Salt and Water Balance

9
Salt and Water Balance


Physiology and pathophysiology


Control of salt balance


Regulation of salt balance is achieved primarily through activation of the renin–angiotensin–aldosterone system and the release of atrial natriuretic peptide. Renin is secreted by the juxtaglomerular cells of the kidney in response to sodium depletion or extracellular fluid volume restriction. Renin converts angiotensinogen to angiotensin I which, in turn, is converted by angiotensin‐converting enzyme to angiotensin II. Angiotensin II stimulates the production of aldosterone from the zona glomerulosa of the adrenal cortex. Adrenocorticotrophic hormone (ACTH) does not play a role in the physiological regulation of aldosterone secretion although serum aldosterone increases upon acute intravenous (IV) ACTH administration. Potassium ions also facilitate the secretion of aldosterone. By contrast, the secretion of both renin and aldosterone may be inhibited by atrial natriuretic peptide.


Aldosterone binds to the mineralocorticoid receptor, resulting in increased reabsorption of sodium in the kidney, sweat and salivary glands. Sodium ions are exchanged for potassium and hydrogen ions in the distal tubule. Cortisol also has a strong binding affinity for the mineralocorticoid receptor but is prevented from doing so as a result of metabolism to inactive cortisone by 11‐β‐hydroxysteroid dehydrogenase‐2 in aldosterone‐sensitive tissues.


Control of water balance


Water balance is maintained by the interrelation between thirst, renal function, and the antidiuretic hormone arginine vasopressin (AVP). Vasopressin is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus in a pre‐pro‐hormone form consisting of vasopressin, neurophysin II, and copeptin. These peptides are then cleaved during transport along the supraoptic–hypophyseal tract to be stored in the posterior pituitary. Vasopressin release is regulated by osmoreceptors in the hypothalamus which detect changes in plasma osmolality from 280 to 295 mOsm/kg as may occur with loss of extracellular water. High concentrations of vasopressin may also be secreted following baroreceptor‐detected reductions in blood volume or blood pressure of 5–10%. Baroreceptors are located in the carotid arch, aortic sinus, and left atrium and modulate vasopressinergic neuronal function via vagal and glossopharyngeal stimulation of the brainstem.


Vasopressin binds to a V2 receptor in the renal collecting tubule which regulates the insertion of water channel proteins (aquaporin 2) into the cell membrane. These allow water to flow along an osmotic gradient from the tubular lumen into the cells lining the collecting duct. Other aquaporins (aquaporin 4) allow this water to pass to the renal interstitium and circulation. This regulatory mechanism maintains plasma osmolality between 282 and 295 mOsm/kg. When the plasma osmolality exceeds 295 mOsm/kg, vasopressin secretion cannot be increased further and fluid balance is maintained by increased thirst leading to increased fluid intake. The vasopressin effect is under negative feedback modulation by locally generated prostaglandins in the medullary collecting duct cells. Glucocorticoids are also required for free water excretion so that initiation of glucocorticoid replacement in hypopituitary patients may unmask diabetes insipidus (DI).


Hyponatraemia


Aetiology


Hyponatraemia may occur either as a result of salt and water depletion in which salt loss exceeds water loss or following fluid overload resulting in relatively more water than salt. The general mechanisms for the development of hyponatraemia are shown in Table 9.1.


Table 9.1 Causes of hyponatraemia.






















































Mechanism Examples
Salt loss
Renal disease Renal tubular defects (e.g. Fanconi, Bartter syndromes)
Chronic renal failure
Interstitial nephritis
Renovascular hypertension
Diuretic treatment
Cisplatin toxicity
Aldosterone deficiency Inherited enzyme disorders (e.g. 21‐hydroxylase deficiency), Addison’s disease
Aldosterone resistance Pseudohypoaldosteronism
Cutaneous loss Excess sweat sodium loss in cystic fibrosis, fluid loss in burns
Gastrointestinal Vomiting and diarrhoea (e.g. in gastroenteritis)
Intestinal obstruction (e.g. intussusception)
Water excess
Renal disease Acute nephritic syndrome, acute and chronic renal failure
Hypovolaemia or decreases in renal perfusion causing increased proximal renal tubular reabsorption Cirrhosis, congestive heart failure, nephrotic syndrome
Excessive water intake Iatrogenic – excessive intravenous fluid replacement
Primary polydipsia
ADH excess Syndrome of inappropriate ADH secretion (e.g. in meningitis, pneumonia)
Over‐treatment with DDAVP

Hyponatraemia associated with extracellular fluid loss is not always a direct consequence of the fluid loss per se, which is frequently hypotonic or isotonic by comparison with plasma, but may be caused by replacement of these fluid losses with hypotonic fluid (e.g. drinking water alone or use of hypotonic IV fluids).


