Authors: Visarat Palitnonkiat, Tharin Thampongsa, Jatuporn Sirikun, Natthida Owattanapanich
Categories: Systematic Review, Multiple Trauma, mortality
Source: Trauma Surgery & Acute Care Open
Association between hypocalcemia and mortality in trauma a systematic review and meta-analysis
Authors: Visarat Palitnonkiat, Tharin Thampongsa, Jatuporn Sirikun, Natthida Owattanapanich
Abstract
Background
The trauma triad of death, consisting of hypothermia, acidosis, and coagulopathy, has long been recognized as a major cause of mortality in trauma patients. Recently, hypocalcemia has emerged as a fourth component that plays a critical role in the prognosis of these patients. The objective of this meta-analysis is to evaluate the association between hypocalcemia and mortality among trauma patients.
Methods
The authors systematically reviewed studies published in English from OVID, EMBASE, and Cochrane databases between January 1, 2000 and October 31, 2024. Randomized controlled trials and cohort studies reporting mortality rates among trauma patients with hypocalcemia were included. A meta-analysis was conducted using random effects models. The methodological quality of the studies was assessed using the Cochrane risk of bias tool.
Results
Of the 4,209 studies identified, 20 were included in the meta-analysis. Trauma patients with hypocalcemia had a statistically significant increase in mortality (OR 2.79; 95% CI 2.01 to 3.89). This increase in mortality was also observed in subgroup analysis based on the timing of calcium level before blood transfusion (OR 2.45; 95% CI 1.75 to 3.43; I2=59%), before or after blood transfusion (OR 1.61; 95% CI 1.26 to 2.05; I2=0%), and no available data on the timing of calcium level measurement (OR 3.97; 95% CI 2.24 to 7.02; I2=78%). Notably, hypocalcemia was associated with increased mortality regardless of whether calcium levels were measured before or after blood transfusion. In terms of hypocalcemia severity, we found that more severe hypocalcemia was associated with higher mortality.
Conclusions
Hypocalcemia in trauma patients is associated with increased mortality. We suggest that hypocalcemia should be closely monitored regardless of the transfusion history.
Trial registration number
INPLASY number, 202330116.
Introduction
The trauma triad of death, consisting of hypothermia, acidosis, and coagulopathy, has long been recognized as a major cause of mortality in trauma patients. Recently, hypocalcemia has emerged as a fourth component that plays a critical role in the prognosis of these patients.^1^
Current management principles for traumatic hemorrhage in patients experiencing shock and hypoperfusion emphasize damage control resuscitation, which includes permissive hypotension, damage control operation, and hemostatic resuscitation. The primary goal of hemostatic resuscitation is to correct trauma-induced coagulopathy and stabilize hemostasis to control bleeding. Ditzel et al first identified hypocalcemia as the fourth component of the “lethal diamond” in hemostatic resuscitation, highlighting its role in this process.^2^ The inter-relationship between calcium and the other components of the trauma triad has been increasingly recognized. Calcium plays a critical role in the coagulation cascade and hemostasis; in vitro data show that thrombin generation and clot formation are inhibited when ionized calcium (iCa) levels fall below 0.25 mmol/L.^3^ Furthermore, calcium is essential for normal cardiac contractility and vasoconstriction, which are necessary to maintain adequate cardiac output and prevent hypoperfusion and acidosis.^4^ Hypocalcemia and hypothermia also have a synergistic detrimental effect on the heart, further compromising cardiac output and worsening trauma outcomes.^2 5^
Hypocalcemia in trauma is a multifactorial condition. Traumatic bleeding leads to both the direct loss of calcium ions and disturbances in calcium homeostasis. Additionally, treatment with a massive blood transfusion protocol for hemorrhagic shock can exacerbate this condition.68 After blood transfusions, the primary cause of hypocalcemia is the citrate used as an anticoagulant in both whole blood and blood products. Under normal physiological conditions, a healthy adult can metabolize 3 g of citrate within 5 min. However, in cases of impaired liver function (common after trauma) or when transfusions exceed a rate of 1 unit per 5 min, iCa levels can fall due to citrate-induced chelation.^9^
Numerous studies have explored the relationship between calcium levels and trauma; however, comprehensive reviews and meta-analyses establishing an association between hypocalcemia and trauma outcomes, particularly mortality, remain limited. A thorough and systematic analysis of this topic is therefore warranted. The objective of this meta-analysis is to evaluate the association between hypocalcemia and mortality among trauma patients.
