Impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients (PEPaNIC trial): Study protocol for a randomized controlled trial

Background: The state-of-the-art nutrition used for critically ill children is based essentially on expert opinion and extrapolations from adult studies or on studies in non-critically ill children. In critically ill adults, withholding parenteral nutrition (PN) during the first week in ICU improved outcome, as compared with early supplementation of insufficient enteral nutrition (EN) with PN. We hypothesized that withholding PN in children early during critical illness reduces the incidence of new infections and accelerates recovery. Methods/Design: The Pediatric Early versus Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC) study is an investigator-initiated, international, multicenter, randomized controlled trial (RCT) in three tertiary referral pediatric intensive care units (PICUs) in three countries on two continents. This study compares early versus late initiation of PN when EN fails to reach preset caloric targets in critically ill children. In the early-PN (control, standard of care) group, PN comprising glucose, lipids and amino acids is administered within the first days to reach the caloric target. In the late-PN (intervention) group, PN completing EN is only initiated beyond PICU-day 7, when EN fails. For both study groups, an early EN protocol is applied and micronutrients are administered intravenously. The primary assessor-blinded outcome measures are the incidence of new infections during PICU-stay and the duration of intensive care dependency. The sample size (n = 1,440, 720 per arm) was determined in order to detect a 5% absolute reduction in PICU infections, with at least 80% 1-tailed power (70% 2-tailed) and an alpha error rate of 5%. Based on the actual incidence of new PICU infections in the control group, the required sample size was confirmed at the time of an a priori- planned interim-analysis focusing on the incidence of new infections in the control group only. Discussion: Clinical evidence in favor of early administration of PN in critically ill children is currently lacking, despite potential benefit but also known side effects. This large international RCT will help physicians to gain more insight in the clinical effects of omitting PN during the first week of critical illness in children

Routine gastric residual volume measurement and energy target achievement in the PICU: A comparison study

Critically ill children frequently fail to achieve adequate energy intake and some care practices, such as the measurement of gastric residual volume (GRV) may contribute to this problem. We compared outcomes in two similar European Pediatric Intensive Care Units (PICUs): one which routinely measures GRV (PICU-GRV) to one unit that does not (PICU-noGRV). An observational pilot comparison study was undertaken. 87 children were included in the study, 42 (PICU-GRV) and 45 (PICU-noGRV). There were no significant differences in the percentage of energy targets achieved in the first four days of PICU admission although PICU-noGRV showed more consistent delivery of median (and IQR) energy targets, and less under and over feeding for PICU-GRV and PICU-noGRV Day 1 37 (14-72) vs 44 (0-100); Day 2 97 (53-126) vs 100 (100-100), Day 3 84 (45-112) vs 100 (100-100) , Day 4 101 (63-124) vs 100 (100-100). The incidence of vomiting was higher in PICU-GRV. No necrotising enterocolitis was confirmed in either unit and ventilator acquired pneumonia rates were not significantly different (7.01 vs 12 5.31 per 1000 ventilator days; p=0.70) between PICU-GRV and PICU-noGRV units. Conclusions: The practice of routine gastric residual measurement did not significantly impair energy targets in the first four days of PICU admission. However, not measuring GRV did not increase vomiting, ventilator acquired pneumonia or necrotising enterocolitis, which is the main reason clinicians cite for measuring GRV. What is known?•The practice of routinely measuring gastric residual volume is widespread in critical care units•This practice is increasingly being questioned in critically ill patients, both as a practice that increases •the likelihood of delivering inadequate enteral nutrition amounts and as a tool to assess feeding tolerance What is new? •Not routinely measuring gastric residual volume did not increase adverse events of ventilator acquired pneumonia, necrotising enterocolitis or vomiting •In the first four days of PICU stay, energy target achievement was not significantly different, but the rates of under and over feeding were higher in the routine GRV measurement uni

Strategies to target drugs to gliomas and CNS metastases of solid tumors

The treatment for central nervous system metastases of solid tumors and gliomas is limited as the blood–brain barrier (BBB) is an obstacle to systemic therapy. Here, we review the physiochemical properties of the BBB and both current and new drug strategies to penetrate brain tumors. We focus on targeting receptor- or carrier-mediated transport mechanisms over the BBB used by drug conjugates, nanoparticles, polymer-based nanocarriers, siRNA, and antibodies

NT-23 * PHASE 1/2A STUDY OF GLUTATHIONE PEGYLATED LIPOSOMAL DOXORUBICIN (2B3-101) IN BREAST CANCER PATIENTS WITH BRAIN METASTASES (BCBM) OR RECURRENT HIGH GRADE GLIOMAS (HGG)

BACKGROUND: Without active delivery across the blood-brain barrier, the efficacy of doxorubicin is limited in the treatment of brain tumors. 2B3-101 was developed as a brain-targeted doxorubicin product. In preclinical studies, 2B3-101 showed a 5-fold increased delivery of doxorubicin to the brain and improved survival of mice with HGG, compared to Caelyx(®). METHODS: This open-label study assessed the safety, tolerability, MTD, PK and anti-tumor activity of 2B3-101. For this analysis, 30 HGG and 25 BCBM patients were included who received a 2B3-101 starting dose of 40-70 mg/m(2) q21d (n = 35) or 60 mg/m(2) q28d (n = 20 all HGG). Treatment continued until disease progression or unacceptable toxicity. Anti-tumor activity was assessed by RANO in HGG or RECIST 1.1 in BCBM patients. RESULTS: As of 30-May-2014, 172 cycles (range 1-10) of 2B3-101 were administrated, 4 HGG and 2 BCBM patients are still on treatment. 2B3-101 was tolerated up to a dose-intensity of 15 mg/m(2)/wk. Cycle 1 MTD was not reached. Phase 2a doses were selected based upon tolerability after repeated dosing. Most frequent reported treatment emergent AEs ≥ grade 2 were: neutropenia (41%), palmar-plantar erythrodysesthesia (PPE) (39%), fatigue (36%), stomatitis (21%), and infusion-reaction (20%). Notable grade 3–4 AEs were neutropenia (26%) and PPE (14%). All were transient and manageable with standard medication or dose delays. Dose reductions were required in 25% of the patients. 2B3-101 showed no neuro-or cardiotoxicity. In 25 evaluable HGG patients, 52% had SD as best response and 3-months PFS rate of 40%. 3 patients had intracranial response of ≥ 20%. In 23 evaluable BCBM patients, 9% had PR and 48% SD as overall best response with 3-months PFS rate of 48%. 4 patients had intracranial response of ≥ 20%. CONCLUSIONS: 2B3-101 is safe, well tolerated and shows promise as a potential treatment option for progressive HGG and BCBM patients

PHASE 1/2A STUDY OF GLUTATHIONE PEGYLATED LIPOSOMAL DOXORUBICIN (2B3-101) IN BREAST CANCER PATIENTS WITH BRAIN METASTASES (BCBM) OR RECURRENT HIGH GRADE GLIOMAS (HGG)

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