Impact of a calcium replacement protocol during massive transfusion in trauma patients at a level 2 trauma center

Article Identification

Article Title: Impact of a Calcium Replacement Protocol During Massive Transfusion in Trauma Patients at a Level 2 Trauma Center

Authors:

• Yana Shandaliy, PharmD
• Kirsten Busey, PharmD, BCCCP
• Nicholas Scaturo, PharmD

Journal Name: American Journal of Health-System Pharmacy (AJHP)

Year: 2024

Type of Study: Retrospective, single-center, pre-post study

DOI/PMID: 10.1093/ajhp/zxae099

Quick Reference Summary

• Implementation of a standardized calcium replacement protocol during massive transfusion protocols (MTP) significantly reduced the incidence of hypocalcemia in trauma patients from 95.2% to 63% within 24 hours (P = 0.006).
• Postprotocol patients received calcium more promptly (median 5.5 minutes vs. 43 minutes, P < 0.0001) and in higher doses (40.8 mEq vs. 27.2 mEq, P = 0.005), without increasing adverse events or mortality.

Core Clinical Question

Does the implementation of a standardized calcium replacement protocol reduce the incidence of hypocalcemia in trauma patients undergoing massive transfusion compared to reactive calcium administration?

Background

Disease/Condition Overview:

• Uncontrolled Hemorrhage in Trauma: Leading cause of death in young adults, progressing to hemorrhagic shock and a “lethal triad” of hypothermia, acidosis, and coagulopathy.

Prior Data on the Topic:

• Hypocalcemia occurs in 85-97% of trauma patients receiving massive transfusions with reactive calcium replacement strategies.
• Established association between hypocalcemia and increased mortality in trauma patients.

Current Standard of Care:

• Reactive calcium administration based on frequent monitoring of ionized calcium (iCa) levels during resuscitation.

Knowledge Gaps Addressed by Study:

• Limited research on proactive, standardized calcium replacement protocols during MTP.

Study Rationale:

• To evaluate whether a protocolized approach can more effectively prevent hypocalcemia compared to reactive strategies, potentially improving patient outcomes.

Methods Summary

Study Design: Retrospective, single-center, before-and-after-intervention cohort study.

Setting and Time Period: Sarasota Memorial Hospital, a 901-bed community teaching hospital and level 2 trauma center, from January 2017 to October 2022.

Population Characteristics:

• Adult trauma patients requiring MTP and receiving at least one round of product transfusion.

Inclusion/Exclusion Criteria:

• Included: Adults receiving MTP for trauma with at least one transfusion round.
• Excluded: Non-trauma MTP indications, unavailable iCa levels, transfer to higher care within 4 hours.

Intervention Details:

• Standardized calcium replacement protocol initiated in December 2020:
  • Initial 2 g of calcium chloride IV push.
  • Additional 1 g calcium chloride IV push per subsequent MTP round.

Control/Comparison Group Details:

• Preprotocol group: Reactive calcium administration based on physician discretion.
• Postprotocol group: Protocolized calcium replacement following the standardized protocol.

Primary and Secondary Outcomes:

• Primary Outcome: Incidence of hypocalcemia (iCa <1.1 mg/dL) within 24 hours of MTP initiation.
• Secondary Outcomes: Incidence of severe hypocalcemia (iCa <0.9 mg/dL), time to first calcium dose, total calcium administered (mEq), resolution of hypocalcemia within 24 hours, hypercalcemia, protocol adherence, adverse events, and mortality.

Statistical Analysis Approach:

• Continuous variables: Mean (SD) or median (IQR), compared using Student’s t-test or Mann-Whitney U test.
• Categorical variables: Percentages, compared using χ² test or Fisher’s exact test.
• Significance threshold: P < 0.05.

Sample Size Calculations: Not performed (exploratory study).

Ethics and Funding Information:

• Institutional Review Board–approved.
• No conflicts of interest reported.

Detailed Results

Participant Flow and Demographics

• Total Screened: 81
• Included: 67 (21 preprotocol, 46 postprotocol)
• Excluded: 14 (primarily due to unavailable iCa levels)
• Baseline Characteristics: Similar between groups (age, sex, ISS, trauma type, anticoagulant use).

Primary Outcome Results

• Hypocalcemia within 24 Hours:
  • Preprotocol: 95.2% (20/21)
  • Postprotocol: 63% (29/46)
  • Statistical Significance: P = 0.006

Secondary Outcome Results

• Severe Hypocalcemia within 24 Hours:
  • Preprotocol: 62% (13/21)
  • Postprotocol: 39.1% (18/46)
  • P = 0.083 (Not statistically significant)
• Time to First Calcium Dose:
  • Preprotocol: Median 43 minutes (IQR 22.8-73)
  • Postprotocol: Median 5.5 minutes (IQR 0-21)
  • Statistical Significance: P < 0.0001
• Total Calcium Administered within 4 Hours:
  • Preprotocol: Median 27.2 mEq (IQR 14-32.2)
  • Postprotocol: Median 40.8 mEq (IQR 27.2-54.4)
  • Statistical Significance: P = 0.005
• Resolution of Hypocalcemia within 24 Hours:
  • Preprotocol: 65% (13/20)
  • Postprotocol: 89.6% (26/29)
  • Statistical Significance: P = 0.035
• Hypercalcemia within 24 Hours:
  • Preprotocol: 67% (14/21)
  • Postprotocol: 76.1% (35/46)
  • P = 0.55 (Not statistically significant)
• Adverse Events/Safety Data:
  • No adverse events related to calcium administration in the postprotocol group.
• Adherence to Protocol:
  • Postprotocol group adherence: 37% (17/46)
• Mortality:
  • Preprotocol: 52.4% (11/21)
  • Postprotocol: 30.4% (14/46)
  • P = 0.085 (Not statistically significant)

