Impact of hypocalcemia on mortality in pediatric trauma patients who require transfusion.

INTRODUCTION: Admission hypocalcemia has been associated with poor outcomes in injured adults. The impact of hypocalcemia on mortality has not been widely studied in pediatric trauma. METHODS: A pediatric trauma center database was queried retrospectively (2013-2022) for children age < 18 years who received blood transfusion within 24 hours of injury and had ionized calcium (iCal) level on admission. Children who received massive transfusion (>40 mL/kg) prior to hospital arrival or calcium prior to laboratory testing were excluded. Hypocalcemia was defined by the laboratory lower limit (iCal <1.00). Main outcomes were in-hospital mortality and 24-hour blood product requirements. Logistic regression analysis was performed to adjust for injury severity score (ISS), admission shock index, Glasgow Coma Score (GCS) and weight-adjusted total transfusion volume. RESULTS: In total, 331 children with median (IQR) age of 7 years (2-13) and median (IQR) ISS 25 (14-33) were included, 32 (10%) of whom were hypocalcemic on arrival to the hospital. The hypocalcemic cohort had higher ISS (median (IQR) 30(24-36) vs 22(13-30)) and lower admission GCS (median (IQR) 3 (3-12) vs 8 (3-15)). Age, sex, race, and mechanism were not significantly different between groups. On univariate analysis, hypocalcemia was associated with increased in-hospital (56% vs 18%; p < 0.001) and 24-hour (28% vs 5%; p < 0.001) mortality. Children who were hypocalcemic received a median (IQR) of 22 mL/kg (7-38) more in total weight-adjusted 24-hour blood product transfusion following admission compared to the normocalcemic cohort (p = 0.005). After adjusting for ISS, shock index, GCS, and total transfusion volume, hypocalcemia remained independently associated with increased 24-hour (Odds Ratio(OR) 95% Confidence Interval(CI) = 4.93(1.77-13.77); p = 0.002) and in-hospital mortality (OR 95% CI =3.41(1.22-9.51); p = 0.019). CONCLUSION: Hypocalcemia is independently associated with mortality and receipt of greater weight-adjusted volumes of blood product transfusion after injury in children. The benefit of timely calcium administration in pediatric trauma needs further exploration. LEVEL OF EVIDENCE: III; prognostic/epidemiological.

Whole blood: total blood product ratio impacts survival in injured children.

INTRODUCTION: Some studies in both children and adults have shown a mortality benefit for the use of low titer group O whole blood (LTOWB) compared to component therapy for traumatic resuscitation. Although LTOWB is not widely available at pediatric trauma centers, its use is increasing. We hypothesized that in children who received whole blood after injury, the proportion of whole blood in relation to the total blood product resuscitation volume would impact survival. METHODS: The trauma database from a single academic pediatric level 1 trauma center was queried for pediatric (age < 18 years) recipients of LTOWB after injury (years 2015-2022). Weight-based blood product (LTOWB, red blood cells, plasma and platelet) transfusion volumes during the first 24 hours of admission were recorded. The ratio of LTOWB to total transfusion volume was calculated. The primary outcome was in-hospital mortality. Multivariable logistic regression model adjusted for the following variables: age, sex, mechanism of injury, injury severity score, shock index, and Glasgow Coma Scale (GCS) score. Adjusted odds ratio representing the change in the odds of mortality by a 10% increase in the LTOWB:total transfusion volume ratio was reported. RESULTS: There were 95 pediatric LTOWB recipients included in the analysis, with median (IQR) age of 10 years (5-14), 58% male, median (IQR) injury severity score of 26 (17-35), 25% penetrating mechanism. The median(IQR) volume of LTOWB transfused was 17 (15-35) mL/kg. LTOWB comprised a median (IQR) of 59% (33-100) of the total blood product resuscitation. Among patients who received LTOWB, there was a 38% decrease in in-hospital mortality for each 10% increase in the proportion of WB within total transfusion volume (p < 0.001) after adjusting for age, sex, mechanism of injury, injury severity score, shock index, and GCS score. CONCLUSION: Increased proportions of LTOWB within the total blood product resuscitation was independently associated with survival in injured children. Based on existing data that suggests safety and improved outcomes with whole blood, consideration may be given to increasing the use of LTOWB over CT resuscitation in pediatric trauma resuscitation. ARTICLE TYPE: Level 3 Evidence; Observational Cohort Study.

