Isotonic Regression Method Research Articles

GLS under monotone heteroskedasticity

The generalized least square (GLS) is one of the most basic tools in regression analyses. A major issue in implementing the GLS is estimation of the conditional variance function of the error term, which typically requires a restrictive functional form assumption for parametric estimation or smoothing parameters for nonparametric estimation. In this paper, we propose an alternative approach to estimate the conditional variance function under nonparametric monotonicity constraints by utilizing the isotonic regression method. Our GLS estimator is shown to be asymptotically equivalent to the infeasible GLS estimator with knowledge of the conditional error variance, and involves only some tuning to trim boundary observations, not only for point estimation but also for interval estimation or hypothesis testing. Simulation studies and an empirical example illustrate excellent finite sample performances of the proposed method.

Exploration of the optimal programmed intermittent epidural bolus volume with the dural puncture epidural technique for labour analgesia: a biased-coin up-and-down sequential allocation study.

To determine the optimal programmed intermittent epidural bolus (PIEB) volume for providing effective analgesia in 90% of patients (EV90) during the first stage of labour using the dural puncture epidural (DPE) technique to initiate labour analgesia. We conducted a biased-coin up-and-down sequential allocation study. We included 40 nulliparous women requiring epidural labour analgesia. We used a 25G Whitacre spinal needle to puncture the dural mater and then administered a loading dose of 12mL of ropivacaine 0.1% and sufentanil 0.3μg·mL-1. Subsequently, the PIEB pump delivered boluses with an identical solution at a fixed 40-min interval, starting 1hr after epidural initiation. The bolus volume for the first patient was 7mL and was adjusted for subsequent patients according to the study protocol (bolus volume, 7-12mL). The primary endpoint was effective analgesia, indicated by no need for patient-controlled or manual boluses within 6hr after analgesia initiation or until complete cervical dilation, whichever came first. Outcome evaluators assessed the patients' pain ratings, Bromage scores, sensory blockade level, and maternal blood pressure hourly. Using the truncated Dixon and Mood method, the estimated EV90 was 9.2mL (95% confidence interval [CI], 8.5 to 9.9) whereas the isotonic regression method yielded a value of 8.8mL (95% CI, 8.6 to 9.8). None of the patients experienced a motor block. Two patients experienced hypotension without the need for vasopressors. The estimated PIEB EV90 for ropivacaine 0.1% and sufentanil 0.3μg·mL-1 approached 9mL when DPE was combined with a fixed 40-min interval. ChiCTR.org.cn ( ChiCTR2300067281 ); first submitted 3 January 2023.

The 50% effective dose of hydromorphone and morphine for epidural analgesia in the hemorrhoidectomy: a double-blind, sequential dose-finding study

BackgroundAlthough previous studies have showed that epidural morphine can be used as a complement to local anesthetics for analgesia after postcesarean delivery under spinal anesthesia, there is little known about the analgesic dosage of epidural morphine and hydromorphone for hemorrhoidectomy. Therefore, we conducted this study to examine the potency ratio of hydromorphone to epidural morphine as well as effective analgesic dose for 50% patients (ED50) undergoing elective hemorrhoidectomy.Methods80 patients under elective hemorrhoidectomy with combined spinal and epidural anesthesia(CSEA) in department of anesthesia, Dongguan Tungwah hospital. To assess the ED50, patients were treated with epidural morphine or epidural hydromorphone randomly using a biased coin method-determined dose with a sequential allocation procedure. Following surgery, standardized multimodal analgesia was administered to all patients. A pain response score of ≤ 3 (on a scale of 0–10) was determined to be the effective dose after 24 h following CSEA. The ED50 in both groups were determined using the probit regression and isotonic regression method. We also measured pain intensity by patient interview using a 10 point verbal numeric rating scale prospectively at 6, 12 and 24 h after CSEA, and adverse effects were also noted.ResultsThe ED50 was 0.350 mg (95% CI, 0.259–0.376 mg) in hydromorphone group and 1.129 mg (95% CI, 0.903–1.187 mg) in morphine group, respectively, estimated by isotonic regression method. Regression analysis with the probit, the ED50 of epidural hydromorphone was 0.366 mg (95% CI, 0.276–0.388 mg) and epidural morphine was 1.138 mg (95% CI, 0.910–1.201 mg). Exploratory findings showed that there was no difference between the most frequent dosages of epidural hydromorphone or epidural morphine in the occurrence of nausea, vomiting and pruritus. When administered with epidural opioids at ED50 doses or higher, 97.5% (39/40) of epidural morphine patients and 97.5% (39/40) epidural hydromorphone of patients were satisfied with their analgesia.ConclusionEffective hemorrhoidectomy analgesia requires a 3:1 ratio of epidural morphine to epidural hydromorphone. Both drugs provide excellent patient satisfaction.

