Hemorrhage due to trauma is the leading cause of preventable death in children and adults,1 and is the most common cause of pediatric cardiac arrest during surgery.2 While Canadian pediatric event rates for trauma-associated transfusions (15%) or large-volume transfusions (3%) in the emergency department are similar to those in adults,3,4 their mortality rates are higher. The care for massively bleeding children is currently either extrapolated from adult literature or is based on biased results of single-centre retrospective or observational pediatric studies. As adult studies have reported improved patient outcomes following massive hemorrhage protocol (MHP) implementation,5 an opportunity exists to reduce the high mortality rates in children by standardizing a pediatric MHP.6
Pediatric-specific MHPs have been reported infrequently.6,7 A recent review found that only two-thirds of hospitals have adult MHPs and that their content was highly variable.8 Further, despite wide adoption of MHPs in most American pediatric centres,9 little is known about MHP adoption in Canadian pediatric hospitals as they are underrepresented in North American studies.6,9,10 Towards standardizing MHP activation in Ontario, the Ontario Regional Blood Coordinating Network (ORBCoN) sponsored the development of the first province-wide standardized adult and pediatric MHP in 2021.11
Given the need for and interest in pediatric MHPs,12,13 a survey of MHP activation criteria, content, and use in Canadian university-affiliated pediatric care centres was performed to inform a national standardized pediatric MHP. The objectives of this study were to describe the availability, content, and use of pediatric MHPs in Canadian university-affiliated pediatric centres and to compare them with each other and with current recommendations.
Methods
The Children’s Hospital of Eastern Ontario Research Institute ethics board waived the need for ethics approval. Transfusion medicine (TM) medical directors at 18 Canadian university-affiliated pediatric centres were invited to complete an electronic survey and provide hospital documents related to pediatric MHPs. We sent the initial request in May 2020 and followed up a maximum of three times.
The survey design included three sections with questions related to: 1) hospital demographics, 2) MHP activation data within the last 12 months, and 3) a description of MHP-specific content according to protocol domains (N = 7) and their corresponding subdomains (N = 15) in Table 1.7, 8, 9–10,12,14 These domains/subdomains were established through our previous Delphi consensus publication,7 with the addition of “traumatic brain injury” resulting from a review of key pediatric references. The TM medical director answered the questions directly in sections 1 and 2. The hospital demographics and volume of pediatric services provided were completed by additional web-based resources (Canadian Institute for Health Information [CIHI], Pediatric Emergency Research Canada). Massive hemorrhage protocol activation details included the annual number of activations, indication for the activation (trauma, surgical, procedure-related, nonsurgical bleeding, other), and the age range of the children. For section 3, one author (V. A.) extracted MHP-specific information from source MHP documents (clinical and laboratory standard operating procedures and policies, algorithms, visual flowcharts, teaching/learning aids, audit tools, and compliance metrics). To ensure data quality, two authors (L. L. and K. M.) performed data extraction and entry from two random sites (error rate < 0.5%). Research Electronic Data Capture (REDCap®, Vanderbilt University, Nashville, TN, USA) was used to collect survey information (Electronic Supplementary Material [ESM] eAppendix).
Table 1. Massive hemorrhage protocol activation domains derived from the literature (“7 Ts”)11
Key protocol domains N = 7 | Subdomains N = 14 |
|---|
1. Trigger (and treat bleeding) | 1. Protocol name 2. Activation criteria |
2. Team (including telecommunication) | 3. Team member make-up and leadership 4. Transfusion medicine and other subspecialty support 5. Patient/family engagement and social support 6. Communication including relay of critical lab values 7. Patient transport and handover |
3. Tranexamic acid | See subdomain 12 |
4. Temperature (and traumatic brain injury) | 8. Temperature and traumatic brain injury management |
5. Testing | 9. Blood work and timing 10. Test availability |
6. Transfusion (and trouble) | 11. Transport containers 12. Blood component/product, fluid and drug dosing (including tranexamic acid) and targets and related complication management (e.g., hyperkalemia) |
7. Termination (and track performance) | 13. Quality assurance and improvement 14. Measures to ensure continuing medical education 15. Termination criteria |
Sample size and analyses
Given the number of TM medical directors associated with Canadian university-affiliated hospitals in 2020–2021 providing pediatric care (N = 18), a 100% response rate provided a 95% confidence interval (CI) half-width of 3%.15 Descriptive data are presented as proportions, means, or medians. We used hospital MHP type (dedicated pediatric, combined pediatric/obstetrical, combined pediatric/adult, or adult MHP) and pediatric service demographics, patient characteristics, and geographic location to analyze massive hemorrhage protocol-specific demographics. Results describing MHP-related domains and subdomains are limited to sites using pediatric-specific MHP content.
