SIADHSIADHSYNDROME OF INAPPROPRIATE SYNDROME OF INAPPROPRIATE

SECRETION OF ANTI DIURETIC HORMONESECRETION OF ANTI DIURETIC HORMONE

22.12.1022.12.10

Outline Of The PresentationOutline Of The Presentation

IntroductionIntroduction Prevalance of hyponatremiaPrevalance of hyponatremia ADHADH SIADH SIADH Causes Causes ClassificationClassification Clinical featuresClinical features Laboratory featuresLaboratory features TreatmentTreatment

IntroductionIntroduction Hyponatraemia is the commonest electrolyte Hyponatraemia is the commonest electrolyte

abnormality found in hospital inpatients, and is abnormality found in hospital inpatients, and is associated with a greatly increased morbidity associated with a greatly increased morbidity and mortality.and mortality.

The syndrome of inappropriate antidiuretic The syndrome of inappropriate antidiuretic hormone (SIADH) is the most frequent cause of hormone (SIADH) is the most frequent cause of hyponatraemia in hospital inpatients. hyponatraemia in hospital inpatients.

SIADH is the clinical and biochemical SIADH is the clinical and biochemical manifestation of a wide range of disease manifestation of a wide range of disease processes, and every case warrants processes, and every case warrants investigation of the underlying cause.investigation of the underlying cause.

Prevalance of hyponatremiaPrevalance of hyponatremia

A Belgian study reported that the prevalence A Belgian study reported that the prevalence of mild hyponatraemia (<135 mmol/l) was 4% of mild hyponatraemia (<135 mmol/l) was 4% in a randomly selected control group of in a randomly selected control group of healthy elderly patients.healthy elderly patients.

The population-based Copenhagen Holter The population-based Copenhagen Holter study showed a higher prevalence of 11%, study showed a higher prevalence of 11%, using a slightly higher cut-off of 137 mmol/l . using a slightly higher cut-off of 137 mmol/l .

Sajadieh A.AJEM 2009 122 679–686

. Gankam Kengne F.QJOM 2008 101 583–588

A large study of 7965 patients with pneumonia A large study of 7965 patients with pneumonia showed that 8% developed hyponatraemia showed that 8% developed hyponatraemia during the course of hospital admission during the course of hospital admission

56% of the patients admitted with subarachnoid 56% of the patients admitted with subarachnoid haemorrhage develop hyponatraemia, with 20% haemorrhage develop hyponatraemia, with 20% developing clinically significant drops in plasma developing clinically significant drops in plasma sodium concentration to <125 mmol/lsodium concentration to <125 mmol/l

Zilberberg MD BMC Pulmonary Medicine 2008 8 16.

Sherlock M Endocrinology 2006 64 250–254

ADH: AntiDiuretic HormoneADH: AntiDiuretic Hormone

Formed in the supraoptic and paraventricular Formed in the supraoptic and paraventricular nuclei of the hypothalamus.nuclei of the hypothalamus.

Transported to the posterior lobe of the Pituitary Transported to the posterior lobe of the Pituitary Gland and stored.Gland and stored.

ADH is released in response to an increase in ADH is released in response to an increase in intravascular osmotic pressure, hypovolemia, intravascular osmotic pressure, hypovolemia, decrease in pulse pressure, and also in decrease in pulse pressure, and also in response to fear, pain, anxiety.response to fear, pain, anxiety.

Function of ADH Function of ADH

ADH increases the permeability of the ADH increases the permeability of the renal distal tubule and collecting ducts to renal distal tubule and collecting ducts to water.water.

Less free water is excreted in urineLess free water is excreted in urineUrine volume is decreasedUrine volume is decreasedConcentration of urine is increasedConcentration of urine is increased

AVP action is mediated via binding to G AVP action is mediated via binding to G protein–coupled V2 receptors on the protein–coupled V2 receptors on the serosal surface of the principal cell of serosal surface of the principal cell of collecting duct, activation of adenyl collecting duct, activation of adenyl cyclase, and insertion into the luminal cyclase, and insertion into the luminal surface of water channels composed of a surface of water channels composed of a protein known as protein known as aquaporin 2aquaporin 2 . .

Syndrome of Inappropriate Syndrome of Inappropriate

AntiDiuretic Hormone AntiDiuretic HormoneSIADH is a clinical condition involving excess of SIADH is a clinical condition involving excess of

ADH secretion. ADH secretion.

