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LC/MS/MS analysis of quaternary ammonium drugs and herbicides in whole blood.

Quaternary ammonium drugs (atracurium, bretylium, edrophonium, ipratropium, mivacurium, neostigmine, pancuronium and rocuronium) and herbicides (difenzoquat, diquat and paraquat) in human whole blood were analysed by LC/MS/MS with positive electrospray ionisation (ESI), following extraction with Bond Elut LRC-CBA cartridges. Internal standards were benzyldimethylphenylammonium chloride monohydrate and ethyl viologen for drug and herbicide analysis, respectively. Ion-pair chromatography used heptafluorobutyric acid (15 mM)-ammonium formate (20 mM) buffer adjusted to pH 3.30 with formic acid and a linear gradient from 5 to 90% methanol run over 18 min. Recoveries ranged from 79.7 to 105.1%, detection limits were between 3.6 and 20.4 ng/ml and the intra- and inter-day precisions were less than 18.6% at a concentration of 10 ng/ml. The method was applied to a case of accidental paraquat poisoning in which the concentration of paraquat in blood was 0.64 mg/l, which is within the range associated with fatal paraquat poisoning.

Androstanols↗

The Combitube as a salvage airway device for paramedic rapid sequence intubation.

STUDY OBJECTIVE: The safety of out-of-hospital rapid sequence intubation depends on a reliable strategy when orotracheal intubation is unsuccessful. Here we describe our experience with the Combitube (esophageal-tracheal twin-lumen airway device) as a salvage airway device for paramedic rapid sequence intubation. METHODS: The San Diego Paramedic Rapid Sequence Intubation Trial was performed to assess the effect of paramedic rapid sequence intubation on outcome in severely head-injured patients. Adults with severe head trauma (Glasgow Coma Scale score 3 to 8) who were unable to be intubated without medications were enrolled. Midazolam and succinylcholine were administered, and paramedics were allowed a maximum of 3 attempts at orotracheal intubation. If the attempts were unsuccessful, Combitube insertion was mandated. After confirmation of tube position, rocuronium was given and standard ventilation protocols were used. The primary outcome measure for this analysis was the success rate for Combitube insertion after unsuccessful orotracheal intubation. In addition, Combitube insertion and orotracheal intubation patients were compared with regard to demographic, clinical, and outcome data. RESULTS: A total of 426 patients were enrolled in the trial, with 420 meeting inclusion criteria for this analysis. Orotracheal intubation was successful in 355 (84.5%) of 420; Combitube insertion was successful in 58 (95.1%) of 61 attempts, with no reported complications. Patients undergoing Combitube insertion had higher Face Abbreviated Injury Scale scores and were more likely to have oropharyngeal blood or vomitus. Arrival Pco(2) values were higher, and arrival Po(2) values were lower but still supranormal in patients undergoing Combitube insertion. There were no mortality differences between patients undergoing Combitube insertion and those undergoing orotracheal intubation. CONCLUSION: The Combitube can be an effective salvage airway device for paramedic rapid sequence intubation in an urban/suburban, high-volume emergency medical services system with paramedics who are experienced in Combitube placement and with stringent protocols for its use. The device should be tested in other sizes and types of systems and under less medical scrutiny than was used in this study.

Abbreviated Injury Scale↗

Succinylcholine: adverse effects and alternatives in emergency medicine.

Succinylcholine has long been the favored neuromuscular blocking agent for emergent airway management because of its rapid onset, dependable effect, and short duration. However, it has a plethora of undesirable side effects, ranging from the inconsequential to the catastrophic. When patients requiring tracheal intubation present with potential contraindications to succinylcholine use, the emergency physician will need to substitute a rapid-onset nondepolarizing neuromuscular blocking agent, such as rocuronium or mivacurium. An understanding of the pharmacology of these agents is essential.

Adult↗

[Allergy investigations after two cases of adverse reactions to a neuromuscular blocking agent and management for subsequent general anaesthesia].

