Rapid Correction Of Chronic Hyponatremia Research Articles

Preoperative Hyponatremia and Cardiopulmonary Bypass: Yet Another Factor for Cerebral Dysfunction?

Hyponatremia is common in patients prior to cardiopulmonary bypass (CPB), usually secondary to diuretic therapy. Rapid correction of chronic hyponatremia, which potentially occurs on commencing CPB, may in susceptible patients result in central pontine myelomatosis. There are three parts to this study. Part 1: Patients (n= 170) undergoing CPB with preoperative hyponatremia were analyzed by degree of hyponatremia, additive EuroSCORE, length of stay – intensive care and total hospital, and mortality. Part 2: Sodium concentrations of different prime constituents used clinically were collated from the literature. Part 3: Mathematical modeling of the effects of patient size, sex, preoperative hemoglobin, prime solution, and prime volume with regard to the effect on serum sodium during cardiopulmonary bypass was analyzed, assuming a preoperative serum sodium of 125 mmol/L. Part 1: Patients with preoperative hyponatremia, even after matching by additive EuroSCORE, have longer length of stay – intensive care and total hospital, but not significantly different mortality rates. Part 2: Sodium concentrations of different primes used clinically varied from 0 mmol/L to 160 mmol/L. Part 3: Mathematical modeling revealed that patient size, sex, preoperative hemoglobin, prime solution, and prime volume all can exert a significant effect on serum sodium on initiation of cardiopulmonary bypass. Further work is needed to evaluate the roles of sudden changes in serum sodium, with regard to a rapid correction of chronic hyponatremia, or the rapid creation of acute hyponatremia, and cerebral outcomes in patients undergoing CPB.

Central pontine myelinolysis secondary to hypokalaemic nephrogenic diabetes insipidus

Central pontine myelinolysis (CPM) has been described in alcoholic patients and in the aftermath of rapid correction of chronic hyponatraemia. We describe a case of CPM occurring secondary to nephrogenic diabetes insipidus (DI), which developed as a consequence of severe hypokalaemia. A 63-year-old man with alcohol dependence was admitted to hospital with severe pulmonary sepsis and type 1 respiratory failure. On admission, he had euvolaemic hyponatraemia of 127 mmol/L, consistent with a syndrome of inappropriate antidiuretic hormone secondary to his pneumonia. Following admission, his plasma potassium dropped from 3.2 to a nadir of 2.3 mmol/L. Mineralocorticoid excess, ectopic adrenocorticotrophic hormone production and other causes of hypokalaemia were excluded. The hypokalaemia provoked significant hypotonic polyuria and a slow rise in plasma sodium to 161 mmol/L over several days. Plasma glucose, calcium and creatinine were normal. The polyuria did not respond to desmopressin, and subsequent correction of his polyuria and hypernatraemia after normalization of plasma potassium confirmed the diagnosis of nephrogenic DI due to hypokalaemia. The patient remained obtunded, and the clinical suspicion of osmotic demyelination was confirmed on magnetic resonance imaging. The patient remained comatose and passed away 10 days later. This is the first reported case of nephrogenic DI resulting in the development of CPM, despite a relatively slow rise in plasma sodium of less than 12 mmol/L/24 h. Coexisting alcohol abuse, hypoxaemia and hypokalaemia may have contributed significantly to the development of CPM in this patient.

Korrektur der Hyponatriämie – Ein schwieriges Unterfangen?

Chronic hyponatraemia and its therapy is a common and often underestimated problem of hospitalized patients. Usually, hyponatraemia is just one of many laboratory features found in such patients. However, rapid correction of chronic hyponatraemia can have devastating neurological consequences, i.e. osmotic myelinolysis. In the following, we describe the mechanisms leading to myelinolysis due to rapid correction of hyponatraemia and answer the questions how much, and at which rate to correct chronic hyponatremia.

