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The diagnosis and management of inpatient hyponatraemia and SIADH

The diagnosis and management of inpatient hyponatraemia and SIADH DOI: 10.1111/eci.12465 CONSENSUS The diagnosis and management of inpatient hyponatraemia and SIADH * † ‡ ‡ § ¶ ** Paul Grant , John Ayuk , Pierre-Marc Bouloux , Mark Cohen , Iain Cranston , Robert D. Murray , Aled Rees , †† ‡‡ Nicholas Thatcher and Ashley Grossman * † Royal Sussex County Hospital, Brighton, UK, Department of Endocrinology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK, Diabetes and Endocrinology, Royal Free London NHS Foundation Trust, London, UK, Diabetes and Endocrinology, Portsmouth Hospitals NHS Trust, Queen Alexandra Hospital, Hampshire, UK, Department of Diabetes and Endocrinology, Leeds Teaching Hospitals NHS Trust, St James’s University ** Hospital, Leeds, UK, Department of Endocrinology and Diabetes, Cardiff University School of Medicine, Cardiff, UK, †† ‡‡ Department of Medical Oncology, Christie Hospital, NHS Trust Manchester, Manchester, UK, Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK ABSTRACT Background Hyponatraemia is a very common medical condition that is associated with multiple poor clinical outcomes and is often managed suboptimally because of inadequate assessment and investigation. Previously published guidelines for its management are often complex and impractical to follow in a hospital environment, where patients may present to divergent specialists, as well as to generalists. Design A group of senior, experienced UK clinicians, met to develop a practical algorithm for the assessment and management of hyponatraemia in a hospital setting. The latest evidence was discussed and reviewed in the light of current clinical practicalities to ensure an up-to-date perspective. An algorithm was largely developed following consensus opinion, followed up with subsequent additions and amendments that were agreed by all authors during several rounds of review. Results We present a practical algorithm which includes a breakdown of the best methods to evaluate volume status, simple assessments for the diagnosis of the various causes and a straightforward approach to treatment to minimise complexity and maximise patient safety. Conclusion The algorithm we have developed reflects the best available evidence and extensive clinical experience and provides practical, useable guidance to improve patient care. Keywords ADH antagonists, Hyponatraemia, SIADH. Eur J Clin Invest 2015; 45 (8): 888–894 even mild hyponatraemia may have detrimental effects Introduction on patients [2,3]. The symptoms of hyponatraemia are Hyponatraemia is the most commonly seen electrolyte distur- nonspecific in the majority, and hyponatraemia is often bance both in hospital inpatients and in the community [1]. discovered coincidentally. Rapid changes in sodium levels or There are numerous recognised causes of hyponatraemia, and acute profound hyponatraemia can be associated with extremes of volume status – such as dehydration or fluid neurological features and are medical emergencies that overload – are common precipitants. The syndrome of inap- require urgent intervention and close supervision in a propriate antidiuretic hormone secretion (SIADH), the oft- monitored environment. quoted cause of hyponatraemia by medical students, is a The two main problems encountered in routine clinical diagnosis of exclusion that, by definition, is associated with a practice relate to the appropriate assessment and initial normal volume status. investigations required to identify the cause of the hypona- The majority of cases of hyponatraemia are mild, and it is traemia in any given patient, and the therapeutic manoeuvres generally thought of as an asymptomatic condition, although necessary to ameliorate the condition. Several guidelines for 888 ª 2015 The Authors European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. CONSENSUS treating hyponatraemia have been proposed [4,5]; however, develop a practical algorithm for the assessment and they often contain algorithms that are complex and impracti- management of hyponatraemia. The latest evidence was cal for use by nonspecialists. As a group of clinicians from discussed and reviewed in the light of clinical practicalities varied specialties, but with a particular interest in hypona- to ensure an up-to-date perspective. The algorithm was lar- traemia, we have therefore created a simple clinical algorithm gely developed during the meeting following consensus that aims to maximise utility and patient safety, whilst being opinion, followed up with subsequent additions and easy to use. amendments that were agreed by all authors during several rounds of review. Methodology Given the dearth of evidence in many aspects of the man- agement of hyponatraemia, we have based the algorithm A group of senior, experienced UK clinicians, many of whom (Fig. 1) on widely accepted recommendations, expert opinion have published in the field of inpatient hyponatraemia and and published consensus guidelines. SIADH, met under the direction of Professor Grossman to Figure 1 UK algorithm for management of inpatients with hyponatraemia. CNS, central nervous system; CT, computed tomography; GCS, Glasgow Coma Score; IV, intravenous; JVP, jugular venous pressure; K, potassium; LVF, left ventricular fibrillation; Na, sodium; od, once daily; Osm, osmolality; SSRI, selective serotonin reuptake inhibitor. European Journal of Clinical Investigation Vol 45 889 P. GRANT ET AL. www.ejci-online.com ance – certain types of lung cancer are well recognised to pre- Box 1 cipitate SIADH. Such knowledge, along with appropriate initial Management of acute symptomatic hyponatraemia investigations and clinical judgement, may thereby allow one to Acute symptomatic hyponatraemia is a medical emergency, circumvent the full algorithm and proceed rapidly with the and patients should be moved to a Level 2 monitored right therapy. These principles should be considered at all environment. A consultant endocrinologist or nephrologist points of the algorithm. should be consulted as soon as possible. Assessment of volume status Treatment involves the use of hypertonic saline to gradually Diagnosis and management of hyponatraemia depends on correct the hyponatraemia, with the goal of ensuring that assessment of whether the patient is hypovolaemic, hypervo- the sodium level does not rise by more than 6 mmol/L in laemic or euvolaemic. However, this is frequently difficult and the first 6 h or 10 mmol/L in the first 24 h. Rapid overcor- often suboptimal, even when performed by experienced clini- rection leads to a risk of osmotic demyelination syndrome. cians [6]. If the volume status is unclear, an infusion of normal We suggest starting with 150 mL of 3% saline IV over saline (e.g. 1 L over 12 h) as a therapeutic trial will often reveal 15 min. If there is no clinical improvement, repeat the dose the true situation. Hypovolaemic patients will respond well after 20 min. Check serum sodium at 6, 12, 24 and 48 h to (typically serum sodium will rise > 5 mmol/L), whereas ensure that overcorrection (serum sodium rise of 10 mmol/L patients with SIADH will often not improve and may experi- or more in 24 h or less) has not occurred. If the sodium does ence a worsening of hyponatraemia. It is imperative that serum rise excessively, then intravenous dextrose or desmopressin sodium is rechecked 6 h after the infusion is started. (e.g. DDAVP) may be required. The serum sodium does not need to be normalised with hypertonic saline; an increase of Acute severe hyponatraemia 4–6 mmol/L often leads to major clinical improvements. If the patient has significant neurological symptoms (see Fig. 1 ‘acute symptomatic hyponatraemia’ for examples), this is a medical emergency and should be treated immediately, without waiting for the diagnosis of the cause of hyponatra- Making the right diagnosis emia. See Box 1 for the management of acute severe The management of patients with hyponatraemia begins with a hyponatraemia. good clinical history and examination, an understanding of the timeline of the change in serum sodium values and some basic Treatment of hyponatraemia tests to rule out obvious or worrying causes. Rates of correction. The treatment of this condition needs to Baseline investigations take into account the duration of the hyponatraemia and the It is important to consider common causes of hyponatraemia, degree of symptoms relating to it. The acute treatment of such as hyperglycaemia, as well as pseudo-hyponatraemia, symptomatic hypotonic hyponatraemia requires an under- whereby unmeasured factors, such as alcohol or triglycerides, standing of its targets and risks, as well as continuous moni- can produce a spuriously low sodium result. A screening toring of the patient’s clinical status and relevant serum investigation panel must therefore be undertaken as soon as biochemical values. the problem is suspected and should include blood glucose, Patients who have hyponatraemia for more than 48 h are at lipid profile, random (ideally at 09:00) cortisol (unless the risk of neurological sequelae if the correction of serum sodium patient is taking synthetic glucocorticoids), thyroid function occurs too rapidly [7] due to the development of osmotic tests, liver function tests and plasma osmolality. A urine sam- demyelination (central pontine demyelination). A safe limit for ple should be taken to check urinary osmolality, sodium and the treatment of hyponatraemia is a rise of no more than potassium. 10 mmol/L in the first 24 h and 8 mmol/L in the subsequent 24 h (18 mmol/L in 48 h). Consider the context Certain medical disorders are known to place patients at an Known conditions may inform the diagnosis. Taking a good increased risk of complications from rapid correction of serum history will reveal the likelihood, for example, of primary sodium concentration. Individuals most at risk for developing polydipsia or recent medication changes that may have an osmotic demyelination syndrome are elderly patients, children influence on serum sodium levels. Other medical conditions, under 16 years of age, malnourished patients, patients with such as an underlying malignancy and its treatment, may alcoholism, patients with central nervous system disease or provide a clear explanation for the revealed electrolyte imbal- hypoxaemia and patients in the post-operative setting. A 890 ª 2015 The Authors European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation CONSENSUS tighter safety limit for correction of 8 mmol/L in 24 h and jugular venous pressure, left ventricular failure and/or asci- 14 mmol/L in 48 h should be considered in such patients. tes. Management should focus on treating the underlying Large-volume polyuria in this context is an ominous sign. For cause to improve hyponatraemia. In these circumstances, these patients, early identification of risk factors, close moni- loop diuretics will produce a diuresis that exceeds the toring of serum sodium correction and the use of 5% dextrose increased 24-h urine sodium losses they produce and so can with or without desmopressin to prevent or reverse overcor- be used safely. rection are important components of treatment [8]. Diagnosis of euvolaemic patients. If a patient is euvolaemic, Stop any offending medications. Where practical, discon- it is important to confirm that the patient has hypotonic hyp- tinue the use of medications that may be causing or exacer- onatraemia. Check plasma osmolality and urine osmolality. If bating hyponatraemia (Table 1). The most common are thiazide plasma osmolality is > 275 mOsm/kg, consider causes of diuretics, selective serotonin reuptake inhibitors, proton pump hypertonic hyponatraemia, such as hyperglycaemia or inhibitors, angiotensin-converting enzyme inhibitors and loop mannitol infusions. diuretics. If urinary osmolality is < 100 mOsm/kg, consider primary polydipsia or ‘beer drinker’s potomania’ (low-solute diet asso- Treatment of hypovolaemic patients. Hypovolaemic hyp- ciated with reduced capacity to excrete free water). onatraemia is common and is usually caused by sodium loss If plasma osmolality is < 275 mOsm/kg, and urine osmolal- through the gastrointestinal or renal tract. Characteristic ity is > 100 mOsm/kg, check urinary sodium concentration. symptoms are reduced skin turgor, dry mucous membranes, SIADH is the likely diagnosis if urinary sodium is > 20 mmol/L. tachycardia, low blood pressure or postural hypotension. If urinary sodium is < 20 mmol/L, reconsider the volume status Patients should be treated with 09% saline. of the patient, as this usually reflects intravascular volume depletion. Treatment of hypervolaemic patients. Hypervolaemic hyp- onatraemia may be caused by cardiac failure, renal failure or Treatment of patients with SIADH. SIADH is characterised liver cirrhosis. Characteristic symptoms are oedema, raised by the presence of hypotonic hyponatraemia in a context of inadequately diluted urine given the hypo-osmolality in plasma, in the absence of a low effective circulating volume (either with hypovolaemia or hypervolaemia) [5]. In most, if not Table 1 Causes of drug-induced hyponatraemia [23] all, cases, the most common cause of hyponatraemia is the Anticancer agents Vinca alkaloids (vincristine, vinblastine) nonosmotic release of arginine vasopressin (AVP) [9]. Platinum compounds (cisplatin, Exclude the following conditions for definitive diagnosis: carboplatin) renal failure, adrenal insufficiency, severe hypothyroidism, as Alkylating agents (intravenous well as nonosmotic physiological stimuli of AVP secretion (e.g. cyclophosphamide, melphalan and ifosfamide) volume depletion, pain, stress and nausea [10]). Causes of SIADH are multiple and varied and range from medication Antidepressants Tricyclic antidepressants side effects to underlying malignancy. If there is no clear cause Selective serotonin reuptake inhibitors following initial investigations, or if there is a repeat admission Monoamine oxidase inhibitors with hyponatraemia, consider systematic radiological investi- Anti-epileptic drugs Carbamazepine gations, such as computed tomography of the chest/abdomen/ Oxcarbazepine pelvis and magnetic resonance imaging of the head. Sodium valproate Fluid restriction is the mainstay of treatment for SIADH; Antihypertensive agents Angiotensin-converting enzyme however, the degree of restriction necessary will vary, inhibitors depending on the patient’s ability to excrete electrolyte-free Amlodipine water. Antipsychotic drugs Phenothiazines Once SIADH has been definitively diagnosed, use the Furst Butyrophenones formula (Box 2) to estimate electrolyte-free water clearance through the urine/plasma electrolyte ratio (U/P). If U/P is 05– Diuretics Thiazides Indapamide 10, then commence fluid restriction of 500 mL/day. If U/P is Amiloride < 05, then commence fluid restriction of 1000 mL/day. If Loop diuretics U/P > 10, then there is no excretion of electrolyte-free water and fluid restriction is unlikely to be beneficial. Proton pump inhibitors Omeprazole European Journal of Clinical Investigation Vol 45 891 P. GRANT ET AL. www.ejci-online.com Box 2 The Furst formula Dilute urine may be considered to have an isotonic portion and an electrolyte-free water portion. The proportions of electrolyte- free water and isotonic urine can be measured by the ratio of effective solutes (principally sodium and potassium, with associated anions) between the plasma and the urine [21]. Restriction of water intake to less than the amount of electrolyte-free water excreted will cause plasma tonicity, and hence serum sodium, to rise. The amount of electrolyte-free water that can be cleared from the kidneys will therefore affect the patient’s response to fluid restriction. A clinically useful equation simplified by Furst et al. for estimating free-water clearance is the urine/ plasma electrolyte ratio measured in a urine sample [22]: Urine sodium concentration (mmol/L) + urine potassium concentration (mmol/L) U/P electrolyte ratio ¼ Serum sodium concentration (mmol/L) The principle of fluid restriction for the management of benefits in patients’ quality of life, as measured by 12-item SIADH should be clearly understood and followed. The degree Short Form General Health Survey scores [11]. The prompt of fluid restriction can be difficult to calculate, initiate and correction of hyponatraemia in patients with SIADH may be maintain for patients in hospital and is also an added burden to associated with a reduction in hospital stay [12]. the patients themselves as well as the nursing staff. When the Before initiating tolvaptan, it is essential to remove any fluid urine to plasma electrolyte ratio is > 10, almost no amount of restriction and ensure that patients can drink in response to water restriction will result in a rise in serum sodium because thirst, as correction of hyponatraemia can occur too rapidly if free water is being retained, a process that will promote hyp- they are combined. Tolvaptan should be initiated at a dose of onatraemia. 15 mg, orally, once daily, and serum sodium should be moni- tored 6 h after starting treatment to exclude overly rapid correction [13]. Clinical experience is limited and its use should Undertaking effective fluid restriction. Important features in be restricted to consultant endocrinologists, oncologists, neph- the practice of fluid restriction include the use of fluid balance rologists or other appropriate specialists with significant expe- sheets, bedside notices and removal of excess bedside fluids. rience of using this medication. We suggest that it should be Paramedical staff, such as volunteers with tea rounds, must be prescribed as single doses and not as a repeated prescription: in made aware of the importance of the practice. Daily assessment many cases, just two or possibly three doses are required. of urea and electrolytes and clinical review must be made on all patients who are fluid restricted. Treatment with demeclocycline. In the United Kingdom, demeclocycline is licensed to treat hyponatraemia associated Specialist review. Patients in whom fluid restriction is not with SIADH secondary to malignant disease, where fluid advised, or patients who have a poor response to fluid restriction restriction is ineffective, and the patient does not have liver after 24–48 h, should be reviewed by a consultant with experi- cirrhosis [13]. Demeclocycline should be started at a dose of ence of treating hyponatraemia – such as a consultant endocri- 150 mg three times daily, assessed after 3 days and increased if nologist – who may consider use of pharmacological treatments, necessary. However, the patient’s response to demeclocycline such as tolvaptan or demeclocycline. However, the latter treat- can be unpredictable, and it has a slow onset of action [5]. The ment may cause problems with subsequent chemotherapy, for evidence base is sparse, and the frequency of its known hepa- example candidiasis or impairment of renal function. totoxic and nephrotoxic side effects [14–17] is unclear. Treatment with tolvaptan. By binding to and blocking the V2 Considerations regarding hyponatraemia and receptor, vaptan drugs can be used to correct hyponatraemia in SIADH management SIADH. This is an attractive therapeutic avenue because it tackles the cause of the underlying fluid retention [11]. There remains controversy in the literature regarding the The SALT-1 and SALT-2 trials have shown that serum importance of prompt intervention in the setting of hypona- sodium can be safely improved in patients with hyponatraemia traemia and its implications for morbidity and inpatient hos- through removal of excess free water, producing additional pital length of stay. Critics suggest that there is a lack of 892 ª 2015 The Authors European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation CONSENSUS evidence regarding the link between hyponatraemia and Acknowledgements worsening patient outcomes, and indeed the majority of the The authors were members of the recent UK hyponatraemia work that has been carried