a b s t r a c t

Introduction: Early recognition and management of hemorrhage, Damage control resuscitation, and blood prod- uct administration have optimized management of severe trauma. Recent data suggest hypocalcemia exacer- bates the ensuing effects of coagulopathy in trauma.

Objective: This narrative review of available literature describes the physiology and role of calcium in trauma re- suscitation. Authors did not perform a systematic review or meta-analysis.

Discussion: Calcium is a divalent cation found in various physiologic forms, specifically the bound, inactive state and the unbound, physiologically active state. While calcium plays several important physiologic roles in multi- ple organ systems, the negative hemodynamic effects of hypocalcemia are crucial to address in trauma patients. The negative ramifications of hypocalcemia are intrinsically linked to components of the lethal triad of acidosis, coagulopathy, and hypothermia. Hypocalcemia has direct and indirect effects on each portion of the lethal triad, supporting calcium’s potential position as a fourth component in this proposed lethal diamond. Trauma patients often present hypocalcemic in the setting of severe hemorrhage secondary to trauma, which can be worsened by necessary transfusion and resuscitation. The critical consequences of hypocalcemia in the trauma patient have been repeatedly demonstrated with the associated morbidity and mortality. It remains poorly defined when to administer calcium, though current data suggest that earlier administration may be advantageous.

Conclusions: Calcium is a key component of trauma resuscitation and the coagulation cascade. Recent data portray the intricate physiologic reverberations of hypocalcemia in the traumatically injured patient; however, future research is needed to further guide the management of these patients.

Published by Elsevier Inc.

1. Introduction

As the management of critically ill, multisystem trauma patients evolves, the key tenets in the management of severe traumatic hemor- rhage continue to focus on Hemorrhage control while mitigating the triad of death: hypothermia, acidosis, and coagulopathy [1,2]. While tra- ditionally a triumvirate, recent data have introduced a fourth compo- nent, hypocalcemia, in this interplay of critical trauma resuscitation factors. Integrally linked to each component of the lethal triad, hypocal- cemia plays a key role in the outcomes of multisystem trauma patients.

* Corresponding author at: 3841 Roger Brooke Dr, Fort Sam Houston, TX, United States of America.

E-mail address: [email protected] (B. Long).

Data guiding the identification of hypocalcemia and treatment algo- rithms remain limited. This narrative review evaluates available evi- dence on hypocalcemia in the setting of trauma relevant to emergency medicine.

1. Methods

To perform this narrative review, authors searched PubMed and Google Scholar for articles using a combination of the keywords ‘hypo- calcemia’, ‘trauma’, ‘massive’, ‘hemorrhage’, and ‘transfusion’. The search was conducted from the database’s inception to September 13th, 2020. Authors reviewed relevant abstracts and full manuscripts. Authors also reviewed guidelines and supporting citations of included articles. The literature search was restricted to studies published in

https://doi.org/10.1016/j.ajem.2020.12.065 0735-6757/Published by Elsevier Inc.

English, with focus on the emergency medicine, trauma, and Critical care literature. Authors decided which studies to include for the review by consensus. When available, randomized controlled trials were preferen- tially selected, followed by prospective studies, retrospective studies, case reports, and other narrative reviews when alternate data were not available. This article is a narrative review and not a systemic review or meta-analysis. Thus, authors did not pool data.

1. Results

Authors selected a total 40 resources for inclusion through consen- sus. Of these, there was 1 randomized controlled trial, 17 prospective studies, 10 retrospective studies, and 12 narrative reviews or expert consensus documents.

1. Discussion
   1. Calcium in the serum

A divalent cation that is found both intracellularly and extracellu- larly, calcium exists in various forms, including a free, unbound, and physiologically active state as well as an inert state in which it is bound to various proteins. Approximately 45% of total calcium is biolog- ically active and exists in the ionized state, while 55% is bound to pro- teins such as albumin and citrate [3,4]. Variations in serum levels of these proteins can lead to derangements in the total body stores and serum levels of calcium [3]. serum calcium is readily assessed by mea- suring ionized calcium, which has a normal concentration of

1.1 mmol/L to 1.3 mmol/L and can be done using handheld, portable de- vices [3,5].

• 1. Physiologic roles of calcium

Various critical components of human physiology require calcium as a cofactor. In addition to playing a key physiologic role in osseous struc- tures, neural transmission, and endocrine physiology, calcium also af- fects cardiac contractility, vasculature constriction and dilation, and hemostasis and the coagulation cascade [6,7]. This article focuses on the latter roles of calcium and the relationship to the critically ill trauma patient.

