Comparative dose-response study of hyperbaric ropivacaine for spinal anesthesia for cesarean delivery in singleton versus twin pregnancies.

STUDY OBJECTIVE: It is controversial whether local anesthetic dose requirement for spinal anesthesia for cesarean delivery differs between patients with singleton and patients with multiple gestation pregnancies. The aim of this study was to determine and compare the ED50 and ED90 for hyperbaric ropivacaine used for spinal anesthesia for cesarean delivery in patients with singleton pregnancies versus patients with twin pregnancies. DESIGN: Prospective, randomized, comparative dose-finding study. SETTING: Operating room, Women's Hospital, Zhejiang University School of Medicine. PATIENTS: 100 patients with singleton pregnancies (Group S) and 100 patients with twin pregnancies (Group T) presenting for scheduled cesarean delivery under combined spinal-epidural anesthesia were enrolled in the study. INTERVENTIONS: Patients in Group S or Group T were randomly allocated to receive 9.5, 11, 12.5, 14 or 15.5 mg of hyperbaric ropivacaine intrathecally. A dose was considered effective when it achieved a bilateral sensory block level at the T6 dermatome or above within 10 min after intrathecal injection, there was no numerical rating scale (NRS) pain score ≥ 3 intraoperatively, and there was no requirement for epidural supplementation at any time during anesthesia and operation. Values for ED50 and ED90 for ropivacaine were determined using probit regression. The difference in ropivacaine dose requirement between patients with singleton pregnancies and patients with twin pregnancies was assessed by calculating relative median potency. MEASUREMENTS: Success rates for different intrathecal doses of ropivacaine, side effects and neonatal outcomes were recorded. MAIN RESULTS: The estimated (95% confidence interval) values for ED50 and ED90 of intrathecal ropivacaine in patients with singleton pregnancies were 11.2 (10.2 to 12.0) mg and 15.7 (14.4 to 18.3) mg, respectively. The values for ED50 and ED90 in patients with twin pregnancies were 10.5 (9.5 to 11.3) mg and 14.8 mg (13.6 to 17.0) mg, respectively. The estimate of relative median potency for ropivacaine between patients with singleton and twin pregnancies was 0.94 (95% confidence interval 0.83 to 1.04). CONCLUSION: Patients with singleton and twin pregnancies have similar dose requirement for hyperbaric ropivacaine used for spinal anesthesia for cesarean delivery in the setting of combined spinal-epidural (CSE) anesthesia, no opioids, low weight cohort, insertion with the patients in the right lateral position, and norepinephrine boluses.

Norepinephrine or phenylephrine during spinal anaesthesia for Caesarean delivery: a randomised double-blind pragmatic non-inferiority study of neonatal outcome.

BACKGROUND: Norepinephrine is an effective vasopressor during spinal anaesthesia for Caesarean delivery. However, before it can be fully recommended, possible adverse effects on neonatal outcome should be excluded. We aimed to test the hypothesis that umbilical arterial cord pH is at least as good (non-inferior) when norepinephrine is used compared with phenylephrine for treatment of hypotension. METHODS: We enrolled 668 subjects having elective and non-elective Caesarean delivery under spinal or combined spinal-epidural anaesthesia in this randomised, double-blind, two-arm parallel, non-inferiority clinical trial. Arterial blood pressure was maintained using norepinephrine 6 µg ml-1 or phenylephrine 100 µg ml-1 according to the practice of the anaesthetist, either prophylactically or therapeutically, as an infusion or bolus. The primary outcome was umbilical arterial pH with a chosen non-inferiority margin of 0.01 units. RESULTS: Of 664 subjects (531 elective and 133 non-elective) who completed the study, umbilical arterial cord blood was analysed for 351 samples from 332 subjects in the norepinephrine group and 343 samples from 332 subjects in the phenylephrine group. Umbilical arterial pH was non-inferior in the norepinephrine group (mean, 7.289; 95% confidence interval [CI], 7.284-7.294) compared with the phenylephrine group (mean, 7.287; 95% CI, 7.281-7.292) (mean difference between groups, 0.002; 95% CI, -0.005 to 0.009; P=0.017). Subgroup analysis confirmed the non-inferiority of norepinephrine for elective cases but was inconclusive for non-elective cases. CONCLUSIONS: Norepinephrine was non-inferior to phenylephrine for neonatal outcome assessed by umbilical arterial pH. These results provide high-quality evidence supporting the fetal safety of norepinephrine in obstetric anaesthesia. CLINICAL TRIAL REGISTRATION: ChiCTR-IPR-15006235.

