Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=icmo20 Current Medical Research and Opinion ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: https://www.tandfonline.com/loi/icmo20 ‘Dos and don’ts’ in the management of hyponatremia Simon Aylwin, Volker Burst, Alessandro Peri, Isabelle Runkle & Nicholas Thatcher To cite this article: Simon Aylwin, Volker Burst, Alessandro Peri, Isabelle Runkle & Nicholas Thatcher (2015) ‘Dos and don’ts’ in the management of hyponatremia, Current Medical Research and Opinion, 31:9, 1755-1761, DOI: 10.1185/03007995.2015.1072706 To link to this article: https://doi.org/10.1185/03007995.2015.1072706 Published online: 14 Jul 2015. Submit your article to this journal Article views: 16727 View related articles View Crossmark data Citing articles: 3 View citing articles
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TF-ICMO150145 1755..1761Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=icmo20
Current Medical Research and Opinion
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: https://www.tandfonline.com/loi/icmo20
‘Dos and don’ts’ in the management of hyponatremia
Simon Aylwin, Volker Burst, Alessandro Peri, Isabelle Runkle & Nicholas Thatcher
To cite this article: Simon Aylwin, Volker Burst, Alessandro Peri, Isabelle Runkle & Nicholas Thatcher (2015) ‘Dos and don’ts’ in the management of hyponatremia, Current Medical Research and Opinion, 31:9, 1755-1761, DOI: 10.1185/03007995.2015.1072706
To link to this article: https://doi.org/10.1185/03007995.2015.1072706
Published online: 14 Jul 2015.
Submit your article to this journal
Article views: 16727
View related articles
View Crossmark data
0300-7995 Article FT-0239.R1/1072706
Commentary ‘Dos and don’ts’ in the management of hyponatremia
Simon Aylwin Department of Endocrinology, King’s College Hospital
London, UK
Rheumatology, Diabetes and General Internal
Medicine, University of Cologne, Cologne, Germany
Alessandro Peri Endocrine Unit, Department of Experimental and
Clinical Biomedical Sciences ‘Mario Serio’, University
of Florence, Florence, Italy
Clnico San Carlos, Madrid, Spain
Nicholas Thatcher Department of Medical Oncology, Christie Hospital
NHS Trust, Manchester, UK
Address for correspondence: Simon Aylwin, Department of Endocrinology, King’s
College Hospital NHS Foundation Trust, Denmark Hill,
London, SE5 9RS, UK. Tel: +44 020 3299 9000;
[email protected]
Sterns’ Safety Rule of Sixes – Syndrome of
inappropriate antidiuretic hormone secretion –
Citation: Curr Med Res Opin 2015; 31:1755–1761
Abstract
Introduction and objective:
The management of hyponatremia has evolved in recent years, particularly with the introduction of tolvaptan
for hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This
commentary presents a summary of recent international recommendations in the form of a series of didactic
‘dos and don’ts’, in order to provide concise, practical guidance for practising clinicians focused on the
investigation and management of euvolemic hyponatremia (SIADH).
Research methods:
A multidisciplinary group of international experts reviewed existing guidelines and the evidence cited within
to summarize the recommendations in a practical method for use in clinical practice.
Recommendations:
The ‘dos and don’ts’ are presented under topic headings that include diagnosis and diagnostic tests,
specific causes, correction of acute hyponatremia, correction rates for chronic hyponatremia,
management of SIADH including fluid restriction, hypertonic saline and pharmacological strategies, and
management of overcorrection. Within each topic, the authors summarize the published recommendations
on managing hyponatremia and the use of specific agents for the treatment of SIADH.
Conclusion:
Practising clinicians can use these ‘dos and don’ts’ to provide clear, up-to-date guidance on how to manage
hyponatremia and the use of tolvaptan in SIADH.
Introduction
It is now well established that hyponatremia is associated with increased morbidity1–3 and mortality4 in a wide variety of settings. However, most pharma- cological treatment options lack good evidence of efficacy and safety. Tolvaptan has recently been licensed by the European Medicines Agency as a treatment for hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH)5. It has become important to establish recommendations as to where tolvaptan fits into the management algorithm, and how that affects the role of other treatment options: for example, fluid restriction, hypertonic saline administration, urea and demeclocycline. Furthermore, it is necessary to define and emphasize the safe limits of sodium correction with tolvaptan and other active therapies. A recent publication (‘Diagnosis, evaluation and treatment of hyponatremia: expert panel recommendations’6) was developed by a multidisciplinary group of international experts and was written for an international audience. This summary is not intended to replicate the process of literature research that has been undertaken by the authors of the
! 2015 Taylor & Francis www.cmrojournal.com ‘Dos and don’ts’ of hyponatremia Aylwin et al. 1755
recommendations and other recently published guidelines. In this article, the recommendations have been abbre- viated to a series of didactic ‘dos and don’ts’ to provide a clear, concise and readable guide for practising clinicians. The authors summarized and commented on the key points that relate to the investigation and management of hypo- natremia. In addition, they specifically address available pharmacological interventions and the use of tolvaptan in relation to the European license for management of hyponatremia in SIADH7.
In the last 2 years, a number of recommendations and guidelines relating to hyponatremia have been published6,8–11. Most of the recommendations in relation to diagnosis, investigation and management in the emergency setting and the role of hypertonic saline are convergent. There is variation in relation to the use of interventions after fluid restriction. Where there is a significant divergence, this is acknowledged in the text.