out in this regard has been through management consensus guideline committee, which was retrospective studies rather than looking at prospective work convened by Otsuka Pharmaceuticals UK Ltd., the with interventions to correct hyponatraemia [18]. Hyponatra- manufacturers of tolvaptan. Venue and attendee travel costs emia is certainly associated with a number of disease states and relating to this meeting were supported by Otsuka Pharma- may be a poor prognostic marker, but is not a discrete disease ceuticals UK Ltd., and Professor Grossman and Dr Cranston state in itself. It is usually a consequence of an inability of the were paid speaker fees to present data at the meeting. kidneys to excrete a free water load, but given the complex The authors have not received any honoraria in relation to aetiology of many medical conditions and their comorbidities, this manuscript. Paul Grant has no competing interests; it can be difficult to ascertain to what degree the hyponatraemia Ashley Grossman received lecture fees and support to attend is independently contributing to morbidity and mortality. educational meetings from Otsuka Pharmaceuticals UK Ltd.; Whether hyponatraemia in a patient with cancer is merely a John Ayuk received lecture fees from Otsuka Pharmaceuticals marker of poor prognosis or whether its presence may alter the UK Ltd., outside the submitted work; Pierre-Marc Bouloux patient’s quality of life has not been definitively answered, but received personal fees from Otsuka Pharmaceuticals UK Ltd., there is increasing evidence that hyponatraemia can no longer outside the submitted work; Mark Cohen received nonfi- be considered just a biochemical ‘bystander’ in the ill patient nancial support from Otsuka Pharmaceuticals UK Ltd., dur- [19]. A systematic diagnostic approach is necessary to deter- ing the conduct of the study; grants received from Otsuka mine the specific aetiology of a patient’s hyponatraemia. Pharmaceuticals UK Ltd and personal fees from Otsuka Therapy must then be dictated not only by recognised revers- Pharmaceuticals UK Ltd., outside the submitted work; Iain ible causes, such as advanced hypothyroidism, adrenal insuf- Cranston received a speaker honorarium from Otsuka Phar- ficiency, diuretics or other medicines, but also by whether the maceuticals UK Ltd., for presenting at BES The Annual hyponatraemia occurs acutely or chronically and the degree of Society for Endocrinology Conference in 2014; Robert D symptoms related to it [5]. Murray received lecture fees and support to attend educa- Critically, most evidence suggests that overenthusiastic tional meetings from Otsuka Pharmaceuticals UK Ltd.; Aled treatment of SIADH is considerably more dangerous than Rees received nonfinancial support from Otsuka Pharmaceu- treatment that is slow or relatively ineffective. It is vital that all ticals UK Ltd., during the conduct of the study; Nicholas doctors should be aware of the need for a slow pace of nor- Thatcher received personal fees from Otsuka Pharmaceuticals malisation of serum sodium except in the most extreme UK Ltd., during the conduct of the study and outside the circumstances: primum non nocere. submitted work. Editorial assistance in the preparation of this article was Summary provided by apothecom and funded by Otsuka Pharmaceuti- cals UK Ltd. Hyponatraemia is under-recognised, incorrectly investigated and suboptimally managed, leading to poor patient out- Author contributions comes. There is a well-recognised association with inpatient All authors contributed equally to the development and design morbidity and mortality. Frequently, insufficient diagnostic of the algorithm. Dr Grant and Professor Grossman were lead assessment and investigations take place, and this can affect authors in drafting the submitted manuscript, to which all both patient management and outcomes [20]. Failure to treat authors contributed. hyponatraemia correctly may impede both patient outcomes and other factors, such as hospital length of stay. With Address regard to medical treatments, AVP antagonists offer a novel Department of Diabetes, Royal Sussex County Hospital, East- therapeutic approach. Currently, clinical experience is limited ern Road, Brighton BN2 5BE, UK (P. Grant); Department of with these agents and randomised controlled trials to Endocrinology, University Hospitals Birmingham NHS Foun- compare vaptans with the current standard of care are dation Trust, Queen Elizabeth Hospital, Queen Elizabeth needed to demonstrate a clear benefit to patients with Medical Centre, Edgbaston, Birmingham B15 2TH, UK (J. SIADH-related hyponatraemia to add to the evidence already Ayuk); Diabetes and Endocrinology, Royal Free London NHS available. We feel that the algorithm we have developed Foundation Trust, Pond Street, London NW3 2QG, UK (P.-M. (Fig. 1) reflects the best available evidence and extensive Bouloux, M. Cohen); Diabetes and Endocrinology, Portsmouth clinical experience and provides practical, useable guidance Hospitals NHS Trust, Level C, Queen Alexandra Hospital, to improve patient care. European Journal of Clinical Investigation Vol 45 893 P. GRANT ET AL. www.ejci-online.com 7 Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med Portsmouth PO6 3LY, Hampshire, UK (I. Cranston); Depart- 2000;342:1581–9. ment of Diabetes and Endocrinology, Leeds Teaching Hospitals 8 Gharaibeh KA, Brewer JM, Agarwal M, Ful € op € T. Risk factors, NHS Trust, St James’s University Hospital, Beckett Street, complication and measures to prevent or reverse catastrophic Leeds, West Yorkshire LS9 7TF, UK (R. D. Murray); Depart- sodium overcorrection in chronic hyponatremia. Am J Med Sci ment of Endocrinology and Diabetes, Cardiff University School 2014;349:170–5. 9 Fenske W, Maier SK, Blechschmidt A, Allolio B, Stork € S. Utility and of Medicine, Sir Geraint Evans Building, Heath Park, Cardiff limitations of the traditional diagnostic approach to hyponatremia: a CF14 4XN, UK (A. Rees); Department of Medical Oncology, diagnostic study. Am J Med 2010;123:652–7. Christie Hospital, NHS Trust, Wilmslow Road, Manchester 10 Hoorn EJ, Zieste R. Hyponatremia revisited: translating physiology M20 4BX, UK (N. Thatcher); Department of Endocrinology, to practice. Nephron Physiol 2008;108:46–59. Oxford Centre for Diabetes, Endocrinology and Metabolism, 11 Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS et al. Tolvaptan, a selective oral vasopressin V2-receptor Radcliffe Department of Medicine, University of Oxford, antagonist, for hyponatremia. N Engl J Med 2006;355:2099–112. Churchill Hospital, Headington, Oxford OX3 7LE, UK (A. 12 Grant P. New drugs for hyponatraemia. Cost effectiveness of Grossman). tolvaptan. BMJ 2011;342:d1947. 