What does the literature recommend regarding the management of hypocalcemia associated with blood transfusion?

Comment by InpharmD Researcher

There is a lack of data evaluating when calcium supplementation should be given during massive blood transfusions to prevent hypocalcemia. The Joint Trauma System recommends the administration of calcium before, during, or immediately after the first unit of blood product. Additionally, it is recommended to supplement every 4 units of blood products with calcium. 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 when to administer calcium replacement.

Background

A clinical practice guideline for prehospital blood use during en route care was published 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 be applicable 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 needs to be supplemented with 1 g of calcium IV/IO. [1]

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. Additionally, the timing of calcium administration relative to the blood transfusions is discussed. [2]

Recent reviews discussed current evidence to identify optimal treatment for hemostatic defects in hemorrhage and massive transfusion. Hypocalcemia has recently been added to hypothermia, acidosis, and coagulopathy as one of four critical factors that interfere with normal hemostasis and coagulation in bleeding patients. Two randomized controlled trials of prehospital plasma for traumatic hemorrhagic shock discovered a relationship between prehospital plasma resuscitation and hypocalcemia; hypocalcemia was found to be associated with higher mortality and massive transfusion. These studies recommended intravenous calcium replacement concurrently with blood product transfusions. This is important in patients with acute hemorrhage due to the high likelihood of hypocalcemia with transfusion as well as calcium’s importance in promoting clotting at the site of bleeding. The authors reported that patients with hemorrhage and severe hypocalcemia have significantly greater mortality rates. Trauma patients who receive blood products in the prehospital phase of care had a 70% incidence rate of hypocalcemia due to citrate content in the preservative of the blood products, as well as calcium honing at the site of bleeding. Whole blood transfusion for traumatic hemorrhage treatment is currently being explored, however, there is not yet a definitive understanding of expected outcomes. The authors concluded that early identification and prompt aggressive calcium replacement are recommended in bleeding patients. However, specific regimens for calcium replacement or the timing of calcium replacement relative to transfusions were not discussed. [3], [4]

Another 2021 review reported similar findings on hypocalcemia and increased mortality rates across three cohort studies, with calcium levels ranging from 1.0 to 1.11 mmol/L showing an association with increased mortality (Table 1). Additionally, during transfusion, Giancarelli et al. (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. [5]

References:

[1] Voller J, Tobin JM, Cap AP, et al. Joint Trauma System Clinical Practice Guideline (JTS CPG): Prehospital Blood Transfusion. 30 October 2020. J Spec Oper Med. 2021;21(4):11-21. doi:10.55460/P685-L7R7
[2] World Health Organization. Clinical Transfusion Practice. Accessed November 21, 2022. https://www.who.int/bloodsafety/transfusion_services/ClinicalTransfusionPracticeGuidelinesforMedicalInternsBangladesh.pdf
[3] Napolitano LM. Hemostatic defects in massive transfusion: an update and treatment recommendations. Expert Rev Hematol. 2021;14(2):219-239. doi:10.1080/17474086.2021.1858788
[4] Ditzel RM Jr, 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;88(3):434-439. doi:10.1097/TA.0000000000002570
[5] Vasudeva M, Mathew JK, Groombridge C, et al. Hypocalcemia in trauma patients: A systematic review. J Trauma Acute Care Surg. 2021;90(2):396-402. doi:10.1097/TA.0000000000003027
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What does the literature recommend regarding the management of hypocalcemia associated with blood transfusion?

Level of evidence

D - Case reports or unreliable data  Read more→


Please see Tables 1-3 for your response.

Summary of Studies - Hypocalcemia and Blood Transfusion
Authors  Patient cohort Study Design Results 
Cherry et al.