The patient is hyponatremic with a low serum The patient is hyponatremic with a low serum osmolality, which normally would inhibit ADH osmolality, which normally would inhibit ADH secretion.secretion.

………….SIADH……..SIADH…….

The first step in the diagnosis of SIADH is The first step in the diagnosis of SIADH is to differentiate it from other causes of to differentiate it from other causes of hyponatraemia.hyponatraemia.

Classification of causation is based on Classification of causation is based on clinical and biochemical estimation of clinical and biochemical estimation of extracellular volume status.extracellular volume status.

This divides hyponatraemia into This divides hyponatraemia into hypovolaemic, euvolaemic and hypovolaemic, euvolaemic and hypervolaemic aetiologies hypervolaemic aetiologies

Clinical signsClinical signs Urinary Na+<20Urinary Na+<20 mmol/l mmol/l

Urinary Na+>40Urinary Na+>40 mmol/l mmol/l

HypovolaemicHypovolaemic Dry mucous Dry mucous membranes,membranes,

Decreased turgor,Decreased turgor,

Tachycardia,Tachycardia,

Hypotension Hypotension (orthostatic),(orthostatic),

Raised urea, renninRaised urea, rennin

GI losses,GI losses,

Mucosal losses,Mucosal losses,

PancreatitisPancreatitis

Sodium depletionSodium depletion

post diureticspost diuretics

DiureticsDiuretics

Addison's diseaseAddison's disease

Cerebral salt wastingCerebral salt wasting

Salt wasting Salt wasting nephropathynephropathy

EuvolaemicEuvolaemic Underlying illnessUnderlying illness HypothyroidismHypothyroidism

SIADH with ongoing SIADH with ongoing fluid restrictionfluid restriction

Primary polydipsiaPrimary polydipsia

Inappropriate fluid Inappropriate fluid replacementreplacement

SIADHSIADH

ACTH deficiencyACTH deficiency

HypervolaemicHypervolaemic Peripheral oedemaPeripheral oedema

AscitesAscites

Raised JVPRaised JVP

Pulmonary oedemaPulmonary oedema

Underlying illnessUnderlying illness

CirrhosisCirrhosis

Cardiac failureCardiac failure

Nephrotic syndromeNephrotic syndrome

Cardiac failure or Cardiac failure or cirrhosis on diuretic cirrhosis on diuretic therapytherapy

Euvolaemic hyponatraemia is the Euvolaemic hyponatraemia is the commonest cause of hyponatraemia in commonest cause of hyponatraemia in hospitalised patients,hospitalised patients,

An important cause of euvolaemic An important cause of euvolaemic hyponatraemia, which must be excluded hyponatraemia, which must be excluded before the diagnosis of SIADH can be before the diagnosis of SIADH can be made, is ACTH deficiency made, is ACTH deficiency

ACTH deficiency is manifested by cortisol ACTH deficiency is manifested by cortisol deficiency.deficiency.

Cortisol is necessary for efficent excretion of Cortisol is necessary for efficent excretion of free water and glucocorticoid deficiency is free water and glucocorticoid deficiency is associated with retention of free water and associated with retention of free water and development of hyponatraemia with a development of hyponatraemia with a biochemical picture identical to SIADH. biochemical picture identical to SIADH.

Patients with ACTH/cortisol deficiency and Patients with ACTH/cortisol deficiency and hyponatraemia have elevated plasma arginine hyponatraemia have elevated plasma arginine vasopressin (AVP) concentrations, which further vasopressin (AVP) concentrations, which further contribute to the tubular reabsorption of water.contribute to the tubular reabsorption of water.

Glucocorticoid therapy has been shown to Glucocorticoid therapy has been shown to suppress AVP secretion , which allows the suppress AVP secretion , which allows the excretion of free water and the normalisation of excretion of free water and the normalisation of plasma sodium concentrations in patients with plasma sodium concentrations in patients with ACTH deficiency. ACTH deficiency.

Diagnosis can be aided by the fact that patients Diagnosis can be aided by the fact that patients with ACTH deficiency have a lower serum with ACTH deficiency have a lower serum bicarbonate and aldosterone concentration than bicarbonate and aldosterone concentration than those with SIADH those with SIADH

Normal approach followed could be to measure cortisol Normal approach followed could be to measure cortisol at 0900 h in all patients with apparent SIADH due to at 0900 h in all patients with apparent SIADH due to neurosurgical conditions such as traumatic brain injury, neurosurgical conditions such as traumatic brain injury, subarachnoid haemorrhage, subdural haematoma and subarachnoid haemorrhage, subdural haematoma and intracranial haemorrhage.intracranial haemorrhage.

