SIADH

1. SIADHSIADH
SYNDROME OF INAPPROPRIATE SYNDROME OF INAPPROPRIATE
SECRETION OF ANTI DIURETIC HORMONESECRETION OF ANTI DIURETIC HORMONE
22.12.1022.12.10

2. 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

3. 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.

4. 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 of mild hyponatraemia (<135 mmol/l) was
4% in a randomly selected control group of 4% 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

5. 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

6. 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.

8. 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 urine
Urine volume is decreasedUrine volume is decreased
Concentration of urine is increasedConcentration of urine is increased

9. 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 . .

10. Syndrome of Inappropriate Syndrome of Inappropriate

AntiDiuretic Hormone AntiDiuretic Hormone
SIADH 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.

11. ………….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

12. Cardiac failure or
cirrhosis on diuretic
therapy
Cirrhosis
Cardiac failure
Nephrotic syndrome
Peripheral oedema
Ascites
Raised JVP
Pulmonary oedema
Underlying illness
Hypervolaemic
SIADH
ACTH deficiency
Hypothyroidism
SIADH with ongoing
fluid restriction
Primary polydipsia
Inappropriate fluid
replacement
Underlying illness Euvolaemic
Diuretics
Addison's disease
Cerebral salt wasting
Salt wasting
nephropathy
GI losses,
Mucosal losses,
Pancreatitis
Sodium depletion
post diuretics
Dry mucous
membranes,
Decreased turgor,
Tachycardia,
Hypotension
(orthostatic),
Raised urea, rennin
Hypovolaemic
Urinary Na+>40
mmol/l
Urinary Na+<20
mmol/l
Clinical signs

13. 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

14. 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.

15. 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

16. 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

17. 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

18. 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
TumourTumour
MeningitisMeningitis
EncephalitisEncephalitis
AbscessAbscess
VasculitisVasculitis
Subarachnoid haemorrhageSubarachnoid haemorrhage
Subdural haemorrhageSubdural haemorrhage
Traumatic brain injuryTraumatic brain injury

19. Miscellaneous : Miscellaneous :
Multiple sclerosis Multiple sclerosis
Guillain–Barre syndromeGuillain–Barre syndrome
Acute intermittent porphyria Acute intermittent porphyria
HIV HIV
IdiopathicIdiopathic

20. 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

21. 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 .

22. 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

23. 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.

24. 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

25. 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.

26. 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

27. 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

28. 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.

29. 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

30. Laboratory Evaluation Laboratory Evaluation
Serum osmolalitySerum osmolality
Serum sodium levels Serum sodium levels
Urine osmolalityUrine osmolality
Urine spot sodium >40mEq/lUrine spot sodium >40mEq/l
Fractional excretion of sodium>0.5%Fractional excretion of sodium>0.5%
FEurea >55% FEurea >55%
Low urea <30mg/dlLow urea <30mg/dl
Low uric acid Low uric acid

31. 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.

32. TREATMENTTREATMENT
FLUID RESTRICTIONFLUID RESTRICTION
Water restriction is regarded as first-line Water restriction is regarded as first-line
treatment for hyponatraemia due to treatment for hyponatraemia due to
SIADHSIADH
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

33. 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 .

34. 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).

35. 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.

36. 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).

37. 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

38. 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.

39. 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.

40. 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.

41.  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.

42. 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

43. 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.

44. 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

45. 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.

46. 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.

47. 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.

48. 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

49. 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.

50. 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.

51. 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.