SA, a 31-year-old man, was brought to the emergency department by paramedics after being found unresponsive near his home. A computed tomographic scan of his head revealed a large left-sided subdural hematoma. SA was taken emergently to the operating room for a craniectomy and clot evacuation. After surgery, he was transferred to the trauma/neurosurgical intensive care unit for management of increased intracranial pressure.
GF, a 43-year-old woman, was brought to the hospital with a severe headache. A computed tomographic scan showed subarachnoid blood, and a cerebral angiogram revealed a ruptured basilar tip aneurysm. Neurosurgeons successfully performed a coil embolization, and GF was transferred to the intensive care unit for frequent monitoring of her neurological status. Although initially alert, 2 days postoperatively she was confused, difficult to arouse, and exhibited a variety of cardiac dysrhythmias.
While driving unrestrained, 24-year-old HM was involved in a high-speed, head-on motor vehicle crash. He was subsequently airlifted to a level I trauma center. The flight crew noted that HM's belly was firm and distended, his pelvis was unstable, and he had an obvious open fracture of the femur. After 3 L of intravenous crystalloids had been administered en route, HM arrived in the emergency department cool, pale, and hypotensive.
Despite their varied clinical manifestations, each patient was treated with an infusion of hypertonic saline at some point during his or her stay in the intensive care unit.
As the most abundant extracellular electrolyte, sodium is essential for the functioning of all body systems. Hypertonic saline is administered for a wide variety of conditions, and this multitude of indications can sometimes seem confusing. What is the physiology of sodium chloride in the body? When is therapy with hypertonic saline clinically warranted? Also, what are the practice implications of administration of hypertonic saline?
Role of Sodium Chloride in the Body
With a normal serum level of 135 to 145 mmol/L, (1) sodium is the most abundant extracellular ion and plays an important role in controlling fluid and electrolyte balance. Sodium is the only cation that exerts significant osmotic pressure; where sodium goes, water quickly follows. Therefore, sodium is inseparably linked to both blood volume and blood pressure. The kidneys are responsible for regulating electrolyte loss, and approximately 90% of the sodium contained in renal filtrate gets reabsorbed in the proximal tubules and loops of Henle. (2)
Management of sodium balance also involves a variety of neural and hormonal controls, and a brief review of the renin-angiotensin-aldosterone system is necessary for understanding sodium regulation. Stimulation of the sympathetic nervous system, decreased blood pressure, and increased renal filtrate osmolarity all cause the juxtaglomerular apparatus of the kidney to respond by releasing renin (Figure 1). Renin, through a series of reactions, produces angiotensin II, which in turn prompts aldosterone release. Then, when sympathetic nervous system activity decreases, blood pressure rises, or filtrate osmolarity drops, juxtaglomerular apparatus stimulation of the renin-angiotensin-aldosterone system ceases. (3,4)
Aldosterone, a mineralocorticoid released from the adrenal cortical cells, is the hormone with the greatest influence on the renal regulation of sodium. The primary job of the hormone is to maintain sodium ion balance. Secretion of aldosterone occurs via several mechanisms. Decreases in blood volume, blood pressure, and serum sodium concentrations and high serum levels of potassium all stimulate production of aldosterone. When the aldosterone level is elevated, sodium is reabsorbed in the distal convoluted tubules and collecting ducts. (5) If the permeability of the tubules has been increased by antidiuretic hormone (ADH), water is also reabsorbed. Therefore, secretion of aldosterone promotes retention of both sodium and water. When aldosterone levels decrease, virtually no sodium reabsorption occurs beyond the loops of Henle. (6) Nearly sodium-free urine can be eliminated, as needed, to achieve water balance. In addition to the mineralocorticoids, the glucocorticoids have aldosterone-like effects. Tubular reabsorption of sodium is also enhanced when glucocorticoid levels are high. (5)