Commence empirical treatment with glucocorticoids if Commence empirical treatment with glucocorticoids if the reading is inappropriately low for the degree of the reading is inappropriately low for the degree of expected stress–response (<300 nmol/l, and between expected stress–response (<300 nmol/l, and between 300 and 500 nmol/l if clinical suspicion is high).300 and 500 nmol/l if clinical suspicion is high).

Important clinical clues that neurosurgical patients with Important clinical clues that neurosurgical patients with apparent SIADH may have acute ACTH deficiency apparent SIADH may have acute ACTH deficiency include the presence of hypoglycaemia or hypotension, include the presence of hypoglycaemia or hypotension, particularly when the latter is resistant to pressor agents. particularly when the latter is resistant to pressor agents.

M J Hannon. European Journal of Endocrinology,2010. Vol 162

Causes of SIADHCauses of SIADH Malignancy Small cell lung cancer Malignancy Small cell lung cancer Nasopharyngeal cancerNasopharyngeal cancer MesotheliomaGI tract malignancyMesotheliomaGI tract malignancy Pancreatic malignancyPancreatic malignancy GU tract malignancy GU tract malignancy

Lymphoma Lymphoma SarcomaSarcoma

Drugs Drugs DesmopressinDesmopressin Selective serotonin reuptake inhibitors Selective serotonin reuptake inhibitors

Carbamazepine Carbamazepine ProstaglandinsProstaglandins Tricyclic antidepressantsTricyclic antidepressants PhenothiazinesPhenothiazines Haloperidol Haloperidol 3,4-Methylenedioxymethamphetamine 3,4-Methylenedioxymethamphetamine

Quinolones Quinolones Leveteiracetam Leveteiracetam Cyclophosphamide Cyclophosphamide VincristineVincristine

Causes of SIADHCauses of SIADH Pulmonary Pneumonia, especially Pulmonary Pneumonia, especially LegionellaLegionella and and MycoplasmaMycoplasma TuberculosisTuberculosis AbscessAbscess VasculitisVasculitis Positive pressure ventilationPositive pressure ventilation Intracranial Intracranial

TumourTumourMeningitisMeningitisEncephalitisEncephalitisAbscessAbscessVasculitisVasculitisSubarachnoid haemorrhageSubarachnoid haemorrhageSubdural haemorrhageSubdural haemorrhageTraumatic brain injuryTraumatic brain injury

Miscellaneous : Miscellaneous : Multiple sclerosis Multiple sclerosis

Guillain–Barre syndromeGuillain–Barre syndrome

Acute intermittent porphyria Acute intermittent porphyria HIV HIV

IdiopathicIdiopathic

Classification of SIADH Classification of SIADH

SIADH occurs by definition when AVP secretion SIADH occurs by definition when AVP secretion is not suppressed when plasma sodium is not suppressed when plasma sodium concentration falls below the osmotic threshold concentration falls below the osmotic threshold for physiological AVP secretion . for physiological AVP secretion .

Zerbe Zerbe et alet al. were able to utilise the . were able to utilise the measurement of plasma AVP with an early RIA measurement of plasma AVP with an early RIA to describe four different types of SIADH, to describe four different types of SIADH, defined by the pattern of AVP secretion across a defined by the pattern of AVP secretion across a range of plasma osmolalities range of plasma osmolalities

Zerbe R Annual Review of Medicine 1980 31 315–327

Type A SIADH Type A SIADH

Commonest form.Commonest form. Occurs in 60–70%.Occurs in 60–70%. Characteristically, type A patients exhibit Characteristically, type A patients exhibit

excessive, random secretion of AVP, with loss excessive, random secretion of AVP, with loss of the close linear relationship between plasma of the close linear relationship between plasma osmolality and plasma AVP. osmolality and plasma AVP.

Type A is common in lung cancer; Type A is common in lung cancer; in vitroin vitro studies have demonstrated that some lung studies have demonstrated that some lung tumours synthesise AVP and that tumour tissue tumours synthesise AVP and that tumour tissue stains positive for AVP mRNA . stains positive for AVP mRNA .

Plasma AVP concentrations in type A SIADH are Plasma AVP concentrations in type A SIADH are not suppressed physiologically by drinking , not suppressed physiologically by drinking , which makes patients vulnerable to the which makes patients vulnerable to the development of severe hyponatraemia.development of severe hyponatraemia.

