Dose-response calculations revisited.
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Biomedical subjects
Publications and source records attributed to B W Brandom.
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Children with cerebral palsy may be resistant to paralysis induced by nondepolarizing neuromuscular blocking drugs. Potency of a bolus of succinylcholine in children with cerebral palsy has not been studied previously. Therefore, we measured the response of the adductor pollicis to succinylcholine in children with cerebral palsy anesthetized with propofol and nitrous oxide. Forty children between the ages of 2 and 10.2 yr with spastic quadriplegic cerebral palsy were randomly assigned to receive 100, 175, 250, or 375 micrograms/kg of succinylcholine during anesthesia with propofol and nitrous oxide. The ulnar nerve was stimulated with a train-of-four supramaximal stimulus every 10 s and the compound electromyogram of the adductor pollicis recorded by a Datex NMT monitor. Plasma cholinesterase activity was measured in all patients with three different substrates (propionylthiocholine, benzoylcholine, and succinylcholine). Dibucaine number was also determined using inhibition of benzoylcholine degradation. ED50 of succinylcholine was 146.8 micrograms/kg with 95% confidence intervals of 111.4-193.7 micrograms/kg. ED95 of succinylcholine was 360.5 micrograms with 95% confidence intervals of 273.3-475.5 micrograms/kg. We conclude that children with cerebral palsy are slightly sensitive to succinylcholine, but probably not sufficiently to be clinically important.
Synergism exists between some combinations of nondepolarizing muscle relaxants. To test the possibility of synergism between mivacurium and atracurium or vecuronium, 60 children anesthetized with propofol-alfentanil-N2O-O2 were randomized to one of five groups. Three groups of 10 patients each received an ED50 dose of a parent drug atracurium (A), vecuronium (V), or mivacurium (M), respectively, and two other groups of 15 patients each received a single-dose combination of atracurium with mivacurium (cAM) or vecuronium with mivacurium (cVM). Dose combinations constituted 0.5 times an ED50 dose of each drug. Neuromuscular response was monitored by adductor pollicis electromyogram (EMG). Maximum neuromuscular block (NMB) established by a single parent drug did not differ between the groups or from 50% NMB. It averaged 5.03 +/- 0.12 probits (51.2% NMB). On the contrary, maximum NMB established by the two-dose combinations, cAM or cVM, was significantly more than NMB produced by either single parent drug of the particular combination (cAM vs A or M; P = 0.0035, and cVM vs V or M; P = 0.0004) without a statistically significant difference between groups cAM and cVM. Maximum NMB established by combinations averaged 6.15 +/- 0.21 probits (87.5% NMB). The onset of maximum NMB for mivacurium was significantly faster compared to that for atracurium or for vecuronium (2.8 +/- 0.3 vs 5.7 +/- 0.4 or 4.0 +/- 0.3 min, respectively; P = 0.0001). Our results indicate that both drug combinations are synergistic even though only vecuronium is markedly different in its molecular structure from mivacurium.
In 30 children under balanced anaesthesia, we have determined dose-response curves and maintenance requirement of three dose ratio combinations of atracurium and vecuronium (10:1, 4:1 or 1.6:1 on a microgram:microgram basis). Neuromuscular block was monitored by adductor pollicis EMG. An equipotent dose ratio (4:1) was most potent, with a mean (SEM) ED95 of atracurium 95 (6) micrograms kg-1 with vecuronium 24 (1) micrograms kg-1. The sum of these doses is only 58% of an ED95 value of one agent (P = 0.0001). The hourly requirement to maintain a 90-95% neuromuscular block was 2.0 (0.1) times an individual ED95 dose of any combination. Recovery index was 8.9 (0.5) min. These results indicate that a combination of atracurium and vecuronium is supra-additive compared with the effects of each drug alone. However, all combinations maintained an intermediate character of neuromuscular block. Combining atracurium with vecuronium may reduce drug requirement by 40%.
