A retrospective study of the yield of next-generation sequencing in the diagnosis of developmental and epileptic encephalopathies and epileptic encephalopathies in 0-12 years aged children at a single tertiary care hospital in South India.

OBJECTIVE: Studies on the genetic yield of developmental and epileptic encephalopathy and Epileptic encephalopathies using next-generation sequencing techniques are sparse from the Indian subcontinent. Hence, the study was conducted to assess the yield of genetic testing and the proportion of children where a positive genetic yield influenced treatment decisions. METHODS: In this retrospective observational study, electronic medical records of children (0-12 years) with suspected genetic epilepsy who underwent genetic testing using whole exome sequencing, focused exome sequencing and epilepsy gene panels were retrieved. Genetic yield was ascertained based on the detection of pathogenic and likely pathogenic variants. RESULTS: A total of 100 patients with epilepsy underwent genetic testing. A yield of 53.8% (42/78) was obtained. Pathogenic variants were identified in 18 (42.8%) cases and likely pathogenic variants in 24 (57.1%) cases. Yield was 66.6% each through whole exome sequencing, focused exome sequencing and 40% through Epilepsy gene panels (p = .07). Yield was not statistically significant across different age groups (p = .2). It was however found to significantly vary across different epilepsy syndromes with maximum yield in Epilepsy in infancy with migrating focal seizures in 2 (100%), followed by developmental and epileptic encephalopathy unspecified in 14 (77.7%), Dravet syndrome in 14 (60.8%), early infantile developmental and epileptic encephalopathy in 3 (60%), infantile epileptic spasm syndrome in 5 (35.7%), and other epileptic encephalopathies in 4 (30.7%) cases (p = .04). After genetic diagnosis and drug optimization, drug-refractory proportion reduced from 73.8% to 45.3%. About half of the cases achieved seizure control. SIGNIFICANCE: A reasonably high yield of 53.8% was obtained irrespective of the choice of panel or exome or age group using next-generation sequencing-based techniques. Yield was however higher in certain epilepsy syndromes and low in Infantile epileptic spasms syndrome. A specific genetic diagnosis facilitated tailored treatment leading to seizure freedom in 28.6% and marked seizure reduction in 54.7% cases.

An Unusual Presentation of Renal Failure: A Case of Myeloperoxidase-Antineutrophil Cytoplasmic Antibody (MPO-ANCA) Vasculitis.

Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) vasculitis manifests as a neutrophilic inflammation impacting small vessels across multiple organs, notably the lungs, kidneys, and skin. We present a unique case of MPO-ANCA vasculitis in a 77-year-old female characterized by glomerulosclerosis, rapidly progressive renal failure necessitating hemodialysis (HD), bullous skin lesions, and hypoxic respiratory failure. The patient, who had a history of type 2 diabetes, presented with progressive dyspnea, hypoxia, and acute kidney injury superimposed on chronic kidney disease (CKD) progressing to renal failure requiring dialysis. A renal biopsy highlighted globally sclerosed glomeruli, interstitial fibrosis, and tubular atrophy, along with increased immunoglobulin M (IgM) deposits on immunofluorescence, differing from typical findings. Prompt initiation of prednisone led to respiratory and cutaneous improvement; however, despite therapy, extensive renal damage led to the permanent requirement of dialysis.  MPO vasculitis primarily targets small vessels, frequently affecting kidneys, with only a subset of patients progressing rapidly to end-stage renal failure necessitating HD, as observed in our case. Contrary to classical histopathological patterns, our patient exhibited augmented IgM deposits. Left untreated, MPO vasculitis with renal involvement poses a mortality risk of up to 90%, underscoring the significance of prompt detection and corticosteroid intervention to avert renal failure and improve patient outcomes. Early recognition and timely treatment are pivotal in mitigating the dire consequences of this condition, emphasizing the importance of considering MPO vasculitis in patients with rapidly deteriorating renal function.

Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion following SARS-CoV-2 Infection-A Rare Case Report.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a clinicoradiological syndrome first recognized during the influenza pandemic in Japanese population in the late twentieth century. 1 In this article, we presented a rare case report of AESD in a young child due to severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2) who presented with febrile status epilepticus, persistent encephalopathy, and had recurrence of seizures on day 4 of illness with characteristic magnetic resonance imaging findings and a relatively fair outcome.

Optimization of intelligent infusion pump technology to minimize vasopressor pump programming errors.

