Background

Intracranial hypertension (IH) resulting from increased intracranial pressure is a common complication of neurological injuries. Research has shown that IH is associated with poor patient outcomes.¹ In an effort to improve morbidity and mortality in these patients, neurologically based research has focused on strategies to reduce IH. Osmotic therapy has long been recognized as a safe and effective treatment for IH.² The most researched and commonly used osmotic agent, mannitol, has been associated with untoward side effects. In an effort to find an effective osmotic agent with a safe side effect profile, other osmotic agents have gained some popularity. This article will review studies performed using HS as an osmotic agent for the reduction of intracranial pressure in patients with neurological injury.

Intracranial Hypertension

Hypersomolar Therapy Principles

A traditionally held belief is that hyperosmolar therapy effectiveness is a result of brain shrinkage caused from the shifting of water out of the brain. Mannitol has been accepted as treatment for IH, and is considered a safe and effective osmotic diuretic. Considered the drug of choice for IH in Guidelines for the Management of Severe Brain Injury, mannitol is not without its drawbacks.² Mannitol, an osmotic diuretic, has been associated with volume depletion and hypotension leading to secondary injury to the brain. Injury to the blood brain barrier (BBB), often found in neurological injuries, can be a confounding factor in the management of IH. One concern is that solutes may escape from the vascular system to the brain tissue. In the presence of an injured BBB, mannitol may escape the intravascular space and accumulate in already edematous tissue, which may lead to an increase in cerebral edema and intracranial hypertension often referred to as rebound phenomenon.

In an attempt to find the “optimal” hyperosmolar agent, the use of other solutions has been explored. An optimal agent should be nontoxic, simple to administer with minimal side effects, have a strong osmotic gradient, and would remain in the intravascular space (reflection coefficient). Reflection coefficient is the measurement of how well a solute crosses a membrane. In regards to treatment of IH, a reflection coefficient of 1 is given to a solute that stays in the intravascular space and is impermeable to an intact BBB (See Table 1).

Figure 1

Table 1. Reflection Coefficients

Research has found other agents such as glycerol and urea, with their low reflection coefficients, to be fairly ineffective osmotic agents in the treatment of IH.⁴ Hypertonic saline with its low cost, ease of administration, and titratable osmotic gradient (by adjusting its concentration), and its reflection coefficient of 1 has been recognized as an effective osmotic agent.

Hypertonic Saline

The use of hypertonic saline in the treatment of cerebral edema was first proposed in 1919 by Weed and McKibben.⁵ Nearly forgotten, more than sixty years later HS reemerged as resuscitation agent for patients in shock. Incidentally found through the resuscitations of patients with multi-organ trauma, use of HS in patients with neurotrauma alone became a focus of research.^6,7 Finding from this early research, in multi-organ trauma, including brain injury, promoted its use in the treatment of intracranial hypertension and herniation syndromes as well.

The proposed mechanism of action of HS is similar to that of mannitol. Through osmosis HS draws water out of the intracellular space, the edematous brain, and back into the intravascular space. In addition, HS has been shown to be effective in resuscitation of patients in shock by the same mechanism. Unlike mannitol which promotes diuresis, HS increases blood volume, decreases viscosity, and increases preload. All of these characteristics lead to an increase in blood pressure, cardiac output, and cerebral perfusion pressure (CPP), thereby improving perfusion to the brain and decreasing secondary injury. Used as a resuscitation agent, HS also has potential to be used as a component of “triple H” therapy (hypervolemia, hemodilution, and hypertension) in the treatment of patients with subarachnoid hemorrhage (SAH) who are at high risk of severe vasospasm.

Findings

Traumatic Brain Injury

According the Centers for Disease Control, 1.4 million Americans suffer from traumatic brain injury (TBI) annually. Of those, more than 200,000 are hospitalized and 50,000 die. Costs related to TBI, direct and indirect, are figured to be approximately $60 billion.⁸ In an effort to improve morbidity and mortality rates in patients with TBI, research to combat and treat IH has been on the forefront of neurological research. Most studies involving TBI, share similar findings that indicate that HS is consistent with a decrease in ICP and an increase in CPP (See Table 2). Maintaining a physiologic normal CPP is as important as decreasing elevated ICP in preventing secondary injury. By increasing blood volume and preload, HS helps to ensure adequate perfusion and oxygenation to at-risk brain tissue.

