CONTENTS

• Phosphate physiology
• Symptoms 
• Phosphate level
• Causes of hypophosphatemia
• Investigation of etiology
• Treatment
• Algorithm
• Podcast
• Questions & discussion
• Pitfalls

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phosphate physiology

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phosphate basics

• 99% of phosphate is present within cells.
• Symptoms from phosphate deficiency result from intracellular phosphate deficiency.   Unfortunately, we can measure only extracellular phosphate levels.   This creates some variability among patients with hypophosphatemia:
  • Symptoms tend to occur in patients with chronic hypophosphatemia and total-body deficiency (e.g. alcoholism, chronic antacid ingestion, chronic malnutrition with re-feeding syndrome).
  • Symptoms are uncommon in patients with acute shifts of phosphate out of the blood (e.g. diabetic ketoacidosis).
• In practice, it is often difficult to tell whether hypophosphatemia represents a total-body deficiency or a transient phosphate shift.  Given the potential consequences of true phosphate deficiency, it is generally better to err on the side of phosphate repletion.

endocrine physiology

• The most common endocrine causes of hypophosphatemia are as follows:
• (1a) Hyperparathyroidism – as shown above, this may cause hypophosphatemia and hypercalcemia.
• (1b) Hungry Bone Syndrome
  • Occurs immediately following resection of a parathyroid adenoma which was causing hyperparathyroidism.
  • Bone mineralization occurs, which pulls phosphate and calcium into the bone.
  • Clinically this should be easy to recognize because it occurs in the immediate postoperative period following parathyroid surgery.
• (2) Vitamin D deficiency – this causes impaired phosphate absorption in the gut and increased phosphate excretion.
• (3) Oncogenic osteomalacia
  • Extremely rare paraneoplastic disorder which usually occurs with small, benign tumors.
  • Tumor secretes phosphaturic hormones that reduce renal phosphate absorption and synthesis of 1,25-OH-vitamin D.
  • Clinical presentation:  hypophosphatemia with paradoxically low 1,25-OH-vitamin D levels (this is paradoxical, because normally hypophosphatemia would stimulate elevation of 1,25-OH-vitamin D).

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symptoms

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neurologic

• Seizures, paresthesias, tremor
• Confusion, dysarthria, stupor, coma
• May promote the development of central pontine myelinolysis

cardiac

• Impaired contractility, heart failure
• Arrhythmia (supraventricular and ventricular tachycardia)

muscular

• Rhabdomyolysis
  • Rare; May mask diagnosis of hypophosphatemia by release of phosphate from muscle!
• Muscle weakness, including diaphragm
  • May sometimes contribute to difficult weaning

other rare manifestations

• Insulin resistance
• Hemolysis

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phosphate level

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When checking a phosphate level, consider obtaining a complete electrolyte panel (including Ca/Mg/Phos).  Electrolyte disorders tend to occur in pairs and triplets (“electrolytic disarray”).  

when should phosphate be checked ?

• When initiating nutrition in patients at-risk for refeeding syndrome.
• Patients with diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic syndrome (HHNS).
• Patients on continuous renal replacement therapy (CRRT).
• Possibly once, upon admission for all patients entering the ICU?
• If there is clinical concern of symptoms due to hypophosphatemia.
  • In patients with difficulty weaning from ventilation (some evidence shows that hypophosphatemia may be a contributory factor by causing diaphragmatic weakness).

spurious hypophosphatemia (pseudohypophosphatemia)

• Uncommon
• Potential causes:  hyperbilirubinemia, mannitol, paraproteins, acute leukemia

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causes of hypophosphatemia

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shifting phosphate into cells

• Insulin
  • Diabetic ketoacidosis
  • Re-feeding syndrome
• Acute respiratory alkalosis
• Hungry bone syndrome (s/p surgery for hyperparathyroidism)

reduced gastrointestinal uptake

• Inadequate oral intake
• Chronic diarrhea
• Drugs
  • Chronic use of antacids containing calcium, magnesium, or aluminum

increased renal loss

• Diuresis or Dialysis
  • Diuretics (loop diuretics, acetazolamide, thiazides)
  • Osmotic diuresis (hyperosmolar hyperglycemic nonketotic syndrome, i.e. HHNS)
  • Auto-diuresis following iatrogenic volume overload
  • Post-ATN or post-obstructive polyuria
  • Hypothermia (“cold diuresis”)
  • Continuous renal replacement therapy (CRRT) – especially prolonged high-intensity runs for intoxication
• Proximal tubule dysfunction (Type II RTA, a.k.a. Fanconi Syndrome)
• Hyperparathyroidism
• Medications
  • Aminoglycosides
  • IV iron
  • Tenofovir
  • Chemotherapeutic agents (especially imatinib, VEGF inhibitors, and target of rapamycin inhibitors such as temsirolimus)
• Oncogenic osteomalacia

multifactorial

• Alcoholism
• Vitamin D deficiency
• Critical illness of most types:
  • Sepsis, systemic inflammation
  • Trauma (especially head trauma)
  • Major surgery (especially cardiothoracic, aortic, or hepatic)
  • Burns

