Skin Reactions to Intradermal Neuromuscular Blocking Agent Injections: A Randomized Multicenter Trial in Healthy Volunteers

Background: Numerous reports confirm the performance of intradermal tests for the diagnosis of anaphylaxis during anesthesia; however, there is controversy over their diagnostic value regarding the newer neuromuscular blocking agents (NMBAs).

Methods: One hundred eleven healthy volunteers were randomly assigned to receive intradermal injections of two NMBAs, at five increasing concentrations. A concentration was considered as a reactive concentration when it led to a positive reaction in more than 5% of the subjects. These concentrations were compared with the maximal concentration recommended for the diagnosis of sensitization to NMBAs.

Results: The maximal nonreactive concentrations were 10-3 m for suxamethonium; 10-4 m for pancuronium, vecuronium, rocuronium, and cisatracurium; and 10-5 m for atracurium and mivacurium. Except for mivacurium, these nonreactive concentrations were close to the maximal concentrations used for the diagnosis of sensitization against NMBAs. For mivacurium, the nonreactive concentrations were higher than the maximal concentration currently recommended in clinical practice.     

Neuromuscular interaction between cisatracurium and mivacurium, atracurium, vecuronium or rocuronium administered in combination

We compared the dose–response relationships of cisatracurium, mivacurium, atracurium, vecuronium and rocuronium and examined the interactions of cisatracurium with mivacurium, atracurium, vecuronium and rocuronium in humans by isobolographic and fractional analyses. We studied 180 adult patients during nitrous oxide–fentanyl–propofol anaesthesia. Neuromuscular block was monitored using mechanomyography to detect the twitch response of the ulnar nerve at the wrist. The dose–response curves were determined by probit analysis. The calculated ED₅₀ values and their 95% confidence intervals were 40.9 (38.1–43.7), 49.8 (47.0–52.6), 187.2 (175.1–199.3), 36.6 (34.7–38.5) and 136.4 (129.2–143.6) μg.kg⁻¹ for cisatracurium, mivacurium, atracurium, vecuronium and rocuronium, respectively. Corresponding ED₉₅ values were 57.6 (53.5–61.7), 91.8 (88.1–95.5), 253.1 (238.9–267.3), 52.9 (49.1–56.7) and 288.7 (276.2–301.2) μg.kg⁻¹, respectively. The interaction between cisatracurium and mivacurium, vecuronium or rocuronium was found to be synergistic, but the interaction between cisatracurium and atracurium was found to be additive. Synergy between cisatracurium and vecuronium or rocuronium was greater than between cisatracurium and mivacurium.     

Distinct pharmacologic properties of neuromuscular blocking agents on human neuronal nicotinic acetylcholine receptors: a possible explanation for the train-of-four fade

BACKGROUND: Nondepolarizing neuromuscular blocking agents (NMBAs) are extensively used in the practice of anesthesia and intensive care medicine. Their primary site of action is at the postsynaptic nicotinic acetylcholine receptor (nAChR) in the neuromuscular junction, but their action on neuronal nAChRs have not been fully evaluated. Furthermore, observed adverse effects of nondepolarizing NMBAs might originate from an interaction with neuronal nAChRs. The aim of this study was to examine the effect of clinically used nondepolarizing NMBAs on muscle and neuronal nAChR subtypes. METHODS: Xenopus laevis oocytes were injected with messenger RNA encoding for the subunits included in the human alpha1beta1epsilondelta, alpha3beta2, alpha3beta4, alpha4beta2, and alpha7 nAChR subtypes. The interactions between each of these nAChR subtypes and atracurium, cisatracurium, d-tubocurarine, mivacurium, pancuronium, rocuronium, and vecuronium were studied using an eight-channel two-electrode voltage clamp setup. Responses were measured as peak current and net charge. RESULTS: All nondepolarizing NMBAs inhibited both muscle and neuronal nAChRs. The neuronal nAChRs were reversibly and concentration-dependently inhibited in the low micromolar range. The mechanism (i.e., competitive vs. noncompetitive) of the block at the neuronal nAChRs was dependent both on subtype and the NMBA tested. The authors did not observe activation of the nAChR subtypes by any of the NMBAs tested. CONCLUSIONS: The authors conclude that nondepolarizing NMBAs concentration-dependently inhibit human neuronal nAChRs. The inhibition of the presynaptic alpha3beta2 nAChR subtype expressed at the motor nerve ending provides a possible molecular explanation for the tetanic and train-of-four fade seen during a nondepolarizing neuromuscular block.     

