Common peroneal nerve stimulation for neuromuscular monitoring: evaluation in awake volunteers and anesthetized patients.

UNLABELLED: The study was conducted in two parts. First, evoked responses to common peroneal nerve stimulation at four electrode positions were tested in 25 awake volunteers. The initial threshold stimulus current (ITS) (minimal current producing dorsiflexion or eversion of the ankle joint and great toe) and the supramaximal stimulus current (SMS) (the point at which further increases in current did not produce increases in twitch tension) were defined. SMS was not reliably achieved using electrodes at each side of the fibular head. However, an exploratory electrode accurately located the nerve and enabled SMS in all volunteers (SMS/ITS = 3.4). Second, 16 anesthetized, paralyzed patients were studied. The common peroneal and ulnar nerves were stimulated simultaneously. Evoked tension was recorded at the adductor pollicis using a force transducer and at the great toe by a blinded observer. Reversal was given when the train-of-four count at the great toe reached four. Onset times were longer, and median posttetanic counts were greater, at the great toe compared with the adductor pollicis. Time from reversal to train-of-four ratio = 0.7 at the adductor pollicis was 207+/-160 s. We conclude that neuromuscular monitoring at the common peroneal nerve was not equivalent to monitoring at the ulnar nerve. IMPLICATIONS: Accurate neuromuscular monitoring is important for patient safety. We studied the accuracy of monitoring at the common peroneal nerve in volunteers and patients. An exploratory electrode accurately located the common peroneal nerve. Monitoring at the common peroneal nerve was not equivalent to monitoring at the ulnar nerve in patients.

The maximum depth of an atracurium neuromuscular block antagonized by edrophonium to effect adequate recovery.

BACKGROUND: The inability of edrophonium to rapidly reverse a deep nondepolarizing neuromuscular block may be due to inadequate dosage or a ceiling effect to antagonism of neuromuscular block by edrophonium. A ceiling effect means that only a certain level of neuromuscular block could be antagonized by edrophonium. Neuromuscular block greater than this could not be completely antagonized irrespective of the dose of edrophonium administered. The purpose of this study was to determine whether a ceiling effect occurred for antagonism of an atracurium-induced neuromuscular block by edrophonium and, if so, the maximum level of block that could be antagonized by edrophonium. METHODS: In 30 adult patients, atracurium was administered to maintain a constant neuromuscular block. The level of block varied between patients. Evoked adductor pollicis twitch tension was monitored. Incremental doses of edrophonium were administered while the infusion of atracurium continued. Increments were given until adequate recovery occurred, as defined by a train-of-four (TOF) ratio > or = 70%, or until no further antagonism of the block could be achieved. The probability of being able to effect adequate recovery by antagonism with edrophonium was determined using a logistic regression model. Cumulative dose-response curves were constructed using the logit transformation of the neuromuscular effect versus the logarithm of the cumulative dose of edrophonium. RESULTS: In 14 patients with a block of 25-77% depression of the first twitch response, antagonism by edrophonium to a TOF ratio > or = 70% was possible, whereas in 16 patients with a 60-92% depression of T1, a TOF ratio > or = 70% was not achievable, indicating that a ceiling effect for antagonism by edrophonium occurred. A block of 67 +/- 3% (mean +/- SE) had a 50% probability of adequate antagonism. In patients in whom block was antagonized to a TOF ratio < 70%, 95% of the peak antagonistic effect occurred with an edrophonium dose of 0.8 +/- 0.33 mg.kg-1 (mean +/- SD). CONCLUSIONS: There is a maximum level of neuromuscular block that can be antagonized by edrophonium to effect adequate recovery. The level corresponds approximately to the reappearance of the fourth response to TOF stimulation. It is probably safest to wait until this level of block occurs before edrophonium is given for reversal. Earlier administration will not hasten recovery.

Pharmacodynamics of atracurium in clinical practice: effect of plasma potassium, patient demographics, and concurrent medication.