Results
Survey population and hospital demographics
Eighteen sites participated in the survey (100% response rate): nine free-standing pediatric hospitals, two combined maternal/pediatric hospitals, and seven adult/pediatric hospitals (ESM eTable 1). Of these 18 hospitals, only 13 had pediatric-specific MHP content, either as a dedicated pediatric MHP (n = 8), a combined pediatric/obstetrical MHP (n = 2), or a combined pediatric/adult MHP (n = 3). Sites with a pediatric-specific MHP were more likely to be a level 1 pediatric trauma centre and provide solid tumour resection and/or scoliosis repair services (ESM eTable 2).
Massive hemorrhage protocol-specific demographics
There were 70 MHP activations in children, including 62 in hospitals with a pediatric MHP. The mean (standard deviation [SD]) number of annual pediatric MHP activations across all hospitals was 3.9 (4.1). Children aged between 7 and 12 yr were the most likely to experience MHP activation (36%), with trauma the most likely (54%) indication (Table 2). Massive hemorrhage protocol activations in the operating room were least likely to occur in Ontario and the Atlantic provinces (see ESM eTable 3).
Table 2. Participant hospital pediatric massive hemorrhage protocol activation demographics, by pediatric or adult-based massive hemorrhage protocol used
MHP activation demographics | All hospitals N = 70b | Hospitals with pediatric MHPa N = 62b | Hospitals with adult MHP N = 8b |
|---|
Number of activations per hospital in previous 12 months, mean (SD)c | 3.9 (4.1) | 4.8 (4.5) | 1.6 (1.3) |
Approximate number of activations per age range, n/total N (%) | | | |
0–1 months | 5/70 (7%) | 4 (6%) | 1 (13%) |
1–12 months | 11/70 (16%) | 10 (16%) | 1 (13%) |
1–6 yr | 19/70 (27%) | 16 (26%) | 3 (38%) |
7–12 yr | 25/70 (36%) | 24 (39%) | 1 (13%) |
13–17 yr | 10/70 (14%) | 8 (13%) | 2 (25%) |
Approximate number of activations per indication, n/total N (%) | | | |
Trauma | 38/70 (54%) | 32 (52%) | 6 (75%) |
Surgical | 13/70 (19%) | 12 (19%) | 1 (13%) |
Procedure | 6/70 (9%) | 5 (8%) | 1 (13%) |
Nonsurgical | 12 (17%) | 12 (19%) | 0 (0%) |
Other | 1 (1%) | 1 (2%) | 0 (0%) |
aPediatric MHP includes dedicated pediatric (n = 8), combined pediatric/obstetrical (n = 2), and combined pediatric/adult (n = 3) MHPs
bTotal number of pediatric MHP activations per site category
cSix hospitals provided an estimated number of pediatric MHP activations over the last 12 months; 12 hospitals provided an actual number of activations over the last 12 months.
MHP = massive hemorrhage protocol; SD = standard deviation
Massive hemorrhage protocol details among sites with pediatric-specific content (N = 13)
Massive transfusion protocol (n = 7) or MHP (n = 4) typically defined a pediatric MHP.
