The central nervous system has an important role in maintaining the sodium (salt) and water balance of the body. In some cases , drugs used to reduce cerebral edema in the treatment of brain damage may also disrupt the sodium and water balance. As a result of this deterioration, a disease called hyponatremia may occur. Sodium disorders can have serious consequences, including death. To reduce this risk, a systematic approach in diagnosis and treatment is very important.
How to Maintain Water and Salt Balance in Our Body?
Sodium is the major cation (positively charged ion) found outside the cell and the most important osmotically active solution. While the concentration difference of sodium between the intracellular and extracellular environment is controlled by the sodium-potassium ATPase pump, the total amount of sodium in the body is regulated by the mechanism of excretion from the kidneys. In the kidneys, sodium is freely filtered from the glomerulus, but most is reabsorbed from the proximal tubule. Reabsorption is controlled by sympathetic nerves, atrial (ANP) and brain (BNP) natriuretic peptide. ANP and BNP increase urinary sodium excretion (natriuresis) by inhibiting sodium transport through the medullary collecting duct, increasing glomerular filtration rate, suppressing renin and aldosterone release. C-type and dendroaspis natriuretic (DNP) peptides have also been shown to have a role in sodium regulation.
Since the main determinant of serum osmolality is sodium concentration, sodium is largely responsible for the regulation and distribution of total body water. Essentially, total body water is controlled by adjusting the water to maintain tonicity as a result of the manipulation of sodium in the kidneys. Sodium and water balance is regulated by serum osmolality and intravascular volume and pressure parameters.
If an increase in the osmolality of the extracellular fluid is detected by the receptors in the hypothalamus, there is an increase in the synthesis of antidiuretic hormone (ADH) from the supraoptic and paraventricular nuclei. ADH is then transported to the posterior lobe of the pituitary gland and released from there. Accordingly, water is reabsorbed from the distal tubule and collecting ducts in the kidney, and urine concentration increases.
A serum osmolality of around 280 mOsm/kg stimulates the release of ADH and around 295 mOsm/kg, the feeling of thirst is stimulated and water intake increases in conscious individuals. ADH is also released as a result of a decrease in intravascular volume and arterial pressure as detected by low pressure baroreceptors in the right atrium and great veins and high pressure baroreceptors in the carotid sinus. Hypovolemia and hypotension also provide activation of the renin-angiotensin-aldosterone system with an increase in sympathetic activity.
Sodium imbalance is a common problem in hospitalized patients. This is even more common in people with brain damage. The signs and symptoms depend not only on the degree of sodium disorder, but also on the rate at which the serum sodium concentration changes. Normally, plasma sodium is 135-145 mmol/liter and plasma osmolality is 285-295 mOsm/kg.
Hyponatremia – Low Salt
Hyponatremia was defined as a serum sodium concentration of less than 135 mmol/liter. It is a problem seen in 15% of hospitalized patients. It can develop 2-7 days after the injury in people who have suffered a brain injury and are in critical condition. It has been associated with an increase in mortality of up to 60%.
Hyponatremia is usually associated with hypotonicity, but may rarely occur in isotonic or hypertonic conditions. Hypotonic hyponatremia causes water to enter the brain through the blood-brain barrier and cerebral edema may develop. The reason for the decrease in serum sodium can be determined according to the associated volume status.
Causes of Hyponatremia
Iatrogenic hyponatremia is not uncommon and is usually the result of inappropriate administration of hypotonic fluids during periods of elevated ADH levels as part of the post-operative stress response. However, after brain injury, hyponatremia most commonly develops due to inappropriate ADH release or cerebral salt wasting syndrome.
The cause of hyponatremia should be identified and treated. In patients with brain damage, supportive treatment may be sufficient if they are asymptomatic, and sodium disorders are often transient and self-limiting. In acute symptomatic hyponatremia, treatment should be started quickly to reduce the risk of neurological complications and side effects. However, correction of hyponatremia may also cause neurological damage, especially central pontine myelinolysis. These risks are minimized by the gradual correction of the sodium deficit. In most cases, serum sodium should not be increased faster than 0.5 mmol/liter per hour or 8-10 mmol/liter per day. The treatment goal should focus on relieving the symptoms of hyponatremia, not on achieving an arbitrary serum sodium concentration target.
Syndrome of Inappropriate Antidiuretic Hormone (IADHS)
The most common neurological causes of inappropriate ADH syndrome are subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), brain tumor, and meningitis/encephalitis. Drug-related hyponatremia may also develop. In this respect, attention should be paid to anti-epileptic drugs, especially carbamazepine.
