Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: A meta-analysis of randomized clinical trials

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*Mannitol, recommended first-line osmotic agent for the treatment of intracranial hypertension

*Numerous studies have shown that mannitol is effective in decreasing ICP

*Reduces mortality compared to barbiturates in patients with elevated ICP from TBI

*

*Adverse effects: renal failure & hypovolemia

*Hypertonic saline (HS), can reduce ICP without causing volume contraction and with less risk

of nephrotoxicity

*Several RCTs have suggested that sodium-based hypertonic solutions may be superior to

mannitol in reducing ICP

*

*

*Limited impact on clinical practice

* different specific formulations, small size studies

*To better understand the relative efficacy of these two forms of osmotic therapy, we

performed a meta-analysis of randomized

clinical trials comparing hypertonic sodium

solutions and mannitol for the treatment of

elevated ICP

*

*Inclusion Criteria:

*Randomized clinical trials

*Quantitative ICP measurement

* IICP without regard for the underlying cause

*Formulation containing at least 3% sodium chloride or equivalent

*Exclusion criteria:

*

*Exclusion criteria:

*varying doses or varying infusion times

*Data Sources:

*Various databases

*any language

*January 1967 ~ April 2010

*Primary outcome:

*

*Primary outcome:

*proportion of cases in which randomized drug administration resulted in control of ICP

*Five studies

*112 patients

*184 episodes of IICP were treated

*absence of blinding

*

*IICP control:

Mannitol - 69 / 89 (78%)

HS - 88 / 95 (93%)

*

*

*Prespecified tests indicated a mild degree of heterogeneity

*No pediatric trials

*Did not perform subgroup analysis based on the type of intracranial pathology

*Another prespecified subgroup analyses: no clear differences in effect size

*

differences in effect size

*Hypertonic sodium solutions are more effective than mannitol in controlling episodes of

elevated ICP

*greater quantitative ICP reduction

*Quantitative ICP reduction:

*HS: 2, 1 trend

*

*HS: 2, 1 trend

*Mannitol: 1

*Equivalent: 1None individually were sufficiently powered to show a difference

*Primary outcome: clinical definition of ICP control

*a more clinically relevant end point than the mean quantitative decrease in ICP

*Lack of a uniform treatment effect among all the trials is not surprising

*

*1 trial failed to show a trend favoring HS

*no obvious methodological differences

*smallest study

*effect of chance

* 7 observational studies demonstrating the effectiveness of HS in lowering ICP after failure of

standard mannitol therapy

*

*Another observational study found no significant difference between the efficacy of

mannitol and hypertonic saline, but the latter

had a longer lasting effect

*2 randomized trials that did not meet our inclusion criteria support the superiority of

hypertonic saline therapy

*

hypertonic saline therapy

*Numerous biochemical and physiologic considerations

HS Mannitol

• volume expansion

• improved cardiac output

• improved regional blood flow

• improved CSF absorption

• brain oxygenation

• cerebral hemodynamics

• microvascular CBF

• reduce blood viscosity

• Improve blood rheology

• reduce CSF production

• promote free-radical

scavenging

• inhibit apoptosis

*

*Conflicting nature

*preferred agent for the treatment of IICP ultimately must be established through large, well-performed, randomized

human trials

• inhibit apoptosis

*Limitations

* small number and size of eligible trials

* methodological differences

* lack of rigorous adverse event reporting

* failure to control for clustering among patients

receiving multiple doses of study drug

*

*Preclude a firm recommendation to

preferentially use hypertonic saline as first-line

therapy

*hypertonic sodium solutions are, on average, superior to mannitol for the treatment of

elevated ICP

* large multicenter study comparing these two

therapies

*

*absolute effect size: 15% in favor of HS

*100 patients in each arm

* 80% power to detect this difference in the rate

of ICP control between the two groups

* uniform hypertonic sodium solution

* include assessment of long-term neurologic

*

* include assessment of long-term neurologic

outcomes

Discussion