MANNITOL: ITS PLACE IN CURRENT CLINICAL PRACTICE

by
Dr. Rajnish K. Jain, M.D.
Associate Professor, Anaesthesiology & Critical Care,
Bhopal Memorial Hospital & Research Centre, Bhopal - 462038

INTRODUCTION
Mannitol is a derivative of the carbohydrate mannose, a six-carbon sugar that does not
undergo any metabolism and is rapidly filtered by the glomeruli, leading to osmotic
diuresis. Its uses are widespread in clinical practice. However, the area of controversy is
its use as a protective and therapeutic agent in neurological or renal compromise and as a
potential scavenger of oxygen free radicals.
Chemistry
Mannitol occurs as a white, crystalline powder. The approximate osmolarity of mannitol
solutions are as follows:

% Mannitol

mOsm/L

275

10

550

15

825

20

1100

25

1375

Mannitol should be stored at 15 - 30 C and protected from freezing. If crystallization

occurs, the solution should be autoclaved or warmed. If all the crystals cannot be
dissolved, the solution should not be used.
MANNITOL AND NEUROCRITICAL CARE
The concept of osmotic agents reducing cerebral water content was suggested by Weed
and McKibben in 1919.1 They noted cerebral dehydration after intravenous hypertonic
saline. Mannitol was introduced in the early 1960s and since then, it has become the most
widely used agent to control ICP in both elective neurosurgery and in traumatic brain
injury.
Mechanisms of neuroprotective effects
Osmotic action
Mannitol is hyperosmolar relative to intracellular fluid hence, intravenous administration
results in movement of free water from the tissues into the plasma. There is a more
pronounced effect in the brain due to the fact that the blood-brain barrier (BBB) differs
from all other capillaries membranes in being relatively impermeable to mannitol, thus
maintaining the osmotic gradient.
Haemodynamic and viscosity changes
Under normal physiological conditions, ICP is principally determined by cerebral blood
volume (CBV) which is in turn, controlled by cerebral perfusion pressure (CPP), cerebral
vascular resistance and blood viscosity. When intracranial compliance is reduced, such as
after a traumatic brain injury (TBI), any maneuver which, improves oxygen delivery
reduces CBV, and thus ICP, by inducing vasoconstriction of cerebral blood vessels.
Mannitol probably improves oxygen delivery both by increasing CPP and reducing blood
viscosity. The increase in CPP comes from its plasma expanding effect, which causes an
increased cardiac output. Factors causing viscosity reduction include haemodilution,
decreased adhesiveness of red cells and increased red cell deformability, thereby reducing
resistance to capillary blood flow. These changes are responsible for the prompt reduction
in ICP seen clinically.
Diuretic action of mannitol
Mannitol could decrease ICP through a fall in CVP as a result of the osmotic diuresis.
However, this is unlikely given that ICP reduction occurs long before the diuresis, and a
normal or elevated CVP is not incompatible with a good response to mannitol.
Mannitol and CSF production/resorption

Although never proven satisfactorily and probably of little significance, mannitol may
increase resorption and reduce production of CSF by increasing plasma osmolality. The
site of action is postulated to occur at the level of the pial circulation or at the cerebral
ventricles.
Mannitol as an oxygen free radical scavenger
An additional, although theoretical, beneficial effect of mannitol could be a reduction of
ischaemic damage and oedema by a free radical scavenging action. This may be as a
result of specific interference with oedema promoting factors or a reduction in brain
tissue necrosis from the primary injury.
Mannitol in traumatic brain injury (TBI)
Although, the outcome from a severe TBI is bleak, nevertheless, it is accepted that
reducing a raised ICP is a useful maneuver, the rationale being that a fall in ICP to near
normal limits improves CBF and CPP, and increases oxygen delivery to the brain, which,
in turn, reduces anaerobic glycolysis and hence cerebral oedema. In a particular study,
persistently raised ICP resulted in a mortality of > 90%, while reduction to near normal
limits (12-15 mmHg) decreased mortality to 26%2.
Although mannitol has become the cornerstone of the pharmacological management of
raised ICP after TBI (Glasgow Coma Scale <8), it has never been subjected to a
controlled trial against placebo. Certain factors do indicate whether mannitol is likely to
be beneficial after a brain injury. These include, its ability to produce a prompt, persistent
reduction of ICP to or below 15 mmHg, to reduce an initially high ICP of >50 mmHg or
the ability to maintain CPP at or below the lower limit of autoregulation. Diffuse
widespread injuries respond more than focal injury and there is a greater benefit seen in
patients <40 years of age with an initial systolic blood pressure >90 mmHg.
Considerations for administration of Mannitol:
Effective dose
The initial recommended doses of 2 g/kg has fallen in recent years to between 0.25-1
g/kg, & larger doses appear to prolong the effect on ICP. Mannitol should be used with
caution in renal impairment.
Rate and timing of administration
Mannitol is usually given by slow bolus infusion over 15-30 min to limit significant
haemodynamic changes. There is no fixed interval for repeat boluses, but it is usually
every 3-4 h, as this is the time taken for mannitol (terminal half life 1-2 h) to clear from
the circulation if renal function is normal. Tachyphylaxis may occur with more than 3-4
doses per 24 hr. Continuous infusion is avoided as small amounts of mannitol may pass

