Mechanical Thromboprophylaxis and Hospital-Acquired Venous Thromboembolism Among Critically Ill Adolescents: A U.S. Pediatric Health Information Systems Registry Study, 2016-2023.

OBJECTIVES: To estimate the rate of mechanical thromboprophylaxis (mTP) prescription among critically ill adolescents using a multicenter administrative database and determine whether mTP prescription is inversely associated with hospital-acquired venous thromboembolism. DESIGN: Multicenter, observational, retrospective study of the Pediatric Health Information Systems (PHIS) Registry cohort, January 2016 to December 2023. SETTING: Thirty PICUs located within quaternary pediatric referral centers in the United States. PATIENTS: Critically ill children 12-17 years old, excluding encounters with a principal diagnosis at admission of venous thromboembolism. INTERVENTIONS: mTP prescription within the first 24 hours of hospitalization. MEASUREMENTS AND MAIN RESULTS: A total of 107,804 children met the study criteria, of which 21,124 (19.6%) were prescribed mTP. Hospital center prescribing rates ranged from 1.4% to 65.4% and decreased by 1.6% per year from 28.2% in 2016 to 17.1% in 2023. As compared with those without mTP, those with mTP more frequently had a concurrent central venous catheter (17.2% vs. 9.4%, p < 0.001), underwent invasive mechanical ventilation (37.4% vs. 24.8%, p < 0.001), were admitted for a primary surgical indication (30.9% vs. 12.7%, p < 0.001), and experienced a longer median duration of hospitalization (7 [interquartile range (IQR): 4-15] vs. 4 [IQR: 2-9] d, p < 0.001). Hospital-acquired venous thromboembolism occurred in 2.7% of the study sample and was more common among those with, as compared with without, prescription of mTP (4% vs. 2.4%, p < 0.001). In multivariable logistic regression models for hospital-acquired venous thromboembolism adjusting for salient prothrombotic risk factors, we failed to identify an association between mTP and greater odds of hospital-acquired venous thromboembolism (HA-VTE) among low-, moderate-, and high-risk tiers. However, we cannot exclude the possibility of 17-50% greater odds of HA-VTE in this population. CONCLUSIONS: In the multicenter PHIS cohort, 2016-2023, the prescribing patterns for mTP among critically ill adolescents showed a low rate of mTP prescription (19.6%) that varied widely across institutions, decreased annually over the study period by 1.6%/year, and was not independently associated with HA-VTE risk reduction.

Circulating High Mobility Group Box-1 Does Not Predict Pulmonary Arterial Hypertension in Children with Congenital Heart Disease: A Prospective Cohort Study.

OBJECTIVES: Pulmonary arterial hypertension (PAH) is a devastating complication of pediatric congenital heart disease (CHD). A recent study has identified the protein high mobility group box-1 (HMGB1) as a diagnostic tool in adults with CHD-associated PAH. HMGB1 levels in adults with CHD-associated PAH correlated with mean pulmonary artery pressure and pulmonary vascular resistance, and HGMB1 levels fell in response to sildenafil therapy. We wanted to assess if HGMB1 was a biomarker of pediatric CHD-PAH. DESIGN: Prospective cohort study. SETTING: Quaternary pediatric academic hospital PARTICIPANTS: Children ≤18 years with CHD with and without known pulmonary hypertension. Controls were children undergoing dental or urologic surgery with no known heart disease. INTERVENTIONS: Pulmonary hemodynamics, echocardiographic assessment, and biomarker measurement. Controls had biomarker measurement only. MEASUREMENTS AND MAIN RESULTS: Patients with CHD-PAH had mean pulmonary vascular resistance index of 10 Wood units/m2. Neither HGMB1 nor N-terminal pro-brain-type natriuretic peptide levels were significantly different between the groups. Neither marker correlated with pulmonary hypertension. CONCLUSIONS: Unlike in adults, HGMB1 is not a biomarker of PAH in pediatric CHD. Further work will continue to explore for biomarkers for this high-risk population.

Methods, precision, and analytical sensitivity of a novel low-plasma-volume assay of fibrinolytic capacity utilizing the euglobulin fraction.