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

BACKGROUND: Norepinephrine 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. METHODS: In 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. RESULTS: The 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. CONCLUSIONS: Under 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 REGISTRATION: ChiCTR1900022322 at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/enindex.aspx).

Dose-Response Study of 4 Weight-Based Phenylephrine Infusion Regimens for Preventing Hypotension During Cesarean Delivery Under Combined Spinal-Epidural Anesthesia.

BACKGROUND: Prophylactic IV infusion of phenylephrine has been recommended to prevent hypotension during spinal anesthesia for cesarean delivery. However, the optimal infusion dose is unknown. This study aimed to determine the infusion dose of phenylephrine that would be effective in preventing hypotension in 50% (ED50) and 90% (ED90) of patients when administered as a prophylactic infusion at a fixed rate based on the individual body weight. METHODS: Eighty parturients scheduled for elective cesarean delivery were randomly allocated to receive IV infusion of prophylactic phenylephrine at 0.25, 0.375, 0.5, or 0.625 µg/kg/min (n = 20 per group) started immediately after intrathecal injection of 10 mg hyperbaric bupivacaine and 5 µg sufentanil using a combined spinal-epidural technique. An effective dose was defined by the occurrence of no hypotension (defined as a decrease in systolic blood pressure by ≥20% below baseline and to <90 mm Hg) during the interval from the initiation of spinal anesthesia to delivery of the infant. Values for ED50 and ED90 of prophylactic phenylephrine were calculated using probit analysis. RESULTS: Hypotension occurred in 13/20, 8/20, 2/20, and 1/20 patients in the groups that received phenylephrine infusion at 0.25, 0.375, 0.5, or 0.625 µg/kg/min, respectively. The calculated values for ED50 and ED90 were 0.31 (95% CI, 0.24-0.36) and 0.54 (95% CI, 0.46-0.76) µg/kg/min, respectively. No difference was found in the incidence of adverse effects and neonatal outcomes among groups. CONCLUSIONS: Under the conditions of this study, when phenylephrine was given as a fixed-rate prophylactic infusion during spinal anesthesia for cesarean delivery to prevent hypotension, the values for ED50 and ED90 were 0.31 (95% CI, 0.24-0.36) and 0.54 (95% CI, 0.46-0.76) µg/kg/min, respectively.

Vasopressor drugs for the prevention and treatment of hypotension during neuraxial anaesthesia for Caesarean delivery: a Bayesian network meta-analysis of fetal and maternal outcomes.