We report two cases of severe anaphylactic reactions to rocuronium. Diagnosis was confirmed by skin tests and specific IgE assay. Cross-reactivity to all neuromuscular blocking agents was investigated by intradermal tests and leucocyte histamine release test. Intradermal tests and leukocyte histamine release were negative for cisatracurium. The two patients had undergone a subsequent general anaesthesia using cisatracurium and did not present any adverse reaction.

Aged↗

Hemodynamic response to tracheal intubation after vital capacity rapid inhalation induction (VCRII) with different concentrations of sevoflurane.

STUDY OBJECTIVE: To evaluate the blood pressure (BP) and heart rate (HR) response to tracheal intubation after vital capacity rapid inhalation induction (VCRII) with four concentrations of sevoflurane followed by nitrous oxide (N2O) 50% and sevoflurane in concentrations administered by clinical judgment. DESIGN: Prospective, randomized study. SETTING: University teaching hospital. PATIENTS: 60 unpremedicated, ASA physical status I and II adult patients undergoing surgery with general anesthesia. INTERVENTIONS: After fentanyl 3 micrograms/kg, VCRII was accomplished with four concentrations of sevoflurane in O2: Group 1 (n = 15): sevoflurane 3%; Group 2 (n = 15): sevoflurane 4%; Group 3 (n = 15): sevoflurane 5%; and Group 4 (n = 15): sevoflurane 6%. At loss of consciousness, rocuronium 0.6 mg/kg was given, and intubation was performed 90 seconds later. Thereafter, anesthesia continued with N2O 50% and sevoflurane. MEASUREMENTS AND MAIN RESULTS: BP and HR measurements were made at the ward (baseline), at loss of consciousness, and just prior to, and each minute after, tracheal intubation during a 5-minute period. The hemodynamic profile among groups was similar, with a slight hypertensive and tachycardic response to intubation. CONCLUSION: VCRII with sevoflurane 3% to 6% following fentanyl 3 micrograms/kg can be considered for blunting the hemodynamic response to tracheal intubation in healthy patients.

Adult↗

Comparison between the Datex-Ohmeda M-NMT module and a force-displacement transducer for monitoring neuromuscular blockade.

BACKGROUND AND OBJECTIVE: The Datex-Ohmeda neuromuscular transmission module (M-NMT) is a new monitor that is part of the AS/3 anaesthesia monitor. It incorporates a mechanosensor, which is a piezoelectric polymer attached to the hand. The module was compared with a force transducer in 30 patients requiring neuromuscular blockade. METHODS: Anaesthesia was induced with fentanyl and propofol, and tracheal intubation was performed without muscle relaxants. Neuromuscular blockade was assessed by the test module on one arm and the force transducer on the other arm. When the response to train-of-four stimulation had been stable in both arms for 3 min, rocuronium 0.2 mg kg(-1) was injected intravenously. During recovery from blockade, the train-of-four ratio was measured in 15 patients, and the ratio of response to double-burst stimulation in the other 15 patients. Data analysis was by difference plots. RESULTS: Both devices had acceptable coefficients of repeatability. The M-NMT module was biased by + 1.3% (upper limit of agreement 14.2%, lower limit -12.9%) for the recovery of the train-of-four ratio, and by + 1.09% (17%, -16%) for the recovery of double-burst stimulation ratio. CONCLUSIONS: The Datex-Ohmeda M-NMT gives measurements that are repeatable and gives good enough correspondence with a force transducer that it can be used clinically to assess recovery of neuromuscular blockade, but the limits of agreement rule out research applications.

Androstanols↗

Decreased number of acetylcholine receptors is the mechanism that alters the time course of muscle relaxants in myasthenia gravis: a study in a rat model.