INTRODUCTION: Fibrinolysis is a critical aspect of the hemostatic system, with assessment of fibrinolytic potential being critical to predict bleeding and clotting risk. We describe the method for a novel low-plasma-volume assay of fibrinolytic capacity utilizing the euglobulin fraction (the "modified mini-euglobulin clot lysis assay [ECLA]"), its analytic sensitivity to alterations in key fibrinolytic substrates/regulators, and its initial applications in acute and convalescent disease cohorts. METHODS: The modified mini-ECLA requires 50 µL of plasma, a maximal read time of 3 h (with most results available within 60 min), and is entirely performed in a 96-well microplate. Assay measurements were obtained in a variety of commercial control and deficient plasmas representing clinically relevant hypo- and hyperfibrinolytic states, and in three distinct adolescent cohorts with acute or convalescent illness: critically ill, following endotracheal intubation; acute COVID-19-related illness; and ambulatory, 3 months following a venous thromboembolic event. RESULTS: In 100% and 75% deficient plasmas, hypofibrinolysis for plasminogen-deficient, fibrinolysis for alpha-2-antiplasmin-deficient, and hyperfibrinolysis for plasminogen activator inhibitor-1-deficient plasmas were observed. CONCLUSION: The modified mini-ECLA Clot Lysis Time Ratio ("CLTR") demonstrated moderate-strength correlations with the Clot Formation and Lysis (CloFAL) assay, is analytically sensitive to altered fibrinolytic states in vitro, and correlates with clinical outcomes in preliminarily-studied patient populations.

Invasive Mechanical Ventilation and Risk of Hospital-Acquired Venous Thromboembolism.

BACKGROUND: This study sought to estimate the overall cumulative incidence and odds of Hospital-acquired venous thromboembolism (VTE) among critically ill children with and without exposure to invasive ventilation. In doing so, we also aimed to describe the temporal relationship between invasive ventilation and hospital-acquired VTE development. METHODS: We performed a retrospective cohort study using Virtual Pediatric Systems (VPS) data from 142 North American pediatric ICUs among children < 18 y of age from January 1, 2016-December 31, 2022. After exclusion criteria were applied, cohorts were identified by presence of invasive ventilation exposure. The primary outcome was cumulative incidence of hospital-acquired VTE, defined as limb/neck deep venous thrombosis or pulmonary embolism. Multivariate logistic regression was used to determine whether invasive ventilation was an independent risk factor for hospital-acquired VTE development. RESULTS: Of 691,118 children studied, 86,922 (12.4%) underwent invasive ventilation. The cumulative incidence of hospital-acquired VTE for those who received invasive ventilation was 1.9% and 0.12% for those who did not (P < .001). The median time to hospital-acquired VTE after endotracheal intubation was 6 (interquartile range 3-14) d. In multivariate models, invasive ventilation exposure and duration were each independently associated with development of hospital-acquired VTE (adjusted odds ratio 1.64 [95% CI 1.42-1.86], P < .001; and adjusted odds ratio 1.03 [95% CI 1.02-1.03], P < .001, respectively). CONCLUSIONS: In this multi-center retrospective review from the VPS registry, invasive ventilation exposure and duration were independent risk factors for hospital-acquired VTE among critically ill children. Children undergoing invasive ventilation represent an important target population for risk-stratified thromboprophylaxis trials.

Epidemiology of clinically unsuspected venous thromboembolism in children with cancer: A population-based study from Maritimes, Canada.

Inconsistencies in the definition of clinically unsuspected venous thromboembolism (VTE) in pediatric patients recently led to the recommendation of standardizing this terminology. Clinically unsuspected VTE (cuVTE) is defined as the presence of VTE on diagnostic imaging performed for indications unrelated to VTE in a patient without symptoms or clinical history of VTE. The prevalence of cuVTE in pediatric cancer patients is unclear. Therefore, the main objective of our study was to determine the prevalence of cuVTE in pediatric cancer patients. All patients 0-18 years old, treated at the IWK in Halifax, Nova Scotia, from August 2005 through December 2019 with a known cancer diagnosis and at least one imaging study were eligible (n = 743). All radiology reports available for these patients were reviewed (n = 18,120). The VTE event was labeled a priori as cuVTE event for radiology reports that included descriptive texts indicating a diagnosis of thrombosis including thrombus, central venous catheter-related, thrombosed aneurysm, tumor thrombosis, non-occlusive thrombus, intraluminal filling defect, or small fragment clot for patients without documentation of clinical history and or signs of VTE. A total of 18,120 radiology reports were included in the review. The prevalence of cuVTE was 5.5% (41/743). Echocardiography and computed tomography had the highest rate of cuVTE detection, and the most common terminologies used to diagnose cuVTE were thrombus and non-occlusive thrombus. The diagnosis of cuVTE was not associated with age, sex, and type of cancer. Future efforts should focus on streamlining radiology reports to characterize thrombi. The clinical significance of these cuVTE findings and their application to management, post-thrombotic syndrome, and survival compared to cases with symptomatic VTE and patients without VTE should be further studied.

