Best Practice & Research Clinical Endocrinology & Metabolism 26 Suppl. 1 (2012) S16–S26
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Considerations regarding the management ofhyponatraemia secondary to SIADH
Alessandro Peri MD PhDa, *, Christian Combe MD PhDb,A
a Department of Clinical Physiopathology, Endocrine Unit, Center for Research, Transfer and High Education on Chronic, Inﬂammatory,Degenerative and Neoplastic Disorders for the Development of Novel Therapies (DENOThe), University of Florence, 50139 Florence, Italyb Centre Hospitalier Universitaire de Bordeaux, Service de N´ephrologie Transplantation Dialyse, Bordeaux, France and Unit´e INSERM1026, Universit´e Bordeaux Segalen, Bordeaux, France
Treatment of hyponatraemia secondary to the syndrome of
inappropriate secretion of antidiuretic hormone (SIADH) should be
guided by the symptomatology of the patient, which can be used
as a surrogate for the duration of the hyponatraemia. However,
in patients with acute symptomatic hyponatraemia (developing
in <48 hours), the need to actively treat hyponatraemia is more
imperative due to the potential risks associated with leaving
hyponatraemia untreated (including the potential for development
of serious neurological manifestations, such as seizures and brain
stem herniation). In patients with hyponatraemia care needs to betaken not to exceed the recommended rates of correction, as thisincreases the risk of osmotic demyelination syndrome. This articlewill discuss the potential impact of prompt intervention in thetreatment of hyponatraemia, particularly secondary to SIADH, andthe need to weigh the beneﬁts of treatment against the potentialrisks associated with overly rapid correction.
2012 Elsevier Ltd. All rights reserved. 1. Introduction
Hyponatraemia – of which the syndrome of inappropriate secretion of antidiuretic hormone (SIADH),also known as the syndrome of inappropriate antidiuresis (SIAD), is one of the most common causes1 –is associated with increased morbidity and mortality.2 However, the optimum management of thiscondition continues to be the subject of debate amongst European physicians. When physicians aredeciding whether or not to treat hyponatraemia (serum sodium concentration ([Na+]) <136 mmol/L),
* Corresponding author. Alessandro Peri MD PhD. Tel.: +39 55 4271366; Fax: +39 55 4271413. E-mail address:[email protected]ﬁ.it. A Tel.: +33 556 795537; Fax: +33 556 796032. E-mail address: [email protected].
This supplement was commissioned by Otsuka Pharmaceutical Europe Ltd. The European Hyponatraemia Network Academy meeting was organised and supported by Otsuka PharmaceuticalEurope Ltd. Otsuka Pharmaceutical Europe Ltd. is the marketing authorisation holder for tolvaptan. information.
1521-690X/$ – see front matter 2012 Elsevier Ltd. All rights reserved. A. Peri, C. Combe / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S16–S26
the risks associated with the hyponatraemia itself (e.g., development of cerebral oedema) are weighedagainst the potential risks of treatment. One of the primary considerations that physicians face whentreating hyponatraemia is the potential for development of osmotic demyelination syndrome, whichmay result from aggressive correction of serum [Na+].3 Therefore, physicians may be over-cautiousand delay treatment in these patients. Consequently, the impact of prompt intervention on patientoutcomes and length of hospital stay was the subject of a debate held during the inaugural meetingof the European Hyponatraemia Network. During this debate, arguments for and against the followingstatement were discussed: ‘A lack of prompt effective treatment of hyponatraemia increases morbidityand length of hospital stay’. Key points raised during this debate are presented here, along withsuggested approaches for the management of hyponatraemia secondary to SIADH. 1.1. Treatment options in patients with hyponatraemia secondary to SIADH
Having identiﬁed a patient as having hyponatraemia secondary to SIADH via differential diagnosis,subsequent management of the condition should take into account the duration of the hyponatraemiaand the degree of symptomatology. In patients with acute hyponatraemia (developing in <48 hours)the primary goal of treatment should be the resolution of symptoms using hypertonic saline, withmodiﬁcation of treatment once symptoms have been resolved.4 Hypertonic saline solution also remainsthe preferred therapy in patients with chronic hyponatraemia (developing in >48 hours) with severesymptoms.
