The History of Extracorporeal Membrane Oxygenation and the Development of Extracorporeal Membrane Oxygenation Anticoagulation.

Extracorporeal membrane oxygenation (ECMO) was first started for humans in early 1970s by Robert Bartlett. Since its inception, there have been numerous challenges with extracorporeal circulation, such as coagulation and platelet activation, followed by consumption of coagulation factors and platelets, and biocompatibility of tubing, pump, and oxygenator. Unfractionated heparin (heparin hereafter) has historically been the defacto anticoagulant until recently. Also, coagulation monitoring was mainly based on bedside activated clotting time and activated partial thromboplastin time. In the past 50 years, the technology of ECMO has advanced tremendously, and thus, the survival rate has improved significantly. The indication for ECMO has also expanded. Among these are clinical conditions such as postcardiopulmonary bypass, sepsis, ECMO cardiopulmonary resuscitation, and even severe coronavirus disease 2019 (COVID-19). Not surprisingly, the number of ECMO cases has increased according to the Extracorporeal Life Support Organization Registry and prolonged ECMO support has become more prevalent. It is not uncommon for patients with COVID-19 to be on ECMO support for more than 1 year until recovery or lung transplant. With that being said, complications of bleeding, thrombosis, clot formation in the circuit, and intravascular hemolysis still remain and continue to be major challenges. Here, several clinical ECMO experts, including the "Father of ECMO"-Dr. Robert Bartlett, describe the history and advances of ECMO.

Anticoagulant Medications: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding the medications used for anticoagulation for pediatric extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE (PEACE). DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: Included studies assessed anticoagulation used in pediatric ECMO. DATA EXTRACTION: Two authors reviewed all citations independently, with a third reviewer adjudicating any conflicts. Eighteen references were used for data extraction as well as for creation of recommendations. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-informed recommendations and, when evidence was lacking, expert-based consensus statements, or good practice statements for anticoagulation during pediatric ECMO. A web-based modified Delphi process was used to build consensus via the Research and Development/University of California Appropriateness Method. Consensus was based on a modified Delphi process with agreement defined as greater than 80%. Two recommendations, two consensus statements, and one good practice statement were developed, and, in all, agreement greater than 80% was reached. CONCLUSIONS: There is insufficient evidence to formulate optimal anticoagulation therapy during pediatric ECMO. Additional high-quality research is needed to inform evidence-based practice for anticoagulation during pediatric ECMO.

Priorities for Clinical Research in Pediatric Extracorporeal Membrane Oxygenation Anticoagulation From the Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To identify and prioritize research questions for anticoagulation and hemostasis management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus. DATA SOURCES: Systematic review was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial consensus conferences of international, interprofessional experts in the management of ECMO for critically ill neonates and children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill neonates and children. DATA EXTRACTION: Within each of the eight subgroups, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: Following the systematic review of MEDLINE, EMBASE, and Cochrane Library databases from January 1988 to May 2021, and the consensus process for clinical recommendations and consensus statements, PEACE panel experts constructed research priorities using the Child Health and Nutrition Research Initiative methodology. Twenty research topics were prioritized, falling within five domains (definitions and outcomes, therapeutics, anticoagulant monitoring, protocolized management, and impact of the ECMO circuit and its components on hemostasis). CONCLUSIONS: We present the research priorities identified by the PEACE expert panel after a systematic review of existing evidence informing clinical care of neonates and children managed with ECMO. More research is required within the five identified domains to ultimately inform and improve the care of this vulnerable population.

Executive Summary: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE (PEACE) Consensus Conference.

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.

Improved survival in COVID-19 related sepsis and ARDS treated with a unique "triple therapy" including therapeutic plasma exchange: A single center retrospective analysis.

