Prophylactic Norepinephrine Infusion Research Articles

Intravenous initial bolus during prophylactic norepinephrine infusion to prevent spinal hypotension for cesarean delivery: A randomized controlled, dose-finding trial

BackgroundPrevious studies have shown that a 0.05 μg/kg/min of norepinephrine infusion in combination with an initial bolus reduces the incidence of spinal hypotension during cesarean delivery. The initial norepinephrine bolus influences the incidence of spinal hypotension during continuous norepinephrine infusion; however, the ideal initial bolus dose for 0.05 μg/kg/min of continuous infusion remains unknown. MethodsThis randomized, controlled, dose-finding study randomly allocated 120 parturients scheduled for elective cesarean delivery to receive initial bolus doses of 0, 0.05, 0.10, and 0.15 μg/kg of norepinephrine, followed by continuous infusion at a rate of 0.05 μg/kg/min. The primary outcome was the dose-response relationship of the initial norepinephrine bolus in preventing the incidence of spinal hypotension. Spinal hypotension was defined as systolic blood pressure (SBP) decreased to <80% of the baseline value or to an absolute value of <90 mmHg from intrathecal injection to delivery, and severe spinal hypotension was defined as SBP decreased to <60% of the baseline value. The secondary outcomes included the incidence of nausea and/or vomiting, hypertension, and bradycardia, as well as the Apgar scores and results of the umbilical arterial blood gas analysis. The effective dose (ED) 90 and ED95 were estimated using probit regression. ResultsThe per-protocol analysis included 117 patients. The incidence of spinal hypotension varied significantly among the groups: Group 0 (51.7%), Group 0.05 (44.8%), Group 0.10 (23.3%), and Group 0.15 (6.9%). The ED90 and ED95 values were 0.150 μg/kg (95% confidence interval [CI], 0.114–0.241 μg/kg) and 0.187 μg/kg (95% CI, 0.141–0.313 μg/kg), respectively. However, the ED95 value fell outside the dose range examined in this study. The incidence of severe spinal hypotension differed significantly (P = 0.02) among Groups 0 (17.2%), 0.05 (10.3%), 0.10 (3.3%), and 0.15 (0.0%); however, the incidence of hypertension and bradycardia did not. The incidence of nausea and/or vomiting decreased with an increase in the initial bolus dose (P = 0.03). The fetal outcomes were comparable among the groups. ConclusionsAn initial bolus of 0.150 μg/kg of norepinephrine may be the optimal dose for preventing spinal hypotension during cesarean delivery with a continuous infusion rate of 0.05 μg/kg/min, and does not significantly increase the incidence of hypertension but substantially reduces the risk of nausea and/or vomiting.

Norepinephrine versus phenylephrine affects prethrombotic response in patients undergoing cesarean section under spinal anesthesia: a randomized, double-blind, controlled study.

Venous thromboembolism (VTE) is one of the most common and serious complications of cesarean section in parturients. Norepinephrine (NE) has been shown to activate coagulation. The aim of this study was to compare the effect of a fixed-rate prophylactic norepinephrine infusion and a fixed-rate prophylactic phenylephrine（PHE） infusion under spinal anesthesia for caesarean section on the prethrombotic response. Sixty-six women undergoing cesarean section under spinal anesthesia were randomly assigned to the NE group or PHE group, starting simultaneously with the administration of the subarachnoid solution, a "study drug" solution containing either NE or PHE was pumped intravenously at a constant rate of 15 ml/h until the end of the operation. Plasma coagulation factor VIII activity (FVIII: C), Fibrinogen, and D-dimer levels were measured in blood samples obtained on admission to the operating theatre and at the end of the procedure. Compared with preoperative levels, there were no significant differences in postoperative fibrinogen and D-dimer levels in the NE group, except for a decrease in FVIII: C levels (P = 0.003). However, postoperative levels of FVIII: C (P = 0.009), fibrinogen (P = 0.035) and D-dimer (P = 0.025) were increased in the NE group compared with postoperative levels in the PHE group. NE does not affect the maternal prethrombotic response and can be safely used in cesarean sections. Compared with PHE infusion, NE infusion increased the level of coagulation molecules, suggesting that NE maybe more beneficial for women with high intraoperative bleeding requiring hemostasis.

Up-and-Down Determination of Different Crystalloid Coload Volumes on the ED 90 of Prophylactic Norepinephrine Infusion for Preventing Postspinal Anesthesia Hypotension During Cesarean Section.