Activation triggers
The most frequent criteria for MHP activation (used in 10/13 sites) was a prespecified amount of blood components anticipated or actually transfused (e.g., 40 mL·kg−1 or 2 units red blood cells) over time (e.g., within one to 24 hr.). A perceived rapid major uncontrolled blood loss (8/13) or an estimated or anticipated specific blood volume loss (e.g., > 40% total blood volume or 40 mL·kg−1) over a similar time frame (6/13) were also common activation trigger criteria, unlike vital signs (4/13), trauma or transfusion scores (2/13), physician’s discretion (2/13), or laboratory thresholds (1/13).
Massive hemorrhage protocol team composition
Team composition was rarely specifically described (3/13) but usually included a physician lead (n = 13), the TM laboratory (n = 13), a nurse lead (n = 10), a porter (n = 10), a TM physician/hematologist (n = 8), the core/hematology/coagulation laboratory (n = 8), and, less frequently, an anesthesiologist (n = 4), a surgical specialist (n = 1), an interventional radiologist (n = 1), or an on-call social worker/spiritual counsellor (n = 1).
Communication including protocol activation, blood component transport, and laboratory results
The MHP was activated by calling the TM laboratory directly (9/13), by an overhead hospital operator announcement (n = 3), or by computerized physician order entry (1/13). Most centres (10/13) used a porter that delivered blood components and/or blood samples, often dedicated for the duration of the MHP (7/10). The type of blood component transport container varied. Transport of red blood cells (RBCs) and of plasma in a cooler was specified in 11 and nine MHPs, respectively, but a specified validated cooler was uncommon. Platelet and cryoprecipitate transportation was specified in eight and four MHPs, respectively. Of these, the majority (6/8) recommended that platelets be transported separately at room temperature, while the recommendations for cryoprecipitate varied. Stored and thawed universal donor AB plasma units were immediately available for MHP activation at one site.
All MHPs referenced predefined component packs issued during MHP activation, which were differentiated into groups based on weight (n = 8), age (n = 1), or weight and age (n = 3) of the children. The most common number of component groupings was three (range, 1–5). Most sites (12/13) indicated ratio-based blood component content within the packs (see Table 3). The majority (8/13) of sites initially only issued RBCs. In addition to RBCs, the second pack commonly included plasma (n = 11) and platelets (n = 7). A few sites (n = 3) only provided platelets upon request, while most sites (n = 9) provided cryoprecipitate or fibrinogen concentrate on request.
Table 3. Sequential predefined container content for pediatric massive hemorrhage protocol, by anonymized hospitals
Pack number | Pack content | Anonymized hospitalsa N = 13 |
|---|
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 |
|---|
First pack | RBC | X | X | X | X | X | X | X | X | X | X | X | X | X |
Plasma | X | | | X | | | | | | X | X | | |
Platelet | | | | X | | | | | | X | | | |
Cryoprecipitate or fibrinogen concentrate | | | | | | | | X | | | | | |
Second pack | RBC | X | X | X | X | X | | X | X | X | | X | X | X |
Plasma | X | X | X | X | X | | X | X | X | | X | X | X |
Platelet | X | X | X | | X | | | X | | | X | X | |
Cryoprecipitate or fibrinogen concentrate | | | | | | | | | | | | | |
Third pack | RBC | X | X | X | X | X | | X | | X | | | X | |
Plasma | X | X | X | X | X | | X | | X | | | X | |
Platelet | X | | | X | X | | | | X | | | | |
Cryoprecipitate or fibrinogen concentrate | | | | | | | X | | X | | | X | |
Fourth pack | RBC | X | X | X | X | X | | X | | X | | | X | |
Plasma | X | X | X | X | X | | X | | X | | | X | |
Platelet | X | X | X | | X | | | | | | | X | |
Cryoprecipitate or fibrinogen concentrate | | | | | | | | | | | | | |
Fifth pack | RBC | X | X | X | X | X | | X | | X | | | X | |
Plasma | X | X | X | X | X | | X | | X | | | X | |
Platelet | X | | | X | X | | | | X | | | | |
Cryoprecipitate or fibrinogen concentrate | | | | | | | | | X | | | X | |
aHospitals 1 to 13 represent the hospitals with a pediatric MHP
X identifies predefined pack content
A blank space for subsequent packs (for example, hospitals 6, 8, 10, 11, and 13), represents pack content that is not predefined, but is ordered as needed
RBC = red blood cells
Blood work was drawn at MHP activation and at predefined intervals, commonly every 30 min (n = 11). Suggested laboratory tests are described in Table 4. While the TM laboratory results were usually communicated by phone (n = 5), critical laboratory results were rarely relayed (n = 1) directly to the clinical team.