BACKGROUND: There is a lack of data evaluating the impact of hard limit implementation into intelligent infusion pump technology (IIPT). The purpose of this study was to determine if incorporation of vasopressor upper hard limits (UHL) into IIPT increases efficacy of alerts by preventing pump programming errors. METHODS: Retrospective review from five hospitals within a single healthcare network between April 1, 2013 and May 31, 2014. A total of 65,680 vasopressor data entries were evaluated; 19,377 prior to hard limit implementation and 46,303 after hard limit implementation. The primary outcome was the percent of effective alerts. The secondary outcome was the proportional dose increase from the soft limit provided. RESULTS: A reduction in alert rate occurred after incorporation of hard limits to the IIPT drug library (pre-UHL 4.7% vs. post-UHL 4.0%) with a subsequent increase in the number of errors prevented as represented by a higher effective alert rate (pre-UHL 23.0% vs. post-UHL 37.3%; p < 0.001). The proportional dose increase was significantly reduced (pre-UHL 188% ± 380%] vs. post-UHL 95% ± 128%; p < 0.001). CONCLUSIONS: Incorporation of UHLs into IIPT in a multi-site health system with varying intensive care unit and emergency department acuity increases alert effectiveness, reduces dosing errors, and reduces the magnitude of dosing errors that reach the patient.

Impact of Norepinephrine Weight-Based Dosing Compared With Non-Weight-Based Dosing in Achieving Time to Goal Mean Arterial Pressure in Obese Patients With Septic Shock.

BACKGROUND: Currently, a lack of standardization exists in norepinephrine dosing units, the first-line vasopressor for septic shock. Timely achievement of goal mean arterial pressure (MAP) is dependent on optimal vasopressor dosing. OBJECTIVE: To determine if weight-based dosing (WBD) of norepinephrine leads to earlier time to goal MAP compared with non-WBD in obese patients with septic shock. METHODS: This was a retrospective, multicenter cohort study. Patients had a body mass index (BMI) ≥30 kg/m2 and received norepinephrine for septic shock with either a non-WBD strategy (between December 2009 and January 2013) or WBD strategy (between January 2013 and December 2015). The primary outcome was time to goal MAP. Secondary outcomes were norepinephrine duration, dose requirements, and development of treatment-related complications. RESULTS: A total of 287 patients were included (WBD 144; non-WBD 143). There was no difference in median time to goal MAP (WBD 58 minutes, interquartile range [IQR] = 16.8-118.5, vs non-WBD 60 minutes, IQR = 17.5-193.5; P = 0.28). However, there was a difference in median cumulative norepinephrine dose (WBD 12.6 mg, IQR = 4.9-45.9, vs non-WBD 10.5 mg, IQR = 3.9-25.6; P = 0.04) and time to norepinephrine discontinuation (WBD 33 hours, IQR = 15-69, vs non-WBD 27 hours, IQR = 12-51; P = 0.03). There was no difference in rates of atrial fibrillation (WBD 15.3% vs non-WBD 23.7%; P = 0.07) or mortality (WBD 23.6% vs non-WBD 23.1%; P = 0.92). CONCLUSION: WBD of norepinephrine does not achieve time to goal MAP earlier in obese patients with septic shock. However, WBD may lead to higher norepinephrine cumulative dose requirements and prolonged time until norepinephrine discontinuation.

Blood glucose response to rescue dextrose in hypoglycemic, critically ill patients receiving an insulin infusion.

BACKGROUND: There is inadequate guidance for clinicians on selection of the optimal dextrose 50% (D50W) dose for hypoglycemia correction in critically ill patients. OBJECTIVE: The purpose of this study was to determine the blood glucose (BG) response to D50W in critically ill patients. METHODS: A retrospective analysis was conducted of critically ill patients who received D50W for hypoglycemia (BG < 70 mg/dL) while on an insulin infusion. The primary objective of this study was to determine the BG response to D50W. The relationship between participant characteristics and the dose-adjusted change in BG following D50W was analyzed using simple and multiple linear mixed-effects models. RESULTS: There were 470 hypoglycemic events (BG < 70 mg/dL) corrected with D50W. The overall median BG response was 4.0 (2.53, 6.08) mg/dL per gram of D50W administered. Administration of D50W per protocol resulted in 32 episodes of hyperglycemia (BG > 150 mg/dL), resulting in a 6.8% rate of overcorrection; 49% of hypoglycemic episodes (230/470) corrected to a BG >100 mg/dL. A multivariable GEE analysis showed a significantly higher BG response in participants with diabetes (0.002) but a lower response in those with recurrent hypoglycemia (P = 0.049). The response to D50W increased with increasinginsulin infusion rate (P = 0.022). Burn patients experienced a significantly larger BG response compared with cardiac, medical, neurosurgical, or surgical patients. CONCLUSIONS: The observed median effect of D50W on BG was approximately 4 mg/dL per gram of D50W administered. Application of these data may aid in rescue protocol development that may reduce glucose variability associated with hypoglycemic episodes and the correction.

Bleeding risk with systemic thrombolytic therapy for pulmonary embolism: scope of the problem.