Fluid loading improves hemodynamic stability and reduces the incidence rate of post-spinal anesthesia hypotension when prophylactic vasopressors are administered. We investigated the impact of different crystalloid coload volumes on the 90% effective dose (ED) of prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension in non-hypertensive patients undergoing cesarean section. Patients were randomly allocated to receive one of the different crystalloid coload volumes (0mL/kg [0mL/kg Group], 5mL kg [5mL/kg Group], and 10mL kg [10mL/kg Group]) in combination with prophylactic norepinephrine infusion immediately after the induction of spinal anesthesia. The prophylactic norepinephrine infusion doses were determined using the up-and-down sequential allocation methodology, with an initial dose of 0.025 μg/kg/min and a gradient of 0.005 μg/kg/min. The primary endpoint was the effective dose at which 90% (ED 90) of patients responded to prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension. The estimated effective dose of norepinephrine infusion, at which 90% (ED 90) of patients responded, was found to be 0.084 (95% CI, 0.070 to 0.86), 0.074 (95% CI, 0.059 to 0.077), and 0.063 (95% CI, 0.053 to 0.064) μg/kg/min in the three groups, respectively. A crystalloid coload of 5 mL/kg or 10 mL/kg, as opposed to the groups receiving 0 mL/kg crystalloid coloads, resulted in a reduction of approximately 11.9% and 25.0%, respectively, in the ED90 of prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension during cesarean section.

Dose-Response Study of Norepinephrine Infusion for Maternal Hypotension in Preeclamptic Patients Undergoing Cesarean Delivery Under Spinal Anesthesia.

Spinal anesthesia remains the preferred mode of anesthesia for preeclamptic patients during cesarean delivery. We investigated the incidence of maternal hypotension under spinal anesthesia during cesarean delivery, by comparing different prophylactic infusion rates of norepinephrine with normal saline. We randomly allocated 180 preeclamptic patients (45 in each groups) aged 18-45 scheduled for cesarean delivery to receive one of four prophylactic norepinephrine infusions at doses of 0 (normal saline group), 0.025 (0.025 group), 0.05 (0.05 group), or 0.075 (0.075 group) µg/kg/min following spinal anesthesia. The primary endpoint was the incidence of maternal hypotension (systolic blood pressure < 80% of baseline). The incidence of maternal hypotension was reduced with different prophylactic infusion rates of norepinephrine (26.7%, 15.6%, and 6.7%) compared with normal saline (37.8%) with a significant decreasing trend (p = 0.002). As the infusion doses of norepinephrine increased, there is a significant decreasing trend in deviation of systolic blood pressure control (median performance error; median absolute performance error) from baseline (p < 0.001; p < 0.001) and need for rescue norepinephrine boluses (p = 0.020). The effective dose 50 and effective dose 90 of prophylactic norepinephrine infusion were - 0.018 (95% confidence interval - 0.074, 0.002) µg/kg/min and 0.065 (95% confidence interval 0.048, 0.108) µg/kg/min, respectively. Prophylactic infusion of norepinephrine, as compared to no preventive measures, can effectively reduce the incidence of maternal hypotension in preeclamptic patients under spinal anesthesia during cesarean delivery, without increasing other adverse events for either the mother or neonate. Clinical trials.gov identifier number NCT04556370.

Minimum effective dose of intrathecal hyperbaric bupivacaine for cesarean section with and without prophylactic norepinephrine infusion: Randomized triple-blinded trial.

Vasopressor usage can affect the rostral spread of intrathecal drug and, hence, its requirement during cesarean delivery. Although a decreased spread is evidenced with phenylephrine, there is no data for norepinephrine usage. The present study aimed to evaluate the minimum effective dose of intrathecal hyperbaric bupivacaine for cesarean section with and without prophylactic norepinephrine infusion. Patients scheduled for elective cesarean section under combined spinal-epidural block were randomized to receive intravenous infusion of norepinephrine (0.05 μg/kg/min) or normal saline (placebo), initiated immediately after intrathecal injection. Postspinal hypotension in either group (systolic arterial pressure ≤0.8 baseline) was treated with norepinephrine 4 μg rescue. Dose of intrathecal hyperbaric bupivacaine (0.5%) was decided for individual patients using up-and-down sequential allocation method. Primary outcome measure was the minimum effective dose of intrathecal hyperbaric bupivacaine (0.5%) defined as ED50, while secondary observations included spinal block characteristics and neonatal outcomes. Demographic parameters were statistically similar between both groups (P > 0.05). ED50 of intrathecal hyperbaric bupivacaine was 7.8 mg (95% confidence interval [CI]: 6.7-8.8) and 7.4 mg (95% CI: 6.1-8.7) for normal saline and norepinephrine group respectively (P = 0.810). Block characteristics were similar between both groups as was neonatal APGAR score, but umbilical artery base excess was greater for norepinephrine versus normal saline group (-4.4 ± 3.6 vs. -6.5 ± 2.4, P = 0.038). Use of prophylactic norepinephrine (0.05 μg/kg/min) during cesarean delivery does not require adjustment of intrathecal hyperbaric bupivacaine.

Comparative dose-response study on the infusion of norepinephrine combined with intravenous ondansetron versus placebo for preventing hypotension during spinal anesthesia for cesarean section: a randomised controlled trial.

