“Never doubt that a small group of thoughtful, dedicated citizens can change the world. In fact, that’s the only thing.”
Cureus’ mission is to change the long-standing medical publishing model in which submitting studies can be expensive, complex and time-consuming.
Calcium supplementation, hypocalcemia, massive transfusion regimen, massive transfusion, blood loss, bleeding
Christopher P. Potestio 、 Noud Van Helmond 、 Nadder Azzam 、 Ludmil V. Mitrev 、 Akhil Patel 、 Talia Ben-Jacob
Cite this article as: Potestio CP, Van Helmond N, Azzam N, et al.(February 10, 2022) Incidence, extent, and duration of hypocalcemia due to massive transfusion: a retrospective study.Cure 14(2): e22093.doi: 10.7759/cureus.22093
Background: In the absence of readily available laboratory values for calcium, electrolyte management during massive transfusions may be ubiquitous but not well standardized.We aimed to quantify the incidence, extent, and duration of hypocalcemia within the first 24 hours after initiation of a massive transfusion using institutional mass transfusion protocols (MTPs).We hypothesized that hypocalcemia was prevalent during acute resuscitation (the first 6 hours) despite efforts by the treatment team to supplement calcium during active resuscitation.
METHODS: A retrospective chart review of all patients who underwent MTP at our institution between January 1, 2017 and December 31, 2017.The primary outcome was hypocalcemia due to massive transfusion within the first 6 hours after initiation of MTP.Secondary outcomes of interest included hypercalcemia, hypomagnesemia, in-hospital mortality, time to peak and nadir of hypocalcemia and hypercalcemia, calcium supplementation, and time to calcium supplementation.Calcium administration and blood product infusion were reported relative to the initiation of MTP.The association between the total amount of calcium administered and the total number of blood products transfused was assessed.
Results: Data from 52 mass transfusions were analyzed.Hypocalcemia occurred in 97% of patients within the first 6 hours of resuscitation.The nadir occurred after a median of 8 units of blood product was administered, (interquartile range {IQR}: 4-16).Calcium supplementation was associated with the total number of blood products transfused (ρ = 0.47, p < 0.01).Calcium-supplemented patients received more blood products than did not calcium-supplemented patients (median: 16, IQR: 12-26 vs. median: 9, IQR: 7-12, p < 0.01).
CONCLUSIONS: Hypocalcemia due to massive blood transfusions is common.The reported incidence of hypocalcemia in MTP is 85-97%.Unstandardized calcium supplementation in MTP may lead to underutilization of calcium during massive transfusions and lead to hypocalcemia in these patients.
Massive blood transfusions are often necessary to treat acute hemorrhagic shock.However, massive blood transfusions are not a benign treatment.Dilution coagulopathy is caused by massive transfusions that replace bleeding whole blood with component blood products [1].Massive transfusions are also associated with hypocalcemia and other electrolyte abnormalities due to citrate toxicity [2].Other complications include hypothermia during blood transfusions without a warmer, which can lead to further patient deterioration in traumatic situations [1].
Mass transfusion protocols (MTPs) have been standardized by many institutions to facilitate effective acute resuscitation while minimizing the side effects of massive resuscitation [3].In addition to standardized intravascular volume replacement, MTPs are often aimed at correcting trauma-induced coagulation dysfunction to curb further blood loss.Optimizing the ratio of packed red blood cell (PRBC) units to plasma units may help prevent dilutional coagulopathy [3].Although citrate toxicity is a well-recognized side effect of massive transfusion and hypocalcemia can exacerbate coagulopathy, there are currently no published guidelines for the management of hypocalcemia [4].
Citrate toxicity in massive transfusions occurs when citrate administration exceeds citrate metabolism.A non-cirrhotic adult needs 5 minutes to metabolize 3 g of citrate in one unit of packed red blood cells [5].Citrate metabolism may take longer in patients with liver dysfunction.Citrate binds to calcium, causing rapid hypocalcemia during massive transfusions.Hypocalcemia can lead to hypotension and coagulopathy, both of which can be devastating during massive blood transfusions.
Current recommendations, based on information extrapolated from animal studies, involve frequent checks of electrolyte levels during massive transfusions, but waiting for laboratory chemistry results is not a pragmatic option during acute resuscitation in centers where point-of-care testing is not available [6].In the United States, PRBCs are stored in solutions containing up to 3 g of citrate per unit of blood, with higher citrate concentrations in plasma and platelets [4].Addressing hypocalcemia as a side effect of mass resuscitation will become increasingly important as resuscitation efforts for MTP move toward citrate-rich plasma, where a 1:1 ratio of PRBC to plasma replaces a 1:2 ratio .
