Complications of mannitol therapy
- Richard H Sterns, MD
Richard H Sterns, MD
- Editor-in-Chief — Nephrology
- Section Editor — Fluid and Electrolytes
- Professor of Medicine
- University of Rochester School of Medicine and Dentistry
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 renal 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 'Treatment'.)
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 .
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 renal 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 or hysteroscopy".)
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 : (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  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 . 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.
- GIPSTEIN RM, BOYLE JD. HYPERNATREMIA COMPLICATING PROLONGED MANNITOL DIURESIS. N Engl J Med 1965; 272:1116.
- Aviram A, Pfau A, Czaczkes JW, Ullmann TD. Hyperosmolality with hyponatremia, caused by inappropriate administration of mannitol. Am J Med 1967; 42:648.
- Dorman HR, Sondheimer JH, Cadnapaphornchai P. Mannitol-induced acute renal failure. Medicine (Baltimore) 1990; 69:153.
- Oster JR, Singer I. Hyponatremia, hyposmolality, and hypotonicity: tables and fables. Arch Intern Med 1999; 159:333.
- Manninen PH, Lam AM, Gelb AW, Brown SC. The effect of high-dose mannitol on serum and urine electrolytes and osmolality in neurosurgical patients. Can J Anaesth 1987; 34:442.
- Fanous AA, Tick RC, Gu EY, Fenstermaker RA. Life-Threatening Mannitol-Induced Hyperkalemia in Neurosurgical Patients. World Neurosurg 2016; 91:672.e5.
- Conte G, Dal Canton A, Imperatore P, et al. Acute increase in plasma osmolality as a cause of hyperkalemia in patients with renal failure. Kidney Int 1990; 38:301.
- Nicolis GL, Kahn T, Sanchez A, Gabrilove JL. Glucose-induced hyperkalemia in diabetic subjects. Arch Intern Med 1981; 141:49.
- Viberti GC. Glucose-induced hyperkalaemia: A hazard for diabetics? Lancet 1978; 1:690.
- Seo W, Oh H. Alterations in serum osmolality, sodium, and potassium levels after repeated mannitol administration. J Neurosci Nurs 2010; 42:201.
- Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.607.
- DiNubile MJ. Serum osmolality (letter). N Engl J Med 1984; 310:1609.
- García-Morales EJ, Cariappa R, Parvin CA, et al. Osmole gap in neurologic-neurosurgical intensive care unit: Its normal value, calculation, and relationship with mannitol serum concentrations. Crit Care Med 2004; 32:986.
- Gadallah MF, Lynn M, Work J. Case report: mannitol nephrotoxicity syndrome: role of hemodialysis and postulate of mechanisms. Am J Med Sci 1995; 309:219.
- Visweswaran P, Massin EK, Dubose TD Jr. Mannitol-induced acute renal failure. J Am Soc Nephrol 1997; 8:1028.
- Pérez-Pérez AJ, Pazos B, Sobrado J, et al. Acute renal failure following massive mannitol infusion. Am J Nephrol 2002; 22:573.
- Better OS, Rubinstein I, Winaver JM, Knochel JP. Mannitol therapy revisited (1940-1997). Kidney Int 1997; 52:886.
- Dickenmann M, Oettl T, Mihatsch MJ. Osmotic nephrosis: acute kidney injury with accumulation of proximal tubular lysosomes due to administration of exogenous solutes. Am J Kidney Dis 2008; 51:491.
- Gondim Fde A, Aiyagari V, Shackleford A, Diringer MN. Osmolality not predictive of mannitol-induced acute renal insufficiency. J Neurosurg 2005; 103:444.
- Lin SY, Tang SC, Tsai LK, et al. Incidence and Risk Factors for Acute Kidney Injury Following Mannitol Infusion in Patients With Acute Stroke: A Retrospective Cohort Study. Medicine (Baltimore) 2015; 94:e2032.
- Kim MY, Park JH, Kang NR, et al. Increased risk of acute kidney injury associated with higher infusion rate of mannitol in patients with intracranial hemorrhage. J Neurosurg 2014; 120:1340.