Water and Sodium Handling / Dysnatraemias

Richard McCrory

Aim of SeminarAim of Seminar

‘‘To progressively develop the ability to undertake To progressively develop the ability to undertake specialist assessment and treatment of patients with specialist assessment and treatment of patients with disorders of disorders of fluidfluid, , electrolyteelectrolyte and acid base and acid base regulation’ regulation’

(JRCPTB Specialty Training Curriculum in Renal Medicine, August 2010)(JRCPTB Specialty Training Curriculum in Renal Medicine, August 2010)

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

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

Key Concepts about Body WaterKey Concepts about Body WaterThe relative size of the compartments and spaces is The relative size of the compartments and spaces is solely determined by the amount of solely determined by the amount of solutesolute trapped in trapped in

the compartments the compartments and spaces.and spaces.

OsmolalityOsmolalityECFECF = Osmolality = Osmolality ICFICF

Water distributes to achieve osmotic Water distributes to achieve osmotic equilibriumequilibrium across cell membranes across cell membranes

Sodium [NaSodium [Na++] predominant cation in Extracellular Space] predominant cation in Extracellular SpacePotassium [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 is The capillary wall is permeable to electrolytes but is impermeable to proteinsimpermeable to proteins

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

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 the Volume receptors and the kidney.kidney.

Thirst and renal ADH Thirst and renal ADH activityactivity

CASE 1CASE 1

50-year-old man admitted to CCU 50-year-old man admitted to CCU with a myocardial infarction has with a myocardial infarction has a [Naa [Na++] of 124 mmol/L. The ] of 124 mmol/L. The sample is lipaemic. Which of the sample is lipaemic. Which of the following is most likely to following is most likely to establish the cause of his low establish 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

CASE 2CASE 2

A 76 year old diabetic patient presents with A 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?

PseudohyponatraemiaPseudohyponatraemia

Pseudohyponatraemia is a decreased serum sodium Pseudohyponatraemia 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 high This 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, and the water fraction of plasma-containing electrolytes is reduced, and

indirect methods, which dilute the sample before analysis, give spurious indirect methods, which dilute the sample before analysis, give spurious low sodium results low sodium results [a][a]

2. Low [Na2. Low [Na++] with a ] with a high plasma osmolality high 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 results spurious potassium and sodium results Clinica Chimica Acta (2011) 412; 14: 1-6Clinica Chimica Acta (2011) 412; 14: 1-6

True HyponatraemiaTrue Hyponatraemia

LowLow [Na [Na++], associated with ], associated with lowlow serum osmolality, is serum osmolality, is due to a patient with due to a patient with more water ingestion than more 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’s Excessive fluid intake exceeds the kidney’s ability to make urineability to make urine

3.3. Decreased water excretionDecreased water excretion

CASE 3 (leading to payout of $16.5 CASE 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 a TBW) took part in a radio contest to win a Wii. She drank 7.5 litres of water in 2 Wii. 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] (140 Assuming she had a normal [Na] (140 mmol/L) before starting the contest and mmol/L) before starting the contest and she excreted 1.5 litres of water, how low she excreted 1.5 litres of water, how low was her sodium when she died?was her sodium when she died?

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

Rapid PhaseRapid PhaseIntracellular Na+/K+ Intracellular Na+/K+ ejected to decrease ejected to decrease osmotic movement of osmotic movement of water.water.

Slow PhaseSlow PhaseOsmolytes (e.g. Sorbitol) Osmolytes (e.g. Sorbitol) ejected to adapt to new ejected to adapt to new equilibriumequilibrium

Water Excretion and ADHWater Excretion and ADH

Anti-diuretic Hormone aka. Arginine Anti-diuretic Hormone aka. Arginine VasopressinVasopressin– Nine amino acid peptide after Nine amino acid peptide after

cleavage from it’s precursorscleavage from it’s precursors– Synthesized in the hypothalamus Synthesized in the hypothalamus

and stored in vesicles at and stored in vesicles at the posterior pituitarythe posterior pituitary

