Upload
aldiansyahrauf
View
216
Download
0
Embed Size (px)
Citation preview
8/10/2019 DD Hyponatremias
1/9
Best Practice & Research Clinical Endocrinology & Metabolism 26 Suppl. 1 (2012) S7S15
Contents lists available atScienceDirect
Best Practice & Research Clinical
Endocrinology & Metabolismj o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b e e m
2
Differential diagnosis of hyponatraemia
Chris Thompson MD FRCPIa, *, Tomas Berl MDb,A , Alberto Tejedor MD PhDc,B ,Gudmundur Johannsson MD PhDd,C
aAcademic Department of Endocrinology, Beaumont Hospital and RCSI Medical School, Beaumont Road, Dublin 9, Irelandb Division of Renal Diseases and Hypertension, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USAcDepartment of Nephrology, Laboratory of Renal Physiopathology, Hospital General Universitario Gregorio Maranon, Doctor
Esquerdo 46, 28007 Madrid, Spaind Department of Endocrinology, Institute of Medicine, Sahlgrenska Academy, University of Goteborg, S-413 45 Goteborg, Sweden
Keywords:
algorithm
diagnosis
hyponatraemia
syndrome of inappropriate secretion of
antidiuretic hormone (SIADH)
sodium
The appropriate management of hyponatraemia is reliant on
the accurate identification of the underlying cause of thehyponatraemia. In the light of evidence which has shown that
the use of a clinical algorithm appears to improve accuracy
in the differential diagnosis of hyponatraemia, the EuropeanHyponatraemia Network considered the use of two algorithms.
One was developed from a nephrologists view of hyponatraemia,
while the other reflected the approach of an endocrinologist. Bothof these algorithms concurred on the importance of assessing
effective blood volume status and the measurement of urine
sodium concentration in the diagnostic process. To demonstrate theimportance of accurate diagnosis to the correct treatment of hy-
ponatraemia, special consideration was given to hyponatraemia in
neurosurgical patients. The differentiation between the syndromeof inappropriate antidiuretic hormone secretion (SIADH), acute
adrenocorticotropic hormone (ACTH) deficiency, fluid overload and
cerebral salt-wasting syndrome was discussed.
In patients with SIADH, fluid restriction has been the mainstayof treatment despite the absence of an evidence base for its use.
An approach to using fluid restriction to raise serum tonicity in
patients with SIADH and to identify patients who are likely to berecalcitrant to fluid restriction was also suggested.
2012 Elsevier Ltd. All rights reserved.
* Corresponding author. Chris Thompson. Tel.: +353 18376532; Fax: +353 18376501.
E-mail address: [email protected] Tel: +1 303 7244803; Fax: +1 303 7244868.E-mail address:[email protected] Tel: +34 914265145; Fax: +34 915868214.E-mail address: [email protected] Tel: +46 313423101; Fax: +46 31821524.E-mail address: [email protected].
This supplement was commissioned by Otsuka Pharmaceutical Europe Ltd.
The European Hyponatraemia Network Academy meeting was organised and supported by Otsuka PharmaceuticalEurope Ltd.
1521-690X/$ see front matter 2012 Elsevier Ltd. All rights reserved.
8/10/2019 DD Hyponatremias
2/9
S8 C. Thompson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S7S15
1. Introduction
Hyponatraemia, defined as a serum sodium concentration ([Na+])
8/10/2019 DD Hyponatremias
3/9
C. Thompson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S7S15 S9
urinary [Na+] below 20 mmol/L reflects extra renal sodium losses. The potential underlying causes of
hyponatraemia in both these circumstances are outlined in Fig. 1.4
Hypotonic hyponatraemia
Assess volume status
Euvolaemia HypervolaemiaHypovolaemia
Urinary [Na ] > 20 mmol/L+
Measure urinary [Na ]+ Measure urinary [Na ]+
Glucocorticoid deficiency
Hypothyroidism
Drugs
SIADH
Acute or chronicrenal failure
Pregnancy
Nephrotic syndrome
Cirrhosis
Heart failure
< 20 mmol/L> 20 mmol/L< 20 mmol/LExtrarenal losses
> 20 mmol/LRenal losses
Vomiting
Diarrhoea
Third spacing offluids in burns,pancreatitis andtrauma
Diuretic excess
Mineralocorticoiddeficiency
Salt-losing nephropathy
Bicarbonaturia withrenal tubular acidosisand metabolic alkalosis
Ketonuria
Cerebral salt-wastingsyndrome
Fig. 1. Algorithm for the differential diagnosis in a patient with hypotonic hyponatraemia. Adapted from Chonchol M & Berl T.