The Effect of Sex on the Remimazolam Dosage Required for Successful i-gel Supraglottic Airway Insertion with Remifentanil in Non-Paralyzed Patients: An Up-and-Down Sequential Allocation Trial

(1) Background: The physiological and pharmacological variations between men and women are known to influence drug efficacy. The objective of this study was to determine the 50% and 95% effective doses (ED50 and ED95) of remimazolam required for i-gel supraglottic airway (ISA) insertion under remifentanil infusion without neuromuscular blocking agents (NMBAs) in both males and females. (2) Methods: Patients aged 19–65 years, scheduled for general anesthesia using ISA, were enrolled in this study. Patients were divided into two groups based on their sex. The anesthesia process began with a remifentanil infusion targeting an effect-site concentration of 3.0 ng/mL, accompanied by a remimazolam injection. The initial remimazolam dose was 0.25 mg/kg, and it was adjusted with a step size of 0.05 mg/kg based on the outcome of ISA insertion in the preceding patient. (3) Results: The ED50 of remimazolam (mean ± standard error) was 0.28 ± 0.02 mg/kg in the male group and 0.18 ± 0.02 mg/kg in the female group (p < 0.001). Additionally, ED95, which was calculated using the isotonic regression method, was significantly comparable between the male and female groups (male: 0.35 mg/kg, 95% confidence interval [CI] = 0.34–0.35; female: 0.29 mg/kg, 95% CI = 0.25–0.30). (4) Conclusions: This study showed that both the ED50 and the ED95 of remimazolam for successful ISA insertion was higher for men than that for women. Therefore, while using remimazolam alongside remifentanil infusion without NMBAs for ISA insertion, one should consider the patient’s sex for appropriate dosing.

Determining the optimum dose of remifentanil in combination with propofol for total intravenous anaesthesia in hysteroscopy under Narcotrend and SPI monitoring.

Outpatient hysteroscopic surgery requires patients to be anaesthetised and recover quickly, and the drugs used must be safe and effective. Remifentanil is typically co-administered with propofol as total intravenous anaesthesia (TIVA) for hysteroscopy because of its favourable pharmacokinetic and pharmacodynamic properties. However, the optimal dose of remifentanil when co-administered with propofol without neuromuscular blocking agents (NMBAs) has not been established. In this sequential dose-finding study, the 90% effective dose (ED90) of remifentanil effect-site concentration (Ce) combined with propofol without NMBAs during outpatient hysteroscopy was calculated to minimise the side effects of using higher doses. This sequential dose-finding study was conducted in August 2022. Forty patients who underwent outpatient hysteroscopy under TIVA were included in the study. With a biased coin up-and-down design, the initial remifentanil Ce was established at 2 ng/mL, and the subsequent remifentanil dosage was determined based on the reaction of the previous patient. The primary outcome was a remifentanil Ce that resulted in successful TIVA by maintaining a Narcotrend index < 60, surgical pleth index (SPI) < 50, and without patient movement throughout hysteroscopy. Secondary outcomes included rates of hypotension-related symptoms and interventions, drug consumption, post-anaesthesia care unit (PACU)-estimated visual analogue scale (VAS) and Ramsay sedation scores, modified Aldrete scores, and other adverse effects of anaesthesia. The ED90 and 95% confidence intervals (CI) were estimated using isotonic regression methods and bootstrapping. For TIVA without NMBAs during outpatient hysteroscopy, the ED90 Ce of remifentanil combined with propofol was determined to be 2.75 ng/mL (95% CI, 2.50-3.00 ng/mL). The incidence of peri-operative adverse effects of anaesthesia was relatively low. All the patients had satisfactory VAS, Ramsay sedation, and modified Aldrete scores in the PACU. Remifentanil at a Ce of 2.75 ng/mL is recommended for TIVA combined with propofol in outpatient hysteroscopic surgery. http://www.chictr.org.cn (ChiCTR2200062284; 31/7/2022).