– Plasma tPlasma t1/2 1/2 = 5 minutes= 5 minutes

ADH StimulationADH Stimulation

ADH is stimulated by three triggers:ADH is stimulated by three triggers:

1. High osmolality: a 1% increase in osmolality will 1. 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

Carotid BodyCarotid Body

Aortic ArchAortic Arch

Vagus NervesVagus Nerves

Glo

ssop

haryn

geal

Glo

ssop

haryn

geal

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 tractus From the nucleus tractus solitarus to the supra-optic solitarus to the supra-optic and paraventricular nuclei of and paraventricular nuclei of hypothalamushypothalamus

ReceptorReceptor LocationLocation ActionsActions

VV1a1a Vascular smooth muscle cellsVascular smooth muscle cells VasoconstrictionVasoconstriction

CardiomyocytesCardiomyocytes HypertrophyHypertrophy

HepatocytesHepatocytes GlycogenolysisGlycogenolysis

PlateletsPlatelets Platelet aggregationPlatelet aggregation

VV1b 1b 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, and Sodium, potassium, and chloride co-transportchloride co-transport

Endothelial cellsEndothelial cells von Willebrand factor secretionvon Willebrand factor secretion

Location and Action of Vasopressin Location and Action of Vasopressin ReceptorsReceptors

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

Concentrating Capacity and Concentrating Capacity and Generation of UrineGeneration of Urine

The kidney is able to concentrate urine to The 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 600mOsmWhat is the minimum amount of urine the patient can What 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)? 500ml500mlWhat is the maximum amount of urine the patient can What is the maximum amount of urine the patient can

make (minimal ADH)? make (minimal ADH)? 12,000ml12,000mlIf the solute load is low (180 mOsm) what is the If the solute load is low (180 mOsm) what is the

minimum amount of urine possible to make?minimum amount of urine possible to make? 150ml 150ml

CASE 4CASE 4An 82 year old woman was referred to clinic with a low An 82 year old woman was referred to clinic with a low

sodium. She described her diet as a sandwich for sodium. She described her diet as a sandwich for breakfast, some fruit and juice with some nuts for breakfast, some fruit and juice with some nuts for lunch and nothing for dinner. Her fluid intake was lunch and nothing for dinner. Her fluid intake was high (4-5 cups of coffee, a large bottle of water, and a high (4-5 cups of coffee, a large bottle of water, and a couple of additional glasses of juice). She is couple of additional glasses of juice). She is otherwise relatively well.otherwise relatively well.

Blood resultsBlood resultsPlasma sodium 128 mmol/LPlasma sodium 128 mmol/LPlasma osmolality 277 mOsm/kgPlasma osmolality 277 mOsm/kgUrine osmolality 180 mOsm/kg Urine Sp.Gravity 1.005Urine osmolality 180 mOsm/kg Urine Sp.Gravity 1.005Urine 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?

Hyponatraemia due to Concentrating DefectHyponatraemia due to Concentrating Defect

Poor dietary intake can lower the daily urinary solute Poor dietary intake can lower the daily urinary solute excretion to below 300 mOsm, resulting in significant excretion to below 300 mOsm, resulting in significant reduction in reduction 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 the Hyponatremia develops if fluid intake is greater than the maximum amount of urine output that can be generated maximum amount of urine output that can be generated to clear solute load.to clear solute load.

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 usually Excess Sweating – Urinary Sodium usually lowlow

Diuretic Use / Salt Losing Nephropathy / Mineralocorticoid Diuretic Use / Salt Losing Nephropathy / Mineralocorticoid Deficiency / Osmotic Diuresis / Cerebral Salt Wasting – Urinary Deficiency / Osmotic Diuresis / Cerebral Salt Wasting – Urinary Sodium usually Sodium usually highhigh

Hyponatraemia during Long Distance Hyponatraemia during Long Distance RunningRunning

• 488 runners, Boston Marathon 2002488 runners, Boston Marathon 2002• 13% hyponatraemic (≤135 13% 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

Exercise Associated Hyponatraemia in Exercise Associated Hyponatraemia in the London Marathon, 2006the London Marathon, 2006

Of 88 volunteers, 11 (12.5%) Of 88 volunteers, 11 (12.5%) developed developed asymptomatic hyponatraemia (serum asymptomatic hyponatraemia (serum sodium 128–134 mmol/l). sodium 128–134 mmol/l).

