Hypophosphatemia

Stress Response

In the early postburn period, the classic “fight or flight” response occurs, with elevation of plasma catecholamines, glucose, glucagon, and cortisol. Exogenous epinephrine administration has been associated with the development of hypophosphatemia, and the profound catecholamine release accompanying thermal injury may contribute to the early decrease in serum phosphorus. The mechanism by which this occurs is uncertain but may be a consequence of the accompanying hyperglycemia, resulting in a redistribution of phosphorus from the extracellular to the intracellular compartment (see the later section on metabolic support ). In acute clinical states of glucagon excess, tubular reabsorption of phosphate is impaired in both the proximal and distal nephron, leading one to expect renal phosphate wastage. Because urinary excretion of phosphate is usually decreased in the early postinjury period, the importance of hyperglucagonemia remains uncertain. Administration of pharmacologic doses of glucocorticoids enhances phosphorus excretion and impairs phosphate absorption by the gut and reabsorption by the kidney. Whether the adrenocortical response significantly contributes to the hypophosphatemia after burn injury is not known.

Resuscitation and Topical Therapy

Administration of large doses of sodium lactate for initial burn resuscitation may decrease the serum phosphorus concentration by several mechanisms. Lactate is converted to glucose in the liver, a process requiring high-energy phosphate availability. Additionally, although it does not usually occur clinically, metabolic alkalosis induced by lactate infusion may result in depression of serum phosphorus concentration. Alkalosis is associated with an increase in glycolysis that promotes transfer of phosphorus to the intracellular space. During resuscitation, alkalemia is uncommon, and patients are more likely to manifest a mild metabolic acidosis, which is compensated by hyperventilation, resulting in a normal or mildly alkaline blood pH. Acidosis markedly inhibits renal phosphate reabsorption, resulting in phosphaturia. The contribution of this mechanism to postburn hypophosphatemia is probably minor; early renal phosphate wastage is not observed, perhaps being obscured by diminished glomerular filtration early in burn injury. In addition, the p -carboxy metabolite of mafenide acetate strongly inhibits carbonic anhydrase. Such inhibition diminishes proximal tubular reabsorption of phosphate and probably occurs after topical burn wound treatment with mafenide, but the magnitude of the effect is unknown.

Expansion of the extracellular fluid volume is also associated with inhibition of proximal tubular phosphate reabsorption. A tight coupling exists between sodium and phosphate transport across the renal epithelial cell. In patients with burns, mobilization and excretion of the large edema volume usually begins by the second postburn day and continues throughout the next week to 10 days. In contrast to the relative paucity of phosphate excretion during the first 24 hours after injury, when glomerular filtration is markedly reduced, a modest loss of phosphate may occur with diuresis of the edema fluid. In fact, the diuretic phase is associated with an increase in the fractional excretion of phosphate despite a concomitant reduction in the serum phosphate concentration. Phosphorus excretion during the natriuretic phase of early burn injury is consistent with the tight coupling observed in other diuretic states.

Ulcer Prophylaxis

Effective prophylaxis against Curling's ulcers with H ₂ antagonists and antacid buffering has been a mainstay of burn care for the past 2 decades. Significant degrees of hypophosphatemia and phosphate depletion occur during continuous or chronic administration of phosphate-binding agents containing magnesium, calcium, and aluminum. These agents bind not only dietary phosphate but also phosphate secreted into the intestinal lumen, often resulting in a net negative phosphate balance. The severity of such hypophosphatemia clearly depends on the dose of phosphate-binding agents, dietary phosphorus intake, and preexisting phosphate balance. To reduce alimentary scavenging of dietary and secreted phosphate, buffering with antacids containing aluminum phosphate salts (Al ₂ PO ₄ ), which do not bind any additional phosphate, may be used. Sucralfate, which is also effective in preventing upper gastrointestinal stress ulceration after thermal injury, is not a buffering agent, but as a complex salt of aluminum hydroxide, is capable of binding phosphate. Its administration has also been associated with the development of hypophosphatemia in critically ill patients.

