Pediatric Nephrology
PediatrNephrol(1992) 6: 280- 286 9 IPNA 1992
Practical pediatric nephrology Hyponatremia: pathophysiology and treatment, a pediatric perspective Alan B. Gruskin and Ashok Sarnaik Departmentof Pediatrics,Children'sHospitalof Michiganand WayneStateUniversitySchoolof Medichae, 3901 Beaubien,Boulevard,Detroit,MI 48 201, USA ReceivedDecember31, 1991;receivedin revisedformand acceptedJanuary2, 1992 Abstract. 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.
(CNS). Three factors related to the development and resolution of hyponatremia influence CNS function. They are the rate of change in SNa, the level of SNa, and the duration of the abnormal SNa. The gradual development of hyponatremia may not result in neurological dysfunction even at SNa levels below 110 mmol/1, and the prognosis in such cases depends upon associated medical conditions rather than hyponatremia itself [2, 3]. Conversely, relatively less severe hyponatremia may be associated with catastrophic CNS damage in situations where the decline in SNa is precipitous [3-5]. Finally, restoration of SNa levels either too slowly or too rapidly has significant implications for outcome.
Pathophysiological considerations Blood-brain barrier
Key words: Hyponatremia- Pathophysiology - Diagnosis - Treatment - Central nervous system- Osmoregulation Central pontine myelinolysis
Introduction Hyponatremia, which is one of the most frequently encountered electrolyte abnormalities in hospitalized patients, is mild and asymptomatic in most cases. An abnormally low serum sodium concentration (SNa) does not exist in isolation, but occurs in clinical settings where the accompanying total body water is either normal (isovolemic hyponatremia), excessive (hypervolemic hyponatremia), or decreased (hypovolemic hyponatremia) [1]. The more serious complications attributable to an abnormally low SNa involve the central nervous system
Correspondence to: A. B. Gruskin
The capillary endothelium which separates interstitial fluid (ISF) and plasma is freely permeable to water and electrolytes, whereas the cell membrane which separates the intracellular fluid (ICF) from extracellular fluid (ECF) is relatively impermeable to various solutes. When SNa decreases, both Na and water move freely across the capillary membrane to maintain osmotic equilibrium between plasma and ISF. At the level of the cell membrane in most organs, osmotic equilibrium is attained only by movement of interstitial water into the cell and the development of intracellular edema. The net size of the tissue does not change significantly as the increased cell size is compensated for by a decreased interstitial space. The CNS behaves differently because the blood-brain barrier (BBB) is composed of tight junctions between capillary endothelial cells and astrocytic end-feet processes. Most solutes, including Na, take several hours to equilibrate across the BBB between plasma and brain interstitium, whereas water moves rapidly in either direction. An osmolal gradient, therefore, has a significant and unique effect on total brain size that is not seen in other organs because the critical boundary impeding osmolar movement is the capillary en-
281
dothelium rather than the cell membrane. The intrinsic characteristics of the BBB causes the brain to respond to osmolal gradients as if it were a single cell [6]. When hyponatremia (hypo-osmolality) is present, osmotic equilibrium is achieved by the movement of water into brain interstitium as well as into the intracellular space resulting in a net increase in tissue size. Consequently, the brain, when compared with other organs, is more likely to experience a change in its total size in response to an acute change in plasma osmolality. It swells in response to decreased osmolality and shrinks when subjected to hyperosmolality.
Intracranial pressure-volume relationship The skull with fused sutures is a rigid container filled with fluid and solid tissues. Since intracranial contents are noncompressible, an increase in volume in any one compartment must be accompanied by an equal decrease in volume in other compartments in order for the intracranial pressure (tCP) to remain constant. When cerebral edema results from hyponatremia, the early ICP homeostatic mechanism consists of displacement of intracranial cerebrospinal fluid (CSF) into the distensible spinal subarachnoid space preventing a rise in ICP. Clinical signs of cerebral edema, such as altered consciousness and seizures, may occur before intracranial hypertension. Once maximal displacement of CSF has occurred, any further increase in cerebral edema results in an exponential increase in ICP with catastrophic consequences - brain stem herniation, apnea, and death. Compared with older children and adults, open fontanelles and unfused sutures offer young infants partial protection from a precipitous rise in ICP to life-threatening levels. Protection, however, is not absolute and serious disturbances in CNS function from acute hyponatremia can occur in any age-group.
