Determination of ED90s of Phenylephrine and Norepinephrine Infusion for Prevention of Spinal Anesthesia-Induced Hypotension in Patients with Preeclampsia During Cesarean Delivery.

Background: Vasopressors remain an important strategy for managing spinal anesthesia-induced hypotension in women with preeclampsia. The aim of this study was to investigate the ED90s and efficacy ratio of phenylephrine and norepinephrine in managing spinal anesthesia-induced hypotension in women with preeclampsia during cesarean delivery. Methods: 60 women with preeclampsia, who underwent cesarean delivery, were randomly assigned to receive either a continuous intravenous infusion of phenylephrine or norepinephrine following spinal anesthesia. The initial dosage of phenylephrine or norepinephrine for the first women was 0.5 or 0.05 µg/kg/min, respectively, and subsequent infusion dosages were adjusted based on their efficacy in preventing spinal anesthesia-induced hypotension (defined as a systolic blood pressure less than 80% of the baseline level). The incremental or decremental doses of phenylephrine or norepinephrine were set at 0.1 or 0.01 µg/kg/min. The primary outcomes were the ED90s and efficacy ratio of phenylephrine and norepinephrine infusions for preventing spinal anesthesia-induced hypotension prior to delivery. Results: The results obtained from isotonic regression analysis revealed that the ED90 values of the phenylephrine and norepinephrine group for preventing spinal anesthesia-induced hypotension were 0.597 (95% CI: 0.582-0.628) and 0.054 (95% CI: 0.053-0.056) µg/kg/min, respectively, with an efficacy ratio of 11.1:1. The results of Probit regression analysis revealed that the ED90 values were determined to be 0.665 (95% CI: 0.576-1.226) and 0.055 (95% CI: 0.047-0.109) µg/kg/min, respectively, with an efficacy ratio of 12.1:1. Conclusion: The administration of 0.6 µg/kg/min phenylephrine and 0.05 µg/kg/min norepinephrine has been found to effectively manage a 90% incidence of spinal anesthesia-induced hypotension in women with preeclampsia.

Determination of the 90% Effective Dose of Dexmedetomidine for Treating Postoperative Catheter­related Bladder Discomfort During Recovery: An Open-label, Single-group Study.

PURPOSE: Catheter-related bladder discomfort (CRBD) is an unpleasant experience for patients during postoperative recovery. Dexmedetomidine is an effective therapy for CRBD; however, little is known about dexmedetomidine administration for treating CRBD during recovery. This study was conducted to determine the 90% effective dose (ED90) of dexmedetomidine to provide adequate treatment for CRBD during recovery. DESIGN: Prospective, single-blind dose-finding study. METHODS: This open-label, single-group trial included severe postoperative CRBD patients aged 18 to 80 years and the American Society of Anesthesiologists' physical status class I or II in the postanesthesia care unit. All patients were assigned to receive intravenous dexmedetomidine. The dose of dexmedetomidine was determined using the modified Dixon's up-and-down method. The first patient was treated with 0.4 mcg/kg dexmedetomidine. An increment or decrement of 0.05 mcg/kg dexmedetomidine was used based on the response of the previous patient. A successful treatment was defined as the transition from severe CRBD to mild CRBD. Probit regression was applied to calculate the ED90 of dexmedetomidine. FINDINGS: A total of 29 patients were recruited, of whom 14 patients (48.3%) underwent successful treatment. The ED90 of dexmedetomidine required for successfully treating postoperative CRBD was 0.55 mcg/kg (95% confidence interval: 0.49-1.54 mcg/kg). CONCLUSIONS: The ED90 of dexmedetomidine for the successful treatment of severe postoperative CRBD during recovery is 0.55 mcg/kg.

Weight-based versus fixed dose oxytocin infusion for preventing uterine atony during cesarean section in laboring patients: A randomized trial.