The authors have selected a list of the most important learning points for other clinicians (Box 1). These key learning points are essential for all clinicians treating hyponatremia; they are not meant to be exhaustive and acknowledge that clinicians refer to more experienced colleagues as appropriate.
Clinical significance
DO recognize that hyponatremia is associated with increased mortality and prolonged hospital stay4.
DO NOT ignore ‘asymptomatic’ hyponatremia, which is associated with reduced cognitive function, gait instability and increased fracture risk2.
Diagnosis
DO distinguish between acute (548 hours’ duration) and chronic (448 hours’ duration) hyponatremia6,12. Patients with acute hyponatremia can deteriorate quickly and present a greater risk for seizure, respiratory arrest and death than those with chronic hyponatre- mia. N.B. There may be an acute component in some cases of chronic hyponatremia.
DO check for current or recent use of glucocorticoids: oral, intranasal, cutaneous, and inhaled13,14. These frequently cause adrenocorticotropic hormone suppression, and hence cortisol insufficiency if inter- rupted, which may lead to hyponatremia.
DO NOT attribute hyponatremia to hypothyroidism unless the patient has severe hypothyroidism, myx- edema coma or very high levels of thyroid-stimulating hormone (e.g.450 mU/L).
DO look for alternative causes, as hypothyroidism is rarely a cause of marked hyponatremia.
DO review the patient’s current use of pharmacological agents to identify potential iatrogenic causes of hyponatremia (e.g. thiazide diuretics, selective serotonin-reuptake inhibitors, carbamazepine, and agents interfering with the renin–angiotensin– aldosterone system).
Diagnostic tests
DO check urine and plasma osmolality: criteria for SIADH include Posmo5275 and Uosmo4100 mOsmol/kg. Uosmo5100 mOsmol/kg con- firms the absence of antidiuretic hormone function, and implies primary polydipsia, increased intake of liquids, and/or low solute intake as the cause of hyponatremia.
DO NOT diagnose hyponatremia without checking serum glucose concentration to exclude transloca- tional hyponatremia, and plasma osmolality to exclude pseudohyponatremia6,15.
DO check urinary sodium concentration ([Naþ]) and potassium concentration ([Kþ]): a low urinary [Naþ] almost always indicates volume depletion, hypervole- mia, primary polydipsia or reduced solute intake (salt and protein).
*Synacthen is a trade name of Alliance Pharma, Chippenham, UK
Box 1. Top ten ‘dos and don’ts’ in hyponatremia.
(1) DO NOT ignore ‘asymptomatic’ hyponatremia. (2) DO distinguish between acute (548 hours’ duration) and chronic
(448 hours’ duration) hyponatremia. (3) DO check urine and plasma osmolality. (4) DO determine the sum of the urinary [Naþ] and [Kþ]: where this is
greater than the serum [Naþ], fluid restriction alone is unlikely to be effective (the basis of the Furst formula).
(5) DO ensure that all the appropriate diagnostic laboratory testing is undertaken in a patient suspected of SIADH. However, therapy can be initiated before results are available.
(6) DO correct acute, severe hyponatremia with bolus(es) of hyper- tonic saline or with an infusion of (3%) hypertonic saline to raise [Naþ] by 4–6 mmol/L – and stop.
(7) DO aim for a correction rate goal of 4–8 mmol/L per day in low-risk patients with chronic SIADH (4–6 mmol/L/day in patients at high risk of osmotic demyelination syndrome).
(8) DO NOT allow [Naþ] overcorrection: greater than 8 mmol/L in high-risk patients, or greater than 12 mmol/L in lower-risk patients, in any 24 hour period.
(9) DO consider active re-lowering measures if overcorrection occurs in patients with initial [Naþ]5120 mmol/L, particularly the high- risk: desmopressin 2–4 mg subcutaneously each 8 hoursþ replace water or 5% dextrose at 3 mL/kg/h).
(10) DO consider pharmacological therapy for SIADH where hypona- tremia persists and where fluid restriction is ineffective, imprac- tical or unpalatable (tolvaptan, urea, demeclocycline, or loop diuretics with NaCl).
Current Medical Research & Opinion Volume 31, Number 9 September 2015
1756 ‘Dos and don’ts’ of hyponatremia Aylwin et al. www.cmrojournal.com ! 2015 Taylor & Francis
DO determine the sum of the urinary [Naþ] and [Kþ]: where this is greater than the serum [Naþ], fluid restric- tion alone is unlikely to be effective (the basis of the Furst formula)16.
DO check serum cortisol level, and consider a tetra- cosactide test (Synacthen*) to exclude glucocorticoid deficiency, in all patients considered to have SIADH regardless of the appearance of adrenals on imaging17.
DO NOT measure the level of arginine vasopressin or copeptin (this is rarely helpful).
DO consider a fluid challenge (1.0–2.0 litre 0.9% NaCl) if the patient’s volume status is unclear (patients with hypovolemic hyponatremia will respond favorably).
DO undertake brain and chest imaging in patients with chronic SIADH to identify central nervous system (CNS) or lung pathology.
DO undertake central nervous system imaging (com- puted tomography or magnetic resonance imaging) in the setting of hyponatremia due to primary polydipsia; abnormally increased water intake can be due to infil- trative or neoplastic causes.
