Introduction

  • Elevated intracranial pressure (ICP) is caused by excess volume in the cerebral spaces, which causes a reduction in the cerebral perfusion pressure and affects blood flow and oxygenation to the brain.
  • Hyperosmolar agents (hypertonic saline and mannitol) are utilized to form a gradient across the blood-brain barrier to draw fluid from the cerebral space into the vasculature, thus reducing ICP.
  • Mannitol was previously considered the gold standard of osmotic therapy, but hypertonic saline has proven to be at least as effective as mannitol at reducing ICP.

Pharmacology

Hypertonic SalineMannitol
MechanismIncreases serum sodium levels, making it more hypertonic. A bolus creates a gradient for water to follow sodium extracellularly and move out of the cerebral spaces into the vasculature, while a continuous infusion aids in resuscitation.Osmotic diuretic that increases the osmolality of the glomerular filtrate, blocking reabsorption of water and excretion of sodium. This draws water into the extracellular and vascular spaces, reducing ICP.
Dose3–23.4% concentrations available.
3%: no single optimal dose is established; a commonly studied bolus is ~1.4–2.5 mL/kg (roughly 250 mL in a typical adult), or a continuous infusion titrated to response.
23.4%: 0.43–0.5 mL/kg IV bolus, max 30 mL/dose.		5–25% solutions available (20% most common).
0.25–1 g/kg/dose IV bolus q6–8h (usually 25–100 g/dose).
Administration3%: intermittent bolus or continuous infusion — strong osmotic gradient is not retained with continuous infusion.
23.4%: intermittent bolus over 15 minutes.		Intermittent IV infusion over 30 minutes.
Adverse EffectsHypervolemia, respiratory distress, electrolyte imbalances (hypernatremia).Hypotension, hypovolemia, AKI, electrolyte disturbances (specifically K+), extravasation.
Cautions/PearlsSolutions >3–5% require a central line.Requires an in-line filter due to risk of crystallization. Avoid in hypovolemia and anuria.
Patient Population to Consider Use InHypovolemic, hypotensive, traumatic resuscitation.Euvolemic, hypertensive, fluid-restricted.
MonitoringSerum sodium 145–155 mEq/L; serum osmolality 300–320 mOsm/L; titrate based on ICP.Serum osmolality 300–320 mOsm/L; titrate based on ICP. The 2020 Neurocritical Care Society guideline suggests monitoring the osmolar gap rather than a serum-osmolality threshold to gauge AKI risk, noting that a >320 mOsm/L osmolality threshold does not reliably predict AKI.

A hospital-stocking/location row from the source document was omitted here — verify local formulary stock and floor availability per your institution’s protocol.

Considerations for Administration

3% Sodium Chloride23.4% Sodium Chloride20% Mannitol
Vascular AccessPeripheral or centralCentral ONLYPeripheral or central
Volume (per dose)~250 mL (≈1.4–2.5 mL/kg)~30 mL125–500 mL (20%)
EquipmentBolus: infusion by gravity
Continuous: IV infusion pump		Syringe pump preferredIV infusion pump

Evidence

Author, yearDesign / sample sizeIntervention & comparisonOutcome
Kerwin et al., 2009Retrospective analysis (22 patients)23.4% HTS vs mannitol; mean ICP reduction in patients with severe TBIHTS was as efficacious as mannitol, if not more so (9.3 vs 6.4 mmHg mean ICP reduction; response rate 92.6% vs 74%), consistent with a growing literature suggesting HTS is an effective modality for elevated ICP in severe TBI.
Burgess et al., 2016Systematic review of RCTs, 7 trials (191 patients)HTS vs mannitol; mortality, neurological outcomes, ICP treatment failureNo clinically important differences in mortality, neurological outcomes, or mean ICP reduction; HTS was associated with fewer ICP treatment failures (RR 0.39, 95% CI 0.18–0.81).
Berger-Pelleiter et al., 2016Systematic review/meta-analysis, 11 studies (1,820 patients)HTS vs other solutions (mixed comparators); mortality and mean ICP reduction in severe TBINo significant difference in mortality (RR 0.96) or ICP control (WMD −1.25 mmHg) versus other solutions; authors concluded HTS could not be recommended as a first-line agent in severe TBI on the available evidence.
Pasarikovski et al., 2017Systematic review, 5 studies (175 patients)HTS vs mannitol; ICP reduction in aneurysmal subarachnoid hemorrhage (aSAH)No difference between mannitol and HTS in reducing ICP in aSAH.
Gu et al., 2019Meta-analysis, 12 RCTs (438 patients)HTS vs mannitol; ICP reduction, ICP control, serum sodium/osmolality change, mortality, neurological functionNo difference in mean ICP reduction, neurological function, or mortality; HTS may be preferred in TBI patients with refractory intracranial hypertension.
Recent Evidence (2021–2025)
Roquilly et al., 2021 (COBI Trial)Multicenter RCT, 9 French ICUs (n = 370, moderate–severe TBI)Continuous 20% HTS infusion + standard care vs standard care aloneContinuous HTS infusion did not significantly improve 6-month neurological outcome (adjusted OR 1.02, 95% CI 0.71–1.47) vs standard care alone.
Bernhardt et al., 2024Systematic review/meta-analysis, 10 RCTs (760 patients), adult TBIHTS vs other ICP-lowering agents, including mannitolNo significant difference in Glasgow Outcome Scale, mortality, or length of stay; HTS was associated with more than double the risk of hypernatremia (RR 2.13, 95% CI 1.09–4.17).
Cai & He, 2024Systematic review/meta-analysis, 15 RCTs (624 patients), TBIHTS vs mannitol; cerebral perfusion pressure (CPP) and ICP over timeHTS produced greater early CPP improvement at 30–60 minutes, but no difference in longer-term ICP control, mortality, or neurological outcomes.
Chong et al., 2025Prospective multicenter cohort, 28 pediatric ICUs (445 children, moderate–severe TBI)3% HTS vs 20% mannitol; mortality and functional outcomes (PCPC, GOS-E-Peds) in childrenNo between-group difference in mortality (7.1% HTS vs 11.0% mannitol, P = .34), discharge PCPC, or 3-month GOS-E-Peds after adjustment.

