Mannitol

Mechanism of Action

Mannitol is a 6-carbon, linear, simple sugar that is only mildly metabolized. When given intravenously, it is excreted rapidly by the kidneys. Mannitol is poorly absorbed orally. The mechanisms of mannitol for FDA-approved indications are detailed below.

Increased Intracranial Pressure

Mannitol may be used to reduce intracranial pressure. In these cases, mannitol administration is intravenous. Mannitol then constitutes a new solute in the plasma, which increases the tonicity of the plasma. Since mannitol cannot cross the intact blood-brain barrier, the increased tonicity from the mannitol draws water out of the brain parenchyma and into the intravascular space. The mannitol travels with the water to the kidneys and is excreted in the urine.[7]

Mannitol causes brain cells to become mildly dehydrated by drawing water inside the cells (intracellular water) out and into the bloodstream. When mannitol gets to the kidneys, it is filtered into the urine. Urinary mannitol continues to draw water with it, and diuresis (increased urination) ensues.

Increased Intraocular Pressure

Mannitol, given intravenously, may be used to reduce intraocular pressure. Mannitol increases the blood plasma's tonicity, drawing water out of the eye's vitreous humor and into the intravascular space. This reduction in plasma volume leads to a decrease in mass and reduced intraocular pressure.[8] This lower pressure is less likely to damage the retina. The kidney then excretes mannitol and its associated plasma volume. 

Acute Renal Failure

Mannitol can be used in acute renal failure to help prevent or treat the oliguric phase. During the oliguric phase, urine output decreases to less than 0.5 mg/kg/h for children and less than 400 mL/d for adults. The fluid remaining in the body causes fluid overload, which is associated with complications that include decreased oxygenation and ventilation, electrolyte abnormalities, swelling, encephalopathy, and cardiac arrest. Intravenous mannitol was previously administered to patients with acute renal failure. Even during acute renal failure, the kidneys still filter and excrete mannitol. As the mannitol gets excreted, it draws water along, increasing the water excretion of the patient and helping avoid or treat the fluid overload caused by oliguria in acute renal failure. Despite this, mannitol causes significant osmotic injury to tubules, causing ATN (acute tubular necrosis). Because of this complication, mannitol is now rarely administered to patients with acute renal failure.

Toxic Material Elimination

Similar to oliguria due to acute renal failure, mannitol can be given to increase the excretion of toxic materials, substances, and drugs. The kidneys excrete mannitol, poorly reabsorbed once filtered, drawing extra water into the renal collecting ducts. The excess water in the renal collecting ducts can help increase the excretion of water-soluble toxic materials, substances, and drugs.

Intradialytic Hypotension Prevention

Intradialytic hypotension and dialysis disequilibrium symptoms are common in patients on dialysis. This is due to a drop in intradialytic osmolality. Mannitol can be used to prevent intradialytic hypotension by raising serum osmolality.[9]

Cystic Fibrosis

Inhaled mannitol improves mucociliary clearance by hydrating airway secretions and reducing sputum viscosity. Additionally, it may stimulate the release of mediators that increase ciliary beat frequency.[10]

Airway Responsiveness in Asthma

Inhaled mannitol elevates the osmolarity of periciliary fluid, causing cell shrinkage as water equilibrates across the cell membrane. This triggers the release of inflammatory mediators like histamine, prostaglandins, and leukotrienes, resulting in significant bronchospasm. Bronchial challenge testing with mannitol is a tool for evaluating bronchial hyperresponsiveness. The outcome is measured as the dose necessary to produce a 15% decrease in forced expiratory volume in 1 second (FEV1), denoted as PD15.[5]

Food Sweetener

Mannitol is a sweet-tasting sugar poorly absorbed in the intestine and excreted in the feces. Thus, mannitol is a sweetener for patients with diabetes, as it can provide sweetness to food without increasing blood sugar levels as much as sucrose.

Pharmacokinetics

Absorption: Following inhalation of mannitol powder, peak plasma concentration (Tmax) is achieved at approximately 1.5 hours. Intracranial pressure (ICP) reduction begins 15 to 30 minutes after administration, with clinical effects lasting 1.5 to 6 hours. Diuresis occurs 30 minutes to 3 hours post-administration.

Distribution: Mannitol largely remains in the extracellular fluid (ECF) compartment, with an approximate distribution volume of 17 L.

Metabolism: Mannitol is primarily metabolized to fructose-6-phosphate but can undergo minimal conversion into glycogen in the liver.

Excretion: Mannitol is primarily eliminated in urine as an unchanged drug. Both inhalation and oral administration routes result in a fraction of the dose being excreted unchanged in the urine. Mannitol's clearance is almost equivalent to the glomerular filtration rate (GFR). The half-life of mannitol ranges from 0.5 to 2.5 hours in individuals with normal kidney function and varies from 6 to 48 hours in patients with renal failure.[11]

Administration

Available Dosage Forms and Strengths

The FDA has approved both intravenous (IV) and inhaled formulations of mannitol.

