Investigation of potential neuropharmacological activity of neostigmine-glycopyrrolate for intraoperative neural monitoring in thyroid surgery.

Intraoperative neuromonitoring (IONM) is frequently used in thyroid surgery to reduce recurrent laryngeal nerve injury. The use of neuromuscular blockade agent to facilitate tracheal intubation, is a common cause of IONM failure. We performed a retrospective analysis to assess the efficacy of neostigmine-glycopyrrolate as a neuromuscular blockade reversal agent for IONM during thyroid surgery. Rocuronium (0.6 mg/kg) was administered for muscle relaxation. Neostigmine (2 mg) and glycopyrrolate (0.4 mg) were administered immediately after intubation. Cricothyroid muscle-twitch response upon external branch of superior laryngeal nerve stimulation and electromyography amplitudes of vagal and recurrent laryngeal nerves before (V1, R1) and after thyroid resection (V2, R2) were recorded. Fifty patients (23 males, 27 females) were included in the analysis. The diagnoses comprised 43 papillary thyroid carcinomas and seven benign diseases. The mean time between rocuronium injection and neostigmine-glycopyrrolate injection was 5.1 ± 1.2 min, and the mean time from neostigmine-glycopyrrolate injection to successful cricothyroid muscle twitching upon external branch of superior laryngeal nerve stimulation was 21.0 ± 4.5 min. All patients had V1 and R1 amplitudes of more than 500 µV each, with mean V1 and R1 amplitudes of 985.3 ± 471.6 µV and 1177.2 ± 572.7 µV, respectively. Neostigmine-glycopyrrolate was effectively used as a neuromuscular blockade reversal agent for IONM in thyroid surgeries without a significant increase in bucking events. Administration of neostigmine-glycopyrrolate immediately after intubation can be recommended for successful NMB reversal to facilitate IONM during thyroid surgery.

Incidence, risk factors, and consequences of residual neuromuscular block in the United States: The prospective, observational, multicenter RECITE-US study.

STUDY OBJECTIVE: To determine the incidence burden and associated risk factors of residual neuromuscular block (rNMB) during routine U.S. hospital care. DESIGN: Blinded multicenter cohort study. SETTING: Operating and recovery rooms of ten community and academic U.S. hospitals. PATIENTS: Two-hundred fifty-five adults, ASA PS 1-3, underwent elective abdominal surgery with general anesthesia and ≥1 dose of non-depolarizing neuromuscular blocking agent (NMBA) for endotracheal intubation and/or maintenance of NMB between August 2012 and April 2013. INTERVENTIONS: TOF measurements using acceleromyography were performed on patients already receiving routine anesthetic care for elective open or laparoscopic abdominal surgery. Measurements allowed assessment of the presence of residual neuromuscular block (rNMB), defined as a train-of-four (TOF) ratio <0.9 at tracheal extubation. We recorded patient and procedural characteristics and assessed TOF ratios (T4/T1) at various times throughout the procedure and at tracheal extubation. Differences in patient and clinical characteristics were compared using Fisher's exact test for categorical variables and t-test for continuous variables. Multivariate logistic regression assessed risk factors associated with rNMB at extubation. MAIN RESULTS: Most of the study population, 64.7% (n = 165) had rNMB (TOF ratio < 0.9), among them, 31.0% with TOF ratio <0.6. Among those receiving neostigmine and/or qualitative peripheral nerve stimulation per clinical decision, 65.0% had rNMB. After controlling for confounders, we observed male gender (odds ratio: 2.60, P = 0.008), higher BMI (odds ratio: 1.04/unit, P = 0.043), and surgery at a community hospital (odds ratio: 3.15, P = 0.006) to be independently associated with increased odds of rNMB. CONCLUSIONS: Assessing TOF ratios blinded to the care team, we found that the majority of patients (64.7%) in this study had rNMB at tracheal extubation, despite neostigmine administration and qualitative peripheral nerve stimulation used for routine clinical care. Qualitative neuromuscular monitoring and clinical judgement often fails to detect rNMB after neostigmine reversal with potential severe consequences to the patient. Our data suggests that clinical care could be improved by considering quantitative neuromuscular monitoring for routine care.

