DOSE-RESPONSE RELATIONSHIPS FOR NEOSTIGMINE ANTAGONISM OF VECURONIUM-INDUCED NEUROMUSCULAR BLOCK IN ADULTS AND THE ELDERLY

We have studied the dose-response relationship for neostigminein 36 adult (ages 18-50 yr) and 36 elderly (ages > 70 yr)subjects during antagonism of neuromuscular block induced byvecuronium. All patients received vecuronium 0.08 mg kg^–1and neuromuscular block was monitoredmechanomyo-graphicallyusing the train-of-four (TOF) mode of stimulation. Six patientsof each age group were allocated randomly to receive neostigmine5, 15, 25, 35 or 45 µg kg^–1 or saline at 10% recoveryof T1 (first response in the TOF). TOF ratios were recordedcontinuously over the next 10 min and the values at 1-min intervalsfrom 5 min onwards were used to construct the dose-responserelationships. There was a significant difference (P < 0,05)in the time to spontaneous recovery of T1 to 10% between theadults (24 (SD 5.5) min) and the elderly (33 (7.8) min). Dose-responsecurves for neostigmine were parallel in the two age groups,but those for the. elderly were significantly to the right ofthe curves for the adults. This sggests an apparently lesserrelative potency of neostigmine, or the requirement of a largerdose, in the elderly for attaining antagonism of a moderatelyintense vecuronium block at the same time as in adults.     

NEOSTIGMINE AND EDROPHONIUM ANTAGONISM OF MODERATE NEUROMUSCULAR BLOCK INDUCED BY PANCURONIUM OR TUBOCURARINE

Edrophonium and neostigmine are anticholin-esterase drugs usedcommonly to antagonize competitive neuromuscular block. Althoughit has a faster onset of action than neostigmine, edrophoniumis unreliable when used to antagonize deep neuromuscular block.We have compared the antagonist characteristics of these twodrugs when used to antagonize a moderate degree of pancuronium-or tubocurarine-induced neuromuscular block. Forty ASA I orII patients undergoing surgical procedures were allocated randomlyto receive either pancuronium 70 kg^-1 or tubo-curarine 0.5 mgkg^-1, and to receive either edrophonium 0.5 mg kg^-1 or neostigmine0.05 mg kgr^-1. Antagonism was attempted when the first responseto train-of-four (TOF) stimulation recovered spontaneously to25% of the control height. Neuromuscular function was monitoredusing the evoked integrated electromyogram of the first dorsalinterosseous muscle of the hand. Adequate recovery was definedas the achievement of a TOF ratio of 0.70 or greater. Only sevenof 20 patients who received edrophonium demonstrated adequaterecovery 30 min after antagonism. Under the conditions describedin this study, edrophonium 0.5 mg kg7 was less effective asan antagonist than neostigmine 0.05 mg kg^-1. (Br. J. Anaesth.1993; 70: 160–162)     

ANTAGONISM OF ATRACURIUM-INDUCED NEUROMUSCULAR BLOCKADE BY NEOSTIGMINE OR EDROPHONIUM

Antagonism of atracurium-induced neuromuscular blockade by neostigmineor edrophonium has been studied using the tetanic (50 Hz) andtrain-of-four (2 Hz) or single twitch responses of the adductorpollicis muscle in 22 anaesthetized patients. A further ninepatients not given an anticholinesterase acted as a controlgroup. In two groups (six patients for each anticholinesterase)in whom antagonism was attempted at 95–98% blockade ofthe tetanic response, recovery of the tetanic response aftertwo or three doses of edrophonium 0.75 mg kg^–1 i.v. wasnot statistically different from that in the control group;recovery after two doses of neostigmine 2.5 mg i.v. was significantlyfaster (P < 0.001). Recovery of the single twitch responseafter antagonism with edrophonium, although longer than thatwith neostigmine (P < 0.01), was significantly shorter thanin the control group (P < 0.05). When edrophonium is givenat the commencement of recovery, the initial rapid antagonismof tetanic block is not sustained, whereas antagonism by neostigmineis more persistent and the recovery phase is significantly shortened.In a further two groups of patients (n = 5) given atracurium0.3 mg kg^–1 i.v. antagonism was not attempted until thepeak height of the tetanic contraction had reached approximately50% of the control value. It was found that recovery of thetetanic and train-of-four responses was significantly faster(P < 0.05–0.001) after antagonism with edrophonium0.75 mg kg^–1 i.v. than with neostigmine 2.5mg i.v. (approx.0.04 mg kg^–1). The train-of-four response recovered moreslowly than did the tetanic response after both agents (P <0.05–0.01). Department of Anaesthetics, University College Hospital, LondonWC1. ^*Clinical Investigation Department, Clinical and Applied researchDivision, The Wellcome Research Laboratories, Beckenham, Kent.     