13 British National Formulary (BNF 68). Joint Formulary Committee. Correspondence to: Professor Ashley Grossman, FMedSci, London: BMJ Publishing Group Ltd and Royal Pharmaceutical Radcliffe Department of Medicine, Oxford Centre for Diabetes, Society; 2014. 14 De Troyer A. Demeclocycline. Treatment for syndrome of Endocrinology and Metabolism, University of Oxford, Chur- inappropriate antidiuretic hormone secretion. JAMA 1977;237: chill Hospital, Headington, Oxford OX3 7LE, UK. Tel.: +44 1865 2723–6. 857308; fax: +44 1865 857311; e-mail: ashley.grossman@ocdem. 15 Forrest JN Jr, Cox M, Hong C, Morrison G, Bia M, Singer I. ox.ac.uk Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 1978;298:173–7. Received 16 March 2015; accepted 16 May 2015 16 Perks WH, Walters EH, Tams IP, Prowse K. Demeclocycline in the treatment of the syndrome of inappropriate secretion of antidiuretic References hormone. Thorax 1979;34:324–7. 1 Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate 17 Trump DL. Serious hyponatremia in patients with cancer: antidiuresis. N Engl J Med 2007;356:2064–72. management with demeclocycline. Cancer 1981;47:2908–12. 2 Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. 18 Hoorn EJ, Lindemans J, Zietse R. 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Am J Kidney Dis 2008;52:144–53. 1987;83:905–8. 894 ª 2015 The Authors European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Clinical Investigation Pubmed Central

The diagnosis and management of inpatient hyponatraemia and SIADH

European Journal of Clinical Investigation , Volume 45 (8) – Jun 28, 2015

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Abstract

DOI: 10.1111/eci.12465 CONSENSUS The diagnosis and management of inpatient hyponatraemia and SIADH * † ‡ ‡ § ¶ ** Paul Grant , John Ayuk , Pierre-Marc Bouloux , Mark Cohen , Iain Cranston , Robert D. Murray , Aled Rees , †† ‡‡ Nicholas Thatcher and Ashley Grossman * † Royal Sussex County Hospital, Brighton, UK, Department of Endocrinology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK, Diabetes and Endocrinology, Royal Free London NHS Foundation Trust, London, UK, Diabetes and Endocrinology, Portsmouth Hospitals NHS Trust, Queen Alexandra Hospital, Hampshire, UK, Department of Diabetes and Endocrinology, Leeds Teaching Hospitals NHS Trust, St James’s University ** Hospital, Leeds, UK, Department of Endocrinology and Diabetes, Cardiff University School of Medicine, Cardiff, UK, †† ‡‡ Department of Medical Oncology, Christie Hospital, NHS Trust Manchester, Manchester, UK, Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK ABSTRACT Background Hyponatraemia is a very common medical condition that is associated with multiple poor clinical outcomes and is often managed suboptimally because of inadequate assessment and investigation. Previously published guidelines for its management are often complex and impractical to follow in a hospital environment, where patients may present to divergent specialists, as well as to generalists. Design A group of senior, experienced UK clinicians, met to develop a practical algorithm for the assessment and management of hyponatraemia in a hospital setting. The latest evidence was discussed and reviewed in the light of current clinical practicalities to ensure an up-to-date perspective. An algorithm was largely developed following consensus opinion, followed up with subsequent additions and amendments that were agreed by all authors during several rounds of review. Results We present a practical algorithm which includes a breakdown of the best methods to evaluate volume status, simple assessments for the diagnosis of the various causes and a straightforward approach to treatment to minimise complexity and maximise patient safety. Conclusion The algorithm we have developed reflects the best available evidence and extensive clinical experience and provides practical, useable guidance to improve patient care. Keywords ADH antagonists, Hyponatraemia, SIADH. Eur J Clin Invest 2015; 45 (8): 888–894 even mild hyponatraemia may have detrimental effects Introduction on patients [2,3]. The symptoms of hyponatraemia are Hyponatraemia is the most commonly seen electrolyte distur- nonspecific in the majority, and hyponatraemia is often bance both in hospital inpatients and in the community [1]. discovered coincidentally. Rapid changes in sodium levels or There are numerous recognised causes of hyponatraemia, and acute profound hyponatraemia can be associated with extremes of volume status – such as dehydration or fluid neurological features and are medical emergencies that overload – are common precipitants. The syndrome of inap- require urgent intervention and close supervision in a propriate antidiuretic hormone secretion (SIADH), the oft- monitored environment. quoted cause of hyponatraemia by medical students, is a The two main problems encountered in routine clinical diagnosis of exclusion that, by definition, is associated with a practice relate to the appropriate assessment and initial normal volume status. investigations required to identify the cause of the hypona- The majority of cases of hyponatraemia are mild, and it is traemia in any given patient, and the therapeutic manoeuvres generally thought of as an asymptomatic condition, although necessary to ameliorate the condition. Several guidelines for 888 ª 2015 The Authors European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. CONSENSUS treating hyponatraemia have been proposed [4,5]; however, develop a practical algorithm for the assessment and they often contain algorithms that are complex and impracti- management of hyponatraemia. The latest evidence was cal for use by nonspecialists. As a group of clinicians from discussed and reviewed in the light of clinical practicalities varied specialties, but with a particular interest in hypona- to ensure an up-to-date perspective. The algorithm was lar- traemia, we have therefore created a simple clinical algorithm gely developed during the meeting following consensus that aims to maximise utility and patient safety, whilst being opinion, followed up with subsequent additions and easy to use. amendments that were agreed by all authors during several rounds of review. Methodology Given the dearth of evidence in many aspects of the man- agement of hyponatraemia, we have based the algorithm A group of senior, experienced UK clinicians, many of whom (Fig. 1) on widely accepted recommendations, expert opinion have published in the field of inpatient hyponatraemia and and published consensus guidelines. SIADH, met under the direction of Professor Grossman to Figure 1 UK algorithm for management of inpatients with hyponatraemia. CNS, central nervous system; CT, computed