[Investigations into neostigmine-induced inhibition of neuromuscular transmission].

BACKGROUND: Fade of the muscle contraction evoked by indirect tetanic nerve stimulation shows residual neuromuscular block. Anticholinesterases can reverse the partial block; however, they may also inhibit normal neuromuscular transmission and can cause fading responses by misuse of these drugs. The aim of this study is to investigate how neostigmine acts on normal neuromuscular function. METHODS: In cats, we observed a series of 8 consecutive muscular compound action potentials (mCAPs; M1-8) of the gastrocnemius muscle evoked by repetitive sciatic nerve stimulation at 100 Hz and calculated the M8/M1 amplitude ratio as an index of fading phenomenon. Neostigmine 0.05 mg x kg(-1) repetitively every 5 minutes before neuromuscular blocking agent had been administered, or after the complete recovery from vecuronium-induced block had been obtained. RESULTS: Neostigmine caused dose-dependent fade in the mCAPs. The mean doses (SD) of neostigmine for depressing M8/M1 ratio to 50% of baseline were 0.087 (0.029) mg x kg(-1) before use of neuromuscular blocking agent and 0.161 (0.070) mg x kg(-1) after the recovery from neuromuscular block. The fading responses induced by neostigmine were paradoxically reversed by small doses of vecuronium. CONCLUSIONS: Therapeutic doses of neostigmine administered during normal neuromuscular function cause fade of the repetitive muscle contractions. Neuromuscular monitoring should be used before the reversal with neostigmine.

Recurarization in the recovery room following the use of magnesium sulphate.

A 67-yr-old man weighing 104 kg, with a history of hypertension, underwent laparoscopic cholecystectomy. His preoperative serum potassium was 3.4 mmol litre(-1). The patient received cisatracurium 14 mg, which was antagonized with neostigmine 2.5 mg and glycoprolate 0.5 mg at the end of the procedure. A repeat dose of neostigmine 2.5 mg and glycoprolate 0.5 mg was required 5 min later, as the neuromuscular block was incompletely antagonized. He was transferred to the recovery room about 10 min after the end of surgery, having had recovery of neuromuscular function demonstrated with no fade on peripheral nerve stimulation at 50 Hz for 5 s. Five minutes later he developed rapid atrial fibrillation, which was treated over 5 min with magnesium sulphate 2 G i.v. Within the next 3 min, the patient developed marked neuromuscular weakness of a non-depolarizing pattern leading to respiratory arrest. This necessitated re-intubation of the trachea and artificial ventilation for 20 min, until there was spontaneous recovery of neuromuscular function demonstrated by peripheral nerve stimulation. Administration of magnesium appears to have caused recurarization in this patient. The dose of magnesium alone would not be expected to cause muscle weakness. Potentiation of neuromuscular blocking drugs by magnesium is well recognized, and we recommend its use is avoided for at least 30 min after reversal of neuromuscular block.

Ventilação pulmonar mecânica em Pediatria / Mechanic pulmonary ventilation in Pediatrics

Os autores analisam exaustivamente todos os aspectos da ventilaçäo pulmonar mecânica em Pediatria, destacando a importância dos diferentes procedimentos e técnicas utilizados, suas indicaçöes, cuidados a observar no seu emprego, objetivos, parâmetros iniciais, uso da sedaçäo, analgesia e bloqueio neuromuscular do paciente, finalizando com a descriçäo da ventilaçäo pulmonar mecânica nas situaçöes clínicas mais encontradiças nos Centros de Terapia Intensiva pediátrica, limitaçöes ao seu emprego e possíveis avanços em futuro próximo

Anticholinergic action of clonidine in rats with sinoaortic denervation.

