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Journal of the American College of Nutrition, Vol. 23, No. 5, 525S-528S (2004)
Published by the American College of Nutrition

The Case for a Subcutaneous Magnesium Product and Delivery Device for Space Missions

William J. Rowe, MD

Former Assistant Clinical Professor of Medicine, Medical College of Ohio at Toledo, Toledo, Ohio

Address reprint requests to: William J. Rowe, M.D. E-mail: rowerun{at}aol.com


   ABSTRACT
TOP
 ABSTRACT
Conclusion
 REFERENCES
 
Cardiovascular (CV) complications, associated with space flight (SF), are caused by microgravity, hypokinesia and radiation, particularly beyond earth orbit, with all three conducive to oxidative stress. Except for emergencies, pharmaceuticals appear to be contraindicated, because of unpredictable side effects from malabsorption (M) and potential hepatic and renal impairment. Magnesium (Mg) depletion and elevations of cytokines (interleukin 6) occur during SF, conducive to self-sustaining vascular inflammation mechanisms. There are potential endothelial injuries (EI) and reduced Cyclic GMP (a second messenger of nitric oxide: NO) and elevated urinary excretion of C-peptide (insulin resistance: IR). Recent findings that show reductions in vascular endothelial growth factor (VEGF) suggest that this may result from SF-related thrombocytopenia since platelets (P) are the major source of VEGF, and that NO might play a role. Both VEGF and Mg are vital for angiogenesis, endothelial function and reendothelialization. Insulin is necessary for VEGF expression. To prevent SF-related CV complications in the presence of IR and M and with the potential for renal insufficiency, closely monitored subcutaneous (SC) Mg should be provided. The dosage can be monitored by sublingual intracellular Mg assays. Needed is development of a SC Mg reservoir device, which can be replenished before extra-vehicular activities (EVA) and which must be reliable despite vigorous movements during EVA, that can last up to 8 hours. This could also be protective against decompression sickness and EVA-related 100% oxygen requirements before and during this activity, both of which predispost to EI.

Key words: space flight (SF), cardiovascular complications, endothelial injury, oxidative stress, malabsorption, renal dysfunction, thrombocytopenia, Mg-deficiency, sublingual Mg-assay, subcutaneous Mg-repletion by subcutaneous device

Key teaching points:


   Discussion
 
Interplanetary travel [1] and even a brief lunar mission (Apollo 15) [2] have the potential of injuring the normal cardiovascular system even without the adverse effects of radiation-induced oxidative stress. Space flight (SF) may be complicated by arrhythmias, and myocardial infarction—in the absence of atherosclerosis or congestive heart failure—and presence of invariable dehydration [3]. In vitro [4], animal [1] and human [5] studies indicate that the endothelium is vulnerable to SF-related dysfunction/injuries with magnesium (Mg) ion deficits playing a central role [1,6].

There is loss of Mg storage sites in skeletal muscle and bone that complicate hypokinesia, invariable malabsorption secondary to microgravity, and several vicious cycles involving or triggered by Mg ion (Mg2+) deficit. As a result, there is oxidative stress [1], elevations of inflammatory cytokines [7] and insulin resistance conducive to self-sustaining vascular inflammation [3] (Fig. 1).



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  		Fig. 1. Four vicious cycles complicating hypokinesia of space flight.

 
SF-related thrombocytopenia [8] is probably responsible for the reductions of vascular endothelial growth factor (VEGF) since platelets are the primary source of VEGF [9]. The etiology of the thrombocytopenia has not been established but could be at least partially precipitated by reductions in nitric oxide (NO) [10], demonstrated by SF-related reductions of cyclic GMP [5]. In addition, it is possible that prevention or correction of an SF-related Mg deficit [8] might prevent Mg-deficiency-induced platelet aggregation and reduction in their numbers in the circulating blood, with complicating platelet-leukocyte adhesions [11].

Both Mg and VEGF regulate endothelial function and repair and are required for angiogenesis [1,6,12,13]. In the presence of SF-related insulin resistance [14] there would be in addition diminished VEGF expression [13] (Fig. 2).



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  		Fig. 2. Space flight-related vicious cycles.

