1. Salt or Sugar: Hypertonic Saline versus Mannitol
Jonathan Sin, Pharm.D., BCPS
PGY-2 Pharmacy Resident, Critical Care
Massachusetts General Hospital
May 3, 2016

2. Disclosure
I have no actual or potential conflicts of interest in relation to this program

3. Objectives
Describe the rationale behind the use of hyperosmolar therapy in the treatment of elevated intracranial pressure
Identify differences between hypertonic saline and mannitol for the management of elevated intracranial pressure

4. Pathophysiology Intracranial contents
Brain
Intravascular blood
Cerebrospinal fluid
Cranial vault represents a fixed volume
Increase in volume will lead to increase in ICP
ICP = intracranial pressure
Stevens RD, et al. Neurocrit Care. 2015;23:S76-82.

5. Pathophysiology Natural response
Expansion of one component  reduction in another
Compensatory mechanism eventually overwhelmed
Intracranial hypertension (> 20 mm Hg for > 5 minutes)
Compression of blood vessels and brainstem
Reduction of cerebral blood flow
Brain herniation
Global brain ischemia and brain death
Once ICP approaches mm Hg, can compress the vessels of the circle of Willis
Ventricles compress + CSF drains from cranial to spinal
Brain Trauma Foundation, et al. J Neurotrauma. 2007;24:S55-8.
Ropper AH. N Engl J Med. 2012;367:

6. Etiology Expansion of intracranial contents Ischemic stroke
Intracranial hemorrhage
Traumatic brain injury
Aneurysmal subarachnoid hemorrhage
Meningitis or encephalitis
Intracranial tumor or abscess
Brain swelling of acute liver failure
Ropper AH. N Engl J Med. 2012;367:
Stevens RD, et al. Neurocrit Care. 2015;23:S76-82.

7. Management Medical / Surgical Interventions Head-of-bed elevation
CSF drainage
Evacuation or resection
Hyperventilation
Hypothermia
Decompressive craniectomy
Pharmacologic Interventions
Mannitol
Hypertonic saline
Propofol
Neuromuscular blockade
Pentobarbital
Brophy GM, et al. Neurocrit Care. 2015;23:S48-68.
Stevens RD, et al. Neurocrit Care. 2015;23:S76-82.

8. Hyperosmolar Therapy Brain parenchyma Hyperosmolar agents ~80% water
Highly responsive to osmotic changes
Hyperosmolar agents
Induce osmotic gradient between blood and brain tissues
Mobilize water from brain tissue into vascular space
Reduce ICP
Passive diffusion
Ropper AH. N Engl J Med. 2012;367:
Fink ME. Continuum Lifelong Learning Neurol. 2012;18:

9. Mannitol vs. Hypertonic Saline: Clinical Effects
Primary mechanism
Increases gradient across BBB
Rapid reduction of ICP
Duration of effect: up to 6 hours
Immediate reduction of ICP
Duration of effect: up to 4 hours
Secondary mechanisms
Cerebral vasoconstriction
Decreases blood viscosity
Increases cerebral blood flow
Mixed immunomodulatory and anti-inflammatory effects
Hemodynamic effects
Transient expansion of intravascular volume
Brisk osmotic diuresis  hypovolemia and hypotension
Expands intravascular volume
Increases mean arterial pressure
Reflection coefficient
0.9 = mostly impermeable
(assuming intact BBB)
1.0 = completely impermeable (assuming intact BBB)
BBB = blood-brain barrier
Marko NF. Crit Care. 2012;16:113.
Diringer MN. Curr Opin Crit Care. 2013;19:77-82.
Brophy GM, et al. Neurocrit Care. 2015;23:S48-68.
Boone MD, et al. Surg Neurol Int. 2015;6:177.

10. Mannitol vs. Hypertonic Saline: Dosing and Administration
0.5-1 g/kg over 5-15 minutes
May ↑ to 1.5 g/kg based on response
May repeat every 4-6 hours as needed
3%: mL/kg over 5-20 minutes
5%: mL/kg over 5-20 minutes
7.5%: mL/kg over 5-20 minutes
23.4%: 30 mL over minutes
Continuous infusion: titrate to Na+
Access
Peripheral or central access
Requires in-line filter
Central access preferred for all cases
Central access required for 23.4%
Effectiveness with
Repeated Dosing
May cause tolerance
Produces sustained hyperosmolarity
Brain’s adaptive response will restore cell size despite hyperosmolar state (idiogenic osmoles)
Does not cause tolerance
Maintains effectiveness when tolerance to mannitol has developed
0.5-1 mL/kg for 23.4%
In-line filter size 4 micron
Marko NF. Crit Care. 2012;16:113.
Diringer MN. Curr Opin Crit Care. 2013;19:77-82.
Brophy GM, et al. Neurocrit Care. 2015;23:S48-68.
Boone MD, et al. Surg Neurol Int. 2015;6:177.

11. Mannitol vs. Hypertonic Saline: Adverse Events and Monitoring
Acute kidney injury
Dehydration
Hypotension
Electrolyte imbalances
Rebound ICP / reverse osmotic shift
Osmotic demyelination syndrome
Fluid overload / pulmonary edema
Hyperchloremic metabolic acidosis
Hyperoncotic hemolysis
Monitoring
Trough osmolar gap (< 20 mOsm/kg)
Renal function
Electrolytes
Serum sodium every 4-6 hours
Hypernatremia goal < 160 mEq/L in most cases
Marko NF. Crit Care. 2012;16:113.
Diringer MN. Curr Opin Crit Care. 2013;19:77-82.
Brophy GM, et al. Neurocrit Care. 2015;23:S48-68.
Boone MD, et al. Surg Neurol Int. 2015;6:177.

