Intravenous magnesium re-establishes neuromuscular block after spontaneous recovery from an intubating dose of rocuronium: a randomised controlled trial.

CONTEXT: Intravenous magnesium deepens non-depolarising neuromuscular block. OBJECTIVE: To assess whether intravenous magnesium has the potential to re-establish paralysis in patients who have just recovered from a non-depolarising neuromuscular block. DESIGN: Prospective randomised double-blind controlled study. PATIENTS: Twenty non-obese patients ranging in age from 18 to 80 years were enrolled. Exclusion criteria were a history of liver, kidney or neuromuscular disease and intake of medications interacting with neuromuscular blocking agents. INTERVENTION: After spontaneous recovery from an intubating dose of rocuronium had been achieved (train-of-four ratio ≥0.9), patients were given either a bolus dose of magnesium 50 mg kg(-1) intravenously or an equivalent volume of isotonic saline over 5 min. MAIN OUTCOME MEASURES: The train-of-four ratio was measured every minute until the end of surgery. The primary endpoint was the proportion of patients who experienced a decrease in train-of-four ratio following administration of magnesium or saline. RESULTS: Following infusion of the study solution, the train-of-four ratio decreased in all patients in the magnesium group in contrast to none in the saline group (P<0.001). On average, magnesium-induced train-of-four ratio depression reached a nadir of 0.49 after 10 min and lasted for 45 min. CONCLUSION: A bolus dose of intravenous magnesium 50 mg kg(-1) re-establishes a clinically relevant degree of muscle paralysis in patients who have just recovered from a non-depolarising neuromuscular block. TRIAL REGISTRATION: EudraCT.ema.europa.eu 2009-017372-24.

Influence of anesthesia on cerebral blood flow, cerebral metabolic rate, and brain functional connectivity.

PURPOSE OF REVIEW: To describe recent studies exploring brain function under the influence of hypnotic anesthetic agents, and their implications on the understanding of consciousness physiology and anesthesia-induced alteration of consciousness. RECENT FINDINGS: Cerebral cortex is the primary target of the hypnotic effect of anesthetic agents, and higher-order association areas are more sensitive to this effect than lower-order processing regions. Increasing concentration of anesthetic agents progressively attenuates connectivity in the consciousness networks, while connectivity in lower-order sensory and motor networks is preserved. Alteration of thalamic sub-cortical regulation could compromise the cortical integration of information despite preserved thalamic activation by external stimuli. At concentrations producing unresponsiveness, the activity of consciousness networks becomes anticorrelated with thalamic activity, while connectivity in lower-order sensory networks persists, although with cross-modal interaction alterations. SUMMARY: Accumulating evidence suggests that hypnotic anesthetic agents disrupt large-scale cerebral connectivity. This would result in an inability of the brain to generate and integrate information, while external sensory information is still processed at a lower order of complexity.

Perioperative management of a child with von Willebrand disease undergoing surgical repair of craniosynostosis: looking at unusual targets.

We report the successful management of a craniosynostosis repair in a child with severe Type I von Willebrand disease diagnosed during the preoperative assessment and treated by coagulation factor VIII and ristocetin cofactor. Collaboration among the anesthesiologist, the neurosurgeon, the clinical pathologist, and the pediatric hematologist is important for successful management.

Awake craniotomy.

Awake craniotomy has become an increasingly frequent procedure. In this paper, the principles of its anaesthetic management are reviewed. The means allowing achievement of anaesthetic objectives are described, with emphasis on points that determine success of the procedure. A careful and adequate selection and preparation of patients are mandatory, and the intervening team must be a skilled team. Choosing an awake technique or general anaesthesia depends on several factors, including the risk of obstructive apnoea, seizures, nausea and vomiting, patient's ability to cooperate, and localization of lesions. The main challenge of intraoperative anaesthetic management relies on the ability of rapidly adjusting the level of sedation and analgesia according to the sequence of surgical events, while ensuring haemodynamic stability, adequate ventilation, and minimal interference with eventual electrophysiological recordings. Throughout the procedure, complications must be anticipated and managed according to predefined guidelines. More prospective randomized clinical trials are still needed to improve safety and efficacy of awake craniotomies, as well as to validate this technique in comparison with more conventional anaesthetic management.

