Atypical Presentation and Evolution of Necrotizing Enterocolitis as a PIK3CA Pathological Variant.

Activating mutation of PIK3CA is linked with cases of overgrowth syndromes and belongs to the PIK3CA-related overgrowth spectrum (PROS). Mutations in this gene are associated with vascular malformations, brain abnormalities, and an increased risk for certain tumors. We report the case of a newborn girl, preterm at 34 weeks of gestation, referred to our center for atypical necrotizing enterocolitis (NEC). At laparotomy, the appearance of the intestinal tract was described as puffy, cauliflower-like with a dark purplish coloration. Subsequently, the colostomy was described as having a consistent proliferative appearance. Medical treatment with sirolimus resulted in minimal improvement. There are no reported cases in the literature of association between NEC and PIK3CA mutation. It is possible that PIK3CA mutation, including the related vascular anomalies, plays a role in the pathogenesis of NEC with this condition.

Case report: Success of allogeneic hematopoietic stem cell transplantation for refractory systemic-onset juvenile idiopathic arthritis.

Objectives: This study reports cases of systemic-onset juvenile idiopathic arthritis (sJIA) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center and reviews published outcomes of allo-HSCT in sJIA. Methods: We present a case report of two patients with sJIA who underwent allo-HSCT at a tertiary pediatric hospital. Each patient's disease course and allo-HSCT protocol/outcome are described. Outcomes of published cases of allo-HSCT in sJIA were compared to our experience. Results: Two patients with sJIA had allo-HSCT. Both failed multiple lines of disease-modifying anti-rheumatic drugs and experienced severe disease/treatment-related complications. Despite post-HSCT complications, both recovered without sequelae. Five years post-HSCT, patient 1 is in complete remission (CR) and is off medications. Patient 2 was in CR until 11 months post-HSCT after which he developed three disease flares. At 4 years post-HSCT he is currently in CR on Adalimumab monotherapy. Engraftment was excellent with a donor chimerism of 100% for patient 1 and 93% for patient 2. In the literature, the outcome of allo-HSCT is reported in 13 sJIA patients. When merging those with our 2 patients, 1/15 patients died and 13/14 achieved CR, of which 12 are off medications (median [range] follow-up: 2.2 [0.2-7.0] years). Extended follow-up data on 11 of the 13 reported sJIA patients showed that an additional 3 patients flared at 3, 4, and 10 years post-HSCT. Conclusion: We report two patients with severe/refractory sJIA who underwent successful allo-HSCT and achieved CR. Allo-HSCT is a potential curative option for severe/refractory sJIA. It should be considered only after failure of conventional sJIA treatments and when an HLA-matched donor is available in order to lower transplant-related mortality. The outcomes of reported sJIA patients who received allo-HSCT are encouraging but long-term follow-up data are needed to better characterized the risk-benefit ratio of this procedure.

Morphine versus hydromorphone in pediatrics: a narrative review of latest indications and optimal use in neonates and children.

The management of pain in pediatrics is multimodal and includes non-pharmacologic and pharmacologic approaches. Opioids, and particularly morphine and hydromorphone, are frequently used to treat moderate-to-severe pain. The goals of this review are to describe the pharmacological characteristics of both drugs, to cover the latest evidence of their respective indications, and to promote their safe use in pediatrics. Morphine is the most studied opioid in children and is known to be safe and effective. Morphine and hydromorphone can be used to manage acute pain and are usually avoided when treating chronic non-cancer pain. Current evidence suggests that both opioids have a similar efficacy and adverse effect profile. Hydromorphone has not been studied in neonates but in some centers, it has been used instead of morphine for certain patients. In palliative care, the use of opioids is often indicated and their benefits extend beyond analgesia; indications include treatment of central neuropathic pain in children with severe neurologic impairment and treatment of respiratory distress in the imminently dying patients. The longstanding belief that the use of well-titrated opioids hastens death should be abandoned as robust evidence has shown the opposite. With the current opioid crisis, a responsible use of opioids should be promoted, including limiting the opioid prescription to the patient's anticipated needs, optimizing a multimodal analgesic plan including the use of non-pharmacological measures and non-opioid medications, and providing information on safe storage and disposal to patients and families. More data is needed to better guide the use of morphine and hydromorphone in children.

The Three W's of Acetaminophen In Children: Who, Why, and Which Administration Mode.

Acetaminophen is one of the oldest medications commonly administered in children. Its efficacy in treating fever and pain is well accepted among clinicians. However, the available evidence supporting the use of acetaminophen's different modes of administration remains relatively scarce and poorly known. This short report summarizes the available evidence and provides a framework to guide clinicians regarding a rational use of acetaminophen in children.