Distinct Pharmacologic Properties of Neuromuscular Blocking Agents on Human Neuronal Nicotinic Acetylcholine Receptors: A Possible Explanation for the Train-of-four Fade

Background: Nondepolarizing neuromuscular blocking agents (NMBAs) are extensively used in the practice of anesthesia and intensive care medicine. Their primary site of action is at the postsynaptic nicotinic acetylcholine receptor (nAChR) in the neuromuscular junction, but their action on neuronal nAChRs have not been fully evaluated. Furthermore, observed adverse effects of nondepolarizing NMBAs might originate from an interaction with neuronal nAChRs. The aim of this study was to examine the effect of clinically used nondepolarizing NMBAs on muscle and neuronal nAChR subtypes.

Methods: Xenopus laevis oocytes were injected with messenger RNA encoding for the subunits included in the human [alpha]1[beta]1[varepsilon][delta], [alpha]3[beta]2, [alpha]3[beta]4, [alpha]4[beta]2, and [alpha]7 nAChR subtypes. The interactions between each of these nAChR subtypes and atracurium, cisatracurium, d-tubocurarine, mivacurium, pancuronium, rocuronium, and vecuronium were studied using an eight-channel two-electrode voltage clamp setup. Responses were measured as peak current and net charge.

Results: All nondepolarizing NMBAs inhibited both muscle and neuronal nAChRs. The neuronal nAChRs were reversibly and concentration-dependently inhibited in the low micromolar range. The mechanism (i.e., competitive vs. noncompetitive) of the block at the neuronal nAChRs was dependent both on subtype and the NMBA tested. The authors did not observe activation of the nAChR subtypes by any of the NMBAs tested.     

Neuromuscular Blocking Agents' Differential Bronchoconstrictive Potential in Guinea Pig Airways

Background: Neuromuscular blocking agents are designed to antagonize nicotinic cholinergic receptors on skeletal muscle but also antagonize muscarinic receptors. Several muscle relaxants have the potential to promote bronchoconstriction due to unintended effects exemplified by histamine release of atracurium or mivacurium and detrimental interactions with muscarinic receptors by rapacuronium. Although interactions of muscle relaxants with muscarinic receptors have been extensively characterized in vitro, limited information is available on their potential interactions with airway tone in vivo.

Methods: Changes in pulmonary inflation pressures and heart rates induced by vagal nerve stimulation and intravenous acetylcholine were measured in the absence and presence of increasing doses of gallamine, pancuronium, mivacurium, vecuronium, cisatracurium, rocuronium, or rapacuronium in guinea pigs. Mivacurium's and rapacuronium's potential of inducing bronchoconstriction by histamine release was also evaluated.

Results: Rapacuronium potentiated both vagal nerve-stimulated and intravenous acetylcholine-induced increases in airway pressures, which were totally blocked by atropine but not pyrilamine. Vecuronium, rocuronium, mivacurium, and cisatracurium were devoid of significant airway effects. Mivacurium, at high doses, increased pulmonary inflation pressures, which were attenuated by pyrilamine.     

