Hyperosmolality and hypernatremia usually occurs as a result of hypotonic fluid losses that are not compensated by sufficient water intake to maintain body fluid homeostasis. Less commonly, excess NaCl ingestion or administration can cause hyperosmolality as a result of solute excess. Although hyperosmolality can develop in association with a broad spectrum of disease processes in people of all ages, infants and elderly individuals are particularly susceptible (4). The neurological symptoms of hyperosmolar states are a result of the cellular dehydration produced by osmotic shifts of water from the intracellular fluid space to the more hypertonic extracellular fluid space. The clinical symptomatology is related both to the severity of the hyperosmolality and also to the rate at which it develops (47). The symptoms of hyperosmolar states are a consequence of neurological dysfunction resulting from cellular dehydration; these include irritability, restlessness, stupor, muscular twitching, hyperreflexia, spasticity, and in severe cases, seizures, coma, and ultimately death (4).
Because cell membranes are relatively more permeable to water than to electrolytes, a rapid increase in plasma osmolality causes the brain to shrink. The brain subsequently undergoes an adaptation process involving the accumulation of solutes to restore the brain volume to its normal level. This adaptation process involves rapid accumulation of inorganic ions and slower accumulation of organic osmolytes, traditionally termed "idiogenic osmoles" (48). Marked differences in symptoms, and hence in recovery from hyperosmolality, exist because of the time-dependent nature of this complex brain adaptation. Optimal treatment of hyperosmolar patients is facilitated by knowledge of the basic mechanisms underlying the process of adaptation to the hyperosmolar state. Just as with hypoosmolality, neurological symptoms and mortality are generally higher in patients with acute rather than chronic hypernatremia. Consequently, it is useful to consider brain adaptation to these different pathological states separately.
Acute hypernatremia, generally defined as the development of serum [Na+] >145 mmol/L in 24 to 48 hours, is relatively uncommon. It can, however, be seen in infants as a result of accidental salt poisoning or severe gastroenteritis. It occurs less commonly in adults, although patients with untreated diabetes insipidus who are unable to drink can develop severe hypernatremia very rapidly. Despite the relative rarity of acute hyperosmolality, it is important to understand the pathophysiology underlying the neurological symptoms associated with this disorder because of its marked morbidity and mortality, which can be as high as 75% in adults and 45% in children (4,47).
Acute hypernatremia is typically induced in animals by intraperitoneal injections of hypertonic NaCI, which causes a prompt reduction in brain water content. However, the rapid loss of brain water is less than would be expected if the brain behaved as a perfect osmometer, because the brain is capable of rapidly accumulating solute to stabilize its volume. In a study using rats, three hours of hypernatremia (serum [Na+] >200 mmol/liter) decreased brain water by 14% and promoted increases in contents of brain Na+ and Cl- of 34% and 60%, respectively; K+ content was unaltered (8). Other studies of acute (15-120 min) hypernatremia in rats showed that the reduction in brain volume was proportional to the increase in plasma osmolality and generally stabilized by 15 to 30 minutes after the NaCI injection. However, by longer periods, i.e., 30 and 120 minutes, the brain water loss was only 35% of that predicted, which indicates that significant volume regulation had already occurred (49,50). This acute but partial volume regulation was due to rapid increases in tissue electrolytes. The accumulation of Na+ and Cl- was attributed to influx from the CSF, whereas the slower rise in tissue K+ content was related to an influx from plasma across the blood-brain barrier.
A central problem in studies of brain volume regulation has been an inability to distinguish the changes that occur in the intracellular versus the extracellular spaces. A seminal study by Cserr and coworkers used ion-selective electrodes to resolve this issue (43). Rats given a single intraperitoneal injection of NaCl experienced a 7% loss of brain water after 30-90 minutes, but this loss was related entirely to a decrease in and extracellular water content; intracellular water content remained at basal levels. Estimates of intracellular and extracellular ion contents indicated that extracellular Na+, Cl-, K+ decreased by 32, 21, and 42%, respectively, whereas intracellular contents of these ions increased by 100, 169, and 5%, respectively. In contrast, studies of organic osmolytes have indicated that acute hypernatremia is not associated with increases in organic solutes that are sufficient to appreciably contribute to brain volume regulation (41,48). Thus, acute hypernatremia is characterized by a rapid loss of total brain water, but protection of intracellular volume by an almost equivalently rapid accumulation of electrolytes from the extracellular fluid, CSF, and plasma.
In most hypernatremic patients, hyperosmolality develops gradually over a period of several days regardless of the etiology (47). Although morbidity and mortality rates are reported to be high in both adults and children, interpretation of these findings is difficult because death is often a result of the underlying disease that caused the fluid imbalance (4). Nonetheless, chronic hypernatremia is generally better tolerated with less neurological symptomatology than occurs during acute hypernatremia of comparable magnitude, which indicates that the brain is able to adapt to hyperosmolar conditions over longer periods of time. This has been attributed to a slower accumulation of organic solutes by the brain, and recent studies have provided greater insights into this adaptation process.
