Target Effect-site Concentration Research Articles

The degree of respiratory depression according to the effect-site concentration in remimazolam target-controlled infusion: A randomised controlled trial.

Remimazolam is not only associated with a lower incidence of respiratory depression than propofol but also in itself has the risk of respiratory depression. We investigated respiratory depression following remimazolam infusion, targeting different effect-site concentrations using target-controlled infusion. A prospective, double-blind, randomised controlled study. Tertiary hospital, Suwon, South Korea, from April 2022 to November 2022. One hundred and seven patients scheduled for general anaesthesia were randomised into three groups targeting remimazolam effect-site concentrations of 500 (RMZ-500) (n = 36), 1000 (RMZ-1000) (n = 35) and 1500 ng ml-1 (RMZ-1500) (n = 36). Remimazolam was solely infused for 10 min according to target effect-site concentrations. According to the degree of SpO2 decrease, oxygen desaturations were managed with the following respiratory supports: jaw-thrust for SpO2 less than 97%, 100% oxygen delivery for SpO2 less than 93% and assisted ventilation for SpO2 less than 90%. The incidence of each respiratory support, along with respiratory variables (at baseline, 5 min and 10 min after remimazolam infusion) and loss of consciousness were observed for 10 min after remimazolam target-controlled infusion. Both RMZ-1000 and RMZ-1500 required more frequent respiratory support than RMZ-500 (both P < 0.001), with nearly identical frequencies between RMZ-1000 and RMZ-1500. In terms of respiratory support, the incidence of assisted ventilation was significantly lower in RMZ-500 (2.8%) than RMZ-1000 (48.6%) and RMZ-1500 (50%) (P < 0.001). RMZ-1000 and RMZ-1500 achieved loss of consciousness in all patients; RMZ-500 only achieved loss of consciousness in 86.1% of patients (P = 0.010). In patients who maintained spontaneous respiration, tidal volume decreased by 41 to 48% and respiratory rate increased by 118 to 158% at 5 and 10 min, significantly compared to baseline in all groups (P < 0.001). Remimazolam infusion, like that of other benzodiazepines, led to respiratory depression, which was more prominent at higher target effect-site concentrations. Therefore, appropriate countermeasures should be developed to prevent oxygen desaturation. CRIS (https://cris.nih.go.kr), identifier: KCT0006952.

Relationship between preinduction electroencephalogram patterns and propofol sensitivity in adult patients.

To determine the precise induction dose, an objective assessment of individual propofol sensitivity is necessary. This study aimed to investigate whether preinduction electroencephalogram (EEG) data are useful in determining the optimal propofol dose for the induction of general anesthesia in healthy adult patients. Seventy healthy adult patients underwent total intravenous anesthesia (TIVA), and the effect-site target concentration of propofol was observed to measure each individual's propofol requirements for loss of responsiveness. We analyzed preinduction EEG data to assess its relationship with propofol requirements and conducted multiple regression analyses considering various patient-related factors. Patients with higher relative delta power (ρ = 0.47, p < 0.01) and higher absolute delta power (ρ = 0.34, p = 0.01) required a greater amount of propofol for anesthesia induction. In contrast, patients with higher relative beta power (ρ = -0.33, p < 0.01) required less propofol to achieve unresponsiveness. Multiple regression analysis revealed an independent association between relative delta power and propofol requirements. Preinduction EEG, particularly relative delta power, is associated with propofol requirements during the induction of general anesthesia. The utilization of preinduction EEG data may improve the precision of induction dose selection for individuals.

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

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. 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. 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). 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.

