Association of Hypocalcemia With Mortality of Combat Casualties With Brain Injury and Polytrauma Transported by Critical Care Air Transport Teams Free

ABSTRACT

Introduction

Hypocalcemia at hospital presentation is associated with increased mortality in trauma patients with hemorrhagic shock. The 2019 updates to the Joint Trauma System Damage Control Resuscitation (DCR) Clinical Practice Guideline recommend calcium supplementation for ionized calcium (iCa) measurements <1.2 mmol/L. Ionized calcium goals for en route critical care (ERCC) following DCR are less defined, and the impact of in-flight hypocalcemia events among critically injured combat wounded is unknown. This study aimed to describe the association between hypocalcemia and mortality for combat-wounded with brain injury and polytrauma requiring transport by Critical Care Air Transport Teams (CCATT).

Methods

We performed a secondary analysis of a retrospective cohort of patients with moderate-to-severe traumatic brain injury transported by CCATT out of combat theater between January 2007 and May 2014. Additional inclusion criteria included polytrauma and at least one documented in-flight iCa measurement. We categorized exposures based on the minimum in-flight iCa measurement as severe hypocalcemia (iCa <0.9 mmol/L), hypocalcemia (iCa 0.9-1.11 mmol/L), and never hypocalcemic (iCa ≥1.12 mmol/L). The primary outcome measure was mortality. We calculated descriptive statistics and performed multivariate logistic regression to assess the association between hypocalcemia and mortality.

Results

We analyzed 190 subjects, with a median age of 24 years (interquartile range [IQR] 21 to 29 years) and 97.7% male gender. Explosive injuries (82.1%) and gunshot wounds (6.3%) were the most common mechanisms of injury. The median injury severity score was 34 (IQR 27 to 43). During the flight, 11.6% of patients had severe hypocalcemia, and 39.5% had hypocalcemia. Among patients with any hypocalcemia measurement in-flight (n = 97), 41.2% had hypocalcemia on pre-flight iCa, 28.9% received blood products in-flight, and 23.7% received in-flight calcium supplementation. Only 32.4% of patients with hypocalcemia or severe hypocalcemia in the setting of vasopressor administration received in-flight calcium supplementation. There was no significant difference in mortality between severe hypocalcemia (9.1%), hypocalcemia (5.3%), and never hypocalcemic (3.2%) patients even after controlling for pre-flight variables.

Conclusion

In-flight hypocalcemia events were common among critically ill combat-wounded polytrauma patients transported by CCATT but were not associated with differences in mortality. Future training should emphasize the need for calcium correction among ERCC patients requiring vasopressors. Future studies with larger sample sizes of patients receiving ERCC are needed to assess the association between in-flight calcium supplementation with clinical outcomes.

INTRODUCTION

Hypocalcemia has long been recognized as a threat to trauma patients undergoing blood product resuscitation with products containing citrate.¹ Recent prospective studies suggesting an association between early hypocalcemia and mortality during initial resuscitation emphasize calcium management.^1,2 The role of calcium replacement in later phases of care is less clear and, to our knowledge, has not been evaluated in the Critical Care Air Transport Teams (CCATT) patient population. CCATT are Air Force teams composed of a physician, nurse, and respiratory therapist.³ CCATT serve as a critical care augmentation asset to aeromedical evacuation platforms for air transport of critically injured combat wounded. CCATT provide advanced en route resuscitation capabilities, including blood product resuscitation and point-of-care laboratory monitoring, to optimize outcomes among combat wounded requiring en route critical care (ERCC).³

Joint Trauma System (JTS) recently revised recommendations to replace calcium earlier and more aggressively during initial trauma resuscitation. The 2019 update to the Damage Control Resuscitation (DCR) Clinical Practice Guideline (CPG) recommended providing calcium concurrently with the first blood product transfusion rather than after four units in prior CPGs.⁴ In addition, recommendations were amended to administer calcium for ionized calcium measurements less than 1.2 mmol/L.⁴ These recommendations differ from current Advanced Trauma Life Support guidelines that state no need for calcium replacement for most blood transfusions.⁵ Evidence supporting the JTS CPG revisions are as follows. Hypocalcemia had a dose-dependent association with mortality in a cohort of hospitalized patients requiring massive transfusion.⁶ Exposure of either hypocalcemia or severe hypocalcemia, defined as <0.9 mmol/L, at hospital presentation was associated with increased mortality in trauma patients with hemorrhagic shock receiving massive transfusion.^2,7 A study of combat-wounded patients found hypocalcemia frequently occurred following a single unit of prehospital blood product administration, and calcium supplementation reduced the incidence of hypocalcemia.⁸ While this evidence resulted in changes to the DCR CPG, ICU protocols targeting normal ionized calcium measurements are discouraged by current civilian critical care recommendations.⁹ Daily calcium replacement for all comers to the ICU was not associated with changes in mortality or normalization of calcium values in one retrospective study.¹⁰

