The effect of co-induction with midazolam upon recovery from propofol infusion anaesthesia

Forty-eight patients undergoing day-case anaesthesia were asked to complete pre- and postoperative tests of psychomotor function in order to study the influence of co-induction with midazolam in conjunction with propofol/alfentanil anaesthesia on postoperative psychomotor recovery. The study was placebo controlled and double blind with patients receiving either 0.03 mgkg⁻¹ of midazolam or saline 2 min before induction of anaesthesia with propofol and alfentanil. Patients who underwent co-induction with midazolam had significantly impaired concentration and rapidity of response but improved accuracy and vigilance when compared with those who received saline. The study confirmed that co-induction with a subanaesthetic dose of midazolam reduced the induction dose of propofol by up to 50%. We conclude that co-induction with midazolam reduces psychomotor recovery in the immediate postoperative phase following propofol infusion anaesthesia.     

Propofol auto-co-induction as an alternative to midazolam co-induction for ambulatory surgery

We propose the use of an intravenous propofol/propofol auto-co-induction technique as an alternative to propofol/midazolam for induction of anaesthesia. We have studied 54 unpremedicated ASA 1 or 2 patients undergoing day-stay anaesthesia for minor orthopaedic surgery. All received 10 micrograms.kg-1 or alfentanil before induction, followed by either midazolam 0.05 mg.kg-1, propofol 0.4 mg.kg-1 or saline, and 2 min later, a propofol infusion at a rate of 50 mg.kg-1.h-1 until loss of eyelash reflex. We compared pre- and postinduction haemodynamic changes, complications at insertion of a laryngeal mask airway and recovery from anaesthesia in the three groups. Both co-induction techniques showed less postinduction hypotension and significant reduction of the total induction dose of propofol when compared to the control group. In the propofol/propofol group there was a decreased incidence of apnoea during induction of anaesthesia. These patients were discharged from hospital 2 h after the end of anaesthesia whereas patients in the midazolam/propofol group were discharged after 2 1/2 h (p < 0.001).     

The contribution of remifentanil to middle latency auditory evoked potentials during induction of propofol anesthesia

There is a debate regarding whether opioids, as a component of general anesthesia, are adequately reflected in the assessment of anesthesia based on derivatives of the electroencephalogram. To test the hypothesis of a possible quantitative contribution of remifentanil on middle latency auditory evoked potentials, we studied its interaction with propofol anesthesia in 45 unpremedicated male patients undergoing elective lower limb orthopedic surgery. They were allocated randomly to three groups. The first two groups received remifentanil either with a high (8 ng mL(-1)) or a low (3 ng mL(-1) target concentration using target-controlled infusion (TCI). The third group received spinal anesthesia instead of remifentanil. Anesthesia was induced by a stepwise increase in propofol concentration using TCI. The auditory evoked potential index (AEPex) and calculated propofol effect site concentrations were determined at loss of consciousness and the reaction to laryngeal mask airway insertion was noted. The propofol infusion was then converted to a closed-loop TCI using an AEPex value of 40 as the target. We found no significant contribution of remifentanil alone on the auditory evoked response, whereas increasing concentrations of remifentanil led to a significant decrease of the calculated propofol effect site concentrations (P = 0.023) necessary for unconsciousness. Prediction probability for AEPex was inversely related to the remifentanil concentration and was best for the control group, which received propofol alone. These results support previous findings of a quantitative interaction between remifentanil and propofol for loss of consciousness but question the specific contribution of remifentanil to auditory evoked potentials.     

Facilitation of laryngeal mask airway insertion: effects of remifentanil administered before induction with target-controlled propofol infusion

Eighty-six adult day-case patients were recruited into a prospective, randomised study and allocated to one of two groups. Patients received either intravenous remifentanil 0.3 microg.kg(-1) or an equivalent volume of sodium chloride 0.9% followed by induction of anaesthesia with propofol target-controlled infusion until the effect (brain) site calculated concentration was 2 microg.ml(-1). Jaw opening and ease of laryngeal mask insertion were assessed immediately after mask insertion. A higher incidence of failure of induction of anaesthesia was observed in the control group compared with the remifentanil group [15 (35%) vs. 3 (7%); p < 0.01] and addition of remifentanil significantly increased the ease and success of laryngeal mask insertion, with grade 1 (no coughing/gagging) conditions observed in 29 (68%) of the remifentanil group and 21 (49%) of the control group (p < 0.01).The doses of remifentanil and propofol used were not associated with any significant cardiorespiratory instability. In conclusion, when combined with propofol target-controlled infusion, remifentanil 0.3 microg.kg(-1) facilitates laryngeal mask insertion with minimal adverse haemodynamic changes.     

