Introduction: Effective treatment of intracranial hypertension (ICH) in severe traumatic brain injury (sTBI) is essential to improve morbidity and mortality. Early identification of patients at risk for refractory ICH could improve outcomes. A Pupillometer non-invasively combines pupillary variables into a Neurological Pupil index (NPi) score. NPi < 3 is considered pathological. Studies in adults demonstrate an inverse correlation between NPi and intracranial pressure (ICP), with report that an abnormal NPi can precede maximum ICP by 15.9 hours. The aim of this study is to evaluate changes in NPi in the preceding 24 hours in pediatric patients with sTBI who have increasing ICP, with a goal to determine if pupillometry may assist in earlier identification of ICH. Methods: In this retrospective analysis of children ≤18 years with sTBI and ICP monitoring at a level 1 trauma center from 2018–2021, hourly ICP and NPi readings were collected up to 72 hours in controls (ICP < 20) and 120 hours in cases (≥ 1 ICP reading ≥20). NPi was reviewed for 24 hours preceding ICP spike. Descriptive statistics and scatter plots were generated. Secondary analysis assessed relationships between ICP and other pupillometry measurements, pupillometry response to pentobarbital, hyperosmolar therapy and decompressive craniectomy (DC). Results: Out of 27 patients, 81.5% had an ICP reading ≥20. The cohort was predominantly male (66.7%) and white (59.3%), with a mean age of 11.5 years (0.7-18). Median GCS was 4, with most common mechanism being blunt trauma (74.1%) and 55.6% had midline shift on CT. An EVD was placed in 63% and intraparenchymal bolt in 52% of patients. 16 patients had non-refractory ICH, while 6 had refractory ICH. Out of 287 ICP readings ≥20, only 17.8% had a NPi < 3 within the preceding 24 hours. In the DC cohort, 128/141(90.8%) ICP readings ≥20 were associated with NPi >3. Pentobarbital infusion initiation was associated with decrease in NPi. Conclusions: There was no association between ICP ≥20mmHg and a preceding NPi < 3, indicating that NPi cannot be used in isolation to predict ICH in sTBI pediatric patients. Patients who underwent DC had normal NPis with ICP ≥20mmHg, likely due to improved brain compliance after DC. Pentobarbital infusion effect on pupil reactivity may diminish utility of NPi in predicting ICH.

OBJECTIVES: Primary objective is to determine if transfusion of short storage RBCs compared with standard issue RBCs reduced risk of delirium/coma in critically ill children. Secondary objective is to assess if RBC transfusion was independently associated with delirium/coma. DESIGN: This study was performed in two stages. First, we compared patients receiving either short storage or standard RBCs in a multi-institutional prospective randomized controlled trial. Then, we compared all transfused patients in the randomized controlled trial with a single-center cohort of nontransfused patients matched for confounders of delirium/coma. SETTING: Twenty academic PICUs who participated in the Age of Transfused Blood in Critically Ill Children trial. PATIENTS: Children 3 days to 16 years old who were transfused RBCs within the first 7 days of admission. INTERVENTIONS: Subjects were randomized to either short storage RBC study arm (defined as RBCs stored for up to seven days) or standard issue RBC study arm. In addition, subjects were screened for delirium prior to transfusion and every 12 hours after transfusion for up to 3 days. MEASUREMENTS AND MAIN RESULTS: Primary outcome measure was development of delirium/coma within 3 days of initial transfusion. Additional outcome measures were dose-response relationship between volume of RBCs transfused and delirium/coma, and comparison of delirium/coma rates between transfused patients and individually matched nontransfused patients. We included 146 subjects in the stage I analysis; 69 were randomized to short storage RBCs and 77 to standard issue. There was no significant difference in delirium/coma development between study arms (79.5% vs 70.1%; p = 0.184). In the stage II analysis, adjusted odds for delirium in the transfused cohort was more than eight-fold higher than in the nontransfused matched cohort, even after controlling for hemoglobin (adjusted odds ratio, 8.9; CI, 2.8-28.4; p < 0.001). CONCLUSIONS: RBC transfusions (and not anemia) are independently associated with increased odds of subsequent delirium/coma. However, storage age of RBCs does not affect delirium risk.

Despite a practice management guideline and risk prediction model for venous thromboembolism (VTE), pediatric-specific evidence on pharmacologic prophylaxis is lacking. In a retrospective study, we characterized receipt of prophylaxis and explored its effectiveness in hospitalized injured patients below 18 years old using data from the Trauma Quality Improvement Program. Concordance of receipt of prophylaxis with guideline and predicted risk of VTE was estimated using κ statistic. Effectiveness was explored using cohorts matched based on the risk prediction model. A total of 11,165 (6.2%) of 180,932 patients received prophylaxis. Those who received prophylaxis were more commonly post-pubertal and more severely injured. Receipt of prophylaxis was fairly concordant with the guideline (κ=0.32) and predicted risk of VTE (κ=0.29). Receipt of prophylaxis was associated with higher rates of VTE likely due to confounding by indication. Low molecular weight heparin seemed more effective against VTE than unfractionated heparin (incidence rate ratio: 0.52; 95% confidence interval: 0.36, 0.75), but less effective when received ≥72 hours after admission to the hospital. We showed that hospitalized injured children did not commonly receive prophylaxis. We also showed that prophylaxis may be effective in hospitalized injured children, but it needs to be proven definitively in a randomized clinical trial.