In moderate hyponatraemia, the recent approval of the vasopressin V receptor antagonist (also
known as a vaptan), tolvaptan, has provided a new therapeutic option speciﬁcally targeted at thetreatment of hyponatraemia secondary to SIADH. Other conventional therapies for hyponatraemia(e.g., water restriction, demeclocycline, urea or lithium) have been used over the past decades;however, although effective in speciﬁc circumstances, they are suboptimal for many different reasons,including variable efﬁcacy, unpredictable compliance, slow responses, intolerable side effects andserious toxicities.5
In patients with mild or ‘asymptomatic’ chronic hyponatraemia, there is no immediate need for
correction, although a therapeutic trial with ﬂuid restriction or a pharmacological agent may beconsidered to discern any potential improvements in the patient’s quality of life.5
1.2. Treatment choice for patients with hyponatraemia secondary to SIADH should promote free water
Fluid restriction is often the standard of care in patients with asymptomatic hyponatraemia secondaryto SIADH. However, the likelihood of ﬂuid restriction successfully raising serum [Na+] in these patientscan be predicted based on the urine concentration. A high urine osmolality usually indicates a highconcentration of vasopressin within the serum; in these cases it is unlikely that ﬂuid restriction willcorrect the hyponatraemia, unless ﬂuid intake is restricted considerably.6 The response of patients toﬂuid restriction can be predicted using a quantiﬁcation of water and electrolyte balance – electrolytefree water clearance (CeH O):7
in which V is the 24 hour urine volume, U
The clinical application of this equation is demonstrated in the following case study. 1.2.1. Case study: clinical application of the equation for free water clearanceA 72 year old man with metastatic lung cancer was admitted to hospital with hyponatraemia. At thetime of admission, he was not exhibiting any symptoms related to hypotonicity and was euvolaemic. Following laboratory evaluation (Table 1), he was diagnosed with paraneoplastic SIADH.
As he was asymptomatic, the initial management prescribed was ﬂuid restriction to 1 L/day. However,
the following day the patient’s serum [Na+] fell to 117 mmol/L. Prior investigation of electrolyte-
A. Peri, C. Combe / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S16–S26
free water clearance would have revealed that this patient was retaining water. Electrolyte freewater clearance can be estimated using the patient’s urinary [K+], urinary [Na+] and serum [Na+],by calculating the urine/plasma (U/P) electrolyte ratio:
is the urinary [Na+], U is the urinary [K+] and P
Table 1 Diagnostic evaluation of a 72 year old man with hyponatraemia and metastatic lung cancer. This case study shows the clinical application of the equation for free water clearance.
[K+] = Potassium concentration. Case study provided by Professor T. Berl. Modiﬁed from Furst H et al. Am J Med Sci 2000; 319: 240–244.7
This simpliﬁed equation can be used to estimate free water loss in relation to the effective osmoles
within the blood plasma. Approaches to raising serum [Na+] by ﬂuid restriction can be guided by thepatient’s U/P ratio (these can be seen in Table 2).7
Table 2 Approaches to raising serum tonicity with ﬂuid restriction. These approaches assume that urine sodium and potassium losses are replaced, that a patient has an average body surface area of 1.73 m2 and eats a normal diet, and calculate for the period during which the next 1 L of urine is excreted.
Reproduced from Furst H et al. Am J Med Sci 2000; 319: 240–2447 with permission.
