Pharmacokinetics of propofol in elderly coronary artery bypass graft patients under total intravenous anesthesia

The present paper investigates the pharmacokinetics of propofol in the plasma of two elderly patients operated on under total intravenous anesthesia using propofol. A 78-year-old (patient A) and a 76-year-old (patient B), both Japanese men with unstable angina pectoris, were operated on for coronary artery bypass grafts. For the induction of anesthesia, 1.5 mg/kg propofol was administered as a single bolus infusion, and anesthesia was maintained using the step-down infusion regimens of propofol. Propofol concentration in the plasma was measured by HPLC with a fluorescence detector. The simulation curves, following the two-compartment model, fitted well to the profiles of the individual data of propofol concentrations in the plasma. When 4 mg/kg/h of propofol was administered to both patients while maintaining anesthesia, propofol concentrations in the plasma were maintained at over 1.0 microg/ml. In patient A, the propofol concentration in the plasma was 140 ng/ml at 6 h after the end of the infusion. In patient B, the propofol concentrations in the plasma were 73 ng/ml at 6 h and 35 ng/ml at 12 h after the end of the infusion. The apparent distribution volumes of patients A and B were 1.43 and 1.62 l/kg, respectively. The half-lives of propofol in the plasma of patients A and B were estimated to be 13.3 and 17.4 min as the a phase, and 10.1 and 10.5 h as the beta phase, respectively. In elderly patients with cardiac surgery, the maintenance concentrations of propofol in the plasma were enough to maintain a concentration of 1.0 microg/ml, and the half-life may be longer than previously reported values in adult patients.     

异丙酚、咪达唑仑在纤维支气管镜检查中的镇静作用比较

目的比较异丙酚和咪达唑仑在纤维支气管镜检查中实施镇静的效果以及患者的满意程度。方法 68例支气管镜检患者随机分为异丙酚组（P组）和咪达唑仑组（M组）。在利多卡因局麻后,P组首次静脉缓慢注入异丙酚1.5mg·kg-1,速度为40～60s,然后以5～10mg/（kg·h）输注;M组首次静脉注入咪达唑仑2mg,2min后根据镇静情况追加,每次追加0.5mg,间隔2min。维持用药均根据镇静分级调整,使患者镇静程度位于闭眼入睡和大声指令可唤醒之间。观察镇静诱导时间、意识恢复时间、低氧血症发生率、咳嗽程度、局麻药物追加量以及患者的满意度。结果两组患者的镇静诱导时间分别为48±16s（P组）、210±49s（M组）,意识恢复时间分别为4.9±1.8min（P组）、15.1±5.7min（M组）,镇静诱导时间和意识恢复时间P组均明显短于M组,差异具有统计学意义（P〈0.05）。两组患者低氧血症发生率、咳嗽程度、局麻药物追加量以及患者满意度比较,均无明显差异（P〉0.05）。结论异丙酚、咪达唑仑均可安全用于纤维支气管镜检查镇静,但异丙酚镇静诱导时间短,意识恢复迅速。     

Hypotensive anesthesia for middle ear surgery: a comparison of propofol infusion and isoflurane.

An infusion of propofol (2,6-diisopropylphenol) was compared with isoflurane to induce hypotension for middle ear surgery. Forty patients (ASA physical status I-II, 16-55 years) scheduled for elective surgery were included in an open randomized study. The pharmacokinetics of propofol infusion were also studied in 6 patients. Both agents produced controlled hypotension (MAP reduction of 30% from the baseline values) with an acceptable visibility of the surgical field. No major complications occurred. The mean total dose of propofol infusion was 6.4 +/- 2.7 mg/kg and the mean concentration of isoflurane was 0.9 +/- 0.4%. Considerable interindividual pharmacokinetic variability was found and propofol was extensively distributed and rapidly cleared from the body after the infusion. Propofol infusion may be a new alternative as a hypotensive agent in middle ear surgery.     