CNS osmoregulatory mechanism The brain has adaptive mechanisms to defend its cellular volume in response to sustained alterations in ECF osmolality that are not found in many other organs. These osmoregulatory mechanisms allow the brain to normalize its water content when subjected to a changing osmolar environment. The time frame over which the brain water content is completely normalized is not established in humans. When an elevated ECF osmolality persists over 12-24 h, the brain generates additional osmols, commonly referred to as idiogenic osmols. The newly generated osmols allow the intracellular compartment to regain some of the water lost during the acute or persistent phase of hyperosmolality. Conversely, the brain can also lower its osmolar content in situations where the ECF osmolality is decreased for a period of time, thereby minimizing the gain in intracellular water. In acute hyponatremia the brain water content is increased whereas in chronic hyponatremia it tends to be normal.
CNS consequences of hyponatremia Hyponatremia and its treatment may result in brain injury by two distinct mechanisms: hypoxic encephalopathy and central pontine myelinolysis (CPM). A significant and precipitous decline in SNa can cause cerebral edema, brain stem herniation, and apnea. Severe hyponatremia of rapid onset can cause seizures, coma, respiratory arrest, and permanent brain damage [3, 5]. Histopathological findings in patients with acute hyponatremia and respiratory arrest are characteristic of cerebral hypoxia. Herniation of the brain stem into the foramen magnum, cerebral edema, and cortical necrosis with sparing of the white matter have been described in this setting. Acute hyponatremic encephalopathy is characterized by cerebral edema resulting from hyponatremia with subsequent intracranial hypertension, apnea, and cerebral hypoxia. An increase in brain volume of 5% can cause these problems [7]. Rapid correction of chronic hyponatremia has been associated with a distinct neurological syndrome termed central pontine myelinolysis (CPM) [8]. The clinical manifestations of CPM include: spastic quadriplegia, pseudobulbar palsy, a decreasing level of consciousness, and behavioral changes without focal findings [9, 10]. CPM, a descriptive term, is characterized by demyelination within the central portion of basal ports with sparing of both the axis cylinders and neurons. Foamy macrophages accumulate and oligodendroglia are diminished [8]. The lesion has been shown to be restricted to the pons alone. Similar changes have been observed in basal ganglia, corpus callosum, internal and external capsule, lateral geniculate nuclei, and thalamus. Originally recognized only at necropsy, the lesion can be recognized by computed tomography, magnetic resonance imaging, and brain stem auditory evoked potentials. In large series of general autopsies the incidence of CPM has ranged from 0.17% to 0.28%, and over 250 cases have been reported [11]. Because similar lesions have been observed in extrapontine regions where gray and white matter are closely associated, the term osmotic demyelination syndrome has been suggested as a better description of the lesion [6]. Extrapontine myelinolysis may also occur without involving the pons. Whether CPM occurs as a consequence of hyponatremia or its treatment has generated much controversy. CPM has been most frequently observed in patients with pre-existing medical conditions such as alcoholism, cirrhosis, increased ICP, malignancy, arteriosclerotic encephalopathy, acquired immunodeficiency syndrome, membranous nephritis, and other infections [12, 13]. A significant number of patients have had malnutrition and dehydration with and without accompanying electrolyte imbalance. Menstruating women appear to be at increased risk of developing CPM. These cfinical associations have cast doubt as to the causal relationship between CPM and hyponatremia or its treatment. Nonetheless, in certain patients rapid correction of hyponatremia is associated with neurological deterioration characterized by an altered level of consciousness, a "locked-in syndrome" (awake but unable to communicate or move), spastic qua& riplegia, pseudobulbar palsy, and the imaging or postmortem findings of CPM.