In animals, when hypernatremia persists beyond several days, total brain tissue water content slowly returns to normal levels (8,41). This restoration of total brain water does not result from continued accumulation of electrolytes but rather from accumulation of specific organic osmolytes (41,42,48,51). The organic osmolyte accumulation generally accounts for 30-50% of the solute accumulation in hypernatremic animals. The organic osmolytes involved with volume regulation to hyperosmolar conditions are essentially the same substances found to be involved with adaptation to chronic hypoosmolality, as described earlier. No single study has quantified the major electrolyte and organic osmolyte changes in the brains of chronically hypernatremic animals. However, using data from several sources, one can estimate the relative contributions of major osmolytes during adaptation to chronic hypernatremia (2) (Fig. 4). As for adaptation to hypoosmolality, NAA is included among the solutes that accumulate during volume regulation in response to hyperosmolality, but this amino acid represents a relatively minor component of the total brain solute losses; studies of in rats indicated that NAA accounted for only 16% of the total increase in brain amino acids after chronic salt loading (42).
Organic osmolytes accumulate relatively slowly in brain following induction of hypernatremia. Indirect measurements of the brain contents of undetermined solutes (i.e., total osmolality minus the sum of tissue electrolytes) indicated that organic osmolytes begin to accumulate after 9 to 24 hours but do not reach a steady-state level until 2 to 7 days (52). In vitro studies of cultured brain cells have corroborated this delayed and slow rate of organic osmolytes accumulation.
3.3. Cellular Mechanisms Underlying Brain Adaptation to Hyperosmolality
With acute increases in external osmolality, cells initially behave as osmometers and shrink in proportion to the reduction in extracellular osmolality as a result of movement of water out of cells along osmotic gradients. Soon thereafter, a process known as volume regulatory increase (VRI) in cell volume begins, in which cells accumulate intracellular solutes together with osmotically obligated water (19). Similar to VRD, the time necessary to activate RVI and restore normal, or near-normal, cell volume is variable across different cell types. However, in general RVI occurs more slowly than VRD in most cell types where this has been carefully studied.
The mechanisms responsible for brain and cell organic osmolytes accumulation during hyperosmolar conditions remain inadequately understood, but likely represent a combination of cellular uptake (e.g., myoinositol and taurine (53)) and synthetic mechanisms (e.g., glutamate), as has been well described in renal medulla where hypertonic conditions predominate (54). Circulating blood levels of many amino acids are increased during hypernatremia, and these may serve as a precursor pool for brain osmolytes (48). One important issue that remains to be resolved is the intracellular/extracellular distribution of organic and inorganic osmolytes in the brain during chronic hyperosmolality. Studies of other systems would suggest that organic osmolytes are preferentially accumulated intracellularly and thus replace the inorganic solutes, which are primarily responsible for the acute phase of brain cell volume regulation.
3.4. Recovery from Hyperosmolality (Deadaptation)
Accumulation of solutes enables the brain to adapt to hyperosmolar states, and thus is life saving, but during correction of the hyperosmolality this increase in total brain solute content can lead to neurological dysfunction due to osmotic shifts of water into the now more hypertonic intracellular fluid space. As with the adaptation process, both the duration of the hyperosmolality and the rate of the correction determine the degree of brain of edema that occurs. When acute hyperosmolar animals are given access to water, they recover relatively rapidly. The recovery phenomenon involves a transient but small increase in tissue water and a relatively rapid loss of the electrolytes that accumulated during the hyperosmolar episode. In contrast, during recovery from chronic hypernatremia, restoration of brain organic solute contents to normal levels occurs slowly over 24 to 48 hours. Studies in rats found that betaine fell to normal levels within 24 hours whereas glutamine, glutamate, taurine, phosphocreatine, and GPC took two days to achieve normal levels, and myoinositol remained significantly elevated even after two days (41). The mechanisms responsible for organic and inorganic solute loss during recovery from hypernatremia are not known, but are likely similar to those responsible for VRD during adaptation to hypoosmolality.
This slow dissipation of accumulated organic solutes is the basis for clinical recommendations that chronic hypernatremia be corrected relatively slowly over 48 hours (4,47). In support of a slow correction, studies of children have reported a high incidence of seizures following rapid correction of severe hypernatremia, presumably caused by brain edema (55,56). Although well-controlled studies of optimal correction rates in adults do not exist, based on what is known about the rates of organic solute losses from brain tissue in animals it seems prudent to continue to recommend the more cautious approach of prompt but gradual correction of chronic hypernatremia and hyperosmolality (57).
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