Approach
Treatment goals include achieving normal fluid balance, relieving symptoms, preventing complications, treating underlying disorders and associated hormonal abnormalities, and preserving quality of life.
Correction of hypernatraemia
If hypernatraemia is a feature at presentation (unusual), correction of water deficit is important. Oral or enteral fluid replacement is the preferred route, as this leads to a smoother change in serum electrolytes.
Intravenous hypotonic fluids (dextrose 5% and sodium chloride [NaCl] 0.45%) may be necessary in some patients. If parenteral correction is required, the infusion rate is determined by the tonicity of the infusate chosen, the degree of hypernatraemia, the desired rate of correction, the ongoing water losses, and the estimated deficit in total body water.[55] Pre-existing treatment with desmopressin will lead to more rapid reduction in serum sodium as renal water loss is reduced. Slower rates of fluid administration are required in this context, with regular serum sodium tests.
Several formulae help in calculating the water deficits and infusate rates.[55] Ongoing water losses also need to be considered. Such formulae are guides. Key is the recognition that correction is taking place in a dynamic (the patient) rather than static system. Frequent electrolyte assessments are required to manage the clinical situation safely.
The free water deficit may be calculated on the basis of the estimated percentage of total body water (TBW) and the baseline serum sodium (Na) concentration.[55]
Free water deficit = total body water × (serum Na/140) -1.
TBW = body weight × correction factor based on patient age and sex (children and adult men, 0.6; adult women and older men, 0.5; older women, 0.45).
As infusions vary in their sodium concentration, an alternative formula (taking into account the effect of giving 1 litre of a particular infusate) may also be used.[55] For example, 0.45% NaCl contains 77 mmol/L sodium; 5% dextrose contains no sodium.
Change in serum sodium = (infusion Na - serum Na)/(TBW +1).[55]
Acute hypernatraemia:
Rapid correction of hypernatraemia improves prognosis without increasing the risk of cerebral oedema.[55] Reducing the serum sodium concentration by up to 1 mmol/L (1 mEq/L) per hour may be appropriate.[55]
Chronic hypernatraemia or hypernatraemia of unknown duration:
Arginine vasopressin deficiency (AVP-D; previously known as central diabetes insipidus)
The long-acting, synthetic arginine vasopressin (AVP) analogue desmopressin (also known as DDAVP) is the treatment of choice as replacement for endogenous AVP.[3] Desmopressin has been structurally modified from native AVP by the removal of the amino group of the cysteine amino acid to prolong its half-life from 5 minutes to 6-8 hours. Additionally, D-arginine is substituted for L-arginine, which eradicates AVP's vasopressor actions.[3]
Desmopressin is effective in pregnancy-associated AVP-D, as it is not metabolised by placental vasopressinase/oxytocinase. Oral, intranasal, and parenteral formulations are available.[3] Parenteral desmopressin is 5 to 20 times more potent than intranasal administration and may be preferred in the acute setting.
Careful management of fluid intake is crucial to prevent water overload and hyponatraemia, a common side effect of desmopressin therapy.[3] Desmopressin treatment in small children can result in rapid changes in serum osmolality.[65] The concurrent use of intravenous fluids and desmopressin further increases the risk of hyponatraemia. To minimise this risk, treatment should begin with low doses of desmopressin, and both clinical status and serum sodium should be closely monitored.[65]
Inpatient management of AVP-D has been reported to be suboptimal, with frequent delays or omissions of desmopressin doses leading to hypernatraemic dehydration.[3] Poor awareness among clinicians is a predominant cause.[3] Key practice points for safe inpatient management include: identifying all AVP-D patients upon admission and referring to an endocrine team for fluid and desmopressin management; developing a perioperative plan for fluid and desmopressin administration and electrolyte monitoring; ensuring oral and parenteral desmopressin are available on all wards; and implementing prescribing alert systems to reduce errors.[3]
Acute presentation
Treatment is with parenteral or oral desmopressin started at the lowest possible dose.
Urine output and thirst typically respond within 1 to 2 hours. Therapeutic effect persists for 6 to 8 hours.
Subsequent dose titration should be based upon clinical and biochemical response.
Patients who are conscious should be encouraged to drink to thirst.
Regular monitoring, with serial measurements of serum sodium and urine and serum osmolality, is recommended.
Patients who develop AVP-D following pituitary surgery or traumatic brain injury may experience fluctuations in fluid balance and thus require careful monitoring. This includes vigilance for a triple-phase response, where initial AVP-D is followed by a transient syndrome of inappropriate antidiuretic hormone (SIADH) before either permanent AVP-D is established or the patient makes a full recovery of AVP function.[12] Given this, a strong consensus supports 'on-demand' postoperative desmopressin rather than regular fixed dosage.[3] Close monitoring of plasma sodium concentration and urine volume is advised, as positive fluid balance and falling plasma sodium indicate SIADH, at which point desmopressin should be held and fluid intake restricted.[3]
Chronic AVP-D
The treatment of choice is desmopressin.[66]
Dosing is tailored on an individual basis, starting with a low dose. A single nocturnal dose is sufficient in some with mild AVP-D.[3]
Patients may be advised to delay, reduce, or omit treatment on 1 day per week to allow unloading of excess water and prevent hyponatraemia associated with slight over-treatment (‘desmopressin escape’).[67] Specific strategies include a 'delayed dose' (waiting for aquaresis once or twice per week before resuming drug treatment), a 'regular delayed dose' (delaying each dose until polyuria develops for a daily low-grade aquaresis), or 'weekly omission of a tablet' (though this can be uncomfortable).[3] Most desmopressin-associated hyponatraemia is mild and asymptomatic, and responds to withholding a dose.[3]
Arginine vasopressin resistance (AVP-R; previously known as nephrogenic diabetes insipidus)
Treatment for AVP-R is challenging. Desmopressin is generally ineffective due to renal resistance. High-dose desmopressin can be partially effective in some with variable acquired nephron insensitivity.
The mainstay of treatment is adequate fluid intake to match output and insensible losses. Adequate intake may be difficult, especially during intercurrent illness, as urine output can be up to 12 litres per day.[10]
Any underlying cause, if identified, should be corrected.
Drug-induced AVP-R may resolve following discontinuation of the offending drug.[68] However, AVP-R secondary to lithium therapy often does not resolve.[43]
Any underlying kidney disease should be treated.
AVP-R secondary to hypercalcaemia or hypokalaemia commonly resolves following correction of the electrolyte disorder.
Other treatment modalities for AVP-R include a low-sodium diet (<500 mg/day), thiazide diuretics, or indometacin.[1] Combinations of these approaches can act synergistically. Given the potential for dehydration and nephrotoxicity, a nephrology specialist should be consulted if pharmacotherapy is considered. Treatment rarely restores urine output to normal.
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