As noted in Table 2, when the U/P ratio is greater than 1 almost no amount of water restriction
will result in an increase in serum [Na+] because free water is being retained; a process that lowersserum [Na+].7 In such cases alternative approaches, involving an increase in solute intake or preferablya treatment that inhibits vasopressin action on the collecting duct and enhances free water excretion(a process that increases serum [Na+]) should be considered. 2. Debate: the need for prompt effective hyponatraemia management
During the European Hyponatraemia Network Academy Meeting, arguments for and against thefollowing statement were debated: ‘a lack of prompt effective treatment of hyponatraemia increasesmorbidity and length of hospital stay’. Key points from either side of this argument are discussedbelow. A. Peri, C. Combe / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S16–S262.1. ‘A lack of prompt effective intervention in hyponatraemia increases morbidity and length of hospitalstay’ – The arguments against2.1.1. Evidence supporting the link between hyponatraemia and worsening patient outcomes is not robustThere is an increasing accumulation of evidence to suggest that hyponatraemia in hospitalisedpatients is associated with increased morbidity,8–10 mortality,2,11 length of hospital stay9,11 and resourceutilisation.12 However, the majority of this evidence is in the form of retrospective investigations andpost-hoc analyses. There is therefore a lack of prospective data illustrating a reduction in patientmorbidity and length of hospital stay with the correction of hyponatraemia. 2.1.2. It is difﬁcult to ascertain to what extent worsening patient outcomes are caused as a direct result ofthe hyponatraemia rather than the underlying condition
It is also important to consider that hyponatraemia is not a disease, but rather a consequence ofan underlying condition that limits the ability of the kidneys to excrete free water.3 In the majorityof cases, this results from the increased secretion of the hormone vasopressin.1,13 In the presence ofco-morbidities, it may be difﬁcult to ascertain the contribution of hyponatraemia to worsening patientoutcomes relative to the underlying condition. 2.1.3. Prompt treatment without taking into account the rate of onset of hyponatraemia could increasethe risk of overcorrection and may lead to more harm than good
The symptoms of hyponatraemia reﬂect the degree of hyponatraemia and the rate of serum [Na+]decline.3 Due to the danger of neurological complications, it is important to take into account the rateof onset when considering management options for hyponatraemia.
Following a fall in extracellular [Na+], there is a movement of water into the brain that results in
cerebral oedema and increased intracranial pressure. When the onset of hyponatraemia is acute, thecranium restricts the swelling of the brain and complications, such as seizures, respiratory arrest andbrain stem herniation may occur. In this situation, rapid correction of hyponatraemia is necessarybecause the risk of brain stem herniation exceeds the risk of osmotic demyelination and treatmentwith hypertonic saline should be initiated.3,4 However, in cases of chronic hyponatraemia, rapid rises inserum [Na+] may increase the risk of overcorrection of serum [Na+]. When the onset of hyponatraemiais gradual, the cerebral oedema is ameliorated by a process of volume adaptation, involving theextrusion of intracellular potassium and organic osmolytes. This normalises brain volume, despitethe presence of persistent hyponatraemia.3,4,14 In light of the changes occurring within the brainin response to hyponatraemia, the importance of treating acute hyponatraemia rapidly and treatingchronic hyponatraemia slowly may be appreciated.
Overly rapid correction of hyponatraemia was demonstrated in a publication from Sterns and
colleagues,14 who investigated the incidence of post-therapeutic complications in 56 patients treatedfor hyponatraemia (serum [Na+] <105 mmol/L). Patients with chronic hyponatraemia had a higherincidence of neurological sequelae than those classiﬁed with acute hyponatraemia (37% versus 0%,respectively, p < 0.01). The degree of serum [Na+] correction at 48 hours was found to be signiﬁcantlyassociated with the occurrence of neurological sequelae following treatment (p = 0.03).14 Given theseﬁndings, it is recommended that the rate of serum [Na+] correction is limited to <10–12 mmol/L in 24hours and to <18 mmol/L in 48 hours. However, it should be taken into consideration that patientswith severe malnutrition, alcoholism or advanced liver disease may be especially susceptible to osmoticdemyelination syndrome. Thus, given the risk of overshooting maximal recommended increases, it isbest to aim for correction by approximately 8 mmol/L per day.6,14
Despite the possibility of complications from treatment, chronic symptomatic hyponatraemia
should not be ignored, as failing to address symptomatic hyponatraemia may result in adversepatient outcomes. In an investigation of 53 post-menopausal women with chronic symptomatichyponatraemia, deﬁned as a serum [Na+] <130 mmol/L (mean serum [Na+] 111 mmol/L) and withcentral nervous system manifestations,15 morbidity was lower and neurological outcomes were betterin patients that received active therapy with hypertonic saline compared with patients treated withﬂuid restriction (p < 0.01). The patients treated promptly with hypertonic saline (n = 17) recovered
A. Peri, C. Combe / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S16–S26
without neurological sequelae or other complications. All patients treated only with ﬂuid restriction(n = 14) died or experienced permanent brain damage, despite having no associated medical conditionthat accounted for their morbidity.15
2.1.4. Although the use of vasopressin V receptor antagonists to correct hyponatraemia secondary toSIADH is an attractive option, there is a need for further assessment in prospective randomisedcontrolled trials
Vasopressin V receptor antagonists, or vaptans, are novel drugs that may provide an alternative avenue
of treatment for the prompt correction of hyponatraemia secondary to SIADH. Tolvaptan, a vasopressinV receptor antagonist, is the ﬁrst vaptan to be approved in Europe for the treatment of hyponatraemia
secondary to SIADH. By binding to and blocking the V receptor, vasopressin-mediated activation
of this receptor is prevented and free water clearance is increased.16–18 As a treatment approachfor hyponatraemia secondary to SIADH, a vaptan is attractive because it addresses the mechanismunderlying water retention (i.e., inappropriate secretion of vasopressin) without resulting in signiﬁcantelectrolyte losses.
