Remote ischemic conditioning in necrotizing enterocolitis: study protocol of a multi-center phase II feasibility randomized controlled trial.

PURPOSE: Remote ischemic conditioning (RIC) is a maneuver involving brief cycles of ischemia reperfusion in an individual's limb. In the early stage of experimental NEC, RIC decreased intestinal injury and prolonged survival by counteracting the derangements in intestinal microcirculation. A single-center phase I study demonstrated that the performance of RIC was safe in neonates with NEC. The aim of this phase II RCT was to evaluate the safety and feasibility of RIC, to identify challenges in recruitment, retainment, and to inform a phase III RCT to evaluate efficacy. METHODS: RIC will be performed by trained research personnel and will consist of four cycles of limb ischemia (4-min via cuff inflation) followed by reperfusion (4-min via cuff deflation), repeated on two consecutive days post randomization. The primary endpoint of this RCT is feasibility and acceptability of recruiting and randomizing neonates within 24 h from NEC diagnosis as well as masking and completing the RIC intervention. RESULTS: We created a novel international consortium for this trial and created a consensus on the diagnostic criteria for NEC and protocol for the trial. The phase II multicenter-masked feasibility RCT will be conducted at 12 centers in Canada, USA, Sweden, The Netherlands, UK, and Spain. The inclusion criteria are: gestational age < 33 weeks, weight ≥ 750 g, NEC receiving medical treatment, and diagnosis established within previous 24 h. Neonates will be randomized to RIC (intervention) or no-RIC (control) and will continue to receive standard management of NEC. We expect to recruit and randomize 40% of eligible patients in the collaborating centers (78 patients; 39/arm) in 30 months. Bayesian methods will be used to combine uninformative prior distributions with the corresponding observed proportions from this trial to determine posterior distributions for parameters of feasibility. CONCLUSIONS: The newly established NEC consortium has generated novel data on NEC diagnosis and defined the feasibility parameters for the introduction of a novel treatment in NEC. This phase II RCT will inform a future phase III RCT to evaluate the efficacy and safety of RIC in early-stage NEC.

Complications Associated with Low Position versus Good Position Umbilical Venous Catheters in Neonates of ≤32 Weeks' Gestation.

OBJECTIVE: This study aimed to determine the incidence of umbilical venous catheter associated infection (UVCAI) in very preterm infants based on UVC tip position. STUDY DESIGN: In this retrospective cohort study, infants born at ≤32 weeks were divided into groups with a UVC tip in either a low-lying or good position. The primary outcome was UVCAI. Survival analysis represented time to infection between groups. Subgroup analyses were based on duration of UVC indwelling time. RESULTS: Of 1,983 infants, 1,638 infants were eligible; 33% had low-lying UVC and 67% had good position UVC. Survival analyses suggested a significantly higher probability of infection was associated with low UVC (adjusted hazard ratio [HR]: 1.9, 95% confidence interval [CI]: 1.1-3.2; p = 0.001). The risk of infection was higher for UVC of >7 days duration (adjusted HR: 2.2, 95% CI: 1.1-4.2). Extravasation as a complication was significantly higher in the low UVC versus good position UVC (1.3 vs. 0.1%; odds ratio: 14.4, 95% CI: 1.8-119). CONCLUSION: Low-lying UVC was associated with higher risk of infection and extravasation. KEY POINTS: · Low-lying UVC are at higher risk of UVCAI.. · Presence of UVC in situ for > 7 days carries higher risk of UVCAI.. · There was a higher risk of UVC extravasation with low UVCs..

Casting Is Effective for Recurrence Following Ponseti Treatment of Clubfoot.

BACKGROUND: Up to 40% of patients with idiopathic clubfoot who are treated with the Ponseti method experience recurrence of deformity. Many of these patients receive surgery (e.g., anterior tibial tendon transfer). An alternative approach for recurrent clubfoot is repeat Ponseti casting. The purpose of this study was to evaluate the outcome of repeat Ponseti casting in the treatment of recurrent clubfoot. METHODS: Patients with recurrent idiopathic clubfoot who were treated at our hospital, between 2004 and 2012, with repeat serial casting and bracing (the recurrent group) were eligible for inclusion in the study. The recurrent group and a control group of randomly selected patients seen during the same period who had not had recurrence were compared with respect to demographic data, age at the time of treatment, number of casts, subsequent surgical intervention(s), and the Disease-Specific Instrument (DSI) clubfoot scale. Patients were deemed to have a successful outcome if they had a well-corrected foot (defined as dorsiflexion of ≥10°, hindfoot in valgus, and a straight lateral border) at the time of follow-up. RESULTS: Of a total of 71 eligible patients with clubfeet, 35 patients participated. At the time of follow-up, success rates were 74% for the recurrent group and 83% for the control group. Dorsiflexion past neutral was significantly higher in the control group than the patient group (20° versus 12°, respectively; p < 0.001). Ninety-five percent of the control subjects had a straight lateral border in comparison with 78% in the recurrent group (p = 0.004). Likewise, 97% of controls had the hindfoot in valgus in comparison with 80% of the recurrent group (p = 0.02). There was a significant difference in the ability to squat (76% in the control group and 43% in the recurrent group; p = 0.03). There was no difference between groups in the total outcome of the DSI. CONCLUSIONS: Recurrence was seen in 19% (71) of 382 children who were eligible for our study who were typically discharged after the age of 5 years from our clinic, indicating the importance of continued follow-up until after that age. Treatment with casting was successful in many patients and may be a reasonable choice for recurrent idiopathic clubfeet. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

