Relationship between bispectral index,auditory evoked potential index and effect-site EC50 for propofol at two clinical end-points

Background. Many anaesthetists are deterred from using totali.v. anaesthesia because of uncertainty over the concentrationof propofol required to prevent awareness. We predicted bloodand effect-site concentrations of propofol at two clinical end-points:loss of consciousness and no response to a painful stimulus. Methods. Forty unpremedicated Caucasian patients were anaesthetizedwith i.v. propofol delivered by a Diprifusor target-controlledinfusion (TCI). Bispectral index (BIS) and auditory evoked potentialindex (AEPex) were measured and blood and effect-site propofolconcentrations were predicted. Logistic regression was usedto estimate population values for predicted blood and effect-sitepropofol concentrations at the clinical end-points and to correlatethese with BIS and AEPex. Results. The effect-site EC₅₀ at loss of consciousness was 2.8 µm ml^–1with an EC₀₅ and an EC₉₅ of 1.5 and 4.1 µm ml^–1,respectively. The predicted EC₅₀ when there was no responseto a tetanic stimulus was 5.2 µm ml^–1 withan EC₀₅ and an EC₉₅ of 3.1 and 7.2 µm ml^–1,respectively. Conclusions. Unconsciousness and lack of response to a painfulstimulus occur within a defined range of effect-site concentrations,predicted by Diprifusor TCI software. Br J Anaesth 2003; 90: 127–31     

A novel method of deriving the effect compartment equilibrium rate constant for propofol

Background. Calculation of the effect compartment concentration(C_e) in non-steady-state conditions requires the equilibriumrate constant, k_eo. Most studies of propofol derive the k_eousing EEG measurements. This study investigated an alternativemethod. Starting from a predicted concentration–time profile,a k_eo value was included so that the predicted C_e at a specificpharmacodynamic end-point was the same when using three differentmethods of injection. Methods. Seventy-five patients were given propofol for inductionof anaesthesia. Twenty-five patients received a single bolus,25 patients received an infusion, and 25 patients received abolus followed by an infusion. Computer simulation was usedto derive the central compartment concentration. The k_eo thatbrought about the same value for C_e at loss of the eyelash reflexusing the three methods of injection was derived. Results. K_eo was found to be 0.80 min^–1. Mean (SD) C_eat loss of the eyelash reflex was 2.27 (0.69) µg ml^–1. Conclusions. The effect compartment equilibrium rate constantand concentration at loss of the eyelash reflex can be derivedwithout the use of electronic central nervous system monitors. Br J Anaesth 2003; 91: 730–2     

Relation between fentanyl dose and predicted EC50 of propofol for laryngeal mask insertion

Background. This study sought to determine the effective concentrationfor 50% of the attempts to secure laryngeal mask insertion (predictedEC_50LMA) of propofol using a target-controlled infusion (Diprifusor^TM)and investigated whether fentanyl influenced these requiredconcentrations, respiratory rate (RR) and bispectral index (BIS). Methods. Sixty-four elective unpremedicated patients were randomlyassigned to four groups (n = 16 for each group) and given saline(control) or fentanyl 0.5, 1 or 2 µg kg^–1.Propofol target concentration was determined by a modificationof Dixon’s up-and-down method. Laryngeal mask airway insertionwas attempted without neuromuscular blocking drugs after equilibrationhad been established for >10 min. Movement was defined aspresence of bucking or gross purposeful muscular movement within1 min after insertion. EC_50LMA values were obtained by calculatingthe mean of 16 patients in each group. Results. Predicted EC_50LMA of the control, fentanyl 0.5, 1 and2 µg kg^–1 groups were 3.25 (0.20), 2.06 (0.55),1.69 (0.38) and 1.50 (0.54) µg ml^–1 respectively;those of all fentanyl groups were significantly lower than thatof control. RR was decreased in relation to the fentanyl doseup to 1 µg kg^–1. BIS values after fentanyl1 and 2 µg kg^–1 were significantly greaterthan in the control and 0.5 µg kg^–1 groups. Conclusions. A fentanyl dose of 0.5 µg kg^–1is sufficient to decrease predicted EC_50LMA with minimum respiratorydepression and without a high BIS value. Br J Anaesth 2004; 92: 238–41     

Predicted values of propofol EC50 and sevoflurane concentration for insertion of laryngeal mask Classic and ProSeal

