emDOCs Podcast – Episode 102: Hypocalcemia in Trauma and the Diamond of Death

Why is hypocalcemia in trauma something we should know about?

• Previous triad of death = hypothermia, acidosis, and coagulopathy. All are associated with critical illness and severe hemorrhage.
• However, this triad does not include hypoCa, which has a major role in trauma.
• HypoCa is common in trauma patients and is associated with poor outcomes.
  • A meta-analysis found that 56% of patients with severe trauma resulting in hypotension have hypoCa.There was an increase in mortality, increased need for transfusion, and increased risk of coagulopathy in patients with hypoCa.

Why is calcium important in trauma or critical illness?

• The normal concentration of ionized Ca is between 1.1 mmol/L to 1.3 mmol/L.
• Ca affects cardiac contractility, vasculature constriction and dilation, and hemostasis and the coagulation cascade. Lower serum Ca is associated with worsening acidosis.
• HypoCa reduces cardiac contractility, prolongs the QT interval, reduces vasoconstriction, and decreases effectiveness of the coagulation panel, clot strength, and platelet binding.

What’s the relationship between Ca and blood products?

• Blood products, including both packed red blood cells and whole blood, are stored with the anticoagulant citrate, with can bind Ca and lower ionized Ca levels.
• Packed red blood cells (pRBCs) are stored with 3 grams of citrate per unit, while whole blood is stored with 1.66 grams of citrate per unit. FFP and platelets also contain citrate.
  • Any transfused blood product can reduce active Ca in the serum.
  • Whole blood does contain less citrate.
• Under normal physiology, the liver can metabolize up to 3 grams of citrate every 5 minutes.
• Liver dysfunction, secondary cirrhosis, critical illness, trauma, and hypothermia reduce citrate metabolism. In massive hemorrhage requiring rapid transfusion, the large quantities of infused citrate surpass the liver’s ability to metabolize citrate.
• All of this further leads to hypoCa.

Calcium plus the lethal triad in trauma

• Ca is linked to coagulopathy. The lower the level, the less the patient can form clots, and clots are also weaker.
• HypoCa is associated with acidosis and hypoperfusion. The lower the value of Ca, the greater the association with acidosis.
• Hypothermia also leads to hypoCa. Hypothermia shifts the oxygen-hemoglobin dissociation curve to the left, and both hypocalcemia and hypothermia reduce cardiac contractility and output.
• With the current data and association of hypoCa with other parts of the lethal triad, the diamond of death is a better interpretation: hypoCa, coagulopathy, acidosis, and hypothermia.

Calcium and resuscitation

• Severely injured trauma patients are commonly hypocalcemic. Up to 56% have an ionized Ca < 1 mmol/L, and this increases mortality and need for transfusion. Increase in mortality ranges between 7-10% (from around 8-16% in those with normal Ca to 15-26% in those with hypoCa).
• There are many different mechanisms in trauma for hypoCa:
  • Ca binding by lactate in lactic acidosis, impaired parathyroid gland and hormone function, and intracellular influx in the setting of ischemia and reperfusion.
• Transfusion induced hypoCa is common in patients undergoing massive transfusion.
  • Giancarelli et al found that 97% of patients who underwent massive transfusion protocols during trauma resuscitation were hypocalcemic (iCa < 1.1 mmol/L), while 71% of these patients were severely hypocalcemic (iCa < 0.9 mmol/L). HypoCa was associated with 49% mortality (vs 24%).
  • While we think of this most commonly in massive transfusion, hypoCa can occur in those with only a single unit transfusion.
    • Kyle et al demonstrated that transfusing a single unit of pRBCs can lead to significant decreases in Ca.
    • Transfusion of any amount of blood product precipitating a drop in Ca level of trauma patients was also supported by Webster et al.
  • Rate of transfusion is also associated with risk of hypoCa.

How does this impact the prehospital environment?

• Prehospital blood product transfusion increases risk of hypoCa.
  • Two randomized controlled trials by Moore et al found that prehospital plasma administration in trauma patients is associated with hypoCa (53% vs 36%). Prehospital transfusion of pRBCs is also associated with lower ionized Ca levels, and the degree of hypoCa correlates with the number of blood products transfused.
• Prehospital Ca administration reduces risk of hypoCa on arrival (70% vs. 28%).

How does this impact what you do in the ED?

