Δευτέρα, 18 Φεβρουαρίου 2019

Pediatric Drugs : Pancreatic Enzyme Supplementation in Patients with Atopic Dermatitis and Food Allergies,Serious Adverse Events Associated with Off-Label Use of Azithromycin or Fentanyl,Neuropathic Pain in Pediatric Oncology,Pharmacotherapeutic Management of Wilms Tumor,,Treatment of Down Syndrome Arthropathy,Treatment of Childhood Absence Epilepsy,Cortisol Replacement Therapy,Changes in Hemoglobin Concentrations Post-immunoglobulin Therapy in Patients with Kawasaki Disease

Neuropathic Pain in Pediatric Oncology: A Clinical Decision Algorithm

Abstract

Neuropathic pain in pediatric oncology can be caused by distinct lesions or disease processes affecting the somatosensory system, including chemotherapy-related neuronal injury, solid tumor-related involvement of neural structures, post-surgical neuropathic pain—including phantom limb pain and pain after limb-sparing surgery—and the complex circumstances of neuropathic pain at the end of life. Treatment algorithms reflect the general treatment principles applied for adult neuropathic pain, but the dose regimens applied in children are modest and rarely escalated to the maximum doses to optimize analgesic efficacy. Pharmacological management of neuropathic pain should be based on a stepwise intervention strategy, as combinations of medications are the most effective approach. Gabapentinoids and tricyclic antidepressants are recommended as first-line therapy. Methadone, ketamine, and lidocaine may be useful adjuvants in selected patients. Prospective studies extended over a substantial length of time are recommended because of the nature of neuropathic pain as persistent, chronic pain and based on the need for sufficient time to escalate medication dose regimens to full analgesic efficacy.



Pharmacotherapeutic Management of Wilms Tumor: An Update

Abstract

Although differences exist in treatment and risk-stratification strategies for children with Wilms tumor (WT) between the European [International Society of Paediatric Oncology (SIOP)] and American [Children's Oncology Group (COG)] study groups, outcomes are very similar, with an overall survival of > 85%. Future strategies aim to de-intensify treatment and reduce toxicity for children with a low risk of relapse and intensify treatment for children with high-risk disease. For metastatic WT, response of lung nodules to chemotherapy is used as a marker to modify treatment intensity. For recurrent WT, a unified approach based on the use of agents that were not used for primary therapy is being introduced. Irinotecan is being explored as a new strategy in both metastatic and relapsed WT. Introduction of biology-driven approaches to risk stratification and new drug treatments has been slower in WT than in some other childhood cancers. While several new biological pathways have been identified recently in WT, their individual rarity has hampered their translation into clinical utility. Identification of robust prognostic factors requires extensive international collaborative studies because of the low proportion who relapse or die. Molecular profiling studies are in progress that should ultimately improve both risk classification and signposting to more targeted therapies for the small group for whom current therapies fail. Accrual of patients with WT to early-phase trials has been low, and the efficacy of these new agents has so far been very disappointing. Better in vitro model systems to test mechanistic dependence are needed so available new agents can be more rationally prioritized for recruitment of children with WT to early-phase trials.



Pancreatic Enzyme Supplementation in Patients with Atopic Dermatitis and Food Allergies: An Open-Label Pilot Study

Abstract

Background

Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects both patients and their families. Current therapies often alleviate symptoms but do not prevent or eradicate the disease.

Objectives

Our objective was to determine whether pancreatic enzyme supplementation is an effective and safe treatment in refractory pediatric AD associated with food allergies.

Methods

We conducted an open-label pilot study using a case–control design. Patients with severe AD and known food allergies refractory to conventional therapies and exclusion diets were recruited and treated for 6 weeks with oral supplementation of pancreatic enzymes. The primary endpoint was the severity of AD, using the Scoring Atopic Dermatitis (SCORAD) index. Secondary measures included markers of intestinal permeability (urinary sucrose and lactulose/mannitol excretion).

Results

A total of 11 patients met all eligibility criteria and completed the trial. Significant improvement in AD was observed after 6 weeks of pancreatic enzyme supplementation (SCORAD index 52.3 ± 5.5 vs. 34.6 ± 7.6; p = 0.0008). Beneficial effect was observed in 9 of 11 patients, without adverse events. Fractional urinary sucrose excretion improved to a level comparable to that of age-matched controls (p < 0.05). However, urinary lactulose:mannitol ratios remained abnormally high compared with those of controls (p = 0.01).

Conclusions

Pancreatic enzyme supplementation was associated with improved AD and gastroduodenal permeability. Additional randomized placebo-controlled studies are required before this treatment can be recommended in this clinical setting.



Serious Adverse Events Associated with Off-Label Use of Azithromycin or Fentanyl in Children in Intensive Care Units: A Retrospective Chart Review

Abstract

Objectives

Half of prescription drugs commonly given to children lack product labeling on pediatric safety, efficacy, and dosing. Two drugs most widely used off-label in pediatrics are azithromycin and fentanyl. We sought to determine the risk of serious adverse events (SAEs) when oral azithromycin or intravenous/intramuscular fentanyl are used off-label compared to on-label in pediatric intensive care units (ICUs).