Re-induction of hyponatremia after rapid overcorrection of hyponatremia reduces mortality in rats

Osmotic demyelination syndrome is a devastating neurologic disorder often seen after the rapid correction of chronic hyponatremia. The permeability of the blood-brain barrier is increased in experimental osmotic demyelination, and some have suggested that corticosteroids protect against this disorder by keeping the permeability of the blood-brain barrier low. We previously reported that re-lowering of the serum sodium after rapid correction of chronic hyponatremia was beneficial if performed early in the course (12 to 24 h). Here we compared mortality, blood-brain barrier permeability, and microglial activation in rats after the rapid correction of chronic hyponatremia. We studied three groups of rats after correction of chronic hyponatremia: and treated them with sodium chloride, with or without dexamethasone; or with sodium chloride followed by re-induction of hyponatremia. We found that treatment with dexamethasone or re-induction of hyponatremia effectively prevented the opening of the blood-brain barrier, reduced neurological manifestations, and decreased microglial activation; however, only re-induction of hyponatremia resulted in a significant decrease in mortality 5 days after the correction of chronic hyponatremia. Restoring the permeability of the blood-brain barrier to normal levels did not decrease mortality. Our results suggest that after inadvertent rapid correction of hyponatremia, treatment options should favor re-lowering serum sodium. The increased permeability of blood-brain barrier seen in osmotic demyelination syndrome may not be a primary pathophysiologic insult of this syndrome.

Central Pontine Myelinolysis in a Patient with Hyperosmolar Hyperglycemia and Consistently Normal Serum Sodium

Central pontine myelinolysis (CPM) is almost always described in association with a disturbance in sodium homeostasis, most commonly rapid correction of chronic hyponatremia. It has only rarely been described in patients with disturbances of serum osmolality in the absence of abnormal serum sodium concentrations. Case report. A 93 year-old-man developed marked gait ataxia 2 days after the diagnosis and treatment of hyperosmolar hyperglycemia. MRI demonstrated a symmetric lesion in the central pons consisting of increased T2 signal intensity and restricted diffusion, consistent with CPM. Calculated serum osmolality on admission was 344 mOsm/kg and fell to 300 mOsm/Kg over 20 h. Serum sodium concentration stayed between 137 and 140 mEq/l throughout the admission. One month after admission, his ataxia had nearly completely resolved and the MRI changes had improved. CPM can develop in the setting of hyperosmolar hyperglycemia without abnormalities of sodium homeostasis. This supports the theory that the pathogenesis of CPM is dependent on a relatively hypertonic insult, which may occur independently of sodium abnormalities. CPM can present as isolated gait ataxia. Clinical manifestations of the disorder may show significant improvement despite a dramatic initial presentation.

Extrapontine myelinolysis after correction of hyponatremia presenting as generalized tonic seizures

Central pontine myelinolysis and extrapontine myelinolysis are rare complications of rapid correction of chronic hyponatremia. Central pontine myelinolysis is more common and more predictable in presentation. Extrapontine myelinolysis' presenting symptoms vary and may be as general as lethargy or altered mood. We report experience with a patient who developed only extrapontine myelinolysis after rapid correction of severe hyponatremia associated with gastroenteritis. His presenting sign, generalized seizures, has not been previously reported. We summarize risk factors for myelinolysis, which may be more common than previously thought, as well as steps to minimize risk while managing vulnerable patients.

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

Although hyponatremia is a common, usually mild, and relatively asymptomatic disorder of electrolytes, acute severe hyponatremia can cause substantial morbidity and mortality, particularly in patients with concomitant disease. In addition, overly rapid correction of chronic hyponatremia can cause severe neurologic deficits and death, and optimal treatment strategies for such cases are not established. An expert panel assessed the potential contributions of aquaretic nonpeptide small-molecule arginine vasopressin receptor (AVPR) antagonists to hyponatremia therapies. This review presents their conclusions, including identification of appropriate treatment populations and possible future indications for aquaretic AVPR antagonists.