Results Tables

Outcome	Intervention Group	Control Group	Difference (95% CI)	P-value
Hypocalcemia within 24 hours	63% (29/46)	95.2% (20/21)	-32.2%	0.006
Severe hypocalcemia within 24h	39.1% (18/46)	62% (13/21)	-22.9%	0.083
Time to first calcium dose (min)	5.5 (0-21)	43 (22.8-73)	-37.5	<0.0001
Total calcium given within 4h (mEq)	40.8 (27.2-54.4)	27.2 (14-32.2)	+13.6	0.005
Resolution of hypocalcemia within 24h	89.6% (26/29)	65% (13/20)	+24.6%	0.035
Hypercalcemia within 24h	76.1% (35/46)	67% (14/21)	+9.1%	0.55
Mortality	30.4% (14/46)	52.4% (11/21)	-22%	0.085

Authors' Conclusions

• Primary Conclusions:
  • A standardized calcium replacement protocol significantly reduced the incidence of hypocalcemia in trauma patients undergoing MTP.
• Interpretation of Results:
  • Proactive calcium administration led to earlier and increased calcium dosing without elevating adverse events.
• Clinical Implications Stated by Authors:
  • Implementing a calcium replacement protocol can enhance calcium management during massive transfusions, potentially improving patient outcomes by reducing hypocalcemia.
• Future Research Recommendations:
  • Further studies with larger sample sizes and in different institutional settings to validate findings and assess long-term outcomes.

Critical Analysis

A. Strengths:

Methodological Strengths:

• Clear definition of hypocalcemia and standardized intervention protocol.
• Use of a before-and-after study design to assess protocol impact.

Internal Validity Considerations:

• Comparable baseline characteristics between pre- and postprotocol groups.
• Significant reduction in primary outcome suggests a strong association.

External Validity Considerations:

• Conducted in a level 2 trauma center, enhancing applicability to similar settings.

B. Limitations:

Study Design Limitations:

• Retrospective, single-center design may introduce bias.

Potential Biases:

• Lack of randomization; potential confounders not controlled.

Generalizability Issues:

• Protocol specific to institutional blood product ratios; may not apply to other settings.

Statistical Limitations:

• Small sample size; not powered to detect differences in some secondary outcomes like mortality.

Missing Data Handling:

• Exclusion of patients without available iCa levels; possible selection bias.

C. Literature Context

A. Previous Studies and Meta-Analyses:

• Giancarelli et al.
  • Found higher mortality in trauma patients with severe hypocalcemia (49% vs. 24%) [J Surg Res. 2016;202(1):182-187.]
• MacKay et al.
  • Demonstrated extreme hypocalcemia associated with 60% mortality vs. 4% in those without [Anesth Analg. 2017;125(3):895-901.]
• Ward et al.
  • Showed hypocalcemia resolution linked to higher survival rates [J Crit Care. 2004;19(1):54-64.]

B. Contrasting Methodological Quality:

• Current study employed a pre-post design without randomization, differing from controlled trials in previous studies.

C. Comparisons with Guidelines:

• Advanced Trauma Life Support (ATLS) 2021:
  • Generally does not recommend routine calcium supplementation for most blood product recipients.

D. This Trial's Contribution:

• Provides evidence supporting proactive calcium supplementation protocols, challenging the standard reactive approach suggested by ATLS guidelines [Am J Emerg Med. 2021;41:104-109.]
• Confirms associations between hypocalcemia and mortality, reinforcing findings from Giancarelli et al. and MacKay et al.

Clinical Application

• Findings Change Current Practice:
  • Shift from reactive to proactive calcium administration during MTP can effectively reduce hypocalcemia incidence.
• Applicable Patient Populations/Scenarios:
  • Trauma patients undergoing massive transfusions requiring MTP, especially in high-acuity settings where rapid intervention is critical.
• Implementation Considerations:
  • Potential need for staff training and protocol adherence mechanisms to ensure effective calcium administration.
• Integration with Existing Evidence:
  • Aligns with emerging literature advocating for standardized calcium management to improve resuscitation outcomes.

How to Use This Info in Practice

Implement a standardized calcium replacement protocol during massive transfusions to proactively prevent hypocalcemia in trauma patients, enhancing patient outcomes without increasing adverse events.

Notes for Clarity

• Statistical Significance: Bolded where applicable.
• Confidence Intervals: Included in results tables where available.
• Conflicts of Interest: None declared by authors.
• Areas of Uncertainty: Mortality impact not statistically significant; protocol adherence low (37%).
• Funding Sources: Not specified; authors declared no conflicts of interest.
• Number Needed to Treat/Harm: Not provided.
• Post-hoc Analyses: Not mentioned.
• Funding Sources: Not specified.