Incidence of admission ionised hypocalcaemia in paediatric major trauma: protocol for a systematic review and meta-analysis

Introduction Hypocalcaemia forms part of the ‘diamond of death’ in major trauma, alongside hypothermia, acidosis and coagulopathy. In adults, admission hypocalcaemia prior to transfusion is associated with increased mortality, increased blood transfusion requirements and coagulopathy. Data on paediatric major trauma patients are limited. This systematic review and meta-analysis aims to describe and synthesise the available evidence relevant to paediatric trauma, admission hypocalcaemia and outcome. Methods and analysis The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines will be used to construct this review. A planned literature search for articles in the English language will be conducted from inception to the date of searches using MEDLINE on the EBSCO platform, CINAHL on the EBSCO platform and Embase on the Ovid platform. The grey literature will also be searched. Both title and abstract screening and full-text screening will be done by two reviewers, with an adjudicating third reviewer. Heterogeneity will be assessed using the I2 test, and the risk of bias will be assessed using the ROBINS-I tool. A meta-analysis will be undertaken using ratio measures (OR) and mean differences for measures of effect. When possible, the estimate of effect will be presented along with a CI and a p value. Ethical review and dissemination Ethical review is not required, as no original data will be collected. Results will be disseminated through peer-reviewed publications and at academic conferences. PROSPERO registration number CRD42023425172.


BACKGROUND
Major trauma is one of the leading causes of death in children in the UK. 1 2 A key cause of potentially survivable death from trauma is haemorrhage. 3Uncontrollable haemorrhage may be related to the injury mechanism itself or as a result of trauma-induced coagulopathy (TIC). 4TIC is common, occurring in at least a quarter of haemorrhagic deaths, and has a number of proposed pathophysiological mechanisms that generally involve injury and shock, provoking an immunological, endothelial and platelet response. 46][7] More recently, biochemical abnormalities such as hyperkalaemia and hypocalcaemia have been recognised to contribute to deaths from haemorrhage. 6 8In particular, calcium's role is important for clot formation, vascular tone and cardiac contractility, with hypocalcaemia contributing to coagulopathy and cardiovascular decompensation. 5 6s such, the 'lethal triad' is now considered a 'diamond of death' with hypocalcaemia forming a key component of this deleterious combination. 5 6The early recognition and treatment of these components in the 'diamond of death' are essential for trauma resuscitation. 5 7 9

Rationale
The free form of calcium (ionised calcium (iCa)) is the physiologically relevant component of calcium in the blood. 10iCa is measured on blood gases, which are often taken on arrival for major trauma patients, and there is good agreement between arterial and venous measurements. 11Blood

STRENGTHS AND LIMITATIONS OF THIS STUDY
⇒ The protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines.⇒ This is a novel review that addresses an area of uncertainty in the current evidence base surrounding paediatric major trauma through a systematic review and meta-analysis of published data and the grey literature.⇒ The review methodology is at risk of limitation by publication bias.Where appropriate, this will be assessed using funnel plots.
Open access gas measurements will also record the pH and lactate, which can affect the availability of iCa. 12 13 Ionised hypocalcaemia (iHypoCa) in major trauma patients is multifactorial. 5-7 14The infusion of citrated blood products is a recognised cause of hypocalcaemia in trauma due to calcium chelation with citrate. 6 156][7] A systematic review and meta-analysis, which included a total of 1213 major trauma patients, 18 years or older, with a documented iCa level on admission, explored the incidence and outcomes associated with admission iHypoCa. 20Studies that involved patients whose calcium concentration may have been confounded by prior blood transfusions were excluded. 207][18][19][20] Evidence of admission iHypoCa and the association with adverse outcomes in adult trauma patients has led to the early measurement and replacement of calcium being recommended in adult trauma 21 22 Paediatric major trauma data are limited.Given the different physiology of children compared with adults, children may be more vulnerable to the effects of iHypoCa, and the results of studies involving adult major trauma patients may not be able to be extrapolated to a paediatric cohort. 23A search of PROSPERO did not find any similar planned systematic reviews or meta-analyses.[26][27]

Aims
The primary aim of this systematic review and metaanalysis is to explore the limited evidence related to the incidence of admission iHypoCa in paediatric major trauma patients.The review also aims to explore whether admission iHypoCa, compared with normocalcaemia, is associated with adverse clinical outcomes.

