Electroencephalographic features of elderly patients during anesthesia induction with remimazolam: a sub-study of a randomized controlled trial.

BACKGROUND: Although remimazolam is used as a general anesthetic in elderly patients due to its hemodynamic stability, the electroencephalogram (EEG) characteristics of remimazolam are not well-known. The purpose of this study was to identify the EEG features of remimazolam-induced unconsciousness in elderly patients and compare them with propofol. METHODS: Remimazolam (n=26) or propofol (n=26) were randomly administered for anesthesia induction in surgical patients. The hypnotic agent was blinded only to the patients. During the induction of anesthesia, remimazolam was administered at a rate of 6 mg/kg/h, and propofol was administered at a target effect-site concentration of 3.5 µg/ml. The EEG signals from 8 channels (Fp1,Fp2,Fz,F3,F4,Pz,P3,P4, referenced to A2, using the 10-20 system) were acquired during the induction of anesthesia and in the postoperative care unit. Power spectrum analysis was performed, and directed functional connectivity between frontal and parietal regions was evaluated using normalized symbolic transfer entropy. Functional connectivity in unconscious processes induced by remimazolam or propofol was compared with baseline. To compare each power of frequency over time of the two hypnotic agents, a permutation test with t statistic was conducted. RESULTS: Compared to the baseline in the alpha band, the feedback connectivity decreased by an average of 46% and 43%, respectively, after the loss of consciousness induced by remimazolam and propofol (95% CI for the mean difference:-0.073 to -0.044 for remimazolam, P<0.001,-0.068 to -0.042 for propofol,P<0.001). Asymmetry in the feedback and feedforward connectivity in the alpha band was suppressed after the loss of consciousness induced by remimazolam and propofol. There were no significant differences in the power of each frequency over time between the two hypnotic agents (minimum q-value=0.4235). CONCLUSIONS: Both regimens showed a greater decrease in feedback connectivity compared to a decrease in feedforward connectivity after loss of consciousness, leading to a disruption of asymmetry between the frontoparietal connectivity.

Pharmacokinetics of dexmedetomidine in pediatric patients undergoing cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass can affect the pharmacokinetics of anesthetic agents. AIMS: We aimed to evaluate the pharmacokinetics of dexmedetomidine for infants and small children undergoing cardiac surgery with cardiopulmonary bypass based on population pharmacokinetics. METHODS: We enrolled 30 pediatric cardiac surgical patients in this study. After anesthetic induction with atropine (0.02 mg/kg), thiopental sodium (5 mg/kg), and fentanyl (2-3 µg/kg), we administered 1 µg/kg of dexmedetomidine for 10 min, followed by administration of 0.5 µg/kg of dexmedetomidine per hour during surgery. At the initiation of cardiopulmonary bypass, 1 µg/kg of dexmedetomidine was infused over 5 min. Arterial blood was obtained at predefined time points. A pharmacokinetic model was developed using NONMEM. Theory-based allometric scaling with fixed exponents was applied. Weight, age, post-menstrual age, fat-free mass, whether to implement cardiopulmonary bypass and temperature were explored as covariates. RESULTS: A total of 376 blood samples were obtained from 29 children (age: 20.3 ± 19.3 months, weight: 9.7 ± 4.1 kg). A two-compartment mammillary model with third compartment associated cardiopulmonary bypass procedure best explained the pharmacokinetics of dexmedetomidine. The pharmacokinetic parameter estimates (95% CI) standardized to a 70-kg person were as follows: V1 (L) = 31.6 (17.9-39.5), V2 (L) = 90.1 (44.0-330), Cl (L/min) = 1.08 (0.70-1.25), Q (L/min) = 2.0 (1.05-3.46). Volume for third compartment associated cardiopulmonary bypass procedure (L) = 39.4 (19.3-50.9). Clearance was not influenced by the presence of cardiopulmonary bypass in this model. CONCLUSION: When cardiopulmonary bypass is applied, the plasma concentration of dexmedetomidine decreases due to an increase in the volume of distribution, so a loading dose is required to maintain the previous concentration.

Population pharmacokinetic and pharmacodynamic model of propofol externally validated in Korean elderly subjects.