History and examination


When a child presents with hyponatraemia for which the cause is not immediately apparent, the following points should be highlighted in the history:



  1. Features suggestive of salt loss:

    • The presence of symptoms causing excess fluid and sodium loss (e.g. weight loss, vomiting, diarrhoea, polyuria) or a compensatory decrease in urine production which may occur when sodium loss has occurred from the skin or gut.
    • Evidence that hyponatraemia is precipitated by intercurrent illness and associated with hyperkalaemia and hypoglycaemia which might suggest adrenal failure.
    • Symptoms of malabsorption or recurrent chest infections or a tendency for hyponatraemia to develop during hot weather which may be indicative of cystic fibrosis.
    • The use of medication (e.g. diuretics) which predispose to hyponatraemia.
    • Family history of consanguinity and of specific disorders such as cystic fibrosis, congenital adrenal hyperplasia or hypoplasia, and pseudohypoaldosteronism.

  2. Features suggestive of water retention:

    • Excess daily fluid intake.
    • Symptoms suggestive of an underlying central nervous system (CNS) or respiratory disorder (e.g. meningitis, raised intracranial pressure, pneumonia) associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
    • Symptoms suggestive of heart failure, renal, liver or thyroid disease.

The following points should be highlighted in the clinical examination:



  1. The patient should always be weighed.
  2. If sodium loss has occurred, clinical signs of volume depletion may be present as shown in Table 9.2. Evidence of growth impairment may suggest a long‐standing cause of hyponatraemia resulting from sodium loss. Careful clinical examination should be undertaken of all systems for signs suggestive of intracranial or respiratory disease, cardiac, hepatic, renal or adrenal failure, or hypothyroidism.
  3. If signs of volume depletion are absent, this may imply either previous fluid replacement with hypotonic fluids or the presence of water retention. In the latter circumstances, there may be evidence of oedema or rapid recent weight gain. The clinical signs of volume overload are shown in Table 9.2. The rapid onset of a hypo‐osmolar state may be associated with neurological manifestations including anorexia, apathy, confusion, headaches, weakness, and muscle cramps. More severe symptoms may include vomiting, depressed deep tendon reflexes, bulbar or pseudobulbar palsy, Cheyne–Stokes breathing, psychotic behaviour, seizures, coma, and death.

Table 9.2 Clinical signs of volume depletion and overload.



















Volume depletion Volume overload


  1. Weight loss


  1. Weight gain


  1. Intravenous compartment depletion with

    • ↓ tissue perfusion
    • fast, low volume pulse
    • blood pressure typically low (but may be normal/high due to vasoconstriction)
    • slow capillary refill (>2 s)
    • impaired consciousness
    • pallor due to vasoconstriction


  1. Intravenous compartment expansion

    • fast, high volume (bounding) pulse
    • high blood pressure
    • raised jugular venous pressure
    • gallop rhythm
    • liver engorgement


  1. Interstitial compartment depletion

    • ↓ skin turgor, sunken eyes
    • dry mucous membranes


  1. Interstitial compartment expansion

    • peripheral oedema with puffy eyes, ankle and sacral oedema, ascites


  1. Increased urine osmolality

    • Urine sodium low or high depending on aetiology


  1. Urine osmolality increased or decreased depending on aetiology

Investigations



  • Serum and urine electrolytes and creatinine to calculate urinary sodium losses.
  • Serum and urinary osmolalities.
  • Plasma renin activity, aldosterone, 17‐hydroxy progesterone and cortisol.
  • Thyroid function tests (TFT).
  • Other investigations as indicated for cardiac, respiratory, hepatic, renal, or intracranial disease.
  • If the patient is normo‐osmolar, plasma proteins, lipids, and glucose.

Differential diagnosis


Hyponatraemia can be spurious either as a result of contamination of the blood sample taken from an IV cannula with hypotonic IV fluids or because of interference with the flame photometer assay by excess serum lipids or proteins.


The key requirement in the assessment of a patient with hyponatraemia is to distinguish between causes associated with excess sodium loss and those associated with water retention, for example, in SIADH. The clinical distinction between these two states is summarized in Table 9.2.


