257 General discussion 8 An intervention to reduce dexamethasone-induced side effects Our previous clinical trial suggested that children who suffer most from dexamethasoneinduced neurobehavioral and sleep problems may benefit from physiological hydrocortisone addition to dexamethasone treatment.5 However, our randomized controlled trial did not establish a beneficial effect of hydrocortisone when compared to placebo (Chapter 6). Of note, both trials did not compare the intervention with a treatment as usual arm, prohibiting a direct comparison between the intervention with hydrocortisone or placebo and the natural course of side effects. Neurobehavioral problems Both hydrocortisone and placebo seemed to diminish dexamethasone-induced neurobehavioral problems, a finding which may be contributed to a placebo-effect. This does not completely exclude the hypothesis that hydrocortisone in itself has a beneficial effect through restored activation of the MR. However, if this is the case, the effect is not stronger than a placebo-effect. The equivalent dose of the physiological dose of hydrocortisone (10mg/m2) is 0.375mg/m2 dexamethasone,57 a fraction of the 6mg/m2 dexamethasone children receive every day during their ALL treatment. It is conceivable, that the high dose of dexamethasone results in upregulation of both the GR and MR, and that the relatively low dose of hydrocortisone is not enough to completely saturate the MR. It has been reported that high dexamethasone doses can activate the MR in the brain, although with lower potency,58 thereby generating competition with the low hydrocortisone dose, and minimizing the potential effect of hydrocortisone addition. For better understanding of the binding of physiological quantities of hydrocortisone in the brain during high dose dexamethasone treatment, future research may use (radioactively) labelled hydrocortisone in animal models.59 Sleep problems Both objective (actigraphy) and subjective sleep outcomes did not improve after hydrocortisone (or placebo) addition. This lack of efficacy could be due to a different pathophysiology of sleep problems than GR:MR imbalance. A previous study in healthy adult volunteers showed that both dexamethasone and hydrocortisone decrease rapid-eyemovement (REM) sleep, whereas slow-wave sleep (SWS) increased during hydrocortisone but decreased during dexamethasone.60 Interestingly, when adding hydrocortisone to dexamethasone treatment, both REM and SWS seemed to improve in comparison with the dexamethasone only condition, albeit not significantly.60 Hence, it would be interesting to use polysomnography to measure sleep in children with ALL under dexamethasone treatment with or without hydrocortisone addition, to further elucidate the effect of hydrocortisone on sleep.
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