ED95 of remimazolam in nasal administration for attenuating preoperative anxiety in children.

Preoperative anxiety often prevails in children at higher levels than adults, which is a common impediment for surgeons and anesthesiologists. It is of great necessity to explore an appropriate medication to improve this situation. Remimazolam, a type of benzodiazepine drug, has been indicated for the induction and maintenance of procedural sedation in adults since 2020. To date, rare studies were reported to investigate the effect of remimazolam on children. In this study, we investigated the safety and efficacy of intranasal drops of remimazolam and tried to determine the 95% effective dose (ED95) of remimazolam in single intranasal administration in attenuating preoperative anxiety in children. In this study, 114 children were enrolled who underwent laparoscopic high-level inguinal hernia ligation between January 2021 and December 2022 and were divided into an early childhood children group and a pre-school children group. The biased coin design (BCD) was used to determine the target doses. A positive response was defined as the effective relief of preoperative anxiety (modified Yale Preoperative Anxiety Scale, mYPAS < 30). The initial nasal dose of remimazolam was 0.5 mg·kg-1 in the two groups. An increment or decrement of 0.1 mg·kg-1 was applied depending on the sedative responses. Isotonic regression and bootstrapping methods were used to calculate the ED95 and 95% confidence intervals (CIs), respectively. A total of 80 children completed the study, including 40 in the early childhood group and 40 in the pre-school children group. As statistical analysis indicated, the ED95 of a single intranasal infusion of remimazolam for the relief of preoperative anxiety is 1.57 mg·kg-1 (95% CI: 1.45-1.59 mg·kg-1) in early childhood children and 1.09 mg·kg-1 (95% CI: 0.99-1.11 mg·kg-1) in pre-school children, and the CIs did not overlap each other. Remimazolam is an effective medication to relieve preoperative anxiety in children. Moreover, the ED95 of single nasal administration of remimazolam for effective relief of preoperative anxiety was 1.57 and 1.09 mg·kg-1 in early childhood children and pre-school children, respectively.

Determination of the 95% effective dose of remimazolam tosylate in anesthesia induction inhibits endotracheal intubation response in senile patients.

Background and Purpose: The prevalence of elderly patients prompts anesthesiologists to determine the optimal dose of medication due to the altered pharmacokinetics and pharmacodynamics of this population. The present study aimed to determine the 95% effective dose (ED95) of remimazolam tosylate in anesthesia induction to inhibit endotracheal intubation-related cardiovascular reaction in frail and non-frail senile patients. Methods: A prospective sequential allocation dose-finding study of remimazolam tosylate was conducted on 80 elderly patients who received general anesthesia between May and June 2022at the First Affiliated Hospital of Nanchang University. The initial dose was 0.3mg/kg. The blood pressure and heart rate fluctuations during intubation were either <20% (negative cardiovascular response) or ≥20% (positive cardiovascular response). If positive, the dose of the next patient was increased by 0.02mg/kg, while if negative, it was reduced by 0.02mg/kg according to the 95:5 biased coin design (BCD). The ED95 and 95% confidence intervals (CIs) were determined using R-Foundation isotonic regression and bootstrapping methods. Results: The ED95 of remimazolam tosylate to inhibit the response during tracheal intubation was 0.297mg/kg (95% CI: 0.231-0.451mg/kg) and 0.331mg/kg (95% CI: 0.272-0.472mg/kg) in frail and non-frail senile patients, respectively. Conculation and Implications: The CI of the two groups overlap, and no difference was detected in the ED95 of remimazolam tosylate in inhibiting endotracheal intubation-related cardiovascular response in frail and non-frail senile patients. These results suggested that remimazolam tosylate is an optimal anesthesia inducer for all elderly patients. Clinical Trial Registration: https://www.chictr.org.cn, identifier ChiCTR2200055709.