Management of the unstable cervical spine: elective versus emergent cases.

PURPOSE OF REVIEW: The present review focuses on similarities and discrepancies in the management of emergent and elective unstable cervical spine (C-spine) patients. RECENT FINDINGS: During mobilization, lifting is superior to rolling in limiting spine movements. Before prone position surgery, the transfer of the patient on a rotating table is preferable to rolling. In trauma patients, helical computed tomography (CT) with sagittal reconstruction is the first choice for clearing the C-spine. In those patients, airway compromise may be related to hidden cervical edema or hematoma. Several devices can be of help in performing safe tracheal intubation in patients with limited neck movements, but awake fiberoptic intubation remains the safest procedure. The muscle relaxant antagonist sugammadex can improve safety for rapid sequence induction. It can rapidly reverse profound steroid-based neuromuscular blockade and allows avoidance of succinylcholine in this indication. Propofol anesthesia better prevents coughing upon emergence than inhaled anesthesia. Neuroprotection in cord-damaged patients is disappointing, and the controversy on the efficacy of high-dose methylprednisolone is not closed. Nevertheless, maintenance of homeostasis remains the cornerstone of neuroprotection. SUMMARY: Subtle details differentiate the management of emergent and elective unstable C-spine patients. In both situations, the presence or the absence of a neurological insult governs the therapeutic strategy.

The effect of clonidine infusion on distribution of regional cerebral blood flow in volunteers.

BACKGROUND: Through their action on the locus coeruleus, alpha2-adrenoceptor agonists induce rapidly reversible sedation while partially preserving cognitive brain functions. Our goal in this observational study was to map brain regions whose activity is modified by clonidine infusion so as to better understand its loci of action, especially in relation to sedation. METHODS: Six ASA I-II right-handed volunteers were recruited. Electroencephalogram (EEG) was monitored continuously. After a baseline H2(15)O activation scan, clonidine infusion was started at a rate ranging from 6 to 10 microg x kg(-1) x h(-1). A sequence of 11 similar scans was then performed at 8 min intervals. Plasma clonidine concentration was measured. Using statistical parametric mapping, we sought linear correlations between normalized regional cerebral blood flow (rCBF), an indicator of regional brain activity, and plasma clonidine concentration or spindle EEG activity. RESULTS: Clonidine induced clinical sedation and EEG patterns (spindles) comparable to early stage nonrapid eye movement sleep. A significant negative linear correlation between clonidine concentration and rCBF or spindle activity was observed in the thalamus, prefrontal, orbital and parietal association cortex, posterior cingulate cortex, and precuneus. CONCLUSIONS: The EEG patterns and decreases in rCBF of specific brain regions observed during clonidine-induced sedation are similar to those of early stage nonrapid eye movement sleep. Patterns of deactivated brain regions are also comparable to those observed during general anesthesia or vegetative state, reinforcing the hypothesis that alterations in the activity of a common network occur during these modified conscious states.

Does propofol alter membrane fluidity at clinically relevant concentrations? An ESR spin label study.

General anesthetics have been shown to perturb the membrane properties of excitable tissues. Due to their lipid solubility, anesthetics dissolve in every membrane, penetrate into organelles and interact with numerous cellular structures in multiple ways. Several studies indicate that anesthetics alter membrane fluidity and decrease the phase-transition temperature. However, the required concentrations to induce such effects on the properties of membrane lipids are by far higher than clinically relevant concentrations. In the present study, the fluidizing effect of the anesthetic agent propofol (2,6-diisopropyl phenol: PPF), a general anesthetic extensively used in clinical practice, has been investigated on liposome dimyristoyl-L-alpha phosphatidylcholine (DMPC) and cell (erythrocyte, Neuro-2a) membranes using electron spin resonance spectroscopy (ESR) of nitroxide labeled fatty acid probes (5-, 16-doxyl stearic acid). A clear effect of PPF at concentrations higher than the clinically relevant ones was quantified both in liposome and cell membranes, while no evident fluidity effect was measured at the clinical PPF doses. However, absorption spectroscopy of merocyanine 540 (MC540) clearly indicates a PPF fluidizing capacity in liposome membrane even at these clinical concentrations. PPF may locally influence the structure and dynamics of membrane domains, through the formation of small-scale lipid domains, which would explain the lack of ESR information at low PPF concentrations.

