Clinical Assessment of Low Calcium In traUMa (CALCIUM)
Conditions: Hypocalcemia
Sponsor: Brooke Army Medical Center

Protocol Title:  Clinical Assessment of Low Calcium In traUMa (CALCIUM) 
Date:  8 Feb 2022  
 
 
HQ USAMRDC IRB Research Protocol Template v_21 SEPTEMBER 2020 
 
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PROTOCOL TITLE: Clinical Assessment of Low Calcium In traUMa (CALCIUM) 
 
SECTION A:  RESEARCH TEAM AND LOCATIONS 
 
A1.  RESEARCH TEAM 
 
 
 
A2.  ROLES AND RESPONSIBILITIES 
      
       A2.1 Principal Investigator   
 
            Name: Steven Schauer  
            Study Responsibilities: Responsible for the conduct of the study in accordance with the protocol.  
Maintenance of a list of appropriately qualified persons to whom significant study-related responsibilities have 
been delegated. 
 
        A2.2 Associate Investigator(s) 
 
           Name(s):   N/A 
Study Role 
Institution/Company and Contact Information 
Sponsor 
Organization/Institution/Company:  The Metis 
Foundation 
Address:  84 NE Loop 410, STE 325, San Antonio, TX 
78216 
Point of Contact:  Noor Obaidi, MD 
Name and Degree:   Noor Obaidi, MD 
Title:   Vice President of Regulatory and Scientific 
Affairs 
Phone Number:  210-201-6001 
Email:  obaidi@metisfoundationusa.org 
 
Principal Investigator 
Name, Rank, and Degree: MAJ Steven G Schauer, 
DO, MSCR 
Title: Physician 
Institution: US Army Institute of Surgical Research 
Address: 3698 Chambers Pass, JBSA Fort Sam 
Houston, TX 78234     
Phone Number: 210-771-0706 
Email:  steven.g.schauer.mil@mail.mil 
 
Associate Investigator(s) 
 
Name, Rank, and Degree:  N/A 
Title:   N/A  
Institution/Company:   N/A  
Address:   N/A  
Phone Number:   N/A 
Email:   N/A 
 
Ombudsperson 
 
Name, Rank, and Degree: N/A 
Title:  N/A 
Institution/Company:  N/A 
Address:  N/A 
Phone Number:  N/A 
Email:  N/A 

          Study Responsibilities:  N/A 
 
           Name(s):  N/A  
          Study Responsibilities:  N/A 
    
        A2.3 Ombudsperson   
 
            Name(s): N/A 
            Study Responsibilities: N/A 
 
 A3.  RESEARCH LOCATIONS 
 
Data Coordinating Center (DCC): Vanderbilt University 
POC:  Alex Cheng, PhD 
Office of Research Informatics, Department of Biomedical Informatics 
Duties:  The Data Coordinating Center (DCC) at Vanderbilt University provides data management, and 
data storage support.  
 
Performance Site: Brooke Army Medical Center 
Performance Site Investigator: Steven Schauer, DO, MS 
 
Performance Site: University Hospital – University of Texas Health at San Antonio 
Performance Site Investigator: Susannah Nicholson, MD 
 
Performance Site: University of Colorado – Denver 
Performance Site Investigator: Franklin Wright, MD 
 
A4.  MULTISITE RESEARCH 
 
Lead Site: US Army Institute of Surgical Research 
Lead Site Investigator: Steven Schauer, DO, MS 
Single IRB: Headquarters, US Army Medical Research and Development Command 
Function/Role of Lead Site: The USAISR will be the Lead Site with the above listed principal 
investigator as the overall project lead. The Lead Site is responsible for establishing and maintaining 
the master protocol in accordance with HQ USAMRDC IRB and USAMRDC Office of Research (ORP), 
Human Research Protection Office (HRPO). The Lead Site in collaboration with the sponsor (Metis 
Foundation) will be responsible for all HQ USAMRDC IRB and USAMRDC ORP, HRPO submissions.  
The Lead Site will be responsible for submitting all participating sites’ HRPO submissions and maintain 
a record of all HRPO/IRB regulatory documents. Each site will submit all approval documents from their 
local regulatory office to the Lead Site and DCC for submission to the sIRB. 
 
The Lead Site will then submit the site’s protocol documents to the USAMRDC Office of Research 
Protections Human Research Protections Office (ORP HRPO) for the DOD-required headquarters level 
administrative review (HLAR).  Any revisions resulting from the headquarters level review will be 
communicated directly from the ORP HRPO to the performance site Principal Investigator (PI), Lead 
Site, and the DCC.  Upon completion of the HLAR, an approval memo from ORP HRPO will be sent to 
the site PI, Lead Site, and the DCC. 
 
Any revisions to the master protocols or supporting documents that are requested by the local 
regulatory office must be reviewed and approved by the Lead Site before the site resubmits the 
protocols to its IRB along with the MRDC IRB.  In the event that participating site IRBs require changes 
to the master protocols, the Lead Site will submit an amended master protocol and/or supporting 
document(s) to the HQ USAMRDC IRB for review and approval.  Upon receipt of the HQ USAMRDC 
IRB amendment approval, the Lead Site will provide all approval documents for participating sites.  The 
Lead Site will disseminate the HQ USAMRDC IRB approved documents to all participating sites for 
local regulatory office approval. All amendments made to the master protocols will be reported with the 

Protocol Title:  Clinical Assessment of Low Calcium In traUMa (CALCIUM) 
Date:  8 Feb 2022  
 
 
HQ USAMRDC IRB Research Protocol Template v_21 SEPTEMBER 2020 
 
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Lead Site’s continuing review to ORP HRPO by the Lead Site. 
 
The DCC will be courtesy copied on electronic communications between the HQ USAMRDC IRB, ORP 
HRPO, and participating sites throughout the study duration. 
 
No participating site will be able to gain DCC REDCap database access or start enrollment until all site-
specific requirements (local regulatory office/HRPO approvals/protocol training/agreements).  Sites will 
join as their documents are approved for participation.  The start of each site will occur independently of 
the status of the other sites. 
 