The Eleveld propofol pharmacokinetic (PK) model, which was developed based on a broad range of populations, showed greater bias (- 27%) in elderly subjects in a previous validation study conducted by Vellinga and colleagues. We aimed to develop and externally validate a new PK-pharmacodynamic (PK-PD) model of propofol for elderly subjects. A population PK-PD model was constructed using propofol plasma concentrations and bispectral index (BIS) values that were obtained from 31 subjects aged 65 years older in previously published phase I studies. The predictive performance of the newly-developed PK-PD model (Choi model) was assessed in a separate Korean elderly population and compared with that of the Eleveld model. A three-compartment mammillary model using an allometric expression and a sigmoid Emax model well-described the time courses of propofol concentrations and BIS values. The V1, V2, V3, Cl, Q1, Q2, E0, Emax, Ce50, γ, and ke0 of a 60-kg subject were 8.36, 58.0, 650 L, 1.26, 0.917, 0.669 L/min, 92.1, 18.7, 2.21 µg/mL, 2.89, and 0.138 /min, respectively. In the Choi model and Eleveld model, pooled biases (95% CI) of the propofol concentration were 7.78 ( 3.09-12.49) and 16.70 (9.46-23.93) and pooled inaccuracies were 22.84 (18.87-26.81) and 24.85 (18.07-31.63), respectively. The Choi PK model was less biased than the Eleveld PK model in Korean elderly subjects (age range: 65.0-79.0 yr; weight range: 45.0-75.3 kg). Our results suggest that the Choi PK model, particularly, is applicable to target-controlled infusion in non-obese Korean elderly subjects.

Assessment of explicit and implicit memories during remimazolam anaesthesia using the process dissociation procedure: A prospective cohort study.

BACKGROUND: Memory formation during remimazolam anaesthesia, where a bispectral index (BIS) is sometimes not maintained at less than 60 despite the maximal dose, is worthy of evaluation. OBJECTIVE: Investigate the formation of explicit and implicit memories using the process dissociation procedure during remimazolam anaesthesia at a BIS of 60 to 80. DESIGN: A prospective cohort study. SETTING: A tertiary medical centre in Seoul, South Korea, between March 2022 and July 2022. PATIENTS: One hundred patients undergoing general anaesthesia using remimazolam. INTERVENTIONS: The BIS was maintained at 60 to 80 during anaesthesia induction with remimazolam. Words were spoken to patients via headphones for 15 min. MAIN OUTCOME MEASURE: The primary outcome was the probability of explicit or implicit memory formation as calculated using the original and extended models, within 24 h after word presentation. Conscious recall memory was assessed using a short-structured interview within 1 and 24 h after surgery. Memory formation was inferred to be absent if 0 was included in the 95% confidence interval (CI) of the probability. RESULTS: The main results showed no evidence of explicit or implicit memory. The 95% CI of the probability of explicit memory formation included 0 for both models, -0.01 (-0.04 to 0.02) and -0.04 (-0.10 to 0.01), respectively. The 95% CI of the probability of implicit memory formation did not include 0 when evaluated using the original model, 0.08 (0.06 to 0.10), but included 0 when evaluated using the extended model, 0.00 (-0.03 to 0.03). The modified Brice interview revealed no evidence of awareness. CONCLUSIONS: There was no evidence of explicit or implicit memory formation during remimazolam anaesthesia (BIS 60 to 80). Further research is warranted to establish whether explicit and implicit memories are still absent even in the presence of surgical stimulation. CLINICAL TRIAL REGISTRATION: KCT0006752 ( http://cris.nih.go.kr ).

Novel temperature-responsive hydrogel injected to the incision site for postoperative pain relief in laparoscopic abdominal surgery: a single-blind, randomized, pivotal clinical trial.

BACKGROUND: A temperature-responsive hydrogel (PF-72; TGel Bio, Inc., Ltd, Seoul, Korea), developed as a sustained drug delivery device, can be mixed with ropivacaine to reduce pain in the incision area. The hydrogel is soluble at low temperatures (2-8 °C) and is converted into a gel at high temperatures (> 30 °C). We aimed to evaluate whether the administration of ropivacaine using PF-72 at incision sites reduces pain until 72 h postoperatively in patients undergoing laparoscopic stomach or colorectal surgery. METHODS: Patients were randomly assigned to the control group (0.75% ropivacaine) or PF-72 group (PF-72 mixed with 0.75% ropivacaine). Before surgical incision closure, 0.75% ropivacaine or PF-72 mixed with 0.75% ropivacaine was injected into the subcutaneous fat and muscle of all incisions. Postoperative pain was evaluated by the Numerical Rating Scale (NRS, 0 = no pain, 10 = most severe pain) for wound pain at 3, 6, 24, 48, and 72 h after the end of surgery. RESULTS: Ninety-nine patients (control, n = 51; PF-72, n = 48) were included in the analysis. The areas under the curve of NRS for wound pain until 72 h in the control group and the PF-72 group were 188.7 ± 46.1 and 135.3 ± 49.9 h, respectively (P < 0.001). The frequency of the administration of rescue analgesics in the general ward was similar between the two groups. CONCLUSION: PF-72 mixed with 0.75% ropivacaine reduced postoperative pain until 72 h in patients undergoing laparoscopic surgery. Although the study population was not large enough for safety evaluation, no adverse events associated with PF-72 were observed.