into the brain and accumulate. This could result in reverse osmotic shift, consequently
increasing the cerebral oedema and exacerbating ICP.
Criteria for administration
Clinical indications for the use of mannitol in the absence of ICP monitoring include
signs of transtentorial herniation or progressive neurological deterioration not attributable
to systemic pathology. Because cerebral oedema occurs soon after the primary event, it
has been suggested that mannitol should be given as soon as possible after injury, even if
this is outside a hospital setting.
Optimal concurrent fluid therapy
Moderate fluid restriction is traditionally advocated in the acute management of TBI.
However, this has to be balanced against the need for adequate fluid replacement to
prevent dehydration, particularly given the diuretic effects of mannitol and the
consequent risks of hyper viscosity and renal impairment. The use of large volumes (> 2
l) of hypotonic 0.45% saline solution over 4-8 h have been advocated to counteract the
hyperosmolar effect of mannitol and also promote its rapid clearance so limiting renal
impairment. Good hydration also maintains intravascular volume and optimises blood
pressure and CPP.
Complications of Mannitol
Haemodynamic changes
Although mannitol increases blood pressure slightly, it can occasionally cause a fall in
blood pressure due to a decrease in systemic vascular resistance. Possible explanations
for this include a fall in plasma pH, increased release of atrial natriuretic factor (ANF),
basophil histamine release and direct impairment of the contractile properties of vascular
smooth muscle. Any hypotension is usually transient, but it could compromise cerebral
perfusion to an extent that offsets any potential benefit of mannitol.
Paradoxical increases in ICP
Bolus infusions of mannitol can double CBV. This is not usually clinically significant,
however, as CBV comprises such a small percentage (approximately 10%) of the total
intracranial space. Any increases in ICP are usually mild and transient and are usually
offset by the reduction in brain water and CSF volume. Mild hyperventilation, often used
in TBI, also tends to counteract any increase in CBV.
Dehydration and electrolyte disturbances
Dehydration is often concealed as mannitol shifts fluid into the intravascular
compartment, thus preserving circulating volume so that clinical signs of haemodynamic
compromise may not develop until intracellular dehydration is severe. Alternately,

accumulation of mannitol due to inadequate urine output or due to rapid administration of

large doses may result in over expansion of extracellular fluid,leading to circulatory
overload. Generally, there is electrolyte depletion, but it is proportionally much less than
fluid loss. Sodium may increase in the long term as a result of the hyperosmolar state, but
is often compensated by an increase in ADH, a common finding in the critically ill.
Conversely, hyponatremia may also occur, due to shift of sodium-free intracellular fluid
into extracellular spaces, resulting in dilutional lowering in serum sodium. Rarely,
hyperkalemia may also occur from haemolysis.
Hyperosmolality and osmotic compensation
Sustained use of mannitol results in a hyperosmolar state, which leads to movement of
osmotically active particles and electrolytes intracellularly. This increase in osmotic
activity within the cell counteracts the dehydrating effect of hyperosmolar plasma and
thus limits the reduction of brain volume. Because of this, mannitol should not be used
when plasma osmolality exceeds 320 mOsm/l. Cerebral oedema may occur if a
hyperosmolar state is reversed too quickly, and the speed of return to normal osmolality
should approximately match the duration of the hyperosmolar state. Cautious use of
isotonic (0.9%) saline is safer than hypotonic fluids such as enteral feeds or dextrose
solutions.
Renal failure
Mannitol in excess of 200 g/day may cause acute renal failure (ARF). This is more likely
in the elderly, in pre-existing renal failure and where patients are having concomitant
treatment with other diuretics.
The future of Mannitol for Neuroprotection
Mannitol has a well-established role in the short-term control of ICP for intracranial
surgery and after TBI. More recently, it has been promoted as a small volume
resuscitation fluid for cerebral protection and volume expansion in multiple trauma
patients. However, mannitol is being increasingly challenged by two other osmotic
agents, glycerol3 and hypertonic saline.4
Glycerols effects on ICP and CPP are similar to those of mannitol but appear to be more
consistent and sustained. Its diuretic action is less pronounced, favoring normovolaemia.
Glycerol crosses the BBB but there is minimal accumulation in the cerebral tissue,
because, it is metabolized by neuronal cells. Reverse osmotic shift is not, therefore,
thought to be a risk. It may also provide nutritional support to the damaged cells thus
having a protein sparing action. Its main side effect is haemolysis, which can be limited
by using a low concentration (< 20%), a slow infusion rate (> 1 h) and adding glucose,
fructose or chloride to the solution. It has been suggested that glycerol be used as the first
line treatment in the management of brain injured patients with increased ICP and
impaired CPP, while mannitol is reserved for sudden increases in ICP.