Studies have also demonstrated a lower osmotic Studies have also demonstrated a lower osmotic threshold for thirst appreciation in this type of threshold for thirst appreciation in this type of SIADH. SIADH.

This type of SIADH is also characteristic of This type of SIADH is also characteristic of nasopharyngeal tumours, which also stain nasopharyngeal tumours, which also stain positive for AVP mRNApositive for AVP mRNA

Smith DSmith D American Journal of Physiology. Endocrinology and American Journal of Physiology. Endocrinology and MetabolismMetabolism 2004 2004 287287 E1019–E1023 E1019–E1023

Type B SIADHType B SIADH Type B is also common (20–40%). Type B is also common (20–40%). The osmotic threshold for AVP release is lowered – a The osmotic threshold for AVP release is lowered – a

‘reset osmostat’ – such that secretion of AVP occurs at ‘reset osmostat’ – such that secretion of AVP occurs at lower plasma osmolalities than normal.lower plasma osmolalities than normal.

Because AVP is suppressed at plasma osmolalities Because AVP is suppressed at plasma osmolalities below the lower, reset threshold, further overhydration below the lower, reset threshold, further overhydration leads to suppression of AVP release, which protects leads to suppression of AVP release, which protects against the progression to severe hyponatraemia.against the progression to severe hyponatraemia.

Although most tumours manifest type A SIADH, some Although most tumours manifest type A SIADH, some also present with type B SIADH, so the pattern of also present with type B SIADH, so the pattern of abnormal AVP secretion cannot be utilised to predict the abnormal AVP secretion cannot be utilised to predict the causation of SIADH. causation of SIADH.

Type C SIADHType C SIADH

Type C is a rare condition characterised by Type C is a rare condition characterised by failure to suppress AVP secretion at plasma failure to suppress AVP secretion at plasma osmolalities below the osmotic threshold. osmolalities below the osmotic threshold.

Plasma AVP concentrations are thus Plasma AVP concentrations are thus inappropriately high at low plasma osmolalities, inappropriately high at low plasma osmolalities, but there is a normal relationship between but there is a normal relationship between plasma osmolality and plasma AVP at plasma osmolality and plasma AVP at physiological plasma osmolalities. physiological plasma osmolalities.

This variant may be due to dysfunction of This variant may be due to dysfunction of inhibitory neurones in the hypothalamus, leading inhibitory neurones in the hypothalamus, leading to persistent low-grade basal AVP secretion to persistent low-grade basal AVP secretion

Type D SIADHType D SIADH

Type D is a rare clinical picture of SIADH with Type D is a rare clinical picture of SIADH with low or undetectable AVP levels and no low or undetectable AVP levels and no detectable abnormality in circulating AVP detectable abnormality in circulating AVP response.response.

It is thought that a nephrogenic SIADH (NSIAD) It is thought that a nephrogenic SIADH (NSIAD) may be responsible for this picture. may be responsible for this picture.

Gain-of-function mutations in the V2 receptor Gain-of-function mutations in the V2 receptor leading to a clinical picture of SIADH, with leading to a clinical picture of SIADH, with undetectable AVP levels, have been described.undetectable AVP levels, have been described.

The identified mutations had different nucleotide The identified mutations had different nucleotide substitutions causing different levels of V2 substitutions causing different levels of V2 receptor activation. receptor activation.

This syndrome appears to be inherited in an X-This syndrome appears to be inherited in an X-linked manner, although heterozygous females linked manner, although heterozygous females may have varying degrees of inappropriate may have varying degrees of inappropriate antidiuresis. antidiuresis.

Owing to variable expressivity of the gene Owing to variable expressivity of the gene involved, NSIAD may be clinically undetectable involved, NSIAD may be clinically undetectable for years, until other contributing factors in later for years, until other contributing factors in later life lead to clinically significant hyponatraemia life lead to clinically significant hyponatraemia

Copyright ©2010 European Society of Endocrinology

Eur J Endocrinol. 2010 Jun;162(Suppl1):S5-S12

Figure 1 Summary of the four different patterns of AVP secretion in SIADH

CLINICAL FEATURESCLINICAL FEATURES Symptoms associated with hyponatraemia are Symptoms associated with hyponatraemia are

varied, and are generally related to the severity varied, and are generally related to the severity of hyponatraemia, the rate of change in plasma of hyponatraemia, the rate of change in plasma sodium concentration, and the osmotic gradient sodium concentration, and the osmotic gradient between intracellular and extracellular fluids. between intracellular and extracellular fluids.