[FIGURE 1 OMITTED]
ADH has an important, albeit indirect, influence on sodium levels. ADH increases permeability of the distal renal tubules and collecting ducts, promoting water reabsorption by the circulation. (2) The dilutional effect of this water on the blood causes serum levels of sodium to decrease. Osmoreceptors in the hypothalamus respond to this decrease in sodium ion concentration by inhibiting further ADH secretion from the posterior lobe of the pituitary gland. A decrease in serum ADH level permits more water to be excreted in the urine, thus restoring normal plasma sodium balance. (6)
Atrial natriuretic factor, released from certain cells of the atria when the cells are stretched, has potent diuretic and natriuretic effects. Atrial natriuretic factor inhibits the ability of the renal tubules to reabsorb sodium. Its overall influence is to decrease blood pressure by allowing sodium (and thus water) to flow out of the body in the urine. Atrial natriuretic factor also blocks the secretion of ADH, renin, and aldosterone. (1,7)
In addition, female sex hormones play a role in maintaining sodium balance. Estrogens enhance reabsorption of sodium by the renal tubules, promoting water retention, explaining why some women experience a bloating sensation when estrogen levels are high. Progesterone, on the other hand, decreases sodium reabsorption and also blocks the effect of aldosterone, promoting sodium and water loss through diuresis. (8)
Finally, the cardiovascular system contains baroreceptors in the aorta and carotid arteries that play an indirect role in sodium homeostasis by alerting the hypothalamus to blood volume status. When signaled that blood pressure is adequate or increasing, the hypothalamus immediately stops transmitting impulses from the sympathetic nervous system to the kidneys, promoting renal excretion of sodium and water. (9) Conversely, decreases in blood pressure trigger the hypothalamus to initiate stimulation of the kidneys via the sympathetic nervous system, activating the renin-angiotensin-aldosterone system, and thereby increasing sodium and water retention. (3,5)
Clinical Indications for Sodium Therapy
Historically, oral sodium chloride has been prescribed for an assortment of conditions, including prevention of heat-related disorders, (10) treatment of orthostatic hypotension related to certain antidepressant medications, (11) and chronic sodium loss in patients with cystic fibrosis (12) (Table 1).
Occasionally, critical care nurses may see a variety of miscellaneous uses for parenteral hypertonic saline therapy. High concentrations of sodium chloride (20%-23.4%) can be injected directly into a vein for sclerotherapy of varices. (13) Some researchers found that administering hypertonic saline (7.5% sodium chloride) with dextran immediately after coronary artery bypass surgery led to improvement in postoperative cardiorespiratory function as a result of ability the solution to move excess interstitial fluid into the vascular space for elimination in the urine. (14)
Parenteral hypertonic saline has several indications for situations outside critical care. A 7% sodium chloride solution can be infused directly into cutaneous lesions to kill parasites in patients with leishmaniasis (15) and intra-amniotically injected solutions of 20% sodium chloride solution have been used to induce midtrimester abortion. (16)
Current Indications in Critical Care
Currently, there are 3 primary indications for the use of hypertonic saline in critically ill patients: hyponatremic states, volume resuscitation in shock, and brain injury.
