CUMULATION OF NEOMYCIN AND ITS RESIDUAL POTENTIATION OF TUBOCURARINE IN THE CAT

Cumulation and interaction of neuromuscular blocking effectsof neomycin and tubocurarine were determined on responses ofthe tibialis anterior muscle of the anaezthetized cat to indirectstimulation. Neuromuscular block produced by neomycin was cumulativedespite rapid and apparent full recovery of twitch tension andan interval of 3 h between dose-response studies. ED₅₀ of neomycinon twitch tension decreased (P<0.05) from 22±4 mgkg^–1 to 12±3 mg kg^–1 after 3 h; marked post-tetanicexhaustion was observed after the antibiotic. Neuromuscularblock (80–90%) with neomycin 25–30 mg kg^–1followed by full recovery and a 3-h interval decreased (P<0.05)the ED₅₀ of tubocurarine on twitch tension from 0.2±0.02mg kg^–1 to 0.13±0.02 mg kg^–1. Tubocurarineexhibited no cumulative effects at intervals of 2 h and didnot significantly affect the response of twitch and tetanictension to neomycrn after an interval of 2 h. It is concludedthat neomycin increases the sensitivity of neuromuscular transmissionto tubocurarine despite apparently normal responses to indirectstimulation and that the post-tetanic exhaustion observed withneomycin alone may explain apnoea reported in patients withthe antibiotic.     

INFUSION OF ATRACURIUM IN NEONATES, INFANTS AND CHILDREN: A Study of Dose Requirements

The doses of atracurium (by infusion) required to maintain steady-state(90–95%) neuromuscular block were assessed in 75 childrenaged 9 days to 17 yr during balanced anaesthesia. Followingthe intubating dose of atracurium 0.4 mg kg^–1 and afterthe recovery of single twitch to 5–10% of control (monitoredby evoked EMG of hypothenar muscle), an infusion of atracurium0.5 mg kg^–1 h^–1 was started. In 22 of the patientsthis initial rate resulted in the desired steady state; 32 patientsrequired one, and 21 required two or more adjustments in rate.The mean single twitch value at steady-state was 6.6±0.3%(SEM), which is equal to 93% neuromuscular block. The infusionrequirement to maintain the steady state neuromuscular blockin all paediatric patients more than 1 month old was constant(0.53±0.01 mg kg^–1 h^–1). The infusion requirementof neonates up to 1 month old was 25% less (0.40±0.02mg kg^–1 h^–1; P = 0.003). A significant correlation(n = 75, r = 0.76, P < 0.001) was found between the infusionrate (mg m^–2 h^–1) and the logarithm of the bodysurface area.     

Low quantal content of the endplate potential reduces safety factor for neuromuscular transmission in the diaphragm of the newborn rat

We have used phrenic nerve-hemidiaphragm preparations from ratsaged 11–28 days to determine the electrophysiologicalbasis of the three-fold increase in sensitivity of the neonatalneuromuscular junction to non-depolarizing neuromuscular blockingdrugs. The mean resting membrane potential (RMP) of intact musclefibres at 19–21°C increased from –67.1 (SEM0.6) mV at 11 days to –75.8 (0.06) mV at 28 days. Overthe same age range the mean size of miniature endplate potentials(MEPP) decreased from 1.7 (0.1) mV to 1.4 (0.03) mV, and thethreshold depolarization to produce a muscle action potentialincreased from 6.8 (0.4) mV to 9.5 (0.6) mV. The quantal contentof the evoked endplate potential (EPP) calculated from EPP andMEPP measured in cut muscle fibres was only 6.6 (0.9) at 11days, but this increased to 21.1 (2.3) at 21 days. As a resultof the low quantal content of the EPP, the safety factor forneuromuscular transmission was only 1.7 at 11 days, comparedwith 2.8 at 20 days. A safety factor of 1.7 in the youngestrats indicates that block of only about 40% of postjunctionalacetylcholine receptors would result in failure of neuromusculartransmission. Hence, a low quantal content of EPP, leading toa low safety factor for neuromuscular transmission, probablyunderlies the increased sensitivity to non-depolarizing neuromuscularblocking drugs of young rats and, by inference, human neonates.     

