IPONATREMIA

Marco Faustini Fustini

UOC Endocrinologia

Centro di Chirurgia dei Tumori Ipofisari e della Base CranicaCentro di Chirurgia dei Tumori Ipofisari e della Base Cranica

IRCCS Istituto delle Scienze Neurologiche di Bologna

Ospedale Bellaria ‐ Azienda USL Bologna

marco.faustini@ausl.bologna.it

Relazione tra la sodiemia al ricovero e la mortalità in ospedale

0.20

53 236

Wald, R. et al. Arch Intern Med 2010;170:294–302.

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0.15n=53.236

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Curva cubica restrittiva

Intervallo di confidenza 95%

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[Na+] nel siero al ricovero mEq/L

Pro

mo

110 115 120 125 130 135 140 145

Adattato da: Wald R, et al. Arch Intern Med. 2010;170(3):294-302.

[Na ] nel siero al ricovero mEq/L

L’iponatremia può essere dovuta a diverse condizionip p

Eziologia della iponatremia ([Na+] siero < 130mmol/L)Eziologia della iponatremia ([Na ] siero < 130mmol/L) presso la Clinica Medica Universitaria di Würzburg1

4%

20%

7%

2%

Primary polydipsia

Hypervolaemia

(n = 121)

35%

Hypervolaemia

Hypovolaemia

SIADH

Di ti i d d32% Diuretic-induced

Adrenal insufficiency

1. Fenske W, et al. Am J Med. 2010;123:652-657.

Signs and symptoms of hyponatraemia

• Anorexia/nausea• Muscle cramps• Headache• Central nervous system symptoms and signs

‐ Letargy/apathy‐ Disorientation, confusion, ataxia, gait disorder, fallsT l it ti /d li i‐ Tremulousness, agitation/delirium

‐ Abnormal sensoriumSeizures (urgent treatment with hypertonic saline!)‐ Seizures (urgent treatment with hypertonic saline!)

‐ Depressed deep tendon reflexes‐ Pathologic reflexes‐ Pathologic reflexes‐ Focal neurologic deficits‐ Pseudobulbar palsyPseudobulbar palsy‐ Cheyne‐Stokes respiration

Diagnosis

Disorders of water homeostasis

Because body water is the primary determinant of theBecause body water is the primary determinant of the osmolality of the ECF, disorders of body water homeostasis can be broadly divided into hypo‐osmolar disorders, in which h i f b d l i b d l dthere is an excess of body water relative to body solute, and hyper‐osmolar disorders, in which there is a deficiency of body water relative to body solute.y y

Because sodium is the main constituent of plasmaBecause sodium is the main constituent of plasma osmolality, these disorders are typically characterized by hyponatremia and hypernatremia, respectively.

Verbalis JG, 2003

Hyponatraemia – first assessment

Hyponatraemia

Iso-osmolalityIsotonic hyponatraemia

HyperosmolalityHypertonic hyponatraemia:

(pseudo-hyponatraemia):- hyperlipidaemia- paraproteinaemia

- hyperglicaemia- mannitol, glicerol

H l litHypo-osmolalityHypotonic hyponatraemia

ECF volume

Normal ECFDecreased ECF Increased ECF

La valutazione dello stato del volumedel fluido extra-cellulare (ECF) è essenziale nell’approccio al paziente con iponatremia

BMJ 2006; 332: 702

Body fluid compartments in man

Volemia

J Verbalis, 2003

EABV

Introito di acqua in eccesso

IponatremiaIponatremia ipotonicaipotonica

Diluizione renale insufficienteIntroito di acqua in eccessoOsmolalità delle urineOsmolalità delle urine

< 100< 100mOsm/kgmOsm/kg

Diluizione renale insufficiente

> 100> 100mOsm/kgmOsm/kg

Sodio nelle urineSodio nelle urineCause frequenti:Cause frequenti:•• Polidipsia primariaPolidipsia primaria•• Basso introito di Basso introito di solutisoluti

Stato clinico

Sodio nelle urineSodio nelle urine

< 30< 30mOsm/kgmOsm/kg

> 30> 30mOsm/kgmOsm/kg

Percorso decisionale

IpervolemiaIpervolemiaIpovolemiaIpovolemia

Volume ECFVolume ECF

IpovolemiaIpovolemia EuvolemiaEuvolemia

Volume ECFVolume ECF

Azione richiesta[Acqua corp. totale[Acqua corp. totale]][Sodio corp. totale[Sodio corp. totale]]