Opioid sensitivity in treated and untreated obstructive sleep apnoea: a prospective cohort study

BackgroundOpioid administration to patients with obstructive sleep apnoea (OSA) is controversial because they are believed to be more sensitive to opioids. However, objective data on opioid effects in OSA are lacking. We tested the hypothesis that subjects with untreated OSA have increased sensitivity to opioids compared with subjects without OSA, or with OSA treated with continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP). MethodsThis was a single-centre, prospective cohort study in subjects without OSA (n=20), with untreated OSA (n=33), or with treated OSA (n=21). OSA diagnosis was verified using type III (in-home) polysomnography. Subjects received a stepped-dose remifentanil infusion (target effect-site concentrations of 0.5, 1, 2, 3, 4 ng ml−1). Primary outcome was miosis (pupil area fractional change), the most sensitive opioid effect. Secondary outcomes were ventilatory rate, end-expired CO2, sedation, and thermal analgesia. ResultsThere were no differences in miosis between untreated OSA subjects (mean=0.51, 95% confidence interval [CI] 0.41–0.61) and subjects without OSA (mean=0.49, 95% CI 0.36–0.62) (mean difference=0.02, 95% CI −0.18 to 0.22); between treated OSA subjects (mean=0.56, 95% CI 0.43–0.68) and subjects without OSA (difference=0.07, 95% CI −0.16 to 0.29); or between untreated OSA and treated OSA (difference=−0.05, 95% CI −0.25 to 0.16). There were no significant differences between subjects without OSA, untreated OSA, and treated OSA in ventilatory rate, end-expired CO2, sedation, or thermal analgesia responses to remifentanil. There was no relationship between OSA severity and magnitude of opioid effects. ConclusionsNeither obstructive sleep apnoea nor obstructive sleep apnoea treatment affected sensitivity to the miotic, sedative, analgesic, or respiratory depressant effects of the opioid remifentanil in awake adults. These results challenge conventional notions of opioid effects in obstructive sleep apnoea. Clinical trial registrationNCT02898792 (clinicaltrials.gov).

Target-controlled infusion – Past, present, and future

Abstract Target-controlled infusion (TCI) is a novel drug delivery system wherein a microprocessor calculates the rate of drug to be infused based upon the target plasma or effect site concentration set by the operator. It has found its place in the operation theaters and intensive care units (ICUs) for safe administration of intravenous anesthesia and analgosedation using drugs like propofol, dexmedetomidine, opioids, and so on. Operating a TCI device requires the user to have a primitive understanding of drug pharmacokinetics and pharmacodynamics and an awareness of the practical problems that can arise during its administration. Ongoing research supports their usage in other clinical settings and for various other drugs such as antibiotics, vasopressors, and so on. In this article, we review the underlying principles and commonly used drugs for TCI, the practical aspects of its implementation, and the scope of this technology in future. TCI technology is increasingly being used in the field of anesthesiology and critical care due to the myriad advantages it offers when compared to manual infusions. It is, therefore, essential for the reader to understand the relevant principles and practical aspects related to TCI technology, as well as to be aware of the commonly used TCI models.

The effects of the administration sequence and the type of hypnotics on the development of remifentanil-induced chest wall rigidity: a randomized controlled trial

BackgroundResearch on remifentanil-induced chest wall rigidity is limited. Furthermore, its incidence is unknown, and the clinical factors influencing its development remain unclear. This prospective, double-blind, randomized controlled trial aimed to investigate the effects of the administration sequence of hypnotics and remifentanil as well as the type of hypnotic administered on the development of remifentanil-induced chest wall rigidity.MethodsA total of 125 older patients aged ge 65 years, who were scheduled to undergo elective surgery under general anesthesia, were enrolled in this study. Participants were randomly assigned to one of four groups; Thio-Remi, Pro-Remi, Remi-Thio, or Remi-Pro. After confirming the loss of consciousness and achieving a target effect-site concentration of 3 ng/mL remifentanil, the development of remifentanil-induced chest wall rigidity was evaluated.ResultsThe incidence of chest wall rigidity was significantly higher in the remifentanil-hypnotic group than in the hypnotic-remifentanil (opposite sequence) group (55.0% vs. 21.7%, P < 0.001). Logistic regression analysis revealed that remifentanil-hypnotic administration was a significant predictor of the development of chest wall rigidity (crude odds ratio 4.42, 95% confidence interval 1.99; 9.81, P < 0.001).ConclusionsPretreatment with hypnotics potentially reduces the development of chest wall rigidity during the induction of balanced anesthesia with remifentanil in older patients.Trial registrationThis article was registered at WHO International Clinical Trials Registry Platform (Trial number: KCT0006542).

