Pharmacodynamics of mivacurium chloride in 13- to 18-yr-old adolescents with thermal injury.

BACKGROUND: Burned patients demonstrate resistance to the effects of non-depolarizing blocking drugs as a result of acetylcholine receptor changes. They also have decreased activity of plasma cholinesterase (PCHE), which metabolizes mivacurium. We hypothesized that decreased PCHE activity would decrease metabolism of mivacurium, and counteract the receptor-related resistance following burns. METHODS: Thirteen burned patients and six controls, aged 13-18 yr were followed in 27 studies. The burned patients were sub-classified as having 10-30% or >30% body surface area burn and were studied whenever possible at < or =6 days, and at 1-12 weeks after the burn. Mivacurium pharmacodynamics were examined following a bolus (0.15 mg kg(-1)) dose, and during and after a continuous infusion. RESULTS: Following a bolus, the onset time and the maximal effect were similar to controls. Recovery was prolonged in the 10-30% burn group at 1-12 weeks (P<0.008), with a similar trend in the >30% burn group at < or =6 days (P<0.082) compared with controls. The infusion requirements for mivacurium were not increased in the burned groups. The PCHE activity was decreased in all burn groups and was inversely related to recovery following the bolus (r=0.73, P<0.001) and the infusion (r=0.69, P<0.001). CONCLUSION: In contrast to previous studies with non-depolarizers in burned patients, normal mivacurium doses can produce paralysis, at least as rapidly as in controls, but with a possibility of a prolonged recovery from block. The standard dose of mivacurium in the presence of decreased PCHE activity is in effect, a relative overdose that explains the above findings. Mivacurium is an effective drug for use in burns, irrespective of time after, or magnitude of burn injury.

Intramuscular rapacuronium in infants and children: a comparative multicenter study to confirm the efficacy and safety of the age-related tracheal intubating doses of intramuscular rapacuronium (ORG 9487) in two groups of pediatric subjects.

BACKGROUND: This multicenter, assessor, blinded, randomized study was conducted to confirm and extend a pilot study in which intramuscular rapacuronium was given to infants and children to confirm efficacy and to evaluate tracheal intubating conditions. METHODS: Ninety-six pediatric patients were studied in two groups: infants aged 1 to 12 months (n = 46) and children aged 1 to 3 yr (n = 50). Infants received 2.8 mg/kg and children 4.8 mg/kg of intramuscular rapacuronium during 1 minimum alveolar concentration halothane anesthesia. These two groups were studied in three subgroups, depending on the time (1.5, 3, or 4 min) at which tracheal intubation was attempted after the administration of intramuscular rapacuronium into the deltoid muscle. Neuromuscular data collected included onset time, duration of action, and recovery data during train-of-four stimulation at 0.1 Hz. Data were analyzed by the Cochran-Mantel-Haenszel procedure. RESULTS: The tracheal intubating conditions were deemed acceptable in 17, 36, and 64% of infants and 20, 47, and 71% of children at 1.5, 3, or 4 min, respectively. The mean values for % of control twitch height (T1) 2 min after rapacuronium in both groups were similar. The mean (SD) time required to achieve more than or equal to 95% twitch depression in infants was 6.0 (3.7) versus 5.5 (3.8) min in children. CONCLUSIONS: Only 27% of patients achieved clinically acceptable tracheal intubating conditions at 1.5 or 3 min after administration of 2.8 mg/kg and 4.8 mg/kg rapacuronium during 1 minimum alveolar concentration halothane anesthesia. Tracheal intubation conditions at 4 min were acceptable in 69% of subjects. The duration of action of 4.8 mg/kg of rapacuronium in children was longer than 2.8 mg/kg of rapacuronium in infants.

Neuromuscular effects of mivacurium in 2- to 12-yr-old children with burn injury.

