Editors Note:

This is the first NeuroEMCrit post. NeuroEMCrit is a section from our newest EMCrit team member, Neha S. Dangayach MD. She is an Assistant Professor of Neurology and Neurosurgery. Dr. Dangayach serves as the Director of Neuroemergencies Management and Transfers (NEMAT) for the Mount Sinai Health System, Neurocritical Care Fellowship Director and Research Co-Director for the Institute for Critical Care Medicine (ICCM). She is also a Co-Director of the Mount Sinai Hospital’s busy NSICU and collaborates with a compassionate team to provide world-class patient-centered Neurocritical Care.

Everything you wanted to know about Hyperosmolar agents for the Management of ICP and Cerebral Edema

by Neha Dangayach

I have been inspired by the consistently awesome content from fellow EMCrit authors and guests. It’s an honor being a part of this team and humbling too. My goal will be to write about core neurocritical care topics, share with you how I navigate controversial areas sometimes with the lack of high-quality literature or definitive guidelines. I will also write posts about new studies in neurocritical care and share practical implications for your clinical practice.

So, let’s get started. You’ve probably taken care of a patient with suspected raised intracranial pressure (ICP) and cerebral edema recently. Cerebral edema-simply speaking is an abnormal increase in the fluid content of brain parenchyma. Cerebral edema could be cytotoxic, vasogenic or interstitial or a combination of these different types of edema. You might have suspected raised ICP and cerebral edema either because of their clinical presentation, radiographic imaging or by invasive measurement of their ICP via an External ventricular drain (EVD) or fiber optic parenchymal probe or via a non-invasive surrogate measure of ICP such as Optic nerve sheath diameter (ONSD). In various stepwise protocols described in literature for treating raised ICP, hyperosmolar therapies have been included as first line treatments to prevent herniation and death (1) (2) (Tweet 1, Figure 1)

In this blog post, let’s review hyperosmolar therapies for management of raised ICP and cerebral edema, key mechanisms of action for mannitol and hypertonic saline (HTS) and what do some recent guidelines say about using hyperosmolar therapies.

Does the presence of Cerebral edema always indicate raised ICP?

Cerebral edema will typically lead to raised ICP however, the change in intracranial compliance over time tends to determine whether cerebral edema will lead to raised ICP or not. For instance, a patient with a slow growing brain tumor that causes breakdown in their blood brain barrier (BBB) leads to the development of surrounding vasogenic edema but this patient may not experience any clinical features of raised ICP. This will be in contrast to a patient with a large middle cerebral artery (MCA) stroke who will experience clinical symptoms of raised ICP due to development of both cytotoxic edema and vasogenic edema over a short period of time. Patients with obstructive or non-obstructive hydrocephalus can have a third type of edema, called interstitial edema, essentially due to transependymal flow. While global cerebral edema will lead to increase in ICP, focal lesions can similarly cause tissue shifts without causing an increase in global ICP. I will dive deeper into intracranial compliance, autoregulation, ICP and different ways of understanding the dynamic nature of cerebral autoregulation in a future blog post.

How do hyperosmolar therapies work?

Let’s recall that the normal blood brain barrier (BBB) is made up on tight junctions between the endothelial cells of cerebral capillaries. (3) This BBB tightly regulates the movement of ions, molecules and cells between the bloodstream and the brain leading to an osmotic gradient for different particles. The osmotic gradient that a particle can create is dependent on the osmotic reflection coefficient which describes how restricted the permeability of an ion/cell or molecule is through this barrier. (4) The osmotic reflection co-efficient, ranges from 0 (for particles that can diffuse freely) to 1.0 (for particles that are excluded from the BBB and end up being the ones that are the most active osmotically). The reflection coefficient for sodium chloride is 1.0 and for mannitol is 0.9. With an intact BBB, Na+ is transported actively across the BBB. This becomes important when we choose bolus hyperosmolar therapies to create those osmotic gradients to draw water out from the brain to treat cerebral edema and ICP crisis. This osmotic gradient which also facilitates cerebrospinal fluid (CSF) absorption from the intracranial space into the intravenous space, leading to a decrease in ICP.