[Acqua corp. totale[Acqua corp. totale]][Sodio corp. totale[Sodio corp. totale]]

Perdita di soluti Perdita di soluti e trarenalee trarenale

Disordini edematosi:Disordini edematosi:Ins fficien a cardiacaIns fficien a cardiaca

[Acqua corp. totale[Acqua corp. totale]][Sodio corp. totale[Sodio corp. totale]]

[Acqua corp. totale[Acqua corp. totale]][Sodio corp. totale[Sodio corp. totale ]]

•• Deficit di Deficit di li ti idili ti idi

Perdita renale di Perdita renale di l tl textrarenale:extrarenale:

•• Perdita Perdita gastrointestinale gastrointestinale

(diarrea, vomito)(diarrea, vomito)•• Ustioni terzo spazioUstioni terzo spazio

P titP tit

•• Insufficienza cardiacaInsufficienza cardiaca•• Cirrosi epaticaCirrosi epatica•• Sindrome nefroticaSindrome nefrotica

•• IpotiroidismoIpotiroidismo•• DoloreDolore•• NauseaNausea

glicocorticoidiglicocorticoidi

•• Nefrite con perdita Nefrite con perdita di saledi sale

•• Diuresi osmoticaDiuresi osmotica

soluto :soluto :•• Eccesso diureticoEccesso diuretico

•• PancreatitePancreatite•• Muscolo traumatizz.Muscolo traumatizz.

•• NauseaNausea•• SIADHSIADH

•• Diuresi osmotica Diuresi osmotica (mannitolo, (mannitolo, glucosio)glucosio)•• Deficit di Deficit di mineralcorticoidimineralcorticoidi

Adattato da: Fenske W, et al. Am J Med. 2010;123:652-657.; Schrier R.W. J Curr Opin Crit Care. 2008;14:627-634.; Verbalis J. Best Pract Res Clin Endocrinol Metab. 2003;17(4):471-503.

N Engl J Med 2005

SIAD(H) is a disorder in which renal water handling is i i d b t l di h dli i limpaired but renal sodium handling is normal

Consider the response of a patient with SIAD(H) given 1 L of p p ( ) gnormal saline (308 mosm).

Assuming  a urine osmolality of 616 mosm/L, the entire load of NaCl will be excreted in 500 ml of fluid. The remaining 500 ml of administered fluid will remain within the body and cause a further lowering of the serum sodium concentration.

In order to avoid worsening hyponatraemia in this setting, the osmolality of the fluid given must exceed the osmolality of theosmolality of the fluid given must exceed the osmolality of the urine.

B. Palmer TEM, 2003

SIADMild expansion of ECF volume

Decreased proximal Na+ reabsorption Increased GFR and renal plasma flow

Increased urinary Na+ excretion(equal to dietary intake)

Decreased proximal reabsorption of substances (such as uric acid and urea nitrogen) which are reabsorbed proximally in concert with Na+which are reabsorbed proximally in concert with Na+

Decreased uric acid and urea nitrogen in serum

AcronimiAcronimi

S d f i iSIADH: syndrome of inappropriate secretion of ADH (1957)

NSIAD: nephrogenic syndrome ofNSIAD: nephrogenic syndrome of inappropriate antidiuresis (2005)

SIAD: syndrome of inappropriateSIAD: syndrome of inappropriate antidiuresis (2005)

N Engl J Med, 2005

CNS disease and the complex journey to hyponatremia

Peters JP et al. (1950) Peters JP et al. (1950) 

A saltA salt‐‐wasting syndrome associated wasting syndrome associated with cerebral disease.with cerebral disease.with cerebral disease.with cerebral disease.