Calcium plays a critical role in cardiac contractility. Intracellular cal- cium released from Sarcoplasmic reticulum is required for contraction of cardiac myocytes; during systole, intracellular calcium levels acutely increase and lead to myocyte contraction [8]. Extracellular calcium also affects cardiac contractility, as demonstrated by variations in ionized calcium correlating with Clinically significant changes in myocardial contractility on echocardiography [9]. As hypocalcemia develops, the heart experiences both electrical and mechanical dysfunction. Hypocal- cemia prolongs the QT interval, increasing likelihood of dysrhythmias. Additionally, hypocalcemia suppresses cardiac contractility and can contribute to acute cardiovascular decompensation [6]. In vivo experi- ments with continuous citrate infusion and serial measurements of cit- rate and calcium demonstrate decreasing cardiac output and blood pressure as citrate induces hypocalcemia [10].

Similar to its role in cardiac myocyte activity, calcium is essential for smooth muscle contraction and relaxation in the vasculature. Calcium moves intracellularly during the excitation phase of smooth myocyte contraction, triggering additional calcium release from the sarcoplasmic reticulum as the muscle contracts [11]. The necessity of adequate cal- cium for maintenance of proper vascular tone is seen clinically with the development of hypotension in the setting of hypocalcemia [4]. One study analyzed the relationship of calcium and blood pressure in patients in an intensive care unit and found a direct relationship be- tween Ionized calcium levels and arterial blood pressure in addition to a higher proportion of hypocalcemic patients requiring vasopressor support compared to normocalcemic patients (41% vs 14%) [12].

Additionally, a similar correlation was found when analyzing ionized calcium levels prior to blood product transfusion and outcomes in trauma patients with a direct association between hypocalcemia and systolic blood pressure <90 mmHg [7].

Calcium performs crucial roles in hemostasis and coagulation. It is critical in the process of platelet adhesion as well as intrinsic function of factors II, VII, IX, X, and protein C and S in the coagulation cascade [13]. Functioning as a binding point on coagulation factors, calcium as- sists in the attachment of these factors to the platelet membrane. Simi- larly, formation of fibrin from fibrinogen requires calcium, with lower calcium levels associated with a decrease in platelet-related activities [3]. The relationship between calcium and coagulation is critical, demon- strated in trauma patients as coagulopathy develops in association with hypocalcemia [1,13,14]. Vasudeva et al. found that pre-transfusion hypo- calcemia in trauma patients was associated with coagulopathy as de- fined by an International normalized ratio > 1.5 with an odds ratio (OR) of 2.9 [14].

In normal physiology, unbound calcium is inversely related to serum pH. Calcium and hydrogen ions compete for binding sites on proteins such as albumin [15]. As serum pH decreases, this increase in hydrogen ion concentration competes with and overcomes calcium for binding sites on serum proteins. In turn, this increases measured serum calcium; the inverse relationship holds true with decreasing calcium levels in the setting of alkalosis [15]. However, in trauma patients, lower serum cal- cium has been tied to worsening acidosis, which is present not only in traumatic injuries but in critically ill patients requiring massive transfu- sion for any reason [16-18]. Vivien et al. described this significant direct relationship between ionized calcium level and arterial pH in trauma patients with a correlation coefficient of 0.760 [17]. Additionally, this re- lationship exists in both trauma and Medical patients with a direct asso- ciation of Severe hypocalcemia and acidosis with an OR of 1.45 [18].

• 1. Calcium and blood products

Blood products, including both Packed red blood cells and whole blood, are stored with the anticoagulant citrate, which is one of the many serum proteins that bind calcium [19]. Packed red blood cells (pRBCs) are stored with 3 g of citrate per unit, while whole blood is stored with 1.66 g of citrate per unit [1]. Under normal physiology, the liver can metabolize up to 3 g of citrate every 5 min [1,20]. This was demonstrated in vivo by Bunker et al. with intravenous infusions of cit- rate while obtaining serial measurements of serum citrate and calcium levels [10]. However, Liver dysfunction, secondary cirrhosis, critical ill- ness, trauma, and hypothermia reduce citrate metabolism [19]. A pro- spective cohort study of critically ill patients demonstrated that Hepatic dysfunction leads to a significant accumulation of citrate [21]. In massive hemorrhage requiring rapid transfusion of either component therapy or whole blood, the large quantities of infused citrate far sur- pass the liver’s ability to metabolize citrate. In turn, increasing levels of citrate bind ionized calcium in the blood and generate hypocalcemia in patients undergoing transfusion [19].