Mechanisms and Therapy of Osmotic Demyelination

Central pontine myelinolysis (CPM) is a rare but serious demyelinative disease that is associated with rapid correction of chronic hyponatremia. Disruption of the blood-brain barrier (BBB) following a rapid increase in serum sodium concentration is considered to play a critical role in the pathogenesis of osmotic demyelination. We investigated the protective effect of dexamethasone (DEX) on osmotic demyelination in rats. After rapid correction of chronic hyponatremia, rats displayed serious neurologic impairments and demyelinative lesions were observed in various brain regions. Conversely, DEX-treated rats exhibited minimal neurologic impairments and demyelinative lesions were rarely seen in the brain. A marked extravasation of endogenous immunoglobulin G and Evans blue dye were observed in the brains of rats that did not receive DEX, indicating disruption of the BBB, but this was not observed in DEX-treated rats. These results indicate that DEX is effective in preventing osmotic demyelination by inhibiting BBB disruption, and suggest that DEX might be useful for the prevention of CPM in clinical practice.

Myoinositol Administration Improves Survival and Reduces Myelinolysis After Rapid Correction of Chronic Hyponatremia in Rats

When chronic hyponatremia is rapidly corrected, reaccumulation of brain organic osmolytes is delayed and brain cell shrinkage occurs, leading to the osmotic demyelination syndrome (ODS). We hypothesized that treatment with myoinositol, a major organic osmolyte, could prevent ODS. Severe hyponatremia was induced in adult male rats by administration of arginine vasopressin and intravenous infusion of dextrose and water. Sixty-four hours after induction of hyponatremia, all animals underwent rapid correction of hyponatremia with infusion of hypertonic saline over 4 hours, increasing the serum sodium from 105 to 135 mM; half of the animals were also given myoinositol intravenously beginning 20 minutes before correction and continuing for 28 hours. Serum sodium concentrations were equivalent in both groups at all time points. At 7 days, 7 of 8 animals that received myoinositol survived compared with one of the 9 control animals (p < 0.01). In a second study, sodium was reduced to 106 mM over 64 hours in 24 animals and then corrected by 20 mM over 4 hours with concomitant loading and infusion of either mannitol (control) or myoinositol. Animals were killed 96 hours after correction of hyponatremia was begun. Myoinositol-treated animals had significantly fewer demyelinating lesions than mannitol (2.25 +/- 1.1 versus 6.42 +/- 1.4 lesions/brain, p < 0.03). We conclude that myoinositol administration improves survival and reduces myelinolysis after rapid correction of chronic hyponatremia in rats.

Osmotic Myelinolysis Following Chronic Hyponatremia Corrected at An Overall Rate Consistent with Current Recommendations

Rapid correction of chronic hyponatremia (CH) may lead to the development of osmotic myelinolysis (OM), a condition with high mortality and high incidence of devastating neurological sequelae. Treatment guidelines suggest "safe" overall rates of correction of serum sodium concentration ([Na](s)) over the first 24 and 48 hours of treatment of CH. We report a patient with CH who developed fatal OM despite overall rates of correction of [Na](s) that were within the recommended rates. The potential risk factors for the development of OM in this patient included short (within a few hours) rises in [Na](s) exceeding 0.5 mmol/l per hour and the presence of severe protein malnutrition. We suggest that the rate of correction of [Na](s) in CH should be uniformly slow and that the overall rate of correction should be slower than the currently recommended rate in severely malnourished patients.

Hyponatrémies en réanimation : actualités

Hyponatremia is a common hydroelectrolytic disturbance which can result from multiple origin, particularly iatrogenic. Usually, hyponatremia is related to hypotonia, inducing intracellular hyperhydration and swelling. The prevention of cellular swelling, especially in the brain, depends on the type of onset, acute or chronic, but also on other factors such as: female gender, young age, hypoxia... The management of hyponatremia is guided by the understanding of the pathophysiology and relies on routinely available data: patient’s history, clinical assessment of the extracellular fluid volume, routine blood and urine laboratory tests. The evaluation of clinical tolerance and of the type of onset are determinant in the therapeutic strategy. It is always more important to treat the symptoms rather than to correct laboratory values. Myelinolysis is a severe neurologic disorder that can occur after a rapid correction of chronic hyponatremia. According to recent preliminary data, myelinolysis could be reversed by reinducing hyponatremia but this point needs further research.

