Should We Pay Attention to the Delay Before Admission to a Pediatric Intensive Care Unit for Children With Cancer? Impact on 1-Month Mortality. A Report From the French Children's Oncology Study Group, GOCE.

Acute complications requiring admission to pediatric intensive care unit (PICU) are frequent for children with cancer. Our objective was to determine early prognostic factors of mortality in a cohort of children with cancer hospitalized in PICU for acute complications and particularly to assess whether the delay before admission to a PICU is an early predictor of mortality. We conduct a retrospective multicenter analysis. All patients transferred in PICU for acute complications between January 2002 and December 2012 were included. One-month mortality of the 224 patients analyzed was 24.5%. Delay before PICU admission was a significant prognostic factor of 1-month mortality with nonsurvivors experiencing a longer median delay than survivors (24 vs. 12 h, respectively, P<0.05). Time from diagnosis to PICU admission (P<0.001), hematopoietic stem cell transplant (P<0.05), the duration of neutropenia (P<0.01), infection type (P<0.001), number of organ dysfunctions (P<0.001), and reaching any grade 4 toxicity before PICU admission (P<0.001) also affected mortality rate at 1-month post-PICU discharge. In the multivariate analysis, only reaching any grade 4 toxicity before PICU admission influenced 1-month mortality (odds ratio, 2.30; 95% confidence interval, 1.07-4.96; P<0.05). These results suggest that PICU admission before severe impairment leads to a better outcome for children with cancer.

Transvesical Intra-Abdominal Pressure Measurement in Newborn: What Is the Optimal Saline Volume Instillation?

OBJECTIVE: To determine the optimal saline volume bladder instillation to measure intravesical pressure in critically ill newborns weighing less than 4.5 kg, and to establish a reference of intra-abdominal pressure value in this population. DESIGN: Prospective monocentric study. SETTING: Neonatal ICU and PICU. PATIENTS: Newborns, premature or not, weighing less than 4.5 kg who required a urethral catheter. MEASUREMENTS AND MAIN RESULTS: Patients were classified into two groups according to whether they presented a risk factor for intra-abdominal hypertension. Nine intravesical pressure measures per patient were performed after different volume saline instillation. The first one was done without saline instillation and then by increments of 0.5 mL/kg to a maximum of 4 mL/kg. Linear models for repeated measurements of intravesical pressure with unstructured covariance were used to analyze the variation of intravesical pressure measures according to the conditions of measurement (volume instilled). Pairwise comparisons of intravesical pressure adjusted mean values between instillation volumes were done using Tukey tests, corrected for multiple testing to determine an optimal instillation volume. Forty-seven patients with completed measures (nine instillations volumes) were included in the analysis. Mean intravesical pressure values were not significantly different when measured after instillation of 0.5, 1, or 1.5 mL/kg, whereas measures after instillation of 2 mL/kg or more were significantly higher. The median intravesical pressure value in the group without intra-abdominal hypertension risk factor after instillation of 1 mL/kg was 5 mm Hg (2-6 mm Hg). CONCLUSIONS: The optimal saline volume bladder instillation to measure intra-abdominal pressure in newborns weighing less than 4.5 kg was 1 mL/kg. Reference intra-abdominal pressure in this population was found to be 5 mm Hg (2-6 mm Hg).

Development and validation of a risk score to predict the probability of postoperative vomiting in pediatric patients: the VPOP score.

BACKGROUND: Few data are available in the literature on risk factors for postoperative vomiting (POV) in children. OBJECTIVE: The aim of the study was to establish independent risk factors for POV and to construct a pediatric specific risk score to predict POV in children. METHODS: Characteristics of 2392 children operated under general anesthesia were recorded. The dataset was randomly split into an evaluation set (n = 1761), analyzed with a multivariate analysis including logistic regression and backward stepwise procedure, and a validation set (n = 450), used to confirm the accuracy of prediction using the area under the receiver operating characteristic curve (ROCAUC ), to optimize sensitivity and specificity. RESULTS: The overall incidence of POV was 24.1%. Five independent risk factors were identified: stratified age (>3 and <6 or >13 years: adjusted OR 2.46 [95% CI 1.75-3.45]; ≥6 and ≤13 years: aOR 3.09 [95% CI 2.23-4.29]), duration of anesthesia (aOR 1.44 [95% IC 1.06-1.96]), surgery at risk (aOR 2.13 [95% IC 1.49-3.06]), predisposition to POV (aOR 1.81 [95% CI 1.43-2.31]), and multiple opioids doses (aOR 2.76 [95% CI 2.06-3.70], P < 0.001). A simplified score was created, ranging from 0 to 6 points. Respective incidences of POV were 5%, 6%, 13%, 21%, 36%, 48%, and 52% when the risk score ranged from 0 to 6. The model yielded a ROCAUC of 0.73 [95% CI 0.67-0.78] when applied to the validation dataset. CONCLUSIONS: Independent risk factors for POV were identified and used to create a new score to predict which children are at high risk of POV.