INFLUENCE OF SUXAMETHONIUM ON THE POTENCY OF ORG NC 45 IN ANAESTHETIZED PATIENTS

The non-depolarizing neuromuscular block produced by Org NC45was potentiated by the previous administration of suxamethonium1 mg kg^–1, shown by twitch depression of 91.3±2.4%when the same dose of Org NC 45 was administered after recoveryfrom suxamethonium compared with the control value of 71.9±6.5%.The recovery index was also prolonged from 8.1±0.3 to10.4±1.0min after suxamethonium. The dose-response curvesfor Org NC 45 showed a 1.66 potentiation factor for ED₅₀ and1.73 for ED_9.5, caused by the previous administration of suxamethonium.This interaction is likely to occur in the plasma.     

THE NATURE OF GENTAMICIN-INDUCED NEUROMUSCULAR BLOCK

Gentamicin in concentrations of 0.05–0.2 mmol litre^–1blocked neuromuscular transmission in the toad sartorius nerve-musclepreparation by decreasing the release of transmitter. In concentrationsof 0.5–1 mmol litre^–1 it decreased the amplitudeof the miniature end-plate current by a curare-like action,without affecting the mean open channel lifetime. Present address: Division of Anaesthesia and Intensive Care,Prince Henry Hospital, Little Bay, N.S.W. 2036, Australia     

EFFECT OF ARTERIAL HYPOTENSION ON ANAESTHETIC REQUIREMENT IN DOGS

In the dog a reduction of mean arterial pressure to 40–50mm Hg decreased MAC by 20±SEM 4% in the 1st hour. Nofurther change resulted during the ensuing 3 h of hypotension(40–50 mm Hg). Arterial and cerebrospinal fluid lactateand pyruvate concentrations were not affected by hypotension,nor did cerebrospinal fluid pH decrease. In a separate groupof dogs, we reduced arterial pressure to 40–50, 30–40and 20–30 mm Hg successively. MAC decreased concomitantly,being 58±11% of control value at the lowest pressure.MAC increased following the restoration of normal pressure,but hysteresis was evident. In a third group of dogs, arterialpressure was reduced rapidly to 20–30 mm Hg. MAC decreasedto 29±5% of control. This decrease was significantlygreater than that associated with the three-stage reduction.     

PROPOFOL POTENTIATES BOTH PRE- AND POSTSYNAPTIC EFFECTS OF VECURONIUM IN THE RAT HEMIDIAPHRAGM

We have measured twitch tension in response to train-of-fourstimulation in rat isolated phrenic nerve-hemidiaphragm preparations.Propofol inhibited nerve evoked twitch tension, with 50% inhibitionoccurring at 420 (sD 29) nwol litre^–1. Although propofol100 umol litre^–1 by itself had no effect on nerve evokedtwitch tension, it potentiated the neuromuscular blocking effectsof vecuronium. The decrease in train-of-four ratio with vecuroniumwas directly proportional to the degree of twitch inhibition,regardless of whether twitch was depressed by vecuronium aloneor in combination with propofol. The finding that the train-of-fourratio was a function of the degree of block, rather than simplya function of vecuronium concentration, indicates that propofolalso contributed to train-of-four fade and potentiated bothpre- and postsynaptic effects of the neuromuscular blocker.The concentrations of propofol used in this study are much greaterthan human therapeutic blood concentrations, which are typically25–35 jimol litre^–1 (4–6 ug ml^–1) immediatelyafter a bolus dose of 2 mg kg^–1, suggesting that neithermuscle weakness nor potentiation of vecuronium-induced neuromuscularblock should be of concern at propofol concentrations occurringclinically.     