If the cause of the hypo‐osmolar state is not clear at presentation, urine osmolalities >100 mOsm/kg associated with urinary sodium concentrations >20 mmol/L suggest acute SIADH or renal, adrenal, or cerebral salt wasting. Urine osmolalities >100 mOsm/kg associated with urinary sodium concentrations <20 mmol/L suggest hypovolaemia or longer‐standing SIADH. Plasma renin is usually suppressed in SIADH but elevated in hypovolaemia.


Diagnosis


The causes of hyponatraemia are summarized in Table 9.1. Mineralocorticoid deficiency may be a consequence of idiopathic congenital adrenal hypoplasia or aplasia, biosynthetic defects of aldosterone synthesis (e.g. congenital adrenal hyperplasia) or acquired primary adrenal failure (e.g. Waterhouse–Friderichsen syndrome, autoimmune disease, or following surgical removal). While combined mineralocorticoid and glucocorticoid deficiency will cause hyponatraemia through salt loss, glucocorticoid deficiency (e.g. in hypopituitarism) will cause hyponatraemia due to impaired water excretion. Resistance to aldosterone may occur as a result of inactivation of the mineralocorticoid receptor or of the epithelial sodium channel. Abnormalities of mineralocorticoid physiology are discussed in more detail in Chapter 8.


The various causes of SIADH are summarized in Table 9.3.


Table 9.3 Causes of syndrome of inappropriate antidiuretic hormone secretion (SIADH).



























Cause Examples
Central nervous system disorders Meningitis, encephalitis, trauma (including surgery), hypoxia, haemorrhage, ventriculo‐peritoneal shunt obstruction, Guillain–Barré syndrome
Respiratory disorders Pneumonia, tuberculosis
Tumours Thymoma, lymphoma, Ewing’s sarcoma
Drugs


  • AVP stimulants
Phenothiazines, tricyclic antidepressants, vincristine, narcotics DDAVP, prostaglandin synthetase inhibitors


  • AVP potentiators


  • Other
Chlorpropamide, cyclophosphamide, carbamazepine

Treatment


Where hyponatraemia is a consequence of sodium loss and in the context of clinical signs of significant hypovolaemia, IV colloid or 0.9% saline should be given until there is clinical evidence of circulatory improvement. Adrenal insufficiency should be treated with fludrocortisone and glucocorticoids (see Chapter 8).


SIADH should be anticipated in individuals who have experienced significant head trauma or intracranial surgery and careful postoperative supervision of fluid balance is required. SIADH should be treated by fluid restriction which may range from only 40% to two‐thirds of normal intake. Where severe or symptomatic hyponatraemia or excessive thirst makes this approach impractical, then treatment to either increase water excretion or to raise the plasma sodium should be used. Water excretion will be enhanced by the tetracycline antibiotic demeclocycline which impairs the renal response to vasopressin and has been used in adults, giving 3–5 mg/kg eight‐hourly. An alternative is the relatively newly available V2 receptor antagonist tolvaptan, though trials of its efficacy in children are ongoing. Plasma sodium can be raised using hypertonic (3%) saline (0.1 ml/kg/min for two hours), aiming to increase plasma sodium concentration by about 10 mmol/L. In this context, it may be necessary to give furosemide with replacement of excreted urinary electrolytes to prevent hypervolaemia. This treatment should be reserved for those with significant neurological symptoms following the relatively acute onset of SIADH, as there is a risk of lethal pontine myelinolysis if serum sodium concentrations rise too rapidly (>10 mmol/L per day).


Endocrine hypertension


Aetiology


Hypertension in childhood as a result of endocrine pathology is usually a consequence of either glucocorticoid or catecholamine excess, as shown in Table 9.4.


Table 9.4 Causes of endocrine hypertension.


























