Mannitol and hypertonic saline

Intravenous mannitol is invaluable as a first aid measure in a patient with brain herniation as a result of raised ICP. In practice, mannitol tends to be given as an intermittent bolus (2 ml/kg of a 20% solution over 15-20 minutes) whenever the individual patient's ICP rises significantly above the threshold of 20-25 mmHg. Effects last for up to four hours. As osmotic diuresis may lead to hypovolaemia it is crucial to avoid dehydration and latent hypotension with careful attention to fluid balance. Another dose of mannitol should not be given if osmolarity exceeds 320 mosm/L for fear of tubular damage and renal failure. Repeated doses of mannitol should not be given unless an ICP monitor is in place. Overenthusiastic bolus administration of an osmotic diuretic may cause abrupt systemic hypertension, an increase in cerebral blood volume if autoregulation is defective or its upper limit is exceeded, and promote herniation rather than the reverse.106

Much uncertainty remains concerning the mechanisms of action of mannitol and its prolonged use. Many attempts have been made to rationalise how much mannitol may be given, and when, for more prolonged effects.107,108 Studies indicate that mannitol, given time, removes water from both normal and oedematous brain, be it intracellular (cytotoxic) or interstitial (vasogenic) oedema.109-111 The oedematous area around many mass lesions may still have an intact blood-brain barrier, at least to the conventional high molecular weight tracers. The time course of this effect is slow and does not account for the immediate effect of mannitol on ICP. In patients with peritumoral oedema, mannitol causes withdrawal of water mainly from brain areas where the barrier is impaired as judged by T1 weighted MRI and in vitro measurements of brain water content.112 Mannitol, however, may accumulate in oedematous white matter with repeated doses.113

The more immediate effects of intravenous mannitol include a fall in whole blood viscosity with reduced red cell rigidity and corpuscular volume, an increase in brain compliance, and possibly cerebral vasoconstriction.114-116 The cerebral vasoconstriction with intravascular bolus administration is short lived: in the cat, both pial arteriolar diameter and ICP returned to normal within 30 minutes and, thereafter, both increased at the same rate as changes in blood viscosity.116 Administration over 15 minutes produced no change in pial arteriolar or venular diameter in another study.117 Why should a sudden change in blood viscosity evoke acute transient vasoconstriction? Chronic changes in blood viscosity, without alterations in haemoglobin or arterial oxygen content, do not change steady state cerebral blood flow in humans.118 Patients with high plasma viscosity or with high viscosity due to large numbers of white cells do not have low cerebral blood flow values. In a series of patients with haematological diseases but no evidence of cerebrovascular disease, arterial oxygen content was the major determinant of cerebral blood flow; blood viscosity per se had no significant effect on cerebral blood flow.119 If a single blood vessel is considered, the apparent viscosity of blood diminishes in proportion to its radius as a result of the marginal sheath of low viscosity and axial flow of red cells.120 The width of this sheath is relatively greatest in small vessels. Furthermore, apparent viscosity increases with falling velocity. Hence with pial arterial dilatation, local blood viscosity will rise both because of the increased proportion of red cells and as a result of the reduction in flow velocity if tissue perfusion remains constant. Simplistically, according to Poiseuille, as viscosity is reduced the pressure gradient along the pial arteriole falls. Hence, the distal intravascular pressure increases if the proximal pressure remains constant. The distal end of the arteriole therefore constricts if autoregulatory mechanisms are intact. "Viscosity" autoregulation should depend on pressure autoregulation unless there is a separate endothelial mechanism that is flow or viscosity sensitive. Alternatively, mannitol may transiently increase cerebral blood flow, increase oxygen delivery, or wash out local vasodilators such as adenosine.116 All these mechanisms would lead to vasoconstriction. Therefore, if the viscosity mechanism is relevant, it will depend upon the distribution gradient of intravascular pressures along the cerebrovascular tree, which may not be easy to predict with different pathologies and cerebral perfusion pressures. Extracellular hyperosmolarity is a potent cerebral vasodilator and it is remarkable that the intravenous vasoconstrictor effect of mannitol so completely dominates the acute cerebrovascular effect. Certainly the reported clinical effects of mannitol on cerebral blood flow are not easy to rationalise.121125 In patients with severe head injuries, in whom autoregulation was absent, intravenous mannitol caused an increase in cerebral blood flow and no reduction in ICP.125 In those patients where autoregulation was intact ICP was reduced. In patients with unruptured aneurysms, however, in most of whom autoregulation was presumably intact, mannitol (bolus or infusion) increased cerebral blood flow for many hours.124 More regional assessments of cerebral blood flow suggest that mannitol may stabilise pH and cerebral blood flow in regions of moderate but not severe ischaemia.126 Other suggested mechanisms for the effect of mannitol include movement of water from CSF into capillaries and scavenging of free radicals.127

Hypertonic saline has recently received much interest for the treatment of cerebral oedema and intracranial hypertension. Hypertonic saline solutions ranging from 16% to 29 2% have been used. In humans, so far only case series and results from small controlled groups of patients have been published. Despite a low frequency of side effects and reproducible reduction of intracranial pressure, more data are needed. Dose-response curves are lacking and future studies should not only compare hypertonic saline to mannitol but also address the question whether bolus injections or continuous infusions are more beneficial. Administrations of 250 ml of NaCl 7 5% as a bolus or 30-60 ml of NaCl 23 4% have been recommended. The action of hypertonic saline is augmented if colloids are administrered at the same time. Durations of action of approximately two hours have been reported.128 The mechanism of action is due to the osmotic action of hypertonic saline that leads to a removal of water from the interstitial and intracellular compartment in areas with intact blood-brain barrier and an increase in regional cerebral blood flow most likely caused by a reduction in size of swollen endothelial cells. However, this effect has not been observed by all investigators.

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