OBJECTIVE: We compared efficacy of weight-based (0.4 IU/kg/h) versus fixed-dose (34 IU/h) oxytocin infusion during cesarean section. METHODS: The oxytocin infusion in either group (n = 32 each) was initiated upon cord clamping. Primary outcome measure was adequacy of uterine tone at 4 min after initiating oxytocin infusion. Oxytocin associated side effects were also observed. RESULTS: Significantly less oxytocin was used with the weight-based versus fixed-dose regimen (16.3 [11.2-22.4] IU vs 20.4 [15.8-26.9] IU; P = 0.036). Incidence of adequate uterine tone was clinically greater but not significantly different with the weight-based versus fixed-dose regimen (81.3% vs 71.9%; P = 0.376). The weight-based regimen was associated with clinically lesser, although not statistically significant need for rescue oxytocin (25% vs 46.9%; P = 0.068) and additional uterotonic (9.4% vs 15.6%; P = 0.708); as well as oxytocin associated side effects (hypotension [34.4% vs 46.9%; P = 0.309], nausea/vomiting [18.8% vs 40.6%; P = 0.055], and ST-T changes [0% vs 3.1%; P = 1.000]). CONCLUSION: Weight-based oxytocin was not significantly different from the fixed-dose regimen in terms of uterotonic efficacy or associated side-effects, despite significantly lower doses being used. Use of weight-based oxytocin infusion (0.4 IU/kg/h) can be considered in clinical practice. TRIAL REGISTRATION: Clinical Trial Registry of India (ctri.nic.in, number. CTRI/2021/01/030642).

ED90 of epidural esketamine with 0.075% ropivacaine for labor analgesia in nulliparous parturients: a prospective, randomized and dose-finding study.

Background: Because it has been reported that racemic ketamine had a local anesthetic-sparing effect when used for epidural analgesia this would suggest the likelihood of a potential advantage (less pruritus) over opioid drugs. Esketamine has greater analgesic efficacy than racemic ketamine, but the optimum dosage regimen for epidural use is undetermined. The aim of this study was to determine the ED90 of epidural esketamine when coadministered with 0.075% ropivacaine for labor analgesia. Methods: A total of 65 laboring nulliparous patients were enrolled in this study from 16 March 2022 to 15 October 2022. The patients were randomly assigned to receive 0, 0.25, 0.5, 0.75 or 1.0 mg/mL esketamine with 0.075% ropivacaine epidurally. An effective response to the epidural loading dose was defined as numerical rating scale pain score ≤3 at 30 min after the end of the epidural loading dose (10 mL of the ropivacaine 0.075% solution with the added esketamine). The ED90 of epidural esketamine coadministered with 0.075% ropivacaine with 95% confidence intervals for labor analgesia was determined using probit regression. Secondary outcomes and side effects were recorded. Results: The estimated value of ED90 with 95% CIs for epidural esketamine with 0.075% ropivacaine was 0.983 (0.704-2.468) mg/mL. The characteristics of sensory and motor block, consumption of ropivacaine per hour, duration of first or second stage, Apgar scores did not differ among the five groups. The incidence of mild dizziness in Group esketamine 1.0 mg/mL was significantly higher than that in other groups (p < 0.05). No statistical differences were found in other side effects among groups. Conclusion: The ED90 value of epidural esketamine coadministered with 0.075% ropivacaine for labor analgesia in nulliparous parturients was about 1.0 mg/mL. Furthermore, our results suggested that epidural esketamine would cause dose-dependent mild dizziness especially at doses up to 1.0 mg/mL. As a single epidural additive, esketamine may not be suitable for labor analgesia. Future studies may investigate the appropriate dosage of esketamine at slightly higher concentrations of local anesthetics or larger initial volume of analgesia, or explore other potential advantages of esketamine. Clinical Trial Registration: (https://www.chictr.org.cn/bin/project/edit?pid=159764), identifier (ChiCTR2200057662).

A biased coin up-and-down sequential allocation trial to determine the ED90 of intrathecal sufentanil combined with ropivacaine 2.5 mg for labor analgesia.