Methods
This protocol was registered in the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY number, 202330116) and reported in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guideline.
Data sources and searches
Two investigators (VP and NO) independently searched and reviewed all citations of studies published in English from OVID, EMBASE, and Cochrane databases between January 1, 2000 and October 30, 2024. The medical subject heading used in this meta-analysis included “Trauma” OR “Traumatic or Critical Illness” AND “Hypocalcemia” OR “Calcium” AND “Mortality”. An additional manual search of the available references was performed. Any disagreements during the process were resolved by discussion with a third reviewer (TT), with the final decision reached by consensus.
Selection criteria and data extraction
The eligible studies for inclusion in this meta-analysis were randomized-controlled trials or cohort studies (prospective or retrospective) that reported the primary outcome of the association between hypocalcemia and mortality in trauma patients. Mortality is defined as any reported mortality in the included studies. The secondary outcomes of interest included comparisons between normocalcemia and mild hypocalcemia, as well as severe hypocalcemia and no severe hypocalcemia, as these variables are strongly associated with mortality. Mild hypocalcemia is defined as serum iCa <1.1 mmol/L (<4.4 mg/dL) or serum total calcium <2.2 mmol/L (<8.8 mg/dL). Severe hypocalcemia is defined as serum iCa <0.9 mmol/L (<3.6 mg/dL) or serum total calcium <1.8 mmol/L (<7.2 mg/dL). However, in certain institutions, iCa is unavailable; therefore, total calcium may be used as an alternative in resource-limited settings.
Quality assessment
Methodological quality is defined as the confidence that the study’s design and report would restrict bias in comparing the outcome. The risk of bias assessment was independently performed by two investigators (VP and NO) using the Cochrane Risk of Bias instrument. The Risk of Bias 2 and the Risk of Bias in Non-randomized studies-of interventions tools were used to assess randomized and non-randomized trials, respectively (online supplemental 2 and 3).
Statistical analysis
All data analyses were conducted using Review Manager V.5.3 software (Cochrane Collaboration, London, UK). Dichotomous data were expressed as OR with 95% CIs for each study and pooled using the random-effects model. Statistical heterogeneity was assessed using the Cochran Q test and I2 statistic. I2 values were interpreted as 0–25% indicated negligible heterogeneity; 26–50% indicated low heterogeneity; 51–75% indicated moderate heterogeneity; and greater than 75% indicated high heterogeneity. A p value of less than 0.05 was considered statistically significant.
Results
Search results
A total of 4,209 potentially relevant articles were identified (3,515 from OVID, 3 from Cochrane, and 691 from EMBASE). After excluding 1,587 duplicated articles using EndNote X9 software, 2,622 articles underwent title and abstract review. After this review, 2,564 articles were excluded, leaving 58 articles for full-length review. Of these, 38 were excluded based on the following (1) reviews or guidelines; (2) unavailable data on the primary endpoint; (3) contamination with other populations; and (4) animal studies. Finally, 20 articles met the inclusion criteria for the meta-analysis. The literature review process is outlined in figure 1, and the study characteristics of these 20 articles are presented in table 1 and fully detailed in online supplemental 1.
Assessment of publication bias
The funnel plot used to assess publication bias displayed relative symmetry, indicating an absence of significant publication bias (figure 2).