ERCC patients have unique injury patterns and have greater time between injury and transport compared to civilian transports.¹¹ Exposure to hypobaria and other stressors of flight may exacerbate the negative consequences of hypocalcemia. Detailed resuscitation guidelines exist for specific patient subgroups, such as traumatic brain injury (TBI) or burns. However, less specific guidance exists for ERCC teams managing polytrauma patients beyond the initial resuscitation.¹² We did not find any studies describing the incidence of hypocalcemia among combat-wounded polytrauma patients requiring ERCC. This study aimed to describe the association between mortality and hypocalcemia for combat-wounded patients with TBI and polytrauma transported by CCATT. Secondary aims were to identify pre-flight variables predictive of in-flight hypocalcemia and an exploratory comparison of mortality among patients who did and did not receive in-flight calcium supplementation.

METHODS

We performed a secondary analysis from a retrospective cohort of moderate-to-severe TBI patients transported by CCATT out of combat theater between January 2007 and May 2014. Additional details of the methodology were previously published.¹³ The U.S. Air Force 59th Medical Wing Institutional Review Board approved this study.

Inclusion criteria for the initial cohort included battle injury, age of 18 or greater, moderate or severe TBI (defined as a head/neck Abbreviated Injury Scale (AIS) of at least 3), transport by CCATT out of combat theater, and availability of CCATT medical record. Transport missions meeting these criteria were generally intercontinental flights with 6-8 hours of flight time. Additional inclusion criteria for this secondary analysis included polytrauma (defined as AIS of at least 3 in an additional body region to head/neck) and availability of at least one in-flight iCa measurement in the CCATT medical record. We excluded subjects with catastrophic brain injury.

Data Sources

We obtained pre-flight data from the Department of Defense Trauma Registry (DoDTR) for injury characteristics and pre-flight care received. Emergency physicians reviewed radiology reports from the Theater Medical Data Store to characterize intracranial injuries from imaging performed at Role 2 and Role 3 forward hospitals before CCATT transport. CCATT medical records, documented on Air Force Form 3899L, provided ERCC and in-flight data. The DoDTR provided outcomes for mortality and hospital length of stay.

Trained research nurses abstracted data from CCATT medical records into a secure Access database (Microsoft Corporation, Redmond, WA, USA). These data included patient demographics, injury patterns, clinical assessments, vital signs, treatments received, lab diagnostics, imaging diagnostics, pre-flight procedures, and in-flight procedures. Additional data elements collected from CCATT medical records for this analysis included tranexamic acid administration, calcium administration, the timing of calcium measurements, and the timing of calcium administration. Additional details for specific variables were previously published.¹³ We conducted usual data quality measures, including abstractor training, regular data entry reviews, and reconciliation of discrepancies, as previously described by the En Route Care Research Center.¹⁴

Exposure Categorization

We divided the in-flight calcium exposure into three categories: severe hypocalcemia, hypocalcemia, and never hypocalcemic. We defined severe hypocalcemia as ionized calcium (iCa) <0.9 mmol/L as per prior literature.¹ A hypocalcemia event was defined as iCa < 1.12 mmol/L on an in-flight iCa measurement as per the Abbott i-STAT reference range (CG8+, EG7+, CHEM8+ test cartridges) for arterial and venous iCa measurements. The “never hypocalcemic” category was defined as no in-flight iCa measurements <1.12 mmol/L. Corrections for albumin and pH are not necessary with iCa as compared with total calcium measurements.⁹

Outcome Measures

The primary outcome was mortality. Secondary outcomes included intensive care unit length of stay and the proportion of patients with hypocalcemia receiving in-flight calcium supplementation.

Statistical Analysis

We performed descriptive statistics for all reported variables. We performed univariate comparisons for clinical characteristics, treatments, and outcomes among the study sample categorized by calcium exposure. Calcium gluconate doses (0.465 mEq/mL of calcium) were converted into calcium chloride equivalents (1.4 mEq/mL of calcium). We used Kruskal–Wallis and chi-square or Fisher’s exact test to identify any significant differences among the calcium exposure groups for pre-flight and in-flight characteristics.

We conducted univariate comparisons of patient outcomes among the exposure groups. We used Fisher’s exact test to compare mortality and log-rank tests to compare time-to-event data (ventilator, ICU, and hospital days) while censoring for mortality.

We constructed a logistic regression model to compare the odds of mortality among exposure groups while controlling for variables of interest. The primary outcome of the study was the impact of the predictor variable, in-flight calcium exposure. Both severe hypocalcemia and hypocalcemia groups were compared to the never hypocalcemic group as the reference group in the model. Additional covariates considered for the model included ISS and pre-flight abdominal surgery. Covariates were chosen based on prior work optimizing model fit for this patient population. Due to low rates of mortality in this sample, we used a Firth penalized logistic regression model and limited the number of covariates. Collinearity was not present as assessed with condition indices, variance inflation factors, and tolerance levels. We excluded subjects from the model with missing data for any of the covariates. All analyses occurred in SAS (version 9.4, SAS Institute, Inc., Cary, NC).

