Continuing Education Activity

Mannitol can be used for the reduction of intracranial pressure and brain mass, to reduce intraocular pressure if this is not achievable by other means, to promote diuresis for acute renal failure to prevent or treat the oliguric phase before irreversible damage, and to promote diuresis to promote excretion of toxic substances, materials, and metabolites. There are also multiple uses of mannitol that are not FDA-approved. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of mannitol, pertinent for interprofessional team members in treating patients with conditions where it is of clinical value.

Objectives:

• Identify the FDA-approved indications for mannitol.
• Explain the mechanism of action for mannitol for each of the four FDA-approved indications.
• Review the adverse effects and contraindications for using mannitol.
• Summarize interprofessional team strategies for improving care coordination and communication to advance mannitol and improve outcomes.

Indications

Mannitol has four Food and Drug Administration (FDA)-approved uses.

1. Mannitol has approval for the reduction of intracranial pressure and brain mass.[1]
2. Mannitol is approved to reduce intraocular pressure if this is not achievable by other means.[2]
3. Mannitol can promote diuresis for acute renal failure to prevent or treat the oliguric phase before irreversible damage.[3] 
4. Mannitol can also promote diuresis to promote the excretion of toxic substances, materials, and metabolites.[4]

 There are multiple uses of mannitol that are not FDA-approved. 

• Mannitol may be used to prime a heart and lung machine before putting the patient on a heart-lung bypass. The mannitol may help to preserve renal function as the kidneys have decreased blood flow.  The mannitol is suspected to decrease renal cell swelling. 
• Mannitol works to protect sharp objects as they get introduced into a vascular space. A mannitol cap on a pacemaker wire will protect the tip from becoming dulled while a clinician introduces it into the vascular system then the mannitol will readily dissolve away with minimal effect.
• Mannitol may have utility as a challenge test for diagnosing asthma.[5]
• Mannitol is a sweetener for diabetic food products. Mannitol is sugar but increases blood glucose to a lesser extent than some other sugars such as sucrose.

Mechanism of Action

Mannitol is a six-carbon, linear, simple sugar that is only mildly metabolized by the body and primarily excreted rapidly by the kidneys when given intravenously and poorly absorbed when taken orally. 

The FDA-approved indications for mannitol are all for intravenous mannitol and are detailed below.

Mannitol for Increased Intracranial Pressure

Mannitol may be used for the reduction of intracranial pressure. In this indication, 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 water then travels with the mannitol to the kidneys, where it gets excreted in the urine.[4]

The mannitol causes the cells in the brain to dehydrate mildly. The water inside the brain cells (intracellular water) leaves the cells and enters the bloodstream as the mannitol draws it out of the cells and into the bloodstream. Once in the bloodstream, the extra water is whisked out of the skull.  When the mannitol gets to the kidneys, the kidneys filter the mannitol into the urine. The mannitol again draws the water with it, and diuresis (increased urination) ensues.

Mannitol to Reduce Intraocular Pressure

Mannitol may be used to reduce intraocular pressure when given intravenously. The mannitol is a new solute in the intravascular space, which increases the tonicity of the blood plasma. The increased tonicity of the blood plasma draws water out of the vitreous humor of the eye and into the intravascular space. Once in the intravascular space, the mannitol and associated water are excreted by the kidney. The decreased water of the vitreous humor lowers the intraocular pressure.[6]

The mannitol dehydrates the vitreous humor. The mannitol draws water out of the vitreous humor and into the blood vessels as it passes by. When the vitreous humor has less water, after being dehydrated by the mannitol, it has less mass and thus creates less pressure. The lower pressure is less likely to damage the retina. The mannitol remains in the blood vessels and is excreted in the urine with its associated water.

Mannitol to Promote Diuresis in 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/hour for children and less than 400 mL/day for adults. The fluid which does not get excreted remains in the body and causes fluid overload. Fluid overload causes issues such as decreased oxygenation and ventilation, electrolyte abnormalities, swelling, encephalopathy, and cardiac arrest. An individual with acute renal failure can sometimes be given intravenous mannitol. Even during acute renal failure, much of mannitol excretion is done by the kidneys. As the mannitol gets excreted, it draws water with it, increasing the water excretion of the patient and helping avoid or treat the fluid overload caused by oliguria in acute renal failure. However, mannitol causes significant osmotic injury to tubules leading to ATN(acute tubular necrosis), so its use for this indication is almost obsolete.

Mannitol to Excrete Toxic Materials

Much like mannitol given for oliguria of acute renal failure, mannitol can be given to increase the excretion of toxic materials, substances, and drugs. The kidneys excrete mannitol, which is poorly reabsorbed once excreted and thus draws extra water with it 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.