The expected advantage of administering prophylactic antibiotics using target- concentration controlled infusion: Development of a new pharmacokinetic model of cefazolin.

The aim of this study was to explore the utility of target-concentration controlled infusion (TCI) as a prophylactic antibiotic administration method based on the results of a population pharmacokinetic model of cefazolin. In patients undergoing elective gastric surgery, 2 g of cefazolin was dissolved in 50 mL of saline and administered for 10 min prior to skin incision. Arterial blood samples were obtained at preset intervals to measure the total and free plasma concentrations of cefazolin. Population pharmacokinetic analysis was performed using non-linear mixed-effects modelling. To evaluate the effectiveness of the TCI method, stochastic simulation was performed based on the model construction results. In total, 360 total and 360 free plasma concentration measurements from 40 patients were used to characterise the pharmacokinetics of cefazolin. The changes in the total concentration of cefazolin over time were well-explained by the three-compartment mammillary model. Fat-free mass and estimated glomerular filtration rate were significant covariates. The probability of target attainment (PTA) to reach the target 100% fraction of time that the free plasma concentration of cefazolin was maintained above its minimal inhibitory concentration (fT > MIC) at MIC of 4 mg/L was also notably higher in the TCI method (90.7%) than in the standard method (17.0%). When cefazolin is administered by the TCI method, patient-tailored antibiotic dosing may be possible. The potential benefits of administering prophylactic antibiotics by the TCI method were observed. Further research is warranted to confirm the effectiveness of the TCI method.

Predictive performance of pharmacokinetic models for target concentration-controlled infusion of cefoxitin as a prophylactic antibiotic in patients with colorectal surgery.

We aimed to evaluate the predictive performance of previously constructed free (Cfree ) and total (Ctotal ) cefoxitin pharmacokinetic models and the possibility of administering cefoxitin via the target-controlled infusion (TCI) method in clinical practice. Two external validation studies (N = 31 for Cfree model, N = 30 for Ctotal model) were conducted sequentially. Cefoxitin (2 g) was dissolved in 50 mL of normal saline to give a concentration of 40 mg mL-1 . Before skin incision, cefoxitin was infused with a TCI syringe pump. Target concentrations of free concentration and total concentration were set to 25 and 80 µg mL-1 , respectively, which were administered throughout the surgery. Three arterial blood samples were collected to measure the total and free plasma concentrations of cefoxitin at 30, 60 and 120 min, after the start of cefoxitin administration. The predictive performance was evaluated using four parameters: inaccuracy, divergence, bias and wobble. The pooled median (95% confidence interval) biases and inaccuracies were - 45.9 (-47.3 to -44.5) and 45.9 (44.5 to 47.3) for Cfree model (Choi_F model), and - 16.6 (-18.4 to -14.8) and 18.5 (16.7 to 20.2) for Ctotal model (Choi_Told model), respectively. The predictive performance of the newly constructed model (Choi_Tnew model), developed by adding the total concentration data measured in the external validation, was better than that of the Choi_Told model. Models constructed with total concentration data were suitable for clinical use. Administering cefoxitin using the TCI method in patients maintained the free concentration above the minimal inhibitory concentration (MIC) breakpoints of the major pathogens causing surgical site infection throughout the operation period.

Development of a new pharmacokinetic model for target-concentration controlled infusion of vancomycin in critically ill patients.