Ketorolac Dosing and Outcomes in Neonates Following Congenital Heart Surgery: A Retrospective Analysis.

BACKGROUND: Pain management is essential for postoperative surgery. Given the association of opioids with adverse outcomes, interest in the use of nonopioid analgesics, such as ketorolac, has increased. Published data on use in neonates are limited. OBJECTIVES: To describe ketorolac dosing and safety and efficacy outcomes in the first 48 hours postcardiac surgery in neonates. DESIGN: We performed a single-center retrospective cohort study of neonates (ages < 28 d) who received ketorolac following cardiac surgery from November 2020 to July 2023 (inclusive). The primary safety outcome was a clinically significant decline in renal function, as defined by the composite of an increase in serum creatinine by greater than or equal to 0.3 mg/dL from baseline within 96 hours of ketorolac initiation and urine output less than or equal to 0.5 mL/kg/hr for 6 hours. The secondary safety outcome was clinically significant bleeding, defined as the composite of major bleeding by the International Society on Thrombosis and Hemostasis pediatric criteria and severe/fatal bleeding by the criteria of Nellis et al (2019). Efficacy was measured by opioid utilization based on a standardized pain score-driven analgesia protocol. INTERVENTIONS: Ketorolac was administered at 0.5 mg/kg every 6 hours as per an institutional clinical management algorithm. MEASUREMENTS AND MAIN RESULTS: Thirty-nine patients met the eligibility criteria. The median ketorolac dose was 0.5 mg/kg/dose, and median (interquartile range [IQR]) duration of therapy was 48 hours (6-48 hr). No patients experienced a significant decline in renal function, and there were no clinically significant bleeding events. The median (IQR) IV morphine milligram equivalents (MMEs)/kg/d of opioid administration was 0.2 MME/kg/d (0.1-0.25 MME/kg/d) at the time of ketorolac initiation and 0.1 MME/kg/d (0.1-0.2 MME/kg/d) at 48 hours post-ketorolac initiation. CONCLUSIONS: If validated prospectively, these findings suggest that a ketorolac regimen of 0.5 mg/kg/dose every 6 hours in neonates postcardiac surgery may be safe with regard to renal function and bleeding risk. Additional randomized studies would be needed to determine efficacy with regard to opioid-sparing capacity.

Evaluation, analysis, and reporting of medication adherence for clinical trials of anticoagulants in children: guidance from the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis.

In response to growing recognition that nonadherence prevents children, adolescents, and young adults from achieving the therapeutic benefits of anticoagulant medication, the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis convened a working party on medication adherence. The primary aim of this article was to synthesize recommendations from the larger adherence science literature to provide guidance regarding the classification, collection, and interpretation of anticoagulation adherence data. The secondary aim of this article was to evaluate the degree to which trials published from 2013 to 2023 adhered to these guidance recommendations. As less than half of all trials reported on adherence and none included all recommended elements, the proposed International Society on Thrombosis and Haemostasis Scientific and Standardization Committee guidance has the potential to enhance the rigor and reproducibility of pediatric anticoagulant research.

Suicide, Stimulants, and Selective Serotonin Reuptake Inhibitors: A Retrospective Chart Review.