tomography; GCS, Glasgow Coma Score; IV, intravenous; JVP, jugular venous pressure; K, potassium; LVF, left ventricular fibrillation; Na, sodium; od, once daily; Osm, osmolality; SSRI, selective serotonin reuptake inhibitor. European Journal of Clinical Investigation Vol 45 889 P. GRANT ET AL. www.ejci-online.com ance – certain types of lung cancer are well recognised to pre- Box 1 cipitate SIADH. Such knowledge, along with appropriate initial Management of acute symptomatic hyponatraemia investigations and clinical judgement, may thereby allow one to Acute symptomatic hyponatraemia is a medical emergency, circumvent the full algorithm and proceed rapidly with the and patients should be moved to a Level 2 monitored right therapy. These principles should be considered at all environment. A consultant endocrinologist or nephrologist points of the algorithm. should be consulted as soon as possible. Assessment of volume status Treatment involves the use of hypertonic saline to gradually Diagnosis and management of hyponatraemia depends on correct the hyponatraemia, with the goal of ensuring that assessment of whether the patient is hypovolaemic, hypervo- the sodium level does not rise by more than 6 mmol/L in laemic or euvolaemic. However, this is frequently difficult and the first 6 h or 10 mmol/L in the first 24 h. Rapid overcor- often suboptimal, even when performed by experienced clini- rection leads to a risk of osmotic demyelination syndrome. cians [6]. If the volume status is unclear, an infusion of normal We suggest starting with 150 mL of 3% saline IV over saline (e.g. 1 L over 12 h) as a therapeutic trial will often reveal 15 min. If there is no clinical improvement, repeat the dose the true situation. Hypovolaemic patients will respond well after 20 min. Check serum sodium at 6, 12, 24 and 48 h to (typically serum sodium will rise > 5 mmol/L), whereas ensure that overcorrection (serum sodium rise of 10 mmol/L patients with SIADH will often not improve and may experi- or more in 24 h or less) has not occurred. If the sodium does ence a worsening of hyponatraemia. It is imperative that serum rise excessively, then intravenous dextrose or desmopressin sodium is rechecked 6 h after the infusion is started. (e.g. DDAVP) may be required. The serum sodium does not need to be normalised with hypertonic saline; an increase of Acute severe hyponatraemia 4–6 mmol/L often leads to major clinical improvements. If the patient has significant neurological symptoms (see Fig. 1 ‘acute symptomatic hyponatraemia’ for examples), this is a medical emergency and should be treated immediately, without waiting for the diagnosis of the cause of hyponatra- Making the right diagnosis emia. See Box 1 for the management of acute severe The management of patients with hyponatraemia begins with a hyponatraemia. good clinical history and examination, an understanding of the timeline of the change in serum sodium values and some basic Treatment of hyponatraemia tests to rule out obvious or worrying causes. Rates of correction. The treatment of this condition needs to Baseline investigations take into account the duration of the hyponatraemia and the It is important to consider common causes of hyponatraemia, degree of symptoms relating to it. The acute treatment of such as hyperglycaemia, as well as pseudo-hyponatraemia, symptomatic hypotonic hyponatraemia requires an under- whereby unmeasured factors, such as alcohol or triglycerides, standing of its targets and risks, as well as continuous moni- can produce a spuriously low sodium result. A screening toring of the patient’s clinical status and relevant serum investigation panel must therefore be undertaken as soon as biochemical values. the problem is suspected and should include blood glucose, Patients who have hyponatraemia for more than 48 h are at lipid profile, random (ideally at 09:00) cortisol (unless the risk of neurological sequelae if the correction of serum sodium patient is taking synthetic glucocorticoids), thyroid function occurs too rapidly [7] due to the development of osmotic tests, liver function tests and plasma osmolality. A urine sam- demyelination (central pontine demyelination). A safe limit for ple should be taken to check urinary osmolality, sodium and the treatment of hyponatraemia is a rise of no more than potassium. 10 mmol/L in the first 24 h and 8 mmol/L in the subsequent 24 h (18 mmol/L in 48 h). Consider the context Certain medical disorders are known to place patients at an Known conditions may inform the diagnosis. Taking a good increased risk of complications from rapid correction of serum history will reveal the likelihood, for example, of primary sodium concentration. Individuals most at risk for developing polydipsia or recent medication changes that may have an osmotic demyelination syndrome are elderly patients, children influence on serum sodium levels. Other medical conditions, under 16 years of age, malnourished patients, patients with such as an underlying malignancy and its treatment, may alcoholism, patients with central nervous system disease or provide a clear explanation for the revealed electrolyte imbal- hypoxaemia and patients in the post-operative setting. A 890 ª 2015 The Authors European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation CONSENSUS tighter safety limit for correction of 8 mmol/L in 24 h and jugular venous pressure, left ventricular failure and/or asci- 14 mmol/L in 48 h should be considered in such patients. tes. Management should focus on treating the underlying Large-volume polyuria in this context is an ominous sign. For cause to improve hyponatraemia. In these circumstances, these patients, early identification of risk factors, close moni- loop diuretics will produce a diuresis that exceeds the toring of serum sodium correction and the use of 5% dextrose increased 24-h urine sodium losses they produce and so can with or without desmopressin to prevent or reverse overcor- be used safely. rection are important components of treatment [8]. Diagnosis of euvolaemic patients. If a patient is euvolaemic, Stop any offending medications. Where practical, discon- it is important to confirm that the patient has hypotonic hyp- tinue the use of medications that may be causing or exacer- onatraemia. Check plasma osmolality and urine osmolality. If bating hyponatraemia (Table 1). The most common are thiazide plasma osmolality is > 275 mOsm/kg, consider causes of diuretics, selective serotonin reuptake inhibitors, proton pump hypertonic hyponatraemia, such as hyperglycaemia or inhibitors, angiotensin-converting enzyme inhibitors and loop mannitol infusions. diuretics. If urinary osmolality is < 100 mOsm/kg, consider primary