Bispectral index profile during carotid cross clamping.

This study aimed at investigating the Bispectral Index (BIS) profile during carotid cross clamping (CXC). The study involved a pilot group of 10 patients undergoing routine carotid endarterectomy with shunt insertion under total intravenous anesthesia, and a study group of 26 additional patients. In all patients, rates of propofol and remifentanil providing a steady-state level of hypnosis (BIS: 40-60) were maintained constant throughout a recording period ranging from 3 minutes before CXC to shunt insertion. BIS was recorded throughout this period and the internal carotid backflow observed at the time of shunt insertion was graded as good, moderate, or poor. In addition, A-Line Autoregressive Index (AAI) and processed electroencephalogram (EEG) parameters were recorded in patients of the study group. All parameters were averaged over 1 minute before CXC, at CXC, 1, 2, and 3 minutes after CXC, and at shunt insertion. Statistical analysis was performed using chi2, Friedman, and Spearman correlation tests. For technical reasons, reliable AAI, BIS monitor-derived, and other processed EEG data were obtained in 24, 25, and 18 patients of the study group, respectively. During the first 3 minutes after CXC, BIS increased over 60 [68.8 (6.1)] in 47%, decreased below 40 [34.9 (4.4)] in 25%, and remained in the 40 to 60 range in 28% of all recruited patients. A BIS increase was more frequently observed in patients with moderate or poor than in those with good internal carotid backflow (78, 67, and 29%, respectively). It was significantly correlated to an increase in AAI and EEG amplitude, a decrease in EEG suppression ratio, and a shorter time between induction of anesthesia and CXC. A BIS decrease was significantly correlated to an increase in suppression ratio and a longer time between induction and CXC. In conclusion, during CXC under a constant level of intravenous anesthesia, BIS may increase, decrease, or remain unchanged. The paradoxical BIS increase could be related to borderline ischemia, a change in brain anesthetic agent concentration, or a change in the nociceptive-antinociceptive balance associated with a CXC-elicited painful stimulation. Caution should be used when interpreting BIS value during CXC.

Quantification of lipid bilayer effective microviscosity and fluidity effect induced by propofol.

Electron spin resonance (ESR) spectroscopy with nitroxide spin probes was used as a method to probe the liposome microenvironments. The effective microviscosities have been determined from the calibration of the ESR spectra of the probes in solvent mixtures of known viscosities. In the first time, by measuring ESR order parameter (S) and correlation time (tau(c)) of stearic spin probes, we have been able to quantify the value of effective microviscosity at different depths inside the liposome membrane. At room temperature, local microviscosities measured in dimyristoyl-l-alpha phosphatidylcholine (DMPC) liposome membrane at the different depths of 7.8, 16.95, and 27.7 A were 222.53, 64.09, and 62.56 cP, respectively. In the gel state (10 degrees C), those microviscosity values increased to 472.56, 370.61, and 243.37 cP. In a second time, we have applied this technique to determine the modifications in membrane microviscosity induced by 2,6-diisopropyl phenol (propofol; PPF), an anaesthetic agent extensively used in clinical practice. Propofol is characterized by a unique phenolic structure, absent in the other conventional anaesthetics. Indeed, given its lipophilic property, propofol is presumed to penetrate into and interact with membrane lipids and hence to induce changes in membrane fluidity. Incorporation of propofol into dimyristoyl-l-alpha phosphatidylcholine liposomes above the phase-transition temperature (23.9 degrees C) did not change microviscosity. At 10 degrees C, an increase of propofol concentration from 0 to 1.0 x 10(-2) M for a constant lipid concentration mainly induced a decrease in microviscosity. This fluidity effect of propofol has been qualitatively confirmed using merocyanine 540 (MC540) as lipid packing probe. Above 10(-2) M propofol, no further decrease in microviscosity was observed, and the microviscosity at the studied depths (7.8, 16.95, and 27.7 A) amounted 260.21, 123.87, and 102.27 cP, respectively. The concentration 10(-2) M was identified as the saturation limit of propofol in dimyristoyl-l-alpha phosphatidylcholine liposomes.

