Abstract
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Several preventive measures and treatments are available to avoid this situation. One such treatment might be glucocorticoids, which are of particular interest because they also reduce symptoms of acute mountain sickness (AMS) (Hackett et al., 1988). In fact, it has been shown that glucocorticoid intake prior to ascent and while at high altitude prevented HAPE in individuals with known susceptibility (Maggiorini et al., 2006). The rational for this prophylactic administration was the known slow effect of steroids dependent upon induction of gene expression (Yang and Zhang, 2004).
It is of interest, of course, whether acute treatment of HAPE is also possible, which would prevent possible adverse side effects of more prolonged intake. There are only a few reports under these circumstances, and the results are conflicting. Two case reports of patients higher than 4000 m indicate that 8 mg and later 4 mg of dexamethasone (Bärtsch et al., 1990) and a total of 20 mg of dexamethasone (Naeije and Melot, 1990) taken to treat AMS at a time when HAPE was not evident or diagnosed, did not prevent the occurrence of HAPE on the following day. It is not clear from these reports whether the individuals already had (mild) HAPE at the time of treatment. Thus, these results indicate no preventive effect of short-term action of glucocorticoids taken within 24 hours.
Another report shows that successful treatment of a patient with severe AMS, but without signs of HAPE, with 4 mg dexamethasone also decreased pulmonary artery systolic pressure (PAsP) at an altitude of 3450 m within a few hours (Kriemler et al., 2006). Based on the concept that exaggerated hypoxic pulmonary vasoconstriction is a necessary antecedent of HAPE (Dehnert et al., 2007), and that preventing this increase also prevents HAPE in susceptible individuals (Bärtsch et al., 1991; Maggiorini et al., 2006), the authors argued that acute dexamethasone may also have prevented HAPE (Kriemler et al., 2006).
Another study, presented only as an abstract at the International Hypoxia Symposium in Lake Louise reported that only one out of eight HAPE-susceptible individuals developed HAPE after taking dexamethasone before the second night at 4559 m because of AMS (Maggiorini et al., 2011), indicating a much lower recurrence rate than the reported value of ∼60% in susceptible individuals (Bärtsch and Gibbs, 2007). Also in this study, dexamethasone decreased PAsP.
Unfortunately, no placebo group has been reported. Glucocorticoids given i.v. decreased mean pulmonary arterial pressure within 60 min in normobaric hypoxia in healthy humans (Bjertnaes and Vaage, 1996), whereas in another study no effect was seen after 2 hours, but pressures were lower after 8 hours (Liu et al., 2013). Taken together, these results provide at best indirect evidence of glucocorticoid action occurring faster than 24 hours in healthy individuals, and no proof of successful treatment because none actually had HAPE.
There are also clinical studies demonstrating decreased PAsP upon treatment with glucocorticoids in patients with pulmonary arterial hypertension of different etiologies. High-dose prednisolone decreased PAsP in a patient with idiopathic pulmonary arterial hypertension (Ogawa et al., 2011), in patients with systemic lupus erythematosus (Jais et al., 2008; Kato et al., 2011), and in acute respiratory distress syndrome (Borg et al., 1985). However, a highly pro-inflammatory state exists in these diseases, and glucocorticoids are known potent immune-suppressants (Oppong et al., 2013). However, Swenson and colleagues (2002) have shown that inflammatory reactions do not play a role in HAPE, putting into question the relevance of these findings for HAPE. Because patients had been treated with steroids for days to weeks, these studies preclude any conclusions on rapid steroid actions.
In order to argue for possible rapid actions of glucocorticoids to treat HAPE based on proposed pathophysiological mechanisms (Bärtsch et al., 2005), one must analyze their mode of action and potential targets relevant to this disease. Gluco- and mineralo-corticosteroids are lipid-soluble molecules, which can easily permeate cell membranes. Most of their effects are mediated by widely distributed cytosolic receptors belonging to the steroid, thyroid, retinoic acid superfamily of nuclear receptors (Stahn and Buttgereit, 2008). These glucocorticosteroid receptors (GR) are primarily cytoplasmic, and after binding of corticosteroids, they translocate to the nucleus and bind to specific DNA sites, leading to increased transcription of a variety of genes (Williams, 2013).
One such genomic action is increased expression of serum glucocorticoid kinase-1, which stimulates reabsorption in a variety of different epithelia (Lang and Shumilina, 2013). Alveolar reabsorption plays a vital role in clearing fluid filtered into the alveolar space. Although there is no direct proof of action in humans, experiments on animal models shows that glucocorticoids increase de novo synthesis and membrane insertion of Na-transporters stimulating alveolar fluid clearance 24 to 48 hours after administration, but not earlier (Noda et al., 2003).
Because the complex also inhibits nuclear factor kappa B (NFκB) and activator protein 1 (AP-1), it also prevents increased iNOS expression (Ehrchen et al., 2007) and inhibition of alveolar reabsorption by inflammation (Fronius, 2013). Treatment with glucocorticoids for several days tightens the endothelial barrier indicated by decreasing trans-endothelial fluid flow and reducing paracellular permeability for macromolecules, both of which depend on the transcriptional regulation of the expression of junctional proteins (Underwood et al., 1999; Romero et al., 2003). These effects require about 4–24 hours to develop as well as high drug concentrations as achieved with typical high daily doses or pulse dosing (Boumpas, 1996). Several days of treatment with dexamethasone also increases alveolar surfactant secretion (Young and Silbajoris, 1986), which will reduce the risk for edema by reducing surface tension and microvascular transmural pressure (Albert et al., 1979).
There are also rapid-onset but short-lasting actions of glucocorticoids mediated by non-genomic effects, likely via membrane-bound GRs affecting activities of many kinases (Williams, 2013), some of which might also affect vascular resistance. Glucocorticoids inhibit norepinephrine uptake (i.e., inactivation of norepinephrine) thus transiently (30 to 90 min) enhancing typical α1-adrenergic receptor-mediated vasoconstriction, but also stimulate epinephrine [i.e., β2 dependent vasodilation (Yang and Zhang, 2004], which requires local concentrations >30 μM far beyond those achieved with doses of dexamethasone typically used, for example, for acute treatment of AMS.
Treatment with lower concentrations increases norepinephrine- and angiotensin-induced vasoconstriction contributing to hypertension, but this response required days to develop (Yang and Zhang, 2004). In the heart, dexamethasone (100 nM) increases eNOS activity and NO formation within 30 min by non-genomic action (Hafezi-Moghadam et al., 2002). Our own preliminary data on four individuals only indicate that a single dose of dexamethasone seems not to have an acute effect on PAsP, whereas it might decrease PAsP during short exposures to normobaric hypoxia 48 and 72 hours after intake (Dehnert et al., unpublished).
The above mentioned results indicate potentially beneficial actions of glucocorticoids such as increased fluid clearance, tightening of the alveolar barrier, and responsiveness of vascular smooth muscles. It needs to be pointed out that these actions require very high doses and at least 24 hours to develop clinically relevant effects. Therefore, it appears unlikely that administration upon diagnosis of HAPE would have any rapid beneficial effects. However, the well-controlled experiments to disprove this contention have yet to be performed. Until then, we suggest more established means of treatments such as descent, increasing oxygenation, and decreasing PAsP by pulmonary vasodilators such as nifedipine or tadalafil.