Mannitol

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

INTRODUCTIONMannitol 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

5 275

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 CAREThe 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 effectsOsmotic 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 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 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 MannitolHaemodynamic 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 NeuroprotectionMannitol 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 PROTECTIONIn 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 effectsMannitol 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 functionAlthough 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 ARFOther 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 rhabdomyolysis10. However, nowadays the first line of treatment for prevention of myoglobinuric ARF is volume expansion with saline.

Mannitol for the management of acute renal failureIn 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 protectionMannitols 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 SCAVENGERMannitol 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 USESReduction of intraocular pressureTo 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 intoxicationsTo 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 ResectionSolutions containing 2.5-5% mannitol are used as irrigating solutions in TURP.Concentrations of at least 3.5% are necessary to prevent hemolysis.

Pediatric DosageMannitol 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.

CONCLUSIONSAlthough 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.