Anesthesiology. First of two parts.

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.

Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d-tubocurarine

Rhabdomyolysis ranges from an asymptomatic illness with elevation in the creatine kinase level to a life-threatening condition associated with extreme elevations in creatine kinase, electrolyte imbalances, acute renal failure and disseminated intravascular coagulation. Muscular trauma is the most common cause of rhabdomyolysis. Less common causes include muscle enzyme deficiencies, electrolyte abnormalities, infectious causes, drugs, toxins and endocrinopathies. Weakness, myalgia and tea-colored urine are the main clinical manifestations. The most sensitive laboratory finding of muscle injury is an elevated plasma creatine kinase level. The management of patients with rhabdomyolysis includes early vigorous hydration.

/pdf/bench-to-bedside-review-rhabdomyolysis-an-overview-for-5bh7j86ysa.pdf

Bench-to-bedside review: Rhabdomyolysis – an overview for clinicians

Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery.

/pdf/guidelines-for-pre-operative-cardiac-risk-assessment-and-24w6qyo5uf.pdf

Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery

The set of guidelines for good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents, which was developed following an international consensus conference in Copenhagen, has been revised and updated following the second consensus conference in Stockholm in 2005. It is hoped that these guidelines will continue to help researchers in the field and assist the pharmaceutical industry and equipment manufacturers in enhancing the standards of the studies they sponsor.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1399-6576.2007.01352.x

Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision.

Mivacurium chloride (BW B1090U), a bis-benzylisoquinolinium diester compound, was found to undergo hydrolysis in vitro by purified human plasma cholinesterase in a pH-stat titrator at 88% of the rate of succinylcholine at pH 7.4, 37 degrees C and 5 microM substrate concentration. In 72 consenting ASA Physical Status I-II patients receiving nitrous oxide/oxygen-narcotic-thiopental anesthesia, the neuromuscular blocking effect of mivacurium was assessed following bolus doses from 0.03 to 0.30 mg/kg, as well as during and following continuous infusions from 35 to 324 min in length. The calculated ED95 for inhibition of adductor pollicis twitch evoked at 0.15 Hz was 0.08 mg/kg. At 0.1 mg/kg, 96% block developed, onset to maximum block required 3.8 +/- 0.5 min, and recovery to 95% twitch height occurred 24.5 +/- 1.6 (SE) min after injection. At 0.25 mg/kg, onset was 2.3 +/- 0.3 min; 95% recovery developed within 30.4 +/- 2.2 min, an increase in duration of action of only 24% versus 150% higher dosage. Comparative recovery indices from 5 to 95% or from 25 to 75% twitch heights did not differ significantly among all dosage groups from 0.1 to 0.3 mg/kg (range 12.9 to 14.7 and 6.6 to 7.2 min, respectively). In 38 patients who received mivacurium by continuous infusion (duration 88.1 +/- 7.1/47.1 min, SE/SD) for maintenance of 95 +/- 4% twitch inhibition, the mean 5-95% and 25-75% recovery indices after discontinuation of infusion were 14.4 +/- 0.6 and 6.5 +/- 0.3 min (P greater than 0.5 vs. all single bolus doses). The train-of-four (T4) ratio, within 2.6 +/- 0.5 min after 95% twitch recovery following bolus doses, averaged 79.5 +/- 1.8% (n = 32). Similarly, after discontinuation of infusions, the T4 ratio reached 73.4 +/- 1.9% within 3.4 +/- 1.9 min after 95% twitch recovery (n = 33). Antagonism of residual block was seldom indicated, but, to test ease of reversal, eight patients electively received neostigmine (0.06 mg/kg) with atropine (0.03 mg/kg) at 67 to 93 (76.6 +/- 3.5) % block. Twitch returned to 95% of control within 4.5 to 9.5 (6.3 +/- 0.5) min after neostigmine. Mivacurium may offer increased versatility in providing clinical muscle relaxation in a variety of situations. Further studies seem appropriate.

The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). A short-acting nondepolarizing ester neuromuscular blocking drug.