Moreover, ﬂuid restriction, which may be difﬁcult for patients to maintain and slow to increase
serum [Na+],6 is not necessary due to the state of aquaresis induced by vaptans.19 Overcorrection isunlikely if serum [Na+] is frequently measured and, to date, there have been no reported cases ofosmotic demyelination associated with its use.19
Vaptans, such as tolvaptan, represent promising treatment alternatives for the correction of
hyponatraemia secondary to SIADH. However, a prospective, randomised trial comparing vaptans withthe standard of care would be useful to conﬁrm the relative effects of these promising agents on thelength of stay in hospital or the intensive care unit, rehospitalisation rates and patient compliance. 2.1.5. Illustrative case historyA 71 year old female presented 3 days after surgery for the removal of a pituitary adenoma(transsphenoidal endoscopic pituitary adenomectomy, presented to Professor G. Johannsson, Universityof G ¨oteborg); at admission she had a serum [Na+] of 146 mmol/L. The next day, the patient’sserum [Na+] fell to 130 mmol/L, and based on her hydration status, cortisol levels, thyroxine levelsand urine osmolality (Table 3), a diagnosis of SIADH induced by pituitary surgery was made. Thepatient was prescribed ﬂuid restriction on post-operative day 4 (ﬂuid restriction was initially 1 L/day). Two days later the patient’s serum [Na+] had continued to decline so ﬂuid was further restrictedto 800 mL/day. Eventually, the patient’s serum [Na+] began to increase and ﬂuid restriction wasreturned to 1 L/day. The patient was ﬁnally discharged on post-operative day 13 with a serum [Na+]of 140 mmol/L. Table 3 Laboratory result from illustrative case history.
BP = Blood pressure; F-T4 = Free thyroxine. Case study provided by Professor G. Johannsson. A. Peri, C. Combe / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S16–S262.2. ‘A lack of prompt effective intervention in hyponatraemia increases morbidity and length of hospitalstay’ – The arguments for2.2.1. Hyponatraemia is frequently encountered in clinical practiceHyponatraemia is the most common electrolyte disorder encountered in clinical practice,3,20 withSIADH accounting for the majority of euvolaemic hyponatraemia cases.1 In a large database analysisof serum [Na+] measurements from 120,137 patients treated at a 1200-bed acute care hospital, andassociated outpatient services and community-care based polyclinics in Singapore, hyponatraemia(serum [Na+] <136 mmol/L) was present in 28.2% of patients admitted to acute hospital care, 21% ofpatients in ambulatory hospital care and 7.2% of hospital care.21 Consequently, any impact of treatmenton outcome measures such as morbidity and length of stay would only have to be small to have aconsiderable impact on patient outcomes. 2.2.2. Hyponatraemia is associated with increased patient mortalityIn a study conducted by Wald and colleagues, hyponatraemia (serum [Na+] <138 mmol/L) was presentin 38% of patients upon admission to a large academic medical centre in Boston during a 7-year period(53,236 patients admitted during this period were analysed).11 Furthermore, hyponatraemia developedin 38.2% of patients during admission (27,897 patients with normonatraemia upon admission and alength of stay >1 day were included in the analysis). An assessment of the relationship betweenin-patient mortality and admission serum [Na+] revealed that a serum [Na+] of 140 mmol/L wasassociated with the lowest risk of in-hospital mortality. Conversely, when serum [Na+] was evaluatedas a continuous variable, the adjusted risk of death was increased by 23% (odds ratio [OR], 1.23; 95%conﬁdence interval [CI], 1.19–1.27) for each 1 mmol/L decline below 138 mmol/L. Furthermore, thelength of hospital stay was increased in patients with hospital-acquired hyponatraemia relative tohospitalised patients without hyponatraemia (7.6 days vs. 4.9 days, respectively, adjusted difference2.7 days; 95% CI 2.5–2.9).11 The same study also reported an association between hospital-acquiredhyponatraemia, community-acquired hyponatraemia and the likelihood of discharge to a long- orshort-term care facility (see Fig. 1).11