Thus, similarities in the mechanisms of action of HTS and mannitol include: a) Dehydration of brain tissue by creating an osmotic gradient b) Reducing blood viscosity by HTS or mannitol causes cerebral vasoconstriction and this cerebral vasoconstriction will lead to decrease in ICP. (5)

Individual Osmotic Agents

Mannitol

• Mannitol is a naturally occurring sugar alcohol and is an isomer of sorbitol. It is usually synthesized by the hydrogenation of specialty glucose syrups.
• Mannitol is commercially available in the form of a white crystalline powder or a granular form both of which are water soluble.
• For clinical use, mannitol is available as sterile solutions of 10%, 20% or 25% in 500 cc bags of water containing 50 gm and 100 gm of mannitol or 25 gm in 100 cc bag of sterile water respectively.
• Mannitol is usually administered as a bolus via a peripheral intravenous line. The usual dose ranges from 0.5 to 1.5 gm/kg via an in-line 0.2 uM filter.
• Mannitol solutions are acidic (pH 6.3) but proprietary preparations have sodium bicarbonate added for pH adjustment. Mannitol may crystallize if stored at room temperature but can be made soluble again by warming the solution. If you see crystals within the mannitol solution, please do not administer it. (6)
• Intravenously administered mannitol will remain in the extracellular space and about 80 gm or 80% of a 100 gm dose will be excreted in urine within 3 hours. Less than 10% of the drug gets reabsorbed. Some of the adverse effects of mannitol may be seen because mannitol increases the osmolarity of the glomerular filtrate preventing reabsorption of free water. (7)This osmotic diuresis will also lead to loss of sodium and chloride and can lead to intravascular volume depletion, hypotension and potentially reduce cerebral perfusion pressure due to hypotension. That’s why it’s important to have a foley in place when using mannitol, both to monitor osmotic diuresis and replete the volume lost with an iso-osmotic fluid like normal saline or plasmalyte.
• While the FDA drug label for mannitol includes anuric renal failure or end-stage renal disease (ESRD) as a contraindication to mannitol, in small studies it has been found to be safe and efficacious with careful attention to volume status and electrolyte balance. After administration of mannitol, some patients may develop a pseudohyponatremia due to the hyperosmolar state which will correct on its own in a few hours. However, mannitol can also cause true hyponatremia due to osmotic diuresis.
• Key adverse effects from mannitol include hypovolemia, electrolyte imbalance: hypokalemia, hyponatremia, acute renal failure. (8)

Hypertonic Saline

There are several concentrations of hypertonic saline available for clinical use different concentrations (2%, 3%, 7%, 10%, 14%, 23.4%). (Table 1)

• Onset of action for HTS can be as quick as 5 minutes and its effects can last for as long as 12 hours without any rebound increases in ICP.
• Specifically for HTS(10)(4) animal studies show that by increasing plasma tonicity, HTS can favor reabsorption of CSF similar to mannitol
• Increase regional brain tissue perfusion: most likely due to dehydration of cerebral endothelial cells improving blood flow through capillaries
• Increased cardiac output and MAP: HTS has a positive inotropic effect. This will augment CPP.
• Anti-Inflammatory response by helping restore the glycocalyx of endothelial cells. Adverse effects include electrolyte imbalances such as hypernatremia, hyperchloremia, hypokalemia, metabolic acidosis, volume overload, heart failure exacerbation, acute renal failure due to hyperosmolar state.
• Caution is advised during the rapid administration of hypertonic saline, patients may develop transient bradycardia or hypotension and keeping pressors like norepinephrine on stand-by can help treat both of these effects and prevent secondary neurological injury due to decreases in cerebral perfusion pressure.
• Adverse effects for HTS are similar in some respects to mannitol i.e. electrolyte imbalances, hypernatremia, hyperchloremic metabolic acidosis, acute renal injury, volume overload, flash pulmonary edema.