282 The pathogenetic mechanism of CPM and extrapontine myelinolysis has not been fully elucidated. Norenberg et al. [ 14] postulated that a rapid rise in SNa results in endothelial osmotic injury and release of myelinotoxic factors. Stems et al. [6] proposed that the neurological syndrome results from CNS dehydration secondary to a rapid rise in serum osmolality in the presence of a normal or reduced brain water content. It has been suggested that many patients with CPM have actually suffered a hypoxic event as a complication of hyponatremia and have the delayed postanoxic encephalopathy (DPAE) syndrome [3, 15]. In DPAE, histological examination shows demyelinating lesions throughout the brain, and degeneration of the cerebral cortex may occur. Differences do exist in the clinical presentation of DPAE and CPM. In DPAE the clinical course is often characterized by initial coma, gradual recovery over a few days, and relapse of CNS symptomatology over the ensuing days to weeks. Cortical and motor dysfunction, seizures, and death may follow. Patients who develop DPAE usually experience clear-cut episodes of documented cerebral hypoxemia, including seizures and respiratory arrest. In CPM the myelinolysis is usually symmetrical and multifocal, while in DPAE myelinolysis is diffuse and often involves the hippocampus, axons, and neurons. Children may experience CPM. We have identified 37 cases (19 male, 16 female, 2 not reported from our institution) of CPM in individuals less than 21 years of age; 17 were less than 11 years old and only 1 case occurred in a child below 1 year of age. The majority had chronic underlying debilitating disorders often involving the liver. The SNa was low, normal, and high in 9, 5, and 3 children, respectively. In 4 of the 5 cases for which data were available, the children experienced rapid and large changes in SNa.
H y p o n a t r e m i a : to t r e a t o r n o t to t r e a t
It is clear that acute hyponatremia causes varying degrees of neurological dysfunction. Milder manifestations such as lethargy and confusion may rapidly progress to seizures, respiratory arrest, and brain stem herniation. Early recognition and rapid correction of severely decreased SNa in symptomatic patients by the administration of hypertonic saline has been considered important in reducing potential mortality and morbidity [5, 9, 16]. In a large series of adults, it has been shown that severe, sustained hyponatremia can be well tolerated with the prognosis being primarily dependent on the underlying disease entity associated with hyponatremia. Because the rapid correction of hyponatremia in such patients has been shown to result in the syndrome of osmotic demyelination [14, 17], many authors have warned against elevating SNa rapidly. Consequently, the management of severe hyponatremia poses a major dilemma for the clinician [14, 17]. The apparent discrepancies in clinical observations and management recommendations among various studies can be explained by the response of the CNS to its changing osmolal environment. Animal experiments have shown that when SNa is decreased acutely, brain water content
increases significantly with the development of seizures and coma [16, 18, 19]. Autopsy studies in fatal cases of acute water intoxication have shown cerebral edema with uncal and brain stem herniation [20]. Consequently, rapid correction of the SNa in acutely hyponatremic patients would be expected to decrease brain water and restore CNS function. Failure to do so may result in a catastrophic increase in brain volume, intracranial hypertension, and irreversible brain damage [5, 16]. With chronic hyponatremia, however, the brain water content tends to normalize with time. The increase in brain water content in hyponatremic rats is less than that predicted by the extent to which the ECF osmolality is decreased [18, 19]. The longer the hyponatremia is sustained, the less the increase in brain water. Total brain solutes diminish with time in this setting. A rapid loss of brain Na and potassium (K) is followed by delayed depletion of non-electrolyte solute - organic osmolytes - thus normalizing the brain water content in the face of sustained hyponatremia. In rats with hyponatremia of 3 days duration, the decrease in brain electrolytes (Na 18%, chloride 18%, and K 36%) accounted for 72% of the observed decrease in brain osmolality [21]. Decreases in organic osmolytes (decrease in brain concentration of myoinositol 41%, glycerophosphocholine 45%, phosphocreatinine/creatinine 60%, glutamine 45%, glutamate 53%, and taurine 37%) accounted