Sugammadex rapidly reverses moderate rocuronium- or vecuronium-induced neuromuscular block during sevoflurane anaesthesia: a dose-response relationship.

BACKGROUND: Sugammadex shows a dose-response relationship for reversal of neuromuscular block (NMB) during propofol anaesthesia. Sevoflurane, unlike propofol, can prolong the effect of neuromuscular blocking agents (NMBAs), increasing recovery time. This open-label, randomized, dose-finding trial explored sugammadex dose-response relationships, safety, and pharmacokinetics when administered for reversal of moderate rocuronium- or vecuronium-induced NMB during sevoflurane maintenance anaesthesia. METHODS: After anaesthesia induction with propofol, adult patients were randomized to receive single-dose rocuronium 0.9 mg kg⁻¹ or vecuronium 0.1 mg kg⁻¹, with maintenance doses as needed. Anaesthesia was maintained with sevoflurane. NMB was monitored using acceleromyography. After the last dose of NMBA, at reappearance of T(2), single-dose sugammadex 0.5, 1.0, 2.0, or 4.0 mg kg⁻¹ or placebo was administered. The primary efficacy variable was time from the start of sugammadex administration to recovery of T4/T1 ratio to 0.9. Safety assessments were performed throughout. RESULTS: The per-protocol population comprised 93 patients (rocuronium, n=46; vecuronium, n=47). A statistically significant dose-response relationship was demonstrated for mean recovery times of T4/T1 ratio to 0.9 with increasing sugammadex dose with both NMBAs: rocuronium, 96.3 min (placebo) to 1.5 min (sugammadex 4.0 mg kg⁻¹); vecuronium, 79.0 min (placebo) to 3.0 min (sugammadex 4.0 mg kg⁻¹). Plasma sugammadex concentrations indicated linear pharmacokinetics, independent of NMBA administered. No study drug-related serious adverse events occurred. Evidence of reoccurrence of block was reported in seven patients [sugammadex 0.5 mg kg⁻¹ (suboptimal dose), n=6; 2.0 mg kg⁻¹, n=1]. CONCLUSIONS: During sevoflurane maintenance anaesthesia, sugammadex provides well-tolerated, effective, dose-dependent reversal of moderate rocuronium- and vecuronium-induced NMB.

[Sugammadex. New pharmacological concept for antagonizing rocuronium and vecuronium]. / Sugammadex. Neues pharmakologisches Konzept zur Antagonisierung von Rocuronium und Vecuronium.

Up to now only acetylcholine esterase inhibitors, such as neostigmine, were available as antagonists of residual neuromuscular blocks. Sugammadex is a modified gamma-cyclodextrin that binds rocuronium and chemically similar aminosteroidal muscle relaxants, such as vecuronium. The underlying mechanism of action is new and differs completely from that of acetylcholine esterase inhibitors. This review summarizes data published so far within the framework of the licensing procedure about the efficacy, safety and side-effects of sugammadex and presents potential new anesthesiological concepts using this compound.

Employing vasopressin as an adjunct vasopressor in uncontrolled traumatic hemorrhagic shock. Three cases and a brief analysis of the literature.

Resuscitation of patients in hemorrhagic shock remains one of the most challenging aspects of trauma care. We showed in experimental studies that vasopressin, but not fluid resuscitation, enabled short-term and long-term survival in a porcine model of uncontrolled hemorrhagic shock after penetrating liver trauma. In this case report, we present two cases with temporarily successful cardiopulmonary resuscitation (CPR) using vasopressin and catecholamines in uncontrolled hemorrhagic shock with subsequent cardiac arrest that was refractory to catecholamines and fluid replacement. In a third patient, an infusion of vasopressin was started before cardiac arrest occurred; in this case, we were able to stabilize blood pressure thus allowing further therapy. The patient underwent multiple surgical procedures, developed multi-organ failure, but was finally discharged from the critical care unit without neurological damage.

[Succinylcholine--update]. / Succinylcholin-Update.