Reduction of pain during induction with target-controlled propofol and remifentanil

BACKGROUND: Pain on injection of propofol is unpleasant. We hypothesized that propofol infusion pain might be prevented by infusing remifentanil before starting the propofol infusion in a clinical setting where target-controlled infusions (TCI) of both drugs were used. A prospective, randomized, double-blind, placebo-controlled trial was performed to determine the effect-site concentration (Ce) of remifentanil to prevent the pain without producing complications. METHODS: A total of 128 patients undergoing general surgery were randomly allocated to receive normal saline (control) or remifentanil to a target Ce of 2 ng ml(-1) (R2), 4 ng ml(-1) (R4), or 6 ng ml(-1) (R6) administered via TCI. After the target Ce was achieved, the infusion of propofol was started. Remifentanil-related complications were assessed during the remifentanil infusion, and pain caused by propofol was evaluated using a four-point scale during the propofol infusion. RESULTS: The incidence of pain was significantly lower in Groups R4 and R6 than in the control and R2 groups (12/32 and 6/31 vs 26/31 and 25/32, respectively, P<0.001). Pain was less severe in Groups R4 and R6 than in the control and R2 groups (P<0.001). However, both incidence and severity of pain were not different between Groups R4 and R6. No significant complications were observed during the study. CONCLUSIONS: During induction of anaesthesia with TCI of propofol and remifentanil, a significant reduction in propofol infusion pain was achieved without significant complications by prior administration of remifentanil at a target Ce of 4 ng ml(-1).     

Haemodynamics during remifentanil induction by high plasma or effect-site target controlled infusion

BACKGROUND: During total intravenous anaesthesia, the target controlled infusion concentration of remifentanil can be achieved either in limiting maximum plasma concentration (Cp) to the effect site target concentration which corresponds to a plasma TCI technique (pTCI) or as fast as possible to achieve the effect-site target without limiting Cp (eTCI). The aim of this study was to compare the haemodynamic effects of remifentanil pTCI and eTCI during induction of anaesthesia in ASA III patients undergoing cardiac surgery. METHODS: 28 ASA III patients, scheduled for cardiac surgery, were randomized in two groups: Group pTCI received remifentanil to achieve an effect-site target of 15 ng ml(-1) by limiting Cp to 15 ng ml(-1) and group eTCI received remifentanil to achieve an effect-site target of 15 ng ml(-1) without limiting remifentanil Cp. Before induction, all patients received 30 microg kg(-1) of midazolam intravenously and 2 ml kg(-1) of a gelatin solution. Heart rate, invasive arterial pressure and bispectral index were continuously measured. Differences from baseline values were compared between the two groups using a Mann-Whitney U test. Baseline population characteristics were compared using an analysis of variance. RESULTS: There were no significant differences in haemodynamic parameters between the two groups. In the group pTCI final effect-site concentration was reached in 7.3 +/- 1.4 minutes and in the group eTCI in 2.2 +/- 0.2 minutes (p < 0.05). CONCLUSION: In ASA III patients scheduled for elective cardiac surgery, remifentanil eTCI can be preferred to remifentanil pTCI for induction because of its shorter onset with the same haemodynamic stability.     

