Systematic review of clinical adverse events reported after acute intravenous lipid emulsion administration.

BACKGROUND: Intravenous lipid emulsions (ILEs) were initially developed to provide parenteral nutrition. In recent years, ILE has emerged as a treatment for poisoning by local anesthetics and various other drugs. The dosing regimen for the clinical toxicology indications differs significantly from those used for parenteral nutrition. The evidence on the efficacy of ILE to reverse acute toxicity of diverse substances consists mainly of case reports and animal experiments. Adverse events to ILE are important to consider when clinicians need to make a risk/benefit analysis for this therapy. METHODS: Multiple publication databases were searched to identify reports of adverse effects associated with acute ILE administration for either treatment of acute poisoning or parenteral nutrition. Articles were selected based on pre-defined criteria to reflect acute use of ILE. Experimental studies and reports of adverse effects as a complication of long-term therapy exceeding 14 days were excluded. RESULTS: The search identified 789 full-text articles, of which 114 met the study criteria. 27 were animal studies, and 87 were human studies. The adverse effects associated with acute ILE administration included acute kidney injury, cardiac arrest, ventilation perfusion mismatch, acute lung injury, venous thromboembolism, hypersensitivity, fat embolism, fat overload syndrome, pancreatitis, extracorporeal circulation machine circuit obstruction, allergic reaction, and increased susceptibility to infection. CONCLUSION: The emerging use of ILE administration in clinical toxicology warrants careful attention to its potential adverse effects. The dosing regimen and context of administration leading to the adverse events documented in this review are not generalizable to all clinical toxicology scenarios. Adverse effects seem to be proportional to the rate of infusion as well as total dose received. Further safety studies in humans and reporting of adverse events associated with ILE administration at the doses advocated in current clinical toxicology literature are needed.

Are Recommended Doses of Acetaminophen Effective for Children Aged 2 to 3 Years? A Pharmacokinetic Modeling Answer.

OBJECTIVES: Acetaminophen (APAP) elixir is a widely used pediatric antipyretic medication. It has been shown that up to 30% of febrile children presenting to a large urban pediatric emergency department received inadequate APAP dosages at home with errors primarily due to age-based dosing. Parental education material in the form of weight-based dosing guides has been proposed; however, validation of current recommended APAP dosages using pharmacokinetic models is needed. This study used a mathematical model of APAP absorption to predict plasma concentrations and to compare them with the range required to reach and achieve antipyresis (10-20 µg/mL). METHODS: A common APAP preparation (Children's Tylenol Elixir) was tested (children aged 2-3 years, 10.9-15.9 kg). The manufacturer's suggested dose of 160 mg was compared with the standard 10 to 15 mg/kg dose range. RESULTS: The model predicts a peak plasma concentration between 6.38 and 8.55 µg/mL for 10 mg/kg dose and 9.57 and 12.8 µg/mL for 15 mg/kg dose. The manufacturer's suggested dose of 160 mg was tested across the limits of the weight range (10.9-15.9 kg). A peak plasma concentration between 9.36 and 12.6 µg/mL was found for the lower weight limit (10.9 kg child) and 6.42 to 8.61 µg/mL for the upper weight limit (15.9 kg child). CONCLUSIONS: With the use of this model, the 10 mg/kg dose does not reach the plasma concentration value for antipyresis (10-20 µg/mL), whereas 15 mg/kg is adequate only if assuming a greater absorption constant. The 160 mg dose is effective only for children weighing 10.9 kg. Individual differences in drug bioavailability, volume of distribution, and absorption/elimination constants undoubtedly exist, and future studies directly measuring plasma APAP concentration and pharmacokinetics are needed. However, these results indicate that dosages for APAP in children should be weight based and manufacturers should review their dosing recommendations.

Communication between nurses and physicians: strategies to surviving in the emergency department trenches.

The emergency department (ED) is a challenging and stressful work environment where communication lapses can lead to negative health outcomes. This article offers strategies to Emergency Medicine residents, nurses and staff physicians on how to improve communication to optimize patient care.

Imatinib mesylate alters the expression of genes related to disease progression in an animal model of uveal melanoma.