Adjusted Admission sodium concentration (mmol/L) Fig. 1. Impact of community-acquired hyponatraemia on mortality, length of hospital stay and discharge to a short- or long-term care facility. In this study, hyponatraemia was deﬁned as serum [Na+] <138 mmol/L. The reference range for normonatraemia was deﬁned as 138–142 mmol/L. LTC = long-term care; STC = short-term care. Adapted with permission from Wald R et al. Arch Intern Med 2010; 170: 294–302.11 2.2.3. Hyponatraemia is underdiagnosed and often incorrectly managed, leading to poor patient
Despite the association between hyponatraemia and in-hospital mortality, this condition is oftenunderdiagnosed and inappropriately managed,22 due in part to a failure to order sufﬁcient diagnostictests.2,23,24 Ordering appropriate diagnostic tests could inﬂuence patient management and, in somecases, outcomes.23
Incorrect management and a failure to treat hyponatraemia appropriately may adversely affect
patient outcomes. In a prospective review of laboratory and chart data from 104 patients with a
A. Peri, C. Combe / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S16–S26
serum [Na+] <125 mmol/L, identiﬁed at a large teaching hospital in England, 33% of cases were deemedto have ‘signiﬁcant management errors’ (including blind infusion of hypertonic saline in non-criticalsituations and ﬂuid restriction in patients with diuretic-induced hyponatraemia). This inappropriatemanagement was associated with a signiﬁcant increase in excess mortality relative to those patientsthat were managed appropriately (41% vs. 20%, respectively, OR 2.8, 95% CI 1.02–7.55; p = 0.002).23
2.2.4. Acute hyponatraemia can be lethal if not recognised and treated appropriatelyThe imperative to correct hyponatraemia is determined largely by the patient’s symptomatology andthe duration of the hyponatraemia.6 In a study of the symptomatology of severe hyponatraemia(serum [Na+] <125 mmol/L) in a small cohort of patients (n = 14) from San Francisco, the occurrenceof stupor or coma, seizures and mortality were all increased in patients with acute hyponatraemiacompared to those with chronic hyponatraemia of greater than 3 days duration (see Table 4).25 Whilemortality in patients with hyponatraemia may stem from underlying co-morbidities, 36% of the deathsoccurring in patients with acute hyponatraemia in this study were directly attributed to the presenceof a low serum [Na+].25 Due to the potential for complications, acute hyponatraemia is a medicalemergency and should be treated urgently with hypertonic saline.6,26
Table 4 Acute versus chronic hyponatraemia.
Consults at 1 hospital in 1 year; serum [Na+] <128 mmol/L. Data from Arieff AI et al. Medicine (Baltimore) 1976; 55: 121–129.25 Reproduced with permission from Sterns RH et al. Semin Nephrol 2009; 29: 282–299.26 2.2.5. Chronic hyponatraemia is not asymptomatic but associated with increased patient morbidityRecent studies suggest that mild or chronic hyponatraemia is associated with increased patientmorbidity. An investigation by Renneboog and colleagues reported deﬁcits in gait and attention inpatients with apparently ‘asymptomatic’ chronic hyponatraemia (mean serum [Na+] 126±5 mmol/L),which was improved following the correction of serum [Na+].8 In a further study of 223 patientswith chronic thiazide-induced hyponatraemia (mean serum [Na+] 116 mmol/L), symptoms reportedincluded malaise/lethargy, dizzy spells, vomiting, falls, headaches and seizures.10
Recently, evidence has also been accumulating to suggest that chronic ‘asymptomatic’ hyponatraemia
may also have long-term consequences pertaining to bone metabolism, with several studies reportingan association between hyponatraemia and fracture occurrence27 or osteoporosis.28 Investigations intothe mechanism of hyponatraemia-induced bone loss, and the beneﬁts of serum sodium correction onmorbidity and reduction in hospital stay in patients with chronic hyponatraemia, are still ongoing. Itshould be noted that a recent study published after the ﬁrst meeting of the European HyponatraemiaNetwork has demonstrated that sustained low extracellular [Na+] directly stimulates osteoclastogenesisand resorptive activity in vitro.29
2.2.6. Correction of hyponatraemia in patients with SIADH using a vaptan is associated with a reduction
The safety and efﬁcacy of the vasopressin V receptor antagonist, tolvaptan, was assessed in the Study
