Hypertonic Fluids

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Last Update: April 17, 2023.

Continuing Education Activity

Clinicians use hypertonic fluids to increase intravascular fluid volume. Hypertonic saline can be utilized in the treatment of hyponatremia. Hypertonic saline and mannitol are both indicated to reduce intracranial pressure. This activity will highlight the mechanism of action, adverse events, and contraindications of hypertonic fluids in the management of hyponatremia and increased intracranial pressure.

Objectives:

  • Describe the mechanisms of action of hypertonic saline and mannitol.
  • Review the adverse effects and contraindications of hypertonic saline and mannitol.
  • Outline the route of administration and appropriate dosing for hypertonic fluids.
  • Explain the importance of improving care coordination among the interprofessional team to improve care for patients with increased intracranial pressure and hypertonic fluids in patient management.
Access free multiple choice questions on this topic.

Indications

Hypertonic Saline

Hypertonic saline is a crystalloid intravenous fluid composed of NaCl dissolved in water with a higher sodium concentration than normal blood serum. Both 3% and 5% hypertonic saline (HS) is currently FDA-approved for use in hyponatremia and increased intracranial pressure (ICP). Patients with hyponatremia with severe features should have their serum sodium gradually corrected with boluses of hypertonic saline. Patients should have their serum sodium monitored at regular intervals and can receive multiple boluses a day.

Hypertonic saline should be discontinued once the patient’s symptoms improve or they have an adequate increase in serum sodium. Cerebral edema and elevated intracranial pressure (ICP) are significant causes of morbidity and mortality in patients with intracranial tumors, cerebral hematomas, traumatic brain injuries, cerebral infarcts, and intracranial hemorrhages. Hypertonic saline increases the osmolarity of the blood, which allows fluid from the extravascular space to enter the intravascular space, which leads to decreases in brain edema, improved cerebral blood flow, and decreased CSF production. Research shows that 3% hypertonic saline decreases ICP similarly to 20% mannitol. Both hypertonic fluids have similar effects on hemodynamics. Hypertonic saline leads to increases in serum sodium and has less of a diuretic effect than mannitol, likely due to the increased serum sodium causing ADH release. Hypertonic saline administered after mannitol in traumatic brain injury has also demonstrated improvement of cerebral oxygenation in addition to lowering ICP.

Due to there being no guidelines regarding the administration of hypertonic saline for increased ICP, various studies have used concentrations of 3% to 23.5% NaCl.

Mannitol

Mannitol is a crystalloid intravenous fluid composed of a six-carbon simple sugar dissolved in water. It is FDA-approved for use in decreasing intracranial pressure and brain mass and decreasing intraocular pressure when other interventions have failed to do so. When needed, 15 to 25% mannitol can be given as a bolus to reduce intracranial pressure and intraocular pressure. Mannitol is solely confined to the intravascular space when administered intravenously, unlike hypertonic saline, which can have some movement of electrolytes into the interstitial space.

Mechanism of Action

Hypertonic fluids contain a higher concentration of solute compared to plasma and interstitial fluid; this creates an osmotic gradient and drives fluid from the interstitial space into the intravascular space. This increase in intravascular volume increases mean arterial pressure (MAP), stroke volume (SV), and cardiac output (CO) when compared with equal volumes of normal saline or other isotonic fluids. There is also a significant increase in end-diastolic pressure and a subsequent decrease in pulmonary vascular resistance. Hypertonic saline requires less overall volume administered to achieve similar plasma volumes as larger volumes of normal saline. Hypertonic saline stimulates vasopressin release from the pituitary gland, which decreases water loss through the kidneys.[7] In comparison, when given intravenously, mannitol is only minimally metabolized by the body and is rapidly excreted by the kidney. Less than 10% of mannitol is reabsorbed, increasing the osmolarity of the glomerular filtrate and inducing diuresis.

Administration

Hypertonic fluids are administered parenterally via intravenous infusion. Infusion volumes and rates depend on clinical indication.

Hypertonic Saline

In patients with severe hyponatremia, serum sodium should undergo correction by 4 to 6 mEq/L per day, which can be achieved with 100 mL boluses of 3% HS at 10-minute intervals up to three total boluses. Some authorities recommend up to  8 mEq/L per day. Less severe hyponatremia can achieve control with enough hypertonic saline to manage symptoms. Due to the insufficient number of patients over age 65 in various trials, hypertonic fluids should start at the lowest ends of the dosing scale in the geriatric population. Pediatric traumatic brain injury generally receives treatment with a 6.5 to 10 mL/kg bolus of hypertonic saline. Administration via a peripheral intravenous catheter is acceptable if no other access is available, but central venous access is the preferred route. 