Miscellaneous Causes Many conditions involve low serum levels of sodium, but treatment generally does not require the administration of hypertonic saline. These include psychogenic polydipsia (therapy involves limiting free water consumption), (17) hyponatremia due to use of diuretics (withhold further administration the diuretics), third-space sequestration (mobilize the fluid), (18) Addison disease (give corticosteroids), (19) and diabetic ketoacidosis (correct the acidosis). Excess loss of gastrointestinal secretions, related to severe vomiting, diarrhea, or continuous suction, can also cause hyponatremia. Treatment entails minimizing further losses of gastrointestinal secretions. (20) Hyponatremia in patients with late-stage cirrhosis, congestive heart failure, or renal disease is usually associated with a poor prognosis. (20)
Although hypertonic saline is rarely indicated for the low sodium states just mentioned, intravenous hypertonic saline may be administered for certain endocrine-mediated hyponatremic disorders, including syndrome of inappropriate antidiuretic hormone (SIADH) release and cerebral salt-wasting (CSW) syndrome. (21)
SIADH SIADH is a common cause of serious hyponatremia in critically ill patients. This syndrome occurs when a drug, tumor, brain surgery, subarachnoid hemorrhage, head injury, or other disorder stimulates the pituitary gland to increase secretion of ADH, leading to renal conservation of water and dilutional hyponatremia. (22) Certain carcinomas, most notably malignant oat cell carcinomas of the lung, can synthesize and release ADH from the tumor site, a situation that can also lead to SIADH. (8)
CSW Syndrome Unlike SIADH, which involves the retention of water, CSW syndrome is due to a direct loss of sodium. (23) To date, the mechanism by which CSW occurs is unclear, but the syndrome has been a topic of interest in the neurosurgical literature for about 50 years. CSW is defined as "the renal loss of sodium during intracranial disease leading to hyponatremia and a decrease in extracellular fluid volume." (23) Many of the same patients who have SIADH develop (eg, patients with intracranial tumors, head injury, infections, stroke, and subarachnoid hemorrhage) are also at risk for CSW syndrome. Hyponatremia in these patients must first be categorized as either SIADH or CSW syndrome before therapy is started. (23)
Treatment of Significant Hyponatremia
Clinical manifestations of significant hyponatremia are largely a consequence of brain edema and include decreased mentation, increased intracranial pressure, seizures, and coma. Severe cases can also precipitate disturbances in cardiac rhythm. (8,23) Although treatment for SIADH consists primarily of restriction of the intake of free water, interventions for CSW syndrome include both water and salt replacement. (23) Care of patients with either SIADH or CSW syndrome begins with addressing the underlying abnormality, and patients with either of the syndromes require frequent monitoring of serum levels of sodium.
In cases of life-threatening hyponatremia, cautious administration of hypertonic saline is appropriate. Usually, intravenous infusion of a 3% to 5% solution of sodium chloride is used. (24) The optimal rate of sodium replacement is unclear, yet aggressive administration in patients with hyponatremia has been associated with rhabdomyolysis (25) and pontine myelinolysis. (23) Therefore, hypertonic saline must be administered slowly to prevent too rapid correction of hyponatremic states. Some investigators (8,26) recommend that in patients with severe hyponatremia, serum levels of sodium should be increased no more than 10 to 20 mmol/L daily. Such increases can be accomplished by cautious administration of hypertonic saline at rates of 1 to 2 mL/kg per hour.
Volume Resuscitation in Shock
Because of its ability to expand plasma volume by mobilizing water along an osmotic gradient (from the body's intracellular and interstitial compartments to the extracellular space), hypertonic saline has been of interest to researchers trying to find the best fluid for resuscitating burn victims, trauma patients, and others after major loss of intravascular volume. However, therapy with hypertonic saline is both confusing and controversial. Although the therapy is theoretically promising, no study has yet clearly established the clinical benefits of use of hypertonic saline rather than standard isotonic crystalloids for resuscitation. (26,27)
In part, the research on use of hypertonic saline is difficult to interpret because concentrations of sodium chloride varying from 2% to 7.5% have been infused both alone and in combination with dextran-70 (6% and 10%) or hydroxyethyl starch (hetastarch, Hespan). (27,28) In some studies, a single bolus (eg, 250 mL) was infused; in others, additional boluses were given on an as-needed basis during initial resuscitation or a continuous infusion was used (Table 2). Patients' conditions included in each series varied as well. In some trials, anyone with hypovolemia was included; in other studies, participants were limited to patients with hemorrhagic shock; and in still other studies, just those patients with concomitant head injuries were included. Another variable is the location where fluid was administered. Certain protocols restricted therapy with hypertonic saline to prehospital use; others have expanded its application to the emergency department resuscitation area, the operating room, and the intensive care unit. (32,33) Likewise, outcome measures are inconsistent between studies. Nonetheless, the ability of hypertonic saline to increase and maintain mean arterial pressure is well documented in both human and animal models of cardiogenic, septic, and hemorrhagic shock. (26)
