Time course of action of sugammadex (Org 25969) on rocuronium-induced block in the Rhesus monkey, using a simple model of equilibration of complex formation.

BACKGROUND: Reversal of neuromuscular block can be accomplished by chemical encapsulation of rocuronium by sugammadex (Org 25969), a synthetic gamma-cyclodextrin derivative. The present study determined the time course of the reversal action of sugammadex on rocuronium-induced block in the anaesthetized Rhesus monkey using train-of-four stimulation. METHODS: A bolus injection of rocuronium 100 microg kg(-1) (about 1xED(90)) was given to determine the degree of neuromuscular block reached by this dose. After complete spontaneous recovery, a rapid bolus injection of sugammadex, 1 mg kg(-1), was given and at different time intervals (15, 30 or 60 min, in three different experiments) the effect of another rocuronium bolus injection of 100 microg kg(-1) was determined. RESULTS: Injection of the first dose of rocuronium resulted in a mean neuromuscular block (depression of first twitch) of 93 (SEM=1.6)%. Fifteen minutes after injection of sugammadex the same rocuronium dose resulted in 17% (SEM=5.6) block. After 30 and 60 min these maximum blocks amounted to 49% (SEM=7.6) and 79% (SEM=4.2), respectively. The estimated half-life of sugammadex in Rhesus monkey is 30 (SEM=4.9) min. CONCLUSIONS: The half-life of sugammadex (Org 25969), a new fast and efficient reversal agent for rocuronium-induced block, is relatively short in the Rhesus monkey, implying the possibility to perform neuromuscular block by rocuronium shortly after reversal of a prior block. In translation to the human situation differences in rocuronium sensitivity and kinetics should be taken into account.

Chemical encapsulation of rocuronium by synthetic cyclodextrin derivatives: reversal of neuromuscular block in anaesthetized Rhesus monkeys.

BACKGROUND: At present, reversal of neuromuscular block induced by steroidal neuromuscular blocking agents (NMBAs) is achieved by administration of cholinesterase inhibitors. Chemical encapsulation of steroidal NMBAs, such as rocuronium, by a cyclodextrin is a new concept in neuromuscular block reversal. The present study evaluates the capacity of nine synthetic cyclodextrin derivatives (Org 25288, Org 25289, Org 25467, Org 25168, Org 25169, Org 25555, Org 25166, Org 26142, and Org 25969) to reverse constant neuromuscular block of approximately 90%, induced by rocuronium infusion in the Rhesus monkey, using single twitch stimulation. The ability of these cyclodextrin derivatives to reverse neuromuscular block was compared with the reversal of the same neuromuscular block by the commonly used combination of neostigmine and atropine. METHODS: After a bolus injection of rocuronium, continuous infusion was started to reduce twitch contractions to approximately 10% of baseline values. After a steady state block of at least 10 min the infusion was stopped and the preparation was allowed to recover spontaneously. This process was repeated, but at the time the infusion was stopped, either one of the nine cyclodextrin derivatives or a combination of neostigmine and atropine was given. RESULTS: Recovery with cyclodextrin derivatives Org 26142 and Org 25969 was faster than after a combination of neostigmine and atropine (P<0.05). Injection of these cyclodextrin derivatives did not affect blood pressure or heart rate. Signs of residual block or recurarization were not observed in any of these experiments. In the experiments in which a combination of neostigmine and atropine was given, two animals showed signs of abdominal discomfort as frequently seen after the administration of neostigmine and significant changes in circulatory variables. CONCLUSIONS: Chemical encapsulation or chelation of rocuronium is a new concept in reversing neuromuscular block induced by rocuronium.

Effect of isoflurane and sevoflurane on the magnitude and time course of neuromuscular block produced by vecuronium, pancuronium and atracurium.