Comparison of postoperative nausea and vomiting between Remimazolam and Propofol in Patients undergoing oral and maxillofacial surgery: a prospective Randomized Controlled Trial

BackgroundRemimazolam is a recently approved, ultra-short-acting benzodiazepine. However, few studies have investigated remimazolam in relation to postoperative nausea and vomiting (PONV). This study aimed to compare the effects of remimazolam and propofol on PONV in patients undergoing oral and maxillofacial surgery.MethodsPatients (n = 206) aged 19–65 years who were scheduled for oral and maxillofacial surgery were randomized into two groups, the remimazolam (R) and propofol group (P). In the R group (n = 94), remimazolam was used to induce anesthesia at 12 mg/kg/h and to maintain anesthesia at 1–2 mg/kg/h. In the P group (n = 95), anesthesia was induced and maintained with propofol (target effect-site concentration: 3–5 µg/ml). In both groups, remifentanil was administered at a target effect-site concentration of 2.5-4 ng/ml. The primary outcome was the overall incidence of PONV during the first 24 h after surgery. Secondary outcomes included the severity of nausea, use of rescue antiemetics, severity of postoperative pain, use of rescue analgesia, and quality of recovery.ResultsThe incidence of PONV during the first 24 h after surgery was 11.7% and 10.5% in the R group and P group, respectively, and there was no significant difference in the severity of nausea (P > 0.05). Ten patients in the R group and ten patients in the P group required rescue antiemetics during the first 24 h after surgery (P = 0.98). No inter-group differences were observed in terms of postoperative pain score, use of rescue analgesia, and quality of recovery (P > 0.05).ConclusionsIn this study, remimazolam did not increase the incidence and severity of PONV compared with propofol.Trial registrationKCT0006965, Clinical Research Information Service (CRIS), Republic of Korea. Registration date: 26/01/2022.

Comparison of Half-Effective Concentration of Propofol in Patients with Parkinson's Disease and Non-Parkinson's Disease.

This study aimed to compare the half-effective concentration (EC50) of propofol required for the bispectral index (BIS) 50 in patients with Parkinson's disease (PD) and non-PD (NPD) during induction by the Dixon's improved sequential method. This prospective study recruited 20 patients with PD undergoing deep brain stimulation and 20 patients with NPD accompanied by meningioma or glioma undergoing intracranial surgery from March 2018 to March 2019. The patients were induced by propofolviatarget-controlledinfusion. The targeteffect-siteconcentrationof propofol was determined by the Dixon's improved sequential method. The results of the pilot experiment showed that the targeteffect-site concentration for the first patient with PD and NPD was 3.5 µg/mL and 2.8 µg/mL, respectively. BIS values were recorded after achievingaconstanteffect-siteconcentrationof propofol. The increment or decrement of the targeteffect-site concentration of the next patient was 0.1 µg/mL. Demographic data, general physical condition, and hemodynamic values were similar between the PD and the NPD groups. The targeteffect-siteconcentrationof propofol induction doses was significantly higher in the PD group than in the NPD group. The EC50 of propofol required for BIS 50 was 3.213 µg/mL [95% confidence interval (CI), 3.085-3.287 µg/mL] in the PD group and 2.77 µg/mL (95% CI, 2.568-2.977 µg/mL) in the NPD group. The EC50 of propofol required for BIS 50 was higher in patients with PD than in patients with NPD.

Multiple sinus pauses during suspension laryngoscopy with external laryngeal manipulation in hyperextended neck position in a patient with enlarged cervical lymph nodes: a case report