BACKGROUND: Burned patients are usually resistant to the neuromuscular effects of nondepolarizing relaxants, mostly because of receptor changes. The magnitude of the resistance is related to burn size and time after burn. Mivacurium is a muscle relaxant, degraded by plasma cholinesterase, whose enzyme activity is decreased in burns. The present study tested the hypothesis that burn-induced depressed plasma cholinesterase activity counteracts the receptor-mediated resistance, resulting in a lack of resistance to mivacurium. METHODS: Burned patients (n = 23), aged 2-12 yr, subclassified into burns of 10-30% or > 30% of body surface, were studied at < or = 6 days and again at 1-12 weeks after burn if possible. Thirteen additional patients served as controls. Neuromuscular variables monitored included onset and recovery following bolus dose, continuous infusion rates required to maintain 95 +/- 4% paralysis, and recovery rates following infusion. RESULTS: The onset times of maximal twitch suppression were not different between burns and controls, but recovery to 25% of baseline twitch height was prolonged in patients with > 30% burn irrespective of time after injury. The continuous infusion rates to maintain twitch suppression at 95 +/- 4% were not different between groups. The recovery indices, including train-of-four to > 75%, 25-75%, or 5-95% in burned patients, were similar or prolonged compared with controls. The prolonged recovery in burned patients was inversely related to plasma cholinesterase activity (R2 = 0.86, r = -0.93, P < 0.001), and the decreased plasma cholinesterase activity was related to burn size and time after burn. CONCLUSIONS: A normal mivacurium dosage (0.2 mg/kg) effects good relaxation conditions in burned patients, with an onset time similar to that in controls. This finding contrasts with the response seen with other nondepolarizing drugs, higher doses of which are required to effect paralysis. The decreased metabolism of mivacurium, resulting from depressed plasma cholinesterase activity, probably counteracts the receptor-mediated potential for resistance. Because succinylcholine is contraindicated in burned patients, larger doses of nondepolarizing agents are advocated to effect rapid onset of paralysis. This generalization does not hold for mivacurium. diatrics; plasma cholinesterase; relaxant resistance; succinylcholine, alternative to.)

Intramuscular rocuronium in infants and children: a multicenter study to evaluate tracheal intubating conditions, onset, and duration of action.

BACKGROUND: This multicenter, assessor-blinded, randomized study was done to confirm and extend a pilot study showing that intramuscular rocuronium can provide adequate tracheal intubating conditions in infants (2.5 min) and children (3 min) during halothane anesthesia. METHODS: Thirty-eight infants (age range, 3-12 months) and 38 children (age range, 1 to 5 yr) classified as American Society of Anesthesiologists physical status 1 and 2 were evaluated at four investigational sites. Anesthesia was maintained with halothane and oxygen (1% end-tidal concentration if <2.5 yr; 0.80% end-tidal concentration if >2.5 yr) for 5 min. One half of the patients received 0.45 mg/kg intravenous rocuronium. The others received 1 mg/kg (infants) or 1.8 mg/kg (children) of intramuscular rocuronium into the deltoid muscle. Intubating conditions and mechanomyographic responses to ulnar nerve stimulation were assessed. RESULTS: The conditions for tracheal intubation at 2.5 and 3 min in infants and children, respectively, were inadequate in a high percentage of patients in the intramuscular group. Nine of 16 infants and 10 of 17 children had adequate or better intubating conditions at 3.5 and 4 min, respectively, after intramuscular rocuronium. Better-than-adequate intubating conditions were achieved in 14 of 15 infants and 16 of 17 children given intravenous rocuronium. Intramuscular rocuronium provided > or =98% blockade in 7.4+/-3.4 min (in infants) and 8+/-6.3 min (in children). Twenty-five percent recovery occurred in 79+/-26 min (in infants) and in 86+/-22 min (in children). CONCLUSIONS: Intramuscular rocuronium, in the doses and conditions tested, does not consistently provide satisfactory tracheal intubating conditions in infants and children and is not an adequate alternative to intramuscular succinylcholine when rapid intubation is necessary.