Repurposing alpelisib, an anti-cancer drug, for the treatment of severe TIE2-mutated venous malformations: Preliminary pharmacokinetics and pharmacodynamic data.

Extensive venous malformations involving limbs severely impact quality of life, mostly due to chronic pain and functional limitations. But patients can also display coagulopathy with associated risks of life-threatening thromboembolism and bleeding. Available pharmacological treatments (e.g., sirolimus) are not universally effective. Novel therapies are urgently needed for patients with treatment-resistant venous malformations. We report three patients with TIE-2 receptor mutations treated with alpelisib for 6 months (daily dosing: 50 mg for children weighing <50 kg and 100 mg for those >50 kg). Pain was controlled, gait improved, size of the abnormal venous network decreased, and coagulopathy dramatically improved. Drug exposure was highly variable, suggesting that alpelisib dosing should be individualized to patient's characteristics and guided by therapeutic drug monitoring.

Defining vascular anomaly phenotypes in children based on a systematic literature search: A critical step in developing a single severity score for interventional clinical trials.

INTRODUCTION: Genetically targeted drugs in vascular anomalies (VA) are used despite the absence of a validated severity score. The aim of this study was to evaluate the feasibility of grouping phenotypic VA clinical characteristics into a single severity score. METHODS: A systematic literature review including children treated with sirolimus accompanied by a detailed description of phenotype and management was conducted. Demographic data and clinical features were extracted to define distinct categories of phenotypes. RESULTS: Children with VA display two main phenotypes regardless of VA subtype, which may overlap. A systemic phenotype results from direct invasion and compression of vital structures generally leading to hospitalization and aggressive management in infancy. A functional phenotype is associated with chronic pain and disability manifesting mainly during early adolescence and managed in the outpatient setting. CONCLUSION: The two distinct phenotypes described could be the basis for developing a unified scoring system for VA severity assessment.

Newly approved IV acetaminophen in Canada: Switching from oral to IV acetaminophen. Is IV worth the price difference? A systematic review.

CONTEXT: The use of intravenous acetaminophen leads to meaningful health cost increases for paediatric institutions. Therefore, strict criteria for intravenous acetaminophen administration are needed. OBJECTIVE: To undertake a systematic review of available evidence comparing oral versus intravenous acetaminophen use in children. METHOD: A systematic literature search was conducted on five databases. All prospective interventional studies comparing intravenous to oral acetaminophen in patients <18 years old were included. Data collection and analysis were done according to PRISMA guidelines. RESULTS: Among 6,417 retrieved abstracts, 29 full-text articles were assessed of which 3 were retained. (1) Pharmacokinetic: Oral bioavailability (72% with a high inter-individual variability) was reported in 47 stable patients in a paediatric intensive care unit. (2) Analgesia: In a double-blind randomized controlled trial of 45 children, no difference in analgesia was found between oral and intravenous administration after cleft palate repair. (3) Fever: In an open-label prospective observational study of 200 children, temperature decreased faster after intravenous than oral administration but was similar 4 hours later. CONCLUSIONS: Available data are insufficient to guide clinicians with a rational choice of route of administration. Oral bioavailability should be studied in paediatric populations outside the intensive care unit. Despite the widespread use of intravenous acetaminophen, there is little evidence to suggest that it improves analgesia compared to the oral formulation. Similarly, fever weans faster but whether this translates into any meaningful clinical outcome is unknown. The lack of data plus the significantly higher costs of intravenous acetaminophen should motivate further research.

Systemic, local, and sclerotherapy drugs: What do we know about drug prescribing in vascular anomalies?

Off-label drug prescribing, frequent in the treatment of vascular anomalies (VA), relies on the quality of the literature reporting drug efficacy and safety. Our objective is to review the level of evidence (LOE) surrounding drug use in VA, which is more prevalent in pediatric care. A list of drugs used in VA was created with a literature review in July 2020. For each drug listed, the article displaying the highest LOE was determined and then compared between efficacy/safety data, routes of administration, pharmacological categories and a subset of VA. The influence of research quality on study results was also explored. The median LOE for the 74 drugs identified poor methodological quality, with a predominance of retrospective studies or case reports. Drug safety is currently inadequately reported. This is alarming as many treatments display significant safety concerns. Also, current literature displays major publication bias that probably leads to overestimation of drug efficacy in VA.

Evaluation of Vaso-occlusive Crisis Management With Patient-Controlled Analgesia in Children With Sickle Cell Disease Requiring Hospitalization.