Interestingly, modern focus on hypertonic saline as a resuscitation fluid was stimulated in part by a nursing error. In 1980, a Brazilian nurse unintentionally gave an obtunded and hypotensive hemodialysis patient an infusion of about 100 mL of 7.5% saline, a solution that was kept in the unit for mixing dialysate. Approximately 1 minute after infusion, the patient's blood pressure and mentation returned to normal. (34)
The primary and immediate benefits of administration of hypertonic saline in resuscitation are due to an expansion in plasma volume. (26,27) Even modestly hypertonic solutions will rapidly cause a fluid shift to the intravascular space by drawing on the vast reservoirs of water contained in the cells and the interstitium (35,36) (Figure 2). Hemorrhagic and septic shock are both associated with intracellular sequestration of sodium, chloride, and water, and administration of hypertonic saline blunts this response. Although these physiological mechanisms alone may eventually be sufficient justification for use of hypertonic saline in shock states, research indicates that hypertonic saline has several additional important and beneficial effects.
Because hypertonic saline is given intravenously, the endothelial cells lining the blood vessels are among the first to be exposed to it. In shock states, these cells swell, a condition that is further aggravated by resuscitation with the usual isotonic solutions. Infusion of hypertonic saline appears to minimize the swelling, thus improving microvascular perfusion. (37) Evidence suggests that therapy with hypertonic saline can produce improvement in pulmonary microvascular and other tissue perfusion, as indicated by the restoration of whole-body and individual organ oxygen consumption. (26,27,38)
Contrary to the tendency to limit sodium intake in patients with myocardial depression, some data indicate that infusion of hypertonic saline may actually enhance cardiac function. Modest increases in osmolarity with administration of sodium-containing solutions has improved cardiac contractility and reduced systemic vascular resistance in patients with shock-induced myocardial depression, possibly via changes in circulating hormone levels. (39,40)
Perhaps the most provocative research on the benefits of hypertonic saline involves its effects on the immune system. Although study findings are difficult to interpret and sometimes inconsistent, hypertonic saline appears to affect immune function, particularly neutrophils, in an advantageous manner when given early in resuscitation in quantities sufficient to achieve a serum osmolarity of about 315 mOsm/kg. (27) Findings indicate that hypertonic saline can decrease leukocyte adherence and migration and may alter production of certain prostaglandins. (41) Hypertonic saline also can increase circulating levels of cortisol and adrenocorticotropic hormone. (41) As a result, hypertonic solutions of sodium chloride seem to provide some degree of protection against serious bacterial illnesses and the development of sepsis, at least in animal models, through modulation of the acute inflammatory response. (42,43)
[FIGURE 2 OMITTED]
Data from theoretical, in vitro, animal, volunteer, and patient studies suggest that hypertonic saline is useful for volume resuscitation in the treatment of hemorrhagic shock, (28,44,45) hypovolemic shock related to major burns, (31,39,46) septic shock, (47,48) and ischemia-reperfusion injuries. (27) Still, not all studies support the use of hypertonic saline, and no consensus has been reached on the optimal dose or regimen of hypertonic saline for any of these conditions. (32,33,49-51)
Hypertonic saline is also given intravenously to critically ill patients with both traumatic and nontraumatic brain injuries to mitigate the devastating effects of hypoperfusion and edema on cerebral tissue. (52) Traditionally, mannitol has been the drug of choice for reducing intracranial pressure. Although mannitol increases cerebral blood flow and reduces intracranial pressure, prolonged administration of it can lead to dehydration of brain parenchyma, hypotension, prerenal azotemia, intravascular volume depletion, and a reduction in cerebral blood flow. (53,54) Data indicate that when substituted for mannitol, hypertonic saline can reduce intracranial pressure and simultaneously support intravascular volume. (54)
As was the case for resuscitation of patients with shock, a multitude of concentrations of sodium chloride (1.6%-29.9%) have been tried both alone and in combination with dextran, hydroxyethyl starch, or mannitol. Protocols for treatment of patients with brain injuries have variously called for administration of hypertonic saline as a single bolus, as a continuous infusion, or as repeat boluses adjusted on the basis of intracranial pressure or serum levels of sodium (52,54-62) (Table 3).
