Clinically Meaningful Responses to Dupilumab Among Children Aged 6 Months to 5 Years with Moderate-to-severe Atopic Dermatitis who did Not Achieve Clear or Almost Clear Skin According to the Investigator's Global Assessment: A Post Hoc Analysis of a Phase 3 Trial.

In young children, atopic dermatitis (AD) imposes a multidimensional burden on many aspects of their quality of life (QoL) and that of their families. LIBERTY AD PRESCHOOL part B was a randomized, double- blinded, placebo-controlled phase 3 trial in 162 children (aged 6 months to 5 years) with moderate-to- severe AD receiving dupilumab or placebo, plus low-potency topical corticosteroids. Post hoc analyses were performed on the full analysis set (FAS) and a subset of patients with Investigator's Global Assessment score > 1 at week 16. The primary outcome was the proportion of patients at week 16 achieving a composite endpoint encompassing clinically meaningful changes in AD signs, symptoms and QoL: ≥ 50% improvement in Eczema Area and Severity Index; and/or ≥ 4-point reduction in worst scratch/itch numerical rating scale; and/or ≥ 6-point reduction in Children's Dermatology Life Quality Index/Infants' Dermatitis Quality of Life Index. Significantly more patients receiving dupilumab vs placebo achieved the composite endpoint in both the FAS (77.7% vs 24.6%, p < 0.0001) and subgroup (68.9% vs 21.5%, p < 0.0001). Dupilumab provided rapid and significant, clinically meaningful improvements in AD signs, symptoms, and QoL in the overall group and subgroup of patients who did not achieve clear or almost clear skin at week 16.

A case series of live attenuated vaccine administration in dupilumab-treated children with atopic dermatitis.

BACKGROUND AND OBJECTIVE: Current regulatory labeling recommends avoiding live vaccine use in dupilumab-treated patients. Clinical data are not available to support more specific guidance for live or live attenuated vaccines administration in dupilumab-treated patients. METHODS: Children (6 months-5 years old) with moderate-to-severe atopic dermatitis (AD) enrolled in a phase 2/3 clinical trial of dupilumab (LIBERTY AD PRESCHOOL Part A/B; NCT03346434) and subsequently participated in the LIBERTY AD PED-OLE (NCT02612454). During these studies, protocol deviations occurred in nine children who received measles, mumps, rubella (MMR) vaccine with or without varicella vaccine; five with a ≤12-week gap between dupilumab administration and vaccination and four with a >12-week gap after discontinuing dupilumab. RESULTS: Nine children (1 female; 8 male) had severe AD at baseline (8-56 months old). Of the nine children, five had a ≤12-week gap ranged 1-7 weeks between dupilumab administration and vaccination who received MMR vaccine (n = 2) or MMR and varicella vaccines (n = 3); among these, one resumed dupilumab treatment as early as 2 days and four resumed treatment 18-43 days after vaccination. No treatment-emergent adverse events, including serious adverse events and infections, were reported within the 4-week post-vaccination period in any children. CONCLUSIONS: In this case series of dupilumab-treated children with severe AD who received MMR vaccine with or without varicella vaccine, no adverse effects (including vaccine-related infection) were reported within 4 weeks after vaccination. Further studies are warranted to evaluate the safety, tolerability, and immune response to live attenuated vaccines in dupilumab-treated patients.

The synergistic effect of dexmedetomidine on propofol for paediatric deep sedation: A randomised trial.

BACKGROUND: Propofol and dexmedetomidine are used separately, and sometimes together, for paediatric deep sedation. Although their combination has been described in adults, the effect of dexmedetomidine as a potential synergist in children has not been studied before. OBJECTIVES: The primary objective was to compare the propofol requirements of children who receive propofol alone with those who receive it in combination with dexmedetomidine for deep sedation for upper and lower endoscopic gastrointestinal procedures. DESIGN: This was a prospective, open-label, randomised study comparing patients who received propofol alone (group P) with those who received dexmedetomidine and propofol (group DP). The depth of sedation was titrated to a target bispectral (BIS) index. SETTING: A Gastroenterology Procedure Unit at a single, tertiary care academic medical centre from April 2018 until December 2019. PATIENTS: Eligible patients were scheduled for upper endoscopy, lower endoscopy or both. A total of 39 patients were enrolled (20 DP) and (19 P). INTERVENTIONS: Patients in Group DP received dexmedetomidine 0.5 µg kg-1 administered over 1 min followed by an infusion of 0.15 µg kg-1 h-1. In both groups, intravenous propofol was given in bolus increments titrated to a BIS index of 40 to 50 and then a continuous infusion of propofol to maintain BIS at 40 to 50. MAIN OUTCOME MEASURES: The primary outcome measure was propofol requirement in each group. Secondary outcome measures were time to achieve the targeted sedation depth, time to achieve an Aldrete recovery score of 9, duration of sedation, mean BIS values, adverse events, 'PAED' scores and time to discharge from the postanaesthesia care unit (PACU). RESULTS: The median (range) total dose of propofol was 0.23 (0.10 to 0.50) mg kg-1 min-1 in group DP and 0.40 (0.20 to 0.50) mg kg-1 min-1 in group P (P = 0.0004). Time of discharge from the PACU was 60 (20 to 121) min in group DP and 63 (46 to 91) min in group P (P = 0.0409). CONCLUSION: The combination of dexmedetomidine and propofol for paediatric procedural sedation achieved a significant reduction in median propofol dose and a slightly shorter median time to discharge from PACU. Large-scale studies may determine whether this reduction decreases the risk of significant adverse events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02952222.