ANTAGONISM OF VERCURONIUM-INDUCED NEUROMUSCULAR BLOCKADE WITH EDROPHONIUM OR NEOSTIGMINE

Antagonism of vecuronium-induced neuromuscular blockade wasattempted, at varying degrees of spontaneous recovery, withedrophonium 0.5 mg kg ^–1 or neostigmine 0.05 mg kg^–1in two groups of 20 patients. Neuromuscular blockade was monitoredusing a train-of-four (TOF) stimulation. Adequate antagonismof neuromuscular blockade, defined as a sustained TOF ratioof 0.7 or more, was attained in all 20 patients given neostigmineand in 13 out of 20 given edrophonium. Five of the remainingseven patients given edrophonium had shown three or less responsesto TOF stimulation before antagonism. While the time to onsetof the action of edrophonium (22 s) was not significantly shorterthan neostigmine (26 s), the time taken to attain a TOF ratioof 0.7 was significantly shorter with edrophonium (67 s comparedwith 194 s with neostigmine). It is concluded that edrophonium0.5 mg kg^–1 does not consistently antagonize vecuronium-inducedneuromusocular blockade, particularly if there are three orless responses to a TOF stimulation present before antagonism.     

EFFECT OF DOXAPRAM ON NEOSTIGMINE EVOKED ANTAGONISM OF VECURONIUM NEUROMUSCULAR BLOCK

We have examined the effect of doxapram on neostigmine-evokedantagonism of vecuronium neuromuscular block in a double-blindstudy in anaesthetized patients. Neuromuscular transmissionwas measured with a Datex Relaxograph. The mean time to recoveryof the first contraction of the train-of-four (T1) from 25%to 75% was significantly longer in the presence of doxapram(138 (SEM 21) s; n = 23) than in its absence (95 (13) s; n =29) (P = 0.014). The recovery of the train-of-four ratio wasprolonged also in the presence of doxapram, although this differencewas not statistically significant.     

CLEARANCE OF NEOSTIGMINE FROM THE CIRCULATION DURING THE ANTAGONISM OF NEUROMUSCULAR BLOCK

The plasma concentration of neostigmine was measured in fivepatients during the antagonism of neuromuscular block. The concentrationof the drug decreased rapidly between 2 and 5 min after administration,and then more slowly. Detectable concentrations of neostigminewere present in plasma after 60 min. In the five patients thedistribution half-life of neostigmine was less than 1 min; theelimination half-life ranged from 15.4 to 30.1 min.     

ANTAGONISM OF MODERATE DEGREES OF VECURONIUM-INDUCED NEUROMUSCULAR BLOCK BY SMALL DOSES OF NEOSTIGMINE

We have studied the influence of a reduced dose of neostigmineon recovery from vecuroniuminduced neuromuscular block in 26adult patients, using electromyographic responses to train-of-four(TOF) stimulation. Neostigmine 10, 20 or 40 µg kg^–1was administered when the first response had recovered spontaneouslyto 5–10% or 40–50% of control. Antagonism was acceptedas adequate when the first response reached 90% of control andthe TOF ratio reached 0.7. At both degrees of spontaneous recovery,neostigmine 40 µg kg^–1 evoked the most rapid antagonism.Clinical recovery was satisfactory with no differences betweengroups. Block produced by neostigmine was not observed. Thepattern of recovery of the single response and the TOF ratiowas not altered by neostigmine in the range of doses studied.We suggest that the dose of neostigmine should not be reducedbelow 40 µ kg^–1, even when all responses of theTOF are present. ^* present address: Royal Perth Hospital, Western Australia     