异丙酚联合瑞芬太尼清醒镇静对呼吸功能的影响

目的 本研究拟通过异丙酚联合瑞芬太尼清醒镇静应用于腰硬联合麻醉下妇科手术中，观察其对呼吸功能的影响，评价其安全性。方法 80例ASAⅠ—Ⅱ级择期拟在腰硬联合麻醉下行子宫切除术的患者。将患者随机分为对照组20例（C组）、异丙酚组20例（P组）、瑞芬太尼组20例（R组）、瑞芬太尼联合异丙酚组20例（R＋P组）。患者腰硬联合麻醉，调整麻醉平面达T6。蛛网膜下腔阻滞麻醉15min后，P组：给予3mg／（kg·h）异丙酚连续输注，R组：给予6ug／（kg·h）瑞芬太尼连续输注，P＋R组：给予3ug／（kg·h）瑞芬太尼和1．5mg／（kg·h）异丙酚同时连续输注，对照组：给予0．3ml／（kg·h）生理盐水连续输注。输注过程中调整输注速度使患者OAA／S=3分。术毕停止输注药物，镇静过程中持续鼻导管吸氧。由于呼吸抑制或维持OAA／S评分需要调整药物剂量时，R组以1ug／（kg·h）增减，P组以0.5mg／（kg·h）增减，P＋R先增减瑞芬太尼0．5ug／（kg·h）如果仍未达到目标再调整异丙酚0．25mg／（kg·h）增减。记录于入室后（T0）、输注药物前（T1）、输注药物后5min（T2）、10min（T3）、15min（T4）、30min（T5）、子宫切除时（T6）、药物停止输注时（T7）、药物停止输注后10min（T8）时点的SpO2、自主呼吸次数（sRR），和呼吸抑制的发生率。于T0、T5、T8时点取动脉血行血气分析。药物停止输注后观察15min，直至OAA／S评分为5分。用VAS评分法测定术中焦虑程度。结果 患者一般资料无差别。P组异丙酚平均输注速度为（2．8±0．6）mg／（kg·h），R组瑞芬太尼平均输注速度为（6．4±1．5）ug／（kg·h），P＋R组瑞芬太尼（2．7±0．4）ug／（kg·h）异丙酚（1．6±0．6）mg／（kg·h）。四组患者的呼吸频率从T1时点较T0开始降低，但只有在R组的T4、T5时点较T0有品著意义的降低（P〈0．05）?     

Pharmacokinetics, induction of anaesthesia and safety characteristics of Propofol 6% SAZN vs Propofol 1% SAZN and Diprivan®-10 after bolus injection

AIMS: In order to avoid the potential for elevated serum lipid levels as a consequence of long term sedation with propofol, a formulation of propofol 6% in Lipofundin(R) MCT/LCT 10% (Propofol 6% SAZN) has been developed. The pharmacokinetics, induction of anaesthesia and safety characteristics of this new formulation were investigated after bolus injection and were compared with the commercially available product (propofol 1% in Intralipid(R) 10%, Diprivan-10) and propofol 1% in Lipofundin(R) MCT/LCT 10% (Propofol 1% SAZN). METHODS: In a randomised double-blind study, 24 unpremedicated female patients received an induction dose of propofol of 2.5 mg kg-1 over 60 s which was followed by standardized balanced anaesthesia. The patients were randomized to receive propofol as Propofol 6% SAZN, Propofol 1% SAZN or Diprivan-10. RESULTS: For all formulations the pharmacokinetics were adequately described by a tri-exponential equation, as the propofol concentrations collected early after the injection suggested an additional initial more rapid phase. The average values for clearance (CL), volume of distribution at steady-state (Vd,ss ), elimination half-life (t1/2,z ) and distribution half-life (t1/2, lambda2) observed in the three groups were 32+/-1.5 ml kg-1 min-1, 2. 0+/-0.18 l kg-1, 95+/-5.6 min and 3.4+/-0.20 min, respectively (mean+/-s.e.mean, n=24) and no significant differences were noted between the three formulations (P >0.05). The half-life of the additional initial distribution phase (t1/2,lambda1 ) in all subjects ranged from 0.1 to 0.6 min. Anaesthesia was induced successfully and uneventfully in all cases, and the quality of induction was adequate in all 24 patients. The induction time did not vary between the three formulations and the average induction time observed in the three groups was 51+/-1.3 s which corresponded to an induction dose of propofol of 2.1+/-0.06 mg kg-1 (mean+/-s.e. mean, n=24). The percentage of patients reporting any pain on injection did not vary between the formulations and was 17% for the three groups. No postoperative phlebitis or other venous sequelae of the vein used for injection occurred in any of the patients at recovery of anaesthesia nor after 24 h. CONCLUSIONS: From the above results, we conclude that the alteration of the type of emulsion and the higher concentration of propofol in the new parenteral formulation of propofol does not affect the pharmacokinetics and induction characteristics of propofol, compared with the currently available product. Propofol 6% SAZN can be administered safely and has the advantage of a reduction of the load of fat and emulsifier which may be preferable when long term administration of propofol is required.     