Specific causes: thiazide-induced hyponatremia
DO recognize that overly rapid correction leading to osmotic demyelination syndrome (ODS) can occur simply by stopping thiazides and/or correction of potas- sium depletion18 (potassium replacement causes a serum [Naþ] rise in all states of potassium depletion).
DO monitor serum [Naþ], urine osmolality and urine volume every 6 hours after cessation of thiazide therapy.
Cerebral salt wasting
DO NOT make the diagnosis of cerebral salt wasting (CSW) in the neurosurgical setting unless there is corroborative evidence of a period of fluid and sodium loss before the development of hyponatremia. Most hyponatremic patients have SIADH in this setting.
DO NOT use fluid restriction in patients with subarachnoid hemorrhage (SAH)19,20.
DO correct hyponatremia in SAH if [Naþ] 5131 mmol/L initially by use of sodium supplementa- tion in the form of isotonic saline with or without additional oral salt tablets.
Primary or secondary adrenal failure
DO use parenteral ‘stress’ doses of hydrocortisone (e.g. 50–100 mg intravenously [IV] or intramuscularly every 8 hours) in a patient with known or suspected primary adrenal failure or glucocorticoid deficiency.
With any suspicion of primary or secondary adrenal insufficiency, DO commence glucocorticoid therapy after drawing blood for cortisol measurement.
DO monitor serum [Naþ] and fluid balance carefully where glucocorticoid deficiency is thought to be the cause of hyponatremia. Fluid restriction should be lifted if a pronounced aquaresis occurs and may necessitate desmopressin and/or fluid replacement.
Strategy for correction of SIADH
DO individualize the nature of treatment and rapidity based on:
(1) Treatment of the underlying condition. (2) The presence of neurological symptoms
(indicating likely acute onset). (3) The speed of onset of the hyponatremia.
DO discontinue any drugs known to be associated with SIADH at the initiation of therapy, if possible.
DO ensure that all the appropriate diagnostic labora- tory testing is undertaken in a patient suspected of SIADH (see Diagnostic tests). However, therapy can be initiated before results are available.
Correction of acute hyponatremia
DO recognize that acute, severe hyponatremia is a life- threatening metabolic emergency21.
DO correct acute, severe hyponatremia with bolus(es) of hypertonic saline (3%): 100 mL over 10 minutes administered up to three times, ideally in a high- dependency unit22.
DO treat acute hyponatremia with mild-to-moderate symptoms with 3% NaCl (0.5–2 mL/kg/h) and monitor response every 4–6 hours23. Some authorities recognize the use of 1.8% hypertonic saline at 1 mL/kg/hour as an alternative therapy in acute (and chronic) hyponatremia24.
DO aim to raise [Naþ] by 4–6 mmol/L in 6 hours to treat acute severe hyponatremia, then pause for 12–24 hours. A small shift in serum [Naþ] is sufficient to reduce intracranial pressure25.
Current Medical Research & Opinion Volume 31, Number 9 September 2015
! 2015 Taylor & Francis www.cmrojournal.com ‘Dos and don’ts’ of hyponatremia Aylwin et al. 1757
Management of exercise-associated hyponatremia
DO NOT encourage runners to drink fluid at 4400–800 mL/h.
DO consider an IV bolus 100 mL of 3% saline over 10 minutes in an individual with severe neurological symptoms after an endurance event, or a [Naþ] 5125 mmol/L repeated up to twice after 30 minutes if required.
Correction rates for chronic hyponatremia
DO monitor urine output during correction of hypona- tremia as a high urine output may alert the clinician to overly rapid correction of serum [Naþ].
DO monitor the serum [Naþ] regularly (e.g. each 4–6 hours) with any active treatment until [Naþ] stabilizes.
DO NOT allow over-correction of hyponatremia in patients with cortisol deficiency, or patients receiving desmopressin or thiazides without monitoring of [Naþ], urine osmolality and urine output. Life-threatening overcorrection can occur in512 hours.
DO NOT continue fluid restriction in subjects once a prompt aquaresis occurs, i.e. in patients with hypo- natremia due to thiazide use, desmopressin use, or glucocorticoid deficiency.
DO stratify for the risk of ODS: at-risk patients have serum [Naþ]5120 mmol/L for448 hours, and high risk if serum [Naþ] 5105 mmol/L, or with hypokalemia, alcoholism, malnutrition, or advanced cirrhosis6,26–28.
DO aim for a correction rate of 4–8 mmol/L per day in low-risk patients with chronic SIADH (4–6 mmol/L/ day in patients at high risk of ODS).
DO NOT allow [Naþ] overcorrection, i.e. greater than 8 mmol/L in high-risk patients, or greater than 12 mmol/L in low-risk patients, in any 24 hour period.
DO NOT exceed 18 mmol/L correction in any 48 hour period.
Sterns’ Safety Rule of Sixes is an often cited and easily remembered rule emphasizing that symptom improvement can be achieved with a [Naþ] correction of 6 mmol/L (‘six a day makes sense for safety; so six in six hours for severe Sx and stop’)24.
Management of overcorrection
DO recognize that overly rapid rates of correction of hyponatremia can lead to neurological sequelae, currently termed osmotic demyelination syndrome or
‘ODS’ (previously termed pontine or extra-pontine myelinolysis)29,30. ODS can manifest as progressive quadriplegia and ophthalmoplegia, or as extrapyram- idal features such as involuntary movements and ataxia. Have a high index of suspicion for any neuro- logical symptoms that appear or progress during correction6.