Effects of intervention
Primary outcome
A pooled analysis of 20 studies using a random-effects model revealed that trauma patients with hypocalcemia had a significant increase in mortality compared with those with normocalcemia (OR 2.79; 95% CI 2.01 to 3.89; I^2^=89%; p<0.00001). This increase in mortality was also observed in subgroup analysis based on the timing of calcium level before blood transfusion (OR 2.45; 95% CI 1.75 to 3.43; I^2^=59%), before or after blood transfusion (OR 1.61; 95% CI 1.26 to 2.05; I^2^=0%), and no available data on the timing of calcium level measurement (OR 3.97; 95% CI 2.24 to 7.02) (figure 3).
Secondary outcomes
Three studies comparing trauma patients with mild hypocalcemia to those with normocalcemia demonstrated that patients with hypocalcemia had a higher mortality rate; however, the result did not reach statistical significance (OR 2.25; 95% CI 0.72 to 7.05; I^2^=23%; p=0.16)(figure 4).
Seven studies comparing trauma patients with severe hypocalcemia to those with no severe hypocalcemia demonstrated that patients with severe hypocalcemia had a significantly higher mortality rate (OR 4.31; 95% CI 2.68 to 6.92; I^2^=52%; p<0.00001) (figure 5).
Discussion
This meta-analysis specifically examines mortality in trauma patients with hypocalcemia and reveals an overall association between hypocalcemia and increased mortality. This trend was observed in both overall and subgroup analyses. Notably, hypocalcemia was associated with increased mortality regardless of whether calcium levels were measured before or after blood transfusion. In terms of hypocalcemia severity, only severe hypocalcemia was significantly associated with higher mortality. Trauma patients with severe hypocalcemia had a fourfold increase in mortality compared with those with no severe hypocalcemia. Although patients with mild hypocalcemia also showed a higher mortality rate than normocalcemic patients, this association did not reach statistical significance.
In the past, hypocalcemia after a traumatic event was primarily attributed to citrated blood transfusion. However, it is now understood that trauma-induced hypocalcemia results from multiple mechanisms^10^ . Ditzel et al^2^ first introduced the term “lethal diamond”, recognizing the interrelated factors of hypothermia, acidosis, coagulopathy, and hypocalcemia as a significant contributor to mortality in trauma patients. Despite the complexity of the relationship between trauma and hypocalcemia, clinicians should remain vigilant and consider early correction of calcium levels during the resuscitation phase.^1^ Additionally, trauma-induced acid-base disturbances can influence iCa levels. In acidosis, hydrogen ions compete with free calcium ions for protein binding sites, increasing iCa levels. The acidosis can be corrected with appropriate resuscitation, and a subsequent decrease in iCa levels is typically observed post-resuscitation.^11^
Previous studies have shown that hypocalcemia can occur in trauma patients both before and after a blood transfusion. Webster et al^12^ and Ciaraglia et al^13^ reported that 43.9–55% of trauma patients presented with hypocalcemia on arrival at the Emergency Department, which worsened after the blood products administration. Hypocalcemia has been associated with hypotension at the scene and increased mortality, regardless of age and Injury Severity Score (ISS). Furthermore, it predicts the requirement for multiple and massive transfusions (MTs).^12 13^ Similarly, our study reveals that hypocalcemia can occur before blood transfusion.
Blood transfusion worsens hypocalcemia, and conversely, hypocalcemia is associated with increasing transfusion requirements in a vicious cycle. Liaud-Laval et al^14^ evaluated the association between severe hypocalcemia (iCa <0.9 mmol/L) at admission and 24-hour transfusion requirements in 137 traumatized adult patients, finding a significant negative correlation between admission iCa levels and 24-hour transfusion volume (r=−0.45, p<0.001). Giancarelli et al^15^ reported that 97.4% of trauma patients who received MTs were hypocalcemic (iCa <1.12 mmol/L), with 71% experiencing severe hypocalcemia (iCa <0.90 mmol/L). This incidence is higher than that observed in recent studies of mixed-intensive care unit population. In comparison, Steele et al^16^ found that 55.2% of critically ill patients admitted to the critical care unit were hypocalcemic (iCa <1.1 mmol/L), with 6.2% of these patients experiencing severe hypocalcemia (iCa <0.9 mmol/L).
