Conceptual and technical insights into the basis of neuromuscular monitoring

We propose a model of drug pharmacodynamic response that when integrated with a pharmacokinetic model allows characterization of the temporal aspects of pharmacodynamics as well as the time-independent sensitivity component. The total model can accommodate extremes of effect. It allows fitting of simultaneous plasma concentration (Cp) and effect data from the initial distribution phase of drug administration, or from any non-equilibrium phase. The model postulates a hypothetical effect compartment, the dynamics of which are adjusted to reflect the temporal dynamics of drug effect. The effect compartment is modeled as an additional compartment linked to the plasma compartment by a first-order process, but whose exponential does not enter into the pharmacokinetic solution for the mass of drug in the body. The hypothetical amount of drug in the effect compartment is then related to the observed effect by the Hill equation, a nonlinear sigmoid form. Nonlinear least-squares data fitting is used for parameter estimation. The model is demonstrated on two different sets of Cp and effect data for the drug d-tubocurarine (dTC). In 7 normal subjects, the (mean +/- SD) rate constant for equilibration of dTC effect (paralysis) and Cp is 0.13 +/- 0.04 min-1 and the (mean +/- SD) steady-state Cp required to produce 50% paralysis is 0.37 +/- 0.05 microgram/ml.

Posttetanic potentiation (PTP) is an essential aspect of synaptic transmission that arises from a persistent presynaptic [Ca2+]i following tetanic stimulation. At crayfish neuromuscular junctions, several inhibitors of mitochondrial Ca2+ uptake and release (tetraphenylphosphonium or TPP+, carbonyl cyanide m-chlorophenylhydrazone or CCCP, and ruthenium red) blocked PTP and the persistence of presynaptic residual [Ca2+]i, while endoplasmic reticulum (ER) Ca2+ pump inhibitors and release channel activators (thapsigargin, 2,5-di-(tert-butyl)-1,4-benzohydroquinone or BHQ, and caffeine) had no effects. PTP apparently results from the slow efflux of tetanically accumulated mitochondrial Ca2+.

Residual neuromuscular blockade remains a problem even after short surgical procedures. The train-of-four (TOF) ratio at the adductor pollicis required to avoid residual paralysis is now considered to be at least 0.9. The incidence of residual paralysis using this new threshold is not known, especially after a single intubating dose of intermediate-duration nondepolarizing relaxant. Therefore, the aim of the study was to determine the incidence of residual paralysis in the postanesthesia care unit after a single intubating dose of twice the ED(95) of a nondepolarizing muscle relaxant with an intermediate duration of action. Five hundred twenty-six patients were enrolled. They received a single dose of vecuronium, rocuronium, or atracurium to facilitate tracheal intubation and received no more relaxant thereafter. Neuromuscular blockade was not reversed at the end of the procedure. On arrival in the postanesthesia care unit, the TOF ratio was measured at the adductor pollicis, using acceleromyography. Head lift, tongue depressor test, and manual assessment of TOF and DBS fade were also performed. The time delay between the injection of muscle relaxant and quantitative measurement of neuromuscular blockade was calculated from computerized anesthetic records. The TOF ratios less than 0.7 and 0.9 were observed in 16% and 45% of the patients, respectively. Two hundred thirty-nine patients were tested 2 h or more after the administration of the muscle relaxant. Ten percent of these patients had a TOF ratio less than 0.7, and 37% had a TOF ratio less than 0.9. Clinical tests (head lift and tongue depressor) and manual assessment of fade showed a poor sensitivity (11-14%) to detect residual blockade (TOF < 0.9). After a single dose of intermediate-duration muscle relaxant and no reversal, residual paralysis is common, even more than 2 h after the administration of muscle relaxant. Quantitative measurement of neuromuscular transmission is the only recommended method to diagnose residual block.