Hyponatraemia. In: DuBose T & Hamm L (eds).Acid-base and electrolyte disorders: a companion to Brenner and Rectors The Kidney,
pp 229240. Saunders; 2002.4
Patients with hypervolaemic hyponatraemia (due to heart failure, cirrhosis and nephrotic syndrome)characteristically also have a sodium retaining disorder in addition to the water retention reflected
in the decrement of sodium serum. Thus, their urinary sodium is 20 mmol/L.4
In euvolaemic hyponatraemia there is an excess of total body water relative to a normal amount of
total body sodium. These patients characteristically have a urinary sodium >20 mmol/L, as this reflects
their sodium intake.
3. Algorithms for the diagnosis of hyponatraemia: an endocrinologists view
The key to the differential diagnosis of hyponatraemia is:
1. The estimation of the blood volume of the patient.
2. The measurement of urine sodium concentration.
The algorithm used in practice is shown in Table 1.
3.1. Classification of volume status
The classification of the patients volume status (as euvolaemic, hypervolaemic or hypovolaemic) is
a critical first step in the diagnosis of the underlying aetiology of hyponatraemia. Bedside evaluation
of the patient relies on a thorough physical examination;6 the key clinical parameters to aid the
judgement of the clinician are shown in Table 1. The most useful is the measurement of central venous
pressure, but this is invasive and not always available. In addition to clinical evaluation, biochemical
8/10/2019 DD Hyponatremias
4/9
S10 C. Thompson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S7S15
parameters such as blood urea and creatinine are valuable. Plasma renin activity is potentially a very
sensitive marker of blood volume status but the results rarely come back in time to make a meaningful
contribution to what remains a predominantly clinical judgement. In many cases it can be difficult
to determine volume status, and the endocrinologists view would be that an algorithm is a usefulguideline, which still requires experienced clinical acumen for optimum use.
Table 1
Proposed matrix for the differential diagnosis of the underlying aetiology of hyponatraemia. Diagnosis of the underlying
aetiology of the hyponatraemia using this system relies on an accurate assessment of the patients volume status and
measurement of urinary [Na+].
Urine [Na+] 40mmol/L
Hypovolaemia
(dry tongue, decreased CVP, increased urea,
increased pulse, decreased BP)
Vomiting, diarrhoea,
skin losses, burns
Diuretics, Addisons,
cerebral salt-wasting syndrome,
salt-losing nephropathy
Euvolaemia Hypothyroidism
Any cause + hypotonic fluids
SIADH
Glucocorticoid deficiency
Drugs
Hypervolaemia(oedema, ascites, LVF, increased JVP,
increased CVP)
CCF, cirrhosisNephrotic syndrome Renal failure, any cause + diuretics
BP = blood pressure; CCF = congestive cardiac failure; CVP = central venous pressure; LVF = left ventricular failure; JVP = jugular
venous pressure; SIADH = syndrome of inappropriate secretion of antidiuretic hormone.
Presented by Prof. Thompson at the European Hyponatraemia Network Academy meeting in February 2011.
Distinguishing hypovolaemic hyponatraemia from euvolaemic hyponatraemia can be particularly
problematic. Hypovolaemic hyponatraemia is typically recognised by clinical signs such as a dry
tongue, decreased central venous pressure, increased urea, increased pulse and decreased blood
pressure. However, evidence suggests that the detection of mild-to-moderate volume contraction may
be difficult in clinical practice.7 Many clinicians find that the differentiation between mild volume
depletion and euvolaemia is difficult and that recommended clinical and biochemical parameters are
insufficiently reliable to accurately make the distinction. In practice, a common approach is to treat
grey cases as if they had volume depletion, and administer intravenous saline when in diagnostic
doubt; however, in any case, the osmolality of the infusate must be higher than the osmolality of theurine in order to prevent worsening of the hyponatraemia.