Hypertonic saline is also being promoted as superior to mannitol. It is effective in

reducing brain volume and ICP in animal and human studies, in elective neurosurgery
and in brain injured children. More significantly, it has also been found to be effective in
reducing a raised ICP refractory to treatment with mannitol. Hypertonic saline also has
the advantage of not significantly reducing intravascualr volume. The diuretic action of
mannitol, once considered beneficial, may, in fact, worsen outcome in TBI, as the
damaged brain appears to be exceptionally vulnerable to a fall in CPP caused by
hypovolaemia-induced hypotension.
Thus, although mannitol is currently the most popular osmotic agent, it may well be that
hypertonic saline, the original osmotic fluid first used by Weed and McKibben almost a
century ago, will become the treatment of choice for raised intracranial pressure in the
next millennium.
MANNITOL AND RENAL PROTECTION
In 1945, mannitol was experimentally found to induce diuresis in dogs subjected to a
renal ischaemic insult.5 Since then, mannitol has been widely, but controversially, used in
the prophylaxis and treatment of acute renal failure (ARF).
Possible mechanisms of Renal effects
Mannitol is effectively inert and is freely filtered at the glomerulus without being secreted
or substantially re-absorbed (< 5%). Diuresis is brisk, with total body water loss up to
30% of the filtered amount. The precise mechanisms by which the diuresis occurs have
not been fully elucidated, but include changes of systemic and renal haemodynamics as
well as local effects at the glomerular and tubular levels.
Systemic haemodynamic changes
Following intravenous administration, mannitol is confined mainly to the inravascular
compartment causing a water shift from the intracellular compartment. This leads to
intravascular volume expansion and to decreased plasma oncotic pressure, blood
viscosity and haematocrit, all of which may improve renal perfusion. Mannitol increases
plasma levels of the vasodilatory hormone, atrial natriuretic factor (ANF), probably as a
result of intravascular volume expansion and may have a synergistic action with it to
improve renal perfusion.
Renal haemodynamic effects
Infusion of mannitol has been shown to improve renal blood flow (RBF) and glomerular
filtration rate (GFR) by reducing renal vascular resistance (RVR). This effect is explained
by a reduction in plasma viscosity, although, mannitol may also stimulate release of
vasoactive agents such as prostacyclin (PGI2). This increased renal perfusion is associated
with proportional increases in both cortical and medullary blood flows. The latter may be
responsible for the loss of medullary hypertonicity observed during osmotic diuresis,