1Medical College of Wisconsin 2Medical College of Wisconsin, Milwaukee, WI 3Medical College of Wisconsin - Division of Quantitative Health Sciences

CONTEXT:Previous criteria for coagulation dysfunction in critically ill children were based mainly on expert opinion. OBJECTIVE:To evaluate current evidence regarding coagulation tests associated with adverse outcomes in children to inform criteria for coagulation dysfunction during critical illness. DATA SOURCES:Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020 by using a combination of medical subject heading terms and text words to define concepts of coagulation dysfunction, pediatric critical illness, and outcomes of interest. STUDY SELECTION:Studies were included if critically ill children with coagulation dysfunction were evaluated, if performance characteristics of assessment and/or scoring tools to screen for coagulation dysfunction were evaluated, and if outcomes related to mortality or functional status, organ-specific outcomes, or other patient-centered outcomes were assessed. DATA EXTRACTION:Data were abstracted from each eligible study into a standard data extraction form, along with risk of bias assessment, by a task force member. RESULTS:The systematic review supports the presence of at least 2 of the following criteria reflecting coagulation dysfunction in the absence of liver dysfunction: platelet count <100 000 cells per μL, international normalized ratio >1.5, fibrinogen level <150 mg/dL, and D-dimer value above 10 times the upper limit of normal, or above the assay's upper limit of detection if this limit is below 10 times the upper limit of normal. LIMITATIONS:The proposed criteria for coagulation dysfunction are limited by the available evidence and will require future validation. CONCLUSIONS:Validation of the proposed criteria and identified scientific priorities will enhance our understanding of coagulation dysfunction in critically ill children.

Snooks, Kellie; McDermott, Katie; Balakrishnan, Binod; Hanson, Sheila Author Information

The effect of positive fluid balance (FB) on extracorporeal membrane oxygenation (ECMO) outcomes in pediatric patients remains unknown. We sought to evaluate if positive FB in pediatric intensive care unit (PICU) patients with respiratory and/or cardiac failure necessitating ECMO was associated with increased morbidity or mortality. This was a multicenter retrospective cohort study of data from the deidentified PEDiatric ECMO Outcomes Registry (PEDECOR). Patients entered into the database from 2014 to 2017, who received ECMO support, were included. A total of 168 subjects met the study criteria. Univariate analysis showed no significant difference in total FB on ECMO days 1–5 between survivors and non-survivors [median 90 ml/kg (IQR 18–208.5) for survivors vs. median 139.7 ml/kg (IQR 11.2–300.6) for non-survivors, p = 0.334]. There was also no difference in total FB on ECMO days 1–5 in patients with no change in functional outcome as reflected by the Pediatric Outcome Performance Category (POPC) score vs. those who had worsening in POPC score ≥2 at hospital discharge [median 98 ml/kg (IQR 18–267) vs. median 130 ml/kg (IQR 13–252), p = 0.91]. Subjects that required 50 ml/kg or more of blood products over the initial 5 days of ECMO support had an increased rate of mortality with an odds ratio of 5.8 (95% confidence interval of 2.7–12.3; p = 0.048). Our study showed no association of the noted FB with survival after ECMO cannulation. This FB trend was also not associated with POPC at hospital discharge, MV duration, or ECMO duration. The amount of blood product administered was found to be a significant predictor of mortality.

Background: While previous studies have described the use of blood components in subsets of children, such as the critically ill, little is known about transfusion practices in hospitalized children across all departments and diagnostic categories. We sought to describe the utilization of red blood cell, platelet, plasma, and cryoprecipitate transfusions across hospital settings and diagnostic categories in a large cohort of hospitalized children. Study Design and Methods: The public datasets from 11 US academic and community hospitals that participated in the National Heart Lung and Blood Institute Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) were accessed. All nonbirth inpatient encounters of children 0-18 years of age from 2013 to 2016 were included. Results: 61,770 inpatient encounters from 41,943 unique patients were analyzed. Nine percent of encounters involved the transfusion of at least one blood component. RBC transfusions were most common (7.5%), followed by platelets (3.9%), plasma (2.5%), and cryoprecipitate (0.9%). Children undergoing cardiopulmonary bypass were most likely to be transfused. For the entire cohort, the median (interquartile range) pretransfusion laboratory values were as follows: hemoglobin, 7.9 g/dl (7.1-10.4 g/dl); platelet count, 27 x 10(9) cells/L (14-54 x 10(9) cells/L); and international normalized ratio was 1.6 (1.4-2.0). Recipient age differences were observed in the frequency of RBC irradiation (95% in infants, 67% in children, p <.001) and storage duration of RBC transfusions (median storage duration of 12 [8-17] days in infants and 20 [12-29] days in children, p <.001). Conclusion: Based on a cohort of patients from 2013 to 2016, the transfusion of blood components is relatively common in the care of hospitalized children. The frequency of transfusion across all pediatric hospital settings, especially in children undergoing cardiopulmonary bypass, highlights the opportunities for the development of institutional transfusion guidelines and patient blood management initiatives.