Baricitinib in adult patients with moderate-to-severe atopic dermatitis: A phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study.

BACKGROUND: Baricitinib, an oral selective inhibitor of Janus kinase 1 and Janus kinase 2, modulates proinflammatory cytokine signaling. OBJECTIVES: The efficacy and safety of baricitinib were evaluated in patients with moderate-to-severe atopic dermatitis (AD). METHODS: In this phase 2, randomized, double-blind, placebo-controlled study, 124 patients with moderate-to-severe AD applied topical corticosteroids (TCSs) for 4 weeks before randomization to once-daily placebo, 2 mg of baricitinib, or 4 mg of baricitinib for 16 weeks. Use of TCSs was permitted during the study. The primary outcome was the proportion of patients achieving at least a 50% reduction in the Eczema Area and Severity Index (EASI-50) compared with placebo. RESULTS: Significantly more patients who received baricitinib, 4 mg, achieved EASI-50 than did patients receiving placebo (61% vs 37% [P = .027]) at 16 weeks. The difference between the proportion of patients receiving baricitinib, 2 or 4 mg, who achieved EASI-50 and the proportion of patients receiving placebo and achieving EASI-50 was significant as early as week 4. Baricitinib also improved pruritus and sleep loss. Treatment-emergent adverse events were reported in 24 of the patients receiving placebo (49%), 17 of those receiving 2 mg of baricitinib (46%), and 27 of those receiving 4 mg of baricitinib (71%). LIMITATIONS: A TCS standardization period before randomization reduced disease severity, limiting the ability to compare results with those of baricitinib monotherapy. Longer studies are required to confirm baricitinib's efficacy and safety in patients with AD. CONCLUSIONS: Baricitinib used with TCSs reduced inflammation and pruritus in patients with moderate-to-severe AD.

Efficacy and Safety of Dupilumab Treatment with Concomitant Topical Corticosteroids in Children Aged 6 Months to 5 Years with Severe Atopic Dermatitis.

INTRODUCTION: Treatment options for children younger than 6 years with severe atopic dermatitis (AD) are limited, as systemic immunosuppressants may present safety concerns in this young age group. Dupilumab is the first systemic treatment option approved for infants and young children with severe AD in the European Union. This study reports the efficacy and safety of dupilumab with concomitant low-potency corticosteroids in children aged 6 months to 5 years with severe AD. METHODS: This was a pre-specified subgroup analysis of data for patients aged 6 months to 5 years with severe AD at baseline (Investigator's Global Assessment [IGA] = 4) from a randomised, double-blind, placebo-controlled, phase III trial of dupilumab. Patients were randomised to either subcutaneously administered dupilumab (200/300 mg) or matched placebo every 4 weeks, plus low-potency topical corticosteroids for 16 weeks. Co-primary endpoints at week 16 were the proportion of patients with IGA ≤ 1 (clear or almost clear skin) and the proportion of patients with ≥ 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Secondary endpoints at week 16 included mean changes in EASI, pruritus, skin pain, sleep loss and quality of life. RESULTS: The analysis included 125 patients (63 receiving dupilumab vs. 62 placebo). At week 16, significantly more patients receiving dupilumab vs. placebo had achieved IGA ≤ 1 (14.3% vs. 1.6%; P = 0.0085) and EASI-75 (46.0% vs. 6.6%; P < 0.0001). Significant improvements with dupilumab were observed in all secondary endpoints, including a least squares mean 48.9% reduction in pruritus. The overall incidence of adverse events (AEs) was similar between the dupilumab and placebo groups (66.7% vs. 73.8%). No dupilumab-related AEs were serious or led to treatment discontinuation. CONCLUSION: Dupilumab significantly improved AD signs, symptoms and quality of life in children aged 6 months to 5 years with severe AD with acceptable safety. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov with ID number NCT03346434, part B.