Although the utilization of whole blood in the resuscitation of pa- tients with acute hemorrhage is becoming more widespread, transfus- ing the individual Blood components of plasma, platelets and pRBCs remain common practice, with many centers having limited access to whole blood. In addition to the citrate stored in pRBCs, fresh frozen plasma and platelets contain significant amounts of citrate [20]. The citrate stored in FFP contributes to hypocalcemia when transfused, while the amount and rate of FFP transfused are risk factors for the de- velopment of hypocalcemia as demonstrated by Cote et al. with the transfusion of FFP to pediatric patients with massive hemorrhage and hypothermia [18,22,23]. The additional citrate burden from FFP and platelets with that of pRBCs exacerbate hypocalcemia from blood com- ponent transfusion. This suggests a potential benefit of whole blood, which contains less citrate per unit than pRBCs, even before considering the additional citrate in FFP and platelets.

• 1. Calcium and the lethal triad

Preceding, during, and after hemorrhage control, resuscitative ef- forts in the critically ill trauma patient focus on combating the lethal triad of acidosis, coagulopathy, and hypothermia. However, prior ap- proaches to treating these physiologic derangements have not focused on managing hypocalcemia, with limited data at this time guiding inter- ventions. Calcium contributes to proper functioning of the coagulation cascade, maintenance of cardiac output and adequate circulation, and serum acid-base status [6,11,13-18].

• • 1. Calcium and coagulopathy

Calcium has multiple key functions in the coagulation cascade, and coagulation abnormalities ensue as calcium stores are depleted [3,13,16]. acute traumatic coagulopathy is independently correlated with hypocalcemia, as in vitro data demonstrate that thrombin gen- eration and therefore clot formation cannot occur with an ionized calcium less than 0.25 mmol/L. [14,24] Additional studies show that clot formation will occur with an ionized calcium above 0.56 mmol/ L, as calcium is crucially linked to coagulopathy [25]. In a retrospec- tive study of 610 actively bleeding trauma patients, ionized calcium was directly related to clot strength as measured by the maximum amplitude on thromboelastography, demonstrating the integral role of hypocalcemia in coagulopathy; additionally, hypocalcemia with an ionized calcium less than 1.1 mmol/L was found in signifi- cantly more patients with coagulopathy [26]. Furthermore, the ex- tent to which hypocalcemia affects coagulopathy in the setting of trauma is likely under recognized with current laboratory testing, as common tests may not represent the current physiologic state of the trauma patient [6].

• • 1. Calcium and acidosis

Appropriate Serum calcium levels are vital for normal cardiac con- tractility and vasoconstriction, and thus appropriate cardiac output, which prevents hypoperfusion and resulting acidosis [6,7,9]. In critically ill patients receiving a massive transfusion protocol, hypocalcemia worsened acidosis, demonstrating calcium’s effects on serum pH [13]. serum calcium levels may be normal, though this does not necessarily correlate with appropriate effects of calcium in the setting of acidemia [1,27]. Hypocalcemia is similarly associated with worsening acidosis in both critically ill trauma and medical patients [16-18].

• • 1. Calcium and hypothermia

While the relationship between calcium and hypothermia is less studied, there are multiple ways these two variables interact in trauma. In the setting of blood product transfusion, hypothermia reduces he- patic metabolism of citrate, which accumulates and contributes to hy- pocalcemia [28]. Additionally, hypothermia and hypocalcemia work in a deleterious combination on the heart, intrinsically linked in worsening cardiac output. Hypothermia shifts the oxygen-hemoglobin dissociation curve leftward, while both hypocalcemia and hypothermia reduce myo- cardial contractility through different mechanisms, further spiraling the state of poor perfusion [1].

As the relationship of calcium with each component of the lethal triad is further clarified, addressing hypocalcemia may be critical in re- versing these abnormalities and improving outcomes of critically ill trauma patients. However, specific data regarding interventions and timing are lacking. Given that calcium has intimate relationships with all components of the lethal triad and is independently associated with outcomes in trauma patients, it appears that calcium stands as a fourth and equal component in this deadly diamond as initially pro- posed by Ditzel et al. (Fig. 1) [1].

Fig. 1. Calcium and its relationship to individual components of the traditional lethal triad demonstrated as the diamond of death.

