1) Blood products and fluid resuscitation in pediatric traumatic hemorrhagic shock

1.1: In traumatically injured children in hemorrhagic shock, we suggest prioritizing the use of blood products over the use of crystalloids for resuscitation. Consensus Panel Expertise, 100% agreement (n=16), median 9, IQR: 8–9.

During and after the Vietnam War, crystalloids and colloids replaced blood as the primary initial resuscitative solution for hemorrhagic shock. This change was in part due to logistic difficulties of using blood and the infectious disease risks of blood products. The shift to crystalloids was supported by research performed by Carrico et al. indicating that the interstitial compartment or “third space” needed to be resuscitated with 1 to 2 liters of crystalloids to perfuse the tissues. This research further recommended that the transfusion of whole blood (WB) would only be indicated if hemodynamic instability persisted following administration of crystalloids.¹² To the detriment of patients with severe bleeding, misinterpretation of these data contributed to overuse of crystalloids before any blood product were administered. When used in practice, this approach could result in dilutional coagulopathy and severe interstitial edema. A shift from early blood product administration to a preference for early crystalloid and colloid use led to an increase in acute respiratory distress syndrome, abdominal compartment syndrome, multiorgan failure, and anasarca in intensive care units (ICUs).¹³

These outcomes were predicted by Shoemaker in 1976¹⁴ when he challenged the notion that the interstitial compartment required resuscitation. He instead emphasized the need for whole blood (WB) to treat significant bleeding when the hematocrit fell below 30%. The overuse of crystalloids continued despite a call for changes in practice recommended by Moore and Shires as early as 1967. In an editorial, Moore and Shires state, “blood should still be replaced during major operative surgery as it is lost. The use of balanced salt solutions appears to be a physiological adjunct to surgical trauma, not a substitute for blood.” Subsequent research has demonstrated that a crystalloid-based resuscitation strategy leads to higher inflammation and vascular permeability compared to WB.¹⁴

Data supporting the use of blood products instead of crystalloids in children include a multicenter prospective observational study performed from April 2018 to Sept 2019.¹⁵ In this study of 712 children from 24 trauma centers, each crystalloid bolus after the first was incrementally associated with an increased odds of more mechanical ventilation and intensive care unit days and longer hospital stays. A longer time to initiate the first transfusion was also associated with more mechanical ventilation days. In another retrospective study of 512 children admitted to combat support hospitals between 2007 and 2016, the authors evaluated the association of high crystalloid use (> 40ml/kg in 24 hours) for patients receiving high or low plasma:RBC ratios (1:2 threshold).¹⁶ In children who received a high ratio of plasma:RBCs and low crystalloid volume, there was an independent association with improved survival (odds ratio [OR] 3.42; 95% confidence interval [CI], 1.04–11.24). In contrast, children with a high ratio of plasma:RBCs with high crystalloid volumes was not associated with improved survival (OR 0.61; [ 0.28–1.29]). The authors concluded that the high crystalloid volume negated the potential survival benefit of high plasma:RBC ratios in children with severe traumatic bleeding.

A secondary analysis of the PAMPer trial showed similar findings. This study of injured adults compared four groups of patients based on prehospital resuscitation with PRBC and plasma, plasma only, PRBC only, and crystalloid only. For patients with severe traumatic bleeding, they found that the exclusive use of crystalloids worsened survival compared to the partial use of blood products in the prehospital resuscitation phase.¹⁷ A second RCT in adults with severe traumatic injury showed the use of crystalloids in the prehospital phase of resuscitation decreased the risk of survival compared to not using any crystalloids or blood products.¹⁸

Pediatric and adult data supports the association of crystalloids with worse outcomes and the increased and early use of blood products (whole blood or balanced approach) with improved survival. These data support our recommendation suggesting the prioritization of blood products over crystalloids for the resuscitation of traumatic hemorrhagic shock in children.

1.2: In traumatically injured children in hemorrhagic shock, the use of low titer (≤ 200 Ig G) group O whole blood might be considered if available over individual blood components (RBC, plasma, and platelets) for resuscitation. Clinical Recommendation, conditional recommendation, very low certainty of evidence, 94% agreement (n=16), Median 8.5, IQR: 7.75–9.

When compared to individual blood components in a balanced ratio, low titer group O whole blood (LTOWB) is more potent due to less anticoagulants, less preservatives increasing hemoglobin, platelet concentrations, and coagulation factors.¹⁹ In addition, storage of platelets at 4°C may also make LTOWB more hemostatic. In addition, whole blood causes less dilutional coagulopathy and less hypocalcemia due to the increased citrate when transfusing multiple blood components.²⁰ Due to the exclusive use of a group O product, whole blood may be safer than use of components by preventing transfusion of incompatible ABO unit(s) that may lead to a fatal hemolytic reaction due to human error.²¹ In addition, the storage of whole blood at 4°C reduces the risk of bacterial contamination that exists with the use of platelets stored at room temperature.²² Finally, whole blood has logistic advantages due to the need to only dispense one product from the blood bank and administer one product at the bedside instead of dispensing and administering individual blood components.