The aim of this prospective study was to construct a new pharmacokinetic model of vancomycin for target-concentration controlled infusion (TCI). As the first loading dose, 25 mg/kg of vancomycin was administered during 60-90 min. Arterial blood samples were obtained at pre-set intervals to measure the serum concentrations of vancomycin. Population pharmacokinetic analysis was performed using the NONMEM software (ICON Development Solutions). In total, 197 serum concentration measurements from 22 patients were used to characterise the pharmacokinetics of vancomycin. A three-compartment mammillary model best described the pharmacokinetics of vancomycin in critically ill patients. The ideal body weight was a significant covariate for the central and slow peripheral volume of distribution. The weight and age converted to categorical variables at a cut-off of 65 years were a significant covariate for the clearance. Based on the results of stochastic simulation, the TCI method maintained the therapeutic concentration range for the longest duration. In addition, assuming that vancomycin was administered by the TCI method for 7 days, the dose was reduced by about 15% compared with the standard administration methods. The daily area under the curve values were maintained between 500 mg·h/L and 600 mg·h/L. TCI has the potential to become a new infusion method for patient-tailored dosing in critically ill patients. To administer vancomycin via TCI in clinical practice, the newly constructed pharmacokinetic model should undergo proper external validation.

Development of a new pharmacokinetic model for target-concentration controlled infusion of cefoxitin as a prophylactic antibiotic in colorectal surgical patients.

AIMS: There are several limitations to the existing method of administering cefoxitin as a prophylactic antibiotic, and the limitations may be overcome by applying the target-concentration controlled infusion (TCI) method. Population pharmacokinetic parameters are required to administer cefoxitin by the TCI method. The aim of this study was to construct a new pharmacokinetic model of cefoxitin for the TCI method in colorectal surgical patients. METHODS: In patients undergoing colorectal surgery, 2 g of cefoxitin was dissolved in 50 mL of saline and administered for 10 minutes prior to skin incision. Arterial blood samples were obtained at preset intervals to measure the total and free plasma concentrations of cefoxitin. Population pharmacokinetic analysis was performed using NONMEM software (ICON Development Solutions, Dublin, Ireland). Additionally, stochastic simulation was used to indirectly evaluate the effectiveness of the two administration methods (standard method vs TCI). RESULTS: In total, 297 plasma concentration measurements from 31 patients were used to characterize the pharmacokinetics of cefoxitin. A three-compartment mammillary model described the pharmacokinetics of cefoxitin. Body weight and creatinine clearance were significant covariates for clearance. The stochastic simulation showed that when compared with the standard method, the TCI method has a significantly higher fraction of time that the free concentration of cefoxitin is maintained above the minimum inhibitory concentration (P < .001). CONCLUSIONS: TCI has the potential to become a new infusion method for patient-tailored dosing in surgical patients. To administer cefoxitin via TCI in clinical practice, the newly constructed pharmacokinetic model should undergo proper external validation.

Population pharmacokinetic analysis of ropivacaine extended-release from a temperature-responsive hydrogel in rats.

Therapeutic agents with a short half-life need to be administered frequently to achieve sustained and effective concentrations. This could be accomplished using sustained drug delivery technology. PF-72 (TGel Bio, Inc., Seoul, Korea) is a drug delivery system based on a powder obtained from lyophilisation of a reverse thermal hydrogel, which could assist in achieving prolonged pain relief if mixed with an anaesthetic and injected into the incision site following surgery. The pharmacokinetic parameters related to the absorption of the local anaesthetic ropivacaine delivered using this hydrogel were quantified. Ten rats were divided into two groups (n = 5 each), and equal doses (4 mg/kg) of different formulations were subcutaneously injected into the abdomen. The experimental group received PF-72 mixed with 0.75% ropivacaine, and the control group received 0.75% ropivacaine. Blood was collected at specific times to measure the plasma concentration of ropivacaine. Population pharmacokinetic analysis was performed using NONMEM VII level 4 (ICON Development Solutions, Dublin, Ireland). The one-compartment absorption model, which combines zero-order absorption and first-order absorption, was used to describe the change in ropivacaine plasma concentration over time. The type of formulation was a significant covariate for zero-order absorption duration (experimental group, 92.9 min; control group, 60.5 min). The addition of PF-72 to 0.75% ropivacaine increased the duration of absorption into the blood, suggesting a longer lasting effect of the analgesic injected into the surgical wound.

Do epoch lengths of hypnotic depth indicators affect estimated of blood-brain equilibration rate constants of propofol?