Atopic dermatitis (AD) is a chronic skin disease that is relatively common in infants and young children worldwide. Severe AD causes skin rashes and intense itch that strongly interfere with sleep quality and normal daily activities, thereby affecting the quality of life of patients and their families. When therapies for AD that are applied to the skin do not work, limited options are available to treat severe AD in children younger than 6 years. In this study, we evaluated the efficacy and safety of dupilumab in children aged 6 months to 5 years with severe AD, recruited from various sites in Europe and North America. Patients received 200 or 300 mg of dupilumab (based on the child's weight) or placebo, together with mild steroids applied to the skin, every 4 weeks for 16 weeks. At the end of treatment, AD severity was greatly improved in patients receiving dupilumab, with 14% of patients achieving almost clear skin. Patients receiving dupilumab also experienced significant improvements in itch intensity, sleep quality, skin pain, and quality of life. Furthermore, dupilumab did not increase the risk of infections. This study demonstrates that dupilumab can be effective at treating severe AD in infants and young children, with important benefits for the quality of life of patients and their families.

Dexmedetomidine offers an option for safe and effective sedation for nuclear medicine imaging in children.

PURPOSE: To determine the safety, efficacy, and outcomes of bradycardia, hypotension, and hypertension with dexmedetomidine (DEX), a recently approved sedative used for procedural sedation that has not been described previously for pediatric nuclear medicine imaging. MATERIALS AND METHODS: Between March 2005 and August 2011, 669 patients (mean age, 5.7 years ± 4.5 [standard deviation]; median age, 4.5 years; age range, 0.1-22.5 years) received DEX in this HIPAA-compliant study. Sedation was administered with DEX, an α-2 adrenergic agonist, as an intravenous bolus (2 µg per kilogram of body weight) over a 10-minute period; this was followed by continuous infusion at a rate of 1 µg/kg/h until imaging was complete. The bolus could be repeated up to two times, if needed, to achieve the targeted level of a Ramsay sedation score of 4. After institutional review board approval, collected quality assurance data were reviewed. RESULTS: Adequate sedation was achieved within 8.6 minutes ± 4.6 (median, 8.0 minutes; range, 1.0-40.0 minutes) on average in studies that averaged 41.3 minutes ± 25.5 (median, 31.5 minutes; range, 9.0-183.0 minutes). Of 669 studies, 667 (99.7%) were completed successfully. Six children (0.9%) had brief periods of oxygen desaturation below 95%, none of which required airway intervention. Hypotension, hypertension, and bradycardia (all defined as deviations of more than 20% from age-adjusted awake norms), occurred in 58.7% (n = 393), 2.1% (n = 14), and 4.3% (n = 29) of patients, respectively. Both hypotension and bradycardia were related to age (P = .033 and P = .002, respectively); older children tended to experience more of these events. None of these fluctuations required pharmacologic therapy. Discharge criteria (modified Aldrete score ≥ 9) were met, on average, within 41.4 minutes ± 27.9 (median, 36.0 minutes; range, 1.0-220.0 minutes). CONCLUSION: DEX offers advantages for pediatric sedation for nuclear medicine imaging. DEX produces a condition similar to natural sleep, with no detrimental effect on respiration. The hemodynamic variability anticipated with DEX did not require pharmacologic treatment, and the drug was well tolerated.

Dupilumab Treatment Leads to Rapid and Consistent Improvement of Atopic Dermatitis in All Anatomical Regions in Patients Aged 6 Months to 5 Years.

INTRODUCTION: Atopic dermatitis (AD) is heterogeneous in distribution pattern and clinical features. This analysis assessed the effect of dupilumab on the extent and severity of AD across various signs (erythema, edema/papulation, excoriation, lichenification) in different anatomical regions (head and neck, trunk, upper extremities, lower extremities) in patients aged 6 months to 5 years. METHODS: In LIBERTY AD PRESCHOOL, a double-blind, placebo-controlled, phase III clinical trial, children aged 6 months to 5 years with moderate-to-severe AD were randomized 1:1 to subcutaneous dupilumab or placebo with concomitant low-potency topical corticosteroids (TCS) every 4 weeks for 16 weeks. Changes in AD signs across anatomical regions were assessed using unweighted Eczema Area and Severity Index (EASI) body region scores. RESULTS: Overall, 162 patients were randomized to dupilumab (n = 83) or placebo (n = 79). A significant improvement in least squares mean EASI area score was seen by week 2 in all four anatomical regions (P < 0.0001 for dupilumab vs. placebo) and sustained throughout treatment. Least squares mean EASI sign scores in erythema, excoriations, and infiltration/papulation showed significant improvement by week 2 in all regions (P < 0.001), while lichenification showed significant improvement in all regions by week 4 (P < 0.001). CONCLUSION: Dupilumab use with concomitant low-potency TCS treatment resulted in rapid and consistent improvement in AD signs in all anatomical regions, in patients aged 6 months to 5 years with moderate-to-severe AD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03346434 Part B.

Laboratory Safety from a Randomized 16-Week Phase III Study of Dupilumab in Children Aged 6 Months to 5 Years with Moderate-to-Severe Atopic Dermatitis.