Influence of atropine on the dose requirements of propofol in humans

OBJECTIVE: The purpose of this study was to evaluate the effect of atropine on the dose requirement of propofol for induction of anesthesia and propofol concentrations during continuous infusion. METHODS: Study 1: Forty patients were randomly allocated to the control or atropine groups. Induction of anesthesia commenced 3 min following the administration of 0.9% saline or atropine (0.01 mg kg(-1)), using a Diprifuser set to achieve propofol concentration of 6.0 microg mL(-1). The primary end point was the propofol dose per kg at the moment of loss of response to a command. Study 2: Fifteen patients undergoing elective surgery were enrolled. Propofol was administered to all subjects via target-controlled infusion to achieve a propofol concentration at 2.0 microg mL(-1) after intubation. Before and after administration of atropine (0.01 mg kg(-1)), cardiac output (CO) was measured using indocyanine green as an indicator and blood propofol concentration was determined using high-performance liquid chromatography. RESULTS: Study 1: The propofol dose for each group was 2.22+/-0.21 mg kg(-1) for control group and 2.45+/-0.28 mg kg(-1) for atropine, respectively (p=0.014). Study 2: After the administration of atropine, CO was significantly increased from 4.28+/-0.83 to 5.76+/-1.55 l min(-1) (p<0.0001). Propofol concentration was significantly decreased from 2.12+/-0.28 to 1.69+/-0.27 microg mL(-1) (p<0.0001). CONCLUSIONS: Following the administration of atropine, the propofol requirements for the induction of anesthesia were increased and propofol concentrations were decreased during continuous infusion by the administration of atropine.     

Pharmacokinetics and sedative effects in healthy subjects and subjects with impaired liver function after continuous infusion of clomethiazole

OBJECTIVE: Clomethiazole is virtually completely eliminated by hepatic metabolism. This study was designed to assess the impact of liver impairment on its elimination and sedative effects. METHODS: Eight patients with mild liver impairment (Child-Pugh grade A), eight patients with moderate/severe liver impairment (Child-Pugh grade B/C) and eight healthy subjects of similar age were given 68 mg/kg clomethiazole edisilate according to a 24-h infusion scheme aimed at producing minimum sedation as it was intended for clinical use in patients with stroke. Concentrations of clomethiazole and its active alpha-carbon hydroxylated metabolite NLA-715 were followed in plasma and urine for 96 h and 24 h, respectively. Sedation was monitored using a scale from 1 to 6. RESULTS: The fraction excreted unchanged in urine was less than 0.2% for clomethiazole and less than 0.4% for NLA-715. Urine concentrations of clomethiazole were strongly correlated (r(2)=0.60) to plasma concentrations and approximately equal to unbound plasma concentrations. Plasma levels of NLA-715 increased steadily during the infusion, eventually reaching mean levels exceeding those of clomethiazole in all groups. Plasma clearance of clomethiazole in subjects with mildly impaired liver function was not statistically different from that of healthy controls (40 l/h vs 44 l/h). In subjects with moderate/severe liver impairment, there was a 50% reduction in clearance. Sedation was not observed except in two subjects in the Child-Pugh A group showing mild sedation. CONCLUSION: The reduced clomethiazole clearance in patients with moderate/severe liver impairment seems to call for a reduction of clomethiazole dosage. However, sedation was not observed in this group at the investigated dose level.     