RESULTS

The initial TBI cohort included 477 subjects. Exclusions for this secondary analysis included catastrophic brain injury (n = 39), no recorded in-flight calcium measurements (n = 136), and head injury without polytrauma (n = 112). This analysis included 190 subjects. The median age was 24 years (interquartile range [IQR] 21 to 29 years). The majority of subjects were male (97.7%). Explosive injuries (82.1%) and gunshot wounds (6.3%) were the most common mechanisms of injury. The median injury severity score was 34 (IQR 27 to 43).

The following in-flight calcium exposures were present: severe hypocalcemia (11.6%), hypocalcemia (39.5%), and never hypocalcemic (48.9%). Pre-flight characteristics of these groups were similar (Table I). Most patients with severe hypocalcemia (86%) had a penetrating injury. Pre-flight hypocalcemia was common (50.6%) among patients with in-flight hypocalcemia. Pre-flight hypocalcemia was associated with increased risk of in-flight hypocalcemia or severe hypocalcemia (OR 2.37, 95% CI, 1.23-4.56). Massive transfusion requirement (OR 1.75, 95% CI, 0.71-4.32), penetrating mechanism of injury (OR 1.56, 95% CI, 0.82-2.97), abdominal surgery (OR 1.40, 95% CI, 0.75-2.61), and presence of intracranial hemorrhage (OR 0.68, 95% CI, 0.36-1.25) had no significant association with in-flight hypocalcemia.

Patients with severe hypocalcemia received a greater number of blood products during pre-flight resuscitation (Table II). During transport, patients had a median of two ionized calcium measurements. Half of the patients with severe hypocalcemia and 16% of patients with hypocalcemia received in-flight calcium supplementation. The median dose of calcium administered was 1 g of calcium chloride. Overall, 29.5% of patients required in-flight vasopressors. While hypocalcemia or severe hypocalcemia was common (60.7%) among this subgroup, only 32.4% of hypocalcemic patients requiring vasopressor administration received in-flight calcium supplementation.

An unadjusted comparison of mortality by calcium exposure found no significant difference with 9.1% mortality in the severe hypocalcemia group, 5.3% in the hypocalcemia group, and 3.2% in the never hypocalcemic group (Table III). Similarly, the number of days spent in the ICU did not significantly vary among the groups. In a multivariate model, the adjusted odds ratios for mortality were 1.16 (95% CI, 0.27-4.99) for hypocalcemia and 2.46 (95% CI, 0.43-13.97) for severe hypocalcemia with the never hypocalcemic group as the reference (Supplementary Table S1).

We performed a subgroup analysis comparing patients receiving in-flight calcium supplementation (n = 23) versus no calcium supplementation (n = 74) among all patients with either hypocalcemia or severe hypocalcemia during flight (n = 97). Calcium supplementation was associated with lower calcium measurements during flight and more critically injured patients with higher ISS (Table IV). Mortality occurred in 8.7% of patients receiving in-flight calcium versus 5.4% of patients who did not receive calcium, but no significant differences in mortality, ICU days, or hospital days were present.

DISCUSSION

We did not find any association between an in-flight exposure of hypocalcemia and mortality in this retrospective cohort of combat-wounded polytrauma and TBI patients transported by CCATT. Our study had wide confidence intervals for outcome comparisons, given the limited sample size and low incidence of mortality. In-flight hypocalcemia was common among this population, with over half of the subjects having at least one hypocalcemic episode in flight. Furthermore, these episodes were usually not treated during usual care at the time of the study. While this practice pattern conflicts with recent revisions of the DCR JTS CPG to target 1.2 mmol/L for iCa, current recommendations for civilian ICU practice do not recommend empiric calcium supplementation based solely on calcium concentrations.⁹ We are unaware of published military-specific guidelines for in-flight ERCC calcium goals during later phases of care following DCR.