Table 4. Laboratory testing types, by time related to massive hemorrhage protocol activation
Laboratory testing type, n/total N (%) | At the beginning of activation N = 13 | At intervals during the MHP N = 13 |
|---|
CBC | 13/13 (100%) | 13/13 (100%) |
Group and screen | 13/13 (100%) | n/aa |
INR/PT | 13/13 (100%) | 13/13 (100%) |
Fibrinogen | 13/13 (100%) | 12/13 (92%) |
aPTT | 11/13 (85%) | 11/13 (85%) |
Blood gas | 11/13 (85%) | 12/13 (92%) |
Electrolytes (Na, K, Cl, CO2) | 11/13 (85%) | 10/13 (77%) |
Ionized calcium | 10/13 (77%) | 12/13 (92%) |
Magnesium | 8/13 (62%) | 7/13 (54%) |
Lactate | 8/13 (62%) | 7/13 (54%) |
Creatinine | 4/13 (31%) | 4/13 (31%) |
Glucose | 2/13 (15%) | 2/13 (15%) |
Urea | 1/13 (8%) | 1/13 (8%) |
ROTEM | 1/13 (8%) | 1/13 (8%) |
Point-of-care testing | 1/13 (8%) | 1/13 (8%) |
aAll hospitals include a request for a second sample to confirm the ABO/RhD blood group, if needed, in their pediatric massive hemorrhage protocol
aPTT = activated partial thromboplastin time; CBC = complete blood count; INR = international normalized ratio; n/a = not applicable; PT = prothrombin time; ROTEM = rotational thromboelastometry
Tranexamic acid and blood conservation
Tranexamic acid (TXA), a clot stabilizing agent, was recommended in all MHPs, with a suggested administration within three hours of trauma (8/13) at a dose of 15 mg·kg−1 (10/13 sites) to a maximum of one gram infused over ten minutes (7/13 sites). Most sites (12/13) recommended a subsequent TXA infusion, the most common being 2 mg·kg−1·hr−1 (8/13 sites) infused over eight hours (8/13 sites) and/or until bleeding stopped (5/13 sites). Five MHPs suggested cell-salvage technology for appropriate patients.
Temperature and traumatic brain injury management
All sites required monitoring of patient temperature. The target temperatures were > 35 °C (n = 4), > 36 °C (n = 4), and ≥ 36.0 °C (n = 1); four sites did not mention a target temperature. All sites recommended rapid infuser and/or iv fluid warmer to increase body temperature. Other recommendations included forced air warmers (n = 6), warm blankets (n = 4), and increasing ambient temperature (n = 4). Only two sites detailed traumatic brain injury (TBI) management.
Treatment of bleeding, including damage control resuscitation, blood component transfusion, and target thresholds
Most sites (12/13) recommended initial ratio-based blood component transfusion, with a quick transition to laboratory test-guided transfusion using weight-based component or product dosing and target thresholds. Recommendations for RBC to plasma ratios varied (1:1 ratio [n = 7], 1–2:1 [n = 4], or 2:1 [n = 1]). Red blood cells to platelet ratios were less common (1:1 ratio [n = 5] and 1–2:1 [n = 1]). There were infrequent recommendations for vasopressors. Table 5 summarizes dose and target thresholds for blood components and fibrinogen concentrate.