Prolonged mivacurium infusion in young and elderly adults.

PURPOSE: This study was designed to evaluate pharmacodynamically and pharmacokinetically if the cis-cis isomer of mivacurium contributed to neuromuscular block during prolonged infusions lasting more than four hours in young adult and elderly (> 60 yr) patients. METHODS: The mechanomyogramic neuromuscular response of the adductor pollicis was recorded in 32 adults 18-59 yr. and 19 elderly (> 60 yr.) patients during N2O:O2:opioid anaesthesia. The mivacurium infusion rate was adjusted to maintain single twitch depression at 95 +/- 4% of control. Blood samples were taken every 30 min to determine the plasma concentration of cis-cis isomer of mivacurium. At the end of the surgical procedure, patients were allowed to recover spontaneously to at least 25% of control twitch response. RESULTS: The mean mivacurium infusion requirement to maintain 97 +/- 1 (mean +/- SD)% depression of the twitch response was 6.0 +/- 0.4 micrograms.kg-1.min-1 in young adults, and 4.3 +/- 0.3 micrograms.kg-1.min-1 in elderly patients (P < 0.001). The infusion requirement in patients with low plasma cholinesterase activity was the lowest 2.4 +/- 1.2 micrograms.kg-1.min-1. Plasma cis-cis isomer concentrations reached peak levels within one-two hours and remained relatively constant throughout the duration of infusion even in patients with low cholinesterase activity. There was no relationship between duration of infusion, plasma concentrations of cis-cis isomer and the early recovery indices of mivacurium (up to 25%). Neuromuscular transmission recovered adequately with or without antagonism in all patients. CONCLUSION: When the mivacurium infusion was titrated to maintain 95 +/- 4% twitch depression, the plasma concentration of the cis-cis isomer did not increase during prolonged infusions (four hours) and neuromuscular transmission recovers satisfactorily.

Potentiation of mivacurium by rocuronium is age- and time-dependent: a study in children, adolescents, and young and elderly adults.

Potentiation occurs when the steroidal muscle relaxant, rocuronium, is coadministered with the benzylisoquinolinium relaxant, mivacurium. The effect of time and age on this interaction was evaluated in four predetermined groups: children, adolescents, young adults, and elderly adults (15 per group) by monitoring the ulnar nerve-evoked force of contraction of the adductor pollicis (twitch response). During recovery from paralysis induced by 800 micrograms/kg of rocuronium, an infusion of mivacurium was started and maintained for at least 90 minutes to retain the twitch response at 1% to 9% of baseline tension (95 +/- 4% paralysis). Rocuronium at 600 micrograms/kg induced greater than 95% paralysis in 57 of the 60 patients within 2.2 +/- 0.4 (mean +/- SE) minutes. The period of recovery from rocuronium-induced paralysis to 5% of baseline twitch height was longest in the elderly (30.1 +/- 2.9 minutes) and shortest in the adolescents (16.5 +/- 2.4 minutes). The mivacurium infusion requirements to maintain 95 +/- 4% paralysis was highest in children and progressively increased with time. In young and elderly adults, the infusion rates remained lower than that of children and did not change with time. The incidence of satisfactory spontaneous recovery within 20 minutes (train-of-four ratio > 75%) was the highest in children, followed by adolescents and young adults, and was least in the elderly. The residual neuromuscular effect of rocuronium on the subsequent mivacurium infusion was most pronounced in the elderly, followed by young adults, then adolescents, and was least in children.

Mivacurium in infants and children.

