Brominated flame retardants (BFRs) are used to reduce the flammability of plastics, textiles, and electronics. BFRs vary in their chemical properties and structures, and it is expected that these differences alter their biological interactions and toxicity. Zebrafish were used as the model organism for assessing the toxicity of nine structurally-diverse BFRs. In addition to monitoring for overt toxicity, the rate of spontaneous movement, and acetylcholinesterase and glutathione-S-transferase (GST) activities were assessed following exposure. The toxicities of BFRs tested can be ranked by LC50 as tetrabromobisphenol A (TBBPA) < 4,4′-isopropylidenebis[2-(2,6-dibromophenoxyl)ethanol] (TBBPA-OHEE) < Pentabromochlorocyclohexane (PBCH) < 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (TBB) < hexabromocyclododecane (HBCD) < hexabromobenzene (HBB) < Tetrabromophthalic anhydride (PHT4). No adverse effect was observed in di(2-ethylhexyl) tetrabromophthalate (TBPH) or dibromoneopentyl glycol (DBNPG)-treated embryos. The rate of spontaneous movement was decreased in a concentration-dependent manner following exposure to four of the nine compounds. GST activity was elevated following treatment with PBCH, TBBPA, HBCD, and HBB. The results indicate that exposure to several BFRs may activate an antioxidant response and alter behavior during early development. Some of the BFRs, such as TBBPA and TBBPA-OHEE, induced adverse effects at concentrations lower than chemicals that are currently banned. These results suggest that zebrafish are sensitive to exposure to BFRs and can be used as a comparative screening model, as well as to determine alterations in behavior following exposure and probe mechanisms of action.

Background/importanceAnesthesiologists frequently use truncal catheters for postoperative pain control but with limited characterization of dosing and toxicity.ObjectiveWe reviewed the published literature to characterize local anesthetic dosing and toxicity of paravertebral and transversus abdominis plane catheters in adults.Evidence reviewWe searched the literature for bupivacaine or ropivacaine infusions in the paravertebral or transversus abdominis space in humans dosed for 24 hours. We evaluated bolus dosing, infusion dosing and cumulative 24-hour dosing in adults. We also identified cases of local anesthetic systemic toxicity and toxic blood levels.FindingsFollowing screening, we extracted data from 121 and 108 papers for ropivacaine and bupivacaine respectively with a total of 6802 patients. For ropivacaine and bupivacaine, respectively, bolus dose was 1.4 mg/kg (95% CI 0.4 to 3.0, n=2978) and 1.0 mg/kg (95% CI 0.18 to 2.1, n=2724); infusion dose was 0.26 mg/kg/hour (95% CI 0.06 to 0.63, n=3579) and 0.2 mg/kg/hour (95% CI 0.06 to 0.5, n=3199); 24-hour dose was 7.75 mg/kg (95% CI 2.1 to 15.7, n=3579) and 6.0 mg/kg (95% CI 2.1 to 13.6, n=3223). Twenty-four hour doses exceeded the package insert recommended upper limit in 28% (range: 17%–40% based on maximum and minimum patient weights) of ropivacaine infusions and 51% (range: 45%–71%) of bupivacaine infusions. Toxicity occurred in 30 patients and was associated with high 24-hour dose, bilateral catheters, cardiac surgery, cytochrome P-450 inhibitors and hypoalbuminemia.ConclusionPractitioners frequently administer ropivacaine and bupivacaine above the package insert limits, at doses associated with toxicity. Patient safety would benefit from more specific recommendations to limit excessive dose and risk of toxicity.

Background/importanceDespite over 30 years of use by pediatric anesthesiologists, standardized dosing rates, dosing characteristics, and cases of toxicity of truncal nerve catheters are poorly described.ObjectiveWe reviewed the literature to characterize dosing and toxicity of paravertebral and transversus abdominis plane catheters in children (less than 18 years).Evidence reviewWe searched for reports of ropivacaine or bupivacaine infusions in the paravertebral and transversus abdominis space intended for 24 hours or more of use in pediatric patients. We evaluated bolus dosing, infusion dosing, and cumulative 24-hour dosing in patients over and under 6 months. We also identified cases of local anesthetic systemic toxicity and toxic blood levels.FindingsFollowing screening, we extracted data from 46 papers with 945 patients.Bolus dosing was 2.5 mg/kg (median, range 0.6–5.0; n=466) and 1.25 mg/kg (median, range 0.5–2.5; n=294) for ropivacaine and bupivacaine, respectively. Infusion dosing was 0.5 mg/kg/hour (median, range 0.2–0.68; n=521) and 0.33 mg/kg/hour (median, range 0.1–1.0; n=423) for ropivacaine and bupivacaine, respectively, consistent with a dose equivalence of 1.5:1.0. A single case of toxicity was reported, and pharmacokinetic studies reported at least five cases with serum levels above the toxic threshold.ConclusionsBolus doses of bupivacaine and ropivacaine frequently comport with expert recommendations. Infusions in patients under 6 months used doses associated with toxicity and toxicity occurred at a rate consistent with single-shot blocks. Pediatric patients would benefit from specific recommendations about ropivacaine and bupivacaine dosing, including age-based dosing, breakthrough dosing, and intermittent bolus dosing.