for 23% of the decrease in osmolality. Only 5% of the decreased osmolality could not be determined. Multiple studies in dogs and rats have shown that rapid correction of sustained hyponatremia of at least 3 days duration with hypertonic saline results in severe neurological abnormalities and demyelinating lesions in the brain [18, 19, 22]. Experimentally, the effects on brain electrolytes and water of rapid and slow correction of hyponatremia differ [21]. Rapid, but not slow, correction with hypertonic saline leads to a transient overshoot of the concentration of brain Na and chloride and transient brain dehydration. The rate of reaccumulation of organic osmolytes does not differ when the SNa is increased rapidly or slowly. Although the concentration of most brain osmolytes returned to normal levels within 7 days, their rate of return differed. Only glycerophosphocholine and glutamate concentrations returned to normal levels. Clinical experience also suggests that the rapid correction of a chronically decreased SNa may result in marked neurological deterioration with CPM, extrapontine myelinolysis, or DPAE in patients who were previously asymptomatic [23, 24]. A rapid rise in SNa after CNS osmoregulatory mechanisms have already normalized brain water content may therefore be deleterious. In this context, correction of SNa at a rate greater than 0.5 mE@ per hour has been considered too rapid [10, 23]. The distinction between acute and chronic hyponatremia is arbitrary. Animal studies associating the duration of hyponatremia and its treatment with hypertonic saline resulting in encephalopathy require at least 3 days of hyponatremia before encephalopathy occurs. Additionally, because it is impossible to accurately determine the duration of hyponatremia in patients unless previous SNa determinations are available, human studies tend to focus on the
283 distinction between symptomatic and asymptomatic hyponatremia rather than emphasizing its duration. Symptomatic hyponatremia, which is likely to occur relatively acutely in a previously well patient or to occur acutely when the SNa falls further in chronically hyponatremic patients, is usually associated with increased brain water. A rapid increase in SNa in such patients results in normalization of brain water content and improvement in symptoms before depletion or further depletion of intracellular organic osmols occurs. Asymptomatic hyponatremia, on the other hand, is encountered when the CNS osmoregulatory mechanism has already reduced or normalized brain water content. In these situations, a rapid increase in SNa could lead to brain dehydration and osmotic demyelination. Virtually all clinical studies describing CPM after a rapid rise in SNa have described a setting of hyponatremia which has likely been present for at least a few days and often for many weeks.
Treatment of hyponatremia
Studies evaluating therapy for hyponatremia in children The number of studies in children examining the relationship between treatment for severe hyponatremia and outcome is limited. A study from our institution examined the relationship between the rate of initial increase in SNa in severe hyponatremia and clinical response in 69 episodes of hyponatremia in 60 children (mean age 23 months, range 3 weeks to 16 years) [25]. Forty-one children presented with seizures. SNa in those with and without seizures was similar at a level of 119 + 5 mmol/1. Causes of symptomatic hyponatremia included excessive water intake in 27, gastrointestinal losses in 6, Syndrome Inapprepinte - Anti-diuretic hormone release (SIADH) in 6, renal disease in 1, and unknown in 1. Twenty-five received an intravenous infusion of 4 - 6 ml/kg of 3% saline (514 mmol/1) over 10-15 min. Twenty-eight children were initially treated with benzodiazepine and/or phenobarbital with or without a subsequent similar bolus of 3% saline. Over the initial 4 h of therapy, those given hypertonic saline experienced a rise in SNa of 3.1+ 1.3 mmolB per hour compared with an increase of 1.7+1.2 mmol/1 per hour in the remaining patients (P 1 : 20
Surine volume Surine volume
60
>1
1,020
60
>1
PediatrNephrol(1992) 6: 280- 286 9 IPNA 1992
Practical pediatric nephrology Hyponatremia: pathophysiology and treatment, a pediatric perspective Alan B. Gruskin and Ashok Sarnaik Departmentof Pediatrics,Children'sHospitalof Michiganand WayneStateUniversitySchoolof Medichae, 3901 Beaubien,Boulevard,Detroit,MI 48 201, USA ReceivedDecember31, 1991;receivedin revisedformand acceptedJanuary2, 1992 Abstract. 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.
