Water, Sodium Handling and Hyponatraemia

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

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

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  • Figure 2. Vasopressin V2 receptor activation. The binding of arginine vasopressin (AVP) to the V2 vasopressin receptor (V2R) stimulates a Gs-coupled protein that activates adenylyl cyclase, in turn causing production of cAMP to activate protein kinase A (PKA). This pathway increases the exocytosis of aquaporin water channel–containing vesicles (AQMCV) and inhibits endocytosis of the vesicles, both resulting in increases in aquaporin 2 (AQ2) channel formation and apical membrane insertion. This allows an increase in the permeability of water from the collecting duct (CD).

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  • 1. Water and SodiumHandling / DysnatraemiasRichard McCrory
  • 2. Aim of SeminarAim of Seminar‘‘To progressively develop the ability to undertakeTo progressively develop the ability to undertakespecialist assessment and treatment of patients withspecialist assessment and treatment of patients withdisorders ofdisorders of fluidfluid,, electrolyteelectrolyte and acid baseand acid baseregulation’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 youcontrol everything.”control everything.”
  • 5. Key Concepts about Body WaterKey Concepts about Body WaterThe relative size of the compartments and spaces isThe relative size of the compartments and spaces issolely determined by the amount ofsolely determined by the amount of solutesolute trapped intrapped inthe compartmentsthe compartments and spaces.and spaces.OsmolalityOsmolalityECFECF = Osmolality= OsmolalityICFICFWater distributes to achieve osmoticWater distributes to achieve osmotic equilibriumequilibrium across cell membranesacross cell membranesSodium [NaSodium [Na++] predominant cation in Extracellular Space] predominant cation in Extracellular SpacePotassium [KPotassium [K++] predominant cation in Intracellular Space] predominant cation in Intracellular SpaceSolute 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 isimpermeable to proteinsimpermeable to proteins
  • 6. Total Body WaterTotal Body WaterInterstitialInterstitialPlasmaPlasmaTBW (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 WaterNa+and H2O are regulated independently[Na+] | [H2O]Disorders of water can present as abnormal sodiumlevels, and disorders of sodium levels present asvolume dysregulation.Volume receptors and theVolume receptors and thekidney.kidney.Thirst and renal ADHThirst and renal ADHactivityactivity
  • 8. CASE 1CASE 150-year-old man admitted to CCU50-year-old man admitted to CCUwith a myocardial infarction haswith a myocardial infarction hasa [Naa [Na++] of 124 mmol/L. The] of 124 mmol/L. Thesample is lipaemic. Which of thesample is lipaemic. Which of thefollowing is most likely tofollowing is most likely toestablish 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 2A 76 year old diabetic patient presents withA 76 year old diabetic patient presents withmarked hyperglycaemiamarked hyperglycaemiaMeasured Sodium = 124 mmol/LMeasured Sodium = 124 mmol/LVenous Glucose = 58 mmol/LVenous Glucose = 58 mmol/LSerum Osmolality = 317 mOsm/LSerum Osmolality = 317 mOsm/LWhat is the cause of his hyponatraemia?What is the cause of his hyponatraemia?
  • 10. PseudohyponatraemiaPseudohyponatraemiaPseudohyponatraemia is a decreased serum sodiumPseudohyponatraemia is a decreased serum sodiumwithout 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 highprotein or lipid levelsprotein or lipid levels– the water fraction of plasma-containing electrolytes is reduced, andthe water fraction of plasma-containing electrolytes is reduced, andindirect methods, which dilute the sample before analysis, give spuriousindirect methods, which dilute the sample before analysis, give spuriouslow 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 ofspurious 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 HyponatraemiaLowLow [Na[Na++], associated with], associated with lowlow serum osmolality, isserum osmolality, isdue to a patient withdue to a patient with more water ingestion thanmore water ingestion thanwater 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’sability to make urineability to make urine3.3. Decreased water excretionDecreased water excretion
  • 12. CASE 3 (leading to payout of $16.5CASE 3 (leading to payout of $16.5million)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 aWii. She drank 7.5 litres of water in 2Wii. She drank 7.5 litres of water in 2hours. 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] (140mmol/L) before starting the contest andmmol/L) before starting the contest andshe excreted 1.5 litres of water, how lowshe excreted 1.5 litres of water, how lowwas her sodium when she died?was her sodium when she died?
