This presentation was done in October 2011 for an SpR seminar. It's exhaustive, but I hope you will learn somethng helpful!

1. Water and Sodium
Handling / Dysnatraemias
Richard McCrory

2. Aim of SeminarAim of Seminar
‘‘To progressively develop the ability to undertakeTo progressively develop the ability to undertake
specialist assessment and treatment of patients withspecialist assessment and treatment of patients with
disorders ofdisorders of fluidfluid,, electrolyteelectrolyte and acid baseand acid base
regulation’regulation’
(JRCPTB Specialty Training Curriculum in Renal Medicine, August 2010)(JRCPTB Specialty Training Curriculum in Renal Medicine, August 2010)

3. Objectives of Seminar SessionObjectives of Seminar Session
• Total Body WaterTotal Body Water
• Regulation of Sodium and Water BalanceRegulation of Sodium and Water Balance
• HyponatraemiaHyponatraemia
– HypovolaemicHypovolaemic
– HypervolaemicHypervolaemic
– EuvolaemicEuvolaemic
• Management of low [NaManagement of low [Na++
]]
• VaptansVaptans

4. ““Control the water, and youControl the water, and you
control everything.”control everything.”

5. Key Concepts about Body WaterKey Concepts about Body Water
The relative size of the compartments and spaces isThe relative size of the compartments and spaces is
solely determined by the amount ofsolely determined by the amount of solutesolute trapped intrapped in
the compartmentsthe compartments and spaces.and spaces.
OsmolalityOsmolalityECFECF = Osmolality= OsmolalityICFICF
Water distributes to achieve osmoticWater distributes to achieve osmotic equilibriumequilibrium across cell membranesacross cell membranes
Sodium [NaSodium [Na++
] predominant cation in Extracellular Space] predominant cation in Extracellular Space
Potassium [KPotassium [K++
] predominant cation in Intracellular Space] predominant cation in Intracellular Space
Solute distribution maintained by active transport (NaSolute distribution maintained by active transport (Na++
/K/K++
ATPase)ATPase)
The capillary wall is permeable to electrolytes but isThe capillary wall is permeable to electrolytes but is
impermeable to proteinsimpermeable to proteins

6. Total Body WaterTotal Body Water
InterstitialInterstitialPlasmaPlasma
TBW (70kg male)TBW (70kg male) == 45L (60% weight)45L (60% weight)
=12L=12L=3L=3L
(5% weight) (15% weight)(5% weight) (15% weight)
IntracellularIntracellular=30L=30L

7. Regulating Sodium and WaterRegulating Sodium and Water
Na+
and H2O are regulated independently
[Na+
] | [H2O]
Disorders of water can present as abnormal sodium
levels, and disorders of sodium levels present as
volume dysregulation.
Volume receptors and theVolume receptors and the
kidney.kidney.
Thirst and renal ADHThirst and renal ADH
activityactivity

8. CASE 1CASE 1
50-year-old man admitted to CCU50-year-old man admitted to CCU
with a myocardial infarction haswith a myocardial infarction has
a [Naa [Na++
] of 124 mmol/L. The] of 124 mmol/L. The
sample is lipaemic. Which of thesample is lipaemic. Which of the
following is most likely tofollowing is most likely to
establish the cause of his lowestablish the cause of his low
[Na[Na++
]?]?
(A) Serum osmolality(A) Serum osmolality
(B) Serum uric acid(B) Serum uric acid
(C) Urine osmolality(C) Urine osmolality
(D) Urine sodium(D) Urine sodium

9. CASE 2CASE 2
A 76 year old diabetic patient presents withA 76 year old diabetic patient presents with
marked hyperglycaemiamarked hyperglycaemia
Measured Sodium = 124 mmol/LMeasured Sodium = 124 mmol/L
Venous Glucose = 58 mmol/LVenous Glucose = 58 mmol/L
Serum Osmolality = 317 mOsm/LSerum Osmolality = 317 mOsm/L
What is the cause of his hyponatraemia?What is the cause of his hyponatraemia?

10. PseudohyponatraemiaPseudohyponatraemia
Pseudohyponatraemia is a decreased serum sodiumPseudohyponatraemia is a decreased serum sodium
without an associated decrease in serum osmolality.without an associated decrease in serum osmolality.
1. Low [Na1. Low [Na++
] with a] with a normal plasma osmolality.normal plasma osmolality.
– This is due to a measurement error which occurs in the presence of highThis is due to a measurement error which occurs in the presence of high
protein or lipid levelsprotein or lipid levels
– the water fraction of plasma-containing electrolytes is reduced, andthe water fraction of plasma-containing electrolytes is reduced, and
indirect methods, which dilute the sample before analysis, give spuriousindirect methods, which dilute the sample before analysis, give spurious
low sodium resultslow sodium results [a][a]
2. Low [Na2. Low [Na++
] with a] with a high plasma osmolalityhigh plasma osmolality
(redistributive)(redistributive)
– This occurs with hyperglycemia or following a mannitol infusion.This occurs with hyperglycemia or following a mannitol infusion.
[a] R.A. Sulaiman, P.J. Twomey, R. Gama. Mitigation and detection of[a] R.A. Sulaiman, P.J. Twomey, R. Gama. Mitigation and detection of
spurious potassium and sodium resultsspurious potassium and sodium results Clinica Chimica Acta (2011) 412; 14: 1-6Clinica Chimica Acta (2011) 412; 14: 1-6