• 1. Calcium and trauma resuscitation
     1. Trauma induced hypocalcemia

Classically, hypocalcemia in the setting of trauma was thought to be solely secondary to the infusion of citrate with blood products. How- ever, recent data have demonstrated that the majority of trauma pa- tients are calcium deficient prior to transfusion of blood products which is further exacerbated by the citrate from the transfusion [1,29,30]. Webster et al. found that 55% of trauma patients were hypo- calcemic upon arrival to the emergency department [30]. This was fur- ther demonstrated by Magnotti et al. in a prospective study analyzing admission ionized calcium levels in Trauma activations with 56% of pa- tients having an ionized calcium < 1 mmol/L. [29] They also found that hypocalcemia on admission was predictive of the need for multiple transfusions and massive transfusion [29].

While trauma induced hypocalcemia is likely multifactorial, suspected mechanisms include calcium binding by lactate in lactic acidosis of trauma patients, impaired parathyroid gland and hormone function, and intracellular influx in the setting of ischemia and reperfusion [17,29]. In vitro studies have demonstrated the phenomenon of lactate binding a sig- nificant amount of ionized calcium [17]. Carlstedt et al. found hypocalce- mia and associated elevations in parathyroid hormone (PTH) were common in critically-ill patients [31]. They further studied this relation- ship and found Proinflammatory cytokines common in critically-ill and traumatically injured patients are associated with suppressed levels and function of PTH [32]. Additionally, hemorrhage with ischemia and reper- fusion is associated with calcium shifting intracellularly, potentiating a decrease in serum ionized calcium levels [17,29]. Although this relation- ship between trauma induced hypocalcemia is complex, clinicians must maintain awareness of this common intrinsic disturbance and the possi- ble need for calcium repletion early in resuscitation.

• • 1. Transfusion induced hypocalcemia

The phenomenon of transfusion induced hypocalcemia has been well described in trauma patients. Giancarelli et al. found that 97% of pa- tients who underwent massive transfusion protocols during trauma re- suscitation were hypocalcemic (iCa < 1.1 mmol/L), while 71% of these patients were severely hypocalcemic (iCa < 0.9 mmol/L) [13]. Addition- ally, they demonstrated severe hypocalcemia is associated with a higher mortality (49% vs 24%), highlighting its important role in these critically ill patients receiving transfusions [13]. A retrospective review of trau- matically injured military personnel found a direct correlation between the degree of hypocalcemia and the amount of blood products trans- fused [33]. Webster et al. also described this relationship in their retro- spective cohort of trauma patients who received blood product in the emergency department [30]. Additionally, a rapid rate of transfusion of blood products is a risk factor for the development of hypocalcemia [19,34]. The concept that infusion of large volumes of blood products in critically ill patients precipitates hypocalcemia is well accepted, how- ever, transfusion of even minimal amounts of blood products can have important clinical implications. Kyle et al. demonstrated that transfus- ing a single unit of pRBCs can lead to significant decreases in calcium [33]. Transfusion of any amount of blood product precipitating a drop in calcium level of trauma patients was also supported by Webster et al. [30] While additional research is needed to clarify when calcium supplementation is needed based on the amount of blood product transfused, one study evaluated the association of blood product trans- fusion and hypocalcemia in over 7000 trauma patients and found that transfusing 4 total units of blood products is associated with severe hy- pocalcemia [20].

• • 1. Prehospital implications

Care of trauma patients often begins at the scene of injury or during transport to hospitals with treatment initiated by prehospital medical pro- viders. Clinicians must therefore be aware of the potential impact of, as well as adverse effects associated with, Prehospital interventions,

especially in the setting of the critically ill trauma patient. A review of two randomized controlled trials by Moore et al. found that prehospital plasma administration in trauma patients is associated with hypocalcemia (53% vs 36%) [35,36]. Prehospital transfusion of pRBCs is also associated with lower ionized calcium levels, and the degree of hypocalcemia corre- lates with the number of blood products transfused [33]. Additionally, pa- tients who received 10 mL of calcium chloride concurrently with blood products in the prehospital setting have a lower incidence of hypocalcemia (28% vs 70%) [33]. Although further prospective studies are needed to fur- ther clarify the impact of these therapies, there is potential for Prehospital providers to improve trauma associated hypocalcemia and therefore im- prove outcomes. Furthermore, given that specific prehospital treatments lead to changes in the physiologic state of trauma patients, it is imperative that prehospital providers and physicians have a transparent and thorough discussion of the care provided during transport.