BACKGROUND AND OBJECTIVE: Previous studies of dupilumab for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents, and severe atopic dermatitis in children aged 6 to < 12 years demonstrate no clinically important changes in laboratory parameters. The objective of this study was to assess laboratory outcomes in children aged 6 months to < 6 years with moderate-to-severe atopic dermatitis treated with dupilumab. METHODS: In this randomized, placebo-controlled, phase III trial of dupilumab, 161 children aged 6 months to < 6 years with moderate-to-severe atopic dermatitis were enrolled from 31 sites in Europe and North America and randomized 1:1 to receive subcutaneous placebo or dupilumab (5 kg to < 15 kg: 200 mg; 15 kg to < 30 kg: 300 mg) every 4 weeks plus topical corticosteroids for 16 weeks. Hematology, serum chemistry, and urinalysis assessments were analyzed on blood and urine samples collected at screening and weeks 4 and 16; descriptive statistics are provided. RESULTS: No clinically meaningful changes in laboratory parameters were observed. While two cases of eosinophilia and one case each of neutropenia and leukocytosis were reported as treatment-emergent adverse events in the dupilumab plus topical corticosteroids group, these events were not associated with clinical symptoms and did not lead to treatment discontinuation or study withdrawal. CONCLUSIONS: These results suggest that routine laboratory monitoring of children aged 6 months to < 6 years treated with dupilumab plus topical corticosteroids is not required. Limitations of this study include short study duration, and exclusion of patients with abnormalities in laboratory test results at screening. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT03346434, part B.

Atopic dermatitis (AD) is a chronic, inflammatory skin disease that often causes itchy rashes. To reduce persistent AD signs and symptoms, patients may need to take medications that require laboratory monitoring. This can add to treatment burden, especially among infants and children. Dupilumab is a drug that specifically targets key molecules that underlie AD and has been tested in several clinical trials, now in patients 6 months and older. Studies in adults, adolescents, and children as young as 6 years of age with moderate-to-severe AD have shown that dupilumab can be used without the need for regular laboratory tests. In this study, the authors analyzed blood and urine samples collected during a clinical trial of dupilumab in 161 infants and children aged 6 months to 5 years with moderate-to-severe AD. Routine laboratory tests revealed no clinically meaningful changes in patients' blood and urine following treatment with dupilumab. In general, the laboratory results in these patients were similar to those in adults, adolescents, and children aged 6­11 years treated with dupilumab. Taken together, these findings suggest that dupilumab can be used for the continuous treatment of moderate-to-severe AD without the need for routine laboratory monitoring. Video abstract: Does dupilumab treatment require routine laboratory monitoring in infants and young children with atopic dermatitis? (MP4 128,088 KB).

Similarities and Differences in the Perception of Atopic Dermatitis Burden Between Patients, Caregivers, and Independent Physicians (AD-GAP Survey).

INTRODUCTION: Atopic dermatitis (AD)-a chronic inflammatory skin disease characterized by intense itching-can have a detrimental impact on quality of life (QoL). We report results of a quantitative assessment of pediatric patient, caregiver, and physician perceptions of AD burden in children and adolescents. METHODS: Pediatric patients (aged 6-11 [children] or 12-17 [adolescents] years) with moderate-to-severe AD, their caregivers, and independent physicians were recruited in 13 countries. Caregivers and their children/adolescents completed an online survey about the impact of AD on 16 key items of patient QoL. Physicians completed surveys on their patients aged 6-11 and 12-17 years. Best-worst scaling was used to rank the importance of the QoL items. RESULTS: Overall, 1447 children/adolescents with moderate-to-severe AD (aged 6-11 years: 701; 12-17 years: 746), 1447 caregivers, and 1092 physicians participated. Patients and caregivers in both age groups ranked disturbed sleep as the most important QoL item, followed by feeling ashamed because of AD. Independent physicians ranked feeling ashamed because of AD as the most important QoL item for both age groups, followed by disturbed sleep for those aged 6-11 years and being singled out for those aged 12-17 years. The relative importance of the 16 QoL items to patients was strongly aligned between patients in both age groups and their caregivers, but somewhat less so between patients and physicians. Between-country differences were more apparent in physician- versus patient-/caregiver-reported results. CONCLUSION: The most burdensome QoL items were impact of AD on sleep and feeling ashamed. Caregivers and physicians correctly identified the QoL items most burdensome to patients. However, patient and caregiver perceptions were generally more closely aligned than patient and physician perceptions. Between-country differences in perceptions (particularly for physicians) were observed, probably due to multifactorial reasons, necessitating further evaluation. Video Abstract (MP4 42,877 kb) INFOGRAPHIC.

Dupilumab Safety and Efficacy in a Phase III Open-Label Extension Trial in Children 6-11 Years of Age with Severe Atopic Dermatitis.