11. True HyponatraemiaTrue Hyponatraemia
LowLow [Na[Na++
], associated with], associated with lowlow serum osmolality, isserum osmolality, is
due to a patient withdue to a patient with more water ingestion thanmore water ingestion than
water excretionwater excretion..
1.1. Renal Failure (fluid intake > urine excretion)Renal Failure (fluid intake > urine excretion)
2.2. Excessive fluid intake exceeds the kidney’sExcessive fluid intake exceeds the kidney’s
ability to make urineability to make urine
3.3. Decreased water excretionDecreased water excretion

12. CASE 3 (leading to payout of $16.5CASE 3 (leading to payout of $16.5
million)million)
In 2007, a 28 year old woman (64 kg, 50%In 2007, a 28 year old woman (64 kg, 50%
TBW) took part in a radio contest to win aTBW) took part in a radio contest to win a
Wii. She drank 7.5 litres of water in 2Wii. She drank 7.5 litres of water in 2
hours. She is dead within 6 hours...hours. She is dead within 6 hours...
Assuming she had a normal [Na] (140Assuming she had a normal [Na] (140
mmol/L) before starting the contest andmmol/L) before starting the contest and
she excreted 1.5 litres of water, how lowshe excreted 1.5 litres of water, how low
was her sodium when she died?was her sodium when she died?

13. Original [NaOriginal [Na++
] X] X
Original TBWOriginal TBW
(Original TBW + Residual H(Original TBW + Residual H22O)O)
= 140 X [32 / (32 + 6)]= 140 X [32 / (32 + 6)]
= 140 X [0.842] == 140 X [0.842] = 117 mmol/L117 mmol/L
Slides from Joel Topf

14. Rapid PhaseRapid Phase
Intracellular Na+/K+Intracellular Na+/K+
ejected to decreaseejected to decrease
osmotic movement ofosmotic movement of
water.water.
Slow PhaseSlow Phase
Osmolytes (e.g. Sorbitol)Osmolytes (e.g. Sorbitol)
ejected to adapt to newejected to adapt to new
equilibriumequilibrium

15. Water Excretion and ADHWater Excretion and ADH

16. Anti-diuretic Hormone aka. ArginineAnti-diuretic Hormone aka. Arginine
VasopressinVasopressin
– Nine amino acid peptide afterNine amino acid peptide after
cleavage from it’s precursorscleavage from it’s precursors
– Synthesized in the hypothalamusSynthesized in the hypothalamus
and stored in vesicles atand stored in vesicles at
the posterior pituitarythe posterior pituitary
– Plasma tPlasma t1/21/2 = 5 minutes= 5 minutes

17. ADH StimulationADH Stimulation
ADH is stimulated by three triggers:ADH is stimulated by three triggers:
1. High osmolality: a 1% increase in osmolality will1. High osmolality: a 1% increase in osmolality will
stimulate ADHstimulate ADH
2. Decrease in effective circulating volume2. Decrease in effective circulating volume
– Baroreceptor ResponseBaroreceptor Response
– Angiotensin-IIAngiotensin-II
3. Non-physiological (‘Inappropriate’) Stimuli3. Non-physiological (‘Inappropriate’) Stimuli

19. Carotid BodyCarotid Body
Aortic ArchAortic Arch
Vagus NervesVagus Nerves
GlossopharyngealGlossopharyngeal
HypothalmusHypothalmus Baroregulation of ADHBaroregulation of ADH
Afferent neuronsAfferent neurons
•Aortic ArchAortic Arch
•Carotid BodiesCarotid Bodies
•Atrial Wall and Great VeinsAtrial Wall and Great Veins
Efferent NeuronsEfferent Neurons
•From the nucleus tractusFrom the nucleus tractus
solitarus to the supra-opticsolitarus to the supra-optic
and paraventricular nuclei ofand paraventricular nuclei of
hypothalamushypothalamus

21. ReceptorReceptor LocationLocation ActionsActions
VV1a1a Vascular smooth muscle cellsVascular smooth muscle cells VasoconstrictionVasoconstriction
CardiomyocytesCardiomyocytes HypertrophyHypertrophy
HepatocytesHepatocytes GlycogenolysisGlycogenolysis
PlateletsPlatelets Platelet aggregationPlatelet aggregation
VV1b1b aka Vaka V33 Anterior pituitaryAnterior pituitary ACTH and Endorphin releaseACTH and Endorphin release
VV22 β-Cells in pancreasβ-Cells in pancreas Insulin and glucagon secretionInsulin and glucagon secretion
Renal collecting ductsRenal collecting ducts Water RetentionWater Retention
Ascending limb of HenléAscending limb of Henlé Sodium, potassium, andSodium, potassium, and
chloride co-transportchloride co-transport
Endothelial cellsEndothelial cells von Willebrand factor secretionvon Willebrand factor secretion
Location and Action of VasopressinLocation and Action of Vasopressin
ReceptorsReceptors

22. Vasopressin V2 receptor activation.Vasopressin V2 receptor activation.
Finley J J et al. Circulation 2008;118:410-421Finley J J et al. Circulation 2008;118:410-421