Though commonly used for adjustment of risk, severity of illness and mortality risk prediction scores, based on the first 24 h of intensive care unit (ICU) admission, have not been validated in the pediatric extracorporeal membrane oxygenation (ECMO) population. We aimed to determine the association of Pediatric Index of Mortality 2 (PIM2), Pediatric Risk of Mortality Score III (PRISM III) and Pediatric Logistic Organ Dysfunction (PELOD) scores with mortality in pediatric patients on ECMO. This was a retrospective cohort study of children ≤18 years of age included in the Pediatric ECMO Outcomes Registry (PEDECOR) from 2014 to 2018. Logistic regression and Receiver Operating Characteristics (ROC) curves were used to calculate the area under the curve (AUC) to evaluate association of mortality with the scores. Of the 655 cases, 289 (44.1%) did not survive until hospital discharge. AUCs for PIM2, PRISM III, and PELOD predicting mortality were 0.52, 0.52, and 0.51 respectively. PIM2, PRISM III, and PELOD scores are not associated with odds of mortality for pediatric patients receiving ECMO. These scores for a general pediatric ICU population should not be used for prognostication or risk stratification of a select population such as ECMO patients.

A previously healthy 12-year-old boy is seen for a health supervision visit by his pediatrician. Clinical examination is significant for cyanosis of his lips, mucus membranes, and hands, and clubbing of fingers. He has not seen a primary care provider in the past 3 years. He is able to play, bike, be involved in physical education activities in school, and keep up with peers in physical activities without shortness of breath or fatigue. He reports self-limiting episodes of epistaxis once or twice a year for the past 2 to 3 years. He has not traveled outside the country. Family history is unrevealing. Pulse oximetry shows oxygen saturation of 75% to 80%. His heart rate is 70 beats/min, respiratory rate is 20 breaths/min, and blood pressure is 100/52 mm Hg in the right arm in a sitting position, with no difference in blood pressure between the upper and lower extremities. His weight is 41 kg (36th percentile for age) and height is 149 cm (33rd percentile for age). Respiratory and cardiac examination findings are normal. He is referred to a local emergency department for further management of severe hypoxemia. In the emergency department he has no improvement in oxygen saturation with oxygen therapy. A capillary blood gas analysis shows oxygen saturation of 79% (reference range, 90%–100%), with arterial partial pressure of oxygen (Pao2) of 40 mm Hg (reference range, 60–80 mm Hg) and partial pressure of carbon dioxide of 35 mm Hg (reference range, 35–35 mm Hg). Blood methemoglobin level is undetectable. Electrolyte levels are normal. Complete blood count is significant for a hemoglobin (Hb) level of 20 g/dL (200 g/L) (reference range, 12–16 g/dL [120–160 g/L]) and a hematocrit value of 59% (reference range, 36%–47%). An echocardiogram, performed without a bubble study, shows no structural abnormalities and normal cardiac function. A chest radiograph shows focal opacity of the left upper lobe. A chest computed tomographic scan reveals the diagnosis.It is important to differentiate between hypoxemia (decreased Pao2 in the blood) and hypoxia (decreased tissue oxygenation).Oxygen content of blood is dependent on Hb and the degree of saturation with oxygen, which in turn is dependent on the partial pressure of oxygen in the blood: oxygen content of blood (mL/dL) = 1.36 × Hb (g/dL) × oxygen saturation / 100 + 0.003 × Pao2 (mm Hg).Patients can compensate for chronic hypoxemia by increasing blood Hb concentrations, thereby increasing the oxygen content of the blood to maintain adequate tissue-level oxygenation. During acute hypoxemia, the body is unable to compensate, and hypoxia often ensues.Conversely, the tissues maybe unable to obtain adequate oxygen, despite normal Pao2, due to conditions affecting either the quality (carbon monoxide poisoning, methemoglobinemia) or quantity (anemia) of Hb.Hypoxemia could be secondary to hypoventilation, diffusion limitation of oxygen at the alveolar capillary membrane, or ventilation-perfusion mismatch (ie, inadequate perfusion of ventilated parts of the lung) or due to a right-to-left shunt (Table 1). Hypoxemia due to all these causes except a shunt lesion is responsive to supplemental oxygen. (1) Shunt lesions could be secondary to intrapulmonary shunt or due to an intracardiac shunt.Rarely, uncorrected cyanotic heart disease can present similarly. By adolescence, patients have growth restriction, poor exercise tolerance, and polycythemia and can have a poor prognosis. They are at risk for complications secondary to polycythemia and paradoxical embolism such as strokes and brain abscesses. Usually emboli in the systemic circulation are derived from thrombi in the ventricle. However, in the presence of an intracardiac or intrapulmonary shunt, an embolus from a thrombus in the venous side can cross over to the arterial