Читать книгу Pathy's Principles and Practice of Geriatric Medicine - Группа авторов - Страница 406

The elderly are prone to disorders of both hyper‐ and hyponatremia.^1‐3,11 These abnormalities may be due to the normal physiological changes in the ageing process, intercurrent illnesses, or side effects of medications. Normal physiological changes due to ageing may result in a tendency toward hypernatremia (sodium >145 mEq/L).⁶ Although renal function declines with age, fluid homeostasis is not affected by this decline until glomerular filtration rates are as low as 30 to 50 mL/minute.¹² Compared with younger individuals subjected to water deprivation, healthy older adults have decreased thirst responses and increased serum ADH levels but decreased urinary concentration and ability to excrete free water.^7,13‐15 The decreased responsiveness of aquaporin‐2 to ADH may be due to a physiological decreased aquaporin‐2 receptor expression associated with ageing.¹⁶ Also, after age >75, there is a decrease in total body water from 60 to 50%, potentiating the risk for dehydration over short periods.^3,11

The institutionalized elderly may be more prone to hypernatremia.^3,11 Whereas normal elderly patients subjected to fluid restriction may have a decrease in thirst response compared to younger subjects, they retain their ability to secrete ADH. Those with Alzheimer’s disease may be more severely compromised by having a more pronounced decrease in both thirst and ADH responses compared to even age‐matched controls.¹⁷ In patients with Alzheimer’s disease, these thirst responses may fall in the range compatible with essential hypernatremia,⁶ and the ADH levels may be inappropriately low for the degree of dehydration and comparable with levels found in states of partial central diabetes insipidus.¹⁷ Unless patients are monitored, elderly institutionalized individuals dependent on caregivers for fluid intake (due to previous stroke or degenerative brain diseases) may not receive adequate fluids at or between meals.¹⁸ These groups of people may have an 18% incidence of hypernatremia.⁶ The incidence of hypernatremia may be exacerbated during acute intercurrent febrile upper respiratory illness to levels as high as 63%.¹⁹ They may also have concurrent illnesses (such as hypercalcemia or hypokalemia) or be prescribed medications (such as lithium), all of which are associated with nephrogenic diabetes insipidus (renal insensitivity to ADH action) and inability to retain water.

Hyponatremia is also very common in the elderly, as outpatients, inpatients, and those in long‐term care.^4,8,20 The prevalence of hyponatremia among elderly outpatients is 7 to 11%¹² and between 11 and 53% for those in long‐term care.^5,20 The causes of hyponatremia are less clearly defined than for hypernatremia. There are physiological changes in the kidneys with ageing, resulting in a decreased ability to concentrate urine and excrete free water.^21,22

The onset of hyponatremia may be associated with medications or involvement in concomitant illnesses such as chronic heart failure and cirrhosis.^4,8,23 Many medications involved in central nervous system modulation and opioid transmission are associated with ADH secretion. Common agents associated with hyponatremia in all people include antidepressants (both tri‐ and tetracyclics), antipsychotic drugs (phenothiazines, butyrophenones), antiepileptic drugs (carbamazepine, oxycarbazepine, sodium valproate), and opioids.¹ The elderly appear to be more sensitive to the hyponatremic effects of selective serotonin reuptake inhibitors (SSRIs).^24,25 Diuretics, due to their frequent use, are probably the most common medication associated with hyponatremia, with a prevalence as high as 11% in the geriatric population.²⁶ Less commonly, other antihypertensive agents such as angiotensin‐converting enzyme inhibitors and calcium channel antagonist produce a decrease in EABV, with physiological ‘appropriate’ increases in ADH.²⁴ True SIADH syndromes, due to ectopic ADH production by cancer or inappropriate ADH due to neurological lesions, are less likely to be the cause of hyponatremia unless there are positive clinical features. Among 50 elderly hospitalized patients with mild to moderate hyponatremia, an exhaustive evaluation did not reveal these causes of inappropriate ADH syndrome. The investigators found that the hyponatremia was associated with pneumonia and medication, although 60% remained idiopathic.²⁷

Many patients may have primary orthostatic hypotension, e.g. due to autonomic neuropathy in Parkinson’s disease and multiple system atrophy, or associated with low renin‐low aldosterone mineralocorticoid deficiency. Older patients may have excessive treatment of their hypertension. The elderly should be monitored for orthostatic blood pressure changes and have more moderate adjustment of systolic hypertension than younger individuals.²⁸

Other medications not specifically used in the elderly are associated with hyponatremia. Anti‐neoplastic agents include vincristine and cyclophosphamide. Vincristine may cause hypothalamic neuropathy, and cyclophosphamide treatment may potentiate the ADH effect at the renal tubule and requires patients to drink large volumes of water to prevent cystitis.²⁴ Uncommon causes of hyponatremia associated with common drugs include non‐steroidal anti‐inflammatory agents (NSAIDs), which may lower the levels of prostaglandins. Prostaglandins have an anti‐ADH effect on the renal tubules, so lowered levels result in potentiated ADH action.² Trimethoprim‐sulfamethoxazole may act as a mild diuretic and cause hyponatremia if given in high doses or when given to a patient with renal impairment.²⁴