23. Concentrating Capacity andConcentrating Capacity and
Generation of UrineGeneration of Urine
The kidney is able to concentrate urine toThe kidney is able to concentrate urine to
1200mOsm/L or dilute urine to 50 mOsm/L1200mOsm/L or dilute urine to 50 mOsm/L
If a patient takes in a solute load of 600mOsmIf a patient takes in a solute load of 600mOsm
What is the minimum amount of urine the patient canWhat is the minimum amount of urine the patient can
make to clear the solute load (maximal ADH)?make to clear the solute load (maximal ADH)? 500ml500ml
What is the maximum amount of urine the patient canWhat is the maximum amount of urine the patient can
make (minimal ADH)?make (minimal ADH)? 12,000ml12,000ml
If the solute load is low (180 mOsm) what is theIf the solute load is low (180 mOsm) what is the
minimum amount of urine possible to make?minimum amount of urine possible to make? 150ml150ml

24. CASE 4CASE 4
An 82 year old woman was referred to clinic with a lowAn 82 year old woman was referred to clinic with a low
sodium. She described her diet as a sandwich forsodium. She described her diet as a sandwich for
breakfast, some fruit and juice with some nuts forbreakfast, some fruit and juice with some nuts for
lunch and nothing for dinner. Her fluid intake waslunch and nothing for dinner. Her fluid intake was
high (4-5 cups of coffee, a large bottle of water, and ahigh (4-5 cups of coffee, a large bottle of water, and a
couple of additional glasses of juice). She iscouple of additional glasses of juice). She is
otherwise relatively well.otherwise relatively well.
Blood resultsBlood results
Plasma sodium 128 mmol/LPlasma sodium 128 mmol/L
Plasma osmolality 277 mOsm/kgPlasma osmolality 277 mOsm/kg
Urine osmolality 180 mOsm/kg Urine Sp.Gravity 1.005Urine osmolality 180 mOsm/kg Urine Sp.Gravity 1.005
Urine sodium 14 mmol/LUrine sodium 14 mmol/L TFTs NormalTFTs Normal
What is the cause of her hyponatraemia?What is the cause of her hyponatraemia?

25. Hyponatraemia due to Concentrating DefectHyponatraemia due to Concentrating Defect
Poor dietary intake can lower the daily urinary solutePoor dietary intake can lower the daily urinary solute
excretion to below 300 mOsm, resulting in significantexcretion to below 300 mOsm, resulting in significant
reduction inreduction in urine volume.urine volume.
Examples:Examples:
• Beer drinker’s potomaniaBeer drinker’s potomania
– high water intake, low solute load, low dietary proteinhigh water intake, low solute load, low dietary protein
• Tea and toast hyponatremiaTea and toast hyponatremia
– a diet that is deficient in salt and proteina diet that is deficient in salt and protein
Hyponatremia develops if fluid intake is greater than theHyponatremia develops if fluid intake is greater than the
maximum amount of urine output that can be generatedmaximum amount of urine output that can be generated
to clear solute load.to clear solute load.

26. Hypovolaemic HyponatraemiaHypovolaemic Hyponatraemia
[Na+] deficit > [H2O] Deficit[Na+] deficit > [H2O] Deficit
Volume Contraction → Ineffective Circulating Volume →Volume Contraction → Ineffective Circulating Volume → Non-osmotic ADHNon-osmotic ADH
Fluid Losses from the GI tract / Burns / Peritonitis / Pancreatitis /Fluid Losses from the GI tract / Burns / Peritonitis / Pancreatitis /
Excess Sweating – Urinary Sodium usuallyExcess Sweating – Urinary Sodium usually lowlow
Diuretic Use / Salt Losing Nephropathy / MineralocorticoidDiuretic Use / Salt Losing Nephropathy / Mineralocorticoid
Deficiency / Osmotic Diuresis / Cerebral Salt Wasting – UrinaryDeficiency / Osmotic Diuresis / Cerebral Salt Wasting – Urinary
Sodium usuallySodium usually highhigh

28. Hyponatraemia during Long DistanceHyponatraemia during Long Distance
RunningRunning
• 488 runners, Boston Marathon 2002488 runners, Boston Marathon 2002
• 13% hyponatraemic (≤13513% hyponatraemic (≤135 μμmol/l)mol/l)
• Hyponatraemia associated with:Hyponatraemia associated with:
– Substantial weight gainSubstantial weight gain
– Consumption of > 3 litres of fluid during raceConsumption of > 3 litres of fluid during race
– Racing time > 4 hoursRacing time > 4 hours
– Female sexFemale sex
– Low body mass indexLow body mass index

30. Exercise Associated Hyponatraemia inExercise Associated Hyponatraemia in
the London Marathon, 2006the London Marathon, 2006
Of 88 volunteers, 11 (12.5%)Of 88 volunteers, 11 (12.5%) developeddeveloped
asymptomatic hyponatraemia (serumasymptomatic hyponatraemia (serum
sodium 128–134 mmol/l).sodium 128–134 mmol/l).
• On average, they consumed more fluidOn average, they consumed more fluid
and gained more weight thanand gained more weight than did thosedid those
without hyponatraemia.without hyponatraemia.
• Four of the 11 hyponatraemic runnersFour of the 11 hyponatraemic runners lostlost weightweight
over the course of the marathon.over the course of the marathon.