Neuromuscular blocking agents' differential bronchoconstrictive potential in Guinea pig airways

BACKGROUND: Neuromuscular blocking agents are designed to antagonize nicotinic cholinergic receptors on skeletal muscle but also antagonize muscarinic receptors. Several muscle relaxants have the potential to promote bronchoconstriction due to unintended effects exemplified by histamine release of atracurium or mivacurium and detrimental interactions with muscarinic receptors by rapacuronium. Although interactions of muscle relaxants with muscarinic receptors have been extensively characterized in vitro, limited information is available on their potential interactions with airway tone in vivo. METHODS: Changes in pulmonary inflation pressures and heart rates induced by vagal nerve stimulation and intravenous acetylcholine were measured in the absence and presence of increasing doses of gallamine, pancuronium, mivacurium, vecuronium, cisatracurium, rocuronium, or rapacuronium in guinea pigs. Mivacurium's and rapacuronium's potential of inducing bronchoconstriction by histamine release was also evaluated. RESULTS: Rapacuronium potentiated both vagal nerve-stimulated and intravenous acetylcholine-induced increases in airway pressures, which were totally blocked by atropine but not pyrilamine. Vecuronium, rocuronium, mivacurium, and cisatracurium were devoid of significant airway effects. Mivacurium, at high doses, increased pulmonary inflation pressures, which were attenuated by pyrilamine. CONCLUSION: Rapacuronium was unique among muscle relaxants evaluated in that it potentiated both vagal nerve- and intravenous acetylcholine-induced bronchoconstriction with no evidence of histamine release. The dual detrimental interactions of rapacuronium with muscarinic receptors previously demonstrated in vitro correlate with in vivo muscarinic receptor mechanisms of bronchoconstriction and may account for the profound bronchoconstriction seen with its clinical use. These findings may establish pharmacologic characteristics to avoid with new muscle relaxants intended for clinical use.     

The use of muscle relaxants for routine induction of anesthesia in Germany

The aim of this study was to evaluate the use of muscle relaxants during induction of anesthesia in patients without risk of aspiration of stomach contents.Of the 2,996 questionnaires sent out, 2,054 (68.6%) could be analysed and the results show that succinylcholine is used regularly in 13.6% of anesthesia departments.The next most commonly used muscle relaxants are atracurium, vecuronium and mivacurium, followed by cis-atracrium, rocuronium and pancuronium. Alcuronium is the least frequently used muscle relaxant. During induction of an elective anesthesia procedure, a priming technique is used by 19% of anesthesiologists, 22% utilize precurarization, and a timing technique is performed in 7.1%.The use of muscle relaxants for on-going relaxation follows the same pattern as for induction of neuromuscular blockade and succinylcholine is used in 1.4% if further relaxation is needed.The desire for specific qualities of muscle relaxants is correlated with higher use of the specific substance: short onset time for rocuronium, good controllability with mivacurium, no side-effects with cisatracurium and economical aspects with alcuronium. Of the participants 76.6% voiced the desire for a non-depolarizing replacement for succinylcholine.Private practices use mivacurium more often than hospitals, level one hospitals use rocuronium and cisatracurium more often.This survey could not show a definite standard of use in terms of muscle relaxants for an elective case.Precurarization, priming and timing are used frequently in patients not at risk of aspiration. This should be reduced by on-going teaching.     

Different Patterns of Mast Cell Activation by Muscle Relaxants in Human Skin

Background: Activation of mast cells and systemic release of histamine are major side effects of intravenously administered muscle relaxants. In the current study, dermal microdialysis was used for the investigation of mast cell activation by muscle relaxants. Dermal microdialysis enabled simultaneous assessment of mediator release, vascular reactions, and sensory effects induced by intradermal application of muscle relaxants without systemic side effects.

Methods: Succinylcholine, the isoquinolines cisatracurium, atracurium, and mivacurium, and the steroids pancuronium, vecuronium, rocuronium, and rapacuronium were tested in human volunteers (n = 6 each). After intradermal insertion of microdialysis capillaries (0.4 mm diameter, cutoff 3,000 kd) and a 60-min equilibration period, the muscle relaxants were delivered via the capillaries for 30 min, followed by a 30-min washout period. Dialysate was sampled at 15-min intervals, and histamine, mast cell tryptase, and protein extravasation were determined. Changes in skin blood flow were measured using a laser Doppler imager. Potency and efficacy were derived from nonlinear fittings of the dose-response curves.