There is currently no guideline specifying the timing of calcium measurement in trauma patients, so clinicians should be vigilant for trauma-induced hypocalcemia. The European guideline recommends promptly correcting serum calcium levels below 7.5 mg/dL or serum iCa below 0.9 mmol/L in trauma patients who have received a blood transfusion.^17 18^ Calcium chloride is the preferred supplement because it contains approximately three times more element calcium than calcium gluconate; however, due to its high potential to irritate veins and surrounding tissues, it should be administered via a central line.^19^ The role of prophylactic calcium administration remains unclear and requires further study to analyze the optimal endpoint for calcium repletion.
Regarding the necessity of calcium supplements, no set procedure has demonstrated their advantages. Moore et al supported administering 1 g of calcium gluconate for every 1–2 units of blood product infused, emphasizing that iCa levels should be monitored early and frequently in patients with hemorrhagic shock.^8^ Additionally, in the presence of MT, Wade et al^20^ conducted a retrospective study on trauma patients with MT to evaluate the relationship between increased intravenous calcium administration during MT and survival, using the calcium-to-blood product ratio (CBR) as a measure. Their findings suggest that a CBR of 50 or higher within the first 4 hours of resuscitation was associated with improved survival, which translates to approximately 1 g of calcium gluconate for every 5 units of blood product.^20^ However, Helsloot et al^11^ found no significant difference in coagulopathy or transfusion requirement between patients with hypocalcemia (iCa <1.10 mmol/L) and those with hypercalcemia (iCa ≥1.30 mmol/L). Their study does not support routine early empiric calcium supplementation. Thus, early calcium administration in trauma patients receiving a blood transfusion to prevent hypocalcemia still requires validation through large prospective studies.^21^
This meta-analysis includes a large number of subjects, making the results applicable to various individuals in similar situations. However, we acknowledge that a key limitation of our study lies in the clinical and methodological heterogeneity among the included studies. The meta-analysis encompasses patients with severe trauma; however, there was variation in the degree of injury severity, patient age, and trauma types across the studies. This heterogeneity may influence the generalizability and interpretation of the pooled results. Though, we attempted to address some of these differences through subgroup analyses, the possibility of bias due to data heterogeneity must be considered. Moreover, the definition of hypocalcemia varied across studies, with different cut-off points used. Some studies816 2225 defined hypocalcemia with a cut-off of 1.0 mmol/L, and others^5 14 15 17 26 27^ used thresholds of either 0.9 mmol/L or 1.1 mmol/L for iCa (online supplemental 3). In our methodology for searching potential studies, we did not include transfusion as a variable, despite its known effect on calcium levels. As a result, some relevant studies may not have been included in our analysis. Moreover, in some studies, hypocalcemic patients had higher ISS than normocalcemic patients, which may have influenced the study outcomes.
Despite these variations, our results indicate hypocalcemia is associated with increased mortality. A large prospective trial is warranted to assess the need for calcium supplementation in the pre-hospital or early in-hospital setting, as well as to analyze the optimal timing for calcium monitoring.
Conclusion
Hypocalcemia in trauma patients is associated with increased mortality. Recent data highlight the integration of hypocalcemia into the trauma lethal triad—comprising hypothermia, acidosis, and coagulopathy—as a predictor of prognosis and mortality in critically injured patients. Based on our findings, we suggest that hypocalcemia should be closely monitored regardless of the history of transfusion. Further prospective evaluation is warranted to validate the benefits of early calcium administration in trauma patients.