• On average, they consumed more fluid On average, they consumed more fluid and gained more weight than and gained more weight than did those did those without hyponatraemia.without hyponatraemia.

• Four of the 11 hyponatraemic runners Four of the 11 hyponatraemic runners lostlost weight weight over the course of the marathon.over the course of the marathon.

CASE 5CASE 5An 80 yr old woman is admitted to hospital alert and An 80 yr old woman is admitted to hospital alert and conscious, but mildly disorientated in time and place conscious, but mildly disorientated in time and place over the past 2 days. She had antihypertensive over the past 2 days. She had antihypertensive therapy added 3 weeks ago. On exam her pulse is therapy 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/lUrea 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

The most appropriate management following The 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 3N Stop 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

Diuretic Induced Diuretic Induced HyponatraemiaHyponatraemia

CortexCortex

MedullaMedulla

NaNa++

KK++

ClCl--

NKCC2NKCC2

Hyponatraemia with Loop DiureticsHyponatraemia with Loop Diuretics

Blocking this channel will ‘dilute’ the medullary gradient

CortexCortex

MedullaMedulla

ClCl-- Na Na++

NCCNCC

Hyponatraemia with ThiazidesHyponatraemia with Thiazides

Relative hypotension stimulates ADH, but the medullary gradient is not altered, leading to free water accumulation

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) → Ineffective Low 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.

Hypervolaemic Hyponatraemia:Hypervolaemic Hyponatraemia:Impact on morbidity / mortalityImpact on morbidity / mortality

Heart FailureHeart FailureHyponatraemic patients had increased risk of Hyponatraemic patients had increased risk of hospitalization or death was an independent predictor of hospitalization or death was an independent predictor of all-cause mortalityall-cause mortality(a)(a)

Liver CirrhosisLiver CirrhosisSodium is an independent predictor of mortality in Sodium is an independent predictor of mortality in patients awaiting liver transplant when used with patients 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

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

Hyponatraemia in Oligo-anuric Hyponatraemia in Oligo-anuric Renal FailureRenal Failure

Decreased number of functioning nephrons leads Decreased 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 of Even 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 generated At GFR of 5ml/min – 7.2 litres of filtrate generated and only 30% reaches the diluting segment of and only 30% reaches the diluting segment of the nephronthe nephron

Another form of hyponatraemia caused by a Another form of hyponatraemia caused by a concentrating defectconcentrating defect

Hyponatraemia in the Hyponatraemia in the Haemodialysis CohortHaemodialysis Cohort

• Follow-up of 1549 patients from the HEMO trial Follow-up of 1549 patients from the HEMO trial (1995-2000)(1995-2000)

• Lower pre-dialysis [Na] serum in dialysis patients Lower 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 Serum Waikar 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

CASE 6CASE 638-year-old, admitted at 37 weeks with pre-38-year-old, admitted at 37 weeks with pre-eclampsia. Her blood pressure was 130/90 and eclampsia. 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 was pre-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 for administering oxytocin and an infusion was continued for poor uterine contractility. The plasma sodium concentration poor 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 had Once oxytocin, the plasma sodium concentration had increased to 133 mmol/l in 24 hours. On discharge it was increased to 133 mmol/l in 24 hours. On discharge it was 137 mmol/l.137 mmol/l.

What are the mechanisms that can promote fluid What are the mechanisms that can promote fluid retention and low sodium in pregnancy?retention and low sodium in pregnancy?