Background: Previous studies suggest that selective serotonin reuptake inhibitors (SSRIs) may increase the risk of suicide among children and youth, although the association between suicide risk and the combination of SSRIs with other medication such as stimulants in this population remains unclear. This study explored whether the combination of SSRIs with stimulants influenced suicide risk. Methods: A retrospective cohort study was conducted at a single children's hospital campus-based ambulatory psychiatric clinic between September 1, 2017, and September 30, 2020. Subjects were 6-21 years of age and prescribed either stimulants or stimulants and SSRIs only. The primary outcome was suicidal thoughts and behaviors (STB), defined by documented suicidal thoughts, plans, or behaviors. Firth logistic regression evaluated associations between medication class and STB. Results: Among 349 patients, the prevalence of STB was 5.7% (n = 20). In unadjusted model, patients prescribed SSRIs and stimulants had a 2.9-fold increase of STB compared to patients prescribed stimulants only, along with increasing age, male sex, and the diagnoses of anxiety and/or depression. In the final model adjusted for each of these factors, the observed association of medication regiment with STB was attenuated (odds ratio [OR]: 1.3, confidence interval [CI]: 0.3-4.9, p = 0.7). The magnitude of the adjusted association between depressive diagnosis and STB was notable (OR: 3.6, CI: 1.0-12.6, p = 0.049). Conclusions: Among patients followed in a children's hospital-based ambulatory psychiatric clinic, a combination medication regimen of SSRIs and stimulants after adjusting for genetic sex, age, anxiety diagnosis, and depression diagnosis, the observed association between STB and combination stimulant and SSRI treatment was attenuated. This finding suggests that other factors, including depression, may have contributed to the association between SSRI treatment and STB. Larger, prospective studies of the relationship between combination pharmacotherapy and suicide risk are warranted to guide clinical/pharmacological decision making and to better clarify these relationships.

Assessment of rare bleeding disorders in adolescents with heavy menstrual bleeding.

INTRODUCTION: There are a significant number of patients with mucocutaneous bleeding, specifically heavy menstrual bleeding (HMB), who do not have a diagnosed bleeding disorder. These patients receive nontargeted interventions and may have suboptimal treatments. Functional assays, particularly for fibrinolytic and rare platelet function defects, are not robust and not readily available. AIM: We aimed to prospectively evaluate the prevalence of genetic defects associated with rare bleeding disorders and describe alterations of coagulation and fibrinolysis in a cohort of adolescents with HMB. METHODS: We performed a prospective observational cohort study of patients with HMB and unexplained bleeding. The study utilized a next generation sequencing panel and investigational global assays of coagulation and fibrinolysis. Additionally, specific functional assays were performed to help characterize novel variants that were identified. RESULTS: In 10 of the 17 patients (∼59%), genetic variants were identified on molecular testing. Thrombin generation by calibrated thromboelastography was not significantly altered in this patient population. The clot formation and lysis assay showed a trend towards increased fibrinolysis with rapid phase of decline in 23% of the patients. Further corresponding functional assays and study population are described. CONCLUSION: Our study describes a unique correlative model in a homogenous cohort of patients with HMB and unexplained bleeding which may inform future diagnostic algorithms, genotype-phenotype correlations as well as aid in specific targeted treatment approaches. Larger future studies may inform risk stratification of patients and improve health related outcomes in patients with HMB.

Considerations for instituting pediatric pulmonary embolism response teams: A tool kit.

The incidence of pediatric pulmonary embolism (PE) has increased by 200 % in the last decade, but at a single center, it is still infrequent. Given the unique epidemiologic features of pediatric PE, diagnosis is often delayed, and the management is empiric, based on individual physician experience or preference. Thus, there is a strong need for center-specific uniform management of pediatric PE patients. In adults, the development of pulmonary embolism response teams (PERTs) or PE critical care pathways has shortened the time to diagnosis and the initiation of definitive management. Evidence to support an improvement in PE outcomes after the development of PERTs does not exist in children. Nonetheless, we have summarized the practical practice guidelines that physicians and institutions can adopt to establish their institutional PERTs or critical pathways. We also provide strategies for resource-challenged institutions for partnering with centers with expertise in the management of pediatric PE.

Bilateral nephrectomy impairs cardiovascular function and cerebral perfusion in a rat model of acute hemodilutional anemia.