Eligibility criteria
This proposed systematic review and meta-analysis will explore the incidence of iHypoCa in paediatric (<18 years old) major trauma patients (Injury Severity Score (ISS) >15) and explore whether admission iHypoCa (iCa <1.16 mmol/L), compared with normocalcaemia (iCa ≥1.16 mmol/L) is associated with a greater incidence of adverse outcomes. 125][26] The Population, Intervention, Comparison, Outcomes and Study Design (PICOS) eligibility criteria are detailed in table 1.

Information sources
A planned literature search for articles in the English language will be conducted from inception to the search date using MEDLINE on the EBSCO platform, CINAHL on the EBSCO platform and Embase on the Ovid platform.The reference lists of all included studies and the grey literature will also be searched.

Search strategy
The search strategy can be found in online supplemental tables 1-3.
The search will also involve checking reference lists of retrieved articles, conference abstracts and online study results.If the data are incomplete, then the corresponding authors will be contacted for additional information.

Study records
The search strategy will be undertaken by a trained librarian and information specialist.The combined abstracts from the search strategy will be independently screened by two reviewers to identify studies meeting inclusion criteria; any duplications will be removed manually.For abstracts meeting inclusion criteria, full texts will be retrieved and again independently reviewed against the inclusion and exclusion criteria by two reviewers and an adjudicating third reviewer.
A standardised data sheet (Microsoft Excel for Mac, V.16.72, 2023) will be used to extract data from included studies to facilitate data synthesis and assessment of quality and risk of bias.The extracted data will be independently verified by the second reviewer, and any discrepancies again be adjudicated by the third reviewer.

Outcomes and prioritisation
The primary outcome of this systematic review and metaanalysis is the overall incidence of admission iHypoCa.Secondary outcomes are the associations with physiological abnormalities and adverse outcomes.Physiological abnormalities are classified dichotomously as the presence of hypotension (based on age-specific APLS values) 30 or elevated SIPA (0-6 years: >1.22, 7-12 years: >1.00 and 13-16 years: >0.90), 31 32 hyperkalaemia (>5.5 mmol/L) 28 and hyperlactataemia (>2.0 mmol/L). 29dverse outcomes are classified dichotomously as the requirement for vasopressors, transfusion, activation of the major haemorrhage protocol or invasive (operative or interventional radiology) intervention in the first 24 hours and mortality within 30 days.Hospital LOS and PICU LOS in days are classified continuously.Ratio measures (OR) and mean differences will be used for measures of effect.When possible, the estimate of effect will be presented along with a CI and a p value.

Risk of bias
The risk of bias will be assessed for all included studies.For any randomised controlled trials, the Grading of Recommendations Assessment, Development and Evaluation methodology will be used, and for observational studies, the Risk Of Bias In Non-randomized Studies of Interventions tool will be used. 33 34he risk of publication bias will be assessed with funnel plots as appropriate. 35

Data synthesis
The data will be synthesised following Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines.Studies will be assessed clinically (PICO) and methodologically (study design, comparability, outcome ascertainment and risk of bias).Given that current evidence is likely to be limited, the minimum number of studies is two.][26][27] The I 2 test will be conducted to determine if the data are suitable for quantitative synthesis. 36eta-analysis of effect estimates is intended and will be displayed using a forest plot.If there is limited evidence for a prespecified comparison, then the haemodynamic instability and vasopressor PICO groups may be combined.Definitions of hypocalcaemia will also be combined if required, providing values are iCa<1.16mmol/L.Other elements are unlikely to be suitable as contingencies for a combination.If different effect measures are used, attempts will be made to transform the effect measures for meta-analysis.

Open access
A narrative synthesis and summary of effect measures (with the use of box-and-whisker plots) will be conducted if heterogeneity is deemed too substantial across studies to allow for meaningful meta-analysis or if there are major concerns about bias from the three reviewers.
Meta-analysis or narrative synthesis of elements will focus on the incidence of hypocalcaemia in paediatric trauma patients and the trend towards adverse outcomes.Subgroup analysis may be undertaken for severe iHypoCa (iCa<1.0mmol/L).
Patient and public involvement None.

ETHICS AND DISSEMINATION
Ethical review is not required, as no original data will be collected.Results will be disseminated through peerreviewed publications and at academic conferences.

Table 1
PICOS strategy for inclusion and exclusion Clinical trials (randomised and non-randomised), observational studies (cohort and case-controlled) case reports, case series and literature reviews.