BACKGROUND: For children aged 6-11 years with uncontrolled severe atopic dermatitis (AD), 16 weeks of treatment with dupilumab resulted in substantial clinical benefit compared with placebo with an acceptable safety profile. However, longer-term safety and efficacy data are important to inform longitudinal AD management. OBJECTIVES: This analysis of data from an open-label extension study (LIBERTY AD PED-OLE, NCT02612454) reports the long-term safety, efficacy, and pharmacokinetics of dupilumab in children with severe AD who had participated in the pivotal dupilumab LIBERTY AD PEDS study (NCT03345914). METHODS: Enrolled patients initially received subcutaneous dupilumab 300 mg every 4 weeks (q4w). The q4w regimen could be uptitrated to dupilumab dose regimens of 200 or 300 mg every 2 weeks (q2w; for body weight < 60 or ≥ 60 kg, respectively) for patients who did not achieve an Investigator's Global Assessment (IGA) score of 0/1 (clear/almost clear skin) at week 16, or prior to week 16 as rescue treatment. Additional patients were uptitrated to a weight-tiered q2w regimen following a protocol amendment. Patients who maintained an IGA score of 0/1 continuously for a 12-week period after week 40 discontinued dupilumab. They were monitored for relapse and were reinitiated on dupilumab if required. RESULTS: Data for 321 patients (mean age 8.6 years) were analyzed, 254 (79%) of whom had completed the scheduled 52-week visit at the database lock. Most treatment-emergent adverse events were mild/moderate. By week 52, 41% of patients achieved an IGA score of 0/1, and 97%, 82%, and 50%, respectively, had at least a 50%, 75%, and 90% improvement from the parent study baseline in Eczema Area and Severity Index (EASI). By week 52, 29% of patients in the overall population had clear/almost clear skin sustained for 12 weeks and had stopped medication; of these, 40% relapsed and were subsequently reinitiated on treatment, with a mean time to reinitiation of 13.5 (standard deviation 5.2) weeks. Following reinitiation of dupilumab, 41% of the patients with evaluable data at the time of database lock had regained an IGA 0/1 clinical response. CONCLUSIONS: Consistent with results seen in adults and adolescents, long-term treatment with dupilumab in children aged 6-11 years with severe AD showed an acceptable safety profile and incremental clinical benefit. A substantial proportion of children who stopped dupilumab treatment after achieving clear/almost clear skin subsequently experienced disease recurrence, and required reinitiation of dupilumab, suggesting that continuous treatment may be necessary for maintenance of clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02612454.

Atopic dermatitis (AD) is a chronic disease that causes recurrent inflamed and rough skin rashes with itching and often soreness. In children with AD, treatment with a medication called dupilumab has shown improvements in their disease and quality of life. But most clinical trials of dupilumab in children have only lasted for 16 weeks. We investigated the effect of dupilumab in children treated for a longer time. The 321 children (aged 6­11 years) who were included in this study had taken part in a clinical trial of dupilumab because they had severe AD. They were treated with either dupilumab or a placebo (a dummy treatment) for 16 weeks. When that trial ended, they were then all treated with dupilumab for up to a year. Their average AD severity continued to get steadily better over a year of extended treatment, with almost all children reaching 50% skin improvement compared with their AD before treatment. Many children reached a point where their skin was clear or almost clear of AD for a period, and following the rules of the study they stopped taking dupilumab. In many of them, their AD slowly returned without treatment. But if they started to take dupilumab again, their AD improved, and some could even achieve skin clearance again. Over the longer term, the safety of dupilumab was similar to what was seen with short-term treatment. This study showed that children with AD aged 6­11 years benefited from receiving dupilumab for a longer period of time.

Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin Administered via Continuous Subcutaneous Insulin Infusion Versus Subcutaneous Injection in Adults With Type 2 Diabetes and High-Dose Insulin Requirements.

INTRODUCTION: Human regular U-500 insulin (U-500R) is approved for subcutaneous (SC) injection in patients with diabetes requiring >200 units/day of insulin. Here, pharmacokinetic and pharmacodynamic (PK/PD) profiles following U-500R administered by continuous subcutaneous insulin infusion (CSII) and SC injection in adults with type 2 diabetes (T2D) on high-dose insulin were studied. METHODS: In this randomized, crossover, euglycemic clamp study, patients received a 100-unit bolus of U-500R via SC injection or CSII with basal infusion using a U-500R specific pump. PK parameters were estimated using non-compartmental methods. PD estimates were derived from the glucose infusion rate during the euglycemic clamp procedure. RESULTS: When corrected for the basal infusion, the PK profiles for the 100-unit bolus of U-500R were similar for CSII and SC injection. Without correction for basal infusion, PK and PD profiles showed a greater insulin concentration and effect when U-500R was administered via CSII compared to SC injection, primarily due to basal insulin infusion for CSII. The ratio of geometric least squares AUC0-tlast means SC:CSII (90% CI) is 0.857 (0.729, 1.01) with correction (mean AUC0-tlast: 5230 pmol*L/h [SC injection] and 6070 pmol*L/h [CSII, with correction]) and 0.424 (0.361, 0.499) without correction (mean AUC0-tlast: 12300 pmol*L/h [CSII, without correction]). Median time-to-peak insulin concentration was six hours (range 0.5-8 hours) via SC injection and five hours (0.5-12 hours) via CSII. CONCLUSIONS: In adults with T2D on high-dose insulin, U-500R PK/PD parameters were similar for a 100-unit bolus when given by SC injection or CSII via a U-500R pump.