瑞芬太尼联合异丙酚清醒镇静在妇科手术中的临床研究

目的拟评价瑞芬太尼联合异丙酚应用于腰硬联合麻醉下妇科手术中清醒镇静的有效性和安全性。方法40例ASAⅠ-Ⅱ级择期拟在腰硬联合麻醉下行子宫切除术的患者。将患者随机分为：对照组（C组）、瑞芬太尼复合异丙酚组（R＋P组）。C组：给予0．3ml／（kg·h）生理盐水连续输注。P＋R组：给予3μg／（kg·h）瑞芬太尼和1．5mg／（kg·h）异丙酚同时连续输注，输注过程中调整输注速度使患者OAA／S=3分。记录于人室后（T0）、输注药物前（T1）、输注药物后5min（T2）、10min（T3）、15min（T4）、30min（T5）、子宫切除时（T6）、药物停止输注时（T7）、药物停止输注后10min（T8）时点记录MAP、HR、SpO2，自主呼吸次数（sRR）。于T0、T5、T8时点取动脉血行血气分析。用VAS评分法评定患者术中的焦虑分数。结果患者一般资料无差别。两组患者的MAP、HR变化：与T0比较差异有统计学（P〈0．05），各时点组间比较差异无统计学。两组患者的呼吸频率从T1时点较T0开始降低，但这种降低无统计学意义。SpO2的变化：C，P＋R组患者的SpO2在各时点组间、组内比较差异无统计学（P〉0．05）。SRR的变化：组内组间均差异无统计学（P〉0．05）。PaCO2在P＋R组的，115时点较T0显著升高（P〈0．05）。P＋R组的焦虑分数（VAS）显著低于C组（P〈0．01）。结论应用瑞芬太尼复合异丙酚在腰硬联合麻醉下行妇科手术中具有良好的清醒镇静作用，患者焦虑分数低，呼吸、循环功能比较稳定。     

Propofol infusion syndrome: an overview of a perplexing disease.

Propofol (2, 6-diisopropylphenol) is a potent intravenous hypnotic agent that is widely used in adults and children for sedation and the induction and maintenance of anaesthesia. Propofol has gained popularity for its rapid onset and rapid recovery even after prolonged use, and for the neuroprotection conferred. However, a review of the literature reveals multiple instances in which prolonged propofol administration (>48 hours) at high doses (>4 mg/kg/h) may cause a rare, but frequently fatal complication known as propofol infusion syndrome (PRIS). PRIS is characterized by metabolic acidosis, rhabdomyolysis of both skeletal and cardiac muscle, arrhythmias (bradycardia, atrial fibrillation, ventricular and supraventricular tachycardia, bundle branch block and asystole), myocardial failure, renal failure, hepatomegaly and death. PRIS has been described as an 'all or none' syndrome with sudden onset and probable death. The literature does not provide evidence of degrees of symptoms, nor of mildness or severity of signs in the clinical course of the syndrome. Recently, a fatal case of PRIS at a low infusion rate (1.9-2.6 mg/kg/h) has been reported. Common laboratory and instrumental findings in PRIS are myoglobinuria, downsloping ST-segment elevation, an increase in plasma creatine kinase, troponin I, potassium, creatinine, azotaemia, malonylcarnitine and C5-acylcarnitine, whereas in the mitochondrial respiratory electron transport chain, the activity of complex IV and cytochrome oxidase ratio is reduced. Propofol should be used with caution for sedation in critically ill children and adults, as well as for long-term anesthesia in otherwise healthy patients, and doses exceeding 4-5 mg/kg/h for long periods (>48 h) should be avoided. If PRIS is suspected, propofol must be stopped immediately and cardiocirculatory stabilization and correction of metabolic acidosis initiated. So, PRIS must be kept in mind as a rare, but highly lethal, complication of propofol use, not necessarily confined to its prolonged use. Furthermore, the safe dosage of propofol may need re-evaluation, and new studies are needed.     

Comparison of bolus versus continuous infusion of propofol for procedural sedation: a meta-analysis

Objective: To compare the efficacy and safety of bolus infusion versus continuous infusion for propofol sedation.

Methods: We searched OVID-MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Google Scholar, Koreamed, and Kmbase databases to identify all randomized controlled trials that compared bolus infusion with continuous infusion for propofol sedation. We evaluated propofol dose used, procedure, sedation, and recovery time. The incidences of respiratory and cardiovascular complications were also evaluated.

Results: A total of 12 studies of 963 patients were included. The required propofol dose was significantly higher in continuous infusion compared with bolus infusion (standardized mean difference [SMD]: ?0.44; 95% confidence interval [CI]: ?0.71 to ?0.16; I²?=?84%). Sedation time was significantly longer in continuous infusion compared with bolus infusion (mean difference [MD]: ?8.58?min; 95% CI: ?15.13 to ?2.03; I²?=?44%). The recovery time and incidences of desaturation, airway intervention, hypotension, and bradycardia were comparable between bolus and continuous infusion.

Conclusions: Propofol sedation by continuous infusion required a higher dose of propofol compared with bolus infusion, but the recovery time and frequency of complications were similar.     