Anemia and renal failure are independent risk factors for perioperative stroke, prompting us to assess the combined impact of acute hemodilutional anemia and bilateral nephrectomy (2Nx) on microvascular brain Po2 (PBro2) in a rat model. Changes in PBro2 (phosphorescence quenching) and cardiac output (CO, echocardiography) were measured in different groups of anesthetized Sprague-Dawley rats (1.5% isoflurane, n = 5-8/group) randomized to Sham 2Nx or 2Nx and subsequently exposed to acute hemodilutional anemia (50% estimated blood volume exchange with 6% hydroxyethyl starch) or time-based controls (no hemodilution). Outcomes were assessed by ANOVA with significance assigned at P < 0.05. At baseline, 2Nx rats demonstrated reduced CO (49.9 ± 9.4 vs. 66.3 ± 19.3 mL/min; P = 0.014) and PBro2 (21.1 ± 2.9 vs. 32.4 ± 3.1 mmHg; P < 0.001) relative to Sham 2Nx rats. Following hemodilution, 2Nx rats demonstrated a further decrease in PBro2 (15.0 ± 6.3 mmHg, P = 0.022). Hemodiluted 2Nx rats did not demonstrate a comparable increase in CO after hemodilution compared with Sham 2Nx (74.8 ± 22.4 vs. 108.9 ± 18.8 mL/min, P = 0.003) that likely contributed to the observed reduction in PBro2. This impaired CO response was associated with reduced fractional shortening (33 ± 9 vs. 51 ± 5%) and increased left ventricular end-systolic volume (156 ± 51 vs. 72 ± 15 µL, P < 0.001) suggestive of systolic dysfunction. By contrast, hemodiluted Sham 2Nx animals demonstrated a robust increase in CO and preserved PBro2. These data support the hypothesis that the kidney plays a central role in maintaining cerebral perfusion and initiating the adaptive increase in CO required to optimize PBro2 during acute anemia.NEW & NOTEWORTHY This study has demonstrated that bilateral nephrectomy acutely impaired cardiac output (CO) and microvascular brain Po2 (PBro2), at baseline. Following acute hemodilution, nephrectomy prevented the adaptive increase in CO associated with acute hemodilution leading to a further reduction in PBro2, accentuating the degree of cerebral tissue hypoxia. These data support a role for the kidney in maintaining PBro2 and initiating the increase in CO that optimized brain perfusion during acute anemia.

Apixaban overdose in children: case report and proposed management. A brief communication from the Pediatric and Neonatal Thrombosis and Hemostasis SSC of ISTH.

Background: Direct oral anticoagulants are commonly prescribed for adults and increasingly also for children requiring anticoagulation therapy. While household medications should not be accessible to children, accidental, and intentional overdoses occur. Key Clinical Question: How should apixaban overdose in children be managed?. Clinical Approach: We present a case of an accidental overdose with the factor Xa antagonist apixaban in a young child and propose an approach to the management of cases of apixaban overdose in children. Conclusion: Given the increasing use of direct oral anticoagulants, it is important to have an approach to the management of overdose of these medications.

Ketorolac in neonates and infants following congenital heart surgery: a retrospective review.

INTRODUCTION: Pain management is essential in the immediate post-surgical period. We sought to describe the ketorolac dose regimen in neonates and infants following cardiac surgery. Secondary outcomes included renal dysfunction, bleeding, and pain management. METHODS: We performed a single-centre retrospective cohort study of neonates and infants (aged < 12 months) who received ketorolac following cardiac surgery, from November 2020 through November 2021 (inclusive). Ketorolac was administered at 0.5 mg/kg every 6 hours. Safety was defined by absence of a clinically significant decline in renal function (i.e., increase in serum creatinine [SCr] by ≥ 0.3 mg/dL from baseline within 48 hours and/or urine output ≤ 0.5 mL/kg/hour for 6 hours) and absence of clinically significant bleeding defined as major by International Society on Thrombosis and Hemostasis paediatric criteria or Severe/Fatal Bleeding Events by Nellis et al. Efficacy measures included pain scores and opioid utilisation. RESULTS: Fifty-five patients met eligibility criteria. The median (range) dose and duration of ketorolac administration was 0.5 mg/kg/dose for 48 (6-90) hours. Among all patients, there was not a statistically significant difference observed in median SCr within 48 hours of baseline (p > .9). There were no major or severe bleeding events. The median (range) opioid requirements (morphine intravenous equivalents per kg per day) at 48 hours post-ketorolac initiation was 0.1 (0-0.8) mg/kg/day. CONCLUSIONS: If validated prospectively, these findings suggest that a ketorolac regimen 0.5 mg/kg/dose every 6 hours in neonates and infants post-cardiac surgery may be safe with regard to renal function and bleeding risk, and effective regarding opioid-sparing capacity.