Comparison of the onset and offset times of two available formulations of rocuronium bromide in an animal model.

Rocuronium bromide is a neuromuscular blocker in widespread use in anaesthesia, emergency and intensive care. Reports of reduced efficacy of a new different formulation of rocuronium bromide were submitted to Medsafe, the New Zealand Medicines and Medical Devices Safety Authority, in 2020. Given the requirement for rapid and predictable paralysis for patient safety the efficacy of the two available formulations of rocuronium bromide was investigated in an animal model. After ethics committee approval, 19 rats were anaesthetised and paralysis, defined as loss of tibialis anterior flexion on direct electrical stimulation of the sciatic nerve, was assessed by mechanomyography in response to ED90 doses of rocuronium.Paralysis was observed at a median of 12 seconds for the new different formulation: A, Hameln Pharma (interquartile range (IQR) 6-106 seconds) and 28 seconds for formulation B: Pfizer (IQR 12-68 seconds) P = 0.48. Offset of paralysis was observed after 293 seconds for formulation A (IQR 250-372 seconds) and 241 seconds for formulation B (IQR 220-263 seconds). While the differences observed were substantial, they were not statistically significant. Moreover, the direction of observed difference was towards a shorter median onset and longer offset for the newer formulation, a finding in the opposite direction to the initial clinical concern.Relevance to the clinical situation is indeterminate given the study was stopped at low numbers for futility and limitations around the clinical applicability of animal pharmacokinetics and dynamics. Nevertheless our findings provide some reassurance that the newly available different formulation of this critical use medication does not exhibit a substantial increase in time to onset.

Premorbid beta blockade in sepsis is associated with a lower risk of a lactate concentration above the lactate threshold, a retrospective cohort study.

Sepsis and septic shock represent a significant worldwide mortality burden. A lactate greater than 4 mmol/L is associated with increased mortality in septic patients. This is the concentration at the "lactate threshold" where serum lactate concentrations rise markedly with increased workload in exercise. Hyperlactatemia in both sepsis and exercise is contributed to by adrenergic agonism which stimulates aerobic glycolysis, increasing lactate production and decreasing lactate clearance. Our hypothesis is that in patients with sepsis, treatment with beta blockers in the community will be associated with a lower probability of initial lactate ≥ 4 mmol/L. This was single centre retrospective cohort study. We used an in-house SQL Database for all admissions to ICU/HDU for the 2017-2020 calendar years. The dataset was filtered for an APACHE III Diagnosis of sepsis. T-tests were used for continuous data, Chi squared and Fisher's exact test were used as appropriate to compare proportions. Logistic regression was used to investigate covariate effects. Of the 160 patient records analysed, 49 were prescribed beta blockers. A greater proportion of patients not prescribed beta blockers in the community had a first lactate ≥ 4 mmol/L (p = 0.049). This was robust to regression analysis. There was no difference in the proportion of patients with lactate ≥ 2 mmol/L (p = 0.52). In our cohort patients previously prescribed beta blockers were less likely to have a lactate of ≥ 4 mmol/mL. This supports the proposed mechanism that treatment with beta blockers increases the lactate threshold in sepsis. Further study is warranted.