ACID-BASE BALANCE AND NEOSTIGMINE ANTAGONISM OF PANCURONIUM NEUROMUSCULAR BLOCKADE

In 40 cats anaesthetized with chloralose and urethane, pancuroniumwas infused i.v. at a constant rate to produce and maintain90% depression of twitch tension of the anterior tibialis musclefollowing supramaximal stimulation of the peroneal nerve. Neitherrespiratory alkalosis nor metabolic acidosis influenced theinfusion rate required to produce 90% depression of twitch tensionor antagonism of this depression by neostigmine. Respiratoryacidosis (pH 7.15; Pa_CO2, 10 kPa) did not alter the requiredinfusion rate but did prevent complete antagonism by neostigmine.Metabolic alkalosis (pH 7.65; Pa^CO2, 4.8 kPa) reduced both therequired infusion rate and prevented complete restoration oftwitch tension by neostigmine. The duration of neostigmine antagonismwas shortened by metabolic alkalosis. We conclude that respiratoryacidosis and metabolic alkalosis prevent antagonism of pancuroniumby neostigmine.     

ELECTRICAL AND MECHANICAL RESPONSES AFTER NEUROMUSCULAR BLOCKADE WITH VECURONIUM, AND SUBSEQUENT ANTAGONISM WITH NEOSTIGMINE OR EDROPHONIUM

Six unpremedicated patients who had given their informed consentwere given vecuronium 0.08 mg kg^–1 before elective surgery.Recovery from neuromuscular blockade was measured electricallyand mechanically. Neuromuscular blockade was antagonized 1 hafter the administration of vecuronium with two doses of neostigmine2.5 mg (three patients) or edrophonium 0.5 mg kg^–1 (threepatients). Although the onset of initial recovery was similar,subsequent recovery was faster when meassured electrically (EMG)than when measured mechanically. Recovery appeared to be fasterin younger patients. Reintroduction of neuromuscular blockadeoccurred after the second dose of neostigmine 2.5 mg, givento antagonize the block. This did not occur after either doseof edrophonium 0.5 mg kg^–1. ^*University College and Middlesex Hospitals, Mortimer Street,London W1 7PN. Department of Anesthesiology, U.C.L.A. Medical School, Los Angeles,U.S.A.     

RECOVERY CHARACTERISTICS FOLLOWING ANTAGONISM OF ATRACURIUM WITH NEOSTIGMINE OR EDROPHONIUM

The evoked reversal characteristics of atracurium were studiedin 21 patients using edrophonium or neostigmine and a train-of-fourpattern of stimulation. Reversal of residual atracurium-inducedneuromuscular blockade was significantly more rapid using edrophoniumcompared with neostigmine. The ratio of the fourth twitch inthe train-of-four to the first twitch—the T₄ ratio—wassignificantly greater when the first twitch (T₁) had recoveredto 75% of control T₁, using edrophonium compared with neostigmine.A T₄ ratio of 0.5 was confirmed to be compatible with the reliableand safe reversal of atracurium-induced neuromuscular blockade.     

BRADYCARDIA DURING ANTAGONISM OF PANCURONIUM-INDUCED NEUROMUSCULAR BLOCK

Heart rate was compared in matched patients during antagonismof neuromuscular block induced by tubocurarine, pancuroniumor alcuronium with neostigmine 0.03 mg kg^–1 preceded byatropine 0.015 mg kg^–1. The frequency of bradycardia wasgreater during antagonism of pancuronium compared with alcuronium.Although there was a difference between the group receivingpancuronium and that receiving tubocurarine, it was not statisticallysignificant. The decrease in heart rate was more rapid and profoundin the pancuronium group; seven of the 15 patients who receivedpancuronium required an additional dose of atropine as comparedwith only one patient who received tubocurarine. However, thedifference in heart rate between those who received pancuroniumand those receiving tubocurarine was short-lasting, whereasthe heart rate of those who received alcuronium was higher thanthat in the other groups during the entire 60-min period ofobservation. The findings with pancuronium may be a result ofits inhibitory effect on serum cholinesterase.     