OBJECTIVE: The aim of this study was to review the use of patient-controlled analgesia (PCA) in sickle cell disease (SCD) for pediatric patients with vaso-occlusive crisis (VOC) in our institution and to compare the effect of early vs late PCA start on pain relief and LOS. METHODS: This retrospective study included all pediatric patients treated with PCA for a severe VOC from 2010 to 2016. "Early-PCA" was defined as start of PCA within 48 hours of arrival. Time to reach adequate analgesia was defined as the time to reach 2 consecutive pain scores less than 5/10 at 4-hour interval. RESULTS: During the study period, 46 patients presented 87 episodes of VOC treated with PCA. Sixty-three patients with VOC were treated with Early-PCA and 24 with Late-PCA. Both groups were comparable except for median pain score at admission; the Early-PCA group had higher scores: 9.0/10 vs 7.0/10. Time to reach adequate analgesia could be evaluated only in a subset of patients (n = 32) but was shorter in the Early-PCA group with a median difference of 41.0 hours (95% CI -82.0 to -6.0). Early-PCA was associated with a median reduction in LOS of 3.4 days (95% CI -4.9 to -1.9). There was no difference between the 2 groups in terms of side effects and occurrence of acute chest syndrome during hospitalization. CONCLUSIONS: In this study, a reduced time to reach adequate analgesia and LOS was noted in the Early-PCA group for severe VOC. A prospective study is required to confirm these results.

Off-Label Use and Safety of Drug Use in Vascular Anomalies.

BACKGROUND: Off-label drug use is associated with an increased risk of adverse drug reactions. It is common in pediatrics and in rare diseases, which are two characteristics applying to vascular anomalies (VA). OBJECTIVES: The aim of this work was to quantify off-label drug use in VA and assess its safety. METHODS: A review was conducted to extract a list of drugs used in VA management. A drug was considered to have significant safety concerns if a black box warning was present or if a serious adverse drug reaction (SADR) was reported in at least 1% of the patients (SADR is defined as a noxious and unintended response to a drug that occurs at any dose and results in hospitalization, prolongation of existing hospitalization, congenital malformation, persistent or significant disability or incapacity, life-threatening condition, or death). The labelling status and safety of each drug was assessed based on the product monograph, Micromedex, and the FDA data. RESULTS: We found that 98.9% of the inventoried drugs were used off-label or unlicensed for VA management. Only the oral solution of propranolol hydrochloride (Hemangeol®) for the treatment of infantile hemangiomas is approved. Significant safety issues concerned 73% of the drugs and were more frequent among systemic than locally delivered drugs. CONCLUSIONS: Off-label drug use in VA is the rule and not the exception. Significant safety concerns are common. It is necessary to carefully weigh risk and benefits for every patient when using systemic and local treatments carrying safety concerns. Patients should be openly informed and involved in the decision-making process.

Is Busulfan Clearance Different in Patients With Sickle Cell Disease? Let's Clear Up That Case With Some Controls.

In busulfan-based conditioning regimen for hematopoietic stem cell transplantation in children, accurate a priori determination of the first dose is important because of its narrow therapeutic window. Sickle cell disease (SCD) influences pharmacokinetics of the commonly used drugs by affecting organs responsible for drug metabolism and elimination. This pharmacokinetics study assesses the influence of SCD on the metabolic pathway of busulfan that is mainly metabolized in the liver. In this retrospective cross-sectional case-control study, 16 patients with SCD were matched to 50 patients without SCD on known busulfan clearance's covariates (glutathione-S-transferase alpha1 polymorphisms, age, weight). Clearance of the first dose of busulfan was not significantly different independently of genetic or anthropometric factors in patients with or without SCD.

Intra-abdominal lymphatic malformation management in light of the updated International Society for the Study of Vascular Anomalies classification.