Efficacy of tranexamic acid in pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial.

BACKGROUND: Extensive blood loss is common in pediatric craniosynostosis reconstruction surgery. Tranexamic acid (TXA) is increasingly used to reduce perioperative blood loss in various settings, but data on its efficacy are limited in children. The purpose of this randomized, double-blind, placebo-controlled, parallel trial was to evaluate the efficacy of TXA in pediatric craniosynostosis correction surgery. The primary and secondary outcome variables were reduction in perioperative blood loss and reduction in blood transfusion, respectively. METHODS: Forty-three children, ages 2 months to 6 yr, received either placebo or TXA in a loading dose of 50 mg·kg(-1), followed by an infusion of 5 mg·kg·h(-1) during surgery. TXA plasma concentrations were measured. RESULTS: The TXA group had significantly lower perioperative mean blood loss (65 vs. 119 ml·kg(-1), P < 0.001) and lower perioperative mean blood transfusion (33 vs. 56 ml· kg(-1), P = 0.006) compared to the placebo group. The mean difference between the TXA and placebo groups for total blood loss was 54 ml·kg(-1) (95% CI for the difference, 23-84 ml·kg(-1)) and for packed erythrocytes transfused was 23 ml·kg(-1) (95% CI for the difference, 7-39 ml·kg(-1)). TXA administration also significantly diminished (by two thirds) the perioperative exposure of patients to transfused blood (median, 1 unit vs. 3 units; P < 0.001). TXA plasma concentrations were maintained above the in vitro thresholds reported for inhibition of fibrinolysis (10 µg·ml(-1)) and plasmin-induced platelet activation (16 µg·ml(-1)) throughout the infusion. CONCLUSIONS: TXA is effective in reducing perioperative blood loss and transfusion requirement in children undergoing craniosynostosis reconstruction surgery.

Pediatric CT sedation: comparison of dexmedetomidine and pentobarbital.

OBJECTIVE: Our institution replaced pentobarbital with dexmedetomidine for pediatric CT sedation. The purpose of this study was to compare the efficacy, incidence of adverse events, and cardiovascular and respiratory profiles of these two sedatives. MATERIALS AND METHODS: Quality assurance data were accessed for a review of demographics, outcome parameters, and adverse events among all children who received either pentobarbital or dexmedetomidine. RESULTS: From January 2004 through June 2009 there were 388 pentobarbital sedations and 1,274 dexmedetomidine sedations. Age, sex, weight, and duration of imaging study were similar in the two groups. Average time to achieve sedation was 12 ± 4 minutes with dexmedetomidine and 6 ± 3 minutes with pentobarbital (p < 0.001). Recovery time was 32 ± 18 minutes with dexmedetomidine and 95 ± 28 minutes with pentobarbital (p < 0.001). There were no differences between groups in incidence of oxygen desaturation and need for brief positive pressure ventilation. The odds of needing additional sedative agents to complete the study were significantly higher with pentobarbital than with dexmedetomidine (odds ratio, 4.0; 95% CI, 2.0-8.4; p < 0.001). There was a significantly lower incidence of agitation and rage with dexmedetomidine (p < 0.01) but higher risk of hypotension (p < 0.01). There was one failed sedation in each group (p = 0.99). CONCLUSION: Dexmedetomidine is a safe and effective alternative to pentobarbital for pediatric CT, being associated with a much shorter recovery time and less need for adjuvant sedatives.

Definition of Clinically Meaningful Within-Patient Changes in POEM and CDLQI in Children 6 to 11 Years of Age with Severe Atopic Dermatitis.