Hyponatremia is associated with a poor overall prognosis.^3,4 There may be two temporal components of the hyponatremia syndrome in the elderly: a chronic hyponatremia syndrome associated with underlying diseases or dementia and an acute deterioration toward hyponatremia as manifested by delirium. However, these may be difficult to distinguish. Hyponatremia is associated with gait disturbances, falls, and bone fractures.^3,4 In case‐control studies (controlled for age and admitting diagnoses), the presence of hyponatremia was associated with an increased incidence of falls in patients admitted to an emergency medical department²⁹ and hospitalized individuals.³⁰ In another case‐control series, the presence of hyponatremia was one component of fall prediction in addition to age and pre‐existing neurological disorders.³¹ Furthermore, people with hyponatremia had a 2.36‐fold higher chance of also having dementia after correcting for age, gender, medications, and comorbidities.³²

Subsequent case‐control studies (adjusting for age)^33,34 and meta‐analyses^35‐37 found higher incidences of bone fractures associated with hyponatremia. There may be a direct relationship of hyponatremia with activation of osteoclastic bone resorption. In a rat model of exogenous inappropriate ADH, Verbalis³⁸ demonstrated that chronic hyponatremia is associated with a substantial reduction in bone mass, as determined by bone density and histomorphology. However, the case studies do not resolve the issue of assigning causality of the hyponatremia with adverse events. Many of the patients with falls and hyponatremia had higher incidences of underlying reasons for falls when compared with case controls.^34,37 Individuals with hyponatremia also were more frequently taking SSRIs (21% vs. 15%, p = 0.006), benzodiazepines (39% vs. 31%, p = 0.007), or other CNS class drugs (59% vs. 49%, p = 0.0004) or had cognitive impairment (17% vs. 7%, p < 0.0001) or orthostatic hypotension (6% vs. 2%, p = 0.003).³³ The simultaneous use of medications associated with neurocognitive impairment and hyponatremia may explain the association of concurrence of hyponatremia with the high rate of falls.

Therefore, it is important to assess the role of hyponatremia within the context of a cause‐and‐effect relationship and determine whether the neurocognitive symptoms are reversible with correction of the hyponatremia independent of correction of the underlying illness or removal of potentially causative medications. Renneboog et al.²⁹ performed a retrospective analysis of patients admitted to an acute care hospital with serum sodium levels between 115 mEq/L and 132 mEq/L. In those with hyponatremia, there was a 21% incidence of falls compared with 5% in the controls (p < 0.001). The researchers then prospectively tested eight subjects with hyponatremia for abnormalities in gait and cognition. The tests for gait and cognitive dysfunction were compared prospectively when they had hyponatremia (serum sodium 128±3 mEq/L) and after correction of hyponatremia (138±2 mEq/L). There were significant improvements in gait abnormalities after correction of hyponatremia (as determined through a standardized test of distance travelled by tandem gait on a pressure‐sensitive calibrated platform). There were improvements in cognitive tests (determined by decreased reaction time on attention tests (from 673 ± 182 msec vs. 615 ± 184 msec, p < 0.001). Despite Renneboog’s finding of an increased incidence of falls, it was not determined whether the falls were due directly to the hyponatremia or whether the hyponatremia was a marker of the severity of the underlying illness or the doses of the offending medication causing the hyponatremia.

Therefore, it was hoped that the issue of causation of mental status changes with hyponatremia would be resolved by the correction of the hyponatremia independent of modifications of either the underlying disease or medication adjustment. Prospective studies using vasopressin antagonists (see the discussion of vaptans below) have shown only modest clinical benefits with correction of hyponatremia.

Lixivaptan, an oral vasopressin receptor2 (V2) antagonist (not approved in the US for hyponatremia), increased the serum sodium by 3 mEq/L over that of controls.³⁹ There were small differences at various time points but no overall benefit compared with controls in a standardized Trail Making Test or Medical Outcomes Survey‐6 Cognitive Function Scale (MOS‐6) score at 28 days.

Tolvaptan, a specific vasopressin receptor antagonist, was assessed in a combined randomized prospective international multicenter study of 448 subjects, the SALT‐1 (US cohort), and SALT‐2 (international cohort).²³ There was a preplanned 30‐day analysis of a standardized quality of life scale, the Medical Outcomes Study 12‐item Short Form of the General Health Survey [SF‐12]. Although subjects were considered to have asymptomatic hyponatremia, about one‐third had cirrhosis, one‐quarter had congestive heart failure, and 40% were diagnosed with SIADH. Baseline quality of life scores for both physical and mental components were lower than the 25th percentile for age‐adjusted measures. In the combined study, there was a small improvement in the overall SF‐12, p = 0.02. However, the changes were significant in the SALT‐1 sub‐study (US, baseline score 42.3 ± 11.7, treatment effect 3.9, p = 0.04) but not in the SALT‐2 sub‐study (international, baseline score 44.7 ± 12.0, treatment effect 2.2, p = 0.15). There were no changes in the physical component summary of the SF‐12. The benefits in the SF‐12 were more relevant in those with marked hyponatremia (baseline serum sodium <130 mEq/L, p = 0.04).²³ Changes in the SF‐12 were not considered in the primary outcome analysis. It is unclear whether there are any clinically relevant benefits of this modest increase in the quality of life score or that the desired improvement in hyponatremia could override other underlying disease symptoms. There was also no predesigned assessment of gait, balance, or cognitive functions.

The neurocognitive effect of tolvaptan was further assessed in 107 patients with asymptomatic hyponatremia with the sole diagnosis of SIADH.⁴⁰ Improvement in serum sodium from 129 mEq/L to 136 mEq/L did not improve the primary cognitive endpoint (composite score on the Cognitive Research system) reaction times, although there was a change in a subset psychomotor speed domain.

A systematic review of the vaptans found that all vasopressin receptor antagonists were beneficial in improving serum sodium, with limited evidence of impact on quality of life or mortality.⁴¹