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Complications of mannitol therapy

Complications of mannitol therapy
Literature review current through: Sep 2023.
This topic last updated: Aug 18, 2022.

INTRODUCTION — Mannitol, given as a hypertonic solution, is primarily used in the treatment of cerebral edema and glaucoma. Although generally well tolerated, a variety of fluid, electrolyte, and kidney complications can occur if the patient is not carefully monitored. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Mannitol' and "Angle-closure glaucoma", section on 'Management'.)

COMPLICATIONS

Volume depletion and hypernatremia — Mannitol is freely filtered by the glomerulus and does not undergo tubular reabsorption. Thus, it acts as an osmotic diuretic, increasing urinary losses of both sodium and electrolyte-free water. Lack of replacement of the fluid losses can lead to both volume depletion and hypernatremia that can be severe [1].

Volume expansion, hyponatremia, hyperkalemia, hypokalemia, and metabolic acidosis — If very high doses of hypertonic mannitol are infused, or if the drug is given to patients with preexisting kidney failure, mannitol is retained in the circulation [2-4]. The ensuing rise in plasma osmolality, similar to that produced by hyperglycemia, results in the osmotic movement of water and potassium out of cells leading to extracellular fluid volume expansion (and possibly pulmonary edema), hyponatremia, metabolic acidosis (by dilution), and hyperkalemia [5,6]. Water losses from brain cells cause neurologic symptoms. Volume expansion and dilutional hyponatremia, without neurologic symptoms, can also be induced when isotonic mannitol is used as a flushing solution during transurethral resection of the prostate or bladder. (See "Hyponatremia following transurethral resection, hysteroscopy, or other procedures involving electrolyte-free irrigation".)

The rise in the plasma potassium concentration following hypertonic mannitol is due to the movement of potassium out of the cells into the extracellular fluid via two mechanisms [6]: (1) the rise in cell potassium concentration induced by water loss favors passive potassium exit through potassium channels in the cell membrane; and (2) the frictional forces between solvent (water) and solute can result in potassium being carried out through the water pores in the cell membrane (a process that is called solvent drag). A similar process can occur with acute hypernatremia [7] and also largely accounts for the hyperkalemia that is commonly seen with marked hyperglycemia in uncontrolled diabetes mellitus [8,9]. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis".)

If kidney function is normal, the transient shift of potassium out of cells due to mannitol seldom leads to hyperkalemia. A study of 45 patients treated for several days with mannitol (average dose, 28 g every six hours) for neurosurgical conditions found only one patient (2.4 percent) with a serum potassium above 5.5 mEq/L on the first day, and no patients with hyperkalemia on subsequent days [10]. By contrast, 22 percent of patients developed hypokalemia (serum potassium <3.5 mEq/L) on the first day, and this proportion increased to 52 percent by the third day. Hypokalemia is likely caused at least in part by increased flow rates in the aldosterone-responsive distal nephron (caused by osmotic diuresis), which leads to increased obligatory potassium losses.

Plasma osmolal gap — The concentration of mannitol in the plasma can be estimated from an increase in the plasma osmolal gap, which is the difference between the measured plasma osmolality (which includes the contribution of mannitol) and the calculated plasma osmolality [11,12]. The latter assumes that sodium salts (chloride and bicarbonate), glucose, and urea nitrogen are the primary solutes in the plasma and can be estimated from the following formula:

 Calculated Posm  =  2  x  Plasma Na (mEq/L) + [Glucose]/18 + Blood urea nitrogen/2.8

The plasma sodium is multiplied by two to account for accompanying anions (chloride and bicarbonate) and dividing by 18 and 2.8 for the glucose and blood urea nitrogen convert units of mg/dL into mmol/L [11]. The corrections for glucose and blood urea nitrogen are not necessary in countries that report the concentrations in mmol/L.

A number of other formulas have been used to estimate the plasma osmolal gap. There appears to be no significant difference between the accuracy of the different formulas and their correlation with plasma mannitol concentrations [13]. To avoid acute kidney injury (AKI), the plasma osmolal gap should not be allowed to exceed 55 mosmol/kg when mannitol is used in the treatment of cerebral edema. In animal models, a plasma mannitol concentration above 1000 mg/dl (ie, above approximately 55 mosmol/kg) produces renal vasoconstriction, whereas lower concentrations are generally associated with increased renal blood flow and decreased renal vascular resistance [3]. (See "Serum osmolal gap".)