(CNS). Three factors related to the development and resolution of hyponatremia influence CNS function. They are the rate of change in SNa, the level of SNa, and the duration of the abnormal SNa. The gradual development of hyponatremia may not result in neurological dysfunction even at SNa levels below 110 mmol/1, and the prognosis in such cases depends upon associated medical conditions rather than hyponatremia itself [2, 3]. Conversely, relatively less severe hyponatremia may be associated with catastrophic CNS damage in situations where the decline in SNa is precipitous [3-5]. Finally, restoration of SNa levels either too slowly or too rapidly has significant implications for outcome.
Pathophysiological considerations Blood-brain barrier
Key words: Hyponatremia- Pathophysiology - Diagnosis - Treatment - Central nervous system- Osmoregulation Central pontine myelinolysis
Introduction Hyponatremia, which is one of the most frequently encountered electrolyte abnormalities in hospitalized patients, is mild and asymptomatic in most cases. An abnormally low serum sodium concentration (SNa) does not exist in isolation, but occurs in clinical settings where the accompanying total body water is either normal (isovolemic hyponatremia), excessive (hypervolemic hyponatremia), or decreased (hypovolemic hyponatremia) [1]. The more serious complications attributable to an abnormally low SNa involve the central nervous system
Correspondence to: A. B. Gruskin
The capillary endothelium which separates interstitial fluid (ISF) and plasma is freely permeable to water and electrolytes, whereas the cell membrane which separates the intracellular fluid (ICF) from extracellular fluid (ECF) is relatively impermeable to various solutes. When SNa decreases, both Na and water move freely across the capillary membrane to maintain osmotic equilibrium between plasma and ISF. At the level of the cell membrane in most organs, osmotic equilibrium is attained only by movement of interstitial water into the cell and the development of intracellular edema. The net size of the tissue does not change significantly as the increased cell size is compensated for by a decreased interstitial space. The CNS behaves differently because the blood-brain barrier (BBB) is composed of tight junctions between capillary endothelial cells and astrocytic end-feet processes. Most solutes, including Na, take several hours to equilibrate across the BBB between plasma and brain interstitium, whereas water moves rapidly in either direction. An osmolal gradient, therefore, has a significant and unique effect on total brain size that is not seen in other organs because the critical boundary impeding osmolar movement is the capillary en-
281
dothelium rather than the cell membrane. The intrinsic characteristics of the BBB causes the brain to respond to osmolal gradients as if it were a single cell [6]. When hyponatremia (hypo-osmolality) is present, osmotic equilibrium is achieved by the movement of water into brain interstitium as well as into the intracellular space resulting in a net increase in tissue size. Consequently, the brain, when compared with other organs, is more likely to experience a change in its total size in response to an acute change in plasma osmolality. It swells in response to decreased osmolality and shrinks when subjected to hyperosmolality.
Intracranial pressure-volume relationship The skull with fused sutures is a rigid container filled with fluid and solid tissues. Since intracranial contents are noncompressible, an increase in volume in any one compartment must be accompanied by an equal decrease in volume in other compartments in order for the intracranial pressure (tCP) to remain constant. When cerebral edema results from hyponatremia, the early ICP homeostatic mechanism consists of displacement of intracranial cerebrospinal fluid (CSF) into the distensible spinal subarachnoid space preventing a rise in ICP. Clinical signs of cerebral edema, such as altered consciousness and seizures, may occur before intracranial hypertension. Once maximal displacement of CSF has occurred, any further increase in cerebral edema results in an exponential increase in ICP with catastrophic consequences - brain stem herniation, apnea, and death. Compared with older children and adults, open fontanelles and unfused sutures offer young infants partial protection from a precipitous rise in ICP to life-threatening levels. Protection, however, is not absolute and serious disturbances in CNS function from acute hyponatremia can occur in any age-group.