 
In addition to the previously mentioned SF-related vicious cycles, another is triggered by elevations of inflammatory cytokines (interleukin 6) [7] and elevations of tumor necrosis factor-a (TNF-a) [15] complicating an Mg ion deficit, with in turn further loss of the skeletal muscle reservoir [16]. TNF-a elevations have also been shown complicating sleep deprivation [17] with the average duration of sleep on SF reduced to 6 hours [14] (Fig. 3).



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  		Fig. 3. Vicious cycle.

 
The calcium (Ca) blocker effect of Mg may serve an important function since it has been postulated that with elevations of carbon dioxide, demonstrated on the space station MIR, there may be an intracellular shift of Ca [14].

The endothelium is vulnerable to injuries, not only because of SF-related vicious cycles as previously emphasized, but also prior to and during a space walk. There is then a requirement of 100% oxygen to reduce the potential for decompression sickness [18], which may also cause endothelial injuries and may trigger further reductions in platelets [19] with in turn further reductions in VEGF [9]. The antioxidant effect of Mg [14] would be helpful in reducing these potential complications of hyperoxia.

Because of microgravity-related malabsorption [14] and potential hepatic [20] and renal [21] dysfunction, which may be at least partially triggered by diffuse [2] endothelial dysfunction, pharmaceuticals other than for emergencies and symptomatic relief appear contraindicated.

A strong case can be made for need of a subcutaneous Mg product. For one thing, intramuscular injections are too painful. There has been very limited experience with subcutaneous Mg in humans. Recently, a subcutaneous portable pump was used in a 28-year-old male with both Mg malabsorption and decreased Mg renal retention. The patient’s symptoms were relieved in this case with "continuous Mg sulphate subcutaneous infusion" [22]. In addition, a chloride (Cl) would be required to correct a potential aldosterone-induced Cl loss complicating microgravity [8] and to prevent hypokalemic alkalosis [14]. Experience with subcutaneous Mg-1-aspartate-hydrochloride in rats indicates that, to maintain a therapeutic level, injections might be required as frequently as every 4 to 6 hours (Personal communication HG Classen) - possibly insufficient to protect the endothelium from oxidative stress and decompression sickness, since space walks can last as long as 8 hours [18]. Classen also believes that, whereas preliminary NASA studies have shown that several pharmaceuticals deteriorate in space, possibly from radiation (personal communication, L Putcha), Mg.-1-aspartate-hydrochloride is stable and thus unlikely to deteriorate from radiation. Because the port can become displaced posteriorly as a result of vigorous movements, during a space walk, for example, a subcutaneous pump [22] would not be reliable.

A device developed by Santini et al. [23]: a subcutaneous computer chip, the size of a pocket watch, containing thousands of micro reservoirs, which can be inserted subcutaneously and operated remotely with electrochemical dissolution of thin anode membranes, opens the door for other devices. The Santini device may be an attractive alternative, but its fault is that it cannot be replenished once it leaves the manufacturer. Such a device must be suitable for SF requirements extending for durations of 2 years or longer, eventually perhaps for interplanetary travel [1].

Finally since there is potential impairment in renal function [21] complicating potential diffuse endothelial dysfunction, frequent monitoring of Mg levels is required with high reliability. Measuring intracellular Mg levels, as developed by Silver [14], would serve this purpose well, if the analytic equipment could be reduced in size, and be made suitable for SF, and for tests to be repeated as often as necessary, by personnel with relatively little technical training (personal communication BB Silver).


   Conclusion
TOP
 ABSTRACT
 Conclusion
REFERENCES
 
To prevent Mg deficiency induced by malabsorption and hypokinesis of SF, that can give rise to diffuse endothelial injuries and cardiovascular complications, close monitoring of Mg levels (by a non-invasive procedure) is important, in order to undertake timely repletion. Furthermore, potential renal dysfunction can interfere with Mg homeostasis, which further enhances the need to develop a small analytic device Mg product to detect onset of Mg depletion and the need for administration of a Mg supplement, preferably a chloride, that can be given subcutaneously - by means of a still to be developed Mg-salt repletable delivery device.

Received August 5, 2004.
   REFERENCES
TOP
 ABSTRACT
 Conclusion
 REFERENCES
 

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This Article
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Right arrow Articles by Rowe, W. J.

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