Evidence-based practice for ERCC is challenging, given the need to translate evidence from other clinical settings to a unique patient population with relatively small sample sizes and operational environment data limitations. Specifically, ERCC patients have fewer comorbidities, more severe injury patterns, and require longer flights than civilian trauma cohorts. The ideal deliverable would be a data-driven protocol with specific indications for calcium supplementation and criteria for different doses of calcium supplementation to guide CCATT, other ERC teams, and autonomous transport. Prior evidence from ICU phases of care suggests hypocalcemia is a marker for critical illness rather than a reversible abnormality to improve outcomes.¹⁵ Practice recommendations must consider task management for ERC teams because of their small size, limited medical supplies, and potential to transport larger volumes of patients in future Large-Scale Combat Operations.¹⁶ In isolation, the current study does not provide sufficient evidence to inform an ERCC calcium repletion protocol for combat-wounded polytrauma patients. In-flight calcium levels may result from initial resuscitation practices, with in-flight calcium management having less impact on clinical outcomes.² While our exploratory analysis of calcium supplementation versus no supplementation among patients with hypocalcemia did not find statistically significant differences in mortality, the small sample size limited the power to detect a difference or enable multivariate analysis controlling for confounding variables. Furthermore, we treated calcium supplementation as a binary variable (administered versus not administered), and the impact of higher doses of calcium is unknown.

The authors suggest the following takeaways inform current care and future research while considering the current study’s limitations. First, future studies should utilize these data as a baseline for incidence of hypocalcemia during ERCC phases of transport to evaluate the impact of more aggressive calcium supplementation during initial resuscitation of combat wounded on clinical outcomes and prevalence of in-flight hypocalcemia. Second, targeting an ionized calcium level of 1.2 mmol/L for all CCATT patients with polytrauma would involve high resource utilization of medical supply (calcium), lab supply (i-STAT cartridges), and personnel time (laboratory monitoring and medication administration). Given the 51% prevalence of hypocalcemia in this cohort, prior evidence of no changes in outcomes from ICU calcium supplementation protocols, and no clear signal of improved outcomes for calcium supplementation in this study of CCATT patients, it is the opinion of the authors that calcium management during ERCC should continue the current practice of targeted calcium supplementation for events such as blood product administration or hypocalcemia with hemodynamic compromise. Current evidence suggests that empiric administration of calcium for severe hypocalcemia (iCa < 0.9 mmol/L) is reasonable.

In addition, this study identified potential areas for improvement for ERCC calcium management in the subgroup of patients requiring in-flight vasopressors. First, approximately one-third of patients who required vasopressor administration did not have a documented in-flight calcium measurement.¹³ These patients did not meet inclusion criteria for this secondary analysis; however, this finding highlights a possible need for CCATT i-STAT CPG revisions to describe indications for laboratory monitoring during ERCC, such as vasopressor administration, and track laboratory monitoring as a quality metric for ERCC teams with laboratory monitoring capabilities. Second, training should emphasize the need for calcium correction in patients requiring vasopressors, as the majority of hypocalcemic patients requiring vasopressors (68%) did not receive calcium supplementation in our study.

In summary, evidence is lacking to support routine calcium goals of 1.2 mmol/L in later phases of ERCC following DCR, and routine supplementation likely does not optimize the allocation of limited ERCC resources of manpower and medical supply. Additional study with a larger sample size is needed to evaluate the impact of calcium supplementation, particularly for ERCC populations without TBI.

LIMITATIONS

This was an observational study, so any identified associations are subject to confounding variables. We attempted to control for these variables by multivariate analysis but were limited to available data from existing medical records of pre-flight and in-flight care. Prior studies finding associations between hypocalcemia and increased mortality were in trauma populations with hemorrhagic shock. However, the applicability to this cohort is unclear as CCATT patients typically are not in active hemorrhagic shock during transport. All polytrauma patients in this cohort had TBI, so additional study in ERCC populations without TBI is needed.

The preferred analysis for the impact of calcium supplementation on outcomes would compare hypocalcemic subjects with in-flight calcium supplementation versus no supplementation. We performed an exploratory analysis comparing these groups, but sample size prevented definitive conclusions and multivariate analysis for confounding variables. Furthermore, we were unable to assess the impact of higher doses of calcium on clinical outcomes.

CCATT medical records are handwritten with significant variability in the documentation of in-flight treatments. Study limitations include the availability of legible data and interpretation by the chart abstractor. Strict quality control measures were in place to improve consistency between different data abstractors. Outcome measures were limited to data available in the DoDTR, so longer-term outcomes were unavailable for analysis.

CONCLUSION

In-flight hypocalcemia events were common among critically ill combat wounded with polytrauma and TBI transported by CCATT. No association was found between in-flight hypocalcemia and mortality. Future training should emphasize the need for calcium monitoring and correction among ERCC patients requiring vasopressors. Additional study is needed to inform calcium supplementation guidelines for different populations of combat wounded during ERCC transport.

ACKNOWLEDGMENTS

ERCC Pilot Unit (Andre Gholson, RN), provision of patient records; En route Care Research Center nurses, data abstraction; Maria Castañeda, Program Manager.

SUPPLEMENTARY MATERIAL

SUPPLEMENTARY MATERIAL is available at Military Medicine online.

FUNDING

Defense Health Agency J-9 - J917EC05.

CONFLICT OF INTEREST STATEMENT

None declared.

REFERENCES

Author notes