Hypophosphatemia and Refeeding Syndrome

I. What every physician needs to know

Acute hypophosphatemia is an iatrogenic development, caused by redistribution of phosphorus from the extracellular to intracellular compartments in patients with underlying depletion of phosphate stores. The classic example of this situation is the refeeding syndrome (RFS), of which hypophosphatemia is the cardinal manifestation; the two phenomena are iseparable so will be discussed together.

The conditions necessary for the development of acute symptomatic hypophosphatemia exist almost exclusively in the hospital; though it may be present (usually to a mild degree) at the time, it is almost never the reason for admission (spontaneous abandonment of a prolonged fast could produce an exception). As the consequences of critical hypophosphatemia may be devastating, early recognition and therapy are vital.

Phosphorus is overwhelmingly an intracellular mineral, most residing in bone; less than 1% is present in extracellular fluid. In all tissues, in the form of organic phosphates, it plays a number of essential physiological roles. Phosphates are critical to the integrity of cell membranes and many enzymatic processes, including muscle function and the coagulation cascade.

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As a component of adenosine triphosphate (ATP), phosphate is essential to normal metabolism and intracellular energy transport. As a component of 2,3-diphosphoglycerate (2,3-DPG) in red blood cells, it also plays a role in oxygen transport and delivery.

The normal serum phosphorus concentration in adults is 2.4-4.5mg/dL (0.8-0.15mmol/L). Mild hypophosphatemia is common and generally asymptomatic. Minor symptoms are possible at levels between 1-2mg/dL, but major manifestations are likely only below 1mg/dL.

It is important to distinguish between total body phosphate depletion and hypophosphatemia, which may develop solely due to intracellular redistribution in patients with normal phosphate stores. Such redistribution in the absence of depletion, as occurs during treatment of diabetic ketoacidosis, is transient and generally inconsequential. However, when intracellular redistribution occurs in the setting of underlying total body phosphorus depletion, profound hypophosphatemia may ensue.

II. Causes and Consequences of Hypophosphatemia

A. Pathophysiology

Clinically significant hypophosphatemia requires a combination of chronic phosphate depletion and acute redistribution from extracellular to intracellular fluid caused by metabolic fluctuations in the course of illness and therapy. It is therefore useful to divide consideration of its etiologies into these two broad categories.

Phosphate depletion

Phosphate depletion generally reflects either impaired intestinal absorption, excessive renal losses, or both (purely inadequate intake is uncommon, phosphate being ubiquitous in most diets, but occurs in severe malnutrition, e.g., anorexia nervosa or rapid weight loss).

Intestinal phosphate absorption is impaired in the presence of vitamin D deficiency, malabsorption of any etiology, or phosphate binding antacids. Common causes of renal phosphate wasting include vitamin D deficiency, hyperparathyroidism, alcoholism, metabolic acidosis and prolonged corticosteroid therapy. Alcoholism is the most common risk factor in medical patients.

Internal redistribution

Internal redistribution from extra- to intracellular fluid is responsible for most clinically significant hypophosphatemia. Normal cellular phosphate uptake is mediated by insulin, thus the most important common pathway to intracellular redistribution is the restoration of deficient insulin, either directly in the course of treatment for diabetic ketoacidosis (DKA) or indirectly through the reintroduction of carbohydrate to patients with malnutrition (RFS).

In recovery from DKA, assuming otherwise intact phosphorus homeostasis, hypophosphatemia is transient and usually inconsequential. But in malnourished patients with preexisting phosphate depletion, hypophosphatemia may be protracted and severe. Intracellular redistribution is also promoted by respiratory alkalosis, which occurs in a variety of conditions common in hospitalized patients including sepsis, liver disease, alcohol withdrawal and anxiety. Resolution of acidosis may contribute as well. Some frequently used medications, including beta-agonists and catecholamine pressors also promote intracellular shift.

B. Pattern Recognition

Acute hypophosphatemia from RFS typically develops within 48 hours following restoration of insulin-mediated carbohydrate metabolism in patients in whom it has been markedly restricted due to inadequate nutrition.

