Dosing Strategy of Ramosetron to Prevent Postoperative Nausea and Vomiting and Development of Prediction Models Using Data Obtained From Randomized Controlled Trials: A Comparative Study.

PURPOSE: The study aimed to compare the postoperative nausea and vomiting (PONV) preventive effect of repeated administration of ramosetron with the standard treatment group and compare models to predict the incidence of PONV using machine-learning techniques. METHODS: A total of 261 patients scheduled for breast surgery were analyzed to evaluate the effectiveness of repeated intravenous administration of ramosetron. All patients were administered 0.3 mg ramosetron just before the end of surgery. For the repeated dose of ramosetron group, an additional dose of 0.3 mg was administered at 4, 22, and 46 hours after the end of the surgery. Postoperative nausea, vomiting, and retching were evaluated using the Rhodes Index of Nausea, Vomiting, and Retching at 6, 24, and 48 hours postoperatively. Previously published randomized controlled data were combined with the data of this study to create a new dataset of 1390 patients, and machine-learning-based PONV prediction models (classification tree, random forest, extreme gradient boosting, and neural network) was constructed and compared with the Apfel model. FINDINGS: Fifty patients (38.5%) and 60 patients (45.8%) reported nausea, vomiting, or retching 48 hours postoperatively in the standard and repeated-dose groups, respectively (P = 0.317, χ2 test). Median sensitivity, specificity, and accuracy of the Apfel model analyzed using the training set were 0.815, 0.344, and 0.495, respectively. IMPLICATIONS: The repeated administration of ramosetron did not reduce the incidence of PONV. The Apfel model had high sensitivity, however, its specificity and accuracy were lower than that in machine-learning-based models.

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.

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 ).

Frequency and characteristics of patients with bispectral index values of 60 or higher during the induction and maintenance of general anesthesia with remimazolam.

In Korea, the approved anesthetic regimen of remimazolam starts with 6 mg/kg/h or 12 mg/kg/h until loss of consciousness, followed by maintenance at 1-2 mg/kg/h. Some patients receiving remimazolam for general anesthesia experience occasional difficulty maintaining bispectral index (BIS) value ˂ 60. This retrospective study aimed to analyze the data from patients undergoing elective surgery under remimazolam based-general anesthesia to determine the frequency and physical characteristics of patients with BIS values ˂ 60. The criterion was established for patients with a poorly maintained BIS value < 60. The frequency and physical characteristics of patients who satisfied this criterion were investigated through their medical records. The modified Brice interview was conducted within 24 h after surgery. Among the 1500 patients included in the analysis, 61 (4.1%) met the criteria for BIS ˂ 60. Based on the modified Brice interview, none of the patients with poorly maintained BIS ˂ 60 complained of intraoperative awareness based on the modified Brice interview or exhibit specific physical characteristics. These patients accounted for less than 5% of the total population studied. Notably, physical characteristics alone are insufficient to predict such patients before surgery.

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.

Effect-site concentration of remimazolam at loss and recovery of responsiveness during general anesthesia: a simulation study.

BACKGROUND: The objective of this study was to investigate the effect-site concentration (Ce) of remimazolam at loss of response (LOR) and recovery of response (ROR) in patients underwent general anesthesia using simulation. In addition, the relationships between patient's factors and simulated Ce at LOR and ROR were examined. METHODS: The medical records of 81 patients who underwent elective surgery under general anesthesia using remimazolam with simulation of Ce between August 4, 2021 and October 12, 2021, were retrospectively reviewed. Remimazolam was administered as an induction dose of 6 or 12 mg/kg/h until the patient became unresponsive, followed by 0.3-2 mg/kg/ h to maintain BIS values below 60. Simultaneously, simulations of manual infusion mode were performed using Asan Pump software and the Ce of remimazolam was simulated using the Schüttler model. Whenever infusion rate of remimazolam was manually changed, the simulated Ce was confirmed almost simultaneously. LOR and ROR, defined as unresponsive and eye-opening to verbal commands, respectively, were recorded in the Asan Pump program. RESULTS: The median (1Q, 3Q) simulated Ce at LOR and ROR were 0.7 (0.5, 0.9) and 0.3 (0.2, 0.4) µg/ml, respectively. LOR was achieved in 1.9 min after remimazolam infusion with cumulative doses of 0.3 mg/kg. There was a significant relationship between age and simulated Ce at ROR (Ce at ROR = -0.0043 × age + 0.57, r = 0.30, P = 0.014). CONCLUSIONS: For optimal dosage adjustment, simulating Ce while administering remimazolam with a weight-based dose during anesthesia is helpful. Elderly patients may recover from anesthesia at lower Ce of remimazolam.