In a single-center retrospective study of trauma patients who received massive transfusions following a PRBC to plasma ratio of 1:1, 97% (n = 152) developed hypocalcemia; 71% of these patients developed hypocalcemia Severe hypocalcemia (ionized calcium <3.6 mg/dL) [7].Patients with severe hypocalcemia have higher lactate levels, lower pH, and higher mortality.Although calcium is important in coagulation, it also plays a key role in neuromuscular and cardiovascular membrane stability, myocardial contractility, and cardiac conduction.Clinical symptoms of hypocalcemia include heart failure, QT prolongation, sinus tachycardia, paresthesia, muscle spasms, spasticity, tetany, perioral numbness, and seizures [8].Given the integral role calcium plays in coagulation and hemodynamics, it is not surprising that several studies have shown an association between hypocalcemia and mortality [7,9-11].
In the absence of readily available laboratory values for calcium, calcium administration during massive transfusions may be ubiquitous but not well standardized in MTP.Therefore, observational data on calcium concentrations during bulk transfusions may be valuable in determining estimated calcium concentration trends and calcium supplementation intervals.
Our primary objective was to quantify the incidence, extent, and duration of hypocalcemia within the first 24 hours after initiation of massive transfusions at institutional MTPs.A secondary objective was to explore calcium supplementation patterns during massive transfusions.We hypothesized that hypocalcemia was prevalent during acute resuscitation despite efforts by the treatment team to supplement calcium during active resuscitation.
We performed a sequential retrospective chart review of patients who initiated institutional MTP.In adults, there are several definitions of massive transfusion based on the volume of blood transfused, the three most common definitions of MTP are (1) ≥10 units transfused in a 24-hour period, (2) a single transfusion of >4 units 1 hour expected to last Requires blood product support, and (3) replacement of >50% of total blood volume with blood products within 3 hours [12].Based on these definitions, we included patients who received more than 4 units after initiation of MTP or more than 10 units of blood products within 24 hours of initiation of MTP.Patients were enrolled from January 1, 2017 to December 31, 2017 at a 600-bed Level 1 trauma center in a densely populated urban setting on the US East Coast.Our Institutional Review Board approved this study (Cooper University Healthcare Institutional Review Board; approval number: 18-115) and waived the requirement to obtain informed consent.
Blood products include PRBC, whole blood, thawed plasma, platelets or cryoprecipitate.Our institution’s MTP follows a 1:1 ratio of PRBC to plasma, with one packet of mixed platelets administered for every 4 units of PRBC/plasma.MTP packages are available immediately at the bedside upon request.Each MTP package contains three units of O+ PRBCs and three units of male plasma A and three units of O-PRBCs and three units of female plasma A plasma.During MTP, two units of single-donor platelets were always provided.At least five MTP packets are kept in the blood bank at all times.
Electrolytes were replaced at the discretion of the clinician.Blood products from our institution are suspended in one of three adenine salt solutions (AS-1, AS-3, AS-5) containing adenine, saline, glucose, citrate, and phosphate [13] .The citrate content in these solutions was approximately 0.042 g/100 mL.Each unit of blood contains a volume of 320ml to 360ml.
Calcium chloride is used in all calcium supplements.Calcium chloride is preferred over calcium gluconate because the solutes in calcium chloride are readily available when injected into the blood.Calcium gluconate, on the other hand, requires adequate hepatic blood flow and liver function to metabolize gluconic acid and release elemental calcium.Calcium gluconate may be ineffective in patients with acute bleeding who experience decreased hepatic blood flow and impaired hepatic function [6].
Demographic and clinical information was retrieved from electronic medical records (Epic; Verona, WI: Epic Systems).Data collected included age, duration of massive transfusion, indication for transfusion, unit of transfusion (including transfusion of whole blood), dose of calcium chloride administered, arterial blood gas analysis, blood cell count, ionized calcium, platelet count, and chemistry panel including total. Serum calcium.For each laboratory value, time from mass transfusion was also recorded.The start of mass transfusion was defined as the time the blood bank received a call to issue blood products in the context of MTP.All laboratory, clinical, and treatment data were collected for the first 24 hours after the initiation of MTP.We recorded the need for CPR, the need for dialysis, and the need for other procoagulant treatments such as tranexamic acid and factor concentrates.