side, causing embolism in the systemic circulation. This is known as paradoxical embolism. (2) Tetralogy of Fallot and Ebstein anomaly are the most common cyanotic lesions presenting in later childhood. Tetralogy of Fallot is characterized by a large ventricular septal defect, an aorta that overrides the left and right ventricles, obstruction of the right ventricular outflow tract, and right ventricular hypertrophy. The degree of cyanosis depends on the degree of obstruction to the right ventricular outflow tract. Mild obstruction is initially well tolerated, but symptoms usually develop by adolescence. In Ebstein anomaly, displacement of posterior and septal leaflets of the tricuspid valves into the right ventricle results in atrialization of a variable amount of right ventricular myocardium. This results in a variable degree of tricuspid regurgitation, leading to development of right-sided heart failure and cyanosis due to increased right atrial pressures and development of a right-to-left shunt in the presence of a patent foramen ovale. If the degree of displacement is not severe, patients may initially remain asymptomatic. Ebstein anomaly is associated with atrial tachycardias and atrioventricular nodal reentrant tachycardias. Adults and adolescents often come to medical attention due to symptoms of these arrhythmias. (3) In Eisenmenger syndrome, a large long-standing left-to-right intracardiac shunt such as a ventricular septal defect or patent ductus arteriosus causes severe pulmonary vascular disease and pulmonary hypertension, with resultant reversal of the direction of shunting and development of cyanosis. (4)Methemoglobin is an altered form of Hb where the iron is present in its oxidized ferric form instead of in the normal ferrous form. Methemoglobin is unable to bind to oxygen. Methemoglobin also causes left shift of the oxyhemoglobin curve, decreasing release of oxygen from normal oxyhemoglobin to the tissues. In methemoglobinemia, only transport of oxygen by Hb is altered, but Pao2 in the blood is normal. Thus, in methemoglobinemia, although oxygen saturation measured by pulse oximetry is low, Pao2 on blood gas is normal. These mechanisms result in tissue hypoxia without hypoxemia. Methemoglobinemia is usually caused by exposure to substances that cause oxidation of iron, such as topical anesthetics (benzocaine and prilocaine) and water with high nitrate content (some well water). Congenital forms of methemoglobinemia secondary to cytochrome b5 reductase deficiency, cytochrome b5 deficiency, or Hb M disease also occur. These forms present with mildly decreased oxygen saturation on pulse oximetry at birth. Hypoxia can be exacerbated by exposure to oxidizing substances. (5)Pulmonary arteriovenous malformations (PAVMs) associated with hereditary hemorrhagic telangiectasia (HHT) 90% of the time can occasionally be idiopathic. They can also occur secondary to infections such as schistosomiasis and actinomycosis, trauma, hepatopulmonary syndrome, and cavopulmonary shunts. Cavopulmonary shunts, such as the Glenn and Fontan shunts, connecting inferior and superior vena cava, respectively, to the pulmonary artery, are surgically created to palliate cardiac lesions with single ventricle physiology. Hepatopulmonary syndrome is thought to result from abnormal vasodilatory metabolites that are not metabolized owing to liver failure entering the lung. They cause microscopic vascular dilatations in the lung. This results in symptoms of an intrapulmonary shunt of hypoxemia and orthodeoxia. (6)(7)(8) Abernethy malformation is a rare cause of PAVM. It is characterized by the persistence of embryonic vessels, resulting in a direct communication between the portal and systemic venous circulations. It is associated with Down syndrome, Turner syndrome, and congenital cardiac disease. Clinical presentation can range from asymptomatic to hepatopulmonary syndrome, encephalopathy secondary to hyperammonemia, and pulmonary hypertension. (7)Capillary malformation AVM (CM-AVM) syndrome, a genetic disorder causing a variety of AVMs, is caused by mutation of the RASA-1 gene and does not result in hypoxemia.Multiple PAVMs were present throughout both lungs. A dominant AVM large enough to account for the opacity on the chest radiograph was present in the posterior portion of the left upper lobe, and numerous smaller AVMs were present throughout the lung (Fig). Based on clinical findings of PAVMs and epistaxis, a diagnosis of possible HHT was made, and the patient underwent genetic testing for HHT. The HHT gene panel identified a pathogenic variant in the ENG gene, confirming the diagnosis. He underwent digital subtraction pulmonary angiography with staged embolization of PAVMs. A complex AVM was present in the left upper lobe with at least 3 dominant arterial feeders. Two more prominent malformations were located in the right middle lobe and the right lower lobe. Numerous smaller AVMs were present throughout the lung. After the procedures his oxygen saturation improved to 90% to 92%, with presence of