What are calcium chloride dosing recommendations for trauma patients receiving massive transfusion protocol?

Comment by InpharmD Researcher

Per the 2020 Joint Trauma System (JTS) practice guideline, 1 g of intravenous/intraosseous calcium supplementation is recommended for every 4 units of transfused blood products in patients undergoing massive transfusion protocol. The World Health Organization recommends maintaining an ionized calcium level of > 1.1 mmol/L in massive transfusion protocols, as ionized calcium levels <1 mmol/L have been found to be associated with a higher risk of mortality. As such, this recommended calcium level may be used as guidance for calcium replacement. The dosing strategy for calcium supplementation in patients receiving massive transfusions varies among retrospective studies (See Tables 1-2).

Background

A clinical practice guideline for prehospital blood use during en route care was published in 2020 by the Joint Trauma System (JTS), an organization that primarily serves the medical needs of combatants in the context of battlefield medicine; however, its principles may apply to all kinds of trauma patients. The guidance states calcium administration should be considered in all patients undergoing en route care blood transfusion to prevent transfusion-induced hypocalcemia and hypotension. As the citrate preservative in blood products can lead to chelation of calcium in the circulation, it is recommended to administer 1 g of calcium (30 mL of 10% calcium gluconate or 10 mL of 10% calcium chloride) intravenous (IV)/intraosseous (IO) before, during (using a secondary access point) or immediately after the first unit of blood product. Every 4 units of blood products need to be supplemented with 1 g of calcium IV/IO. [1]

A 2021 review discussed findings on hypocalcemia and increased mortality rates across three retrospective cohort studies, with calcium levels ranging from 1.0 to 1.11 mmol/L showing an association with increased mortality. Additionally, one retrospective study (Table 2) found an ionized calcium level of 0.9 mmol/L might be indicated for 2 g of calcium chloride for every 2 to 4 U of blood products transfused. The overall level of evidence of this review was moderate and continued prospective studies are needed to further explore possible therapeutic measures. [2], [3]

The World Health Organization (WHO) recommended in its clinical transfusion practice that a massive transfusion protocol should be used in critically bleeding patients anticipated to require massive transfusion. Ionized calcium level in particular should be measured early and frequently (every 30-60 minutes, or after transfusion of blood component) to maintain a level of > 1.1 mmol/L in adults. Specific dosing regimens for calcium supplementation are not addressed in the document. [4]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Regarding trauma patients, what is the current calcium chloride dosing recommendations in patients receiving massive transfusion protocol (I.e. calcium chloride 1g IV for every 4 - 8 units of red blood cells)?

Please see Tables 1-2 for your response.

Summary of Retrospective Studies on Optimal Calcium Repletion in Patients Undergoing Massive Transfusion
Citation	Design	Population	Main outcomes
Robinson et al. (2023)	Single-center, retrospective cohort	Aged ≥18 years; undergoing surgery or presenting with traumatic injury N= 308 iCa <0.9 mmol/L (n= 165) iCa ≥0.9 mmol/L (n= 143)	On average, patients in the iCa <0.9 mmol/L group received significantly more units of RBC, median 12 vs 7 (p< 0.001), and units of FFP, median 9 vs 4 (p< 0.001), within 24 h of activation. There was no difference in mEq of elemental calcium administered between groups (55.8 vs 36.3, respectively). The ratio of Citrate:Ca for each patient was not significantly associated with mortality at 24 h (p= 0.79) or 30 days (p= 0.91) at a repletion Citrate:Ca ratio of median 1.97 (IQR 1.14–2.91). Mortality rate was lowest at a Citrate:Ca of 2 in both <24-h mortality and 30-day mortality.
Potestio et al. (2022)	Single-center, retrospective chart review	N= 51 Adult trauma patients; received massive transfusions following 1:1 PRBC to plasma ratio Among eligible patients, 97% were hypocalcemic during the first 6 hours of resuscitation. During MTP, 0.17 g of calcium chloride per blood product was administered.	Calcium supplementation correlated with the total number of blood products transfused (p< 0.01). Patients in whom calcium was supplemented received more blood products when compared to patients in whom calcium was not supplemented (median 16, IQR: 12-26 vs. median 9, IQR: 7-12, p< 0.01).
Chanthima et al. (2021)	Single-center, retrospective cohort study	N= 346 Lived (n= 254) Died (n= 92) Aged ≥15 years with a MTP activation; received blood products during transport or during the first 3 hours of in-hospital care	Among patients, 83.2% had hypocalcemia at first iCa determination; 85.6% had hypocalcemia in the last determination in the first 3 hours; 51.2% received at least 1 calcium replacement dose during that time. Mortality was associated with receiving greater numbers of units of plasma (8 vs 5) and RBC (8 vs 6, p< 0.001 for both components). Mortality was also associated with receiving larger total doses of calcium in the first 3 hours (10.7 vs 7.3 mmol, p= 0.04). There was no association between mortality and the first iCa or calcium dose corrected for citrate load.
Hall et al. (2021)	Single-center, retrospective chart review	N= 71 Trauma patients aged ≥18 years; required MTP activation and received at least one unit of PRBC The median amount of transfused packed PRBCs: 10 units (range 1–52). A total of 42 (59.1%) patients had periods of severe hypocalcemia.	Patients receiving 13 or more units of PRBC had a greater prevalence of hypocalcemia with 83.3% having at least one measured ionized calcium ≤1.0 mmoL/L (p= 0.001). The amount of supplemental calcium varied considerably: median amount of 2,000 g (range 500–19,000 mg) of calcium supplementation given over three doses (IQR 2 to 6); median time between doses 14 min (IQR 5 to 41). The amount of calcium supplementation given increased with the units of PRBC transfused.
Kyle et al. (2018)	Single-center, retrospective chart review	N= 297 Ca treatment (n= 237) Non-Ca treatment (n= 60) iCa levels upon admission were compared between those who received blood products without prehospital intravenous calcium supplement (non-treatment) and patients who were treated with 10 mL of intravenous calcium chloride (10%) concurrently with blood products (treatment).	Serum calcium levels were significantly different between the groups: 1.03 mmol/L vs 1.25 mmol/L (difference 0.22 mmol/L; 95% CI 0.15 to 0.27). In the non-treatment group, 26.6% had calcium levels within the normal range compared with 41.7% in those who received calcium. There was a dose-response of calcium levels to blood products with a significant decrease in calcium levels as the volume of blood products increased.
Abbreviations: iCa, ionized calcium; IQR, interquartile range; PRBC, packed red blood cells; MTP, massive transfusion protocols; FFP, fresh frozen plasma; RBC, red blood cell

