Hyponatremia with hypoxia: effects on brain adaptation, perfusion, and histology in rodents.

Hypoxia appears to be a prominent component of brain damage among patients with hyponatremic encephalopathy. Effects of hypoxia on brain in the presence of hyponatremia are not known. In order to evaluate the contributions of hypoxia to brain damage, three separate experiments were conducted in three groups of rodents. Experiment I evaluated the effects of hypoxia and acute (< 4 h) hyponatremia (plasma Na < 120 mmol/l) on brain adaptation in rabbits. Experiment II evaluated the effects of hypoxia and chronic (4 days) hyponatremia on cerebral perfusion in rats. Experiment III evaluated the effects of hypoxia and chronic hyponatremia on brain histology in rats. In experiment I, rabbits with acute hyponatremia demonstrated brain adaptation with significant falls in brain Na content (by 14.2%, P < 0.01) and osmolality (by 8.3%, P < 0.01), and a rise in brain water (by 10.6%, P < 0.05). Rabbits with combined hypoxia and hyponatremia failed to demonstrate brain adaptation. In experiment II, rats with chronic hyponatremia plus hypoxia had a decrease in cerebral perfusion index by more than 50% (P < 0.01). In experiment III, 23% of hypoxic rats had brain lesions, which were in the cerebellum, thalamus, reticular formation, and basal ganglia. Hyponatremia without hypoxia resulted in no brain lesions. Hypoxia in normonatremic animals results in cerebral edema and histopathologic lesions similar to those found in rats whose plasma Na was overcorrected. Hypoxia in hyponatremic animals aggravates cerebral edema, impairs brain adaptation, and decreases cerebral perfusion.

Na-K-ATPase activity decreases with aging in female rat brain synaptosomes.

To understand why elderly females are better able to tolerate hyponatremia, we measured brain Na-K-ATPase activity to determine whether this adaptive mechanism was affected by age. Using synaptosomes from 2-, 12-, and 19-mo-old female rats, we show in our results that Na-K-ATPase activity changes with age in female rats. Enzyme activity was significantly (P = 0.0026) reduced (17%) from 0.416 +/- 0.01 at 2 mo to 0.345 +/- 0.01 at 12 mo and reduced (P = 0.0001) (34%) to 0.274 +/- 0.02 micromol. min(-1). mg protein(-1) at 19 mo. To determine whether this decrease was due to reduced transport function of the Na-K-ATPase pump, we performed potassium transport using rubidium ((86)Rb+) as tracer. Ouabain-sensitive potassium uptake at 2 mo was 16.18 +/- 1.31 nmol/mg protein, was significantly (P = 0.0063) reduced (39%) to 9.79 +/- 1.44 nmol/mg at 12 mo, and was significantly (P = 0.0003) reduced (62%) to 6.12 +/- 1.05 nmol/mg protein at 19 mo. On the contrary, Na-K-ATPase activity remained elevated in males during aging. These data suggest that the Na-K-ATPase pump in female rat brain synaptosomes is decreased with increased age, and that this decrease is probably due in part to decreased potassium transport by the Na-K-ATPase pump.

Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.

BACKGROUND: Noncardiogenic pulmonary edema is often associated with increased intracranial pressure and can be the initial manifestation of hyponatremic encephalopathy. Marathon runners tend to develop conditions that lead to hyponatremia. OBJECTIVE: To describe the development and treatment of noncardiogenic pulmonary edema in marathon runners that was associated with hyponatremic encephalopathy. DESIGN: Case series. SETTING: One university hospital and two community hospitals. PATIENTS: Seven healthy marathon runners who had a history of nonsteroidal anti-inflammatory drug use. The runners collapsed after competing in a marathon and were hospitalized with pulmonary edema. MEASUREMENTS: Plasma sodium levels, chest radiograph, electrocardiogram, cardiac enzyme levels, and magnetic resonance imaging or computed tomographic scans of the brain. RESULTS: Patients had nausea, emesis, and obtundation. The mean (+/-SD) plasma sodium level was 121 +/- 3 mmol/L, and oxygen saturation was less than 70%. Electrocardiograms and echocardiograms were normal. Chest radiographs showed pulmonary edema with a normal heart. Creatine phosphokinase-MB bands, troponin levels, and pulmonary wedge pressure were not elevated. Scanning of the brain showed cerebral edema. All patients were intubated and mechanically ventilated. Treatment with intravenous NaCl, 514 mmol/L, increased plasma sodium levels by 10 mmol/L in 12 hours. Pulmonary and cerebral edema resolved as the sodium level increased. One patient had unsuspected hyponatremic encephalopathy and died of cardiopulmonary arrest caused by brainstem herniation. All six treated patients recovered and were well after 1 year of follow-up. CONCLUSIONS: In healthy marathon runners, noncardiogenic pulmonary edema can be associated with hyponatremic encephalopathy. The condition may be fatal if undiagnosed and can be successfully treated with hypertonic NaCl.

Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality.

CONTEXT: Chronic hyponatremia in postmenopausal women is a common clinical problem often viewed as benign. Fluid restriction is usually the recommended therapy, largely because the extent of morbidity is unknown and because it has been postulated that intravenous (IV) sodium chloride may cause brain damage. OBJECTIVE: To compare IV sodium chloride with fluid restriction in the treatment of postmenopausal women with chronic symptomatic hyponatremia. DESIGN: Nonrandomized prospective study. SETTING: Two university medical centers and affiliated community hospitals. PATIENTS: A total of 53 postmenopausal women with chronic symptomatic hyponatremia (chronic plasma sodium <130 mmol/L in the presence of central nervous system manifestations) treated consecutively from 1988-1997 and followed up for 1 year. The mean (SD) age of the patients was 62 (11) years. INTERVENTIONS: The therapeutic interventions were IV sodium chloride before respiratory insufficiency (n = 17), IV sodium chloride after respiratory insufficiency (n = 22), and fluid restriction only (n = 14). MAIN OUTCOME MEASURES: Morbidity and neurological outcome at 4 months or longer as assessed by cerebral performance category (CPC) in relation to the therapy, initial plasma sodium level, and rate of correction. RESULTS: Chronic symptomatic hyponatremia (mean [SD] sodium level 111 [12] mmol/L) was present for 5.2 [4.5] days. Death or major morbidity occurred in 44 (83%) of 53 patients, including 10 with orthopedic injury. Twelve patients had hypoxemia (PO2 = 63 [25] mm Hg) and cerebral edema. Among patients who received IV sodium chloride before respiratory insufficiency, plasma sodium levels were increased by 22 (10) mmol/L in 35 hours and patients had a CPC of 1.0 (normal or slight disability). Among patients who received IV sodium chloride after respiratory insufficiency, plasma sodium levels were increased by 30 (6) mmol/L in 41 hours and patients had a CPC of 3.0 (1.2) (severe disability). Among patients who had fluid restriction only, plasma sodium levels were increased by 3 (2) mmol/L in 41 hours and patients had a CPC of 4.6 (0.7) (4 = persistent vegetative state; 5 = death). The outcomes did not correlate with either the initial plasma sodium level (r=0.05, P>.12) or the rate of correction (r=0.31, P>.10). CONCLUSIONS: Chronic symptomatic hyponatremia in postmenopausal women can be associated with major morbidity and mortality. Therapy with IV sodium chloride was associated with significantly better outcomes than fluid restriction.

Fatal child abuse by forced water intoxication.

BACKGROUND: Although water intoxication leading to brain damage is common in children, fatal child abuse by forced water intoxication is virtually unknown. METHODS: During the prosecution of the homicide of an abused child by forced water intoxication, we reviewed all similar cases in the United States where the perpetrators were found guilty of homicide. In 3 children punished by forced water intoxication who died, we evaluated: the types of child abuse, clinical presentation, electrolytes, blood gases, autopsy findings, and the fate of the perpetrators. FINDINGS: Three children were forced to drink copious amounts of water (over 6 L). All had seizures, emesis, and coma, presenting to hospitals with hypoxemia (PO2 = 44 +/- 8 mm Hg) and hyponatremia (plasma Na = 112 +/- 2 mmol/L). Although all showed evidence of extensive physical abuse, the history of forced water intoxication was not revealed to medical personnel, thus none of the 3 children were treated for their hyponatremia. All 3 patients died and at autopsy had cerebral edema and aspiration pneumonia. The perpetrators of all three deaths by forced water intoxication were eventually tried and convicted. INTERPRETATION: Forced water intoxication is a new generally fatal syndrome of child abuse that occurs in children previously subjected to other types of physical abuse. Patients present with coma, hyponatraemia, and hypoxemia of unknown etiology. If health providers were made aware of the association, the hyponatremia is potentially treatable.

Fatal postoperative pulmonary edema: pathogenesis and literature review.