  • 13. Original [NaOriginal [Na++] X] XOriginal 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/LSlides from Joel Topf
  • 14. Rapid PhaseRapid PhaseIntracellular Na+/K+Intracellular Na+/K+ejected to decreaseejected to decreaseosmotic movement ofosmotic movement ofwater.water.Slow PhaseSlow PhaseOsmolytes (e.g. Sorbitol)Osmolytes (e.g. Sorbitol)ejected to adapt to newejected to adapt to newequilibriumequilibrium
  • 15. Water Excretion and ADHWater Excretion and ADH
  • 16. Anti-diuretic Hormone aka. ArginineAnti-diuretic Hormone aka. ArginineVasopressinVasopressin– Nine amino acid peptide afterNine amino acid peptide aftercleavage from it’s precursorscleavage from it’s precursors– Synthesized in the hypothalamusSynthesized in the hypothalamusand stored in vesicles atand stored in vesicles atthe posterior pituitarythe posterior pituitary– Plasma tPlasma t1/21/2 = 5 minutes= 5 minutes
  • 17. ADH StimulationADH StimulationADH 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 willstimulate ADHstimulate ADH2. Decrease in effective circulating volume2. Decrease in effective circulating volume– Baroreceptor ResponseBaroreceptor Response– Angiotensin-IIAngiotensin-II3. Non-physiological (‘Inappropriate’) Stimuli3. Non-physiological (‘Inappropriate’) Stimuli
  • 18. Carotid BodyCarotid BodyAortic ArchAortic ArchVagus NervesVagus NervesGlossopharyngealGlossopharyngealHypothalmusHypothalmus Baroregulation of ADHBaroregulation of ADHAfferent neuronsAfferent neurons•Aortic ArchAortic Arch•Carotid BodiesCarotid Bodies•Atrial Wall and Great VeinsAtrial Wall and Great VeinsEfferent NeuronsEfferent Neurons•From the nucleus tractusFrom the nucleus tractussolitarus to the supra-opticsolitarus to the supra-opticand paraventricular nuclei ofand paraventricular nuclei ofhypothalamushypothalamus
  • 19. ReceptorReceptor LocationLocation ActionsActionsVV1a1a Vascular smooth muscle cellsVascular smooth muscle cells VasoconstrictionVasoconstrictionCardiomyocytesCardiomyocytes HypertrophyHypertrophyHepatocytesHepatocytes GlycogenolysisGlycogenolysisPlateletsPlatelets Platelet aggregationPlatelet aggregationVV1b1b aka Vaka V33 Anterior pituitaryAnterior pituitary ACTH and Endorphin releaseACTH and Endorphin releaseVV22 β-Cells in pancreasβ-Cells in pancreas Insulin and glucagon secretionInsulin and glucagon secretionRenal collecting ductsRenal collecting ducts Water RetentionWater RetentionAscending limb of HenléAscending limb of Henlé Sodium, potassium, andSodium, potassium, andchloride co-transportchloride co-transportEndothelial cellsEndothelial cells von Willebrand factor secretionvon Willebrand factor secretionLocation and Action of VasopressinLocation and Action of VasopressinReceptorsReceptors
  • 20. 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
  • 21. Concentrating Capacity andConcentrating Capacity andGeneration of UrineGeneration of UrineThe kidney is able to concentrate urine toThe kidney is able to concentrate urine to1200mOsm/L or dilute urine to 50 mOsm/L1200mOsm/L or dilute urine to 50 mOsm/LIf 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 canWhat is the minimum amount of urine the patient canmake to clear the solute load (maximal ADH)?make to clear the solute load (maximal ADH)? 500ml500mlWhat is the maximum amount of urine the patient canWhat is the maximum amount of urine the patient canmake (minimal ADH)?make (minimal ADH)? 12,000ml12,000mlIf the solute load is low (180 mOsm) what is theIf the solute load is low (180 mOsm) what is theminimum amount of urine possible to make?minimum amount of urine possible to make? 150ml150ml