Ondansetron has been reported to attenuate the incidence of spinal anaesthesia-induced hypotension (SAIH) and norepinephrine requirement during caesarean section. However, no quantitative study has evaluated the extent of this effect. This study aimed to determine the dose-response of prophylactic infusion of norepinephrine to prevent SAIH in parturients who received intravenous ondansetron or placebo before spinal anaesthesia for caesarean section. The median effective dose (ED 50 ) and 90% effective dose (ED 90 ) were compared to evaluate the effect of ondansetron versus placebo on the norepinephrine requirement. One hundred fifty parturients undergoing caesarean section were randomized to receive either 0.1mg/kg ondansetron (group O) or saline control (group C) 10 min before spinal anaesthesia. The parturients were randomly assigned to one of five different norepinephrine infusion groups: 0.02, 0.04, 0.06, 0.08 or 0.10µg/kg/min. An effective infusion dose of norepinephrine was defined as non-occurrence of hypotension during the study period. The values for ED 50 and ED 90 of norepinephrine infusion were determined using probit regression. Differences between the two groups were evaluated by comparing the relative median potency with 95% CIs. The ED 50 values were 0.033 (95% CIs, 0.024-0.043) µg/kg/min in group C and 0.021 (95% CIs, 0.013-0.029) µg/kg/min in group O. The ED 90 values were 0.091 (95% CIs 0.068-0.147) µg/kg/min in group C and 0.059 (95% CIs 0.044-0.089) µg/kg/min in group O, respectively. The estimate of the relative median potency for norepinephrine in group C versus group O was 0.643 (95% CIs, 0.363-0.956). The incidence of side effects was comparable between groups. No significant difference in neonatal outcomes. Intravenous ondansetron 0.1mg/kg before spinal anaesthesia significantly reduced the dose requirement of prophylactic norepinephrine infusion in parturients undergoing elective caesarean section. This finding is potentially useful for clinical practice and further research.

Prophylactic infusion of norepinephrine does not affect the rostral spread of spinal anesthesia in pregnancy: a prospective, randomized, double-blinded study.

Background: The infusion of phenylephrine to prevent spinal-induced hypotension (SIH) in cesarean delivery may decrease the rostral spread of a spinal local anesthetic. We hypothesized that infusion of norepinephrine may decrease the rostral spread of spinal anesthesia, similar to that caused by phenylephrine. The aim of this study was to compare the block height of spinal anesthesia in the presence or absence of norepinephrine infusion administered to prevent SIH during cesarean delivery. Methods: Eighty patients were enrolled and allocated into groups receiving a norepinephrine infusion (group N) or saline infusion (group C). After intrathecal injection of hyperbaric bupivacaine 10mg, the block height for cold and pinprick sensation was checked 10 and 20min after the injection. The demographic characteristics, spinal anesthesia, side effects, and neonatal outcomes were also recorded. Results: The block height for cold and pinprick sensation was similar between the two groups, although the incidence of hypotension was significantly lower (p < 0.00) in group N than in group C. Systolic blood pressure was also more stable in group N than in group C, with the incidence of interventions being significantly lower in group N. There was no significant difference in patient satisfaction between the two groups. Conclusion: Evidence from this study suggested that prophylactic norepinephrine infusion does not reduce the rostral spread of spinal anesthesia in pregnancy. We suggest that it is not necessary to increase the dose of an intrathecal local anesthetic for cesarean delivery when prophylactic norepinephrine is administered. Clinical Trial Registration: https://www.chictr.org.cn/bin/project/edit?pid=152899, identifier [ChiCTR2200057439].

Comparison of crystalloid and colloid co-load combined with norepinephrine prophylaxis on post-spinal anesthesia hypotension during cesarean delivery: a randomized sequential allocation dose-finding study.

Fluid loading is an essential component of treatment for reducing the incidence of post-spinal anesthesia hypotension and is necessary to maintain intravascular volume, perfuse tissues, and control spinal anesthesia hypotension after sympathetic blockade. We performed a randomized sequential allocation dose-finding study to compare the effects of 10 mL/kg crystalloid and 6% hydroxyethyl starch (130/0.4) co-load on the ED90 of prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension during cesarean delivery. Eighty patients were randomly allocated to receive either a 10 mL/kg crystalloid (Crystalloid Group, n = 40) or 6% hydroxyethyl starch (130/0.4) (Colloid Group, n = 40) co-load combined with prophylactic norepinephrine infusion during spinal anesthesia for cesarean delivery. The first patient received an initial prophylactic norepinephrine infusion rate of 0.025 μg/kg/min. Subsequent patients received a 0.005 μg/kg/min gradient dose of prophylactic norepinephrine. This dose was administered as a gradient based on its effectiveness for preventing post-spinal anesthesia hypotension (defined as SBP < 80% of baseline value) and determined by the up-and-down sequential allocation methodology. The primary study outcome was the ED90 of prophylactic norepinephrine infusion. Secondary outcomes included the incidence of post-spinal anesthesia hypotension, bradycardia, hypertension, Apgar scores, and umbilical artery blood gas values were also measured. The ED90 values of prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension during cesarean delivery were 0.063 μg (95% CI: 0.050 to 0.064) and 0.062 μg (95% CI: 0.045 to 0.064) using isotonic regression analysis, and 0.068 μg (95% CI: 0.056 to 0.353) and 0.060 μg (95% CI: 0.050 to 3.590) using probit regression analysis in the Crystalloid Group and Colloid Group, respectively. The secondary outcomes were comparable between the two groups. The administration of a 10 mL/kg 6% hydroxyethyl starch (130/0.4) does not provide additional benefits compared to crystalloid co-load in reducing the ED90 of prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension during cesarean delivery.