Physiologic Changes in Salt and Water Physiologic Changes in Salt and Water Homeostasis in pregnancyHomeostasis in pregnancy

• Sodium (900mmol) and HSodium (900mmol) and H22O retention (8-10 litres) is O 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 corpus Relaxin and oestrogenic hormones, secreted by corpus

luteum / placentaluteum / placenta• Increase in GFR (50% increase by the end of the first Increase 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 (also Activation of Angiotensin / ADH (also

pain/nausea/anxiety)pain/nausea/anxiety)• Average plasma-osmolality is decreased by 5-10 Average 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 is significant hyponatraemia is rarerare

• Oxytocin has ADH effects that can promote water Oxytocin has ADH effects that can promote water retentionretention

CASE 7CASE 7A 49-year-old woman presented to the emergency department with A 49-year-old woman presented to the emergency department with nausea and vomiting that had occurred for 5 days and slurred nausea and vomiting that had occurred for 5 days and slurred speech for 1 day prior to presentation. The patient denied use of speech 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 125/70 Physical examination revealed her blood pressure to be 125/70 mmHg; she had no postural drop and had a regular pulse of 72 mmHg; she had no postural drop and had a regular pulse of 72 beats/min. She had no fever and no signs of contracted extracellular beats/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.

What is the working diagnosis?What is the working diagnosis?

After 48 hours of 500ml fluid restriction, her After 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], low The differential diagnosis of low [Na], low PPosmosm and high U and high Uosmosm is consistent with ADH is consistent with ADH

activity. But is it activity. But is it inappropriateinappropriate??????

What are the other causes of a high urinary What are the other causes of a high urinary sodium in this setting?sodium in this setting?

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/L Synacthen Test – increment increase of 57nmol/L (Normal >500)(Normal >500)

Parietal cell / Adrenal cortex / Thyroid peroxidase Parietal cell / Adrenal cortex / Thyroid peroxidase antibodies detectedantibodies detected

Final Diagnosis: Autoimmune Polyglandular Final Diagnosis: Autoimmune Polyglandular Syndrome Syndrome (a)(a)

(a) van der Hoek. (a) van der Hoek. Clinical Chemistry.Clinical Chemistry. 2009;55:1905-1908 2009;55:1905-1908

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 of And then you start hunting for the cause of

the SIADH!the SIADH!

SIADH – The Laundry ListSIADH – The Laundry List

Lung diseases and interventionsLung diseases and interventionsPneumoniaPneumonia TuberculosisTuberculosis

Lung abscess, empyemaLung abscess, empyema

Acute respiratory failureAcute respiratory failure

Positive pressure ventilationPositive pressure ventilation

Perioperative Period - associated with the stress Perioperative Period - associated with the stress response to injury and painresponse to injury and pain

DrugsDrugsCyclophosphamideCyclophosphamide 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 ADHNeuropsychiatric disordersNeuropsychiatric disordersInfections: Infections: meningitismeningitis, encephalitis, brain abscess, encephalitis, brain abscessVascular: thrombosis, Vascular: thrombosis, subarachnoid or subdural subarachnoid or subdural

hemorrhagehemorrhage, temporal arteritis, cavernous sinus , temporal arteritis, cavernous sinus thrombosis, strokethrombosis, stroke

Neoplasm: primary or metastaticNeoplasm: primary or metastaticSkull fracture, traumatic brain injurySkull fracture, traumatic brain injuryPsychosis, delirium tremensPsychosis, delirium tremensOther: Guillain-Barré syndrome, acute intermittent Other: Guillain-Barré syndrome, acute intermittent

porphyria, autonomic neuropathy, postpituitary porphyria, autonomic neuropathy, postpituitary surgery, multiple sclerosis, epilepsy, surgery, multiple sclerosis, epilepsy, hydrocephalus, lupus.hydrocephalus, lupus.

Ectopic production of ADHEctopic production of ADHSolid 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

LymphosarcomaLymphosarcomaMesotheliomaMesotheliomaEwing sarcomaEwing sarcomaHodgkin's diseaseHodgkin's diseaseLeukemiaLeukemia

Management of HyponatraemiaManagement of Hyponatraemia

• How quick is duration of onset? How low How 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 or Is 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]

Rapid PhaseIntracellular Na+/K+ ejected to decrease osmotic movement of water.