Photoplethysmogram based vascular aging assessment using the deep convolutional neural network.

Arterial stiffness due to vascular aging is a major indicator during the assessment of cardiovascular risk. In this study, we propose a method for age estimation by applying deep learning to a photoplethysmogram (PPG) for the non-invasive assessment of the vascular age. The proposed deep learning-based age estimation model consists of three convolutional layers and two fully connected layers, and was developed as an explainable artificial intelligence model with Grad-Cam to explain the contribution of the PPG waveform characteristic to vascular age estimation. The deep learning model was developed using a segmented PPG by pulse from a total of 752 adults aged 20-89 years, and the performance was quantitatively evaluated using the mean absolute error, root-mean-squared-error, Pearson's correlation coefficient, and coefficient of determination between the actual and estimated ages. As a result, a mean absolute error of 8.1 years, root mean squared error of 10.0 years, correlation coefficient of 0.61, and coefficient of determination of 0.37, were obtained. A Grad-Cam, used to determine the weight that the input signal contributes to the result, was employed to verify the contribution to the age estimation of the PPG segment, which was high around the systolic peak. The results of this study suggest that a convolutional-neural-network-based explainable artificial intelligence model outperforms existing models without an additional feature detection process. Moreover, it can provide a rationale for PPG-based vascular aging assessment.

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.

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.

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.

Performance of the Surgical Pleth Index and Analgesia Nociception Index in Healthy Volunteers and Parturients.

Various commercially available nociception devices have been developed to quantify intraoperative pain. The Surgical Pleth Index (SPI) and Analgesia Nociception Index (ANI) are among the analgesic indices that have been widely used for the evaluation of surgical patients. This study aimed to evaluate the clinical performance of the SPI and ANI in conscious healthy volunteers and parturients. Ten healthy volunteers and 10 parturients participated in this study. An algometer was used to induce bone pain in the volunteers until they rated their pain as five on the numerical rating scale (NRS); this procedure was repeated during the administration of remifentanil or normal saline. The study comprised two periods, and the volunteers were infused with different solutions in each period: normal saline during one period and remifentanil during the other in a randomized order. The parturients' SPI and ANI data were collected for 2 min when they rated their pain levels as 0, 5, and 7 on the NRS, respectively. Both the SPI and ANI values differed significantly between NRS 0 and NRS 5 (P < 0.001) in the volunteers, irrespective of the solution administered (remifentanil or normal saline). At NRS 5, the SPI showed similar values, irrespective of remifentanil administration, while the ANI showed significantly lower values on remifentanil administration (P = 0.028). The SPI and ANI values at NRS 5 and NRS 7 did not differ significantly in the parturients (P = 0.101 for SPI, P = 0.687 for ANI). Thus, the SPI and ANI were effective indices for detecting pain in healthy volunteers and parturients.

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.

Interpretation of volume kinetics in terms of pharmacokinetic principles.

Volume kinetics is the pharmacokinetics of infusion fluids and describes the distribution and elimination of infused volume. Generally, pharmacokinetic parameters can be estimated by measuring the concentration of a drug. However, it is almost impossible to directly measure the concentration of fluids. Therefore, in volume kinetics, the disposition of fluids is indirectly quantified by measuring the hemoglobin concentration under the premise of no hemoglobin loss. If the hemoglobin concentration is repeatedly measured while administering the fluids, the dilution (relative change of the plasma volume) for each corresponding hemoglobin concentration can be obtained. The dilution is based on the concept of plasma volume expansion. The method of quantifying the drugs disposition with compartmental analysis has been equally applied to volume kinetics. The transfer of fluids between compartments is explained by first-order kinetics, and it is assumed that fluid is only removed from the central compartment. Population analysis can be used to identify covariates that can account for inter-individual variability in volume kinetic parameters. Body weight and mean blood pressure are well-known representative covariates of kinetic volume parameters. Using volume kinetic parameters, the volume expansion effects of crystalloid and colloid solutions can be understood more effectively, thereby facilitating appropriate fluid therapy. Although limitations exist in volume kinetics, its implications are important for clinicians when administering fluids.

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.

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.

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.