The action profile of succinylcholine is unmatched even 50 years after its introduction into anaesthestic practice. This is probably why succinylcholine, despite its many and partly life-threatening side-effects, is still considered to be indispensable by many anaesthetists and emergency doctors. The main indication for succinylcholine--the facilitation of endotracheal intubation in patients considered to be at an increased risk of aspiration of gastric fluid, e.g. patients undergoing a Caesarean section or presenting with an ileus--remains undisputed. Some of the side-effects of succinylcholine can be diminished by precurarisation. However, just like priming, this technique holds some considerable dangers (such as a clinically significant attenuation of the protective reflexes) and has become a matter of increasing controversy. Rocuronium (> or = 1 mg/kg) is currently the best alternative to succinylcholine for rapid sequence induction. The routine use of succinylcholine as a relaxant for intubation is questionable, mainly because there are a number of modern anaesthetic techniques (laryngeal mask airway) and new drugs (rocuronium, mivacurium, remifentanil) which make succinylcholine quite dispensable except for a few situations (e.g. re-positioning of fractures). In the case of an expected difficult airway no muscle relaxant should be given, because severe hypoxaemia in these patients probably can only be prevented by a professional airway management. Succinylcholine is no longer an option in elective paediatric anaesthesia. The drug, however, retains its value in critical situations where a rapid onset but a short duration of action is of prime importance.

Newer neuromuscular blocking agents: how do they compare with established agents?

Rapacuronium bromide (rapacuronium; ORG-9487) is a nondepolarising muscle relaxant (NMBA) with a low potency [90% effective dose (ED90) 1 mg/kg], which to some extent is responsible for its rapid onset of action. Because of the high plasma clearance (5.3 to 11.1 mg/kg/min) of rapacuronium, its clinical duration of action following single bolus doses up to 2 mg/kg in adults is short (i.e. <20 minutes). Rapacuronium forms a pharmacologically active 3-desacetyl metabolite, ORG-9488, which may contribute to a delay in spontaneous recovery after repeat bolus doses or infusions. After rapacuronium 1.5 mg/kg clinically acceptable intubating conditions are achieved within 60 to 90 seconds in the majority of adult and elderly patients undergoing elective anaesthesia. However, in a rapid-sequence setting. intubating conditions are less favourable after rapacuronium 1.5 to 2.5 mg/kg than after succinylcholine. The most prominent adverse effects of rapacuronium (tachycardia, hypotension and bronchospasm) are dose-related, and in particular pulmonary adverse effects are observed more frequently under conditions of a rapid-sequence induction in adults. Therefore, it seems worthwhile to consider only doses of rapacuronium < or = 1.5 mg/kg to facilitate rapid tracheal intubation, and to use succinylcholine or rocuronium rather than rapacuronium in a rapid-sequence setting. Rapacuronium, however, is a suitable alternative to mivacurium chloride (mivacurium) and succinylcholine for short procedures (e.g. ambulatory anaesthesia). Rocuronium bromide (rocuronium) is a relatively low-potent, intermediateacting NMBA. Its main advantage is the rapid onset of neuromuscular block whereby good or excellent intubating conditions are achieved within 60 to 90 seconds after rocuronium 0.6 mg/kg (2 x ED95), and within 60 to 180 seconds after smaller doses (1 to 1.5 x ED95). Larger doses of rocuronium (> or = 1 mg/kg) seem to be suitable for rapid-sequence induction under relatively light anaesthesia. However, it is still a matter of controversy whether, in the case of an unanticipated difficult intubation, the long duration of rocuronium administered in such large doses outweighs the many adverse effects of succinylcholine. Rocuronium has mild vagolytic effects and does not release histamine, even when administered in large doses. Rocuronium is primarily eliminated via the liver and its pharmacokinetic profile is similar to that of vecuronium bromide (vecuronium). Unlike vecuronium, rocuronium has no metabolite. Cisatracurium besilate (cisatracurium), the IR-cis, 1'R-cis isomer of atracurium besilate (atracurium) is approximately 4 times more potent than atracurium. The onset time of cisatracurium is significantly slower than after equipotent doses of atracurium. The recommended intubating dose is 0.15 to 0.2 mg/kg (3 to 4 times ED95). Over a wide range of clinically relevant doses the recovery properties of cisatracurium are affected by neither the size of the bolus dose nor by the duration of infusion. Unlike atracurium, cisatracurium does not trigger histamine release. Like atracurium, cisatracurium undergoes Hofmann elimination. In contrast to atracurium, cisatracurium does not undergo hydrolysis by nonspecific plasma esterases. Moreover, about 77% of the drug is cleared by organ-dependent mechanisms.