First described among inmates liberated from prison camps at the end of World War II, RFS is a routine concern for clinicians engaged in famine relief work. The most extreme and obvious example encountered in developed nations is that of a patient with anorexia nervosa hospitalized for therapeutic feeding, but it can occur with less obvious degrees of malnutrition.

Among general medical patients, alcoholic ketoacidosis and its treatment present a classic scenario for development of severe iatrogenic hypophosphatemia. Ketosis identifies the absence of carbohydrate intake. On the background of chronic malnutrition, alcohol-induced phosphate depletion and metabolic acidosis, reintroduction of carbohydrate with attendant resumption of physiologic insulin secretion leads to rapid cellular uptake of residual phosphate, potentially resulting in profound hypophosphatemia.

The following major manifestations reflect the diverse physiologic roles of phosphates in energy metabolism, enzyme function and cell membrane integrity:

Myocyte dysfunction may produce not only profound skeletal muscle weakness, but cardiac and respiratory failure, which are the major mechanisms of death from RFS (in a mechanically ventilated patient, incident hypophosphatemia should be considered as a cause of failure to wean). Smooth muscle function is impaired as well, contributing to gastrointestinal symptoms such as nausea and constipation.

Failure of cell membrane integrity is most evident as rhabdomyolysis and hemolysis. Impaired leukocyte and platelet function has also been demonstrated in vitro.

Nonspecific neurologic manifestations may include peripheral neuropathy, encephalopathy, seizures and coma.

Deficient production of 2,3-DPG may lead to impaired tissue oxygen delivery, which along with impaired oxidative metabolism may produce lactic acidosis, in addition to exacerbating diffuse organ dysfunction.

It is also vital to recognize that as a marker of RFS, the development of hypophosphatemia should alert the physician to its other important features which may include hypokalemia, hypomagnesemia and thiamine deficiency, each of which may have disastrous consequences in its own right.

C. Prevalence

The reported prevalence of hypophosphatemia at admission in medical patients varies widely, but seems to approximate 2-3% in larger series. Alcoholic patients appear to be at higher risk, with a prevalence as high as 30% at admission. An increased prevalence of roughly 20% has also been reported in patients with chronic obstructive pulmonary disease (COPD), apparently due in part to pharmacologically-induced renal phosphate wasting.

The major concern for the hospitalist is incident hypophosphatemia during hospitalization. Patients at risk are those with nutritional depletion subject to RFS, including those with alcoholism, anorexia, malignancy, malabsorption, gastric bypass, and those without nutrition for more than two days, or with marked recent weight loss for any reason.

Critically ill patients have a high incidence of hypophosphatemia, approximating 30% in two reported series. Several risk factors may converge to promote intracellular redistribution in these patients, including resumption of interrupted nutrition, correction of metabolic or respiratory acidosis, respiratory alkalosis, administration of insulin, beta-agonist and catecholamine pressor agents. One study reported a prevalence of 80% within the first 24 hours of admission for sepsis, apparently mediated by inflammatory cytokines.

The duration of nutritional interruption needed to create a risk of refeeding hypophosphatemia in a previously healthy and nutritionally replete individual is reported to be 7-10 days, however in malnourished, critically ill patients it may occur after as little as 48 hours without carbohydrate input. It does not require obvious feeding as such, but can occur even with minimal carbohydrate reintroduction in the form of 5% dextrose infusion.

III. Management

A. Management of Hypophosphatemia

General principles

The treatment of hypophosphatemia depends upon its severity and the presence of symptoms. With mild to moderate hypophosphatemia and intact gastrointestinal function, oral or enteral therapy is preferred. One packet of the widely available powder formulations Neutra-Phos (R) or Phos-Nak(R) contains 8mmol of phosphorus (a quantity found more economically in 250ml of cow’s milk) and 7.1mEq of potassium. The major side effect is diarrhea, less likely if given after meals.