In IADHS, the thirst threshold is lowered. Control over ADH release is lost and plasma ADH concentration is not affected by continuous fluid intake or osmotic stimulation. Although concentrated urine is produced in small volumes, the ADH concentration remains inappropriately high.
Absence of dehydration in the diagnosis of SADHS is the key to distinguish it from cerebral salt wasting. It is very important to distinguish these two problems because their treatments are contradictory. IADHS diagnostic criteria:
- Hypotonic hyponatremia (serum sodium < 135 mmol/liter and serum osmolality < 280 mOsm/kg)
- İdrar osmolalitesi > serum osmolalitesi
- Urine sodium concentration > 18 mmol/liter
- Thyroid, adrenal and renal function are normal.
- Clinical euvolemia – no peripheral edema or dehydration
SIADH is often a self-limiting disease after brain injury and treatment should be initiated if the patient is symptomatic, when serum sodium is markedly low or falling rapidly. Initially, electrolyte-free fluid restriction of 800-1000 ml/day constitutes the main treatment and generally provides a slow rise in serum sodium of 1.5 mmol/liter/day. However, this degree of fluid restriction can be difficult, disturbing in conscious patients, worsening cardiopulmonary instability, and increasing the risk of cerebral ischemia in critically ill patients. The use of hypertonic saline (1.8%) should be limited to severe symptomatic acute hyponatremia in the treatment of inappropriate ADH syndrome. This treatment is given especially in subarachnoid hemorrhage where fluid restriction is contraindicated.
If the diagnosis of SIADH is definite, there is also the option of pharmacological treatment. Different drugs may act through different mechanisms.
Specific Treatment and Water Expulsion
Furosemide and other diuretics increase water excretion. Simultaneous saline or salt supplementation should be given to compensate for sodium loss.
The renal response of ADH can be inhibited by demeclocycline or lithium. Demeclocycline is less toxic and the starting dose of 900-1200 mg/day should be reduced to 600-900 mg/day when therapeutic effect is achieved. The therapeutic effect is usually achieved between 3 days and 3 weeks after the start of treatment.
ADH-receptor antagonists (conivaptan, lixivaptan) prevent ADH from binding to renal receptors. In small clinical studies, they have been shown to be effective by inducing aquaresis (electrolyte removal of free water).
Cerebral Salt Loss Syndrome (STKS)
STKS is a central nervous system-related problem characterized by the loss of sodium from the kidneys and consequently polyuria, natriuresis, hyponatremia, and hypovolemia. It is most commonly associated with subarachnoid hemorrhage and traumatic brain injury, but can also be seen in brain tumor, ischemic stroke, and tuberculous meningitis. It usually occurs in the first week after brain injury and resolves spontaneously within 2-4 weeks.
The pathophysiology of STKS is not clearly understood, but elevated ANP and BNP levels may play a role in natriuresis and hyponatremia, especially after SAH. In addition, an increase in sympathetic activity can lead to an increase in renal perfusion pressure and associated natriuresis.
Diagnosis in Cerebral Salt Loss Syndrome (STKS)
Biochemical criteria for diagnosis are low or normal serum sodium, high or normal serum osmolality, high or normal urine osmolality, elevation of hematocrit, urea, bicarbonate, and albumin as a result of hypovolemia. However, these criteria often do not make a definitive diagnosis. Total daily urine output is greater than intake in STKS and equal to intake in UADS. Total sodium balance is negative in STKS and neutral in SIADH.
Diagnosis is made by careful clinical evaluation in addition to biochemical examination. The most important clinical feature is volume loss in STKS. In this respect, daily weight monitoring and examination of mucous membranes should be done; skin turgor, capillary refill time, jugular vein pressure, and cardiovascular parameters should be evaluated. Monitoring the fluids he takes in and out can also indicate a total negative balance.
Clinical assessment of volume status can be difficult. Hypovolemia may be seen in some patients who meet the diagnostic criteria for SIADH. The reason for this may be that the volume loss in STKS can cause a secondary increase in ADH. In such a case, the correct diagnosis should be STKS, not UADH.