Choice of the muscle relaxant for rapid-sequence induction.

Muscle relaxants are given as part of a rapid-sequence induction to facilitate tracheal intubation. Among all the muscle relaxants available, succinylcholine is the only one with a fast (approximately equal to 1 min) onset and a fast recovery. Therefore it is still the most frequently used muscle relaxant for rapid-sequence induction despite its well-known side-effects. The short duration of action of succinylcholine is, however, no substitute for aggressive airway management in the case of an unexpectedly difficult intubation in order to prevent life-threatening hypoxia. A preoperative assessment of the airway is mandatory in any patient and may indicate the need for using intubation techniques without a muscle relaxant. Rocuronium in large doses (i.e. > or = 1 mg kg-1) is an alternative to succinylcholine in a classical rapid-sequence setting under relatively light anaesthesia. With respect to rapid tracheal intubation, the timing and priming principles offer little advantage over the use of rocuronium in doses of 0.6 mg kg-1 in combination with an appropriate induction technique (i.e. including an opioid) or over the use of larger doses of rocuronium (> or = 1.0 mg kg-1) under relatively light anaesthesia, and may even be potentially harmful. In contrast to rocuronium, the use of rapacuronium in a rapid-sequence setting has been associated with dose-dependent respiratory side-effects that limit its usefulness in doses higher than 1.5 mg kg-1 for this indication.

Rapacuronium 2.0 or 2.5 mg kg-1 for rapid-sequence induction: comparison with succinylcholine 1.0 mg kg-1.

The purpose of this nine-centre study in 602 patients was to show that the frequency of acceptable intubating conditions after rapacuronium 2.0 or 2.5 mg kg-1 is not more than 10% lower than the frequency after succinylcholine 1.0 mg kg-1 during rapid-sequence induction of anaesthesia with fentanyl 1-2 micrograms kg-1 and thiopental 2-7 mg kg-1. Laryngoscopy and intubation were carried out 60 s after administration of muscle relaxant by an anaesthetist blinded to its identity. Intubating conditions were clinically acceptable (excellent or good) in 91.8% of patients given succinylcholine and in 84.1 and 87.6% of patients given rapacuronium 2.0 and 2.5 mg kg-1 respectively. With respect to the percentage of clinically acceptable intubating conditions, the estimated difference (and the upper limit of the one-sided 97.5% confidence interval) between succinylcholine and rapacuronium 2.0 mg kg-1 was 7.8 (14.4)% and between succinylcholine and rapacuronium 2.5 mg kg-1 it was 4.0 (10.2)%. For both comparisons, the upper limit of the one-sided confidence interval exceeded the predefined 10% difference. Hence, it could not be demonstrated that the intubating conditions with either of the two doses of rapacuronium were not inferior to those with succinylcholine 1.0 mg kg-1. The increase in heart rate was significantly greater during the first 5 min in the rapacuronium groups, but the arterial pressure increased significantly only in the succinylcholine group (P < 0.001). Respiratory side-effects were observed in 4.0, 13.5 and 18.5% of patients after succinylcholine and rapacuronium 2.0 and 2.5 mg kg-1 respectively (P < 0.05). As the non-inferiority of intubating conditions after rapacuronium 2.0 and 2.5 mg kg-1 could not be proven, succinylcholine should be considered the neuromuscular blocking agent that provides better intubating conditions for rapid-sequence induction.

Direct measurement of mucosal pressures exerted by cuff and non-cuff portions of tracheal tubes with different cuff volumes and head and neck positions.

