Читать книгу Pathy's Principles and Practice of Geriatric Medicine - Группа авторов - Страница 407

There may be a recognized history of excessive water intake that overwhelms the ability of the kidneys to clear free water, such as primary polydipsia (purposeful intake of 16–20 litres per day), so‐called beer potomania (beer intake of similar volumes), or excessive water intake during prolonged exercise (e.g. in long‐distance runners).^1,8 However, without that history, the usual cause of hyponatremia is increased water retention, although there may also be a component of solute loss. Tests should be obtained of the serum for basal metabolic profile [BMP] and measured serum osmolality and of the urine for osmolality and sodium concentration. The BMP helps in the evaluation of acute renal disease (hyponatremia due to acute tubular necrosis, renal obstruction) and hyperosmolar pseudo‐hyponatremia due to hyperglycaemia. The serum osmolality confirms hypo‐osmolality (defined as <275 mOsm/kg) and excludes conditions of pseudo‐hyponatremia due to excess lipids (triglycerides) or hyperosmolar hyponatremia due to excess circulating osmoles from hyperglycemia or elevated proteins (macroglobulinemia). The urine osmolality is usually inappropriately elevated, i.e. >100 mOsmol/kg, and in many cases is greater than serum osmolality. The urine sodium is usually paradoxically elevated for the apparent serum sodium and is greater than 30 mEq/L, and in many cases is close to 100 mEq/kg. The cause of the paradoxical natriuresis is not completely determined and may be due to other factors such as elevations in cardiac‐derived atrial natriuretic peptide (ANP) or cardiac‐ or brain‐derived brain natriuretic peptide (BNP) or a direct renal compensatory effect to maintain constant intravascular volume despite hyponatremia.^1,2

The evaluation of hypo‐osmolar hyponatremia should then focus on secondary causes of elevated ADH levels. Decreased EABV may be associated with physiologically appropriate elevations in ADH levels that may be inappropriate for serum osmolality. These elevated ADH levels may be corrected by treating the underlying condition. The history and physical examination will help in the determination of volume depletion states (gastrointestinal losses, diuretic losses), low effective arterial blood volume states (orthostatic hypotension due to either primary or secondary adrenocortical insufficiency, hypo‐reninemic hypoaldosteronism), autonomic neuropathic hypotension (Parkinson’s disease, multiple system atrophy), or drug‐induced states (diuretics, angiotensin‐converting enzyme inhibitors, calcium channel blockers). In diuretic‐induced hyponatremia, the urinary sodium is usually in a lower range (<20 mEq/L) due to the sodium‐retaining effect of secondary hyperaldosteronism. Oedema states are those with decreased EABV with hypoalbuminemia (e.g. cirrhosis, nephrotic syndrome) or decreased perfusion to the carotid baroreceptors resulting from congestive heart failure, cardiac tamponade, negative cardiac inotropic medications, and possibly poor cardiac contractility associated with hypothyroidism. All medications should be reviewed for the potential to cause hyponatremia (see Figure 15.5). Further workup should include evaluation for hypothyroidism (serum TSH) and both primary and secondary adrenal insufficiency (by cosyntropin stimulation testing).^2,42

Other causes of hyponatremia and, more specifically, SIADH syndrome include tumours (bronchogenic carcinoma, thymoma), central nervous system lesions (tumours, subarachnoid haemorrhage, neurosurgical procedures), cerebral salt wasting (a possible variant of SIADH syndrome due to acute central nervous system trauma or surgery associated with hyponatremia, hypotension, and urinary sodium loss), pulmonary disease (associated with increased intrathoracic pressure, COPD, and positive pressure ventilation), and HIV‐AIDS syndromes (which may be associated with relative adrenal or mineralocorticoid insufficiency).

The decision to treat hyponatremia depends on the symptoms of neurocognitive dysfunction. Those with serum sodium between 130 and 135 mEq/L are usually asymptomatic. If chronic, the hyponatremia may have allowed time for the development of central nervous system compensation and may not require any therapy. Symptoms of gait disturbances and cognitive impairment found in patients with serum sodium between 125 mEq/L and 130 mEq/L have been shown to improve with correction of hyponatremia.²⁹ Review and withholding of possible causative medications may be of benefit.^24,26 Correction of hypothyroidism and hypoadrenalism is mandatory.

