Hyponatraemia as a risk factor for hospital mortality
From the 1Liverpool School of Tropical Medicine, and 2Department of Diabetes and Endocrinology, University Hospital Aintree, Liverpool, UK
Address correspondence to Dr G. Gill, Department of Diabetes and Endocrinology, University Hospital Aintree, Liverpool L9 1AE. email: g.gill{at}liv.ac.uk
 |
Summary |
|---|
 Top Summary IntroductionHyponatraemia and mortalityDiscussionFuture research?References |
|---|
Hyponatraemia is a common abnormality in hospitalized patients, with about 15% having levels below the lower limit of the laboratory reference range. Accepted wisdom is that hyponatraemia is a marker of poor prognosis. However, a critical analysis of the literature reveals significant problems. Researchers have used various cut-off levels for plasma sodium, often concentrating on more severely hyponatraemic groups. Many studies were small, and most did not include control groups. Nevertheless, the literature available does suggest an excess mortality associated with hyponatraemia. Whether this is a direct adverse effect of low serum sodium levels, or if hyponatraemia is simply a marker for ‘sicker’ patients, is not known. It is also uncertain whether mortality is increased with more severe hyponatraemia, or whether active correction of hyponatraemia will improve outcome. These issues should be addressed by adequately-powered, prospective, suitably controlled studies.
|
Introduction |
|---|
|
TopSummaryIntroductionHyponatraemia and mortalityDiscussionFuture research?References |
|---|
Hyponatraemia is one of the most common biochemical abnormalities in clinical practice.1–3 Estimates of its prevalence in the literature understandably depend on the population studied (e.g. medical, surgical, intensive care etc.), and the cut-off level for plasma or serum sodium used. A common lower limit for the reference range is 134 or 135 mmol/l, although many prevalence studies have concentrated on more severe levels of hyponatraemia (e.g. <130 mmol/l or <125 mmol/l). Table 1 reviews hyponatraemia prevalence studies:4–12 as may be expected, prevalence falls as severity increases. Thus, for general hospital admissions, about 15% have sodium levels <135 mmol/l,11 3–4% have <130 mmol/l,8,9 and 1–2% have <125 mmol/l5,12 (often considered as ‘severe’ hyponatraemia). The effect of speciality is demonstrated by the 30% prevalence of Na levels <134 mmol/l in intensive care unit (ICU) patients,6 compared to 15% in general admissions using a similar cut-off level.
|
Hyponatraemia has a wide variety of causes, but thiazide diuretics are one of the commonest causes in hospitalized patients,1,7,12 as is the ‘syndrome of inappropriate antidiuresis’ (SIADH) related to a variety of underlying illnesses or prescribed drugs.13,14 Iatrogenic fluid overload (especially with hypotonic solutions) may be a significant problem, especially in surgical patients. The concept that ‘sick’ patients are more likely to be hyponatraemic was refined by Flear and Singh in 1973 when they hypothesized the ‘sick cell syndrome’15—an area of some controversy, but not without recent scientific support.16,17
Hyponatraemia is generally thought to be associated with increased mortality risk, but many relevant studies have methodological problems. In this article we review the literature on hyponatraemia and mortality, and explore potentially useful future research. We have used PubMed, Ovid and Athens to search the literature, using the keywords ‘hyponatraemia’ and ‘mortality’. Reference lists in individual papers were also manually checked. Only articles in English were examined.
|
Hyponatraemia and mortality |
|---|
|
TopSummaryIntroductionHyponatraemia and mortalityDiscussionFuture research?References |
|---|
The major outcome studies are shown in Table 2: most have been small, retrospective and uncontrolled. An early report from Canada by Baran and Hutchinson23 is much quoted, but involved only 78 patients with modest hyponatraemia (Na <128 mmol/l). The mortality of 27% certainly appeared high, but there was no control group for comparison. A number of other studies have suffered similar problems, as well as varying definitions of hyponatraemia.4,5,7,9,19–24 A study by Natkunam et al. prospectively analysed the outcome of 202 patients with severe (Na <125 mmol/l) hyponatraemia.5 Mortality was 42%, and though there was no control group, the authors quoted a general hospital mortality rate of 3% at the time.
|
A similar approach was taken by Clayton and colleagues in a recent British report. In 108 severely hyponatraemic patients (Na <125 mmol/l), hospital mortality was 20%, compared to a mortality of 7% in other patients admitted to the same department (general medicine) over the same time period.24 Interestingly, at a follow-up of approximately 2 years, mortality had increased to 45% in the hyponatraemic group, compared with 22% in the normonatraemic patients.
