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SODIUM

SODIUM. AND THE. BRAIN. PHYSIOLOGY: KIDNEY AND SODIUM ADH BRAIN CELL VOLUME REGULATION HYPONATRAEMIA: PATHOPHYSIOLOGY ENCEPHALOPATHY MANAGEMENT OSMOTIC DEMYELINATION SYNDROME HYPERNATRAEMIA: PATHOPHYSIOLOGY ENCEPHALOPATHY MANAGEMENT.

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SODIUM

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  1. SODIUM AND THE BRAIN

  2. PHYSIOLOGY: KIDNEY AND SODIUM ADH BRAIN CELL VOLUME REGULATION • HYPONATRAEMIA: PATHOPHYSIOLOGY ENCEPHALOPATHY MANAGEMENT • OSMOTIC DEMYELINATION SYNDROME • HYPERNATRAEMIA: PATHOPHYSIOLOGY ENCEPHALOPATHY MANAGEMENT OUTLINE

  3. PHYSIOLOGY – KIDNEYS

  4. Sodium: - content: 3% intracellular; 40% in bone; remainder interstitial and intravascular - intake: readily absorbed through GIT; presence of glucose enhances sodium absorption due to co-transporter; intake recommended not to exceed 2500mg/d - excretion: stool minimal unless diarrhoea sweat normally 5-40mmol/l (cystic fibrosis, aldosterone deficiency, pseudohypoaldosteronism) kidneys principal site PHYSIOLOGY – KIDNEYS

  5. Sodium concentration determined by water balance, not sodium balance; renal excretion of sodium therefore not regulated by plasma osmolality • Proximal tubule: 60% reabsorbed; Na-H exchange Thick ascending loop: 30%; Na-2Cl-K cotransporter Distal tubule: 7%; Na-Cl cotransporter Collecting ducts: 3%; ENaC channels aldosterone • Factors affecting sodium excretion - changes in GFR - changes in tubular reabsorption, esp at collecting ducts (aldosterone and other adrenocortical hormones, natriuretic hormones, rate of tubular secretion of H and K PHYSIOLOGY – KIDNEYS

  6. Arginine vasopressin: peptide hormone which is most important regulator of water excretion, also vasoconstrictor • Stimuli: • Mechanism: hypothalamus posterior pituitary V2 receptor on basolateral aspect collecting duct cells aquaporin2 insertion on luminal membrane PHYSIOLOGY – ADH Blood volume: Low pressure receptors in great veins, atria, pulmonary vessels Plasma osmolarity: Osmoreceptors anterior hypothalamus Blood pressure: Carotid and aortic baroreceptors

  7. PHYSIOLOGY – ADH

  8. Brain particularly vulnerable to changes in body fluid osmolality - oedema with hypo-osmolar states - dehydration with cell shrinkage in hyperosmolar states • Brain adapts to osmotic stresses through many mechanisms - transient changes in water content - sustained changes in electrolyte and organic osmolyte contents PHYSIOLOGY – BRAIN MECHANISMS *Ref: Review in 2010 Neuroscience issue by JG Verbalis “Brain volume regulation in response to changes in osmolality”

  9. Hypo-osmolality/hyponatremia: - water into intracellular compartment oedema - brain adapts by losing solute, thus decreasing cellular water content. Movement by diffusion, not energy-dependent carriers. solutes (a) electrolytes (K, Cl) (b) organic osmolytes (amino acids [glycine, GABA, glutamate, aspartate], polyalcohols, sugars, methylamines) - rate of fall of sodium correlates with morbidity and mortality acute greater volume of water accumulates before brain loses enough solute to compensate (acute=24-48hrs) chronicalmost complete normalization of water content in hyponatremia maintained over 21 days - Deadaptation: takes longer for brain to re-accumulate its solutes – risk of cellular dehydration with rapid correction PHYSIOLOGY – BRAIN MECHANISMS

  10. Hyperosmolality/hypernatremia: - osmotic shifts of intracellular water into extracelullar compartment cellular dehydration - brain cells adapt by accumulating solutes; rapid accumulation of electrolytes, more gradual accumulation of organic osmolytes, AKA idiogenicosmoles - Mechanisms of brain organic osmolyte accumulation remain poorly understood, but likely combination of uptake and synthesis - acute developing in 24-48hours; less likely; accidental salt poisoning, severe diarrhoea 45% morbidity and mortality in children: rapid accumulation of electrolytes - chronic developing over several days; generally better tolerated with less neurological symptoms than acute; gradual accumulation of organic solutes beginning after 9-24hrs, steady state at 2-7 days - Neurological symptoms and mortality higher in acute rather than chronic hypernatremia PHYSIOLOGY – BRAIN MECHANISMS

  11. PHYSIOLOGY – BRAIN MECHANISMS Fig. 4. Relative increases in individual brain electrolytes and organic osmolytes during adaptation to chronic hypernatremia in rats. The category “other” represents GPC, urea, and several other amino acids. Reproduced with permission from (Gullans and Verbalis, 1993).

