Osmolality Disturbances
PHYSIOLOGIC CONSIDERATIONS
In normal individuals, the serum osmolality is virtually constant from day to day.
It is useful to define effective ECF osmolality, because the osmoregulatory mechanisms that adjust water balance in normal individuals are determined primarily by changes in cell volume that result from variations in effective ECF osmolality.
The serum osmolality can be approximated from the following formula: where the glucose and blood urea nitrogen (BUN) concentrations are expressed as milligrams per deciliter and the serum sodium concentration is expressed as milliequivalents per liter.
In normal circumstances, glucose contributes 5.5 mOsm/kg H2 O to the serum osmolality.
When hyperglycemia occurs, the effective ECF osmolality rises because glucose entry into cells is limited.
Cell Volume Regulation
Starling forces regulate fluid transfer between the ICF and the ECF.
Because plasma membranes the operational Starling forces between ICF and ECF are almost entirely osmotic.
Significant changes in cell volume, particularly in the CNS, are by themselves potentially lethal.
Thus the goals of fluid transport between the ECF and ICF are to maintain constancy of cell volume and to maintain a negligible hydrostatic pressure gradient between cells and the ECF.
Because most cell membranes are freely permeable to water, these two goals are achieved when the ECF osmolality is normal and intracellular and extracellular osmolalities are identical.
Because cell membranes are partially permeable to sodium and potassium, there is a tendency for sodium to leak into cells and for potassium to leak out of cells.
Specifically, both sodium leakage from the ECF into cells and potassium leakage out of cells into the ECF are counterbalanced exactly by active outward sodium transport coupled to active inward potassium transport.
These auxiliary mechanisms are particularly important in minimizing potentially lethal changes in brain volume because of osmotic water shifts into or out of brain cells.
In chronic hypotonic disorders, cell swelling is offset by the loss of potassium chloride from cells.
This potassium chloride efflux mechanism appears to be activated by small increases in cell volume produced by ECF dilution.
In chronic hypernatremia, brain shrinkage is minimized by the accumulation of additional solutes within brain cells.
These latter solutes, often called "idiogenic osmoles," include amino acids and other solutes, including myoinositol betaine, and urea.
Water Balance
The osmoreceptors, both for ADH release and for thirst, respond to small changes in effective ECF osmolality, whereas baroreceptors respond to changes in CBU.
As little as a 2% increase in effective ECF osmolality shrinks osmoreceptor cells and stimulates both ADH release from the posterior pituitary and thirst.
A second way of stimulating both ADH release and thirst involves volume-mediated stimuli that can operate independently of changes in plasma osmolality.
When the CBU is reduced by approximately 10%, these volume-dependent mechanisms stimulate ADH release.
SENSORS AND EFFECTORS.
Three kinds of sensor elements adjust water balance.
Two of these, osmoreceptors and the thirst center, respond to small changes in effective ECF osmolality, whereas baroreceptors respond to changes in CBU.
The osmoreceptors are situated in the supraoptic and paraventricular nuclei of the hypothalamus, whereas the thirst center is in the organum vasculosum of the anterior hypothalamus.
As little as a 2% increase in effective ECF osmolality produced by solutes such as sodium chloride, but not urea, shrinks osmoreceptor cells and thirst center cells.
The osmoreceptors stimulate the release of the effector hormone ADH from storage sites in the posterior pituitary gland.
The stimulation of thirst by the thirst centers depends on centrally produced angiotensin II.
Endothelin-1 is also released from the posterior pituitary in response to water deprivation.
Moreover, administered endothelin-1 increases plasma ADH levels.
Thus, endothelin-1 may have a central role in modulating ADH release.
When the CBU is reduced by more than 10%, volume-dependent blood produces afferent signals, carried by the ninth and tenth cranial nerves, which result in non-osmotic ADH release.
Volume contraction also acts as a potent stimulus to thirst by means of angiotensin II.
THE ANTIDIURETIC RESPONSE.
The cardinal characteristics of the antidiuretic response depend primarily on the integrated activity of two nephron regions: the medullary thick ascending limb of Henle, which concentrates the medullary interstitium, and the collecting duct, which, with ADH present, allows water reabsorption from this segment.