Use of whole blood in pediatric trauma: a narrative review.

Balanced hemostatic resuscitation has been associated with improved outcomes in patients with both pediatric and adult trauma. Cold-stored, low-titer group O whole blood (LTOWB) has been increasingly used as a primary resuscitation product in trauma in recent years. Benefits of LTOWB include rapid, balanced resuscitation in one product, platelets stored at 4°C, fewer additives and fewer donor exposures. The major theoretical risk of LTOWB transfusion is hemolysis, however this has not been shown in the literature. LTOWB use in injured pediatric populations is increasing but is not yet widespread. Seven studies to date have described the use of LTOWB in pediatric trauma cohorts. Safety of LTOWB use in both group O and non-group O pediatric patients has been shown in several studies, as indicated by the absence of hemolysis and acute transfusion reactions, and comparable risk of organ failure. Reported benefits of LTOWB included faster resolution of shock and coagulopathy, lower volumes of transfused blood products, and an independent association with increased survival in massively transfused patients. Overall, pediatric data are limited by small sample sizes and mostly single center cohorts. Multicenter randomized controlled trials are needed.

Endotheliopathy of trauma in children: The association of syndecan-1 with injury and poor outcomes.

BACKGROUND: The contribution of the endothelium to trauma-induced coagulopathy has not been thoroughly investigated in injured children. METHODS: This is a prospective cohort study of children (younger than 18 years) who presented with a potentially severe injury to an academic pediatric trauma center. Syndecan-1 level was collected on arrival and 24 hours following hospital arrival. Children were categorized as injured versus uninjured based on results of trauma evaluation. Demographics, injury characteristics, vital signs, and clinical laboratories were recorded. A composite clinical outcome was defined as death or blood product transfusion within 24 hours of hospital arrival. Statistical tests determined the impact of injury characteristics and therapeutics on syndecan-1 levels and assessed for associations between syndecan-1 level and outcomes. RESULTS: A total of 121 subjects were included in the analysis: 96 injured (79%) and 25 uninjured (21%). There were no differences between groups in age (median [interquartile range (IQR)], 11 [4-14] years), sex, or race. The injured cohort had a median (IQR) Injury Severity Score of 16 (9-21), 75% had blunt mechanism, 26% were transfused within 6 hours, 3% had 24-hour mortality, and 6% had in-hospital mortality. Median (IQR) syndecan-1 level on admission was significantly higher in injured versus uninjured cohort (44 [21-75] vs. 25 [17-42]; p = 0.04). Admission base deficit was significantly correlated with syndecan-1 level ( r = 0.8, p < 0.001); no association with traumatic brain injury or injury mechanism was seen. Children with elevated syndecan-1 on admission had significantly increased odds of poor outcome; every 10 ng/mL increase in syndecan-1 was associated with 10% increased odds of death or transfusion ( p < 0.001). Transfusion with any blood product was associated with a significant decrease in syndecan-1 from arrival to 24 hours (Δ syndecan-1, -17 [-64 to -5] vs. -8 [-19 to +2]; p < 0001). CONCLUSION: Elevated admission syndecan-1 level, suggestive of endotheliopathy, was associated with shock and poor outcomes in pediatric trauma. Larger cohort studies are required to fully describe the complexities of trauma-induced coagulopathy and investigate the benefit of therapies targeting endotheliopathy in children. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.

Age-related changes in thromboelastography profiles in injured children.