STUDY OBJECTIVES: Pulmonary edema is a known postoperative complication, but the clinical manifestations and danger levels for fluid administration are not known. We studied (1) 13 postoperative patients (11 adult, 2 pediatric) who developed fatal pulmonary edema, and (2) one contemporaneous year of inpatient operations at two university teaching hospitals to determine the clinical manifestations, causes, epidemiology, and guidelines for fluid administration. DESIGN: Retrospective analysis of 13 patients with fatal postoperative pulmonary edema and one contemporaneous year of major inpatient surgery. PATIENTS AND METHODS: Thirteen patients had net fluid retention of at least 67 mL/kg in the initial 24 postoperative hours and developed pulmonary edema. Ten were generally healthy while three had serious associated medical conditions. MEASUREMENTS AND RESULTS: There was no measurement, laboratory value, or clinical finding predictive of impending pulmonary edema. The most common clinical manifestation following the onset of pulmonary edema was cardiorespiratory arrest (n = 8). Patients had metabolic acidosis (pH = 7.15 +/- .33), hypoxia (PO2 = 45 +/- 18 mm Hg), and normal electrolytes. The diagnosis of pulmonary edema was established by chest radiograph and confirmed by autopsy and pulmonary artery pressure (21 +/- 4 mm Hg). The mean net fluid retention was 7.0 +/- 4.5 L (90 +/- 36 mL/kg/d) and exceeded 67 mL/kg/d in all patients. Autopsy revealed pulmonary edema with no other cause of death. Among 8,195 major operations, 7.6% developed pulmonary edema with a mortality of 11.9%. Extrapolation to the 8.2 million annual major surgeries in the United States yields a projection of 8,000 to 74,000 deaths. CONCLUSIONS: Pulmonary edema can occur within the initial 36 postoperative hours when net fluid retention exceeds 67 mL/kg/d. There are no known predictive warning signs and cardiorespiratory arrest is the most frequent clinical presentation. The monitoring systems currently in use neither detect nor predict impending pulmonary edema, and as yet, there are no known panic values for excessive fluid administration or retention.

Transient cerebral ischemia. Association of apoptosis induction with hypoperfusion.

Apoptosis is thought to be important in the pathogenesis of cerebral ischemia. The mechanism of apoptosis induction remains unclear but several studies suggest that it is preferentially triggered by mild/moderate microcirculatory disturbances. We examined in cats whether induction of apoptosis after 2.5 h of unilateral middle cerebral artery occlusion plus 10 h of reperfusion is influenced by the degree of cerebral microcirculatory disturbance. Quantitative monitoring over time of the disturbances of cerebral microcirculation in ischemic brain areas and evaluation of cytotoxic edema associated with perfusion deficits was achieved by using two noninvasive magnetic resonance imaging techniques: (a) high-speed echo planar imaging combined with a bolus of magnetic susceptibility contrast agent; and (b) diffusion-weighted imaging. Apoptosis-positive cells were counted in anatomic areas with different severity of ischemic injury characterized by magnetic resonance imaging, triphenyltetrazolium chloride, and hemotoxylin and eosin staining. The number of apoptosis-positive cells was significantly higher in anatomic areas with severe perfusion deficits during occlusion and detectable histologic changes 10 h after reperfusion. In contrast, in areas where perfusion was reduced but maintained during occlusion there were no detectable histological changes and significantly fewer apoptosis-positive cells. A similar number of cells that undergo apoptosis were shown in regions with transient or prolonged subtotal perfusion deficits. These results suggest that the apoptotic process is induced in the ischemic core and contributes significantly in the degeneration of neurons associated with transient ischemia.

Epidemiology, pathophysiology, and management of hyponatremic encephalopathy.

Hyponatremia is the most common electrolyte abnormality among hospitalized patients. Death or brain damage associated with hyponatremia has been described since 1935, and it is now evident that hyponatremia can lead to death in otherwise healthy individuals. In the past, it had been assumed that the likelihood of brain damage from hyponatremia was directly related to either a rapid decline in plasma sodium or a particularly low level of plasma sodium. Recent studies have demonstrated that other factors may be more important. These factors include the age and gender of the individual, with children and menstruant women the most susceptible. Although many clinical settings are associated with hyponatremia, those most often associated with brain damage are postoperative, polydipsia, pharmacological agents, and heart failure. Morbidity and mortality associated with hyponatremia are primarily a result of brain edema, hypoxemia, and associated hormonal factors. Management of hyponatremia is largely determined by symptomatology. If the patient is asymptomatic, discontinuation of drugs plus water restriction is often sufficient. If the patient is symptomatic, active therapy to increase the plasma sodium with hypertonic NaCl is usually indicated. Although inappropriate therapy of hyponatremia can lead to brain damage, such an occurrence is rare. Thus, the risk of not treating a symptomatic patient for exceeds that of improper therapy.