The primary outcome was hypocalcemia due to massive transfusion within the first 6 hours after initiation of MTP.Hypocalcemia was defined as total serum calcium levels less than 8.5 mg/dL or whole blood ionized calcium less than 4.5 mg/dL.These are the lower limits of normal as determined by our chemistry laboratory (8.5-10.5 mg/dL total serum calcium and 4.5-5.24 mg/dL whole blood ionized calcium).Severe hypocalcemia was defined as a total serum calcium level less than 6.5 mg/dL or ionized calcium less than 2.0 mg/dL based on a previous study of hypocalcemia during massive transfusion [14].Serum calcium levels and ionized calcium levels were used in this analysis because the former is measured in the intensive care unit and the latter is used in the acute setting of MTP, where waiting more than an hour for results is impractical .Secondary outcomes of interest included hypercalcemia, in-hospital mortality, time to peak and nadir of hypocalcemia and hypercalcemia, calcium supplementation, and time to calcium supplementation.Hypercalcemia was defined as total serum calcium levels higher than 10.5 mg/dL or whole blood ionized calcium higher than 5.24 mg/dL.
If the time of blood product transfusion was not accurately recorded in the electronic medical record (EMR) (eg, 40 units administered at a single time point), we excluded data from the analysis.The Shapiro-Wilk test was used to assess the distribution of the data.Group data for continuous variables are expressed as the mean with standard deviation (SD) or the median with interquartile range (IQR), depending on the distribution of the data.Categorical data are represented by n (%).For the visual presentation of the data, calcium concentrations were normalized as a percentage of the lower limit of the normal concentration range to allow for an integrated presentation of whole blood ionized calcium values as well as total serum calcium concentrations.Median nadir and peak calcium concentrations and their times were calculated and plotted.We plotted the timing of calcium supplementation versus volume of blood transfused, and assessed the association between total calcium volume and volume of blood transfused using Spearman’s rank correlation.Normally distributed data were compared using the unpaired t-test, while the Mann-Whitney rank-sum test was used for non-normally distributed data.P-values are reported for statistical tests.
We included 51 adult patients who received massive blood transfusions using MTP during the study period.One patient received MTP on two separate occasions during hospitalization, and these were counted as personal encounters because the events were more than 24 hours apart.Patients who started MTP but ended up receiving less than four units were excluded from the study.Therefore, data from 52 mass transfusion encounters were analyzed.Patient demographics and clinical characteristics are shown in Table 1.The laboratory values in Table 1 represent the first registered values after MTP is started.
*Lab values represent the first recorded values after the start of the massive transfusion protocol.
**Estimated blood loss was extracted from surgical records and recorded values were sometimes much lower than the total blood loss that may have occurred prior to arrival.
During the 52 massive transfusions, 50 (97%) patients developed hypocalcemia during the first 6 hours of resuscitation, and 42 (81%) patients developed severe hypocalcemia.Figure 1 shows individual and median calcium nadirs and peaks normalized to the lower limits of ionized calcium and serum calcium starting from massive transfusion.The median calcium nadir relative to the lower limit of normal occurred 110 minutes after initiation of massive transfusion (IQR: 55-315).The absolute lowest median ionized calcium in whole blood was 2.9 mg/dL (IQR: 2.2-3.3).The absolute median minimum total serum calcium was 6.3 (IQR: 6.1-7.4 mg/dL).The nadir occurred after an average of 8 units (IQR: 4-16) of blood products were administered.Thirteen of 52 massive transfusions (25%) did not measure calcium concentrations within the normal range within 24 hours of MTP initiation.Only one patient (3%) developed hypercalcemia within the first 24 hours after MTP initiation.The median calcium peak relative to the lower limit of normal occurred at 168 minutes (IQR: 100-433) from initiation of massive transfusion and after a median total of 12 (IQR: 6-19) blood products were transfused.The median absolute peak whole blood ionized calcium was 4.9 mg/dL (IQR: 4.1-5.4).The median absolute peak total serum calcium was 9.2 mg/dL (IQR: 8.6-11.0).
Figure 2 depicts cumulative calcium supplementation for each supplemented patient (n = 44, 85%).In these patients, 0.17 g of calcium chloride was administered per blood product transfusion.Incremental calcium supplementation appears to fit best in a straight line, suggesting that supplementation may be similar in the early stages of massive transfusions as in the later stages of massive transfusions.Calcium-supplemented patients received more blood products than did not calcium-supplemented patients (median: 16, IQR: 12-26 vs. median: 9, IQR: 7-12, p < 0.01).