Practical tips on monitoring while administering hypertonic therapies

1. Access: For Mannitol, peripheral intravenous lines can be used safely. Please make sure that your patients have a working foley catheter to both monitor the urine output and to determine how much volume of a crystalloid solution you need to infuse after giving mannitol to prevent intravascular volume depletion and renal failure. 2% and 3% HTS solutions can be administered via peripheral intravenous lines safely. For higher concentrations, 7%,14%, 23.4% central access is advisable as these higher concentrations can lead to iv infiltration, tissue ischemia, thrombophlebitis. A direct femoral vein stick under ultrasound guidance can also be performed to save time using an angiocath or a femoral arterial line catheter for a single time use.
2. Electrolyte and fluid balance monitoring: Monitoring basic metabolic panel (BMP) and volume status frequently can help guide which agent to choose; mannitol versus hypertonic saline for the next ICP crises in your patient. We typically monitor BMP and osmolarity every six or eight hours. If the serum sodium is less than 160 meq/dl then the patient may benefit from a hypertonic saline bolus, if the serum osmolarity is less than 320 or if the osmolar gap is than 20, then the patient may benefit from another dose of mannitol. A caveat here, you can administer both hypertonic saline and mannitol for treating a patient with ICP crisis
3. Sodium goal: Targeting a specific sodium goal cannot be recommended based on current evidence for SAH, ICH, TBI, acute ischemic stroke patients. Bolus therapy instead of continuous drips is the current strategy that the NCS guidelines recommend. Physiologically it makes sense since plasma Na and brain Na content take about 1-4 hours to equilibrate. So, when a bolus of HTS is given, plasma Na will rise and draw water out from brain parenchyma but eventually the brain’s Na content will also rise and no further cerebral dehydration will occur until a new gradient is established.
4. How do I choose between Mannitol versus Hypertonic saline? For patients who have only peripheral intravenous lines, are hemodynamically stable you can use mannitol or HTS depending upon what is available quickly, what type of access do they have. You may not always know who has underlying renal injury or who is developing acute renal injury, so it would still be ok if you have mannitol handy and administered it as long as you ask your team to place a foley and follow up that mannitol bolus with a crystalloid solution like plasmalyte or normal saline. My go to tends to be 23.4% HTS given that HTS has a faster onset of action, can augment cardiac output and blood flow, has a more long lasting effect (almost 12 hours). So, particularly useful in patients with trauma and hypovolemic shock.

Summarizing key guidelines

• For AIS with cerebral edema: The AHA recommendation for management of swelling in cerebral and cerebellar strokes addresses medical management briefly. While they recommend using mannitol or HTS, they don’t suggest using one over the other. “Osmotic therapy for patients with clinical deterioration from cerebral swelling associated with cerebral infarction is reasonable (Class IIa; Level of Evidence C)” (11)

• For AIS, SAH, TBI, meningitis: Overall, the most important themes from the NCS guidelines were: (5) (Tweet 2, 3)

1. 1. Hyperosmolar therapies in acute brain injury doesn’t improve neurological outcomes
   2. HTS may be preferred over Mannitol for a sustained effect on ICP and a lower risk of rebound increase in ICP. While the guidelines acknowledge that there is only low quality of evidence to support this, they suggest HTS over mannitol given other potential benefits over mannitol as described earlier in the blogpost
   3. There are only a few RCTs comparing mannitol to HTS as well different concentrations of HTS so more research is needed in this area. In head to head comparisons of different HTS solutions, there was no difference in outcomes except in one study evaluating 20% HTS in TBI patients that showed a mortality benefit at 90 days.
   4. Prophylactic mannitol: Should be avoided in acute ischemic stroke patients

Tweet 2 and 3 from the Neurocritical Care Journal: Visual abstracts from the Guidelines for the Acute Treatment of Cerebral Edema in Neurocritical Care Patients

For TBI: (12) The Brain Trauma Foundation guidelines 4th edition does not make any firm recommendation regarding hyperosmolar therapies citing that the quality of literature did not meet their requirements for making recommendations. They re-stated the recommendation from the 3rd edition. Hyperosmolar therapy with mannitol (0.5 g/kg to 1 gm/kg) can be used but avoid arterial hypotension. The more  recent SIBICC algorithm (2) suggests using mannitol or HTS for reducing ICP according to a tiered algorithm for ICP management.

My Take on the Guidelines

Triage and Prehospital setting

The problem with expecting that HTS or mannitol will improve outcomes is that they are meant to help reverse an ICP crisis till more definitive therapies can be instituted. They themselves are not going to improve outcome. So, in a pre-hospital setting my suggestion would be to use HTS or mannitol depending upon availability and access as needed to treat an ICP crisis but not necessarily with a goal to improve outcomes but with a goal to buy time for definitive therapies.