Background. A new laryngeal mask airway, the ProSeal^TM (PLMA),is said to be more difficult to insert than the laryngeal maskairway Classic^TM (CLMA) using propofol anaesthesia. Therefore,we expected a greater dose of propofol and sevoflurane to berequired to insert the PLMA compared with the CLMA. We determinedthe effective concentration 50% (EC₅₀) of propofol and end-tidalsevoflurane to allow insertion of the PLMA and the CLMA. Methods. Seventy-six elective female patients (aged 20–60yr and ASA I–II) were randomly assigned to one of fourgroups. Either a PLMA or a CLMA was inserted using either propofoltarget controlled infusion or sevoflurane. Both propofol andsevoflurane targets were determined with a modified Dixon’sup-and-down method. After equilibration between the predeterminedblood and effect site concentrations, which had been held steadyfor more than 10 min, LMA insertion was attempted without neuromuscularblock. Results. The predicted EC_50CLMA and EC_50PLMA for propofol were3.14 (0.33) and 4.32 (0.67) µg ml^–1. E'_CLMAand E'_PLMA of sevoflurane (mean (SD)) were 2.36 (0.22) and 2.82(0.45)% (P<0.01 and 0.05, respectively). Conclusions. The estimated concentration of propofol and thesevoflurane concentration needed to allow insertion of the ProSeal^TMare respectively 38 and 20% greater than those needed for insertionof the Classic LMA. Br J Anaesth 2004; 92: 242–5     

DOSE REQUIREMENTS OF PROPOFOL BY INFUSION DURING NITROUS OXIDE ANAESTHESIA IN MAN: I: Patients Premedicated with Morphine Sulphate

The study was performed to determine the ED₅₀ and ED₉₅ of acontinuous infusion of the emulsion formulation of propofolduring 67% nitrous oxide anaestheisa in 57 patients premed-icatedwith morphine sulphate 0.15 mg kg^–1. Anaesthesia was inducedwith propofol 2 mg kg^–1, and maintained before incisionwith a fixed-rate infusion of propofol to supplement nitrousoxide. The response to the first surgical incision, made atleast 30 min after induction of anaesthesia, was observed. TheED₅₀; was 53.5 µg kg^–1 min^–1 and the ED₉₅was 112.2 µg kg^–1 min^–1. At the time of thefirst surgical incision, the venous whole blood concentrationsof propofol at the ED₅₀ and ED₉₅ infusion rates (EC₅₀and EC₉₅were 1.66 µg ml^–1 and 3.39 fig ml^–1 respectively.The satisfactory maintenance of anaesthesia provided by nitrousoxide supplemented with propofol was associated with stabilityand rapid, uncomplicated recovery.     

Influence of acute normovolaemic haemodilution on the dose-response relationship, time-course of action and pharmacokinetics of rocuronium bromide

Background. Acute normovolaemic haemodilution (ANH) is an effectivestrategy for avoiding or reducing allogeneic blood transfusion.We aimed to study its effect on the pharmacological profileof rocuronium. Methods. In two study centres, 28 patients undergoing majorsurgery with ANH were matched with 28 control patients. In thedose–response groups, using the mechanomyograph, neuromuscularblock of six consecutive incremental doses of rocuronium 50µg kg^–1, followed by 300 µg kg^–1, wasevaluated. In the pharmacokinetics groups, serial arterial bloodsamples were withdrawn for rocuronium assay after a single doseof rocuronium 600 µg kg^–1. Results. ANH resulted in a shift to the left of rocuronium dose–responsecurve. Rocuronium effective dose₉₅ (ED₉₅) was 26% lower (P<0.05)in the ANH group [283.4 (92.0) µg kg^–1] comparedwith the control group [383.5 (127.3) µg kg^–1].Times from administration of last incremental dose until 25%of first response of train-of-four (TOF) recovery (Dur₂₅) and0.8 TOF ratio recovery (Dur_0.8) were 28% longer in the ANH group[39.9 (8.4), 66.7 (14.2) min] compared with the control group[31.1 (6.6), 52.1 (15.8) min] (P<0.01, P<0.05), respectively.Volume of distribution was higher (P<0.01), central clearancewas lower (P<0.05) and terminal elimination half-life waslonger (P<0.0001) in the ANH group [234.97 (47.11) ml kg^–1,4.70 (0.94) ml kg^–1 min^–1, 77.29 (12.25) min] comparedwith the control group [181.22 (35.73) ml kg^–1, 5.71 (1.29)ml kg^–1 min^–1, 56.86 (10.05) min, respectively]. Conclusion. ANH resulted in prolongation of rocuronium time-courseof action, thus careful monitoring of neuromuscular block isrecommended in patients who undergo ANH.     