BACKGROUND: Throughout the COVID-19 pandemic, the mortality of critically ill patients remained high. Our group developed a treatment regimen targeting sepsis and ARDS which we labeled "triple therapy" consisting of (1) corticosteroids, (2) therapeutic plasma exchange (TPE), and (3) timely intubation with lung protective ventilation. Our propensity analysis assesses the impact of triple therapy on survival in COVID-19 patients with sepsis and ARDS. METHODS: Retrospective propensity analysis comparing triple therapy to no triple therapy in adult critically ill COVID-19 patients admitted to the Intensive Care Unit at Lexington Medical Center from 1 March 2020 through 31 October 2021. RESULTS: Eight hundred and fifty-one patients were admitted with COVID-19 and 53 clinical and laboratory variables were analyzed. Multivariable analysis revealed that triple therapy was associated with increased survival (OR: 1.91; P = .008). Two propensity score-adjusted models demonstrated an increased likelihood of survival in patients receiving triple therapy. Patients with thrombocytopenia were among those most likely to experience increased survival if they received early triple therapy. Decreased survival was observed with endotracheal intubation ≥7 days from hospital admission (P < .001) and there was a trend toward decreased survival if TPE was initiated ≥6 days from hospital admission (P = .091). CONCLUSION: Our analysis shows that early triple therapy, defined as high-dose methylprednisolone, TPE, and timely invasive mechanical ventilation within the first 96 hours of admission, may improve survival in critically ill septic patients with ARDS secondary to COVID-19 infection. Further studies are needed to define specific phenotypes and characteristics that will identify those patients most likely to benefit.

Aberrant Fibrin Clot Structure Visualized Ex Vivo in Critically Ill Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

OBJECTIVES: Disseminated fibrin-rich microthrombi have been reported in patients who died from COVID-19. Our objective is to determine whether the fibrin clot structure and function differ between critically ill patients with or without COVID-19 and to correlate the structure with clinical coagulation biomarkers. DESIGN: A cross-sectional observational study. Platelet poor plasma was used to analyze fibrin clot structure; the functional implications were determined by quantifying clot turbidity and porosity. SETTING: ICU at an academic medical center and an academic laboratory. PATIENTS: Patients admitted from July 1 to August 1, 2020, to the ICU with severe acute respiratory syndrome coronavirus 2 infection confirmed by reverse transcription-polymerase chain reaction or patients admitted to the ICU with sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Blood was collected from 36 patients including 26 ICU patients with COVID-19 and 10 ICU patients with sepsis but without COVID-19 at a median of 11 days after ICU admission (interquartile range, 3-16). The cohorts were similar in age, gender, body mass index, comorbidities, Sequential Organ Failure Assessment (SOFA) score, and mortality. More patients with COVID-19 (100% vs 70%; p = 0.003) required anticoagulation. Ex vivo fibrin clots formed from patients with COVID-19 appeared to be denser and to have smaller pores than those from patients with sepsis but without COVID-19 (percent area of fluorescent fibrin 48.1% [SD, 16%] vs 24.9% [SD, 18.8%]; p = 0.049). The turbidity and flow-through assays corroborated these data; fibrin clots had a higher maximum turbidity in patients with COVID-19 compared with patients without COVID-19 (0.168 vs 0.089 OD units; p = 0.003), and it took longer for buffer to flow through these clots (216 vs 103 min; p = 0.003). In patients with COVID-19, d-dimer levels were positively correlated with percent area of fluorescent fibrin (ρ = 0.714, p = 0.047). Denser clots (assessed by turbidity and thromboelastography) and higher SOFA scores were independently associated with delayed clot lysis. CONCLUSIONS: We found aberrant fibrin clot structure and function in critically ill patients with COVID-19. These findings may contribute to the poor outcomes observed in COVID-19 patients with widespread fibrin deposition.

Thromboelastography profiles in critically ill children with multisystem inflammatory syndrome.