We have compared the ability of equipotent concentrations of isoflurane and sevoflurane to enhance the effect of non-depolarizing neuromuscular blocking drugs. Ninety ASA I and II patients of both sexes, aged 18-50 yr, were stratified into three blocker groups (Vec, Pan and Atr), to undergo neuromuscular block with vecuronium (n = 30), pancuronium (n = 30) or atracurium (n = 30), respectively. Within each group, patients were allocated randomly to one of three anaesthetic subgroups to undergo maintenance of anaesthesia with: (1) alfentanil-nitrous oxide-oxygen (n = 10); (2) alfentanil-nitrous oxide-oxygen-isoflurane (n = 10); or (3) alfentanil-nitrous oxide-oxygen-sevoflurane (n = 10) anaesthesia. During maintenance of anaesthesia, end-tidal concentrations of isoflurane, sevoflurane and nitrous oxide were 0.95, 1.70 and 70%, respectively. Both the evoked integrated electromyogram and mechanomyogram of the adductor pollicis brevis muscle were measured simultaneously. In the Vec and Pan groups, a total dose of 40 micrograms kg-1 of vecuronium or pancuronium, respectively, was given, and in the Atr group a total dose of atracurium 100 micrograms kg-1. Each blocker was given in four equal doses and administered cumulatively. We showed that 0.95% isoflurane and 1.70% sevoflurane (corresponding to 0.8 MAC of each inhalation anaesthetic, omitting the MAC contribution of nitrous oxide) augmented and prolonged the neuromuscular block produced by vecuronium, pancuronium and atracurium to a similar degree.

Effects of acupuncture and transcutaneous stimulation analgesia on plasma hormone levels during and after major abdominal surgery.

The effects of acupuncture and transcutaneous electrical stimulation (TES) on plasma adrenaline (A) and noradrenaline (NA), adrenocorticotropic hormone (ACTH), beta-endorphin (beta E), anti-diuretic hormone (ADH) and hydrocortisone (cortisol) were evaluated during and, for four days after surgery in 42 male patients submitted to a standardized major abdominal operation in a comparative study of three different anaesthetic techniques. Group 1 received acupuncture and transcutaneous stimulation as the main non-pharmacological analgesic during surgery. Group 2 received moderate-dose fentanyl (initial bolus of 10 micrograms kg-1 followed by continuous infusion of 5 micrograms kg-1 h-1 for the first hour, and then 4 micrograms kg-1 h-1. Group 3 received a combination of both methods. In all three groups analgesia was supplemented, if necessary, by small bolus injections of 50 micrograms fentanyl. Anaesthesia was induced in all groups with thiopentone 5 mg kg-1 and vecuronium 0.1 mg kg-1 and patients were ventilated (N2O:O2 = 2:1) to achieve normocapnia without the use of a halogenated agent. Pre-operatively acupuncture plus TES in Groups 1 and 3 led to a rise in beta E (P < 0.05) without changes of haemodynamics. After intubation beta E did not increase further. Intubation in Group 2 led to an increase of beta E (P < 0.05) also, and to a rise in pulse rate and blood pressure (P < 0.05) in all three groups. Per-operatively acupuncture plus TES in Group 1 showed a response of circulating NA and cortisol similar to that in Groups 2 and 3, whereas the responses of the circulating A, ACTH, beta E and ADH in Group 1 were more pronounced (P < 0.01). Post-operatively no differences in the hormonal profiles could be discerned between the groups with or without acupuncture plus TES (Group 2 vs. Group 3) nor between those with or without moderate-dose fentanyl anaesthesia (Group 1 vs. Group 3). It is concluded that acupuncture and TES have no effect on the cardiovascular response to laryngoscopy and intubation. They can replace moderate-dose fentanyl anaesthesia in major abdominal surgery at the cost of a more enhanced per-operative neuroendocrine stress response, which does not, however, influence the postoperative hormonal profiles nor the rapidity of return to pre-operative values.

Acupuncture and transcutaneous stimulation analgesia in comparison with moderate-dose fentanyl anaesthesia in major surgery. Clinical efficacy and influence on recovery and morbidity.