Midazolam coinduction does not delay discharge after very brief propofol anaesthesia

Previous reports have demonstrated synergism of midazolam and propofol for induction of anaesthesia in humans. We tested the hypothesis that in the presence of alfentanil, the combination of midazolam with propofol for a very brief operative procedure would not affect the recovery phase. During pre-oxygenation, 64 outpatients scheduled for dilatation and curettage received placebo, or low-dose midazolam (0.03 mg · kg^?1), or high-dose midazolam (0.06 mg · kg^?1) iv, in a randomized double-blind manner. They then received alfentanil 10 μg · kg^?1 iv, followed by titrated doses of propofol iv for induction and maintenance of anaesthesia. Ventilation with 70% N₂O in O₂ by mask was controlled to achieve a PETCO₂ 30–40 mmHg. Outcome measures were: propofol dose (induction and maintenance), time until eye-opening to command, and time to discharge-readiness. Propofol induction dose was decreased by increasing doses of midazolam (P = 0.00005). Midazolam delayed time to eye-opening (P = 0.02) but not time to discharge-readiness. This study had an 80% power to detect a 39 min difference in time to discharge-readiness. We conclude that midazolam propofol co-induction in the presence of alfentanil delays eye-opening, but does not delay discharge after anaesthesia.     

Pharmacokinetic-based total intravenous anaesthesia using remifentanil and propofol for surgical myocardial revascularization

BACKGROUND AND OBJECTIVE: We investigated the following aspects of pharmacokinetic-guided total intravenous anaesthesia with remifentanil and propofol in patients undergoing surgical myocardial revascularization: anaesthetic efficacy, haemodynamic effects, impact on extubation of the trachea and analgesia after operation. METHODS: Thirty-two patients undergoing on-pump coronary bypass surgery received intravenous anaesthesia with remifentanil and propofol. Both drugs were dosed and titrated based on computer-assisted pharmacokinetic models to maintain constant plasma concentrations. The propofol target plasma concentration was 1.2 microg mL(-1) throughout the procedure. A remifentanil target plasma concentration of 8 ng mL(-1) was achieved over 2 min for induction. After tracheal intubation, the opioid plasma concentration was reduced to 4 ng mL(-1), and then titrated up to 8 ng mL(-1) during surgery. Postoperative analgesia was managed with remifentanil infusion until 4 h after tracheal extubation, and a continuous infusion of tramadol was started 1 h before the remifentanil was stopped. RESULTS: After induction of anaesthesia, heart rate (-20%) and cardiac index (-6%) decreased significantly. No hypotensive episodes (mean arterial pressure < 60 mmHg) occurred. Intraoperative haemodynamics were stable. Three cases of myocardial ischaemia were detected: two by transoesophageal echocardiography and one with ST-segment monitoring. The duration of postoperative mechanical ventilation of the lungs was 95 +/- 13 min and the time to extubation was 150 +/- 18 min. Postoperative analgesia was satisfactory in all patients. CONCLUSIONS: Pharmacokinetic-based total intravenous anaesthesia with remifentanil and propofol provides adequate anaesthesia during coronary surgery with cardiopulmonary bypass and allows safe early extubation after operation.     

A comparison between midazolam co-induction and propofol predosing for the induction of anaesthesia in the elderly

In a prospective, double-blind, randomised, placebo-controlled trial, we have compared the effects of midazolam co-induction with propofol predosing on the induction dose requirements of propofol in elderly patients. We enrolled 60 patients aged > 70 years, attending for urological surgery. The patients were allocated randomly to one of three groups, to receive either midazolam 0.02 mg.kg(-1), propofol 0.25 mg.kg(-1), or normal saline 2 ml (placebo) 2 min prior to induction of anaesthesia using propofol 1% infusion at 300 ml.h(-1). The propofol dose requirements for induction were recorded for two end-points (loss of verbal contact and insertion of an oropharyngeal airway). Cardiovascular parameters were recorded at 1-min intervals for each patient until induction was complete. The midazolam group showed a significant reduction in propofol dose requirements for induction (p = 0.05) compared to the placebo group. The propofol group did not show a significant dose reduction compared to placebo. There were no demonstrable differences in terms of improved cardiovascular stability between groups. We conclude that propofol predosing does not significantly reduce the induction dose of propofol required in the elderly, and there were no cardiovascular benefits to either midazolam co-induction or propofol predosing in the elderly.     