Mannitol

Mannitol boluses should be given as 0.25 to 2 g/kg body weight of 15 to 25% mannitol over 30 minutes to 1 hour for the treatment of increased intracranial or intraocular pressures. Pediatric patients should receive a similar 1 to 2g/kg body weight bolus over the same timeframe. Peripheral intravenous catheters are acceptable routes of administration.

Adverse Effects

Hypertonic Saline

There are few adverse effects associated with hypertonic saline, though most are associated with longer infusion periods, as opposed to boluses. One possible side effect is hyperchloremic metabolic acidosis due to the addition of NaCl. Patients may also develop hypernatremia with long-term administration for the same reasons. One other known effect is osmotic demyelination syndrome, when severe hyponatremia is corrected too rapidly. Hypertonic saline is also pregnancy category C and is only used if necessary. The most common adverse effects are related to the route of administration and include infection at the IV site, thrombophlebitis, extravasation, and hypervolemia.

Mannitol

Common adverse reactions after mannitol administration are pulmonary congestion, electrolyte abnormalities, acidosis, marked diuresis, dehydration, headache, and injection site reactions, among others. There have been no animal reproduction studies performed with mannitol, so it is unknown whether it would harm a human fetus. Mannitol should only be used in pregnant women if necessary.

Contraindications

Hypertonic Saline

There are no known specific contraindications for hypertonic saline, according to the FDA. However, caution is necessary with hypertonic saline in patients with congestive heart failure or renal insufficiency due to their already increased fluid and sodium loads.

Mannitol

Mannitol has several contraindications, including:

  • Established anuria due to severe renal disease
  • Pulmonary congestion and frank pulmonary edema
  • Active internal bleeding
  • Severe dehydration
  • Hypersensitivity to mannitol

Monitoring

Fluid and electrolytes require monitoring with the administration of all hypertonic fluids, with particular attention paid to serum sodium, potassium, and fluid ins/outs. Evaluation of circulatory and renal function is necessary before administering mannitol and evaluated during treatment. When treating increased ICP with mannitol, a CSF pressure measurement should take place within fifteen minutes after administration.

Enhancing Healthcare Team Outcomes

An interprofessional team approach, comprised of clinicians, nurses, and pharmacists, is most appropriate when administering hypertonic fluids — extra care is necessary to monitor circulatory and renal function as well as serum electrolyte concentrations. Fluid ins and outs must be carefully monitored by nursing staff, particularly with mannitol, reporting abnormalities right away. Hypertonic fluids should be stopped if significant abnormalities in electrolytes or fluid volumes develop. It is noteworthy that there is a lack of research regarding hypertonic fluids. More work remains to determine the value of hypertonic fluids not only in the management of critically ill patients but in the pre-hospital setting for cases of hypovolemia and shock.

In summary, administration of hypertonic saline and/or mannitol requires an interprofessional team approach, including clinicians (MDs, DOs, NPs, PAs), specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level 5]

Mechanisms and applications of hypertonic saline

Mark R Elkins and Peter TP Bye
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Introduction

Hypertonic saline is a strong sterile solution of salt water that can be inhaled as a nebulized medication for people with cystic fibrosis (CF). To examine how it should be applied clinically, it is worth considering the mechanisms by which it affects the disease process, and which signs, symptoms and other clinical outcomes it influences. Finally, it is worth considering how the effect is influenced by the dose received, and whether this should influence how it is applied in clinical practice. This paper will review this information and relate it to the clinical application of hypertonic saline.

Mechanisms of action

The taxonomy of mucoactive agents consists of several classes of medications defined by their mode of action: mucolytics, expectorants, mucokinetics, ion-transport modifiers and other mucoregulatory compounds. It is difficult to classify hypertonic saline within this taxonomy because it has multiple mechanisms of action.