BACKGROUND: In myasthenic patients, the time course of action of non-depolarizing neuromuscular blocking agents is prolonged and the sensitivity is increased. We used our antegrade perfused rat peroneal nerve anterior tibialis muscle model to investigate if this altered time course of effect and sensitivity can be explained by the decreased acetylcholine receptor concentration that is caused by the disease. METHODS: Functional acetylcholine receptors were reduced by administration of alpha-bungarotoxin or by injecting monoclonal antibodies against rat acetylcholine receptors (experimental autoimmune myasthenia gravis). After induction of anaesthesia, the model was set up and perfusion of the tibialis anterior muscle with blood was started. After stabilization of the twitch, rocuronium or pancuronium were infused until 90% block was obtained. Twitch data and infusion data were recorded and used to calculate the time course of effect and potency. RESULTS: The potency of neuromuscular blocking agents was increased and the offset of the neuromuscular block was prolonged in both the alpha-bungarotoxin groups and the experimental autoimmune myasthenia gravis groups compared to controls. CONCLUSION: This study shows that the increased sensitivity to neuromuscular-blocking agents in myasthenia gravis can be accounted for by a decreased number of acetylcholine receptors. It also shows that the antegrade perfused rat peroneal nerve anterior tibialis muscle model is a suitable model to study the effects of myasthenia gravis on the time course of effect of neuromuscular blocking agents.

Androstanols↗

Posttetanic count revisited: are measurements more reliable using the TOF-Watch accelerographic peripheral nerve stimulator?

OBJECTIVE: Measurement of profound neuromuscular block using posttetanic count is among the most subjective measurements made in clinical anesthesia. The TOF-Watch accelerographic peripheral nerve stimulator provides objective measurements of neuromuscular block that may improve our ability to quantitate intense blockade. METHODS: The TOF-Watch and Digi Stim III peripheral nerve stimulators were used to monitor onset and early recovery of neuromuscular response induced by rocuronium 0.6 mg/kg i.v. in 30 patients anesthetized with general anesthesia. After induction, train-of-four count (when present) was measured at one-min intervals. Subsequently, posttetanic count was measured at three-min intervals until the first response to train-of-four stimulation reappeared. RESULTS: Posttetanic count and train-of-four count measurements were determined to be consistently unreliable throughout the study in seven (23%) patients with the TOF-Watch stimulator and three (10%) patients with the Digi Stim III stimulator (p = NS). Among stimulators yielding reliable measurements, decreases in train-of-four count to 0/4 were noted earlier with the Digi Stim III monitor (median = 2 min) as compared with the TOF-Watch device (median = 4 min) (p < 0.05). Also, posttetanic count decreased to zero in only 35% of patients with the TOF-Watch stimulator versus 67% of patients with the Digi Stim III stimulator (p < 0.05). CONCLUSIONS: Both monitors were similar in their ability to predict return to TOFC = 1 as a function of PTC measurements. The TOF-Watch monitor is easy to apply even in inexperienced hands. However, the device yielded erroneous data in 23% of patients.

Adult↗

The use of neuromuscular blocking agents in noncardiac surgery after dynamic cardiomyoplasty.

Dynamic cardiomyoplasty is a surgical treatment to improve cardiac performance in patients with end-stage heart failure by wrapping the latissimus dorsi muscle around the heart. The use of skeletal muscle raises concerns about the safety of neuromuscular blocking agents used during general anaesthesia in noncardiac surgery in patients after cardiomyoplasty. We describe the administration of rocuronium to a patient undergoing carotid endarterectomy 18 months after cardiomyoplasty. No clinically relevant effects on haemodynamics were observed. We conclude that the use of nondepolarising neuromuscular blocking agents for noncardiac surgery in patients after cardiomyoplasty does not compromise cardiac performance in a clinically relevant way, although the time between the cardiomyoplasty procedure and the use of nondepolarising neuromuscular blocking agents remains a concern.

Androstanols↗

Do muscle relaxants influence vascular tone in isolated coronary artery segments?