polydipsia or ‘beer drinker’s potomania’ (low-solute diet asso- Treatment of hypovolaemic patients. Hypovolaemic hyp- ciated with reduced capacity to excrete free water). onatraemia is common and is usually caused by sodium loss If plasma osmolality is < 275 mOsm/kg, and urine osmolal- through the gastrointestinal or renal tract. Characteristic ity is > 100 mOsm/kg, check urinary sodium concentration. symptoms are reduced skin turgor, dry mucous membranes, SIADH is the likely diagnosis if urinary sodium is > 20 mmol/L. tachycardia, low blood pressure or postural hypotension. If urinary sodium is < 20 mmol/L, reconsider the volume status Patients should be treated with 09% saline. of the patient, as this usually reflects intravascular volume depletion. Treatment of hypervolaemic patients. Hypervolaemic hyp- onatraemia may be caused by cardiac failure, renal failure or Treatment of patients with SIADH. SIADH is characterised liver cirrhosis. Characteristic symptoms are oedema, raised by the presence of hypotonic hyponatraemia in a context of inadequately diluted urine given the hypo-osmolality in plasma, in the absence of a low effective circulating volume (either with hypovolaemia or hypervolaemia) [5]. In most, if not Table 1 Causes of drug-induced hyponatraemia [23] all, cases, the most common cause of hyponatraemia is the Anticancer agents Vinca alkaloids (vincristine, vinblastine) nonosmotic release of arginine vasopressin (AVP) [9]. Platinum compounds (cisplatin, Exclude the following conditions for definitive diagnosis: carboplatin) renal failure, adrenal insufficiency, severe hypothyroidism, as Alkylating agents (intravenous well as nonosmotic physiological stimuli of AVP secretion (e.g. cyclophosphamide, melphalan and ifosfamide) volume depletion, pain, stress and nausea [10]). Causes of SIADH are multiple and varied and range from medication Antidepressants Tricyclic antidepressants side effects to underlying malignancy. If there is no clear cause Selective serotonin reuptake inhibitors following initial investigations, or if there is a repeat admission Monoamine oxidase inhibitors with hyponatraemia, consider systematic radiological investi- Anti-epileptic drugs Carbamazepine gations, such as computed tomography of the chest/abdomen/ Oxcarbazepine pelvis and magnetic resonance imaging of the head. Sodium valproate Fluid restriction is the mainstay of treatment for SIADH; Antihypertensive agents Angiotensin-converting enzyme however, the degree of restriction necessary will vary, inhibitors depending on the patient’s ability to excrete electrolyte-free Amlodipine water. Antipsychotic drugs Phenothiazines Once SIADH has been definitively diagnosed, use the Furst Butyrophenones formula (Box 2) to estimate electrolyte-free water clearance through the urine/plasma electrolyte ratio (U/P). If U/P is 05– Diuretics Thiazides Indapamide 10, then commence fluid restriction of 500 mL/day. If U/P is Amiloride < 05, then commence fluid restriction of 1000 mL/day. If Loop diuretics U/P > 10, then there is no excretion of electrolyte-free water and fluid restriction is unlikely to be beneficial. Proton pump inhibitors Omeprazole European Journal of Clinical Investigation Vol 45 891 P. GRANT ET AL. www.ejci-online.com Box 2 The Furst formula Dilute urine may be considered to have an isotonic portion and an electrolyte-free water portion. The proportions of electrolyte- free water and isotonic urine can be measured by the ratio of effective solutes (principally sodium and potassium, with associated anions) between the plasma and the urine [21]. Restriction of water intake to less than the amount of electrolyte-free water excreted will cause plasma tonicity, and hence serum sodium, to rise. The amount of electrolyte-free water that can be cleared from the kidneys will therefore affect the patient’s response to fluid restriction. A clinically useful equation simplified by Furst et al. for estimating free-water clearance is the urine/ plasma electrolyte ratio measured in a urine sample [22]: Urine sodium concentration (mmol/L) + urine potassium concentration (mmol/L) U/P electrolyte ratio ¼ Serum sodium concentration (mmol/L) The principle of fluid restriction for the management of benefits in patients’ quality of life, as measured by 12-item SIADH should be clearly understood and followed. The degree Short Form General Health Survey scores [11]. The prompt of fluid restriction can be difficult to calculate, initiate and correction of hyponatraemia in patients with SIADH may be maintain for patients in hospital and is also an added burden to associated with a reduction in hospital stay [12]. the patients themselves as well as the nursing staff. When the Before initiating tolvaptan, it is essential to remove any fluid urine to plasma electrolyte ratio is > 10, almost no amount of restriction and ensure that patients can drink in response to water restriction will result in a rise in serum sodium because thirst, as correction of hyponatraemia can occur too rapidly if free water is being retained, a process that will promote hyp- they are combined. Tolvaptan should be initiated at a dose of onatraemia. 15 mg, orally, once daily, and serum sodium should be moni- tored 6 h after starting treatment to exclude overly rapid correction [13]. Clinical experience is limited and its use should Undertaking effective fluid restriction. Important features in be restricted to consultant endocrinologists, oncologists, neph- the practice of fluid restriction include the use of fluid balance rologists or other appropriate specialists with significant expe- sheets, bedside notices and removal of excess bedside fluids. rience of using this medication. We suggest that it should be Paramedical staff, such as volunteers with tea rounds, must be prescribed as single doses and not as a repeated prescription: in made aware of the importance of the practice. Daily assessment many cases, just two or possibly three doses are required. of urea and electrolytes and clinical review must be made on all patients who are fluid restricted. Treatment with demeclocycline. In the United Kingdom, demeclocycline is licensed to treat hyponatraemia associated Specialist review. Patients in whom fluid restriction is not with SIADH secondary to malignant disease, where fluid advised, or patients who have a poor response to fluid restriction restriction is ineffective, and the patient does not have liver after 24–48 h, should be reviewed by a consultant with experi- cirrhosis [13]. Demeclocycline should be started at a dose of ence of treating hyponatraemia – such as a consultant endocri- 150 mg three times daily, assessed after 3 days and increased if nologist – who may consider use of