31. CASE 5CASE 5
An 80 yr old woman is admitted to hospital alert andAn 80 yr old woman is admitted to hospital alert and
conscious, but mildly disorientated in time and placeconscious, but mildly disorientated in time and place
over the past 2 days. She had antihypertensiveover the past 2 days. She had antihypertensive
therapy added 3 weeks ago. On exam her pulse istherapy added 3 weeks ago. On exam her pulse is
70/min and regular, BP 150/90 with no postural drop.70/min and regular, BP 150/90 with no postural drop.
She has no oedemaShe has no oedema
[Na[Na++
] 105 mmol/l] 105 mmol/l [K[K++
] 3.3 mmol/l] 3.3 mmol/l
[Cl-] 66 mmol/l[Cl-] 66 mmol/l [HCO3-] 29 mmol/l[HCO3-] 29 mmol/l
Urea 4 mmol/lUrea 4 mmol/l Creatinine 90 µmol/LCreatinine 90 µmol/L
UrinalysisUrinalysis:: Specific gravity 1.020 Otherwise NADSpecific gravity 1.020 Otherwise NAD

32. The most appropriate management followingThe most appropriate management following
admission isadmission is
1.1. Stop drugs and administer N-salineStop drugs and administer N-saline
2.2. Stop drugs and administer hypertonic 3NStop drugs and administer hypertonic 3N
salinesaline
3.3. Stop drugs and administer a loop diureticStop drugs and administer a loop diuretic
4.4. Stop drugs and administer desmopressinStop drugs and administer desmopressin
5.5. Strop drugs and permit free oral intakeStrop drugs and permit free oral intake

33. Diuretic InducedDiuretic Induced
HyponatraemiaHyponatraemia

35. CortexCortex
MedullaMedulla
NaNa++
KK++
ClCl--
NKCC2NKCC2
Hyponatraemia with Loop DiureticsHyponatraemia with Loop Diuretics
Blocking this channel
will ‘dilute’ the medullary
gradient

36. CortexCortex
MedullaMedulla
ClCl--
NaNa++
NCCNCC
Hyponatraemia with ThiazidesHyponatraemia with Thiazides
Relative hypotension
stimulates ADH, but the
medullary gradient is not
altered, leading to free
water accumulation

37. Hypervolaemic HyponatraemiaHypervolaemic Hyponatraemia
[Na+] excess < [H2O] Excess[Na+] excess < [H2O] Excess
Poor cardiac output (Heart Failure) ORPoor cardiac output (Heart Failure) OR
Splanchnic Vessel Dilatation (Cirrhosis) ORSplanchnic Vessel Dilatation (Cirrhosis) OR
Low Oncotic Pressure (Nephrotic Syndrome) → IneffectiveLow Oncotic Pressure (Nephrotic Syndrome) → Ineffective
Circulating Volume →Circulating Volume →
Non-osmotic ADH secretionNon-osmotic ADH secretion
Two seemingly different causes of hyponatremia, share
a single pathophysiologic explanation.

38. Hypervolaemic Hyponatraemia:Hypervolaemic Hyponatraemia:
Impact on morbidity / mortalityImpact on morbidity / mortality
Heart FailureHeart Failure
Hyponatraemic patients had increased risk ofHyponatraemic patients had increased risk of
hospitalization or death was an independent predictor ofhospitalization or death was an independent predictor of
all-cause mortalityall-cause mortality(a)(a)
Liver CirrhosisLiver Cirrhosis
Sodium is an independent predictor of mortality inSodium is an independent predictor of mortality in
patients awaiting liver transplant when used withpatients awaiting liver transplant when used with
prognostic scores such as MELDprognostic scores such as MELD(b)(b)
(a)(a) Balling et al.Balling et al. Eur J Heart Fail (2011) 13 (9): 968-973.Eur J Heart Fail (2011) 13 (9): 968-973.
(b)(b) Kim et al N Engl J Med 2008; 359:1018-1026Kim et al N Engl J Med 2008; 359:1018-1026

39. From Kim et alFrom Kim et al N Engl J Med 2008; 359:1018-1026N Engl J Med 2008; 359:1018-1026

40. Hyponatraemia in Oligo-anuricHyponatraemia in Oligo-anuric
Renal FailureRenal Failure
Decreased number of functioning nephrons leadsDecreased number of functioning nephrons leads
to impairment in excretion of [Na] and [H2O]to impairment in excretion of [Na] and [H2O]
Even modest fluid intake may exceed threshold ofEven modest fluid intake may exceed threshold of
clearing excess water, leading to hypervolaemiaclearing excess water, leading to hypervolaemia
At GFR of 5ml/min – 7.2 litres of filtrate generatedAt GFR of 5ml/min – 7.2 litres of filtrate generated
and only 30% reaches the diluting segment ofand only 30% reaches the diluting segment of
the nephronthe nephron
Another form of hyponatraemia caused by aAnother form of hyponatraemia caused by a
concentrating defectconcentrating defect

41. Hyponatraemia in theHyponatraemia in the
Haemodialysis CohortHaemodialysis Cohort
• Follow-up of 1549 patients from the HEMO trialFollow-up of 1549 patients from the HEMO trial
(1995-2000)(1995-2000)
• Lower pre-dialysis [Na] serum in dialysis patientsLower pre-dialysis [Na] serum in dialysis patients
are associated with an increased risk of death,are associated with an increased risk of death,
even adjusting for multiple variableseven adjusting for multiple variables(a)(a)
(a)(a) Waikar et al. Mortality Associated with Low SerumWaikar et al. Mortality Associated with Low Serum
Sodium Concentration in Maintenance Hemodialysis.Sodium Concentration in Maintenance Hemodialysis.
The American Journal of Medicine (2011) 124, 77-84The American Journal of Medicine (2011) 124, 77-84