  • 22. CASE 4CASE 4An 82 year old woman was referred to clinic with a lowAn 82 year old woman was referred to clinic with a lowsodium. She described her diet as a sandwich forsodium. She described her diet as a sandwich forbreakfast, some fruit and juice with some nuts forbreakfast, some fruit and juice with some nuts forlunch and nothing for dinner. Her fluid intake waslunch and nothing for dinner. Her fluid intake washigh (4-5 cups of coffee, a large bottle of water, and ahigh (4-5 cups of coffee, a large bottle of water, and acouple of additional glasses of juice). She iscouple of additional glasses of juice). She isotherwise 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 NormalWhat is the cause of her hyponatraemia?What is the cause of her hyponatraemia?
  • 23. Hyponatraemia due to Concentrating DefectHyponatraemia due to Concentrating DefectPoor dietary intake can lower the daily urinary solutePoor dietary intake can lower the daily urinary soluteexcretion to below 300 mOsm, resulting in significantexcretion to below 300 mOsm, resulting in significantreduction 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 proteinHyponatremia develops if fluid intake is greater than theHyponatremia develops if fluid intake is greater than themaximum amount of urine output that can be generatedmaximum amount of urine output that can be generatedto clear solute load.to clear solute load.
  • 24. Hypovolaemic HyponatraemiaHypovolaemic Hyponatraemia[Na+] deficit > [H2O] Deficit[Na+] deficit > [H2O] DeficitVolume Contraction → Ineffective Circulating Volume →Volume Contraction → Ineffective Circulating Volume → Non-osmotic ADHNon-osmotic ADHFluid 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 lowlowDiuretic Use / Salt Losing Nephropathy / MineralocorticoidDiuretic Use / Salt Losing Nephropathy / MineralocorticoidDeficiency / Osmotic Diuresis / Cerebral Salt Wasting – UrinaryDeficiency / Osmotic Diuresis / Cerebral Salt Wasting – UrinarySodium usuallySodium usually highhigh
  • 25. Hyponatraemia during Long DistanceHyponatraemia during Long DistanceRunningRunning• 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
  • 26. Exercise Associated Hyponatraemia inExercise Associated Hyponatraemia inthe London Marathon, 2006the London Marathon, 2006Of 88 volunteers, 11 (12.5%)Of 88 volunteers, 11 (12.5%) developeddevelopedasymptomatic hyponatraemia (serumasymptomatic hyponatraemia (serumsodium 128–134 mmol/l).sodium 128–134 mmol/l).• On average, they consumed more fluidOn average, they consumed more fluidand gained more weight thanand gained more weight than did thosedid thosewithout hyponatraemia.without hyponatraemia.• Four of the 11 hyponatraemic runnersFour of the 11 hyponatraemic runners lostlost weightweightover the course of the marathon.over the course of the marathon.