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

Determination of the 95% effective dose of remimazolam to achieve loss of consciousness during anesthesia induction in different age groups.

Remimazolam is a new ultra short-acting benzodiazepine originally developed as an improved version of midazolam. Recent studies have demonstrated non-inferiority of remimazolam to propofol in general anesthesia. However, to date, few studies have investigated the induction bolus dose of remimazolam required to achieve general anesthesia. We aimed to determine the 95% effective dose (ED95) of remimazolam bolus required to achieve loss of consciousness (LOC) and the appropriate doses for different age groups. Patients aged 20-79 years with the American Society of Anesthesiologists physical status of I or II were enrolled in this study. A total of 120 patients were included representing young, middle-aged, and elderly groups. Loss of eyelash reflex and verbal response after the administration of remimazolam was considered successful LOC. The ED95 of remimazolam was determined using a biased coin up-and-down design with sequential allocation and the isotonic regression method. The ED95 of remimazolam for induction of general anesthesia was 0.367 mg/kg (95% CI [0.277, 0.392]) in the young group, 0.369 mg/kg (95% CI [0.266, 0.394]) in the middle-aged group, and 0.249 mg/kg (95% CI [0.199, 0.288]) in the elderly group. During the study period, none of the patients required rescue medications for hypotension or bradycardia. This study investigated the ED95 of remimazolam bolus for anesthesia induction. The precise dosing of the ED95 can help maintain hemodynamic stability during the induction of anesthesia.

Optimization of programmed intermittent epidural bolus volume for different concentrations of ropivacaine in labor analgesia: a biased coin up-and-down sequential allocation trial

Background and objectivesTo date, programmed intermittent epidural bolus (PIEB) has been widely used in obstetric analgesia, while no optimal PIEB regimen has been proposed. This study aimed to assess effective analgesia in 90% of women (EV90) with different concentrations of ropivacaine (0.075% and 0.1%) combined with 0.5 µg/mL sufentanil, at an interval of 40 min using the biased coin design-up-and-down method (BCD-UDM), and to explore whether there is a difference in EV90 with the increase of ropivacaine concentration.MethodsIn total, 103 primiparous women were assigned to two groups, including group A (n = 52) and group B (n = 51). Parturients in group A were treated with 0.075% ropivacaine and 0.5 µg/mL sufentanil, while those in group B were treated with 0.1% ropivacaine and 0.5 µg/mL sufentanil. Used the biased coin up-and-down sequential allocation method to determine the EV90. The secondary outcomes were sensory block level, motor block, and adverse events (hypotension, urinary retention, and pruritus).ResultsThe results revealed that EV90 was 10 mL (95% confidence interval (CI):8.03–11.54) in group A, and EV90 was 9 mL (95% CI:7.49–10.51) in group B by the isotonic regression method. The highest level of the sensory block was T8, and the lowest was T12. No case of hypotension was recorded,and only 4 parturients complained of motor block.ConclusionWith an interval of 40 min, the optimal PIEB bolus volume of 0.075% ropivacaine and 0.5 µg/mL sufentanil was 10 mL, 0.1% ropivacaine and 0.5 µg/mL sufentanil was 9 mL. Moreover, the PIEB volume decreased along with the higher concentration of ropivacaine.Trial registrationChiCTR registration number: ChiCTR2000040917. Registration date: December 15, 2020.

The Effect of Ramosetron on Remifentanil in Preventing Emergence Cough from Sevoflurane Anesthesia in Female Patients.