Mechanism Examples
Steroid‐mediated
Glucocorticoid excess Iatrogenic (pharmacological doses, or over‐replacement in deficiency states)
Cushing’s syndrome
Apparent mineralocorticoid excess (AME)
Mineralocorticoid excess 11β‐hydroxylase deficiency, 17α‐hydroxylase deficiency
Liddle’s syndrome
Dexamethasone‐suppressible hyperaldosteronism
Catecholamine‐mediated Phaeochromocytoma, paraganglioma, neuroblastoma

History and examination


Key points to highlight in the history and on clinical examination include the following:



  • A history of intermittent headaches, sweating, flushes, nausea or vomiting is suggestive of a phaeochromocytoma.
  • Other affected family members. An autosomal recessive inheritance suggests congenital adrenal hyperplasia caused by 11β‐hydroxylase or 17α‐hydroxylase deficiency whereas an autosomal dominant pattern might suggest a phaeochromocytoma associated with a multiple endocrine neoplasia syndrome or hereditary phaeochromocytoma‐paraganglioma syndrome.
  • Virilization in a girl might suggest congenital adrenal hyperplasia.
  • Clinical signs of Cushing’s syndrome (see Chapter 8).
  • The presence of cutaneous signs suggestive of neurofibromatosis, or of mucosal neuromas, which are associated with von Hippel–Lindau disease, may suggest the presence of an associated phaeochromocytoma.

Investigations


The following preliminary investigations should be considered if an endocrine cause of hypertension is suspected:



  • serum electrolytes and creatinine;
  • three 24‐hour urinary‐free cortisol (and creatinine) collections;
  • urinary steroid metabolite profiling;
  • plasma free metanephrine and urinary catecholamine metabolites;
  • abdominal ultrasound.

If Cushing’s syndrome seems likely, additional investigations to confirm the diagnosis and treatment are described (see Chapter 8). If the urinary excretion of catecholamine metabolites is increased, then a blood sample should be taken for the measurement of free metanephrine. Two‐thirds of phaeochromocytomas are located in the adrenal medulla but they may also be found anywhere in the sympathetic chain, most commonly close to the renal hilum or aortic bifurcation. Abdominal imaging, preferably with computerized tomography (CT), magnetic resonance imaging (MRI), 123I‐metaiodobenzylguanidine (MIBG) scanning and, possibly, selective venous catecholamine sampling by catheterization may be necessary to locate the site(s).


Diagnosis


The various causes of endocrine hypertension are shown in Table 9.4. Hypertension in 11β‐hydroxylase‐ and 17α‐hydroxylase‐deficient congenital adrenal hyperplasia results from accumulation of the potent mineralocorticoid deoxycorticosterone, resulting in sodium and water retention with suppression of renin and aldosterone. 11β‐hydroxylase deficiency is also associated with excess androgen production and virilization, whereas 17α‐hydroxylase deficiency leads to female external genitalia in 46,XY subjects and lack of development of secondary sexual characteristics in both sexes.


Primary aldosteronism is associated with hypernatraemia, increased plasma volume, hyporeninaemia, and hypokalaemia. Hypertension is common in childhood Cushing’s syndrome. The syndrome of apparent mineralocorticoid excess (AME) is characterized by low plasma renin and aldosterone concentrations and is associated with a deficiency of 11β‐hydroxysteroid dehydrogenase 2 which is responsible for metabolizing cortisol to cortisone to prevent high concentrations of cortisol from binding to the mineralocorticoid receptor.


Liddle’s syndrome arises from an abnormality of renal tubular transport caused by an activating mutation of the amiloride‐sensitive sodium channel, resulting in increased sodium reabsorption and potassium loss with a biochemical and clinical picture similar to that of AME. Glucocorticoid‐suppressible hyperaldosteronism is a rare disorder in which primary aldosteronism is regulated by ACTH rather than renin–angiotensin because of the fusion of regulatory sequences of the 11β‐hydroxylase gene to coding sequences of the aldosterone synthase gene.


Treatment


In 11β‐hydroxylase‐ and 17α‐hydroxylase‐deficient congenital adrenal hyperplasia, hypertension responds to glucocorticoid therapy which suppresses ACTH secretion and thus deoxycorticosterone production. The treatment of Cushing’s syndrome is discussed in detail in Chapter 8.


A phaeochromocytoma requires surgical removal in an experienced specialist centre with skilled anaesthetic support. Pre‐ and perioperative control of blood pressure must be achieved by the initial use of an adequate alpha blockade such as phenoxybenzamine. As this is achieved, supplemental salt intake is needed to expand the extracellular fluid volume. Beta blockers are also necessary to treat alpha‐blocker‐induced tachycardia. When a neuroblastoma causes catecholamine‐induced hypertension, similar medical management will be necessary in the pre‐operative period.


