Читать книгу Disorders of Fluid and Electrolyte Metabolism - Группа авторов - Страница 12

Although the availability of radioimmunoassays allowed the characterization of the physiological control of AVP secretion and the relationship of abnormal osmoregulation to the development of hyponatremia, the establishment of animal models of hyponatremia allowed more complex pathophysiological issues to be explored. The neurological sequelae and high mortality of acute and chronic hyponatremia did not readily allow clinical research protocols in humans, which suggested the need for translational studies in animal models.

The first published description of symptoms of water intoxication in humans was reported in 1923 [14], followed by studies in experimental animals that showed cerebral edema as the likely cause of neurological symptoms [15]. Not much later, the first case of fatal cerebral edema was reported in a post-operative patient [16], which was quickly followed just 3 years later by a report of the first successful treatment of hyponatremic encephalopathy using hypertonic NaCl [17], a remarkable example of rapid translation from basic studies in animals to an effective clinical therapy that is still used today.

Over subsequent years, many studies were carried out in animals using protocols employing administration of AVP in conjunction with water loading, usually by intraperitoneal administration of 5% dextrose solution. Although important discoveries were made, notably the first description of brain electrolyte losses during adaptation to hyponatremia [18], all of these early models were accompanied by high rates of morbidity and mortality, making studies of chronic hyponatremia difficult to perform and even more challenging to interpret. A more stable rat model of SIAD was developed in the US using desmopressin-induced antidiuresis in combination with water loading via self-ingestion of a liquid diet that had negligible effects on mortality and proved to be a good model for human osmoregulation [19], which then allowed studies of the abnormal osmoregulation during sustained hyponatremia [20]. Having established credentials as a valid animal model for human SIAD, a series of studies was then able to establish the patterns of osmolyte fluxes across the brain and the abnormalities that were present during hyponatremia [21]; the data from these studies were also used to develop a model to explore the abnormal osmolyte fluxes after overly rapid correction of hyponatremia [22]. The knowledge gained from the use of an experimental animal model of SIAD has provided the basis for much of what we understand about the pathophysiology of osmotic demyelination, the dreaded sequel of overly rapid correction of chronic hyponatremia [23], which can lead to spastic paraplegia and cranial nerve palsies. The knowledge gained from these translational studies complemented observational studies in human patients [27], which in combination directly led to the guidelines for the treatment of hyponatremia that reduced the risk of osmotic demyelination [8].