Performance Site: Brooke Army Medical Center 
Performance Site Investigator: Steven Schauer, DO, MS 
IRB that will review for the Performance Site: Headquarters, US Army Medical Research and 
Development Command  
Function/Role of Performance Site: Screen, enroll, data collection, and preparation of manuscripts. 
 
Performance Site: University Hospital – University of Texas Health at San Antonio 
Performance Site Investigator: Susannah Nicholson, MD 
IRB that will review for the Performance Site: Headquarters, US Army Medical Research and 
Development Command 
Function/Role of Performance Site: Screen, enroll, data collection, and preparation of manuscripts. 
 
Performance Site: University of Colorado – Denver 
Performance Site Investigator: Franklin Wright, MD 
IRB that will review for the Performance Site: Headquarters, US Army Medical Research and 
Development Command  
Function/Role of Performance Site: Screen, enroll, data collection, and preparation of manuscripts. 
 
 
 
SECTION B:  RESEARCH METHODOLOGY 
 
B1.  ABSTRACT 
 
Major trauma frequently occurs in the deployed, combat setting and is especially applicable in the recent 
conflicts with explosives dominating the combat wounded.  In future near-peer conflicts we will likely face even 
more profound weapons including mortars and artillery.  As such, the number of severely wounded will likely 
increase.  Hypocalcemia frequently occurs after blood transfusions secondary to the preservatives in the blood 
products, however, recent data suggests that major trauma in and of itself is a risk factor for hypocalcemia.  
Calcium is a major ion involved in heart contractility and thus hypocalcemia can lead to poor contractility. 
Smaller studies have linked hypocalcemia to worse outcomes, but it remains unclear what causes 
hypocalcemia and if intervening could potentially save lives.  The objective of this study is to determine the 
incidence of hypocalcemia on hospital arrival and the association with survival.  We are seeking to address the 
following scientific questions, (1) Is hypocalcemia present following traumatic injury prior to transfusion during 
resuscitation? (2) Does hypocalcemia influence the amount of blood products transfused? (3) To what extent is 
hypocalcemia further exacerbated by transfusion? (4) What is the relationship between hypocalcemia following 
traumatic injury and mortality?  We will conduct a multicenter, prospective, observational study.  We will gather 
ionized calcium levels at 0, 3, 6, 12, 18, and 24 hours as part of scheduled calcium measurements.  This will 
ensure that we have accurate data to assess the early and late effects of hypocalcemia throughout the course 
of resuscitation and hemorrhage control.  These data will be captured by a trained study team personnel at 
every site.  Our findings will inform clinical practice guidelines and optimize the care delivered in the combat 
and civilian trauma setting. 
 
B2.  BACKGROUND AND SIGNIFICANCE 

 
Hypocalcemia occurs frequently in critically ill patients including severely injured trauma patients.1,2  Currently 
the Joint Trauma System guideline on Damage Control Resuscitation (Clinical practice guideline [CPG] ID:18, 
12 July 2019), recommends, “Earlier calcium use recommended. One gram of calcium (30 ml of 10% calcium 
gluconate or 10 ml of 10% calcium chloride) IV/IO should be given to patients in hemorrhagic shock during or 
immediately after transfusion of the first unit of blood product and with ongoing resuscitation after every 4 units 
of blood products. Ideally, ionized calcium should be monitored, and calcium should be given for ionized 
calcium less than 1.2mmol/L.”  The reason for the administration of calcium after 4 units of blood has been 
attributed to the citrate compounds in the blood preservative that bind free calcium resulting in hypocalcemia.3  
The hypocalcemia leads to decreased heart contractility and overall hypoperfusion that can occur after 
massive hemorrhage.4-6  However, new data suggests that our current paradigm with hypocalcemia in trauma 
maybe be inadequate.  In a study by Conner et al. in Military Medicine, they prospectively collected data on 
casualties arriving to one forward surgical team in Afghanistan.7  In their study, they assessed 101 patients, of 
which 55 (54.5%) experienced hypocalcemia on arrival to the FST with a mean ionized calcium (iCa) of 1.16 
mmol/L (95% confidence interval [CI] 1.14 to 1.18) prior to receiving any blood products.  They found that 
casualties injured by explosion conferred an increased risk of hypocalcemia compared to all other patterns of 
injury (odds ratio = 2.42, p = 0.042).  Of the 101 assessed, 38 (37.6%) patients required blood product 
transfusion, of whom 33 (86.8%) of the patients requiring blood product transfusion were hypocalcemic on 
arrival.  This suggests that the major trauma itself maybe a contributing factor to the hypocalcemia and it may 
not be attributable solely to the blood product administration.  In other words, it maybe that blood product 
administration exacerbates a pre-existing or developing hypocalcemia. 
 
There is currently limited clinical evidence assessing hypocalcemia in trauma patients and no outcome studies 
looking at the association of mortality and hypocalcemia or the association of calcium replacement with 
survival in trauma patients.2 Giancarelli et al. studied the incidence of hypocalcemia during massive transfusion 
(MT) and found that out of 156 patients 97% experienced hypocalcemia and 71% experienced severe 
hypocalcemia; hypocalcemia was frequently associated with elevated lactate, other markers of coagulopathy, 
and lower survival for those with severe hypocalcemia.8  We must note that in this study, hypocalcemia 
occurred during the MT which does not account for those that may have arrived already hypocalcemic.8  Vivien 
et al. prospectively studied 212 patients that were given crystalloid or colloid in the prehospital setting finding 
that 74% became hypocalcemic after fluid infusion without blood suggesting that hemodilution itself may 
exacerbate this finding – before receiving blood products.9  In a study of non-trauma, non-septic patients that 
were critically ill, out of 99 they found that up to 88% of them had hypocalcemia – this further suggests that 
critical illness in and of itself may cause hypocalcemia.10  Webster et al. studied 55 trauma patients that were in 
the ED receiving blood – they found that 55% were hypocalcemic on arrival and 89% were hypocalcemia after 
blood product administration – however, no mortality effect was examined.11  Ho et al., unlike in other studies, 
assessed mortality, finding a linear relationship between decreasing calcium and mortality among 352 patients 
– however, they only assessed the lowest documented value and did not trend the data over the initial 24 
hours nor control for the supplementation given.12   
 
