The human body tightly regulates blood volume and plasma osmolality as both are essential for normal cellular function. Blood volume is important because it is a determinant of effective tissue perfusion which is required to deliver oxygen and nutrients to and remove metabolic waste products from tissues.
The homeostatic mechanisms for controlling blood volume are focused on controlling sodium balance.
Hyponatremia is defined as serum sodium less than 135 mEq/L. Hyponatremia is the most common electrolyte abnormality encountered in clinical practice.
The Genesis of Osmosis
When a substance is dissolved in water, the concentration of water molecules in the solution is less than that in pure water, because the addition of solute to water results in a solution that occupies a greater volume than dose the water alone. If the solution is placed on one side of a membrane that is permeable to water but not to the solute, and an equal volume of water is placed on the other, water molecules diffuse down their concentration (chemical) gradient into the solution. This process – the diffusion of solvent molecules into a region in which the membrane is impermeable – is called osmosis.
The tendency for movement of solvent molecules to a region of greater solute concentration can be prevented by applying pressure to the more concentrated solution. The pressure necessary to prevent solvent migration is the osmotic pressure of the solution. Just like shown in picture below.
Sodium and Water Homeostasis
60% of total body water is located intracellularly, whereas 40% is contained in the extracellular space. Sodium and its accompanying anions, chloride and bicarbonate, comprise more than 90% of the total osmolality of the extracellular fluid (ECF), whereas intracellular osmolality is primarily dependent on the concentration of potassium and its accompanying anions (mostly organic and inorganic phosphates). Most cell membranes are freely permeable to water.
The process – the diffusion of solvent molecules into a region in which there is a higher concentration of a solute to which the membrane is impermeable – is called osmosis. The tendency for movement of solvent molecules to a region of greater solute concentration can be prevented by applying pressure to the more concentrated solution. The pressure nenessary to prevent solvent migration is the osmotic pressure of the solution.
However, the body fluids are not ideal solutions. Thus it is actually the effective concentration (activity) in the body fluids rather than the number of equivalents of an electrolyte in solution that determines its osmotic capacity. This is why, for example, 1 mmol of NaCl per liter in the body fluids contributes somewhat less than 2 mOsm of osmotically active particles per liter. The more concentrated the solution, the greater the deviation from an ideal solution.
Solutes that cannot freely cross cell membranes are referred to as effective osmoles. The concentration of effective osmoles in the ECF determines the tonicity of the ECF, which directly affects the distribution of water between the extra– and intracellular compartments. Addition of an isotonic solution to the ECF will result in no change in intracellular volume since there will be no change in the effective osmolality of the ECF. Addition of a hypertonic solution to the ECF, however, will result in a decrease in cell volume, whereas addition of a hypotonic solution to the ECF will result in an increase in cell volume. Generally, the plasma osmolality can be estimated as:
Sosm = (2 x SNa) + (Bglucose/18) + (BUN/2.8)
The volume of the ECF is determined primarily by the total amount of osmotically active solute in the ECF (sodium, chloride, and bicarbonate). Generally the amount of sodium in the ECF is the most important determinant of ECF volume.
The regular of extracellular fluids is based on vasopressin (ADH) and renin-angiotensin system. The detail regulation mechanisms of ADH and RAS can be found here (http://www.tomhsiung.com/wordpress/2014/03/the-regular-of-extracellular-fluids-adh-secretion-and-renin-angiotensin-system/).
Hyponatremia can be associated with normal, increased, or decreased plasma osmolality. Hyponatremia in patient with normal serum osmolality can be caused by hyperlipidemia or hyperproteinemia. Historically this form of hyponatremia is termed pseudohyponatremia since it cause is the method of serum sodium concentration measurement, which is a laboratory artifact and is uncommon today.
Hyponatremia associated with increased serum osmolality, termed hypertonic hyponatremia, suggests the presence of excess, nonsodium-effective osmoles in the ECF. This is most frequently encountered in patients with hyperglycemia. Elevated concentrations of glucose provide effective plasma osmoles, resulting in diffusion of water from the cells into the extracellular compartment thereby expanding the ECF, which results in decrease in the serum sodium concentraion. For every 100 mg/dL increase in the serum glucose concentration, the serum sodium level decreases by 1.7 mEq/L, and the serum osmolality increases by 2 mOsm/kg.