There are two studies with true control groups. Tierney in the USA retrospectively studied 763 patients with moderate (Na <130 mmol/l) hyponatraemia, and compared them with single normonatraemic case controls matched for age, gender and date of admission.8 Mortality was 9% in hyponatraemic and 1% in normonatraemic patients (p < 0.0001). A more recent British study showed a 27% mortality in 104 retrospectively recruited patients with a serum Na <125 mmol/l.18 In the normonatraemic control group (similar size, but matched only for date of admission) mortality was 9% (p = 0.009).
|
Discussion |
|---|
|
TopSummaryIntroductionHyponatraemia and mortalityDiscussionFuture research?References |
|---|
The few controlled studies available show that hyponatraemia does confer an increased mortality risk.8,18 Whether this is a direct effect of hyponatraemia, or whether hyponatraemia is simply a marker for underlying disease severity, remains uncertain. It is possible that age is a confounding factor. In one of the two controlled studies earlier discussed,18 the control group was significantly younger than the hyponatraemic group, and this may have contributed to the excess mortality observed. However, Tierney et al.8 did use age-matched controls, and an excess mortality was still found.
The studies that have looked at causes of death have found no consistent associations with particular mortality causes. Although it seems likely that mortality risk would increase with more severe levels of hyponatraemia, this has also not been consistently demonstrated. In one study it was the nadir (i.e. lowest) serum sodium level during the admission (rather than the initial level), which showed a correlation between severity of hyponatraemia and mortality.18 This observation raises the possibility that ongoing disease severity, or possibly even mismanagement, may predispose to worsening hyponatraemia and poor prognosis.25
|
Future research? |
|---|
|
TopSummaryIntroductionHyponatraemia and mortalityDiscussionFuture research?References |
|---|
Key questions concerning this most common of biochemical abnormalities still remain unanswered after over 20 years of research. Is hyponatraemia per se dangerous, or is it the underlying disease which increases mortality risk? Does therapeutic elevation of sodium levels improve outcome, and if so, is this true at all levels, and for all causes of hyponatraemia?
Another biochemical abnormality—hyperglycaemia (outside the context of known diabetes)—has more recently aroused prognostic interest. A variety of well constructed studies have clearly demonstrated increased mortality risk,26 as well as a suggestion of improved outcome with therapeutic lowering of plasma glucose levels by insulin infusion.27,28 Hyponatraemia deserves similar critical investigation.
We propose an adequately powered, appropriately controlled prospective study of hyponatraemic patients (of all grades of severity and all ages), to determine whether mortality is linked to the severity of hyponatraemia, and what causes of morbidity and mortality are over-represented in hyponatraemic patients.
Additionally, we believe that a randomized intervention study on severely hyponatraemic (Na <125 mmol/l) patients should be considered. This may pose more practical problems than in the hyperglycaemic scenario, as therapy (e.g. strict fluid restriction or saline infusion) will depend on the cause of hyponatraemia. Care would also be needed not to raise sodium levels too quickly, because of the risk of the osmotic demyelination syndrome (‘central pontine myelinolysis’).1,2 Nevertheless, we hope that the literature review and research suggestions in this paper will open a new debate on hyponatraemia—the research ‘Cinderella’ of metabolic abnormalities.
|
References |
|---|
|
TopSummaryIntroductionHyponatraemia and mortalityDiscussionFuture research?References |
|---|
1. Gill G and Leese G. (1998) Hyponatraemia: biochemical and clinical perspectives. Postgrad Med J 74 516–23.
2. Smith MD, McKenna K, Thompson JC. (2000) Hyponatraemia. Clin Endocrinol 52 667–78.[CrossRef][Medline]
3. Adrogue HJ and Madias NE. (2000) Hyponatremia. N Eng J Med 342 1581–9.
4. Erasmus RT and Matsha TE. (1998) The frequency, aetiology and outcome of severe hyponatraemia in adult hospitalised patients. Cent Afr J Med 44 154–8.[Medline]
5. Natkunam A, Shek CC, Swaminathan R. (1991) Hyponatraemia in a hospital population. J Med 22 83–96.[Web of Science][Medline]
6. Devita MV, Gardenswartz MH, Konecky A, Zabetakis PM. (1990) Incidence and etiology of hyponatraemia in an intensive care unit. Clin Nephrol 34 163–6.[Web of Science][Medline]
7. Hochman I, Cabili S, Peer G. (1989) Hyponatraemia in internal medicine wards: causes, treatment and prognosis. Isr J Med Sci 25 73–6.[Web of Science][Medline]
8. Tierney WM, Martin DK, Greenlee MC, Zerbe RL, McDonald CJ. (1986) The prognosis of hyponatremia at hospital admission. J Gen Intern Med 1 380–5.[Web of Science][Medline]
9. Anderson RJ, Chung H, Kluge R, Schrier RW. (1985) Hyponatraemia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med 102 164–8.[CrossRef][Web of Science][Medline]