Propofol scavenges reactive oxygen species and inhibits the protein nitration induced by activated polymorphonuclear neutrophils.

Activated polymorphonuclear neutrophils may damage tissues through the release of biochemical mediators. Among them, peroxynitrite is responsible for hydroxylation reactions and nitration of proteins, or is metabolised into nitrate. We investigated the effect of propofol on the production of reactive oxygen species, the nitration of proteins and the formation of nitrate by activated human polymorphonuclear neutrophils. Propofol dose-dependently inhibited chemiluminescence, nitration of proteins and nitrate production in a concentration range from 10(-3) to 10(-6) mM. A significant correlation was observed between the logarithm of propofol concentration and the intensity of chemiluminescence (r2=0.90), the nitration of proteins (r2=0.67) and the production of nitrate (r2=0.79). Those results are consistent with the scavenging effect of propofol on peroxynitrite and could confer a protective property to propofol in pathological situations involving polymorphonuclear neutrophils activation.

Epidural hematoma after cervical spine surgery.

The authors report an acute epidural hematoma after the surgical removal of a cervical C6-C7 disc herniation through an anterolateral approach of the cervical spine. Clinical history consisted of respiratory distress and flaccid tetraplegia that appeared 2.5 hours after surgery. Without any complementary radiologic investigation, the patient was immediately transferred to the operating room for a second look, which was unsuccessful. Magnetic resonance imaging performed after this second surgical procedure showed an anterior cervical hematoma extending from C3 to T3 without significant spinal cord compression. A cervical laminectomy was performed to evacuate the hematoma. The patient was extubated the next morning and discharged from the hospital after 5 days with no residual neurologic deficit. An extensive postoperative investigation revealed no coagulation disorder.

Epidural administration of low-dose morphine combined with clonidine for postoperative analgesia after lumbar disc surgery.

This study evaluates the efficacy and side effects of a low dose of epidural morphine combined with clonidine for postoperative pain relief after lumbar disc surgery. In 36 of 51 patients who accepted the procedure, an epidural catheter was inserted (L1-L2 level). General anesthesia was induced with propofol and sufentanil, and maintained with sevoflurane in O2/N2O. After emergence from anesthesia, epidural analgesia was initiated according to two randomly assigned protocols: 1 mg of morphine with 75 microg of clonidine (Group M) or 12.5 mg of bupivacaine with 75 microg of clonidine (Group B), in 10 mL saline. Piritramide was administered during the first postoperative 24 hours using a patient-controlled analgesia device (PCA). The following parameters were recorded: piritramide consumption during the first 24 hours; pain at rest during the first postoperative hours (D0), during the first night (D1), and during the first mobilization; [visual analogue scale (VAS)]; and the occurrence of drowsiness, motor blockade, respiratory depression, nausea, vomiting, itching, micturition problems, and bladder catheterization during D0 and D1. Epidural administration of morphine-clonidine significantly improved postoperative pain relief and reduced piritramide consumption as compared to epidural bupivacaine-clonidine. Side effects did not differ between groups except for a higher incidence of micturition problems in Group M during D1. The occurrence of bladder catheterization was not significantly higher in that group. We conclude that a low dose of epidural morphine combined with clonidine offers a better postoperative analgesia than does bupivacaine-clonidine. The excellent analgesic conditions were obtained at the expense of a higher incidence of difficulties in initiating micturition.

Acid-base status and hemodynamic stability during propofol and sevoflurane-based anesthesia in patients undergoing uncomplicated intracranial surgery.