Individual differences in pharmacokinetics and pharmacodynamics of anesthetic agent propofol with regard to CYP2B6 and UGT1A9 genotype and patient age

Propofol (2,6-diisopropylphenol) is administered intravenously for induction and maintenance of anesthesia; however, cases of progressive myocardial failure (propofol syndrome) related to the use of propofol have been reported. In the present study, the individual differences in pharmacokinetics and/or pharmacodynamics of propofol were investigated in patients who were genotyped for CYP2B6 and UGT1A9. Fifty-one patients treated with propofol in St. Marianna University Hospital were recruited for this study and provided written informed consent. The following parameters were analyzed: awakening time as a pharmacodynamic parameter, duration of propofol infusion, drug concentration in plasma after treatment, genotypes of CYP2B6 and UGT1A9, and age (42-84 years, mean of 65 years). Propofol was rapidly cleared from the blood of the subjects as a result of distribution and elimination. The awakening time after stopping propofol infusion was significantly correlated with the duration of infusion and the maximum concentration of propofol in these subjects. The maximum plasma concentration of propofol after normalizing with the duration of infusion was affected by the CYP2B6 G516T variant (related to impaired function) and was significantly affected by a propofol risk index score that incorporated CYP2B6 G516T and UGT1A9 I399C>T (high expression) genotypes and advanced age. These results provide important information indicating that the genotypes of the two enzymes studied and advanced age are combinative determinant factors of the pharmacokinetics and/or pharmacodynamics of propofol.     

麻黄碱对全身麻醉患者丙泊酚镇静深度的影响

目的:探讨麻黄碱对全身麻醉(全麻)患者丙泊酚镇静深度的影响,为麻醉过程中合理应用麻黄碱提供参考。方法:选择美国麻醉医师协会(ASA)分级Ⅰ～Ⅱ级、年龄>18岁、拟行非神经外科手术、需要丙泊酚行全麻的患者纳入研究。靶控输注丙泊酚,待血压下降、警觉/镇静评分(OAA/S)=2、脑电双频指数(BIS)稳定持续5 min后,在20～30 s内静脉滴注麻黄碱0.15 mg/kg。记录静脉滴注麻黄碱前、后不同时段心率、脉搏血氧饱和度(SpO2)、右侧桡动脉平均动脉压(MAP)、BIS和OAA/S。结果:共8例患者纳入研究,男性3例,女性5例,平均年龄(50±2)岁,平均体重指数(25.1±3.7)kg/m2。拟行腹腔镜下胆囊切除术者5例,鼻内镜下鼻窦开放术者3例。靶控输注丙泊酚前2 min,患者心率和MAP分别为(81.1±3.0)次/min和(93.3±6.4)mm Hg(1 mmHg=0.133 kPa),给予丙泊酚(13.7±2.3)min后分别下降为(60.2±0.9)次/min和(72.3±5.6)mm Hg,差异有统计学意义(均P<0.01)。给予丙泊酚前、后SpO2分别为(98.1±1.5)%和(97.8±2.4)%,差异无统计学意义(P>0.05)。静脉滴注麻黄碱前2 min MAP为(81.2±6.01)mm Hg,静脉滴注麻黄碱后1～2和3～4 min时段MAP分别升高为(87.0±6.5)和(92.6±7.4)mm Hg,差异均有统计学意义(均P<0.05)。静脉滴注麻黄碱前2 min BIS为68.9±2.1,静脉滴注麻黄碱后5～6、7～8和9～10 min时段BIS分别升高为73.6±2.97、7.7±3.1和79.5±3.0,差异均有统计学意义(P<0.05、P<0.01、P<0.01)。静脉滴注麻黄碱前2 min OAA/S为2.0±0.0,静脉滴注麻黄碱后10 min OAA/S评分升高至3.5±0.3,差异有统计学意义(P<0.05)。BIS峰值较MAP峰值滞后2～4 min出现。结论:丙泊酚全麻过程中静脉滴注麻黄碱可减浅镇静深度,建议根据手术种类和患者情况在静脉滴注麻黄碱后2～4 min内采用有效措施维持麻醉镇静深度。     