DO NOT continue active measures (e.g. saline or tol- vaptan therapy) if the daily target (8–12 mmol/L/day) is exceeded. Omit the next day’s dose of tolvaptan if prescribed31.
DO replace water losses and/or consider administering desmopressin in all patients where overcorrection occurs32.
DO consider active re-lowering measures if overcorrec- tion occurs in patients with initial [Naþ]5120 mmol/L, particularly the high risk: (desmopressin 2–4mg subcutaneously each 8 hoursþ replace water or 5% dextrose at 3 mL/kg/h)32.
DO monitor [Naþ] after each 1 hour dextrose infusion during active re-lowering and stop once target is reached.
Use of fluid restriction in SIADH
DO use fluid restriction as first-line therapy in selected patients with chronic hyponatremia provided such patients do not meet the exclusions below. The typical fluid restriction should be 500 mL/day less than the 24 hour urine output.
DO NOT use fluid restriction: If the urine osmolality is4500 mOsm/kg. If the sum of urine [Naþ] and [Kþ]4serum [Naþ]
(Furst formula)16. If its use leads to the discontinuation or delay of
needed therapy (surgery, artificial nutrition, IV medication, chemotherapy, etc.)33.
DO NOT restrict protein or sodium intake inadvert- ently or deliberately during fluid restriction.
DO NOT continue fluid restriction alone if the initial [Naþ] correction is52 mmol/L in the first 24–48 hours.
DO reconsider the diagnosis of euvolemic hyponatre- mia (possible subclinical hypovolemia) after a few days if an effective fluid restriction fails to lead to correction.
Hypertonic saline in SIADH
DO treat symptomatic chronic hyponatremia with either bolus (100 mL 3% hypertonic saline over 10 min) or infusion of hypertonic saline (3% at
Current Medical Research & Opinion Volume 31, Number 9 September 2015
1758 ‘Dos and don’ts’ of hyponatremia Aylwin et al. www.cmrojournal.com ! 2015 Taylor & Francis
0.5–1.0 mL/kg/h or 1.8% hypertonic saline at 1–2 mL/kg/h) as for acute hypernatremia (above)22.
DO NOT forget that the actual response of the [Naþ] and the patient’s condition is more important than the initial infusion rate of hypertonic saline.
DO monitor serum [Naþ], e.g. every 4–6 hours or more frequently, during treatment with hypertonic saline.
Pharmacological strategies in SIADH
DO consider pharmacological therapy for SIADH where hyponatremia persists and where fluid restric- tion is ineffective, impractical or unpalatable.
Use of tolvaptan in SIADH
DO consider tolvaptan therapy for patients with hypo- natremia due to SIADH without severe symptoms6, in accordance with its license in the EU7.
DO NOT commence tolvaptan as an outpatient6. DO NOT initiate tolvaptan immediately after use
of hypertonic saline6. DO monitor patients from the time of initiation of
tolvaptan to avoid overly rapid correction31. DO use caution in treating patients with tolvaptan
if their serum [Naþ] is 5120 mmol/L, owing to the higher risk of overly rapid correction31.
DO encourage oral fluid intake when using tolvaptan31.
DO consider interrupting therapy for 1–2 days once [Naþ] reaches 125 mmol/L if the initial [Naþ] was 5120 mmol/L to allow slower equilibration6.
DO consider the likely need for continued tolvaptan therapy in relation to the underlying cause of SIADH6.
DO check liver function tests if there are symptoms suggesting liver toxicity34.
Note: the joint European Society of Endocrinology guideline does not recommend the use of vasopressin receptor antagonists for the management of moderate (or indeed any level of) hyponatremia. In this regard, the guideline represents an outlier in relation to other recommendations35.
Use of urea in SIADH
DO consider use of urea at a dose of 15–60 g/day (dis- solved in orange juice) as a treatment for SIADH. Although urea is not available in an approved formu- lation, it is recommended by some authorities8,36,37.
DO ensure adequate fluid intake, as marked hyperna- tremia can be a complication of treatment37.
Use of demeclocycline in SIADH
DO consider demeclocycline (300–1200 mg/day)38 to manage chronic SIADH in the context of malignancy with careful renal function monitoring (only licensed for this indication in UK and France)35. Irreversible renal failure has been reported as a complication of its use6.
Use of loop diuretics and NaCl
DO recognize the potential for use of a low-dose loop diuretic in conjunction with sodium tablets or saline to treat hyponatremia as recommended by some authorities8,36,37.
Long-term management of hyponatremia
In many patients, specific treatment of hyponatremia due to SIADH is only required short term. In patients with chronic SIADH, tolvaptan at least appears to be safe in longer-term use39. Demeclocycline (600–1200 mg/day) is the only alternative treatment that has been used exten- sively. However, it is only licensed in the UK and France for the chronic treatment of hyponatremia due to SIADH, and requires close monitoring of renal function38. Use of urea long term has been reported but is limited by practical availability and lack of evidence-based data on long-term efficacy and safety35,40.
Decisions in regard to longer-term treatment need to consider a balance between the ongoing cost of therapy and the patient’s benefit, and these issues need to be addressed on an individual basis. Future studies are required to establish whether correction of hyponatremia with tolvaptan and maintenance of a normal serum [Naþ] obviates the increased risk of adverse outcomes associated with hyponatremia.