The efficacy of acupuncture and transcutaneous stimulation analgesia, supplemented by small doses of fentanyl (mean 1.2 micrograms/kg, SD 1.7) was compared with moderate-dose fentanyl anaesthesia (mean 22.9 micrograms/kg, SD 2.8) in 29 patients who underwent surgery for retroperitoneal lymph node dissection. The present study describes the anaesthetic techniques and comparison of haemodynamics, demand for analgesics after surgery, recovery and blood gases, restoration of urinary and bowel functions, convalescence in terms of self-reliance and the postoperative course in respect of fatigue and morbidity. A more rapid return of consciousness, an absence of hypercapnia and a smaller decrease in pH were observed in patients who received acupuncture and transcutaneous stimulation (p less than 0.05). No clinically relevant disadvantages attributable to the method were demonstrated.

Lack of influence of acupuncture and transcutaneous stimulation on the immunoglobulin levels and leucocyte counts following upper-abdominal surgery.

The changes in immunoglobulins (IgA, IgG and IgM) and total and differential leucocyte counts in the peripheral blood during, and for 6 days after, surgery were evaluated in 29 male patients submitted to standardized upper-abdominal surgery performed under two different anaesthetic techniques. Group 1 received stimulation of ear and paravertebral points, supplemented by small doses of fentanyl (mean 1.2 micrograms kg-1, range 0.0-5.7) and Group 2 received moderate-dose fentanyl (mean 22.9 micrograms kg-1, range: 17.5-29.8). All were induced with thiopentone 5 mg kg-1, intubated after vecuronium 0.1 mg kg-1 and ventilated with 67% nitrous oxide in oxygen. Inhalation anaesthesia was not used. Surgery was followed by a fall in immunoglobulins, lymphocyte and eosinophil counts and a rise in leucocyte and neutrophil counts in both groups (P less than 0.01). No recovery was observed until the last assessment on Day 6 after surgery in IgA, IgG, leucocyte, neutrophil and lymphocyte counts in both groups, whereas IgM and eosinophil counts recovered by Day 4. Monocyte and basophil counts were unchanged in either group. Acupuncture and transcutaneous stimulation analgesia performed for major abdominal surgery did not influence the body's immune system either during or after surgery as measured by the concentrations of immunoglobulin and total and differential WBC counts.

The patterns of stress response in patients undergoing thyroid surgery under acupuncture anaesthesia in China.

The patterns of catecholamines (adrenaline and noradrenaline), peptide hormones (adrenocorticotropic hormone, antidiuretic hormone, beta-endorphin, growth hormone and prolactin), hydrocortisone (cortisol) and those of immunoglobulins (IgA, IgG and IgM) and total and differential leucocyte counts in the peripheral blood were investigated during and for 6 days after thyroid surgery in 20 patients (F/M: 18/2) performed under acupuncture anaesthesia, supplemented by small doses of pethidine (mean: 45.0 mg, s.d. 8.9). Throughout surgery the patients remained conscious. During surgery a significant increase in the level of catecholamines and the above-mentioned circulating hormones and a decrease of immunoglobulins were observed, whereas the leucocyte and differential counts demonstrated leucocytosis due to lymphocytosis, a decreased percentage of eosinophils and a remarkably reduced percentage of neutrophils. In the postoperative phase, levels of noradrenaline and beta-endorphin remained elevated, whereas the other circulating hormones gradually returned to normal values. Immunoglobulin levels and eosinophil counts returned to the preinduction values within 24 h, and those of neutrophil and lymphocyte counts within 2 days. Changes in number of monocytes and basophils could not be detected peri- and postoperatively.

Acupuncture anaesthesia. Observations on its use for removal of thyroid adenomata and influence on recovery and morbidity in a Chinese hospital.

Acupuncture anaesthesia, supplemented by small doses of pethidine, was evaluated in 20 patients who had surgery for removal of a thyroid adenoma. There were significant increases in mean arterial pressure and respiratory rate during surgery, but no significant change in heart rate. The mean dose of pethidine given during surgery was 45 mg (SD 8.9). Postoperative recovery was rapid and complication free. Acupuncture anaesthesia did not provide complete analgesia, but was safe and preferable to general anaesthesia where there was a shortage of facilities.

Effects of two benzodiazepines and a benzodiazepine antagonist on neuromuscular blockade in the anaesthetized cat.