Trans Assoc Am Physicians Trans Assoc Am Physicians 63: 5763: 57‐‐6464

In their report, the authors described 3 patients with neurological disorders who3 patients with neurological disorders who presented with:

‐ hyponatremiayp‐ renal sodium wasting‐ clinical evidence of volume depletion‐ no obvious disturbance in the pituitary‐

adrenal axis

Pathophysiology of CSW

IMCD: inner medullary collecting duct; EABV: effective arterial blood volume

Hyponatraemia with natriuresis in CNS diseases

• SIAD (syndrome of inappropriate antidiuresis):‐ hyponatraemia with plasma osmolality < 275 mOsm/L‐ hyponatraemia with plasma osmolality < 275 mOsm/L,‐ inappropriately concentrated urine (>100 mOsm/L),‐ natriuresis (UNa > 40 mmol/L),‐ fluid overload (expansion of the ECF volume with normal or slightly increased intravascular volume).

SIAD is a volume‐expanded state.pTreatment: fluid restriction (in mild‐moderate hyponatremia); 3% NaCl hypertonic saline (in severe hyponatremia); vaptans.

• CSW (cerebral salt wasting): traditional laboratory criteria for SIAD, but with decreased ECF and intravascular volume (hypovolemia).

CSW is a volume depleted stateCSW is a volume‐depleted state.Treatment: fluid and salt replacement (saline in mild‐moderate hyponatremia; saline or 3% NaCl hypertonic saline in severe h t i fl d ti ?)hyponatremia; fludrocortisone?)

CSW and SIAD: differential diagnosis

CSWCSW SIADSIAD

ECF volumeECF volume decreaseddecreased increasedincreased

Postural changes in A.P. Postural changes in A.P. l ( b )l ( b )

presentpresent absentabsentand pulse rate (> 30 bpm)and pulse rate (> 30 bpm)

Central venous pressureCentral venous pressure decreaseddecreased normalnormal

Plasma albuminPlasma albumin increasedincreased normalnormal

HaematocritHaematocrit increasedincreased normalnormal

Plasma BUN/creatininePlasma BUN/creatinine increasedincreased decreaseddecreased

Fluid balanceFluid balance negativenegative normal (equilibrium)normal (equilibrium)

Plasma uric acidPlasma uric acid normal/decreasednormal/decreased decreaseddecreased

Plasma KPlasma K++ normal/increasednormal/increased normalnormal//

Palmer BF. TEM 2003, 14:182‐187 (modified)

Algorithm for evaluation of patients with hyponatraemia and hypouricemia at presentation

Nephron 1999

Central Nervous System disease and hyponatraemia – Does CSW exist?

Treatment

The challenge of hyponatraemiaThe challenge of hyponatraemia

Alth h bidit i id l i it i• Although morbidity varies widely in severity, serious complications can arise from:

– the disorder itself (hyponatraemic encephalopathy)

– as well as from errors in management leading to the rapid g g pshift in sodium (central pontine and extrapontine myelinolysis ‐ the osmotic demyelination syndromes).

Effects of hyponatraemia on the brain and adaptive responses (NEJM 2000)

MRI findinds in extrapontine myelinolysisMRI findinds in extrapontine myelinolysisAxial T2Axial T2‐‐weighted image showing bilateral symmetrical high weighted image showing bilateral symmetrical high intensity in the caudate heads, basal ganglia, and thalami. intensity in the caudate heads, basal ganglia, and thalami. Clin Clin 

Radiol 57:800, 2002Radiol 57:800, 2002

MRI findings in central pontine myelinolysisMRI findings in central pontine myelinolysisT2T2‐‐weighted axial scan, showing the weighted axial scan, showing the 

characteristic “batcharacteristic “bat‐‐wing” appearance of CPMwing” appearance of CPM((Clin Radiol 57: 800 2002Clin Radiol 57: 800 2002))((Clin Radiol 57: 800, 2002Clin Radiol 57: 800, 2002))

Maximum suggested correction of Maximum suggested correction of di i 24 hdi i 24 hsodium in 24 hrs sodium in 24 hrs (Martin RJ, JNNP 2004)(Martin RJ, JNNP 2004)

Photograph by Mike Yamashita

Utilizzare la modalità di insorgenza dell’iponatremia secondaria a SIAD(H) come guida per la scelta del trattamento

IponatremiaIponatremia

Insorgenza24–48ore > 48oreAcuta Insorgenza

graduale

Sintomi i

Sintomi lievi/moderati o i i i

Soluzione salina 3%± diuretici dell’ansa

severi paziente asintomatico

Soluzione salina 3%± diuretici dell’ansa

TolvaptanRestrizione idrica

Se non si conosce la rapidità con cui è insorta, l’iponatremia dovrebbe essere trattata come se fosse ad esordio gradualeg

Verbalis J, et al. Am J Med. 2007;120(11 Suppl 1):S1-21 (modified).