Effect of dexmedetomidine on propofol requirements in healthy subjects

Dexmedetomidine-propofol pharmacodynamic interaction was evaluated in nine healthy subjects in a crossover design. Dexmedetomidine/placebo was infused using a computer-controlled infusion pump (CCIP) to maintain a pseudo-steady-state plasma concentration of 0.66 +/- 0.080 or 0 ng/mL, respectively. Forty-five minutes after the dexmedetomidine/placebo infusion was started, propofol was infused using a second CCIP to achieve a stepwise logarithmically ascending propofol concentration (1.00 to 13.8 microg/mL) profile. Each propofol step lasted 10 min. Blood was sampled for plasma concentration determination, and pharmacodynamic endpoint assessments were made during the study. Propofol and dexmedetomidine/placebo infusions were terminated when three endpoints (subjects were too sedated to hold a syringe, followed by loss of eyelash reflex, followed by loss of motor response to electrical stimulation) were achieved sequentially. The concentration of propofol associated with 50% probability of achieving a pharmacodynamic endpoint in the absence of dexmedetomidine (EC50; placebo treatment) was 6.63 microg/mL for motor response to electrical stimulation and ranged from 1.14 to 1.98 microg/mL for the ability to hold a syringe, eyelash reflex, and sedation scores. The apparent EC50 values of propofol (EC50APP; concentration of propofol at which the probability of achieving a pharmacodynamic endpoint is 50% in the presence of dexmedetomidine concentrations observed in the current study; dexmedetomidine treatment) were 0.273, 0.544-0.643, and 3.89 microg/mL for the ability to hold a syringe, sedation scores, and motor response, respectively. Dexmedetomidine reduced propofol concentrations required for sedation and suppression of motor response. Therefore, the propofol dose required for sedation and induction of anesthesia may have to be reduced in the presence of dexmedetomidine.     

Modelling of the Sedative Effects of Propofol in Patients undergoing Spinal Anaesthesia: A Pharmacodynamic Analysis

Sedation can increase patient comfort during spinal anaesthesia. Understanding the relationship between the propofol effect‐site concentration (Ce) and patient sedation level could help clinicians achieve the desired sedation level with minimal side effects. We aimed to model the relationship between the propofol Ce and adequate and deep sedation and also incorporate covariates. Thirty patients scheduled for orthopaedic surgery received spinal anaesthesia with 0.5% bupivacaine. Propofol was administered via an effect‐site target‐controlled infusion device using the Schnider pharmacokinetic model. The pharmacodynamic models for both adequate sedation [Observer's Assessment of Alertness/Sedation (OAA/S) scores of 3–4] and deep sedation (OAA/S scores of 1–2) were developed using nonlinear mixed‐effects modelling. Increments in the propofol Ce were associated with increased depths of sedation. In the basic model, the estimated population Ce₅₀ values for adequate and deep sedation were 0.94 and 1.52 μg/ml, respectively. The inclusion of the patient's age and sensory block level for adequate sedation and of age for deep sedation as covariates significantly improved the basic model by decreasing the objective function's minimum value from 10696.72 to 10677.92 (p = 0.0003). The simulated Ce₅₀ values for adequate sedation in 20‐year‐old patients with a T₁₂ sensory level and in 80‐year‐old patients with a T₄ level were 1.63 and 0.53 μg/ml, respectively. Both age and sensory block level should be considered for adequate sedation, and the propofol concentration should be reduced for elderly patients with a high spinal block to avoid unnecessarily deep levels of sedation.     

Pharmacokinetics and pharmacodynamics of propofol 6% SAZN versus propofol 1% SAZN and Diprivan-10 for short-term sedation following coronary artery bypass surgery

Objective: A new formulation of propofol 6% in Lipofundin MCT/LCT 10% (propofol 6% SAZN) has been developed in order to reduce the fat, emulsifier and volume load that is given during prolonged infusions of propofol. The pharmacokinetics, pharmacodynamics and safety characteristics of propofol 6% SAZN were investigated during a short-term infusion and compared with the commercially available product propofol 1% in Intralipid 10% (Diprivan-10) and propofol 1% in Lipofundin MCT/LCT 10% (propofol 1% SAZN). Methods: In a randomised double-blind study, 24 male patients received a 5-h infusion of propofol at the rate of 1 mg/kg/h for sedation in the immediate postoperative period following coronary artery bypass surgery. Results: The average pharmacokinetic parameter estimates of clearance (Cl), volume of distribution at steady state (V_d,ss), elimination half-life (t _1/2,β) and distribution half-life (t _1/2,α) observed in the three groups were 28 ± 1.1 ml/kg/min, 1.8 ± 0.12 l/kg, 94 ± 4.1 min and 3.1 ± 0.26 min, respectively (mean ± SEM, n=24) and no significant differences were noted between the three formulations (P > 0.05). In one patient receiving propofol 6% SAZN, in two patients receiving propofol 1% SAZN and in three patients receiving Diprivan-10, the level of sedation was inadequate and additional sedative medication had to be given. In all other 18 patients, the level of sedation was adequate. The mean propofol concentration in these six inadequately sedated patients was lower than the adequately sedated patients (P=0.015). The serum triglyceride concentrations were not significantly different between the groups studied. No adverse events occurred in any of the patients. Conclusions: The pharmacokinetics, pharmacodynamics and safety characteristics of propofol 6% SAZN are in good agreement with those of the 1% formulations. Propofol 6% SAZN therefore provides a useful alternative to the commercially available 1% formulation for short-term sedation in the intensive care unit. Expected advantages in long-term sedation of the 6% over 1% formulation are the subject of an ongoing study. Received: 11 June 1999 / Accepted in revised form: 23 December 1999     