Slow PhaseOsmolytes (e.g. Sorbitol) ejected to adapt to new equilibrium

Acute Symptomatic HyponatraemiaAcute Symptomatic Hyponatraemia

Typically seen in patients with loading of free fluids Typically 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 oedema symptoms the risk of untreated cerebral oedema is greater than the risks of over rapid correctionis greater than the risks of over rapid correction

Acute Symptomatic Hyponatraemia (2)Acute Symptomatic Hyponatraemia (2)

Hypertonic saline should be given at a Hypertonic saline should be given at a OsmolalityOsmolalityFluidFluid > Osmolality > OsmolalityUrineUrine to achieve a to 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 are then you are

prescribing excess free water!prescribing excess free water!

(Osmolality of 3% Saline ≈ 1000 mOsm)(Osmolality of 3% Saline ≈ 1000 mOsm)

CASE 8CASE 842 year old man with chronic alcoholism presented with 42 year old man with chronic alcoholism presented with

confusion. Clinical examination noted he was confusion. Clinical examination noted he was malnourished. On the day of admission his serum malnourished. On the day of admission his serum sodium was sodium 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 sodium osmolar 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 mmol He was given 2 litres of 0.9% saline with 40 mmol potassium chloride over the next 24 hours. His serum potassium chloride over the next 24 hours. His serum sodium level increased to sodium level increased to 119 mmol/l119 mmol/l by 11 am the by 11 am the following day and reached a peak of following day and reached a peak of 132 mmol/l132 mmol/l on the on the fourth day after admission. fourth day after admission.

Ten days after his initial presentation he was readmitted Ten days after his initial presentation he was readmitted with confusion, ataxia and dysphagia. He had brisk with confusion, ataxia and dysphagia. He had brisk reflexes throughout, including jaw jerk with extensor reflexes throughout, including jaw jerk with extensor plantars. plantars. What is the diagnosis?What is the diagnosis?

Osmotic Demyelination SyndromeOsmotic Demyelination Syndrome

Within one to several days central demyelinating Within one to several days central demyelinating lesions may occur, particularly in the pons lesions 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

CASE 9CASE 9

A 52 year old man is admitted with nausea and A 52 year old man is admitted with nausea and vomiting. PMHx of CKD 4 for 1 year, HTN 2 vomiting. 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

Strategies for dialyzing aStrategies for dialyzing apatient 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 minimize dextrose via the venous lumen to minimize sodium rise.sodium rise.

Uraemia appears to be protective against Uraemia appears to be protective against CPM as large amounts of brain osmolyte CPM as large amounts of brain osmolyte are producedare produced

CASE 10CASE 1039 year old lady with cirrhosis found obtunded at home. She is 39 year old lady with cirrhosis found obtunded at home. She is

tubed and ventilated. Blood pressure on admission tubed and ventilated. Blood pressure on admission 75/35mmHg, Temp 39.5, Pulse 113/min75/35mmHg, Temp 39.5, Pulse 113/min

Initial labsInitial labsNa 113 mmol/lNa 113 mmol/l K 4 mmol/lK 4 mmol/lUrea 10 mmol/L Urea 10 mmol/L Creatinine 113Creatinine 113CK 10,000CK 10,000 Glucose 6Glucose 6Serum Osmolality 258 mOsm/kgSerum Osmolality 258 mOsm/kgUrinary sodium <5mmol/LUrinary sodium <5mmol/LUrinary Osmolality 500 mOsm/kgUrinary Osmolality 500 mOsm/kgWCC 21WCC 21 CRP 230CRP 230

She receives a 2 litre fluid bolus of NaCl 0.9% and BP improves She 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 rate to 85/60. She is transferred to ICU and receives fluid at a rate of 500ml/h.of 500ml/h.