pharmacological treatments, necessary. However, the patient’s response to demeclocycline such as tolvaptan or demeclocycline. However, the latter treat- can be unpredictable, and it has a slow onset of action [5]. The ment may cause problems with subsequent chemotherapy, for evidence base is sparse, and the frequency of its known hepa- example candidiasis or impairment of renal function. totoxic and nephrotoxic side effects [14–17] is unclear. Treatment with tolvaptan. By binding to and blocking the V2 Considerations regarding hyponatraemia and receptor, vaptan drugs can be used to correct hyponatraemia in SIADH management SIADH. This is an attractive therapeutic avenue because it tackles the cause of the underlying fluid retention [11]. There remains controversy in the literature regarding the The SALT-1 and SALT-2 trials have shown that serum importance of prompt intervention in the setting of hypona- sodium can be safely improved in patients with hyponatraemia traemia and its implications for morbidity and inpatient hos- through removal of excess free water, producing additional pital length of stay. Critics suggest that there is a lack of 892 ª 2015 The Authors European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation CONSENSUS evidence regarding the link between hyponatraemia and Acknowledgements worsening patient outcomes, and indeed the majority of the The authors were members of the recent UK hyponatraemia work that has been carried out in this regard has been through management consensus guideline committee, which was retrospective studies rather than looking at prospective work convened by Otsuka Pharmaceuticals UK Ltd., the with interventions to correct hyponatraemia [18]. Hyponatra- manufacturers of tolvaptan. Venue and attendee travel costs emia is certainly associated with a number of disease states and relating to this meeting were supported by Otsuka Pharma- may be a poor prognostic marker, but is not a discrete disease ceuticals UK Ltd., and Professor Grossman and Dr Cranston state in itself. It is usually a consequence of an inability of the were paid speaker fees to present data at the meeting. kidneys to excrete a free water load, but given the complex The authors have not received any honoraria in relation to aetiology of many medical conditions and their comorbidities, this manuscript. Paul Grant has no competing interests; it can be difficult to ascertain to what degree the hyponatraemia Ashley Grossman received lecture fees and support to attend is independently contributing to morbidity and mortality. educational meetings from Otsuka Pharmaceuticals UK Ltd.; Whether hyponatraemia in a patient with cancer is merely a John Ayuk received lecture fees from Otsuka Pharmaceuticals marker of poor prognosis or whether its presence may alter the UK Ltd., outside the submitted work; Pierre-Marc Bouloux patient’s quality of life has not been definitively answered, but received personal fees from Otsuka Pharmaceuticals UK Ltd., there is increasing evidence that hyponatraemia can no longer outside the submitted work; Mark Cohen received nonfi- be considered just a biochemical ‘bystander’ in the ill patient nancial support from Otsuka Pharmaceuticals UK Ltd., dur- [19]. A systematic diagnostic approach is necessary to deter- ing the conduct of the study; grants received from Otsuka mine the specific aetiology of a patient’s hyponatraemia. Pharmaceuticals UK Ltd and personal fees from Otsuka Therapy must then be dictated not only by recognised revers- Pharmaceuticals UK Ltd., outside the submitted work; Iain ible causes, such as advanced hypothyroidism, adrenal insuf- Cranston received a speaker honorarium from Otsuka Phar- ficiency, diuretics or other medicines, but also by whether the maceuticals UK Ltd., for presenting at BES The Annual hyponatraemia occurs acutely or chronically and the degree of Society for Endocrinology Conference in 2014; Robert D symptoms related to it [5]. Murray received lecture fees and support to attend educa- Critically, most evidence suggests that overenthusiastic tional meetings from Otsuka Pharmaceuticals UK Ltd.; Aled treatment of SIADH is considerably more dangerous than Rees received nonfinancial support from Otsuka Pharmaceu- treatment that is slow or relatively ineffective. It is vital that all ticals UK Ltd., during the conduct of the study; Nicholas doctors should be aware of the need for a slow pace of nor- Thatcher received personal fees from Otsuka Pharmaceuticals malisation of serum sodium except in the most extreme UK Ltd., during the conduct of the study and outside the circumstances: primum non nocere. submitted work. Editorial assistance in the preparation of this article was Summary provided by apothecom and funded by Otsuka Pharmaceuti- cals UK Ltd. Hyponatraemia is under-recognised, incorrectly investigated and suboptimally managed, leading to poor patient out- Author contributions comes. There is a well-recognised association with inpatient All authors contributed equally to the development and design morbidity and mortality. Frequently, insufficient diagnostic of the algorithm. Dr Grant and Professor Grossman were lead assessment and investigations take place, and this can affect authors in drafting the submitted manuscript, to which all both patient management and outcomes [20]. Failure to treat authors contributed. hyponatraemia correctly may impede both patient outcomes and other factors, such as hospital length of stay. With Address regard to medical treatments, AVP antagonists offer a novel Department of Diabetes, Royal Sussex County Hospital, East- therapeutic approach. Currently, clinical experience is limited ern Road, Brighton BN2 5BE, UK (P. Grant); Department of with these agents and randomised controlled trials to Endocrinology, University Hospitals Birmingham NHS Foun- compare vaptans with the current standard of care are dation Trust, Queen Elizabeth Hospital, Queen Elizabeth needed to demonstrate a clear benefit to patients with Medical Centre, Edgbaston, Birmingham B15 2TH, UK (J. SIADH-related hyponatraemia to add to the evidence already Ayuk); Diabetes and Endocrinology, Royal Free London NHS available. We feel that the algorithm we have developed Foundation Trust, Pond Street, London NW3 2QG, UK (P.-M. (Fig. 1) reflects the best available evidence and extensive Bouloux, M. Cohen); Diabetes and Endocrinology, Portsmouth clinical experience and provides practical, useable guidance Hospitals NHS Trust, Level C, Queen Alexandra Hospital, to improve patient care. European Journal of Clinical Investigation Vol 45 893 P. GRANT ET AL. www.ejci-online.com 7 Adrogue HJ, Madias NE. Hyponatremia. 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