Pharmacokinetics of levobupivacaine 0.25% following caudal administration in children under 2 years of age

Background. Levobupivacaine, the S(–)enantiomer of racemicbupivacaine is less cardiotoxic than racemic bupivacaine andthe R(+)enantiomer dexbupivacaine, while retaining similar localanaesthetic properties and potency to racemic bupivacaine. Thepharmacokinetic profiles of the two bupivacaine enantiomersdiffers and that of racemic bupivacaine may be age dependent.We examined the pharmacokinetics of levobupivacaine after itssingle shot caudal epidural administration in children. Methods. An open-label phase 2 study was undertaken to examinethe pharmacokinetics of levobupivacaine 0.25% 2 mg kg^–1in 49 children aged less than 2 yr, after single shot caudalepidural administration. Plasma concentrations were determinedat intervals up to 60 min after caudal injection. Results. Time to peak plasma concentration (T_max) ranged between5 and 60 min (median 30 min) and was reached later in childrenaged less than 3 months (P<0.005). Peak plasma concentration(C_max) ranged between 0.41 and 2.12 µg ml^–1 (median0.80, mean (SD) 0.91 (0.40) µg ml^–1). Conclusion. After the caudal epidural administration of levobupivacaine2 mg kg^–1 in children less than 2 yr of age, C_max waswithin the accepted safe range for racemic bupivacaine. T_maxvaried and occurred later in some children, particularly thoseaged less than 3 months. Sampling in future pharmacokineticstudies in this age group should extend beyond 60 min. Br J Anaesth 2004; 92: 218–22     

Dexmedetomidine as an anaesthetic adjuvant in patients undergoing intracranial tumour surgery: a double-blind, randomized and placebo-controlled study

Background. Dexmedetomidine (DEX) has been shown to providegood perioperative haemodynamic stability with decreased intraoperativeopioid requirements. It may have neural protective effects,and thus may be a suitable anaesthetic adjuvant to neurosurgicalanaesthesia. Methods. Fifty-four patients scheduled for elective surgeryof supratentorial brain tumour were randomized to receive ina double-blind manner a continuous DEX infusion (plasma targetconcentration 0.2 or 0.4 ng ml^–1) or placebo, beginning20 min before anaesthesia and continuing until the start ofskin closure. The DEX groups received fentanyl 2 µg kg^–1at the induction of anaesthesia and before the start of operation,the placebo group 4 µg kg^–1, respectively. Anaesthesiawas maintained with nitrous oxide in oxygen and isoflurane. Results. The median times from the termination of N₂O to extubationwere 6 (3–27), 3 (0–20) and 4 (0–13) min inplacebo, DEX-0.2 and DEX-0.4 groups, respectively (P<0.05ANOVA all-over effect). The median percentage of time pointswhen systolic blood pressure was within more or less than 20%of the intraoperative mean was 72, 77 and 85, respectively (P<0.01),DEX-0.4 group differed significantly from the other groups.DEX blunted the tachycardic response to intubation (P<0.01)and the hypertensive response to extubation (P<0.01). DEX-0.4group differed in the heart rate variability from placebo (93vs 82%, P<0.01). Conclusions. DEX increased perioperative haemodynamic stabilityin patients undergoing brain tumour surgery. Compared with fentanyl,the trachea was intubated faster without respiratory depression.      

