What are the causes of hypocalcemia (low calcium levels) in critically ill patients, especially those with intracerebral hemorrhage (ICH) in the Intensive Care Unit (ICU)?

Causes of Hypocalcemia in ICU Patients

Hypocalcemia in the ICU is extremely common (occurring in 55-88% of critically ill patients) and results from multiple mechanisms including kidney replacement therapy-related losses, citrate toxicity from blood products, hypomagnesemia, critical illness itself, and nutritional deficiencies. 1, 2

Primary Mechanisms in the ICU Setting

Kidney Replacement Therapy (KRT)-Related Causes

• Intensive KRT modalities (CKRT, PIKRT) cause hypocalcemia through high-efficiency electrolyte removal, particularly when standard phosphate-free and calcium-free dialysis solutions are used 1
• Regional citrate anticoagulation during CKRT chelates ionized calcium, with magnesium also lost as magnesium-citrate complexes in the effluent 1
• The initiation of KRT itself represents a major risk factor for developing or worsening hypocalcemia 1

Transfusion and Citrate Toxicity

• Each unit of packed red blood cells or fresh frozen plasma contains approximately 3 grams of citrate, which binds ionized calcium and removes it from circulation 3
• Citrate-mediated calcium chelation is the primary mechanism during massive transfusion protocols 4, 3
• Impaired citrate metabolism due to hypoperfusion, hypothermia, or hepatic insufficiency exacerbates hypocalcemia, as these conditions prevent the liver from metabolizing citrate to bicarbonate and releasing bound calcium 4, 3
• Colloid infusions (but not crystalloids) independently contribute to hypocalcemia beyond citrate toxicity 4

Critical Illness and Sepsis

• Hypocalcemia correlates with illness severity (APACHE II score) rather than any specific disease process, occurring across medical, surgical, trauma, neurosurgical, burn, respiratory, and coronary ICU settings 2
• The frequency of hypocalcemia does not depend on ICU setting or presence of sepsis, but severity correlates with mortality 2
• Critical illness itself disrupts calcium homeostasis through mechanisms that remain incompletely understood 5, 6

Electrolyte Interdependencies

Hypomagnesemia is present in 28% of hypocalcemic ICU patients and prevents calcium correction - this is a critical pitfall as hypocalcemia cannot be fully corrected without adequate magnesium 4, 7, 2

Additional electrolyte associations include:

• Low magnesium, sodium, and albumin are independently associated with hypocalcemia on admission 8
• Hypomagnesemia (serum magnesium <0.70 mmol/L) occurs in 60-65% of critically ill patients and is exacerbated by CKRT 1

Refeeding Syndrome

• Initiation of medical nutrition, especially when carbohydrate calories are privileged, can trigger refeeding syndrome - a constellation of electrolyte derangements including hypocalcemia, hypophosphatemia, and hypomagnesemia 1
• This occurs after acute or chronic caloric deprivation when nutrition is reintroduced 1

Underlying Kidney Disease

• Kidney failure is characterized by baseline hypocalcemia along with hyperphosphatemia and hyperkalemia, though these typically improve when KRT is initiated 1
• Secondary hyperparathyroidism in chronic kidney disease contributes to calcium dysregulation 4

Vitamin D Deficiency

• Vitamin D insufficiency (25-hydroxyvitamin D <30 ng/mL) impairs intestinal calcium absorption 4
• Losses of water-soluble vitamins including vitamin D occur through CKRT effluent 1

Context-Specific Considerations for ICH Patients

While the provided evidence does not specifically address intracerebral hemorrhage, ICH patients in the ICU are subject to all the above mechanisms, with particular relevance to:

• Massive transfusion protocols if surgical intervention or coagulopathy requires blood product administration 3
• Critical illness severity correlating with hypocalcemia depth 2
• Potential KRT requirement if acute kidney injury develops 1

Clinical Significance

Hypocalcemia on admission predicts mortality with greater accuracy than fibrinogen levels, acidosis, or platelet counts 3, 7

Associated complications include:

• Impaired platelet function and decreased clot strength 3, 7
• Cardiac dysrhythmias (particularly concerning when ionized calcium <0.8 mmol/L) 4, 3
• Compromised cardiovascular function 7, 6
• Prolonged ICU length of stay 2

Critical Pitfalls

• Adjusted calcium (AdjCa) <2.2 mmol/L has only 78.2% sensitivity and 63.3% specificity for predicting low ionized calcium - always measure ionized calcium directly in critically ill patients rather than relying on total calcium corrections 8
• Standard coagulation tests may appear normal despite significant hypocalcemia-induced coagulopathy because laboratory samples are citrated then recalcified before analysis 4, 7
• Acidosis increases ionized calcium levels, so correction of acidosis may unmask or worsen hypocalcemia 4