Question 10

Compare and contrast the pharmacology of mannitol and hypertonic saline.

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College Answer

A structured approach is important and a table worked best for most candidates, although a few attempted this in free text. Despite attempting a structured answer very few candidates  provided information in regards to preparation, dose, monitoring of osmolarity, adverse  effects or contraindications. Understanding of the action of these drugs was expected and factual inaccuracies were common with many candidates suggesting hypertonic saline acts as an osmotic diuretic. Better answers mentioned other potential mechanisms of action of mannitol. Many candidates failed to appreciate the impact on raised intracranial pressure.

Discussion

Osmotherapy for management of raised intracranial pressure is where this topic usually comes up, in questions from the Second Part exam (for example, in Question 8 from the first paper of 2001). From the college comments here, it is not clear that the typical ADME pharmacology structure would have won the day. "Preparation, dose, monitoring of osmolarity, adverse effects or contraindications" do not fit the normal pharmacokinetics / pharmacodynamics mould which is usually seen in questions starting with "Compare and contrast the pharmacology". This is probably why only 8% of them passed. Thus, here, two example answers are offered: one which does the typical "absorption, distribution, elimination" thing, and the other which duplicates the answer to the more mature questions from the Second Part papers:

Name 20% saline 20% mannitol
Class Concentrated electrolyte Osmotherapy agent
Chemistry Monovalent cation salt Sugar alcohol
Routes of administration IV only (specifically, can only be administered through CVC) IV only (though can be taken orally for osmotic laxative effect
Dose 20-40 mmol 0.25-1.0g/kg
Absorption Well absorbed in the small intestine. largely because of paracellular transport (high concentration). Good bioavailability Zero absorption; 0% bioavailability
Solubility pKa 3.09; good water solubility pKa 12.59, reasonable water solubility (but precipitates at low temperatures)
Distribution VOD=0.2L/kg, basically confined to the extracellular fluid
(thus: 25% remains intravascular, 75% becomes interstitial)
VOD=0.2L/kg, basically confined to the extracellular fluid
(thus: 25% remains intravascular, 75% becomes interstitial)
Target receptor Mechanism of action does not involve receptor binding; you might say the target is the blood brain barrier Mechanism of action does not involve receptor binding; you might say the target is the blood brain barrier
Metabolism Does not undergo any metabolism; excreted unchanged in the urine Does not undergo any metabolism; excreted unchanged in the urine
Elimination Eliminated renally, where specific reabsorption mechanisms in the renal tubule regulate the rate of sodium and chloride excretion Eliminated renally; filtered in the glomerulus and does not undergo any reabsorption, which results in a profound osmotic diuresis
Monitoring Serum sodium (endoint: Na+ 145-150 mmol/L) Serum osmolality can be monitored
Time course of action For control of intracranial pressure, onset of effect is very rapid (within tens of seconds of the infusion starting) For control of intracranial pressure, onset of effect is very rapid (within tens of seconds of the infusion starting)
Mechanism of action Increases the osmolality of the extracellular fluid, and therefore decreases the volume of the intracellular compartment by producing an osmotic shift of intracellular water of of the cells. This produces the desirable clinical effect of decreasing the volume of brain tissue, and therefore reducing the intracranial pressure. Increases the osmolality of the extracellular fluid, and therefore decreases the volume of the intracellular compartment by producing an osmotic shift of intracellular water of of the cells. This produces the desirable clinical effect of decreasing the volume of brain tissue, and therefore reducing the intracranial pressure.
Also increases the osmolality of renal tubular fluid, which prevents the reabsorption of water via the countercurrent multiplier mechanism, and produces diuresis - which is usually an undesirable effect
Clinical effects Increase in serum osmolality, which produces the desireable osmotic decrease in intracranial pressure.
A smaller increase in circulating volume than with mannitol, and without the diuresis.
Produced hypernatremia and hyperchloraemia, of which the latter may be associated with a metabolic acidosis
Initally, circulatory volume expansion, with the potential to create circulatory overload and pulmonary oedema.
Later, increase in serum osmolality, which produces the desireable osmotic decrease in intracranial pressure
Subsequently, decreased circulating volume due to massive diuresis.
Also, this leads to electrolyte depletion.

And now,  for something a bit more grown-up:

A Comparison of Mannitol and Hypertonic Saline Osmotherapy
Advantages
  • Still fairly cheap
  • Rapid effect
  • Seems to have some sort of rheological benefit (increaes red cell deformability)
  • Acts as a transient volume expander
  • May have a better effect on cerebral blood flow for a given reduction in ICP.
  • Safe endpoint (serum sodium) is easily monitored with ABGs.
  • Cheap
  • Stable in storage
  • Very rapid effect
  • Seems to have some sort of intrinsic anti-inflammatory effect
  • May also have some rheological benefits
  • At least as potent as mannitol when it comes to reducing intracranial pressure
  • Less potential for hypovolemia than with mannitol- the diuretic effect is less potent
  • May have a better effect on cerebral blood flow for a given reduction in ICP.
  • Safe endpoint (serum sodium around 145-155) is easily monitored with serial ABGs.
Disadvantages
  • Unstable in storage: at low temperatures and at altitude, it precipitates.
  • Medium for bacteria and fungus.
  • Causes a brief state of volume overload
  • Causes torrential diuresis and hypovolemia
  • Causes hyponatremia while in the serum, and hypernatremia after the inevitable diuresis
  • Endpoint is serum osmolality(320), which is cumbersome to measure
  • May cause ICP to "rebound" after prolonged use
  • Need for central venous access
  • No standards for which concentration to use, or how to give it
  • Hypokalaemia
  • Hyperchloraemic acidosis
  • Should not be used if the patient is chronically hyponatremic
  • Possible seizures due to wild fluctuations in serum sodium
  • Increase in circulating volume with risk of fluid overload.
  • Coagulopathy (APTT and INR)
  • Altered platelet aggregation.
  • May affect normal brain more that injured brain which theoretically may worsen herniation

References

Shenkin, Henry A., et al. "The use of mannitol for the reduction of intracranial pressure in intracranial surgery." Survey of Anesthesiology 8.5 (1964): 405-406.

Francony, Gilles, et al. "Equimolar doses of mannitol and hypertonic saline in the treatment of increased intracranial pressure*." Critical care medicine 36.3 (2008): 795-800.

Lazaridis, Christos, et al. "High-Osmolarity Saline in Neurocritical Care: Systematic Review and Meta-Analysis*." Critical care medicine 41.5 (2013): 1353-1360.

Bhardwaj, Anish, and John A. Ulatowski. "Hypertonic saline solutions in brain injury." Current opinion in critical care 10.2 (2004): 126-131.