OBJECTIVES: To describe critically ill children's coagulation profile with the multisystem inflammatory syndrome (MIS-C) related to coronavirus. STUDY DESIGN: Single-center, observational study at a tertiary, pediatric intensive care unit (PICU) in children aged 1 month to 18 years. MEASUREMENTS AND MAIN RESULTS: Sixteen children, with a median age of 5.4 years (interquartile range [IQR] 2.1, 11.75), 56% female, admission Pediatric Logistic Organ Dysfunction-2 (PELOD-2) score of 3.5 (IQR 2, 5), and median PICU length of stay 3 days (IQR 1.5, 4), met criteria of MIS-C. All patients received acetylsalicylic acid (80-100 mg/kg) and none received anticoagulation. Sixty-three percent (10/16) of children had out-of-normal range values on thromboelastography (TEG) (44% [7/16] with hypercoagulability and 19% [3/16] with hypocoagulability). Of those with hypercoagulability, 19% (3/16) had rapid clot formation, and 25% (4/16) had increased clot strength. In 69% (11/16) of children, there was impaired fibrinolysis (0% lysis at 30 minutes) on TEG. Seventy-five percent (12/16) of children had out-of-normal range value on standard coagulation assays (37.5% [6/16] with hypocoagulability and 37.5% [6/16] with hypercoagulability). TEG-G (clot strength as measured by TEG) value (ρ -.553, p = .033) and platelet count (ρ -.840, p < .0001) were correlated with admission PELOD-2 score. TEG-G value (ρ -.506, p = .04) and platelet count (ρ -.539, p = .03) were correlated with the duration of intensive care unit stay. CONCLUSIONS: Coagulation abnormalities are frequent in children with MIS-C. TEG parameter and platelet count are correlated with the severity of multiorgan dysfunction and the duration of intensive care stay. Multicenter studies are needed to confirm the clinical implications of these coagulation abnormalities.

Pediatric Plasma and Platelet Transfusions on Extracorporeal Membrane Oxygenation: A Subgroup Analysis of Two Large International Point-Prevalence Studies and the Role of Local Guidelines.

OBJECTIVES: To describe the indications and thresholds for plasma and platelet transfusions for pediatric extracorporeal membrane oxygenation, to compare responses to these transfusions and to describe institutional protocols directing their administration. DESIGN: Subgroup analysis of two prospective, observational studies paired with survey of sites who enrolled subjects into this cohort. SETTING: Fifty-one PICUs in 13 countries. PATIENTS: Children (3 d to 16 yr old) were enrolled if they received a plasma or platelet transfusion while on extracorporeal membrane oxygenation during one of the predefined screening weeks. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-eight children on extracorporeal membrane oxygenation received plasma transfusions and 90 received platelet transfusions. Sixty percent of plasma transfusions (29/48) and 79% of the platelet transfusions (71/90) were given for prophylaxis of bleeding. The median (interquartile range) international normalized ratio prior to transfusion, known in 75% of the patients (36/48), was 1.45 (1.20-1.85). The median (interquartile range) total platelet count prior to transfusion, known in all of the patients, was 70 × 10/L (52-90 × 10/L). The international normalized ratio and total platelet count values prior to transfusion did not vary based on bleeding versus nonbleeding indications. The median (interquartile range) reduction in international normalized ratio for mild coagulopathies (international normalized ratio ≤ 2.0) was 0.1 (0.4-0), median (interquartile range) increase in fibrinogen was 0.2 g/L (0.1-0.4 g/L) and median increase in total platelet count was 34 × 10/L (10-74 × 10/L). Through the course of their admission, children supported by extracorporeal membrane oxygenation received a total median (interquartile range) dose of 75 mL/kg (36-159 mL/kg) of plasma transfusions and 92 mL/kg (42-239 mL/kg) of platelet transfusions. Institutional protocols varied but provided guidance for platelet transfusions more commonly. CONCLUSIONS: Children supported by extracorporeal membrane oxygenation receive large volumes of plasma and platelet transfusions with some institutional guidance in the form of protocols, but significant variation in practice. Interventional studies are necessary to provide evidence to direct the transfusion of hemostatic products in children supported by extracorporeal membrane oxygenation.

Platelet Transfusion Practice and Related Outcomes in Pediatric Extracorporeal Membrane Oxygenation.