This study aimed to quantify the incidence, extent, and duration of hypocalcemia within the first 24 hours after initiation of massive transfusion using MTP.To our knowledge, this is the only study that addresses the time course of hypocalcemia during MTP.Consistent with our hypothesis, we found that 97% of patients developed hypocalcemia during acute resuscitation (the first 6 hours) despite efforts by the treatment team to supplement calcium during resuscitation.During massive transfusions, calcium nadirs tend to occur earlier than calcium peaks.The median peak whole blood ionized calcium and total serum calcium were slightly above the lower limit of the normal range.In a substantial proportion of patients, no normal serum calcium values are recorded within 24 hours of MTP initiation.
Giancarelli et al.A retrospective study of trauma patients who received massive blood transfusions at a center in the southern United States [7].Similar to our results, the majority of patients had severe hypocalcemia (71%), which was associated with higher mortality.Our results showed a higher proportion of patients with severe hypocalcemia, probably because we presented all patients who received MTP, not just trauma patients.Given that some of our MTP patients may be transferred to nonsurgical services that may not be aware of the side effects of hypocalcemia, laboratory evaluation and supplementation may delay response.Giancarelli et al.Ionized calcium was only observed at one point, whereas we observed a period of time to review the trajectory and assess potential timing of intervention.Several recent studies have measured the incidence of hypocalcemia during massive transfusions and found similarly high incidences [7,9-11].
In addition, other studies have examined calcium levels in less acute settings, such as mixed ICU populations [15] and trauma ICU patients receiving total parenteral nutrition [16,17].The reported incidence of hypocalcemia in these patients was 55%, but the calcium levels in these studies may not be appropriate for acute resuscitation of MTP in which transfusion rates exceed the rate of citrate metabolism.In addition, the physiologic effects of hypocalcemia—decreased myocardial contractility and impaired coagulation—are detrimental to bleeding patients and may be better tolerated by other ICU populations.
It takes a healthy liver five minutes to metabolize 3 g of citrate in one unit of packed red blood cells, so the rate of transfusion of one unit of blood product every five minutes will reliably and predictably lead to citrate toxicity.In addition, patients who experience acute blood loss may suffer liver damage and impaired liver function due to changes in hepatic blood flow.During MTP, transfusion rates of more than one unit per 5 minutes of PRBC and liver dysfunction are common, and both lead to elevated citrate levels and hypocalcemia [4,14,18].The high transfusion rate of MTP leads to a high risk of severe hypocalcemia, which explains the high incidence of severe hypocalcemia in this study (82% in the first 6 hours and 85% in the 24 hours).
Our findings confirmed a dose-response relationship between blood transfusion and calcium supplementation, but many patients remained hypocalcemic.Recommendations extrapolated from animal studies suggest the use of mathematical equations to quantify the amount of calcium required for a given transfusion rate and citrate load, but no formal guidelines have been published nor proven to work.Further studies in humans are required to determine the correct dose-response relationship.
The stimulatory event leading to provider activation of MTP is usually acute bleeding, and most transfusions occur within the first 120 minutes of transfusion.Rapid transfusion rates may exceed the liver’s ability to metabolize citrate, predictably leading to severe hypocalcemia.Severe hypocalcemia is most common in the first 120 minutes after MTP initiation, as evidenced by the lowest calcium levels in Figure 2.Peak calcium levels occurred more than 240 minutes after the onset of MTP.The reported incidence of hypocalcemia in MTP is 85-97% when a similar definition of hypocalcemia is used [7,10].With more aggressive calcium supplementation early in resuscitation during MTP, providers can avoid the predictable severe hypocalcemia associated with rapid transfusions.
Calcium is required for activation of coagulation factors II, VII, IX and X and proteins C and S.In addition, calcium plays a role in stabilizing fibrinogen and platelets in thrombosis [7,19].The contractility of cardiac and smooth muscle cells is calcium-dependent.Hypocalcemia can lead to coagulopathy, myocardial depression, and vasodilation: Physiological changes that complicate treatment of hemorrhagic shock.