Plasma sodium concentrations between 125 and Plasma sodium concentrations between 125 and 130 mmol/l, anorexia, nausea, vomiting and 130 mmol/l, anorexia, nausea, vomiting and abdominal pain may develop.abdominal pain may develop.

As plasma sodium concentration falls to As plasma sodium concentration falls to between 115 and 125 mmol/l, agitation, between 115 and 125 mmol/l, agitation, confusion, hallucinations, incontinence and confusion, hallucinations, incontinence and other neurological symptoms predominate.other neurological symptoms predominate.

CLINICAL FEATURESCLINICAL FEATURES Hyponatraemia below 115 mmol/l may induce serious Hyponatraemia below 115 mmol/l may induce serious

adverse neurological sequelae, such as seizures and adverse neurological sequelae, such as seizures and coma, due to increased intracranial pressure.coma, due to increased intracranial pressure.

If there is intracranial illness, space-occupying lesion or If there is intracranial illness, space-occupying lesion or neurosurgical intervention, the onset of symptoms may neurosurgical intervention, the onset of symptoms may occur at higher plasma sodium concentrations than occur at higher plasma sodium concentrations than usual. usual.

In acute hyponatraemia, the main pathological In acute hyponatraemia, the main pathological consequence is the development of cerebral oedema, consequence is the development of cerebral oedema, which may lead to raised intracranial pressure, cerebral which may lead to raised intracranial pressure, cerebral herniation, hypoxia and even death herniation, hypoxia and even death

Laboratory Evaluation Laboratory Evaluation

Serum osmolalitySerum osmolalitySerum sodium levels Serum sodium levels Urine osmolalityUrine osmolalityUrine spot sodium >40mEq/lUrine spot sodium >40mEq/lFractional excretion of sodium>0.5%Fractional excretion of sodium>0.5%FEurea >55% FEurea >55% Low urea <30mg/dlLow urea <30mg/dlLow uric acid Low uric acid

Table 1Table 1 Diagnostic criteria for Diagnostic criteria for SIADH SIADH

EssentialEssential Plasma osmolality <270 mosmol/kg H2O Plasma osmolality <270 mosmol/kg H2O Inappropriate urinary concentration (Uosm>100 mosmol/kg H2O) Inappropriate urinary concentration (Uosm>100 mosmol/kg H2O) Patient is clinically euvolaemic Patient is clinically euvolaemic Elevated urinary sodium (>40 mmol/l), with normal salt and water intake Elevated urinary sodium (>40 mmol/l), with normal salt and water intake Exclude hypothyroidism and glucocorticoid deficiencyExclude hypothyroidism and glucocorticoid deficiency

SupplementalSupplemental Abnormal water load test, i.e. inability to excrete at least 90% of a 20 ml/kg water load Abnormal water load test, i.e. inability to excrete at least 90% of a 20 ml/kg water load

in 4 h and/or failure to dilute urine to Uosm<100 mosmol/kg H2Oin 4 h and/or failure to dilute urine to Uosm<100 mosmol/kg H2O Plasma AVP levels inappropriately elevated relative to plasma osmolalityPlasma AVP levels inappropriately elevated relative to plasma osmolality Tests for supplemental criteria should only be performed in rare situations and in Tests for supplemental criteria should only be performed in rare situations and in

units with expertise in this area as they may aggravate hyponatraemia.units with expertise in this area as they may aggravate hyponatraemia.

Smith DM, McKenna K & Thompson CJ. Hyponatremia. Smith DM, McKenna K & Thompson CJ. Hyponatremia. Clinical EndocrinologyClinical Endocrinology 2000 2000 5252 679–678. 679–678.

TREATMENTTREATMENT

FLUID RESTRICTIONFLUID RESTRICTIONWater restriction is regarded as first-line Water restriction is regarded as first-line

treatment for hyponatraemia due to SIADHtreatment for hyponatraemia due to SIADH In patients in whom there is no question of In patients in whom there is no question of

hypovolaemia, this treatment is safe hypovolaemia, this treatment is safe Fluid restriction of 800–1200 ml/day is Fluid restriction of 800–1200 ml/day is

generally advised, according to severity of generally advised, according to severity of hyponatraemia hyponatraemia

As long as background water losses from the As long as background water losses from the kidney, skin and lungs exceed this amount, there kidney, skin and lungs exceed this amount, there is progressive depletion of total body water and is progressive depletion of total body water and a gradual rise in plasma sodium concentration a gradual rise in plasma sodium concentration

The principal drawback is that patients find it The principal drawback is that patients find it extremely difficult to maintain fluid restriction, as extremely difficult to maintain fluid restriction, as thirst in SIADH is inappropriately normal due to a thirst in SIADH is inappropriately normal due to a downward resetting of the osmotic thirst downward resetting of the osmotic thirst threshold .threshold .