Table 5. Blood component or product administration during massive hemorrhage protocol activation, by dose and target threshold
Blood component/product | Dose | Number of sites | Target threshold | Number of sites |
|---|
N = 12a | N = 12a |
|---|
Red blood cells | Most common: 20 mL·kg−1, n | 3 | 80–100 g·L−1, n | 1 |
Range: 10–20 mL·kg−1, n | 8 | 80 g·L−1, n | 6 |
Other: RBCs as per rate of blood loss (dose: MD discretion), n | 1 | 70–100 g·L−1, n | 3 |
| | 70 g·L−1, n | 1 |
| | 80 g·L−1 for ≥ 5 kg and 100 g·L−1 for < 5 kg, n | 1 |
Frozen plasma | Most common: | | INR 1.4, n | 1 |
20 mL·kg−1, n | 4 | INR 1.5, n | 5 |
10–15 mL·kg−1, n | 4 | INR 1.7, n | 2 |
Range: 10–20 mL·kg−1, n | 10 | INR 1.8, n | 2 |
| | INR 2.0, n | 1 |
| | PT 1.5 × normal, n | 1 |
| | aPTT 1.5 × normal (in addition to INR/PT), n | 2 |
| | aPTT > 40 sec (in addition to INR/PT), n | 1 |
Platelets | Most common: 10 mL·kg−1, n | 6 | 50 × 109·L−1, n | 7 |
Range: 5–15 mL·kg−1, n | 9 | 70 × 109·L−1, n | 1 |
Other: 1 unit/10 kg (adult dose = 5 units), n | 1 | 75 × 109·L−1, n | 4 |
| | Increased to 100 × 109·L−1: | |
| | Intracranial bleeding/injury, n | 8 |
| | Going to the OR, n | 2 |
| | Intraocular bleed, n | 1 |
| | Taking antiplatelet drug, n | 1 |
| | Empiric transfusion (regardless of platelet count): | |
| | Platelet dysfunction, n | 2 |
| | Taking antiplatelet drug, n | 2 |
| | Chronic renal insufficiency, n | 1 |
| | On ECMO, n | 1 |
Cryoprecipitateb | Most common: 1 unit/10 kg (max 10 units), n | 7 | 1 g·L−1, n | 3 |
| Range: 1 unit/5 kg to 1 unit/10 kg (max 10 units), n | 9 | 1.5 g·L−1, n | 7 |
| Other: 0.1 unit/kg, n | 1 | 1.75 g·L−1, n | 1 |
Fibrinogen concentrateb | Most common: n/ac | n/a | 2 g·L−1, n | 1 |
| Range: 30–60 mg·kg−1 (max 1–4 g), n | 3 | Increased to: | |
| | | 1.8 g·L−1, if trauma, n | 1 |
| | | 2.5 g·L−1 if CV surgery, n | 1 |
aOf the 13 hospitals with pediatric massive hemorrhage protocol, one site did not report target thresholds and dosing per weight as transfusion was ratio-based until massive hemorrhage protocol deactivation. Blood components were transfused as per pack content arrival for the entire duration of the protocol. This hospital was therefore excluded from this table. Moreover, not all sites reported blood component or product dosing for every blood component.
bAmong the 13 hospitals with pediatric massive hemorrhage protocol, fibrinogen replacement source was cryoprecipitate for seven sites, fibrinogen concentrates for one site, and one or the other for five sites.
cThe hospitals who reported fibrinogen administration within their pediatric massive hemorrhage protocol all used different doses. Therefore, there was not a most common fibrinogen dose.
aPTT = activated partial thromboplastin time; CV = cardiovascular; ECMO = extra-corporal membrane oxygenation; INR = international normalized ratio; MD = physician
Administration of fractionated blood products
Six sites suggested fibrinogen concentrate at a typical dose of 30–60 mg·kg−1 (maximum 1–4 g). Recombinant factor VIIa administration was suggested (n = 5), usually in association with specific criteria (e.g., fibrinogen > 1.5 g·L−1) and in consultation with a hematologist. Prothrombin complex concentrate (PCC) was included (n = 7) primarily for warfarin reversal (n = 6).