Transparency Declaration of funding Editorial assistance and publication support for this article was funded by Otsuka Pharmaceutical Europe Ltd. The authors have not received any honorarium from Otsuka Pharmaceutical Europe Ltd in relation to this article. The company has checked the medical accuracy of the article; however, final editorial con- tent resides with the authors.
Current Medical Research & Opinion Volume 31, Number 9 September 2015
! 2015 Taylor & Francis www.cmrojournal.com ‘Dos and don’ts’ of hyponatremia Aylwin et al. 1759
Declaration of financial/other relationships V.B. has disclosed that he has received honoraria and consult- ancy fees from Otsuka, grants from Fresenius Kabi and is on the speaker’s bureau for Otsuka and Astra Zeneca. A.P. has disclosed that he…
Current Medical Research and Opinion
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: https://www.tandfonline.com/loi/icmo20
‘Dos and don’ts’ in the management of hyponatremia
Simon Aylwin, Volker Burst, Alessandro Peri, Isabelle Runkle & Nicholas Thatcher
To cite this article: Simon Aylwin, Volker Burst, Alessandro Peri, Isabelle Runkle & Nicholas Thatcher (2015) ‘Dos and don’ts’ in the management of hyponatremia, Current Medical Research and Opinion, 31:9, 1755-1761, DOI: 10.1185/03007995.2015.1072706
To link to this article: https://doi.org/10.1185/03007995.2015.1072706
Published online: 14 Jul 2015.
Submit your article to this journal
Article views: 16727
View related articles
View Crossmark data
0300-7995 Article FT-0239.R1/1072706
Commentary ‘Dos and don’ts’ in the management of hyponatremia
Simon Aylwin Department of Endocrinology, King’s College Hospital
London, UK
Rheumatology, Diabetes and General Internal
Medicine, University of Cologne, Cologne, Germany
Alessandro Peri Endocrine Unit, Department of Experimental and
Clinical Biomedical Sciences ‘Mario Serio’, University
of Florence, Florence, Italy
Clnico San Carlos, Madrid, Spain
Nicholas Thatcher Department of Medical Oncology, Christie Hospital
NHS Trust, Manchester, UK
Address for correspondence: Simon Aylwin, Department of Endocrinology, King’s
College Hospital NHS Foundation Trust, Denmark Hill,
London, SE5 9RS, UK. Tel: +44 020 3299 9000;
[email protected]
Sterns’ Safety Rule of Sixes – Syndrome of
inappropriate antidiuretic hormone secretion –
Citation: Curr Med Res Opin 2015; 31:1755–1761
Abstract
Introduction and objective:
The management of hyponatremia has evolved in recent years, particularly with the introduction of tolvaptan
for hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This
commentary presents a summary of recent international recommendations in the form of a series of didactic
‘dos and don’ts’, in order to provide concise, practical guidance for practising clinicians focused on the
investigation and management of euvolemic hyponatremia (SIADH).
Research methods:
A multidisciplinary group of international experts reviewed existing guidelines and the evidence cited within
to summarize the recommendations in a practical method for use in clinical practice.
Recommendations:
The ‘dos and don’ts’ are presented under topic headings that include diagnosis and diagnostic tests,
specific causes, correction of acute hyponatremia, correction rates for chronic hyponatremia,
management of SIADH including fluid restriction, hypertonic saline and pharmacological strategies, and
management of overcorrection. Within each topic, the authors summarize the published recommendations
on managing hyponatremia and the use of specific agents for the treatment of SIADH.
Conclusion:
Practising clinicians can use these ‘dos and don’ts’ to provide clear, up-to-date guidance on how to manage
hyponatremia and the use of tolvaptan in SIADH.
Introduction
It is now well established that hyponatremia is associated with increased morbidity1–3 and mortality4 in a wide variety of settings. However, most pharma- cological treatment options lack good evidence of efficacy and safety. Tolvaptan has recently been licensed by the European Medicines Agency as a treatment for hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH)5. It has become important to establish recommendations as to where tolvaptan fits into the management algorithm, and how that affects the role of other treatment options: for example, fluid restriction, hypertonic saline administration, urea and demeclocycline. Furthermore, it is necessary to define and emphasize the safe limits of sodium correction with tolvaptan and other active therapies. A recent publication (‘Diagnosis, evaluation and treatment of hyponatremia: expert panel recommendations’6) was developed by a multidisciplinary group of international experts and was written for an international audience. This summary is not intended to replicate the process of literature research that has been undertaken by the authors of the
! 2015 Taylor & Francis www.cmrojournal.com ‘Dos and don’ts’ of hyponatremia Aylwin et al. 1755
recommendations and other recently published guidelines. In this article, the recommendations have been abbre- viated to a series of didactic ‘dos and don’ts’ to provide a clear, concise and readable guide for practising clinicians. The authors summarized and commented on the key points that relate to the investigation and management of hypo- natremia. In addition, they specifically address available pharmacological interventions and the use of tolvaptan in relation to the European license for management of hyponatremia in SIADH7.
In the last 2 years, a number of recommendations and guidelines relating to hyponatremia have been published6,8–11. Most of the recommendations in relation to diagnosis, investigation and management in the emergency setting and the role of hypertonic saline are convergent. There is variation in relation to the use of interventions after fluid restriction. Where there is a significant divergence, this is acknowledged in the text.