  • 27. CASE 5CASE 5An 80 yr old woman is admitted to hospital alert andAn 80 yr old woman is admitted to hospital alert andconscious, but mildly disorientated in time and placeconscious, but mildly disorientated in time and placeover the past 2 days. She had antihypertensiveover the past 2 days. She had antihypertensivetherapy added 3 weeks ago. On exam her pulse istherapy added 3 weeks ago. On exam her pulse is70/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/LUrinalysisUrinalysis:: Specific gravity 1.020 Otherwise NADSpecific gravity 1.020 Otherwise NAD
  • 28. The most appropriate management followingThe most appropriate management followingadmission isadmission is1.1. Stop drugs and administer N-salineStop drugs and administer N-saline2.2. Stop drugs and administer hypertonic 3NStop drugs and administer hypertonic 3Nsalinesaline3.3. Stop drugs and administer a loop diureticStop drugs and administer a loop diuretic4.4. Stop drugs and administer desmopressinStop drugs and administer desmopressin5.5. Strop drugs and permit free oral intakeStrop drugs and permit free oral intake
  • 29. Diuretic InducedDiuretic InducedHyponatraemiaHyponatraemia
  • 30. CortexCortexMedullaMedullaNaNa++KK++ClCl--NKCC2NKCC2Hyponatraemia with Loop DiureticsHyponatraemia with Loop DiureticsBlocking this channelwill ‘dilute’ the medullarygradient
  • 31. CortexCortexMedullaMedullaClCl--NaNa++NCCNCCHyponatraemia with ThiazidesHyponatraemia with ThiazidesRelative hypotensionstimulates ADH, but themedullary gradient is notaltered, leading to freewater accumulation
  • 32. Hypervolaemic HyponatraemiaHypervolaemic Hyponatraemia[Na+] excess < [H2O] Excess[Na+] excess < [H2O] ExcessPoor cardiac output (Heart Failure) ORPoor cardiac output (Heart Failure) ORSplanchnic Vessel Dilatation (Cirrhosis) ORSplanchnic Vessel Dilatation (Cirrhosis) ORLow Oncotic Pressure (Nephrotic Syndrome) → IneffectiveLow Oncotic Pressure (Nephrotic Syndrome) → IneffectiveCirculating Volume →Circulating Volume →Non-osmotic ADH secretionNon-osmotic ADH secretionTwo seemingly different causes of hyponatremia, sharea single pathophysiologic explanation.
  • 33. Hypervolaemic Hyponatraemia:Hypervolaemic Hyponatraemia:Impact on morbidity / mortalityImpact on morbidity / mortalityHeart FailureHeart FailureHyponatraemic patients had increased risk ofHyponatraemic patients had increased risk ofhospitalization or death was an independent predictor ofhospitalization or death was an independent predictor ofall-cause mortalityall-cause mortality(a)(a)Liver CirrhosisLiver CirrhosisSodium is an independent predictor of mortality inSodium is an independent predictor of mortality inpatients awaiting liver transplant when used withpatients awaiting liver transplant when used withprognostic 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
  • 34. From Kim et alFrom Kim et al N Engl J Med 2008; 359:1018-1026N Engl J Med 2008; 359:1018-1026
  • 35. Hyponatraemia in Oligo-anuricHyponatraemia in Oligo-anuricRenal FailureRenal FailureDecreased number of functioning nephrons leadsDecreased number of functioning nephrons leadsto 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 ofclearing excess water, leading to hypervolaemiaclearing excess water, leading to hypervolaemiaAt GFR of 5ml/min – 7.2 litres of filtrate generatedAt GFR of 5ml/min – 7.2 litres of filtrate generatedand only 30% reaches the diluting segment ofand only 30% reaches the diluting segment ofthe nephronthe nephronAnother form of hyponatraemia caused by aAnother form of hyponatraemia caused by aconcentrating defectconcentrating defect
  • 36. Hyponatraemia in theHyponatraemia in theHaemodialysis 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 patientsare 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 SerumSodium 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
  • 37. 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 andeclampsia. Her blood pressure was 130/90 andthere 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 treatedpre-emptively with magnesium and labour waspre-emptively with magnesium and labour wasinduced.induced.Her plasma [NaHer plasma [Na++] decreased to 129 mmol/l after] decreased to 129 mmol/l afteradministering oxytocin and an infusion was continued foradministering oxytocin and an infusion was continued forpoor uterine contractility. The plasma sodium concentrationpoor uterine contractility. The plasma sodium concentrationthen 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 hadincreased to 133 mmol/l in 24 hours. On discharge it wasincreased to 133 mmol/l in 24 hours. On discharge it was137 mmol/l.137 mmol/l.What are the mechanisms that can promote fluidWhat are the mechanisms that can promote fluidretention and low sodium in pregnancy?retention and low sodium in pregnancy?