Effect site concentrations of remifentanil and pupil response to noxious stimulation

Background. Opioid drugs block reflex pupillary dilatation inresponse to noxious stimulation. The relationship between thetarget effect site concentration (Ce_T) of remifentanil and thepupil diameter and reactivity in response to a standard noxiousstimulus were evaluated. Methods. Anaesthesia was induced with propofol TCI to obtainloss of consciousness (LOC) in 12 ASA I/II patients. Thereafter,remifentanil Ce_T was titrated by increments of 1 up to 5 ngml^–1. In the awake state, at LOC and at each plateau levelof remifentanil Ce_T, arterial pressure, heart rate, and BIS(A2000) were recorded. Pupil size and dilatation after a 100Hz tetanic stimulation (T100) were measured at LOC and at eachplateau level of remifentanil Ce_T. Results. LOC was observed at a mean propofol Ce_T of 3.53 (SD0.43) µg ml^–1. Arterial pressure and heart ratedecreased progressively from LOC to 5 ng ml^–1 remifentanilCe_T without any statistical difference between each incrementaldose of remifentanil. Mean BIS values decreased from 96 (2)in the awake state, to 46 (12) at LOC (P<0.05) and then remainedunchanged at all remifentanil Ce_T. Pupil dilatation in responseto 100 Hz tetanic stimulation decreased progressively from 1.55(0.72) to 0.01 (0.03) mm and was more sensitive than pupil diametermeasured before and after 100 Hz tetanus. An inverse correlationbetween pupil dilatation in response to 100 Hz tetanus and anincrease in remifentanil Ce_T from 0 to 5 ng ml^–1 was found(R²=0.68). Conclusions. During propofol TCI in healthy patients, the decreasein pupil response to a painful stimulus is a better measurementof the progressive increase of remifentanil Ce_T up to 5 ng ml^–1than haemodynamic or BIS measurements. Br J Anaesth 2003; 91: 347–52     

Propofol sparing effect of remifentanil using closed-loop anaesthesia

Background. General anaesthesia is a balance between hypnosisand analgesia. We investigated whether an increase in remifentanilblood concentration would reduce the amount of propofol requiredto maintain a comparable level of anaesthesia in 60 patientsundergoing ambulatory surgery. Methods. Patients were allocated randomly to receive remifentanilto a target blood concentration of 2 ng ml^–1 (low), 4ng ml^–1 (medium), or 8 ng ml^–1 (high), administeredby target-controlled infusion (TCI). After equilibration, propofolTCI was commenced in closed-loop control, with auditory evokedpotentials (AEPex) as the input signal, aiming for an AEPexof 35. This was to ensure a comparable and unbiased level ofanaesthesia in all patients. Results. We found a dose-dependent decrease in propofol requirementswith increasing remifentanil concentrations. The mean (95% CI)propofol target blood concentration during adequate anaesthesiawas 4.96 (3.85–6.01) µg ml^–1 in the low, 3.46(2.96–3.96) µg ml^–1 in the medium, and 3.01(2.20–3.38) µg ml^–1 in the high group. Therewas no significant difference when recovery end points wereachieved between the groups. Cardiovascular changes were moderate,but most pronounced in the high concentration group, with adecrease in heart rate of 21% compared with baseline. The meancalculated effect site propofol concentration at loss of consciousnesswas 2.08 (1.85–2.32) µg ml^–1, and at recoveryof consciousness was 1.85 (1.68–2.00) µg ml^–1. Conclusions. This study confirms a synergistic interaction betweenremifentanil and propofol during surgery, whereas the contributionof remifentanil in the absence of stimulation seems limited.In addition, our results suggest that the propofol effect siteconcentration provides a guide to the value at which the patientrecovers consciousness. Br J Anaesth 2003; 90: 623–9     

Comparison of three different epidural solutions in off-pump cardiac surgery: pilot study

Background. Immediate extubation using thoracic epidural analgesia(TEA) has become more popular after off-pump coronary arterybypass grafting (OPCAB). In this randomized prospective double-blindstudy, we present the first comparison of preoperative and postoperativehaemodynamics during different regimens of TEA for immediateextubation after cardiac surgery. Methods. Sixty patients undergoing OPCAB were enrolled in thisstudy. TEA was installed >1 h before application of heparinat levels T2–T4. Analgesia was provided by bupivacaine0.25%, 8 ml, 15 min before surgery and extubation, and at 10ml h^–1 during surgery and up to 72 h afterwards usingone of the following regimens: bupivacaine 0.125% alone, bupivacaine0.125% with fentanyl 3 µg ml^–1 or bupivacaine 0.125%with clonidine 0.6 µg ml^–1. Patients were block-randomizedfor one of the three treatments. Pain scores and infusion ratesof TEA were assessed up to 48 h after surgery. Respiratory functionwas assessed by Pa_O2 and Pa_O2 immediately after surgery, andhaemodynamic stability was recorded in the form of heart rateand diastolic and systolic blood pressure. Results. Patient characteristics, respiratory function and haemodynamicstability did not vary between the three groups. Pain controlwas very good and was not significantly different between thegroups using similar infusion rates after surgery. Paraesthesiain dermatomes T1 or C8 occurred equally in all three groups.There was no neurological complication related to TEA in thisstudy. Conclusions. We conclude that immediate extubation after OPCABusing TEA is feasible with different TEA regimens. Respiratoryfunction, haemodynamic stability and pain control are not differentbetween TEA with bupivacaine alone, bupivacaine with fentanylor bupivacaine with clonidine.     