Imatinib mesylate (IM) is a compound that inhibits both BCR-ABL tyrosine kinase and c-kit receptors. Tyrosine kinases are important in cellular signaling and mediate major cellular processes such as proliferation, differentiation, apoptosis, attachment, and migration. Twenty-six albino rabbits were injected with 1 × 10(6) human uveal melanoma (UM) cells (92.1) into the suprachoroidal space. Animals were immunosuppressed (cyclosporin A) over the course of the 12-week experiment and divided into two groups (n = 13). The experimental group received IM once daily by gavage while the control group received a placebo. One animal per group was sacrificed every week after the 2nd week. Upon necropsy, organs were harvested for histopathological examination. Cells from the primary tumors were recultured and tested in proliferation and invasion assays. A PCR array was used to investigate the differences in expression of 84 genes related to tumor metastasis. In the treated group, 4 rabbits developed intraocular tumors, with an average largest tumor dimension (LTD) of 2.5 mm and 5 animals reported metastatic disease. Whereas 6 rabbits in the control group developed intraocular tumors, with an average LTD of 5.8 mm and 6 animals reported metastatic disease. The recultured cells from the treated group demonstrated lower proliferation rates and were less invasive (p < 0.001). The PCR array showed differences in expression of genes related to metastasis. Notably, there was 290-fold increase in SERPINB5, a tumor suppressor gene, and a 10-fold higher expression of KISS1, a metastasis suppressor gene, in the treated group. Proangiogenic genes such as VEGFA, PDGFA and PDGFB were downregulated in the treated group. To the best of our knowledge, this is the first report detailing the altered expression of specific genes in UM cells after treatment with IM.

Expression of vascular endothelial growth factor in retinoblastoma.

OBJECTIVES: To investigate the immunohistochemical expression of vascular endothelial growth factor (VEGF) and to determine its possible association with tumor differentiation status, optic nerve and/or choroidal invasion, anterior chamber invasion, vitreous seeding, and basophilic staining of the vascular walls. METHODS: A retrospective study was performed to identify the expression of VEGF in 47 of 129 consecutive patients with retinoblastoma treated at the Ocular Pathology Laboratory of the Anatomy and Pathology Institute of the Central University of Venezuela in Caracas from January 1, 2000, through December 31, 2007. RESULTS: A positive correlation between VEGF staining intensity and time of progression and mitotic and apoptotic indexes was observed. However, no correlation was found between VEGF expression and other prognostic factors in this malignant neoplasm, including tumor stage as assessed by the Grabowski and Abramson classification. CONCLUSIONS: Although the isolated characterization of VEGF in retinoblastoma is not grounds for this protein to be considered a prognostic factor, its association with mitotic and apoptotic indexes suggests it may play a role in the progression of this disease. Thus, therapeutic targeting of VEGF in retinoblastoma may be an effective strategy to reduce tumor progression.

Lysyl oxidase expression and inhibition in uveal melanoma.

Lysyl oxidase is a marker of poor prognosis in several malignancies and is hypothesized to promote a migratory phenotype in hypoxic breast carcinomas. This study aims to characterize the expression of the lysyl oxidase and lysyl oxidase-like proteins in human uveal melanoma cell lines and archival choroidal melanomas using immunohistochemistry. The transcriptional control of lysyl oxidase will also be investigated under simulated hypoxic conditions using cobalt chloride. Lastly, changes in cellular proliferation and invasion will be assessed after the treatment of cell lines with beta-aminopropionitrile, a lysyl oxidase catalytic inhibitor. Retrospective analysis of lysyl oxidase expression in primary human uveal melanoma showed 82% (27 of 33) of tumors being stained positive. High lysyl oxidase expression correlated with the aggressive epithelioid cell type and was associated with shorter metastasis-free survival. Simulated hypoxia resulted in a significant increase in lysyl oxidase mRNA expression. Inhibiting lysyl oxidase's catalytic activity significantly reduced cellular invasion but had no effect on cell proliferation. Our study is the first to show lysyl oxidase expression in primary choroidal melanomas. This protein may represent a potential therapeutic target that warrants further study in this malignancy.

Expression profiling of formalin-fixed paraffin embedded primary human uveal melanomas using DASL matrices.

PURPOSE: Fresh biopsied ocular tumor tissues are difficult to obtain for the purpose of performing microarray experiments on extracted nucleic acids. Present technology allows for extraction of total RNA from formalin-fixed paraffin embedded (FFPE) tissue analyzed by the cDNA mediated Annealing Sectioning and Ligation (DASL) method. We aimed to correlate gene transcript differences between two uveal melanoma (UM) clinical-histopathological parameters (metastasis, cell type). METHODS: A total of 43 FFPE UM were used. The expression of RPL13a, a ribosomal protein gene, for each sample was used to evaluate the quality of RNA extracted from FFPE tissue. Gene expression values generated from the array were analyzed using the GeneSpring GX software (Agilent). Immunohistochemistry was used in order to validate transcriptional findings at the protein level. RESULTS: A total of 106 genes were identified with (P < 0.05, Welch ANOVA test) a difference in transcript abundance for the metastasis clinical parameter. Furthermore, we identified 64 genes with a statistically significant (P < 0.05) difference in transcript abundance between the spindle and epithelioid cell types. Each individual sample for both groups (metastasis, cell type) exhibited distinct transcriptional profiles that were separated on a PCA. Positive nuclear immunostaining for LIG4-metastasis, ErbB3-cell type was found to be associated with better patient prognosis and outcome. CONCLUSIONS: To the best of our knowledge, this is the first time that a successful retrospective analysis has been done with UM FFPE RNA. This data may lead to future customized therapeutic targets, which may improve the now unchanged mortality rate of this particular malignancy.