residual shunting in the smaller AVMs. He continues to be managed by a multidisciplinary team of pulmonologists, geneticists, and radiologists.HHT (or Osler-Weber-Rendu disease) is an autosomal dominant disorder characterized by AVMs predominantly in the lungs, liver, brain, gastrointestinal tract, and mucocutaneous telangiectasias. Diagnosis is based on the Curaçao criteria (Table 2) and confirmed by genetic testing for pathogenic variants in the ENG, ACVRL1, SMAD4, GDF2, and BMP9 genes. ENG and ACVRL1 gene variations account for 85% of cases. The SMAD4 mutation increases the risk of juvenile polyposis. (9) HHT exhibits age-related penetrance, with almost all affected individuals exhibiting symptoms by age 40 years. Although visceral AVMs are mostly congenital, new visceral AVMs can develop over time in HHT. (9)(10)Epistaxis is the most common clinical symptom, developing in approximately 50% of patients by age 10 years and in 85% to 90% by age 20 years. Severe epistaxis, typically described as nosebleeds unresponsive to local pressure, is common with truncating pathogenic variants involving ACVRL1. (11)PAVMs are present in 30% to 60% of patients with HHT. PAVMs tend to increase in size over time. PAVMs consist of 1 or more feeding arteries, an aneurysmal sac, and 1 or more draining veins, without an intervening capillary bed. Most feeding arteries arise from the pulmonary arteries, and draining veins drain into branches of the pulmonary vein. Diffuse PAVMs involve multiple subsegmental arteries and have poorer prognosis and higher rates of complications. (12)PAVMs result in right-to-left shunting, leading to significant hypoxemia. PAVMs are most frequent in the lower lobes of the lungs, which can cause orthodeoxia (desaturation when the patient is upright) due to preferential redistribution of blood into the PAVMs in the upright position. Rarely, the aneurysmal sac wall can rupture, causing massive hemoptysis. Right-to-left shunting can also lead to strokes and brain abscesses. Rarely, PAVM rupture into the pleural space can lead to air embolism. Pulmonary hypertension secondary to hypoxic vasoconstriction can develop over time.Transthoracic contrast echocardiography is the recommended screening tool. Transthoracic contrast echocardiography with agitated saline, also known as a bubble study, has 99% to 100% sensitivity. Agitated saline with air bubbles is injected through a peripheral intravenous catheter. Visualization of air bubbles in the left side of the heart after 3 to 4 cardiac cycles is suggestive of an intrapulmonary shunt, whereas visualization within 1 to 2 seconds is suggestive of an intracardiac shunt. (13)Chest computed tomography is the gold standard; contrast injection is typically unnecessary for visualization of these lesions. Magnetic resonance angiography can also be helpful, especially in planning for intervention and avoidance of radiation exposure.The decision to intervene on PAVMs is based on multiple factors, including size of feeding arteries. Intervention is recommended for PAVMs with feeder arteries greater than 3 mm. Other factors that influence decision making to intervene on PAVMs with smaller feeder arteries include presence of and perceived risk of neurologic complications and pulmonary hemorrhage, exercise limitations of the patient, and technical challenges of the procedure. Percutaneous image-guided embolotherapy is currently the treatment of choice. Diffuse type of PAVMs can involve an entire segment of the lung and are harder to manage and can require surgical intervention or, rarely, lung transplant. (10)(13)(14)In the absence of PAVMs, if HHT is suspected based on Curaçao criteria, and is confirmed by genetic testing, screening for PAVMs should be undertaken at the time of diagnosis of HHT. If negative, rescreening is recommended at puberty, within 5 years of a planned pregnancy, after a pregnancy, and every 5 to 10 years. Antibiotic prophylaxis for procedures with risk of bacteremia is recommended. Avoidance of scuba diving is also recommended due to a theoretical increased risk of cerebral embolism from decompression and paradoxical embolism through the PAVM. Extra care must be taken to avoid air embolism when any intravenous access is placed. (15)Cerebrovascular malformations, including cerebral AVMs, micro AVMs (<1 cm in size), AV fistulas, and telangiectasias, are present in 11% to 16% of patients with HHT. Screening for cerebrovascular malformations for all patients with HHT using brain MRI is recommended. (15)Screening for gastrointestinal AVMs is recommended only in symptomatic patients and in patients with juvenile polyposis/HHT subtype because gastrointestinal AVMs in the former subtypes are usually asymptomatic. When symptomatic, they present as iron deficiency anemia, secondary to chronic gastrointestinal bleeding. Screening for liver AVMs with Doppler ultrasonography should be considered in patients with elevated liver enzyme levels, symptoms of portal hypertension, biliary or intestinal ischemia, or high-output heart failure. (15)