丙泊酚复合瑞芬太尼靶控输注在腹腔镜胆囊切除术中的应用

目的:观察丙泊酚复合瑞芬太尼靶控输注全凭静脉麻醉对腹腔镜胆囊切除术血流动力学及术后苏醒时间的影响。方法:50例择期行腹腔镜胆囊切除术的患者均采用丙泊酚复合瑞芬太尼靶控输注全凭静脉麻醉。设定诱导时静注咪达唑仑2mg,先血浆靶控输注瑞芬太尼4ng/ml,1min后血浆靶控输注丙泊酚3μg/ml或3.5μg/ml,患者意识消失后静注维库溴铵0.1mg/kg,3min后气管内插管,插管后丙泊酚靶浓度调至2μg/ml,术中维持根据需要调整丙泊酚靶浓度,以0.2μg/ml递增或递减,瑞芬太尼维持不变。记录诱导前、诱导后2min、插管即刻、插管后5min、气腹时、气腹后5min的收缩压(systolic bloodpressure,SBP)、舒张压(diastolic blood pressure,DBP)、心率(heart rate,HR)及术后呼吸恢复时间、呼之睁眼时间。结果:诱导后2min的SBP、DBP、HR与诱导前差异均有统计学意义(P0.05),气腹时SBP、DBP、HR有所升高,但差异无统计学意义,其他时点经适当调整丙泊酚靶浓度处理后逐渐平稳,术后呼吸恢复时间为(6.5±2.2)min,呼之睁眼时间(8.9±3.1)min。结论:丙泊酚复合瑞芬太尼靶控输注用于腹腔镜胆囊切除术安全,术中血流动力学平稳,术后苏醒快。     

Modelling the pharmacodynamic interaction between remifentanil and propofol by EEG-controlled dosing

BACKGROUND AND OBJECTIVE: Knowledge of the pharmacodynamic interaction between remifentanil and propofol is important to permit optimal dosage strategies. We studied this pharmacodynamic interaction using the median power frequency of the processed electroencephalogram as a control parameter for feedback-controlled dosing of propofol. METHODS: Twenty-one patients were given total intravenous anaesthesia with remifentanil and propofol. During three target-controlled infusion regimens, the target concentrations of remifentanil (5, 10, 15 ng mL(-1)) and propofol dosing were automatically adjusted to keep the median power frequency in the range 2 +/- 0.5 Hz. In each patient and during each remifentanil target concentration, four arterial propofol/remifentanil concentration pairs were measured. The type of interaction was tested using the relative distance from the line of additivity and the isobole was modelled using Bernstein splines. RESULTS: The results from 13 patients were used for data analysis. The measured remifentanil concentrations during the three targets were (mean +/- SD): 3.6 +/- 0.9, 8.1 +/- 2.5 and 12.4 +/- 2.8 ng mL(-1). The corresponding propofol concentrations were 2.64 +/- 0.86, 2.13 +/- 0.58 and 2.09 +/- 0.58 microg mL(-1). The data were best described with an additive type of interaction and the isobole was estimated using: ((c)Remifentanil/64.2 ng mL(-1)) + ((c)Propofol/2.61 microg mL(-1)) = 1. CONCLUSIONS: Within the studied concentration range, remifentanil and propofol showed an additive type of pharmacodynamic interaction on the electroencephalogram.     

Cardiovascular changes after achieving constant effect site concentration of propofol

Target controlled infusions of propofol use a pharmacokinetic/pharmacodynamic model to calculate an effect site concentration of the drug. We assessed the cardiovascular stability of 10 healthy patients using non-invasive thoracic bioimpedance and their 'depth' of anaesthesia using the Bispectral index after they had been anaesthetised to a constant effect site concentration of propofol (6.5 min from starting). Each patient had no surgical stimulus and received no intravenous fluid during the study period. The patients also received effect site target controlled remifentanil (steady state 2.5 min from starting) and a bolus of vecuronium to facilitate intubation and ventilation. We mathematically calculated when each measured parameter would reach a state of stability (i.e. with 95% certainty). Heart rate levelled off at 20 min, Bispectral index at 32 min, and cardiac index and mean arterial pressure at 47 min after achieving effect site stability, the final levels being, respectively, 21%, 47%, 14% and 28% lower than those at effect site stability. We conclude that cardiovascular parameters continue to change to a clinically significant degree after achieving a constant effect site concentration of propofol via target controlled infusions.     