Hypernatraemia


The mechanisms of hypernatraemia are shown in Table 9.5 and include gastrointestinal fluid loss in which relatively more water is lost than salt, excessive salt intake (e.g. due to deliberate poisoning as in Munchausen‐by‐proxy), decreased water intake through impaired thirst, and excessive renal water losses, including diabetes insipidus. It is important to recognize that some patients with neurological disability may have a combination of impaired thirst and central diabetes insipidus. Rarely, congenital adipsia/hypodipsia may be seen in the context of a mid‐line defect with single central incisor. Unexplained episodic hypernatraemia should raise the possibility of factitious illness caused by the deliberate administration of salt by the child’s parent or carer.


Table 9.5 Causes of hypernatraemia.




































































Mechanism Examples
Gastrointestinal fluid loss with relatively more water loss than salt loss Gastroenteritis with hypertonic dehydration
Decreased water intake Water deprivation

Impaired thirst



  • Congenital adipsia and hypodipsia



  • Acquired osmoreceptor damage
Excessive salt intake Salt poisoning
Vasopressin deficiency (central diabetes insipidus)


  1. Congenital causes




    • Brain malformation
Septo‐optic dysplasia, holoprosencephaly




    • Familial gene disorder
Autosomal dominant vasopressin deficiency


  1. Acquired causes




    • Tumours and infiltrations
Craniopharyngioma, germinoma, Langerhans cell histiocytosis, sarcoidosis




    • Inflammatory
Autoimmune




    • Trauma
Head injury, neurosurgery




    • Other
Narcotic agonists
Vasopressin resistance (nephrogenic diabetes insipidus)


  1. Primary defect in vasopressin/aquaporin responsiveness
V2 receptor or aquaporin 2 gene defect


  1. Secondary causes




    • Renal parenchymal disease
Nephrocalcinosis, nephronophthisis, polycystic kidney disease




    • Obstructive uropathy
Urethral valves




    • Electrolyte disturbances
Hypercalcaemia, hypokalaemia




    • Drugs
Lithium, demeclocycline, tolvaptan




    • Other

Diabetes insipidus


Aetiology


Diabetes insipidus may occur either as a result of inadequate secretion of AVP (cranial or central diabetes insipidus) or when there is resistance to the antidiuretic effect of AVP (nephrogenic diabetes insipidus). Cranial diabetes insipidus may be congenital due to a gene defect or to a cerebral malformation (e.g. septo‐optic dysplasia (SOD), holoprosencephaly); or caused by acquired disease (e.g. craniopharyngioma, Langerhans cell histiocytosis, or surgery) of the hypothalamo–pituitary axis (Table 9.5). Autosomal dominant cranial diabetes insipidus may be caused by a mutation of the AVP–neurophysin II gene which leads to impaired processing of the AVP hormone precursor, causing progressive damage to the neurosecretory neurones of the hypothalamus and the development of increasingly severe symptoms of diabetes insipidus with advancing age. In the much less common autosomal recessive form, the symptoms occur earlier. Nephrogenic diabetes insipidus may occur as a consequence of mutations affecting the V2 receptor gene (X‐linked) or aquaporin 2 gene (autosomal recessive) or because of disorders of the kidney which impair the function of other components of the urinary concentrating mechanism (Table 9.5).


History and examination


The cardinal symptoms of diabetes insipidus are polyuria and polydipsia. Other causes of these symptoms must be considered – osmotic diuresis from glycosuria in diabetes mellitus and reduced nephron mass in chronic renal failure; excessive intake in habit drinking (psychogenic polydipsia); and impaired renal tubular function in hypercalcaemia and hypokalaemia. Additional clinical features of diabetes insipidus include constipation, fever, vomiting, loss of weight, failure to thrive, and dehydration.


The following points should be highlighted in the history and clinical examination:



  • The nature and severity of the polyuria and polydipsia. Excess consumption of flavoured liquids only as opposed to water suggests habitual excess drinking. Drinking from unusual places, such as from the toilet or bath, or unusual fluids, such as shampoo, suggests severe thirst due to an underlying organic disorder.
  • Whether the symptoms were present from birth, suggesting a congenital abnormality, or developed later in life, suggesting an acquired disorder.
  • Associated neurological symptoms (e.g. blindness, neurodevelopmental delay, headache) and signs (e.g. optic atrophy) or history of a recent neurological disorder suggesting risk factors for hypothalamo–pituitary dysfunction.
  • Past medical history of renal disease.
  • Symptoms suggestive of diabetes mellitus (weight loss and hyperphagia within the past six weeks) or hypercalcaemia (anorexia, abdominal pain, constipation).
  • Medication (e.g. lithium treatment).
  • Family history of similarly affected cases.
  • Congenital abnormalities especially in the mid‐line of the brain and face.
  • Blood pressure or presence of enlarged kidneys.
  • Growth status – short stature suggestive of associated growth hormone (GH) deficiency in hypopituitarism.