The goal of this study was to describe a technique which could shorten the time from mivacurium administration to peak neuromuscular block (NMB) after administration of the maximum recommended dose of mivacurium. Forty-eight pediatric patients were randomized into three groups and studied during nitrous oxide-alfentanil-thiopental anesthesia. Every patient received two blinded injections 3 min apart: either 15 micrograms/kg of pancuronium in 1 mL of saline followed by 170 or 200 micrograms/kg of mivacurium or saline followed by 200 micrograms/kg of mivacurium. Intravenous induction of anesthesia followed the first injection. Thenar electromyogram response to supramaximum train-of-four stimulation of the ulnar nerve at 10-s intervals was used for neuromuscular monitoring. Pretreatment with pancuronium significantly shortened the time to NMB and prolonged spontaneous recovery from NMB in comparison to the temporal course of NMB after administration of 200 micrograms/kg of mivacurium. Time from injection to 90% NMB averaged 116 (SEM 11) s after administration of 200 micrograms/kg of mivacurium, and 71 (7) s and 94 (11) s when 200 micrograms/kg or 170 micrograms/kg of mivacurium, respectively, was preceded by pancuronium (P = 0.0095). Mean times from injection to recovery of neuromuscular function to > 25% of baseline (T25) and to train-of-four ratio of 0.75 were 9.1 (0.7) and 15.8 (1.2) min, respectively, after administration of 200 micrograms/kg of mivacurium alone. T25 and train-of-four of 0.75 occurred significantly later at 21.9 (1.8) and 35.0 (2.8) min, respectively (P = 0.0001), when 200 micrograms/kg of mivacurium was preceded by 15 micrograms/kg of pancuronium.(ABSTRACT TRUNCATED AT 250 WORDS)
We determined the dose-response relationship of mivacurium in infants 2-6 and 7-11 mo of age during nitrous oxide-halothane anesthesia. The neuromuscular and cardiovascular effects of a bolus dose of mivacurium larger than the ED95 in infants and young children from 2-23 mo of age were observed. The infusion rate of mivacurium required to maintain approximately 95% neuromuscular block was determined. There was no significant difference between the estimated dose-response relationship in infants 2-6 mo and that in infants 7-11 mo. The ED50 and ED95 were 44 micrograms/kg and 85 micrograms/kg for infants 2-11 mo (n = 70), r = 0.53. A bolus dose of 150 micrograms/kg mivacurium in infants (2-6 mo) produced 100% depression of the initial twitch height (T1) in 8 out of 9 infants and 85% depression in 1 infant. The time to onset of maximum block was 1.6 +/- 0.3 (0.7-2.7) (mean, SEM [range]) min, and time to recovery to 25% of T1 (T25) was 7.5 +/- 0.7 (5.5-11) min after 150 micrograms/kg in these patients. A bolus dose of 200 micrograms/kg mivacurium in infants and young children (7-23 mo) produced 100% depression of T1 in 14 of 17 patients, 97% depression in 2, and 90% depression in 1. The time to onset of maximum block was 1.5 +/- 0.1 (0.8-3) min and T25 was 10.3 +/- 1.5 (4.8-30.5) min after 200 micrograms/kg in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)
It has been claimed that the combination of halothane and succinylcholine, commonly used for anesthetic induction during short pediatric otolaryngologic procedures, is associated with a 1% incidence of masseter spasm (MS) which may be an early sign of malignant hyperthermia (MH). An 18-month retrospective chart review of all patients undergoing general anesthesia at the Children's Hospital of Pittsburgh (n = 14, 112) was conducted to assess the incidence of MS and its management. In addition, a separate subgroup of patients identified as being at risk for MH was also evaluated. In the otolaryngology service, the incidence of developing MS was 2 of 206 (1%) in children who were anesthetized with halothane and received succinylcholine, patients were identified in the MH high-risk group, and none developed MH. The findings affirmed the risks of using this combination of anesthetic and neuromuscular blocking agents during induction and the need for establishing management guidelines.