Hyponatremia associated with decreased plasma osmolality is the most common forum of hyponatremia. Hypotonic hyponatremia can be divided into three categories: hypotonic hyponatremia with, decreased, increased, or normal ECF volume.
Hypovolemic Hypotonic Hyponatremia
Most patients with ECF volume contraction lose fluids that are hypotonic relative to plasma and thus can be transiently hypernatremiac. This includes patients with fluid losses caused by diarrhea, excessive sweating, and diuretics. This transient hypernatremic hyperosmolality results in osmotic release of AVP and stimulation of thirst (also you can find detail information about regulation mechahnisms of ADH in the post I have mentioned above earlier). If sodium and water losses continue, more AVP is released as a result of hypovolemia. Patients who drink water or who are given hypotonic fluids intravenously retain water and develop hyponatremia. These patients typically have a urine osmolality greater than 450 mOsm/kg, reflecting the presence of AVP and formation of a concentrated urine. The urine sodium concentration is <20 mEq/L when sodium losses are extrarenal (the decreased effective circulatory volume enhances the reabsorption of sodium in kidneys), as in patients with diarrhea, and >20 mEq/L in patients with renal sodium losses, as occurs in the setting of diuretic use or adrenal insufficiency.
Second, the decreased effective circulating volume due to lose of ECF fluids stimulates the release of AVP.
Hypotonic hyponatremia is relatively common in patients taking thiazide diuretics (but infrequently with loop diuretics since less AVP-induced water reabsorption by disturbing countercurrent mechanism). Thiazide-induced hyponatremia is usually mild, but can occasionally be severe and symptomatic. The pathophysiology is as the same as I have described above (decrease effective circulating volume). It typically develops within 2 weeks of the initiation of therapy, but can occur late in therapy, particularly if there has been a recent increase in the diuretic dose or other causes of hyponatremia develop.
Euvolemic Hypotonic Hyponatremia
Euvolemic hypotonic hyponatremia is associated with a normal or slightly decreased ECF sodium content and increased total body water and ECF volume. The increase in ECF volume is usually not sufficient to cause peripheral or pulmonary edema, and thus patients appear clinically euvolemic.
Euvolemic hyponatremia is most commonly the result of SIADH release (syndrome of inappropriate antidiuretic hormone secretion), which abnormal increased release of AVP causes excessive water reabsorption in kidneys. Urine is concentrated with urin sodium usually greater than 20 mEq/L.
Hypervolemic Hypotonic Hyponatremia
Hyponatremia associated with an increase in ECF (different with euvolemic hypotonic hyponatremia which is associated with increased total body water and ECF volume but not sufficient to cause peripheral or pulmonary edema) occurs in conditions in which renal sodium and water excretion are impaired. Hypervolemic status is caused by cirrhosis, congestive heart failure, or nephrotic syndrome. But these disease status also cause decreased effective circulating volume (low perphieral perfusion), which stimulates the release of AVP.
The Management of Hypotonic Hyponatremia
Before make correction of hypotonic hyponatremia one should balancing the risks of the hyponatremia versus the risk of osmotic demyelination syndrome. In general, patients who acutely developed moderate to severe hyponatremia and/or patients who have severe symptoms are at greatest risk and potentially benefit most from more rapid correction of their hyponatremia.
The management of hypotonic hyponatremia consists of acute or severe symptomatic hypotonic hyponatremia, and nonemergent hypotonic hyponatremia. Here we just discuss acute or severe symptomatic hypotonic hyponatremia.
First it is important to treat the underlying cause of hyponatremia.
For all hypovolemic hypotonic hyponatremia, the goal of treating patients is to resolve the underlying cause of the sodium and ECF deficits, and safely correct the hyponatremia.
For all hypervolemic and euvolemic hypotonic patients the goal of treatment depends on the underlying cause of the hyponatremia and the severity of the patient’s symptoms.
For acute or severe symptomatic hypotonic hyponatremia the goal is to correct the hypotonicity with aggressive therapy enough to control the symptoms.
Here we discuss a little about the brain’s compensation to hypotonic hyponatremia. The presence of the neurologic symptoms and their severity depend on both the magnitude of the hyponatremia and the rate at which the hyponatremia developed. The magnitude of hyponatremia is directly associated with the water movement into brian cells increasing as serum osmolality decreases. The rate of osmolality change is also important because brain cells are able to adjust their intracellular osmolality to minimize cellular volume changes in response to volume changes, but time is required for this adaptation to occur.