A review of the causes of central pontine myelinosis: yet another apoptotic illness?

One of the well recognized stimuli for central pontine myelinosis (CPM) is the rapid correction of chronic hyponatraemia. Conventionally this has been perceived to lead to pontine glial cell swelling through osmosis and eventually to cell death. However, although a purely osmotic argument has been central to any patho-physiological understanding of CPM, there are deficiencies in this approach that do not account for why certain individuals develop CPM with relatively mild osmotic insults. Here we review the varying aetiologies of CPM and propose a novel hypothesis for CPM causation by suggesting that individuals predisposed to CPM have inadequate energy provision as well as other factors that result in a pro-apoptotic drive, which renders them susceptible to brain injury from diverse causes. In CPM, the precipitant of brain injury appears to be osmotic stress. Furthermore, this model suggests a number of therapeutic interventions that may prevent or at least mitigate the consequences of CPM.

Blood–Brain Barrier Disruption and Complement Activation in the Brain Following Rapid Correction of Chronic Hyponatremia

In previous studies we developed a rat model in which demyelination is reproducibly produced following rapid correction of chronic hyponatremia and demonstrated that the development of demyelination in this model is strongly associated with NMR indices of blood–brain barrier (BBB) disruption. Because complement is toxic to oligodendrocytes, we evaluated the hypothesis that BBB disruption precipitated by correction of hypoosmolality is followed by an influx of complement into the brain, which then contributes to the demyelination that occurs under these conditions. We studied four groups of rats with immunocytochemical analysis using primary antibodies to IgG and the C3d split-fragment of activated complement: (1) normal rats; (2) rats in which hyponatremia was maintained for 7 days; (3) chronically hyponatremic rats in which the plasma [Na+] was rapidly corrected with hypertonic saline administration 20 h prior to perfusion; and (4) chronically hyponatremic rats in which the plasma [Na+] was rapidly corrected with hypertonic saline administration 5 days prior to perfusion. In normonatremic and uncorrected hyponatremic rats only background staining was observed in areas lacking a BBB and in blood vessel walls, whereas marked increases in IgG and C3d staining were seen in the brains of rats both 20 h and 5 days after rapid correction of hyponatremia. The staining intensity was significantly correlated with the degree of neurological impairment. These results provide evidence for functional BBB disruption following rapid correction of hyponatremia and support the hypothesis that complement activation may be involved in the pathogenesis of osmotic demyelination.

Changes in Cerebral Blood Flow and Distribution Associated with Acute Increases in Plasma Sodium and Osmolality of Chronic Hyponatremic Rats

The cause of the osmotic demyelination syndrome that follows too rapid correction of chronic hyponatremia (CHN) is unknown. Recently, we reported in CHN rats an association between blood–brain barrier (BBB) disruption occurring as early as 3 h into correction and subsequent demyelination. Given the changes in brain water and blood volume which occur during correction of CHN, we hypothesized that the same correction protocol that causes demyelination might alter cerebral blood flow (CBF) during correction, thereby possibly contributing to BBB disruption and demyelination. Ten CHN rats were given hypertonic sodium intraperitoneally and its effect on CBF was continuously monitored for 3 h by magnetic resonance flow imaging. Over the subsequent 3 h, plasma sodium rose from 110.8 to 127.6 mEq/liter (P < 0.001) but neither mean arterial blood pressure nor arterial CO2 tension changed significantly. By 30 min, CBF increased by 50% in cortical and subcortical areas (P < 0.001) and remained elevated for the next 60 min. After 2 h, cortical flow was no longer elevated significantly and by 3 h it had returned to control values. Subcortical flow, however, significantly exceeded control values throughout the 3 h so that after 2 h the ratio of cortical to subcortical blood flow had fallen from 1.17 to 0.91 (P < 0.05). Although the mechanism by which increased plasma sodium and osmolality alters CBF is uncertain, the results suggest that changes in CBF may be part of a cascade of cerebrovascular disturbances including endothelial or parenchymal damage, mechanical events, metabolic disturbances, or cytokine release which eventually lead to BBB disruption and subsequent demyelination.