Several studies compared mannitol boluses versus HS boluses.^9,10 In one study, Vialet et al. compared 20% mannitol with 7.5% sodium chloride (NaCl) bolus for the treatment of ICP above 25mmHg. This study demonstrated that patients given mannitol have two times more events of elevated ICP compared with HS. In addition, treatment failures were 7 out of 10 for the mannitol group versus those treated with HS. Shackford et al. took a unique approach and compared the use of slightly hypertonic solution of 1.6% NaCl with a slightly hypotonic solution of Lactated Ringers in the TBI population.¹¹ Intracerebral pressures decreased in the HS group while the patients receiving Lactated Ringers showed an upward trend in ICP. While most of the studies used bolus dosing, a retrospective chart review by Quareshi et al. reviewed the use of HS as a continuous drip with varying infusion rates with the goal of achieving a serum sodium value between 145-155 meq/dl. The investigators found that patients receiving continuous HS had poor long-term outcomes as identified by the Glasgow Outcome Scale (GOS).¹² The GOS ranks patients on five levels based on functional recovery with 1 corresponding with death and 5 corresponding with good recovery. Another unique study design examined the effects of a bolus of 20% NaCl on not only the ICP but the measurable effect on brain tissue using computed tomography.¹³ The results of this study revealed that HS may lower ICP by decreasing the overall volume of the healthy brain tissue.

Figure 2

Table 2. Summary of Study Findings for Traumatic Brain Injury

Mixed Neurological Insults

Samples with mixed neurological injuries were examined in six studies (See Table 3). Battison et al. examined the effect of equiosmolar does of mannitol versus HS. Findings supported that both agents decreased ICP. Mannitol decreased ICP on average by 7.5 mmHg, whereas, HS decreased by 13.5 mmHg. The investigators also suggested that patients who received HS appeared to have a longer duration of effect than those who received mannitol.¹⁴ Francony et al. also compared equiosmolar doses of mannitol with HS.¹⁵ Findings contrasted the research by Battison et al. showing that mannitol decreased ICP better than HS, though none of the findings were statistically significant. Becoming more popular as a rescue therapy for malignant IH (i.e., ICPs refractory to traditional treatments), Koenig et al. reviewed the effect of 23.4 % bolus in patients with signs of impending herniation syndromes. Concentrated HS was successful at reversing herniation syndromes in 57 of the 76 events.¹⁶

Figure 3

Table 3. Summary of Study Findings for Mixed Neurological Injuries

Subarachnoid Hemorrhage

Stroke

Patient Outcomes

While the majority of the studies showed decreases in ICP values and an improvement in CPP, a decrease in morbidity and mortality has yet to be proven. The studies that examined the Glasgow Outcome Scale (GOS) found that those patients treated with HS were more likely to survive but without significant improvement in quality of life. When assessed the majority of patients treated with HS had outcomes that correlates with severe disability or death.^{12, 16, 23,24} One reason for this finding may be related to use of HS in higher acuity patients. As seen in the studies reviewed, HS is often used as a second line therapy or as a rescue therapy in the face of refractory IH.

Figure 4

Table 4. Summary of Study Findings for Non-Traumatic Injuries

Limitations

All studies reviewed included small sample sizes and a few studies revealed some selection bias. Often the use of HS was used as a rescue therapy or after the standard of care had already failed to control intracranial pressure in the most critically ill patients. Using HS earlier in the course of the patients’ treatment, instead of as a last resort may provide better success. Another potential limitation to the studies as a group was that saline concentrations varied greatly among investigators. Concentrations ranged from 2-20% sodium chloride. Not all studies that compared mannitol with HS used equiosmolar dosing (See Table 5).

Figure 5

Table 5. Comparing Osmolarity of IV Agents

Agents with a stronger osmotic action may affect the ICP values. Therefore, comparing two agents of unequal osmolar activity may be considered unjust. Varying doses among the study groups as a whole, as well as in individual studies, occurred throughout many of the studies. This lack of consistency make findings difficult to generalized the entire neurological population.