Post traumatic cerebral sinovenous thrombosis in children: A retrospective and multicenter study.

CONTEXT: Cerebral sinovenous thrombosis (CSVT) is a rare but life-threatening condition in the pediatric population and there is no pediatric guidelines regarding anticoagulation for post traumatic CSVT. OBJECTIVE: This study aims to describe a cohort of children with post traumatic CSVT and the use of anticoagulant therapy in this population. METHODS: A multicenter retrospective study. Patients admitted with post traumatic CSVT in the six participating Pediatric Intensive Care Unit were included. RESULTS: Overall, 29 patients (median age 8.2 years [IQR 4.8-14.6], n = 22 (76%) males) were included in the study (Table 1). CSVT was observed within the first 24 h after admission for a half of the patients (n = 14, 50%). Anticoagulation was initiated in 18 patients (62%). No patient received thrombolytic therapy or endovascular treatment. The presence of epidural hematoma was associated with the absence of anticoagulation (n = 0 versus n = 10, p = 0.003). One patient (3%) died of extracranial injury (not related with adverse event of anticoagulation) and in survivors, median Pediatric Overall Performance Category Outcome (POPC) score at discharge from PICU was 2 [IQR 2-4] (i.e., mild disability). Regarding the outcomes of patients, we found no association according to the anticoagulation status (p = 1). Overall, 23 patients (79%) had a follow-up cerebral imaging with a median delay of 42 days [IQR 6-63] after admission. CSVT was still seen in 9 patients (31%). We found no difference regarding the persistence of CSVT between patients according to the anticoagulation status (p = 0.36). The median duration of anticoagulant treatment was 58 days [IQR 44-91] and one patient (3%) experienced adverse event related to anticoagulation. CONCLUSION: There were minimal adverse events in patients with post traumatic CSVT treated with therapeutic anticoagulation. However, the effect of anticoagulation on outcomes needs to be confirmed in further studies.

Chemical Delivery System of MIBG to the Central Nervous System: Synthesis, 11C-Radiosynthesis, and in Vivo Evaluation.

The norepinephrine transporter (NET) plays an important role in neurotransmission and is involved in a multitude of psychiatric and neurodegenerative diseases. [123I/131I]meta-iodobenzylguanidine (MIBG) is a widely used radiotracer in the diagnosis and follow-up of peripheral neuroendocrine tumors overexpressing the norepinephrine transporter. MIBG does not cross the blood-brain barrier (BBB), and we have demonstrated the "proof-of-concept" that 1,4-dihydroquinoline/quinolinium salt as chemical delivery system (CDS) is a promising tool to deliver MIBG to the brain. To improve BBB passage, various substituents on the 1,4-dihydroquinoline moiety and a linker between CDS and MIBG were added. A series of CDS-MIBG 1a-d was synthesized, labeled with carbon-11, and evaluated in vivo into rats. The in vivo results demonstrated that, although adding substituents on CDS in 1a-c is of no benefit for brain delivery of MIBG, the presence of a linker in CDS-MIBG 1d greatly improved both brain penetration and the release rate of MIBG in the central nervous system.

N-[18F]-FluoropropylJDTic for κ-opioid receptor PET imaging: Radiosynthesis, pre-clinical evaluation, and metabolic investigation in comparison with parent JDTic.

INTRODUCTION: To image kappa opioid receptor (KOR) for preclinical studies, N-fluoropropylJDTic 9 derived from the best-established KOR antagonist JDTic, was labeled with fluorine-18. METHODS: Radiosynthesis of [18F]9 was achieved according to an automated two-step procedure from [18F]-fluoride. Peripheral and cerebral distributions were determined by ex vivo experiments and by PET imaging in mouse. Radiometabolism studies were performed both in vivo in mice and in vitro in mouse and human liver microsomes. Identification of the major metabolic fragmentations was carried out by UPLC-MS analysis of enzymatic cleavage of non-radioactive ligand 9. Microsomal metabolic degradation of parent JDTic was also achieved for comparison. RESULTS: The radiotracer [18F]9 was produced after 140±5min total synthesis time (2.2±0.4% not decay corrected radiochemical yield) with a specific activity of 41-89GBq/µmol (1.1-2.4Ci/µmol). Peripheral and regional brain distributions of [18F]9 were consistent with known KOR locations but no significant specific binding in brain was shown. [18F]9 presented a typical hepatobiliary and renal elimination, and was rapidly metabolized. The in vivo and in vitro radiometabolic profiles of [18F]9 were similar. Piperidine 12 was identified as the major metabolic fragment of the non-radioactive ligand 9. JDTic 7 was found to be much more stable than 9. CONCLUSION: Although the newly proposed radioligand [18F]9 was concluded to be not suitable for KOR PET imaging due to the formation of brain penetrating radiometabolites, our findings highlight the metabolic stability of JDTic and may help in the design of novel JDTic derivatives for in vivo applications.