Target-controlled remifentanil in combination with propofol for spontaneously breathing day-case patients

Remifentanil is a new potent opioid with a very short duration of action irrespective of duration of infusion. It may have a role in day-case anaesthesia as part of a balanced total intravenous anaesthetic technique with propofol. We examined the respiratory depressant effects of remifentanil in 20 patients undergoing day-case anaesthesia. The target plasma concentration of remifentanil was varied while maintaining a constant target-controlled infusion of 4.5 microg x ml-1 propofol. In only 12 patients was satisfactory spontaneous respiration maintained. In these patients the median remifentanil target concentration was 1.6 ng x ml-1 and was achieved with a median infusion rate of 0.05 microg x kg-1 x min-1. The range of target concentrations associated with satisfactory spontaneous respiration was wide and varied over a 4.7-fold range from 0.6 to 2.8 ng x ml-1.     

Tracheal intubating conditions using propofol and remifentanil target-controlled infusions

Using target-controlled infusions (TCI) we aimed to determine the most appropriate dose of remifentanil required for intubation, using a steady effect-site concentration of propofol and without the use of neuromuscular blocking drugs. Sixty ASA III patients presenting for elective surgery were randomly allocated to one of three groups. Anaesthesia was induced in all patients using a target-controlled infusion of propofol 6.5 microg x ml(-1). This was reduced to 3 microg x ml(-1) after 1 min. Each group received a different TCI of remifentanil, 19, 15 or 11 ng x ml(-1), which was reduced to 10, 8 or 6 ng x ml(-1), respectively, after 1 min. Laryngoscopy and intubation were attempted at 4 min. Laryngoscopy and ease of intubation were assessed using a standard scoring system. Intubation was considered satisfactory in 75% of patients in groups 1 and 2 and 35% of patients in group 3. Intubation was successful in 20/20, 19/20 and 15/20 patients in groups 1, 2 and 3, respectively. Pulse oximetry, heart rate and noninvasive arterial pressure were measured pre-induction, and at intervals until after laryngoscopy and intubation. Mean arterial pressure (MAP) and heart rate decreased following induction of anaesthesia in all groups, which was statistically significant. Following laryngoscopy, MAP and heart rate increased, but were significantly less than the corresponding baseline values.     

The effect of remifentanil on propofol requirements to achieve loss of response to command vs. loss of response to pain

When providing total intravenous anaesthesia, careful selection of end‐points is required in titrating dose to effect during induction. Although propofol and remifentanil have predominantly different pharmacodynamic effects, they are seen to interact in achieving loss of consciousness and analgesia. To highlight these differences, we performed a double‐blind, randomised controlled trial, comparing one group of patients receiving propofol alone (n = 42) with another group receiving remifentanil plus propofol (n = 46) as a target‐controlled infusion of remifentanil (Minto; 3 ng.ml^?1). Propofol was also titrated using a target‐controlled infusion (Marsh effect model) to produce loss of response to tactile and vocal stimuli, and subsequently to loss of response to pain. The effect‐site concentration of propofol at which 50% of patients lost tactile/verbal response was 2.9 μg.ml^?1 in the propofol only group and 2.4 μg.ml^?1 in the remifentanil with propofol group. In contrast, loss of pain response occurred at 4.4 μg.ml^?1 in the propofol group, and 2.7 μg.ml^?1 in the remifentanil with propofol group, with correspondingly lower bispectral index values. Judicious use of analgesia in total intravenous anaesthesia can have a propofol‐sparing effect and potentially minimise the suppression of brain electrical activity.     

Pharmacodynamic Interaction between Propofol and Remifentanil Regarding Hypnosis, Tolerance of Laryngoscopy, Bispectral Index, and Electroencephalographic Approximate Entropy

Background: The purpose of this investigation was to describe the pharmacodynamic interaction between propofol and remifentanil for probability of no response to shaking and shouting, probability of no response to laryngoscopy, Bispectral Index (BIS), and electroencephalographic approximate entropy (AE).

Methods: Twenty healthy volunteers received either propofol or remifentanil alone and then concurrently with a fixed concentration of remifentanil or propofol, respectively, via a target-controlled infusion. Responses to shaking and shouting and to laryngoscopy were assessed multiple times after allowing for plasma effect site equilibration. The raw electroencephalogram and BIS were recorded throughout the study, and AE was calculated off-line. Response surfaces were fit to the clinical response data using logistic regression or hierarchical response models. Response surfaces were also estimated for BIS and AE. Surfaces were visualized using three-dimensional rotations. Model parameters were estimated with NONMEM.