References:

[1] Robinson A, Rech MA, DeChristopher PJ, et al. Defining the optimal calcium repletion dosing in patients requiring activation of massive transfusion protocol. Am J Emerg Med. 2023;70:96-100. doi:10.1016/j.ajem.2023.05.017
[2] Potestio CP, Van Helmond N, Azzam N, Mitrev LV, Patel A, Ben-Jacob T. The Incidence, Degree, and Timing of Hypocalcemia From Massive Transfusion: A Retrospective Review. Cureus. 2022;14(2):e22093. Published 2022 Feb 10. doi:10.7759/cureus.22093
[3] Chanthima P, Yuwapattanawong K, Thamjamrassri T, et al. Association Between Ionized Calcium Concentrations During Hemostatic Transfusion and Calcium Treatment With Mortality in Major Trauma. Anesth Analg. 2021;132(6):1684-1691. doi:10.1213/ANE.0000000000005431
[4] Hall C, Nagengast AK, Knapp C, et al. Massive transfusions and severe hypocalcemia: An opportunity for monitoring and supplementation guidelines. Transfusion. 2021;61 Suppl 1:S188-S194. doi:10.1111/trf.16496
[5] 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. doi:10.1136/emermed-2017-206717

Hypocalcemia in trauma patients receiving massive transfusion
Design	Retrospective cohort study N= 156
Objective	To determine the incidence of hypocalcemia and severe hypocalcemia in trauma patients who receive massive transfusion and to compare characteristics of patients with severe versus nonsevere hypocalcemia
Study Groups	Ionized calcium (iCa): ≥ 0.9 (n= 45) < 0.9 (n= 111)
Inclusion Criteria	All trauma patients aged 18 years who had activation of massive transfusion protocol (MTP)
Exclusion Criteria	MTP activated for any indication other than trauma, did not receive a massive transfusion, no iCa available within 24 hours of MTP initiation, blood bank records not available
Methods	Electronic medical records at a single trauma center were retrospectively reviewed to identify eligible patients and collect data on blood product administration for the duration of MTP activation and iCa monitoring and calcium replacement up to 24 h after MTP discontinuation. Hypocalcemia was defined as an iCa < 1.12 mmol/L, and severe hypocalcemia was defined as an iCa < 0.90 mmol/L. Patients with prothrombin time (PT) or activated partial thromboplastin time (aPTT) > 1.5 times the upper limit of normal were considered to have coagulopathy. A receiver-operating characteristics (ROC) analysis was used to identify the cutoff value of total blood volume associated with development of severe hypocalcemia.
Duration	Between January 2009 and November 2013
Outcome Measures	Primary outcome: incidence of hypocalcemia and severe hypocalcemia Other outcomes: calcium monitoring and management of hypocalcemia during MTP (calcium replacement reported in grams of calcium chloride) and the correction of coagulopathy at the end of MTP
Baseline Characteristics		iCa ≥ 0.9 (n= 45)	iCa < 0.9 (n= 111)	p-value
	Median age, years (interqualite range [IQR])	42 (23 to 55)	35 (25 to 50)	0.573
	Male	37 (82%)	88 (79%)	0.826
	Injury Severity Score (IQR)	27 (17 to 33)	21 (16 to 27)	0.054
	Mortality	11 (24%)	54 (49%)	0.007
	Trauma type Blunt Penetrating Other	37 (82%) 7 (16%) 1 (2%)	55 (50%) 48 (43%) 8 (7.2%)	0.001 - - -