Figure 15.5 Algorithm of workup and therapy for hyponatremia. Review medications associated with hyponatremia (drugs with central nervous system action: nicotine, opioids, antidepressants [such as tricyclic, tetracyclic, selective serotonin reuptake inhibitors], anti‐psychotic agents [phenothiazines, butyrophenones], anti‐seizure agents [carbamazepine, oxcarbazepine, valproic acid], 3,4, methlenedioxymetamphetamine [MDMA, ‘Ecstasy’]; drugs used as chemotherapeutic agents [vincristine, cyclophosphamide]).

If there is orthostatic hypotension or low urine sodium (<20 mEq/L), it is presumed that the hyponatremia is secondary to ‘appropriate’ physiological vagal stimulation due to low EABV. Similarly, copeptin, a stable component of the precursor peptide to arginine vasopressin, when used with the urinary sodium ratio, also helps distinguish volume‐depleted from normovolemic hyponatremia.⁴³ If the hyponatremia is diuretic‐induced, withholding of diuretics or a trial of 1 to 2 litres of intravenous 0.9% saline may partially reverse the hyponatremia. Usually, 0.9% saline will not affect a true SIADH syndrome, as the sodium infused is quantitatively lost and the water is retained. If the orthostatic hypotension is due to antihypertensive treatment with excessive blood pressure reduction beyond requirements for the elderly, readjustment of the medication should be performed. If the orthostasis is due to autonomic neuropathy (Parkinson’s disease, multiple system atrophy), cautious use of oral salt (4–8 grams per day) and antigravity support stockings may help correct the underlying low EABV.

Those with serum sodium <125 mEq/L or symptoms will need therapy. There are controversies regarding the various protocols for correcting hyponatremia.¹⁰ It is agreed that two major complications should be avoided: (i) cerebral oedema due to the delay in correcting hyponatremia and (ii) osmotic demyelination syndrome due to overly rapid correction of the hyponatremia. The former may occur during states of acute hyponatremia, i.e. in rare occurrences in women or children after general anaesthesia, athletes with exercise‐associated hyponatremia (overingestion of water relative to salt loss associated with sweating during prolonged running), or patients after neurological surgery or subarachnoid haemorrhage.⁸ In these situations, delayed correction of serum sodium of only 3–4 mEq/L over 24 hours has been associated with a deteriorating mental state due to cerebral oedema.⁸ However, osmotic demyelination syndrome (ODS) occurs due to overly rapid correction of serum sodium, which may occur at a change of greater than 8–12 mEq/L over 24 hours and more than 18 mEq/L over 48 hours.⁸

There have been expert panel changes in guidelines for correcting symptomatic hyponatremia.⁸ The rationale for changes involved a retrospective cohort of neurosurgical patients with transtentorial herniation with serum sodium of 141± 9 mEq/L who received a bolus infusion of 23.4% saline (30 mL to 60 mL).⁴⁴ Those who had an improvement of serum sodium >5 mEq/L had a reversal of herniation. Guidelines⁸ now consider the use of a 100 mL bolus of 3% saline with the goal of limiting the change in serum sodium to 4–8 mEq/L over 24 hours (and 4–6 mEq/L in those with a high risk of osmotic demyelinization syndrome [ODS]: i.e. serum sodium <105 mEq/L, hypokalemia, alcoholism, malnutrition, or advanced liver disease). Those whose changes in serum sodium are above these levels may be considered for re‐correction of the sodium by infusion of free water with or without DDAVP. In a historical case‐control comparison study,⁴⁵ a 100 mL bolus of 3% saline was preferable when compared to the slow infusion of 20 mL/h of 3% saline with quicker restoration of the Glasgow coma scale. Those in the slow‐infusion protocol had a trend toward increased mortality in 4 of 28 subjects (compared with 0 of 22 subjects in the bolus infusion group), especially in those with an increase in serum sodium of only 2 mEq/L in 3 of the 4 subjects who died. The bolus regimen required intravenous dextrose with or without DDAVP in 14% of the patients to adjust for overcorrection of serum sodium of 6 mEq/L over the first 6 hours or a predicted increase over 24 hours of 8 mEq/L (high‐risk group) or 12 mEq/L in the remaining cohort.