• If you’re giving blood and the patient is hemorrhaging, give Ca up front with the first unit. That’s 2 g of Ca gluconate with the first unit and then another 2 g every 2-6 units.
• Make Ca administration a part of your massive transfusion protocol.
• Target an ionized Ca level over 1.2 mmol/L.
• However, avoid overcorrection causing hyperCa, which is also associated with mortality.

What is still needed in the literature?

• We need RCTs to determine if Ca administration in trauma impacts mortality and other patient-centered outcomes.
• We also need studies looking at hypoCa and the other factors of the deadly diamond to determine if giving Ca affects other components of the triad.
• Other questions: What’s the appropriate dosing in trauma for Ca, what’s the target, how often should we check ionized Ca levels?

Keys:

• Critically ill trauma patients are often hypocalcemic prior to resuscitation, and this is worsened by transfusion of necessary blood products.
• Inadequate Ca and hypoCa contributes to the triad of death with worsening cardiac output, decreased vasomotor tone, acidosis, and coagulopathy.
• HypoCa in critically ill trauma patients has a clear association with increased mortality.
• If you’re giving blood, give Ca.

References

• Wray JP, Bridwell RE, Schauer SG, Shackelford SA, Bebarta VS, Wright FL, Bynum J, Long B. The diamond of death: Hypocalcemia in trauma and resuscitation. Am J Emerg Med. 2021 Mar;41:104-109.
• Vasudeva M, Mathew JK, Groombridge C, Tee JW, Johnny CS, Maini A, Fitzgerald MC. Hypocalcemia in trauma patients: A systematic review. J Trauma Acute Care Surg. 2021 Feb 1;90(2):396-402.
• Ditzel RM, Anderson JL, Eisenhart WJ, et al. A review of transfusion- And trauma-induced hypocalcemia: Is it time to change the lethal triad to the lethal diamond? J Trauma Acute Care Surg. 2020. doi:10.1097/TA.0000000000002570
• Cannon JW, Khan MA, Raja AS, et al. Damage control resuscitation in patients with severe traumatic hemorrhage. J Trauma Acute Care Surg. 2017. doi:10.1097/ta.0000000000001333
• Giancarelli A, Birrer KL, Alban RF, Hobbs BP, Liu-DeRyke X. Hypocalcemia in trauma patients receiving massive transfusion. J Surg Res. 2016;202(1):182-187.
• Vasudeva M, Mathew JK, Fitzgerald MC, Cheung Z, Mitra B. Hypocalcaemia and traumatic coagulopathy: an observational analysis. Vox Sang. 2020. doi:10.1111/vox.12875
• Ho KM, Leonard AD. Concentration-Dependent Effect of Hypocalcaemia on Mortality of Patients with Critical Bleeding Requiring Massive Transfusion: A Cohort Study. Anaesth Intensive Care. 2011;39(1):46-54.
• Li K, Xu Y. Citrate metabolism in blood transfusions and its relationship due to metabolic alkalosis and respiratory acidosis. Int J Clin Exp Med. 2015.
• Byerly S, Inaba K, Biswas S, et al. Transfusion-Related Hypocalcemia After Trauma. World J Surg. 2020:1.
• Magnotti LJ, Bradburn EH, Webb DL, et al. Admission Ionized Calcium Levels Predict the Need for Multiple Transfusions: A Prospective Study of 591 Critically Ill Trauma Patients. J Trauma Inj Infect Crit Care. 2011;70(2):391-397.
• Webster S, Todd S, Redhead J, Wright C. Ionised calcium levels in major trauma patients who received blood in the Emergency Department. Emerg Med J. 2016;33(8):569-572.
• Kyle T, Greaves I, Beynon A, Whittaker V, Brewer M, Smith J. Ionised calcium levels in major trauma patients who received blood en route to a military medical treatment facility. Emerg Med J. 2018;35(3):176-179.
• Cherry RA, Bradburn E, Carney DE, Shaffer ML, Gabbay RA, Cooney RN. Do early ionized calcium levels really matter in trauma patients? J Trauma – Inj Infect Crit Care. 2006.
• MacKay EJ, Stubna MD, Holena DN, et al. Abnormal Calcium Levels During Trauma Resuscitation Are Associated With Increased Mortality, Increased Blood Product Use, and Greater Hospital Resource Consumption. Anesth Analg. 2017;125(3):895-901.