Positive association between blood brain barrier disruption and osmotically-induced demyelination

Rapid correction of chronic hyponatremia can cause osmotic brain demyelination in animals and humans. Why demyelination develops is unknown, but blood brain-barrier disruption might expose oligodendrocytes to substances normally excluded from the brain. To test this hypothesis, chronic hyponatremia was induced and corrected using a new, reproducible rat model for producing osmotic brain demyelination. Blood brain barrier integrity was assessed by NMR imaging at either 3, 16 or 24 h during the first day of correction. Demyelination was determined histopathologically 5 - 6 days later. Of 96 rats studied, demyelination developed 5 - 6 days later in 37 rats, 89% of whom showed barrier disruption. In the 59 rats who did not develop demyelination, 45 (76%) had no barrier disruption. Thus, blood-brain barrier disruption during the first 24 h of correction was associated with a 70% risk of developing demyelination. By contrast, the risk of developing subsequent demyelination was only 8% when the barrier was intact. This strong association between barrier disruption and subsequent demyelination provides new insights into the role of blood brain barrier function in demyelinative disorders such as the osmotic demyelination syndrome and by extension to other demyelinative disorders such as multiple sclerosis.

Role of organic osmolytes in myelinolysis. A topographic study in rats after rapid correction of hyponatremia.

Organic osmolytes have been implicated in the pathogenesis of myelinolysis because some of them are accumulated slowly during correction of chronic hyponatremia. I investigated whether there was a topographic correlation between demyelinative lesions and the regional changes of organic osmolytes after rapid correction of chronic hyponatremia. In normal female Sprague-Dawley rats, concentrations of glutamate, glutamine, taurine, and betaine were highest in the cerebral cortex and decreased toward the brain stem. Conversely, glycine level was highest in the brainstem, and decreased toward the cortex. Myoinositol, glycerophosphorylcholine, glycerophosphorylethanolamine, and creatine were distributed more evenly. In chronic hyponatremic rats (plasma Na 110 +/- 4 meq/liter), organic osmolytes decreased globally with the total loss ranging from 13 (medulla) to 24 (cerebellum) mmol/kg H2O. After rapid correction with intraperitoneal injection of hypertonic saline, the recovery of the loss of organic osmolytes was 48% in the cerebral cortex, cerebellum, and medulla oblongata, 44% in pons, but only 17% in midbrain and 36% in striatum. Histopathology of the brain was examined in nine rats 2-7 d after correction of hyponatremia. Large demyelinative lesions were seen persistently in the midbrain and striatum, and smaller lesions in cerebrum, cerebellum, and pons were found less frequently. This is the first report of regional distribution of brain organic osmolytes. After rapid correction of chronic hyponatremia, a topographic correlation between demyelination lesions and delayed accumulation of organic osmolytes exists.

Hyponatremia: pathophysiology and treatment, a pediatric perspective.

Hyponatremia is the most commonly observed electrolyte abnormality in hospitalized children. The most serious consequences of hyponatremia and its treatment involve the central nervous system (CNS). Important factors determining the development of clinical symptomatology include: the rate of fall in serum sodium, and the severity and duration of hyponatremia. Acute hyponatremia is associated with increased brain water resulting in varying grades of encephalopathy whereas the osmoregulatory mechanism allows normalization of CNS water content in chronic hyponatremia. It is recommended that the therapy for hyponatremia be initiated on the basis of the presence or absence of symptoms. An increase of 4-6 mmol/l in serum sodium over 10-15 min is recommended in symptomatic patients. Rapid correction of chronic hyponatremia may result in osmotic dehydration syndrome and therefore should be avoided.