Typically, hypervolaemic hyponatraemia is more easily recognised, by the presence of peripheral or
sacral oedema, signs of pulmonary oedema, ascites, increased jugular venous pressure and increased
central venous pressure. Euvolaemia may be diagnosed in the absence of any clinical signs of volume
depletion or volume expansion, as outlined above.8
Following determination of the volume status, the next step in the differential diagnosis of
hyponatraemia is the assessment of urinary [Na+]. In patients with hypovolaemic hyponatraemia,
a urinary [Na+] 40 mmol/L
indicates that the mineralocorticoid effects of secondary hyperaldosteronism are not conserving renal
sodium. This is indicative of renal solute loss and demonstrates that the kidney is the site of the
problem. Thiazide diuretic use is the commonest cause of hypovolaemic hyponatraemia with high
urine [Na+]. Primary adrenal insufficiency, with loss of aldosterone and cortisol secretion also falls intothis category, as do cerebral salt-wasting syndrome and salt-losing nephropathy. Urine [Na +] between
2040 mmol/L may occur in patients with renal or extra-renal sodium loss and is a diagnostic grey
area which still requires individual clinical judgement. In patients with hypervolaemia, a urinary [Na +]
40 mmol/L suggest the hyponatraemia
results from renal failure.
8/10/2019 DD Hyponatremias
5/9
C. Thompson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S7S15 S11
It is important to recognise a number of caveats to the use of algorithms:
1. They are only guidelines, and it is important to exercise clinical acumen in the application of all
algorithms.
2. Differential diagnosis of hyponatraemia can be complicated in patients receiving diuretics; diureticsdecrease the reabsorption of sodium within the nephron and increase urinary sodium excretion.
They can affect the clinical presentation and laboratory results for hyponatraemia, and may lead
to misdiagnosis. Diseases classified as typically associated with low urine [Na +] may present with
high urine [Na+].7 Consequently, urinary sodium excretion should be used cautiously as a diagnostic
marker in patients treated with diuretics.9 In these patients, fractional uric acid excretion (FE-UA)
can instead be used to aid the differential diagnosis of hyponatraemia, particularly in differentiating
between SIADH and hypovolaemic hyponatraemia (an FE-UA cut-off value of 12% appears to be
optimal to confirm the diagnosis of SIADH [positive predictive value of 100%], whereas an FE-UA
8/10/2019 DD Hyponatremias
6/9
S12 C. Thompson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S7S15
Table 2
Essential and supporting criteria for the diagnosis of hyponatraemia secondary to SIADH. These diagnostic criteria should be
used to confirm a diagnosis of hyponatraemia secondary to SIADH. 10,11
Essential diagnostic criteria for SIADH
Decreased measured serum osmolality ( 100mOsm/kg H2O during hypo-osmolality
Clinical euvolaemia
No clinical signs of contraction of extracellular fluid (e.g., no orthostasis a, tachycardia, decreased skin turgor or dry
mucous membranes)
No clinical signs of expansion of extracellular fluid (e.g., no oedema or ascites)
Urinary [Na+] > 40mmol/L with normal dietary sodium intake b
Normal thyroid and adrenal function determined by both clinical and laboratory assessment
No use of diuretic agents within the week prior to evaluation
Supporting diagnostic criteria for SIADH
Serum uric acid
8/10/2019 DD Hyponatremias
7/9
C. Thompson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S7S15 S13
Although cerebral salt wasting is rare, the authors do believe it exists as an entity separate from
SIADH. There are several shared characteristics of SIADH and cerebral salt-wasting syndrome (outlined
in Table 4); both conditions are associated with a low serum [Na+] and an elevated urinary [Na+].14 The
main feature unique to cerebral salt-wasting syndrome is the presence of clinical hypovolaemia asa result of this volume depletion, patients may exhibit signs such as hypotension or reduced skin
turgor.13,23 The mechanism of cerebral salt-wasting syndrome is yet to be well defined, although
evidence from patients who experienced subarachnoid haemorrhage suggests that the inappropriately
elevated secretion of atrial and brain natriuretic peptides contribute to hyponatraemia following
neurosurgery.24,25
Table 4
Characteristics of SIADH and cerebral salt-wasting syndrome. For a diagnosis of SIADH, the criteria outlined in Table 2
should be used to confirm diagnosis.
SIADH Cerebral salt-wasting syndrome
Serum [Na+] Low Low
Blood urea Normal/low Raised
BP Normal Normal/postural fall
Urine volume Low High
Urinary [Na+] Raised Raised
CVP Normal Low
BP = blood pressure; CVP = central venous pressure; SIADH = syndrome of inappropriate secretion of antidiuretic hormone.
Reproduced from Sherlock M et al. Postgrad Med J2009; 85: 171175.14 With permission.
