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Osmotherapy and brain pathology

  • widely held generalizations that osmotherapy works only on undamaged brain regions because it requires an intact osmotic gradient are probably not warranted. When a pathological process alters the delivery of exogenous solute to the site of a lesion or the lesion itself involves the structure or function of the BBB, the effectiveness of the osmotherapy is likely to be altered:
  • reduction of the effective tonicity of any given hyperosmolar solution due to an increase in the permeability of the BBB tends to reduce movement of water from the lesion site.
  • in contrast, elevation of hydraulic conductivity associated with a damaged BBB tends to enhance removal of water from damaged tissue for any given transmural osmotic force.
  • in practice canít measure the net effect (note that they are separate features of the BBB and may be affected to different degrees)

Non-osmotic actions of mannitol

Haemodynamic and antiviscosity effects

- decreases the viscosity of blood (not only by decreasing haematocrit, but by decreasing the volume, rigidity, and cohesiveness of RBC membranes thereby decreasing the mechanical resistance to passage through the microvasculature)

- also decreases systemic vascular resistance, mild positive inotropic effect on the heart

- net effect is an increase in CO and oxygen delivery

Free radical scavenging

- has been known for some time that mannitol has free radical scavenging properties

- in combination with the above this makes it an attractive agent for promoting blood flow in areas of focally compromised perfusion

- may also have a role in prevention of no-reflow phenomena

- however there are no controlled data supporting the beneficial role of mannitolís free radical scavenging properties independent of the other well studied actions of mannitol


- there is relatively little information on the pharmacokinetics of mannitol infusions

- T1/2 elimination is about 30 to 60 mins for doses of 0.25 to 1.5 g/kg body weight

- Vd is theoretically the extracellular fluid volume but is limited by rapid renal clearance

Uses of mannitol in neurocritical care


  • ICP lowering effect is rapid, usually appearing within minutes, although the maximal effect may not be seen for 20-40 minutes or more.
  • Decrease in the ICP depend on the compliance at the time
  • Different CNS pathological conditions produce different patterns of change in volume dynamics and intracranial compliance because of the differential effects on the cardinal components of the intracranial space: parenchyma (~80%), cerebral blood volume (~10%), and CSF (~10%).

Osmotic theory of ICP reduction

- although difficult to prove it is reasonable to infer that bolus mannitol at the higher end of the clinically relevant dose range generates substantial blood-brain osmotic gradients and exerts at least some of its ICP lowering effect by direct removal of water from the parenchyma.

Haemodynamic theory of ICP reduction

- several variants exist, but all emphasise the importance of dynamic changes in the cerebral blood volume (CBV)

- osmotherapy is believed to reduce CBV by reducing blood viscosity, increasing CPP, or both.

- Muizelaar et al. reported a rapid reduction of the diameter of arterioles and venules on the surface of the brain immediately after a mannitol bolus. Extrapolation has led to the hypothesis that mannitol may induce a decrease in total CBV adequate to explain the reduction in ICP.

- other indirect evidence:if the CPP is low at the time of the mannitol bolus the ICP reduction is maximal and vice versa.

- shortcomings in the theory:

  • to date the report of vasoconstriction of brain vessels after mannitol have not been reproducible
  • serial measurements of CBV indicate that CBV may actually be increased not decreased

Diuretic Theory of ICP Reduction

- all osmotic agents can produce a variably brisk diuresis that ultimately can result in reduction of the circulating plasma volume and hence CVP

- in most circumstances the ICP is virtually identical to the CVP , and it is thus reasonable to assume that at least part of the ICP lowering effect of osmotic agents can be ascribed to their diuretic action.

- it is important to note however, the period of ICP reduction precedes the diuretic phase by a substantial period

- reduction of CVP probably plays a role in sustaining the effect of osmotherapy rather than producing acute effects on ICP

- in support of this: giving a bolus of furosemide will sustain the effect produced by mannitol

- on the other hand excessive reduction of circulating volume may negate any beneficial effect of osmotherapy if hyperviscosity is produced or organ perfusion is otherwise compromised.