To determine which factors influenced the pharmacodynamics of atracurium in clinical practice, the steady-state plasma concentration of atracurium for 90% paralysis (Cpss90) was measured in 100 adult patients. Neuromuscular block was maintained at 88%-92% of the control response by adjusting the target concentration being delivered by preprogrammed intravenous atracurium infusion. The Cpss90 was measured empirically from plasma samples taken when the block had been stable for 15 min with no adjustment in the infusion rate for 20 min. To describe how factors influenced the Cpss90 of atracurium, a model was developed by multiple stepwise linear regression analysis. Influencing variables retained in the final model were plasma potassium concentration, intraoperative administration of gentamicin, and premedication with papaveretum and hyoscine. The model predicted that the Cpss90 of atracurium would decrease with decreasing serum potassium according to the relationship log10(Cpss90) = 2.380 + 0.171 x [K mmol/L] (n = 100; ANOVA, P < 0.001). Intraoperative administration of gentamicin modified this relationship resulting in a 25.1% decrease in the predicted Cpss90 (n = 15; ANOVA, P < 0.001). Premedication with papaveretum and hyoscine also modified this relationship resulting in a 21.2% decrease in predicted Cpss90 (n = 30; ANOVA, P < 0.001). The model predicted that administration of both would decrease the Cpss90 by 41.0%. Patients aged > or = 70 yr had a slight, but statistically insignificant, increase in the Cpss90 compared to younger adult patients. No other factor was found to influence the Cpss90, including patient sex, body fluid, and other drugs administered in the perioperative period, including calcium channel antagonists and ranitidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of body build on the clearance of atracurium: implication for drug dosing.

To determine factors that influenced the clearance (Cl) of atracurium, 80 adult patients of varying body build were given an atracurium infusion according to a predetermined profile, which was scaled by lean body mass (LBM). Cl was estimated at 50-60 min by the constant infusion rate required to maintain the steady-state plasma concentrations. The efficacy of scaling the absolute Cl estimate by body build variables, in which the absolute Cl estimate is divided by the body build variable to achieve similar scaled estimates in all patients, was assessed by the bias and precision of the individual scaled Cl estimates to those in patients with a "normal" body build (23%-27% body fat). The efficacy of scaling the dose of atracurium by differing body build variables to achieve similar plasma concentrations was also assessed by bias and precision, in which the plasma concentrations from an infusion scaled by other body build variables were generated by linear simulation. Body size, as quantified by LBM, total body mass (TBW), height, and body surface area, had a significant influence on Cl, with the effect best described by LBM (respective R2, 0.487, 0.368, 0.265, 0.445). No other factors could be identified, including blood pH, serum creatinine, and drugs given during the peroperative period. The efficacy of scaling Cl by TBW (absolute Cl estimate divided by patient TBW) to achieve similar estimates in all patients was poor; Cl.TBW estimates varied inversely with patient body fat content and resulted in obese patients having smaller estimates, a mean bias of -29%, compared with those in patients with a normal body build (P = 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Preprogrammed infusion of alfentanil to constant arterial plasma concentration.

A variable rate infusion regimen, designed to rapidly achieve and maintain a target arterial concentration (CT) of 100 micrograms.L-1 of alfentanil, was developed using the method of Plasma Drug Efflux. This method uses a series of clearance values (Ep), calculated as the ratio of instantaneous infusion rate/arterial plasma drug concentration normalized to lean body mass (LBM), at various sampling times during a suboptimal infusion regimen. Values of Ep are used to calculate an infusion rate versus time profile to achieve CT, and the process is repeated in consecutive small groups of subjects to yield an optimal result, i.e., it is an iterative process. Thirty-three adult surgical patients were given alfentanil during anesthesia for approximately 1 h before cardiopulmonary bypass. In an initial group of four patients, who received a simple two-stage infusion, plasma alfentanil concentration was measured at frequent intervals and Ep(L.min-1.kg LBM-1) was estimated at each sampling time. The calculated infusion-rate-versus-time profile to produce CT was obtained from the product Ep x CT for each time point and was transferred to the read-only memory of a computerized infusion pump. This new variable infusion profile was used in four patients, and the process was repeated in three further groups of 5, 8, and 12 patients using infusion profiles calculated from the previous group. Each set of concentration data was assessed by calculating the performance error (PE), the median performance error (MDPE), i.e., bias, and the median absolute value of PE (MDAPE), i.e., inaccuracy.(ABSTRACT TRUNCATED AT 250 WORDS)

Stability of fentanyl, bupivacaine and adrenaline solutions for extradural infusion.