Complications and anticoagulant management
Common MHP-associated complications and their management, particularly hypocalcemia and hyperkalemia, were identified by multiple sites (see ESM eTable 4). Hyperkalemia mitigation strategies included using fresh RBCs in infants (n = 2) or supernatant removal in RBC units > 7 days old in children < 10 kg (n = 1). Seven MHPs recommended avoiding excessive crystalloid administration and/or hypertension and allowing permissive hypotension (n = 2) except in TBI (n = 1). Transfusion of rhesus factor D (RhD)-positive RBCs to RhD-negative or unknown patients was considered (n = 8) mostly in males (7/8). To prevent alloimmunization, transfusion of Kell-negative RBCs to females was specified by five sites. Nine MHPs included guidance regarding the management of patients on anticoagulants or antiplatelet agents (ESM eTable 5).
Termination, team hand-over, quality improvement, and education
All hospitals with MHPs had variably defined termination criteria, but they all notified the blood bank. Nine sites defined specific termination criteria (e.g., hemostasis/hemodynamic stability or resuscitation efforts withdrawn) and 11 identified the need to return unused blood components. A laboratory checklist (n = 5), a nursing checklist (n = 2), or a handover tool (n = 1) was used infrequently.
Eight sites provided an audit tool to review all MHP activations. Common educational tools included algorithms/dosing tables (n = 10), training modules (n = 3), simulated mock codes (n = 2), and a power point presentation (n = 2). One MHP provided guidance for when a patient refused blood.
Discussion
In this survey study and comprehensive national overview of Canadian university-affiliated pediatric centres, we found that pediatric MHP activation was uncommon and MHP content varied significantly, reflecting the paucity of pediatric MHP literature and a lack of standardized best practice guidelines for MHP activation in children.
The frequency and distribution of MHP activations by indication were similar to previous reports;9,16 however, the proportion of trauma-related MHP activations was higher (54% vs 35%),10 and suggests an underuse in nontrauma settings. This may indicate a lack of awareness by anesthesiologists for MHP activation criteria, who are rarely identified as an active team member. This is concerning because 24 hr mortality due to bleeding in children is substantial in both medical (36%) and surgical (11%) settings,16 which in adults17 and likely children18 can be reduced by MHP activation. The broad patient age range and the diversity of activation settings highlights the need to account for patient size (e.g., weight-based component dosing), unique anatomy (e.g., prone to hypothermia), age-specific physiology (e.g., resilient hemodynamic response to hemorrhage), and clinical context (e.g., trauma vs elective surgery) in pediatric MHPs.14,19 Key MHP domains to be adapted to pediatric-specific populations are provided in Table 1.14
Despite variable-validated MHP activation criteria for adults20,21 and their absence in children,6 few Canadian sites relied on physician discretion for MHP activation, contrary to previous North American studies.6,9 Although an optimal definition for massive transfusion (MT) in children is not yet defined, actionable weight and time-based definitions of pediatric MT (either ≥ 20–40 mL·kg−1/24 hr22,23 or recently ≥ 40 mL·kg−1/4–6 hr of transfused blood components)16,24 generally triggered activation in most Canadian pediatric MHPs, consistent with blood component “resuscitation intensity” or “critical administration thresholds” that best predict mortality in traumatic critical bleeding.16,22, 23, 24, 25–26 As reported previously,9 vital signs and laboratory thresholds for MHP activation were used infrequently, as they are not good predictors of critical hemodynamic compromise in children,27,28 because of their larger physiologic reserve.12 Hypotension, however, is considered a late and preterminal event in pediatric trauma.29,30 While perhaps not triggering an activation, laboratory results may inform hemorrhagic shock class diagnosis (e.g., base-deficit > −6 mEq·L−1 suggests ≥ class III hemorrhagic shock),30 identify poor prognosis (e.g., elevated lactate and international normalized ratio [INR]),31,32 and provide evidence for “blood failure,” (i.e., low tissue oxygen delivery, endotheliopathy, platelet dysfunction, and coagulopathy).33 Massive hemorrhage protocol activation criteria should incorporate patient factors (e.g., weight), clinical setting, and course (e.g., hemodynamics/responsiveness to fluid challenge), associated injuries (e.g., penetrating injury), volume/timing of blood component administration and evidence for blood failure.31