CSF Dynamics and ICP Reduction

  • accelerated absorption of CSF from the SA space has been postulated to occur at the level of the pial circulation, within the perivascular Virchow-Robin spaces, or across the ependymal lining of the cerebral ventricles.

The hyperosmolar state and osmotic compensation

- mechanisms are complex and not well understood

- involves increases in the intracellular electrolytes, amino acids, and so called idiogenic osmoles

- idiogenic osmoles represent the generation of osmotically active particles of unknown chemistry or dynamic changes in the osmotic activity of intracellular macromolecules

- it is an active process whereby the absolute cellular contents of osmotically active particles or sites are increased.

- the elevated osmotic activity serves to counteract the dehydrating influence of hyperosmolar plasma

Main clinical significance

It places limits on the reduction of brain volume that osmotherapy can be expected to achieve

- the threshold for osmotic compensation is unknown but has been suggested to occur at ~25 mOsm/kg above normal osmolality

osmotic compensation creates the conditions whereby iatrogenic brain oedema may occur if a hyperosmolar state is reversed too quickly eg dilute tube feeding etc

- fluid replacement should be carefully carried out with normal saline (still need caution)

- need to gradually but purposefully return the plasma osmolality towards normal whilst maintaining haemodynamic stability and renal function.

- as a rule of thumb the duration of return to normal osmolality should approximate the duration of the hyperosmolar state

Mannitol and midline shift

- asymmetric increases in brain volume may develop under a number of conditions

  • ischaemic infarction
  • necrotising encephalitis
  • neoplasia
  • oedema surrounding haematoma

- it may or may not be accompanied by an increase in ICP

Do osmotic agents have a role in the circumstance then with a lateralising lesion but no increased ICP? Do osmotic agents worsen midline shift by selectively debulking normal tissue?

- the net effects of altered osmotic effectiveness and hydraulic conductivity are difficult to predict a priori

- Cascino et al. and Bell et al. have presented neuroimaging data that suggests a preferential reduction in the water content of altered brain regions surrounding neoplasm

- animal studies show a similar effect

- didnít measure midline shift directly but can reasonably be inferred because of the enhanced reduction in brain water content in the abnormal hemispheres

Haemorrheologic Effects

- can be achieved using an infusion

- may avoid some of the adverse haemodynamic effects

- relatively contraindicated in those with impaired renal function

Adverse effects

Acute adverse haemodynamic effects

- variable effects on BP following a bolus of mannitol

- a slight increase in pulse pressure and MAP is most commonly observed, but transient decreases in BP secondary to decreases in SVR are not uncommon.

- the acute vasodilatory effect of mannitol is not well understood and may be due to the following

  • decrease in plasma pH
  • release of ANP
  • histamine release from basophils
  • direct impairment of contractile properties of vascular smooth muscle

- acute mannitol induced hypotension is not frequently a serious clinical problem: give slowly over 15 to 30 minutes.

- precipitation of acute heart failure is not common and is rarely observed in those with impaired renal function

Elevation of ICP

- transient usually mild elevations in ICP may parallel the increase in CBV, but sustained or severe increases in ICP are rarely if ever encountered

Dehydration and Electrolyte Disturbances

- ratio of volume of fluid diuresed to the volume of mannitol administered may be high

- osmotic diuretics result in net free water clearance

- result is hypernatraemia

- other electrolytes occur especially potassium, phosphate and magnesium

- cardiac arrhythmias and neuromuscular complications are common

Rebound phenomena

- Probably multiple mechanisms

- definition is any unexpected rise in ICP after the administration of osmotherapy

- most widely held explanation is due to penetration of osmotically active particles into the brain, their accumulation creating an osmotic gradient favouring movement of water into the brain, and oedema formation

- not commonly reported or encountered clinically

- other possible mechanisms

  • rapid volume depletion stemming from overzealous administration of osmotic diuretics
  • overly rapid administration of hypotonic fluids to patients after a prolonged period of hyperosmolar dehydration

- in the former case, volume depletion sets the stage for hyperviscosity and haemodynamic compromise leading to reactive cerebral hyperaemia

- in the latter case, a CNS adjusted to the hyperosmolar state is suddenly exposed to plasma of reduced osmolality

© Ross Calcroft September 1999



©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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