Isotonic salineIsotonic saline

Plasma sodium concentration will rise in some Plasma sodium concentration will rise in some patients with SIADH who are treated with i.v. patients with SIADH who are treated with i.v. normal (0.9%) saline, particularly if urine normal (0.9%) saline, particularly if urine osmolality is <530 mosmol/kg osmolality is <530 mosmol/kg

However, treatment with normal saline is However, treatment with normal saline is generally reserved for patients in whom the generally reserved for patients in whom the differentiation between hypovolaemia and differentiation between hypovolaemia and euvolaemia is difficult.euvolaemia is difficult.

In this situation, i.v. saline is a safer first–line In this situation, i.v. saline is a safer first–line treatment than fluid restriction (as fluid restriction treatment than fluid restriction (as fluid restriction may exacerbate hypovolaemic hyponatraemia). may exacerbate hypovolaemic hyponatraemia).

Hypertonic salineHypertonic saline

If a patient is symptomatic due to a rapid If a patient is symptomatic due to a rapid decrease in serum sodium concentration, decrease in serum sodium concentration, treatment with hypertonic saline should be treatment with hypertonic saline should be considered .considered .

Several formulae have been developed to Several formulae have been developed to estimate the effect of a given infusate on estimate the effect of a given infusate on the serum sodium concentration. the serum sodium concentration.

The Adrogué–Madias formulaThe Adrogué–Madias formula

This formula was shown to predict correction This formula was shown to predict correction rates using hypertonic saline with reasonable rates using hypertonic saline with reasonable accuracy, and is listed below.accuracy, and is listed below.

The formula derives the change in plasma The formula derives the change in plasma sodium concentration (Δ[Na]) that is produced sodium concentration (Δ[Na]) that is produced by 1 l of infusate with given sodium and by 1 l of infusate with given sodium and potassium concentrations ([Na]infusate + potassium concentrations ([Na]infusate + [K]infusate) from the present serum sodium [K]infusate) from the present serum sodium concentration and the (new) volume of concentration and the (new) volume of distribution (total body water + 1). distribution (total body water + 1).

Simple Rule Of ThumbSimple Rule Of Thumb

In order to induce a correction rate of 1 In order to induce a correction rate of 1 mmol/L per hour, using 3% NaCl, one mmol/L per hour, using 3% NaCl, one should infuse the body weight as millilitres should infuse the body weight as millilitres per hour (i.e. a man with a body weight of per hour (i.e. a man with a body weight of 70 kg will increase by approximately 1 70 kg will increase by approximately 1 mmol/L per hour when infused with 3% mmol/L per hour when infused with 3% NaCl at a rate of 70 mL/h NaCl at a rate of 70 mL/h

Verbalis JGVerbalis JG Am J Med. Am J Med. 2007;120(Suppl 1):S1–S212007;120(Suppl 1):S1–S21

DemeclocyclineDemeclocycline

It is a tetracycline derivative which is utilised in the It is a tetracycline derivative which is utilised in the treatment of SIADH because it causes nephrogenic treatment of SIADH because it causes nephrogenic diabetes insipidus in about 60% of patientS.diabetes insipidus in about 60% of patientS.

The mode of action is unknown and may interfere with The mode of action is unknown and may interfere with the vasopressin-aquaporin signalling cascade .the vasopressin-aquaporin signalling cascade .

The onset of action is also unpredictable, usually The onset of action is also unpredictable, usually occurring after 2–5 days, but occasionally taking longer.occurring after 2–5 days, but occasionally taking longer.

In some patients, polyuria can be profound, and patients In some patients, polyuria can be profound, and patients can become markedly symptomatic, occasionally can become markedly symptomatic, occasionally developing hypernatraemia if access to water is developing hypernatraemia if access to water is compromised.compromised.