Glycine-induced hypo-osmolar hyponatremia.

BACKGROUND: Hyponatremia is commonly observed following transurethral resection of the prostate or endometrial resection when the operative field is irrigated with hypotonic glycine. Although glycine-induced hyponatremia has been associated with brain damage, the mortality is low, and it has been suggested that the condition might not be hypo-osmolar and thus might not cause brain edema. OBJECTIVE: To determine if glycine-induced hyponatremia is a hypo-osmolar condition. METHODS: The study was a retrospective evaluation of 13 men who underwent transurethral resection of the prostate and 5 women who underwent transcervical endometrial resection at 2 university medical centers. In all patients, hypotonic glycine (200 mmol/L) was the irrigating solution. Measurements were made of the plasma sodium, osmolality, glucose, urea, glycine, and ammonia; and arterial pH, PO2 and PCO2. Mortality and the occurrence of respiratory arrest were recorded. Data are given as mean (+/- SE). RESULTS: The plasma sodium in 18 patients was 106 +/- 2 mmol/L and the measured osmolality was 235 +/- 5 mOsm/kg H2O. Glycine was measured as the difference between measured and calculated plasma osmolality and was 18 +/- 2 mmol/L. Four patients suffered respiratory arrest; all died. One patient had elevated blood ammonia (130 mumol/L) with a plasma sodium level of 110 mmol/L. She was treated with endotracheal intubation and respiratory support plus hypertonic sodium chloride, and recovered. The other 14 surviving patients were treated with hypertonic sodium chloride. CONCLUSIONS: Patients who undergo transurethral resection of the prostate or endometrial resection with hypotonic glycine as the irrigating medium can experience symptomatic hyponatremia that is hypo-osmolar and can be fatal. Therapy with hypertonic sodium chloride was associated with survival in 14 of 14 patients. Ammonia intoxication also can develop, and can be managed with respiratory support.

Abnormalities of water metabolism in the elderly.

Hypernatremia is a frequent problem at the extremes of age, but particularly so in elderly individuals. Changes in the physiological responses to water deprivation with increasing age may be of particular interest in understanding the pathogenesis of hypernatremia in the elderly. When comparing healthy elderly men to younger controls, there are differences in the response to water deprivation. In older men, there are deficits in both the intensity and threshold of the thirst response. The ability to concentrate the urine also declines with age. There is both a decline in glomerular filtration rate and an increased incidence of renal disease with advancing age, which may contribute to impaired ability to conserve water. Because of a decrease in the percent total body water with age, equal volumes of fluid loss in young and old individuals may represent more severe dehydration in the elderly. Hyponatremia is seen in all age groups, but there are important differences in the elderly. When compared with postmenopausal women, menstruant (of childbearing age) women are over 25 times more likely to suffer permanent brain damage as a complication of hyponatremic encephalopathy. Furthermore, menstruant women suffer seizures or respiratory arrest at far higher levels of plasma sodium (110 to 130 mmol/L) than occurs in postmenopausal women (95 to 123 mmol/L).

Effects of hypernatraemia in the central nervous system and its therapy in rats and rabbits.

1. We studied the effects of acute (1 or 4 h) and chronic (1 week) hypernatraemia (plasma [Na+], 170-190 mM) on brain histology, and brain water and solute contents in rats and rabbits. 2. In rabbits with acute hypernatraemia, there was significant loss of intracellular brain water, with increases in brain [Na+ + K+], amino acid concentration, and undetermined solute (idiogenic osmole). After 1 week of recovery, brain intracellular water content had returned to normal. 3. In hypernatraemic rats there was myelinolysis of brain white matter, with karyorrhexis and necrosis of neurons. 4. Hypernatraemic rabbits were treated with 77 mM NaCl (i.v.) to normalize plasma [Na+] over 4-24 h intervals. Therapy of either acute or chronic hypernatraemia resulted in significant brain oedema because brain osmolality failed to decrease at the same rate as plasma osmolality. 5. It is concluded that: (a) untreated hypernatraemia results in brain lesions demonstrating myelinolysis and cellular necrosis; (b) normalization of hypernatraemia over 4-24 h results in cerebral oedema, due primarily to failure of brain amino acids and idiogenic osmoles to dissipate as plasma [Na+] is decreased to normal.