The medullary thick ascending limb absorbs much (possibly as much as 25%) of the filtered load of sodium.
Some of this reabsorbed sodium is trapped in the renal medullary interstitium, thus accounting largely for the hypertonicity of the renal medullary interstitium.
However, the medullary thick limb of Henle is also impermeable to water.
Consequently, salt abstraction from the thick limb of Henle accounts simultaneously for the development of medullary hypertonicity, thus permitting--in the presence of ADH--maximal antidiuresis, and the appearance of maximally dilute urine in early distal convolutions, thus permitting--in the absence of ADH--maximal water diuresis.
In normal individuals, approximately 18 L/d of tubular fluid reaches the early distal tubule; the osmolality of this fluid is quite dilute, approximately 50 mOsm/kg H2 O.
Thus, in the total absence of ADH and volume contraction, maximal rates of water diuresis include a urinary volume of 18 L/d having an osmolality of 50 mOsm/kg H2 O.
During antidiuresis, ADH increases the water permeability of collecting ducts .
Tubular fluid equilibrates osmotically with the hypertonic medullary interstitium, reducing urinary volume, concentrating the urine, and conserving body water.
When ADH is absent, the water permeability of collecting ducts is low, and absorption of tubular fluid is reduced, so it escapes unchanged as hypotonic urine.
Finally, because collecting ducts are partially permeable to water in the absence of ADH, a reduced volume of hypotonic fluid reaching collecting ducts equilibrates partially with the medullary interstitium, thereby limiting the ability to dilute urine maximally.
NEGATIVE FEEDBACK.
Water repletion activates a negative feedback of water conservation by at least two systems, atriopeptin and the oropharyngeal reflex.
Immunoreactive atriopeptin is released both within the CNS and by secretory granules in cardiac atria.
The centrally released atriopeptin can suppress by ADH release and thirst.
Oropharyngeal stimulation by water suppresses both ADH release and thirst before absorbing water or producing a fall in plasma osmolality.
This oropharyngeal reflex probably depends on neural traffic between the oropharynx and the CNS.
Finally, intrarenal prostaglandin E2 suppresses the effects of ADH on nephron segments.
Prostaglandin E2 is produced by renal interstitial cells in response to increases in medullary osmolality.
In turn, prostaglandin E2 impairs water conservation by inhibiting the actions of ADH on nephron segments involved in the antidiuretic response, namely, the medullary thick ascending limb and the collecting duct.
HYPOTONIC DISORDERS
DEFINITION.
In a hypotonic disorder, the ratio of solutes to water in body fluids is reduced, and the serum osmolality and serum sodium are both reduced in parallel.
True hypotonicity must be distinguished from disorders in which the measured serum sodium is low while the measured serum osmolality is either normal or increased.
The measured serum sodium concentration can be reduced either because there is an increased concentration of small, non-sodium solutes restricted to the ECF or because of a laboratory artifact.
In hyperglycemia or excessive mannitol administration, these solutes, which are restricted to the ECF, draw water from the cellular compartment.
The serum sodium level is therefore reduced, even though the serum osmolality may be increased.
When a small, non-sodium solute is distributed in total body water, as in ethanol intoxication or in azotemia, the serum osmolality rises but the serum sodium concentration remains normal, resulting in an "osmolar gap."
Instances of spurious hyponatremia due to hyperlipemia or hyperproteinemia are becoming less common as more laboratories use ion-selective electrodes to measure the serum sodium concentration.
ETIOLOGY AND PATHOGENESIS.
Hyponatremia and simultaneous body water hypotonicity develop whenever water intake exceeds the sum of renal plus extrarenal water losses; in chronic hyponatremia, the net water intake and net water output may be equal.
Thus, hyponatremia and body fluid hypotonicity occur when there is a
primary increase in water ingestion,
when the ability of the kidney to dilute urine maximally is limited
when a combination of these factors is operative.
The kidney regulates serum sodium concentration by increasing or decreasing free water excretion.
Free water is generated by the kidney across the diluting segments by absorbing salt without water.
