SODIUM AND THE

BRAIN

OUTLINE PHYSIOLOGY: KIDNEY AND SODIUM

ADH BRAIN CELL VOLUME REGULATION

HYPONATRAEMIA: PATHOPHYSIOLOGY

ENCEPHALOPATHY MANAGEMENT

OSMOTIC DEMYELINATION SYNDROME

HYPERNATRAEMIA: PATHOPHYSIOLOGY ENCEPHALOPATHY MANAGEMENT

PHYSIOLOGY – KIDNEYS

PHYSIOLOGY – KIDNEYS 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 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 exchangeThick ascending loop: 30%; Na-2Cl-K cotransporterDistal tubule: 7%; Na-Cl cotransporterCollecting 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 – ADH 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

Plasma osmolarity:

Osmoreceptors anterior

hypothalamus

Blood volume:Low pressure receptors in

great veins, atria, pulmonary

vessels

Blood pressure:Carotid and

aortic baroreceptors

PHYSIOLOGY – ADH

PHYSIOLOGY – BRAIN MECHANISMS 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

*Ref: Review in 2010 Neuroscience issue by JG Verbalis “Brain volume regulation in response to changes in osmolality”

PHYSIOLOGY – BRAIN MECHANISMS 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)chronic almost 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 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 idiogenic osmoles- 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

Fig. 4. Relative increases in individual brain electrolytes and organicosmolytes during adaptation to chronic hypernatremia in rats. Thecategory “other” represents GPC, urea, and several other amino acids.Reproduced with permission from (Gullans and Verbalis, 1993).

HYPONATREMIA – PATHOPHYSIOLOGY

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

Table 2 Disorders in impaired renal water excretion1. Effective circulating volume depletiona) Gastrointestinal losses: vomiting, diarrheab) Skin losses: cystic fibrosisc) Renal losses: salt-wasting nephropathy, diuretics, cerebral saltwasting, hypoaldosteronismd) Oedematous states: heart failure, cirrhosis, nephrosis,hypoalbuminemiae) Decreased peripheral vascular resistance: sepsis, hypothyroidism2. Thiazide diuretics3. Renal failurea) Acuteb) Chronic4. Non-hypovolemic states of antidiuretic hormone (ADH)

excessa) Syndrome of inappropriate secretion of antidiuretic hormone(SIADH)b) Nausea, emesis, pain, stressc) Post-operative stated) Cortisol deficiency5. Nephrogenic syndrome of inappropriate antidiuresis

(NSIAD)

HYPONATREMIA – PATHOPHYSIOLOGY

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

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 – ENCEPHALOPATHY Most serious complication of hyponatremia and is

medical emergency Primary symptoms are those of cerebral oedema

coma

EARLY ADVANCED

headache seizures

N&V coma

lethargy apnoea

weakness pulmonary oedema

confusion decorticate posturing

altered LOC dilated pupils

agitation anisocoria

gait disturbances papilloedema

cardiac arrythmia

myocardial ischemia

central diabetes insipidus

HYPONATREMIA – ENCEPHALOPATHY 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 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 lesionshydrocephalus

(2) impaired brain cell volume regulation and decreased cerebral perfusionincreased ADH levelsfemale sex steroids (oestrogens reduce Na/K/ATPase pump activity, androgens enhance it)

hypoxia(3) CNS disorders

infection (meningitis, encephalitis)encephalopathy (metabolic, hepatic, ischaemic, toxic)cerebritisbrain injury and neurosurgeryseizure disorders

HYPONATREMIA – ENCEPHALOPATHY 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 – MANAGEMENT

HYPONATREMIA – MANAGEMENT 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 hypernatraemia if 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 100mlsingle bolus results in 2mmol/l acute rise in sNa which would quickly reduce cerebral oedemabolus 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

OSMOTIC DEMYELINATION SYNDROME

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

Pontine myelinolysisExtrapontine myelinolysis: 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 pontine myelination; therefore, extrapontine myelinolysis 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

EXTRA-PONTINE MYELINOLYSIS:T2 weighted magnetic resonance scan image showing bilaterally symmetrical hyperintensities in caudate nucleus, putamen, with sparing of globus pallidus.

CENTRAL PONTINE MYELINOLYSIS: Axial fat-saturated T2-weighted image showing hyperintensity in the pons with sparing of the peripheral fibres.

HYPERNATREMIA – PATHOPHYSIOLOGY

sNA >145mmol/l, life-threatening when >155mmol/l Predisposing factors:

CNS disease decreased fluid intakehigh solute fluids aldosterone excess

infant’s immature and diarrhoea normally inefficient decreased GFR renal concentration insensible losses

Classification:

isovolemic Hypovolemic hypervolemic

Debilitated, CNS dysfunction

Renal losses Iatrogenic

Insensible losses Gastrointestinal Mineralocorticoid excess

Respiratory losses Respiratory

Diabetes insipidus Skin losses (burns)

HYPERNATREMIA – CLINICAL MANIFESTATION

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 Hypernatraemia may cause fever, although usually

from underlying process Hypernatraemia associated with hyperglycaemia

and mild hypocalcaemia – mechanism unknown

HYPERNATRAEMIA – ENCEPHALOPATHY

CNS symptoms prominent; tend to parallel degree of hypernatraemia and 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

HYPERNATREMIA – MANAGEMENT

HYPERNATREMIA – MANAGEMENT

Hypernatraemia should 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 hypernatraemia due to sodium

administration, can correct faster or peritoneal dialysis severe

Cerebral Oedema: 3%NaCl stop hypotonic solution