BACKGROUND: The role of age in mediating coagulation characteristics in injured children is not well defined. We hypothesize thromboelastography (TEG) profiles are unique across pediatric age groups. METHODS: Consecutive trauma patients younger than 18 years from a Level I pediatric trauma center database from 2016 to 2020 with TEG obtained on arrival to the trauma bay were identified. Children were categorized by age according to the National Institute of Child Health and Human Development categories (infant, ≤1 year; toddler, 1-2 years; early childhood, 3-5 years; older childhood, 6-11 years; adolescent, 12-17 years). Thromboelastography values were compared across age groups using Kruskal-Wallis and Dunn's tests. Analysis of covariance was performed controlling for sex, Injury Severity Score (ISS), arrival Glasgow Coma Scale (GCS) score, shock, and mechanism of injury. RESULTS: In total, 726 subjects were identified; 69% male, median (interquartile range [IQR]) ISS = 12 (5-25), and 83% had a blunt mechanism. On univariate analysis, there were significant differences in TEG α-angle ( p < 0.001), MA ( p = 0.004), and fibrinolysis 30 minutes after MA (LY30) ( p = 0.01) between groups. In post hoc tests, the infant group had significantly greater α-angle (median, 77; IQR, 71-79) and MA (median, 64; IQR, 59-70) compared with other groups, while the adolescent group had significantly lower α-angle (median, 71; IQR, 67-74), MA (median, 60; IQR, 56-64), and LY30 (median, 0.8; IQR, 0.2-1.9) compared with other groups. There were no significant differences between toddler, early childhood, and middle childhood groups. On multivariate analysis, the relationship between age group and TEG values (α-angle, MA, and LY30) persisted after controlling for sex, ISS, GCS, shock, and mechanism of injury. CONCLUSION: Age-associated differences in TEG profiles across pediatric age groups exist. Further pediatric-specific research is required to assess whether the unique profiles at extremes of childhood translate to differential clinical outcomes or responses to therapies in injured children. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

Admission maximum amplitude-reaction time ratio: Association between thromboelastography values predicts poor outcome in injured children.

INTRODUCTION: Thromboelastography (TEG)-derived maximum amplitude-reaction time (MA-R) ratio that accounts for both hypocoagulable and hypercoagulable changes in coagulation is associated with poor outcomes in adults. The relationship between these TEG values and outcomes has not been studied in children. METHODS: In a retrospective cohort study, a level I pediatric trauma center database was queried for children younger than 18 years who had a TEG assay on admission between 2016 and 2020. Demographics, injury characteristics, and admission TEG values were recorded. The MA-R ratio was calculated and divided into quartiles. Main outcomes included mortality, transfusion within 24 hours of admission, and thromboembolism. A logistic regression model was generated adjusting for age, Injury Severity Score, injury mechanism, admission shock, and Glasgow Coma Scale. RESULTS: In total, 657 children were included, of which 70% were male and 75% had blunt mechanism injury. The median (interquartile range) age was 11 (4-14) years, the median (interquartile range) Injury Severity Score was10 (5-22), and in-hospital mortality was 7% (n = 45). Of these patients, 17% (n = 112) required transfusion. Most R and MA values were within normal limits. On unadjusted analysis, the lowest MA-R ratio quartile was associated with increased mortality (15% vs. 4%, 5%, and 4%, respectively; p < 0.001) and increased transfusion need (26% vs. 12%, 16%, and 13%, respectively; p = 0.002) compared with higher quartiles. In the logistic regression models, a low MA-R ratio was independently associated with increased in-hospital mortality (odds ratio [95% confidence interval], 4.4 [1.9-10.2]) and increased need for transfusion within 24 hours of admission (odds ratio [95% confidence interval], 2.0 [1.2-3.4]) compared with higher MA-R ratio. There was no association between MA-R ratio and venous thromboembolic events (venous thromboembolic event rate by quartile: 4%, 2%, 1%, and 3%). CONCLUSION: Although individual admission TEG values are not commonly substantially deranged in injured children, the MA-R ratio is an independent predictor of poor outcome. Maximum amplitude-reaction time ratio may be a useful prognostic tool in pediatric trauma; validation is necessary. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Resuscitative practices and the use of low-titer group O whole blood in pediatric trauma.