OBJECTIVES:One essential requirement of trustworthy guidelines is that they should be based on systematic reviews of the best available evidence. The GRADE Working Group has provided guidance for evaluating the certainty of evidence based on several domains. However, for many clinical questions, published evidence may be limited, too indirect or simply not exist. In this brief report (GRADE notes), we describe our method of developing evidence-based recommendations when publisheddirect evidence was lacking.STUDY DESIGN AND SETTING:When direct published literature was absent, an expert evidence survey was administered to panel members about their unpublished observations and case series. Focus was on collecting data about cases and outcome, not panel opinions.RESULTS:Out of 26 questions prioritized by the panel for pediatric venous thromboembolism, 12 had no, very limited, or very low certainty of evidence to inform them. The panel survey was administered for these questions.CONCLUSIONS:Areas of sparse evidence often reflect key questions that are critical to address in clinical practice guidelines due to the uncertainty among health care providers. The expert evidence approach used in this study is one method for panels totransparently deal with the lack of published evidence to directly inform recommendations.

Background: The Glasgow Coma Scale (GCS), used to classify the severity of traumatic brain injury (TBI), is associated with mortality and functional outcomes. However, GCS can be affected by sedation and neuromuscular blockade. GCS-Pupil (GCS-P) score, calculated as GCS minus Pupil Reactivity Score (PRS), was shown to better predict outcomes in a retrospective cohort of adult TBI patients. We evaluated the applicability of GCS-P to a large retrospective pediatric severe TBI (sTBI) cohort. Methods: Admissions to pediatric intensive care units in the Virtual Pediatric Systems (VPS, LLC) database from 2010 to 2015 with sTBI were included. We collected GCS, PRS (number of nonreactive pupils), cardiac arrest, abusive head trauma status, illness severity scores, pediatric cerebral performance category (PCPC) score, and mortality. GCS-P was calculated as GCS minus PRS. χ2 or Fisher’s exact test and Mann-Whitney U test compared categorical and continuous variables, respectively. Classification and regression tree analysis identified thresholds of GCS-P and GCS along with other independent factors which were further examined using multivariable regression analysis to identify factors independently associated with mortality and unfavorable PCPC at PICU discharge. Results: Among the 2,682 patients included in the study, mortality was 23%, increasing from 4.7% for PRS = 0 to 80% for PRS = 2. GCS-P identified more severely injured patients with GCS-P scores 1 and 2 who had worse outcomes. GCS-P ≤ 2 had higher odds for mortality, OR = 68.4 (95% CI = 50.6–92.4) and unfavorable PCPC, OR = 17.3 (8.1, 37.0) compared to GCS ≤ 5. GCS-P ≤ 2 also had higher specificity and positive predictive value for both mortality and unfavorable PCPC compared to GCS ≤ 5. Conclusions: GCS-P, by incorporating pupil reactivity to GCS scoring, is more strongly associated with mortality and poor functional outcome at PICU discharge in children with sTBI.

BACKGROUND:The risks of venous thromboembolism (VTE) and bleeding in critically ill adolescents based on interventions received and anatomic site of trauma or major surgery may identify a cohort eligible for enrollment in a trial of pharmacologic prophylaxis.METHODS:This retrospective cohort study using the Virtual Pediatric Systems database included adolescents admitted to pediatric intensive care units after trauma or major surgery between 2013 and 2017. Mixed effects logistic regression was used to determine the adjusted risks of VTE and bleeding with central venous catheterization (CVC), mechanical ventilation (MV) and anatomic site of trauma or major surgery. The adjusted risks were used to identify the cohort eligible for enrollment.MEASUREMENTS AND MAIN RESULTS:VTE developed in 212 (0.8%) of 27,647 adolescents. The adjusted risk of VTE was >2% with CVC and 2 or more of MV and trauma or major surgery to the brain or abdomen. Excluding those with bleeds present on admission or at high risk of bleeding, 375 (1.4%) adolescents would be eligible for enrollment.CONCLUSIONS:VTE is generally uncommon in adolescents after trauma or major surgery. The small proportion of adolescents who are at high risk of VTE and at low risk of bleeding impacts the feasibility of a trial.LEVEL OF EVIDENCE:Prognostic Study Level II.