This study aimed to investigate the effect of epoch length of hypnotic depth indicators on the blood-brain equilibration rate constant (ke0) estimates of propofol. Propofol was administered by zero-order infusion (1.5, 3.0, 6, and 12 mg·kg-1·h-1) for one hour in 63 healthy volunteers. The ke0 of propofol was estimated using an effect-compartment model linking pharmacokinetics and pharmacodynamics, in which response variables were electroencephalographic approximate entropy (ApEn) or bispectral index (BIS) (n = 32 each for propofol infusion rates of 6 and 12 mg·kg-1·h-1). Epoch lengths of ApEn were 2, 10, 30, and 60 seconds (s). The correlations between plasma propofol concentrations (Cp) and BIS and ApEn 2, 10, 30, and 60 s were determined, as was the Ce associated with 50% probability of unconsciousness (Ce50,LOC). The pharmacokinetics of propofol were well described by a three-compartment model. The correlation coefficient between Cp and ApEn 2, 10, 30, and 60 s were -0.64, -0.54, -0.39, and -0.26, respectively, whereas correlation coefficient between Cp and BIS was -0.74. The blood-brain equilibration half-life based on the ke0 estimates for ApEn at 2, 10, 30, 60 s and BIS were 4.31, 3.96, 5.78. 6.54, 5.09 min, respectively, whereas the Ce50,LOC for ApEn at 2, 10, 30, 60 s and BIS were 1.55, 1.47, 1.28, 1.04, and 1.55 µg·ml-1, respectively. Since ke0, which determines the onset of drug action, varies according to the epoch length, it is necessary to consider the epoch length together when estimating ke0.

Novel Analgesic Index for Postoperative Pain Assessment Based on a Photoplethysmographic Spectrogram and Convolutional Neural Network: Observational Study.

BACKGROUND: Although commercially available analgesic indices based on biosignal processing have been used to quantify nociception during general anesthesia, their performance is low in conscious patients. Therefore, there is a need to develop a new analgesic index with improved performance to quantify postoperative pain in conscious patients. OBJECTIVE: This study aimed to develop a new analgesic index using photoplethysmogram (PPG) spectrograms and a convolutional neural network (CNN) to objectively assess pain in conscious patients. METHODS: PPGs were obtained from a group of surgical patients for 6 minutes both in the absence (preoperatively) and in the presence (postoperatively) of pain. Then, the PPG data of the latter 5 minutes were used for analysis. Based on the PPGs and a CNN, we developed a spectrogram-CNN index for pain assessment. The area under the curve (AUC) of the receiver-operating characteristic curve was measured to evaluate the performance of the 2 indices. RESULTS: PPGs from 100 patients were used to develop the spectrogram-CNN index. When there was pain, the mean (95% CI) spectrogram-CNN index value increased significantly-baseline: 28.5 (24.2-30.7) versus recovery area: 65.7 (60.5-68.3); P<.01. The AUC and balanced accuracy were 0.76 and 71.4%, respectively. The spectrogram-CNN index cutoff value for detecting pain was 48, with a sensitivity of 68.3% and specificity of 73.8%. CONCLUSIONS: Although there were limitations to the study design, we confirmed that the spectrogram-CNN index can efficiently detect postoperative pain in conscious patients. Further studies are required to assess the spectrogram-CNN index's feasibility and prevent overfitting to various populations, including patients under general anesthesia. TRIAL REGISTRATION: Clinical Research Information Service KCT0002080; https://cris.nih.go.kr/cris/search/search_result_st01.jsp?seq=6638.

A modified method of measuring plasma volume with indocyanine green: reducing the frequency of blood sampling while maintaining accuracy.

Among various methods for measuring the plasma volume (PV), the indocyanine green (ICG) dilution technique is a relatively less invasive method. However, the ICG method is rather cumbersome because 10 blood samples need to be obtained within a short time after ICG administration. Thus, reducing the frequency of blood sampling while maintaining the accuracy would facilitate plasma volume measurement in clinical situations. We here developed a modified method to measure plasma volume using 2260 ICG plasma concentration data from 115 surgical patients. The mean relative error (MRE) and the percentage of cases with relative error (RE) greater than 5% in total (PRE) were used to quantify the difference between plasma volumes obtained by the original and modified methods. RE was determined as follows. RE(%) = (PV obtained by original method (PVoriginal)-PV obtained by modified method (PVmodified))/PVoriginal × 100. PVmodified was assumed to be equal to PVoriginal when the RE was < 5%. When the number of samples selected for the plasma volume estimation was 4 or less, the PRE was mostly 10% or more. Five out of the 10 blood samples (order: 1st, 2nd, 3rd, 9th, and 10th) showed similar accuracies with the plasma volume obtained by the original method (original: 2.72 ± 0.64 l, modified: 2.72 ± 0.65 l). This modified method may be able to aptly replace the original method and lead to a wider clinical application of the ICG dilution technique. Further validation is needed to determine if the results of this study may be applied in other populations.

