Children with idiopathic generalized epilepsy those underwent at least two years seizure remission: a retrospective analysis

Background: The aim of the retrospective study was to evaluate the effectiveness of the index antiepileptic drugs in children with idiopathic generalized epilepsy who underwent at least 2 years remission.Methods: A total of 52 children with idiopathic generalized epilepsy who underwent at least 2 years remission were identified retrospectively from the records of the paediatric and neurology care clinic from April 2017 to December 2020.Results: The seizure patterns of 52 cases were tonic-clonic seizures alone (73%), a combination of tonic-clonic seizures and absences (13.5%), and combined tonic-clonic seizures and myoclonus (13.5%). The total number of seizures at enrolment in all (age at seizure onset 7.44±5.12 years, male-female ratio (31:21) was 651 (mean 12.52±26.60). The total number of follow-up visits in all was 6.62±14.44 consisting of 1177.5±772.86 days of follow-up periods. All patients continued index antiepileptic drugs with initial target doses varies from low to moderate ranges. Add-on therapy was initiated in 43% of cases around the titration phase of index antiepileptic drugs (i.e. very early add-on). Treatment trends reveal increased use of 1st generation antiepileptic drugs than 2nd and 3rd generation. 2 years seizure remission rates were 55.77% by index antiepileptic drugs only therapy and 44.23% by very early add-on therapy. The seizure remission period was mean±SD 858.71±209.08 days.Conclusions: Index antiepileptic drugs with low to moderate initial target doses lead to achieving 2 years or more seizure remission. Very early add-on therapy is the novelty and leads to achieving the goal.

Lung ultrasound guided pulmonary recruitment during mechanical ventilation in neonates: A case series

BACKGROUND: Recently, the first report of lung ultrasound (LUS) guided recruitment during open lung ventilation in neonates has been published. LUS guided recruitment can change the approach to open lung ventilation, which is currently performed without any measure of lung function/lung expansion in the neonatal population. METHODS: We included all the newborn infants that underwent a LUS-guided recruitment maneuver during mechanical ventilation as a rescue attempt for an extremely severe respiratory condition with oxygen saturation/fraction of inspired oxygen (SpO2/FIO2) ratio below 130 or the inability to wean off mechanical ventilation. RESULTS: We report a case series describing 4 LUS guided recruitment maneuvers, underlying crucial aspects of this technique that can improve the effectiveness of the procedure. In particular, we describe a novel pattern (the S-pattern) that allows us to distinguish the recruitable from the unrecruitable lung and guide the pressure titration phase. Additionally, we describe the optimal LUS-guided patient positioning. CONCLUSIONS: We believe that the inclusion of specifications regarding patient positioning and the S-pattern in the LUS-guided protocol may be beneficial for the success of the procedure.

Model-informed precision dosing of levetiracetam in pediatrics population

Aims: Assessing the suitability and safety of doses of levetiracetam in pediatrics using physiologic-based pharmacokinetic (PBPK) modeling. Methods: A PBPK model of levetiracetam was developed and validated for healthy adults and scaled for children (0.5 to 12 years old). Prediction of levetiracetam exposure at steady- state, were carried out for different therapeutic regimens to achieve the target of Cmax values within the therapeutic range of 5 to 46 µg ml-1. Then, a multivariate linear regression analysis (MLR) was applied to correlate the simulated data with covariates: dose, therapeutic regimen, sex, age and body weight (BW), to describe the best model prediction for the initial dosing in pediatrics. Results: The results indicated the suitability of the PBPK model for adults and pediatrics. For children aged 0.5 to 6 y.o. the dose range capable of reaching the pharmacokinetic target is between 10 and 100 mg kg-1 day-1, for 7 to 9 y.o. doses between 20 and 90 mg kg-1 day-1, and for 10 to 12 y.o. doses between 20 to 80 mg kg-1 day-1. Further, the MLR related Cmax to dose, therapeutic regimen, and BW. Conclusions: For 3 daily administrations, it is suggested that maximum daily doses of 80 mg kg-1 could be used for ages between 0.5 and 6 y.o. and 100 mg kg-1 for ages above 7 years old, since they weigh below 50 kg. The PBPK model lumped to MLR could be very supportive for clinical decisions to safety and effectiveness of prescription of levetiracetam along the titration phase.