Investigations


Habitual excess drinking is common in toddlers and preschool children, and if often part of a wider management problem including a poor sleeping pattern. The child is otherwise healthy and the problem can usually be both diagnosed and cured by asking parents to stop flavoured fluids but allow the child unrestricted access to water. If symptoms persist, the child should be admitted for observation and the severity of the polyuria and polydipsia be confirmed by measurement of the 24‐hour fluid intake and urinary losses. A fasting blood sample should be taken for the measurement of plasma glucose and serum sodium, potassium, calcium, and creatinine concentrations. Urine should be tested for glycosuria and proteinuria.


In a significantly symptomatic individual, simultaneous early morning blood and urine samples should be taken for the measurement of serum electrolytes and osmolality and urinary osmolality. Diabetes insipidus may be confirmed by the presence of a hyperosmolar state (i.e. serum osmolality >295 mOsm/kg) with inappropriately dilute urine (urine osmolarity around <750 mOsm/kg). The plasma or urine sample should then be sent for the measurement of AVP or plasma copeptin concentrations to confirm whether the cause is cranial or nephrogenic (Figure 9.1). In these circumstances, a water deprivation test would be dangerous and is contraindicated. Furthermore, a water deprivation test is not required when there is a clear history of polydipsia and polyuria in the context of underlying disease or treatment (e.g. craniopharyngioma, histiocytosis, and postoperative phase of craniopharyngioma) which is known to cause cranial diabetes insipidus.


Water deprivation test


This test is time‐consuming for staff and unpleasant for the child and family. It can usually be avoided, being either unnecessary (young child with habit drinking), unsafe (e.g. postoperative craniopharyngioma) or both. It should only be carried out after consultation with an experienced physician and must be undertaken with particular care in young children. The following protocol can be used:



  1. Allow the child to consume their normal overnight fluid intake.
  2. Weigh child at 8.00 a.m. at start of the fluid deprivation and measure plasma and urinary osmolalities.
  3. Repeat weight, blood and urine samples every two hours and monitor the child carefully to prevent fluid intake.
  4. For most children, an eight‐hour fast is adequate and the test should be discontinued before then if more than 5% of body weight is lost or the thirst cannot be tolerated longer.
  5. At the end of the fluid deprivation, administer desmopressin (DDAVP) either as an injection of 0.3 mg (subcutaneously, intramuscularly, or intravenously) or 5 μg by the intranasal route and collect simultaneous urine and blood samples for osmolality measurements about four hours later. During the four hours following DDAVP, the child can be allowed to drink up to 1.5 times the volume of any urine voided.

Central nervous system testing and other investigations


If a diagnosis of cranial diabetes insipidus is made, an MRI of the hypothalamo–pituitary axis should be performed as there may be a pituitary tumour or stalk abnormality. The serum tumour markers β‐human chorionic gonadotrophin (β‐hCG) and α‐foetoprotein should also be measured. If the MRI demonstrates thickening of the pituitary stalk, repeat scans should be performed over the next several years to monitor the development of infiltrative disorders, such as Langerhans cell histiocytosis or a germinoma, especially if symptoms, such as headache or additional pituitary hormone deficiencies develop.


Tests of wider anterior pituitary function may also be indicated. Diabetes insipidus may be masked by concurrent glucocorticoid insufficiency so that glucocorticoid replacement should be instituted before diagnostic tests for diabetes insipidus are performed.


Diagnosis


If during the water deprivation test, the plasma osmolality remains between 282 and 295 mOsm/kg and the urine osmolality increases to >750 mOsm/kg, the patient does not have diabetes insipidus and the possibility of primary polydipsia because of abnormal drinking habits should be considered.


A diagnosis of cranial diabetes insipidus is suggested by the development of increased plasma osmolality >295 mOsm/kg in the presence of a urine osmolality <300 mOsm/kg which is then increased to >750 mOsm/kg following the administration of DDAVP. Failure of the urine to respond to DDAVP is indicative of nephrogenic diabetes insipidus. A partial urinary response (300–750 mOsm/kg) to water deprivation or DDAVP suggests partial cranial or nephrogenic diabetes insipidus.