Regardless of the mechanism of cerebral salt-wasting syndrome, its treatment is dependent on
restoring the patients volume status through the administration of isotonic saline;13 therefore, fluid
restriction is not appropriate and, as mentioned previously, may worsen the condition. In contrast,
patients with SIADH may be treated with fluid restriction or a vasopressin receptor antagonist (vaptan).
Neurosurgeons are reluctant to contemplate fluid restriction because of their perception that volume
expansion is integral to the management of subarachnoid haemorrhage. It has been noted that there
is a paucity of data regarding the use of vaptans in the neurosurgical patient. It is crucial to confirm
that SIADH is the true cause of the hyponatraemia prior to administration13
as a misdiagnosis maylead to incorrect treatment that may worsen the hyponatraemia. Consequently, the initial monitoring
of therapy should always be rigorous regardless of the choice of therapy.
4. Summary
Accurate diagnosis of hyponatraemia is necessary to determine appropriate treatment and algorithms
can be developed and used to aid this process. However, clinical acumen is still important as algorithms
should act only as guidance, and are of most use when applied by physicians who understand them.
While diagnostic approaches for hyponatraemia can vary, the careful assessment of volume status
and urinary [Na+] is critical, as outlined in both of the approaches in this article. In neurosurgical
hyponatraemia, differentiation between euvolaemia and hypovolaemia is essential for the diagnosis
of SIADH and cerebral salt-wasting syndrome, respectively.
5. Acknowledgements
This supplement was commissioned by Otsuka Pharmaceutical Europe Ltd. and summarises the
proceedings of a meeting organised and supported by Otsuka Pharmaceutical Europe Ltd. The authors
have not received any honorarium in relation to this supplement. Otsuka Pharmaceutical Europe Ltd.
has had the opportunity to comment on the medical content and accuracy of the article and editorial
support has been provided by Otsuka Pharmaceutical Europe Ltd.; however, final editorial content
resides with the authors and Best Practice & Research: Clinical Endocrinology & Metabolism.
8/10/2019 DD Hyponatremias
8/9
S14 C. Thompson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S7S15
Practice points
In patients with serum hypotonicity, translocational hyponatraemia and pseudohypona-
traemia must be ruled out before a diagnosis of hyponatraemia can be made.
Differential diagnosis of the aetiology of the hyponatraemia requires assessment of volume
status and urine sodium concentration.
In neurosurgical patients, hyponatraemia is caused most frequently by SIADH or acute ACTH
deficiency; cerebral salt-wasting syndrome is rare. It is important to differentiate between
these conditions (and to rule out any alternative causes of hyponatraemia) before initiating
treatment.
SIADH may be treated with fluid restriction, though neurosurgeons are reluctant to
contemplate this in subarachnoid haemorrhage patients. Vasopressin receptor antagonists
offer an alternative treatment but have not been studied in the neurosurgical context. Acute
ACTH deficiency requires glucocorticoid therapy and the rare cerebral salt-wasting syndrome
may be treated by administration of 0.9% isotonic saline.
Research agenda
There is a need to further elucidate the mechanisms underlying hyponatraemia in patients
with cerebral salt-wasting syndrome.
The usefulness of proposed algorithms in the differential diagnosis of the underlying aetiology
of hyponatraemia needs to be assessed in a clinical setting.
6. Conflict of interest
Prof. Thompson is on the Otsuka Pharmaceutical advisory board for tolvaptan and has received
honoraria from Otsuka Pharmaceutical for speaking at symposia. Prof. Berl is on the Otsuka
Pharmaceutical advisory board for tolvaptan and has received honoraria from Otsuka Pharmaceuticalfor speaking at symposia. Dr. Tejedor acts as an expert in nephrology for the European Medicines
Agency and belongs to the Steering Committee of the European Hyponatraemia Network. He has
been scientific advisor for drugs related to the kidney: torasemide (Boehringer Ingelheim) and
tolvaptan (Otsuka Pharmaceutical Europe Ltd.). Dr. Tejedor also owns a patent on cilastatin as a broad
nephroprotector. Prof. Johannsson has received honoraria from Otsuka Pharmaceutical for speaking at
symposia.
References
1. Adrogue HJ & Madias NE. Hyponatremia. N Engl J Med 2000;342: 15811589.
2. Hoorn EJ, Lindemans J & Zietse R. Development of severe hyponatraemia in hospitalized patients: treatment-related risk
factors and inadequate management. Nephrol Dial Transplant2006; 21: 7076.