Remifentanil reduces cough during extubation. Ramosetron, a 5-HT3 receptor antagonist, is a potent antiemetic. Regarding the antitussive property of 5-HT receptor agonists, ramosetron can mediate the cough reflex by increasing the remifentanil requirement. This study evaluated the effect of ramosetron on the optimal effect-site concentration (Ce) of remifentanil for preventing emergence cough from sevoflurane anesthesia in female patients. Forty-seven randomly selected female patients undergoing laparoscopic cholecystectomy received either ramosetron 0.3 mg (n = 23) or the same volume of normal saline (n = 24) intravenously at the end of surgery. The remifentanil Ce using target-controlled infusion in 50% of patients (EC50) and 95% of patients (EC95) were assessed using Dixon's up-and-down or isotonic regression method with a bootstrapping approach. Using Dixon's up-and-down method, the EC50 of remifentanil in the control group (1.33 ± 0.38 ng/mL) was comparable to that of ramosetron group (1.50 ± 0.69 ng/mL) (P = 0.615). Using isotonic regression analysis, the EC50 (83% confidence interval) did not differ between the two groups (1.17 [0.86-1.43] ng/mL and 1.13 [0.68-1.56] ng/mL in control and ramosetron groups). However, the EC95 (95% confidence interval) was significantly lower in the control group than in the ramosetron group (1.90 [1.45-1.96] ng/mL and 2.92 [2.35-2.97] ng/mL). Remifentanil Ce for preventing emergence cough was higher in the ramosetron group than in the control group. It may indicate the lowering effect of ramosetron on the antitussive activity of remifentanil.

Optimum programmed intermittent epidural bolus interval time between 8 mL boluses of Ropivacaine 0.1% with sufentanil 0.3 μg/mL with dural puncture epidural technique for labor analgesia: A biased-coin up-and-down sequential allocation trial

ObjectiveThe combination of dural puncture epidural (DPE) technique and programmed intermittent epidural bolus (PIEB) is a novel alternative labor analgesia regimen providing rapid analgesia onset and improved analgesia quality. However, the optimum PIEB settings for using the DPE technique remain unclear. DesignBiased-coin up-and-down sequential allocation design. SettingLabor analgesia. PatientsForty nulliparous women requesting labor analgesia. InterventionsDural was punctured using a 25-gauge Whitacre needle. 12 mL of 0.1% ropivacaine with 0.3 μg/mL of sufentanil was used for initiation. Labor analgesia was maintained using the same solution with a fixed 8 mL volume beginning 1 h after initiation. The interval for the first patient was 60 min and varied for subsequent patients according to the biased-coin design (groups 60, 50, 40, and 30; interval 60, 50, 40, and 30 min, respectively). MeasurementsThe primary outcome was adequate analgesia, defined as no request of patient-controlled epidural analgesia or provider boluses for 6 h after the epidural analgesia initiation or until the maternal cervix was fully dilated, whichever came first. The secondary outcomes included sensory blockade level, motor strength, maternal hypotension, and pruritus. ResultsThe estimated effective interval in 90% of participants was 41.5 min (95% CI 39.5–43.5 min) and 40.5 min (95% CI 33.7–47.5 min) by the truncated Dixon and Mood method and the isotonic regression method, respectively, for the 40 women included. The proportions of patients with the highest sensory block level achieving or above T6 were 60%, 26%, 27%, and 0% in groups 30, 40, 50, and 60, respectively. One patient presented a Bromage score of 1. There was a low incidence of hypotension in all the groups with no need for vasopressor treatment. ConclusionsThe optimum PIEB interval time between 8 mL boluses of ropivacaine 0.1% and sufentanil 0.3 μg/mL when using the DPE technique was approximately 41 min.

Effect of maternal body mass index on the prophylactic dose of phenylephrine for preventing hypotension in parturients after spinal anaesthesia

BackgroundTo compare the median effective dose (ED50) of phenylephrine for prophylactic continuous infusion in parturients with different body mass indices (BMIs) during combined spinal-epidural anaesthesia for caesarean section and to investigate the impact of maternal BMI on the prophylactic dose of phenylephrine. MethodsParturients receiving combined spinal-epidural anaesthesia for elective caesarean section were divided into a standard group (Group S, BMI < 30 kg/m2) and an obesity group (Group O, BMI > 30 kg/m2), each with 30 patients. A sequential allocation design was used to administer the prophylactic infusion of phenylephrine after the completion of a spinal anaesthetic injection to prevent hypotension (defined as a reduction of systolic blood pressure ≥ 20% of the baseline value or systolic blood pressure < 90 mmHg), with an initial infusion rate of 50 μg/min for the first parturient subsequent adjusted up or down by 10 μg/min depending on whether the previous parturient developed hypotension or not during the study period. The Dixon and Massey method and the isotonic regression method were used to calculate and compare the ED50 and 95% confidence interval (CI) of phenylephrine between the two groups. ResultsThe results were 21.92 μg/min (95% CI, 14.90–28.94 μg/min) for Group S and 42.14 μg/min (95% CI, 24.58–59.70 μg/min) for Group O. The ratio of relative potency of Group O to Group S is 1.92 (95% CI 1.09–3.14), P = 0.034. ConclusionsThe dose of phenylephrine for the prevention of hypotension after spinal anaesthesia for caesarean section is dependent on maternal BMI. Therefore, a weight-based phenylephrine dose is reasonable.