The aim of this study was to elucidate the influence of four neuromuscular blocking substances on coronary vascular tone using the model of isolated porcine coronary artery segments. We studied the effects of four muscle relaxants, atracurium, pancuronium, rocuronium, and vecuronium (0.1, 1, and 10 microg mL-1 each), on the contractile response to three vasoconstrictors: acetylcholine, histamine, and serotonin. None of the neuromuscular blocking agents under investigation exerted a significant influence on the vasoconstricting effects of these mediators except for pancuronium, which dose-dependently attenuated acetylcholine-mediated contractions (-10.8% attenuation for 10 microg mL-1 pancuronium, P < 0.05). There was no difference between vessels with intact endothelium and denuded preparations. It is concluded that high-dose pancuronium exerts an antimuscarinic effect in vascular smooth muscle. The other neuromuscular agents studied do not alter vascular reactivity of isolated porcine coronary arteries.

Acetylcholine↗

An assessment of desflurane for use during cardiac electrophysiological study and radiofrequency ablation of supraventricular dysrhythmias in children.

Desflurane has several properties making it a desirable agent for use in electrophysiological studies (EPS) for diagnosis and treatment of cardiac dysrhythmias. We studied 47 children, mean age 12.8+/-4.6 years, mean weight 52.9+/-24.0 kg, with clinical history of supra- ventricular tachycardia (SVT) during EPS using desflurane in a crossover comparison with fentanyl. The patients served as their own controls. All received oral premedication with lorazepam, and intravenous induction with thiopentone, rocuronium, and oxygen. Group 1 (n=24) were administered fentanyl 10 microg.kg-1 bolus i.v. with an infusion of 3 microg.kg-1.h-1 during initial EPS. Fentanyl was discontinued and desflurane, 6% endtidal, was administered and the EPS repeated. Group 2 (n=23) were initially administered 6% desflurane after induction, and following EPS the desflurane was discontinued and the patients administered fentanyl 3 microg.kg-1 bolus and EPS repeated (explanations of EPS abbreviations are provided). Desflurane reduced the mean arterial pressure (MAP) in all patients. In Group 1, desflurane shortened the sinus cycle length (SCL), i.e. increasing the heart rate, and atrial effective refractory period (AERP) while Group 2 demonstrated no such effect on AERP. There were no other significant differences between fentanyl or desflurane techniques in terms of EPS measurements. SVT was inducible with both agents in both groups. Desflurane seems an acceptable agent for use during EPS procedures.

Administration, Oral↗

[Influence of neuromuscular blockade on the airway leak pressure of the ProSeal laryngeal mask airway].

BACKGROUND: The ProSeal laryngeal mask airway (PLMA) is increasingly used for surgical procedures that might require the intraoperative use of neuromuscular blocking agents. The airway seal of the PLMA depends on the interplay of the surrounding soft tissue of the neck and the cuff of the mask. An intraoperative neuromuscular blockade could lead to a decrease of the airway leak pressure (P (leak)) secondary to the relaxation of the muscles of the neck. With this study we tested the hypothesis that a neuromuscular blockade can result in a decreased P (leak) of the PLMA. METHODS: The P (leak) of the PLMA was studied in 73 female patients under total intravenous anaesthesia with propofol (0.1 - 0.15 mg kg (-1) min (-1)) and remifentanil (0.1 - 0.3 microg kg (-1) min (-1)) before and after a complete neuromuscular blockade produced by intravenous injection of 0.6 mg kg (-1) Rocuronium. RESULTS: The P (leak) decreased by more than 10 % of the baseline P (leak) in 8 out of 73 patients (11 %); however, in the entire study population there was no significant difference between the mean baseline P (leak) (28.5 +/- 7.3 cm H(2)O) and the mean P (leak) after complete neuromuscular blockade (29.1 +/- 7.0 cm H(2)O); (p = 0.128). CONCLUSION: No general correlation between application of a neuromuscular blocking agent and a decrease of the mean P (leak) was found. However, the decrease of the P (leak) by more than 10 % in 11 % of the patients shows that in certain patients the application of neuromuscular blocking agents can result in a decreased P (leak) of the PLMA and indicates the necessity to control the P (leak) of the PLMA under complete muscle paralysis preoperatively when neuromuscular blocking agents are used.