The interaction of diazepam and midazolam with non-depolarizing neuromuscular blocking drugs was studied in the sciatic nerve-tibialis anterior muscle preparation of the anaesthetized cat. Both diazepam and midazolam (0.3 mg/kg i.v.) caused a significant enhancement of a constant 50% neuromuscular block, produced by infusions of vecuronium or pancuronium. Increasing the dose of midazolam from 0.3 to 1.5 mg/kg, caused no significant further potentiation of vecuronium, but decreased the onset time of potentiation. Ro 15-1788, a selective benzodiazepine antagonist, did not antagonize the vecuronium potentiation caused by midazolam 0.3 mg/kg. However, when given before midazolam (1.5 mg/kg), Ro 15-1788 delayed the onset of potentiation. Ro 15-1788 antagonized and prevented the considerable blood pressure decrease produced by midazolam 0.3 and 1.5 mg/kg. There appears to exist a ceiling to the benzodiazepine-induced blood pressure decrease and potentiation of vecuronium in the cat.

Pharmacodynamics of vecuronium, atracurium, tubocurarine and their combinations in the rat in vivo.

In the in vivo rat sciatic nerve tibialis muscle preparation the potency and pharmacodynamics of vecuronium, atracurium, pancuronium, tubocurarine and their combinations were studied. Considering the potency only, there was no beneficial difference between the pure compounds and their combinations. As both vecuronium and atracurium are almost free from side-effects individually, a combination of the two relaxants brings no advantage.

Lack of effects of emulsified propofol ('Diprivan') on vecuronium pharmacodynamics--preliminary results in man.

The possible interaction between vecuronium and propofol or thiopentone has been investigated. Cumulative dose response curves for vecuronium and the pharmacodynamic variables measured were similar with both anaesthetic agents. Patients were intubated following the topical application of lignocaine to the larynx and before the administration of vecuronium. A greater degree of relaxation of the vocal cords was noted in patients anaesthetized with propofol.

In vitro interaction of diazepam and oxazepam with pancuronium and suxamethonium.

In vitro studies using the rat phrenic nerve-hemidiaphragm preparation were performed to investigate the effects of diazepam and three of its metabolites on indirectly evoked twitch tension. Diazepam, desmethyldiazepam and temazepam alone caused an increase in twitch tension in lower concentrations, followed by complete depression in higher concentrations. Oxazepam did not cause an initial increase in twitch tension, but showed an immediate and dose-dependent depression. Cumulative concentration-response curves for pancuronium and suxamethonium in the presence of different concentrations of diazepam or oxazepam showed that small concentrations of diazepam, which did not change twitch tension alone, caused antagonism of the action of pancuronium, but not of suxamethonium. With oxazepam no such antagonism was observed. In liminal and supraliminal concentrations, both diazepam and oxazepam potentiated the action of pancuronium and suxamethonium. Possible implications for in vivo interactions are discussed.

Some effects of diisopropyl phenol (ICI 35 868) on the pharmacodynamics of atracurium and vecuronium in anaesthetized man.

The effects of a bolus injection of diisopropyl phenol 2 mg kg-1 i.v. and an infusion (150 micrograms kg-1 min-1 for 30 min and 75 micrograms kg-1 min-1 thereafter) on the pharmacodynamics and dose-response curves of atracurium and vecuronium were studied in 52 healthy (ASA I or II) patients. Under anaesthesia with diisopropyl phenol, the cumulative dose-response curves of both myoneural blocking drugs were shifted to the left when compared with previously reported results. However, there was no clinically significant change in the pharmacodynamics of either drug after the bolus injection of the blocking drug. Diisopropyl phenol 2 mg kg-1 i.v. administered during steady-state infusions of vecuronium and atracurium increased the depth of the constant neuromuscular blockade. When diisopropyl phenol alone was given to four patients there was no change in the twitch height. These results show that diisopropyl phenol, given according to the regimen in this study, potentiates both of the neuromuscular blockers studied but does not prolong the duration of action of either drug. During the infusion of diisopropyl phenol, vecuronium was found to be five times more potent, to have a more rapid onset time, and to be shorter acting than an equipotent dose of atracurium.