We measured directly mucosal pressures against the cuff and non-cuff portions of the tracheal tube in different head-neck positions and tested the reliability of calculated mucosal pressures, in vivo intracuff pressures and cuff volume as determinants of directly measured mucosal pressures. We studied 10 anaesthetized, paralysed adult patients. An 8.5-mm, high volume, low pressure PVC tracheal tube was used. Microchip sensors were attached to three cuff locations (anterior, lateral and posterior) and two non-cuff locations (anterior tip and anterior aspect of the tube, 5 cm proximal to the cuff). Directly measured mucosal pressures, in vivo intracuff pressures and calculated mucosal pressures (in vivo minus in vitro intracuff pressures) were determined after brief inflation (< 15 s) to 0, 5, 10 and 15 ml. In vivo intracuff pressures were then set at 30 mm Hg and the measurements repeated, first in the neutral position and then with the head-neck extended, flexed and rotated. Cuff mucosal pressures were highest anteriorly and lowest posteriorly. Non-cuff mucosal pressures did not vary with cuff volume and were approximately 15 mm Hg. Compared with the neutral position, in vivo intracuff pressures were higher in the rotated, extended and flexed positions. Compared with the neutral position, mucosal pressure increased on the anterior aspect of the tube in the flexed position by 22 mm Hg (P = 0.003), at the anterior tip in the extended position by 11 mm Hg (P = 0.002) and at the anterior tip (5 mm Hg, P = 0.05) and lateral aspect of the cuff (5 mm Hg, P = 0.03) in the rotated position. In vivo intracuff pressures and calculated mucosal pressures were moderate predictors of measured mucosal pressures; cuff volume was a poor predictor. We conclude that tracheal mucosal pressures were highest anteriorly, that non-cuff portions of the tube exerted substantial mucosal pressures and that the rotated position caused a greater increase in tracheal mucosal pressure than the extended or flexed position. Indirect methods of measuring mucosal pressure were of moderate predictive value.

Spontaneous or neostigmine-induced recovery after maintenance of neuromuscular block with Org 9487 (rapacuronium) or rocuronium following an initial dose of Org 9487.

We have examined spontaneous and neostigmine-induced recovery after an initial dose of Org 9487 1.5 mg kg-1 followed by three repeat doses of Org 9487, a 30-min infusion of Org 9487 or two incremental doses of rocuronium. Mean clinical duration after incremental doses of Org 9487 0.5 mg kg-1 increased from 12.3 (SD 3.4) min to 14.0 (4.0) and 15.9 (5.9) min (P < 0.01), and after rocuronium from 14.4 (5.2) min to 19.2 (5.9) min (P < 0.01). Times for spontaneous recovery from a T1 of 25% to a TOF ratio of 0.8 after the last bolus dose of Org 9487 and after a 30-min infusion were 72.4 (16.5) and 66.1 (26.9) min compared with 36.7 (15.8) min in the group receiving reocuronium. These times were significantly reduced to 9.9 (4.5), 8.6 (6.1) and 5.7 (2.5) min, respectively, after neostigmine administration at a T1 of 25% (P < 0.05). We conclude that administration of Org 9487 by repeat bolus doses or infusion was associated with slow spontaneous recovery but neostigmine administration resulted in adequate recovery in less than 10 min.

Comparison of intubating conditions after rapacuronium (Org 9487) and succinylcholine following rapid sequence induction in adult patients.