Adult↗

Calculation of an effect compartment rate constant using recovery indices obtained with an isolated arm technique.

We have examined the implications of the theoretical single pharmacokinetic compartment associated with blocker-induced paralysis, in relation to the isolated arm technique. It is assumed that the blocker concentration-effect relationship can be characterized by a sigmoid curve, which incorporates an exponent, s. After tourniquet release, the concentration gradient between the effect compartment and plasma should be large, and elimination related to the rate constant, keo. The major measurement of spontaneous recovery with the isolated arm is the time interval between 75% and 25% twitch depression, T25-T75. The general equation relating these three variables is developed: keo = 2.2/(s x (T25-T75)). Insertion of published values for T25-T75 with isolated arm studies into this equation gave estimates for an intrinsic keo for atracurium, vecuronium, rocuronium and pancuronium.

Androstanols↗

Effects of non-depolarizing neuromuscular blocking agents on norepinephrine release from human atrial tissue obtained during cardiac surgery.

We have studied the effect of non-depolarizing neuromuscular blocking agents, at concentrations present in serum during anaesthesia, on release of [3H]-norepinephrine ([3H]NE) from superfused atrial appendage obtained during cardiac surgery from 48 patients. Three of the neuromuscular blocking agents (pancuronium, gallamine and rocuronium), which are known to cause an increase in heart rate during anaesthesia, increased stimulation-evoked release of [3H]NE. In contrast, (+)tubocurarine and pipecuronium, neuromuscular blocking agents that do not cause tachycardia, did not affect release of NE. Org 9487 significantly enhanced release while SZ1677 was ineffective, even at concentrations higher than those expected after administration of a 2 x ED95 dose. Atropine enhanced release. These data suggest that the axon terminals of sympathetic nerves in human heart have muscarinic heteroreceptors whose activation by acetylcholine (ACh) released from the vagal nerve reduces release of NE. This action contributes to lowering of heart rate. Therefore, any neuromuscular blocking agent with antimuscarinic actions and capable of increasing the release of NE may produce tachycardia.

Analysis of Variance↗

Correlation and agreement between bispectral index and state entropy of the electroencephalogram during propofol anaesthesia.

BACKGROUND: Bispectral index (BIS) and state entropy (SE) monitor hypnosis. We evaluated the correlation and the agreement between those parameters during propofol anaesthesia and laryngoscopy with and without muscle relaxation. METHODS: A total of 25 patients were anaesthetized with propofol. At steady state (SS: BIS 40-50), they randomly received rocuronium (R) or saline (S); 3 min thereafter, a 20 s laryngoscopy was performed. Correlation (regression analysis) and agreement (Bland-Altman analysis) were evaluated before induction (baseline), at loss of eyelash reflex (LER), at SS and during the first 3 min after laryngoscopy (L). RESULTS: The correlation coefficient r (95% CI), the mean difference (MD) (95% CI), and the limits of agreement [lower-upper limits of 95% CI of MD (sd 1.96)] between BIS and SE were as follows. Overall recordings: 0.87 (0.83 to 0.90), 2.5 (1.2 to 3.0), and [-19.5 to 24.6]; Baseline: 0.45 (0.06 to 0.72), 7.6 (6.0 to 9.2), and [-2.7 to 17.9]; LER: 0.74 (0.47 to 0.88), 8.3 (3.5 to 13.2), and [-22.6 to 39.3]; SS, all patients: 0.41 (0.14 to 0.63), 2.0 (-0.5 to 4.6), and [-19.0 to 23.3]; SS, Group S: 0.36 (-0.07 to 0.68), 1.9 (-2.5 to 6.3), and [-25.0 to 28.8]; SS, Group R: 0.63 (0.32 to 0.82), 0.2 (-2.0 to 2.3), and [-14.0 to 14.4]; L, all patients: 0.49 (0.32 to 0.63), 0.7 (-1.6 to 3.0), and [-25.6 to 27.1]; L, Group S: 0.41 (0.13 to 0.63), 2.3 (-2.4 to 7.1), and [-36.7 to 41.3]; L, Group R: 0.72 (0.56 to 0.83), -0.6 (-2.2 to 1.0), and [-14.3 to 13.1]. The correlation was good except for SS in Group S. The MD was significantly different from 0 for overall recordings, during baseline and LER, but not for the other conditions. The agreement was poor except for baseline, and SS and L in Group R. CONCLUSIONS: BIS and SE are globally well correlated. In contrast, agreement is poor as differences of more than 20 units are frequently observed, except for awake and paralysed patients.