The primary treatment for STKS is volume and sodium resuscitation, but the use of saline solution is controversial. As a general rule, 0.9% saline is indicated in the initial situation, but hypertonic (1.8%-3%) saline is recommended in acute symptomatic hyponatremia. Concomitant furosemide can also be administered to reduce the risk of cardiovascular overload. However, in some patients with STKS, sodium administration may increase natriuresis and associated water loss and worsen the clinical condition. Once normovolaemia and normonatremia are restored, continued losses should be replaced with either iv saline or water and sodium tablets until STKS resolves. Fluid balance, serum sodium concentration, and total sodium balance should continue to be monitored throughout this period.
In some cases, STKS may be resistant to standard treatment. Fludrocortisone 0.1-0.4 mg daily can limit sodium loss by increasing sodium reabsorption from the renal tubule. Serum potassium should be closely monitored, as this treatment may lead to hyperkalemia.
Hypernatremia is defined as serum sodium greater than 145 mmol/liter. It is less common than hyponatremia. Its incidence in hospitalized patients is around 1%. The frequency increases to 9% in those hospitalized in the intensive care unit. It is more common in patients with brain damage and is a marker for the severity of the underlying disease.
Hypernatremia is usually associated with insufficient water intake or excessive water loss. Naidren are due to excessive salt intake. After brain injury, hypernatremia is most commonly associated with central diabetes insipidus (DI) or overuse of osmotic diuretics such as mannitol. Iatrogenic causes are relatively easy to recognize and respond to normalization of sodium intake. Nephrogenic DI can also cause hypernatremia in hospitalized persons.
Diabetes insipidus may occur in association with traumatic brain injury, SAH, intracerebral hemorrhage, and pituitary surgery. The incidence of DI after traumatic brain injury is as high as 35%; associated with more severe morbidity and increased mortality. DI developing for reasons other than pituitary surgery is usually associated with severe, fatal cerebral edema. DI is a common finding in brain stem death.
DI is associated with failure of ADH release from the hypothalamic-pituitary axis. The inability to concentrate the urine results in the formation of high volumes of dilute urine. Inappropriate water loss leads to increased serum sodium and osmolality, leading to a clinical state of dehydration.
Damage to the level of the hypothalamus above the median eminence region can cause permanent DI, while damage to the hypothalamus below this level and disorders in the posterior lobe of the pituitary can cause transient DI. The reason for the temporary deficiency of inferior injuries is that the nerve endings in the median eminence can secrete ADH after a while. This difference explains why DI is permanent in some patients and temporary in others.
In conscious patients, the classic symptoms of excessive drinking (polydipsia), excessive urination (polyuria) and thirst make the diagnosis of DI easier. Hyperglycemia should be differentiated as it can cause similar symptoms. It is also important to distinguish hypovolemic hyponatremia due to water loss (dehydration or DI) from the less common hypervolemic hypernatremia associated with excess sodium intake. Clinical examination is helpful in this respect. Then, simple dehydration must be distinguished from DI. It should be kept in mind that the feeling of thirst is often absent in patients with brain damage and is an unreliable symptom. If there is no renal failure in dehydration, low urine volume is seen, whereas urine output is high in DI; often exceeds 6 liters per day. Other possible causes of high urine volume should also be reviewed.
Diagnosis and Urine
High urine output and serum sodium as well as urine density below 1.005 support DI.
Increased urine volume (above 3000 ml in 24 hours), high serum sodium (above 145 mmol/liter), high serum osmolality (above 305 mmol/kg), and abnormally low urine osmolality (below 350 mmol/kg) are in the diagnosis of DI. are the criteria used.
Measurement of plasma ADH concentration can be used to distinguish between nephrogenic and central DI. Confirmation of the diagnosis is based on observation of the response to synthetic ADH.
The DI method has two main purposes: supplementation and retention of water and supplementation of ADH. Conscious patients can increase their water intake on their own and this may be an adequate treatment if DI is temporary. In unconscious patients, fluid supplementation can be done with water through the nasogastric tube or with iv 5% dextrose. Giving excess fluid in unconscious patients can be risky, so the volume status should be evaluated correctly. If urine output is above 250 ml per hour, synthetic ADH should be given. 1-deamino-8-D-arginine vasopressin can be given in small doses intranasally (100-200 micrograms) or iv (0.4 micrograms). Small doses are preferred to avoid excessive or prolonged effect and to achieve the desired clinical effect.
Rapid correction of hypernatremia may cause serious side effects such as pulmonary and cerebral edema. In general, serum sodium should not be reduced faster than 10 mmol/liter/day. However, in patients whose hypernatremia has developed within a few hours, faster correction may be safe.