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Hypertonic Saline & Mannitol for Raised Intracranial Pressure
Acute brain injuries of all sorts increase the pressure inside the skull (intracranial pressure). Traumatic brain injury, bleeding in or around the brain, severe ischemic stroke, and acute hepatic failure all raise intracranial pressure, and increased intracranial pressure often becomes the most severe and immediate threat to life and long-term neurologic function in these conditions.
Hyperosmolar therapy with hypertonic saline or mannitol can rapidly reduce intracranial pressure, possibly saving lives and brain cells. In ideal circumstances, every patient with raised intracranial pressure would be treated at a center providing advanced neurologic critical care; however, this is not the case in most of the world. Therefore, every intensivist should be at least familiar with the principles of hypertonic / hyperosmolar therapy for the treatment of acute increased intracranial pressure.
Pathophysiology of Increased Intracranial Pressure
Raised intracranial pressure (ICP) appears to be quite lethal: in traumatic brain injury patients, those with ICP > 40 mm Hg had a mortality of 56%, compared to 18% for those with ICP < 20 mm Hg. Most traumatic brain injuries causing long-term disability also initially presented with raised intracranial pressure.
As volume increases inside the skull, intracranial pressure exponentially rises after it passes an inflection point of ~20-25 mm Hg. As ICP passes 50-60 mm Hg and approaches arterial pressure, global brain ischemia and eventual brain death result. The brain is 80% water, so using hyperosmolar agents to create an osmolar gradient between the inside of the brain and the systemic circulation has strong theoretical appeal. Hypertonic saline and mannitol are effective because they do not cross the blood-brain barrier (much), and thereby draw cerebrospinal fluid out of the cranium and fluid out of the injured brain, reducing pressure and further injury.
In brain injuries that include disruption of the blood-brain barrier, hyperosmolar therapy may be less effective.
There is no definitive evidence from prospective randomized trials that reducing intracranial pressure with hyperosmolar therapy saves lives or prevents disability. The theoretical evidence for its benefit is so persuasive, though, that placebo-controlled trials will not be performed. Post hoc analyses of randomized trials of brain injured patients, along with observational trials, suggest that reducing intracranial pressure does improve outcome.
Hypertonic Saline Vs. Mannitol: Dealer's Choice
There is no clear evidence of superiority of either mannitol or hypertonic saline at reducing intracranial pressure. One small trial suggested mannitol was better, others have favored hypertonic saline. The absolute differences of effects between agents have been quite small in these studies.
If a ventricular drain is placed, CSF can be removed and intracranial pressure can be measured directly; this invasive approach carries a slight infection risk and has not been shown to improve outcomes.
If a direct-pressure monitoring device is not in place, the goal of hyperosmolar therapy is to either:
- Increase the serum osmolarity initially to a target of 300-320 mOsm/L. Calculate osmolarity by (2 x Na) + (glucose / 18) + (BUN / 3), or use an osmolarity calculator, or your lab's true measured osmolality.
- Increase serum sodium to 145-150 mmol/L.
Both these methods work whether using mannitol (an osmotic diuretic that causes generalized dehydration and hypernatremia) or hypertonic saline (which increases sodium concentration directly).
Mannitol sig: 20% mannitol bolus 0.25-1.0 grams / kg body weight q. 2-4 hours; use higher doses in emergencies, lower doses for maintenance. Check osmolarity 20 minutes after infusion. If there is an osmolar gap between measured and calculated osmolarity, mannitol is still circulating; wait and check again.
Hypertonic saline sig includes boluses of either:
- 3% NaCl (513 mmol/L) bolus 150 ml;
- 7.5% NaCl (1283 mmol/L) bolus 75 ml;
- 23.4% NaCl (4008 mmol/L) bolus 30 ml
Use boluses; don't use continuous infusions of 3%, the author advises; it doesn't work as well.
Use the formula to determine the number of millimoles of sodium to infuse to achieve the 145-150 mmol/L serum Na goal:
sodium needed in mmol = (lean body weight in kg × 0.5 for a woman or 0.6 for a man) × (target sodium − current sodium in mmol/L).
Divide the result of this (# of mmol) by the concentration of your NaCl solution (in mmol/L) to get a total volume (L) to bolus in measured aliquots (see above).
Hypertonic saline greater than 3% concentration should be infused through a central line.
Adverse Effects of Hyperosmolar Therapy for Increased ICP
Mannitol can cause renal failure in high doses; this seems to occur only when > 200 g of mannitol are given daily, from published reports. Dialysis / renal replacement therapy usually reverses the renal failure.
Mannitol can also cause a volume contraction alkalosis (metabolic alkalosis) with hypokalemia and hypochloremia. Providing normal saline infusion (0.9%) as a replacement fluid and maintaining euvolemic hypernatremia during therapy can prevent/treat this.
Hypertonic saline causes volume overload even when used properly, which can exacerbate congestive heart failure. Furosemide may be provided to reduce volume expansion. Hypertonic saline also can cause hypokalemia and hyperchloremia, as well as a mild metabolic acidosis.
Mannitol (and less often hypertonic saline) can cause a hyperglycemic, hyperosmolar state with encephalopathy, confusion, seizures, and focal neurologic signs. Diabetics and the elderly are more susceptible; insulin should be given if this occurs, or for patients with unexplained seizures or rapidly rising glucose level, the author advises.
Hypertonic saline can cause skin sloughing if infused into the subcutaneous tissues through an infiltrated I.V.; monitor I.V.s closely for patients receiving 3% peripherally and use a central line for higher concentrations.
Serum osmolarity of 320 mOsm/L has been traditionally considered the upper limit for safety, but some expert clinicians exceed this in practice and have not reported any safety problems, according to the author.
Increased Intracranial Pressure: Other Things to Consider
Surgical evacuation of subdural hematoma can be highly effective, but for more diffuse processes (brain contusion, cerebral edema, etc), surgery has not been shown to be superior than medical management.
Avoid serum hypo-osmolarity by not infusing anything with lower osmolarity than 0.9% NaCl normal saline -- no lactated Ringer's, D-5-W, half-normal saline, etc.
Hyperventilation is worthwhile as a bridge to other therapies, but its reductions in ICP through cerebral vasoconstriction last less than an hour.
External ventricular drains can reduce ICP quickly, but their effects may also be short-lived (limited to how much CSF is in the ventricles).
Glucocorticoids reduce edema surrounding brain masses, but don't reduce intracranial pressure in other situations.
Induced hypothermia reduces intracranial pressure initially, but can cause cerebral edema during rewarming, and is not advisable as a treatment for raised ICP (except possibly for another purpose, such as post-cardiac arrest).
Ropper AH. Hyperosmolar Therapy for Raised Intracranial Pressure. NEJM 2012;367:746-752.