We propose a study to track the ionized calcium level over 24 hours and adjusted outcomes based on 
supplementation provided.  Magnotti et al. assessed the ionized calcium (iCa) in 591 patients finding that low 
calcium was associated with increased mortality, however, they assessed the iCa on admission and not based 
on prehospital arrival.13  MacKay et al. assessed 77 patients noting no difference in mortality since their 
mortality rate was low, but they did note that hypocalcemic patients more frequently received supplementation 
and blood products.14  While not assessing mortality, Cherry et al. found that hypocalcemia was associated 
with prehospital hypotension and a worse base deficit.15  These findings hold the potential to change the 
paradigm that hypocalcemia in the setting of trauma is caused purely by transfusion during resuscitation to the 
concept that hypocalcemia in the trauma setting may have its origins from the injured state with exacerbation 
by transfusion.  This parallels previously published findings that coagulopathy often exists before interventions 
are done because of the serious trauma itself.16,17  Previously, it was proposed that coagulopathy was related 
to the infusion of large volumes of crystalloid – which is likely a contributing factor – however, more recent data 
suggests that coagulopathy is associated with traumatic injuries before dilutional effects occur.18,19  Treatment 
of prehospital hypocalcemia may therefore represent an early intervention that could reduce morbidity and 
mortality following traumatic injury.  Similar to the manner in which the exogenous and endogenous pathways 
impact coagulopathy, the same may be the case for hypocalcemia – our study proposes to test this hypothesis.  

Protocol Title:  Clinical Assessment of Low Calcium In traUMa (CALCIUM) 
Date:  8 Feb 2022  
 
 
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With the more widespread and accepted use of prehospital blood products, and the potential for prolonged 
casualty care scenarios, we need to further investigate this premise to determine the need for calcium 
supplementation closer to the point-of-injury.20,21 
 
We are rapidly moving into operational planning for future conflicts in which we may not have ready access to 
surgical teams or locations with laboratory testing capabilities.21,22  As such, the DoD needs to identify effective 
methods for early life-saving interventions, which are feasible for the prehospital combat setting.  Calcium 
administration can be easily accomplished through an intraosseous or intravenous line.23,24  Furthermore, 
ionized calcium levels may be assessed even in far-forward Role 2 environments without full laboratory 
capacity due to portable hand-held cartridges allowing iCa level testing. We are seeking to determine the 
incidence of hypocalcemia in the setting of trauma before and during blood product administration.   If our 
hypothesis is supported, this potentially represents a target for a low-cost, easy-to-administer invention in the 
prehospital combat setting.25  The findings of our study will potentially inform a future interventional clinical trial 
to study the association of early calcium replacement on survival in trauma patients. 
 
B3.  MILITARY RELEVANCE  
 
In a recent study in Military Medicine, data was prospectively collected on casualties arriving to one forward 
surgical team in Afghanistan.  In their study, they assessed 101 patients, of which 55 (54.5%) experienced 
hypocalcemia on arrival to the FST with a mean ionized calcium (iCa) of 1.16 mmol/L (95% confidence interval 
[CI] 1.14 to 1.18) prior to receiving any blood products.  This study took place in Afghanistan during recent 
combat operations which demonstrates the significant relevance of hypocalcemia to the combat casualty care 
mission during the recent and ongoing conflicts in Afghanistan, Iraq, and Syria.  Furthermore, these findings 
are likely to be more dramatic if we are to engage in a near-peer conflict in which we do not have continuous 
air superiority and will likely face far more dangerous weapons, such as mortar and artillery rounds.  Our study 
will inform clinical practice guidelines that are promulgated by the Joint Trauma System to guide medical care 
throughout the combat theaters medical system. 
 
B4.  OBJECTIVES/SPECIFIC AIMS/RESEARCH QUESTIONS 
 
We will determine the incidence of hypocalcemia on hospital arrival and the association with survival. 
Aim 1: Overall incidence of hypocalcemia on ED arrival in major trauma patients 
Aim 2: Association of hypocalcemia with severity of hemorrhage 
Aim 3: Association of hypocalcemia with the number of blood products transfused and supplemental 
calcium administration 
Aim 4: The association of hypocalcemia with early and 24-hour mortality. 
 
B5.  RESEARCH PLAN 
 
       B5.1  Research Design 
 
We will conduct prospective, observational study. 
 
      B5.2  Research Subjects/Population(s)    
 
                B5.2.1  Subject Population(s) 
 
All trauma patients that are admitted to the emergency department or trauma department using institutional 
trauma activation protocols. 
 
                B5.2.2  Number of Subjects, Records, and/or Specimens 
 
We are seeking 391 patients with complete data that meet our a prior inclusion criteria.  We are estimating that 
with drop out and missing data we will need 450 – 90 at BAMC, 180 at UTHSA, 180 at UCD.  Since we will be 

relying on trauma activation protocols at each site, the actual number with data capture will be higher. This is 
because our predefined inclusion criteria are more narrow than the general trauma activation protocols. 
 
               B5.2.3  Inclusion Criteria 
 
For our primary outcome analysis, they must meet one or more of the below inclusions: 
 
• 
Penetrating trauma to the head, neck, torso, or extremities (proximal to the elbow/knee) 
• 
Traumatic arrest or CPR at any time 
• 
Glasgow Coma Scale of 9 or less or deteriorating from initial arrival 
• 
Systolic blood pressure <100mmHg 
• 
Respiratory rate <10 or >29 
• 
Intubated or requiring airway assistance (e.g. bag-valve mask, etc.) 
• 
Any blood administered prehospital 
• 
Vasopressors administered 
• 
Pulseless, degloved, crushed, or mangled extremity proximal to the wrist 
• 
Evidence of arterial bleeding with or without tourniquet application 
• 
Amputations proximal to the wrist/ankle 
• 
Chest needle decompression or chest thoracostomy 
 
We will capture additional subjects that do not meet our primary inclusion analysis but may be used for 
secondary analyses (e.g. they had the calcium studies done, but do not meet the above listed criteria). 
 