Acute pulmonary embolism represents a major complication of venous thromboembolism that is associated with high morbidity and mortality. Guidelines recommend the rapid initiation of anticoagulation and consideration of thrombolytic therapy in select patients, including those with hypotension or at high risk of developing hypotension. Evaluation for thrombolytic therapy should only be considered after assessment of contraindications and risk for major bleeding. The objective of this perspective article is to evaluate the bleeding risk associated with systemic thrombolytic therapy in the management of acute pulmonary embolism and discuss strategies to minimize this risk. Risk stratification of acute pulmonary embolism will be discussed to identify patient populations that warrant specific consideration of risk for major bleeding with thrombolytic therapy. In addition, the incidence, patient-specific risk factors, and pharmacologic characteristics, including concurrent anticoagulation and thrombolytic therapy, will be evaluated in the context of risk for major hemorrhage. Finally, supporting evidence for strategies to minimize risk of hemorrhage, including evaluation of contraindications, weight adjusted dosing, infusion strategy and catheter-directed thrombolytic administration will be evaluated. Despite published guidelines and review articles, select aspects to thrombolytic therapy for the management of pulmonary embolism remain controversial and under recognized, including risk of major hemorrhage. When making decisions about the role of thrombolytic therapy in pulmonary embolism, clinicians must be knowledgeable about the associated risks of thrombolytic therapy and individually evaluate patient risk factors prior to determining appropriate candidacy for thrombolytic therapy. For patients considered to be at high risk of major bleeding, strategies to minimize risk should be considered, including weight-adjusted doses and catheter directed therapy. Additional research is needed specific to the acute pulmonary embolism setting to validate risk factors and strategies to minimize major hemorrhage.

Length of Stay Comparison between Rivaroxaban and Warfarin in the Treatment of Pulmonary Embolism: Results from a Real-World Observational Cohort Study.

Background. Trials have shown that novel oral anticoagulants may decrease length of stay versus warfarin. A comparison of length of stay in the treatment of pulmonary embolism (PE) has not been performed outside post hoc analysis of a large clinical trial. Objective. To evaluate if rivaroxaban decreases length of stay compared to warfarin plus enoxaparin in the treatment of PE. Methods. This was a multicenter, retrospective, observational cohort study. Patients were identified based on discharge diagnosis of PE and were excluded if they received anticoagulants prior to admission and had additional indications for anticoagulation or reduced creatinine clearance. The primary endpoint was length of stay. Secondary endpoints included time from initial dose of oral anticoagulant to discharge and length of stay comparison between subgroups. Results. Inclusion criterion was met by 158 patients (82 warfarin, 76 rivaroxaban). The median length of stay was 4.5 days (interquartile range [IQR], 2.7, 5.9) in the warfarin group and 1.8 days (IQR, 1.2, 3.7) in the rivaroxaban group (P < 0.001). Time interval from first dose of oral anticoagulant to discharge was shorter with rivaroxaban (P < 0.001). Conclusions. Patients given rivaroxaban had decreased length of stay versus those given warfarin plus enoxaparin for the treatment of PE.

Bivalirudin in pediatric patients maintained on extracorporeal life support.

OBJECTIVE: Anticoagulation with heparin is standard of care for patients maintained on extracorporeal life support. Very limited evidence exists for the use of alternative anticoagulants during extracorporeal life support. Patients with heparin-induced thrombocytopenia, heparin resistance, and evidence of significant thrombosis while on heparin may be candidates for alternative anticoagulation. The objective of this analysis is to present evidence for the use of bivalirudin during extracorporeal life support in pediatric patients. DESIGN: Case series. SETTING: University of California, Davis Medical Center. PATIENTS: Twelve critically ill, pediatric patients receiving bivalirudin for anticoagulation during extracorporeal life support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twelve patients meeting entry criteria received bivalirudin during the study period. The median patient age was 8 days (range, 1 d to 6 yr). Eight patients were neonates. Eight patients were male. Nine patients were supported with venoarterial extracorporeal life support. Median duration of extracorporeal life support was 226 hours (range, 111-913) and median time on bivalirudin was 92 hours (range, 60-230). Bivalirudin bolus doses were administered to select patients without bleeding complications. The maintenance dose that corresponded with initial target activated partial thromboplastin time ranged from 0.045 to 0.48 mg/kg/hr with a median rate of 0.16 mg/kg/hr. The median dose for days 1, 3, and 5 was 0.135, 0.175, and 0.267 mg/kg/hr, respectively. The correlation (r2) between dose adjustment and activated partial thromboplastin time response was 0.264. CONCLUSIONS: This is the largest case series describing the use of a direct thrombin inhibitor in pediatric extracorporeal life support patients. The maintenance dose range reflected considerable inter-patient variability. There was an observed increase in dose requirements with time. Bivalirudin, with close monitoring, is a potential option for pediatric patients on extracorporeal life support who have developed heparin-induced thrombocytopenia, heparin resistance, or significant thrombosis while on heparin.