Fentanyl and bupivacaine were tested for their stability when diluted with 0.9% sodium chloride to 4 micrograms ml-1 and 0.1% respectively, in 100-ml polyvinyl chloride (PVC) bags, alone and in combination, with and without adrenaline 1:200,000. Changes in drug concentration and pH were investigated for 56 days. The combination of fentanyl, bupivacaine and adrenaline was tested under varying environmental conditions of 35 degrees C, 4 degrees C, -18 degrees C, room temperature, darkness and after autoclaving. Fentanyl and bupivacaine were adsorbed onto PVC, resulting in reductions of 12.6% and 9.6% drug mass, respectively, at day 3, but remained stable thereafter. Adrenaline was progressively degraded to a maximum reduction of 37.3% at 35 degrees C by day 56. Solutions containing adrenaline became more acidic over 56 days. Fentanyl and bupivacaine were stable.

Determinants of the reversal time of competitive neuromuscular block by anticholinesterases.

We have assessed, in 200 patients, the determinants of the reversal time of competitive neuromuscular block by anticholinesterase when alcuronium and atracurium neuromuscular block were antagonized by neostigmine 0.04 and 0.08 mg kg-1 and edrophonium 0.5 and 1.0 mg kg-1. A biexponential relationship was found between the reversal time (time from injection of anticholinesterase to a train-of-four ratio of 70%) and the degree of neuromuscular block at reversal (all groups; F ratio, P less than 0.05). Reversal time was determined by two processes: direct antagonism by the anticholinesterase and spontaneous recovery of the neuromuscular blocking agent, with the latter becoming the major determinant at profound levels of neuromuscular block (0-10% of control twitch height). Neostigmine, in the doses studied, appeared to have a higher "ceiling" of neuromuscular block which it completely antagonized, although edrophonium had a more rapid onset of action. The reversal time for alcuronium became progressively longer relative to atracurium as neuromuscular block increased because of the slower spontaneous recovery rate. Avoidance of profound neuromuscular block at the completion of surgery is required to ensure reliable antagonism of the block within 5-10 min by an anticholinesterase. Neostigmine 0.08 mg kg-1 was found to be the most effective agent in antagonizing profound neuromuscular block.

Pharmacokinetics of atracurium during continuous infusion.

The pharmacokinetics of atracurium were investigated by a model-independent method during continuous infusion under propofol anaesthesia. Following an intubating dose of suxamethonium, atracurium was infused according to a predetermined profile which continually set the infusion rate to maintain stable muscle paralysis and a target steady state plasma concentration when equilibrium between the biophase and plasma had occurred. Atracurium was infused for the first 1 h to maintain a target steady state plasma concentration of 1.0 microgram ml-1. Thereafter, the target plasma concentration was adjusted to maintain 90% muscle paralysis. The maintenance infusion rate required to maintain 90% paralysis was 4.25 (SD) 1.11 micrograms kg-1 min-1, with an estimated steady state plasma concentration of atracurium required to maintain 90% paralysis (Cpss90) of 1.13 (0.24) microgram ml-1. The clearances of atracurium, estimated by the constant infusion rate required to maintain the steady state plasma concentration, at 50-60 min and during estimation of Cpss90 were 3.8 (1.0) and 3.9 (1.1) ml kg-1 min-1 (ns), respectively. The volume of distribution at steady state of atracurium after 1 h of infusion, calculated using the clearance and the area under the plasma concentration-time curve to 1 h, was 130 (50) ml kg-1. These estimates of the pharmacokinetic parameters of atracurium are markedly different from those derived from pharmacokinetic analysis of single bolus dose data. Normalization of the pharmacokinetic parameter estimates by lean body mass decreased interpatient variability and improved precision in comparison with the un-weighted data and normalization by total body weight.

Pharmacodynamics of atracurium during propofol, thiopentone and opioid anaesthesia.