  • 38. Physiologic Changes in Salt and WaterPhysiologic Changes in Salt and WaterHomeostasis in pregnancyHomeostasis in pregnancy• Sodium (900mmol) and HSodium (900mmol) and H22O retention (8-10 litres) isO retention (8-10 litres) isneeded 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 corpusluteum / placentaluteum / placenta• Increase in GFR (50% increase by the end of the firstIncrease in GFR (50% increase by the end of the firsttrimester) but decreased effective fluid volumetrimester) but decreased effective fluid volume– Activation of Angiotensin / ADH (alsoActivation of Angiotensin / ADH (alsopain/nausea/anxiety)pain/nausea/anxiety)• Average plasma-osmolality is decreased by 5-10Average plasma-osmolality is decreased by 5-10mOsmol. [NamOsmol. [Na++] can decrease by 5 mmol/l but] can decrease by 5 mmol/l butsignificant hyponatraemia issignificant hyponatraemia is rarerare• Oxytocin has ADH effects that can promote waterOxytocin has ADH effects that can promote waterretentionretention
  • 39. CASE 7CASE 7A 49-year-old woman presented to the emergency department withA 49-year-old woman presented to the emergency department withnausea and vomiting that had occurred for 5 days and slurrednausea and vomiting that had occurred for 5 days and slurredspeech for 1 day prior to presentation. The patient denied use ofspeech for 1 day prior to presentation. The patient denied use ofalcohol and illicit drugs.alcohol and illicit drugs.Physical examination revealed her blood pressure to be 125/70Physical examination revealed her blood pressure to be 125/70mmHg; she had no postural drop and had a regular pulse of 72mmHg; she had no postural drop and had a regular pulse of 72beats/min. She had no fever and no signs of contracted extracellularbeats/min. She had no fever and no signs of contracted extracellularfluid volume. Remaining exam normal. Normal CT brain.fluid volume. Remaining exam normal. Normal CT brain.
  • 40. 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/LWhat’s gone wrong?What’s gone wrong?The differential diagnosis of low [Na], lowThe differential diagnosis of low [Na], lowPPosmosm and high Uand high Uosmosm is consistent with ADHis consistent with ADHactivity. But is itactivity. But is it inappropriateinappropriate??????What are the other causes of a high urinaryWhat are the other causes of a high urinarysodium in this setting?sodium in this setting?
  • 41. More tests are sent!More tests are sent!TSH 63 IU/L T4 5 pmol/LTSH 63 IU/L T4 5 pmol/LRandom Cortisol 105 nmol/LRandom Cortisol 105 nmol/LSynacthen 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 peroxidaseantibodies detectedantibodies detectedFinal Diagnosis: Autoimmune PolyglandularFinal Diagnosis: Autoimmune PolyglandularSyndromeSyndrome (a)(a)(a) van der Hoek.(a) van der Hoek. Clinical Chemistry.Clinical Chemistry. 2009;55:1905-19082009;55:1905-1908
  • 42. Euvolaemic HyponatraemiaEuvolaemic HyponatraemiaDon’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 ofthe SIADH!the SIADH!