BARORECEPTOR CONTROL OF REGIONAL HAEMODYNAMICS DURING HALOTHANE ANAESTHESIA IN THE DOG

Regional haemodynamic control by the cardiovascular baroreceptorswas examined in dogs anaesthetized with 1+ MAC of halothanein oxygen (1%). The open-loop relationships between carotidsinus pressure (CSP) and regional haemodynamics in the iliac,renal, mesenteric, aortic and coeliac beds were examined beforevagotomy, following vagotomy and following thoracotomy. Aroundthe carotid sinus reflex set point, the ratio of the reflexdecrease in systemic arterial pressure to an increase in CSP(reflex gain) was –0.744±0.089 (mean ±SEM):the latter increased to –1.275 ±0.093 followingvagotomy. Reflex resistance changes were greatest in the renalbed and least in the coeliac bed, reflecting blood flow homeostasiswhich was well preserved in the renal bed but minimal in thecoeliac bed. Thoracotomy in the dogs in which vagotomy had beenperformed resulted in no significant changes in the dependentvariables studied. It is concluded that, in these dogs anaesthetizedwith 1 + MAC of halothane, baroreceptor control of regionalpressure flow relationships is well preserved.     

PHARMACOKINETICS AND PHARMACODYNAMICS OF VERCURONUIUM IN PATIENTS WITH CHOLESTASIS

pharmacokinetics and pharmacodynamics of vecuronium were studiedin nine surgical patients with cholestasis, and in 14 patientswithout hepatic or renal disease. After the administration ofvecuronium 0.2 mg kg^–1 the plasma concentration of vecuroniumand the degree of neuromuscular blockade were measured. Theplasma clearance of vecuronium was decreased significantly (P< 0.01) from 4.30± 1.56 ml min^–1 kg^–1(mean±SD) in normal patients to 2.36± 0.80 mlmin^–1 kg^–1 in patients with cholestasis. The eliminationhalf-life was of 58±22 min in normal patients and wasprolonged to 98±57 min (P < 0.05) in patients withcholestasis. The total apparent volume of distribution was unchangedin patients with cholestasis. A prolonged neuromuscular blockadeinduced by vecuronium was observed in patients with cholestasis:the duration of effect from injection to 75% recovery of thetwitch height was prolonged from 74 ± 19 min in normalpatients to 111 ± 13 min in patients with cholestasis.The plasma concentration corresponding to 50% recovery fromparalysis did not differ significantly between the two groups.Vecuronium has a prolonged effect in patients with cholestasiswhich is caused by a delay in its elimination.     

VARIATION IN THE DISPOSITION OF MORPHINE AFTER I.M. ADMINISTRATION IN SURGICAL PATIENTS

The disposition of morphine when administered by i.m. injectionwas studied in 36 patients receiving morphine as part of premedicationbefore general anaesthesia, and in five patients who receivedmorphine as a postoperative analgesic after median sternotomyfor coronary artery surgery (PCA group). Maximum plasma concentrationof morphine (Cp_max) was 75.3 ± 6.0 (mean±standarderror (SEM)) ng ml^–1 (range 30–160 ng ml(^–1),mean elimination rate constant (k) 4.85 x 10^–3 min^–1and half-life (T₁₂) = 143 min for the preanaesthetic group.The corresponding values for PCA group were Cp_max = 58.0 ±18.0 ng ml^–1 (range 30–130 ng ml^–1), k = 5.63x 10^–3 min^–1 and T₁₂ = 123 min. Analysis of varianceshowed no differences between the groups. Within the preanaestheticgroup, there was a significant difference in k between males(k = 4.01 x 10^–3 min^–1) and females (6.30 x 10^–3min^–1, P<0.01). The corresponding T₁₂ for males was173 min; and 110 min for females. The variation in the dispositionof morphine is thought to be the result of variations in restingmuscle blood flow and inadvertent injection into adipose tissue.There were no significant differences between males and femalesin the preanaesthetic group with respect to age, CP_max timefrom injection to Cp_max.     