Prophylactic Fixed-Rate Phenylephrine Versus Norepinephrine Infusion in the Prevention of Post-spinal Anesthesia Hypotension During Cesarean Delivery.

Background Maternal hypotension following spinal anesthesia can be actively countered by the use of vasopressors. Prophylactic infusion of vasopressors with a rescue bolus dosing was observed to be more effective for hemodynamic stability when compared to administering a bolus dose alone. Although phenylephrine is the recommended drug to treat spinal hypotension, many recent studies have focussed on the role of norepinephrine infusions during cesarean section. In this study, we compared prophylactic fixed-rate intravenous infusions of phenylephrine and norepinephrine during cesarean delivery under spinal anesthesia and the requirement of intraoperative provider-administered rescue bolus of phenylephrine needed to overcome post-spinal anesthesia hypotension. Methodology A total of 208 patients undergoing elective cesarean section under spinal anesthesia were randomly assigned to two groups (group P and group N). Group N included 104 patients who received norepinephrine infusion at a rate of 2.5 μg/minute (0.04 μg/kg/minute), and group P included 104 patients who received phenylephrine infusion at a rate of 50 μg/minute (0.8 μg/kg/minute)to treat spinal hypotension. The primary outcome of our study was to compare the reduction in the number and total dose of intraoperative provider-administered rescue bolus of phenylephrine needed to maintain systolic blood pressure. The secondary outcome of our study was to compare the neonatal outcome using umbilical venous blood gas sampling and Apgar score at one and five minutes. Results The total number of phenylephrine rescue bolus required to treat hypotension was significantly lower in group N (p = 0.0005) compared to group P. The neonatal outcome was similar between the two groups. Conclusions Prophylactic norepinephrine infusion when compared to prophylactic phenylephrine infusion is associated with a lesser requirement of rescue phenylephrine boluses.

Comparison of efficacy of low-dose norepinephrine infusion with low-dose boluses of norepinephrine in managing hypotension among parturients undergoing caesarean section under the subarachnoid block

: Spinal anesthesia is increasingly popular over general anesthesia due to several advantages. Hypotension can complicate spinal anesthesia during a cesarean section, which could have negative repercussions on the mother and fetus. This study is aimed to compare the efficacy of low-dose norepinephrine infusion with low-dose boluses of norepinephrine in managing hypotension among parturients undergoing cesarean section under subarachnoid block.: Ninety-nine parturients without comorbidities who underwent caesarean section with spinal anesthesia received norepinephrine were considered. They were divided into three groups. Group A- Parturient received a norepinephrine infusion of 1 mcg/min and a rescue bolus of 3 mcg to treat hypotension. Group B- Parturient received a Norepinephrine bolus of 3mcg to treat hypotension. Group C- Parturient received a Norepinephrine bolus of 5 mcg to treat hypotension. All the vitals at different intervals, number of norepinephrine boluses, the total amount of norepinephrine consumed, maximum sensory level achieved, time for baby extraction following subarachnoid block, and any adverse events were documented.No statistical difference was noted in the study group's demographics. However, there was a significant difference in mean systolic blood pressure between the groups from skin incision to baby extraction at T6 and T8. In addition, the mean arterial blood pressure of the two groups differed significantly throughout the period from baby extraction to skin suturing. Between the groups, there was a substantial difference in the total number of boluses needed. The total number of boluses required was maximum in group B, followed by group C. Group A required the minimum number of total norepinephrine boluses.A prophylactic norepinephrine infusion is an effective and straightforward method of reducing the incidence and magnitude of hypotension following spinal anesthesia for cesarean section with no adverse effect.

Comparison of Prophylactic Infusion of Phenylephrine Versus Norepinephrine for the Prevention of Post Spinal Hypotension in Parturients Undergoing Elective Caesarean Section-a Randomized, Double-Blinded, Non-Inferiority Trial.