Monitoring neuromuscular transmission provides valuable information to the anesthesiologist. The aquisition of relevant data contributes to a more predictable and rational approach to the use of muscle relaxants and assures improved patient care during and in the immediate postoperative period.

Monitoring of neuromuscular function.

SUMMARY Study of the literature on the physiology of neuromuscular transmission suggested two new methods of assessing the degree of neuromuscular block in the human subject. These were, first, a comparison of the height of the recorded twitch tensions developed in response to repeated single stimuli applied at differing frequencies and, second, examination of the extent of reduction in amplitude of twitch tensions developed in response to a short train of four stimuli. In assessing the first method the use of three frequencies of stimulation was tried (i.e., 0.1 Hz (c.p.s.), 0.3 Hz and 1.0 Hz). It was found that as the frequency of stimulation was increased there was reduction in the amplitude of the recorded twitch response in curarized subjects, and that this reduction appeared to depend on the degree of curarization. In assessing the second method a short train of four stimuli at 2 Hz was used, and it was found that there was a progressive fade of successive recorded mechanical twitch responses in curarized subjects which again appeared to depend on the degree of curarization. It is suggested that the amplitude of the twitch response at a higher frequency expressed as a percentage of that at the slower rate, and the last response of the train of four expressed as a percentage of the first may be useful in measuring degree of neuromuscular block in man.

Stimulus frequency in the detection of neuromuscular block in humans

SUMMARY The effect of tubocurarine on the respiratory function of conscious, non-medicated volunteers was correlated with the degree of neuromuscular blockade measured with the train-of-four technique (the evoked response of the adductor pollicis brevis muscle to trains of four supramaximal ulnar nerve stimuli at 2 Hz, repeated once every 10 sec). Respiratory frequency, tidal volume, vital capacity, inspiratory force and peak expiratory flow rate were measured, (a) before administration of tubocurarine, (b) when the ratio of the amplitude of the fourth response to the amplitude of the first response of the train-of-four reached 60% and (c) during recovery of the ratio until the control (100%) value was reached. Respiratory frequency, tidal volume and peak expiratory flow rate were not altered. Vital capacity and inspiratory force were both reduced significantly at the 60% level and the former also at the 70% level when compared with the control. The magnitude of change in all variables is of minor clinical importance, however, since the lowest measured values are well above acceptable minimum limits required for adequate respiratory function.

The effect of tubocurarine on indirectly elicited train-of-four muscle response and respiratory measurements in humans

Monitoring neuromuscular transmission provides valuable information to the anesthesiologist. The acquisition of relevant data contributes to a more predictable and rational approach to the use of muscle relaxants and assures improved patient care during and in the immediate postoperative period. Clinical noninvasive criteria such as the presence or absence of diplopia and or ptosis, the ability to open the eyes widely, protrude the tongue or swallow, measurement of hand grip strength or head lift or assessment of the vital capacity are limited to awake and cooperative patients. Measurement of inspiratory force and tidal volume can be evaluated in anesthetized patients breathing spontaneously. Central depressant drugs tend to depress these respiratory parameters. Accordingly, the assumption that relaxants are responsible for respiratory depression at the end of an anesthetic can only be documented when impairment of neuromuscular transmission can be demonstrated. The most reliable method of measuring neuromuscular function is to stimulate an accessible peripheral motor nerve and measurement of the evoked response of the skeletal muscle or muscles innervated by the stimulated motor nerve. The evoked muscle response depends on the pattern of motor nerve stimulation: Single twitch stimuli at a defined frequency, tetanic stimulation, posttetanic single twitch stimulation or train-of-four stimulation. The response to these different modes of stimulation can be assessed either mechanically (evoked tension response) or electrically (evoked electromyography: EMG or integrated EMG). These response criteria can be employed either individually or combined to evaluate the response to muscle relaxants and to assess the adequacy of recovery from neuromuscular blockade.

Hassan H. Ali

Papers

The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). A short-acting nondepolarizing ester neuromuscular blocking drug.

Monitoring of neuromuscular function.

Stimulus frequency in the detection of neuromuscular block in humans

The effect of tubocurarine on indirectly elicited train-of-four muscle response and respiratory measurements in humans

Monitoring of neuromuscular function