Failure to generate free water occurs in those clinical circumstances in which less salt is delivered to the diluting segments.
Free water is absorbed in the collecting duct.
The rate of free water reabsorption is regulated in large part by ADH.
Thus, the higher the ADH concentration, the greater is the rate of free water reabsorption, assuming that other driving forces for water reabsorption remain constant.
Conditions with increased ADH concentrations are generally associated with hyponatremia.
The collecting duct can maintain large osmotic gradients; however, this capacity is limited, and the minimal osmolality of the urine is approximately 50 mOsm/kg H2 O.
If more dilute fluid is delivered to the collecting duct, this water will be reabsorbed even in the absence of ADH, as occurs in psychogenic polydipsia and in beer potomania.
REDUCED SOLUTE DELIVERY TO DISTAL NEPHRON SEGMENTS.
Decreased sodium delivery generally occurs in a setting of decreased effective arterial blood volume (e.g., congestive heart failure, hypoalbuminemic states, and decreases in systemic vascular resistance), as in sepsis and cirrhosis.
An example of decreased solute delivery to the collecting duct is beer potomania.
Without beer, a normal individual on a normal diet produces roughly 1000 mOsm of solute for urinary excretion.
Because maximally dilute urine is 50 mOsm/kg, each 50 mOsm of solute can capture no more than 1 L of free water.
Thus, on a normal diet, an individual can consume up to 20 L of fluid without becoming hyponatremic.
However, beer has a low concentration of salts and other solutes, except it has a relatively high carbohydrate content that prevents metabolic generation of solutes by preventing protein catabolism.
Indeed, it has been estimated that total urinary osmolal clearance is no more than 200 mOsm.
Thus, beer drinkers who get most of their calories from beer cannot drink more than 4 L of free water (most of which will be consumed as beer) without becoming hyponatremic.
Hyponatremia due to reduced solute intake is not restricted to individuals with beer potomania but may occur during starvation, when intake may be dramatically reduced without parallel reductions in water intake.
This form of hyponatremia occurs with increasing frequency in elderly patients in nursing homes who are inadequately supervised.
PRIMARY EFFECTOR ADH EXCESS.
In SIADH, hyponatremia occurs as a result of sustained endogenous production and release of ADH or ADH-like substances; the ECF volume is normal or increased, and there are no other physiologic or pharmacologic stimuli to ADH release.
About one third of patients with SIADH have a "reset osmostat"; there is an abnormally low threshold for ADH secretion, but if sufficiently hyponatremic, these patients with SIADH can produce a maximally dilute urine.
MAJOR CHARACTERISTICS OF SIADH
Hyponatremia
Volume expansion without edema
Natriuresis
Hypouricemia
Normal or reduced serum creatinine level
Normal thyroid and adrenal function
The cardinal results of the sustained water conservation in SIADH are twofold:
hyponatremia
volume expansion.generally gain about 3 kg in water weight or, in other words, nearly 10% of body water.
However, patients with SIADH, although volume expanded, do not develop edema and thus differ in that respect from patients with congestive heart failure or cirrhosis.
When total body water is expanded by about 10% by water conservation in SIADH, a natriuresis occurs even with hyponatremia.
Thus, the patient with SIADH reaches a steady state when body water is expanded by water retention and when natriuresis, even with hyponatremia, prevents edema formation.
The causes for the natriuresis that is characteristic of SIADH are multiple.
First, volume expansion will result in enhanced release of atriopeptin, which enhances urinary sodium wasting both by enhancing glomerular filtration and by suppressing tubular sodium absorption.
Second, the volume expansion of SIADH also reduces the rate of proximal tubular sodium absorption, as well as the rate of proximal uric acid absorption.
the urinary osmolality in patients with SIADH may be either inappropriately high for the level of serum osmolality or maximally dilute.
Other Causes of Excessive ADH Production and/or Release.
MIXED DISORDERS.
when filling of the arterial tree is impaired.
deranged Starling forces, notably local or systemic increases in venous pressure, which result in inadequate filling of the arterial tree.