A study was carried out relating to the anticholinergic action of clonidine on the cardiovascular responses to i.c.v. injection of neostigmine, a quaternary anticholinesterase, in conscious sham-operated animals and rats with sinoaortic denervation, 7 days after the corresponding operation. Neostigmine (0.1-1 micrograms i.c.v.) induced a dose-dependent pressor and bradycardic responses in sham-operated rats but induced only an increase in blood pressure in sinoaortic-denervated animals. However, the pressor response in sinoaortic-denervated rats was significantly greater than in sham-operated animals. Clonidine (10 micrograms kg-1 i.v.) induced a fall in mean arterial pressure in sinoaortic-denervated rats but not in sham-operated animals. Moreover, sinoaortic denervation reduced the bradycardic action of this antihypertensive drug. The anticholinesterase activity of clonidine (10 micrograms kg-1 i.v.), given 30 min previously, prevented the bradycardic action of neostigmine (0.1-1 micrograms i.c.v.) but failed to modify the pressor effect in sham-operated rats. This alpha2-adrenergic agent reduced the pressor response to i.c.v. administration of neostigmine in sinoaortic-denervated rats. Alternatively, the i.c.v. administration of clonidine (3 micrograms i.c.v.), given either 15 or 30 min before neostigmine, only prevented the bradycardic effect of the anticholinesterase (0.3 micrograms i.c.v.) in sham-operated rats but not the pressor action of this drug. In sinoaortic denervated rats, 3 micrograms of clonidine i.c.v. reduced an increase in blood pressure by i.c.v. injection of the anticholinesterase. The results suggest different central cholinergic mechanisms and different cholinergic-adrenergic interactions on the cardiovascular responses elicited by centrally injected neostigmine in sinoaortic denervated rats.

[Effect of shashen maidong decoction on gastric motility in vivo].

Effect of Shashen Maidong Decoction (SSMDD) on the gastric motility of mice and rats was observed in vivo. Results showed that the gastric phenol red excretion rate of mice could be reduced markedly by SSMDD given in various dosages (23 g.kg-1.d-1, 9 g.kg-1.d-1 or 23 g.kg-1.d-1 for 5 days successively), P < 0.05. By administration of 9 g.kg-1.d-1 or 23 g.kg-1.d-1 could antagonize the acceleration of gastric emptying induced by neostigmine in mice (P < 0.05, P < 0.01). 7 g/kg of SSMDD by gastrogavage could inhibit the frequency and amplitude of contraction of fundic longitudinal muscle using strain gauge transducer in rats, but the effect was not obvious on that of antral circular muscle. By water-ballon method, it was observed that SSMDD 3.5 g/kg or 7 g/kg intraduodenal perfusion could slow down the frequency and decrease the amplitude of gastric peristalsis, 7 g/kg could inhibit significantly the gastric hypermotility induced by subcutaneous injection of indomethacin (40 mg/kg), but had no obvious effect on the gastric hypermotility induced by intramuscular injection of reserpine (0.4 mg.kg-1.d-1 x 4 d).

Pressor response induced by the hippocampal administration of neostigmine is suppressed by M1 muscarinic antagonist.

We investigated the roles played by three muscarinic receptors (M1, M2, and M3) in the pressor response with bradycardia that followed the injection of neostigmine (5 x 10(-8) mol) into the hippocampus of anesthetized rats. These changes were blocked by the co-administration of methylatropine (5 x 10(-8) mol). The intrahippocampal injection of pirenzepine (M1 antagonist) (5 x 10(-9) - 5 x 10(-7) mol) suppressed the neostigmine-induced pressor response dose-dependently. However injection of gallamine (M2 antagonist) (5 x 10(-8) - 5 x 10(-7) mol) and of 4-DAMP (M1 and M3 antagonist) (5 x 10(-8) - 5 x 10(-7) mol) did not suppress this hypertensive response. These findings suggest that the neostigmine-induced pressor response with bradycardia is mediated through the M1 muscarinic receptor subtype.

Antinociceptive effects of spinal cholinesterase inhibition and isobolographic analysis of the interaction with mu and alpha 2 receptor systems.

