Hypocalcemia in Trauma
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Giancarelli, A., Birrer, K., Alban, R., Hobbs, B., Liu-DeRyke, X. (2016). Hypocalcemia in trauma patients receiving massive transfusion Journal of Surgical Research 202(1), 182-187. https://dx.doi.org/10.1016/j.jss.2015.12.036
Introduction
We are all familiar with the “lethal triad” of trauma – coagulopathy, hypothermia, and acidosis. We have multiple methods wherein we attempt to prevent or reverse these physiologic derangements. In particular, in recent years many teams have focused heavily on limited crystalloid infusions, increasing our early blood product transfusion (especially plasma), and early administration of tranexamic acid.
One of the main reasons we focus on these interventions is to address trauma-induced coagulopathy. Trauma-induced coagulopathy has a multifactorial etiology and is contributed to by the other corners of the triad (hypothermia and acidosis). However, one of the least appreciated contributing factors are electrolyte deficiencies, in particular calcium.
Calcium plays an important role in platelet adhesion and coagulation, as well as contractility of myocardial and smooth muscle cells (meaning it also acts similarly to a vasopressor and inotrope). Calcium is required by clotting factors II, VII, IX, and X, as well as proteins C and S for activation at the damaged endothelium. Finally, calcium has a role in stabilizing platelets and fibrinogen in the developing thrombus.
Hypocalcemia during massive transfusion could actually be seen as an inadvertent iatrogenic process. Serum calcium is chelated due to the citrate used as a preservative in the Packed Red Blood Cells (PRBC’s), Fresh Frozen Plasma (FFP), and even the Liquid Never-Frozen Plasma we use in our Med Flight blood coolers. In healthy patients, this citrate is normally quickly hepatically metabolized. However, in patients with hemorrhagic shock, this clearance is greatly decreased, and the often-concomitant rapid transfusion of large amounts of blood products also contributes to citrate accumulation.
Hypocalcemia by itself is associated with increased mortality in critically ill adults, presumably due to a combination of factors including cardiac dysrhythmias, poor vascular tone (vasoplegia), and impaired coagulation. When you combine hypocalcemia with hemorrhagic shock, we have to assume mortality will increase significantly. Unfortunately, the incidence and severity of hypocalcemia in trauma patients receiving massive transfusion was not well-described at the time of this study. In addition, there are limited data regarding the timing and dosage of calcium supplementation needed after administration of blood products. Many centers now have monitoring of calcium levels and supplementation included in their Massive Transfusion Protocols (MTP), but as far as I am aware there is no nationally or internationally recognized standard.
This paper was a retrospective chart review done at the Orlando Regional Medical Center, a large level 1 trauma center. All adult trauma patients who had activation of MTP were identified over a period of approximately 4 years. At this particular institution, MTP used coolers containing 6 units of PRBC, 6 units of FFP, and one pack (equal to 6 units) of apheresis platelets. MTP activation had specific physiologic, radiographic, and prognosticated criteria. Patients were excluded if they had MTP activated for reasons other than trauma, had incomplete records, or had no ionized Calcium levels available within 24 hours of MTP initiation.
The primary outcome of the study was to determine the incidence of hypocalcemia and severe hypocalcemia in trauma patients who received massive transfusion. Hypocalcemia was defined as an iCa < 1.12 mmol/L, and severe hypocalcemia was defined as an iCa <0.90 mmol/L. Calcium replacement is reported in terms of grams of calcium chloride. Coagulopathy was defined as PT or aPTT >1.5 times the upper limit of normal.
Results
A total of 172 patients were identified in the trauma database during the study period, and 156 were included in the final analysis.
The overall incidence of hypocalcemia was 97.4%, and the incidence of severe hypocalcemia was 71%. Patients were further divided into two groups for additional analysis, iCa <0.90 mmol/L and iCa > 0.90 mmol/L. There were no significant differences in Injury Severity Scores (ISS), home antiplatelet or anticoagulant use, or demographics except for trauma type. Patients with iCa <0.90 mmol/L had significantly higher aPTT and lactic acid, and lower platelets and pH on admission compared with those with higher iCa levels. Mortality was also significantly higher in the iCa <0.90 mmol/L group (49% versus 24%).