The authors have selected a list of the most important learning points for other clinicians (Box 1). These key learning points are essential for all clinicians treating hyponatremia; they are not meant to be exhaustive and acknowledge that clinicians refer to more experienced colleagues as appropriate.
Clinical significance
DO recognize that hyponatremia is associated with increased mortality and prolonged hospital stay4.
DO NOT ignore ‘asymptomatic’ hyponatremia, which is associated with reduced cognitive function, gait instability and increased fracture risk2.
Diagnosis
DO distinguish between acute (548 hours’ duration) and chronic (448 hours’ duration) hyponatremia6,12. Patients with acute hyponatremia can deteriorate quickly and present a greater risk for seizure, respiratory arrest and death than those with chronic hyponatre- mia. N.B. There may be an acute component in some cases of chronic hyponatremia.
DO check for current or recent use of glucocorticoids: oral, intranasal, cutaneous, and inhaled13,14. These frequently cause adrenocorticotropic hormone suppression, and hence cortisol insufficiency if inter- rupted, which may lead to hyponatremia.
DO NOT attribute hyponatremia to hypothyroidism unless the patient has severe hypothyroidism, myx- edema coma or very high levels of thyroid-stimulating hormone (e.g.450 mU/L).
DO look for alternative causes, as hypothyroidism is rarely a cause of marked hyponatremia.
DO review the patient’s current use of pharmacological agents to identify potential iatrogenic causes of hyponatremia (e.g. thiazide diuretics, selective serotonin-reuptake inhibitors, carbamazepine, and agents interfering with the renin–angiotensin– aldosterone system).
Diagnostic tests
DO check urine and plasma osmolality: criteria for SIADH include Posmo5275 and Uosmo4100 mOsmol/kg. Uosmo5100 mOsmol/kg con- firms the absence of antidiuretic hormone function, and implies primary polydipsia, increased intake of liquids, and/or low solute intake as the cause of hyponatremia.
DO NOT diagnose hyponatremia without checking serum glucose concentration to exclude transloca- tional hyponatremia, and plasma osmolality to exclude pseudohyponatremia6,15.
DO check urinary sodium concentration ([Naþ]) and potassium concentration ([Kþ]): a low urinary [Naþ] almost always indicates volume depletion, hypervole- mia, primary polydipsia or reduced solute intake (salt and protein).
*Synacthen is a trade name of Alliance Pharma, Chippenham, UK
Box 1. Top ten ‘dos and don’ts’ in hyponatremia.
(1) DO NOT ignore ‘asymptomatic’ hyponatremia. (2) DO distinguish between acute (548 hours’ duration) and chronic
(448 hours’ duration) hyponatremia. (3) DO check urine and plasma osmolality. (4) DO determine the sum of the urinary [Naþ] and [Kþ]: where this is
greater than the serum [Naþ], fluid restriction alone is unlikely to be effective (the basis of the Furst formula).
(5) DO ensure that all the appropriate diagnostic laboratory testing is undertaken in a patient suspected of SIADH. However, therapy can be initiated before results are available.
(6) DO correct acute, severe hyponatremia with bolus(es) of hyper- tonic saline or with an infusion of (3%) hypertonic saline to raise [Naþ] by 4–6 mmol/L – and stop.
(7) DO aim for a correction rate goal of 4–8 mmol/L per day in low-risk patients with chronic SIADH (4–6 mmol/L/day in patients at high risk of osmotic demyelination syndrome).
(8) DO NOT allow [Naþ] overcorrection: greater than 8 mmol/L in high-risk patients, or greater than 12 mmol/L in lower-risk patients, in any 24 hour period.
(9) DO consider active re-lowering measures if overcorrection occurs in patients with initial [Naþ]5120 mmol/L, particularly the high- risk: desmopressin 2–4 mg subcutaneously each 8 hoursþ replace water or 5% dextrose at 3 mL/kg/h).
(10) DO consider pharmacological therapy for SIADH where hypona- tremia persists and where fluid restriction is ineffective, imprac- tical or unpalatable (tolvaptan, urea, demeclocycline, or loop diuretics with NaCl).
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DO determine the sum of the urinary [Naþ] and [Kþ]: where this is greater than the serum [Naþ], fluid restric- tion alone is unlikely to be effective (the basis of the Furst formula)16.
DO check serum cortisol level, and consider a tetra- cosactide test (Synacthen*) to exclude glucocorticoid deficiency, in all patients considered to have SIADH regardless of the appearance of adrenals on imaging17.
DO NOT measure the level of arginine vasopressin or copeptin (this is rarely helpful).
DO consider a fluid challenge (1.0–2.0 litre 0.9% NaCl) if the patient’s volume status is unclear (patients with hypovolemic hyponatremia will respond favorably).
DO undertake brain and chest imaging in patients with chronic SIADH to identify central nervous system (CNS) or lung pathology.
DO undertake central nervous system imaging (com- puted tomography or magnetic resonance imaging) in the setting of hyponatremia due to primary polydipsia; abnormally increased water intake can be due to infil- trative or neoplastic causes.
Specific causes: thiazide-induced hyponatremia
DO recognize that overly rapid correction leading to osmotic demyelination syndrome (ODS) can occur simply by stopping thiazides and/or correction of potas- sium depletion18 (potassium replacement causes a serum [Naþ] rise in all states of potassium depletion).
DO monitor serum [Naþ], urine osmolality and urine volume every 6 hours after cessation of thiazide therapy.