42. CASE 6CASE 6
38-year-old, admitted at 37 weeks with pre-38-year-old, admitted at 37 weeks with pre-
eclampsia. Her blood pressure was 130/90 andeclampsia. Her blood pressure was 130/90 and
there was bipedal oedema. Proteinuria was 1.9g/there was bipedal oedema. Proteinuria was 1.9g/
24h. Plasma [Na24h. Plasma [Na++
] was 131 mmol/l. She was treated] was 131 mmol/l. She was treated
pre-emptively with magnesium and labour waspre-emptively with magnesium and labour was
induced.induced.
Her plasma [NaHer plasma [Na++
] decreased to 129 mmol/l after] decreased to 129 mmol/l after
administering oxytocin and an infusion was continued foradministering oxytocin and an infusion was continued for
poor uterine contractility. The plasma sodium concentrationpoor uterine contractility. The plasma sodium concentration
then decreased to 123 mmol/l. She was asymptomatic.then decreased to 123 mmol/l. She was asymptomatic.
Once oxytocin, the plasma sodium concentration hadOnce oxytocin, the plasma sodium concentration had
increased to 133 mmol/l in 24 hours. On discharge it wasincreased to 133 mmol/l in 24 hours. On discharge it was
137 mmol/l.137 mmol/l.
What are the mechanisms that can promote fluidWhat are the mechanisms that can promote fluid
retention and low sodium in pregnancy?retention and low sodium in pregnancy?

43. Physiologic Changes in Salt and WaterPhysiologic Changes in Salt and Water
Homeostasis in pregnancyHomeostasis in pregnancy
• Sodium (900mmol) and HSodium (900mmol) and H22O retention (8-10 litres) isO retention (8-10 litres) is
needed for the mother and the growing foetus.needed for the mother and the growing foetus.
• Systemic and renal vasodilatationSystemic and renal vasodilatation
– Relaxin and oestrogenic hormones, secreted by corpusRelaxin and oestrogenic hormones, secreted by corpus
luteum / placentaluteum / placenta
• Increase in GFR (50% increase by the end of the firstIncrease in GFR (50% increase by the end of the first
trimester) but decreased effective fluid volumetrimester) but decreased effective fluid volume
– Activation of Angiotensin / ADH (alsoActivation of Angiotensin / ADH (also
pain/nausea/anxiety)pain/nausea/anxiety)
• Average plasma-osmolality is decreased by 5-10Average plasma-osmolality is decreased by 5-10
mOsmol. [NamOsmol. [Na++
] can decrease by 5 mmol/l but] can decrease by 5 mmol/l but
significant hyponatraemia issignificant hyponatraemia is rarerare
• Oxytocin has ADH effects that can promote waterOxytocin has ADH effects that can promote water
retentionretention

44. CASE 7CASE 7
A 49-year-old woman presented to the emergency department withA 49-year-old woman presented to the emergency department with
nausea and vomiting that had occurred for 5 days and slurrednausea and vomiting that had occurred for 5 days and slurred
speech for 1 day prior to presentation. The patient denied use ofspeech for 1 day prior to presentation. The patient denied use of
alcohol and illicit drugs.alcohol and illicit drugs.
Physical examination revealed her blood pressure to be 125/70Physical examination revealed her blood pressure to be 125/70
mmHg; she had no postural drop and had a regular pulse of 72mmHg; she had no postural drop and had a regular pulse of 72
beats/min. She had no fever and no signs of contracted extracellularbeats/min. She had no fever and no signs of contracted extracellular
fluid volume. Remaining exam normal. Normal CT brain.fluid volume. Remaining exam normal. Normal CT brain.

45. What is the working diagnosis?What is the working diagnosis?
After 48 hours of 500ml fluid restriction, herAfter 48 hours of 500ml fluid restriction, her
[Na[Na++
] remains 102 mmol/L] remains 102 mmol/L
What’s gone wrong?What’s gone wrong?
The differential diagnosis of low [Na], lowThe differential diagnosis of low [Na], low
PPosmosm and high Uand high Uosmosm is consistent with ADHis consistent with ADH
activity. But is itactivity. But is it inappropriateinappropriate??????
What are the other causes of a high urinaryWhat are the other causes of a high urinary
sodium in this setting?sodium in this setting?

46. More tests are sent!More tests are sent!
TSH 63 IU/L T4 5 pmol/LTSH 63 IU/L T4 5 pmol/L
Random Cortisol 105 nmol/LRandom Cortisol 105 nmol/L
Synacthen Test – increment increase of 57nmol/LSynacthen Test – increment increase of 57nmol/L
(Normal >500)(Normal >500)
Parietal cell / Adrenal cortex / Thyroid peroxidaseParietal cell / Adrenal cortex / Thyroid peroxidase
antibodies detectedantibodies detected
Final Diagnosis: Autoimmune PolyglandularFinal Diagnosis: Autoimmune Polyglandular
SyndromeSyndrome (a)(a)
(a) van der Hoek.(a) van der Hoek. Clinical Chemistry.Clinical Chemistry. 2009;55:1905-19082009;55:1905-1908

47. Euvolaemic HyponatraemiaEuvolaemic Hyponatraemia
Don’t forgetDon’t forget
• Glucocorticoid deficiencyGlucocorticoid deficiency
• HypothyroidismHypothyroidism
• DrugsDrugs
• SIADH is a diagnosis of exclusionSIADH is a diagnosis of exclusion
– And then you start hunting for the cause ofAnd then you start hunting for the cause of
the SIADH!the SIADH!