               B5.2.4  Exclusion Criteria 
 
We will exclude prisoners from our data analysis.  While the blood draws may occur during routine clinical 
care, we will exclude them from any data analyses. 
 
We will not exclude pediatric patients and pregnant women.  The justification for this is that the study sites 
routinely provide trauma care to pregnant women and pediatric patients.  As such, since we are relying on 
modification of standard order sets for clinical care that includes these blood draws.  It would not be feasible to 
alter routine healthcare operations for this subset of patients.  In other words, the laboratory studies will be 
performed regardless of whether we utilize their data.  We could only exclude their data from our analysis after 
the fact.  However, since these populations have unique physiology, data specific to these populations would 
greatly improve the science of trauma resuscitation within these populations.  Know that we have data that 
could benefit these populations, exclusion of this data from analyses would be unethical. 
 
      B5.3  Research Procedures 
 
1.  Identification of Trauma Subjects 
Trauma patients for enrollment in the study will be identified using site-specific trauma activation protocols in 
the emergency department or trauma department.  The trauma activation criteria at Brooke Army Medical 
Center (BAMC) is provided as an example.  Each site will have slight variations of this, which will be outlined 
in the site-specific documents.  The decision to use trauma team activations will be solely at the discretion of 
the clinical team.  All trauma patients coming in the emergency department that meet criteria for trauma 
activation will have routine laboratory tests done as part of the standardized order set.  Of note, we will 
modify the existing order set to include the calcium studies as outlined in this protocol.  In other words, the 
calcium studies will become the de facto new standard.  We will enroll a continuous sample as part of 
routine trauma care operations via the modified order set.  We will promote capture by way of staff 
education, staff reminders, staff-facing signage, and dissemination via routine department communications. 
2.  Obtaining Trauma Subject Blood Samples 
All patients coming in as part of site-specific trauma activations have blood draws as part of routine clinical 
care.  Blood draw happens as part of routine clinical care for all trauma activations.  Specific to this study, 
we will collect samples at 0, 3, 6, 12, 18, and 24 hours after trauma center arrival.  Laboratory studies are 
outlined in section B5.4 of the protocol.  We will strive to have draws occur within +/- 1 hour of the goal 
times.  However, given that the blood draws will be performed by way of the clinical team and the 

Protocol Title:  Clinical Assessment of Low Calcium In traUMa (CALCIUM) 
Date:  8 Feb 2022  
 
 
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unpredictable nature of trauma care, missed draws or draws out of the goal time frame will not be 
considered protocol deviations.  We are estimating the total blood draw volume for the calcium studies will 
be <30mL with <10-15mL representing additional draws (2) beyond current clinical care standards. Only 1-2 
calcium values are outside of the current clinical practices.  The remainder of the draws are part of the 
routine clinical care. 
3.  Storage of the Blood Samples 
The tubes of blood will be handled based on local standard operating procedures (SOP).  No banking or 
repository of blood samples is planned for this study so all specimen storage and destruction will be based 
on the site laboratory SOPs. 
4.  Data Extraction 
Data extraction will occur by local study site personnel through the electronic medical records systems 
and/or the local trauma registry.  Of note, each site has a participating trauma registry established. 
5.  Data Aggregation 
Data will be aggregated by a local study team member.  The de-identified data will be transferred to the DCC 
using methods established in the site-specific documentation.  
 
      B5.4  Data Collection 
 
Data/Element 
Source 
Operational Specific 
Demographics 
Electronic medical record system, 
prehospital documentation, local 
trauma registry 
Age, sex, military status, height, 
weight, body mass index, 
mechanism of injury, admission 
diagnoses, discharge diagnoses, 
past medical history, past surgical 
history 
Injury severity scores 
Electronic medical record system, 
prehospital documentation, local 
trauma registry 
Numeric 
Timing of events 
Electronic medical record system, 
prehospital documentation, local 
trauma registry 
Date and time of injury, EMS 
arrival time, air transport arrival 
time, transferring center arrival 
time, trauma center arrival time, 
blood product infusions – type of 
infusion (whole blood, packed red 
blood cells, plasma, platelets), 
vital signs, labs, medications, 
procedures  
Vital signs prehospital, first 24 
hours of hospital stay 
Electronic medical record system, 
prehospital documentation, local 
trauma registry 
Heart rate, blood pressure, 
temperature, oxygen saturation, 
respiratory rate 
Laboratory studies at 
(0,3,6,12,18,24 
Electronic medical record system, 
prehospital documentation, local 
trauma registry 
Electrolytes including magnesium, 
ionized calcium, serum calcium, 
hemoglobin, hematocrit, platelets, 
coagulation studies, metabolic 
studies, blood gas values, lactate, 
haptoglobin, 
thromboelastography, white blood 
cell count 
Prehospital medications 
Electronic medical record system, 
prehospital documentation, local 
trauma registry 
Analgesics, sedatives, paralytics, 
vasopressors, calcium (in all 
medically administered forms), IV 
fluids, tranexamic acid, blood 
products 