Results: For succinylcholine and the isoquinolines, dose-response curves for the vascular and sensory effects paralleled the histamine and tryptase release. In contrast, aminosteroids evoked a rapid histamine release that was accompanied by a delayed increase in tryptase.     

Neuromuscular blocking effects and train-of-four fade with cisatracurium: comparison with other nondepolarising relaxants

Neuromuscular blocking drugs exhibit different degrees of fade in response to train-of-four stimulation believed to represent their relative prejunctional effects. The present study was designed to compare the train-of-four fade after cisatracurium and compare this with other commonly used muscle relaxants. Train-of-four fade during onset and recovery of block were recorded after administration of cisatracurium 0.05 or 0.1 mg.kg-1, atracurium 0.5 mg.kg-1, vecuronium 0.08 mg.kg-1, mivacurium 0.15 mg.kg-1 or rocuronium 0.6 mg.kg-1 to patients anaesthetised with fentanyl, nitrous oxide and a propofol infusion. Neuromuscular monitoring was by stimulation of the ulnar nerve and recording the force of contraction of the adductor pollicis muscle. The onset and recovery of block were also measured. Train-of-four fade during onset of block was greater with the lower dose of cisatracurium compared with the higher dose of cisatracurium and all other relaxants. Train-of-four fade during recovery was similar. The median times (and ranges) for the onset of maximum block were 3.4 (2.1-5.6), 1.5 (1.2-2.3), 2.1 (1.2-2.6), 2.0 (1.5-2.7) and 1.0 (0.7-1.3) min for cisatracurium 0.1 mg.kg-1 and atracurium, mivacurium, vecuronium and rocuronium, respectively. The median times (and ranges) for the recovery of T1 to 25% of control and to a train-of-four ratio of 0.8 were 41 (21-50) and 65 (40-78); 43 (37-54) and 69 (58-79); 15 (11-20) and 25 (19-30); 31 (23-46) and 60 (45-117); and 33 (18-57) and 50 (28-76) min following cisatracurium, 0.1 mg.kg-1, atracurium, mivacurium, vecuronium and recuronium, respectively.     

Molar Potency Is Predictive of the Speed of Onset of Neuromuscular Block for Agents of Intermediate, Short, and Ultrashort Duration

Background: The times to peak effect of rocuronium, vecuronium, cisatracurium, mivacurium, and succinylcholine were evaluated to confirm that the correlation between potency and onset time observed for long-acting relaxants also held for drugs of intermediate and short duration.

Methods: The authors recruited 99 patients classified as American Society of Anesthesiologists physical status score 1 or 2 for the study. After anesthesia was induced, tracheal intubation was accomplished without relaxants. Anesthesia was maintained with nitrous oxide and 3% or 4% end-tidal desflurane plus intravenous narcotic supplementation. The evoked electromyographic response to single stimuli administered at 0.10 Hz was recorded continuously. Drug doses were selected to produce approximately 95% twitch depression. If peak twitch depression did not fall in the range of 90% to 98%, the patient was excluded from the study. The time to 50% to 90% of peak effect was plotted as a function of the administered dose.

Results: There was no difference in the onset profiles of mivacurium and vecuronium, or in the time to 50% of peak effect between succinylcholine and rocuronium. For all other parameters, onset times ranked as follows: succinylcholine < rocuronium < vecuronium-mivacurium < cisatracurium (P < 0.05). When the log of the ED95 in micromoles per kilogram for all five drugs was plotted against the log of onset time to 50% peak effect, the R2 value for the best fit line was more than 0.98.     