In-Hospital settings

Practically speaking, choose what you have available and administer it correctly: choose the right dose, right route, monitor electrolytes and osmolarity. ICP crisis is a sign of other abnormalities. Use hyperosmolar agents in conjunction with other ICP lowering strategies, identify and treat the primary drivers of the ICP crisis to prevent secondary neurological injuries. Based on current evidence and guidelines, it’s reasonable to use HTS over mannitol for all types of acute brain injuries with cerebral edema and elevated ICP.

Related content

• PulmCrit- Ocular Sonography
• Podcast 78 – Increased Intra-Cranial Pressure (ICP) and Herniation, aka Brain Code

Bibliography

1. Robba C, Citerio G: How i manage intracranial hypertension [Internet]. Crit Care 2019; 23:243[cited 2020 Aug 4] Available from: https://ccforum.biomedcentral.com/articles/10.1186/s13054-019-2529-z
2. Chesnut R, Aguilera S, Buki A, et al.: A management algorithm for adult patients with both brain oxygen and intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC). Intensive Care Med 2020; 46:919–929
3. Daneman R, Prat A: The blood–brain barrier [Internet]. Cold Spring Harb Perspect Biol 2015; 7[cited 2020 Aug 2] Available from: /pmc/articles/PMC4292164/?report=abstract
4. Suarez JI: Suarez. Cleve Clin J Med 2004; 71:S9–S13
5. Cook AM, Morgan Jones G, Hawryluk GWJ, et al.: Guidelines for the Acute Treatment of Cerebral Edema in Neurocritical Care Patients [Internet]. Neurocrit Care 2020; 32:647–666[cited 2020 Jul 14] Available from: https://doi.org/10.1007/s12028-020-00959-7
6. USP MI: Mannitol Intravenous [Internet]. Hospira 2015; 1–5[cited 2020 Aug 5] Available from: https://www.hospira.com/en/images/EN-4083_tcm81-5668.pdf
7. Fandino W: Understanding the physiological changes induced by mannitol: From the theory to the clinical practice in neuroanaesthesia [Internet]. J Neuroanaesth Crit Care 2017; 04:138–146[cited 2020 Jul 14] Available from: http://www.thieme-connect.de/DOI/DOI?10.4103/jnacc-jnacc-31.17
8. Shawkat H, Chb MB, Frca M, et al.: Mannitol: a review of its clinical uses [Internet]. [cited 2020 Jul 14] Available from: https://academic.oup.com/bjaed/article-abstract/12/2/82/251486
9. Hyperosmolar Therapy for the Treatment of Cerebral Edema [Internet]. [cited 2020 Aug 4] Available from: https://www.uspharmacist.com/article/hyperosmolar-therapy-for-the-treatment-of-cerebral-edema
10. Diringer MN: New trends in hyperosmolar therapy? [Internet]. Curr Opin Crit Care 2013; 19:77–82[cited 2016 Dec 19] Available from: http://www.ncbi.nlm.nih.gov/pubmed/23385373
11. Wijdicks EFM, Sheth KN, Carter BS, et al.: Recommendations for the management of cerebral and cerebellar infarction with swelling: A statement for healthcare professionals from the American Heart Association/American Stroke Association [Internet]. Stroke 2014; 45:1222–1238[cited 2020 Jul 14] Available from: https://www.ahajournals.org/doi/10.1161/01.str.0000441965.15164.d6
12. Carney N, Totten AM, OʼReilly C, et al.: Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition [Internet]. Neurosurgery 2016; [cited 2016 Dec 15] Available from: www.neurosurgery-online.com

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Neha Dangayach

NeuroIntensivist at Mount Sinai

#SOME Committee @SCCM#SOME group @accpchest#FOAMed #FOAMcc #COVID19 Love my family, my job, being positive & thankful #Neurocritcare #Inthistogether

Latest posts by Neha Dangayach (see all)

• NeuroEMCrit – Everything you wanted to know about Hyperosmolar agents for the Management of ICP and Cerebral Edema - October 11, 2020