Hospital medications within the 
first 24 hours of admission 
including timing 
Electronic medical record system, 
prehospital documentation, local 
trauma registry 
Analgesics, sedatives, paralytics, 
vasopressors, calcium (in all 
medically administered forms), IV 
fluids, tranexamic acid, blood 
products 
Major procedures within the first 
24 hours of admission 
Electronic medical record system, 
prehospital documentation, local 
trauma registry 
Hemorrhage control interventions, 
chest needle decompression, 
chest tube, thoracotomy, 
intubation, REBOA, central line 
placement, interventional 
radiology procedures, exploratory 
laparotomy, irrigation and 
debridement, fracture stabilization, 
open vascular procedures, 
compressive hemorrhage 
procedures (e.g. liver packing, 
etc.) 
Imaging studies within the first 24 
hours 
Electronic medical record system, 
prehospital documentation, local 
trauma registry 
CT scans, x-ray studies, 
ultrasound studies 
Blood products and fluids within 
the first 24 hours to include time of 
administration and volumes 
Electronic medical record system, 
prehospital documentation, local 
trauma registry 
Whole blood, packed red cells, 
plasma, platelets, cryoprecipitate 
Outcome data 
Electronic medical record system, 
prehospital documentation, local 
trauma registry 
Discharge status, time to death (if 
applicable), ventilator days, 
intensive care unit days, hospital 
days, discharge location, total 
blood products and fluids received 
(first 24 hours), cardiac events 
(e.g. myocardial infarction, 
dysrhythmias, etc.); all truncated 
at 30 days if LOS exceeds 
 
      B5.5  Managing Data and/or Human Biological Specimens for this Research 
 
All study data will be managed electronically.  Subjects will be assigned a study identifier number by a study 
team member which will allow for easy removal of PHI after study completion. PHI (source documents) will be 
maintained at the participating sites for the purpose of data verification.  De-identified data will be uploaded into 
the DCC REDCap with a goal of entry within 30 days of the subject hospitalization complete (truncated at 30 
days if longer).  The DCC utilizes the clinical research data management tool REDCap to manage clinical 
research studies.  REDCap Data Management which is a full clinical research electronic data capture 
application, compliant with HIPAA and 21 CFR Part 11 regulations for data storage.  Use of study data in 
publications, presentations, grant proposals, and other uses will require approval of the principal investigator in 
consultation with the site PIs.  The overall de-identified data will be stored at the direction of the overall PI for 
data verification and/or related subanalyses indefinitely.  Local site data will be stored based on institutional 
requirements and at the direction of the site PI.  The local study keys linking the PHI to the data will be 
destroyed upon study closure.  De-identified data may be shared with the sponsor at their request. 
 
      B5.6  Managing Data and/or Human Biological Specimens for Future Research 
 
N/A – This section is not applicable as we will not be creating a data repository. 
 
      B5.7  Devices, Drugs, Dietary Supplements, Nutritional Supplements, And Biologics 
 
                B5.7.1  Devices 
 

Protocol Title:  Clinical Assessment of Low Calcium In traUMa (CALCIUM) 
Date:  8 Feb 2022  
 
 
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                             5.7.1.1 FDA-approved device being used in this research according to the approved 
labeling 
 
N/A – This section is not applicable. 
 
                              5.7.1.2 FDA-approved device being used in this research in a manner other than its 
approved labeling 
 
N/A – This section is not applicable. 
 
 
 
      5.7.1.3 Any device not approved by the FDA 
 
N/A – This section is not applicable. 
 
                B5.7.2  Drugs 
 
                             B5.7.2.1 FDA-approved and used in accordance with the approved labeling 
 
N/A – This section is not applicable. 
 
                             B5.7.2.2 FDA-approved and used in a manner not in accordance with its approved 
labeling 
 
N/A – This section is not applicable.      
 
                             B5.7.2.3 Any drug not approved by the FDA 
 
N/A – This section is not applicable.     
 
B8  Statistical Analysis 
 
          B5.8.1  Sample Size Estimation 
 
Based on prior estimates of hypocalcemia in trauma patients, the percentage of patients exposed can range 
between 50% to 55%.7,11  Based on this estimate of exposure to hypocalcemia, with an alpha of 0.05, and 
power of 80%, we estimate a total sample size requirement of 391 trauma patients that would need to be 
enrolled in the study.  Additional data captured as part of the routine healthcare operations that do not meet the 
above primary inclusion criteria will not count towards the sample size estimate of 391. 
 

 
 
 
 
B5.8.2  Data analysis 
 
We will primarily use descriptive and inferential statistics along with regression modeling.  Significance for 
results will be established when p-values are less than 0.05.  Categorical Data will be summarized using 
percentages and Chi-Squared tests or Fisher’s exact test where appropriate. Means and standard deviations 
or medians and interquartile ranges will be used as summary statistics for continuous variables, and they will 
be analyzed using Student’s t-test and ANOVA or Wilcoxon’s Test where appropriate. Data may be log-
transformed for normalization.  We will use Discrete-Time (eg. Complementary Log-Log) or Cox Proportional 
Hazards to assess associations between baseline and time-dependent covariates with time-to-hypocalcemia.  

Protocol Title:  Clinical Assessment of Low Calcium In traUMa (CALCIUM) 
Date:  8 Feb 2022  
 
 
HQ USAMRDC IRB Research Protocol Template v_21 SEPTEMBER 2020 
 
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Treatment variables, such as blood product transfusion, will be measured at time-dependent covariates.  Cox 
Proportional Hazards models will be used to assess associations between baseline covariates, time-dependent 
covariates (treatments and hypocalcemia), and mortality. We will analyze data using relevant statistical 
software including SAS (v9.4, Cary, North Carolina), JMP Statistical Discovery (v15, Cary, North Carolina), 
Microsoft Excel (v360, Redmond, Washington).  
 
 
 
SECTION C:  HUMAN RESEARCH PROTECTIONS 
 
C1.  RECRUITMENT AND CONSENT 
 
       C1.1  Identification and Selection of Subjects 
 
Our study will result in minimal additional blood draw beyond the usual clinical blood draws.  Subjects will be 
identified by the clinical staff based on the trauma activation protocols.  Our primary outcome will be based on 
the “a priori” inclusion criteria as outlined above. 
 
       C1.2  Recruitment Process 
 
All clinical care will remain at the direction of the attending clinician.  All blood draws will occur by way of the 
clinical personnel. 
 
