The August 23rd issue of the New England Journal of Medicine has a review article about the treatment of raised intracranial pressure. A patient with head trauma is the index case. Patients who are known to have increased intracranial pressure or more commonly thought to have it are typically treated with agents that increase serum osmolality, ie hypertonic saline or mannitol. The rationale is to have fluid move from the brain across the blood-brain barrier to the blood secondary to the osmotic force generated by the infused hyperosmotic solution thus decompressing the brain and saving it from irreversible injury secondary to dangerously high intracranial pressure. The paper starts with a review of the catastrophic consequences of increased pressure on the brain. It goes on to mention that infusion of hypertonic salt solution has been known for almost a century to decrease cerebrospinal pressure in animals and that hyperosmolar therapy has been part of the treatment of brain injury for many years.
Hypertonic salt causes water to leave cells because of osmosis as sodium remains almost entirely in extracellular fluid. Mannitol, a sugar alcohol, exerts the same effect through the same mechanism. After reviewing all the therapeutic options available for a variety of causes of increased intracranial pressure the article focuses on hyperosmolar therapy. It’s here that a little confusion enters the piece.
Let’s start with osmolarity and osmolality. Under the usual clinical conditions both are almost the same. Osmolarity is a measure of the number of particles in solution for a unit of volume. Thus one mole of glucose in one liter of water is one osmole per liter or 1,000 mosm/L. One mole of NaCl when dissolved in one liter of water gives two osmoles because it dissociates into two particles – a Na and a Cl ion. Osmolality is the number of particles per unit weight. It is measured directly by measuring the freezing point depression in a liquid caused by the particles in solution. A normal value is 280 mosm/kg.
Osmolarity is calculated from lab values routinely measured on virtually all patients. The various formulas used to make the calculation are all approximations. This is because they all make the incorrect assumption that every sodium ion in serum is accompanied by a single anion. The reason this assumption is incorrect is that one albumin molecule has numerous anionic sites on it. Thus the positive charge of many sodium ions will be balanced by the negative charges on a single albumin molecule meaning that there is less than one negatively charged particle for every sodium ion. Here’s a typical formula for calculation the serum osmolarity:
Osmolarity = 2[Na] + Glucose/18 + BUN/2.8
The Na is measured in mmol/L. Glucose is measured in mg/dl (hence its divided by a tenth of its molecular weight). BUN is also measured in mg/dl. There are two nitrogens in urea. The atomic weight of nitrogen is 14, thus two weigh 28 and we use a tenth again because we measure blood urea nitrogen in tenths of a liter. Imagine a subject with a Na of 140, a glucose of 90, and a BUN of 14. The osmolarity calculates to 290. But if we measure the osmolality (which should be about the same) we get 280. The best and easiest approximation of the osmolarity is twice the sodium concentration. This shortcut benefits from offsetting errors. It’s too low because it ignores the effect of glucose and BUN and too high because it ignores the effect of albumin.
The NEJM paper states that “the serum osmolarity can be used as a surrogate measure of the effect of therapy with either mannitol or hypertonic saline.” This not quite true. The paper goes on to say: “To assess the effect of mannitol, solute and osmolarity measurements should generally be obtained 20 minutes or more after an infusion. A discrepancy between the measured and calculated serum osmolarity (osmolar gap) reflects the circulation of molecules of mannitol and indicates that the blood sample was obtained too soon after an infusion to be useful in gauging the sustained effect of mannitol as an osmotic diuretic.” All of the above would be true if mannitol’s diuretic effect was limited to water, but it also increases sodium excretion. It’s also unlikely that all of a mannitol bolus will be excreted 20 minutes after infusion. Thus, if mannitol is to be used in patients with increased intracranial pressure the best course is to pick a target osmolality and measure it a regular intervals.
If hypertonic sodium is used the serum sodium will be a good marker of osmolality. Sodium is excreted more slowly than either an osmotic diuretic or a water load. Furthermore, all these comments about urinary excretion assume normal renal perfusion which is a big assumption in patients with compromised and changing brain function.
The article also says: “The question of whether control of intracranial pressure has a beneficial effect on survival and clinical outcome has tentatively been answered affirmatively.” To support this claim this reference is cited. This study in the Journal of Neurosurgery does not examine the effect of hyperosmolar therapy on outcomes of patients with increase intracranial, rather it simply documents that: “The most powerful predictor of neurological worsening was the presence of intracranial hypertension (ICP ≥ 20 mm Hg) either initially or during neurological deterioration.” There is no intervention arm to the work.
We have been arguing for decades about the real efficacy of hyperosmolar therapy for increased intracranial pressure. The truth is that we still can’t be sure that it works. Consider this admission from the NEJM paper, “Hyperosmolar therapy is assumed to be beneficial on the basis of its ability to lower intracranial pressure, but no trials have been carried out in which hyperosmolar therapy has been omitted from the treatment regimen. Monitoring of intracranial pressure, which requires the insertion of a device into the cranial cavity, has not been validated as a method for improving the outcome, as compared with treatment that is based on a fixed regimen of hyperosmolar therapy. However, gauging the dose and interval for hyperosmolar therapy is difficult without monitoring of intracranial pressure and poses a risk of either overtreatment or undertreatment.
“The ideal osmotic agent and method of administration have not been established. The patient’s blood pressure, cardiac output, and renal function often determine the choice between a dehydrating osmotic agent such as mannitol and a volume-expanding solution of sodium. The maximum serum sodium level and osmolarity that can be tolerated without causing hypotension or renal failure have not been established and depend on the patient’s initial renal function, age, and medical status.”
Another problem with this type of therapy is that it requires great facility with fluid and electrolyte metabolism – an expertise that often lies outside the domain of neurosurgery. If this therapy is to be used it is best to enlist the aid of physicians fluent in water pathophysiology.
Medicine commonly reduces to making important decisions on the basis of inadequate information. The treatment of patients with hyperosmolar fluid with impaired brain function is a good example of this limitation.