Electrographic seizures are frequent and associated with worse outcomes following traumatic brain injury (TBI). Despite this, the use of continuous electroencephalogram (cEEG) remains low. Our study describes cEEG usage and treatment dosing antiseizure medications (ASMs) in an international pediatric TBI population, hypothesizing that children monitored with cEEG have an increased rate of treatment ASMs because of electrographic seizure detection, compared with children who are not monitored with cEEG. This subanalysis of the TBI cohort of the international PANGEA study included children, 7 days to 17 years of age, with acute neurological insults admitted to pediatric intensive care units. We analyzed demographics, injury severity, and therapies including prophylactic or treatment ASMs. We evaluated the relationships between cEEG use, seizure frequency, and receipt of treatment ASMs. $$\chi^{2}$$ or Fisher’s exact test was used to analyze categorical variables, and the Kruskal–Wallis or Mann–Whitney U-test was used for continuous variables. Multivariable analysis for treatment ASM use was performed using logistic regression. One hundred-twenty-three of 174 patients with TBI were included. Twenty-seven patients (21.9%) underwent cEEG at any point during pediatric intensive care unit admission. Preexisting seizure disorder (18.2% vs. 2.3%, p = 0.014) and neuromuscular blockade use (52.4% vs. 24.1%, p = 0.011) were more frequently observed in the group monitored on cEEG when compared with those that were not. Presenting median Glasgow Coma Scale score was worse in the cEEG group (7 vs. 9, p = 0.044). There was no significant difference in age, use of intracranial pressure monitoring, or hyperosmolar therapy between the cEEG monitored and nonmonitored groups. Patients who were monitored on cEEG were more likely to receive a treatment dose ASM than those without cEEG monitoring (66.7% vs. 28.1%, p = 0.0002). When compared with those without treatment ASM, the treatment ASM group had more electrographic seizures on their first electroencephalogram following injury (51.6% vs. 4%, p = 0.0001) and more clinical seizures (55.8% vs. 0%, p < 0.0001). Children monitored with cEEG after TBI have an increased prescription of treatment ASMs and clinical and electrographic seizures. The increased rate of treatment ASMs in the cEEG group may indicate increased recognition of electrographic seizures.

OBJECTIVES: To describe blood component usage in transfused children with congenital heart disease undergoing cardiopulmonary bypass surgery across perioperative settings and diagnostic categories. DESIGN: Datasets from U.S. hospitals participating in the National Heart, Lung, and Blood Institute Recipient Epidemiology and Donor Evaluation Study-III were analyzed. SETTING: Inpatient admissions from three U.S. hospitals from 2013 to 2016. PATIENTS: Transfused children with congenital heart disease undergoing single ventricular, biventricular surgery, extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eight hundred eighty-two transfused patients were included. Most of the 185 children with single ventricular surgery received multiple blood products: 81% RBCs, 79% platelets, 86% plasma, and 56% cryoprecipitate. In the 678 patients undergoing biventricular surgery, 85% were transfused plasma, 75% platelets, 74% RBCs, and 48% cryoprecipitate. All 19 patients on extracorporeal membrane oxygenation were transfused RBCs, plasma, and cryoprecipitate, and 18 were transfused platelets. Intraoperatively, patients commonly received all three components, while postoperative transfusions were predominantly single blood components. Pretransfusion hemoglobin values were normal/low-normal for age for all phases of care for single ventricular surgery (median hemoglobin 13.2–13.5 g/dL). Pretransfusion hemoglobin values for biventricular surgeries were higher intraoperatively compared with other timing (12.2 g/dL vs 11.2 preoperative and postoperative; p < 0.0001). Plasma transfusions for all patients were associated with a near normal international normalized ratio: single ventricular surgeries median international normalized ratio was 1.3 postoperative versus 1.8 intraoperative and biventricular surgeries median international normalized ratio was 1.1 intraoperative versus 1.7 postoperative. Intraoperative platelet transfusions with biventricular surgeries had higher median platelet count compared with postoperative pretransfusion platelet count (244 × 10 9 /L intraoperative vs 69 × 10 9 /L postoperative). CONCLUSIONS: Children with congenital heart disease undergoing cardiopulmonary bypass surgery are transfused many blood components both intraoperatively and postoperatively. Multiple blood components are transfused intraoperatively at seemingly normal/low-normal pretransfusion values. Pediatric evidence guiding blood component transfusion in this population at high risk of bleeding and with limited physiologic reserve is needed to advance safe and effective blood conservation practices.

Purpose: To evaluate transfusion practices in pediatric oncology and hematopoietic stem cell transplant (HSCT) patients. Methods: This is a multicenter retrospective study of children with oncologic diagnoses treated from 2013-2016 at hospitals that participated in the National Heart Lung and Blood Institute Recipient Epidemiology and Donor Evaluation Study-III (REDS-III). Transfusion practices were evaluated by diagnosis code and pre-transfusion laboratory values. Results: A total of 4766 inpatient encounters of oncology and HSCT patients were evaluated, with 39.3% (95% CI 37.9-40.7%) involving a transfusion. Red blood cells (RBCs) were the most commonly transfused component (32.4%; 95% CI 31.1-33.8%), followed by platelets (22.7%; 95% CI 21.5-23.9%). Patients in the 1 to <6-year old age range were most likely to be transfused and HSCT, acute myelogenous leukemia, and aplastic anemia were the diagnoses most often associated with transfusion. The median hemoglobin (Hb) prior to RBC transfusion was 7.5 g/dL (10-90th percentile: 6.4-8.8 g/dL), with 45.7% of transfusions being given at 7-<8 g/dL. The median platelet count prior to platelet transfusion was 20x109/L (10-90th percentile: 8-51x109/L), and 37.9% of transfusions were given at platelet count of >20-50x109/L. The median international normalized ratio (INR) prior to plasma transfusion was 1.7 (10-90th percentile: 1.3-2.7), and 36.3% of plasma transfusions were given at an INR between >1.4-1.7. Conclusion: Transfusion of blood components is common in hospitalized children with cancer. Relatively high pre-transfusion Hb and platelet values and relatively low INR values prior to transfusion across the studied diagnoses highlight the need for evidence- based practice in this population.

