Skip OutlineFree

FasttoFeatures Skip toAccess AccountsSkip toProducts

Topic Skip to References Help
×
Gift for you Donate Now x
Procurar no UpToDate

Universidad de ConcepcionUniversidad de Concepcion

Registro
Entrar

Conteúdo

Novidades
Atualizações sobre mudanças na prática
Informação sobre medicamentos
Orientação a paciente
Tópicos por especialidade
Autores e editores

Calculadoras
Interações de Medicamentos
UpToDate Pathways

Registro
Entrar

Menu

Saiba como o UpToDate pode ajudar você

Selecione a opção que o descreva melhor

Profissional Médico

Residente, Fellow ou Estudante

Hospital ou Instituiçõe

Consultório ou clínica

Paciente ou Cuidador

Assinar

Ver tópico
Encontrar
Imprimir
Compartilhar

Feedback
Ferramentas

Voltar
Complications of mannitol therapy

Topic Outline
 SUMMARY AND RECOMMENDATIONS
INTRODUCTION
COMPLICATIONS
Volume depletion and hypernatremia
Volume expansion, hyponatremia, hyperkalemia, hypokalemia, and metabolic acidosis
Plasma osmolal gap
Acute kidney injury
SUMMARY AND RECOMMENDATIONS
REFERENCES

RELATED TOPICS
Angle-closure glaucoma
Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis
Evaluation and management of elevated intracranial pressure in adults
Hyponatremia following transurethral resection, hysteroscopy, or other procedures involving electrolyte-free irrigation
Serum osmolal gap

Complications of mannitol therapy

Author:
Richard H Sterns, MD
Section Editor:
Michael Emmett, MD
Deputy Editor:
John P Forman, MD, MSc

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2020. | This topic last updated: Jul 27, 2020.

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 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 '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 renal insufficiency. 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 renal
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.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES
1. GIPSTEIN RM, BOYLE JD. HYPERNATREMIA COMPLICATING PROLONGED MANNITOL DIURESIS. N Engl J Med 1965;
 272:1116.
2. Aviram A, Pfau A, Czaczkes JW, Ullmann TD. Hyperosmolality with hyponatremia, caused by inappropriate administration of
mannitol. Am J Med 1967; 42:648.
3. Dorman HR, Sondheimer JH, Cadnapaphornchai P. Mannitol-induced acute renal failure. Medicine (Baltimore) 1990; 69:153.
4. Oster JR, Singer I. Hyponatremia, hyposmolality, and hypotonicity: tables and fables. Arch Intern Med 1999; 159:333.
5. 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.
6. Fanous AA, Tick RC, Gu EY, Fenstermaker RA. Life-Threatening Mannitol-Induced Hyperkalemia in Neurosurgical Patients. World
Neurosurg 2016; 91:672.e5.
7. 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.
8. Nicolis GL, Kahn T, Sanchez A, Gabrilove JL. Glucose-induced hyperkalemia in diabetic subjects. Arch Intern Med 1981; 141:49.
9. Viberti GC. Glucose-induced hyperkalaemia: A hazard for diabetics? Lancet 1978; 1:690.
10. Seo W, Oh H. Alterations in serum osmolality, sodium, and potassium levels after repeated mannitol administration. J Neurosci Nurs
2010; 42:201.
11. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.607.
12. DiNubile MJ. Serum osmolality (letter). N Engl J Med 1984; 310:1609.
13. 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.
14. 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.
15. Visweswaran P, Massin EK, Dubose TD Jr. Mannitol-induced acute renal failure. J Am Soc Nephrol 1997; 8:1028.
16. Pérez-Pérez AJ, Pazos B, Sobrado J, et al. Acute renal failure following massive mannitol infusion. Am J Nephrol 2002; 22:573.
17. Better OS, Rubinstein I, Winaver JM, Knochel JP. Mannitol therapy revisited (1940-1997). Kidney Int 1997; 52:886.
18. 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.
19. Gondim Fde A, Aiyagari V, Shackleford A, Diringer MN. Osmolality not predictive of mannitol-induced acute renal insufficiency. J
Neurosurg 2005; 103:444.
20. 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.
21. 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.

Topic 2333 Version 15.0

Close

© 2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Language

Language
Suscripción y Acuerdo de licencia
Políticas
Etiqueta de soporte

Contacto
Acerca de nosotros
Noticias sobre UpToDate
Opciones de acceso a UpToDate
Ayuda y Formación
Demos

Wolters Kluwer Health

Emmi®
Facts & Comparisons®
Lexicomp®
Medi-Span®

Loading
Please wait