When a decline in plasma osmolality causes movement of water into brain cells, sodium, potassium, and organic osmolytes move out of the cells to decrease intracellular osmolality and minimize intracellular water movement. But this compensatory mechanism takes time and maximal compensation for a decrease in plasma osmolality typically requires up to 48 hours. Thus acute changes in plasma osmolality are not compensated for instantaneously and are more likely to be associated with symptoms.
Attention must be paid to that in all cases one should avoid an increase in the serum sodiuim concentration of more than 12 mEq/L in 24 hours.
If the serum sodium is observed to be increasing at a rate greater than 12 mEq/L per day, the infusate should be changed to 0.45% sodium chloride, and the infusion rate set to one that approximates urine output to slow the rate of increase in the serum sodium concentration.
A patient who has or is at high risk of experiencing severe symptoms caused by hypotonic hyponatremia should receive either 3% (513 mEq/L of sodium) or 0.9% (154 mEq/L of sodium) sodium chloride solution until severe symptoms resolve. Resolution of severe symptoms frequently requires only a small, 5% increase in serum sodium, although some suggest that the initial target should be to increase serum sodium to approximately 120 mEq/L.
To ensure the net effect of solute-free water excretion (ensure net increase in total effective osmoles) after the infusate the concentration of sodium in the infusate must exceed the sum of the sodium and potassium concentration in the urine.
For instance, patients with SIADH often have urinary concentrations of osmotically effective urine cations that exceed the sodium concentration of 0.9% sodium thus in this case we should give these patients 3% sodium chloride. However, when the urine osmolality exceeds 300 mOsm/kg, it is generally advisable to add an intravenous loop diuretic, not only to increase the excretion of solute-free water (since we use 3% NaCl the sodium concentration in the infusate is much higher than it would be expected in the urine after addition of loop diuretics), but also to prevent volume overload possibly resulting from infusion of hypertonic sodium chloride.
Patients with hypovolemic hypotonic hyponic hyponatremia can be treated with 0.9% sodium chloride. In contrast to patients with SIADH, patients with this condition avidly reabsorb sodium throughout the nephron when the effective circulating blood volume is decreased. Thus the urine osmolality is primarily comprised of urea, and the concentration of urine sodium is often less than 20 mEq/L, which is substantially less than the sodium concentration in 0.9% sodium chloride solution. Use of 3% sodium chloride solution will also effectively correct hyponatremia but its use should be reserved for situations requiring very rapid correction.
Once we decide to give infusate of 3% or 0.9% sodium chloride solution we should certain the right infusion regimen. There is a formula to estimate the change in SNa with 1 L of infusate.
Change in SNaith 1 L of infustate = [IVNa-S1Na] ÷ (BW + IVvol)
where S1Na = initial patient serum sodium concentration; IVNa = sodium concentration of infusate (154 mEq/L for 0.9% sodium chloride and 513 mEq/L for 3% sodium chloride); IVvol = 1 L of infusate; and BW= total body water.
Total boday water can be estimated as follows:
0.6 × body weight for children and men <70 years of age; 0.5 × body weight for men ≥70 years of age and females <70 years of age; and 0.45 body weight for women ≥70 years of age.
In the presence of symptoms, the serum sodium should be increased by approximately 1.5 mEq/L per hour over the first 2 to 4 hours or until symptoms have resolved. Thus for the first 2 to 4 hours the rate of infusion should be 114 ml per hour of 3% sodium chloride and then 23 to 31 ml per hour for the next 20 to 22 hours respectively.
Evaluation of Therapeutic Outcome
Patients with severely symptomatic hypotonic hyponatremia should be admitted to the intensive care unit or to a highly monitored setting for close monitoring of neurologic and volume status. Serial physical examinations of the heart, lungs, and neurologic status should be performed several times over the initial 12 hours of hospitalization. The serum sodium concentration should be measured every 2 to 4 hours, and the urine osmolality, sodium, and potassium should be measured every 4 to 6 hours over the first day of therapy. The rate of administration of the infusate should then be adjust to avoid exceeding a rise in the serum sodium greater than 12 mEq/L per 24 hours.