Propofol-alfentanil vs propofol-remifentanil for posterior spinal fusion including wake-up test

Background. Wake-up test can be used during posterior spinalfusion (PSF) to ensure that spinal function remains intact.This study aims at assessing the characteristics of the wake-uptest during propofol–alfentanil (PA) vs propofol–remifentanil(PR) infusions for PSF surgery. Methods. Sixty patients with scoliosis and candidates for PSFsurgery were randomly allocated in either alfentanil (PA) orremifentanil (PR) group. After an i.v. bolus of alfentanil 30µg kg^–1 in the PA group or remifentanil 1 µgkg^–1 in the PR group, anaesthesia was induced with thiopentaland atracurium. During maintenance, opioid infusion consistedof alfentanil 1 µg kg^–1 min^–1 or remifentanil0.2 µg kg^–1 min^–1, in the PA group and thePR group, respectively. All patients received propofol 50 µgkg^–1 min^–1. Atracurium was given to maintain therequired surgical relaxation. At the surgeon's request, allinfusions were discontinued. Patients were asked to move theirhands and feet. Time from anaesthetic discontinuation to spontaneousventilation (T₁), and from then until movement of the handsand feet (T₂), and its quality were recorded. Results. The average T₁ and T₂ were significantly shorter inthe PR group [3.6 (2.5) and 4.1 (2) min] than the PA group [6.1(4) and 7.5 (4.5) min]. Quality of wake-up test, however, didnot show significant difference between the two groups studied. Conclusion. Wake-up test can be conducted faster with remifentanilcompared with alfentanil infusion during PSF surgery.     

Duration of exposure to sevoflurane affects dose-response relationship of vecuronium

The purpose of this study was to quantify the relationship betweenthe dose–response curve of vecuronium and duration ofexposure to an end-tidal concentration of 1.7% sevoflurane in67% nitrous oxide and oxygen. Forty adult patients, in groupsof 10, were allocated randomly to receive vecuronium by a cumulativedose method at intervals of 15 min (group 15), 30 min (group30), 60 min (group 60) or 90 min (group 90) after starting inhalationof sevoflurane. Neuromuscular function was monitored by acceleromyographictrain-of-four (TOF) responses of the adductor pollicis muscleto ulnar nerve stimulation. Dose–response curves wereconstructed by least-squares regression analysis and the effectivedoses of vecuronium (ED₅₀, ED₉₀ and ED₉₅) were estimated andcompared between groups. Mean (SEM) ED₅₀, ED₉₀ and ED₉₅ were16.8 (0.5), 32.6 (1.7) and 40.9 (2.4) µg kg^–1, respectively,in group 15; 10.6 (1.0), 20.8 (1.7) and 26.2 (2.2) µgkg^–1, respectively, in group 30; 11.2 (1.1), 21.7 (1.6)and 27.3 (1.8) µg kg^–1, respectively, in group 60;and 11.0 (1.1), 21.7 (1.6) and 27.5 (1.9) µg kg^–1,respectively, in group 90. The values obtained in group 15 weresignificantly higher than those in the other three groups (P<0.05).The results indicate that the duration of sevoflurane anaesthesiainfluences the dose–response of vecuronium and 30 mininhalation of 1.7% end-tidal concentration is sufficient toachieve a stable potentiating effect. Br J Anaesth 2000; 85: 732–4 ^* Corresponding author     

Effect of propofol anaesthesia on the event-related potential mismatch negativity and the auditory-evoked potential N1