48. SIADH – The Laundry ListSIADH – The Laundry List
Lung diseases and interventionsLung diseases and interventions
PneumoniaPneumonia TuberculosisTuberculosis
Lung abscess, empyemaLung abscess, empyema
Acute respiratory failureAcute respiratory failure
Positive pressure ventilationPositive pressure ventilation
Perioperative Period - associated with the stressPerioperative Period - associated with the stress
response to injury and painresponse to injury and pain
DrugsDrugs
CyclophosphamideCyclophosphamide CarbamazepineCarbamazepine
Vincristine or vinblastineVincristine or vinblastine PhenothiazinesPhenothiazines
HaloperidolHaloperidol TCAs or SSRIsTCAs or SSRIs
MAOIsMAOIs BromocriptineBromocriptine
LorcainideLorcainide ClofibrateClofibrate
General anesthesiaGeneral anesthesia OpiatesOpiates
NicotineNicotine
Increased Hypothalmic Production of ADHIncreased Hypothalmic Production of ADH
Neuropsychiatric disordersNeuropsychiatric disorders
Infections:Infections: meningitismeningitis, encephalitis, brain abscess, encephalitis, brain abscess
Vascular: thrombosis,Vascular: thrombosis, subarachnoid or subduralsubarachnoid or subdural
hemorrhagehemorrhage, temporal arteritis, cavernous sinus, temporal arteritis, cavernous sinus
thrombosis, strokethrombosis, stroke
Neoplasm: primary or metastaticNeoplasm: primary or metastatic
Skull fracture, traumatic brain injurySkull fracture, traumatic brain injury
Psychosis, delirium tremensPsychosis, delirium tremens
Other: Guillain-Barré syndrome, acute intermittentOther: Guillain-Barré syndrome, acute intermittent
porphyria, autonomic neuropathy, postpituitaryporphyria, autonomic neuropathy, postpituitary
surgery, multiple sclerosis, epilepsy,surgery, multiple sclerosis, epilepsy,
hydrocephalus, lupus.hydrocephalus, lupus.
Ectopic production of ADHEctopic production of ADH
Solid Organ Cancer:Solid Organ Cancer:
Lung (especially small cell)Lung (especially small cell), duodenum,, duodenum,
pancreas, thymus, olfactory neuroblastoma,pancreas, thymus, olfactory neuroblastoma,
bladder, prostate, uterusbladder, prostate, uterus
LymphosarcomaLymphosarcoma
MesotheliomaMesothelioma
Ewing sarcomaEwing sarcoma
Hodgkin's diseaseHodgkin's disease
LeukemiaLeukemia

49. Management of HyponatraemiaManagement of Hyponatraemia
• How quick is duration of onset? How lowHow quick is duration of onset? How low
is [Nais [Na++
]? And are they symptomatic of]? And are they symptomatic of
cerebral oedema?cerebral oedema?
• What is their fluid status?What is their fluid status?
• Is ADH acting appropriately orIs ADH acting appropriately or
inappropriately?inappropriately?
Acute ↓[Na] = Acute correction of [Na]Acute ↓[Na] = Acute correction of [Na]
Chronic ↓[Na] = Slow correction of [Na]Chronic ↓[Na] = Slow correction of [Na]

50. Rapid Phase
Intracellular Na+/K+ ejected
to decrease osmotic
movement of water.
Slow Phase
Osmolytes (e.g. Sorbitol)
ejected to adapt to new
equilibrium

51. Acute Symptomatic HyponatraemiaAcute Symptomatic Hyponatraemia
Typically seen in patients with loading of free fluidsTypically seen in patients with loading of free fluids
– primary polydipsia, excess iv hypotonic fluids– primary polydipsia, excess iv hypotonic fluids
– No opportunity for chronic compensationNo opportunity for chronic compensation
If low [NaIf low [Na++
] induces seizures/severe neurological] induces seizures/severe neurological
symptoms the risk of untreated cerebral oedemasymptoms the risk of untreated cerebral oedema
is greater than the risks of over rapid correctionis greater than the risks of over rapid correction

52. Acute Symptomatic Hyponatraemia (2)Acute Symptomatic Hyponatraemia (2)
Hypertonic saline should be given at aHypertonic saline should be given at a
OsmolalityOsmolalityFluidFluid > Osmolality> OsmolalityUrineUrine to achieve ato achieve a
rise in [Narise in [Na++
] of 1.5-2.0 mmol/hr until] of 1.5-2.0 mmol/hr until
symptoms have abated.symptoms have abated.
If OsmolalityIf OsmolalityFluidFluid ≤ Osmolality≤ OsmolalityUrineUrine then you arethen you are
prescribing excess free water!prescribing excess free water!
(Osmolality of 3% Saline ≈ 1000 mOsm)(Osmolality of 3% Saline ≈ 1000 mOsm)

53. CASE 8CASE 8
42 year old man with chronic alcoholism presented with42 year old man with chronic alcoholism presented with
confusion. Clinical examination noted he wasconfusion. Clinical examination noted he was
malnourished. On the day of admission his serummalnourished. On the day of admission his serum
sodium wassodium was 105 mmol/l105 mmol/l at 5 pm. His serum was hypo-at 5 pm. His serum was hypo-
osmolar at 212 mmol/kg and his urine sodiumosmolar at 212 mmol/kg and his urine sodium
concentration was 22 mmol/l, suggesting hypovolaemia.concentration was 22 mmol/l, suggesting hypovolaemia.
He was given 2 litres of 0.9% saline with 40 mmolHe was given 2 litres of 0.9% saline with 40 mmol
potassium chloride over the next 24 hours. His serumpotassium chloride over the next 24 hours. His serum
sodium level increased tosodium level increased to 119 mmol/l119 mmol/l by 11 am theby 11 am the
following day and reached a peak offollowing day and reached a peak of 132 mmol/l132 mmol/l on theon the
fourth day after admission.fourth day after admission.
Ten days after his initial presentation he was readmittedTen days after his initial presentation he was readmitted
with confusion, ataxia and dysphagia. He had briskwith confusion, ataxia and dysphagia. He had brisk
reflexes throughout, including jaw jerk with extensorreflexes throughout, including jaw jerk with extensor
plantars.plantars. What is the diagnosis?What is the diagnosis?