  • 43. SIADH – The Laundry ListSIADH – The Laundry ListLung diseases and interventionsLung diseases and interventionsPneumoniaPneumonia TuberculosisTuberculosisLung abscess, empyemaLung abscess, empyemaAcute respiratory failureAcute respiratory failurePositive pressure ventilationPositive pressure ventilationPerioperative Period - associated with the stressPerioperative Period - associated with the stressresponse to injury and painresponse to injury and painDrugsDrugsCyclophosphamideCyclophosphamide CarbamazepineCarbamazepineVincristine or vinblastineVincristine or vinblastine PhenothiazinesPhenothiazinesHaloperidolHaloperidol TCAs or SSRIsTCAs or SSRIsMAOIsMAOIs BromocriptineBromocriptineLorcainideLorcainide ClofibrateClofibrateGeneral anesthesiaGeneral anesthesia OpiatesOpiatesNicotineNicotineIncreased Hypothalmic Production of ADHIncreased Hypothalmic Production of ADHNeuropsychiatric disordersNeuropsychiatric disordersInfections:Infections: meningitismeningitis, encephalitis, brain abscess, encephalitis, brain abscessVascular: thrombosis,Vascular: thrombosis, subarachnoid or subduralsubarachnoid or subduralhemorrhagehemorrhage, temporal arteritis, cavernous sinus, temporal arteritis, cavernous sinusthrombosis, strokethrombosis, strokeNeoplasm: primary or metastaticNeoplasm: primary or metastaticSkull fracture, traumatic brain injurySkull fracture, traumatic brain injuryPsychosis, delirium tremensPsychosis, delirium tremensOther: Guillain-Barré syndrome, acute intermittentOther: Guillain-Barré syndrome, acute intermittentporphyria, autonomic neuropathy, postpituitaryporphyria, autonomic neuropathy, postpituitarysurgery, 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, uterusLymphosarcomaLymphosarcomaMesotheliomaMesotheliomaEwing sarcomaEwing sarcomaHodgkins diseaseHodgkins diseaseLeukemiaLeukemia
  • 44. Management of HyponatraemiaManagement of Hyponatraemia• How quick is duration of onset? How lowHow quick is duration of onset? How lowis [Nais [Na++]? And are they symptomatic of]? And are they symptomatic ofcerebral oedema?cerebral oedema?• What is their fluid status?What is their fluid status?• Is ADH acting appropriately orIs ADH acting appropriately orinappropriately?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]
  • 45. Rapid PhaseIntracellular Na+/K+ ejectedto decrease osmoticmovement of water.Slow PhaseOsmolytes (e.g. Sorbitol)ejected to adapt to newequilibrium
  • 46. Acute Symptomatic HyponatraemiaAcute Symptomatic HyponatraemiaTypically 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 compensationIf low [NaIf low [Na++] induces seizures/severe neurological] induces seizures/severe neurologicalsymptoms the risk of untreated cerebral oedemasymptoms the risk of untreated cerebral oedemais greater than the risks of over rapid correctionis greater than the risks of over rapid correction
  • 47. Acute Symptomatic Hyponatraemia (2)Acute Symptomatic Hyponatraemia (2)Hypertonic saline should be given at aHypertonic saline should be given at aOsmolalityOsmolalityFluidFluid > Osmolality> OsmolalityUrineUrine to achieve ato achieve arise in [Narise in [Na++] of 1.5-2.0 mmol/hr until] of 1.5-2.0 mmol/hr untilsymptoms have abated.symptoms have abated.If OsmolalityIf OsmolalityFluidFluid ≤ Osmolality≤ OsmolalityUrineUrine then you arethen you areprescribing excess free water!prescribing excess free water!(Osmolality of 3% Saline ≈ 1000 mOsm)(Osmolality of 3% Saline ≈ 1000 mOsm)
  • 48. CASE 8CASE 842 year old man with chronic alcoholism presented with42 year old man with chronic alcoholism presented withconfusion. Clinical examination noted he wasconfusion. Clinical examination noted he wasmalnourished. On the day of admission his serummalnourished. On the day of admission his serumsodium 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 sodiumconcentration 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 mmolpotassium chloride over the next 24 hours. His serumpotassium chloride over the next 24 hours. His serumsodium level increased tosodium level increased to 119 mmol/l119 mmol/l by 11 am theby 11 am thefollowing day and reached a peak offollowing day and reached a peak of 132 mmol/l132 mmol/l on theon thefourth day after admission.fourth day after admission.Ten days after his initial presentation he was readmittedTen days after his initial presentation he was readmittedwith confusion, ataxia and dysphagia. He had briskwith confusion, ataxia and dysphagia. He had briskreflexes throughout, including jaw jerk with extensorreflexes throughout, including jaw jerk with extensorplantars.plantars. What is the diagnosis?What is the diagnosis?