We had only one patient (3%) who had hypercalcemia at any time during the first 24 hours after MTP initiation, and this patient’s serum calcium was only slightly elevated at 11.2, which is above the normal range but insufficient to cause arrhythmias, muscle weakness, or other side effects of hypercalcemia.Our data suggest that calcium supplementation has clear room for improvement during MTP.Although hypocalcemia is a predictable side effect of rapid transfusion, calcium supplementation at our institution was not rapid or aggressive enough to maintain normal calcium levels during the first 120 minutes after MTP initiation.
Our provider administered 0.17 grams of calcium chloride to each blood product during MTP.This dosing rate resulted in hypocalcemia in the majority of patients, with a very low incidence of hypercalcemia.Other studies recommend 0.5 g to 1.0 g of calcium chloride per blood product [6,7].Our data suggest that despite knowledge of citrate toxicity, providers often underestimate the amount of calcium required during MTP and rarely, if ever, overestimate.Future research is needed to determine whether such recommendations lead to additional calcium supplementation and a reduced incidence of hypocalcemia.
Our study has some limitations in the retrospective design.EMR registries may not accurately reflect the timing of blood transfusions or replenishments.Due to the acute nature of resuscitation during MTP, calcium supplementation may be drawn during review, which may lead to inaccurate recordings and may lead to recall bias.More severe bleeding may trigger calcium supplementation and more frequent laboratory measurements.Therefore, the findings may not be relevant for all mass transfusions.There is also considerable variation between patients, which can make calcium supplementation (ie, “g calcium/blood product”) challenging in a standardized manner.
It is not mandatory to measure serum calcium levels prior to administration of calcium.It is unclear whether the calcium supplementation described in this study was empirical treatment or the result of measuring serum calcium levels.Future studies may investigate the amount of calcium given empirically versus the amount given as a result of measuring serum calcium levels.
We did not address the dose-response relationship of calcium dose during MTP, nor in any previous studies.It would be ideal to be able to standardize the administration of calcium, but no studies have been able to establish this relationship.A key variable affecting calcium administration during MTP is the rate of transfusion.A slower transfusion, such as a unit transfusion every 10 minutes, will require a lower dose of calcium than a rapid transfusion of a unit every 30 seconds through a rapid transfusion device.Variability in transfusion rates between patients makes calcium dose a dynamic target.MTP activation usually results in a high rate of blood transfusion, which will overcome the rate at which citrate is removed by the liver, thus requiring administration of calcium as shown in our study.
Clearly, providers should target normal calcium levels in patients receiving rapid blood transfusions.However, it is unclear whether more aggressive calcium supplementation would have a meaningful impact on patient outcomes.Further research should aim to establish this relationship.
Hypocalcemia due to massive blood transfusions is common.Calcium supplementation was positively associated with the total number of blood products transfused, but hypocalcemia remained widespread.Lack of standardization of calcium supplementation in MTP may result in insufficient calcium utilization during massive transfusions.Although citrate toxicity is recognized as a common side effect of MTP, calcium supplementation is not sufficient to avoid hypocalcemia, especially during the first few hours of resuscitation.
Human subjects: All participants in this study gave or withheld consent.The Cooper University Healthcare Institutional Review Board issued approval #18-115EX.Animal Subjects: All authors have confirmed that this study did not involve animal subjects or tissues.Conflicts of Interest: In accordance with the ICMJE Uniform Disclosure Form, all authors declare the following: Payment/Service Information: All authors declare that they have not received financial support from any organization for submitted work.Financial Relationships: All authors declare that they have no current or within the past three years financial relationships with any organization that may be interested in the submitted work.Other Relationships: All authors declare that there are no other relationships or activities that may affect the submitted work.
Potestio CP, Van Helmond N, Azzam N, et al.(February 10, 2022) Incidence, extent, and duration of hypocalcemia due to massive transfusion: a retrospective study.Cure 14(2): e22093.doi: 10.7759/cureus.22093
Peer Review Begins: January 5, 2022 Peer Review Ends: February 9, 2022 Published: February 10, 2022
© Copyright 2022Potestio et al.This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0. Unrestricted use, distribution, and reproduction in any medium is permitted as long as the original author and source are credited.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which allows unrestricted use, distribution, and reproduction in any medium, provided the original author and attribution are credited.
*Lab values represent the first recorded values after the start of the massive transfusion protocol.
**Estimated blood loss was extracted from surgical records and recorded values were sometimes much lower than the total blood loss that may have occurred prior to arrival.
Scholarly Impact Quotient™ (SIQ™) is our unique post-publication peer review rating process.Learn more here.
Post time: Feb-15-2022