Hypertonic Saline or Mannitol for treatment of raised ICP?




Physiological and pathological basis


Monro-Kelly Doctrine:-

It represents the homeostasis of intra cerebral volume. The summative volume of brain parenchyma, Cerebrospinal fluid and blood volume remains constant.(1) The rise in ICP becomes exponential beyond the physiological limit of compensation.


Anatomy of BBB:-

Composition- Figure 1

  • BBB is formed primarily by endothelial layer of brain capillaries → comprises of : 

                  -  (a) Physical component → capillary endothelial cells (i) possess “tight junctions” (zona 
occludens) and lack fenestrations b/t adjacent cells (Ie.                            prevents free passage of substances across barrier) and (ii) have a ↑ mitochondrial content (Ie. substances actively transported across                                  barrier) 

                  -  (b) Chemical component → enzymes within capillary endothelial cells (Eg. MAO, DA decarboxylase) degrades toxic substances crossing the                                barrier 


  • A reflection co-efficient (sigma) represents the impartibility of a substance through the blood brain barrier. HTS saline has a sigma = 1(completely impermeable) and mannitol has a sigma =0.9. (2)



M/A of Mannitol & HTS to lower the ICP (Figure 2)


  1. Expansion of Circulating blood volume- There by improving microcirculation through the brain. This causes vasoconstriction of pial-arterioles causing decrease in cerebral blood volume.(6,7)

  2. Creation of osmotic gradient across an intact BBB and thereby decreasing intracellular edema

  3. Anti-inflammatory and antiapoptotic action


Traumatic brain injury leads to primary and secondary brain insult. Hyperosmolar therapy is useful in prevention and treatment of secondary brain insult. There are multiple mechanisms proposed for initiation and progress of secondary brain insult. The initiation happens by activation of microglia and astrocytes. It leads to a cascade of inflammatory process predominantly mediated by Tumor necrosis Facor Alfa (TNF alfa), Interleukin 1 Beta which lead to activation of caspase-3 and subsequent apoptosis.(Figure 2)


Aquaporin 4 has been demonstrated to regulate CSF resorption and brain edema. A downregulation of Aquaporin 4 induced by TBI leads to decreased CSF absorption and increase in brain edema. HTS acts via negating the synthesis and release of above cytokines and upregulating the Aquaporin expression. (Figure 2)

Figure 1: Structure of Blood Brain Barrier

Pros and Cons of the practices :-

Figure 3.png

Figure 2: Mechanism of action - HTS & Mannitol

Evidence, Guidelines & Critical appraisal :-



Two reviews looked at Mannitol for treatment of raised ICP in trauma setting. The first review identified four studies, out of which one was designated as level 1 with only 20 patients.(4)The second review included seven more studies with one level 2 study and rest all are level 3 studies. Based on these studies, Mannitol was designated as gold standard for intracranial hypertension.(5)

The recent Brain Trauma Foundation (BTF)10quotes a retrospective observational study with increased ICP burden (number of days with raised ICP >25mm Hg) and length of ICU stay in mannitol group but the mortality difference was non-significant when compared to HTS group.(8) A RCT with 47 patients documented better ICP control with HTS compared to Mannitol.(9)


Based on this evidence the recent BTF guidelines suggests “Although hyperosmolar therapy may lower intracranial pressure, there was insufficient evidence about effects on clinical outcomes to support a specific recommendation, or to support use of any specific hyperosmolar agent, for patients with severe traumatic brain injury.”(10)


Practice points:-

  • Use HTS (20%) as bolus 10-20 ml for sustained ICP >20mm Hg for >5mins after ruling out precipitating causes, such as- pain, fever, lack of sedation. Sedation, analgesic and muscle relaxant boluses can be used as adjunctive therapy.

  • HTS is preferred over Mannitol, though nil concrete evidence in favour but most of the current literature favours this practice. Mannitol may worsen the brain edema in case of damaged BBB (Lower reflection co-efficient)

  • Aim for a higher serum Na level 145-155mmol/lit (3% or 20% saline infusion can be useful for reaching the target. Avoid acute changes in serum sodium (aim <8-10mol/lit)

References :-

  1. Monro A. Creech & Johnson; Edinburgh: 1783. Observations on the Structure and Function of the Nervous System.

  2. Boone MD, Oren-Grinberg A, Robinson TMChen CCKasper EM.. Mannitol or hypertonic saline in the setting of traumatic brain injury: What have we learned?Surg Neurol Int. 2015; 6: 177.

  3. Marko NF. Hypertonic saline, not mannitol, should be considered gold-standard medical therapy for intracranial hypertension. Crit Care. 2012; 16(1): 113.

  4. Wakai A, Roberts Ian G, Schierhout G: Mannitol for acute traumatic brain injury. Cochrane Database of Systematic Reviews 2007, 1:CD001049. 

  5. Guidelines for the management of severe traumatic brain injury. J Neurotrauma 2007;24(1):S1-S106. 

  6. Muizelaar JP, Wei EP, Kontos HA, Becker DP. Mannitol causes compensatory cerebral vasoconstriction and vasodilation in response to blood viscosity changes.J Neurosurg. 1983;59(5):822-828.

  7. Muizelaar JP, Wei EP, Kontos HA, Becker DP. Cerebral blood flow is regulated by changes in blood pressure and in blood viscosity alike. Stroke.1986;17(1):44-48. 

  8. Mangat HS, Chiu YL, Gerber LM, Alimi M, Ghajar J, Hartl R. Hypertonic saline reduces cumulative and daily intracranial pressure burdens after severe traumatic brain injury. J Neurosurg. Nov 2014;122(1):1-9. 

  9. Cottenceau V, Masson F, Mahamid E, et al. Comparison of effects of equiosmolar doses of mannitol and hypertonic saline on cerebral blood flow and metabolism in traumatic brain injury. J Neurotrauma. 2011;28(10):2003-2012. ​

  10. https://braintrauma.org/uploads/03/12/Guidelines_for_Management_of_Severe_TBI_4th_Edition.pdf

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