Postspinal hypotension occurs in nearly 50% of women undergoing cesarean section (CS). Although phenylephrine (PE) is currently the vasopressor of choice, severe maternal bradycardia may adversely affect the fetal status due to the reduction in the maternal cardiac output. Norepinephrine (NE) is not associated with bradycardia and is now being evaluated for the treatment of post-spinal hypotension in obstetric patients. The hypothesis of this study was that the prophylactic NE infusion was non-inferior to PE infusion when used for the prevention of postspinal hypotension. This was a randomized, double-blinded controlled study conducted in 130 parturients scheduled for CS. The participants received either prophylactic NE (5 μg min-1) or PE (25 μg min-1) infusion beginning at the time of spinal injection. The primary outcome was the incidence of hypotension in both groups. Maternal bradycardia, reactive hypertension, nausea and vomiting, requirement of rescue boluses of vasopressor and/or atropine, and neonatal acid base status were also recorded. The incidence of hypotension was 33.80% (22 of 65) in Group PE and 26.10% (17 of 65) in Group NE (P=0.85). The absolute risk difference [90% confidence interval (CI)] in the incidence of hypotension between the groups was -7.7% (-20.9, 5.4). The upper limit of the CI was less than the non-inferiority margin of 20%, indicating that the NE infusion was non-inferior to PE. Prophylactic infusion of NE is not inferior to prophylactic PE infusion in the prevention of postspinal hypotension in patients undergoing CS.

Colloid Preload versus Crystalloid Co-Load in the Setting of Norepinephrine Infusion during Cesarean Section: Time and Type of Administered Fluids Do Not Matter.

Background and Goal of Study: Spinal anesthesia for cesarean section is frequently associated with a high incidence of hypotension, which may bring about untoward effects for both the mother and fetus. Recently, norepinephrine has emerged as a promising alternative in maintaining blood pressure in the obstetric setting. Fluid administration is another technique still widely used to prevent maternal hypotension. The optimal fluid strategy to prevent maternal hypotension has not been elucidated yet. It has been recently suggested that the main strategy in the prevention and management of hypotension should be the combination of vasoconstrictive medications and fluid administration. The aim of this randomized study was to compare the incidence of maternal hypotension in parturients receiving either colloid preload or crystalloid co-load in the setting of prophylactic norepinephrine infusion during elective cesarean section under combined spinal-epidural anesthesia. Materials and Methods: After ethics committee approval, 102 parturients with full-term singleton pregnancies were randomly allocated to either 6% hydroxyethyl starch 130/0.4 5 mL/kg before the onset of spinal anesthesia (colloid preload group) or Ringer's lactate solution 10 mL/kg concurrent with the subarachnoid injection (crystalloid co-load group). In both groups, norepinephrine 4 μg/min starting simultaneously with the administration of the subarachnoid solution was also administered. The primary outcome of the study was the incidence of maternal hypotension, defined as systolic arterial pressure (SAP) <80% of baseline. The incidence of severe hypotension (SAP < 80 mmHg), total dose of vasoconstrictive agents administered, as well as the acid-base status and Apgar score of the neonate and any incidence of maternal side effects were also recorded. Results: Data analysis was performed on 100 parturients: 51 in the colloid preload group and 49 in the crystalloid co-load group. No significant differences were demonstrated between the colloid preload group and the crystalloid co-load group in the incidence of hypotension (13.7% vs. 16.3%, p = 0.933) or the incidence of severe hypotension (0% vs. 4%, p = 0.238). The median (range) ephedrine dose was 0 (0-15) mg in the colloid preload group and 0 (0-10) mg in the crystalloid co-load group (p = 0.807). The incidence of bradycardia, reactive hypertension, requirement for modification of vasopressor infusion, time to the first occurrence of hypotension, and maternal hemodynamics did not differ between the two groups. There were no significant differences in other maternal side effects or neonatal outcomes between groups. Conclusions: The incidence of hypotension with a norepinephrine preventive infusion is low and comparable with both colloid preload and crystalloid co-load. Both fluid-loading techniques are appropriate in women undergoing cesarean delivery. It appears that the optimal regimen for prevention of maternal hypotension is a combined strategy of a prophylactic vasopressor such as norepinephrine and fluids.

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.

BackgroundAlthough 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.MethodsTwo 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.ResultsThe 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).ConclusionUnder 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.

Comparative study on the manually-controlled variable-rate versus fixed-rate infusion of norepinephrine for preventing hypotension during spinal anesthesia for cesarean delivery