  • 49. Osmotic Demyelination SyndromeOsmotic Demyelination SyndromeWithin one to several days central demyelinatingWithin one to several days central demyelinatinglesions 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/hror <10-12 mmol/l in 24 hrsor <10-12 mmol/l in 24 hrs
  • 50. CASE 9CASE 9A 52 year old man is admitted with nausea andA 52 year old man is admitted with nausea andvomiting. PMHx of CKD 4 for 1 year, HTN 2vomiting. PMHx of CKD 4 for 1 year, HTN 2years, 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 47Creatinine 1000Creatinine 1000Dialysis was initiatedDialysis was initiated2.5 hours / qB @ 150 mL/min2.5 hours / qB @ 150 mL/minPost dialysis [NaPost dialysis [Na++] – 121 mmol/L] – 121 mmol/L24 hours later, develops pontine myelinosis24 hours later, develops pontine myelinosis
  • 51. Strategies for dialyzing aStrategies for dialyzing apatient with hyponatraemiapatient with hyponatraemiaLower the dialysate sodiumLower the dialysate sodiumLower the blood and dialysate flowLower the blood and dialysate flowShorten 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 minimizesodium rise.sodium rise.Uraemia appears to be protective againstUraemia appears to be protective againstCPM as large amounts of brain osmolyteCPM as large amounts of brain osmolyteare producedare produced
  • 52. CASE 10CASE 1039 year old lady with cirrhosis found obtunded at home. She is39 year old lady with cirrhosis found obtunded at home. She istubed and ventilated. Blood pressure on admissiontubed and ventilated. Blood pressure on admission75/35mmHg, Temp 39.5, Pulse 113/min75/35mmHg, Temp 39.5, Pulse 113/minInitial labsInitial labsNa 113 mmol/lNa 113 mmol/l K 4 mmol/lK 4 mmol/lUrea 10 mmol/LUrea 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 230She 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 improvesto 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 rateof 500ml/h.of 500ml/h.
  • 53. 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 isSIADHSIADH2.2. The cause of this lady’s hyponatraemia is partThe cause of this lady’s hyponatraemia is partdue to secretion of ADH in response todue to secretion of ADH in response todecreased effective circulating volumedecreased effective circulating volume3.3. The patient is at decreased risk of osmoticThe patient is at decreased risk of osmoticdemyelinationdemyelination4.4. The patient’s sodium should be checked everyThe patient’s sodium should be checked every24-36 hours to monitor response to therapy24-36 hours to monitor response to therapy
  • 54. 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 12hours, 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. Herserum sodium is now 130 mmol/L. Urine output overserum sodium is now 130 mmol/L. Urine output overpast 2 hours has been 800 ml/h and is being matchedpast 2 hours has been 800 ml/h and is being matchedwith saline. Urinary sodium is now 60 mmol/Lwith saline. Urinary sodium is now 60 mmol/LChoose 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 rapidShe is at risk of acute cerebral oedema from her rapidsodium risesodium rise3.3. Her current sodium concentration reflects ongoingHer current sodium concentration reflects ongoingvolume depletionvolume depletion4.4. Her diuresis reflects decreased ADH activity due to anHer diuresis reflects decreased ADH activity due to anincrease in effective circulating volumeincrease in effective circulating volume