Cardiac rehabilitation improves coronary endothelial function in patients with heart failure due to dilated cardiomyopathy: A positron emission tomography study.

BACKGROUND: Endothelial dysfunction is common in patients with heart failure and is associated with poor clinical outcome. Cardiac rehabilitation is able to enhance peripheral endothelial function but its impact on coronary vasomotion remains unknown. We aimed to evaluate the effect of cardiac rehabilitation on coronary vasomotion in patients with heart failure. METHOD: We prospectively enrolled 29 clinically stable heart failure patients from non-ischaemic dilated cardiomyopathy and without coronary risk factors. Myocardial blood flow was quantified using (15)-O water positron emission tomography at rest and during a cold pressor test, before and after 12 weeks of cardiac rehabilitation and optimization of medical therapy. RESULTS: Rest myocardial blood flow was significantly improved after the completion of rehabilitation compared to baseline (1.31 ± 0.38 mL/min/g vs. 1.16 ± 0.41 mL/min/g, p = 0.04). The endothelium-related change in myocardial blood flow from rest to cold pressor test and the percentage of myocardial blood flow increase during the cold pressor test were both significantly improved after cardiac rehabilitation (respectively from -0.03 ± 0.22 mL/min/g to 0.19 ± 0.22 mL/min/g, p < 0.001 and from 101.5 ± 16.5% to 118.3 ± 24.4%, p < 0.001). Left ventricular ejection fraction, plasma levels of brain natriuretic peptide, maximal oxygen consumption and the Minnesota Living with Heart Failure Questionnaire score were also significantly improved. The improvement was not related to uptitration of medical therapy. CONCLUSIONS: Coronary endothelial function is altered in patients with heart failure due to non-ischaemic dilated cardiomyopathy. In these patients, cardiac rehabilitation significantly improves coronary vasomotion.

Fully automated radiosynthesis of 2-[18F]fludarabine for PET imaging of low-grade lymphoma.

PURPOSE: An efficient and fully automated radiosynthesis of 2-[(18)F]fluoro-9-ß-D-arabinofuranosyl-adenine (2-[(18)F]fludarabine, [(18)F]-5) based on a GE TRACERlab™ FX-FN module has been developed. PROCEDURES: A 2-nitro purine derivative 3 was developed as precursor for labeling with fluorine-18. The radiosynthesis of [(18)F]-5 was performed in two steps in a single reactor with an intermediary purification on Sep-Pak® silica which involved the addition of a three-way valve on the original module. After hydrolysis, [(18)F]-5 was purified by semi-preparative high-pressure liquid chromatography (HPLC) and a quality control was established. RESULTS: The labeling precursor 3 was obtained in 45% overall yield. Nucleophilic substitution with K(18)F/K2.2.2 afforded protected 2-[(18)F]fludarabine ([(18)F]-4) in 73 ± 4%, radiochemical yield (decay corrected to the end of bombardment (EOB)) and based on the initial [(18)F]F(-) activity. An aqueous ammonia/methanol solution was used for the deprotection reaction and gave the desired [(18)F]-5 in 67 ± 3% yield after 20 min at 70 °C based on HPLC profile. CONCLUSIONS: The process afforded pure 2-[(18)F]fludarabine in 48 ± 3% yield (decay corrected to the EOB) in 85 min, with a specific activity of 310 ± 72 GBq/µmol at the end of synthesis (EOS) and a radiochemical purity up to 99%.

2-[18F]fludarabine, a novel positron emission tomography (PET) tracer for imaging lymphoma: a micro-PET study in murine models.