Mannitol to Prevent Intradialytic Hypotension

Intradialytic hypotension and dialysis disequilibrium symptoms are common in hemodialysis patients.  This is due to a drop in intradialytic osmolality. Mannitol can be used to prevent intradialytic hypotension by raising serum osmolality.[7]

Additional Mechanisms of Action

Since mannitol is a sugar and it provides a sweet taste when ingested orally. Mannitol also mostly passes through the intestine and is excreted in the feces as the small intestine absorbs it poorly. Thus, mannitol is used as a sweetener in food for diabetic patients as mannitol can provide sweetness to the food without increasing the blood sugar as much as sucrose.

Administration

When using mannitol for medical purposes, it is given intravenously. Mannitol can be found in varying concentrations from 5% mannitol (5 gm mannitol dissolved in 100 mL of fluid) up to 25% mannitol (25 gm of mannitol dissolved in 100 mL of fluid). A commonly encountered solution is 20% mannitol (20 grams of mannitol dissolved in 100 mL of fluid).[2]

• For increased intracranial pressure, dosages typically range from 0.25 g/kg to 2 g/kg administered intravenously over 30 to 60 minutes with effect within 5 to 10 minutes and lasting up to approximately 6 hours.
• For increased intraocular pressure, dosages typically range from 0.25 g/kg to 2 g/kg administered intravenously over 30 to 60 minutes with effect within 5 to 10 minutes and lasting up to approximately 6 hours.
• For prevention or treatment of oliguria, a test dose should be strongly considered of around 0.2 g/kg intravenous to ensure a response to urine output. The mannitol infusion can be adjusted to provide a urine flow rate of at least 30 mL/hour to 50 mL/hour in adults.
• For excretion of toxic materials, the clinician may consider a dose of 0.25 g/kg to 2 g/kg to observe its effects. If the patient receives more than 200 gm of mannitol without benefit, mannitol use should be discontinued.

Adverse Effects

There are multiple adverse effects that mannitol can cause, including:

• Masking or worsening dehydration as it causes diuresis
• Precipitate heart failure due to the rapid fluid shifts as water enters the intravascular compartment
• Cause or worsen electrolyte abnormalities due to the shift of free water into the intravascular space. Electrolyte abnormalities may include but are not limited to hyponatremia, hypokalemia, and hypocalcemia.[8]
• Precipitate into crystals at low temperatures, which can cause vascular and end-organ damage
• Worsen cerebral edema. Although mannitol poorly crosses the vessel wall, it does cross to some degree, and mannitol more easily crosses injured vessels such as patients with intracranial hemorrhage. Frequent doses of mannitol can cause mannitol to leach across the blood-brain barrier and worsen cerebral edema as the mannitol, which has leached into the brain, draws water into instead of out of the brain. Patients, especially children with cerebral hyperemia, may have worsening cerebral edema with mannitol administration.[8]

Contraindications

There are multiple contraindications to giving mannitol, including:

• Established anuria due to renal disease
• Pulmonary edema or severe pulmonary congestion
• Active intracranial bleeding except for during a current craniotomy
• Severe dehydration
• Progressive heart failure
• Known mannitol hypersensitivity
• Renal damage caused by mannitol
• Patients with impaired renal function: If the patient has impaired renal function, a small test dose should be given, and the patient observed for a response. If there is no response, a small test dose is repeatable, but the clinician should administer no more than two test doses.[9]
• Electrolyte abnormalities. As mannitol works, it first 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 with mannitol use.[9]
• Mannitol may worsen intracranial hypertension in patients, especially children with hyperemia, which can be fatal.
• Repeated frequent doses of mannitol can leach into the brain and 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.[10]
• Mannitol should only be given intravenously and never given intramuscularly or subcutaneously.
• Mannitol should not be administered with whole blood.

Monitoring

When giving mannitol, it is essential to monitor cardiac function as the fluid shifts can precipitate heart failure. Additional electrolytes, including sodium, potassium, and osmolality, all require monitoring. The clinician should stop mannitol if significant electrolyte abnormalities develop or the osmolality reaches 320 mOsm or higher. Finally, urine output also requires monitoring; failure for urine output to increase after administration of mannitol should prompt cessation of mannitol and evaluation for possible renal or genitourinary issues.[9]

Toxicity

Dialysis partially removes mannitol. Repeated doses of mannitol lead to the build-up of mannitol even with dialysis.[11]

Enhancing Healthcare Team Outcomes

An interprofessional team approach is an optimal approach with mannitol administration. It is essential to monitor cardiac function 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 communication to all members of the team. Mannitol administration should stop if significant electrolyte abnormalities develop or the osmolality reaches 320 mOsm or higher. When mannitol is used to treat cerebral edema, serum osmolality should be checked every 4 to 6 hours. If serum osmolality is more than 320 mOsm, alternative agents like the hypertonic solution should be used.

The nursing staff should pay particular attention to urine output and monitor it carefully, reporting any concerns to the treating clinician. The pharmacist can verify dosing and perform medication reconciliation and alert the team if any interactions are present. They can also collaborate with the treating physician regarding potential alternative therapies in the event of therapeutic failure or intolerance of mannitol. With open interprofessional communication between all healthcare team members, any treatment, including mannitol, has the best chance at optimal results. [Level 5]