EFFECT OF IONIZED CALCIUM ON THE NEUROMUSCULAR BLOCKING ACTIONS OF ATRACURIUM AND VECURONIUM IN THE CAT

We have determined neuromuscular blocking effects of atracuriumand vecuronium at normal, high and low plasma concentrationsof ionized calcium ([Ca²⁺]) in the cat. Twitch responses weremeasured bilaterally in the anterior tibialis muscles, usingintact central innervation in one preparation. Plateaus of highand low [Ca²⁺] were created by infusions of calcium chlorideand citrate, respectively. The interactions with changes in[Ca²⁺] were similar for atracurium and vecuronium, and wereunaffected by central muscle innervation. The median increasein [Ca²⁺] from 1.27 to 1.59 mmol litre-1 shifted the dose-responsecurves of the drugs to the right, increasing ED50 by 7–13%,whereas the decrease to median 0.78 mmol litre^–1 potentiatedthe drugs by a similar order. This indicates a lesser influenceof [Ca²⁺] on the action of neuromuscular blockers than reportedin a previous in vitro study. Even though the interactions werestatistically significant, their moderate magnitude suggestsminor clinical significance.     

ONSET AND RECOVERY OF ATRACURIUM AND SUXSMETHONIUM-INDUCED NEUROMUSCULAR BLOCKADE WITH SIMULTANEOUS TRAIN-OF-FOUR AND SINGLE TWITCH STIMULATION

Single twitch and train-of-four stuimulation were applied at0.08 Hz to each ulnar nerve and the force of contraction ofthe adductor pollicis was recorded during onset of and recoveryfrom neuromuscular blockade by suxamethonium 1mg kg^–1or atracuirm 0.4 mg kg^–1. Times to 90% first twitch blockadeof train-of-four were (mean ± SEM) 0.82 ± 0.08and 1.98 ± 0.18 min for suxmaethonium and atracurium,respectively, compared with times to 90% single twitch blockadeof 1.00±0.07 and 3.35 ± 0.37 min, respectively(p < 0.05 in both cases). Apparent onset time also dependedon how long train-of-four stimulation had been applied beforeinjection of atracurium. The mode of stimulation had littleeffect on time to 10% recovery. The results are consitent withstimulation-induced augmentation in muscle blood flow, whichincreased delivery of the drug to the neuromuscular junction.     

PHARMACOKINETICS OF FENTANYL IN THE ELDERLY

The pharmacokinetics of fentanyl were determined in seven elderly(71–82 yr) and seven younger adults (18–41 yr) anaesthetizedwith thiopentone, nitrous oxide in oxygen and morphine. Fentanylwas administered as a 2-min i.v. infusion at doses of 15 µgkg^–1 for elderly patients and 20 µg kg^–1 forthe younger patients. Plasma samples were obtained for 4 h andfentanyl concentrations determined by radio-immunoassay. Fentanylconcentration, per µg kg^–1 administered, was higherin elderly than in young patients at 2 min (7.73±3.14v. 4.54 ± 1.83 ng ml^–1 (mean±SD), respectively)and at 4 min after the start of infusion (3.26 ± 1.44v. 1.78 ±0.72 ng ml^–1, respectively). Concentrationswere similar at all other sampling times. Pharmacokinetic variableswere determined by non-compartmental techniques. Total plasmaclearance was similar for the two age groups. Volume of distributionat steady-state (VD^ss) was smaller in elderly patients (1.36± 0.44 v. 2.27 ± 0.82 litre kg ^–1). Despiteage-related changes in VD^ss, plasma fentanyl concentrationsfor the two groups were similar throughout the 4-h samplingperiod except immediately following administration. These resultssuggest that, if there are age-related differences in responseto fentanyl, the likely pharmacokinetic explanation is the higherconcentration of fentanyl in the elderly immediately followingits administration.     