Fluid restriction is indicated for symptomatic euvolemic and hypervolemic hyponatremia and contraindicated in hypovolemic hyponatremia. In hypovolemic hyponatremia, for example, when the hypo‐osmolality is due to diuretic or gastrointestinal volume losses, the serum aldosterone and ADH levels are elevated due to physiological responses to the decreased EABV. Infusion of 0.9% saline or the addition of oral salt will correct the serum sodium since the elevated aldosterone will retain sodium, and the increased EABV will lower ADH levels. Infusion of 0.9% saline solution is usually ineffective for euvolemic and hypervolemic hyponatremia because the hyponatremia may actually worsen as the infused sodium is quantitatively lost in the urine, and the elevated levels of ADH will cause water retention.

In euvolemic or hypervolemic hyponatremia, total fluid restriction between 500 and 1500 mL/day may be required.^1,8 Symptomatic hyponatremia with serum sodium less than 120 mEq/L usually requires correction with intravenous sodium. The concept is to eliminate presumed excess water and restore fluid balance (assuming non‐solute losses).^9,10 The treatment plan is to remove a calculated proportion of the free water excess over 24 hours to accommodate an increase in serum sodium of 4–8 mEq/L and not to completely correct the serum sodium to normal. Recommendations for correcting symptomatic hyponatremia are therefore made using 3.0% (513 mEq/L) saline solutions. Various protocols have been described^9,10 with a recommendation to infuse 3% saline at 0.5–1.0 mL/kg per hour, which may depend on the urine output. Therefore, the 3% saline infusion may replace urinary sodium losses to maintain total body sodium and intravascular volume, and urinary volume losses may only be in the range of 2–4 litres over 24 hours. Serum sodium measurements are then monitored at two‐hour intervals with the goal of discontinuing the saline infusion if the rate of rise of serum sodium is greater than 0.5 mEq/L/hour. There were no overcorrections in one study involving the continuous‐infusion protocol.⁴⁵ From these limited data, it is unknown whether bolus or continuous infusions or a hybrid combination of both protocols will be better in real‐world conditions or whether ‘reversal’ of overcorrection of hyponatremia will reverse ODS once started.

Medications have been used to assist in free water clearance and may be used in patients with mild symptomatic hyponatremia in the place of fluid restriction, or may be used as adjuvants to hypertonic saline infusions in cases of symptomatic euvolemic or hypervolemic hyponatremia. Demeclocycline, in doses as high as 1200 mg per day, may induce nephrogenic diabetes insipidus. Other agents such as lithium, diphenylhydantoin, and urea have not been as reproducible or effective.⁸

The newer vaptans allow a further dimension in the therapy of mild symptomatic hyponatremia. Two vasopressin receptor antagonists are currently approved for use in correcting euvolemic and hypervolemic hyponatremia.^4,46 The vaptans are nonpeptide, small‐molecular‐weight antagonists of the vasopressin receptor. They bind to an internal domain in the receptor molecule and alter the configuration for normal vasopressin binding and coupling to the internal G protein.⁴⁶ Conivaptan is a combined V1a receptor and V2 receptor antagonist, and tolvaptan is a selective V2 receptor antagonist. Conivaptan is approved for intravenous administration, and tolvaptan is an oral antagonist, but both are to be started in hospitalized patients.⁴⁶ Conivaptan is administered by intravenous infusion of 20 mg over 30 minutes followed by 20 mg over 24 hours, with the subsequent dose increased to 40 mg/24 hours if required. It is approved only for four days. Tolvaptan may be given at 15 mg once daily and may be titrated up as needed once daily to a maximum dose of 60 mg per day. Both drugs are metabolized by the hepatic cytochrome P‐450 system of CYP3A and are contraindicated for use with other drugs that are CYP3A inhibitors (clarithromycin, itraconazole, fluconazole, ritonovir, and cyclosporine).⁴⁶ Both drugs have been shown to improve serum sodium, with rare increases in the level above the desired 12 mEq/L over 24 hours.

Tolvaptan has been shown to have modest clinical benefits as determined by a quality of life questionnaire in hyponatremic subjects with serum sodium less than 130 mEq/L²³ and patients with acute congestive heart failure by alleviating feelings of fatigue and dyspnea.⁴⁷

A recent meta‐analysis suggests that the vaptans significantly improve serum sodium, but there was no evidence of any benefit to mortality or clinically significant cognitive improvement.⁴¹ Long‐term tolvaptan has been associated with liver disease in people treated for polycystic kidney disease, with the recommendation that vaptans should not be used in patients with liver disease and should not be used for longer than 30 days.² Clinical treatment indications for the outpatient management of hyponatremia with tolvaptan are not well defined, and the cost is approximately $360 per day.⁴⁸