  • 55. 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/h2.2. Administration of 5% Dextrose at 3ml/kg/hAdministration of 5% Dextrose at 3ml/kg/h3.3. Stopping all fluidsStopping all fluids4.4. Administering Vasopressin 0.2mcg 8 hourlyAdministering Vasopressin 0.2mcg 8 hourlywith 5%Detrose to match free water losseswith 5%Detrose to match free water losses5.5. Administering Vasopressin 0.2mcg once withAdministering Vasopressin 0.2mcg once with5%Dextrose to match free water losses5%Dextrose to match free water losses
  • 56. CASE 11CASE 11You 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 thatfluctuates between 128-132 mmol/L. She reports nofluctuates between 128-132 mmol/L. She reports nosymptoms. Which of these statements is true regardingsymptoms. Which of these statements is true regardingchronic hyponatraemia?chronic hyponatraemia?1.1. Studies have shown a decreased incidence of hypertension inStudies have shown a decreased incidence of hypertension inpatients with chronic hyponatraemiapatients with chronic hyponatraemia2.2. Studies have shown a decreased rate of falls in patients withStudies have shown a decreased rate of falls in patients withchronic hyponatraemiachronic hyponatraemia3.3. ‘‘Asymptomatic’ hyponatraemia has been associated withAsymptomatic’ hyponatraemia has been associated withimpaired performance in both attention and tandem gait testingimpaired performance in both attention and tandem gait testing4.4. There is no current therapeutic rationale for treating chronicThere is no current therapeutic rationale for treating chronicasymptomatic hyponatraemiaasymptomatic hyponatraemia
  • 57. Vaptans andVaptans andHyponatraemiaHyponatraemia
  • 58. 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/V2receptorsreceptors– Covivaptan – IV formulation (V1/V2 affinity)Covivaptan – IV formulation (V1/V2 affinity)– Tolvaptan – Oral (V2 affinity)Tolvaptan – Oral (V2 affinity)
  • 59. The Evidence BaseThe Evidence BaseSALT-1 and SALT-2SALT-1 and SALT-2(NEJM 2006)(NEJM 2006)
  • 60. 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 withplacebo. Weight on discharge however similar.placebo. Weight on discharge however similar.• There were no differences in worsening heartThere were no differences in worsening heartfailure or mortality at 60 days between thefailure or mortality at 60 days between thetolvaptan 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 intolvaptan-treated patients with renal dysfunction ortolvaptan-treated patients with renal dysfunction orsevere systemic congestion.severe systemic congestion.
  • 61. Vaptans in Heart Failure (2)Vaptans in Heart Failure (2)EVEREST (JAMA 2007)EVEREST (JAMA 2007)Tolvaptan corrected hyponatraemia, butTolvaptan corrected hyponatraemia, butthere was no effect on long-term mortalitythere was no effect on long-term mortalityor 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 marginstight!tight!
  • 62. £74.68 per tab£74.68 per tab
  • 63. Vasopressin antagonists in ADPKDVasopressin antagonists in ADPKD• TTolvaptanolvaptan EEfficacy and safety infficacy and safety in MManagement ofanagement ofPPolycystic kidney disease and itsolycystic kidney disease and its OOutcomesutcomes((TEMPOTEMPO))• Evaluate long-term efficacy of tolvaptan inEvaluate long-term efficacy of tolvaptan inADPKD through rate of renal volume changeADPKD through rate of renal volume changeand a composite of ADPKD progression clinicaland a composite of ADPKD progression clinicalmarkers (hypertension, renal pain, albuminuriamarkers (hypertension, renal pain, albuminuriaand renal function).and renal function).
  • 64. ‘‘In your thirst for knowledge, beIn your thirst for knowledge, besure not to drown in all thesure not to drown in all theinformation.’information.’Anthony J. DAngeloAnthony J. DAngelo