Background. Studies on the effects of anaesthesia on event-relatedpotentials and long latency auditory-evoked potentials (AEP)are sparse. Both provide information on cortical processingand may have potential as monitors of awareness. We studiedthe effect of propofol on the event-related potential mismatchnegativity (MMN) and the long-latency AEP N1. Methods. Twenty-one patients received 1 µg ml^–1stepped increases in the target concentration of propofol usingDiprifusor^TM until a maximum of 6 µg ml^–1 was achievedor the patient had lost consciousness. Neurophysiological responses(MMN and N1) and the patients’ level of consciousnesswere recorded before the administration of propofol and at atarget effector site concentration of propofol of 1, 2, 3, 4,and 6 µg ml^–1. Grand average evoked potentials werecomputed at baseline, before the administration of propofol(A); at the highest propofol concentration at which each patientwas responsive (B); and at the concentration of propofol atwhich the patient became unconscious (C). Results. Patients lost consciousness at different target concentrationsof propofol, all being unresponsive by 4 µg ml^–1.The response to the deviant stimuli used to elicit duration-shiftMMN was significantly more negative than to the standard stimuliat A (mean difference 2.58 µV, P=0.0011) but this differencewas virtually abolished at point B, before the patients lostconsciousness (mean difference 0.63 µV, P=ns). The amplitudeof N1 evoked by standard stimuli was negative compared withelectrical baseline at both point A (mean amplitude –3.81µV, P<0.001) and at point B (mean amplitude –2.2µV, P=0.002), but was no longer significantly differentto baseline at point C (mean amplitude 0.51 µV, P=ns).The change in the mean amplitude of N1 from last awake (pointB) to first unconscious (point C) was also significant (meandifference in amplitude 1.69 µV, P=0.02). Conclusions. MMN is unlikely to be a clinically useful toolto detect awareness in surgical patients. In contrast, the lossof N1 may identify the transition from consciousness to unconsciousnessand deserves further study. Br J Anaesth 2002; 89: 382–8     

Target concentrations of remifentanil with propofol to blunt coughing during intubation, cuff inflation, and tracheal suctioning

Background. The target blood concentrations of propofol andremifentanil, when used in combination, required to blunt thecough response to tracheal intubation, cuff inflation, and trachealsuctioning without neuromuscular blocking agents are not known. Methods. In a randomized prospective study, 81 patients wereenrolled to determine which of three target remifentanil bloodconcentrations was required to blunt coughing during intubation,cuff inflation, and tracheal suctioning. Anaesthesia was achievedwith propofol at a steady effect-site concentration of 3.5 µgml^–1. The target blood remifentanil concentrations were5, 10, or 15 ng ml^–1. These concentrations were maintainedfor 12 min before intubation. Results. There was no cough response to intubation in more than74% of patients and no significant difference in the incidenceof coughing with intubation between the three groups. Significantdifference in coughing, diminishing with increasing remifentaniltarget concentration, was observed with cuff inflation (P=0.04)and tracheal suctioning (P=0.007). Bradycardia and hypotensionwas more frequent with the remifentanil target concentrationof 15 ng ml^–1. Tracheal suctioning resulted in more coughingthan intubation (P=0.01) or cuff inflation (P=0.004). Conclusion. Target remifentanil blood concentrations of 5, 10,and 15 ng ml^–1 associated with a 3.5 µg ml^–1propofol target blood concentration provided good intubatingconditions and absence of cough about 75% of the time. Highertarget remifentanil concentrations were associated with lesscoughing during tracheal tube cuff inflation and tracheal suctioning.     

Safety of patient-maintained propofol sedation using a target-controlled system in healthy volunteers{dagger}

We investigated the safety of a patient-maintained system thatallows individuals to operate a target-controlled infusion ofpropofol to achieve sedation. Ten healthy volunteers were recruitedand instructed to try to anaesthetize themselves with the system.A target-controlled infusion of propofol was set to delivera target propofol concentration of 1 µg ml^–1,and the subjects allowed to increase the target in incrementsof 0.2 µg ml^–1 by pressing a control button twicein 1 s. There was a lockout time of 2 min and a maximum permittedtarget concentration of 3 µg ml^–1. Heartrate and pulse oximetry oxygen saturation (Sp_O2) were monitored continuously,and non-invasive arterial pressure, ventilatory frequenciesand sedation scores were measured every 5 min. Sedation wascontinued until the subject stopped pressing the button. A keywordwas then read for the individual to remember and sedation discontinued.There were no instances of significant decrease of Sp_O2 or lossof airway control. Maximum target blood concentration of propofolrecorded ranged from 1.4 to 3 µg ml^–1.Two subjects became oversedated, one of whom was unrousablewith loss of eyelash reflex. No subject could recall the keyword,although one recognized it from a list of 10 words. We concludethat the patient-maintained sedation system described couldnot be guaranteed to produce only conscious sedation in all patients,and that close clinical supervision by an anaesthetist would stillbe required for safe operation. Br J Anaesth 2000; 85: 299–301 Footnotes ^* Corresponding author: Department of Anesthesiology, Duke UniversityMedical Center, Box 3094, Durham, North Carolina 27710, USA     