CNS osmoregulatory mechanism The brain has adaptive mechanisms to defend its cellular volume in response to sustained alterations in ECF osmolality that are not found in many other organs. These osmoregulatory mechanisms allow the brain to normalize its water content when subjected to a changing osmolar environment. The time frame over which the brain water content is completely normalized is not established in humans. When an elevated ECF osmolality persists over 12-24 h, the brain generates additional osmols, commonly referred to as idiogenic osmols. The newly generated osmols allow the intracellular compartment to regain some of the water lost during the acute or persistent phase of hyperosmolality. Conversely, the brain can also lower its osmolar content in situations where the ECF osmolality is decreased for a period of time, thereby minimizing the gain in intracellular water. In acute hyponatremia the brain water content is increased whereas in chronic hyponatremia it tends to be normal.
CNS consequences of hyponatremia Hyponatremia and its treatment may result in brain injury by two distinct mechanisms: hypoxic encephalopathy and central pontine myelinolysis (CPM). A significant and precipitous decline in SNa can cause cerebral edema, brain stem herniation, and apnea. Severe hyponatremia of rapid onset can cause seizures, coma, respiratory arrest, and permanent brain damage [3, 5]. Histopathological findings in patients with acute hyponatremia and respiratory arrest are characteristic of cerebral hypoxia. Herniation of the brain stem into the foramen magnum, cerebral edema, and cortical necrosis with sparing of the white matter have been described in this setting. Acute hyponatremic encephalopathy is characterized by cerebral edema resulting from hyponatremia with subsequent intracranial hypertension, apnea, and cerebral hypoxia. An increase in brain volume of 5% can cause these problems [7]. Rapid correction of chronic hyponatremia has been associated with a distinct neurological syndrome termed central pontine myelinolysis (CPM) [8]. The clinical manifestations of CPM include: spastic quadriplegia, pseudobulbar palsy, a decreasing level of consciousness, and behavioral changes without focal findings [9, 10]. CPM, a descriptive term, is characterized by demyelination within the central portion of basal ports with sparing of both the axis cylinders and neurons. Foamy macrophages accumulate and oligodendroglia are diminished [8]. The lesion has been shown to be restricted to the pons alone. Similar changes have been observed in basal ganglia, corpus callosum, internal and external capsule, lateral geniculate nuclei, and thalamus. Originally recognized only at necropsy, the lesion can be recognized by computed tomography, magnetic resonance imaging, and brain stem auditory evoked potentials. In large series of general autopsies the incidence of CPM has ranged from 0.17% to 0.28%, and over 250 cases have been reported [11]. Because similar lesions have been observed in extrapontine regions where gray and white matter are closely associated, the term osmotic demyelination syndrome has been suggested as a better description of the lesion [6]. Extrapontine myelinolysis may also occur without involving the pons. Whether CPM occurs as a consequence of hyponatremia or its treatment has generated much controversy. CPM has been most frequently observed in patients with pre-existing medical conditions such as alcoholism, cirrhosis, increased ICP, malignancy, arteriosclerotic encephalopathy, acquired immunodeficiency syndrome, membranous nephritis, and other infections [12, 13]. A significant number of patients have had malnutrition and dehydration with and without accompanying electrolyte imbalance. Menstruating women appear to be at increased risk of developing CPM. These cfinical associations have cast doubt as to the causal relationship between CPM and hyponatremia or its treatment. Nonetheless, in certain patients rapid correction of hyponatremia is associated with neurological deterioration characterized by an altered level of consciousness, a "locked-in syndrome" (awake but unable to communicate or move), spastic qua& riplegia, pseudobulbar palsy, and the imaging or postmortem findings of CPM.