Study Design

Six pediatric hospitals participated in a retrospective chart review of patients administered oral azithromycin (n = 241) or intravenous/intramuscular fentanyl (n = 367) between January 5, 2013 and December 26, 2014. Outcomes were SAEs by drug and labeling status: off-label compared to on-label by Food and Drug Administration (FDA)-approved age and/or indication. Statistical analysis was performed using logistic regression to estimate odds ratios (ORs) and Cox regression to estimate hazard ratios (HRs).

Results

Twenty-one (9%) children receiving azithromycin experienced SAEs. Off-label use of azithromycin was not associated with a higher risk of SAE (OR 0.87, 95% CI 0.27–2.71, p = 0.81). Ninety-five (26%) children receiving fentanyl experienced SAEs. Fentanyl off-label use by both age and indication was not associated with a higher risk of overall SAEs compared to on-label use (OR 1.99, 95% CI 0.94–4.19, p = 0.07). However, the risk of the SAE respiratory depression was significantly greater when fentanyl was used off-label by both age and indication (OR 5.05, 95% CI 1.08–23.56, p = 0.044). Results based on HRs were similar.

Conclusions

Azithromycin off-label use in pediatric ICUs does not appear to be associated with an increased risk of SAEs. Off-label use of fentanyl appears to be more frequently associated with respiratory depression when used off-label by both age and indication in pediatric ICUs. Prospective studies should be undertaken to assess the safety and efficacy of fentanyl in the pediatric population so that data can be added to the FDA labeling.



Clinical Features and Treatment of Down Syndrome Arthropathy: Experience from Two US Tertiary Hospitals

Abstract

Background

Arthropathy of Down syndrome (DA) is largely under-recognized, with an average 2-year delay in diagnosis. Most patients present with polyarthritis, and treatment has historically been challenging.

Objectives

Our objective was to investigate the clinical features and treatment of DA in the largest cohort reported to date.

Methods

In a retrospective chart review at two tertiary care hospitals, International Classification of Diseases, ninth revisionclinical modification (ICD-9-CM) codes for Down syndrome (DS) and juvenile idiopathic arthritis (JIA), between 1 January 1995 and 31 December 2015, were identified and charts reviewed.

Results

In total, 43 patients were identified, with an average (± standard deviation [SD]) follow-up period of 6 ± 4.4 years. The average age of symptom onset was 7.4 ± 3.9 years, with a mean delay of 19 ± 17 months from symptom onset to diagnosis. At diagnosis, 77% of patients had morning stiffness and 72% had abnormal laboratory values; there was an average of 15 ± 13 active joints (range 1–56). Treatment approaches varied, and there was a significant decrease in joints with active arthritis (p < 0.001), with 25% and 39% having at least one change in disease-modifying antirheumatic drug (DMARD) and biologic therapy, respectively. DMARD therapy was discontinued in 60% because of side effects, and 39% had inadequate response to first-line biologic therapy.

Conclusions

DA remains under-recognized, with delays in diagnosis and extensive musculoskeletal symptoms at presentation. While DA can improve with current therapy for JIA (corticosteroids, DMARDs, biologics), barriers include medication toxicity, intolerance, and ineffectiveness. Earlier diagnosis through improved screening and more targeted treatment may allow for earlier disease control and better outcomes.



Topical Pharyngeal Lidocaine Reduces Respiratory Adverse Events During Upper Gastrointestinal Endoscopies Under Ketamine Sedation in Children

Abstract

Background

Upper gastrointestinal endoscopies (UGEs) performed under ketamine sedation may increase the risk of respiratory adverse events (RAEs) due to pharyngeal stimulation. Topical lidocaine prevents general anesthesia-induced laryngospasm.

Objective

Our objective was to determine whether topical lidocaine may reduce the incidence of RAEs induced by pharyngeal stimulation in UGEs performed on children sedated with ketamine.

Methods

We conducted a single-center prospective study. We included every patient admitted for an elective diagnostic UGE under ketamine sedation who received lidocaine prior to the technique. Patients requiring any other medication were excluded. Our main outcome measure was the number of desaturation episodes. We then compared these results with those obtained in an historic group who did not receive topical lidocaine, in which we registered a total of 54 desaturation episodes.

Results

In total, 88 children (52.3% boys) were included. The median age was 7 years [interquartile range (IQR) 3–11]. The mean duration of the procedure was 6.5 ± 2.4 min, and the median initial ketamine dose was 1.76 mg/kg (IQR 1.56–2.03). The total number of desaturation episodes was 3 (3.4%), and two of these occurred prior to the introduction of the endoscope. This result represents a lower incidence than in previously reported series, and a significant decrease (p < 0.0001) with respect to the 54 RAEs registered in the historic group of 87 children.