In both sets of disorders, two factors contribute, individually or in unison, to the pathogenesis of hyponatremia:
non-osmotic, volume-mediated ADH release and
reductions in the rate of sodium delivery to the diluting segment.
CLINICAL MANIFESTATIONS.
Acute hyponatremia represents a medical emergency.
brain swelling
lethargy, weakness, and somnolence, which proceed rapidly to seizures, coma, and death as hyponatremia worsens.
Untreated nearly uniformly fatal
In chronic hyponatremia,
CNS manifestations are far less common
because the loss of brain solutes, principally potassium chloride, minimizes brain cell swelling for a given reduction in body water osmolality.
DIAGNOSIS
Hyponatremia should be considered whenever there is a
sudden deterioration in CNS function, particularly in circumstances such as
intractable heart failure,
hepatic cirrhosis with ascites, or
when large volumes of intravenous fluids are administered.
This evaluation should include a careful history and physical examination; measurement of the serum creatinine, BUN, and electrolyte levels; measurement of the urinary sodium concentration, or the fractional excretion of sodium; measurement of serum and urinary osmolalities; and, when appropriate, evaluation of thyroid and adrenal function.
The history and physical examination are generally adequate for recognizing disorders such as
beer potomania or
compulsive water
for noting the ingestion of drugs that stimulate ADH release or enhance ADH action.
The presence of edema is characteristic of individuals in whom hyponatremia occurs because of a reduced effective arterial blood volume coupled to ECF volume expansion.
The most difficult differential diagnosis among hyponatremic disorders involves the distinction between patients who are modestly volume contracted and those who have SIADH.
In both circumstances, the serum sodium and the serum osmolality are reduced, whereas the urinary osmolality is inappropriately high with respect to the reduced serum osmolality.
Patients with SIADH are generally normovolemic or slightly volume expanded and therefore exhibit none of the signs of volume contraction.
DISTINGUISHING FEATURES OF APPROPRIATELY VERSUS INAPPROPRIATELY INCREASED ADH CONCENTRATIONS
The serum BUN and creatinine levels are normal, and the serum uric acid level is generally reduced.
The urinary sodium concentration is usually greater than 30 mEq/L, and the fractional excretion of sodium is greater than 1%.
Tests of adrenal function yield normal results
A useful diagnostic and therapeutic maneuver in this situation is to observe the results of water restriction.
When water intake is restricted to 600 to 800 mL/d, patients with SIADH exhibit a highly characteristic response: a 2- to 3-kg weight loss is accompanied by correction of hyponatremia and cessation of salt wasting, usually over 2 to 3 days.
If weight loss fails to correct both hyponatremia and urinary sodium wasting simultaneously, the diagnosis of SIADH is doubtful.
TREATMENT
Neurologic symptoms secondary to osmotic swelling of the brain are much more common when hyponatremia develops rapidly in menstruant women and prepubescent children (i.e., age, gender, and hormonal status of patients are important factors in predisposing to symptoms of hyponatremia), but the most severe neurologic complications of acute treatment of hyponatremia are more common if existing hyponatremia is of long standing and developed chronically.
The rate and magnitude of this correction can be considered conveniently as a two-step process: acute correction of symptomatic hyponatremia and chronic correction of asymptomatic or residual hyponatremia.
ACUTE CORRECTION OF HYPONATREMIA.requires immediate therapy.
Acute hyponatremia
serum sodium concentration less than 120 mEq/L
CNS manifestations
In volume-contracted states
raise the serum sodium concentration to levels of 120 to 125 mEq/L by administering 250 ml hypertonic 3 to 5% saline over 4 to 6 hours. .
Elevating serum sodium too quickly to values more than 125 mEq/L may be hazardous. Too-rapid hyponatremia correction may be associated with osmotic demyelination syndrome,
CHRONIC CORRECTION OF HYPONATREMIA.
Restrict electrolyte-free water intake.to less than 1 L/d, coupled with high dietary salt intake. If this cannot be accomplished
Alternative is to use normal saline in combination with a loop diuretic.
lithium carbonate or demeclocycline. block the effect of ADH at the level of the collecting duc