Results: Remifentanil alone had no appreciable effect on response to shaking and shouting or response to laryngoscopy. Propofol could ablate both responses. Modest remifentanil concentrations dramatically reduced the concentrations of propofol required to ablate both responses. The hierarchical response surface described the data better than empirical logistic regression. BIS and AE are more sensitive to propofol than to remifentanil.     

The influence of esmolol on the dose of propofol required for induction of anaesthesia

Cardiac output may be an important determinant of the induction dose of intravenous anaesthetic. Esmolol is known to reduce cardiac output, and we examined its effect on the propofol dose required for induction of anaesthesia. The size of the effect seen with esmolol was compared with midazolam co-induction. Sixty patients were randomly allocated to placebo (saline), esmolol (1mg x kg(-1) bolus, followed by an infusion at 250 microg x kg(-1)min(-1)) or midazolam (0.04 mg x kg(-1)) groups. Induction of anaesthesia commenced 3 min following the administration of the study drug, using a Diprifusor set to achieve plasma propofol concentrations of 10 microg x ml(-1) at 5 min. The primary end point used was the propofol dose per kg at loss of response to command. The mean (SD) propofol dose for each group was 2.38 (0.48) mg x kg(-1) for placebo, 1.79 (0.36) mg x kg(-1) for esmolol and 1.34 (0.35) mg x kg(-1) for midazolam (all means significantly different; p < 0.0005). We found that predosing with esmolol reduces the propofol requirements for induction of anaesthesia by 25%.     

Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy

BACKGROUND: The purpose of this investigation was to describe the pharmacodynamic interaction between propofol and remifentanil for probability of no response to shaking and shouting, probability of no response to laryngoscopy, Bispectral Index (BIS), and electroencephalographic approximate entropy (AE). METHODS: Twenty healthy volunteers received either propofol or remifentanil alone and then concurrently with a fixed concentration of remifentanil or propofol, respectively, via a target-controlled infusion. Responses to shaking and shouting and to laryngoscopy were assessed multiple times after allowing for plasma effect site equilibration. The raw electroencephalogram and BIS were recorded throughout the study, and AE was calculated off-line. Response surfaces were fit to the clinical response data using logistic regression or hierarchical response models. Response surfaces were also estimated for BIS and AE. Surfaces were visualized using three-dimensional rotations. Model parameters were estimated with NONMEM. RESULTS: Remifentanil alone had no appreciable effect on response to shaking and shouting or response to laryngoscopy. Propofol could ablate both responses. Modest remifentanil concentrations dramatically reduced the concentrations of propofol required to ablate both responses. The hierarchical response surface described the data better than empirical logistic regression. BIS and AE are more sensitive to propofol than to remifentanil. CONCLUSIONS: Remifentanil alone is ineffective at ablating response to stimuli but demonstrates potent synergy with propofol. BIS and AE values corresponding to 95% probability of ablating response are influenced by the combination of propofol and remifentanil to achieve this endpoint, with higher propofol concentrations producing lower values for BIS and AE.     

A comparison of midazolam co-induction with propofol predosing for induction of anaesthesia

In a double-blind, placebo-controlled study of 90 ASA 1 and 2 patients scheduled for elective surgery we compared the effect of pre-administering midazolam 2 mg or propofol 30 mg on the dose of propofol subsequently required to induce anaesthesia. Using loss of response to verbal command and tolerance to placement of a facemask as end-points, the dose of propofol required to induce anaesthesia was significantly smaller in the patients given propofol (1.87 mg.kg-1) or midazolam (1.71 mg.kg-1) when compared to the control group (2.38 mg.kg-1). Although the decrease in blood pressure following induction was no difference between the two study groups and the decrease was felt not to be of clinical significance in this group of patients. As propofol is presented ' ... for use in a single patient only' and the technique of predosing with propofol allowed induction of all patients with less than 200 mg (a single ampoule), we question on a cost basis whether midazolam co-induction is necessary to reduce propofol induction doses.