BACKGROUND: Spinal cholinergic receptors have been shown to have a potent antinociceptive action, an effect that can be mimicked by spinal cholinesterase inhibitors. We (1) characterized the cholinergic receptor system through which intrathecally applied cholinesterase inhibitors produce their antinociceptive effect and (2) examined their interaction with spinal mu opioid and alpha 2-adrenergic receptors. METHODS: Rats were prepared with chronic intrathecal catheters and the nociceptive threshold was assessed by the use of the radiant heat-evoked hind paw withdrawal. RESULTS: Spinal administration of neostigmine, edrophonium, carbachol, clonidine, and morphine produced a dose-dependent increase on the thermally evoked hind paw withdrawal latency. The order of potency (dose producing a 50% effect, in nanomoles) was morphine (1.1) = neostigmine (1.2) > clonidine (4.4) > carbachol (15) >> edrophonium (112). Spinal pretreatment with atropine (35 nmol) attenuated the antinociceptive effect of intrathecal carbachol (55 nmol), neostigmine (15 nmol), and edrophonium (500 nmol) but did not affect the potency of intrathecal morphine (15 nmol) or clonidine (435 nmol). In addition, intrathecal pretreatment with naloxone (31 nmol) and yohimbine (28 nmol) attenuated the effects of intrathecally administered morphine and clonidine, respectively, but did not significantly affect the potency of carbachol, neostigmine, or edrophonium. The nicotinic receptor antagonist mecamylamine (60 nmol) did not affect thermal nociception. Isobolographic analysis revealed a synergistic interaction after the coadministration of neostigmine-clonidine (P < 0.001), edrophonium-clonidine (P < 0.0001), and edrophonium-morphine (P < 0.01) mixtures. Neostigmine-morphine exhibited simple additivity. CONCLUSIONS: These data indicate that analgesia after spinal cholinesterase inhibition is mediated through muscarinic, but not nicotinic cholinergic, opioid, or alpha 2-adrenergic receptor systems, and that these spinal effects of cholinesterase inhibition interact synergistically with the antinociceptive effects of intrathecal mu and alpha 2 agonists.

Pharmacological relevance of peripheral type benzodiazepine receptors on motor nerve and skeletal muscle.

1. Effects of agonists and antagonists of peripheral and central benzodiazepine receptors (pBZR and cBZR) on neuromuscular transmission were studied in mouse isolated phrenic nerve-diaphragm preparations. 2. Ro5-4864, a pBZR agonist, had no effect on the neuromuscular transmission but increased muscle contractility and antagonized the tetanic fade induced by neostigmine. 3. Ro5-4864 inhibited the regenerative tonic endplate depolarization caused by repetitive stimulation in the presence of neostigmine without affecting the amplitude and decay time of miniature and evoked single endplate potentials. 4. All the effects of Ro5-4864 were shared by PK11195, a pBZR antagonist, but not by clonazepam and flumazenil, a cBZR agonist and antagonist, respectively. 5. It is suggested that peripheral type benzodiazepine receptors modulate presynaptic function and muscle contraction.

Activation of GABAA receptor in the brain suppresses neostigmine or histamine-induced central nervous system-mediated hyperglycemia.

We investigated the effect of GABA receptor agonists on the central nervous system (CNS)-mediated hyperglycemia induced by neostigmine or histamine in anesthetized fed rats. The injection of muscimol, GABAA receptor agonist (1, 2.5 nmol) into the third cerebral ventricle suppressed the hyperglycemia induced by intraventricular injection of neostigmine (1 x 10(-8) mol) or histamine (5 x 10(-7) mol). Baclofen, GABAB receptor agonist (1, 2.5 nmol), however, did not suppress these hyperglycemia. Neither muscimol nor baclofen (2.5 nmol) affected plasma glucose levels. These findings suggest that activation of GABAA receptor in the CNS suppresses the hyperglycemia induced by the stimulation of cholinoceptive neuron or histaminergic neuron, but activation of GABAB receptor does not affect them.

[Effects of trimebutine on colonic propulsion in mice].

Effects of oral administration of trimebutine on colonic propulsion in conscious mice were studied by measuring the time required to evacuate a bead which had been inserted into the colon, and compared with those of metoclopramide and domperidone. In normal animals, trimebutine (10 and 50 mg/kg), metoclopramide (50 mg/kg) and domperidone (50 mg/kg) had no effect on the bead evacuation. Metoclopramide and domperidone at 30 mg/kg showed no effect on the delay of colonic propulsion induced by clonidine, while trimebutine (10 and 30 mg/kg) restored the delay significantly. Trimebutine also showed restoration of the delay induced by loperamide. On the acceleration of the propulsion induced by neostigmine, trimebutine (10 and 30 mg/kg) showed an inhibition. In addition, trimebutine (3-30 mg/kg) dose-dependently suppressed the development of soft feces and/or diarrhea induced by neostigmine. According to the results, it is concluded that trimebutine produces both acceleration and inhibition on the colonic propulsion in mice.