右美托咪啶、丙泊酚与咪达唑仑辅助于臂丛阻滞麻醉的比较

目的 比较右美托咪啶、丙泊酚与咪达唑仑辅助于臂丛阻滞麻醉中的镇静效果及对呼吸循环的影响.方法 选择60例ASA Ⅰ ～Ⅱ级拟行上肢手术的患者,随机分为3组,每组各20例.超声引导下臂丛阻滞成功后,右美托咪定组（D组）患者给予右美托咪啶0.5μg/kg静脉泵注10 min后按0.2～0.7 μg/（kg·h）的速率维持;丙泊酚组（P组）给予丙泊酚2 mg/kg静脉注射后以2～4 mg/（kg·h）维持;咪达唑仑组（M组）静脉注射咪达唑仑0.05 mg/kg后以0.05～0.1 mg/（kg·h）维持.调整各组患者的输注速度使镇静目标维持Ramsay镇静评分为3～4分.术中监测不同时间点的心率（HR）、平均动脉压（MAP）、血氧饱和度（SpO2）、呼吸频率（RR）、脑电双频（BIS）指数值、Ramsay镇静评分,并记录术中出现的不良反应.结果 在相同镇静评分下,D组的BIS值明显低于P、M组（P＜0.05）;3组均出现不同程度的血压下降和心率减慢,D组HR下降较P、M组明显（P＜0.05）,P组MAP下降较D、M组明显（P＜0.05）;P、M组RR减慢较D组明显,需要辅助呼吸的比例明显高于D组（P＜0.05）.结论 丙泊酚和咪达唑仑能明显抑制呼吸,而右美托咪啶对呼吸和循环的影响小,辅助于臂丛阻滞麻醉镇静效果比较好,但易诱发心动过缓.     

Evidence of Different Propofol Pharmacokinetics under Short and Prolonged Infusion Times in Rabbits

Propofol is an anaesthetic widely used in both human beings and animals. However, the characterization of propofol pharmacokinetics (PK) is not well understood when long‐term infusions are used. The main objective of this study was to explore the PK behaviour of propofol in a rabbit model during short and prolonged propofol infusions and to develop an internally validated PK model, for propofol dose individualization in the rabbit for future use. Population 1 (P1) was constituted by seven New Zealand rabbits and was used to characterize the PK profile of propofol at short infusions. Animals were anaesthetized with a bolus of 20 mg/kg, followed by an infusion rate of 50 mg/kg/hr of propofol at 1%, which was then maintained for 30 min. A second rabbit population (P2, n = 7) was sedated according to reflexes responses and Index of Consciousness values, for 20 consecutive hours using propofol 2% aiming at characterizing propofol behaviour at long‐term infusions. Clinical data and blood samples were collected at specific time‐points in both populations. Propofol plasma concentrations were determined by gas chromatography/ion trap mass spectrometry. The NONMEM VII software was used to evaluate the relationships between dose and plasma concentrations. A linear two‐compartment model with different central compartment volume and plasma clearance (separately modelled in the two populations) was the one that best described propofol concentrations. The time course of propofol plasma concentrations was well characterized by the PK model developed, which simultaneously accounts for propofol short‐ and long‐term infusions and can be used to optimize future PK studies in rabbits.     