The blood component ratios and targeted transfusion thresholds used by the Canadian sites reflect pediatric transfusion guidelines.34,35 In our study, most (12/13) MHPs reported initial ratio-based blood component transfusion, specifically targeting a balanced (1:1) or high (≥ 1:2) ratio of plasma to RBC, while fewer than half of the sites (n = 6) indicated an initial high or balanced random donor/apheresis platelet unit to RBC ratio. These findings are consistent with recent consensus guidelines, where resuscitation strategies of RBCs, plasma, and platelets in ratios between 2:1:1 and 1:1:1 “might be considered.”36,37 Unlike a previous survey of pediatric MHPs,9 Canadian sites did not include plasma and/or platelets in the initial pack, likely to account for protocol overactivation,38 component wastage, and unnecessary exposure/associated risks (e.g., higher adverse reaction rate).39,40 In addition, most sites transitioned quickly to laboratory-guided transfusion, as evidenced by the high level of interval laboratory hemostatic testing following MHP activation (100%), compared with 50% reported previously in USA sites.9 There are opportunities to reduce unnecessary exposure to blood components given the wide range of threshold INRs reported requiring treatment with plasma (50% of sites used an INR ≤ 1.5),36 the large number of sites providing platelets despite a lack of evidence in pediatric trauma settings,12,37,41 and literature cautioning against balanced resuscitation in adult surgical settings.42,43 The variability in managing critical bleeding in children on anticoagulants/antiplatelet agents, reflects the lack of pediatric-specific guidelines. Current pediatric transfusion guidelines favour using clinical judgement and early expert consultation over achieving normal lab values.34, 35–36,44
In contrast to a previous study,9 all sites reported TXA administration during MHP. This synthetic lysine derivative reduces all-cause mortality in adult trauma (including from hemorrhage) when administered within three hours of injury.45 While intravenous TXA is considered off-label in children (< 18 yr) including trauma,46 it can safely reduce blood loss and transfusion requirements in the pediatric perioperative environment,47,48 and is associated with a 70% and a 55% reduction in mortality rate at six and 24 hr, respectively, in children who experienced MT for trauma, surgical or medical bleeding.49 Suggested TXA doses observed were consistent with the literature; however, a higher infusion rate (5–10 mg·kg−1·hr−1 up to eight hours) within three hours of injury/onset of hemorrhage is recommended.48 Contraindications for TXA include active thromboembolic disease, consumptive coagulopathy, and high doses (> 100 mg·kg−1 load), particularly in those with a seizure disorder.48 Pediatric trauma trials investigating TXA including in the presence of “fibrinolysis shutdown” are ongoing.50
Similar to previous reports,6,8,9 this study found an underuse of viscoelastic testing (VET), which, unlike conventional coagulation testing (CCT), can measure the initiation, amplification, propagation, and termination of clot formation.51 This underuse reflects the limited literature on pediatric outcome-related viscoelastic testing and the associated high cost.12,36,52 Our results suggest that factor concentrates are increasingly being used in Canadian pediatric MHPs.53 Fibrinogen depletion is a key factor determining early hemostatic incompetence during critical bleeding,35,44 and fibrinogen replacement should be available early during critical bleeding resuscitation.5,54 This is unlike thrombin, which increases in the early stages of trauma-related bleeding but later decreases during massive hemorrhage.55 While there is no consensus for a critical fibrinogen level during massive bleeding, 1.5 g·L−1 is commonly reported using a 50–70 mg·kg−1 dose of fibrinogen concentrate.56 Over half the sites used four-factor PCC as a plasma substitute to reverse a vitamin K antagonist (e.g., warfarin). While PCC use in pediatric trauma is limited, a mean PCC dose of 21.8 U·kg–1 can correct a prolonged INR and reduce bleeding and transfusion in infants after cardiac surgery.57,58 Advantages include no need for ABO typing, immediate access, and a negligible risk, making both fibrinogen concentrate and PCCs more attractive than cryoprecipitate and plasma-substitutes, respectively, in resource-limited settings.