Conclusions

Topical lidocaine premedication significantly reduced the incidence of RAEs in children during UGEs under ketamine sedation. Our findings should be confirmed by a double-blind randomized controlled trial.



A Practical Guide to Treatment of Childhood Absence Epilepsy

Abstract

Childhood absence epilepsy (CAE) is a common pediatric epilepsy syndrome with distinct seizure semiology, electroencephalography (EEG) features, and treatment. A diagnosis of CAE can be obtained during an office visit with a careful history, physical exam including prolonged hyperventilation, and a routine EEG. The treatment of choice for CAE with absence seizures only is ethosuximide. Valproic acid and lamotrigine are also effective treatments for many patients, but when compared to ethosuximide, valproic acid has more adverse effects and lamotrigine is less effective. Attention to predictors of response to treatment, including clinical, electrographic, and genetic factors, is increasing. Refractory CAE occurs in fewer than half of patients, and treatment strategies are available, though efficacy data are lacking. Careful assessment and treatment of psychosocial comorbidities is essential in caring for patients with CAE.



Acknowledgement to Referees


The Challenges of Cortisol Replacement Therapy in Childhood: Observations from a Case Series of Children Treated with Modified-Release Hydrocortisone

Abstract

Background

Hydrocortisone is the preferred treatment for adrenal insufficiency in childhood. A small minority of children experience low cortisol concentrations and symptoms of cortisol insufficiency, poorly responsive to modifications in dosing. We speculated that treatment with modified-release hydrocortisone Plenadren® may be beneficial in these selected patients.

Objective

The aim of this article was to report cortisol profiles during treatment with standard formulation hydrocortisone and Plenadren, and growth and weight gain during treatment with Plenadren in selected children with adrenal insufficiency.

Patients and Methods

Data are reported as median (range). Eight patients (5 male) age 11.0 years (8.8–13.3), with adrenal insufficiency for 4.3 years (2.2–10.0) were treated with Plenadren in doses derived from cortisol concentrations measured during treatment with standard formulation hydrocortisone.

Results

Plasma cortisol was 262 nmol/L (114–654) 2 h after the morning dose (hydrocortisone dose 6.1 mg/m2 [4.3–7.1]) of standard formulation hydrocortisone. After 4 h, cortisol concentration was 81 nmol/L (56–104) and was < 100 nmol/L in six patients. Two hours after Plenadren administration (hydrocortisone dose 12.1 mg/m2 [8.3–17.6]), plasma cortisol concentration was 349 nmol/L (150–466), and after 4 h it was 239 nmol/L (99–375) and < 100 nmol/L in one patient. Six hours after the Plenadren dose, cortisol concentration was < 100 nmol/L in four patients and after 8 h cortisol concentration was < 100 nmol/L in seven patients (sample not obtained in one patient). Six patients elected to continue treatment with Plenadren. After 4.2 years (2.7–6.0), change in height standard deviation score (SDS) was 0.1 SD (− 0.2 to 0.2) and body mass index SDS was 0.3 SD (0–1.1).

Conclusion

Smoother cortisol profiles and more sustained cortisol exposure were achieved during treatment with Plenadren, which was the preferred treatment in most patients. Robust clinical trials are required to determine the place of this medication in paediatric practice.



Changes in Hemoglobin Concentrations Post-immunoglobulin Therapy in Patients with Kawasaki Disease: A Population-Based Study Using a Claims Database in Japan

Abstract

Background

We sought to quantify the degree of anemia after high-dose intravenous immunoglobulin (IVIG) therapy in patients with Kawasaki disease (KD) by assessing hemoglobin (Hb) dynamics and determining the risk of transfusion.

Methods

We analyzed data from a database containing inpatient data collected from 230 hospitals in Japan. In addition to administrative records, this database included laboratory results for some patients. We searched for individuals aged ≤ 18 years with a diagnosis of KD (International Statistical Classification of Diseases and Related Health Problems, 10th revision, code M30.3) who had received high-dose (≥ 1 g/kg) IVIG therapy. The primary outcome measure was post-IVIG therapy Hb dynamics in patients for whom laboratory findings were available. Secondary outcomes included the proportion of patients whose Hb value decreased below a specified threshold (e.g., 1 g/dL) and the number who received red blood cell transfusions, identified by a Japanese administrative code, in the whole cohort.

Results

Laboratory data were available for 979 of 8262 patients with KD receiving high-dose IVIG. Hb dynamics assessed on spline curves showed that mild anemia commonly occurred 1–2 days after IVIG infusion and returned to the baseline thereafter. Declines of Hb > 1 g/dL and > 2 g/dL were found in 21.8% and 4.3% of patients, respectively. Two of the 8262 individuals with KD had received transfusions after IVIG therapy (incidence rate 0.024%; 95% confidence interval 0.003–0.087), but the indication for transfusion could not be determined from our records.

Conclusions

Although mild anemia commonly occurred post-IVIG therapy in Japanese individuals with KD, severe anemia necessitating transfusion was rare in these patients.



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