Development of Duration-Based Non-Mutagenic Thresholds of Toxicological Concern (TTCs) Relevant to Parenteral Extractables and Leachables (E&Ls).

The threshold of toxicological concern (TTC), i.e., the dose of a compound lacking sufficient experimental toxicity data that is unlikely to result in an adverse health effect in humans, is important for evaluating extractables and leachables (E&Ls) as it guides analytical testing and minimizes the use of animal studies. The Extractables and Leachables Safety Information Exchange (ELSIE) consortium, which consists of member companies that span biotechnology, pharmaceutical, and medical device industries, brought together subject matter expert toxicologists to derive TTC values for organic, non-mutagenic E&L substances when administered parenterally. A total of 488 E&L compounds from the ELSIE database were analyzed and parenteral point of departure (PPOD) estimates were derived for 252 compounds. The PPOD estimates were adjusted to extrapolate to subacute, subchronic, and chronic durations of nonclinical exposure and the lower fifth percentiles were calculated. An additional 100-fold adjustment factor to account for nonclinical species and human variability was subsequently applied to derive the parenteral TTC values for E&Ls. The resulting parenteral TTC values are 35, 110, and 180 µg/day for human exposures of >10 years to lifetime, >1-10 years, and ≤1 year, respectively. These parenteral TTCs are expected to be conservative for E&Ls that are considered non-mutagenic per ICH M7(R1) guidelines.

Oral sodium citrate increases nausea amongst elective Cesarean delivery patients.

PURPOSE: Historically, aspiration of gastric contents with subsequent pneumonia was a major cause of anesthesia-related maternal mortality. Before elective Cesarean delivery, gastric fluid can be neutralized with histamine-2 blockers or with oral sodium citrate. Although sodium citrate is commonly used, many patients dislike its taste. We designed this study to determine whether or not patients are more likely to experience nausea during Cesarean delivery when sodium citrate is administered preoperatively. METHODS: One hundred and twenty-three healthy women carrying a singleton fetus and scheduled for elective Cesarean delivery under spinal anesthesia were randomized to receive either sodium citrate 30 mL p.o. and saline 2 mL i.v. (sodium citrate group), or water 30 mL p.o. and famotidine 20 mg i.v. (famotidine group). Spinal anesthesia consisted of 1.6 mL of 0.75% bupivacaine (12 mg), fentanyl 20 microg, and preservative-free morphine 200 microg. Patients were asked to rate the degree of nausea present at one and five minutes after spinal placement, at the time of uterine exteriorization, and upon arrival to the recovery room. At each time point, the patient's systolic blood pressure and heart rate were recorded. RESULTS: At all recorded intervals, the average degree of nausea was greater in the sodium citrate group compared to the famotidine group. The frequency of nausea was also greater in the sodium citrate group compared with the famotidine group (37% vs 14% respectively, P < 0.05) five minutes after establishment of spinal anesthesia. The frequencies of nausea were not significantly different between groups at other time periods. CONCLUSION: Nausea is more common during Cesarean delivery in women who receive oral sodium citrate rather than i.v. famotidine for aspiration prophylaxis.

General anesthesia for cesarean delivery in a patient with paroxysmal nocturnal hemoglobinuria and thrombocytopenia.

UNLABELLED: Pregnancy in patients with paroxysmal nocturnal hemoglobinuria (PNH) increases the risk of complement activation, hemolysis, and thrombosis. We describe the anesthetic management of a patient with PNH who underwent general anesthesia for cesarean delivery. Steroids, heparin, and blood products were administered early to minimize the likelihood of a hematologic emergency. IMPLICATIONS: Pregnancy in patients with paroxysmal nocturnal hemoglobinuria increases the risk of hemolysis, thrombosis, anemia, and thrombocytopenia. We describe the anesthetic management of a patient with paroxysmal nocturnal hemoglobinuria and thrombocytopenia who underwent general anesthesia for cesarean delivery.