Mivacurium is the only available short-acting nondepolarizing muscle relaxant in clinical use. It is a bis-quaternary benzylisoquinolinium ester hydrolysed by plasma-cholinesterase into inactive compounds. The ED50 and ED95 in children are about 50 micrograms.kg-1 and 90 micrograms.kg-1 respectively. In infants, they have a tendency to be lower. A standard intubating dose of 0.25 mg.kg-1 causes complete neuromuscular depression in 1.5-2 min, recovery to 5% in 6-10 min, and complete recovery in 15-20 min. The recent tendency is to use 0.3 mg.kg-1 to obtain better intubating conditions with slight prolongation of effect. Since the recovery profile of mivacurium is independent of the dose and duration, it is most suitable for administration by continuous infusion. The infusion requirement in children is 10-16 micrograms.kg-1 min-1, which is about twice that of adults. Cutaneous flushes from histamine release are commonly seen with the larger doses of mivacurium; however, the associated hypotensive effects are minimal and counteracted by the tracheal intubation. The duration of action of mivacurium is prolonged in patients with cholinesterase deficiency. Mivacurium's neuromuscular effects can be satisfactorily antagonized by edrophonium or neostigmine.

Efficacy and safety of divided dose administration of mivacurium for a 90-second tracheal intubation.

STUDY OBJECTIVE: To compare the safety and effectiveness of 0.25 mg divided doses of mivacurium chloride to succinylcholine for a 90-second tracheal intubation. DESIGN: Randomized, double-blind, multicenter study in two groups. SETTING: Operating rooms at four university medical centers. PATIENTS: 200 healthy ASA status I and II adult patients scheduled for elective surgery with general anesthesia and endotracheal intubation. INTERVENTIONS: Patients were premedicated with 1 to 2 mg midazolam and 2 micrograms/kg fentanyl. Anesthesia was induced with 2 mg/kg propofol. Group A received 0.25 mg/kg mivacurium given as a divided dose (0.15 mg/kg followed in 30 seconds with 0.1 mg/kg). Group B (control) received 1.5 mg/kg succinylcholine (SCh) preceded two minutes earlier by 50 micrograms/kg d-tubocurarine (dtc). MEASUREMENTS AND MAIN RESULTS: Tracheal intubation grading, train-of-four response of the adductor pollicis, heart rate (HR), and mean arterial blood pressure (MAP) were measured and evaluated. Chi-square analysis was performed for comparison between Group A and Group B with respect to the frequency distribution of intubation using the scores excellent, good, and poor and not possible (combined). Group B had a significantly higher excellent score of intubation than Group A, 84% versus 56% (p < 0.0001). No significant difference was found between the two groups when the scores excellent and good were combined (Fisher's Exact test, p = 0.28). The changes in MAP and HR were similar for the two groups. CONCLUSIONS: When Sch is not desirable, mivacurium 0.25 mg/kg given as a divided dose provides good to excellent intubation conditions 90 seconds after the initial dose without significant changes in MAP or HR. It can be an appropriate alternative for short surgical procedures. It must be emphasized that this conclusion does not apply to rapid-sequence induction-intubation.

The human lumbar endplate. Evidence of changes in biosynthesis and denaturation of the extracellular matrix with growth, maturation, aging, and degeneration.

STUDY DESIGN: The authors measured concentrations of specific molecules reflecting matrix synthesis and degradation in 121 human endplates and correlated them with aging and grade of degeneration. OBJECTIVES: Abnormal endplate development has been implicated in many spinal abnormalities, yet little is known about endplate matrix component turnover. SUMMARY OF BACKGROUND DATA: Techniques are available to perform an in situ investigation of matrix component turnover with aging and degeneration. METHODS: Newly synthesized aggrecan and Type I and Type II procollagens were measured with recently developed immunoassays. Percentage of denatured Type II collagen was assessed with a new enzyme-linked immunosorbent inhibition assay. RESULTS: Synthesis in endplates, measured by content of an aggrecan marker (846) and content of Types I and II procollagen markers (CPI and CPII), is highest in the neonatal and 2- to 5-year age groups and steadily diminishes with increasing age. However, in the oldest age group and in highly degenerated discs, the CPI epitope level increased significantly. Percentage of denatured Type II collagen, assessed by the presence of an epitope exposed with the cleavage of Type II collagen, increased from the neonatal to the 2- to 5-year age groups. The percentage progressively decreased with increasing age. However, it significantly increased in endplates from highly degenerated discs. CONCLUSIONS: The authors identified three matrix turnover phases, related to age and grade of degeneration. Phase I (growth) is characterized by active synthesis of matrix molecules and active denaturation of Type II collagen. Phase II (aging and maturation) is distinguished by a drop in synthetic activity and a reduction in denaturation of Type II collagen. Phase III (degenerative) is illustrated by an increase in Type II collagen denaturation and Type I procollagen synthesis, both related to grade of tissue degeneration.