Researchers reported an inverse relationship between the serum concentration of sodium and intracranial pressure; higher sodium levels are associated with improved control of intracranial pressure and decreased requirements for other therapy. (56,62,63) Hypertonic saline reduces intracranial hypertension through a variety of mechanisms, including optimization of systemic and cerebral hemodynamics, reduction of cerebral edema, modulation of cerebral vasospasm, and alterations in cerebral immunology and neurochemistry. However, the single greatest advantage of hypertonic saline appears to be its ability to restore mean arterial pressure without increasing cerebral edema or intracranial pressure, making it especially useful for resuscitation of multitrauma patients with concomitant head injuries. (45,64)
Although clinical trials have not demonstrated improved survival in patients treated with hypertonic saline in lieu of conventional treatments, research in both animals and humans has clearly established the ability of hypertonic saline to acutely lower intracranial pressure. (26) Research in both animals and humans has clearly established the ability of therapy with hypertonic saline to decrease intracranial pressure. (26) Nonetheless, the data are difficult to interpret because of inconsistencies in the regimens used, population differences, and small sample sizes. (26) Unfortunately, in many studies, (26,59,61) hypertonic saline was used solely as salvage therapy, when the efficacy of mannitol or barbiturates had already been exhausted.
Although most research on use of hypertonic saline in brain-injured patients addressed patients with head trauma, the advantages of this intervention are not necessarily restricted to patients with traumatic injuries. In limited trials, therapy with hypertonic saline showed promise in patients with aneurysmal subarachnoid hemorrhage, brain tumors, basal ganglia hemorrhage, and stroke. (54,63) Other researchers (57) concluded that hypertonic saline therapy was not useful in patients with nontraumatic intracranial hemorrhage or cerebral infarction. Because the spinal cord and the brain share many of the same characteristics, it has been hypothesized that therapy with hypertonic saline would be advantageous in patients with spinal cord injuries. Tuma et al (65) tested this hypothesis in rats and concluded that administration of hypertonic saline after acute spinal cord injury increased blood flow, helped preserve function, and hastened recovery. This intervention has not yet been investigated in humans.
Risks of Therapy With Hypertonic Saline
Because much of the effect of hypertonic saline in normonatremic patients is due to its ability to move water from the intercellular space to the vascular space, use in patients with preexisting dehydration seems to be contraindicated. Still, limited evidence suggests that even in dehydrated patients, the benefits gained from hypertonic saline may outweigh the potential hazards. (27)
Among the most obvious potential risks associated with the use of hypertonic saline are hypernatremia and hyperosmolality. However, in several studies, elevations of serum levels of sodium to 160 mmol/L and serum osmolarity to 330 mOsm/L appear to be well tolerated and have not been linked to significant complications. (52) In several studies (59) in patients with elevated intracranial pressure, substantial decreases in intracranial pressure occurred after treatment with hypertonic saline despite only mild (mean, 2 mmol/L) increases in sodium concentrations. (59) Still, at some point these gains cease. A review by Peterson et al (52) of patients with head injuries treated with hypertonic saline revealed that patients with serum sodium levels greater than 180 mmol/L had a universally poor outcome. Dramatically elevated sodium concentrations and plasma osmolarities increase the risk of renal failure, pulmonary edema, congestive heart failure, and neurological complications. (52)
Theoretical concerns associated with the administration of all hypertonic substances include shrinking of the brain causing mechanical shearing of the bridging vessels and resulting in subarachnoid hemorrhage, impairment of the blood-brain barrier, and rebound intracranial hypertension. In an animal model, severe shrinkage of the brain and subarachnoid hemorrhage occurred after rapid and marked increases in the serum concentrations of sodium (from normal to 206 mmol/L). (66) These potential complications did not occur in trials with much more moderate increases in sodium levels in humans. (52)
