A Hypothesis: The Role of Magnesium and Possibly Copper Deficiency in the Pathogenesis of the Adult or Acute Respiratory Distress Syndrome (ARDS) as it Occurs in Infants, Children, and Adults

Abstract

This is a hypothesis that magnesium (Mg) deficiency, often with associated copper (Cu) deficiency, contributes to the pathogenesis of the adult or acute respiratory distress syndrome (ARDS). ARDS occurs at all ages and is particularly lethal to infants and children. ARDS is an acute, life-threatening respiratory failure after widely diverse insults in patients with no prior history of cardiopulmonary dysfunction. The multiple predisposing factors include shock, sepsis, alcoholism, burns, gastroenteritis, and trauma. These are often treated with Mg-poor sodium-rich infusions, which increase renal excretion of Mg, or with multiple emergency transfusions of citrated blood, which temporarily binds Mg. Glucose or amino acid-rich infusates may result in translocation of Mg into intracellular space. Gastrointestinal loss of both Mg and Cu may be high. Unless specifically repleted, there may be major Mg and Cu losses. Within four d, about 1% of such patients in intensive care units, or 200,000 Americans a year, develop acute respiratory distress, with a survival rate of only 35%. The common denominator of injury is damage to the alveolar endothelium and epithelium, leading to increased permeability to protein, protein-rich alveolar edema, microatelectasis, and hyaline membranes. The pathogenesis is unknown. This hypothesis focuses on one aspect of this complex syndrome: The possible role of Mg deficiency and possibly Cu deficiency in the pathogenesis of ARDS. Deficiency of Mg leads to increased intracellular calcium (Ca), enhanced platelet aggregation, and increased secretion of thromboxane A2 (TXA2) from aggregated platelets. TXA2 is pro-aggregratory, and is a potent vasoconstrictor and bronchoconstrictor. As more platelets aggregate and are activated, there may be waves of exaggerated release of major vasoconstrictors that include TXA2, serotonin, and epinephrine, leading to pulmonary hypertension. Platelets release histamine which contributes to increased vascular permeability. Microvascular thrombosis of platelets, leukocytes, and thrombin lead to microatelectasis. Intrapulmonary shunting causes hypoxemia that is refractive to oxygen therapy. Cu is required for enzymes such as CuZn-superoxide dismutase (CuZnSOD) that provide major defense against damaging oxygen radicals. Mg and Cu are each required for normal immune response against infection and for oxidative phosphorylation (energy metabolism). Mg is required for protein synthesis, Cu for collagen and elastin synthesis. It appears to be of critical importance to investigate the roles of Mg and Cu in ARDS.