30
| Page 31
| Page 32
| Page 33
| Page 34
| Page 35
| Page 36
| Page 37
| Page 38
| Page 39
| Page 40
| Page 41
| Page 42
| Page 43
| Page 44
| Page 45
| Page 46
| Page 47
| Page 48
| Page 49
| Page 50
| Page 51
| Page 52
| Page 53
| Page 54
| Page 55
| Page 56
| Page 57
| Page 58
| Page 59
| Page 60
| Page 61
| Page 62
| Page 63
| Page 64
| Page 65
| Page 66
| Page 67
| Page 68