ROC analysis showed that total volume of blood products transfused had strong predictability for development of severe hypocalcemia. 15 units of total blood products was the best predictor for severe hypocalcemia. Neither group reached a median iCa >1.12 mmol/L despite an average repletion of 2 grams of calcium chloride, suggesting a persistent, refractory level of mild hypocalcemia in these patients.
Limitations
Several limitations exist in regard to this study. It is a retrospective analysis of pre-existing data, and so is not the gold-standard prospective randomized controlled trial. They were not able to assess the effect of blood product administration rate on hypocalcemia. There was also a limitation in regard to consistent laboratory monitoring, with many patients lacking baseline iCa, PT, and aPTT, and others lacking follow-up PT or aPTT. The latter may mean that the incidence of coagulopathy was actually underestimated. Next, the baseline vitals reported were the first available vital signs but given that many of these patients presented in near or complete cardiac arrest, and vitals were only obtained after ROSC, these likely underestimate the true severity of illness. Lastly, they did not specifically examine the incidence of hypercalcemia in patients who received calcium supplementation, but this was less likely considering that the median iCa after supplementation was still less than 1.12 mmol/L.
Discussion
This is an important study, that highlights what I believe is one of the weaknesses of many current guidelines. After discussing prehospital blood product transfusion with many of our regional, national, and international colleagues, we found that there lacked a clear consensus as to the “when” and “how much” calcium to give during resuscitation. The general feeling seemed to be that “some” needed to be given after “a few units” of blood products.
We sought to examine the research to gain additional clarity in this area, as well as potentially add a protocol for this to our teams. As we know, when best practices are vague or undefined, it becomes very difficult to recall specific dosages or design systems to support the individual practicing in the moment. We found that even our own institutional in-hospital Massive Transfusion Protocol did not specifically address checking of ionized Calcium levels or provide guidelines to supplementation, furthering the need for own research.
This study was the first to systematically evaluate the incidence of hypocalcemia during massive transfusion secondary to trauma. They found a very high incidence of hypocalcemia (>90%!), and a high incidence of severe hypocalcemia. Their finding also confirmed an apparent dose-response relationship between the volume of blood products administered and degree of hypocalcemia. Other studies also support a relationship between rate of administration and hypocalcemia.
Various proposed replacement strategies exist, including variety in doses as well as type of calcium (chloride versus gluconate). As a reminder, calcium chloride is commonly said to be 3x as potent as calcium gluconate but is more sclerotic. A common prior recommendation was for 2 g of calcium gluconate to be given for every 2-4 blood products transfused. Both groups in this study received 2 g of calcium chloride (equivalent of 6 g of calcium gluconate, 3x the usual recommendation) after 4 units of blood product, but despite this still did not significant acute improvements in their iCa. Their final median iCa’s were also low, but this is likely contributed to by the fact that most patients only received 3-4 g of total calcium chloride despite receiving an in excess of 20-30 units. The authors conclude that calcium chloride may be the preferred salt form during massive transfusion, and 2 or more grams may be necessary for every 2-4 units of blood product transfused.
For our teams, we’ve been reviewing our guidelines, and are recommending our teams give at least 1 g of Calcium Chloride for every 3 units of products transfused. We currently carry 1 unit of PRBC’s and 2 units of Liquid Never-Frozen Plasma.
It is important to remember that calcium supplementation would NOT be our first priority. It would only be done if adequate blood product resuscitation was on-going, and after TXA was administered (if appropriate). We do think that early administration of calcium will not only help preserve/improve vascular tone and cardiac contractility, but also ameliorate iatrogenic hypocalcemia. Finally, just as with TXA, we believe that giving it early will help ensure that it is not later lost amongst the complicated demands of the trauma bay and OR.
AUTHORSHIP
Andrew Cathers, MD - Dr. Cathers is an Emergency Medicine Physician as well as Flight Physician, and Assistant Medical Director of University of Wisconsin Med Flight with a focus on Education and Training in their Program. He is kind enough to share recaps of recently published HEMS literature which should be posted quarterly here on TamingtheSRU