	Admission laboratories (IQR) Hemoglobin, g/dL Platelets, 10³/µL aPTT, s PT, s pH Lactic acid, mmol/L	11.2 (9.7 to 12.6) 208 (169 to 272) 25.8 (22.3 to 35.9) 12.7 (11.8 to 14.6) 7.23 (7.14 to 7.33) 4.0 (3.1 to 7.8)	10.5 (8.5 to 12.1) 176 (108 to 237) 29.7 (23.7 to 50.9) 13.8 (11.9 to 16.4) 7.14 (6.98 to 7.28) 5.8 (4.1 to 9.8)	0.076 0.003 0.024 0.050 0.005 0.019
	No significant differences were noted in systolic blood pressure, heart rate, temperature, and home medications (antiplatelets and anticoagulants).
Results	Endpoint	iCa ≥ 0.9 (n= 45)	iCa < 0.9 (n= 111)	p-value
	Blood product administration (IQR) Duration MTP, h Total blood product units Total PRBC units Total FFP units Total platelets units Total cryoprecipitate units Avg # MTP coolers^a	9 (4.5 to 15) 22 (18 to 30) 14 (10 to 17.5) 6 (4.5 to 12) 2 (1 to 3) 0 (0) 1.7 (1.3 to 2.3)	8 (4 to 13) 34 (23 to 58) 19 (13 to 30) 13 (8 to 24) 3 (2 to 5) 0 (0 to 1) 2.6 (1.7 to 4.4)	0.552 < 0.001 < 0.001 < 0.001 < 0.001 0.013 < 0.001
	Calcium monitoring and replacement (IQR) Calcium replacement Total calcium replacement, grams CaCl₂ Total number of iCa measurements Blood units before first iCa First iCa, mmol/L Initial calcium replacement, grams CaCl₂ Repeat iCa, mmol/L Final iCa, mmol/L Coagulopathy at the end of MTP	35 (78%) 3 (1 to 4) 6 (4 to 8) 4 (2 to 13) 1.04 (0.96 to 1.16) 2 (1 to 2) 1.05 (0.99 to 1.18) 1.10 (1.03 to 1.19) 1 (2.2)	103 (93%) 4 (2 to 7) 6 (5 to 9) 4 (2 to 11) 0.88 (0.78 to 0.99) 2 (1 to 3) 0.91 (0.74 to 1.08) 1.07 (0.94 to 1.14) 11 (9.9)	0.012 0.002 0.209 0.846 < 0.001 0.406 < 0.001 0.094 0.180
	The ROC analysis showed that 15 units of blood product, or just greater than one cooler of blood, was the best predictor of severe hypocalcemia. Both groups received a median of 27.2 mEq of elemental calcium (2 g of calcium chloride) initially, but neither group had a median iCa > 1.12 mmol/L on repeat check. ^aMTP cooler = 6 units; PRBC = 6 units; FFP = 1 unit (=6 pack) platelets.
Adverse Events	N/A
Study Author Conclusions	The incidence of hypocalcemia and severe hypocalcemia in trauma patients receiving massive transfusion is high, which demonstrates the importance of vigilant calcium monitoring during massive transfusion. Aggressive calcium supplementation for severe hypocalcemia should also be considered, and future trials evaluating the appropriate calcium doses, the optimal iCa target, and the effect of blood product administration rate on hypocalcemia are warranted.
InpharmD Researcher Critique	Although the study does not answer the question of how much calcium replacement is needed during MTP, the findings do support that calcium chloride may be the preferred salt form during massive transfusion, and 2 g or more may be necessary for every 2 to 4 units of blood product transfused. Given the retrospective nature of the study, the effect of blood product administration rate on hypocalcemia was not analyzed. Additionally, follow-up laboratory values, such as iCa, PT, and aPTT, were not monitored to further assess coagulopathy.

References:

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. doi:10.1016/j.jss.2015.12.036