Mucolytics disrupt the structure of the mucus gel, thereby reducing its viscosity and elasticity. The intention of mucolytic therapy is therefore to make the viscoelasticity of the airway secretions better to facilitate their clearance from the airways. It has been suggested that hypertonic saline is not a mucolytic because mucolysis is not its primary mode of action. However, hypertonic saline is capable of disrupting ionic bonds within the mucus gel, which could reduce cross-linking and entanglements. This mucolytic effect may be why sputum markedly reduces its viscosity when hypertonic saline is added to it. The thread-forming ability of CF sputum also reduces significantly with the addition of hypertonic saline. These saline-mediated changes to the rheological properties of CF sputum are associated with improved transportability in a bovine tracheal model., A similar mechanism – which does not directly affect the mucus gel itself – is that hypertonic saline dissociates DNA from the mucoprotein, which allows natural proteolytic enzymes to then digest the mucoprotein. Therefore hypertonic saline appears to have several mucolytic mechanisms that do improve in vitro transportability of the mucus.

Another mucoactive class of medication is the expectorants, which add water to the airway surface. This is particularly relevant in the CF airway, because the abnormal or absent cystic fibrosis transmembrane conductance regulator (CFTR) protein does not initiate chloride ion secretion into the airway lumen and does not inhibit the absorption of sodium ions from the airway lumen via the epithelial sodium channel. Because sodium ion absorption is increased and chloride ion secretion is decreased, insufficient salt is kept in the airway to maintain the usual hydration of the epithelial surface. This also results in dehydrated airway secretions and disruption to the mucociliary mechanism. This allows the retention of mucus, which becomes a nidus for infection. In vitro measurements of the airway surface liquid on the epithelial surface show that hypertonic saline markedly increases the depth of this liquid layer – not just by depositing itself onto the surface, but also by osmotically drawing additional water onto the airway surface. Depending on the dose of hypertonic saline achieved locally, the degree of restoration of the airway surface liquid varies, but it typically reaches a high peak transiently and returns close to its pre-treatment level within about 10 minutes, although it may have a prolonged milder effect if the dose is adequate., If excess water is drawn in to the airway, the mucus layer is able to accept it and to donate liquid back to the airway surface when required. Thus excess water entering the airway osmotically is stored in the mucus layer, making its rheological properties more favourable for clearance.,

Another mucoactive class is the mucokinetics, which improve cough-mediated clearance by increasing airflow or reducing sputum adhesivity. We are unaware of any evidence that hypertonic saline has either of these immediate benefits, but it does trigger cough and the cough increases the amount of mucus cleared from the lungs even further. The increase in mucociliary clearance with hypertonic saline and the extra clearance with cough have been objectively demonstrated in vivo in cystic fibrosis using radioaerosol studies.,

Hypertonic saline may also have some other mechanisms that are not strictly mucoactive. Recent in vitro research has shown that hypertonic saline reduces biofilm formation by Pseudomonas aeruginosa and the production of associated virulence factors. Finally, hypertonic saline appears to increase the levels of two thiols that are protective against oxidative injury – glutathione and thiocyanate – in the airway surface liquid.

Clinical benefits

An immediate benefit of the increase in mucus clearance is the opportunity to make a microbiological diagnosis in those patients who are unable to expectorate a sputum sample spontaneously. A single dose increases the chance of obtaining a sample in this population.– Of the 40 patients tested in these studies, 39 (97%) were able to produce a sample after inhaling various concentrations of saline up to 6%. Nineteen of these samples were tested for the presence of alveolar macrophages, and in 16 (84%) they were present. For patients who can spontaneously expectorate, hypertonic saline significantly increases the size of their sample, whether measured by weight, or volume. The colony counts and the percentage of non-squamous cells were also higher., However, despite these better quality samples, the detection of pathogens did not improve, suggesting that hypertonic saline is not necessary when obtaining sputum samples for microbiological testing from patients with CF who can expectorate a sample spontaneously.

Riedler and colleagues performed a cross-over trial in 10 adolescents with an exacerbation of their CF lung disease. Prior to a session of physiotherapy, subjects were randomized to inhale either 6% hypertonic saline or a normal saline control. On the following day, the alternate solution was inhaled prior to an identical physiotherapy session. Sputum was collected between the start of the inhalation and 60 min after the end of the physiotherapy regimen. Significantly more sputum was expectorated after hypertonic saline than control (p = 0.006). Subjects also rated how much clearer their chest felt after the physiotherapy, with significantly better scores when hypertonic saline had been used (p = 0.04) – an effect also reported in adults and children. Eng and colleagues randomized 52 children and adults with CF to twice-daily inhalations of 6% hypertonic saline or a normal saline control. Within two weeks, the average FEV1 improvement among those taking hypertonic saline was 15% (SD 16), while the control group improved only 3% (SD 13) (p = 0.004). Two weeks after ceasing the inhalations, there was no significant difference in lung function.