       C1.3  Eligibility 
 
Eligibility will be determined by the clinical staff who make a decision on when a patient should be a trauma 
activation. 
 
       C1.4  Consent Process 
 
We are seeking a waiver of consent as detailed below. 
 
                 C1.4.1  Research involving subjects with cognitive impairment or who lack capacity to 
provide informed consent 
 
N/A – This section is not applicable to our protocol.  We are seeking a waiver of consent. 
 
                 C1.4.2  Research involving non-English speaking subjects 
 
N/A – This section is not applicable to our protocol.  We will not be interacting with any patients that do not 
speak English. 
 
                 C1.4.3  Research involving a waiver of the requirement to obtain informed consent OR 
alteration of the elements of informed consent 
 
32 CFR 219.111(d) An IRB may approve a consent procedure which does not include, or which alters, some or 
all of the elements of informed consent set forth in this section or waive the requirements to obtain informed 
consent provided the IRB finds four criteria are met as outlined below.   
 
(1) The research involves no more than minimal risk to the subjects; and 
 
Our research involves no more than minimal risk of the subjects.  The research primarily involves 2 components.  
First, it involves obtaining a small amount of blood in an additional tube during their initial trauma evaluation and 
resuscitation.  These are routine blood draws using standard clinical tubes and therefore considered no more than 

minimal risk.(URL: https://www.nimh.nih.gov/funding/clinical-research/nimh-guidance-on-risk-based-
monitoring.shtml, last accessed 20 March 2021)  As a point of reference, the current BAMC trauma admissions 
has blood draws occurring at least every 6 hours, and thus our protocol only represents a marginal increase the 
amount of blood drawn by <5mL total.  Other sites have protocols that generally mirror that of BAMC.  Moreover, 
critically injured patients frequently have additional blood draws ordered beyond the current every 6 hours, and 
thus in the sickest of trauma patients they will almost certainly have blood draws that exceed what we are 
requesting as part of routine clinical care (e.g. serial lactate testing, serial coagulation studies, etc.).   
 
Second, it involves accessing the medical records.  We are seeking to perform observational data extraction from 
their medical records that were gathered as part of their routine healthcare operations.  Extraction of the data from 
the medical records falls under exemption category #4 and therefore we believe it to be low risk. 
 
(2) The waiver or alteration will not adversely affect the rights and welfare of the subjects; 
 
The presence of our study will not alter their medical care in any anticipated way.  The blood draws are already 
happening as part of their routine trauma evaluation and resuscitation.  The additional tubes that we are drawing 
for this study are not expected to have any notable physiologic consequences given that critically injured trauma 
patients are subjected to blood draws every 6 hours and  frequently after any major trauma for the first 24 hours 
post injury.  All the medical care will be at the direction of the attending clinician without any involvement or 
interference by with the study staff.  The request for a consent waiver will ensure that no delays in care occur due 
to the consent process. 
 
(3) The research could not practicably be carried out without the waiver or alteration;  
 
Trauma patients brought in by way of trauma activation are frequently critically injured and in need of immediate 
resuscitation.  It would be impractical and unsafe to delay their medical care for the purposes of obtaining consent.  
Patients are not normally consented for blood draws as part of the trauma resuscitation process.  Introducing a 
consent process as part of the study would hinder their medical care and potentially result in deleterious outcomes 
as a result of the delays in care.  The use of a legally authorized representative would delay enrollment in the 
study in which the primary outcome is  calcium measurement on arrival. 
 
(4) Whenever appropriate, the subjects will be provided with additional pertinent information after participation. 
 
As previous stated, it is expected that many patients brought in as trauma patients may not survive.  Of those 
that survive, many will not regain consciousness or the ability to participate in the consent process for a 
prolonged period.  As such, it would be impractical to attempt to provide them information afterwards when 
they are still in critical condition.  Additionally, by the time they can participate in the consent process their care 
will have been completed.  Moreover, given that many of the blood draws represent routine clinical care, it 
would be inappropriate to attempt to consent them for routine clinical care that has already been delivered. 
 
                 C1.4.4  Research involving a waiver of the requirement for investigator to obtain a signed 
consent form 
 
Our research involves no more than minimal risk of the subjects.  The research primarily involves 2 components.  
First, it involves obtaining a small amount of blood in additional tubes during their initial trauma evaluation and 
resuscitation.  These are routine blood draws using standard clinical tubes and therefore considered no more than 
minimal risk.(URL: https://www.nimh.nih.gov/funding/clinical-research/nimh-guidance-on-risk-based-
monitoring.shtml, last accessed 20 March 2021)  Second, it involves accessing the medical records.  We are 
seeking to perform observational data extraction from their medical records that were gathered as part of their 
routine healthcare operations.  Extraction of the data from the medical records falls under 32 CFR 219 exemption 
category #4 and therefore we believe it to be low risk. 
 
                 C1.4.5  Waivers of assent or parental permission when the research involves children 
 
N/A – This section is not applicable. 
 

Protocol Title:  Clinical Assessment of Low Calcium In traUMa (CALCIUM) 
Date:  8 Feb 2022  
 
 
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                 C1.4.6  Research involving data collection for the USAMRDC Volunteer Registry Database 
 
N/A – This section is not applicable. 
 
C2.  COMPENSATION FOR PARTICIPATION 
 
Subjects will not be compensated.     
 
C3.  WITHDRAWAL FROM RESEARCH PARTICIPATION 
 
We do not anticipate any subjects or withdrawal from the research participation given that the subject would 
likely not know about the additional blood draws since we are requesting both a waiver of consent and a 
HIPAA waiver.  In the event a subject does request withdrawal for participation, we will not collect any 
additional clinical data from their medical records for this study.  All data captured up until that point including 
their blood tests will be used for research.   
 