which could explain the inhibition of salt and water resorption in the loop of Henle.
Conversely, high doses of mannitol may cause renal artery vasospasm and increased RVR
resulting in decreased renal perfusion, which may paradoxically impair renal function.
Glomerular effects
There are conflicting accounts of the glomerular effects of mannitol on GFR. In many in
vitro studies, mannitol has been shown to restore GFR of a hypoperfused kidney to near
normal values. Mechanisms proposed include preferential dilatation of the afferent
glomerular arteriole due to suppression of rennin release and intrarenal formation of
angiotensin II.
Tubular effects
Mannitol is completely filtered at the glomerulus, without any reabsorption and as a
result, there is increase in osmolarity of renal tubular fluid and this prevents reabsorption
of water. Sodium is diluted in this retained water in the renal tubules, leading to less
reabsorption of this ion. Hence, along with the osmotic diuretic effect, there is urinary
excretion of water, sodium, chloride and bicarbonate ions.
Renal ischaemia of whatever origin leads to tubular cell oedema. This compresses the
interstitial and vascular spaces, resulting in poor renal perfusion and impaired renal
function. Mannitol has been shown to reduce tubular cell swelling, particularly in the
proximal tubule and thick ascending limb of the loop of Henle and it is assumed that this
helps to maintain both tubular flow and glomerular filtration. In addition, mannitol has
been found to increase intratubular pressure by increasing the flow of urine, which may
also help maintain patency of the tubular lumen.
The diuresis seen with mannitol leads to decreased tubular resorption of water and
solutes. As resorption is an energy requiring process, this reduction may be protective in
situations where impaired renal perfusion leads to poor oxygen delivery.
Mannitol and effects on Renal function
Although there are good theoretical reasons for mannitol to have a role in the prophylaxis
and salvaging of renal function, they are not convincingly supported by the available
evidence.
Nevertheless, one area where mannitol has been found to be invaluable is in preserving
renal function and reducing the incidence of ARF after cadaveric renal transplantation.6 A
number of well controlled prospective studies have shown that mannitol in the perfusate
of a cadaveric kidney prior to transplantation substantially reduced the incidence of both
graft rejection and the incidence of post-transplant ARF (in one study from 55% to 14%).
The same effect can be seen if mannitol is given just prior to restoration of blood flow to
the transplanted kidney.

Mannitol for the prophylaxis of ARF

Other than in renal transplantation, prophylactic mannitol does not appear to have any
significant protective effect on renal function. For example, pre-dosing with mannitol
prior to the use of radiocontrast agents in interventional radiology has shown no
protective effect on renal function.7 Despite initial hopes8, the results have also been
equally disappointing in preserving renal function after surgical relief of obstructive
jaundice. Patients who have infrarenal cross clamping during abdominal aortic aneurysm
surgery are particularly at risk of ARF, but here too, most studies have found mannitol to
be of little value9.
Mannitol has also been used to preserve renal function in rhabdomyolysis 10. However,
nowadays the first line of treatment for prevention of myoglobinuric ARF is volume
expansion with saline.
Mannitol for the management of acute renal failure
In established acute renal failure, mannitol is not only ineffective but can be hazardous
due to the risk of fluid overload. Its role in early renal failure is less clear as it can be
difficult to determine whether patients have pre-renal failure or have crossed the line into
established failure given that biochemical measurements are too insensitive to be helpful
in the early stages.
There are concerns that mannitol may actually increase the risk of ARF by increasing
renal artery oxygen consumption. In spite of receiving approximately 20% of cardiac
output, the kidney is very susceptible to ischaemia. There are two main reasons for this.
Firstly, the kidney extracts relatively little oxygen for metabolic processes and, secondly,
the medullary part of the kidney receives only 6% of renal blood flow (94% is supplied to
the cortex) despite being responsible for most of the energy requiring work of the kidney
(i.e. active resorption of solutes and water). Oxygen delivery to the medulla is thus
critical. If it is reduced by any means (e.g. hypoxaemia or hypoperfusion), renal function
will be compromised and this may occur even when total renal blood flow appears to be
adequate.
Mannitol increases both renal blood flow and glomerular filtration and thus there is a
greater solute and water load to be reabsorbed by the tubules. This leads to energy
expenditure and a concomitant rise in oxygen demand, so that mannitol may do more
harm than good in situations where there is impaired oxygen delivery. This increase in
solute load, however, needs to be balanced against mannitols ability to inhibit resorptive
processes in the loop of Henle by loss of medullary hypertonicity, and thus, presumably,
decrease the potential for increased oxygen consumption. The relative importance of
these two opposing forces is unknown.
Summary of the role of Mannitol in renal protection