Suspension laryngoscopy is a commonly performed procedure for effective laryngeal microsurgery (LMS). Although it is associated with few adverse events, cardiac complications such as severe arrhythmia induced by exaggerated vagal tone may arise during this procedure. Here, I present the case of a 52-year-old female patient who presented with a suspected thyroid follicular neoplasm and enlarged cervical lymph nodes. LMS was planned to remove a vocal fold polyp before the thyroid surgery. The patient was placed in a Boyce-Jackson position, and suspension laryngoscopy was performed. However, several sinus pauses were detected whenever external laryngeal manipulation (ELM) was performed to improve surgical field exposure, which was presumed to be attributed to vagal stimulation or reflex induced by numerous external and internal factors during laryngeal manipulation. The suspected mechanism was the direct stimulation of the vagus nerve termed the laryngo-cardiac reflex, or carotid sinus reflex, a type of baroreceptor reflex. When the first episode of sinus pause occurred, the effect-site target concentration of propofol was unadjusted after checking the bispectral index level indicating an adequate anesthetic depth, but ELM was discontinued. When the second episode occurred, ELM could not be stopped until good laryngeal visualization was achieved. Then, the patient received 0.2 mg of intravenous glycopyrrolate. Her heart rate returned within the normal range whenever ELM was not applied. When performing suspension laryngoscopy, the head and neck positioning, the procedure itself and laryngeal manipulation may act as external factors that could induce an exaggerated vagal response. Further, patients with head and neck tumors have various internal factors, such as tumor itself, cervical lymphadenopathy or post-irradiation fibrosis, which can affect the carotid sinus and deteriorate the vagal response. Therefore, careful preoperative evaluation is required to identify these internal factors in advance and take proper care to minimize the additional influence of external factors.

Optimal Propofol Concentration at Effect Site for Esophagogastroduodenoscopy under Moderate to Deep Sedation with Target-controlled Infusion

Background: The target-controlled infusion (TCI) of propofol is being increasingly used for moderate-to-deep sedation during esophagogastroduodenoscopies (EGDs). Objective: To determine the target effect-site concentration (Cet) of propofol required for EGD scope insertions during sedation using TCI. Materials and Methods: Dixon’s up-and-down sequential allocation method was used with patients scheduled for elective EGD at Srinagarind Hospital, Thailand. The patients were divided into Group A aged 18 to 64 years and Group B aged over 65 years. Anesthesia was induced with propofol via TCI (Schnider model). The propofol Cet commenced at 3 mcg/mL and 2 mcg/mL in Groups A, and B, respectively. The response during an EGD scope insertion determined the Cet for the next patient, with intervals of 0.3 mcg/mL. Calculations of the effective concentration without response during EGD scope insertion in 50% and 95% of patients (EC50 and EC95) values of propofol, with 95% confidence intervals (CIs), were performed using the isotonic regression method. Results: Twenty-one and nineteen patients were enrolled in Groups A, and B, respectively. In Group A, the EC50 of propofol for EGD was 3.30 mcg/mL (95% CI 3.05 to 3.55), while the EC95 was 3.75 mcg/mL (95% CI 3.34 to 4.16). In the case of Group B, the EC50 was 3.05 mcg/mL (95% CI 2.75 to 3.35) and the EC95 was 3.05 mcg/mL (95% CI 2.92 to 3.18). Hypotension occurred in 52.3% and 31.5% of patients in group A, and B, respectively. Conclusion: The appropriate Cet of propofol for anesthesia during EGD using TCI is 3.75 mcg/mL for patients aged 18 to 64 years, and 3.05 mcg/mL for patients aged 65 years and over. Hypotension is the most common adverse event of moderate-to-deep sedation with propofol using TCI. Keywords: Sedation; Esophagogastroduodenoscopy; Propofol; Target-controlled infusion

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Time interval between alfentanil and rocuronium administration necessary to prevent rocuronium-induced withdrawal movement

BackgroundWe aimed to determine the time interval between alfentanil and rocuronium administration, at a 50% probability of preventing pain-induced withdrawal movement from rocuronium injection (TimeAR50).MethodsA total of 64 patients scheduled for general anesthesia were enrolled in this study (33 men and 31 women). Anesthesia was induced with target-controlled infusion of propofol, at an effect-site target concentration of 3 μg/mL. Then, alfentanil 15 μg/kg was injected for 30 s. After 60 s, rocuronium 0.6 mg/kg was administered to the first patient. The Dixon’s up-and-down method was used to determine the time interval for each subsequent patient (interval of 5 s). Mean arterial pressure (MAP) and heart rate (HR) were recorded at three time points: T0, pre-induction; T1, before rocuronium injection; and T2, 1 min after rocuronium injection.ResultsThe TimeAR50 ± standard deviation (SD) was 5.6 ± 3.7 s and 21.9 ± 5.6 s in the male and female patients, respectively. Based on the probit regression, the TimeAR50 was 4.7 s (95% confidence interval [CI], 1.2–7.6 s) and 20.3 s (95% CI, 7.7–26.1 s) in the male and female patients, respectively. The TimeAR95 was 10.6 s (95% CI, 7.7–25.3 s) and 35.0 s (95% CI, 28.1–95.5 s) in the male and female patients, respectively, with significantly higher values in females than in males (P < 0.001). Compared with the T0, MAP and HR decreased significantly at T1 and T2 in both groups.ConclusionThe TimeAR50 required for preventing rocuronium-induced withdrawal movement were 4.7 s and 20.3 s in male and female patients, respectively.Trial registrationThis study was registered with the Chinese Clinical Trials Registry on April 7, 2021 (URL: http://www.chictr.org.cn. Registry number: ChiCTR2100045137) .