OBJECTIVE: To describe factors associated with platelet transfusion during pediatric extracorporeal membrane oxygenation and the relationships among platelet transfusion, complications, and mortality. DESIGN: Secondary analysis of data collected prospectively by the Collaborative Pediatric Critical Care Research Network between December 2012 and September 2014. SETTING: Eight Collaborative Pediatric Critical Care Research Network-affiliated hospitals. PATIENTS: Age less than 19 years old and treated with extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 511 children, 496 (97.1%) received at least one platelet transfusion during extracorporeal membrane oxygenation. Neonatal age, venoarterial extracorporeal membrane oxygenation, and various acute and chronic diagnoses were associated with increased average daily platelet transfusion volume (milliliters per kilogram body weight). On multivariable analysis, average daily platelet transfusion volume was independently associated with mortality (per 1 mL/kg; odds ratio, 1.05; CI, 1.03-1.08; p < 0.001), whereas average daily platelet count was not (per 1 × 10/L up to 115 × 10/L; odds ratio, 1.00; CI, 0.98-1.01; p = 0.49). Variables independently associated with increased daily bleeding risk included increased platelet transfusion volume on the previous extracorporeal membrane oxygenation day, a primary cardiac indication for extracorporeal membrane oxygenation, adolescent age, and an acute diagnosis of congenital cardiovascular disease. Variables independently associated with increased daily thrombotic risk included increased platelet transfusion volume on the previous extracorporeal membrane oxygenation day and venoarterial extracorporeal membrane oxygenation. Variables independently associated with decreased daily thrombotic risk included full-term neonatal age and an acute diagnosis of airway abnormality. CONCLUSIONS: Platelet transfusion was common in this multisite pediatric extracorporeal membrane oxygenation cohort. Platelet transfusion volume was associated with increased risk of mortality, bleeding, and thrombosis.

Concurrent Use of Calcium Chloride and Arginine Vasopressin Infusions in Pediatric Patients with Acute Cardiocirculatory Failure.

Acute heart failure (AHF) can cause low cardiac output and poor end-organ perfusion. Inotropic agents along with vasodilators can improve organ perfusion. Arginine vasopressin (AVP) and calcium chloride (CaCl) infusions are increasingly being used in low cardiac output states in pediatric AHF. We retrospectively reviewed 77 patients (0-18 years) with AHF admitted between January 2014 and May 2017 who received concurrent AVP and CaCl infusions. Surrogates of cardiac output and organ perfusion included hemodynamic vital signs, laboratory parameters, and urine output (UO). Organ dysfunction and vasopressor inotropic scores were also calculated. Median (IQR) age was 0.88 years (0, 3.75), and median weight was 6.62 kg (3.5, 13.7). Congenital heart disease was present in 70% (46/77) patients. Univentricular physiology was present in 25% (25/77) patients. None of the patients were in the immediate postoperative period. Median durations of AVP and CaCl were 2 days (1, 3) and 3 days (2, 6), respectively. Using Wilcoxon-signed rank test and Bonferroni correction, post hoc comparison showed that at 8 h post infusion, all systolic blood pressure (SBP) and diastolic blood pressure (DBP) results, and UO were greater than those 1 h prior to infusion. Median SBP increased from 79 mm Hg (71, 92) 1 h prior to 97 mm Hg (84, 107) 8 h post. Median DBP increased from 44 mm Hg (35, 52) 1 h prior to 54 mm Hg (44, 62) 8 h post. Heart rate showed a decrease between measurements 1 h prior to infusion and 8 h post, with median scores 146 (127, 162) and 136 (114, 150) beats per minute, respectively. Within first 8 h, median UO continuously increased from 6 mL/h. (0, 25) at 1 h post infusion to 20 mL/h. (2, 62) at 8 h post infusion. Median pediatric logarithmic organ dysfunction scores on days 4 through 7 post infusion were lower compared to day 1; median vasopressor inotropic scores on day 2 through 7 post infusion were lower compared to day 1. Serum lactate level, arterial pH, and base excess all showed favorable trend. Concurrent use of AVP and CaCl infusions may improve surrogates of cardiac output, and intensive care outcomes, and prevent organ dysfunction in children with AHF.