Atracurium, cisatracurium, vecuronium and rocuronium in patients with renal failure

AIM: The cumulative index, the recovery, the onset and the duration of action, of atracurium, cisatracurium, vecuronium and rocuronium in uremic patients undergoing kidney transplantation compared to healthy patients undergoing general surgery were studied. METHODS: In all patients (64 uremic vs 62 "healthy" patients) after anesthesia induction, atracurium 0.5 mgxkg(-1) or cisatracurium 0.15 mgxkg(-1) or vecuronium 0.1 mgxkg(-1) or rocuronium 0.6 mgxkg(-1) were administered, and at the end of surgery when T1 reached 25% neostigmine 0.05 mgxkg(-1) was given. Neuro-muscu-lar transmission was monitored by accelerometry (TOF-GUARD, Organon). RESULTS: Cumulative index of vecuronium (1.3+/-0.1 vs 1.06+/-0.11, p<0.001) and rocuronium (1.45+/-0.18 vs 1.04+/-0.16, p<0.001), recovery index (time of T1 25-75) of atracurium (14.2+/-5 vs 9+/-4, p<0.005), cisatracurium (18.7+/-3 vs 9.1, p<0.001), vecuronium (18.5+/-3 vs 12.5+/-3, p<0.001) and rocuronium (18+/-6 vs 11+/-4, p<0.001) and interval T1 25% to TOF 0.8 of cisatracurium (20.5+/-1.2 vs 16+/-2.1, p<0.001) and vecuronium (27+/-6.3 vs 20+/-3.3, p<0.001) were longer in uremic patients. The onset time and the duration of action of atracurium, cisatracurium, vecuronium and rocuronium were similar in all groups compared to controls one. CONCLUSION: In patients with renal failure the use of atracurium, cisatracurium, vecuronium and rocuronium is suitable and predictable in terms of onset, and duration of action. Care has to be taken to vecuronium and rocuronium cumulative index. Neuromuscular trasmission has to be always monitored.     

The pharmacoeconomics of neuromuscular blocking drugs: a perioperative cost-minimization strategy in children

The purpose of this investigation was to compare the costs of intermediate-acting neuromuscular blocking drugs in children during routine ambulatory surgery. We studied 200 healthy, 2-10-yr-old children undergoing elective dental restorative surgery. During Part 1 of the study, children received an inhaled anesthetic with halothane and nitrous oxide, whereas in Part 2, the anesthetic was IV propofol with nitrous oxide. The study drugs were atracurium, cisatracurium, mivacurium, rocuronium, and vecuronium. Patients were initially administered 2x the effective dose for 95% of the study drug. After recovery to 10% of baseline neuromuscular function, the neuromuscular blockade was rigidly maintained with an infusion of the study drug at about 10% of baseline function. Neuromuscular drug costs were approximated as drug usage x cost/unit. The initial drug costs were not substantially different for both Parts 1 and 2, but over time, mivacurium became the most expensive drug and cisatracurium the least expensive. In conclusion, based on current costs, cisatracurium is the least expensive intermediate-acting neuromuscular drug. IMPLICATIONS: For children undergoing minor ambulatory procedures of 1-2 h, and continuous intraoperative neuromuscular blockade is indicated, cisatracurium currently is the least expensive drug.     

Variability of duration of action of neuromuscular-blocking drugs in elderly patients

BACKGROUND: Steroid-based, non-depolarizing neuromuscular-blocking (NMB) drugs (e.g. rocuronium, vecuronium) are characterized by organ-dependent elimination and significantly longer durations of action in elderly compared to young patients. Cisatracurium is a benzylisoquinolinium NMB drug with a duration of action not altered by ageing. The objective of the study was to determine if elderly patients had less variability in duration of action with 2 x ED95 of cisatracurium compared to equipotent doses of rocuronium or vecuronium. METHODS: Informed consent was obtained from 66 elderly patients with normal renal and liver function. Preoperative midazolam (1 mg) was given IV. The anaesthestic induction was with 5 mg kg(-1) thiopental and 2 microg kg(-1) fentanyl. The patients received 0.6 mg kg(-1) rocuronium, 0.1 mg kg(-1) vecuronium or 0.1 mg kg(-1) cisatracurium. Anaesthetic maintenance was with sevoflurane in oxygen/nitrous oxide. Neuromuscular-blocking duration of action was defined as the return of T1 twitch height to 25% of control. Variability was determined by subtracting the actual duration of action from the mean duration of action for each drug. RESULTS: The durations of action (range, min) were: cisatracurium, 37-81; vecuronium, 35-137; and rocuronium, 33-119. The median of the variability of duration was significantly less with cisatracurium (7 min) compared to vecuronium (18 min) and rocuronium (18 min) (P < 0.05). CONCLUSION: When used with sevoflurane/N(2)O, there was a two-fold greater variability of duration of neuromuscular blockade in elderly patients receiving rocuronium or vecuronium compared with cisatracurium.     