An allometric pharmacokinetic model and minimum effective analgesic concentration of fentanyl in patients undergoing major abdominal surgery.

BACKGROUND: We aimed to characterise the population pharmacokinetics of fentanyl in adults and to determine the minimum effective concentration (MEC) and minimum effective analgesic concentration (MEAC) of i.v. fentanyl in patients after major abdominal open surgery. METHODS: In the pharmacokinetic study, subjects received an intravenous bolus of fentanyl 100 µg during operation, and arterial blood was sampled at pre-set intervals. In addition, data from previously published fentanyl pharmacokinetic studies were incorporated to build a pharmacokinetic model. In the MEAC study, subjects were asked to rate their pain every 10 min using a VAS (0=no pain, 10=most severe pain) in the PACU. The first blood sample was obtained when wound pain was rated as ≥3 at rest or ≥5 during compression. Then, fentanyl 50 µg was administered every 10 min until the pain intensity had decreased to <3 at rest and <5 during compression, at which point the second blood was sampled and the first MEAC of fentanyl was measured. The same procedure was repeated to obtain a third sample (MEC) and a fourth sample (second MEAC). RESULTS: In the population pharmacokinetic study (n=95), the plasma concentration of fentanyl over time was well-described by the three-compartment mammillary model using an allometric expression. The V1, V2, V3, Cl, Q1, and Q2 of a 70 kg subject were 10.1, 26.5, 206 L, 0.704, 2.38, and 1.49 L min-1, respectively. In the MEAC study (n=30), the median (inter-quartile range) MEC and MEAC were 0.72 (0.58-1.05) ng ml-1, and 0.99 (0.76-1.28) ng ml-1, respectively. CONCLUSION: These results provide a scientific basis for the use of fentanyl for acute postoperative pain management in surgical patients. CLINICAL TRIAL REGISTRATION: KCT0003273 (http://cris.nih.go.kr).

Evaluation of Surgical Pleth Index and Analgesia Nociception Index as surrogate pain measures in conscious postoperative patients: an observational study.

We evaluated the performance of the Surgical Plethysmographic Index (SPI) and the Analgesia Nociception Index (ANI) as surrogate pain measures and determined their respective cut-off values for detecting pain in conscious postoperative patients. In total, 192 patients after elective surgery were enrolled. Baseline SPI and ANI data were acquired for 10 min in the operating room prior to surgery when the patients rated their pain as 0 on the numerical rating scale (NRS). Upon arrival in the post-anaesthesia care unit (PACU) after surgery, SPI and ANI data were recorded for 10 min. The means of the recorded data at OR and PACU were defined as the values representing baseline and postoperative pain, respectively. SPI and ANI data obtained from 189 patients were analysed, who were anesthetized with propofol (n = 149) or sevoflurane (n = 40). Remifentanil was continuously infused intraoperatively in all patients. The values of SPI and ANI were significantly different in conscious patients without (NRS = 0) and with pain (NRS > 0). The areas under the receiver operating curves for SPI and ANI were 0.73 (P < 0.0001) and 0.67 (P < 0.0001), respectively. The cut-off values for SPI and ANI in predicting postoperative pain were 44 (sensitivity: 84%, specificity: 53%) and 63 (sensitivity: 52%, specificity: 82%), respectively, which are different from those suggested by their respective manufacturers for use in intraoperative state under general anaesthesia. The cut-off values of SPI and ANI for detecting pain were similar regardless of the type of anesthesia.

Population-based volume kinetics of Ringer's lactate solution in patients undergoing open gastrectomy.