RELATIONSHIP BETWEEN DECAY OF PLASMA CONCENTRATION OF FAZADINIUM AND RECOVERY FROM ITS NEUROMUSCULAR BLOCKING EFFECT

The relationship of the time-course of the decay of plasma concentrationof fazadinium and neuromuscular block has been investigatedafter i.v. administration ofO.75mgkg^–1 to six anaesthetizcdpatients. The phar acokinctic of fazadinium were analysed accordingto a two-compartment open model. A significant correlation wasfound between the plasma concentration of fazadinium and thetwitch height (TH) values during recovery from the block (P<0.001). The mean total plasma concentrations for 25,50and75%THrecoverywere: 1.90±0.17; 1.44±0.l8and 1.08±0.l2µgm^–1,respectivcly.Elapsed time between fazadinium administrationand the Th recovery to 50% (0-TH and the recovery period TH_25–75were 47±4mm and 25±2mm, respectively. Plasma logdecay rate of fazadinium during TH_25–75 period (K_{app 25–75})was: 0.0249±0.0032min^–1. Significant correlations(P<0.01) were observed between the elimination rate constant(k₁₀ ) of the pharmacokinetic model, K_{app 25 –75} (P<0.01)and the pharmacodynamic parameters: time interval 0-TH₅₀ andrecovery rate TH _25-73. These results showed that part of theindividual pharmacodynamic variation had its origin in the interindividualpharmacokinenc variation.     

MAGNITUDE, DOSE-REQUIREMENT AND MODE OF DEVELOPMENT OF TACHYPHYLAXIS TO SUXAMETHONIUM IN MAN

Tachyphylaxis to suxamethonium infused at a constant rate wasstudied in 15 surgical patients under enflurane—nitrousoxide—oxygen anaesthesia. The compound electromyographicresponse of the adductor pollicis muscle to stimulation of theulnar nerve was monitored. A short-lasting and a long-lastingnearly steady state were observed in Phase I and in Phase II,respectively, during both of which a constant infusion resultedin a constant block. Tachyphylaxis occurred during the transitionof phases, beginning after infusion of 1.4 ±0.6 (SD)mg kg^–1 of suxamethonium, and 36±14(SD) minutesof exposure. Tachyphylaxis peaked after 2.6±1.3 (SD)mg kg^–1, and 72±38 (SD) minutes of exposure. Themaximum gain in neuromuscular transmission from the initialmaintenance level of block as the result of tachyphylaxis was53±24 (SD) % of the control. The results are thoughtto reconcile previously reported conflicting clinical observationson tachyphylaxis.     

NEUROMUSCULAR AND CARDIOVASCULAR EFFECTS OF DOXACURIUM IN CHILDERN ANAESTHETIZED WITH HALOTHANE

The neuromuscular and cardiovascular effects of doxacurium chloride(BW A938U) were evaluated in 27 children (2–12 yr) anaesthetizedwith 1% halothane and nitrous oxide in oxygen. In nine childrenthe incremental technique was used to establish a cumulativedose-response curve by train-of-four stimulation. The remainingchildren received either 30 or 50 µg kg^–1 of thedrug as a single bolus. The median ED₅₀ and ED ₉₅ of doxacuriumin children were 19 and 32 µg kg^–1, respectively.No clinically significant change in heart rate or arterial pressureoccurred. Following doxacurium 30 µg kg^–1 and 50µg kg^–1, recovery to 25% of control occurred in25 (SEM 6) and 44 (3) min, respectively. The recovery index(25–75% of control) was 27 (2) min. The duration of actionof doxacurium is similar to that of tubocurarine and dimethyl-tubocurarinein children. Compared with adults, children seem to requiremore doxacurium (µg kg^–1) to achieve a comparabledegree of neuromuscular depression, and they recover more rapidly. Presented in part at the American Society of AnesthesiologistsAnnual Meeting, October 1987, and the International AnesthesiaResearch Society Meeting, March 1988.     

PHARMACOKINETICS OF THE INFUSION OF ALFENTANIL IN MAN

The pharmacokinetics of alfentanil under the conditions of anempirically derived 1 -h continuous infusion of 3µg kg^–1min^–1, with a bolus of 80 µg kg^–1, both i.v.,were determined in five patients. The distribution half-life(mean±SD) (7.4±3.1 min), elimination half-life(86.7 ± 15.8 min), apparent volume of distribution, V^area(0.44±0.15 litre kg^–1) and elimination clearance(3.33 ± 0.75 ml kg^–1 min^–1) were nimilarto those previously reported for a single bolus of alfentanil.These values for apparent volume of distribution and clearancecan be used to calculate correct bolus and infusion doses tomaintain any desired steady state plasma concentration usingstandard formulae: for example, to maintain a steady state plasmaconcentration of 400 ng ml^–1, a bolus doseof 176 µgkg^–1 and an infusion of 1.3 µg kg^–1min wouldbe required.     