The mechanism of pancuronium potentiation of mivacurium block: use of the isolated-arm technique

The neuromuscular blocking effects of mivacurium are greatly enhanced when mivacurium is preceded by a subparalyzing dose of pancuronium. The mechanism of this potentiation has not been elucidated. This study investigated the effects of the anticholinesterase activity of a small dose of pancuronium on the neuromuscular blocking effects of mivacurium. Forty patients were enrolled in the study. The neuromuscular effects of 7.5 and 15 microg/kg pancuronium, followed by 50 and 100 microg/kg mivacurium, were assessed in Groups PM1 and PM2 (n = 20), respectively. The neuromuscular effects of 65 and 130 microg/kg mivacurium were assessed in Groups M1 and M2 (n = 20), respectively. One arm was excluded from circulation with a tourniquet, which was inflated before the injection of pancuronium and deflated 3 min after the injection of mivacurium. The plasma cholinesterase activity was measured before induction for all patients and 3 min after the injection of pancuronium for Groups PM1 and PM2. The plasma cholinesterase activity was decreased by 16% and 33% after pancuronium administration in Groups PM1 and PM2, respectively. In the nonexcluded arm, pancuronium significantly potentiated the effects of mivacurium. In the excluded arm, no significant block was detected for Groups M1 and M2, whereas the maximal degree of neuromuscular block was 79% and 100% for Groups PM1 and PM2, respectively. Using the isolated-arm technique, we suggest that pancuronium potentiation of the neuromuscular blocking effects of mivacurium is more likely attributable to an increase in the effective plasma concentration of mivacurium than to occupancy of postsynaptic acetylcholine receptors. Implications: Using the isolated-arm technique, we suggest that pancuronium potentiation of the neuromuscular blocking effects of mivacurium is more likely attributable to an increase in the effective plasma concentration of mivacurium than to occupancy of postsynaptic acetylcholine receptors.     

The potency of new muscle relaxants on recombinant muscle-type acetylcholine receptors

We studied the inhibition of fetal (gamma-nAChR) and adult (epsilon-nAChR) muscle-type nicotinic acetylcholine receptors by the two new nondepolarizing muscle relaxants (NDMRs) rocuronium and rapacuronium, the metabolite 3-desacetyl rapacuronium (Org 9488), and five other, longer-used NDMRs (pancuronium, vecuronium, mivacurium, d-tubocurarine, and gallamine). Receptors were expressed in Xenopus laevis oocytes by cytoplasmic injection of subunit complementary RNAs. Functional channels were activated with 10 microM acetylcholine, alone or in combination with various concentrations of the NDMRs. Currents were recorded with a whole-cell two-electrode voltage clamp technique. All NDMRs reversibly inhibited acetylcholine-activated currents in a dose-dependent fashion. Potencies of rapacuronium and Org 9488 were not statistically different at either gamma-nAChR (half-maximal response = 58.2 and 36.5 nM, respectively) or epsilon-nAChR (half-maximal response = 80.3 and 97.7 nM, respectively). The rank order of potencies at the epsilon-nAChR (pancuronium > vecuronium similar mivacurium > rocuronium similar d-tubocurarine > rapacuronium similar Org 9488 > gallamine) correlated highly with the clinical doses needed to produce 50% twitch depression at the adductor pollicis muscle in adults. Neuromuscular blockade by rapacuronium may be enhanced by its metabolite Org 9488. Different drug-receptor affinities of the tested NDMRs contribute to the differences in clinical dose requirements of these drugs needed to achieve appropriate muscle relaxation. IMPLICATIONS: Potencies of nondepolarizing muscle relaxants, studied at muscle nicotinic acetylcholine receptors expressed in a recombinant expression system, correlate highly with the clinical doses needed in adults to produce 50% twitch depression at the adductor pollicis muscle.     