ABSTRACT: Increasing rates of penetrating trauma in the United States makes rapid identification of hemorrhagic shock, coagulopathy, and early initiation of balanced resuscitation in injured children of critical importance. Hemorrhagic shock begins early after injury and can be challenging to identify in children, as hypotension is a late sign that a child is on the verge of circulatory collapse and should be aggressively resuscitated. Recent data support shifting away from crystalloid and toward early resuscitation with blood products because of worse coagulopathy and clinical outcomes in injured patients resuscitated with crystalloid. Multicenter studies have found improved survival in injured children who receive balanced resuscitation with higher fresh frozen plasma: red blood cell ratios. Whole blood is an efficient way to achieve balanced resuscitation in critically injured children with limited intravenous access and decreased exposure to multiple donors. Administration of cold-stored, low-titer O-negative whole blood (LTOWB) appears to be safe in adults and children and may be associated with improved survival in children with life-threatening hemorrhage. Many pediatric centers use RhD-negative LTOWB for all female children because of the risk of hemolytic disease of the fetus and newborn (0-6%); however. there is a scarcity of LTOWB compared with the demand. Low risks of hemolytic disease of the fetus and newborn affecting a future pregnancy must be weighed against high mortality rates in delayed blood product administration in children in hemorrhagic shock. Survey studies involving key stakeholder's opinions on pediatric blood transfusion practices are underway. Existing pediatric-specific literature on trauma resuscitation is often limited and underpowered; multicenter prospective studies are urgently needed to define optimal resuscitation products and practices in injured children in an era of increasing penetrating trauma.

Recognizing life-threatening bleeding in pediatric trauma: A standard for when to activate massive transfusion protocol.

BACKGROUND: Traumatic hemorrhage is the most common cause of preventable death in civilian and military trauma. Early identification of pediatric life-threatening hemorrhage is challenging. There is no accepted clinical critical administration threshold (CAT) in children for activating massive transfusion protocols. METHODS: Children 0 to 17 years old who received any transfusion in the first 24 hours after injury between 2010 and 2019 were included. The type, volume, and time of administration for each product were recorded. The greatest volume of weight-adjusted products transfused within 1 hour was calculated. The cut point for the number of products that maximized sensitivity and specificity to predict in-hospital mortality, need for urgent surgery, and second life-threatening bleeding episode was determined using Youden's index. A binary variable (CAT+) was generated using this threshold for inclusion in a multivariable logistic regression model. RESULTS: In total, 287 patients were included. The median (interquartile range) age was 6 (2-14) years, 60% were males, 83% sustained blunt trauma, and the median (interquartile range) Injury Severity Score was 26 (17-35). The optimal cutoff to define CAT+ was >20 mL/kg of product; this optimized test characteristics for mortality (sensitivity, 70%; specificity, 77%), need for urgent hemorrhage control procedure (sensitivity, 65%; specificity, 74%). and second bleeding episode (sensitivity, 77%; specificity, 74%). There were 93 children (32%) who were CAT+. On multivariate regression, being CAT+ was associated with 3.4 increased odds of mortality (95% confidence interval, 1.67-6.89; p = 0.001) after controlling for age, hypotension, Injury Severity Score, and Glasgow Coma Scale. For every unit of product administered, there was a 10% increased risk of mortality (odds ratio, 1.1; p < 0.001). CONCLUSION: Transfusion of more than 20 mL/kg of any blood product within an hour should be used as a threshold for activating massive transfusion protocols in children. Children who meet this CAT are at high risk of mortality and need for interventions; this population may benefit from targeted, timely, and aggressive hemostatic resuscitation. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis. METHODS: A multi-institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB-HCC). Univariate and multivariate analyses identified predictors of mortality and relapse. RESULTS: In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB-HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio [HR], 1.63; P = .038), elevated α-fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease-free status at any point predicted survival. CONCLUSIONS: This multi-institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk-stratified algorithms for children with HCC. LAY SUMMARY: This is the largest reported granular data set on children with hepatocellular carcinoma. The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes. This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.

Interhospital variability in localization techniques for small pulmonary nodules in children: A pediatric surgical oncology research collaborative study.