Some researchers have described rebound increases in intracranial pressure after discontinuation of hypertonic saline therapy in brain-injured patients. Yet it remains unclear whether this increase in intracranial pressure is truly a "rebound" phenomenon or merely a reflection of the short half-life of osmotic agents. (26,67)
Vassar et al (68) identified 8 cases of significant hyperchloremic acidemia in association with infusion of 7.5% sodium chloride in 106 critically injured patients. Of note, all 8 patients were moribund before administration of hypertonic saline and many factors other than hyperchloremia could have contributed to their acidemic state. (68)
Central pontine myelinolysis, also referred to as osmotic demyelination syndrome, is a devastating acute neurological condition characterized by loss of myelin and supportive structures in the pons and, occasionally, in other areas of the brain. (24,26) This disorder occurs one to several days after rapid correction of hyponatremia and is characterized by gradual, irreversible neurological deterioration. Importantly, central pontine myelinolysis has been documented only in patients who had very low serum levels of sodium (<120 mmol/L) before therapy with hypertonic saline. (69) Hypertonic solutions of sodium chloride have not been associated with central pontine myelinolysis in patients with normal concentrations of sodium. When hypertonic saline is used to treat hyponatremia, slow and prudent administration is warranted. When given for volume resuscitation or treatment of brain injury in patients with grossly normal sodium levels, hypertonic saline can be safely infused as either a bolus or a continuous infusion. (26,27,52)
Various authors have postulated that rapid expansion of plasma volume with hypertonic solutions could interfere with platelet aggregation as a result of inhibition or dilution of clotting elements. Substantial experimental evidence indicates that this concern most likely is unwarranted. (70)
Another theoretical risk is that hypertonic saline could cause endothelial damage near the catheter insertion site when administered into a peripheral vein. Such damage did not occur in clinical trials. (71) Hypertonic solutions of sodium chloride have osmolalities comparable to those of solutions of sodium bicarbonate and 50% dextrose in water, so care should be taken to prevent extravasation by infusing the solutions into a large vein with good blood flow. These fluids can be given concomitantly with isotonic crystalloids to provide dilution at the catheter site. Intraosseous use of hypertonic saline also appears to be both safe and efficacious. (72)
Sodium is the most abundant extracellular ion. Historically, therapy with hypertonic saline was widely used for a variety of conditions. Currently, there are 3 primary indications for its use in critical care: hyponatremia, volume resuscitation, and brain injury. SIADH and CSW syndrome may require sodium replacement, but most cases of hyponatremia can be managed without administration of hypertonic saline. Studies of use of hypertonic saline in hypovolemia and brain injury are promising, but additional research is needed to better define optimal dosing regimens and to determine the relative risks associated with hypertonic saline versus conventional treatment for the management of patients with head injuries and for volume resuscitation in shock states.
To receive CE credit for this article, visit the American Association of Critical-Care Nurses' (AACN) Web site at http://www.aacn.org, click on "Education" and select "Continuing Education," or call AACN's Fax on Demand at (800) 222-6329 and request item No. 1106.
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Andrea L. Johnson, RN, BSN, CCRN
Laura M. Criddle, RN, MS, CCRN, CCNS
Andrea L. Johnson was a staff nurse in the trauma/neuro intensive care unit at Oregon Health & Science University, Portland, Ore, for 3 years. She is now a master's student at the University of Minnesota in Minneapolis, specializing in nurse anesthesia.
Laura M. Criddle was the emergency, trauma, and neuro clinical nurse specialist at Oregon Health & Science University, Portland, Ore. She is now a doctoral student there.
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