ANTAGONISM OF VECURONIUM AND ATRACURIUM: COMPARISON OF NEOSTIGMINE AND EDROPHONIUM ADMINISTERED AT 5% TWITCH HEIGHT RECOVERY

In 39 healthy patients antagonism, by neostig-mine 0.07 mg kg^–1or edrophonium 0.8 mg kg^–1, of neuromuscular blockadeinduced by vecuronium or atracurium, was compared. Reversalwas attempted when the height of the single twitch (TH) hadrecovered spontaneously to 5% of the control value. The evokedresponses, initially single twitch, then train-of-four (TOF)were observed until the TOF ratio was 70%. Induced recoveryfrom TH 5% to 25% was shorter following edrophonium than followingneostigmine with both vecuronium (P < 0.05) and atracurium(P < 0.05). The recovery indices and times until TH was 75%of control and until the TOF ratio was 70% were not different.The time from a TH of 75% to a TOF ratio of 70% was shorterfollowing neostigmine than following edrophonium with both vecuronium(P < 0.01) and atracurium (P < 0.01). Edrophonium hada much more variable effect on vecuronium than on atracurium.These results show that although the onset of action of edrophoniumwas faster than that of neostigmine, this did not lead to afaster clinical recovery, and antagonism by edrophonium maybe delayed in a number of patients if vecuronium is the neuromuscularblocker.     

DOSE-RESPONSE RELATIONSHIPS AND NEUROMUSCULAR BLOCKING EFFECTS OF VECURONIUM AND PANCURONIUM DURING KETAMINE ANAESTHESIA

The dose-response curves of vecuronium and pancuronium werecompared during ketamine anaesthesia in 60 patients (ASA I).The relationship between the probit transformed depression oftwitch height and the logarithm of the dose was analysed by1ink regression. Vecuronium was found to be 1.2 times more potentthan pancuronium. ED₅₀ of vecuronium and pancuronium were 30.5µg kg^–1 and 37.0 µg kg^–1, and the ED₉₅45.6 µg kg^–1 and 59.5 µg kg^–1, respectively.Using equipment doses of vecuronium and pancuronium (1.6ED₉₅)indices of neuromuscular blockade were compared in a further20 patients (ASAI). No statistically signifimnt difference wasfound in onset time. The duration of action following vecuroniumwas significantly shorter than after pancuronium. The time to25% recovery of twitch height following vecuronium 73 µgkg^–1 was 22.2 min compared with 66.6 min following pancuronium99 µg kg^–1. Following supplementary doses of vecuronium,a statistically significant increase in duration of action wasseen following the fourth and fifth doses. Reversal timr ofvecuronium to a train-of-four ratio of 0.7 was significantlyshorter than that of pancuronium (8.3 min and 13.6 min, respectively)     

DIURETIC-INDUCED HYPOKALAEMIA, PANCURONIUM NEUROMUSCULAR BLOCKADE AND ITS ANTAGONISM BY NEOSTIGMINE

The effect of hypokalaemia on a neuromuscular blockade inducedby pancuronium and its antagonism by neostigmine was studiedin the cat anterior tibialis-peroneal nerve preparation usingthe constant infusion of pancuronium technique. Hypokalaemiawas induced by chronic administration of chlorothiazide. Theinfusion rate of pancuronium required to maintain a 90% depressionof twitch tension was reduced from 0.72 ±0.06 µgkg^–1 min^–1 in the cats with a normal serum concentrationof potassium (K⁺ = 4.4±0.2 mmol litre^–1; n = 7)to 0.41±0.07 µg kg^–1 min^–1 in the hypokalaemiccats (K⁺ = 2.3±0.1 mmol litre^–1; n = 8). The doseof neostigmine necessary for 50% antagonism of the pancuronium-induceddepression of twitch tension (ED₅₀) was 10.0 µg kg^–1in the cats with a normal potassium concentration and 18.5 µgkg^–1 in hypokalaemic cats. We conclude that hypokalaemiadecreases the dose of pancuronium required for neuromuscularblockade and increases the dose of neostigmine required forantagonism of the block.     