We have assessed intubating conditions provided by rapacuronium (Org 9487) and succinylcholine after rapid sequence induction of anaesthesia in adult patients undergoing elective surgery. We studied 335 patients, ASA I and II, in five centres. Two hundred and thirty-four subjects with normal body weight and 101 obese subjects were allocated randomly to one of four treatment groups differing in the neuromuscular blocking drug administered (rapacuronium 1.5 mg kg-1 or succinylcholine 1 mg kg-1) and in the technique used for induction of anaesthesia (fentanyl 2-3 micrograms kg-1 with thiopental 3-6 mg kg-1 or alfentanil 20 micrograms kg-1 with propofol 1.5-2 mg kg-1). Intubation was started at 50 s by an anaesthetist blinded to the drugs used. Intubating conditions were clinically acceptable (excellent or good) in 89.4% of patients after rapacuronium and in 97.4% after succinylcholine (P = 0.004), the estimated difference being 8.1% (95% confidence interval (CI) 2.0-14.1%). Neither anaesthetic technique nor subject group had an influence on intubating conditions. After intubation, the maximum increase in heart rate averaged 23.1 (SD 25.4%) and 9.4 (26.1%) after rapacuronium and succinylcholine, respectively (P < 0.001). Pulmonary side effects (bronchospasm and increased airway pressure) were observed in 10.7% (95% CI 5.8-17%) and 4.1% (95% CI 1.3-8.8%) of patients given rapacuronium and succinylcholine, respectively (P = 0.021). We conclude that after rapid sequence induction of anaesthesia in adults, clinically acceptable intubating conditions were achieved less frequently after rapacuronium 1.5 mg kg-1 than after succinylcholine.

Patient outcomes with positive pressure versus spontaneous ventilation in non-paralysed adults with the laryngeal mask.

PURPOSE: To compare patient outcomes for positive pressure ventilation (PPV) and spontaneous ventilation (SV) in non-paralysed patients with the LMA using either isoflurane or sevoflurane anaesthesia. METHODS: One hundred and sixty four adult patients were studied. Anaesthesia was with fentanyl/propofol and N2O 66% in O2 with 0.75 MAC isoflurane or sevoflurane and either PPV or SV. Positive pressure ventilation was with tidal volumes of 6-8 ml.kg-1. Peak airway pressures were < 15 cm H2O. Patients were evaluated for airway problems, cardiorespiratory effects, and anaesthesia emergence times. RESULTS: There were no failed episodes of PPV or SV. Gastric insufflation was not detected by epigastric auscultation. Airway problems and cardiovascular effects were similar among groups. During maintenance: SpO2 was greater in the PPV group than in the SV group (98.4 vs 97%, P < 0.001); also, (PETCO2) (34 vs 43 mmHg) and the respiratory rate (RR) (15 vs 19 min-1) were higher and the minute ventilation (MV) (5.7 vs 7.2 L) were lower in the SV groups (P < 0.0001). Shorter times to LMA removal and orientation were observed in the sevoflurane groups (P < 0.0001). CONCLUSIONS: Patient outcome is similar for SV and PPV in non-paralysed adult patients with the LMA. Isoflurane and sevoflurane at 0.75 MAC provide suitable conditions for maintenance and emergence, but emergence is more rapid with sevoflurane.

Thiopental or etomidate for rapid sequence induction with rocuronium.

We have assessed the effect of the choice of i.v. induction agent on intubation conditions, 60 s after administration of rocuronium 0.6 mg kg-1. We studied 60 adult patients, allocated randomly to one of two groups. Anaesthesia was induced with alfentanil 10 micrograms kg-1 followed by thiopental 5 mg kg-1 (AT-R group; n = 30) or etomidate 0.3 mg kg-1 (AE-R group; n = 30). Both groups received rocuronium 0.6 mg kg-1. Laryngoscopy was started 60 s later and intubation conditions were evaluated according to a standard score, which considered ease of laryngoscopy, condition of the vocal cords and reaction to intubation. In the AT-R group, overall intubation conditions were scored as excellent in 20 patients, good in nine and fair in the remaining patient. In the AE-R group, overall intubating conditions were excellent in 24 and good in six patients. The difference between the two groups was not significant. Of the three components of the intubation score assessed, response to intubation stimulus was significantly less pronounced in group AE-R compared with group AT-R (P < 0.05): group AE-R, no reaction in 24 patients, slight diaphragmatic movement in five and mild coughing in one patient; group AT-R, no reaction in 13, slight diaphragmatic movement in 14, mild coughing in two and severe coughing in one patient. We conclude that etomidate as part of an induction regimen containing alfentanil and rocuronium attenuated the reaction to intubation to a greater extent than thiopental.