High acetylsalicylic acid dosing in infants after modified Blalock-Taussig shunt.

OBJECTIVE: Shunt-related adverse events are frequent in infants after modified Blalock-Taussig despite use of acetylsalicylic acid prophylaxis. A higher incidence of acetylsalicylic acid-resistance and sub-therapeutic acetylsalicylic acid levels has been reported in infants. We evaluated whether using high-dose acetylsalicylic acid can decrease shunt-related adverse events in infants after modified Blalock-Taussig. METHODS: In this single-centre retrospective cohort study, we included infants ⩽1-year-old who underwent modified Blalock-Taussig placement and received acetylsalicylic acid in the ICU. We defined acetylsalicylic acid treatment groups as standard dose (⩽7 mg/kg/day) and high dose (⩾8 mg/kg/day) based on the initiating dose. RESULTS: There were 34 infants in each group. Both groups were similar in age, gender, cardiac defect type, ICU length of stay, and time interval to second stage or definitive repair. Shunt interventions (18 versus 32%, p=0.16), shunt thrombosis (14 versus 17%, p=0.74), and mortality (9 versus 12%, p=0.65) were not significantly different between groups. On multiple logistic regression analysis, single-ventricle morphology (odds ratio 5.2, 95% confidence interval of 1.2-23, p=0.03) and post-operative red blood cells transfusion ⩾24 hours [odds ratio 15, confidence interval of (3-71), p<0.01] were associated with shunt-related adverse events. High-dose acetylsalicylic acid treatment [odds ratio 2.6, confidence interval of (0.7-10), p=0.16] was not associated with decrease in these events. CONCLUSIONS: High-dose acetylsalicylic acid may not be sufficient in reducing shunt-related adverse events in infants after modified Blalock-Taussig. Post-operative red blood cells transfusion may be a modifiable risk factor for these events. A randomised trial is needed to determine appropriate acetylsalicylic acid dosing in infants with modified Blalock-Taussig.

Platelet Transfusions in the PICU: Does Disease Severity Matter?

OBJECTIVES: Pediatric intensivists frequently prescribe platelet transfusions to critically ill children, but there are limited data on platelet transfusion practice and platelet transfusion-related outcomes in the PICU. In this study, we evaluated the current platelet transfusion practice and platelet transfusion-related outcomes in the PICU. DESIGN: Institutional review board-approved, retrospective cohort study from January 2010 to March 2016. SETTING: Tertiary-level PICU. PATIENTS: Children less than 19 years old who received platelet transfusions in the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-six percent (1,547/4,339) of platelet transfusions in the institution were given to 2.4% of PICU patients (232/9,659). The patients who received a platelet transfusion (platelet transfusions, n = 232) compared with those who did not receive platelets (no platelet transfusions, n = 9,427) were younger, had similar gender distribution, had a higher median Pediatric Risk of Mortality-3 score, and stayed longer in the PICU. Fifty percent of platelet transfusions were prescribed prophylactically for thrombocytopenia to patients without extracorporeal membrane oxygenation support. The mortality was higher for platelet transfusions group (30% vs 2.3%) with an 18 times increased unadjusted odds of mortality when compared with no platelet transfusion group (odds ratio, 18.2; 95% CI, 13.3-24.8; p < 0.0001). In a multiple logistic regression analysis, the predicted probability of dying for platelet transfusion group compared with no platelet transfusion group depended on the median Pediatric Risk of Mortality-3 score. Patients who received platelet transfusion versus no platelet transfusion have increased odds of dying at lower median Pediatric Risk of Mortality-3 scores, but decreased odds of dying at higher median Pediatric Risk of Mortality-3 scores. CONCLUSIONS: This PICU cohort demonstrates that the odds or predicted probability of dying change in patients who received platelet transfusions based on underlying disease severity measured by Pediatric Risk of Mortality-3 score compared with patients who did not receive platelet transfusions. A large, prospective trial is required to confirm this association and determine whether to consider underlying disease severity in estimating risks and benefits of prophylactic platelet transfusions in critically ill children.