Treatment of SIAD with mild orTreatment of SIAD with mild or asymptomatic hyponatraemia

Fl id t i ti l- Fluid restriction alone- Vaptans?Vaptans?

Tolvaptan (Samsca)Tolvaptan (Samsca)

• Samsca (tolvaptan, study name OPC‐41061)

• Benzazepine derivative1

• Oral Selective V2‐Receptor AntagonistOral Selective V2 Receptor Antagonist1. Yamamura Y, et al. J Pharmacol Exp Ther. 1998;287(3):860-867.

Treatment of SIAD with severe symptomsTreatment of SIAD with severe symptoms (seizures, coma, respiratory distress) 

or moderate symptoms (nausea disorientationor moderate symptoms (nausea, disorientation, unsteady gait) if hyponatraemia is known to be 

acute (i e < 48 hrs duration)acute (i.e. < 48 hrs duration)

Hypertonic saline

Hypertonic saline

…The controversy as to how hyponatremic patients should best be treated can be traced to the fact that not a single prospectivetreated can be traced to the fact that not a single prospective, randomized, controlled trial is designed to address the optimal management of this most common of electrolyte disorders. There 

h f l l bl h d d f l dare, therefore, no clearly established and uniformly agreed‐on national or international guidelines, and those that are put forth in various publications are based primarily on retrospective a ous pub cat o s a e based p a y o et ospect eobservational analysis on a limited number of patients. None has the virtue of comparing prospectively two or more therapeutic 

ti d it i f ll d fi d l i l t ioptions and monitoring for well‐defined neurological outcomes in a randomized, controlled trial or even in a robust prospective, observational trial. Ultimately, the published recommendations are y plargely opinion based and reflect the experience of the various authors.’

Tomas Berl   Clin J Am Soc Nephrol 2: 1098, 2007

Hypertonic salineHypertonic saline…’In the midst of the controversy that surrounds the rate and 

it d th t h ld id th t t t f h t imagnitude that should guide the treatment of hyponatremia, the most accepted intervention is the one that calls for the use of hypertonic sodium chloride (3% NaCl) to treat patientsuse of hypertonic sodium chloride (3% NaCl) to treat patients who have severe hyponatremia (Na < 125 mmol/L) and present with marked neurologic symptoms, especially seizures. This intervention is designed to reverse promptly the accompanying cerebral edema that could in turn result in t t i l h i ti d l i t i th ti t’ d thtentorial herniation and culminate in the patient’s death. There is, however, essentially no literature as to the use of this approach ’approach.

Tomas Berl  Clin J Am Soc Nephrol 2: 1098, 2007

N Engl Med 2007

La soluzione salina ipertonicaLa  soluzione  salina  ipertonica

• The primary shortcoming of the formula is its failure to assess ongoing renal and extrarenal losses. This is particularly critical in hypovolemic patients when the nonosmotic release ofin hypovolemic patients, when the nonosmotic release of vasopressin is no longer operant (because of the restoration of volume over 24‐48 hrs) and a water diuresis ensues.)

• The formula does not allow for the increase in serum sodium concentration that accompanies the administration of potassium in the potassium‐depleted group (e.g., role of potassium in hypokalemia‐induced hyponatremia).

Clin J Am Soc Nephrol 3: 331, 2008

Formulas for estimating the effect of any infusate on serum sodium

The Bellaria Hospital’s jazz bandThe Bellaria Hospital s jazz band

Giorgio Frank (trumpet and conductor)

Ernesto PasquiniDiego Mazzatenta

Matteo ZoliVittorio Sciarretta

Antonella BacciMarco Faustini Fustini

Approach to the hyponatraemic patienthyponatraemic patient

EABV: effective arterial bloodlvolume

ECF: extra-cellular fluid

Patient with extracellular fluidPatient with extracellular fluid volume depletion:- orthostatic- dry skindry skin- light-headed