55. Osmotic Demyelination SyndromeOsmotic Demyelination Syndrome
Within one to several days central demyelinatingWithin one to several days central demyelinating
lesions may occur, particularly in the ponslesions may occur, particularly in the pons
(central pontine myelinolysis or CPM)(central pontine myelinolysis or CPM)
• Symptoms: dysarthria, cranial nerve palsies,Symptoms: dysarthria, cranial nerve palsies,
quadriparesis, coma, “locked-in” syndromequadriparesis, coma, “locked-in” syndrome
– Often irreversibleOften irreversible
• Risk of CPM low if [NaRisk of CPM low if [Na++
] raised by < 0.5 mmol/hr] raised by < 0.5 mmol/hr
or <10-12 mmol/l in 24 hrsor <10-12 mmol/l in 24 hrs

57. CASE 9CASE 9
A 52 year old man is admitted with nausea andA 52 year old man is admitted with nausea and
vomiting. PMHx of CKD 4 for 1 year, HTN 2vomiting. PMHx of CKD 4 for 1 year, HTN 2
years, last eGFR at clinic 16 ml/min.years, last eGFR at clinic 16 ml/min.
[Na[Na++
] was 100 mmol/L on admission, Urea 47] was 100 mmol/L on admission, Urea 47
Creatinine 1000Creatinine 1000
Dialysis was initiatedDialysis was initiated
2.5 hours / qB @ 150 mL/min2.5 hours / qB @ 150 mL/min
Post dialysis [NaPost dialysis [Na++
] – 121 mmol/L] – 121 mmol/L
24 hours later, develops pontine myelinosis24 hours later, develops pontine myelinosis

58. Strategies for dialyzing aStrategies for dialyzing a
patient with hyponatraemiapatient with hyponatraemia
Lower the dialysate sodiumLower the dialysate sodium
Lower the blood and dialysate flowLower the blood and dialysate flow
Shorten the initial treatments and give 5%Shorten the initial treatments and give 5%
dextrose via the venous lumen to minimizedextrose via the venous lumen to minimize
sodium rise.sodium rise.
Uraemia appears to be protective againstUraemia appears to be protective against
CPM as large amounts of brain osmolyteCPM as large amounts of brain osmolyte
are producedare produced

59. CASE 10CASE 10
39 year old lady with cirrhosis found obtunded at home. She is39 year old lady with cirrhosis found obtunded at home. She is
tubed and ventilated. Blood pressure on admissiontubed and ventilated. Blood pressure on admission
75/35mmHg, Temp 39.5, Pulse 113/min75/35mmHg, Temp 39.5, Pulse 113/min
Initial labsInitial labs
Na 113 mmol/lNa 113 mmol/l K 4 mmol/lK 4 mmol/l
Urea 10 mmol/LUrea 10 mmol/L Creatinine 113Creatinine 113
CK 10,000CK 10,000 Glucose 6Glucose 6
Serum Osmolality 258 mOsm/kgSerum Osmolality 258 mOsm/kg
Urinary sodium <5mmol/LUrinary sodium <5mmol/L
Urinary Osmolality 500 mOsm/kgUrinary Osmolality 500 mOsm/kg
WCC 21WCC 21 CRP 230CRP 230
She receives a 2 litre fluid bolus of NaCl 0.9% and BP improvesShe receives a 2 litre fluid bolus of NaCl 0.9% and BP improves
to 85/60. She is transferred to ICU and receives fluid at a rateto 85/60. She is transferred to ICU and receives fluid at a rate
of 500ml/h.of 500ml/h.

60. Choose the one best answer:Choose the one best answer:
1.1. The cause of this lady’s hyponatraemia isThe cause of this lady’s hyponatraemia is
SIADHSIADH
2.2. The cause of this lady’s hyponatraemia is partThe cause of this lady’s hyponatraemia is part
due to secretion of ADH in response todue to secretion of ADH in response to
decreased effective circulating volumedecreased effective circulating volume
3.3. The patient is at decreased risk of osmoticThe patient is at decreased risk of osmotic
demyelinationdemyelination
4.4. The patient’s sodium should be checked everyThe patient’s sodium should be checked every
24-36 hours to monitor response to therapy24-36 hours to monitor response to therapy

61. CASE 10 (continued)CASE 10 (continued)
6 hours later the patient is alert and is extubated. At 126 hours later the patient is alert and is extubated. At 12
hours, her BP is 123/70.hours, her BP is 123/70.
She becomes confused and complains of a headache. HerShe becomes confused and complains of a headache. Her
serum sodium is now 130 mmol/L. Urine output overserum sodium is now 130 mmol/L. Urine output over
past 2 hours has been 800 ml/h and is being matchedpast 2 hours has been 800 ml/h and is being matched
with saline. Urinary sodium is now 60 mmol/Lwith saline. Urinary sodium is now 60 mmol/L
Choose one best answer:Choose one best answer:
1.1. Current medical therapy should continueCurrent medical therapy should continue
2.2. She is at risk of acute cerebral oedema from her rapidShe is at risk of acute cerebral oedema from her rapid
sodium risesodium rise
3.3. Her current sodium concentration reflects ongoingHer current sodium concentration reflects ongoing
volume depletionvolume depletion
4.4. Her diuresis reflects decreased ADH activity due to anHer diuresis reflects decreased ADH activity due to an
increase in effective circulating volumeincrease in effective circulating volume