We have assessed in 20 patients the accuracy and precision of an infusion profile for atracurium, which continually set the infusion rate to maintain stable muscle paralysis and a target steady state plasma concentration, when equilibrium between the biophase and plasma had occurred. Muscle paralysis was stable after 20 min, with a mean absolute drift in muscle paralysis in the succeeding 40 min of 0.13 (SD 0.07)% T1/Tc (height of first twitch/height of control twitch) per min. The plasma samples after 30 min, which were assessed empirically as being in equilibrium with the biophase, had an overall mean bias of 8.0 (SEM 3.7)% (P less than 0.05) and an overall mean absolute prediction error of 16.4 (SEM 2.5)% from the target steady state concentration being delivered by the infusion. The profile was then used to estimate the steady state plasma concentration of atracurium required to maintain 90% paralysis (Cpss90), by manually adjusting the delivered target concentration of the infusion until muscle paralysis was stable at 88-92% inhibition of T1/Tc for 15-20 min, with three plasma samples taken over the next 10 min. Measurements were completed within 60-90 min. The mean Cpss90 of atracurium with propofol was 1.039 (SD 0.224) microgram ml-1 (n = 10), with thiopentone 1.334 (0.378) microgram ml-1 (n = 10), and with opioid anaesthesia 0.915 (0.221) microgram ml-1 (n = 10). These differences in the Cpss90 explain some of the variability in response which occurs with neuromuscular blocking drugs. The technique enables the Cpss90 of a myoneural blocker to be determined by a simple model-independent method.

Accurate monitoring of neuromuscular blockade using a peripheral nerve stimulator--a review.

For normal anaesthetic practice, monitoring of neuromuscular blockade is best performed by stimulation of the ulnar nerve at the wrist with a peripheral nerve stimulator and evaluation of the response of the thumb. Determination of the initial threshold for stimulation in the awake patient to allow estimation of the current required for supramaximal stimulation is an important set-up procedure to improve accuracy. The degree of paralysis of specific muscle groups such as the diaphragm can be inferred from their sensitivity to neuromuscular blocking agents relative to adductor pollicis. Monitoring with different stimulation patterns allows a wide spectrum of muscle paralyses to be evaluated.

Production of laudanosine following infusion of atracurium in man and its effects on awakening.

Twenty patients were given maximal doses of atracurium or vecuronium by infusion during surgery. Anaesthesia was maintained with an infusion of thiopentone, nitrous oxide and fentanyl. In patients administered atracurium, the plasma laudanosine concentration at cessation of surgery was 0.34 (SD 0.22) micrograms ml-1; there was little tendency to cumulate during operation. A 20% higher arterial concentration of thiopentone was found at awakening in patients given atracurium, suggesting CNS stimulation by laudanosine, although the effect is too modest to be of clinical significance.

Adverse reactions to atracurium and alcuronium. A prospective surveillance study.

A multicentre prospective surveillance study was undertaken to compare the incidence and severity of adverse reactions attributed to atracurium and alcuronium. Clinical manifestations were used by the anaesthetist to diagnose an adverse reaction (a cutaneous reaction, a greater than 20% change in arterial pressure or heart rate, and bronchospasm). Of the 1956 patients receiving atracurium, 10.1% had adverse reactions compared with 17.9% of the 1425 patients receiving alcuronium (P less than 0.001). There were no longterm sequelae. The atracurium group had a markedly lower incidence of hypotension (3.4% v. 13.7%; P less than 0.0001), but a higher incidence of cutaneous reactions (4.6% v. 2.3%; P less than 0.005) which were not associated with other adverse reactions. There was a low incidence of bronchospasm in both groups (0.2% v. 0.1%).

An evaluation of eight peripheral nerve stimulators for monitoring neuromuscular blockade.

The features of eight commercially available peripheral nerve stimulators were compared with those evolved as ideal for monitoring neuromuscular blockade. The pulse waveforms were satisfactory except for that delivered by the CIG series 80 nerve/muscle stimulator. The error in timing of the stimulation patterns was up to 60% in the Professional Instruments NS-2C compared with 8% or less in the other devices. All of the stimulators had maximum current outputs suitable for monitoring with surface stimulating electrodes. The current delivered by the CIG series 80 nerve/muscle stimulator and the Stimlocator SL1.4 sagged by 21% and 25% respectively during a tetanus. The Digistim III, Bard Biomedical 750 digital and the Professional Instruments NS-2C had accurate digital readouts of delivered current.