Nephrotoxicity can arise, particularly in patients with Nephrotoxicity can arise, particularly in patients with cirrhosis, and although renal impairment is usually cirrhosis, and although renal impairment is usually reversible with discontinuation, cases with permanent reversible with discontinuation, cases with permanent renal failure have been reported renal failure have been reported

It has also been associated with photosensitive skin It has also been associated with photosensitive skin rash, leading to discontinuation of treatment and return rash, leading to discontinuation of treatment and return of symptomatic hyponatraemia. of symptomatic hyponatraemia.

LithiumLithium

It also causes nephrogenic diabetes insipidus in 30% of It also causes nephrogenic diabetes insipidus in 30% of patients , by downregulation of vasopressin-stimulated patients , by downregulation of vasopressin-stimulated aquaporin-2 expression .aquaporin-2 expression .

An even larger proportion of patients have attenuation of An even larger proportion of patients have attenuation of maximal urine concentrating ability, and this property of maximal urine concentrating ability, and this property of lithium has been utilised by some centres to treat lithium has been utilised by some centres to treat SIADH.SIADH.

Nephrogenic diabetes insipidus is usually but not always Nephrogenic diabetes insipidus is usually but not always reversible , with chronic treatment sometimes producing reversible , with chronic treatment sometimes producing interstitial nephritis and end-stage renal failure.interstitial nephritis and end-stage renal failure.

The efficacy of lithium is unpredictable. The efficacy of lithium is unpredictable.

Additional side effects include Additional side effects include hypothyroidism, tremor and rarely, hypothyroidism, tremor and rarely, hyperparathyroidism.hyperparathyroidism.

Because of these side effects,the use of Because of these side effects,the use of lithium to treat SIADH has been mostly lithium to treat SIADH has been mostly abandoned.abandoned.

UreaUrea It is a major osmotic constituent of urine, accounting for It is a major osmotic constituent of urine, accounting for

half of the daily osmolar load excreted.half of the daily osmolar load excreted. Brodsy and Rapoport demonstrated that as solute Brodsy and Rapoport demonstrated that as solute

excretion increases, the osmolality of urine decreases, excretion increases, the osmolality of urine decreases, despite maximal doses of vasopressin . This has led despite maximal doses of vasopressin . This has led investigators to pursue the effects of increasing free investigators to pursue the effects of increasing free water clearance by administering urea .water clearance by administering urea .

Urea can be given by mouth, either as a powder or in Urea can be given by mouth, either as a powder or in capsules, and thus results in an osmotic diuresis. capsules, and thus results in an osmotic diuresis.

Due to its bitter taste, its use has not met wide Due to its bitter taste, its use has not met wide acceptance. acceptance.

Brodsky WABrodsky WA J Clin Invest. J Clin Invest. 1951;30:282–2911951;30:282–291

Extracorporeal treatmentsExtracorporeal treatments

Rapid correction of hyponatraemia may occur Rapid correction of hyponatraemia may occur during haemodialysis, in some instances leading during haemodialysis, in some instances leading to pontine myelinolysis. to pontine myelinolysis.

Veno-venous haemofiltration has been shown to Veno-venous haemofiltration has been shown to induce a more gradual correction of induce a more gradual correction of hyponatraemia and other forms of slow dialysis hyponatraemia and other forms of slow dialysis treatment, such as slow low-efficiency daily treatment, such as slow low-efficiency daily dialysis (SLEDD), may be equally effective.dialysis (SLEDD), may be equally effective.

Cost is the limitation.Cost is the limitation.

The vaptans The vaptans A vasopressin-receptor antagonist A vasopressin-receptor antagonist Also called as ‘Also called as ‘aquaretics'aquaretics' Vasopressin exerts its antidiuretic effect by binding to the Vasopressin exerts its antidiuretic effect by binding to the

V2 receptors, which are situated in the basolateral V2 receptors, which are situated in the basolateral surface of the cells of the collecting duct of the kidney.surface of the cells of the collecting duct of the kidney.

Receptor binding initiates an intracellular cascade which Receptor binding initiates an intracellular cascade which generates adenyl cyclase and an increase of intracellular generates adenyl cyclase and an increase of intracellular cAMP. This causes protein synthesis, which leads to the cAMP. This causes protein synthesis, which leads to the production of mRNA for aquaporin-2, and insertion of production of mRNA for aquaporin-2, and insertion of pre-formed aquaporin into the apical membrane of the pre-formed aquaporin into the apical membrane of the cell, allowing passage of free water across the cell, to be cell, allowing passage of free water across the cell, to be reabsorbed into the renal vasculature reabsorbed into the renal vasculature

The vaptans competitively bind to the V2 receptors, The vaptans competitively bind to the V2 receptors, preventing vasopressin-mediated generation of preventing vasopressin-mediated generation of aquaporin-2, thus causing a solute-free aquaresis aquaporin-2, thus causing a solute-free aquaresis

V2 receptor antagonists in the V2 receptor antagonists in the treatment of SIADH.treatment of SIADH.