• 1. Hypocalcemia and outcomes in trauma

Transfusion induced hypocalcemia has been demonstrated repeat- edly in the current body of trauma literature and is associated with mul- tiple Clinically important outcomes. Hypocalcemia, defined as an ionized calcium of 1.0 mmol/L or less, prior to transfusion of blood prod- ucts in trauma patients was associated with Prehospital hypotension as defined by a systolic blood pressure < 90 mmHg [7]. Magnotti et al. de- scribed a similar relationship and found that hypocalcemia (ionized cal- cium <1.00 mmol/L) on admission was associated with an increased need for transfusion [29]. This association of hypocalcemia as a predic- tor for blood product transfusion was further demonstrated by Moore et al. [35] The association of pre-transfusion hypocalcemia and acute traumatic coagulopathy (INR >1.5) was found by Vasudeva et al. in an analysis of trauma patients with a Shock Index of 1 or higher [14]. Hypo- calcemia is strongly associated with worse patient outcomes, and mul- tiple studies have demonstrated the inverse relationship between both pre-transfusion and post-transfusion hypocalcemia and mortality in trauma patients [14,20,29,35,37,38]. Furthermore, hypocalcemia upon initial evaluation after traumatic injury is more predictive of mor- tality than historical indicators such as Base deficit [7]. Given its crucial role and intrinsic links to both mortality and the components of the le- thal triad, hypocalcemia correction appears to be a key factor in the re- suscitation of multisystem trauma patients.

• 1. Recommendations

Although there is no current consensus on the timing and degree of calcium repletion needed in trauma, clinicians should be aware of the morbidity and mortality associated with hypocalcemia and be ready to treat hypocalcemia. The use of calcium administration is supported by the current body of limited literature with a lower incidence of hypo- calcemia in trauma patients who are empirically treated with calcium; however, the associated outcomes after Empiric treatment remain un- clear [33]. The review by Lier et al. recommended that ionized calcium concentration should be kept to >=0.9 mmol/L in trauma patients [3]. The European guideline on management of major bleeding and coagu- lopathy following trauma recommends that ionized calcium levels be monitored and maintained in normal range during massive transfusion [39]. Current military guidelines recommend administering 1 g of cal- cium after the first unit of blood product, followed by an additional gram after every 4 units of blood products [40]. These guidelines also recommend calcium repletion if ionized calcium is less than

1.2 mmol/L. [40].

• 1. Future directions

Hypocalcemia is an independent risk factor for mortality in critically ill patients [7,13,18,29,30]. However, future research is needed to clarify if correction of hypocalcemia leads to improvement in mortality and

other patient-centered outcomes. Additionally, prospective studies are needed to evaluate the impact of correcting hypocalcemia on other fac- tors of the deadly diamond. While the necessity of hypocalcemia correc- tion has been established, the threshold and parameters, whether empiric or laboratory based, for calcium repletion should be investigated. Empiric correction of hypocalcemia is generally safe, however, hypercal- cemia has also been associated with mortality, so clinicians must avoid overcorrection [38]. Further investigation is needed to determine the end point of calcium repletion to avoid this overcorrection. Additional questions remain as to how to best correct hypocalcemia, including the most efficacious formulation and dose, indications for empiric correction, and the frequency of reassessment of ionized calcium levels.

As discussed previously, pRBCs and whole blood are stored with dif- ferent amounts of citrate. Although it is intuitive that the smaller amount of citrate transfused with whole blood would lead to smaller derangements in patient calcium levels than packed red blood cells, it is yet to be determined if this results in significant differences in calcium levels in vivo [1,19]. If a significant difference exists, this would be an- other clinically important benefit of whole blood.

1. Conclusion

Critically ill trauma patients are often hypocalcemic prior to resusci- tation, and this state is worsened by transfusion of necessary blood products. Inadequate calcium contributes to the triad of death with worsening cardiac output, acidosis, and coagulopathy. Hypocalcemia in critically ill trauma patients has a clear association with increased mortality. In the management of patients with hemorrhage, transfusion of blood products with concurrent calcium repletion is recommended. Resuscitation leaders caring for these trauma patients must aggressively target this new vertex of the “deadly diamond”. Further research is needed to clarify target thresholds and methods for calcium repletion in the critically-ill trauma patient, especially those requiring blood transfusion.

Funding

None.

Disclaimer

The views expressed herein are those of the author(s) and do not re-

flect the official policy or positon of Brooke Army Medical Center, the

U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, or the Department of Defense, or the U.S. Government.

Ethics

This narrative review did not involve any human subjects or animals.

Therefore, ethical approval is not applicable.

Declaration of Competing Interest

None for any author.

Acknowledgements

None.

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