G.H. Beemer

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 greater or equal to 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 greater or equal to 70% was possible, whereas in 16 patients with a 60-92% depression of T1, a TOF ratio > 70% was not achievable, indicating that a ceiling effect for antagonism by edrophonium occurred. A block of 67 plus/minus 3% (mean plus/minus 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 plus/minus 0.33 mg *symbol* kg sup -1 (mean plus/minus 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.

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

&NA; 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 estimates 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 perioperative 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). Scaling Cl by LBM seemed optimal; it had the best precision compared to the other methods of scaling (LBM versus TBW, height; P < 0.05) and Cl.LBM estimates had no relationship with patient body fat content. LBM also seemed optimal for dosing with the best precision (LBM versus TBW, height, body surface area; P < 0.05). Dosing by TBW underdosed lean patients and overdosed obese patients (P < 0.001). We conclude that body size and build are important determinants of the disposition of atracurium. Dosage of atracurium, particularly in patients at the extremes of body build, should be adjusted by LBM. (Anesth Analg 1993;76:1296‐303)

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

&NA; To determine which factors influenced the pharmacodynamics of atracurium in clinical practice, the steadystate 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 preprogramed 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 × [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 ≥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 build, and other drugs administered in the perioperative period, including calcium channel antagonists and ranitidine. These findings should assist anesthesiologists in more accurately predicting dosage of atracurium in clinical practice. (Anesth Analg 1993;76:1288‐95)