There’s a reason that 3 the 10 of the most frequently accessed in “Up to Date” articles relate to the management of hyponatremia. It makes doctors nervous, and I think the main reason for this is the threat of the terrifying osmotic demyelination syndrome (ODS). A murky and poorly understood entity, ODS hangs over every management decision you make and, even if you’ve done all the right things (kept the rate of rise in sodium to less than 8 meq per day, paid attention to the K, given DDAVP and H2O back if necessary) you may still get burned, particularly in alcoholics, cirrhotics and the malnourished. Worst of all, you may not learn your fate until over a week later, when early signs of severe neurological injury start to appear.
During hyponatremia, exchangeable intracellular solutes are redistributed to prevent cerebral edema, leading to gradual loss of intracellular organic osmotically active particles. It can take over 5 days to rebuild these stores. A rapid rise in serum Na forces cerebral vascular endothelial cells to contract, opening the blood-brain barrier and allowing pro-inflammatory cells and cytokines to enter the brain. This causes oligodendrocyte injury, microglial activation and demyelination. An agent that could be given to hyponatremic patients before attempting Na correction, and which prevents this dreaded complication occurring, has enormous appeal. In this month’s JASN, two studies in rats suggest minocycline might be just that.
Minocycline is a tetracycline antibiotic most widely used for the topical treatment of acne. It also appears to prevent spots on the brain, having protective properties in animal models of CNS injury, including demyelination, where it seems work by preventing microglial activation. Both of these JASN studies test its effectiveness, when started several hours before rapid Na correction, in preventing ODS in rats. In the first study, minocycline-treated rats showed less microglial activation, less inflammatory infiltrate and much better survival, although some demyelinating brain lesions did still occur. In the second study, minocycline resulted in a marked reduction in the incidence and severity of neurologic symptoms, although half of the rats died.
These are important studies, not least because they highlight the central role of inflammation and microglial activation in ODS, which I formerly held to be a form of direct osmotic injury. Given that ODS is so rare, it’s going to be quite difficult to study the effectiveness of minocycline in humans. So, don’t be surprised if you start to hear suggestions to give minocycline “just in case” in the ICU. I would resist this for a few reasons. First, I develop a little demyelination of my own (from banging my head against the wall) each time I see a renal patient prescribed N-acetylcysteine -but no iv fluids- pre-contrast. Untested therapies can creep into clinical practice, diverting focus from proven interventions and, once established, are very difficult to expunge. Second, very large doses were used in these animals. We’re a long way from knowing how to dose this in humans. Finally, minocycline frequently causes causes vestibular disturbances (dizziness, ataxia, vertigo and tinnitus), particularly in women (50-70% of the time!). Personally, I can’t think of anything more stressful than being called in the middle of the night because the patient I’m treating with hypertonic saline has just developed nystagmus or ataxic movements. No thanks!