282 The pathogenetic mechanism of CPM and extrapontine myelinolysis has not been fully elucidated. Norenberg et al. [ 14] postulated that a rapid rise in SNa results in endothelial osmotic injury and release of myelinotoxic factors. Stems et al. [6] proposed that the neurological syndrome results from CNS dehydration secondary to a rapid rise in serum osmolality in the presence of a normal or reduced brain water content. It has been suggested that many patients with CPM have actually suffered a hypoxic event as a complication of hyponatremia and have the delayed postanoxic encephalopathy (DPAE) syndrome [3, 15]. In DPAE, histological examination shows demyelinating lesions throughout the brain, and degeneration of the cerebral cortex may occur. Differences do exist in the clinical presentation of DPAE and CPM. In DPAE the clinical course is often characterized by initial coma, gradual recovery over a few days, and relapse of CNS symptomatology over the ensuing days to weeks. Cortical and motor dysfunction, seizures, and death may follow. Patients who develop DPAE usually experience clear-cut episodes of documented cerebral hypoxemia, including seizures and respiratory arrest. In CPM the myelinolysis is usually symmetrical and multifocal, while in DPAE myelinolysis is diffuse and often involves the hippocampus, axons, and neurons. Children may experience CPM. We have identified 37 cases (19 male, 16 female, 2 not reported from our institution) of CPM in individuals less than 21 years of age; 17 were less than 11 years old and only 1 case occurred in a child below 1 year of age. The majority had chronic underlying debilitating disorders often involving the liver. The SNa was low, normal, and high in 9, 5, and 3 children, respectively. In 4 of the 5 cases for which data were available, the children experienced rapid and large changes in SNa.
H y p o n a t r e m i a : to t r e a t o r n o t to t r e a t
It is clear that acute hyponatremia causes varying degrees of neurological dysfunction. Milder manifestations such as lethargy and confusion may rapidly progress to seizures, respiratory arrest, and brain stem herniation. Early recognition and rapid correction of severely decreased SNa in symptomatic patients by the administration of hypertonic saline has been considered important in reducing potential mortality and morbidity [5, 9, 16]. In a large series of adults, it has been shown that severe, sustained hyponatremia can be well tolerated with the prognosis being primarily dependent on the underlying disease entity associated with hyponatremia. Because the rapid correction of hyponatremia in such patients has been shown to result in the syndrome of osmotic demyelination [14, 17], many authors have warned against elevating SNa rapidly. Consequently, the management of severe hyponatremia poses a major dilemma for the clinician [14, 17]. The apparent discrepancies in clinical observations and management recommendations among various studies can be explained by the response of the CNS to its changing osmolal environment. Animal experiments have shown that when SNa is decreased acutely, brain water content
increases significantly with the development of seizures and coma [16, 18, 19]. Autopsy studies in fatal cases of acute water intoxication have shown cerebral edema with uncal and brain stem herniation [20]. Consequently, rapid correction of the SNa in acutely hyponatremic patients would be expected to decrease brain water and restore CNS function. Failure to do so may result in a catastrophic increase in brain volume, intracranial hypertension, and irreversible brain damage [5, 16]. With chronic hyponatremia, however, the brain water content tends to normalize with time. The increase in brain water content in hyponatremic rats is less than that predicted by the extent to which the ECF osmolality is decreased [18, 19]. The longer the hyponatremia is sustained, the less the increase in brain water. Total brain solutes diminish with time in this setting. A rapid loss of brain Na and potassium (K) is followed by delayed depletion of non-electrolyte solute - organic osmolytes - thus normalizing the brain water content in the face of sustained hyponatremia. In rats with hyponatremia of 3 days duration, the decrease in brain electrolytes (Na 18%, chloride 18%, and K 36%) accounted for 72% of the observed