Left main coronary artery dissection in pediatric sport-related chest trauma.

BACKGROUND: Traumatic coronary artery dissection (CAD) after blunt chest trauma (BCT) is extremely rare, particularly in children. Among coronary dissections, left main coronary artery (LMCA) dissection is the least common, with only two pediatric cases reported previously. Manifestations of coronary dissections can range from ST segment changes to sudden death. However, these manifestations are not specific and can be present with other cardiac injuries. To our knowledge we present the first pediatric case of traumatic LMCA dissection after sport-related BCT that was treated successfully with coronary stenting. CASE REPORT: A 14-year-old child sustained BCT during a baseball game. Early in the clinical course, he had episodes of ventricular dysrhythmias, diffuse ST changes, rising troponin I, and hemodynamic instability. Emergent cardiac catheterization revealed an LMCA dissection with extension into the proximal left anterior descending artery (LADA). A bare metal stent was placed from the LMCA to the LADA, which improved blood flow through the area of dissection. He has had almost full recovery of myocardial function and has been managed as an outpatient with oral heart failure and antiplatelet medications. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Our case highlights that CAD, although rare, can occur after pediatric BCT. Pediatric emergency responders must have a heightened awareness that evidence of ongoing myocardial ischemia, such as evolving and focal myocardial infarction on electrocardiogram, persistent elevation or rising troponin I, and worsening cardiogenic shock, can represent a coronary event and warrant further evaluation. Cardiac catheterization can be both a diagnostic and therapeutic modality in such cases. Early recognition and management is vital for myocardial recovery.

Elevated Copeptin Levels Are Associated with Heart Failure Severity and Adverse Outcomes in Children with Cardiomyopathy.

In children with cardiomyopathy, the severity of heart failure (HF) varies. However, copeptin, which is a biomarker of neurohormonal adaptation in heart failure, has not been studied in these patients. In this study, we evaluated the correlation of copeptin level with functional HF grading, B-type natriuretic peptide (BNP), and echocardiography variables in children with cardiomyopathy. Furthermore, we determined if copeptin levels are associated with adverse outcomes, including cardiac arrest, mechanical circulatory support, heart transplant, or death. In forty-two children with cardiomyopathy with a median (IQR) age of 13.1 years (2.5-17.2) and a median follow-up of 2.5 years (2.2-2.7), seven (16.7%) children had at least one adverse outcome. Copeptin levels were highest in the patients with adverse outcomes, followed by the patients without adverse outcomes, and then the healthy children. The copeptin levels in patients showed a strong correlation with their functional HF grading, BNP level, and left ventricular ejection fraction (LVEF). Patients with copeptin levels higher than the median value of 25 pg/mL had a higher likelihood of experiencing adverse outcomes, as revealed by Kaplan-Meier survival analysis (p = 0.024). Copeptin level was an excellent predictor of outcomes, with an area under the curve of 0.861 (95% CI, 0.634-1.089), a sensitivity of 86%, and a specificity of 60% for copeptin level of 25 pg/mL. This predictive value was superior in patients with dilated and restrictive cardiomyopathies (0.97 (CI 0.927-1.036), p < 0.0001, n = 21) than in those with hypertrophic and LV non-compaction cardiomyopathies (0.60 (CI 0.04-1.16), p = 0.7, n = 21).

Multi-center retrospective study of children with sickle cell disease admitted to pediatric intensive care units in the United States.