BACKGROUND: Pulmonary nodules that are deep within lung parenchyma and/or small in size can be challenging to localize for biopsy. This study describes current trends in performance of image-guided localization techniques for pulmonary nodules in pediatric patients. METHODS: A retrospective review was performed on patients < 21 years of age undergoing localization of pulmonary nodules at 15 institutions. Localization and resection success, time in interventional radiology (IR), operating room (OR) and total anesthesia time, complications, and technical problems were compared between techniques. RESULTS: 225 patients were included with an average of 1.3 lesions (range 1-5). Median nodule size and depth were 4 mm (range 0-30) and 5.4 mm (0-61), respectively. The most common localization techniques were: wire + methylene blue dye (MBD) (28%), MBD only (25%), wire only (14%), technetium-99 only (11%), coil + MBD (7%) and coil only (5%). Localization technique was associated with institution (p < 0.01); technique and institution were significantly associated with mean IR, OR, and anesthesia time (all p < 0.05). Comparing techniques, there was no difference in successful IR localization (range 92-100%, p = 0.75), successful resection (94-100%, p = 0.98), IR technical problems (p = 0.22), or operative complications (p = 0.16). CONCLUSIONS: Many IR localization techniques for small pulmonary nodules in children can be successful, but there is wide variability in application by institution and in procedure time. LEVEL OF EVIDENCE: Retrospective review, Level 3.

Characteristics and Outcomes in Pediatric Non-Central Nervous System Malignant Rhabdoid Tumors: A Report from the National Cancer Database.

BACKGROUND: Pediatric non-central nervous system (CNS) malignant rhabdoid tumors (MRTs) are rare and aggressive malignancies without standard treatment strategies. The National Cancer Database (NCDB) was utilized to describe the incidence, characteristics, treatment strategies, and outcomes in pediatric patients. METHODS: Patients <18 years of age and diagnosed with non-CNS MRTs were analyzed from the NCDB from 2004 to 2014. Log-rank tests compared differences in Kaplan-Meier survival distributions. Univariate and multivariable Cox proportional hazard regression models identified predictors of mortality. RESULTS: Overall, 202 patients were identified. Soft tissue tumors were most common and metastatic disease was present at diagnosis in 34.2% of patients. The 1- and 5-year overall survival (OS) rates were 48.8% and 35.9%, respectively. Multivariable analysis revealed that age <1 year and the presence of metastasis were negative prognostic indicators (p = 0.058). The 1- and 5-year OS rates were 59.9% and 46.5%, respectively, for patients who received surgical intervention (n = 143) compared with 12.3% and 7.4%, respectively, for those treated nonoperatively (n = 59; p < 0.01). Surgical resection was associated with improved outcomes on univariate analysis, although it was no longer an independent predictor of survival on multivariate analysis (p = 0.18). In the cohort of surgical patients, the presence of residual disease trended towards clinically significant worse outcomes (p = 0.13). CONCLUSIONS: Patients with non-CNS MRTs who were diagnosed in infancy and had metastatic disease had worse survival outcomes. Although surgical resection was associated with improved survival in non-CNS MRTs, it was not independently associated with survival on multivariate analysis. Efforts to improve survival may instead depend on improving chemotherapeutic strategies and developing targeted therapies.

Microcoil localization as an effective adjunct to thoracoscopic resection of pulmonary nodules in children.

BACKGROUND/PURPOSE: Thoracoscopic excision of pulmonary nodules is often required for diagnostic or therapeutic purposes, however subpleural and sub-centimeter nodules can be difficult to visualize. Various CT-guided localization techniques have been described, though there is minimal published pediatric data regarding the use of microcoils. We hypothesize that microcoil localization facilitates thoracoscopic resection of pulmonary nodules in children. METHODS: A multi-institutional retrospective review of children who underwent preoperative CT-guided localization of lung nodules was conducted from 2012 to 2019. A combination of methylene blue dye (MBD), wires, and microcoils were utilized for CT-guided localization. When microcoils were utilized, fluoroscopy assisted in lesion identification and resection. RESULTS: Eighteen patients (mean age 13 years, range 2-21 years) underwent thoracoscopic resection of 24 preoperatively localized pulmonary nodules. Mean size and depth of the lesions were 5.5 mm and 10 mm, respectively. Microcoil placement was successful 95% of the time and assisted in lesion localization in 88% of cases. Wire localization was not a durable technique, as 3 of 5 wires became dislodged upon lung  isolation. CONCLUSIONS: Preoperative CT-guided localization with microcoils can assist in fluoroscopic-guided resection of pulmonary nodules in children. This technique avoids the pitfall of wire dislodgement, and provides surgeons an additional technique to localize sub-centimeter, subpleural nodules. TYPE OF STUDY: Retrospective Review. LEVEL OF EVIDENCE: Level III.