BACKGROUND: The International Society for the Study of Vascular Anomalies (ISSVA) classification distinguishes between common lymphatic malformations and complex lymphatic anomalies. These entities have overlapping features but differing responses to treatment. Surgery has been the mainstream treatment in intra-abdominal lymphatic malformation, with variable reported success in the literature. OBJECTIVE: The aim of this study was to review the outcome of different treatments for intra-abdominal lymphatic malformations in children. MATERIALS AND METHODS: We retrospectively reviewed all intra-abdominal lymphatic malformations from 1999 to 2019 in children treated by the surgical team or followed in the vascular anomalies clinic of our institution. Children were classified into one of three groups: group A, isolated intra-abdominal lymphatic malformation; group B, common lymphatic malformation in continuity with other regions; or group C, intra-abdominal involvement as part of a complex lymphatic anomaly or associated syndrome. RESULTS: Fifty intra-abdominal lymphatic malformations were diagnosed; five of these were excluded. In group A (n=28), the treatment was surgical resection (n=26) or sclerosing treatment (n=1), with one case of spontaneous regression; no recurrence was observed in 25 patients. In group B (n=7), three patients had partial resection and all had recurrence; four had sclerotherapy alone with good response. In group C (n=10), therapeutic options included surgery, sclerosing treatment and pharmacotherapy, with variable outcomes. CONCLUSION: The management of intra-abdominal malformations requires a team approach. Sclerotherapy is successful in treating macrocystic lymphatic malformation. Surgery is successful in treating isolated intra-abdominal common lymphatic malformation, albeit at times at the cost of intestinal resection, which could be avoided by combining surgery with preoperative sclerotherapy. With surgery there is often limited resectability, and therefore recurrence in intra-abdominal lymphatic malformations that are part of complex lymphatic anomalies associated with syndromes, or in common lymphatic malformations in continuity with other regions. Sclerotherapy is an effective modality in these instances along with pharmacotherapy.

Morphine or hydromorphone: which should be preferred? A systematic review.

OBJECTIVE: To systematically review available paediatric literature on comparisons between morphine (Mo) and hydromorphone (Hm), to guide clinicians to rationally use these medications. DESIGN: Systematic review within four databases for all studies published from 1963 to July 2019. SETTING: All paediatric settings. ELIGIBILITY: All studies comparing Mo to Hm in individuals younger than 21 years. MAIN OUTCOME MEASURES: The primary outcome was to compare clinical efficacy and side effects of Mo and Hm. The secondary outcomes were the comparison of pharmacokinetic profiles and the description of predefined Mo to Hm conversion ratios used across the paediatric literature. RESULTS: Among 754 abstracts reviewed, 59 full-text articles met inclusion criteria and 24 studies were included in the analysis: 4 studies compared pharmacodynamics of Mo and Hm and 20 studies reported the use of a predefined Mo to Hm conversion ratio. Most studies had a poor methodological quality. Available evidence suggests that, when given intravenously, the equianalgesic ratio of Mo to Hm is 5:1. Intravenous administration with this ratio results in a similar rate of adverse effects, including pruritus and nausea. The epidural administration with a ratio of 10:1 results in more pruritus and urinary retention with Mo than Hm. Pharmacokinetic data were reported in only one study. A wide range of pre-established ratios for different routes of administration were reported, but few were based on evidence. CONCLUSION: Current literature does not permit a rational choice between Mo and Hm. A ratio of 5:1 seems adequate for intravenous administration and leads to a similar rate of adverse effects.

Comparison of two vitamin D supplementation strategies in children with sickle cell disease: a randomized controlled trial.

Previously, we showed that nearly 70% of children followed in our sickle cell disease (SCD) clinic were vitamin D- deficient and had low vitamin intake with poor use of supplements. We compared the change in serum 25-hydroxyvitamin D [25(OH)D], safety and clinical impact of two vitamin D supplementation regimens in children with SCD. Children (5-17 years, all genotypes) were randomized to a single bolus of vitamin D3 (300 000 IU; n = 18) or placebo (n = 20). All children received a prescription for daily 1 000 IU vitamin D3 . Serum 25(OH)D and calcium, urinary calcium/creatinine ratio, musculoskeletal pain, quality of life, haematology and bone markers were assessed at baseline and three months post intervention. Bolus administration led to a greater rise in 25(OH)D levels from baseline compared to placebo (20 ± 16 nmol/l vs. 2 ± 19 nmol/l; P = 0·003) and correction of vitamin D deficiency. No hypercalcaemia nor hypercalciuria occurred during the study, but more children in the bolus group experienced gastrointestinal symptoms within the first month (P = 0·04). There were no differences between groups for other outcomes. The use of a high-dose vitamin D bolus combined with daily 1 000 IU vitamin D3 was more efficient in raising 25(OH)D levels than daily supplementation alone in children with SCD.

Suspected Overlap Between Serotonin Syndrome and Neuroleptic Malignant Syndrome in a Child Treated With Metoclopramide?

A 19-month-old child presented with fever and acute neurological deterioration with hypertonia, tremors, and clonus 1 day after starting metoclopramide. The clinical course of the patient was suggestive of neuroleptic malignant syndrome (NMS) and serotonin syndrome (SS), which can both be triggered by metoclopramide. This first pediatric report of an overlap between NMS and SS associated to metoclopramide highlights the importance of considering this new entity and its consequences on treatment.

Valproic Acid Induced Pancreatitis Presenting With Decreased Level of Consciousness in a Child With Tuberous Sclerosis Complex.