Irrespective of age, weight-based administration of blood components (mL·kg−1) is recommended to avoid overtransfusion (e.g., transfusion-associated circulatory overload), dilutional coagulopathy (e.g., due to excessive crystalloid), hyperkalemia (due to RBCs), hypocalcemia (due to citrate toxicity), and hypothermia (< 36 °C).6 While most MHPs accounted for these complications, few provided treatment guidance. Although over half of the MHPs recommend limiting crystalloid administration, a minority of sites recognized hypothermia as < 36 °C, and only two MHPs provided TBI treatment guidance.59 Few sites addressed using Kell-negative RBCs in females, to prevent alloimmunization, a risk factor for hemolytic disease of the newborn.60
Eight sites had an audit tool to review all MHP activations, suggesting a willingness to incorporate standards-based benchmarking. Audit tools should be used to monitor appropriate MHP activation/termination, protocol compliance, and outcomes, even in the absence of consensus MHP quality performance indicators.61,62
This study has provided a comprehensive national overview of Canadian MHP practice in pediatric tertiary care settings and provides recommendations to inform a national standardized pediatric MHP. Limitations of our study include the exclusion of community hospital settings and the inability to measure/compare MHP compliance and patient outcome measures. Finally, leukodepleted low-titer O negative whole blood, which is currently only approved in military settings, was not assessed.
Conclusions
Pediatric MHP underuse and variability in content is evident in Canada. There are several opportunities for further investigation of the massively bleeding child. First, a consensus definition for pediatric massive hemorrhage is required for consistency in clinical guidelines and research. Second, a validated universal pediatric MHP activation trigger tool is needed. Third, age-specific and goal-directed blood component therapy endpoints for children are required. Fourth, a prospective randomized controlled trial is needed to compare conventional coagulation testing vs viscoelastic testing and to compare “low” vs “high” plasma with RBC transfusion ratios and whole blood on morbidity and mortality. Fifth, best practices regarding hemostatic adjuncts (e.g., TXA and recombinant factor concentrates) should be established. Sixth, noninvasive technologies to guide RBC transfusion need to be investigated.63,64 Finally, a national pediatric MHP repository is required to validate activations in the CIHI database, monitor compliance and develop core outcome and quality improvement metrics to improve outcomes for massively bleeding children.
Author contributions
Valérie Arsenault and Lani Lieberman contributed to all aspects of this manuscript, including study conception and design; acquisition, analysis, and interpretation of data; and reviewing/editing the article. Pegah Akbari contributed to the design and deployment of the survey and building the RedCap© database, analysis, and interpretation of data and reviewing/editing the article. Kimmo Murto contributed to most aspects of this manuscript, including study conception and design; analysis, and interpretation of data; and drafting the article.
Acknowledgement
Thank you to Johanna Spaans for reviewing and editing the manuscript.
Disclosures
Drs Lani Lieberman and Kimmo Murto have an ongoing noncommercial and unfunded relationship with the Ontario Regional Blood Coordinating Network (ORBCoN), an Ontario Ministry of Health funded organization, in the design, development, deployment and monitoring of a province-wide standardized massive hemorrhage protocol for children. Dr Valerie Arsenault and Pegah Akbari have no conflicts of interest.
Funding statement
There was no funding source.
Prior conference presentations
Preliminary study dated was presented by Valérie Arsenault at the virtual 2021 Canadian Society for Transfusion Medicine Annual Conference (13–15 May, Moncton, NB, Canada).
Editorial responsibility
This submission was handled by Dr. Vishal Uppal, Associate Editor, Canadian Journal of Anesthesia/Journal canadien d’anesthésie.
Publisher's Note
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