Using LTOWB instead of individual blood components in children more rapidly provides RBCs, plasma and platelets to children with severe traumatic bleeding, more effectively resolves shock and coagulopathy,²³ is associated with less total amount of blood products administered and mechanical ventilation days,²⁴ and is independently associated with increased 72 hour (OR 0.23; [0.08–0.70]), and 28 day mortality (OR 0.41; [ 0.23–0.98]) in a single center retrospective study.⁸

Adult data indicates the use of LTOWB compared to individual blood components is independently associated with improved 24 hour and 28 day survival and is also associated with less (40–60%) total blood products administered.^25–27 Data from studies performed on children and adults suggest no increased risk of hemolysis in non-group O recipients and no increase in any other adverse outcomes to include organ failure.^28–30

1.3: In traumatically injured children in hemorrhagic shock, when utilizing blood component resuscitation, we suggest targeting high plasma:RBC ratios (1:1) to minimize the plasma deficit. Consensus Panel Expertise, 100% agreement (n=16), median 9, IQR: 8–9.

Children with life threatening hemorrhage from traumatic injuries develop shock due to hypoperfusion. This hypoperfusion causes endothelial injury with loss of the glycocalyx and increased endothelial permeability. The endothelial injury leads to inflammation which can further exacerbate endothelial injury and lead to the production of increased activated protein C and tissue plasminogen activator directly causing trauma induced coagulopathy. While this pathophysiology has been mainly described in adults, there is data indicating it may also occur in children.^31–33 Differences in hemostasis mechanisms between children and adults will require additional study to establish whether these mechanisms are also observed in children.³⁴ To address the shock, endothelial, immune and hemostatic dysfunction, a balanced resuscitation with plasma and RBCs may be optimal because plasma may repair the endothelium and mitigate capillary leak and improve intravascular volume. Plasma may also improve hemostasis by providing coagulation factors for patients who have developed a consumptive coagulopathy. These potential effects of plasma may improve intravascular volume, reduce extravascular edema and bleeding which can all lead to improved oxygen delivery.

A two-year retrospective review of the pediatric trauma quality improvement program (TQIP) supports that the increased plasma:RBC ratios minimize plasma deficit. In this study of over 500 massively transfused children, the plasma:RBC ratio, as a continuous variable, was associated with improved 24-hour mortality (OR 0.47; [0.28–0.80]). In this same study, a plasma:RBC ratio > 1:1 was also independently associated with reduced 24-hour mortality (OR 0.48; [0.26–0.88]). In a multi-institutional prospective observational study that included 191 children with traumatic injury and life-threatening hemorrhage, there was an independent association with a plasma:RBC ratio of > 1:2 with improved 24-hour survival (OR 0.36; [0.13–0.99]). When the plasma deficit (RBC ml/kg – plasma ml/kg) was analyzed, an increased deficit was also associated with increased 24 hour mortality (OR 1.2; [1.05–1.3]).⁴ Additional publications that do not report an association of increased plasma:RBC ratios with improved outcomes have significant limitations to include the lack of adjusted analyses and small sample size or single center studies.^{27, 35, 36} Adult data supporting the use of high ratios targeting 1:1 include the PROPPR trial that reported reduced death from bleeding at 24 hours and improved time to cessation of bleeding.³⁷ The PAMPer trial also reported improved survival when plasma was used early in the prehospital phase of resuscitation.³⁸

1.4: In traumatically injured children in hemorrhagic shock, when utilizing blood component resuscitation, targeting a high platelet to RBC weight-based ratio of 1:1 to minimize the platelet deficit is suggested. Consensus Panel Expertise, 100% agreement (n=16), median 8, IQR: 7–9.

Platelet dysfunction occurs early in traumatic blood failure in adults and the transfusion of platelets may reverse it.³⁷ The importance of the platelets within hemostasis is another reason to hypothesize that the use of platelets may reduce bleeding and improve outcomes. In addition, in vitro and animal evidence suggest that platelet transfusion may repair the injured endothelium, which could also improve outcomes.^{39, 40}

Data supporting the early use of platelets in children was also published in the aforementioned multi-institutional prospective observational study in children with life threatening bleeding. In this study, a platelet deficit (RBC ml/kg – platelet ml/kg) was independently associated with increased mortality at 24 hours (OR 1.1 [1.05–1.2]) but there was no survival advantage associated with the platelet: RBC ratio.⁴ A plausible explanation for this may be that the deficit more accurately reflects the lack of balance between platelets and RBCs more than a ratio which does not incorporate the magnitude of the imbalance. Additional adult data supporting the early use of platelets, a secondary analysis of PROPPR trial focusing on platelet transfusions, demonstrated improved survival in these patients who achieved a more balanced resuscitation.⁴¹