Adult↗

Bronchial mucus transport velocity in paralyzed anesthetized patients: a comparison of the laryngeal mask airway and cuffed tracheal tube.

UNLABELLED: We compared bronchial mucus transport velocity (BTV), an index of mucociliary clearance, between the laryngeal mask airway (LMA) and the tracheal tube (TT). Forty patients were studied during propofol anesthesia and muscle relaxation with rocuronium. BTV was measured 10 and 60 min after insertion of the airway device by fiberoptic observation of the movement of methylene blue dye injected onto the dorsal surface of the left main bronchus. BTV for the LMA was similar at 10 and 60 min (13.9 +/- 2.0 and 13.6 +/- 2.1 mm/min, respectively). BTV for the TT was significantly faster at 10 min that at 60 min (13.0 +/- 1.4 vs 6.9 +/- 1.2 mm/min, respectively; P < 0.00001). BTV was similar for both devices at 10 min (TT 13.0 +/- 1.4 mm/min versus LMA 13.9 +/- 2.0 mm/min), but was significantly faster for the LMA than for the TT at 60 min (LMA 13.6 +/- 2.1 mm/min versus TT 6.9 +/- 1.2 mm/min; P < 0.00001). We conclude that the LMA impedes mucociliary clearance less than the TT in anesthetized patients. This may have implications for reducing the risk of retention of secretions, atelectasis, and pulmonary infection. IMPLICATIONS: This study compares bronchial mucus transport velocity, an index of mucociliary clearance, in anesthetized patients between two airway devices, the cuffed tracheal tube and the laryngeal mask airway. We have shown that the laryngeal mask airway impairs mucociliary clearance less than the tracheal tube. This may have implications for reducing the risk of retention of secretions, atelectasis, and pulmonary infection.

Adult↗

Precurarization and priming: a theoretical analysis of safety and timing.

UNLABELLED: The priming principle suggests that the onset of neuromuscular block may be accelerated if an intubating dose is preceded by a priming dose administered a few minutes earlier. We thought it would be instructive to use a pharmacodynamic/pharmacokinetic model to estimate the risk associated with different priming doses and intervals. In any normal population, there is wide variability in the response to neuromuscular blocking drugs. For most relaxants, the coefficient of variation for the 50% effective dose (ED(50)) approximates 20%-25%. Thus, 1 patient in 50 (-2.05 SD) may have an ED(50) only half of the commonly cited value. By using published pharmacodynamic/pharmacokinetic data, we calculated the effect of administering 10%, 20%, or 30% of the ED(95) on the response of the adductor pollicis muscle in a population normally distributed with respect to drug sensitivity. A dose equivalent to 10% of the ED(95) will rarely produce a measurable neuromuscular effect. As this dose is increased, the potential for clinical weakness rapidly escalates. In 1 in 50 individuals, the usual recommendation of 10% of the intubation dose will produce measurable neuromuscular depression. For vecuronium, the optimal priming interval is 5 min. The safety and dependability of the priming principle is very much subject to the laws of probability. IMPLICATIONS: When using the priming principle to accelerate the onset of neuromuscular block, the initial dose should not exceed 10% the drug's ED(95). For drugs other than rocuronium, the optimal priming interval is not <5 min.

Androstanols↗