Ethanol reduces the minimum alveolar concentration of sevoflurane in rats

A high number of trauma patients are under the influence of alcohol. Since many of them need immediate surgical procedures, it is imperative to be aware of the interaction of alcohol with general anesthesia. To counter challenges that arise from clinical studies, we designed an animal experiment in which 48 adult Wistar rats either received 1 g · kg−1 ethanol, 2 g · kg−1 ethanol or placebo via intraperitoneal application. Subsequently, they were anesthetized with an individual concentration of sevoflurane. The minimum alveolar concentration (MAC) of the different groups was assessed using Dixon’s up-and-down design and isotonic regression methods. The bootstrap estimate of the MAC of sevoflurane in the placebo group was 2.24 vol% (95% CI 1.97–2.94 vol%). In the low dose ethanol group, the bootstrap estimate was 1.65 vol% (95% CI 1.40–1.98 vol%), and in the high dose ethanol group, it was 1.08 vol% (95% CI 0.73–1.42 vol%). We therefore report that intraperitoneal application of 1 g · kg−1 or 2 g · kg−1 ethanol both resulted in a significant reduction of the MAC of sevoflurane in adult Wistar rats: by 26.3% and 51.8% respectively as compared to placebo.

An Explainable Machine Learning Model for Material Backorder Prediction in Inventory Management.

Global competition among businesses imposes a more effective and low-cost supply chain allowing firms to provide products at a desired quality, quantity, and time, with lower production costs. The latter include holding cost, ordering cost, and backorder cost. Backorder occurs when a product is temporarily unavailable or out of stock and the customer places an order for future production and shipment. Therefore, stock unavailability and prolonged delays in product delivery will lead to additional production costs and unsatisfied customers, respectively. Thus, it is of high importance to develop models that will effectively predict the backorder rate in an inventory system with the aim of improving the effectiveness of the supply chain and, consequentially, the performance of the company. However, traditional approaches in the literature are based on stochastic approximation, without incorporating information from historical data. To this end, machine learning models should be employed for extracting knowledge of large historical data to develop predictive models. Therefore, to cover this need, in this study, the backorder prediction problem was addressed. Specifically, various machine learning models were compared for solving the binary classification problem of backorder prediction, followed by model calibration and a post-hoc explainability based on the SHAP model to identify and interpret the most important features that contribute to material backorder. The results showed that the RF, XGB, LGBM, and BB models reached an AUC score of 0.95, while the best-performing model was the LGBM model after calibration with the Isotonic Regression method. The explainability analysis showed that the inventory stock of a product, the volume of products that can be delivered, the imminent demand (sales), and the accurate prediction of the future demand can significantly contribute to the correct prediction of backorders.

Determination of the 90% Effective Dose of Phenylephrine Boluses to Treat Spinal Anesthesia-Induced Hypotension in Patients with Severe Preeclampsia during Cesarean Delivery: A Pilot Study.