Hyperventilation

Respiratory alkalosis is often present during the first week postburn and may be enhanced by anxiety or pain and even by the inhibition of carbonic anhydrase induced by mafenide acetate burn cream. As fluid resuscitation progresses, the respiratory rate and tidal volume progressively increase, resulting in minute ventilation that may be twice normal. Mild hyperventilation induces only a slight decline of serum phosphorus levels; prolonged, intense hyperventilation, however, may result in serum phosphorus values less than 1.0 mg/dL. During respiratory alkalosis, phosphorus virtually disappears from the urine, eliminating renal losses as the causative mechanism. Respiratory alkalosis induces a rapid movement of carbon dioxide from the intracellular to the extracellular space. Intracellular pH increases, activating glycolysis and increasing the formation of intracellular phosphorylated carbohydrate compounds. The readily diffusible inorganic phosphate pool supplies the required phosphorus, and serum phosphorus concentrations consequently fall abruptly. The extent to which this mechanism contributes to postburn hypophosphatemia is uncertain.

Metabolic Support

Administration of carbohydrates may play a major role in the development of postburn hypophosphatemia. Infusion of glucose solutions or oral intake of carbohydrates produces mild hypophosphatemia in healthy individuals. This decrease in serum phosphate is associated with an increase of inorganic phosphate, adenosine triphosphate (ATP), and glucose 6-phosphate in muscle cells. The mechanism by which such carbohydrate administration induces hypophosphatemia is somewhat speculative. Experience with phosphate-deficient total parenteral nutrition and subsequent development of hypophosphatemia has provided some insight into the etiology. As carbohydrates are absorbed, insulin secretion increases, shifting phosphorus from the extracellular to the intracellular space. If phosphate reserve is low, ATP is poorly regenerated because hypophosphatemia inhibits glucose 3-phosphate dehydrogenase. Inorganic phosphates in the intracellular pool become further diminished because of incorporation, initially as newly synthesized ATP, but eventually as triose phosphates when the ATP is consumed in the hexokinase reaction. Glucose utilization by red blood cells (RBCs) requires ATP at the hexokinase and phosphofructokinase steps, but regeneration of ATP does not occur during phosphate deficiency or acute hypophosphatemia because of a block at the glucose 3-phosphate dehydrogenase step. In states of phosphate depletion, the scant phosphate that enters the RBC is incorporated into 1,3-diphosphoglycerate, but most is diverted to 2,3-diphosphoglycerate (2,3-DPG), also preventing complete glycolysis to regain the ATP consumed.

In thermally injured patients, infusion of dextrose-containing solutions usually begins 24 hours postburn, and enteral nutrition, in which most of the calories are supplied as carbohydrates, is initiated within several days of injury. These interventions are temporally correlated with the rapid descent of serum phosphorus concentrations. In other clinical states, severe hypophosphatemia after the initiation of enteral or parenteral nutrition is most commonly associated with the feeding of patients with advanced protein-calorie malnutrition. When total body phosphorus is depleted by starvation, serum phosphorus levels usually remain normal, but carbohydrate administration produces a rapid marked decline in serum phosphorus concentration. If untreated, this may result in multisystem organ dysfunction, respiratory and cardiac failure, or death. Thermally injured patients are usually well nourished before burn injury, and the clinical scenario of refeeding hypophosphatemia may not apply to them. Similar findings, however, have been described recently in previously well-nourished surgical intensive care unit patients in whom the initiation of isotonic enteral feedings resulted in a decrease of serum phosphorus from normal levels to approximately 1 mg/dL, a level that is considered to be dangerously low and to require prompt supplementation. In addition, the authors have reported that hypophosphatemia in thermally injured patients is exacerbated by the initiation of enteral feeding and occurs regardless of the postburn day when feeding is initiated. This further reduction of serum phosphorus during the first postburn week, when levels are already low, may be particularly hazardous and speaks for aggressive phosphorus supplementation before and during the initiation of enteral alimentation.