Propofol anesthesia may induce metabolic disturbances and sevoflurane anesthesia arterial hypotension. This study compares both techniques regarding acid-base and hemodynamic status during intracranial surgery. Sixty-one patients were randomized into 2 groups according to anesthesia maintenance, a propofol group (n=30), and a sevoflurane group (n=31). The anesthesia protocol including rocuronium and remifentanil infusion was otherwise similar in both groups. Arterial blood samples were drawn every 2 hours during the procedure and upon arrival in the intensive care unit to assess acid-base status. The number of hypotensive and hypertensive events served to assess hemodynamic stability. Metabolic acidosis was more frequent during propofol than sevoflurane anesthesia (7 out of 29 and 1 out of 31, P=0.02). Its severity was linearly correlated with lactate concentration (R=0.32), total dose of propofol (R=0.2), and length of procedure (R=0.28). Hyperlactacidemia was also observed during sevoflurane anesthesia, but without acidosis. Hypertension occurred more frequently during propofol than sevoflurane anesthesia (13 out of 30 vs. 1 out of 31, P<0.001), particularly in patients with a past medical history of hypertension. Higher remifentanil infusion rates reduced the risk of hypertension. Conversely, sevoflurane anesthesia favored arterial hypotension (22 out of 31 vs. 12 out of 30, P=0.015). Preoperative morning administration of antihypertensive medications to patients with a history of arterial hypertension was associated with a low probability of hypertensive events, at the cost of more frequent hypotension. In conclusion, propofol anesthesia for intracranial surgery is more frequently associated with lactic acidosis and hypertension; sevoflurane anesthesia may favor arterial hypotension.

Effective reversal of moderate rocuronium- or vecuronium-induced neuromuscular block with sugammadex, a selective relaxant binding agent.

BACKGROUND: Sugammadex rapidly reverses rocuronium-induced neuromuscular block. This study explored the dose-response relation of sugammadex given as a reversal agent at reappearance of the second muscle twitch after rocuronium- and vecuronium-induced block. A secondary objective was to investigate the safety of single doses of sugammadex. METHODS: In this two-center, phase II, dose-finding study, 80 patients (age >or= 18 yr, American Society of Anesthesiologists physical status I or II, surgery >or= 60 min requiring muscle relaxation for intubation) were randomly assigned to receive rocuronium (0.60 mg/kg) or vecuronium (0.10 mg/kg). Sugammadex or placebo was administered at reappearance of the second muscle twitch. The primary efficacy endpoint was time from starting sugammadex administration until recovery of the train-of-four ratio to 0.9. RESULTS: Compared with placebo, sugammadex produced dose-dependent decreases in mean time to recovery for all train-of-four ratios in the rocuronium and vecuronium groups. The mean time for recovery of the train-of-four ratio to 0.9 in the rocuronium group was 31.8 min after placebo compared with 3.7 and 1.1 min after 0.5 and 4.0 mg/kg sugammadex, respectively. The mean time for recovery of the train-of-four ratio to 0.9 in the vecuronium group was 48.8 min after placebo, compared with 2.5 and 1.4 min after 1.0 and 8.0 mg/kg sugammadex, respectively. Sugammadex was well tolerated. CONCLUSION: Sugammadex rapidly reversed rocuronium- or vecuronium-induced neuromuscular block at reappearance of the second muscle twitch and was well tolerated. A dose-response relation was observed with sugammadex for reversal of both rocuronium- and vecuronium-induced neuromuscular block.

Why we still use intravenous drugs as the basic regimen for neurosurgical anaesthesia.

PURPOSE OF REVIEW: Evolution of neurosurgery mainly trends towards minimally invasive and functional procedures including endoscopies, small-size craniotomies, intraoperative imaging and stereotactic interventions. Consequently, new adjustments of anaesthesia should aim at providing brain relaxation, minimal interference with electrophysiological monitoring, rapid recovery, patients' cooperation during surgery and neuroprotection. RECENT FINDINGS: In brain tumour patients undergoing craniotomy, propofol anaesthesia is associated with lower intracranial pressure and cerebral swelling than volatile anaesthesia. Hyperventilation used to improve brain relaxation may decrease jugular venous oxygen saturation below the critical threshold. It decreases the cerebral perfusion pressure in patients receiving sevoflurane, but not in those receiving propofol. The advantage of propofol over volatile agents has also been confirmed regarding interference with somatosensory, auditory and motor evoked potentials. Excellent and predictable recovery conditions as well as minimal postoperative side-effects make propofol particularly suitable in awake craniotomies. Finally, the potential neuroprotective effect of this drug could be mediated by its antioxidant properties which can play a role in apoptosis, ischaemia-reperfusion injury and inflammatory-induced neuronal damage. SUMMARY: Although all the objectives of neurosurgical anaesthesia cannot be met by one single anaesthetic agent or technique, propofol-based intravenous anaesthesia appears as the first choice to challenge the evolution of neurosurgery in the third millennium.

