Influence of Acidosis on Ionized Calcium Levels
Direct Effect: Acidosis Increases Ionized Calcium
Acidosis increases ionized calcium levels by displacing calcium from albumin binding sites, with a fall in pH of 0.1 unit causing approximately a 0.1 mEq/L rise in ionized calcium. 1
Mechanism of Acute Changes
- A 0.1 unit increase in pH decreases ionized calcium concentration by approximately 0.05 mmol/L, meaning the reverse occurs with acidosis—pH decreases cause proportional increases in ionized calcium 2, 3
- This occurs because acidosis reduces calcium binding to albumin, liberating more free (ionized) calcium into the circulation 1
- The effect is immediate and reversible with correction of the acidosis 4
Type-Specific Responses
Both metabolic and respiratory acidosis increase ionized calcium, but metabolic acidosis produces a more pronounced and progressive elevation. 5
- In metabolic acidosis, ionized calcium increases progressively as pH falls, and can rise sufficiently to suppress PTH secretion despite the direct stimulatory effect of acidosis on the parathyroid glands 5
- In respiratory acidosis, ionized calcium increases by approximately 0.04 mM initially and then plateaus despite further pH reductions 5
- For the same degree of acidosis-induced hypercalcemia, PTH values increase more in metabolic than respiratory acidosis 5
Chronic Acidosis: Complex Bone and Calcium Homeostasis Effects
Chronic metabolic acidosis alters the homeostatic relationships between blood ionized calcium, PTH, and 1,25(OH)₂D₃ such that bone dissolution is exaggerated, contributing to osteodystrophy in patients with chronic kidney disease. 1
Long-Term Consequences
- Chronic metabolic acidosis causes increased calcium efflux from bone while simultaneously impairing renal calcium excretion in patients with renal insufficiency, leading to severe hypercalcemia 4
- Bone fractures are a relatively common manifestation of chronic metabolic acidosis 1
- Studies utilizing dynamic histomorphometry demonstrate reduction in bone mineral density and bone formation rates with chronic acidosis 1
- Linear growth in children is reduced by chronic metabolic acidosis 1
Clinical Implications for Specific Populations
Patients with Chronic Kidney Disease
In CKD Stages 3,4, and 5, serum levels of total CO₂ should be maintained at >22 mEq/L to prevent exacerbation of bone disease and alterations in calcium homeostasis. 1
- The fraction of total calcium bound to complexes is increased in advanced CKD, resulting in decreased free (ionized) calcium levels despite normal total serum calcium levels 1, 3
- Acidosis can mask underlying hypocalcemia in CKD patients—when acidosis is corrected, ionized calcium may fall precipitously 2
- A cross-sectional study of 76 CKD patients showed those with normal bone biopsy had serum bicarbonate of 23 mmol/L, while those with osteodystrophy had levels below 20 mmol/L 1
Critically Ill Patients
In lactic acidosis, plasma ionized calcium and blood lactate concentrations are inversely associated (r² = 0.78, p ≤ 0.001), contrary to the expected increase in ionized calcium with acidosis. 6
- This unexpected finding in lactic acidosis suggests a different mechanism than simple pH-mediated displacement from albumin 6
- The clinical significance is that hypocalcemia may complicate lactic acidosis despite the acidotic state 6
Patients with Chronic Respiratory Disease
- In compensated respiratory acidosis from chronic lung disease, ionized calcium shows high variability (range 1.01-1.25 mmol/L) despite minimal pH variation 7
- Ionized calcium correlates negatively with base excess (r = -0.81, P < 0.0001) and positively with PO₂ (r = 0.71, P < 0.002) in these patients 7
- These correlations differ entirely from acute respiratory disturbances, indicating chronic adaptation mechanisms 7
Critical Clinical Pitfalls
Correction of Acidosis May Unmask Hypocalcemia
When correcting metabolic acidosis with sodium bicarbonate, ionized calcium can decrease dramatically (correlation r = -0.93, P < 0.001), potentially causing symptomatic hypocalcemia. 4
- Monitor ionized calcium closely during acidosis correction, especially in patients with renal insufficiency or primary hyperparathyroidism 4
- The decrease in ionized calcium with bicarbonate administration occurs even without improvement in renal function 4
Avoid Citrate-Containing Alkali in CKD
- Citrate alkali salts increase absorption of dietary aluminum in CKD patients, both before dialysis and in those treated with dialysis 1
- Use non-citrate alkali preparations for acidosis correction in CKD patients exposed to aluminum salts 1
Measurement Considerations
Always measure ionized calcium directly in acidotic patients rather than relying on corrected total calcium, as the correction formulas do not account for pH-mediated changes in calcium binding. 1, 2, 3