In order to maintain stable blood pressure and heart rate during surgery, anesthesiologists need to administer the appropriate amount of fluid with appropriate fluid type to the patient, then quantifying how fluid is distributed and eliminated from the body is useful for establishing a fluid administration strategy. In this study we characterized the volume kinetics of Ringer's lactate solution in patients undergoing open gastrectomy. When propofol and remifentanil reached a pseudosteady state at the target concentration and blood pressure was stabilized following surgical stimulation, enrolled patients were administered 1000 mL of Ringer's lactate solution for 20 min, followed by continuous infusion at a rate of 6 mL/kg/h until the time of the last blood collection for volume kinetic analysis. Arterial blood samples were collected to measure the hemoglobin concentration at different time points. The change in hemoglobin-derived plasma dilution induced by the administration of Ringer's lactate solution was evaluated by nonlinear mixed effects modeling. Three hundred and twenty-three plasma dilution data points from 27 patients were used to determine the pharmacokinetic characteristics of Ringer's lactate solution. A two-volume model best described the pharmacokinetics of Ringer's lactate solution. The mean arterial pressure (MAP) and body weight (WT) were significant covariates for the elimination clearance (kr) and central volume of distribution at baseline (Vc0), respectively. The parameter estimates were as follows: kr (mL/min) = 124 + (MAP/70)14.2, Vc0 (mL) = 0.95 + 3440 × (WT/63), Vt0 (mL) = 2730, and kt (mL/min) = 181. A higher MAP was associated with a greater elimination clearance and, consequently, less water accumulation in the interstitium. As body weight increases, volume expansion in the blood vessels increases.

Predictive performance of a new pharmacokinetic model for propofol in underweight patients during target-controlled infusion.

BACKGROUND: In a previous study, the modified Marsh and Schnider models respectively showed negatively- and positively-biased predictions in underweight patients. To overcome this drawback, we developed a new pharmacokinetic propofol model-the Choi model-for use in underweight patients. In the present study, we evaluated the predictive performance of the Choi model. METHODS: Twenty underweight patients undergoing elective surgery received propofol via TCI using the Choi model. The target effect-site concentrations (Ces) of propofol were 2.5, 3, 3.5, 4, 4.5, and 2 µg/mL. Arterial blood samples were obtained at least 10 minutes after achieving pseudo-steady-state. Predicted propofol concentrations with the modified Marsh, Schnider, and Eleveld pharmacokinetic models were obtained by simulation (Asan pump, version 2.1.3; Bionet Co. Ltd., Seoul, Korea). The predictive performance of each model was assessed by calculation of four parameters: inaccuracy, divergence, bias, and wobble. RESULTS: A total of 119 plasma samples were used to determine the predictive performance of the Choi model. Our evaluation showed that the pooled median (95% CI) bias and inaccuracy were 4.0 (-4.2 to 12.2) and 23.9 (17.6-30.3), respectively. The pooled biases and inaccuracies of the modified Marsh, Schnider, and Eleveld models were clinically acceptable. However, the modified Marsh and Eleveld models consistently produced negatively biased predictions in underweight patients. In particular, the Schnider model showed greater inaccuracy at a target Ce ≥ 3 µg/mL. CONCLUSION: The new propofol pharmacokinetic model (the Choi model) developed for underweight patient showed adequate performance for clinical use.

Pharmacodynamic Analysis of the Influence of Propofol on Left Ventricular Long-Axis Systolic Performance in Cardiac Surgical Patients.

BACKGROUND: Propofol induced a decline in the left ventricular (LV) systolic performance in non-cardiac surgery. We tested the hypothesis that propofol decreased the LV contractile function by dose dependent manner in cardiac surgery patients. METHODS: Anesthesia was maintained with target-controlled infusions of propofol and remifentanil in cardiac surgery patients. With a fixed effect-site concentration (Ce) of remifentanil (20 ng/mL) after sternotomy, the Ce of propofol was adjusted to maintain a Bispectral index of 40-60 (Ce1). Mitral annular Doppler tissue image tracings and other echocardiographic variables, including end-diastolic and end-systolic volumes, stroke volume, and mitral inflow pulse wave Doppler profile at Ce1, were recorded using transesophageal echocardiography. Echocardiographic recordings were repeated after the Ce-values of propofol were doubled and tripled at 10-minute intervals (defined as Ce2 and Ce3, respectively). Serial changes in echocardiographic variables for each Ce of propofol were assessed using generalized linear mixed effect modeling. The pharmacodynamic relationship between the Ce of propofol and peak systolic mitral annular velocity (Sm) was analyzed by logistic regression using non-linear mixed effect modeling (NONMEM). RESULTS: Means of Ce1, Ce2, and Ce3 were 0.8, 1.6, and 2.4 µg/mL, respectively, and their means of Sm (95% confidence interval) were 9.7 (9.3-10.2), 8.7 (8.2-9.1), and 7.5 cm/sec (7.0-8.0), respectively (P < 0.01). Ce values of propofol and Sm showed a significant inter-correlation and predictability (intercept, 10.8; slope-1.0 in generalized mixed linear modeling; P < 0.01). Ce values producing 10% and 20% decline of Sm with 50%-probability were 1.4 and 2.1 µ/mL, respectively. CONCLUSION: Propofol reduces LV systolic long-axis performance in a dose-dependent manner. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01826149.