  12. Most common electrolyte disturbance in children • More serious than previously believed • Primary defence to development of hyponatremia: kidney excretes free water • For hyponatremia to occur: excess free water coupled with underlying renal impairment of free water excretion • Disorders: - marked decrease in GFR - renal hypoperfusion - excess of ADH HYPONATREMIA – PATHOPHYSIOLOGY

  13. Table 2 Disorders in impaired renal water excretion 1. Effective circulating volume depletion a) Gastrointestinal losses: vomiting, diarrhea b) Skin losses: cystic fibrosis c) Renal losses: salt-wasting nephropathy, diuretics, cerebral salt wasting, hypoaldosteronism d) Oedematous states: heart failure, cirrhosis, nephrosis, hypoalbuminemia e) Decreased peripheral vascular resistance: sepsis, hypothyroidism 2. Thiazide diuretics 3. Renal failure a) Acute b) Chronic 4. Non-hypovolemic states of antidiuretic hormone (ADH) excess a) Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) b) Nausea, emesis, pain, stress c) Post-operative state d) Cortisol deficiency 5. Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) HYPONATREMIA – PATHOPHYSIOLOGY

  14. Cerebral Salt Wasting: - cerebral disease causes disorder in sodium and water handling - renal function usually normal - natriuresis hyponatremia and hypovolaemia - clinically: polyuria dehydration (despite adequate intake) elevated urine sodium levels - postulated mechanism: (a) interference with sympathetic input to kidney decrease in renin secretion decreased aldosterone. Also dilatation of afferent arteriole increased glomerular filtration of plasma and sodium (b) circulating natriuretic factors abnormally elevated dilatation of afferent arteriole with increased filtration of water and sodium; inhibit angiotensin-induced sodium reabsorption at proximal convoluted tubule; antagonize action of ADH at collecting ducts - NB: Differentiate cerebral salt wasting (hypovolemic) from SIADH (euvolemic) HYPONATREMIA – PATHOPHYSIOLOGY

  15. Asymptomatic hyponatremia: - in adults with mild chronic hyponatremia with Na mean of 128mmol/l found to have subtle neurological impairment affecting gait and attention - preterm neonates show impaired growth and development and have increased sodium intake as adolescents - lacking data in older children • Hyponatremia also significant risk factor for sensorineural hearing loss, CP and intracranial haemorrhage • Risk factor for increased mortality in neonates with perinatal asphyxia HYPONATREMIA – PATHOPHYSIOLOGY

  16. Most serious complication of hyponatremia and is medical emergency • Primary symptoms are those of cerebral oedema coma HYPONATREMIA – ENCEPHALOPATHY

  17. Progression from mild to advanced symptoms can be abrupt with no consistent progression • Common yet under-recognised feature is non-cardiogenic pulmonary oedema called Ayus-Arieff syndrome - mechanism 1: centrally mediated increase in pulmonary vascular permeability to proteins, leading to increased alveolar and interstitial fluid - mechanism 2: increased sympathetic neuronal activity with catecholamine release, resulting in pulmonary vasoconstriction with increased capillary hydrostatic pressure and capillary wall injury - primarily reported in patients with post-op and exercise-associated hyponatremia - rapidly reversible with hypertonic saline, and almost universally fatal if untreated. HYPONATREMIA – ENCEPHALOPATHY

  18. Risk factors: (1) decreased cranial capacity children>adults – average Na in children with encephalopathy is 120mmol/l, in adults 111mmol/l – children have relatively larger brain to intracranial volume ratio (brain reaches adult size by age 6, skull only by age 16) space-occupying lesions hydrocephalus (2) impaired brain cell volume regulation and decreased cerebral perfusion increased ADH levels female sex steroids (oestrogens reduce Na/K/ATPase pump activity, androgens enhance it) hypoxia (3) CNS disorders infection (meningitis, encephalitis) encephalopathy (metabolic, hepatic, ischaemic, toxic) cerebritis brain injury and neurosurgery seizure disorders HYPONATREMIA – ENCEPHALOPATHY

  19. Hypoxaemia combined with hyponatremia more deleterious than either factor alone – hypoxaemia impairs brain’s ability to adapt to hyponatremia leading to worsening encephalopathy • Patient with CNS disorder already at risk for raised ICP and have impaired brain cell volume regulation, additional water movement into brain from even mild hyponatremia can be lethal • One study in children with pneumococcal meningitis showed mortality of 100% in those with sNa <130mmol/l • In maple-syrup-urine disease, hyponatremia found to lead to progressive cerebral oedema during episodes of acute metabolic intoxication • In DKA, mild hyponatremia sNa <135mmol/l appears to play role in development of cerebral oedema NO DEGREE OF HYPONATREMIA SHOULD BE CONSIDERED SAFE IN PATIENTS WITH CNS DISEASE HYPONATREMIA – ENCEPHALOPATHY