In vitro protection of acetylcholinesterase and butyrylcholinesterase by tetrahydroaminoacridine. Comparison with physostigmine.

The protective action of 1,2,3,4-tetrahydro-9-aminoacridine (THA) against the long-lasting inactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) brought about by diisopropylfluorophosphate (DFP) and physostigmine, as well as by neostigmine in the case of AChE only, was evaluated by a dilution technique using Electrophorus electricus AChE and horse serum BuChE as target enzymes. In parallel experiments, the ability of physostigmine itself to protect these enzymes from DFP was evaluated and compared with that of THA. THA pretreatment was seen to prevent in a dose-dependent manner the inhibition of both AChE and BuChE. However, it was appreciably more potent towards AChE than towards BuChE. THA mean EC50 values for protecting AChE against 10, 40 and 100 microM DFP were 0.04, 0.16 and 0.45 microM, respectively; against 1 microM physostigmine the value was 1.8 microM and against 1.2 microM neostigmine it was 3.0 microM. The THA mean EC50 value for protecting BuChE against 3 microM physostigmine was 0.55 microM and the values for protecting against 3, 10 and 40 microM DFP were 1.5, 3 and greater than 10 microM, respectively. The protective action of THA was time independent: recovery of the maximal enzymic activity was immediate upon dilution. Unlike THA, the protective action of physostigmine developed progressively after dilution and was maximal within 3-4 (AChE) or 6-8 hr (BuChE). Under our experimental conditions, 0.3 microM physostigmine protected approximately 70% of AChE from 40 microM DFP and 5 microM physostigmine protected 9 and 47% of BuChE from 40 and 3 microM DFP, respectively. The results of this work suggest that THA exerts its protective action by shielding the active site of AChE and BuChE from the attack of the inactivating agents on account of its higher enzymic affinity, whereas the protective action of physostigmine against DFP takes advantage also of the carbamylation of the enzyme. These results are in line with the hypothesis that protection of AChE is the primary mechanism responsible for the antidotal action of THA against organophosphorus poisoning.

Role of brain histamine H1- and H2-receptors in neostigmine-induced hyperglycemia in rats.

We previously reported that when neostigmine, an inhibitor of acetylcholine esterase, was injected into the third cerebral ventricle, the concentration of hepatic venous plasma glucose was increased via central muscarinic receptors in anesthetized rats. To determine whether brain histamine receptors are involved in cholinergic system transmission with regard to central nervous system (CNS)-mediated glucoregulation, we examined the effects of the H1 receptor antagonist pyrilamine and the H2 receptor antagonist ranitidine on neostigmine-induced hyperglycemia in anesthetized rats. The injection of pyrilamine (5 x 10(-9)-5 x 10(-7) mol) into the third cerebral ventricle suppressed hyperglycemia induced by intraventricular injection of neostigmine (1 x 10(-9) mol) in a dose-dependent manner. Injection of ranitidine (5 x 10(-9)-5 x 10(-7) mol) into the third cerebral ventricle did not suppress the hyperglycemia induced by neostigmine, but enhanced it in a dose-dependent manner. These findings suggest that neostigmine-induced CNS-mediated hyperglycemia is transmitted by not only brain cholinergic muscarinic receptors but also in part by histamine H1 receptors.

Hyperglycemia induced by hippocampal administration of neostigmine is suppressed by intrahypothalamic atropine.

We investigated the relationship between the hyperglycemia induced by the administration of neostigmine into the hippocampus and the hypothalamus. Prior to the injection of neostigmine (5 x 10(-8) mol) into the hippocampus, 1 microliter each of atropine or hexamethonium (5 x 10(-11)-5 x 10(-8) mol) was injected into the bilateral ventromedial hypothalamus (VMH). Atropine suppressed in a dose-dependent manner the hyperglycemia induced by hippocampal administration of neostigmine, whereas hexamethonium had no significant effect. These observations suggest that the pathway for this experimental hyperglycemia involves, at least in part, the muscarinic cholinergic neurons in the VMH.