62. CASE 10 (cont)CASE 10 (cont)
The case should now be managed by:The case should now be managed by:
1.1. Administration of 0.45% NaCl at 1ml/kg/hAdministration of 0.45% NaCl at 1ml/kg/h
2.2. Administration of 5% Dextrose at 3ml/kg/hAdministration of 5% Dextrose at 3ml/kg/h
3.3. Stopping all fluidsStopping all fluids
4.4. Administering Vasopressin 0.2mcg 8 hourlyAdministering Vasopressin 0.2mcg 8 hourly
with 5%Detrose to match free water losseswith 5%Detrose to match free water losses
5.5. Administering Vasopressin 0.2mcg once withAdministering Vasopressin 0.2mcg once with
5%Dextrose to match free water losses5%Dextrose to match free water losses

63. CASE 11CASE 11
You are asked to see a 72 year old lady with a serum sodium thatYou are asked to see a 72 year old lady with a serum sodium that
fluctuates between 128-132 mmol/L. She reports nofluctuates between 128-132 mmol/L. She reports no
symptoms. Which of these statements is true regardingsymptoms. Which of these statements is true regarding
chronic hyponatraemia?chronic hyponatraemia?
1.1. Studies have shown a decreased incidence of hypertension inStudies have shown a decreased incidence of hypertension in
patients with chronic hyponatraemiapatients with chronic hyponatraemia
2.2. Studies have shown a decreased rate of falls in patients withStudies have shown a decreased rate of falls in patients with
chronic hyponatraemiachronic hyponatraemia
3.3. ‘‘Asymptomatic’ hyponatraemia has been associated withAsymptomatic’ hyponatraemia has been associated with
impaired performance in both attention and tandem gait testingimpaired performance in both attention and tandem gait testing
4.4. There is no current therapeutic rationale for treating chronicThere is no current therapeutic rationale for treating chronic
asymptomatic hyponatraemiaasymptomatic hyponatraemia

64. Vaptans andVaptans and
HyponatraemiaHyponatraemia

65. Vaptans e.g. TolvaptanVaptans e.g. Tolvaptan
• Vasopressin Receptor AntagonistsVasopressin Receptor Antagonists
– bio-active nonpeptide moleculesbio-active nonpeptide molecules
– competitive antagonists at the V1/V2competitive antagonists at the V1/V2
receptorsreceptors
– Covivaptan – IV formulation (V1/V2 affinity)Covivaptan – IV formulation (V1/V2 affinity)
– Tolvaptan – Oral (V2 affinity)Tolvaptan – Oral (V2 affinity)

66. The Evidence BaseThe Evidence Base
SALT-1 and SALT-2SALT-1 and SALT-2
(NEJM 2006)(NEJM 2006)

67. Vaptans in Heart Failure (1)Vaptans in Heart Failure (1)
• ACTIV in CHF (JAMA 2004)ACTIV in CHF (JAMA 2004)
• Weight lower in first 24 hours compared withWeight lower in first 24 hours compared with
placebo. Weight on discharge however similar.placebo. Weight on discharge however similar.
• There were no differences in worsening heartThere were no differences in worsening heart
failure or mortality at 60 days between thefailure or mortality at 60 days between the
tolvaptan and placebo groups.tolvaptan and placebo groups.
– In post hoc analysis, 60-day mortality was lower inIn post hoc analysis, 60-day mortality was lower in
tolvaptan-treated patients with renal dysfunction ortolvaptan-treated patients with renal dysfunction or
severe systemic congestion.severe systemic congestion.

68. Vaptans in Heart Failure (2)Vaptans in Heart Failure (2)
EVEREST (JAMA 2007)EVEREST (JAMA 2007)
Tolvaptan corrected hyponatraemia, butTolvaptan corrected hyponatraemia, but
there was no effect on long-term mortalitythere was no effect on long-term mortality
or heart failure–related morbidity.or heart failure–related morbidity.
Post-hoc analyses suggest reduced in-Post-hoc analyses suggest reduced in-
patient stay for patients but cost marginspatient stay for patients but cost margins
tight!tight!

69. £74.68 per tab£74.68 per tab

70. Vasopressin antagonists in ADPKDVasopressin antagonists in ADPKD
• TTolvaptanolvaptan EEfficacy and safety infficacy and safety in MManagement ofanagement of
PPolycystic kidney disease and itsolycystic kidney disease and its OOutcomesutcomes
((TEMPOTEMPO))
• Evaluate long-term efficacy of tolvaptan inEvaluate long-term efficacy of tolvaptan in
ADPKD through rate of renal volume changeADPKD through rate of renal volume change
and a composite of ADPKD progression clinicaland a composite of ADPKD progression clinical
markers (hypertension, renal pain, albuminuriamarkers (hypertension, renal pain, albuminuria
and renal function).and renal function).

71. ‘‘In your thirst for knowledge, beIn your thirst for knowledge, be
sure not to drown in all thesure not to drown in all the
information.’information.’
Anthony J. D'AngeloAnthony J. D'Angelo