PURPOSE: Fludarabine has proven to be of considerable efficacy in the treatment of low-grade lymphomas. We have developed the labeling of this drug with fluorine-18 and evaluated 2-[(18)F]fludarabine as a novel positron emission tomography (PET) probe for in vivo imaging. PROCEDURES: Preclinical studies were conducted with 2-[(18)F]fludarabine, in parallel with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG), in Swiss CD-1 and CB17 severely combined immunodeficient (SCID) mice, both as tumor-free control groups, and SCID mice bearing RL lymphomas. RESULTS: In Swiss mice, micro-PET studies with 2-[(18)F]fludarabine showed a distribution restricted to the organs of excretion and the spleen, the latter being less evident in SCID animals. In lymphoma-bearing SCID mice, 2-[(18)F]fludarabine demonstrated a rapid tumor uptake over the first 20 min which subsequently plateaued and provided an improved contrast than that of [(18)F]FDG. CONCLUSION: This radiotracer merits further evaluation to establish its clinical usefulness to image low-grade lymphoma in humans in future clinical investigations.

Synthesis, evaluation and metabolic studies of radiotracers containing a 4-(4-[18F]-fluorobenzyl)piperidin-1-yl moiety for the PET imaging of NR2B NMDA receptors.

In this study, novel specific PET radioligands containing the 4-(4-fluorobenzyl)piperidine moiety and selectively antagonistic for the NR2B subunit containing NMDA receptors were developed. Two antagonists, RGH-896 (1a) and 4-(4-fluorobenzyl)piperidinyl-1-methyl-2-benzimidazol-5-ol (2a), belonging to two different structural families, were radiolabeled by an aromatic nucleophilic radiofluorination followed by a reduction of the para-position carbonyl function. Radiotracers [18F]1a, [18F]2a or the pattern 4-(4-[18F]-fluorobenzyl)piperidine ([18F]6) demonstrated an identical in vivo behavior with high accumulation of radioactivity in bone and cartilage which would suggest a radiodefluorination of the radiotracers. The identification of metabolites from 6 by LC-MS-MS confirmed the significant degree of defluorination as a result of the in vivo hydroxylation in the benzyl ring. In conclusion, [18F]1a or [18F]2a are not suitable for imaging the NR2B NMDA receptors due to their poor brain penetration. We also argue for a cautious use of the radiolabeled pattern, 4-(4-[18F]-fluorobenzyl)piperidine, to develop PET radiotracers.

Chemical delivery system of metaiodobenzylguanidine (MIBG) to the central nervous system.

The aim of the present investigation was to apply a chemical delivery system (CDS) to MIBG (4) with the purpose of delivering this drug to the CNS. Compound 4 has been linked to a 1,4-dihydroquinoline moiety in order to achieve its CNS penetration, and here we report the synthesis to link 4 to the chemical delivery system and the radiosynthesis with carbon-11 of the "CDS-4 entity". After iv injection into rats of the [(11)C]CDS-4, the follow-up study of the radioactivity distribution in blood samples and brain homogenates and the analysis by HPLC and LC-MS/MS have confirmed the release of 4 into the CNS.

Effect of oropharyngeal decontamination by povidone-iodine on ventilator-associated pneumonia in patients with head trauma.

OBJECTIVE: To evaluate the effect of a regular oropharyngeal application of povidone-iodine on the prevalence of ventilator-associated pneumonia in patients with severe head trauma. DESIGN: Prospective randomized study. SETTING: A surgical intensive care unit of a university hospital. INTERVENTIONS: Patients with severe head trauma (Glasgow Coma Score of < or =8) expected to need ventilation for > or =2 days were prospectively randomized into three groups: those receiving nasopharynx and oropharynx rinsing with 20 mL of a 10% povidone-iodine aqueous solution, reconstituted in a 60-mL solution with sterile water (povidone-iodine group); those receiving nasopharynx and oropharynx rinsing with 60 mL of saline solution (saline group); or those undergoing a standard regimen without any instillation but with aspiration of oropharyngeal secretions (control group). MEASUREMENTS AND MAIN RESULTS: The prevalence of ventilator-associated pneumonia was compared among the three groups. A total of 98 patients were analyzed (povidone-iodine group, n = 36; saline group, n = 31; and control group, n = 31). A total of 28 cases of ventilator-associated pneumonia were diagnosed. There was a significant decrease in the rate of ventilator-associated pneumonia in the povidone-iodine group when compared with the saline and control groups (3 of 36 patients [8%] vs. 12 of 31 patients [39%] and 13 of 31 patients [42%], respectively; p = .003 and .001, respectively). The length of stay and mortality in the surgical intensive care unit were not statistically different between the three groups. CONCLUSIONS: The regular administration of povidone-iodine may be an effective strategy for decreasing the prevalence of ventilator-associated pneumonia in patients with severe head trauma.