INTRODUCTION: The Patient-Oriented Eczema Measure (POEM) assesses patient-reported severity of atopic dermatitis (AD) symptoms, whereas the Children's Dermatology Life Quality Index (CDLQI) measures how AD affects health-related quality of life (HRQoL) in children. Although the POEM and CDLQI have established thresholds for clinically meaningful within-patient change in adolescents (aged 12-17 years), there are no defined within-patient responder thresholds for clinically meaningful change in children aged 6-11 years. METHODS: Data from the LIBERTY AD PEDS phase 3 randomized, double-blind, placebo-controlled trial of dupilumab in children aged 6-11 years with severe AD were used to define the threshold for within-patient meaningful change in POEM and CDLQI scores. Anchor-based methods were applied to estimate mean change in POEM and CDLQI scores from baseline to week 16, with anchors of a 1-point improvement in the Patient Global Impression of Disease (PGID) scale and an improvement in score of ''A little better'' on the Patient Global Impression of Change (PGIC) scale. The distribution-based methods, a one-half standard deviation (SD) at baseline and a standard error mean (SEM) were also used. RESULTS: The mean POEM change scores associated with the anchors were a change of - 8.40 with the PGID anchor and - 6.30 with the PGIC anchor. Distribution-based estimates for POEM were one-half SD at baseline of 2.76, with a SEM of 3.32. Mean CDLQI change scores corresponding to the PGID and PGIC anchors were - 7.30 and - 6.80, respectively, while distribution-based estimates for CDLQI were a one-half SD at baseline of 3.69, with a SEM of 3.52. CONCLUSIONS: In children with severe AD, an appropriate minimum threshold of clinically meaningful within-patient change was estimated as 6 points for both the POEM and CDLQI scores. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03345914. What is the clinically meaningful within-person change in Patient-Oriented Eczema Measure and Children's Dermatology Life Quality Index scores in children 6 to 11 years old with severe atopic dermatitis? (MP4 289443 KB).

Effect of Dupilumab on Laboratory Parameters in Adolescents with Atopic Dermatitis: Results from a Randomized, Placebo-Controlled, Phase 3 Clinical Trial.

BACKGROUND: Laboratory testing is typically required for patients with atopic dermatitis (AD) treated with systemic immunosuppressants. A previous analysis of laboratory outcomes in randomized, double-blinded, placebo-controlled clinical trials of dupilumab in adults with moderate-to-severe AD found no clinically important changes in hematologic, serum chemistry, and urinalysis parameters, supporting the use of dupilumab without routine laboratory monitoring. OBJECTIVE: The aim was to assess laboratory results in adolescents with moderate-to-severe AD treated with dupilumab in a phase 3, randomized, double-blind, placebo-controlled trial. METHODS: Adolescents aged ≥ 12 to < 18 years with moderate-to-severe AD were randomized 1:1:1 to subcutaneous dupilumab 200/300 mg every 2 weeks (q2w) (200 mg for patients < 60 kg at baseline; 300 mg for patients ≥ 60 kg at baseline); dupilumab 300 mg every 4 weeks (q4w); or placebo for 16 weeks. Laboratory evaluations included hematology, serum chemistry, and urinalysis parameters. RESULTS: Of 251 patients enrolled in the study, 250 received treatment and were included in the analysis. 4.7%, 2.4%, and 4.8% of patients receiving placebo, dupilumab 200/300 mg q2w, and dupilumab 300 mg q4w, respectively, had laboratory abnormalities reported as treatment-emergent adverse events, none of which prompted discontinuation of study treatment or study withdrawal. Mean eosinophil counts were elevated at baseline in all treatment groups. Patients in both dupilumab regimens, but not the placebo group, showed mild transient increases in mean eosinophil counts above baseline that returned to near-baseline values by week 16. Mean levels of lactate dehydrogenase trended towards the upper limit of normal at baseline and decreased with treatment; greater decreases were seen in dupilumab-treated patients than placebo-treated patients. There were no meaningful changes in other laboratory parameters, and none of the laboratory abnormalities were clinically significant. CONCLUSION: No clinically meaningful changes in laboratory parameters were seen in adolescents, similar to that observed in adults. The findings of this study indicate no routine laboratory monitoring is required in this population prior to or during dupilumab treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03054428. Video abstract: Effect of Dupilumab on Laboratory Parameters in Adolescents with Atopic Dermatitis: Results from a Randomized Placebo-Controlled Phase 3 Clinical Trial (MP4 175137 KB).

Incidence and predictors of hypertension during high-dose dexmedetomidine sedation for pediatric MRI.

UNLABELLED: This study reviewed the hypertensive response of a large population of children to high-dose dexmedetomidine sedation with the aim of determining the incidence and predictors of hypertension. BACKGROUND: When dexmedetomidine is used to provide sedation for children, fluctuations in blood pressure have been described in case reports. We report the incidence and predictors of hypertension in a large series of children who received dexmedetomidine. METHODS/MATERIALS: At our institution, a computerized database holds patient demographics, sedation outcomes, adverse events, and hemodynamic data for all children who receive dexmedetomidine sedation for radiological imaging studies. After Institutional Review Board approval, this database was reviewed. RESULTS: Three thousand five hundred twenty-two (3522) children received dexmedetomidine sedation between May 1, 2007 and December 31, 2008 for magnetic resonance imaging studies. Median age was 3.6 years (interquartile range: 1.8-5.9). A total of 172 patients (4.9%) developed hypertension, with a higher incidence in the younger age group (0-3 years) when compared to the older age groups (3-18 years) (P < 0.05). Multivariable logistic regression modeling confirmed that younger age (Wald test = 43.5 of 5 degrees of freedom, P < 0.001) and more than one bolus (Wald test = 22.7, P < 0.001) were highly significant predictors of the occurrence of hypertension. CONCLUSION: When high-dose dexmedetomidine is used for pediatric sedation for MR imaging, the incidence of hypertension is low. Hypertension is most likely to occur in children <1 year of age during the continuous infusion, after they have received more than one bolus of dexmedetomidine.