A benefit in lung function appears to be maintained with long-term use. In a randomized trial in which 164 adults and children with CF participated, the hypertonic saline group maintained significantly higher lung function across the 48-week follow-up period. Other clinical benefits were a reduction in the frequency and duration of exacerbations and fewer days missed from usual activities due to the disease. These benefits were accompanied by an improvement in several domains of quality of life. There was also close monitoring of sputum samples throughout the trial to check for any adverse effects on acquisition of organisms, organism density and inflammation. Overall, these outcomes showed no detrimental effect of long-term use of the twice-daily regimen of hypertonic saline inhalations. An often overlooked benefit was that patients in the active arm of the study rated their ease of clearing sputum as significantly greater at the end of the trial. This probably has important social implications. If patients can clear their secretions more effectively at the time of airway clearance, it allows them to go about their work, study and social events with less concern about productive coughing during interactions with others.

No study has identified a subgroup of CF patients that responds particularly well to hypertonic saline therapy. For example, in the long-term trial, the effect of hypertonic saline on exacerbations did not differ significantly between users and non-users of physiotherapy, between subjects with mild or severe lung function impairment, nor between users and non-users of recombinant human deoxyribonuclease (rhDNase). We therefore recommend the therapy for most people with CF who find it tolerable. Appropriate tolerability testing is described below.

Current research

An interesting feature of much of the research discussed above is the presence of dose-response relationships for hypertonic saline. The effects on viscosity and thread-forming ability increase as the concentration of saline increases., The effect on the airway surface liquid also is much greater when a greater volume of hypertonic saline is applied to the epithelial surface., The acceleration in mucociliary clearance also significantly increases as greater concentrations of saline are used., However, side-effects such as cough also increase as the concentration increases. Therefore, some clinicians question whether patients who do not tolerate the standard dose would still benefit from a lower (but more tolerable) concentration of hypertonic saline. We have embarked on a randomized clinical trial (ACTRN12610000754044) that will compare the standard concentration of saline against a lower concentration of hypertonic saline, as well as against normal saline as a control condition.

Another approach to the issue of tolerability is to modify the hypertonic saline solution. Buonpensiero and colleagues investigated hypertonic saline mixed with 0.1% hyaluronic acid – a naturally occurring polysaccharide. Hyaluronic acid appears to have several other mechanisms that may be beneficial in the CF airway, but Buonpensiero and colleagues examined its effects on tolerability and perceived saltiness of the combined solution compared to hypertonic saline alone. They noted improvements in the tolerability of hypertonic saline and reductions in the perceived salty taste when hyaluronic acid was included in the solution. These changes were both statistically and clinically significant.

The original long-term controlled trial of hypertonic saline only recruited participants as young as 6 years of age. The Infant Study of Inhaled Saline in Cystic Fibrosis (ISIS) will address this by examining the use of hypertonic saline in infants and children from 4 to 59 months (NCT00709280). The primary outcome of this trial will be the rate of protocol-defined pulmonary exacerbations requiring treatment with antibiotics, compared to the rate in the control group who will inhale normal saline.

While awaiting the outcome of these trials, we continue to recommend that hypertonic saline can be considered with most adults and older children with CF. If hypertonic saline therapy is being commenced with a patient, the first dose should be supervised, with spirometry and pulse oximetry before and after the dose to ensure that no clinically important airway narrowing occurs (i.e. a greater than 15% fall in FEV1 or marked desaturation after a dose). All doses, including the initial test dose, should be preceded by a bronchodilator. Tolerability often improves over the first 10 doses, so patients who find the first doses difficult to tolerate should be encouraged to persevere, provided they are not showing signs of marked airway narrowing. Patients who do not pass their initial tolerability test can be re-tested at a later time; often the second test dose is tolerated much more readily.

Hypertonic saline is also being investigated as a treatment for non-CF bronchiectasis and chronic obstructive pulmonary disease (COPD). Although hydration of the airway surface may be less important than in CF, the other mechanisms of action of hypertonic saline all have the potential to work in bronchiectasis. The rationale behind the use in COPD is less clear, although clearance of retained secretions is accepted as a valid treatment target where they occur. Some studies have shown substantial overlap in pathology between COPD and bronchiectasis., As hypertonic saline can cause airway narrowing, this should be very carefully monitored in trials of hypertonic saline in obstructive lung diseases such as COPD. Future trials will also assess the effect of hypertonic saline in combination with other classes of medications such as antibiotics or anti-inflammatory agents.

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