Catalytic activation of copper (II) salts on the reaction of peroxynitrite with propofol in alkaline medium.

We report here on the role of copper (II) salts on the acceleration of peroxynitrite (ONOO-) decomposition and ONOO- reaction with the anaesthetic agent propofol (2,6-diisopropylphenol) in alkaline medium. We observed a strong acceleration of the ONOO- decomposition in alkaline medium in the presence of copper (I and II) salts. After 18 h of ONOO- reaction with propofol, we observed nitrosated, nitrated, and oxidized (quinone and diphenylquinone) derivatives of propofol, but in the presence of Cu(II) (20% molar vs ONOO-), the yields of quinone and nitrosopropofol strongly increased. We also observed that the temperature and the atmosphere influenced the effects of Cu(II) on ONOO- reactions with propofol: low temperatures promoted nitrosation and high temperatures promoted oxidation; O2 atmosphere increased the general reactivity and the yield of nitrated and oxidized products. We highlighted the influence of Cu(II) salts on the radical character of the reaction by direct EPR technique. The exact mechanism of the Cu(II) catalysis remains unexplained, but we suggest the formation of a copper complex with propofol or, more probably, the oxidation of ONOO- into ONOO. by copper ions promoting the formation of quinone and nitrosopropofol according to a previously reported mechanism [M. Cudic, C. Ducrocq, Transformations of 2,6-diisopropylphenol by NO-derived nitrogen oxides, particularly peroxynitrite, Nitric Oxide 4 (2000) 147-156].

Investigation of singlet oxygen reactivity towards propofol.

The reaction between the anaesthetic agent 2,6-diisopropylphenol (propofol, PPF) and singlet oxygen (1O2) has been investigated in aqueous solution by means of HPLC, GC, absorption spectroscopy and laser flash photolysis with infrared luminescence detection. The rate constants for the physical and chemical quenching of 1O2 by PPF (kPPF) are found to be 2.66 x 10(5) M(-1) s(-1) and approximately 3.2 x 10(6) M(-1) s(-1) in CD3OD and D2O-CD3OD (75:25 v/v), respectively. The reaction of propofol with singlet oxygen produced by light irradiation of Rose Bengal leads essentially to two reaction products, 2,6-diisopropyl-p-benzoquinone and 3,5,3',5'-tetraisopropyl-(4,4')-diphenoquinone that are unambiguously identified from comparison with authentic samples.

Investigation of the reaction of peroxynitrite with propofol at acid pH: predominant production of oxidized, nitrated, and halogenated derivatives.

We reported here the reaction, in acidic conditions, of peroxynitrite (ONOO(-)) with the anaesthetic agent propofol (2,6-diisopropylphenol, PPF). The most interesting finding is that peroxynitrite is able to nitrate and to oxidize propofol leading to 4-nitropropofol, quinone, and diphenylquinone as the major products. More surprisingly, we also found that peroxynitrite is capable of halogenating propofol in the presence of halide ions, suggesting the formation of nitrosyl chloride (NOCl) or nitryl chloride (NO(2)Cl) from the reaction of peroxynitrite with chloride ions. A significant enhancement of the halogenation yield is observed with a simultaneous decrease of the yields of the other products in the presence of methanol or hydrogen peroxide. Increased halogenation of PPF probably results from the formation of peroxynitrate (O(2)NOO(-)), that further oxidizes chloride ions in hypochlorous acid (HOCl) or molecular chlorine (Cl(2)). Spontaneous decay of peroxynitrate is relatively slow in acidic medium, thus explaining the decrease of the yields of the other products. By direct EPR techniques, we also observed that this reaction occurs via a radical pathway.