N= 396
Trauma center
aLoCa ≤1.0 mmol/L

 Retrospective cohort

Mortality: 26.4%* vs. 16.7%**; p< 0.05; OR, 1.92
Magnotti et al. N= 591
Trauma center
LoCa <1.0 mmol/L		 Prospective cohort

Mortality: 15.5%* vs. 8.7%**; p= 0.036
Transfusion (≥5 U): 17.1%* vs. 7.1%**; p= 0.005
Transfusion (≥10 U): 8.2%* vs. 2.2%**; p= 0.017
Vasudeva et al. N= 226
Trauma center
LoCa <1.11 mmol/L		 Retrospective cohort 

Mortality: 25.6%* vs. 15.0%**; p= 0.047
Transfusion: 62.5%* vs. 37.5%**; p< 0.001
Coagulopathy*: aOR, 2.9; 95% CI, 1.01 to 8.3; p= 0.048
aLoCa — ionized hypocalcemia. *Hypocalcemic cohort. **Normocalcemic cohort. OR, odds ratio.
References:

Adopted from:
Vasudeva M, Mathew JK, Groombridge C, et al. Hypocalcemia in trauma patients: A systematic review. J Trauma Acute Care Surg. 2021;90(2):396-402. doi:10.1097/TA.0000000000003027

 

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 coolersa

 

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

 

Ionised calcium levels in major trauma patients who received blood en route to a military medical treatment facility

Design

Retrospective chart review 

N= 297

Objective

To identify the incidence of hypocalcemia in military trauma patients receiving blood products en route to a deployed hospital facility and to determine if intravenous calcium, given during the prehospital phase, has an effect on admission calcium levels

Study Groups

Treatment (n= 60)

Non-treatment (n= 237) 

Inclusion Criteria

Patients who had been treated with blood products en route to a military medical treatment facility and transported by the UK Medical Emergency Response Team (MERT)

Exclusion Criteria

Did not have ionized calcium (iCa) recorded within 30 min of arrival at the hospital, had intravenous calcium for treatment other than supplementary to blood products (eg, during cardiac arrest), or if iCa results were unobtainable

Methods

A retrospective review of the UK Joint Theatre Trauma Registry (JTTR) was conducted to identify eligible patients. Patients were further divided into two groups based on the status of calcium therapy. Patients who were treated with 10 mL intravenous calcium chloride minijet (10%) concurrently with blood products were considered as the treatment group. Hypocalcemia in this study was defined as an iCa level of < 1.12mmol/L.

Duration

Between January 2010 and December 2014

Outcome Measures

 Incidence of hypocalcemia, association between blood product administration and calcium levels 

Baseline Characteristics

  

Treatment (n= 60)

Non-treatment (n= 237) 

    

Age, years (interquartile range [IQR])

 23 (18 to 70) 24 (18 to 77)    

Injury Severity Score

 28 (16 to 75) 26 (4 to 75)    

Transfusion, units 

Fresh frozen plasma

Red blood cells 

Total blood product

 

2 (0)

2 (1)

4 (1)

 

2 (2)

2 (2)

4 (0)

    

No significant differences were noted in baseline vital signs. 

Results

Endpoint

Treatment (n= 60)

Non-treatment (n= 237) 

p-value

Difference (95% confidence interval)

Overall incidence of hypocalcemia

 17 (28.3%) 166 (70%) < 0.001 -

Ionized calcium levels, mmol/L

 1.25

1.03

 < 0.001 0.22 (0.15 to 0.27)

Normal iCa levels

 25 (41.7%) 63 (26.6%) - -

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.

The small sample of patients who did not have blood products on MERT had a higher initial calcium level with a score of 1.2 (0.8–1.4) for this subgroup.

Adverse Events

 N/A

Study Author Conclusions

This study has shown that the prehospital administration of blood and blood products is associated with hypocalcemia on admission to the hospital and that this can be ameliorated by the administration of 10 mL of intravenous calcium in the prehospital phase. The study also found that calcium levels dropped below the normal range after 1 unit of blood. These findings add weight to a growing body of evidence suggesting that adjunctive calcium therapy during blood transfusion may have the required effect of increasing serum calcium levels. 

InpharmD Researcher Critique

As the study evaluated calcium replacement prior to hospital arrival, the results might not be readily applied to other clinical settings. The study is also subject to limits inherent to its retrospective chart review design. 



References:

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