A small grant funding program to promote innovation at an academic research hospital.

Innovation is important for the improvement of health care. A small grant innovation funding program was implemented by the Hospital for Sick Children(SickKids) for the Perioperative Services group, awarding relatively small funds (approximately $10 000) in order to stimulate innovation. Of 48 applications,26 (54.2%) different innovation projects were funded for a total allocation of $227 870. This program demonstrated the ability of small grants to stimulate many applications with novel ideas, a wide range of innovations and reasonable academic productivity.

The validity of level of evidence ratings of articles submitted to JBJS.

BACKGROUND: In 2003, The Journal of Bone & Joint Surgery (American Volume) implemented a requirement for submitted clinical research articles to include a level of evidence rating. The aim of this study was to analyze the agreement between authors and JBJS regarding the level of evidence rating of accepted clinical articles. METHODS: A random sample of 353 clinical research articles accepted by JBJS from 2010 to 2012 was analyzed; 188 had a level of evidence rating provided by the author. Articles were grouped by study type and subspecialty. An unweighted kappa value was calculated to measure agreement between the authors and the JBJS editor, whose decision was used as the gold standard. In a secondary analysis, the articles in each subspecialty were categorized according to the year of submission to evaluate temporal trends. RESULTS: Of the 353 articles, 69.4% (245) were classified by JBJS as representing a therapeutic study, 17.6% (sixty-two) were classified as representing Level-I evidence, and 25.2% (eighty-nine) dealt with arthroplasty. Agreement between the author and the JBJS editor was 0.79 (95% confidence interval [CI], 0.71 to 0.89; p < 0.001) for the study type, 0.62 (95% CI, 0.53 to 0.70; p < 0.001) for the level of evidence, and 0.65 (95% CI, 0.58 to 0.73; p < 0.001) for the full level of evidence rating (study type and level of evidence). CONCLUSIONS: Level of evidence ratings suggested by authors from 2010 to 2012 had moderate to substantial agreement with the ratings assigned by the JBJS editor. This suggests that the level of evidence rating system is being properly understood by authors of articles published in JBJS. However, the low frequency of reporting suggests that JBJS needs to strictly enforce requirements for submission of a level of evidence rating at the time of manuscript submission.

Phase I study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors.

BACKGROUND: The combination of vinblastine and mammalian target of rapamycin (mTOR) inhibitor sirolimus inhibits the growth of neuroblastoma xenografts through pro-apoptotic and anti-angiogenic mechanisms. This phase I study aimed to explore the safety and toxicity of this combination in pediatric patients with advanced solid tumors. PROCEDURE: Patients ≤21 years of age with recurrent/refractory solid tumors (including CNS) were eligible. Sirolimus was administered daily by mouth or nasogastric (NG) tube, with doses adjusted to achieve a target trough concentration of 10-15 ng/ml, with weekly intravenous vinblastine (dose escalated 4-6 mg/m(2)/dose according to 3 + 3 phase I design). RESULTS: Fourteen patients were enrolled (median age 8.7 years; range 2.3-19) of whom 12 were evaluable for toxicity and 11 for response. One patient experienced a dose-limiting toxicity (grade 3 mucositis) at the highest vinblastine dose level. Myelosuppression was the most common toxicity. Dose-adjusted sirolimus trough concentrations were significantly lower in patients receiving drug via NG tube (1.50 ± 0.75 ng/ml/mg vs. 2.25 ± 1.07 ng/ml/mg for oral administration). Correlative biomarker analysis demonstrated a significant reduction in serum concentration of soluble vascular endothelial growth factor receptor (sVEGFR2) at 28 days compared to baseline consistent with inhibition of angiogenesis. One patient had a partial response and three had stable disease for more than 3 months. CONCLUSIONS: The combination of mTOR inhibitor and vinblastine given over an extended continuous schedule is safe, associated with a reduction in circulating angiogenic factor (CAF) VEGFR2 and resulted in clinical responses. Future studies using the intravenously administered mTOR inhibitor temsirolimus are planned.