A single-center pilot study comparing dexmedetomidine continuous infusion versus propofol TCI for drug-induced sleep endoscopy (DISE)

Background: Drug-induced sleep endoscopy (DISE) has become a routine diagnostic tool to assess the upper airway in obstructive sleep apnea patients, enabling effective diagnosis and appropriate treatment of the obstruction site. A number of protocols with different drugs and availability of target-controlled infusion (TCI) systems have been reported and published, making comparisons between studies difficult. In recent years, dexmedetomidine has claimed a role as a potential alternative to propofol for DISE sedation. In a real-life study we compared the effects of dexmedetomidine continuous infusion or propofol-TCI in patients undergoing DISE on time to reach adequate observation conditions, cardio-respiratory parameters, and recovery. Methods: Pilot prospective, randomized not blinded, single center study. A total of 28 patients scheduled to have DISE were randomly assigned to either group P (N=14; propofol-TCI, initial propofol effect-site target concentration 2.0 µg/mL, increased by 0.3 µg/mL every 2 min) or group D (N=14; dexmedetomidine bolus 1 µg/kg over 10 min, followed by infusion at 0.7 µg/kg/h). Hemodynamic and respiratory variables (including SpO2 nadir), time to reach the observation window and overall DISE duration were recorded. Results: A total of 28 patients were enrolled and completed the study: the cohort included 26 males (92.85%) and 2 females (7.14%). The mean age was 45.4±11.1 years [interquartile (IQ), 25.0–65.0], body mass index 30.5±3.4 kg/m2 (IQ, 21.0–36.0), and apnea-hypopnea index 36.9±21.1 events/hour (IQ, 7.8–95.0). There were no statistically significant differences between the 2 groups in baseline apnea-hypopnea index, oxygen desaturation index, Epworth Sleepiness Scale score, preprocedural SpO2 nadir, age, sex, or body mass index. Compared with group P, group D showed significant differences in SpO2 (higher nadir during DISE, 87.09±5.4% vs. 75.0±11.0; P&lt;0.001) and heart rate (80.4±8.9 vs. 62.8±6.6; P&lt;0.001). While group D had longer duration of endoscopic examination times and emergence time from sedation, the grading of site of obstructions were similar in the 2 groups. Conclusions: Dexmedetomidine seems a limited, if viable, clinical alternative for DISE when propofol is contraindicated or not available: while causing higher SpO2 nadirs compared with propofol, it has a slow onset and longer recovery time, increasing total procedural time. Studies with greater patient numbers are needed to confirm these observations.

Analysis of influence factors of pharmacodynamics of propofol with target-controlled infusion during anesthetic recovery period.

To explore the pharmacodynamic (PD) characteristics of propofol during anesthetic recovery period with target-controlled infusion (TCI), and to identify the clinical variables related to the PD parameters. 20 patients scheduled for otolaryngology surgery were enrolled. After the surgery was finished, target effect site concentration was gradually decreased, blood samples were measured at 7 time points and the differences between the target and measured plasma concentration were compared. Observer's assessment of alertness/sedation (OAA/S) and Narcotrend index (NI) were used as two PD indicators by fitting sigmoid Emax model. Correlations between PD parameter and clinical variables were evaluated. Performance of the TCI system showed a positive bias at the end of the anesthesia sedation period and a negative bias in the anesthetic recovery period. PD parameters (EC50, r) calculated with OAA/S and NI were significantly different, EC50 of OAA/S was lower than EC50 of NI (1.53 ± 0.70 vs. 2.16 ± 0.99 µg/mL), r of OAA/S was higher than r of NI (57.07 ± 56.39 vs. 4.35 ± 4.42). Propofol dosage and hemodynamic parameters were significantly correlated with EC50 (OAA/S), lean body weight and gender were significantly correlated with EC50 (NI). NI provided a more stable and adequate assessment of the depth of anesthesia than OAA/S, and the influence factors should be taken into account for precise dosing.