Effects of depth of neuromuscular block on postoperative pain during laparoscopic gastrectomy: A randomised controlled trial.

BACKGROUND: Evidence on whether the use of deep neuromuscular block (NMB) influences postoperative pain after laparoscopic surgery is limited, and existing studies have shown conflicting results. We studied the effect of the depth of NMB during laparoscopic gastrectomy on postoperative pain. OBJECTIVE: The aim of this study was to evaluate the effect of depth of NMB during laparoscopic gastrectomy on postoperative pain by allocating patients randomly to either deep or moderate NMB with a standard-pressure pneumoperitoneum. DESIGN: A randomised, controlled, double-blind study. SETTING: A university-affiliated hospital. PARTICIPANTS: One hundred patients. INTERVENTIONS: Patients were allocated randomly to receive either deep (posttetanic count 1 to 2) or moderate (train-of-four count 1 to 2) levels of NMB. Following surgery, the patients were asked to rate their pain every 10 min using a visual analogue scale (VAS) (0 = no pain, 10 = most severe pain) in the postanaesthesia care unit (PACU). Patients received intravenous oxycodone, 2 mg every 10 min, until the pain intensity (VAS) had decreased to less than 3 at rest and less than 5 on wound compression, at which point the minimum effective analgesia dose (MEAD) of oxycodone was determined. MAIN OUTCOME MEASURES: The primary endpoint was the MEAD of oxycodone. Secondary endpoints included area under the curve of VAS for wound pain, VAS scores for wound and shoulder pain at 6 and 24 h after the end of surgery, rescue analgesics, a five-point surgical rating scale, Rhodes index of nausea vomiting retching at 6 and 24 h after the end of surgery and duration of pneumoperitoneum. RESULTS: The median value for the MEAD of oxycodone was 8 mg in both groups. Area under the curves of VAS over time were similar in both groups. Variables associated with postoperative pain including mean VAS at PACU and frequency of rescue analgesics in the ward did not differ significantly between the two groups. The duration of pneumoperitoneum was a significant variable in determining the MEAD of oxycodone (linear regression, R = 0.07, P = 0.008). The number of patients who reached the acceptable surgical score was not significantly different between the two groups. However, the moderate NMB group did have a significantly higher proportion of cases that required additional muscle relaxants (P < 0.001). CONCLUSION: Deep, compared with moderate, NMB did not significantly reduce the MEAD of oxycodone administered in the PACU. The duration of pneumoperitoneum was positively correlated with the MEAD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03266419.

Quantitative analysis of the effect of end-tidal carbon dioxide on regional cerebral oxygen saturation in patients undergoing carotid endarterectomy under general anaesthesia.

AIMS: Regional cerebral oxygen saturation (rSO2 ) is currently the most used measure in clinical practice to monitor cerebral ischaemia in patients undergoing carotid endarterectomy (CEA). Although end-tidal carbon dioxide (PET CO2 ) is known as a factor that influences rSO2 , the relationship between PET CO2 and rSO2 has not been quantitatively evaluated in patients with severe arteriosclerosis. This study aimed to evaluate the effect of PET CO2 on rSO2 in patients undergoing CEA under general anaesthesia. METHODS: The intervention to change PET CO2 was conducted between skin incision and clamping of the carotid artery. The rSO2 values were observed by changing PET CO2 in the range of 25-45 mmHg. The PET CO2 -rSO2 relationship was characterized by population analysis using a turnover model. RESULTS: In total, 1651 rSO2 data points from 30 patients were used to determine the pharmacodynamic characteristics. Hypertension (HTN) and systolic blood pressure (SBP) were significant covariates on the slope factor in the stimulatory effect of PET CO2 on rSO2 and fractional turnover rate constant (kout ), respectively. The estimates of the parameters were kout (min-1 ): 3.59 for SBP <90 mmHg and 0.491 for SBP ≥90 mmHg, slope: 0.00321 for patients with HTN and 0.00664 for patients without HTN. CONCLUSION: The presence of HTNattenuates the response of rSO2 after a change in PET CO2 . When cerebral blood flow is in a state of decline caused by a decrease in SBP to <90 mmHg, the response of rSO2 to PET CO2 is increased. It is advisable to maintain SBP >90 mmHg in patients with HTNduring CEA.