Study objectivePrevious studies have shown that prophylactic norepinephrine infusion is superior to intermittent bolus administration in preventing post-spinal hypotension. Nevertheless, it is still controversial whether manually-controlled variable-rate infusion is more effective than fixed-rate infusion. The purpose of the present study was to compare the efficacy of variable-rate infusion and fixed-rate infusion of norepinephrine for prophylaxis against maternal hypotension and maintaining hemodynamic stability during spinal anesthesia for cesarean delivery to determine more effective mode for clinical practice. DesignA prospective randomized, controlled study. SettingOperating room, Women's Hospital, Zhejiang University School of Medicine. PatientsA total of 161 parturients scheduled for elective cesarean delivery with spinal anesthesia were randomized into Group F (fixed-rate infusion) and Group V (variable-rate infusion). InterventionsParturients received prophylactic norepinephrine infusion concurrent with the intrathecal injection at rate started at 0.05 μg/kg/min. In Group F, norepinephrine was administered continuously at a fixed (on-off) rate, and a bolus of norepinephrine 5 μg or 10 μg was given when systolic blood pressure (SBP) decreased by 20% or more of baseline. In Group V, manually adjusted norepinephrine infusion within the range 0–0.14 μg/kg/min, according to SBP at 1-min intervals until delivery, aim to maintain values close to the baseline. MeasurementsDuring the study period, the incidence of maternal hypotension, hemodynamic performance, the number of physician interventions, reactive hypertension, bradycardia, nausea, vomiting, norepinephrine cumulative dose (before delivery), and neonatal outcomes were recorded. Main resultsThe incidence of maternal hypotension was significantly lower in Group V than that in Group F (9% versus 30%) (P < 0.001). No significant difference was found in the serial changes in SBP and heart rate (HR) for the first 15 min. Group V showed higher frequency of physician interventions compared with the Group F (P < 0.001). The incidence of hypertension, severe hypotension, nausea, vomiting, bradycardia, norepinephrine cumulative dose, and neonatal outcome were comparable between the two groups. ConclusionWhen norepinephrine was infused at an initial dose of 0.05 μg/kg/min for preventing hypotension during spinal anesthesia for cesarean delivery, due to technical limitations of inadequate dose design in this study, neither a variable-rate infusion (need more physician intervention) nor a fixed-rate infusion regimen (experience more transient hypotension) was optimal. However, in terms of clinical importance, how to prevent the parturients from experiencing more incidence of hypotension might be a greater concern for anesthesiologists.

The ED50 and ED95 of Prophylactic Norepinephrine for Preventing Post-Spinal Hypotension During Cesarean Delivery Under Combined Spinal-Epidural Anesthesia: A Prospective Dose-Finding Study.

Background: Hypotension commonly occurs with spinal anesthesia during cesarean delivery. Norepinephrine is an alternative to phenylephrine which can be used to prevent or treat hypotension, with better maintained cardiac output and less bradycardia. However, an appropriate initial prophylactic infusion dose of norepinephrine remains unclear. The aim of this study was to describe the dose-response relationship of prophylactic norepinephrine infusion during cesarean delivery under combined spinal-epidural anesthesia. Methods: We performed a prospective, randomized, double-blinded dose-finding study. One hundred patients undergoing elective cesarean delivery were randomly assigned to receive an infusion of norepinephrine at 0, 0.025, 0.05, 0.075 or 0.1 μg/kg/min initiated immediately after intrathecal injection of 10 mg bupivacaine combined with 5 µg sufentanil. An effective dose was considered when there was no hypotension (systolic blood pressure < 90 mm Hg or < 80% of baseline) during the time period from injection of intrathecal local anesthetic to delivery of the neonate. The primary aim was to determine the dose-response relationship of norepinephrine to prevent spinal anesthesia-induced hypotension. The median effective dose (ED50) and 95% effective dose (ED95) for norepinephrine were calculated utilizing probit analysis. Results: The proportion of patients with hypotension was 80, 70, 40, 15 and 5% at norepinephrine doses of 0, 0.025, 0.05, 0.075 and 0.1 μg/kg/min, respectively. The ED50 and ED95 were 0.042 (95% CI, 0.025–0.053) µg/kg/min and 0.097 (95% CI, 0.081–0.134) µg/kg/min, respectively. There were no differences in the Apgar scores (p = 0.685) or umbilical arterial pH (p = 0.485) measurements of the newborns among the treatment groups. Conclusion: A norepinephrine infusion of 0.1 μg/kg/min as an initial starting dose was effective for the prevention of spinal-induced hypotension.

Prophylactic Norepinephrine Infusion Reduces Postoperative Complications and Hospitalization Time in Elderly Patients Undergoing Posterior Lumbar Spinal Fusion.

This single-center prospective randomized controlled trial explores the effect of prophylactic norepinephrine infusion on the incidence of complications and hospitalization time in elderly patients (60-85 years old) undergoing posterior lumbar spinal fusion. In total, 129 elderly patients were randomized into two groups: a group that received norepinephrine during general anesthesia and a control group not receiving norepinephrine. The primary outcomes were in-hospital complications and 90-day postoperative complications and hospitalization time. The results show that in-hospital complications occurred in 24 of 60 patients (40%) in the control group versus 11 of 60 patients (18.3%) in the norepinephrine group (RR, 2.182; 95% CI, 1.177–4.045; P = 0.015). Cardiac events occurred significantly more frequently in the control than in the norepinephrine group. Total number of patients experiencing complications within 90 days postoperatively was lower in the norepinephrine (11 of 60; 18.3%) than in the control group (26 of 60; 43.3%; RR, 2.364; 95% CI, 1.288–4.339; P = 0.005). The median length of hospital stay was 17 days (11–27) in the control group and 15 days (10– 23) in the norepinephrine group (P = 0.01). The secondary outcomes were serum levels of syndecan-1, hyaluronic acid, heparan sulfate, and brain natriuretic peptide. Logistic regression analysis is used to describe the relationship between selected independent variables and in-hospital complications. Intraoperative total fluid, crystalloid, and colloid volumes were significantly higher in the control than in the norepinephrine group. The patients in the norepinephrine group had a higher MAP but a lower heart rate than those in the control group after the induction of anesthesia and intraoperatively. Syndecan-1, hyaluronic acid, and heparan sulfate serum levels showed a different course in the two groups. In conclusion, prophylactic norepinephrine infusion during posterior lumbar spinal fusion is preferable for elderly patients undergoing lumbar spinal fusion under general anesthesia. It can reduce postoperative complications and hospitalization time by reducing the injury to the vascular endothelium. This trial is registered with Clinical Trial Registration http://www.chictr.org.cn/showproj.aspx?proj=33660, identifier ChiCTR-1900021309.