C4.  PRIVACY FOR SUBJECTS 
 
We are not intending any direct interaction between study team members and subjects for the study.  Clinical 
personnel may interact with the subjects only for routine healthcare and will not be for the purposes of this 
study.  As we are requesting a HIPAA waiver and consent waiver, additional privacy for recruitment and such 
will not be required and standard measures for privacy will be maintained per usual methods for healthcare 
delivery.  The data will be maintained and stored as outlined. 
 
C5.  CONFIDENTIALITY PROCEDURES FOR RESEARCH RECORDS, DATA, HUMAN BIOLOGICAL 
SPECIMENS 
 
Data will be stored on computer systems that are approved by local site network administrators.  We will collect 
only the minimal amount of data necessary for the conduct of the study.  Data will be de-identified upon study 
closure.  No identifiable data will be shared across the sites.  Subjects will be assigned a study identifier 
number by a study team member which will allow for easy removal of PHI after study completion. PHI (source 
documents) will be maintained at the participating sites for the purpose of data verification.  The DCC utilizes 
the clinical research data management tool REDCap to manage clinical research studies.  REDCap Data 
Management which is a full clinical research electronic data capture application, compliant with HIPAA and 21 
CFR Part 11 regulations for data storage.  REDCap will serve as the primary method for sharing data across 
sites.  Other methods will include the use of official email addresses and/or DOD SAFE.  Local site data will be 
stored based on institutional requirements and at the direction of the site PI.  The local study keys linking the 
PHI to the data will be destroyed upon study closure.  De-identified data may be shared with the sponsor at 
their request.  All data will be de-identified upon protocol closure.  The overall de-identified data will be stored 
at the direction of the overall PI for data verification and/or related subanalyses indefinitely.  Local datasets will 
be managed based on institutional policies. 
 
C6.  RISKS OF HARM, MEASURES TO REDUCE THE RISKS OF HARM, AND BENEFITS OF 
PARTICIPATION 
 
       C6.1 Risks of Harm 
 
We do not anticipate any additional risks of harm associated with the study beyond that of routine clinical care 
and the potential risk for a data breech.  The subjects of the study are already undergoing routine clinical blood 
draws, and we are seeking an additional tube of blood in very small amount that is unlikely to have any 
physiologic effect.(URL: https://www.nimh.nih.gov/funding/clinical-research/nimh-guidance-on-risk-based-
monitoring.shtml, last accessed 20 March 2021)  The primary risk comes in the form of data breech, which we 
will utilize confidentiality measures as outlined in this protocol. 
 

      C6.2  Incidental or Unexpected Findings 
 
We do not anticipate any incidental or expected findings because of the study.  We are seeking patients that 
are already having their blood drawn as part of routine clinical care.  The only addition as part of the study is 
that we are drawing a small amount of blood beyond that of the usual amount drawn for routine clinical care.  
Blood draws are a part of routine clinical care.  The data extracted from the medical records are all part of 
routine clinical care, and we are not getting any additional data beyond that of what is seen in the EMR system.  
As such, all the EMR data is available to the clinical team in real time. 
 
      C6.3  Potential Benefits 
 
The study subjects will experience additional monitoring of their calcium as a result of the study.  Moreover, 
their participation may optimize future clinical practice of trauma management of hemorrhage.  Since trauma 
patients often experience future trauma (e.g. repeated visits for firearm wounds, interpersonal violence, etc.) it 
is plausible that they may benefit in the future from the science learned from this study. 
 
C7.  DATA AND SAFETY MONITORING 
 
       C7.1 Monitoring 
 
Subject records may be inspected by the USAISR Quality Management and Research Regulatory Compliance 
Divisions, HQ USAMRDC IRB, the USAMRDC Army Human Research Protection Office and other applicable 
regulatory authorities responsible for human subject’s protections and the integrity of the data. 
 
       C7.2 Research Monitor (as applicable) 
 
N/A 
 
C8.  REPORTABLE EVENTS 
 
       C8.1  Expected adverse events 
 
The only expected adverse events related to the study are related to that of the blood draw.  Common adverse 
events include pain during the procedure which will be minor, minor bleeding at the site, or development of a 
hematoma.  More significant risks include the possibility of a foreign body retained or infection.  We do not 
anticipate these events would be common.  Since the blood draws are occurring as part of the clinical care, the 
additional draws for the study is unlikely to alter that risk.  Patients that are admitted to the hospital frequently 
have blood draws several times a day, and thus the risk associated with drawing a small amount of extra blood 
is negligible. 
 
       C8.2  Unexpected adverse events and unanticipated problems 
 
We do not anticipate unexpected adverse events as blood draws are routine clinical events.  Any adverse 
event that occurs as part of the blood draw is the same as that of routine clinical care.  If an adverse event 
occurs specific to the research, the adverse event will be reported to the PI or a member of the study team.  If 
the event is determined to be related to the research the PI will follow standard site-specific reporting 
procedures for reporting the event to the regulatory office. All unanticipated problems involving risk to subjects 
or others, and serious adverse events that are unexpected and determined to be at least possibly or definitely 
related to study participation, will be reported to the HQ USAMRDC IRB within five working days by phone 
(301-619-6240), or by e-mail (usarmy.detrick.medcom-usamrmc.other.irb-office@mail.mil) 
 
       C8.3  Adverse device effects 
 
N/A – This section is not applicable. 
 
       C8.4  FDA-regulated research under IND and IDE 

Protocol Title:  Clinical Assessment of Low Calcium In traUMa (CALCIUM) 
Date:  8 Feb 2022  
 
 
HQ USAMRDC IRB Research Protocol Template v_21 SEPTEMBER 2020 
 
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N/A – This section is not applicable.      
 