OBJECTIVES:We obtained preliminary evidence on the efficacy of early prophylaxis on the risk of central venous catheter-associated deep venous thrombosis and its effect on thrombin generation in critically ill children.DESIGN:Bayesian phase 2b randomized clinical trial.SETTING:Seven PICUs.PATIENTS:Children less than 18 years old with a newly inserted central venous catheter and at low risk of bleeding.INTERVENTION:Enoxaparin adjusted to anti-Xa level of 0.2-0.5 international units/mL started at less than 24 hours after insertion of central venous catheter (enoxaparin arm) versus usual care without placebo (usual care arm).MEASUREMENTS AND MAIN RESULTS:At the interim analysis, the proportion of central venous catheter-associated deep venous thrombosis on ultrasonography in the usual care arm, which was 54.2% of 24 children, was significantly higher than that previously reported. This resulted in misspecification of the preapproved Bayesian analysis, reversal of direction of treatment effect, and early termination of the randomized clinical trial. Nevertheless, with 30.4% of 23 children with central venous catheter-associated deep venous thrombosis on ultrasonography in the enoxaparin arm, risk ratio of central venous catheter-associated deep venous thrombosis was 0.55 (95% credible interval, 0.24-1.11). Including children without ultrasonography, clinically relevant central venous catheter-associated deep venous thrombosis developed in one of 27 children (3.7%) in the enoxaparin arm and seven of 24 (29.2%) in the usual care arm (p = 0.02). Clinically relevant bleeding developed in one child randomized to the enoxaparin arm. Response profile of endogenous thrombin potential, a measure of thrombin generation, was not statistically different between trial arms.CONCLUSIONS:These findings suggest the efficacy and safety of early prophylaxis that should be validated in a pivotal randomized clinical trial.

Backround: To evaluate the feasibility of a randomized controlled trial (RCT) of the fibrinolytic tissue plasminogen activator (t-PA) vs unfractionated heparin (UFH) central venous catheter (CVC) dwell therapy to reduce risk of CVC-associated deep venous thrombosis (CADVT) in critically ill children. Methods: This single center quadruple blinded pilot RCT enrolled children ≤18 years of age with CVC placed within 72 hours of admission to the pediatric intensive care unit (ICU)Weight-adjusted dose of study drug dwell (t-PA vs UFH) was installed to alternating lumen of CVC every 3 days for 10 doses, CVC removal or ICU discharge. Ultrasound with doppler was performed at study completion.Main Results: Of 426 children screened from April-Dec 2019, 86 (20%) were eligible with 20 enrolled and randomized. Primary outcome measure of enrollment rate was 23%. One child was withdrawn immediately after randomization due to development of exclusion criterion. Secondary feasibility outcome measures were proportion of children who received study drug within 24 hours of consent (100%), proportion with ultrasound (100%), and proportion completing the study (95%). Eighteen of 19 children received the first dose within 48 hours of CVC placement. All children missed some dose days because of lumen specified to be in continuous use. Median dwell time for doses received was >2 hours. There were no protocol violations. Six of 19 patients (31.6%) developed CADVT, 1 of which was occlusive. There were no catheter-associated blood stream infection or significant bleeding.Conclusion: Critically ill children requiring CVC are at high risk for CADVT. A future multicenter, blinded, RCT to determine the effectiveness of t-PA vs UFH dwell in reducing CADVT is feasible.Registered August 10, 2018 on ClinicalTrials.gov NCT03672006

Prior criteria for organ dysfunction in critically ill children were based mainly on expert opinion. We convened the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) expert panel to summarize data characterizing single and multiple organ dysfunction and to derive contemporary criteria for pediatric organ dysfunction. The panel was composed of 88 members representing 47 institutions and 7 countries. We conducted systematic reviews of the literature to derive evidence-based criteria for single organ dysfunction for neurologic, cardiovascular, respiratory, gastrointestinal, acute liver, renal, hematologic, coagulation, endocrine, endothelial, and immune system dysfunction. We searched PubMed and Embase from January 1992 to January 2020. Study identification was accomplished using a combination of medical subject headings terms and keywords related to concepts of pediatric organ dysfunction. Electronic searches were performed by medical librarians. Studies were eligible for inclusion if the authors reported original data collected in critically ill children; evaluated performance characteristics of scoring tools or clinical assessments for organ dysfunction; and assessed a patient-centered, clinically meaningful outcome. Data were abstracted from each included study into an electronic data extraction form. Risk of bias was assessed using the Quality in Prognosis Studies tool. Consensus was achieved for a final set of 43 criteria for pediatric organ dysfunction through iterative voting and discussion. Although the PODIUM criteria for organ dysfunction were limited by available evidence and will require validation, they provide a contemporary foundation for researchers to identify and study single and multiple organ dysfunction in critically ill children.