First-Line Methadone For Cancer Pain. Titration Time Analysis

Background. Methadone is a low-cost, strong opioid that is increasingly used as a first-line treatment for pain in palliative care (PC). Its long and unpredictable half-life and slow elimination phase can make titration challenging. Evidence for titration modalities is scarce.Objective. To describe the titration phase of the treatment with low dose first-line methadone and the use of methadone for breakthrough pain.Methods. Prospective study with strong opioid-naïve patients with moderate to severe cancer pain followed at a tertiary PC unit in Argentina. Starting methadone dose was 2.5-5 mg/day every 8, 12, or 24 hours. Titration allowed daily dose increases from Day 1, and prescription of oral methadone 2.5 mg every 2 hours with a maximum of 3 rescue doses/day for breakthrough pain. Pain control, methadone stabilization dose, and adverse effects, among other variables, were daily assessed over the first 7 days (T0 –T7).Results. 62 patients were included. Initial median (IQR) methadone dose was 5(2.5) mg/day. Pain intensity decreased from a median (IQR) of 8(2.3) at T0 to 4(2.3) at T1 and remained ≤4 until T7 (all p<0.0001 compared to T0). Similar results were obtained through the categorical and tolerability scales for pain. Fifty patients (81%) reached pain control, 66% in the first 48 hours. Methadone daily dose at T2 and T7 were higher than that at T0: 7.5(3) and 6.7(5.5) versus 5(2.5); respectively (all p<0.05). The opioid escalation index at T7 was 1.7%. The median (IQR) number of rescues, stabilization dose and time for stabilization were 0 (1), 5(4.5) mg and 3(2) days, respectively. Two patients were discontinued due to delirium. All the other side effects were mild.Conclusions. First-line, low-dose methadone using rescue methadone resulted in a pronounced and rapid decrease in pain, with minimal need for titration and for breakthrough doses, and no evidence of accumulation or sedation by the end of the week.

Early experience with selexipag for the treatment of adults with pulmonary arterial hypertension associated with congenital heart disease

Background Recently, selexipag, a new orally available and selective prostacyclin receptor agonist, has become available for treatment of pulmonary arterial hypertension (PAH), but experience in patients with PAH associated with congenital heart disease (CHD) is limited to patients with closed defects. Purpose We present our early multi-centre experience using selexipag in the heterogeneous PAH-CHD population. Methods We prospectively evaluated adults with PAH-CHD from five PAH-CHD expert centres who were treated with selexipag. Patients were titrated to highest tolerable individualized dose (200 to 1,600 μg twice daily), after which patients entered the maintenance phase. Data on functional class (FC), 6-minute walk distance (6MWD), imaging and biochemical (N terminal pro-brain natriuretic peptide [NT-proBNP]) parameters were collected. Results Thirty-four patients (age 43±14 years, 56% female, 60% Eisenmenger syndrome, 22% Down syndrome, 60% dual PAH therapy) were started on selexipag. All patients experienced at least 2 side effects during the initial uptitration phase. Most side effects were manageable and diminished after reaching the maintenance dose, but eight patients discontinued treatment due to side effects during the titration phase. The most frequent side effects were consistent with the known side effects of prostacyclins, including headache, nausea, diarrhoea and jaw pain. Majority (68%) of patients reached lower maintenance doses of 200–600 μg. At 12 months, FC improved in three patients and remained unchanged in the others. 6-minute walk distance remained stable throughout follow-up (475 to 470 m; p=n.s.) in patients who remained on-treatment compared to patients who stopped selexipag (485 to 370 m). NT-proBNP levels remained stable in patients on-treatment (520 to 600 ng/L) but worsened in patients who stopped (700 to 1000 ng/L). One patient died during follow-up from end-stage heart failure. Conclusion There is a promising role for selexipag in the treatment of adults with PAH-CHD. However, based on our experience, the use is challenging due to complexity in dosing and side effect profiles, which limit patients' tolerability and acceptance during the titration phase. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Actelion Pharmaceuticals

P0242SUBGROUP EFFICACY ANALYSIS OF SODIUM ZIRCONIUM CYCLOSILICATE (SZC) IN HYPERKALAEMIC HAEMODIALYSIS PATIENTS IN THE DIALIZE STUDY

Background and Aims Patients with end-stage renal disease have severely reduced renal potassium excretion and many require haemodialysis (3 days/week) to maintain normal serum potassium (sK+). The phase 3b DIALIZE study (NCT03303521) showed that sodium zirconium cyclosilicate (SZC) reduces predialysis sK+ after the long interdialytic interval and is well tolerated in haemodialysis patients with hyperkalaemia. This post-hoc analysis of the DIALIZE data assessed the efficacy of SZC in patient subgroups. Method The DIALIZE study randomised 196 patients 1:1 to placebo (n=99) or SZC (n=97). The study consisted of an 8-week treatment period, comprising a 4-week SZC dose titration phase followed by a 4-week evaluation phase. The starting dose of SZC was 5 g orally once daily on non-dialysis days (4 days/week) for the 4-week dose titration phase (titrated in 5 g increments to a maximum of 15 g) to achieve predialysis sK+ 4.0–5.0 mmol/L. Patients maintained a stable SZC dose for the 4-week evaluation phase (SZC 5, 10 or 15 g). Here, we assessed the proportion of treatment responders, i.e. those who during the 4-week evaluation phase achieved predialysis sK+ of 4.0–5.5 mmol/L during ≥3 of 4 haemodialysis treatments after the long interdialytic interval and who did not require potassium-lowering rescue therapy. Treatment responders were stratified by patient subgroups: sex, country, race, age (years), baseline weight (kg) and baseline sK+ (mmol/L). Results For patients receiving SZC, at baseline 59% were male, mean age was 55.7 years, 52% were white, 11% were Black or African American and 34% were Asian, and mean predialysis sK+ was 5.8 mmol/L. Using a predialysis sK+ range of 4.0–5.5 mmol/L, 69.1% (n=67/97) of SZC patients and 19.2% (n=19/99) of placebo patients were deemed treatment responders. Response to SZC was generally consistent across patient subgroups vs placebo for sex, country, race, age, baseline weight and baseline sK+, with some variation between subgroup subcategories (Table). Conclusion Our results suggest that SZC is generally effective across all groups of haemodialysis patients with hyperkalaemia. SZC responder rates for some patient subgroup subcategories were limited by low patient numbers.