Drug Receptor Mode ofDrug Receptor Mode of Name Action administration Name Action administration

Tolvaptan V2 Oral Tolvaptan V2 Oral Conivaptan V1a and V2 I.v./oral Conivaptan V1a and V2 I.v./oral Lixivaptan V2 Oral Lixivaptan V2 Oral Mozavaptan V2 OralMozavaptan V2 Oral

Satavaptan V2 OralSatavaptan V2 Oral

V1 and V2, vasopressin receptors 1 and 2. V1 and V2, vasopressin receptors 1 and 2.

Indicaton- chronic SIADH and persistently Indicaton- chronic SIADH and persistently elevated levels of vasopressin .elevated levels of vasopressin .

Fluid restriction is usually a burden to the Fluid restriction is usually a burden to the patient, unreliable, impractical and slow to patient, unreliable, impractical and slow to work.work.

Trials and proven data still lacking.Trials and proven data still lacking.

Only marketed in Europe and US so far.Only marketed in Europe and US so far.

Contraindication -Contraindication -severe symptomatic severe symptomatic hyponatraemia (serum sodium <120 mmol/L)hyponatraemia (serum sodium <120 mmol/L)

hypovolaemic forms of hyponatraemia hypovolaemic forms of hyponatraemia

The problem is that volume status is not always The problem is that volume status is not always easy to estimate clinically.easy to estimate clinically.

If the sodium concentration in the urine is above If the sodium concentration in the urine is above 40 mmol/L, in a patient with preserved renal 40 mmol/L, in a patient with preserved renal function, normal dietary salt intake and not on function, normal dietary salt intake and not on diuretics, one can assume with reasonable diuretics, one can assume with reasonable safety that the patient is not volume depleted. safety that the patient is not volume depleted.

Diuretic use and adrenal insufficiency Diuretic use and adrenal insufficiency should be excluded .should be excluded .

Patients with anuria, volume depletion, Patients with anuria, volume depletion, hypernatraemia or in those who cannot hypernatraemia or in those who cannot perceive thirst, and, in addition, during perceive thirst, and, in addition, during pregnancy or breastfeeding also drug is pregnancy or breastfeeding also drug is contraindicatedcontraindicated

How should treatment be How should treatment be monitored?monitored?

Occurrence of hypernatraemia Occurrence of hypernatraemia Increased thirst secondary to increase in Increased thirst secondary to increase in

serum osmolality could be limitation thus serum osmolality could be limitation thus leading to increase water intake and leading to increase water intake and prevent hypernatremiaprevent hypernatremia

Discontinuation of a vaptan every 6–8 Discontinuation of a vaptan every 6–8 weeks, in order to observe whether weeks, in order to observe whether hyponatraemia recurs, before treatment is hyponatraemia recurs, before treatment is continued. continued.

SUMMARYSUMMARY

SIADH is one of the most common cause SIADH is one of the most common cause of hyponatremia in in-hospital admissions.of hyponatremia in in-hospital admissions.

The patient is hyponatremic with a low The patient is hyponatremic with a low serum osmolality, which normally would serum osmolality, which normally would inhibit ADH secretion.inhibit ADH secretion.

Exclude hypothyroid and adrenal Exclude hypothyroid and adrenal insufficiency.insufficiency.

Look at the volume status of the patient.Look at the volume status of the patient.

sodium concentration in the urine >40 sodium concentration in the urine >40 mmol/L, with preserved renal function, mmol/L, with preserved renal function, normal dietary salt intake and not on normal dietary salt intake and not on diuretics, essentially rules out hypovolemic diuretics, essentially rules out hypovolemic state. state.

Fluid restriction is the main stay of Fluid restriction is the main stay of treatment which is practically tough.treatment which is practically tough.

Hyertonic saline to be preferred in Hyertonic saline to be preferred in moderate to severe symptomatic moderate to severe symptomatic hyponatremia .hyponatremia .

Future medical therapy like vaptans offer Future medical therapy like vaptans offer better treatment options but still safety and better treatment options but still safety and efficacy trials are lacking.efficacy trials are lacking.