12. Is one agent better than the other?

13. History Hyperosmolar agents available for nearly a century
Use of mannitol dominated through the 1980s
Mannitol traditionally considered first-line
Long history of use
Clinician comfort and experience
Changes in usage: recent survey of neurointensivists
55% now prefer hypertonic saline over mannitol
Almost all respondents reported using a combination
Hays AN, et al. Neurocrit Care. 2011;14:222-8.
Marko NF. Crit Care. 2012;16:113.
Diringer MN. Curr Opin Crit Care. 2013;19:77-82.

14. Meta-Analysis of Randomized Trials
Patients
5 randomized clinical trials
112 adult patients with 189 episodes of elevated ICP
Traumatic brain injury, intracranial hemorrhage, stroke, brain tumor
Randomly treated with hypertonic saline or mannitol
Results
ICP control: hypertonic saline, 88/95 (93%) vs. mannitol, 69/89 (78%)
ICP control: RR, 1.2; 95% CI, ; p = 0.007
Difference in reduction, 2 mmHg; 95% CI, mmHg; p = 0.036
Conclusion
Hypertonic saline may be superior to mannitol for ICP control
Results of this meta-analysis are limited by: inclusion of small trials, usage of different hypertonic saline formulations and doses
RR = relative risk
CI = confidence interval
Kamel H, et al. Crit Care Med. 2011;39:554-9.

15. Mannitol vs. Hypertonic Saline
No formal consensus
Lack of strong evidence supporting one over the other
Both agents known to be effective
Lack of large randomized controlled trials comparing both
Many clinicians will use a combination of both agents
Choice of agent driven mainly by:
Safety profile
Patient-specific factors
Hays AN, et al. Neurocrit Care. 2011;14:222-8.
Torre-Healy A, et al. Neurocrit Care. 2012;17:
Mortazavi MM, et al. J Neurosurg. 2012;116:

16. Patient-Specific Factors
Serum sodium concentrations
Plasma osmolality
Fluid status
Renal function
Intravenous access
Serum chloride concentrations and acid-base status
Damaged BBB
Diringer MN. Curr Opin Crit Care. 2013;19:77-82.
Brophy GM, et al. Neurocrit Care. 2015;23:S48-68.

17. Summary
There is a lack of strong evidence supporting use of one hyperosmolar agent over the other
Choice between mannitol and hypertonic saline should be based on the different characteristics of the agents
Patient-specific factors should be taken into consideration prior to selecting an agent

18. Assessment Question #1 Which situation(s) would you consider
mannitol over hypertonic saline
for elevated intracranial pressure?
Anasarca with severe pulmonary edema
Hypovolemia causing hypotension and prerenal azotemia
Trough osmolar gap = 30 mOsm/kg after last mannitol dose
Serum sodium = 172 mEq/L, which increased from 160 mEq/L within the past 24 hours
A and D

19. Assessment Question #2 Which situation(s) would you consider
hypertonic saline over mannitol
for elevated intracranial pressure?
Anasarca with severe pulmonary edema
Hypovolemia causing hypotension and prerenal azotemia
Serum chloride = 125 mEq/L and pH = 7.25
Serum sodium = 155 mEq/L, which increased from 133 mEq/L within the past 24 hours
B and D

20. Acknowledgments Michael J. Bodock
Senior Attending Clinical Pharmacist, Neurocritical Care
Department of Pharmacy
Massachusetts General Hospital

21. References
Stevens RD, Shoykhet M, Cadena R. Emergency Neurological Life Support: Intracranial hypertension and herniation. Neurocrit Care. 2015;23:S76-82.
Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. VIII. Intracranial pressure thresholds. J Neurotrauma. 2007;24:S55-8.
Ropper AH. Hyperosmolar therapy for raised intracranial pressure. N Engl J Med. 2012;367:
Brophy GM, Human T, Shutter L. Emergency Neurological Life Support: Pharmacotherapy. Neurocrit Care. 2015;23:S48-68.
Fink ME. Osmotherapy for intracranial hypertension: mannitol versus hypertonic saline. Continuum Lifelong Learning Neurol. 2012;18:
Marko NF. Hypertonic saline, not mannitol, should be considered gold-standard medical therapy for intracranial hypertension. Crit Care. 2012;16:113.
Diringer MN. New trends in hyperosmolar therapy? Curr Opin Crit Care. 2013;19:77-82.
Boone MD, Oren-Grinberg A, Robinson TM, et al. Mannitol or hypertonic saline in the setting of traumatic brain injury: what have we learned? Surg Neurol Int. 2015;6:177.
Hays AN, Lazaridis C, Nevens R, et al. Osmotherapy: use among neurointensivists. Neurocrit Care. 2011;14:222-8.
Kamel H, Navi BB, Nakagawa W, et al. Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: a meta-analysis of randomized clinical trials. Crit Care Med. 2011;39:554-9.
Torre-Healy A, Marko NF, Weil RJ. Hyperosmolar therapy for intracranial hypertension. Neurocrit Care. 2012;17:
Mortazavi MM, Romeo AK, Deep A, et al. Hypertonic saline for treating raised intracranial pressure: literature review with meta-analysis. J Neurosurg. 2012;116:

22. Salt or Sugar: Hypertonic Saline versus Mannitol
Jonathan Sin, Pharm.D., BCPS
PGY-2 Pharmacy Resident, Critical Care
Massachusetts General Hospital