Changes in electroencephalographic power and bicoherence spectra according to depth of dexmedetomidine sedation in patients undergoing spinal anesthesia.

Background: Assessment the depth of dexmedetomidine sedation using electroencephalographic (EEG) features can improve the quality of procedural sedation. Previous volunteer studies of dexmedetomidine-induced EEG changes need to be validated, and changes in bicoherence spectra during dexmedetomidine sedation has not been revealed yet. We aimed to investigate the dexmedetomidine-induced EEG change using power spectral and bicoherence analyses in the clinical setting.Patients and Methods: Thirty-six patients undergoing orthopedic surgery under spinal anesthesia were enrolled in this study. Dexmedetomidine sedation was conducted by the stepwise increase in target effect site concentration (Ce) while assessing sedation levels. Bispectral index (BIS) and frontal electroencephalography were recorded continuously, and the performance of BIS and changes in power and bicoherence spectra were analyzed with the data from the F3 electrode.Results: The prediction probability values for detecting different sedation levels were 0.847, 0.841, and 0.844 in BIS, 95% spectral edge frequency, and dexmedetomidine Ce, respectively. As the depth of sedation increased, δ power increased, but high β and γ power decreased significantly (P <0.001). α and spindle power increased significantly under light and moderate sedation (P <0.001 in light vs baseline and deep sedation; P = 0.002 and P <0.001 in moderate sedation vs baseline and deep sedation, respectively). The bicoherence peaks of the δ and α-spindle regions along the diagonal line of the bicoherence matrix emerged during moderate and deep sedation. Peak bicoherence in the δ area showed sedation-dependent increases (29.93%±7.38%, 36.72%±9.70%, 44.88%±12.90%; light, moderate, and deep sedation; P = 0.008 and P <0.001 in light sedation vs moderate and deep sedation, respectively; P = 0.007 in moderate sedation vs deep sedation), whereas peak bicoherence in the α-spindle area did not change (22.92%±4.90%, 24.72%±4.96%, and 26.96%±8.42%, respectively; P=0.053).Conclusions: The increase of δ power and the decrease of high-frequency power were associated with the gradual deepening of dexmedetomidine sedation. The δ bicoherence peak increased with increasing sedation level and can serve as an indicator reflecting dexmedetomidine sedation levels.

Prospective clinical validation of the Eleveld propofol pharmacokinetic-pharmacodynamic model in general anaesthesia

BackgroundTarget-controlled infusion (TCI) systems incorporating pharmacokinetic (PK) or PK-pharmacodynamic (PK-PD) models can be used to facilitate drug administration. Existing models were developed using data from select populations, the use of which is, strictly speaking, limited to these populations. Recently a propofol PK-PD model was developed for a broad population range. The aim of the study was to prospectively validate this model in children, adults, older subjects, and obese adults undergoing general anaesthesia. MethodsThe 25 subjects included in each of four groups were stratified by age and weight. Subjects received propofol through TCI with the Eleveld model, titrated to a bispectral index (BIS) of 40–60. Arterial blood samples were collected at 5, 10, 20, 30, 40, and 60 min after the start of propofol infusion, and every 30 min thereafter, to a maximum of 10 samples. BIS was recorded continuously. Predictive performance was assessed using the Varvel criteria. ResultsFor PK, the Eleveld model showed a bias < ±20% in children, adults, and obese adults, but a greater bias (−27%) in older subjects. Precision was <30% in all groups. For PD, the bias and wobble were <5 BIS units and the precision was close to 10 BIS units in all groups. Anaesthetists were able to achieve intraoperative BIS values of 40–60 using effect-site target concentrations about 85–140% of the age-adjusted Ce50. ConclusionsThe Eleveld propofol PK-PD model showed predictive precision <30% for arterial plasma concentrations and BIS predictions with a low (population) bias when used in TCI in clinical anaesthesia practice.