PurposeTreatment of spinal anesthesia-induced hypotension in patients with severe preeclampsia assumes special concern as hypotension may further reduce placental perfusion. Phenylephrine is still the first-line vasopressor for treating spinal anesthesia-induced hypotension. However, the optimal dose of phenylephrine used as intravenous (IV) boluses in patients with severe preeclampsia has not been clearly determined. We aim to calculate the 90% effective dose (ED90) of phenylephrine as IV boluses for treating spinal anesthesia-induced hypotension in patients with severe preeclampsia undergoing cesarean delivery.Patients and MethodsForty patients with severe preeclampsia were enrolled in this prospective sequential allocation dose-finding trial. Using the biased coin up-and-down (BCUD) method, all patients in our study received an IV bolus phenylephrine of either 40, 50, 60, 70, or 80 µg when the mean arterial pressure (MAP) decreased to less than 80% of the baseline level and the ED90 was determined. The primary outcome was the success of the assigned phenylephrine bolus to maintain the MAP at or above 80% of baseline value between the induction of spinal anesthesia and delivery of the fetus. Secondary outcomes included hypertension, nausea, vomiting, bradycardia, upper sensory level of anesthesia, umbilical blood gases, and Apgar score. Estimating of the ED90 with 95% confidence interval (CI) was achieved by isotonic regression method.ResultsThe ED90 of phenylephrine was estimated as 62.00 µg (95% CI=50.00–67.40 µg) using the isotonic regression method. No patients enrolled in our study experienced bradycardia and those patients who developed hypertension were all observed at the dose level 70 µg.ConclusionFor clinical practice, we recommend that phenylephrine 60 µg may be both effective and safe for treatment of spinal anesthesia-induced hypotension in severe preeclampsia during cesarean delivery.

The 90% Effective Dose of Sufentanil for Epidural Analgesia in the Early First Stage of Labor: A Double-blind, Sequential Dose-Finding Study

PurposeEpidural analgesia in the latent phase of the first stage of labor has been recognized and accepted by anesthesiologists worldwide. However, there is no unified consensus on the exact dosage of sufentanil with the combination of ropivacaine in the induction of epidural analgesia in the early first stage of labor. In this sequential dose-finding study, the 90% effective dose (ED90) of sufentanil for epidural administration in the early first stage of labor was estimated to minimize the adverse effects of using higher doses. MethodsForty parturients with cervical dilatation of 2 to 4 cm who requested epidural analgesia were enrolled in this study. Parturients received 15 mL of a combination of ropivacaine 13 mg and the test dose of sufentanil. The initial dose of sufentanil in epidural administration was 1 μg, and the dose of sufentanil for the next parturient was based on the response of the preceding participant as per a biased coin up-and-down design. The primary outcome was the dose of sufentanil that resulted in successful epidural administration by maintaining the parturients’ visual analog scale scores at ≤30 mm in the first 15, 30, and 45 minutes of induction. The ED90 and 95% CIs were estimated using isotonic regression methods and bootstrapping. FindingsThe estimated ED90 of sufentanil in epidural administration in the early first stage of labor was 1.91 μg (95% CI, 1.82–2.35 μg) in this sequential dose-finding study. ImplicationsSufentanil at a dosage of 2 μg is recommended for the administration of epidural analgesia in parturients in the early first stage of labor. ChiCTR.org.cn identifier: 1900021683.

Effects of smoking on the optimal effect-site concentration of remifentanil required for preventing cough during anesthetic emergence in male patients undergoing laparoscopic or robotic cholecystectomy.

Target-controlled infusion of remifentanil is known to reduce cough effectively during emergence from general anesthesia. The effect of smoking on emergence cough remains controversial. Therefore, we aimed to investigate the effect-site concentration (Ce) of remifentanil in the male patients undergoing laparoscopic or robotic cholecystectomy for suppressing emergence cough in smokers and non-smokers.Twenty smokers and 24 non-smokers (sex, male; age range, 20–65 years) were enrolled in this study. Anesthesia was maintained using sevoflurane and remifentanil. The Ce of remifentanil in 50% (EC50) and 95% (EC95) of the patients required for suppressing emergence cough were determined for each group (smokers and non-smokers) using Dixon up-and-down method and isotonic regression method with a bootstrapping approach.Dixon up-and-down method revealed that the EC50 value was significantly higher in smokers (3.51 ± 0.60 ng/mL) than in non-smokers (2.71 ± 0.30 ng/mL) (P < 0.001). In smokers and non-smokers, isotonic regression revealed EC50 to be 4.40 (83% CI, 4.17–4.58) ng/mL and 2.58 (83% CI, 2.31–2.87) ng/mL, respectively, and EC95 to be 4.76 (95% CI, 4.73–4.78) ng/mL and 3.15 (95% CI, 3.04–3.18) ng/mL, respectively.The Ces of remifentanil required to prevent cough during emergence were significantly higher in smokers than in non-smokers. Therefore, clinicians should pay attention to the smoking history of a patient to prevent cough during emergence.