It is essential to consider the adverse effects of each agent and the comorbidities of the individual patient rather than relying on a simple efficacy comparison between hypertonic saline and mannitol.

Conclusions

  • Older trials and meta-analyses (2009–2019) show a mixed but generally neutral signal: several found no significant difference between HTS and mannitol in mortality or ICP reduction, while others (Burgess 2016, Gu 2019) found HTS associated with fewer ICP treatment failures or a possible edge in refractory intracranial hypertension.
  • The largest and most rigorous evidence to date — the COBI multicenter RCT (2021, n = 370) — found that continuous 20% HTS infusion did not improve 6-month neurological outcomes compared with standard care, tempering earlier optimism about HTS superiority.
  • A 2024 meta-analysis (Bernhardt et al.) reinforced that neither agent has a clear outcome advantage but found HTS carries a meaningfully higher risk of hypernatremia — an important consideration for electrolyte monitoring.
  • HTS may offer a faster early reduction in ICP and improvement in cerebral perfusion pressure (Cai & He 2024), which can matter in acute herniation or refractory-hypertension scenarios, even though this has not translated into a proven mortality or long-term functional benefit.
  • A 2025 multicenter pediatric cohort (Chong et al.) found a similarly neutral efficacy signal in children, suggesting these findings extend across age groups — though pediatric dosing differs from the adult regimens above.
  • In practice, agent selection should be individualized: HTS may be preferred in hypovolemic or hypotensive patients (it avoids mannitol’s diuretic effect) and requires central access at higher concentrations, while mannitol remains reasonable in euvolemic, hypertensive patients but requires caution in hypovolemia, anuria, or renal impairment.
  • No current guideline designates one agent as unequivocally superior. Both remain first-line hyperosmolar options; the choice should weigh volume status, hemodynamics, renal function, and monitoring capability (serum sodium/osmolality), as outlined in the Pharmacology table above.

References

  1. Burgess S, et al. Annals of Pharmacotherapy. 2016;50(4):291-300. PMID: 26825644.
  2. Dastur C, Yu W. Stroke and Vascular Neurology. 2017;2(1):21-29. PMID: 28959487.
  3. Kerwin AJ, et al. J Trauma. 2009;67(2):277-282. PMID: 19667879.
  4. Pasarikovski CR, et al. World Neurosurg. 2017;105:1-6. PMID: 28549643.
  5. Gu J, et al. Neurosurg Rev. 2019;42(2):499-509. PMID: 29905883.
  6. Berger-Pelleiter E, et al. CJEM. 2016;18(2):112-120. PMID: 26988719.
  7. Farrokh S, Cho SM, Suarez JI. Curr Opin Crit Care. 2019;25(2):105-109. PMID: 30676327.
  8. Witherspoon B, Ashby NE. Nurs Clin North Am. 2017;52(2):249-260. PMID: 28478873.
  9. Roquilly A, et al. Effect of continuous infusion of hypertonic saline vs standard care on 6-month neurological outcomes in patients with traumatic brain injury: the COBI randomized clinical trial. JAMA. 2021;325(20):2056-2066. PMID: 34032829.
  10. Bernhardt K, McClune W, et al. Neurocrit Care. 2024;40(2):769-784. PMID: 37380894.
  11. Cai L, He W. Brain Injury. 2024;38(12):977-984. PMID: 38853675.
  12. Chong SL, et al. Clinical outcomes of hypertonic saline vs mannitol treatment among children with traumatic brain injury. JAMA Network Open. 2025;8(3):e250438. PMID: 40067302.
  13. Cook AM, Morgan Jones G, Hawryluk GWJ, et al. Guidelines for the acute treatment of cerebral edema in neurocritical care patients. Neurocrit Care. 2020;32(3):647-666. PMID: 32227294.
  14. Susanto M, Riantri I. Optimal dose and concentration of hypertonic saline in traumatic brain injury: a systematic review. Medeni Med J. 2022;37(2):203-211. PMID: 35735001.
  15. Micromedex [Electronic]. Greenwood Village, CO: Truven Health Analytics. Retrieved August 12, 2019, from www.micromedexsolutions.com.
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