Prophylactic norepinephrine infusion for postspinal anesthesia hypotension in patients undergoing cesarean section: A randomized, controlled, dose-finding trial.

Prophylactic norepinephrine infusion effectively lowers the incidence of postspinal anesthesia hypotension. The optimal prophylactic dose of norepinephrine remains undefined. The purpose of this study was to investigate the optimal prophylactic dose of norepinephrine to prevent postspinal anesthesia hypotension in patients undergoing cesarean section. Prospective, double-blind, randomized, controlled, dose-finding trial. Operating room from March 2020 to June 2020. Ninety nine primipara or multipara women 18 - 40 years of age, singleton pregnancy ≥ 37 weeks, American Society of Anesthesiologists' physical status 1 or 2, scheduled for elective cesarean section under spinal anesthesia were included in this study. Patients were randomly assigned into groups to receive normal saline (NS) or one of four different prophylactic doses (0.025 [NE25], 0.05 [NE50], 0.075 [NE75], and 0.1 [NE100] ug/kg/min) of norepinephrine. The primary end point was the incidence of postspinal anesthesia hypotension (systolic blood pressure [SBP] < 80% of baseline) within 15 min after spinal anesthesia. Secondary outcomes included the overall stability of SBP control versus baseline (median performance error [MDPE] and median absolute performance error [MDAPE]), the dose that would be effective in preventing postspinal anesthesia hypotension in 50% (effective dose, ED 50) and 90% (ED90) of patients, other adverse events (bradycardia, nausea, vomiting, hypertension, and the total additional bolus of norepinephrine and atropine), and neonatal outcomes (blood gas values and Apgar scores). The incidence of postspinal anesthesia hypotension in NS, NE25, NE50, NE75, and NE100 groups was 68.42% (13/19), 40.00% (8/20), 20.00% (4/20), 15.00% (3/20), and 10.00% (2/20), respectively. With increasing prophylactic doses of norepinephrine, the incidence of postspinal anesthesia hypotension decreased (p < 0.001), SBP was maintained closer to the baseline (MDPE, p < 0.001; MDAPE, p = 0.001), and the total additional bolus of norepinephrine decreased (p < 0.001). The ED50 and ED90 values of norepinephrine were 0.016 (95% CI: -0.014 - 0.033) and 0.088 (95% CI: 0.068 - 0.133) ug/kg/min, respectively. Other adverse effects, neonatal outcomes, and the total additional bolus of atropine did not differ among the five groups. A prophylactic dose of 0.05 or 0.075 μg/kg/min norepinephrine prevents postspinal anesthesia hypotension in patients undergoing cesarean section.

Prevention of hypotension during elective cesarean section with a fixed-rate norepinephrine infusion versus a fixed-rate phenylephrine infusion. Α double-blinded randomized controlled trial

BackgroundSpinal anesthesia for cesarean section can be complicated by hypotension, with untoward effects for both the mother and fetus. Frequently used phenylephrine can lead to baroreceptor-mediated reflex bradycardia. The aim of the present study was to compare a fixed-rate prophylactic norepinephrine infusion to a fixed-rate prophylactic phenylephrine infusion during elective cesarean section under combined spinal-epidural anesthesia. Materials and methodsEighty-two parturients were randomized to either norepinephrine 4 μg/min or phenylephrine 50 μg/min fixed-rate infusions, starting simultaneously with the administration of the subarachnoid solution. The primary endpoint was the incidence of maternal bradycardia. Maternal hemodynamics at specific timepoints, the incidence of hypotension or hypertension, the requirement for ephedrine or atropine bolus administration as well as the acid-base status and Apgar score of the neonate were recorded. ResultsThe incidence of bradycardia as well as the requirement for atropine administration was lower in the norepinephrine group (4.8% vs. 31.7%, p = 0.004 and 2.4% vs. 24.3%, p = 0.01, respectively). Fetal pH, and fetal blood glucose concentration were higher in the norepinephrine group (p = 0.027 and 0.019, respectively). No difference in the occurrence of hypotension, hypertension, in the requirement for bolus vasoconstrictive medication or in Apgar scores was demonstrated. ConclusionsA fixed-rate infusion of norepinephrine is as effective in the management of hypotension during regional anesthesia for cesarean section as a fixed-rate infusion of phenylephrine, with the avoidance of phenylephrine-induced bradycardia. The more favourable neonatal acid-base profile of noradrenaline might be due to better maintenance of placental blood flow in the noradrenaline group due to its beta action, while the higher fetal glucose concentration in the same group might result from a catecholamine-stimulated glucose metabolism increase and a β-receptor mediated insulin decrease.