  20. HYPONATREMIA – MANAGEMENT

  21. Preventing hospital-acquired hyponatremia - 0.9% NaCl in patients at risk for ADH excess - abandonment of routine administration of hypotonic and near- isotonic IV fluids (Na<130) NB: 0.9%NaCl not suited to all clinical circumstances, e.g. causes hypernatraemiaif used in diabetes insipidus or profuse watery diarrhoea; may not always prevent hyponatremia in CNS injury where there is cerebral salt wasting or SIADH • Management: Hypertonic saline (3%NaCl, 513mmol/l) 2ml/kg bolus over 10mins, with maximum of 100ml single bolus results in 2mmol/l acute rise in sNa which would quickly reduce cerebral oedema bolus can be repeated one or two times • Goal of correction 5-6mmol/l in first 1-2hr. Thereafter, various recommendations of safe limits for correction: 6-8mmol/l In 24hr, or 10mmol/l in 24hours, or 15 mmol/l in 24hrs, or 20mmol/l in 48hrs HYPONATREMIA – MANAGEMENT

  22. Rare and acute demyelinating process commonly associated with rapid correction of hyponatremia – sNa increased by more than 12mmol/l/d • Initially described in 1959 as condition seen in alcoholic and malnourished patients • Pathophysiology: - not fully understood - linked to intramyelinitic splitting, vacuolization, and rupture of myelin sheaths presumably caused by osmotic effects - oligodendrocytes particularly sensitive to osmotic changes; distribution of changes of ODS parallel distribution of oligodendroglial cells - damage is characteristically symmetrical - J Am Soc Nephr 2011, Kengne et al: apoptosis in astrocytes followed by a loss of trophic communication between astrocytes and oligodendrocytes, secondary inflammation, microglial activation, and finally demyelination. OSMOTIC DEMYELINATION SYNDROME

  23. Pontine myelinolysis Extrapontinemyelinolysis: basal ganglia, cerebral white matter, peripheral cortex, hippocampi, lateral geniculate bodies • Very infrequently seen in infants possibly due to ongoing myelination process which occurs under age 2yrs - Supratentorial white matter myelination occurs later than pontinemyelination; therefore, extrapontinemyelinolysis is even more rare • Predisposing factors: prolonged use of diuretics, liver failure, organ transplantation, extensive burns, diabetes mellitus, metabolic disorders, uraemia, dialysis, hypoxic-ischaemic states • Clinical: - spastic quadriplegia - pseudobulbar palsy - loss of consciousness - cranial nerve palsies OSMOTIC DEMYELINATION SYNDROME

  24. OSMOTIC DEMYELINATION SYNDROME CENTRAL PONTINE MYELINOLYSIS: Axial fat-saturated T2-weighted image showing hyperintensity in the pons with sparing of the peripheral fibres. EXTRA-PONTINE MYELINOLYSIS: T2 weighted magnetic resonance scan image showing bilaterally symmetrical hyperintensities in caudate nucleus, putamen, with sparing of globuspallidus.

  25. sNA >145mmol/l, life-threatening when >155mmol/l • Predisposing factors: CNS disease decreased fluid intake high solute fluids aldosterone excess infant’s immature and diarrhoea normally inefficient decreased GFR renal concentration insensible losses Classification: HYPERNATREMIA – PATHOPHYSIOLOGY

  26. In hypernatremic dehydration, 2/3 water lost is intracellular with better preservation of intravascular compartment – skin turgor may be normal despite loss of 10% body weight • BP and urine output also maintained • Abdominal skin has doughy feel probably due to intracellular water loss • Hypernatraemiamay cause fever, although usually from underlying process • Hypernatraemiaassociated with hyperglycaemia and mild hypocalcaemia – mechanism unknown Hypernatremia – clinical manifestation

  27. CNS symptoms prominent; tend to parallel degree of hypernatraemiaand acuity of the increase • CNS cells attempt to increase osmolarity: - water moves out of the cells - Intracellular proteins break down to form solutes severe disruption of intracellular proteins could account for drastic and sometimes permanent impairment of brain function • Manifestations: - pronounced irritability, restlessness - convulsions - weak and lethargic - coma - muscular hypertonicity - subdural haematomas - cerebral petechiae - cerebral haemorrhage - cerebral vein thrombosis - stroke HYPERNATRAEMIA – ENCEPHALOPATHY

  28. HYPERNATREMIA – MANAGEMENT

  29. Hypernatraemiashould not be corrected rapidly due to risk of oedema with resultant seizures and coma. • Decrease at rate of not more than 12mmol/l/d or 0.5mmol/l/hr • Managing shock: 0.9%NaCl preferable over Ringers • Correction: - 0.45% NaCl with fluid rate only 20-30% greater than maintenance - if hypernatraemiadue to sodium administration, can correct faster or peritoneal dialysis severe • Cerebral Oedema: 3%NaCl stop hypotonic solution HYPERNATREMIA – MANAGEMENT

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