Intravenous

• Mannitol concentrations range from 5% mannitol (5 g of mannitol dissolved in 100 mL of fluid) to 25% mannitol (25 g of mannitol dissolved in 100 mL of liquid). The 20% mannitol solution (20 grams of mannitol dissolved in 100 mL of fluid) is commonly used.[2]

Inhaled

• Mannitol is available in 5 mg, 10 mg, 20 mg, and 40 mg of dry powder per capsule for the bronchial provocation test.
• Inhaled mannitol capsules with a 40 mg dosage are available to manage cystic fibrosis.

Adult Dosage

• For increased intracranial or intraocular pressure, dosages range from 0.25 g/kg to 2 g/kg, administered intravenously over 30 to 60 minutes. The drug's effects are observable within 5 to 10 minutes and last up to approximately 6 hours.
• An intravenous test dose of 0.2 g/kg is advised to prevent or treat oliguria to ensure a response in urine output. A mannitol infusion can be adjusted to achieve a 30 to 50 mL/h urine flow rate.
• A dose of 0.25 g/kg to 2 g/kg is advised to aid the excretion of toxic materials. Mannitol use should be discontinued if the patient receives more than 200 g without benefit.
• For bronchial hyperresponsiveness testing, each kit contains graduated doses of dry powder capsules and a single-use inhaler tailored for a single bronchial challenge examination. Inhaled mannitol capsules are advised only for adults who have passed the hyperresponsiveness to inhaled mannitol tolerance test. Each mannitol test kit includes graduated doses of dry powder mannitol capsules and a single-use inhaler for a single bronchial challenge test. The patient should inhale capsule contents incrementally until a positive response occurs or all capsules (maximum total dose 635mg) are depleted.
• For cystic fibrosis management, the recommended oral inhalation is 400 mg (or 10 capsules) twice daily, once in the morning and once in the evening, with the latter dose administered 2 to 3 hours before bedtime. This is also the recommended dosage for children 6 years or older.

Specific Patient Populations

Hepatic impairment: No dose adjustment is required.

Renal impairment: Patients with pre-existing kidney conditions, individuals at risk for renal failure, or those on nephrotoxic medications or diuretics should undergo renal and cardiac assessment to correct fluid or electrolyte imbalances before receiving IV mannitol.

Pregnancy considerations: Available clinical data on mannitol have not identified a drug-associated risk of significant congenital disabilities or adverse maternal/fetal outcomes. However, mannitol crosses the placenta, potentially causing fluid shifts that could lead to adverse fetal effects. While published animal studies have not reported adverse developmental effects from mannitol, fluid shifts can be harmful. Mannitol is known to be present in amniotic fluid following administration to pregnant women during the third trimester.[12]

Breastfeeding considerations: There is insufficient data regarding mannitol's presence in human or animal milk and its effects on breastfed infants. When administering mannitol, it is crucial to balance the benefits of breastfeeding against the mother's clinical needs and potential risks to the infant from both the injection and the mother's condition.

Pediatric patients: Mannitol injection is approved to reduce intracranial and intraocular pressure. While the safety profile of mannitol in pediatric patients is similar to that of adults at labeled doses, caution is advised for children younger than 2 years old, especially neonates. This population may be at an increased risk of fluid and electrolyte abnormalities post-administration due to their reduced glomerular filtration rate and limited urine concentration ability.

Older patients: As the kidneys predominantly excrete mannitol, the risk of adverse reactions may be elevated for older adults, especially those with impaired renal function. Before administering mannitol, the patient's renal, cardiac, and pulmonary status should be assessed, and any fluid and electrolyte imbalances should be corrected.

Adverse Effects

Adverse drug reactions associated with the use of mannitol include:

• Masking or worsening dehydration, as mannitol causes diuresis
• Precipitation of heart failure due to the rapid fluid shifts as water enters the intravascular compartment
• Worsening of electrolyte abnormalities due to the shift of free water into the intravascular space. These abnormalities may include hyponatremia, hypokalemia, and hypocalcemia.[13]
• Precipitation of crystals at low temperatures can cause vascular and end-organ damage.

Mannitol crosses the vessel wall, albeit poorly, and more easily crosses injured vessels, such as in patients with intracranial hemorrhage. Frequent doses of mannitol can result in the drug crossing the blood-brain barrier and exacerbating cerebral edema by drawing water into (instead of out of) the brain. This is particularly true for children with cerebral hyperemia.[13]

Drug-Drug Interactions

Nephrotoxic drugs: Concurrent administration of mannitol and nephrotoxic drugs, including aminoglycosides and diuretics, should be avoided due to the potential for nephrotoxicity.[14]

Neurotoxic Drugs: Concurrent administration of neurotoxic drugs may exacerbate the CNS toxicity associated with mannitol and should be avoided.