P0220EFFECTIVENESS OF SODIUM ZIRCONIUM CYCLOSILICATE (SZC) IN HAEMODIALYSIS PATIENTS WITH SEVERE HYPERKALAEMIA IN THE DIALIZE STUDY

Background and Aims Patients with severe hyperkalaemia require urgent intervention to avoid serious adverse outcomes and mortality. The phase 3b DIALIZE study (NCT03303521) showed that sodium zirconium cyclosilicate (SZC) reduces predialysis serum potassium (sK+) after the long interdialytic interval and is well tolerated in haemodialysis patients with hyperkalaemia. This post-hoc analysis of the DIALIZE data assessed the efficacy of SZC in patients with severe hyperkalaemia (defined as sK+ ≥6.0 mmol/L) at baseline. Method The DIALIZE study randomised 196 patients 1:1 to placebo (n=99) or SZC (n=97). The study consisted of an 8-week treatment period, comprising a 4-week SZC dose titration phase followed by a 4-week evaluation phase. The starting dose of SZC was 5 g orally once daily on non-dialysis days (4 days/week) for the 4-week dose titration phase (titrated in 5 g increments to a maximum of 15 g on non-dialysis days) to achieve predialysis sK+ 4.0–5.0 mmol/L. Patients maintained a stable dose of SZC for the 4-week evaluation phase (SZC 5, 10 or 15 g). Here, treatment response was defined as achievement of predialysis sK+ of 4.0–5.5 mmol/L during ≥3 of 4 haemodialysis treatments after the long interdialytic interval during the 4-week evaluation phase and not requiring potassium-lowering rescue therapy. Rates of response were compared between those patients with and without baseline severe hyperkalaemia (sK+ ≥6 mmol/L and &lt;6 mmol/L, respectively). The sK+ measurement on Visit 1 (Day –7) was used as the baseline value. Results At baseline, 88 patients had sK+ ≥6 mmol/L (SZC n=46, placebo n=42) and 106 patients had sK+ &lt;6 mmol/L (SZC n=49, placebo n=57); data were missing for two SZC patients. The overall proportion of treatment responders (irrespective of treatment and dose) in patients with baseline sK+ ≥6 mmol/L and &lt;6 mmol/L was 44.3% and 43.4%, respectively. The proportion of treatment responders was greater with SZC compared with placebo in patients with baseline sK+ ≥6 mmol/L and sK+ &lt;6 mmol/L (Figure). For patients receiving SZC, the proportion of treatment responders was consistent in those with baseline sK+ ≥6 mmol/L (67.4%) compared with those with baseline sK+ &lt;6 mmol/L (71.4%; Figure). Conclusion Our results suggest that SZC is effective in haemodialysis patients with severe hyperkalaemia.

Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures

ObjectiveTo evaluate the efficacy and safety of adjunctive cenobamate 200 mg/d in patients with uncontrolled focal (partial-onset) seizures despite treatment with 1 to 3 antiepileptic drugs.MethodsIn this multicenter, double-blind, placebo-controlled study, adults 18 to 65 years of age with focal seizures were randomized 1:1 (cenobamate:placebo) after an 8-week baseline period. The 12-week double-blind treatment period consisted of a 6-week titration phase and a 6-week maintenance phase. The primary outcome was percent change in seizure frequency (from baseline) per 28 days during double-blind treatment.ResultsTwo hundred twenty-two patients were randomized; 113 received cenobamate and 109 received placebo; and 90.3% and 90.8% of patients, respectively, completed double-blind treatment. Median baseline seizure frequency was 6.5 in 28 days (range 0–237). Compared to placebo, cenobamate conferred a greater median percent seizure reduction (55.6% vs 21.5%; p < 0.0001) The responder rate (≥50% reduction in seizure frequency) was 50.4% for cenobamate and 22.2% for placebo (p < 0.0001). Focal seizures with motor component, impaired awareness, and focal to bilateral tonic-clonic seizures were significantly reduced with cenobamate vs placebo. During maintenance, 28.3% of cenobamate-treated and 8.8% of placebo-treated patients were seizure-free. Treatment-emergent adverse events reported in >10% in either group (cenobamate vs placebo) were somnolence (22.1% vs 11.9%), dizziness (22.1% vs 16.5%), headache (12.4% vs 12.8%), nausea (11.5% vs 4.6%), and fatigue (10.6% vs 6.4%).ConclusionAdjunctive treatment with cenobamate 200 mg/d significantly improved seizure control in adults with uncontrolled focal seizures and was well tolerated.ClinicalTrials.gov identifierNCT01397968.Classification of evidenceThis study provides Class I evidence that, for patients with uncontrolled focal seizures, adjunctive cenobamate reduces seizures.