Positive pressure ventilation with the laryngeal mask airway in non-paralysed patients: comparison of sevoflurane and propofol maintenance techniques.

We have compared anaesthetic maintenance and emergence characteristics of propofol and sevoflurane with the laryngeal mask airway (LMA) at commonly used doses in 185 ASA I-II patients, in a randomized, prospective study. Anaesthesia was induced with propofol 2.5-3.5 mg kg-1 and fentanyl 1-3 micrograms kg-1. Neuromuscular blocking agents were not used. All patients underwent positive pressure ventilation (PPV) with tidal volumes of 6-8 ml kg-1 to maintain normal end-tidal carbon dioxide concentration. Anaesthesia was maintained with 66% nitrous oxide in oxygen and infusion of propofol 6 or 8 mg kg-1 h-1, or 1% or 1.5% end-tidal sevoflurane. There were no failed insertion attempts and adequate ventilation was achieved in all patients. During emergence, there was a greater incidence of excitatory phenomena with 1% and 1.5% sevoflurane (95% confidence intervals (CI) 4-19%) compared with propofol (95% CI 0-4%). Sevoflurane 1.0% (95% CI 37-71%) was associated with the greatest overall incidence of respiratory and haemodynamic problems. This was significantly higher compared with propofol 6 mg kg-1 h-1 (95% CI 19-36%). Shorter times to LMA removal were observed with 1% and 1.5% sevoflurane compared with propofol (P < 0.0002). Postoperative problems did not differ between groups. We conclude that propofol 6-8 mg kg-1 h-1 and 1.5% sevoflurane were suitable for maintenance of anaesthesia for musculoskeletal surgery in non-paralysed ASA I-II patients undergoing PPV with the LMA. Emergence was more rapid with sevoflurane, but was associated with more excitatory phenomena.

Laryngeal mask bite blocks--rolled gauze versus Guedel airway.

BACKGROUND: Biting on the silicone tube and pilot balloon of the laryngeal mask airway (LMA) may obstruct or damage them with the teeth and a bite block is recommended. The recommended bite block is a wad of gauze swabs rolled into a cylindrical shape and placed alongside the LMA. It is considered that this avoids irritating the posterior pharyngeal wall and damage to teeth whilst supporting the LMA tube when taped to it. The Guedel airway is commonly used as a bite block with the tracheal tube and many anaesthetists also use it with the LMA. The aim of the following study was to compare rolled gauze swabs with a Guedel airway as a bite block for the LMA. METHODS: We compared the Guedel airway with rolled gauze swabs as a bite block for the laryngeal mask airway (LMA) in 120 ventilated patients in whom cuff pressures were limited to 5.87 kPa (60 cm H2O) and anaesthesia management was standardised. RESULTS: In the Guedel airway group, there was a higher incidence of ventilatory problems (0 vs 4, P < 0.05), bleeding (0 vs 8, P < 0.01), hoarseness (0 vs 4, P < 0.05) and sore throat (2 vs 12, P < 0.01). CONCLUSION: 1. The Guedel airway is an unsuitable bite block for the LMA. 2. Cuff pressure limitation is compatible with adequate ventilation. 3. The combination of LMA and Guedel airway probably prevents either from sitting in the correct anatomical position.

Laryngeal mask lubrication. A comparative study of saline versus 2% lignocaine gel with cuff pressure control.

We compared 2% lignocaine gel with saline as a lubricant for the laryngeal mask airway in 126 patients receiving positive pressure ventilation in whom cuff pressures were limited to 60 cmH2O and peak airway pressures to less than 17 cmH2O. The incidence of sore throat was similar for both groups and there were no emergence problems. There were significantly more intra- and postoperative complications in the lignocaine group (p < 0.05) but the frequency of sore throat was similar when the device was inserted at the first attempt. Positive pressure ventilation to normal end-tidal CO2 values was possible in all patients. Lignocaine gel is an unsuitable lubricant for the laryngeal mask airway. Cuff pressure limitation to 60 cmH2O does not necessarily impede ventilation and may be an important factor in reducing emergence and postoperative complications.