ORG-9426 is a new steroidal nondepolarizing neuromuscular blocking drug. We determined the dose-response relationship of ORG-9426 in 62 children (aged 1-5 yr) during nitrous oxide-halothane anesthesia by means of log-probit transformation and least-squares linear regression of the initial dose and response. Twelve additional patients received a bolus of 600 micrograms/kg (2 X the dose estimated to produce 95% depression of neuromuscular function [ED95]) of ORG-9426. Neuromuscular blockade was monitored by recording the electromyographic activity of the adductor pollicis muscle resulting from supramaximal stimulation of the ulnar nerve at 2 Hz for 2 s at 10-s intervals. To determine the dose-response relationship, patients randomly received initial bolus doses of 120 (n = 15), 160 (n = 16), 200 (n = 16), or 240 (n = 15) micrograms/kg ORG-9426. The resulting dose estimated to produce 50% depression of neuromuscular function (ED50) and ED95 were 179 and 303 micrograms/kg, respectively. Time from administration of 600 micrograms/kg to onset of 90% and 100% neuromuscular block was 0.8 +/- 0.1 (0.5-1.3) and 1.3 +/- 0.2 (0.7-2.8) min. The time to recovery of neuromuscular transmission to 25% (T25) was 26.7 +/- 1.9 (17.2-39.0) min. The recovery index (T25-75) was 11.0 +/- 1.6 (6.0-22.8) min, and the time to complete recovery of the magnitude of the fourth response to a train-of-four stimuli divided by the magnitude of the first response (T4/T1) greater than or equal to 0.75 was 41.9 +/- 3.2 (26.5-57.7) min.(ABSTRACT TRUNCATED AT 250 WORDS)
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We were interested in determining the infusion rate of vecuronium required to maintain approximately 95% neuromuscular blockade in children during halothane-narcotic-nitrous oxide (0.8% end-tidal concentration), isoflurane-narcotic-nitrous oxide (1.0% end-tidal concentration), or narcotic-nitrous oxide anesthesia. Neuromuscular blockade was monitored by recording the electromyographic activity (Datex NMT) of the adductor pollicis muscle resulting from supramaximal stimulation of the ulnar nerve at 2 Hz for 2 s at 10-s intervals. Effective vecuronium infusion requirements averaged 1.5 +/- 0.1 micrograms.kg-1.min-1 (mean +/- SEM) during isoflurane-narcotic-nitrous oxide anesthesia, 1.9 +/- 0.1 micrograms.kg-1.min-1 during halothane-narcotic-nitrous oxide anesthesia, and 2.4 +/- 0.3 micrograms.kg-1.min-1 during narcotic-nitrous oxide anesthesia. Infusion requirements significantly decreased after the first 30 min of infusion in the presence of both potent inhalation anesthetics, but did not change with time during narcotic-nitrous oxide anesthesia. There was no evidence of decreasing infusion requirements during prolonged vecuronium infusion (2.5 h). There was no difference in the rate of spontaneous or pharmacologically induced recovery between anesthetic groups. The mean recovery index (T25-75) after termination of the infusion was 13.7 min.
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The effects of bolus administration of large doses of vecuronium on the onset and duration of neuromuscular blockade and histamine release were studied during fentanyl-nitrous oxide anesthesia. Forty adults were randomly assigned to receive a bolus injection of either 0.1, 0.2, 0.3, or 0.4 mg/kg of vecuronium. The evoked electromyogram of thumb adduction to train-of-four stimulation was monitored. The time of onset and clinical duration (mean +/- SEM) after each dose were as follows: 0.1 mg/kg, 164 +/- 27 s and 42 +/- 5 min; 0.2 mg/kg, 120 +/- 17 s and 68 +/- 8 min; 0.3 mg/kg, 88 +/- 17 s and 111 +/- 19 min; 0.4 mg/kg, 78 +/- 19 s and 115 +/- 19 min. Both time of onset and duration after doses of 0.3 or 0.4 mg/kg were significantly different from values after the lower doses. No dose-related changes in blood pressure, heart rate, or histamine release were observed. The authors conclude that large bolus doses of vecuronium can be safely used to speed the onset of blockade, but with a significantly prolonged duration of action.
Most studies of the effects of inhalation anesthetics on somatosensory evoked potentials (SSEPs) have examined SSEP at single times after initiation of an anesthetic. This study describes SSEP changes as functions of time of exposure to isoflurane. Both transient and sustained SSEP changes were observed. Nonlinear regression was used to fit exponential terms to the trend curves for end-tidal anesthetic concentration and SSEP peak latency. End-tidal concentrations could be well described by two exponential terms, one with a long and one with a short time constant. Isoflurane at 1% inspired concentration produced a sustained SSEP latency change that could be fit by a single exponential term; the time constant was essentially identical to the long time constant of end-tidal concentration. The long time constants ranged from 7 to 33 min. At 0.5% isoflurane, SSEP changes were often small or not sustained, and the changes could not always be well described by an exponential curve. These data suggest that the time-course of anesthetic effects on SSEPs may be prolonged and complex, and the possibility of changes over time should be considered both in experimental studies and during intra-operative monitoring.