10. Jamieson MJ. (1985) Hyponatraemia. Br Med J 290 1723–8.
11. Flear CT, Gill GV, Burn J. (1981) Hyponatraemia: mechanisms and management. Lancet 2 26–31.[Web of Science][Medline]
12. Kennedy PGE, Mitchel DM, Hoffbrand BI. (1978) Severe hyponatraemia in hospital in-patients. Br Med J 2 1251–3.
13. Saeed BO, Beaumont D, Handley GH, Weaver JU. (2002) Severe hyponatraemia: investigation and management in a district general hospital. J Clin Pathol 55 893–6.
14. Callewart CC, Minchew JT, Kanim LE, Salehmoghaddam S, Tsai YC, Dawson EG, Delamarter RB. (1994) Hyponatraemia and syndrome of inappropriate antidiuretic hormone secretion in adult spinal surgery. Spine 19 1674–9.[CrossRef][Web of Science][Medline]
15. Flear CTG and Singh CM. (1973) Hyponatraemia and sick cells. Brit J Anaesth 45 976–94.
16. Guglielminotti J, Present P, Mausy E, et al. (2002) Osmolar gap hyponatraemia in critically ill patients: evidence for the sick cell syndrome? Crit Care Med 30 1051–5.[CrossRef][Web of Science][Medline]
17. Gill GV, Osypiw JC, Shearer E, English PJ, Watson ID. (2005) Critical illness with hyponatraemia and impaired cell membrane integrity the ‘sick cell syndrome’ revised. Clin Biochem 38 1045–8.[CrossRef][Web of Science][Medline]
18. Gill GV, Huda MSB, Wile D, Boyd A, Skagen K, Watson ID, van Heynigen C. (2006) Characteristics and outcome of severe hyponatraemia—a case control study. Clin Endocrinol 65 246–9.[CrossRef][Medline]
19. Nzerue CM, Baffoe-Bonnie H, Falana B, Dai S. (2003) Predictors for outcome in hospitalized patients with severe hyponatraemia. J Nat Med Assoc 95 335–43.[Medline]
20. Lee CT, Guo HR, Chen JB. (2000) Hyponatraemia in the emergency department. Am J Emerg Med 18 264–8.[CrossRef][Web of Science][Medline]
21. Crook MA, Valuthar V, Moran L, Griffith SW. (1999) Review of investigation and management of severe hyponatraemia in a hospital population. Ann Clin Biochem 36 158–62.
22. Sterns RH. (1987) Severe symptomatic hyponatraemia: treatment and outcome. Ann Intern Med 107 656–64.
23. Baran D and Hutchinson TA. (1984) The outcome of hyponatraemia in a general hospital population. Clin Nephrol 22 72–6.[Web of Science][Medline]
24. Clayton JA, Le Jeune IR, Hall IP. (2006) Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome. Q J Med 99 505–11.
25. Huda B, Boyd A, Skajeu K, et al. (2006) Investigation and management of severe hyponatraemia in a hospital setting. Postgrad Med J 82 216–19.
26. Umpierrez GE, Isaac SD, Bazargan N, et al. (2002) Hyperglycaemia—an independent marker of in-patient mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 87 978–82.
27. Van den Berghe G, Wouters P, Weekers F, et al. (2001) Intensive insulin therapy in critically ill patients. New Eng J Med 345 1359–67.
28. Barber VS and Young JD. (2006) Strict glucose control in the critically ill. Br Med J 332 865–6.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  B. Whelan, K. Bennett, D. O'riordan, and B. Silke Serum sodium as a risk factor for in-hospital mortality in acute unselected general medical patients QJM, March 1, 2009; 102(3): 175 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Hanson, A. Hossain, P. Charunwatthana, M. U. Hassan, T. M. E. Davis, S. W. K. Lam, S. A. P. Chubb, R. J. Maude, E. B. Yunus, G. Haque, et al. Hyponatremia in Severe Malaria: Evidence for an Appropriate Anti-diuretic Hormone Response to Hypovolemia Am J Trop Med Hyg, January 1, 2009; 80(1): 141 - 145. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||