Effects of halothane, sevoflurane and propofol on left ventricular diastolic function in humans during spontaneous and mechanical ventilation

Background. There is limited knowledge of the effects of anaestheticson left ventricular (LV) diastolic function in humans. Our aimwas to evaluate these effects in humans free from cardiovasculardisease. Methods. Sixty patients (aged 18–47 yr) who had no historyor signs of cardiovascular disease were randomized to receivegeneral anaesthesia with halothane, sevoflurane or propofol.Echocardiography was performed at baseline and during spontaneousrespiration at 1 minimum alveolar concentration (MAC) of theinhalational agents or propofol 4 µg ml^–1 (step1), and repeated during positive-pressure ventilation with 1and 1.5 MAC of the inhalational agents or with propofol 4 and6 µg ml^–1 (steps 2A and 2B). Analysis of echocardiographicmeasurements focused on heart rate corrected isovolumic relaxationtime (IVRT_c) and early diastolic peak velocity of the lateralmitral annulus (E_a). Results. IVRT_c decreased from baseline to step 1 in the halothanegroup (82 [95% CI, 76–88] ms and 74 [95% CI, 68–80]ms respectively; P=0.02), remained stable in the sevofluranegroup (78 [95% CI, 72–83] ms and 73 [95% CI, 67–81]ms; n.s.) and increased in the propofol group (80 [95% CI, 74–86]ms and 92 [95% CI, 84–102] ms; P=0.02). E_a decreased inthe propofol group only (18.8 [95% CI, 16.5–19.9] cm s^–1and 16.0 [95% CI, 14.9–17.9] cm s^–1; P=0.003). Fromstep 2A to step 2B, IVRT_c increased further in the propofolgroup (109 [95% CI, 99–121] ms and 119 [95% CI, 99–135]ms; P=0.04) but remained stable in the other two groups. E_adid not change from step 2A to step 2B. Conclusions. Halothane and sevoflurane did not impair LV relaxation,whereas propofol caused a mild impairment. However, the impairmentby propofol was of a magnitude that is unlikely to cause clinicaldiastolic dysfunction.      

Effects of sevoflurane and propofol on left ventricular diastolic function in patients with pre-existing diastolic dysfunction

Background. The effects of anaesthetics on left ventricular(LV) diastolic function in patients with pre-existing diastolicdysfunction are not well known. We hypothesized that propofolbut not sevoflurane will worsen the pre-existing LV diastolicdysfunction. Methods. Of 24 randomized patients, 23 fulfilled the predefinedechocardiographic criterion for diastolic dysfunction. Theyreceived general anaesthesia with sevoflurane 1 MAC (n=12) orpropofol 4 µg ml^–1 (n=11). Echocardiographic examinationswere performed at baseline and in anaesthetized patients underspontaneous breathing and under positive pressure ventilation.Analysis focused on peak early diastolic velocity of the mitralannulus (E_a). Results. During spontaneous breathing, E_a was higher in thesevoflurane than in the propofol group [mean (95% CI) 7.0 (5.9–8.1)vs 5.5 (4.7–6.3) cm s^–1; P<0.05], reflectingan increase of E_a from baseline only in the sevoflurane group(P<0.01). Haemodynamic findings were similar in both groups,but the end-tidal carbon dioxide content was more elevated inthe propofol group (P<0.01). During positive pressure ventilation,E_a was similarly low in the sevoflurane and propofol groups[5.3 (4.2–6.3) and 4.4 (3.6–5.2) cm s^–1, respectively]. Conclusions. During spontaneous breathing, early diastolic functionimproved in the sevoflurane but not in the propofol group. However,during positive pressure ventilation and balanced anaesthesia,there was no evidence of different effects caused by the twoanaesthetics.     