We were interested in determining the infusion rate of mivacurium required to maintain approximately 95% neuromuscular blockade during nitrous oxide-halothane (0.8% end-tidal) or nitrous oxide-narcotic anesthesia. Neuromuscular blockade was monitored by recording the electromyographic activity (Datex NMT) of the adductor pollicis muscle resulting from supramaximal stimulation of the ulnar nerve at 2 Hz for 2 s at 10-s intervals. Mivacurium steady-state infusion requirements averaged 315 +/- 26 micrograms.m-2.min-1 during nitrous oxide-halothane anesthesia and 375 +/- 19 micrograms.m-2.min-1 (mean +/- SEM) during nitrous oxide-narcotic anesthesia. Higher levels of pseudocholinesterase activity were generally associated with a higher mivacurium infusion requirement. During both anesthetics, younger age was associated with a higher infusion requirement when the infusion requirement was calculated in terms of micrograms.kg-1.min-1. This difference was not present when the infusion rate was calculated in terms of micrograms.m-2.m-1. There was no evidence of cumulation during prolonged mivacurium infusion. There was no difference in the rates of spontaneous or reversal-mediated recovery between anesthetic groups. After the termination of the infusion, spontaneous recovery to T4/T1 greater than or equal to 0.75 occurred in 9.8 +/- 0.4 min, with a recovery index, T25-75, of 4.0 +/- 0.2 min (mean +/- SEM). In summary, pseudocholinesterase activity is the major factor influencing mivacurium infusion rate in children during nitrous oxide-narcotic or nitrous oxide-halothane (0.8% end-tidal) anesthesia.
We determined the cumulative dose-response relations of pipecuronium in infants and children during nitrous oxidehalothane anesthesia. Neuromuscular blockade was monitored by recording the electromyographic activity of the adductor pollicis muscle resulting from supramaximal stimulation of the ulnar nerve at 2 Hz for 2 s at 10-s intervals. Patients were stratified into four groups according to age: 3 mo or older but not yet 6 mo (n = 10), 6 mo or older but not yet 12 mo (n = 10), 1 yr or older but not yet 3 yr (n = 10), and 3 yr or older but not yet 6 yr (n = 9). The mean ED50 of pipecuronium in these age groups was 18, 20, 21, and 24 micrograms/kg, respectively; the mean ED95 was 33, 38, 47, and 49 micrograms/kg, respectively. The ED95 of pipecuronium was statistically significantly less for the 3-6-mo-old patients than for children between 1 and 6 yr of age. Similarly, pipecuronium dosage requirements calculated on the basis of body surface area were significantly less in infants 3-12 mo of age than in children 1-6 yr of age. Thus, compared with children, infants appear to be more sensitive to the neuromuscular blocking effects of pipecuronium. Duration (T25) of action after cumulative dosing with pipecuronium was approximately 20 min in infants and 30 min in children. Spontaneous recovery indices were not prolonged in the younger patients. The average T25-75 recovery index was 27.1 +/- 9.6 min. There were no changes in cardiac rhythm, heart rate, or blood pressure attributable to pipecuronium during this study.
Mivacurium chloride is a new, short-acting nondepolarizing neuromuscular blocking agent presently undergoing clinical evaluation. The neuromuscular effects of mivacurium and suxamethonium given by bolus and infusion were compared in adult patients during nitrous oxide-oxygen-opioid anaesthesia. Neuromuscular block was monitored by recording the compound electromyogram of the adductor pollicis muscle resulting from supramaximal train-of-four stimuli applied to the ulnar nerve. Time to onset of complete block and recovery to T5 were significantly shorter for suxamethonium than for mivacurium (1.0 (0.1) v. 2.5 (0.3) min and 6.4 (0.7) v. 17.5 (1.8) min; mean (SEM]. Conditions for tracheal intubation were similar in the two groups although intubation was performed 0.75-1.3 min later following mivacurium. The infusion rate required to maintain neuromuscular block was 88.6 (10.4) micrograms kg-1 min-1 for suxamethonium and 7.8 (1.2) micrograms kg-1 min-1 for mivacurium. There was a significant negative correlation between recovery to T5 and infusion rate for mivacurium and for suxamethonium. It was equally easy to titrate the infusion rate to the desired degree of block in each group. The recovery index (T25-T75) after the infusion stopped was similar in patients who received mivacurium and those who received suxamethonium.
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