Choose the one best answer:Choose the one best answer:

1.1. The cause of this lady’s hyponatraemia is The cause of this lady’s hyponatraemia is SIADHSIADH

2.2. The cause of this lady’s hyponatraemia is part The cause of this lady’s hyponatraemia is part due to secretion of ADH in response to due to secretion of ADH in response to decreased effective circulating volumedecreased effective circulating volume

3.3. The patient is at decreased risk of osmotic The patient is at decreased risk of osmotic demyelinationdemyelination

4.4. The patient’s sodium should be checked every The patient’s sodium should be checked every 24-36 hours to monitor response to therapy24-36 hours to monitor response to therapy

CASE 10 (continued)CASE 10 (continued)6 hours later the patient is alert and is extubated. At 12 6 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. Her She becomes confused and complains of a headache. Her

serum sodium is now 130 mmol/L. Urine output over serum sodium is now 130 mmol/L. Urine output over past 2 hours has been 800 ml/h and is being matched past 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 continue2.2. She is at risk of acute cerebral oedema from her rapid She is at risk of acute cerebral oedema from her rapid

sodium risesodium rise3.3. Her current sodium concentration reflects ongoing Her current sodium concentration reflects ongoing

volume depletionvolume depletion4.4. Her diuresis reflects decreased ADH activity due to an Her diuresis reflects decreased ADH activity due to an

increase in effective circulating volumeincrease in effective circulating volume

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 hourly Administering 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 with Administering Vasopressin 0.2mcg once with 5%Dextrose to match free water losses5%Dextrose to match free water losses

CASE 11CASE 11You are asked to see a 72 year old lady with a serum sodium that You are asked to see a 72 year old lady with a serum sodium that

fluctuates between 128-132 mmol/L. She reports no fluctuates between 128-132 mmol/L. She reports no symptoms. Which of these statements is true regarding symptoms. Which of these statements is true regarding chronic hyponatraemia?chronic hyponatraemia?

1.1. Studies have shown a decreased incidence of hypertension in Studies 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 with Studies have shown a decreased rate of falls in patients with chronic hyponatraemiachronic hyponatraemia

3.3. ‘‘Asymptomatic’ hyponatraemia has been associated with Asymptomatic’ 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 chronic There is no current therapeutic rationale for treating chronic asymptomatic hyponatraemiaasymptomatic hyponatraemia

Vaptans and Vaptans and HyponatraemiaHyponatraemia

Vaptans e.g. TolvaptanVaptans e.g. Tolvaptan

• Vasopressin Receptor AntagonistsVasopressin Receptor Antagonists– bio-active nonpeptide moleculesbio-active nonpeptide molecules– competitive antagonists at the V1/V2 competitive 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)

The Evidence BaseThe Evidence BaseSALT-1 and SALT-2 SALT-1 and SALT-2

(NEJM 2006)(NEJM 2006)

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 with Weight 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 heart There were no differences in worsening heart

failure or mortality at 60 days between the failure or mortality at 60 days between the tolvaptan and placebo groups.tolvaptan and placebo groups.– In post hoc analysis, 60-day mortality was lower in In post hoc analysis, 60-day mortality was lower in

tolvaptan-treated patients with renal dysfunction or tolvaptan-treated patients with renal dysfunction or severe systemic congestion. severe systemic congestion.

Vaptans in Heart Failure (2)Vaptans in Heart Failure (2)

EVEREST (JAMA 2007)EVEREST (JAMA 2007)

Tolvaptan corrected hyponatraemia, but Tolvaptan corrected hyponatraemia, but there was no effect on long-term mortality there 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 margins patient stay for patients but cost margins tight!tight!

£74.68 per tab£74.68 per tab

Vasopressin antagonists in ADPKDVasopressin antagonists in ADPKD

• TTolvaptan olvaptan EEfficacy and safety in fficacy and safety in MManagement of anagement of PPolycystic kidney disease and its olycystic kidney disease and its OOutcomes utcomes ((TEMPOTEMPO))

• Evaluate long-term efficacy of tolvaptan in Evaluate long-term efficacy of tolvaptan in ADPKD through rate of renal volume change ADPKD through rate of renal volume change and a composite of ADPKD progression clinical and a composite of ADPKD progression clinical markers (hypertension, renal pain, albuminuria markers (hypertension, renal pain, albuminuria and renal function). and renal function).

‘‘In your thirst for knowledge, be In your thirst for knowledge, be sure not to drown in all the sure not to drown in all the information.’ information.’

Anthony J. D'Angelo Anthony J. D'Angelo