Pseudocholinesterase-mediated hydrolysis is superior to neostigmine for reversal of mivacurium-induced paralysis in vitro.

BACKGROUND: The metabolic hydrolysis of mivacurium (and succinylcholine) is markedly impaired in the presence of hereditary or acquired defects of pseudocholinesterase. Clinical reports are conflicting as to the utility of anticholinesterases, in the reversal of mivacurium paralysis. In the current study, the role of exogenous cholinesterases and/or of anticholinesterase, neostigmine, in the reversal of deep mivacurium-induced paralysis, was studied. The rat phrenic-diaphragm preparation, in a fixed volume of Krebs solution, was chosen to eliminate the confounding effects on the dissipation of neuromuscular effects caused by hydrolysis, elimination, and redistribution of the drug. METHODS: In the phrenic-diaphragm preparation, mivacurium was administered to obtain >90% single twitch inhibition. Single twitch responses (0.1 Hz) were monitored for 60 min, after which the response to train-of-four stimulation was tested. The reversal of mivacurium by 0.5, 1.0, or 2.0 units/ml of (true) acetylcholinesterase, bovine pseudocholinesterase, or human plasma cholinesterase and by neostigmine, 0.1, 1.0, or 10.0 micrograms/ml tested. The efficacy of human plasma cholinesterase, 1 unit/ml in combination with each of the above neostigmine concentrations, also was examined. The reversal of succinylcholine-induced paralysis by the acetylcholinesterase, bovine pseudocholinesterase, or human plasma cholinesterase (1 unit/ml) alone and in the presence of neostigmine (10.0 micrograms/ml) was additionally tested as a positive control. A train-of-four ratio > 0.75 was considered adequate reversal. RESULTS: Acetylcholinesterase was a poor hydrolyzer of mivacurium, as bioassayed by reversal of paralysis. Bovine pseudocholinesterase in concentrations of 0.5 and 1.0 units/ml did not effectively reverse single twitch and train-of-four responses by 60 min, but bovine pseudocholinesterase (2 units/ml) and all concentrations of human plasma cholinesterase did. Neostigmine alone, tested at all concentrations, was an incomplete reversal drug. Clinical or therapeutic concentrations (0.1 and 1.0 micrograms/ml) of neostigmine did not, but pharmacologic concentrations (10 micrograms/ml) interfere with the efficacy of human plasma cholinesterase (1 unit/ml). Bovine pseudocholinesterase and human plasma cholinesterase equally reversed the effects of succinylcholine but acetylcholinesterase did not, whereas the addition of 10 micrograms/ml neostigmine to the enzymes inhibited the reversal of succinylcholine. CONCLUSIONS: Human plasma cholinesterase will reverse mivacurium more effectively than bovine pseudocholinesterase, but both will effectively reverse succinylcholine. Acetylcholinesterase has no effects on either relaxant. The anticholinesterase neostigmine was an incomplete reversal drug. Pharmacologic concentrations of anticholinesterases do, while clinical or therapeutic concentrations do not, completely inhibit the metabolic activity of pseudocholinesterases.

Comparison of neuromuscular, cardiovascular, and histamine-releasing properties of doxacurium and pipecuronium.