Purpose: To determine the 90 percent effective dose (ED90) of intrathecal sufentanil combined with ropivacaine 2.5 mg for labor analgesia and observe its safety for parturients and neonates. Methods: We conducted a prospective, double-blind, biased coin up-and-down study. We injected a fixed 2.5 mg ropivacaine combined with a designated dose of sufentanil intrathecally to observe the labor analgesic effect. The initial dose of sufentanil was assigned 1.0 µg, and the remaining doses were assigned as per the biased coin up-and-down method. The criterion of successful response was defined as VAS ≤ 30 mm after intrathecal injection at 10 min. Safety was evaluated in terms of maternal and neonatal outcomes. Results: The ED90 dose of intrathecal sufentanil combined with ropivacaine 2.5 mg (0.1%, 2.5 mL) was 2.61 µg (95% CI, 2.44 to 2.70 µg) by isotonic regression. No respiratory depression, hypotension, or motor block was observed. Thirty-one (77.5%) parturients complained of pruritus, and 14 (35.0%) suffered nausea and vomiting. Three neonates reported a 1 min Apgar score of ≤7, and none reported a 5 min Apgar score of ≤7. Conclusion: The ED90 of intrathecal sufentanil combined with ropivacaine 2.5 mg for labor analgesia was 2.61 µg. The dose is safe for parturients and neonates.

Comparative Dose-Response Study on the Infusion of Norepinephrine Combined with Crystalloid Coload versus Colloid Coload for Preventing Hypotension During Spinal Anesthesia for Cesarean Delivery.

Background: Although the optimal infusion dose of norepinephrine combined with crystalloid coload for preventing spinal anesthesia-induced hypotension (SAIH) for cesarean delivery has been established, the infusion regimen of norepinephrine combined with colloid coload has not been fully quantified. The objective of this study was to compare and determine the median effective dose (ED50) and 90% effective dose (ED90) of norepinephrine infusion combined with crystalloid coload versus colloid coload for preventing SAIH during cesarean delivery. Methods: Two hundred parturients were randomly assigned to receive norepinephrine infusion at 0.02, 0.04, 0.06, 0.08, or 0.10 µg/kg/min in combination with 10 mL/kg crystalloid coload or colloid coload to prevent SAIH. The study period was defined as the interval from the commencement of intrathecal injection to delivery of the neonate. The primary outcome was non-occurrence of hypotension, defined as systolic blood pressure (SBP) less than 80% of the baseline before delivery. The ED50 and ED90 of norepinephrine infusion dose were determined using probit regression analysis. By calculating the 95% confidence intervals (CIs) of relative median potency to determine whether the prophylactic infusion of norepinephrine requirement was different between the two groups. Results: The derived ED50 and ED90 of norepinephrine infusion combined with crystalloid coload were 0.030 (95% CIs 0.020 to 0.038) and 0.097 (95% CIs 0.072 to 0.157) µg/kg/min, respectively. The ED50 and ED90 of norepinephrine infusion combined with colloid coload were 0.021 (95% CIs 0.013 to 0.029) and 0.070 (95% CIs 0.053 to 0.107) µg/kg/min, respectively. The estimate of relative median potency for norepinephrine between the two groups was 1.37 (95% CIs 0.94 to 2.23). Conclusion: Under the conditions of this study, 10 mL/kg colloid coload reduced the dose of prophylactic norepinephrine infusion by approximately 30% in parturients during spinal anesthesia for cesarean delivery compared with the crystalloid coload.

Up-down determination of the 90% effective dose (ED90) of remimazolam besylate for anesthesia induction.

BACKGROUND: Remimazolam besylate for injection is a novel benzodiazepine. Reasonable selection and proper application of anesthetics is critical for patients. This study aims to determine the 90% effective dose (ED90) of remimazolam besylate for anesthesia induction in patients undergoing painless colonoscopy. METHODS: A dose-response study was carried out in 112 patients undergoing painless colonoscopy between December 2020 and January 2021. The initial dose of remimazolam was 7.5 mg. The anesthesiologist assessed whether the depth of sedation was satisfactory according to the Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale. If the MOAA/S score of one patient was >1 point, the loading dose for the next patient was increased by 2.5 mg. If the MOAA/S score was ≤1 point, the current dose was maintained or reduced by 2.5 mg for the next patient according to a 9:1 biased coin design. The ED90 of remimazolam besylate for anesthesia induction for painless colonoscopy was calculated. The adverse events and complications of remimazolam besylate were recorded. RESULTS: When the drug concentration was 1 mg/mL and the infusion rate was 1,000 mL/h, the ED90 of remimazolam besylate for painless colonoscopy was 11.43 mg [95% confidence interval (CI): 9.85-13.02 mg]. CONCLUSIONS: A loading dose of 12 mg remimazolam besylate for healthy adult patients undergoing painless colonoscopy can safely, effectively, and quickly induce patients to fall asleep and shorten the anesthesia induction time.