decrease in brain osmolality [21]. Decreases in organic osmolytes (decrease in brain concentration of myoinositol 41%, glycerophosphocholine 45%, phosphocreatinine/creatinine 60%, glutamine 45%, glutamate 53%, and taurine 37%) accounted for 23% of the decrease in osmolality. Only 5% of the decreased osmolality could not be determined. Multiple studies in dogs and rats have shown that rapid correction of sustained hyponatremia of at least 3 days duration with hypertonic saline results in severe neurological abnormalities and demyelinating lesions in the brain [18, 19, 22]. Experimentally, the effects on brain electrolytes and water of rapid and slow correction of hyponatremia differ [21]. Rapid, but not slow, correction with hypertonic saline leads to a transient overshoot of the concentration of brain Na and chloride and transient brain dehydration. The rate of reaccumulation of organic osmolytes does not differ when the SNa is increased rapidly or slowly. Although the concentration of most brain osmolytes returned to normal levels within 7 days, their rate of return differed. Only glycerophosphocholine and glutamate concentrations returned to normal levels. Clinical experience also suggests that the rapid correction of a chronically decreased SNa may result in marked neurological deterioration with CPM, extrapontine myelinolysis, or DPAE in patients who were previously asymptomatic [23, 24]. A rapid rise in SNa after CNS osmoregulatory mechanisms have already normalized brain water content may therefore be deleterious. In this context, correction of SNa at a rate greater than 0.5 mE@ per hour has been considered too rapid [10, 23]. The distinction between acute and chronic hyponatremia is arbitrary. Animal studies associating the duration of hyponatremia and its treatment with hypertonic saline resulting in encephalopathy require at least 3 days of hyponatremia before encephalopathy occurs. Additionally, because it is impossible to accurately determine the duration of hyponatremia in patients unless previous SNa determinations are available, human studies tend to focus on the
283 distinction between symptomatic and asymptomatic hyponatremia rather than emphasizing its duration. Symptomatic hyponatremia, which is likely to occur relatively acutely in a previously well patient or to occur acutely when the SNa falls further in chronically hyponatremic patients, is usually associated with increased brain water. A rapid increase in SNa in such patients results in normalization of brain water content and improvement in symptoms before depletion or further depletion of intracellular organic osmols occurs. Asymptomatic hyponatremia, on the other hand, is encountered when the CNS osmoregulatory mechanism has already reduced or normalized brain water content. In these situations, a rapid increase in SNa could lead to brain dehydration and osmotic demyelination. Virtually all clinical studies describing CPM after a rapid rise in SNa have described a setting of hyponatremia which has likely been present for at least a few days and often for many weeks.
Treatment of hyponatremia
Studies evaluating therapy for hyponatremia in children The number of studies in children examining the relationship between treatment for severe hyponatremia and outcome is limited. A study from our institution examined the relationship between the rate of initial increase in SNa in severe hyponatremia and clinical response in 69 episodes of hyponatremia in 60 children (mean age 23 months, range 3 weeks to 16 years) [25]. Forty-one children presented with seizures. SNa in those with and without seizures was similar at a level of 119 + 5 mmol/1. Causes of symptomatic hyponatremia included excessive water intake in 27, gastrointestinal losses in 6, Syndrome Inapprepinte - Anti-diuretic hormone release (SIADH) in 6, renal disease in 1, and unknown in 1. Twenty-five received an intravenous infusion of 4 - 6 ml/kg of 3% saline (514 mmol/1) over 10-15 min. Twenty-eight children were initially treated with benzodiazepine and/or phenobarbital with or without a subsequent similar bolus of 3% saline. Over the initial 4 h of therapy, those given hypertonic saline experienced a rise in SNa of 3.1+ 1.3 mmolB per hour compared with an increase of 1.7+1.2 mmol/1 per hour in the remaining patients (P 1 : 20
Surine volume Surine volume
60
>1
1,020
60
>1