Effects of dexmedetomidine as an adjuvant in thoracic paravertebral block on EC50 of propofol for successful laryngeal mask insertion: a randomized controlled trial.

BackgroundDexmedetomidine as an adjuvant can improve the duration and the quality of thoracic paravertebral block (TPVB); however, its quantitative effect on propofol infusion is unclear. This study aimed to investigate the effect of dexmedetomidine as an adjuvant in TPVB on the medium effective concentration (EC50) of propofol for successful laryngeal mask insertion.MethodsSixty breast cancer patients who underwent elective modified radical mastectomy were enrolled and randomized at a 1:1 ratio into control group (Group C, n=30) or dexmedetomidine group (Group D, n=30). Ultrasound-guided T3 paravertebral block was performed before induction of anesthesia. In Group C, 0.5% ropivacaine 0.3 mL/kg was injected into T3 paravertebral space, while subjects in Group D received 0.5% ropivacaine 0.3 mL/kg with dexmedetomidine (1 µg/kg). Propofol target-controlled infusion (TCI) was performed, with an initial target effect-site concentration of 5 µg/mL determined for both groups. The laryngeal mask was inserted once the effect chamber achieved the target concentration. Subsequent target concentrations were adjusted by Dixon up-down sequential method, where dose modifications were performed by 0.5 mg/mL intervals, based on the success of the laryngeal mask insertion. Probit analysis was used to determine the propofol EC50. Mean arterial pressure (MAP), heart rate (HR), bispectral index (BIS) and application of atropine or ephedrine was recorded. Participants, TPVB giver, and data recorder were blinded to group assignment.ResultsPropofol EC50 for successful laryngeal mask insertion were statistically significant, with 5.256 µg/mL (95% CI: 4.833, 5.738 µg/mL) in Group C and 3.172 µg/mL (95% CI: 2.701, 3.621 µg/mL) in Group D. Both groups displayed significantly lower MAP and HR, post propofol TCI (P<0.05). However, subjects in Group D exhibited lower MAP and HR levels compared to patients in Group C (P<0.05). Application of atropine (0% vs. 10%) and ephedrine (20.0% vs. 13.3%) were not significantly different between two groups.ConclusionsDexmedetomidine, administered as an adjuvant in TPVB, can reduce the TCI concentration of propofol for successful laryngeal mask placement in females. The target concentration of propofol requires adjustment and close monitoring of hemodynamic changes, post induction is warranted.Trial registrationChinese Clinical Trial Registry ChiCTR1800016614.

Improved haemodynamic stability and cerebral tissue oxygenation after induction of anaesthesia with sufentanil compared to remifentanil: a randomised controlled trial