The effect of cardiopulmonary bypass on plasma protein binding of alfentanil.

The effect of cardiopulmonary bypass (CPB) on plasma concentration and protein binding of alfentanil was studied during continuous infusions in five cardiac surgical patients. Patients were given a loading infusion of 10 micrograms.min-1.kg-1 lean body mass (LBM) over 30 s followed by a fixed rate maintenance infusion of 1 microgram.min-1.kg-1 LBM for the duration of surgery. Prior to the commencement of CPB the total plasma alfentanil concentration was 177 micrograms.l-1. This fell to 92 micrograms.l-1 2 min after commencement of CPB and rose to 155 micrograms.l-1 at the end of CPB 2.01 h later. During the same period the unbound fraction of alfentanil rose from 0.16 to 0.35 two min after the start of CPB and fell gradually to 0.22 at the end of CPB. The unbound concentration prior to CPB was 29 micrograms.l-1 and was essentially unchanged by the onset of CPB, being 35 micrograms.l-1 at two min and then 31 micrograms.l-1 at the end of CPB. There was a good correlation between alfentanil bound/unbound concentration ratio and plasma albumin concentration (r = 0.57) and plasma alpha 1-acid glycoprotein concentration (r = 0.80), indicating that the decrease in binding during CPB was due primarily to haemodilution. In assessing the effects of CPB on plasma drug concentrations, it is therefore necessary to monitor unbound as well as total concentrations because the effects on these differ greatly.

Monitoring neuromuscular blockade with calf stimulators.

The efficacy of monitoring neuromuscular blockade during surgery based on visual assessment of the response to calf stimulation was determined in twenty-five patients. The calf stimulator was adjusted before the administration of any muscle relaxant to produce a brisk ankle jerk. Following an initial bolus dose of atracurium (0.5 mg/kg), further incremental doses (0.2 mg/kg) were administered when the response to calf stimulation was small and obvious. The resultant neuromuscular blockade was judged to be adequate throughout the surgical procedures, with an average of five incremental doses of atracurium being administered. In the presence of neuromuscular blockade the response to calf muscle stimulation was often greater than that produced by supramaximal stimulation of the ulnar nerve with a peripheral nerve stimulator. The response to calf muscle stimulation often persisted after that resulting from ulnar nerve stimulation was abolished. The technique has only limited accuracy in assessing neuromuscular blockade. However, it may be useful in helping to avoid the wide fluctuations in blockade which are prone to occur with the intermediate duration competitive neuromuscular blocking agents.

Continuous infusions of muscle relaxants--why and how.

The degree of neuromuscular blockade that occurs in an individual patient following the administration of competitive neuromuscular blocking agents cannot be accurately predicted because of the large individual variation in the pharmacokinetics and pharmacodynamics of these agents. Without monitoring of the neuromuscular blockade, this unpredictability predisposes to the occurrence of residual curarisation with its potentially lethal consequences. Variable rate continuous infusion of a short-acting competitive neuromuscular blocking agent with monitoring of the neuromuscular blockade is a flexible and accurate method for maintaining a precise degree of neuromuscular blockade during prolonged surgical procedures which ensues reliable reversability of the residual neuromuscular blockade. A system for the continuous infusion of atracurium with manual monitoring of the neuromuscular blockade is described, together with the results of a study demonstrating its efficacy.

Postoperative neuromuscular function.

One hundred patients who received a competitive neuromuscular blocking agent during anaesthesia were randomly selected for evaluation of neuromuscular function immediately on their arrival in the recovery room. The anaesthetist was not aware that the patient would be evaluated in the recovery room. Neuromuscular function was assessed by a train-of-four (TOF) ratio, and in conscious and co-operative patients by a series of bedside tests of neuromuscular function. Twenty-one patients had a TOF ratio of less than 0.70 and seven patients a TOF ratio of less than 0.60. Bedside tests of neuromuscular function did not reliably detect this defect in neuromuscular transmission. It is concluded that a relatively large number of patients have a defect in neuromuscular transmission on their arrival in the recovery room, and suggested that this reflects the inadequacy of clinical methods used for the administration and antagonism of competitive neuromuscular blocking agents at this institution.