Mannitols theoretical promise of effective protection against ischaemic injury of the

kidney proves in practice as illusory as its role in neuroprotection after acute brain injury.
Clinical trials fail to adequately demonstrate convincing advantages for mannitol except
in the case of cadaveric renal transplantation.
MANNITOL AS AN OXYGEN FREE RADICAL SCAVENGER
Mannitol has been proposed to act as an antioxidant OFR scavenger, specifically
targeting the OH- radical to cause its dimerization to non-toxic metabolites. Much of the
research on mannitols OFR scavenging capabilities has looked at reperfusion injury
following the restoration of oxygen supply to an ischaemic organ.11 Cardiac surgery
provides one of the easiest models for study in this field. In spite of cardioplegia solutions
and cooling for myocardial protection, there is often some postoperative depression of
myocardial function, which is thought largely to be due to an excess of OFRs produced
after cardiopulmonary bypass (CPB). Cardioplegia solutions also provide a relatively
simple and convenient method for introducing intervention therapies, such as mannitol.
Both, animal and human studies have shown a slight decrease in the incidence and
duration of atrial and ventricular arrhythmias as well as evidence of histological
preservation of the myocardial cell architecture and improvement in ventricular
function12. However, given the problem of detecting and measuring OFR production
accurately, it is difficult to know whether the results of these studies are directly related to
mannitols OFR scavenging capabilities or not.
There are several valid explanations for mannitols ineffectiveness in protecting against
reperfusion injury. OFRs are produced intracellularly and need to be mopped up
instantaneously in order to prevent molecular damage. Mannitol, on the other hand, tends
to remain in the extracellular compartment, with minimal amounts crossing the cell
membrane. It is thus unlikely that mannitol plays a significantly intracellular role in
preventing any significant oxidative damage.
Mannitol may act indirectly to reduce OFR production. It is an effective chelating agent
of ferric ions, which play a key role in converting poorly reactive oxygen species into
highly reactive and damaging OH- radicals. It may thus protect against such damage by
removing iron from the cellular molecules and structures at risk of oxidative damage.
Mannitol also forms a stable compound with hydrogen peroxide (H2O2), which is not a
free radical itself but can generate OH- radicals in the presence of ferric iron. This effect
has been investigated in patients undergoing CPB, where mannitol appears to react
directly with H2O2 to decrease its formation, although it has yet to be determined how
this significantly improves clinical outcome.
Another potentially advantageous and indirect action of mannitol may be through a
modifying action on complement formation. Complement fractions C3a and C5a are
released during CPB and bind to polymorphonuclear leukocytes (PMNL), which are then
stimulated to produce OFRs. Sequestered PMNL and complement fragments have been
found in the lung after CPB and have been proposed to be responsible for post bypass

lung changes such as reduction in the incidence of postoperative pulmonary oedema, and
this may reflect an OFR scavenging reaction, although its diuretic action cannot be
excluded.
One final area where mannitol has been successfully used is in the management of acute
compartment syndrome.13 Its uncertain, however, whether the reduction in the
reperfusion oedema and injury are due to its hyperosmolar or OFR scavenging effects or
both.
Summary of the role of Mannitol as an oxygen free radical scavenger:
On balance, inconclusiveness is a recurring theme in any discussion of mannitols role as
an OFR scavenger. Nevertheless, although the evidence for any significant effect is
scanty, it cannot be totally discounted and more conclusive research is required.
OTHER PARENTERAL USES
Reduction of intraocular pressure
To reduce intraocular pressure, the usual dose of mannitol is 1.5-2.0 g/kg administered as
a 15, 20, or 25% solution over a period of 30-60 minutes, administered 1- 1.5 hours prior
to surgery in order to achieve maximum reduction of pressure before surgery.
Adjunctive in drug intoxications
To promote diuresis in the adjunctive treatment of severe drug intoxications, various
mannitol regimens have been used. In general, a urinary output of at least 100 ml/hour,
but preferably 500 ml/hour, and a positive fluid balance of 1-2 L should be maintained.
Transurethral Prostate Resection
Solutions containing 2.5-5% mannitol are used as irrigating solutions in
TURP.Concentrations of at least 3.5% are necessary to prevent hemolysis.
Pediatric Dosage
Mannitol dosage requirements for patients 12 years of age & younger have not been
established.However, some clinicians have suggested the following dosages. In oliguria
or anuria, a test dose of 0.2 g/kg or 6 g/m2 may be given as a single dose over 3-5
minutes. For therapeutic purposes, 2g/kg or 60g/m2 may be given.For the oedema &
ascites, it may be given as a 15 or 20% solution over 2-6 hours.To reduce cerebral or
ocular oedema, it may be given as a 15 or 20% solution over 30-60 minutes.For the
treatment of intoxications, the drug may be given as a 5 or 10 % solution as needed.
CONCLUSIONS

Although mannitol is still widely used in many areas of medicine and its worth in renal
transplantation is unsurpassed, the evidence for its continued use for the management of
head injuries and renal failure is limited, while its value as an OFR scavenging agent has
yet to be finally decided.