Effects of propofol and midazolam on lipids, glucose, and plasma osmolality during and in the early postoperative period following coronary artery bypass graft surgery: a randomized trial

It is not clear how levels of serum lipids and glucose and plasma osmolality change during propofol infusion in the pre- and postoperative period of coronary artery bypass graft surgery (CABG). This prospective, randomized, controlled trial evaluated changes in these parameters during propofol or midazolam infusion during and in the early postoperative period following surgery. Twenty patients undergoing CABG were randomized preoperatively into two groups: 10 patients received propofol (induction 1.5 mg/kg, maintenance 1.5 mg kg(-1) h(-1)) and 10 patients received midazolam (induction 0.5 mg/kg, maintenance 0.1 mg kg(-1) h(-1)). Both groups also received fentanyl (induction 20 mug/kg, maintenance 10 microg kg(-1)). Serum lipids, glucose, and plasma osmolality were measured preinduction, precardiopulmonary bypass, at the end of cardiopulmonary bypass, at the end of surgery, and 4 and 24 h postoperatively. In the propofol group, we observed a significant increase in triglycerides and very low-density lipoprotein levels 4 h postoperatively. In the midazolam group, we observed a significant decrease in low-density lipoprotein, cholesterol at the end of cardiopulmonary bypass, end of surgery, and 4 and 24 h postoperatively and significant increase in osmolality at the end of cardiovascular bypass. Changes in glucose levels did not differ significantly different between the two groups. In patients with normal serum lipids, glucose, and plasma osmolality undergoing CABG, propofol infusion for maintenance anesthesia is not associated with dangerous changes in serum lipids, glucose, and plasma osmolality compared with midazolam. A propofol infusion technique for maintenance of anesthesia for cardiac surgery where serum lipids and glucose may be of concern could be recommended as an alternative to midazolam.     

Pharmacodynamics of midazolam in pediatric intensive care patients

The aim of the study was to study a possible pharmacokinetic-pharmacodynamic (PK-PD) relationship for midazolam in pediatric intensive care patients and to determine how adequate sedation could be reached using the COMFORT scale as sedation scale. Twenty-one pediatric intensive care patients (2 days to 17 years) received a midazolam infusion (0.05-0.4 mg/kg/h, 3.8 hours to 25 days). Sedation levels were determined using the COMFORT scale as well as plasma concentrations of midazolam and metabolites. An evident PK-PD relationship was not found. In 20 of the 21 patients midazolam dosing could be effectively titrated to the desired level of sedation, assessed by the COMFORT scale. Based on our findings that there is no relationship between pharmacokinetic parameters and pharmacodynamic outcome, we recommend that midazolam dosing should be titrated according to the desired clinical effect in combination with a validated assessment instrument, eg, the COMFORT scale.     

Pharmacokinetics and clinical effects of multidose sublingual triazolam in healthy volunteers

Triazolam is increasing in popularity as a premedication prescribed by dentists to help their fearful and anxious patients tolerate the potentially aversive nature of some dental procedures. Recent anecdotal reports suggest that incremental sublingual dosing of triazolam may be an effective technique for producing conscious sedation in the dental setting. Although promising, no laboratory or clinical data have been available to evaluate the efficacy or safety of this approach. This study was designed to determine the pharmacokinetics and sedative effects of incremental sublingual dosing of triazolam (total, 1.0 mg) in healthy adults. Ten healthy adult volunteers received sublingual triazolam (0.25 mg) followed by additional doses after 60 (0.50 mg) and 90 (0.25 mg) minutes. Plasma triazolam concentrations, clinical effects (Observer's Assessment of Alertness/Sedation score), and processed electroencephalogram (bispectral index score) were measured intermittently for 3 hours. Plasma triazolam concentrations (mean +/- SD, 5.1 +/- 1.1 ng/mL) and drug effects (Observer's Assessment of Alertness/Sedation score, 2 +/- 1; and the bispectral index score, 62 +/- 16) were greatest in all subjects at the end of the 3-hour evaluation period. Eight of the subjects had Observer's Assessment of Alertness/Sedation scores consistent with the definition of deep sedation or general anesthesia (Observer's Assessment of Alertness/Sedation score, <3) at some of the later time points in the 180 minutes of data collection. In comparison, 4 of the subjects had bispectral index scores less than 60 during these later time points of data collection. Given the considerable intersubject variability in triazolam concentrations and effects, additional research is needed to assess this multidosing strategy before it can be endorsed as a useful and safe sedation technique for managing fearful and anxious patients in dental practice.