Treatment


Cranial diabetes insipidus


This should be treated with the long‐acting AVP analogue DDAVP and the following preparations are available:



  • DDAVP subcutaneous injection containing 4 μg/ml. This should only be given in hospital and is not administered on a regular basis.
  • DDAVP nasal solution containing 100 μg/ml and given via an intranasal catheter. This preparation is suitable for giving doses of 0.05 ml = 5 μg. For very young children, the pharmacy may need to dilute the solution to 25 μg/ml so that doses of 1.25 μg can be given.
  • DDAVP nasal spray (Desmospray) delivering a fixed dose of 10 μg/spray. A low dose DDAVP delivers 2.5 μg/spray.
  • DDAVP tablets (Desmotabs) 100 or 200 μg which are scored.
  • DDAVP sublingual tablets (Desmomelt) 60, 120 or 240 μg.

Widely varying dose regimens may be required, usually in two or three divided doses. The complete replacement dose of intranasal DDAVP is around 15 μg/m2 per day, and 10 μg of nasal DDAVP is roughly equivalent to 100 μg of oral DDAVP and to 60 μg of sublingual DDAVP. In those individuals taking DDAVP by the nasal route, an increase in the dosage of medication may be required during upper respiratory tract illnesses which may cause congestion of the nasal mucosa and impaired drug absorption. For this reason there has been a shift from nasal to oral DDAVP and, in recent years, a further move towards the sublingual preparation.


Patients with cranial diabetes insipidus fall into three broad categories: postoperative craniopharyngioma patients who require very careful monitoring; cranial diabetes insipidus with intact thirst; and cranial diabetes insipidus with impaired thirst.



  1. Postoperative craniopharyngioma patients: These patients show a triphasic pattern with initial diabetes insipidus for up to 24 hours, followed by a period of vasopressin excess for 2–4 days as the necrosing posterior pituitary gland releases this hormone, followed by permanent diabetes insipidus. DDAVP should not be given regularly during the first phase, will not be required during the second phase, but will be needed regularly thereafter.
  2. Cranial diabetes insipidus with intact thirst: Since patients may be very sensitive to DDAVP, treatment should start with small doses and gradually increase according to the clinical and biochemical responses. The initial response to therapy should be monitored closely by measurement of fluid intake and output and serum electrolytes and osmolality every few days at the start of therapy. Over‐treatment may be recognized by an abnormally low serum sodium concentration and osmolality. Once stabilized on treatment, patients should be reviewed in clinic at least three‐monthly as seasonal changes in temperature may alter their requirements for DDAVP. Patients who are experienced in the management of their diabetes insipidus may be allowed to adjust their own doses if they detect recurrence of polyuria. However, patients must be instructed to allow a short period (1–2 hours) of diuresis at a convenient time during the day to allow the excretion of any excess water, which may have occurred during the day and before taking the next dose of DDAVP.
  3. Cranial diabetes insipidus with impaired thirst: This is seen in some children with neurodisability who have impaired osmoreceptor but normal baroreceptor responses so that they will produce inadequate vasopressin until they become hypovolaemic. It is also seen in some craniopharyngioma patients who have sustained hypothalamic osmoreceptor damage either from the tumour or from surgery. Correction of any hypernatraemia, which may be of long standing, should be gradual in these patients to avoid seizures. A small dose of DDAVP is given initially together with a fixed daily volume of water, for example, 1500 ml/1.73 m2.

Nephrogenic diabetes insipidus


This should be managed by treatment of any underlying metabolic cause. In the absence of this, treatment with indomethacin (0.5–1.0 mg/kg twice daily) and/or a thiazide diuretic (e.g. hydrochlorothiazide 0.5–1.0 mg/kg twice daily from birth to 12 years of age, or 12.5–25 mg twice daily in older children) together with a potassium‐sparing diuretic such as amiloride (5–10 mg/1.73 m2 twice daily) can be tried. Unfortunately, patients with nephrogenic diabetes insipidus often respond poorly to treatment and must be allowed adequate access to liberal amounts of water intake as required.


When to involve a specialist centre



  • If the investigation and diagnosis of individuals with disturbances of their salt and water balance are proving difficult (e.g. in determining whether hyponatraemia is caused by salt loss or water retention, whether diabetes insipidus is cranial or nephrogenic, or in cases of suspected diabetes insipidus in infants).
  • When a water deprivation test is contemplated.
  • Endocrine causes of hypertension which usually require specialist investigations and expertise (e.g. endocrine surgeons).
  • Diabetes insipidus, particularly when associated with impaired thirst sensation which can be difficult to manage.
  • If patients fail to thrive following the introduction of apparently appropriate treatment for salt or water loss.
  • Patients with oncological causes of their salt and water imbalance.
  • Multiple hormone dysfunction.