Data on outcomes and interventions for children with sickle cell disease (SCD) admitted to a pediatric intensive care units (PICU) are unknown. We provide the first comprehensive multi-center report on PICU interventions associated with death, the need for invasive respiratory support or stroke among critically ill children with SCD. We collected retrospective multi-center cohort data from January 1, 2012 to December 31, 2019 utilizing the Virtual Pediatric Systems, LLC database. We identified 3388 unique children with SCD, accounting for a total of 5264 PICU admissions from 138 PICUs. The overall mortality rate for the PICU admissions cohort was 1.8% (95/5264 PICU admissions, 95/3388 [2.8%] of all unique patients), the rate of needing of needing Invasive Respiratory Support (IRS, a composite category of exposure) was 21.3% (872/4093 PICU admissions with complete data) and the overall rate of stroke (ischemic or hemorrhagic) was 12.5% (657/5264 PICU admissions). In multivariable analysis adjusting for admission age category, sex, race/ethnicity, PRISM-3 score at admission, exposure to IRS, quartile of unit volume of patients with SCD, and patient origin, admitted children who needed invasive respiratory support (IRS) had higher adjusted odds ratios for mortality (adjusted odds ratio [aOR], 19.72; 95% confidence interval [CI] 8.98-43.29; p < 0.001), although admitted children > 2 years old had decreased aOR for needing IRS (aOR 0.25-0.62; 95% CI 0.16-0.94; p < 0.001-0.025). By contrast, admitted children > 2 years old had a strikingly increased aOR for stroke (aOR 7.57-16.32; 95% CI 2.25-52.15; p < 0.001). These groups may represent PICU-specific subsets of patients with SCD who are at higher risk for more serious illness and should deserve early consideration for referral to a pediatric institution providing comprehensive care for patients with SCD.

Pediatric Swine Model of Methicillin-Resistant Staphylococcus aureus Sepsis-Induced Coagulopathy, Disseminated Microvascular Thrombosis, and Organ Injuries.

Sepsis-induced coagulopathy leading to disseminated microvascular thrombosis is associated with high mortality and has no existing therapy. Despite the high prevalence of Gram-positive bacterial sepsis, especially methicillin-resistant Staphylococcus aureus (MRSA), there is a paucity of published Gram-positive pediatric sepsis models. Large animal models replicating sepsis-induced coagulopathy are needed to test new therapeutics before human clinical trials. HYPOTHESIS: Our objective is to develop a pediatric sepsis-induced coagulopathy swine model that last 70 hours. METHODS AND MODELS: Ten 3 weeks old piglets, implanted with telemetry devices for continuous hemodynamic monitoring, were IV injected with MRSA (n = 6) (USA300, Texas Children's Hospital 1516 strain) at 1 × 109 colony forming units/kg or saline (n = 4). Fluid resuscitation was given for heart rate greater than 50% or mean arterial blood pressure less than 30% from baseline. Acetaminophen and dextrose were provided as indicated. Point-of-care complete blood count, prothrombin time (PT), activated thromboplastin time, d-dimer, fibrinogen, and specialized coagulation assays were performed at pre- and post-injection, at 0, 24, 48, 60, and 70 hours. Piglets were euthanized and necropsies performed. RESULTS: Compared with the saline treated piglets (control), the septic piglets within 24 hours had significantly lower neurologic and respiratory scores. Over time, PT, d-dimer, and fibrinogen increased, while platelet counts and activities of factors V, VII, protein C, antithrombin, and a disintegrin and metalloproteinase with thrombospondin-1 motifs (13th member of the family) (ADAMTS-13) decreased significantly in septic piglets compared with control. Histopathologic examination showed minor focal organ injuries including microvascular thrombi and necrosis in the kidney and liver of septic piglets. INTERPRETATIONS AND CONCLUSIONS: We established a 70-hour swine model of MRSA sepsis-induced coagulopathy with signs of consumptive coagulopathy, disseminated microvascular thrombosis, and early organ injuries with histological minor focal organ injuries. This model is clinically relevant to pediatric sepsis and can be used to study dysregulated host immune response and coagulopathy to infection, identify potential early biomarkers, and to test new therapeutics.

Concomitant hypercalcemia and hyperammonemia associated with distal renal tubular acidosis.