Do we need muscular blockers in ambulatory anaesthesia?

Since the introduction of the laryngeal mask airway, the majority of day case patients can safely be anaesthetized without the administration of muscle relaxants. If muscle relaxation is required, the modern non-depolarizing agents, vecuronium, rocuronium, atracurium, cisatracurium and mivacurium, provide an excellent choice. Succinylcholine should be regarded mainly as an option in the event of an emergency intubation, especially in paediatric patients.     

Rocuronium and cisatracurium-positive skin tests in non-allergic volunteers: determination of drug concentration thresholds using a dilution titration technique

BACKGROUND: Muscle relaxants are believed to be responsible for 2/3 of the cases of anaphylactic reactions during anesthesia. This assumption is based mainly on positive skin tests obtained in individuals that have experienced anesthesia-related anaphylaxis. A positive skin test is supposed to be associated with mast cell degranulation of vasoactive amines. In the present study we tested the frequency of positive skin tests with two commonly used muscle relaxants, rocuronium and cisatracurium, in a selected group of volunteers with low potential for allergic reactions. METHODS: Thirty healthy volunteers without known allergy or previous exposure to muscle relaxants were studied. Low potential for allergic reactions was determined prior to inclusion in the study, using various allergy tests. Each individual was tested with intradermal and skin prick tests, and molar drug concentration thresholds for positive skin reactions were determined using a dilution titration technique. The presence or absence of mast cell degranulation was tested by electron microscopic investigation of skin biopsies obtained from positive and negative skin reactions. RESULTS: None of the volunteers had a positive skin prick test. More than 90% of the volunteers had a positive intradermal test with both rocuronium and cisatracurium. The highest molar drug concentration that was not associated with a positive intradermal test was 10(-6) M (rocuronium) and 10(-7) M (cisatracurium), equivalent to vial dilution 1 : 1000 for both drugs. In none of the volunteers was mast cell degranulation detected. CONCLUSION: Non-mast-cell-mediated positive intradermal skin reactions are frequently occurring with rocuronium and cisatracurium, even at vial dilution 1 : 1000. A clinically applicable test technique is needed that is able to separate positive skin tests associated with mast cell degranulation from non-mast-cell-mediated reactions.     

Comparative potency of steroidal neuromuscular blocking drugs and isobolographic analysis of the interaction between rocuronium and other aminosteroids

We have determined the relative potency of rocuronium, pancuronium, pipecuronium and vecuronium, and examined the nature of the interaction of rocuronium with the other three steroidal neuromuscular blocking drugs. We studied the dose-response relationships of each drug and their combination with rocuronium in 200 ASA I or II patients during propofol-fentanyl-nitrous oxide-oxygen anaesthesia. Neuromuscular block was recorded as the evoked thenar mechanomyographic response to single twitch stimulation of the ulnar nerve at 10-s intervals. The dose- response curves were determined by probit analysis. Isobolographic and algebraic (fractional) analyses were used to assess the combined effect of equipotent doses of rocuronium and vecuronium, pipecuronium or pancuronium and to define the type of interaction between these drugs. The isobolograms were constructed by plotting single-drug ED50 points on the dose co-ordinates, and a combined ED50 point in the dose field. The calculated doses producing 50% depression (ED50) of the twitch height for rocuronium, pancuronium, pipecuronium and vecuronium were 144.8 (95% confidence intervals 140.4-149.3), 32.4 (31.7-32.9), 27.1 (26.5-27.6) and 23.7 (22.7-24.8) micrograms kg-1, respectively. Corresponding doses producing 95% depression (ED95) of twitch height were, respectively, 322.1 (307.5-337.3), 58.1 (56.2-60.1), 48.7 (46.9- 50.5) and 39.9 (38.4-41.4) micrograms kg-1. Based on the estimate of ED50, the relative potency was 1:4.5:5.4:6, respectively. The interaction between rocuronium and vecuronium, pipecuronium or pancuronium was found to be additive.      