Electronic Health Record-Based Prediction of 1-Year Risk of Incident Cardiac Dysrhythmia: Prospective Case-Finding Algorithm Development and Validation Study.

BackgroundCardiac dysrhythmia is currently an extremely common disease. Severe arrhythmias often cause a series of complications, including congestive heart failure, fainting or syncope, stroke, and sudden death.ObjectiveThe aim of this study was to predict incident arrhythmia prospectively within a 1-year period to provide early warning of impending arrhythmia.MethodsRetrospective (1,033,856 individuals enrolled between October 1, 2016, and October 1, 2017) and prospective (1,040,767 individuals enrolled between October 1, 2017, and October 1, 2018) cohorts were constructed from integrated electronic health records in Maine, United States. An ensemble learning workflow was built through multiple machine learning algorithms. Differentiating features, including acute and chronic diseases, procedures, health status, laboratory tests, prescriptions, clinical utilization indicators, and socioeconomic determinants, were compiled for incident arrhythmia assessment. The predictive model was retrospectively trained and calibrated using an isotonic regression method and was prospectively validated. Model performance was evaluated using the area under the receiver operating characteristic curve (AUROC).ResultsThe cardiac dysrhythmia case-finding algorithm (retrospective: AUROC 0.854; prospective: AUROC 0.827) stratified the population into 5 risk groups: 53.35% (555,233/1,040,767), 44.83% (466,594/1,040,767), 1.76% (18,290/1,040,767), 0.06% (623/1,040,767), and 0.003% (27/1,040,767) were in the very low-risk, low-risk, medium-risk, high-risk, and very high-risk groups, respectively; 51.85% (14/27) patients in the very high-risk subgroup were confirmed to have incident cardiac dysrhythmia within the subsequent 1 year.ConclusionsOur case-finding algorithm is promising for prospectively predicting 1-year incident cardiac dysrhythmias in a general population, and we believe that our case-finding algorithm can serve as an early warning system to allow statewide population-level screening and surveillance to improve cardiac dysrhythmia care.

Determination of the ED95 of a single bolus dose of dexmedetomidine for adequate sedation in obese or nonobese children and adolescents

BackgroundWith the increasing prevalence of children who are overweight and with obesity, anaesthesiologists must determine the optimal dosing of medications given the altered pharmacokinetics and pharmacodynamics in this population. We therefore determined the single dose of dexmedetomidine that provided sufficient sedation in 95% (ED95) of children with and without obesity as measured by a minimum Ramsay sedation score (RSS) of 4. MethodsForty children with obesity (BMI >95th percentile for age and gender) and 40 children with normal weight (BMI 25th–84th percentile), aged 3–17 yr, ASA physical status 1–2, undergoing elective surgery, were recruited. The biased coin design was used to determine the target dose. Positive responses were defined as achievement of adequate sedation (RSS ≥4). The initial dose for both groups was dexmedetomidine 0.3 μg kg−1 i.v. infusion for 10 min. An increment or decrement of 0.1 μg kg−1 was used depending on the responses. Isotonic regression and bootstrapping methods were used to determine the ED95 and 95% confidence intervals (CIs), respectively. ResultsThe ED95 of dexmedetomidine for adequate sedation in children with obesity was 0.75 μg kg−1 with 95% CI of 0.638–0.780 μg kg−1, overlapping the CI of the ED95 estimate of 0.74 μg kg−1 (95% CI: 0.598–0.779 μg kg−1) for their normal-weight peers. ConclusionsThe ED95 values of dexmedetomidine administered over 10 min were 0.75 and 0.74 μg kg−1 in paediatric subjects with and without obesity, respectively, based on total body weight. Clinical trial registrationChiCTR1800014266.