3. Huda MS, Boyd A, Skagen K et al. Investigation and management of severe hyponatraemia in a hospital setting. Postgrad
Med J2006; 82: 216219.
4. Chonchol M & Berl T. Hyponatraemia. In: DuBose, T & Hamm L (eds). Acid-base and electrolyte disorders: a companion toBrenner and Rectors The Kidney, pp 229240. Saunders; 2002.
5. Verbalis JG, Goldsmith SR, Greenberg A et al. Hyponatremia treatment guidelines 2007: expert panel recommendations.
Am J Med2007; 120(11 Suppl. 1): S1S21.
6. Freda BJ, Davidson MB & Hall PM. Evaluation of hyponatremia: a little physiology goes a long way.Cleve Clin J Med 2004;
71: 639650.
7. Fenske W, Maier SK, Blechschmidt A et al. Utility and limitations of the traditional diagnostic approach to hyponatremia:
a diagnostic study. Am J Med 2010;123: 652657.
8. Schrier RW & Bansal S. Diagnosis and management of hyponatremia in acute illness. Curr Opin Crit Care 2008; 14: 627
634.
8/10/2019 DD Hyponatremias
9/9
C. Thompson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S7S15 S15
9. Fenske W, Stork S, Koschker AC et al. Value of fractional uric acid excretion in differential diagnosis of hyponatremic patients
on diuretics. J Clin Endocrinol Metab 2008;93: 29912997.
10. Ellison DH & Berl T. Clinical practice. The syndrome of inappropriate antidiuresis.N Engl J Med 2007; 356: 20642072.
11. Janicic N & Verbalis JG. Evaluation and management of hypo-osmolality in hospitalized patients.Endocrinol Metab Clin North
Am2003; 32: 459481.12. Agha A, Rogers B, Mylotte D et al. Neuroendocrine dysfunction in the acute phase of traumatic brain injury. Clin Endocrinol
(Oxf)2004;60: 584591.
13. Upadhyay UM & Gormley WB. Etiology and management of hyponatremia in neurosurgical patients. J Intensive Care Med
2011; doi: 10.1177/0885066610395489.
14. Sherlock M, OSullivan E, Agha A et al. Incidence and pathophysiology of severe hyponatraemia in neurosurgical patients.
Postgrad Med J2009;85: 171175.
15. Peters JP, Welt LG, Sims EA et al. A salt-wasting syndrome associated with cerebral disease. Trans Assoc Am Physicians1950;
63: 5764.
16. Nelson PB, Seif SM, Maroon JC & Robinson AG. Hyponatremia in intracranial disease: perhaps not the syndrome of
inappropriate secretion of antidiuretic hormone (SIADH). J Neurosurg1981; 55: 938941.
17. Wijdicks EF, Vermeulen M, ten Haaf JA et al. Volume depletion and natriuresis in patients with a ruptured intracranial
aneurysm.Ann Neurol 1985; 18: 211216.
18. Sivakumar V, Rajshekhar V & Chandy MJ. Management of neurosurgical patients with hyponatremia and natriuresis.
Neurosurgery 1994; 34: 269274.
19. Oh MS & Carroll HJ. Cerebral salt-wasting syndrome. We need better proof of its existence. Nephron1999;82: 110114.
20. Maesaka JK, Gupta S & Fishbane S. Cerebral salt-wasting syndrome: does it exist?Nephron 1999; 82: 100109.
21. Agha A, Thornton E, OKelly P et al. Posterior pituitary dysfunction after traumatic brain injury. J Clin Endocrinol Metab.
2004;89: 59875992.
22. Hannon MJ, Behan LA, Rogers B et al. Hyponatraemia in aneurysmal subarachnoid haemorrhage is due to the syndrome of
inappropriate antidiuresis and acute glucocorticoid deficiency. Endocr Rev 2011; 32. Abstract OR16-5.
23. Momi J, Tang CM, Abcar AC et al. Hyponatremia-what is cerebral salt wasting? Perm J2010; 14: 6265.
24. Isotani E, Suzuki R, Tomita K et al. Alterations in plasma concentrations of natriuretic peptides and antidiuretic hormone
after subarachnoid hemorrhage. Stroke1994; 25: 21982203.
25. Berendes E, Walter M, Cullen P et al. Secretion of brain natriuretic peptide in patients with aneurysmal subarachnoid
haemorrhage.Lancet 1997;349: 245249.