Optimum dose of spinal ropivacaine with or without single intravenous bolus of S-ketamine during elective cesarean delivery: a randomized, double-blind, sequential dose-finding study.

BACKGROUND: Maternal hypotension after spinal anaesthesia occurs at a high rate during caesarean delivery and can lead to adverse maternal or foetal outcomes. The aim of this study was to determine the optimal dose of spinal ropivacaine for caesarean section with or without intravenous single bolus of S-ketamine and to observe the rates of hypotension associated with both methods. METHODS: Eighty women undergoing elective caesarean delivery were randomly allocated into either a ropivacaine only or ropivacaine with intravenous S-ketamine group. If the upper sensory level of the patient reached T6 and the visual analogue scale (VAS) scores remained below 3 points before delivery, the next patient had a 1/9th chance of receiving a lower dose or an 8/9th chance of receiving the same dose as the previous patient. If the patient had VAS scores of more than 2 points or needed an extra epidural rescue bolus before delivery, a higher dose was used for the next patient. The primary outcome was the successful use of spinal ropivacaine to maintain patient VAS score of < 3 points before delivery and the incidence of post-spinal hypotension in both groups. Secondary outcomes included the rates of hypotension-related symptoms and interventions, upper sensory level of anaesthesia, level of sedation, neonatal outcomes, Edinburgh Postnatal Depression Scale scores at admission and discharge, and post-operative analgesic effect. The 90% effective dose (ED90) and 95% confidence interval (95% CI) were estimated by isotonic regression. RESULTS: The estimated ED90 of ropivacaine was 11.8 mg (95% CI: 11.7-12.7) with and 14.7 mg (95% CI: 14.6-16.0) without intravenous S-ketamine, using biased coin up-down sequential dose-finding method. The rates of hypotension and associated symptoms were significantly lower in S-ketamine group than in the ropivacaine only group. CONCLUSIONS: A spinal dose of ropivacaine 12 mg with a single intravenous 0.15 mg/kg bolus dose of S-ketamine may significantly reduce the risk of hypotension and induce sedation before delivery. This method may be used with appropriate caution for women undergoing elective caesarean delivery and at a high risk of hypotension or experiencing extreme nervousness. TRIAL REGISTRATION: http://www.chictr.org.cn ( ChiCTR2000040375 ; 28/11/2020).

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.

PURPOSE: Treatment 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 METHODS: Forty 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. RESULTS: The 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. CONCLUSION: For 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.

PURPOSE: Epidural 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. METHODS: Forty 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. FINDINGS: The 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. IMPLICATIONS: Sufentanil 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.

The optimal dose of oral midazolam with or without intranasal S-ketamine for premedication in children: a randomised, double blinded, sequential dose-finding trial.

