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:


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

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 (El) 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 El.

Key teaching points:

• Space flight (SF) can cause endothelial damage, decreased vascular endothelial growth factor (VEGF), platelet aggregation— related thrombocytopenia and insulin-resistance (IR), leading to cardiovascular complications (CVC).

Malabsorption and hypokinesia contribute to Mg depletion of SF, and to the CVC and secondary inflammatory processes.

• Need for Mg repletion during SF mandates availability of a Mg salt, that can be administered subcutaneously - preferably by a (to be developed) repletable automatic device, and a means to monitor sublingual Mg levels.


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 deficit. As a result, there is oxidative stress [I], elevations of inflammatory cytokines [7] and insulin resistance conducive to self-sustaining vascular inflammation [3] (Figure 1).

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] (Figure 2).

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] (Figure 3).

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.-l-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).


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.


1. Rowe WJ: Interplanetary travel and permanent injury to normal heart. ACTA Astronaut 40:719-722, 1997.
2. Rowe WJ: The Apollo 15 Space Syndrome. Circulation 97:119-120,1998.
3. Rowe WJ (July 13-16, 2002): Spaceflight-related endothelial dysfunction with potential congestive heart failure. (Abstract) Proceedings of the 8th World Congress on Heart Failure, Mechanisms and Management, Washington, D.C.
4. Buravkova LB, Romanov YA: The role of cytoskeleton in cell changes under condition of simulated microgravity. ACTA Astronaut.  48:647-650, 2001.
5. Roessler A, Hinghofer-Szalkay H, Noskov V, Laszlo Z, Polyakow VV: Diminished plasma c-GMP during weightlessness. J Gravitat Physiol     4:101- 102, 1997.
6. Banai S, Haggroth L, Epstein SE, Casscells W: Influence of extracellular magnesium on capillary endothelial cell proliferation and migration. CircRes   67:645-650, 1990.
7. Stein TP, Schluter MD: Excretion of IL-6 by astronauts during spaceflight. Am J Physiol 266:E448-E452, 1994.
8. Atkov OY, Bednenko VS: "Hypokinesia and Weightlessness: Clinical and Physiologic Aspects." Madison: International Universities Press, ppl- 66, 1992.
9. Gunsillius E, Petzer AL, Gasti G: Space flight and growth factors (letter). Lancet 353:1529, 1999.
10. Battinelli E, Willoughby SR, Foxall T, Valeri CR, Loscaizo J: Induction of platelet formation from megakaryocytoid cells by nitricoxide. Proc Nat Acad Sci 98:14458-14463, 2001.
11. Gawaz M, Reininger A, Neumann FJ: Platelet function and plate-let-leukocyte adhesion in symptomatic coronary heart disease. Effects of intravenous magnesium. ThrombRes 83:341-349, 1996.
12. Rajagopalan S, Shah M, Luciano A, Crystal R, Nabel EG: Adenovirus-mediated gene transfer of VEGF121 improves lower extremity endothelial function and flow reserve. Circulation 104:753-755, 2001.
13. Chou E, Suzuma I, Way KJ, Opiand D, Clermont AC, Naruse K, Suzuma K, Bowling NL, Vlahos CJ, Aiello LP, King GL: De­creased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic states. A possible explanation for impaired collateral formation in cardiac tissue. Circulation 105:373-379, 2002.
14. Rowe WJ: Potential myocardial injuries to normal heart with prolonged space missions: The hypothetical key role of magnesium. Magnes Bull 22:15-19, 2000.
15. Weglicki WB, Phillips TM, Freedman AM, Cassidy MM, Dickens BF: Magnesium deficiency elevates circulating levels of inflammatory cytokines and endothelin. Mol Cell Biochem 110:169-173, 1992.
16. Yi-Ping L, Reid MB: Effect of tumour necrosis factor-a on skel­eton muscle metabolism. Curr Opin Rheumatol 13:483-187, 2001.
17. Shearer WT, Reuben JM, Mullington JM, Price NJ, Bang-Nmg L, 0'Brian-Smith E, Szuba MD, Van Dongen HPA, Dinges DF: Soluble TNF-a receptor I and IL-6 plasma levels in humans subjected to the sleep deprivation model of spaceflight. J Allergy Clin Immunol 107:165-170,         2001.                                    
18. Churchill SE: Fundamentals of space life sciences. Malabar Fla Krieger 2:355-364, 1997.                                      
19. Philp RB: A review of blood changes associated with compression-decompression: Relationship to decompression sickness. Undersea Biomed Res 1:117-150, 1974.  
20. Tietze KJ, Putcha L: Factors affecting drug bioavailability in space. J Clin Pharmacol 34:671-676, 1994.  
21. Wade CE, Morey-Holton E: Alteration of renal function of rats following spaceflight. Am J Physiol 275:Rl058-1065, 1998.
22. Aries PM, Schubert M, Muller-Wieland D, Krone W: Subcutaneous magnesium pump in a patient with a combined magnesium transport defect. Otsch Med Woehenschr 125:970-972, 2000.
23. Santini JT, Cima MJ, Langer R: A controlled-release microchip. Nature 397:335-338, 1999.


Received August 5, 2004