Skin sensitivity to rocuronium and vecuronium: a randomized controlled prick-testing study in healthy volunteers

Prick tests are frequently used for the authentication of neuromuscular blocking drugs (NMBDs) as causative drugs for anaphylactic reactions during anesthesia. Unfortunately, the actual threshold concentration for skin testing remains debatable for most NMBDs. We studied the flare and wheal responses to prick tests with rocuronium and vecuronium. Thirty healthy, nonatopic, anesthesia-naive male and female volunteers (14 men and 16 women) from 18 to 40 yr of age were assigned randomly to receive a total of 10 prick tests-4 ascending dilutions (1:1000, 1:100, 1:10, and 1) of rocuronium and vecuronium and 2 controls-on both forearms. An assessor blinded to the assignment monitored systemic and skin responses to NMBDs and measured wheal and flare surfaces immediately after and 15 min after prick tests. None of the volunteers experienced any immediate systemic or cutaneous responses to rocuronium or vecuronium. Although a dilution of 1:1000 of both NMBDs failed to promote any skin response at 15 min, 50% and 40% of the subjects had a positive skin reaction to undiluted rocuronium and vecuronium, respectively. We demonstrated a sex effect related to smaller threshold concentration-induced cutaneous reactions in female volunteers to both muscle relaxants. Our observation questions the reliability of prick testing with undiluted solutions of rocuronium and vecuronium for the diagnosis of allergy. IMPLICATIONS: Building concentration-skin response curves to prick tests with rocuronium and vecuronium in healthy, nonatopic, anesthesia-naive male and female volunteers demonstrated that the nonreactive concentration for both muscle relaxants is the 1:1000 dilution of the stock solutions. Our observation calls into question the past practice of prick-testing skin for sensitivity to neuromuscular blocking drugs by using undiluted solutions.     

Incidence of residual neuromuscular blockade and use of neuromuscular blocking agents with or without antagonists: A systematic review and meta-analysis of randomized controlled trials

ObjectivesNeuromuscular blocking agents (NMBAs) have revolutionized the field of anesthesiology as they facilitate airway management and ensure optimal surgical conditions. Despite their beneficial and ubiquitous use during surgery, delayed or partial recovery from NMBAs, referred to as residual neuromuscular block (rNMB), is a common clinical problem. While it is well accepted that the antagonist sugammadex, compared to neostigmine, can more rapidly reverse rocuronium-induced NMB regardless of depth of block, the occurrence of rNMB for routinely used combinations of NMBAs with sugammadex or neostigmine has not yet been quantified or evaluated systematically.Review methodsWe conducted a systematic literature review and meta-analysis of randomized controlled trials (RCTs) to quantify and compare the incidence of rNMB [defined as train-of-four ratio (TOFR) <0.9] in patients with moderate and deep neuromuscular block. Methods recommended by Cochrane Collaboration and PRISMA group were followed.ResultsA total of 35 RCTs were identified, of which 20 contributed to the meta-analysis. For moderate block, rNMB incidence at 2 min after sugammadex administration was 19.2% (95% CI 0.0–57.8; 122 patients) and declined to 2.8% (95% CI 0.0–16.7; 93 patients) at 6 min post administration. For timepoints 10 to 60 min after administration, rNMB incidence ranged between 0.05% to 2.8%. In contrast, rNMB incidence at 2 min after neostigmine administration was 100% (95% CI 89.9–100; 182 patients) and was 82% (95% CI 71.4–91.2; 93 patients) at 6 min post administration. For timepoints 10 to 60 min after administration, rNMB incidence ranged between 14 and 32%. For deep block, rNMB incidence following sugammadex was essentially reduced to 1% at 15 min after administration. Residual NMB incidence following neostigmine remained at or above 95% for the first 60 min after administration.ConclusionsOverall, based on evidence from 20 RCTs, our results suggest that the combination of rocuronium or vecuronium plus sugammadex is more effective and more rapid in reversing NMB compared with combinations of rocuronium, vecuronium, cisatracurium, or pancuronium plus neostigmine.