BACKGROUND: Oral administration of midazolam syrup is one of the most favorable methods of premedication, the optimal dose of midazolam and midazolam with S-ketamine for preschool children has not been determined. This prospective, double-blind, randomized, sequential dose-finding study was designed to estimate the 90% effective doses of oral midazolam with and without intranasal S-ketamine in a grade III child medical center. METHODS: Eighty successive children were recruited and randomly allocated to midazolam group and midazolam with S-ketamine group. The initial oral doses of midazolam were 0.25 mg/kg in both groups, and the dose of midazolam for the next child was based on the response of the preceding child as the biased coin up-and-down designed. The primary outcome was parental separation anxiety score = 1 throughout the period of transferring from premedication center to the operation room 30 min after premedication. Secondary outcomes were the preoperative and post-operative observations. Finally, the 90% effective dose and 95% confidence intervals were estimated by isotonic regression. RESULTS: The 90% effective dose of oral midazolam or oral midazolam with intranasal S-ketamine was 0.461 mg/kg (95% confidence interval: 0.425-0.488) and 0.253 mg/kg (95% confidence interval: 0.242-0.278), respectively. Oral midazolam with intranasal S-ketamine was quicker onset (8.9±3.8 vs. 19.7±7.4 min, P<0.001), had less incidence of behavioral changes (7.5% vs. 32.5%, P=0.010) and faster recovery (21.6±14.1 vs. 31.6±13.5 min, P=0.002) than solely oral midazolam. CONCLUSIONS: A suggestion of oral midazolam 0.3 mg/kg with intranasal small dose of S-ketamine could be used as premedication for preschool children. TRIAL REGISTRATION: Chinese Clinical Trial Registry.

Norepinephrine intravenous prophylactic bolus versus rescue bolus to prevent and treat maternal hypotension after combined spinal and epidural anesthesia during cesarean delivery: a sequential dose-finding study.

BACKGROUND: As a relatively new drug in obstetrical anesthesia, norepinephrine is less likely to induce bradycardia and decrease cardiac output, which makes it a potential alternative to phenylephrine. The purpose of this study was to determine the optimal norepinephrine bolus dose needed to either prevent or reverse hypotension after the use of combined spinal and epidural (CSE) anesthesia in 90% of women during elective cesarean delivery (CD). METHODS: Eighty women undergoing elective CD were randomly allocated into either a prophylactic group or a rescue group in this dose finding study. If the women's systolic blood pressure (SBP) was maintained above 80% of their baseline, the next patient had an 8/9th chance of receiving the same dose or a 1/9th chance of receiving a lower dose. If the patient's SBP was not maintained, a higher dose was used for next patient. The primary outcome was the successful use of the norepinephrine bolus dose to maintain SBP above 80% of the baseline until after delivery. Secondary outcomes included nausea, vomiting, breathlessness, dizziness, hypertension, bradycardia due to hypotension and supplemental use of atropine and norepinephrine, upper sensory level of anesthesia, umbilical vein (UV) blood gases, and 1- and 5-minute Apgar scores. The 90% effective dose (ED90) and 95% confidence interval (95% CI) were estimated using isotonic regression methods. RESULTS: The estimated ED90 of the norepinephrine prophylactic bolus was 10.85 µg (95% CI, 9.20-11.67 µg) and that of the norepinephrine rescue bolus was 12.3 µg (95% CI, 10.0-12.8 µg) using isotonic regression methods. CONCLUSIONS: For norepinephrine, either a prophylactic bolus dose of 11 µg or a rescue bolus dose of 12 µg was recommended for clinical practices.

Determination of the 90% effective dose of intranasal dexmedetomidine for sedation during electroencephalography in children.

BACKGROUND: The intranasal route of dexmedetomidine (DEX) administration is becoming increasingly popular for providing adequate sedation during short examinations in infants and children. However, data on the 90% effective dose (ED90) of intranasal DEX are rare in children under 3 years old. METHODS: This is a double-blind trial using a biased coin design up-and-down sequential method (BCD-UDM). Fifty-three children aged under 3 years old requiring DEX for EEG were included in our study. The first patient received 2.5 µg kg-1 DEX, and the dose of DEX administered to the subsequent patient was determined by the response of the previous patient. The patient responses were recorded and analysed to calculate the ED90 by isotonic regression. The 95% confidence interval (CI) was estimated using a bootstrapping method. RESULTS: Fifty-three patients were included in our study, of which 45 patients were successfully sedated, and the 8 instances of failed sedation were rescued using sevoflurane inhalation, allowing the completion of the procedure. The 90% effective dose of DEX was calculated to be 3.28 µg kg-1 , and the 95% CI was 2.74 ~ 3.39 µg kg-1 . No significant adverse events occurred in any of the patients. CONCLUSION: The 90% effective dose of intranasal DEX sedation for EEG was 3.28 µg kg-1 in children under 3 years old.