Future developments



  • The management of nephrogenic diabetes insipidus remains difficult and further research is required to understand the mechanisms more clearly so that more effective treatments can be developed.
  • Excessive urine output and natriuresis leading to hyponatraemia is a recognized complication of a serious CNS insult (so‐called ‘cerebral salt wasting’) which is distinct from SIADH. Clarification of whether this is a consequence of inappropriate atrial natriuretic peptide secretion and appropriate treatment options are required.
  • Recent research has suggested that the endocrine control of blood pressure in foetal and early postnatal life may be responsible for the ‘programming’ of blood pressure in adult life. This hypothesis requires further examination.

Controversial points



  • Should intranasal DDAVP be replaced by oral or sublingual DDAVP in most patients?
  • What is the most appropriate treatment for nephrogenic diabetes insipidus?

Potential pitfalls



  • Failure to recognize the tri‐phasic pattern of vasopressin problems following craniopharyngioma surgery, resulting in hypernatraemia in the initial post‐operative phase followed by hyponatraemia two to four days later due to the syndrome of inappropriate antidiuretic hormone (ADH) secretion.
  • Inappropriate and potentially life‐threatening management of hyponatraemia due to failure to undertake a sufficiently careful history and clinical examination to distinguish between causes due to salt loss and those due to water retention.
  • An inconclusive water deprivation test result due to inadequate supervision of the patient who surreptitiously obtained water to drink (e.g. from the tap in the toilet while producing a urine sample for measurement of osmolality) or failure to extend the test for a sufficient length of time.
  • Symptomatic hyponatraemia following administration of DDAVP at the end of the water deprivation test due to failure to prevent the thirsty child consuming excess water.
  • Symptomatic hyponatraemia in a child with cranial diabetes insipidus receiving regular DDAVP due to failure to allow a short period of diuresis each day to excrete any excess fluid intake or due to inadequately frequent outpatient review and adjustment of DDAVP dose to take into account changing fluid requirements through the seasons.
  • Failure to plan and frequently adjust the fluid intake in a child with cranial diabetes insipidus and adipsia.
  • Inadequately aggressive management of nephrogenic diabetes insipidus leading to failure to thrive.
  • Inadequate cortisol replacement in hypopituitary states resulting in poor control of DI; this relates to the role of cortisol in facilitating free water excretion.

Emergencies



  • Hypernatraemic dehydration with impairment of consciousness, particularly if accompanied by convulsions, is an indication for admission to a high dependency unit for careful fluid input and output balance, twice daily weight, and cardiovascular monitoring. Shock (capillary refill >2 seconds ± hypotension) is treated with 20 ml/kg boluses of 0.9% saline, otherwise the estimated fluid deficit is replaced slowly (over 48–72 hours), checking the plasma sodium at least 6‐hourly in the first instance. NB: If severe hypernatraemia is long‐standing, as seen in adipsic and hypodipsic patients, slow oral rehydration over several days is carried out in preference to IV fluids.
  • Severe hyponatraemia due to sodium loss is managed with 20 ml/kg boluses of 0.9% saline to correct shock, and replacement of the remaining deficit over 24–36 hours.
  • Salt and water management can be particularly difficult in patients with hypopituitarism and diabetes insipidus who are on hormone replacement. Such patients may present to the emergency department with illnesses accompanied by vomiting and/or diarrhoea. In this situation, there may be uncertainty as to their cortisol status. In the context of cortisol deficiency, DDAVP may be ineffective, resulting in dehydration, while the cortisol deficiency itself may cause water retention since cortisol is required to enable water excretion. In the latter situation, a relative excess of DDAVP may lead to water intoxication, dilutional hyponatraemia and possible convulsions, and neurological injury. Where doubt exists about the patient’s cortisol status, it is safer to provide the correct dose of cortisol, stop the DDAVP and monitor the input/output balance with regular paired plasma and urine electrolytes and osmolality, which may need to be done hourly initially. High fluid volumes may be required but, provided that water and salt balance are monitored meticulously, this will be safe.
Aug 9, 2020 | Posted by in ENDOCRINOLOGY | Comments Off on Salt and Water Balance
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