Drugs affecting Electrolyte Balance: Serum electrolytes should be monitored. Mannitol administration should be discontinued if cardiac status worsens.

Renally-Eliminated Drugs: Concomitant administration of medications eliminated in urine may reduce the efficacy of these drugs. Lithium levels should be monitored closely if simultaneous administration with lithium is unavoidable.[15]

Contraindications

There are multiple contraindications to giving mannitol, including:

• Anuria due to renal disease
• Pulmonary edema or severe pulmonary congestion
• Active intracranial bleeding
• Severe dehydration
• Progressive heart failure
• Known hypersensitivity to mannitol or the gelatin (inhaled)
• Failure to pass the mannitol tolerance test (inhaled) [16]

Box Warning (Inhaled Mannitol)

Inhaled mannitol can induce severe bronchospasm. Bronchial challenge testing with mannitol is solely for diagnostic purposes. Inhaled mannitol should be administered only by trained professionals, under a physician's supervision, and in settings where acute bronchospasm can be adequately managed. Essential medications like short-acting inhaled β-agonists and equipment for severe bronchospasm treatment must be readily available during testing. Given the risk of severe bronchoconstriction, avoid performing bronchial challenge testing with mannitol in patients with evident asthma or significantly reduced baseline pulmonary function (FEV1 <1-1.5 liters or <70% of predicted values).

Warnings and Precautions

• If the patient has impaired renal function, a small test dose should be given, and the patient should be observed for a response. If there is no response, a small test dose is repeatable, but the clinician should administer no more than 2 test doses.[17]
• Mannitol initially increases the intravascular free water content, which can worsen electrolyte abnormalities, including hyponatremia. In the second phase of action, mannitol gets excreted in the urine with excess free water, potentially causing hypernatremia due to the induced diuresis. Electrolytes should be monitored carefully during mannitol therapy.[17]
• Mannitol may exacerbate intracranial hypertension, especially in children with hyperemia, which can be fatal.
• Repeated frequent doses of mannitol can worsen cerebral edema in the long term. Thus, mannitol is frequently recommended as a bolus spaced apart every 6 to 8 hours, limiting the number of boluses given.
• Mannitol can worsen renal function and precipitate renal failure.[18]
• Mannitol should only be given intravenously and never given intramuscularly or subcutaneously.
• Mannitol should not be administered with whole blood.
• Hemoptysis may occur with the use of inhaled mannitol. Close monitoring is required for patients with a history of hemoptysis episodes. If hemoptysis occurs, discontinue inhaled mannitol.[19]

Monitoring

When administering mannitol, it is essential to monitor cardiac function as fluid shifts can precipitate heart failure. Electrolyte levels, including sodium, potassium, and osmolality, all require monitoring. Mannitol should be discontinued if significant electrolyte abnormalities develop or the osmolality reaches 320 mOsm or higher. Finally, urine output also requires monitoring; failure to increase urine output after administration of mannitol should prompt discontinuation and evaluation for possible renal or genitourinary issues.[17] Renal function should be monitored in patients receiving mannitol due to the risk of acute kidney injury.[20]

Toxicity

Signs and Symptoms of Overdose

Clinical features of overdose include hypervolemia/hypovolemia, hyperosmolarity, acute kidney injury, CNS toxicity-like coma or seizures, and electrolyte imbalances.

Management of Overdose

Management of mannitol injection overdose is primarily symptomatic and supportive. This management involves discontinuing the infusion and addressing fluid and electrolyte imbalances. Dialysis partially removes mannitol. Repeated doses of mannitol lead to the build-up of mannitol even with dialysis.[21]

Enhancing Healthcare Team Outcomes

An interprofessional team approach is optimal for mannitol administration. Monitoring cardiac function is essential as the fluid shifts can precipitate heart failure. Additional electrolytes, including sodium, potassium, and osmolality, require monitoring by the nurses and physicians. Abnormalities in these laboratory values necessitate prompt action from team members. Mannitol administration should stop if significant electrolyte abnormalities develop or the osmolality reaches 320 mOsm or higher. When mannitol treats cerebral edema, serum osmolality should be checked every 4 to 6 hours. If serum osmolality exceeds 320 mOsm, alternative agents like the hypertonic solution should be used.[20] Neurosurgery and neurocritical care consultation is indicated for cerebral edema cases. Pulmonology consultation is indicated for cystic fibrosis/asthma.

The nursing staff should carefully monitor urine output, reporting concerns to the treating clinician. The pharmacist can verify dosing, perform medication reconciliation, and alert the team for potential interactions. They can also collaborate with the attending physician regarding potential alternative therapies in the event of therapeutic failure or mannitol intolerance. With open interprofessional communication between all healthcare team members, mannitol therapy has the best chance at optimal results. An interprofessional team approach and open communication between clinicians (MDs, DOs, NPs, PAs), pharmacists, nurses, and specialists are necessary to optimize patient outcomes with mannitol therapy.