Intravenous therapy with sodium or potassium phosphate is recommended in the presence of symptoms or phosphorus levels below 1mg/dL. The dosage of parenteral formulations is weight based and expressed as millimoles of phosphorus. Potassium phosphate is preferred with serum potassium less than 4.0mmol/L. Intravenous phosphate infusion has risks, chiefly hypocalcemia and metastatic calcium phosphate deposition, and therefore must be administered slowly.

Older texts suggested a maximum dose of 0.24mmol/kg infused over at least 6 hours, however several studies have demonstrated the safety of total doses as large as 1mmol/kg, infused as rapidly as 15-20mmol per hour in extreme situations.

Specific recommendations

There are no standardized practice guidelines specifying the details of phosphorus replacement. The following approach is synthesized from the published protocols, which vary with respect to treatment thresholds and dosages employed. Sample orders are provided for each scenario. The literature on phosphorus replacement regimens is largely a product of hospital pharmacists, who may provide valuable input for individual therapeutic decisions.

Mild-moderate hypophosphatemia (1.0-2.0mg/dL)

Oral or enteral replacement with 32-64mmol, (4-8 packets of Neutra-Phos or Neutra-Phos-K) daily in 3-4 divided doses. For patients unable to receive enteral medications, lower dose intravenous infusions of 0.08-0.24mmol/kg over 4-6 hours are reasonable.

Example: For a post-operative patient with resolving ileus resuming oral diet, weight 80kg, serum phosphorus 1.5mg/dL and potassium 4.2mmol/L: “Neutra-Phos 2 packets given orally TID after meals.” Or if unable to take orally or enterally: “Sodium phosphate 12mmol IV, infuse over 4-6 hours.”

Severe hypophosphatemia (<1.0mg/dL) or life-threatening symptoms

Intravenous infusion of up to 0.64mmol/kg at a rate of no more than 15-20mmol per hour.

Example: For an alcoholic patient with ketoacidosis and sepsis begun on dextrose containing fluids, with new onset of muscle weakness and respiratory failure. Weight 80kg, Serum phosphorus 0.8mg/dL and potassium 3.2mmol/L: “Potassium phosphate 45mmol IV, infuse over 3-4 hours.”

Additional considerations with intravenous phosphorus administration

Renal insufficiency requires dose reduction; precise guidelines are unavailable, but the aggressive regimens above were not used in patients with markedly reduced glomerular filtration rate. For obese patients, dosing based on adjusted ideal body weight (IBW + 30% of excess) is suggested. Response is unpredictable; serum phosphorus should be monitored every 6 hours, with redosing as indicated. Ionized calcium levels should be monitored as well. Transition to enteral therapy is recommended when the patient is able and serum phosphorus is above 1.5mg/dL.

It is very important to note that RFS also leads to hypokalemia and hypomagnesemia by the same mechanism of extracellular to intracellular redistribution, so levels of these electrolytes should be monitored and supplemented as necessary. Thiamine depletion may also develop with the potentially devastating consequence of Wernicke-Korsakoff Syndrome. While thiamine supplementation is traditional for patients hospitalized with alcohol intoxication or withdrawal, it should be strongly considered for any malnourished medical patient undergoing nutritional repletion.

B. Prevention of Hypophosphatemia

The main opportunity to prevent hypophosphatemia lies in recognition of patients at risk of developing RFS based on the risk factors noted above. Especially in critically ill patients, in whom multiple risk factors are present, refeeding hypophosphatemia may be quite common after as little as 48 hours without carbohydrate intake.

Logic dictates that initiation of therapeutic nutrition will nearly always follow some period of deprivation, therefore protocols for initiation of tube feedings and parenteral nutrition include gradual escalation of carbohydrate content, baseline levels and monitoring of serum phosphorus, potassium and magnesium over the first several days.

Nutritionists are well versed in the anticipation, recognition and management of the RFS and should always play an important role in the multidisciplinary management of these patients.

What's the evidence?

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