Potential Adverse Effects

Like other osmotic agents, side effects from the administration of HS are potential risks that must be balanced with the potential benefits of its use. In the studies reviewed, no significant complications were mentioned. Most studies listed exclusion criteria, to minimize harm to patients who may be a highest risk for untoward effects. Patients commonly excluded were those with heart failure, pulmonary edema, and kidney failure who may be harmed from an increase in intravascular volume. In one study, lung water was evaluated and unchanged over three hours post HS administration.¹⁷ In a retrospective chart review, three patients that received HS developed pulmonary edema. Of the three patients, one of them had underlying cardiomyopathy.¹² In a study, that specifically looked at complication in patients with neurological injury receiving continuous infusion of HS, the incidence of renal failure was not found to correlate with HS use.¹² Hypernatremia, serum sodium levels greater than 155, did correlate with a small yet statistically significant increase in BUN and creatinine levels.²⁵

Central pontine myelinolysis (CPM), a demyelination of the pons is a concern during administration of any concentrated sodium solution. First described in 1958, CPM is associated with chronically hyponatremic patients who undergo rapid correction hyponatremia with a concentrated saline solution. No evidence exists to support the fear of CPM in patients with acute cerebral salt wasting, excessive renal secretion of sodium in the face of neurological injury, or traumatic brain injury. Since CPM is an irreversible and devastating condition, practitioners should continue to be cautious when administrating HS until significant research proves whether or not this population is at risk.

Electrolyte and acid base imbalances are frequent occurrence in the critical care patient population. Several studies included potassium levels as dependent variables.^{23, 26} These studies collectively revealed a mild decrease in potassium immediately following administration with a rebound in potassium near baseline levels after a few hours. While these studies suggest that hypokalemia may not be a concern for patients receiving HS therapy, it may be wise to monitor potassium levels in patients who are receiving frequent boluses of HS especially patients who are at risk of arrhythmias. Hyperchloremic metabolic acidosis may result from continuous or frequent bolus doses of HS. In the above studies, some institutions alternated sodium chloride concentrations with sodium acetate concentrations to decrease its incidence.

In hemorrhagic neurological insults, an injured BBB may result in the translocation of hyperosmolar solutions which have the potential to cause rebound IH. Animal studies have found mannitol and HS to cross an injured BBB, but no studies have been done in humans to evaluate post mortem effects of HS in the brain. Impaired platelet aggregation and coagulopathy is a concern in hemorrhagic neurologic injuries. Animal studies have suggested that hypertonic saline may be responsible for increased bleeding. In one human study, clotting factors diminished when 10% of plasma was replaced with HS versus normal saline.²⁷ In another study, HS/dextran was similarly mixed with human plasma at 1:5 and 1:10 concentrations, with only minimal increase in PT.²⁸ While none of the above studies mentioned bleeding complications, no study has specifically looked at bleeding complications in neurological patients receiving HS. Therefore, the clinician should consider this possible complication in any patient receiving HS until research in this area is completed.

Research Implications

The above studies provide a foundation for future research. In order to strengthen the current foundation, future studies should strive for larger sample size. Noted in the above studies were the varying concentrations and doses of HS. These variations make assessment of the overall effectiveness of this solution difficult. Further research is needed to strengthen the evidence for a standard therapy or to assess the effectiveness of one concentration compared with another. Research is also needed in the SAH with vasospasm population, who may benefit from the intravascular volume expansion that HS offers. At this time, HS has not been shown to improve long-term outcomes, which may be due to its use in refractory IH. Studies are needed in which HS is used as a treatment of cerebral edema prior to other treatments. Finally, studies that focus on HS use in other than severe traumatic brain injury should be considered for future research.

Conclusions

Hypertonic saline offers promise as a treatment for IH. Current research seems to support its effectiveness in reducing intracranial pressures. Each patient’s co-morbidities and expected results before choosing an osmotic therapy is an important consideration. Whether used as an initial treatment for elevated intracranial pressure or as a rescue therapy for refractory IH, HS appears to offer an additional means for lowering ICP and may provide a bridge to surgical decompression.