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investigation of etiology

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Generally, the cause of hypophosphatemia can be determined by a history and review of labs and medications.   In rare situations where hypophosphatemia persists and the cause is unclear, a fractional excretion of phosphate might be helpful (Fe-Phos).

fractional excretion of phosphate

• Calculated in the same fashion as fractional excretion of sodium (FeNa)
  • You can use any calculator for FeNa (just insert phosphate in place of sodium).
  • Or you can use this online calculator for fractional excretion of phosphate.
• Fe-Phos should be <5% as a normal response to hypophosphatemia.  Thus:
  • Fe-Phos <5%:  Gastrointestinal problem, shifting into cells
  • Fe-Phos >5%:  Renal phosphate wasting
  • Multifactorial etiologies should be considered regardless of the Fe-Phos.

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treatment

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cautions

• Significant hypophosphatemia (e.g. phosphate <2 mg/dL or <0.65 mM) should generally be repleted, with the following potential exceptions:
• (1) Renal insufficiency
  • Phosphate should be given only if truly necessary, since these patients tend to develop hyperphosphatemia over time.
• (2) Hypercalcemia
  • Increasing phosphate may risk precipitation of calcium-phosphate in tissues (calciphylaxis).
  • Try to keep the calcium-phosphate product <70 (calcium multiplied by phosphate, both in mg/dL).
• (3) Hypocalcemia
  • Rapid infusion of IV phosphate may reduce calcium level.
  • If hypotension occurs during infusion of IV phosphate, consider possibility of hypocalcemia.

intravenous phosphate

• Indications:
  • Severe hypophosphatemia (<1 mg/dL or <0.32 mM)
  • Symptoms
  • Lack of enteral access
  • Malabsorption
• Either potassium phosphate or sodium phosphate may be used, depending on the potassium level.
• Typical dose:
  • Phosphate <1.5 mg/dL (<0.48 mM) ==> Initial dose of 30 mM phosphate infused over 4 hours
  • Phosphate >1.5 mg/dL (<0.48 mM) ==> Initial dose of 15 mM phosphate infused over 2 hours
• Repeat electrolytes and provide more as needed.  Patients with severe hypophosphatemia often require several doses (e.g. 60-90 mM total).
• Should probably be infused slowly:
  • Sources disagree about the safe rate of infusion.¹
  • Rapid infusion may cause transient hyperphosphatemia (which leads to hypocalcemia).  However, studies suggest that infusion at rates up to 20 mM/hour are safe.  A rate of 7.5 mM/h is definitely safe (as recommended in the algorithms here):²

oral phosphate

• Used if there isn't an indication for IV phosphate (listed above).
• High bioavailability, but tends to cause diarrhea.
• Available in increments of 8 mM phosphate.  One of the following options may be chosen, depending on the patient's potassium level:
  • (a) PHOS-NAK packet (8 mM phosphate, 7 mEq potassium, 7 mEq sodium)
  • (b) Oral sodium phosphate liquid
  • (c) Oral potassium phosphate liquid
• Dosing depends roughly on patient's phosphate level, for example:
  • Phosphate <1.5 mg/dL (<0.48 mM) ==> 16 mM q6hr
  • Phosphate >1.5 mg/dL (<0.48 mM) ==> 8 mM q8hr
• For patients with active refeeding syndrome, consider using higher doses than would otherwise be indicated based solely on the phosphate level.

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algorithm

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podcast

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Patients with alcoholism, diabetes, or malnutrition may initially have a normal phosphate level, but develop hypophosphatemia later on during their hospital course (following administration of carbohydrate and/or insulin).
• Don't overlook the possibility of refeeding syndrome in patients with hypophosphatemia after initiation of nutrition.  In this situation, other electrolytes and thiamine may be needed.
• In severe hypophosphatemia treated with IV repletion, several doses may be required.  Don't assume that a single dose will be effective.

Going further: 

• Hypophosphatemia (Chris Nickson, LITFL)

References