A 2-year-old Caucasian boy with tuberous sclerosis complex presented to the emergency department with lethargy and new onset myoclonias. Pancreatitis, thrombocytopenia, and coagulopathy associated to a decreased level of consciousness were diagnosed. Valproic acid had been initiated 13 months before and had been slowly increased to a dose of approximately 38 mg/kg/day. All the symptoms resolved after discontinuation of the medication. The clinical presentation of this child highlights that valproic acid-related pancreatitis can present with decreased level of consciousness without associated gastrointestinal symptoms. Adverse drug reactions associated with valproic acid can lead to damage of multiple organs and may prove fatal if not promptly recognized and managed.

Enteral Acetaminophen Bioavailability in Pediatric Intensive Care Patients Determined With an Oral Microtracer and Pharmacokinetic Modeling to Optimize Dosing.

OBJECTIVES: Decreasing morbidity and mortality by rationalizing drug treatment in the critically ill is of paramount importance but challenging as the underlying clinical condition may lead to large variation in drug disposition and response. New microtracer methodology is now available to gain knowledge on drug disposition in the intensive care. On the basis of studies in healthy adults, physicians tend to assume that oral doses of acetaminophen will be completely absorbed and therefore prescribe the same dose per kilogram for oral and IV administration. As the oral bioavailability of acetaminophen in critically ill children is unknown, we designed a microtracer study to shed a light on this issue. DESIGN: An innovative microtracer study design with population pharmacokinetics. SETTING: A tertiary referral PICU. PATIENTS: Stable critically ill children, 0-6 years old, and already receiving IV acetaminophen. INTERVENTIONS: Concomitant administration of an oral C radiolabeled acetaminophen microtracer (3 ng/kg) with IV acetaminophen treatment (15 mg/kg every 6 hr). MEASUREMENTS: Blood was drawn from an indwelling arterial or central venous catheter up to 24 hours after C acetaminophen microtracer administration. Acetaminophen concentrations were measured by liquid chromatography-mass spectrometry and C concentrations by accelerated mass spectrometry. MAIN RESULTS: In 47 patients (median age of 6.1 mo; Q1-Q3, 1.8-20 mo) the mean enteral bioavailability was 72% (range, 11-91%). With a standard dose (15 mg/kg 4 times daily), therapeutic steady-state concentrations were 2.5 times more likely to be reached with IV than with oral administration. CONCLUSIONS: Microtracer studies present a new opportunity to gain knowledge on drug disposition in the intensive care. Using this modality in children in the pediatric intensive care, we showed that enteral administration of acetaminophen results in less predictable exposure and higher likelihood of subtherapeutic blood concentration than does IV administration. IV dosing may be preferable to ensure adequate pain relief.

Visual disorders with psychostimulants: A paediatric case report.

Methylphenidate- and amphetamine-based psychostimulants are the most common medications used to treat the symptoms of attention-deficit/hyperactivity disorder in children. Ocular side effects including dry eyes, mydriasis, accommodation disturbance, and blurry vision are listed in the product monograph but interestingly, are rarely reported in the paediatric literature. Our patient, a 9-year-old boy, presented a significant decrease in visual acuity secondary to accommodation disorder after being treated with methylphenidate hydrochloride controlled release (Biphentin) and lisdexamfetamine (Vyvanse). The unusual acute adverse effect, altered accommodation leading to a decline in visual acuity, emphasizes the importance of considering any change in vision following the introduction of psychostimulant medication as a potential adverse effect. This case highlights the importance of pharmacovigilance especially in paediatrics where data are lacking.

Patient access to compounded drugs in paediatrics after discharge from a tertiary centre.

OBJECTIVE: To describe the problems faced by young patients and their parents when obtaining and using compounded drugs. METHODS: This prospective observational descriptive study included patients 0 to 21 years of age who were discharged from a mother-child tertiary hospital with a prescription containing at least one compounded drug between February 2016 and July 2016. Families were called 7 to 10 business days after discharge to complete a telephone follow-up questionnaire. Retail pharmacies were contacted to obtain additional information in order to compare the dispensed compounded drug with the prescription and published master formulas. RESULTS: The parents of 71 patients with a median age of 6.9 months were surveyed regarding 99 compounded drugs corresponding to 34 different oral formulations. Out of 314 issues identified, 252 were considered as problems: 9 involved major and 243 minor problems with real or potential consequences. CONCLUSION: This study identified a significant number of compounding-related problems. It suggests that current practice standards are insufficient and action should be taken to improve the use and the dispensation of compounded drugs to ensure patients' safety.