THE USE OF FAZADINIUM IN CHILDREN: An Electromyographic Study

To evaluate the use fazadinium in children and to compare itwith pancuronium, 64 children aged 6 months to 12 yr receivedfazadinium 0.75, 1.0, 1.25 mg kg^–1 and pancuronium 0.1mg kg^–1 in groups of 16. Neuromuscular transmission wasevaluated electromyographically using train-of-four stimuli.The times to first effect, maximum effect, first sign of recovery,reversal and full recovery after reversal were recorded andneuromuscular transmission was monitored continuously untilcomplete recovery was obtained. Duration of satisfactory clinicalrelaxation and neuromuscular transmission when relaxation becameinadequate were recorded. The speed, duration and depth of effect,and the duration and degree of neuromuscular blockade increasedsignificantly depending on dose. Fazadinium was found to bea potent drug providing satisfactory relaxation in a dose of1.0–1.25 mg kg^–1 for operations of medium to longduration in children under light halothane anaesthesia. Whenrelaxation became inadequate neuromuscular transmission stillshowed marked depression. Duration and degree of blockade offaradinium and pancuronium were not age-dependent. In all groupsthe neuromuscular blockade was reversed easily. Apart from thespeed of onset of action, pancuronium 0.1 mg kg^–1 correspondedto a dose of fazadinium between 1.0 and 1.25 mg kg^–1.Train-of-four ratio was found to be more sensitive than singletwitch as an index of the recovery of transmission during recoveryand in the period after operation. ^*Presented to the VIth European Congress of Anaesthesiology,London, 1982.     

THE NEUROMUSCULAR EFFECTS OF SUXAMETHONIUM IN MAN

The neuromuscular effects of suxamethonium (single dose andcontinuous infusion) were determined in anaesthetized patients.A marked variation in patient response was observed. The blockwas initially depolarizing but with increasing dosage and timebecame desensitizing. Tachyphylaxis was observed with repeateddoses of suxamethonium but not with continuous infusion. Thedepth of anaesthesia was an important factor in determiningthe amount of suxamethonium required to produce satisfactoryoperating conditions. If suxamethonium was infused continuouslyfor no more than 1 hour or infused intermittently for severalhours, recovery was always rapid (3–21 minutes). However,in four of nine patients who received suxamethonium by continuousinfusion for 2 hours recovery required 51–69 minutes.     

DETERMINANTS OF THE REVERSAL TIME OF COMPETITIVE NEUROMUSCULAR BLOCK BY ANTICHOLINESTERASES

We have assessed, in 200 patients, the determinants of the reversaltime of competitive neuromuscular block by anticholinesterasewhen alcuronium and atracurium neuromuscular block were antagonizedby neostigmine 0.04 and 0.08 mg kg^–1 and edrophonium 0.5and 1.0 mg kg^–1. A biexponential relationship was foundbetween the reversal time (time from injection of anticholinesteraseto a train-of-four ratio of 70%) and the degree of neuromuscularblock at reversal (all groups; F ratio, P < 0.05). Reversaltime was determined by two processes: direct antagonism by theanticholinesterase and spontaneous recovery of the neuromuscularblocking agent, with the latter becoming the major determinantat profound levels of neuromuscular block (0–10% of controltwitch height). Neostigmine, in the doses studied, appearedto have a higher "ceiling" of neuromuscular block which it completelyantagonized, although edrophonium had a more rapid onset ofaction. The reversal time for alcuronium became progressivelylonger relative to atracurium as neuromuscular block increasedbecause of the slower spontaneous recovery rate. Avoidance ofprofound neuromuscular block at the completion of surgery isrequired to ensure reliable antagonism of the block within 5–10min by an anticholinesterase. Neostigmine 0.08 mg kg^–1was found to be the most effective agent in antagonizing profoundneuromuscular block.