of Ascending Levels of Tolvaptan in Hyponatraemia 1 and 2 (SALT-1 and SALT-2), identical prospective,multicentre, randomised, double-blind, placebo-controlled trials comparing treatment with tolvaptan
A. Peri, C. Combe / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S16–S26
to placebo in raising serum [Na+] in patients with euvolaemic and hypervolaemic hyponatraemia. Thepooled analysis of the SALT-1 and SALT-2 studies included patients with hypotonic hyponatraemiadiagnosed with cirrhosis, heart failure or SIADH and other (i.e., patients that did not meet the diagnosticcriteria for cirrhosis or heart failure).30 In these, tolvaptan was reported to raise serum [Na+] within8 hours of treatment.30 A post-hoc analysis of the SALT-1 and SALT-2 trials conﬁrmed the efﬁcacyand tolerability of tolvaptan in patients with SIADH. Tolvaptan treatment signiﬁcantly improvedserum [Na+] in patients with SIADH over the ﬁrst 4 days of treatment (p < 0.0001), and throughoutthe 30-day study period compared to patients who received placebo.19 This was associated witha signiﬁcantly shorter length of stay in hospital for tolvaptan compared to placebo (4.70 vs. 8.40,respectively, p = 0.045). 2.2.7. Correction of hyponatraemia in patients with SIADH using a vaptan increases patient-reported
In addition to assessing changes in serum [Na+], the SALT-1 and SALT-2 trials also investigated changesin self-assessed health status following tolvaptan treatment. In the post-hoc analysis of patients withSIADH, treatment with tolvaptan was reported to increase scores on the 12 Item Short Form (SF-12)General Health Survey.19 A signiﬁcantly greater change in Physical Component Summary (PCS) scorefrom baseline was also noted in patients with SIADH treated with tolvaptan compared to those whoreceived placebo (3.64 vs. −0.16, respectively, p = 0.019). These ﬁndings suggest that patients whoreceived treatment with tolvaptan perceived an improvement in physical functioning.19
Interestingly, a tendency towards an improvement in Mental Component Summary (MCS) score from
baseline was also reported (5.47 change from baseline with tolvaptan vs. −0.45 change from baselinewith placebo, p = 0.051). This increase in MCS score was of comparable magnitude to that observedin the full analysis of the SALT trials and approached, but failed to reach, statistical signiﬁcance. Theauthors attributed this to the reduced patient numbers available within the SIADH subgroup analysisreducing the power of the analysis to detect differences between the treatment groups.19
Questions remain about the optimum degree of correction of hyponatraemia in speciﬁc patient
populations; however, there is a growing body of evidence to suggest that prompt effective treatmentof hyponatraemia decreases morbidity and length of hospital stay. 2.2.8. Illustrative case historyA 64 year old female was admitted to hospital with a serum [Na+] of 114 mmol/L and fast atrialﬁbrillation, but was discharged after a slow [Na+] increase and a change in medication (bisoprolol inplace of propafenone). The patient was referred to a consultant endocrinologist (Professor C. Thompson,Beaumont Hospital) with poor cognition, myoclonus, a change in personality and serum [Na+] of 125–130 mmol/L. Further investigations were performed (outlined in Table 5). Thyroid function was normal,as was cortisol response to ACTH stimulation test, a CT of the brain, thorax, abdomen and brain MRI. Table 5 Laboratory results from illustrative case history.
ACTH = Adrenocorticotropic hormone; CT = Computed tomography; T4 = Thyroxine;TSH = Thyroid stimulating hormone; MRI = Magnetic resonance imaging. Case study provided by Professor C. Thompson. A. Peri, C. Combe / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S16–S26
The patient was provisionally diagnosed with SIADH and initially treated with ﬂuid restriction
(restricted to 1 L/day). However, as can often be the case in patients with hyponatraemia, shefound it difﬁcult to comply with ﬂuid restriction, even with hospital supervision. Consequently, thepatient’s serum [Na+] remained between 125 and 130 mmol/L during which time she experiencedepisodic absences and myoclonic jerking. Demeclocycline was subsequently prescribed to decreaseher serum [Na+], however, it had no treatment effect.