Cerebral salt wasting
DO NOT make the diagnosis of cerebral salt wasting (CSW) in the neurosurgical setting unless there is corroborative evidence of a period of fluid and sodium loss before the development of hyponatremia. Most hyponatremic patients have SIADH in this setting.
DO NOT use fluid restriction in patients with subarachnoid hemorrhage (SAH)19,20.
DO correct hyponatremia in SAH if [Naþ] 5131 mmol/L initially by use of sodium supplementa- tion in the form of isotonic saline with or without additional oral salt tablets.
Primary or secondary adrenal failure
DO use parenteral ‘stress’ doses of hydrocortisone (e.g. 50–100 mg intravenously [IV] or intramuscularly every 8 hours) in a patient with known or suspected primary adrenal failure or glucocorticoid deficiency.
With any suspicion of primary or secondary adrenal insufficiency, DO commence glucocorticoid therapy after drawing blood for cortisol measurement.
DO monitor serum [Naþ] and fluid balance carefully where glucocorticoid deficiency is thought to be the cause of hyponatremia. Fluid restriction should be lifted if a pronounced aquaresis occurs and may necessitate desmopressin and/or fluid replacement.
Strategy for correction of SIADH
DO individualize the nature of treatment and rapidity based on:
(1) Treatment of the underlying condition. (2) The presence of neurological symptoms
(indicating likely acute onset). (3) The speed of onset of the hyponatremia.
DO discontinue any drugs known to be associated with SIADH at the initiation of therapy, if possible.
DO ensure that all the appropriate diagnostic labora- tory testing is undertaken in a patient suspected of SIADH (see Diagnostic tests). However, therapy can be initiated before results are available.
Correction of acute hyponatremia
DO recognize that acute, severe hyponatremia is a life- threatening metabolic emergency21.
DO correct acute, severe hyponatremia with bolus(es) of hypertonic saline (3%): 100 mL over 10 minutes administered up to three times, ideally in a high- dependency unit22.
DO treat acute hyponatremia with mild-to-moderate symptoms with 3% NaCl (0.5–2 mL/kg/h) and monitor response every 4–6 hours23. Some authorities recognize the use of 1.8% hypertonic saline at 1 mL/kg/hour as an alternative therapy in acute (and chronic) hyponatremia24.
DO aim to raise [Naþ] by 4–6 mmol/L in 6 hours to treat acute severe hyponatremia, then pause for 12–24 hours. A small shift in serum [Naþ] is sufficient to reduce intracranial pressure25.
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Management of exercise-associated hyponatremia
DO NOT encourage runners to drink fluid at 4400–800 mL/h.
DO consider an IV bolus 100 mL of 3% saline over 10 minutes in an individual with severe neurological symptoms after an endurance event, or a [Naþ] 5125 mmol/L repeated up to twice after 30 minutes if required.
Correction rates for chronic hyponatremia
DO monitor urine output during correction of hypona- tremia as a high urine output may alert the clinician to overly rapid correction of serum [Naþ].
DO monitor the serum [Naþ] regularly (e.g. each 4–6 hours) with any active treatment until [Naþ] stabilizes.
DO NOT allow over-correction of hyponatremia in patients with cortisol deficiency, or patients receiving desmopressin or thiazides without monitoring of [Naþ], urine osmolality and urine output. Life-threatening overcorrection can occur in512 hours.
DO NOT continue fluid restriction in subjects once a prompt aquaresis occurs, i.e. in patients with hypo- natremia due to thiazide use, desmopressin use, or glucocorticoid deficiency.
DO stratify for the risk of ODS: at-risk patients have serum [Naþ]5120 mmol/L for448 hours, and high risk if serum [Naþ] 5105 mmol/L, or with hypokalemia, alcoholism, malnutrition, or advanced cirrhosis6,26–28.
DO aim for a correction rate of 4–8 mmol/L per day in low-risk patients with chronic SIADH (4–6 mmol/L/ day in patients at high risk of ODS).
DO NOT allow [Naþ] overcorrection, i.e. greater than 8 mmol/L in high-risk patients, or greater than 12 mmol/L in low-risk patients, in any 24 hour period.
DO NOT exceed 18 mmol/L correction in any 48 hour period.
Sterns’ Safety Rule of Sixes is an often cited and easily remembered rule emphasizing that symptom improvement can be achieved with a [Naþ] correction of 6 mmol/L (‘six a day makes sense for safety; so six in six hours for severe Sx and stop’)24.
Management of overcorrection
DO recognize that overly rapid rates of correction of hyponatremia can lead to neurological sequelae, currently termed osmotic demyelination syndrome or
‘ODS’ (previously termed pontine or extra-pontine myelinolysis)29,30. ODS can manifest as progressive quadriplegia and ophthalmoplegia, or as extrapyram- idal features such as involuntary movements and ataxia. Have a high index of suspicion for any neuro- logical symptoms that appear or progress during correction6.
DO NOT continue active measures (e.g. saline or tol- vaptan therapy) if the daily target (8–12 mmol/L/day) is exceeded. Omit the next day’s dose of tolvaptan if prescribed31.
DO replace water losses and/or consider administering desmopressin in all patients where overcorrection occurs32.
DO consider active re-lowering measures if overcorrec- tion occurs in patients with initial [Naþ]5120 mmol/L, particularly the high risk: (desmopressin 2–4mg subcutaneously each 8 hoursþ replace water or 5% dextrose at 3 mL/kg/h)32.