Comparison of two Norepinephrine rescue bolus for Management of Post-spinal Hypotension during Cesarean Delivery: a randomized controlled trial

BackgroundData on the best norepinephrine bolus dose for management of hypotension are limited. The aim of this study was to compare the efficacy and safety of two norepinephrine bolus doses in the rescue management of maternal hypotension during cesarean delivery.MethodsThis randomized, controlled trial included mothers scheduled for cesarean delivery with spinal anesthesia with a prophylactic norepinephrine infusion. Following spinal anaesthesia administration, a participant was considered hypotensive if systolic blood pressure was ≤80% compared to the baseline reading. Participants were allocated to receive either 6 mcg or 10 mcg norepinephrine bolus for the management of hypotensive episodes. The hemodynamic response after administration of norepinephrine bolus was recorded. The episode was considered successfully managed if systolic blood pressure returned to within 80% from the baseline reading within 2 min after norepinephrine bolus administration, and did not drop again within 6 min after the norepinephrine bolus. The primary outcome was the incidence of successful management of the first hypotensive episode. Other outcomes included systolic blood pressure, heart rate, incidence of maternal bradycardia, and reactive hypertension.ResultsOne hundred and ten mothers developed hypotensive episodes and received norepinephrine boluses for management. The number of successfully managed first hypotensive episodes was 50/57 (88%) in the 6 mcg-treated episodes and 45/53 (85%) in the 10 mcg-treated episodes (p = 0.78). Systolic blood pressure was comparable after administration of either bolus dose. Heart rate was lower after administration of 10 mcg bolus compared to 6 mcg bolus, without significant bradycardia requiring atropine administration. The incidence of reactive hypertension was comparable between both groups.ConclusionIn mothers undergoing elective cesarean delivery under prophylactic norepinephrine infusion at 0.05 mcg/kg/min, there was no advantage to the use of 10 mcg norepinephrine bolus over 6 mcg norepinephrine bolus for the rescue management of first hypotensive episode. Neither of the 2 bolus doses reached a 100% success rate. The incidences of bradycardia and reactive hypertension were comparable between both norepinephrine doses.Trial registrationAt clinicaltrial.gov registry system on January 4, 2019 Clinical trial identifier: NCT03792906.

A randomised double-blind dose–response study of weight-adjusted infusions of norepinephrine for preventing hypotension during combined spinal–epidural anaesthesia for Caesarean delivery

BackgroundNorepinephrine infusion has been suggested as an effective method for preventing hypotension during spinal anaesthesia for Caesarean delivery. However, optimal dosing regimens for norepinephrine have not been well established. This study aimed to determine the dose–response characteristics of a weight-adjusted fixed-rate infusion of norepinephrine to prevent hypotension during neuraxial anaesthesia for Caesarean delivery. MethodsIn a double-blind, randomised controlled trial, 80 parturients having elective Caesarean delivery received a prophylactic norepinephrine infusion at 0.025 μg kg−1 min−1 (Group N1), 0.05 μg kg−1 min−1 (Group N2), 0.075 μg kg−1 min−1 (Group N3), or 0.10 μg kg−1 min−1 (Group N4), starting immediately after induction of combined spinal–epidural anaesthesia. The primary outcome was non-occurrence of hypotension, defined as a decrease in systolic arterial pressure ≥20% below baseline value or to ≤90 mm Hg, before delivery. Values for 50% effective dose (ED50) and ED90 were calculated using probit regression. ResultsThe incidence of hypotension was 11/20 (55%), 6/20 (30%), 2/20 (10%), and 1/20 (5%) in Groups N1, N2, N3, and N4, respectively (P<0.0001). The ED50 and ED90 (95% confidence interval) of norepinephrine infusions for preventing hypotension were 0.029 (–0.002 to 0.043) and 0.080 (0.065–0.116) μg kg−1 min−1, respectively. The incidence of reactive hypertension increased with increasing norepinephrine dose (P=0.002). Other adverse effects were similar among groups. ConclusionsUnder the conditions of this study, an infusion of norepinephrine 0.08 μg kg−1 min−1 was effective for preventing hypotension in 90% of patients. This information should provide a guide for initiating norepinephrine infusions. Clinical trial registrationChiCTR1900022322 at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/enindex.aspx).