STUDY OBJECTIVES: To determine the neuromuscular, cardiovascular, and histamine releasing properties of doxacurium and pipecuronium at three times effective ED95 doses (3XFD95). DESIGN: Prospective, randomized clinical trial of adult patients. SETTING: University teaching hospital. PATIENTS: 20 ASA status I and II adult patients. INTERVENTIONS: Subjects were anesthetized with thiopental sodium, fentanyl, and nitrous oxide and oxygen (N2O:O2). Plasma samples were taken preoperatively, after thiopental, and 2 and 5 minutes after doxacurium 75 micrograms/kg or pipecuronium 123 micrograms/kg were given for the determination of histamine levels. The ulnar nerve was stimulated via surface electrodes using train-of-four stimulation at 0.1 Hz. The force of contraction of adductor pollicis was recorded using a mechanomyograph. Recovery of the twitch response was followed and, if necessary, neuromuscular block was antagonized with neostigmine and glycopyrrolate. MEASUREMENTS AND MAIN RESULTS: Three patients in the doxacurrium group and one patient in the pipecuronium group exhibited a marked increase in plasma histamine levels. In both groups statistically significant changes were seen in heart rate (HR) measurements (p < 0.02). Doxacurium had a slower onset than pipecuronium [3.1 +/- 0.2 min vs. 1.8 +/- 0.1 min (p < 0.0003)] and a more rapid recovery [72 +/- 8 min vs. 123 +/- 9 min (p < 0.01)]. CONCLUSION: Neither drug caused a clinically significant change in HR or histamine release. In the doses chosen for this study, the rate of onset of block is slower with doxacurium while recovery is more rapid. Histamine release in three patients was caused by thiopental, while in a fourth patient it may have been due to doxacurium.

The influence of the age of the rat on the neuromuscular response to mivacurium in vitro.

The effective concentrations of mivacurium induced neuromuscular block were studied in the phrenic nerve-hemidiaphragm preparations of forty male Sprague-Dawley rats in four groups according to body weight, 10 g, 25 g, 100 g, and 200 g. Mivacurium was added to the Krebs' solution to obtain an initial concentration of 0.275 microgram.ml-1 (2.5 x 10(-7) mole.litre-1). Thereafter, the concentration of mivacurium was increased in increments to obtain more than 90% neuromuscular twitch inhibition at 0.1 Hz. Data were analysed by probit and logistic models. The two statistical techniques yielded very similar results, almost identical values of EC50 and EC95. There were significant decreases in the effective concentrations of mivacurium needed to depress the twitch response in neonatal rats (10 g) compared to older rats. No significant differences were observed between 25, 100 and 200 g rats. We conclude that the neonatal neuromuscular junctions of rats show increased sensitivity to mivacurium related to pharmacodynamic factors.

The use of the laryngeal mask airway in children with bronchopulmonary dysplasia.

Airway maintenance with the laryngeal mask airway (LMA) was evaluated and compared to the endotracheal (ET) tube in 27 former premature infants and children with bronchopulmonary dysplasia (BPD) during second stage open-sky vitrectomy. The children were randomly assigned to a study group and anesthetized with halothane in N2O:O2. The airway was maintained with the LMA (n = 13) or the ET tube (n = 14). Respiratory and hemodynamic variables were recorded. Intraoperative and postoperative complications were noted. The respiratory rate and the end-tidal CO2 were significantly higher in the LMA group as compared with the ET tube group (P < 0.01); however, the pulse rate and both systolic and diastolic blood pressures throughout the surgical procedure were lower in the LMA group (P < 0.05). The incidence of coughing, with and without desaturation, wheezing, and hoarseness in the postoperative period was higher in the ET tube group. Awakening, after discontinuation of the anesthetic (P < 0.01) was more rapid, and home discharge time (P < 0.002) was shorter in the LMA group (P < 0.0025), although our study design could not isolate the use of the LMA as the factor responsible for this. This study in patients with mild chronic lung disease demonstrated that the LMA can maintain a satisfactory airway during minor surgical procedures in children with bronchopulmonary dysplasia and result in fewer respiratory adverse effects than with the ET tube.