Adaptive decreases in amino acids (taurine in particular), creatine, and electrolytes prevent cerebral edema in chronically hyponatremic mice: rapid correction (experimental model of central pontine myelinolysis) causes dehydration and shrinkage of brain.

The experimental model of central pontine myelinolysis--chronic (4-day) hyponatremia induced by daily injections of hypotonic dextrose solutions and vasopressin followed by rapid correction with saline--was used in young fasted and thirsted mice. In normal controls chronic fasting and thirsting lowered plasma and brain glucose levels and cerebral glycolytic and tricarboxylic acid cyclic metabolic fluxes. The fasting state had little effect on brain amino acids. Clinically, the animals became semistuporous; about one-third died. Chronic hyponatremia in fasted mice almost tripled the plasma glucose concentrations and increased the brain carbohydrate reserve. Levels of other brain glycolytic and Krebs citric acid cycle intermediates were similar to those of controls. Severe hyponatremia and hypoosmolality induced profound decreases in levels of brain electrolytes, amino acids (especially taurine), and creatine. These changes permitted a new osmotic balance between blood and brain and a normal brain water content. The behavior and mortality of the hyponatremic animals were not different from those of the fasted control mice. Correction of hyponatremia to normonatremic levels over a 9-hr period returned brain Na+ and K+ levels to normal but the contents of the measured amino acids and creatine were still reduced one-third or more. As a result, treatment produced a significant degree of dehydration and shrinkage of the brain. The findings stress the importance of amino acids (taurine in particular) and creatine levels, as well as electrolytes, in brain osmoregulation and suggest a role for an osmotic disequilibrium--blood osmolality higher than brain--in the production of brain lesions following rapid correction of chronic hyponatremia in animals and possibly in humans. Replenishment of depleted brain K+ and amino acid levels, as well as slow elevation of the chronically depressed level of plasma Na+, is recommended.

Brain amino acids decrease in chronic hyponatremia and rapid correction causes brain dehydration: Possible clinical significance

In animals, rapid correction of chronic hyponatremia produces brain lesions similar to those seen in central pontine myelinolysis. This is the first study of the effects of rapid correction (9 h) of chronic hyponatremia (3 d) on brain electrolyte, water, and amino acid contents in young mice. Despite profound hyponatremia, decreases in brain electrolytes and amino acids permitted an apparent osmotic balance between blood and brain with a normal brain water content. Rapid elevation of the depressed plasma sodium concentration to normonatremic levels caused dehydration of the brain. Although brain Na + and K + levels were returned to normal, the relatively brief interval of treatment was insufficient to allow complete recovery of brain amino acid levels. Findings support an osmotic disequilibrium - plasma osmolality higher than brain - in the pathogenesis of the brain lesions following rapid correction of chronic hyponatremia and suggest caution in the rate of elevation of the depressed plasma Na + levels.

Osmotic demyelination syndrome following correction of hyponatremia.

The treatment of hyponatremia is controversial: some authorities have cautioned that rapid correction causes central pontine myelinolysis, and others warn that severe hyponatremia has a high mortality rate unless it is corrected rapidly. Eight patients treated over a five-year period at our two institutions had a neurologic syndrome with clinical or pathological findings typical of central pontine myelinolysis, which developed after the patients presented with severe hyponatremia. Each patient's condition worsened after relatively rapid correction of hyponatremia (greater than 12 mmol of sodium per liter per day)--a phenomenon that we have called the osmotic demyelination syndrome. Five of the patients were treated at one hospital, and accounted for all the neurologic complications recorded among 60 patients with serum sodium concentrations below 116 mmol per liter; no patient in whom the sodium level was raised by less than 12 mmol per liter per day had any neurologic sequelae. Reviewing published reports on patients with very severe hyponatremia (serum sodium less than 106 mmol per liter) revealed that neurologic sequelae were associated with correction of hyponatremia by more than 12 mmol per liter per day; when correction proceeded more slowly, patients had uneventful recoveries. We suggest that the osmotic demyelination syndrome is a preventable complication of overly rapid correction of chronic hyponatremia.