BackgroundBalanced anaesthesia with propofol and remifentanil, compared to sufentanil, often decreases mean arterial pressure (MAP), heart rate (HR) and cardiac index (CI), raising concerns on tissue-oxygenation. This distinct haemodynamic suppression might be attenuated by atropine. This double blinded RCT, investigates if induction with propofol-sufentanil results in higher CI and tissue-oxygenation than with propofol-remifentanil and if atropine has more pronounced beneficial effects on CI and tissue-oxygenation in a remifentanil-based anaesthesia.MethodsIn seventy patients scheduled for coronary bypass grafting (CABG), anaesthesia was induced and maintained with propofol target controlled infusion (TCI) with a target effect-site concentration (Cet) of 2.0 μg ml− 1 and either sufentanil (TCI Cet 0.48 ng ml− 1) or remifentanil (TCI Cet 8 ng ml− 1). If HR dropped below 60 bpm, methylatropine (1 mg) was administered intravenously. Relative changes (∆) in MAP, HR, stroke volume (SV), CI and cerebral (SctO2) and peripheral (SptO2) tissue-oxygenation during induction of anaesthesia and after atropine administration were analysed.ResultsThe sufentanil group compared to the remifentanil group showed significantly less decrease in MAP (∆ = − 23 ± 13 vs. -36 ± 13 mmHg), HR (∆ = − 5 ± 7 vs. -10 ± 10 bpm), SV (∆ = − 23 ± 18 vs. -35 ± 19 ml) and CI (∆ = − 0.8 (− 1.5 to − 0.5) vs. -1.5 (− 2.0 to − 1.1) l min− 1 m− 2), while SctO2 (∆ = 9 ± 5 vs. 6 ± 4%) showed more increase with no difference in ∆SptO2 (∆ = 8 ± 7 vs. 8 ± 8%). Atropine caused higher ∆HR (13 (9 to 19) vs. 10 ± 6 bpm) and ∆CI (0.4 ± 0.4 vs. 0.2 ± 0.3 l min− 1 m− 2) in sufentanil vs. remifentanil-based anaesthesia, with no difference in ∆MAP, ∆SV and ∆SctO2 and ∆SptO2.ConclusionInduction of anaesthesia with propofol and sufentanil results in improved haemodynamic stability and higher SctO2 compared to propofol and remifentanil in patients having CABG. Administration of atropine might be useful to counteract or prevent the haemodynamic suppression associated with these opioids.Trial registrationClinicaltrials.gov on June 7, 2013 (trial ID: NCT01871935).

Relationship Between Propofol Target Concentrations, Bispectral Index, and Patient Covariates During Anesthesia.

Internationally, propofol is commonly titrated by target-controlled infusion (TCI) to maintain a processed electroencephalographic (EEG) parameter (eg, bispectral index [BIS]) within a specified range. The overall variability in propofol target effect-site concentrations (CeT) necessary to maintain adequate anesthesia in real-world conditions is poorly characterized, as are the patient demographic factors that contribute to this variability. This study explored these issues, hypothesizing that the variability in covariate-adjusted propofol target concentrations during BIS-controlled anesthesia would be substantial and that most of the remaining interpatient variability in drug response would be due to random effects, thus suggesting that the opportunity to improve on the Schnider model with further demographic data is limited. With ethics committee approval and a waiver of informed consent, a deidentified, high-resolution, intraoperative database consisting of propofol target concentrations, BIS values, and vital signs from 13,239 patients was mined to identify patients who underwent general endotracheal anesthesia using propofol (titrated to BIS), fentanyl, remifentanil, and rocuronium that lasted at least 1 hour. The propofol target concentrations and BIS values 30 minutes after incision (CeT30 and BIS30) were considered representative of stable intraoperative conditions. The data were plotted and analyzed by descriptive statistics. Confidence intervals were computed using a bootstrap method. A linear model was fit to the data to test for correlation with factors of interest (eg, age and weight). A total of 4584 patients met inclusion criteria and were entered into the analysis. Of the propofol target concentrations, 95% were between 1.5 and 3.5 µg·mL-1. Higher BIS30 values were correlated with higher propofol concentrations. Except for age, all the patient-related variables analyzed entered the regression model linearly. Only 10.2% of the variability in CeT30 was explained by the patient factors of age and weight combined. Our hypothesis was confirmed. The variability in covariate-adjusted propofol CeT30 titrated to BIS in real-world conditions is considerable, and only a small portion of the remaining variability in drug response is explained by patient demographic factors. This finding may have important implications for the development of new pharmacokinetic (PK) models for propofol TCI.

Bolus pharmacokinetics: moving beyond mass-based dosing to guide drug administration.

Despite the common approach of bolus drug dosing using a patient's mass, a more tailored approach would be to use empirically derived pharmacokinetic models. Previously, this could only be possible though the use of computer simulation using programs which are rarely available in clinical practice. Through mathematical manipulations and approximations, a simplified set of equations is demonstrated that can identify a bolus dose required to achieve a specified target effect site concentration. The proposed solution is compared against simulations of a wide variety of pharmacokinetic models. This set of equations provides a near-identical solution to the simulation approach. A boundary condition is established to ensure the derived equations have an acceptable error. This approach may allow for more precise administration of medications with the use of point of care technology and potentially allows for pharmacokinetic dosing in artificial intelligence problems.