Hemodynamic effects of dexmedetomidine sedation for CT imaging studies.

BACKGROUND: Dexmedetomidine sedation for radiological imaging studies is a relatively recent application for this drug. Previous studies have demonstrated some haemodynamic effects of dexmedetomidine, however, the effects remain poorly described in children. The aim of this study was to better define the effect of age on heart rate (HR) and blood pressure changes in children sedated for CT imaging with dexmedetomidine. METHODS/MATERIALS: At our institution dexmedetomidine is given for sedation for CT imaging as a bolus of 2 mcg.kg(-1) over 10 min followed by an infusion of 1 mcg.kg(-1).h(-1) with a second bolus if required. Detailed quality assurance data sheets document patient demographics, sedation outcomes, adverse events, and hemodynamic data are recorded for each patient. RESULTS: A total of 250 patients (range 0.1-10.6 years) received dexmedetomidine. ANOVA revealed strong evidence for changes in HR and mean arterial blood pressure during bolus and infusion relative to presedation values (P < 0.001). These changes were apparent in each age group and similar between groups. During the first bolus and during infusion, 82% and 93% of patients respectively were within the age-based normal range for HR. For mean arterial blood pressure, 70% of patients were within the normal range during first bolus and 78% during infusion. CONCLUSION: In the pediatric population studied, intravenous dexmedetomidine sedation was associated with modest fluctuations in HR and blood pressure. Hemodynamic changes were independent of age, required no pharmacologic interventions and did not result in any adverse events. By anticipating these possible hemodynamic effects and avoiding dexmedetomidine in those patients who may not tolerate such fluctuations in HR and blood pressure, dexmedetomidine is an appropriate sedative for children undergoing CT imaging.

Influence of goldenseal root on the pharmacokinetics of indinavir.

Goldenseal root was identified as the most potent inhibitor of CYP3A4 in a study that tested 21 popular herbal products for in vitro inhibitory activity. The purpose of this investigation was to examine the influence of goldenseal root on the disposition of the CYP3A4 substrate indinavir in humans. Using a crossover study design, the pharmacokinetics of indinavir were characterized in 10 healthy volunteers before and after 14 days of treatment with goldenseal root (1140 mg twice daily). Indinavir was given as a single 800-mg oral dose, and blood samples were collected for 8 hours following the dose. No statistically significant differences in peak concentration (11.6 vs. 11.9 mg/L) or oral clearance (26.8 vs. 23.9 mg*h/L) were observed following treatment with goldenseal root. Half-life and time to reach peak concentration were also unchanged by goldenseal. These results suggest that patients being treated with indinavir can safely take goldenseal root and that interactions with other drugs metabolized by CYP3A4 in the liver are unlikely.

Prevalence of fetal exposure to environmental toxins as determined by meconium analysis.

OBJECTIVE: The primary objective was to determine whether environmental pollutants, specifically lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As) and organochlorine and organophosphate pesticides can be detected in meconium. STUDY DESIGN: Prospective, cohort study. Infants were randomly recruited from the nurseries of five hospitals in Manila, Philippines. Their stools (meconium) were collected and analyzed for heavy metals by atomic absorption spectrophotometry and for pesticides by gas chromatography/mass spectrometry (GCMS). RESULTS: A total of 426 infants were studied. The exposure rate (based on meconium analysis) and the median concentration of the pollutants in the positive samples were as follows: lead (26.5%; 35.77 microg/ml), cadmium (8.5%; 13.37 microg/ml), mercury (83.9%; 3.17 ng/ml), chlordane (12.7%; 22.48 microg/ml), chlorpyrifos (11.0%; 8.26 microg/ml), diazinon (34.3%; 12.96 microg/ml), DDT (26.5%; 12.56 microg/ml), lindane (73.5%; 2.0 microg/ml), malathion (53.0; 6.80 microg/ml), parathion (32.0%; 2.30 microg/ml) and pentachlorphenol (16.1%; 90.00 microg/ml). Some maternal and neonatal factors that were significantly associated with the presence of environmental toxins in meconium included multi-gravidity, multiparity, multiple gestation, meconium stained fluid, smoking, gestational age, low birth weight and infant gender. CONCLUSION: Meconium analysis is a new and sensitive tool to detect fetal exposure to environmental toxins and its clinical use awaits further investigation.