Impact of peripheral elimination on the concentration-effect relationship of remifentanil in anaesthetized dogs

Background. This study elucidates the impact of sampling sitewhen estimating pharmacokinetic-pharmacodynamic (PK-PD) parametersof drugs such as remifentanil that undergo tissue extractionin the biophase. The interrelationship between the concentrationsof remifentanil predicted for the effect compartment and thosemeasured in arterial, venous, and cerebrospinal fluid were investigatedunder steady-state conditions. Methods. Following induction of anaesthesia with pentobarbital,an arterial cannula (femoral) and two venous catheters (jugularand femoral) were inserted. Electrodes were placed for EEG recordingof theta wave activity. Each dog received two consecutive 5-mininfusions for the PK-PD study and a bolus followed by a 60-mininfusion was started for the steady-state study. Cerebrospinalfluid, arterial and venous blood samples were drawn simultaneouslyafter 30, 40, and 50 min. At the end of the infusion, arterialblood samples were collected for pharmacokinetic analysis. Results. Remifentanil PK-PD parameters based on theta wave activitywere as follows: apparent volume of distribution at steady-state(V_ss) (231±37 ml kg^–1), total body clearance (Cl)(63±16 ml min^–1 kg^–1), terminal eliminationhalf-life (t_1/2ß) (7.71 min), effect compartment concentrationat 50% of maximal observed effect (EC₅₀) (21±13 ng ml^–1),and equilibration rate constant between plasma and effect compartment(k_e0) (0.48±0.24 min). The mean steady-state cerebrospinalfluid concentration of 236 ng ml^–1 represented 52 and74% of that in arterial and venous blood, respectively. Conclusions. Our study re-emphasizes the importance of a samplingsite when performing PK-PD modelling for drugs undergoing eliminationfrom the effect compartment. For a drug undergoing tissue eliminationsuch as remifentanil, venous rather than arterial concentrationswill reflect more exactly the effect compartment concentrations,under steady-state conditions. Declaration of interest. Remifentanil was provided by AbbottLaboratories.     

Effect of lidocaine on ischaemic preconditioning in isolated rat heart

Background. Lidocaine is frequently used as an agent to treatventricular arrhythmias associated with acute myocardial ischaemia.Lidocaine is a potent blocker not only of sodium channels, butalso of ATP-sensitive potassium channels. The opening of thesechannels is a key mechanism of ischaemic preconditioning. Weinvestigated the hypothesis that lidocaine blocks the cardioprotectioninduced by ischaemic preconditioning. Methods. Isolated rat hearts (n=60) were subjected to 30 minof no-flow ischaemia and 60 min of reperfusion. Control hearts(CON) underwent no further intervention. Preconditioned hearts(PC) received two 5-min periods of ischaemia separated by 10min of reflow before the 30 min ischaemia. In three groups,lidocaine was infused at concentrations of 2, 10 or 20 µgml^–1 for 5 min before the preconditioning ischaemia. Leftventricular developed pressure (LVDP) and infarct size (IS)(triphenyltetrazolium choride staining) were measured as variablesof ventricular function and cellular injury, respectively. Results. PC reduced IS from 24.8 (SEM 4.1) % to 4.0 (0.7) %of the area at risk (P<0.05). Adding 2 or 10 µg ml^–1lidocaine had no effect on IS compared with PC alone (3.7 (0.7)%, 6.9 (1.8) %). Adding 20 µg ml^–1 lidocaine increasedIS to 14.1 (2.5) % compared with PC (P<0.05). Baseline LVDPwas similar in all groups (111.4 (2.1) mm Hg). Compared withCON, PC improved functional recovery (after 60 min of reperfusion;52.3 (5.9) mm Hg vs 16.0 (4.0) mm Hg, P<0.01). The improvedventricular function was not influenced by addition of 2 or10 µg ml^–1 lidocaine (47.3 (5.7) mm Hg, not significant;45.3 (7.3) mm Hg, not significant), but was blocked by the infusionof 20 µg ml^–1 lidocaine (22.5 (8.0) mm Hg, P<0.01vs PC). Conclusions. Lidocaine blocks the cardioprotection induced byischaemic preconditioning only at supratherapeutic concentrations.