We describe an infant with concomitant hypercalcemia and hyperammonemia associated with nonanion gap metabolic acidosis secondary to distal renal tubular acidosis (dRTA). The levels of both serum calcium and ammonia rapidly normalized with the correction of dehydration and metabolic acidosis. To the best of our knowledge, there has been only one previous case report of concomitant hypercalcemia and hyperammonemia associated with dRTA that has been reported in the literature. We describe the causes and emergent management of hypercalcemia and review the possible mechanisms of this rare association with dRTA.

Viscoelastic Testing in Pediatric Mechanical Circulatory Support.

Pediatric mechanical circulatory support can be lifesaving. However, managing anticoagulation is one of the most challenging aspects of care in patients requiring mechanical circulatory support. Effective anticoagulation is even more difficult in pediatric patients due to the smaller size of their blood vessels, increased turbulent flow, and developmental hemostasis. Recently, viscoelastic testing (VET) has been used as a qualitative measure of anticoagulation efficacy in patients receiving extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VAD). Thromboelastography (TEG®) and thromboelastometry (ROTEM®) provide a global qualitative assessment of hemostatic function from initiation of clot formation with the platelet-fibrin interaction, platelet aggregation, clot strength, and clot lysis. This review focuses on the TEG®/ROTEM® and important laboratory and patient considerations for interpretation in the ECMO and VAD population. We summarize the adult and pediatric ECMO/VAD literature regarding VET values, VET-platelet mapping, utility over standard laboratory monitoring, and association with outcome measures such as blood product utilization, bleeding, and thrombosis.

Extracorporeal Membrane Oxygenation in Critically Ill Children.

Neonatal and pediatric extracorporeal membrane oxygenation (ECMO) has evolved over the past 50 years. Advances in technology, expertise, and application have increased the number of centers providing ECMO with expanded indications for use. However, increasing the use of ECMO in recent years to more medically complex critically ill children has not changed overall survival despite increased experience and improvements in technology. This review focuses on ECMO history, circuits, indications and contraindications, management, complications, and outcome data. The authors highlight important areas of progress, including unintubated and awake patients on ECMO, application during the COVID-19 pandemic, and future directions.

Correlation between Thrombin Generation, Standard Coagulation Assays, and Viscoelastic Assays for Hemostatic Assessment in Critically Ill Children.

BACKGROUND: Accurate assessment of hemostatic function is essential to guide care in critically ill children with acute and acquired coagulopathies. Thrombin generation (TG) provides a global assessment of procoagulant and anticoagulant factors and is commonly used in hemostasis research laboratories. Our objective was to determine the correlation of clinically available hemostasis assays with TG in critically ill children. METHODS: Children (<18 years old, >3 kg in weight) in the intensive care unit were enrolled from March 2016 to December 2019 in a prospective 2-center study. Coagulation tests were prothrombin time, activated thromboplastin time, anti-Xa assay, viscoelastic assays (thromboelastography [TEG], rotational thromboelastometry [ROTEM]), and TG (induced by 20 pM tissue factor in platelet poor plasma and reported as endogenous thrombin potential [ETP; nM*min]). Data are reported as median (interquartile range) or Spearman coefficient (ρ). RESULTS: Patients (n = 106, age 10.2 years [3.8-15.3]) were divided into 3 groups: (a) no anticoagulation (n = 46), (b) anticoagulation (unfractionated heparin) without extracorporeal life support (n = 34), or (c) with extracorporeal life support (n = 26). ETP was decreased in anticoagulated compared to non-anticoagulated patients (group 1: 902.4 [560.8-1234], group 2: 315.6 [0.0-962.2], group 3: 258.5 [0.0-716.6]; P < 0.0001). Across all patients, ETP correlated best with TEG kinetic time (TEG-K), in min (ρ = -0.639), followed by TEG reaction time, in min (ρ = -0.596). By group, ETP correlated best with international normalized ratio for group 1 (ρ = -0.469), TEG-K time for group 2 (ρ = -0.640), and anti-Xa for group 3 (ρ = -0.793). CONCLUSIONS: Standard and viscoelastic assays have varying correlation with TG in critically ill children. TEG-K time had the most consistent moderate correlation with ETP across all groups.