 
 
SECTION D:  REFERENCES 
 
1. 
Kyle T, Greaves I, Beynon A, Whittaker V, Brewer M, Smith J. Ionised calcium levels in major trauma patients 
who received blood en route to a military medical treatment facility. Emerg Med J. 2018;35(3):176-179. 
2. 
Wray JP, Bridwell RE, Schauer SG, et al. The diamond of death: Hypocalcemia in trauma and resuscitation. The 
American Journal of Emergency Medicine. 2020. 
3. 
Lim F, Chen LL, Borski D. Managing hypocalcemia in massive blood transfusion. Nursing2020. 2017;47(5):26-32. 
4. 
Altunbaş H, Balci MK, Yazicioğlu G, Semiz E, Ozbilim G, Karayalçin U. Hypocalcemic cardiomyopathy due to 
untreated hypoparathyroidism. Horm Res. 2003;59(4):201-204. 
5. 
Kudoh C, Tanaka S, Marusaki S, et al. Hypocalcemic cardiomyopathy in a patient with idiopathic 
hypoparathyroidism. Intern Med. 1992;31(4):561-568. 
6. 
Wrong-Patient Blood Transfusion Error: Leveraging Technology to Overcome Human Error in Intraoperative 
Blood Component Administration. Joint Commission journal on quality and patient safety. 2019;45(3):190-198. 
7. 
Conner JR, Benavides LC, Shackelford SA, et al. Hypocalcemia in Military Casualties From Point of Injury to 
Surgical Teams in Afghanistan. Mil Med. 2021;186(Suppl 1):300-304. 
8. 
Giancarelli A, Birrer KL, Alban RF, Hobbs BP, Liu-DeRyke X. Hypocalcemia in trauma patients receiving massive 
transfusion. J Surg Res. 2016;202(1):182-187. 
9. 
Vivien B, Langeron O, Morell E, et al. Early hypocalcemia in severe trauma. Crit Care Med. 2005;33(9):1946-
1952. 
10. 
Zivin JR, Gooley T, Zager RA, Ryan MJ. Hypocalcemia: a pervasive metabolic abnormality in the critically ill. Am 
J Kidney Dis. 2001;37(4):689-698. 
11. 
Webster S, Todd S, Redhead J, Wright C. Ionised calcium levels in major trauma patients who received blood in 
the Emergency Department. Emerg Med J. 2016;33(8):569-572. 
12. 
Ho KM, Leonard AD. Concentration-dependent effect of hypocalcaemia on mortality of patients with critical 
bleeding requiring massive transfusion: a cohort study. Anaesth Intensive Care. 2011;39(1):46-54. 
13. 
Magnotti LJ, Bradburn EH, Webb DL, et al. Admission ionized calcium levels predict the need for multiple 
transfusions: a prospective study of 591 critically ill trauma patients. J Trauma. 2011;70(2):391-395; discussion 
395-397. 
14. 
MacKay EJ, Stubna MD, Holena DN, et al. Abnormal Calcium Levels During Trauma Resuscitation Are 
Associated With Increased Mortality, Increased Blood Product Use, and Greater Hospital Resource Consumption: 
A Pilot Investigation. Anesth Analg. 2017;125(3):895-901. 
15. 
Cherry RA, Bradburn E, Carney DE, Shaffer ML, Gabbay RA, Cooney RN. Do early ionized calcium levels really 
matter in trauma patients? J Trauma. 2006;61(4):774-779. 
16. 
Cardenas JC, Wade CE, Holcomb JB. Mechanisms of trauma-induced coagulopathy. Curr Opin Hematol. 
2014;21(5):404-409. 
17. 
Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy 
of trauma. J Trauma. 2007;62(2):307-310. 
18. 
Cohen MJ, Kutcher M, Redick B, et al. Clinical and mechanistic drivers of acute traumatic coagulopathy. J 
Trauma Acute Care Surg. 2013;75(1 Suppl 1):S40-47. 
19. 
Meledeo MA, Herzig MC, Bynum JA, et al. Acute traumatic coagulopathy: The elephant in a room of blind 
scientists. J Trauma Acute Care Surg. 2017;82(6S Suppl 1):S33-s40. 
20. 
Shackelford SA, Del Junco DJ, Powell-Dunford N, et al. Association of Prehospital Blood Product Transfusion 
During Medical Evacuation of Combat Casualties in Afghanistan With Acute and 30-Day Survival. JAMA. 
2017;318(16):1581-1591. 
21. 
Keenan S, Riesberg JC. Prolonged Field Care: Beyond the "Golden Hour". Wilderness Environ Med. 
2017;28(2s):S135-s139. 
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Cap AP, Pidcoke HF, DePasquale M, et al. Blood far forward: Time to get moving! J Trauma Acute Care Surg. 
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Rosenberg H, Cheung WJ. Intraosseous access. CMAJ. 2013;185(5):E238-E238. 
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Orlowski JP, Porembka DT, Gallagher JM, Lockrem JD, VanLente F. Comparison study of intraosseous, central 
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55. 

 
 
 
SECTION E:  ABBREVIATIONS AND ACRONYMS 
 
BAMC = Brooke Army Medical Center 
CDMRP = Congressionally Directed Medical Research Program 
CPG = Clinical practice guideline 
CPR = Cardiopulmonary resuscitation 
CRADA = Cooperative research and development agreement 
DSA = Data sharing agreement 
EFIC = Exception from informed consent 
iCa = ionized calcium 
IO = Intraosseous 
IV = Intravenous 
JTS = Joint Trauma System 
MT = Massive transfusion 
TCCC = Tactical Combat Casualty Care 
SOCOM = Special Operations Command 
STaRC = Strategic Trauma Readiness Center of San Antonio 
 
 
 
SECTION F: DoD PRIVACY RULE AND PROTECTED HEALTH INFORMATION (HIPAA) 
 
 
NA – institution is not a covered entity 
 
 
NA – will not use or disclose protected health information 
 
 
HIPAA authorization will be obtained  
 
X An application for waiver/alteration of HIPAA authorization will be submitted 
 
 

Protocol Title:  Clinical Assessment of Low Calcium In traUMa (CALCIUM) 
Date:  8 Feb 2022  
 
 
HQ USAMRDC IRB Research Protocol Template v_21 SEPTEMBER 2020 
 
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APPENDIX – Sample trauma activation criteria from BAMC