Reversal of antihypertensive agent-induced postural hypotension with physostigmine.

Physostigmine, administered intravenously, reversed postural hypotension induced by hypotensive agents, guanethidine, clonidine and dopamine2-receptor agonists. Postural hypotension, induced by pentobarbital sodium, was also reversed by physostigmine. Neostigmine reversed postural hypotension induced by clonidine following intracerebroventricular, but not intravenous administration. It is proposed that centrally acting cholinomimetic agents may be used to manage postural hypotension resulting from suppression of sympathetic nervous system activity.

Ketamine antagonizes toxic action of anticholinesterase agents.

Ketamine is an anaesthetic interacting with several neurotransmitters. Among others, ketamine exerts some cholinergic actions (ACh). This paper presents the results of studying the interaction of ketamine with ACh in two animal species. Atropine slightly increased the time of immobility produced by ketamine injections in rats. Meanwhile, neostigmine slightly decreased such immobility. Ketamine resulted similar in behavioral actions and shared some electroencephalographic (EEG) actions of scopolamine in cats. The most striking interaction consisted on an antagonism of ketamine on the action of anticholinesterase agents. In both species, ketamine blocked the EEG and the behavioral toxic effects of neostigmine and physostigmine. Notwithstanding, the anticholinesterase agents were unable in reducing the actions of ketamine. This partial cholinergic agonist action of ketamine support certain but limited use of the anesthetic against insecticidal anticholinesterase poisoning.

Effects of calcium channel blocking agents on neostigmine-induced fasciculations.

Male Sprague-Dawley rats were anesthetized with pentobarbital and prepared for monitoring contractions of the gastrocnemius muscle evoked by stimulation of the sciatic nerve. Animals received atropine prior to a dose of neostigmine of 0.02 mg/kg i.v. The effects on contractile strength and the number of fasciculations in a 2-min period were assessed. Pretreatment with phenytoin, 20 mg/kg, reduced the number of fasciculations to 32% of control without altering contractile strength. Both nifedipine and nitrendipine, 1 mg/kg each, virtually abolished fasciculations without altering twitch strength. Verapamil, 4 and 8 mg/kg, depressed fasciculation frequency to 50% of control without affecting pre-neostigmine twitch height. The dihydropyridine calcium blocking agents did however reduce the neostigmine-induced augmentation of contraction strength. These data suggest that a calcium-mediated current at presynaptic motor endings participates in the generation of repetitive nerve terminal discharges leading to muscle fasciculations.

Atropine-neostigmine mixture: a dose-response study.

The dose-response relationship and the doses of atropine required to prevent neostigmine from lowering heart rates below baseline in 50 per cent (ED50) and 95 percent (ED95) of patients after antagonism of pancuronium-induced neuromuscular blockade were determined in 70 patients with neostigmine-atropine mixtures. Neostigmine 0.04 mg.kg-1 (group A, n = 35) or 0.06 mg.kg-1 (group B, n = 35) was randomly mixed with one of seven doses of atropine (ranging from 0.014 to 0.04 mg.kg-1) in group A and from 0.02 to 0.04 mg.kg-1 in group B), with dose-response curves for atropine being constructed for both groups 5 and 10 min after injection of the mixture. These dose-response curves were found to be parallel in both groups. The calculated ED50 and ED95 values of atropine were similar in both groups. The estimated ED50 doses of atropine in groups A and B at 5 min were 0.031 and 0.033 mg.kg-1 respectively, and at 10 min the ED50 doses were 0.037 and 0.037 mg.kg-1 respectively. The calculated ED95 doses of atropine in groups A and B at 5 min were 0.05 and 0.046 mg.kg-1, and at 10 min the ED95 doses were also similar, being 0.06 and 0.055 mg.kg-1 respectively. Under the conditions employed in this study it would seem that in order to prevent late reductions in heart rates, the appropriate doses of atropine when used with neostigmine should be greater than that commonly used.