Eventually, 17 days after hospitalisation, the patient received tolvaptan which immediately resulted
in a controlled increase in serum [Na+] to 140 mmol/L. This corresponded with relief of the patient’ssymptoms and she was discharged four days later (before Christmas). However, after Christmas thepatient’s neurological symptoms returned. A subsequent test for potassium channel antibodies and arepeat MRI revealed hippocampal abnormalities leading to a diagnosis of limbic encephalitis.
Although SIADH associated with limbic encephalitis is rare, this is not the ﬁrst reported case in
the literature.31–33 In this instance, resolution of the hyponatraemia provided diagnostic clarity, as thepersistence of symptoms indicated an underlying cerebral pathology. The use of tolvaptan provided aprompt resolution of hyponatraemia, which resulted in clinical improvement (the low-grade seizuresexperienced by the patient occurred less frequently). Prior to treatment, the patient had spent 17 daysin hospital but was discharged 4 days after treatment with tolvaptan was initiated. It is possiblethat the prompt resolution of hyponatraemia could translate to a reduction in the ﬁnancial impact ofhyponatraemia secondary to SIADH following treatment with tolvaptan. 3. Summary
Hyponatraemia may be considered across a spectrum of diseases. While it is necessary to treathyponatraemia, the speed at which treatment is initiated should depend on the presentation of thepatient. Treatment of patients with hyponatraemia with hypertonic saline has been known to causeosmotic demyelination syndrome with overly rapid correction. Other conventional treatments, suchas ﬂuid restriction, have been shown not to be very satisfactory. Novel drugs, such as the vasopressinV receptor antagonist, tolvaptan, may provide an alternative avenue of treatment for the prompt
correction of hyponatraemia in patients with hyponatraemia secondary to SIADH. There is a need forfurther randomised controlled trials assessing the relative beneﬁts of newer pharmacological agents,such as tolvaptan, compared with the standard of care. Practice points • Failure to promptly correct acute, symptomatic hyponatraemia can result in adverse patient
• The speed of correction of the hyponatraemia should reﬂect its speed of onset – overly rapid
correction of chronic hyponatraemia can lead to osmotic demyelination syndrome. Research agenda • Ongoing randomised, controlled trials comparing treatment with tolvaptan to standard of care
in patients with hyponatraemia secondary to SIADH, will add to the evidence already availablefrom existing subgroup analyses. • Reductions in length of hospital stay in patients treated for hyponatraemia need to be
• The link between hyponatraemia and osteoporosis needs to be investigated further in order
to determine the value of treating mild, asymptomatic hyponatraemia. A. Peri, C. Combe / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) S16–S264. Acknowledgements
This supplement was commissioned by Otsuka Pharmaceutical Europe Ltd. and summarises theproceedings of a meeting organised and supported by Otsuka Pharmaceutical Europe Ltd. The authorshave not received any honorarium in relation to this supplement. Otsuka Pharmaceutical Europe Ltd. has had the opportunity to comment on the medical content and accuracy of the article and editorialsupport has been provided by Otsuka Pharmaceutical Europe Ltd.; however, ﬁnal editorial contentresides with the authors and Best Practice & Research: Clinical Endocrinology & Metabolism. 5. Conﬂict of interest
Prof. Peri has worked as an advisor for Otsuka Pharmaceutical Europe Ltd. and Otsuka PharmaceuticalItaly S.r.l. and has no other conﬂict of interest related to this publication. Prof. Combe reports to havereceived lecture fees from Otsuka Pharmaceutical and has no other conﬂict of interest related to thispublication. References
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Goettingen Journal of International Law 2 (2010) 2, 689-711 Amendments to the Rome Statute of the International Criminal Court Considered at the first Review Conference on the Court, Kampala, 31 May-11 June 2010 Non-Deletion of Article 124 of the Statute . 691 I. The Basic Structure of Article 8 bis – the Definition . 695 II. Structure of Articles 15bis and 15ter – Conditi