ANTAGONISM OF NEUROMUSCULAR BLOCK BY PHYSOSTIGMINE IN MAN

In 20 adult patients undergoing inguinal herniorhaphy neuromuscularblock was induced with tubocurarine 10 mg. In 10 patient, neostigmine1–2 mg antagonized the block and restored the twitch responseto its baseline value. Physostigmine, up to 4 mg, did not producesignificant antagonism of the neuromuscular block.     

ANTAGONISM OF INTENSE ATRACURIUM-INDUCED NEUROMUSCULAR BLOCK IN CHILDREN

Antagonism of intense neuromuscular block induced by atracurium0.5 mg kg^–1 was attempted in four groups of six childrenusing one of two doses of neostigmine (0.05 mg kg^–1 and0.1 mg kg^–1) or of edrophonium (0.5 mg kg^–1 and1.0 mg kg^–1) when the first twitch of the post-tetaniccount (PTC1) was 10% of control. For comparison with normalpractice, a fifth group received neostigmine 0.05 mg kg^–1when the first twitch of the train-of-four was 10% of control.Total recovery time from PTC1 10% to a train-of-four ratio of0.8 was not reduced by early administration of the anticholinesterases,compared with conventional administration of neostigmine atT1 10%. However, recovery from intense block was faster afterneostigmine than edrophonium (P < 0.01). Doubling the dosesof the anticholinesterases did not reduce the recovery timeand had the effect of increasing variability. We conclude thatthere is no clinical advantage in attempting to antagonize intenseneuromuscular block in children using normal or increased dosesof neostigmine or edrophonium.     

ANTAGONISM OF ORG NC45 (VECURONIUM) AND PANCURONIUM NEUROMUSCULAR BLOCKADE BY NEOSTIGMINE

The antagonism, by neosngmine, of neuromuscular blockade producedby either Org NC45 or pancurorium was studied in 29 anaesthetizedpatients during a continuous infusion of the myoneural blockerThe ED₅₀ of neostigmine (dose which produced a 50% antagonism)when antagonizing Org NC45 and pancuronium was 0.01 lmg kg^–1and 0.011mgkg^–1 respectively. The dose-response relationshipsfor the antagonism of Org NC 45 and pancuronium neuromuscularblockades were not significantly different. The duration ofthe effect of neostigmine was not different when antagonizingan Org NC45- or pancurornium-induced blockade We concluded thatOrg NC45 and pancuronium are effectively and equally (independentof their pharmacokinetics) antagonized by neostigmine in man.     

GLYCOPYRROLATE--NEOSTIGMINE MIXTURE FOR ANTAGONISM OF NEUROMUSCULAR BLOCK: COMPARISON WITH ATROPINE--NEOSTIGMINE MIXTURE

Glycopyrrolate, a new anticholinergic agent, was evaluated andcompared with atropine. Glycopyrrolate 0.2 mg to neostigmine1.0 mg was found to be safe and effective. The heart rates remainedmore stable with glycopyrrolate, and the frequency of arrhythmia,which was both transient and of no consequence, was similarin the two groups. The antisialogogue action of glycopyrrolatewas superior to that of atropine.     

COMPARISON OF ATROPINE AND GLYCOPYRROLATE IN A MIXTURE WITH PYRIDOSTIGMINE FOR THE ANTAGONISM OF NEUROMUSCULAR BLOCK

Neuromuscular block was antagonized using pyridostigmine 250µg kg^–1 in two groups of 50 patients; one groupreceived atropine 20µg kg^–1 and the other glycopyrrolate10 µg kg^–1 with the anticholinesterase drug. Atropinewas associated with a greater initial tachycardia than was glycopyrroUte.The subsequent bradycardia was also greater in this group, althoughthe decreases in heart rate were smaller than those generallyobserved following mixtures of atropine and neostigmine. Arrhythmiaswere transient and required no treatment in either group. Bettercontrol of secretions was achieved with glycopyrrolate.