Acute kidney injury — Patients with marked mannitol accumulation (plasma osmolal gap greater than 60 to 75 mosmol/kg, which reflects a plasma mannitol concentration above 1080 mg/dL) may develop reversible AKI [3,14-16]. This complication is essentially limited to patients treated with more than 200 to 300 g of mannitol per day [17,18]. The required dose varies with baseline kidney function. AKI in patients with normal baseline kidney function is usually seen when the total mannitol dose exceeds 1100 g. By contrast, much smaller doses (>300 g) can precipitate AKI in patients with preexisting kidney disease.

The incidence of AKI in patients treated with mannitol has ranged from 6 to 11 percent in various studies [19-21]. The existence of comorbid conditions (eg, heart failure, diabetes, preexisting kidney disease) appear to increase the risk. The following studies illustrate the range of findings:

A prospective study of 95 patients treated with mannitol for increased intracranial pressure caused by a variety of insults, including trauma, found that 11 patients (11.6 percent) developed AKI (defined as a 0.5 mg/dL [44.2 micromol/L] or greater increase in serum creatinine or a 1 mg/dL [88.4 micromol/L] or greater increase if the baseline creatinine was >2 mg/dL [177 micromol/L]) [19]. Patients who did and did not develop AKI received similar total mannitol doses (7.9±9.3 versus 10.2±10.7 g/kg) as well as maximum single mannitol doses (3.4±1.9 versus 3.1±2 g/kg). Similarly, there were no differences in the peak osmolality or the osmotic gap before the onset of kidney function impairment. The presence of heart failure and a high APACHE II score were the only factors independently associated with a higher likelihood of mannitol-induced AKI. Kidney function spontaneously returned to baseline in all patients.

A larger retrospective study of 432 mannitol-treated patients who were critically ill following a stroke found that the incidence of AKI (defined as a 0.3 mg/dL [26.5 micromol/L] or 50 percent increase in serum creatinine) was only 6.5 percent (with none requiring kidney replacement therapy) [20]. Diabetes, lower baseline estimated glomerular filtration rate, higher initial National Institutes of Health Stroke Scale (NIHSS) score, and concurrent use of diuretics increased the risk of mannitol-related AKI. Risk of AKI was greater among those treated with higher mannitol doses, but this was not statistically significant. The lower incidence of AKI in this study compared with the study mentioned previously may be due to the lower cumulative doses of mannitol that were used or to the fact that none had traumatic brain injury.

Although tubular vacuolization also may contribute, renal vasoconstriction appears to be of primary importance in this setting, an effect which may be potentiated by the concomitant administration of cyclosporine [15]. Coadministration of furosemide may also increase the risk of kidney injury [18].

AKI can be minimized by keeping the mannitol dose below 0.25 g/kg every four hours (1.5 g/kg daily) [3]. Patients who develop AKI may recover kidney function rapidly (within 24 hours) if treated with one to two hemodialysis sessions to remove the excess mannitol; by contrast, patients managed without dialysis may recover kidney function more slowly (7 to 10 days) [14]. In the presence of oliguric AKI, mannitol has a half-life of 36 hours; with hemodialysis, the half-life decreases to six hours.

SUMMARY AND RECOMMENDATIONS

Mannitol acts as an osmotic diuretic, resulting in fluid losses that can lead to both volume depletion and hypernatremia. (See 'Volume depletion and hypernatremia' above.)

Retention of mannitol due to underlying kidney failure or mannitol-induced acute kidney injury (AKI) results in hyperosmolality and osmotic movement of water and potassium out of the cells, which can cause volume expansion, hyponatremia and metabolic acidosis (by dilution), and hyperkalemia. (See 'Volume expansion, hyponatremia, hyperkalemia, hypokalemia, and metabolic acidosis' above.)

The concentration of mannitol in the plasma can be estimated from the plasma osmolal gap, the difference between the measured plasma osmolality (which includes the contribution of mannitol) and the calculated plasma osmolality (which does not). (See 'Plasma osmolal gap' above.)

A plasma osmolal gap greater than 55 mosmol/kg and a mannitol dose exceeding 250 mg/kg every four hours increase the risk of reversible AKI. Higher mannitol doses are, however, sometimes used in patients judged to be at risk for brain herniation. Patients who develop kidney injury appear to recover kidney function rapidly if treated with hemodialysis to remove the excess mannitol.

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