DO monitor [Naþ] after each 1 hour dextrose infusion during active re-lowering and stop once target is reached.
Use of fluid restriction in SIADH
DO use fluid restriction as first-line therapy in selected patients with chronic hyponatremia provided such patients do not meet the exclusions below. The typical fluid restriction should be 500 mL/day less than the 24 hour urine output.
DO NOT use fluid restriction: If the urine osmolality is4500 mOsm/kg. If the sum of urine [Naþ] and [Kþ]4serum [Naþ]
(Furst formula)16. If its use leads to the discontinuation or delay of
needed therapy (surgery, artificial nutrition, IV medication, chemotherapy, etc.)33.
DO NOT restrict protein or sodium intake inadvert- ently or deliberately during fluid restriction.
DO NOT continue fluid restriction alone if the initial [Naþ] correction is52 mmol/L in the first 24–48 hours.
DO reconsider the diagnosis of euvolemic hyponatre- mia (possible subclinical hypovolemia) after a few days if an effective fluid restriction fails to lead to correction.
Hypertonic saline in SIADH
DO treat symptomatic chronic hyponatremia with either bolus (100 mL 3% hypertonic saline over 10 min) or infusion of hypertonic saline (3% at
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0.5–1.0 mL/kg/h or 1.8% hypertonic saline at 1–2 mL/kg/h) as for acute hypernatremia (above)22.
DO NOT forget that the actual response of the [Naþ] and the patient’s condition is more important than the initial infusion rate of hypertonic saline.
DO monitor serum [Naþ], e.g. every 4–6 hours or more frequently, during treatment with hypertonic saline.
Pharmacological strategies in SIADH
DO consider pharmacological therapy for SIADH where hyponatremia persists and where fluid restric- tion is ineffective, impractical or unpalatable.
Use of tolvaptan in SIADH
DO consider tolvaptan therapy for patients with hypo- natremia due to SIADH without severe symptoms6, in accordance with its license in the EU7.
DO NOT commence tolvaptan as an outpatient6. DO NOT initiate tolvaptan immediately after use
of hypertonic saline6. DO monitor patients from the time of initiation of
tolvaptan to avoid overly rapid correction31. DO use caution in treating patients with tolvaptan
if their serum [Naþ] is 5120 mmol/L, owing to the higher risk of overly rapid correction31.
DO encourage oral fluid intake when using tolvaptan31.
DO consider interrupting therapy for 1–2 days once [Naþ] reaches 125 mmol/L if the initial [Naþ] was 5120 mmol/L to allow slower equilibration6.
DO consider the likely need for continued tolvaptan therapy in relation to the underlying cause of SIADH6.
DO check liver function tests if there are symptoms suggesting liver toxicity34.
Note: the joint European Society of Endocrinology guideline does not recommend the use of vasopressin receptor antagonists for the management of moderate (or indeed any level of) hyponatremia. In this regard, the guideline represents an outlier in relation to other recommendations35.
Use of urea in SIADH
DO consider use of urea at a dose of 15–60 g/day (dis- solved in orange juice) as a treatment for SIADH. Although urea is not available in an approved formu- lation, it is recommended by some authorities8,36,37.
DO ensure adequate fluid intake, as marked hyperna- tremia can be a complication of treatment37.
Use of demeclocycline in SIADH
DO consider demeclocycline (300–1200 mg/day)38 to manage chronic SIADH in the context of malignancy with careful renal function monitoring (only licensed for this indication in UK and France)35. Irreversible renal failure has been reported as a complication of its use6.
Use of loop diuretics and NaCl
DO recognize the potential for use of a low-dose loop diuretic in conjunction with sodium tablets or saline to treat hyponatremia as recommended by some authorities8,36,37.
Long-term management of hyponatremia
In many patients, specific treatment of hyponatremia due to SIADH is only required short term. In patients with chronic SIADH, tolvaptan at least appears to be safe in longer-term use39. Demeclocycline (600–1200 mg/day) is the only alternative treatment that has been used exten- sively. However, it is only licensed in the UK and France for the chronic treatment of hyponatremia due to SIADH, and requires close monitoring of renal function38. Use of urea long term has been reported but is limited by practical availability and lack of evidence-based data on long-term efficacy and safety35,40.
Decisions in regard to longer-term treatment need to consider a balance between the ongoing cost of therapy and the patient’s benefit, and these issues need to be addressed on an individual basis. Future studies are required to establish whether correction of hyponatremia with tolvaptan and maintenance of a normal serum [Naþ] obviates the increased risk of adverse outcomes associated with hyponatremia.
Transparency Declaration of funding Editorial assistance and publication support for this article was funded by Otsuka Pharmaceutical Europe Ltd. The authors have not received any honorarium from Otsuka Pharmaceutical Europe Ltd in relation to this article. The company has checked the medical accuracy of the article; however, final editorial con- tent resides with the authors.
Current Medical Research & Opinion Volume 31, Number 9 September 2015
! 2015 Taylor & Francis www.cmrojournal.com ‘Dos and don’ts’ of hyponatremia Aylwin et al. 1759
Declaration of financial/other relationships V.B. has disclosed that he has received honoraria and consult- ancy fees from Otsuka, grants from Fresenius Kabi and is on the speaker’s bureau for Otsuka and Astra Zeneca. A.P. has disclosed that he…
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