BACKGROUND: The optimal choice of vasopressor drugs for managing hypotension during neuraxial anaesthesia for Caesarean delivery is unclear. Although phenylephrine was recently recommended as a consensus choice, direct comparison of phenylephrine with vasopressors used in other healthcare settings is largely lacking. Therefore, we assessed this indirectly by collating data from relevant studies in this comprehensive network meta-analysis. Here, we provide the possible rank orders for these vasopressor agents in relation to clinically important fetal and maternal outcomes. METHODS: RCTs were independently searched in MEDLINE, Web of Science, Embase, The Cochrane Central Register of Controlled Trials, and clinicaltrials.gov (updated January 31, 2019). The primary outcome assessed was umbilical arterial base excess. Secondary fetal outcomes were umbilical arterial pH and Pco2. Maternal outcomes were incidences of nausea, vomiting, and bradycardia. RESULTS: We included 52 RCTs with a total of 4126 patients. Our Bayesian network meta-analysis showed the likelihood that norepinephrine, metaraminol, and mephentermine had the lowest probability of adversely affecting the fetal acid-base status as assessed by their effect on umbilical arterial base excess (probability rank order: norepinephrine > mephentermine > metaraminol > phenylephrine > ephedrine). This rank order largely held true for umbilical arterial pH and Pco2. With the exception of maternal bradycardia, ephedrine had the highest probability of being the worst agent for all assessed outcomes. Because of the inherent imprecision when collating direct/indirect comparisons, the rank orders suggested are possibilities rather than absolute ranks. CONCLUSION: Our analysis suggests the possibility that norepinephrine and metaraminol are less likely than phenylephrine to be associated with adverse fetal acid-base status during Caesarean delivery. Our results, therefore, lay the scientific foundation for focused trials to enable direct comparisons between these agents and phenylephrine.

A Prospective, Randomized, Double-Blinded Study of the Effect of Intravenous Ondansetron on the Effective Dose in 50% of Subjects of Prophylactic Phenylephrine Infusions for Preventing Spinal Anesthesia-Induced Hypotension During Cesarean Delivery.

BACKGROUND: Ondansetron has been shown to reduce the incidence of hypotension and vasopressor requirement during spinal anesthesia for obstetric and nonobstetric surgery. However, the magnitude of this effect has not been fully quantified. In this parallel-group, randomized, double-blinded study, we determined the effective dose in 50% of subjects (ED50) of a prophylactic phenylephrine infusion for preventing hypotension in patients who received a single dose of intravenous ondansetron 4 mg or saline control before combined spinal-epidural anesthesia for elective cesarean delivery. ED50 values obtained were compared to estimate the effect of ondansetron versus placebo on vasopressor requirement. METHODS: Sixty parturients were randomly assigned to receive ondansetron (group O) or saline control (group C) 10 minutes before positioning for induction of spinal anesthesia. A prophylactic phenylephrine infusion was used to prevent hypotension. The first patient in each group received a phenylephrine infusion at the rate of 0.5 µg/kg/min. The infusion rate for each subsequent patient was varied with increments or decrements of 0.05 µg/kg/min based on the response of the previous patient, and the effective dose of the phenylephrine infusion for preventing hypotension in 50% of patients (ED50) was calculated for each group and compared using up-down sequential analysis. Probit regression was applied as a backup and sensitivity analysis was used to compare ED50 values for phenylephrine between groups by comparing calculated relative mean potency. RESULTS: The ED50 (mean [95% confidence interval (CI)]) of the rate of phenylephrine infusion was lower in group O (0.24 µg/kg/min [0.10-0.38 µg/kg/min]) compared with group C (0.32 µg/kg/min [0.14-0.47 µg/kg/min]) (P < .001). The total consumption of phenylephrine (mean ± standard deviation [SD]) until delivery was lower in group O (316.5 ± 25.9 µg) than in group C (387.7 ± 14.7 µg, P = .02). The estimate of relative median potency for phenylephrine for group O versus group C was 0.74 (95% CI, 0.37-0.95). CONCLUSIONS: Under the conditions of this study, intravenous ondansetron 4 mg reduced the ED50 of a prophylactic phenylephrine infusion by approximately 26% in patients undergoing cesarean delivery under combined spinal-epidural anesthesia.

Prophylactic Norepinephrine Infusion for Preventing Hypotension During Spinal Anesthesia for Cesarean Delivery.

BACKGROUND: The use of norepinephrine for maintaining blood pressure (BP) during spinal anesthesia for cesarean delivery has been described recently. However, its administration by titrated manually controlled infusion in this context has not been evaluated. METHODS: In a double-blinded, randomized controlled trial, 110 healthy women having spinal anesthesia for elective cesarean delivery were randomly allocated to 1 of 2 groups. In group 1, patients received an infusion of 5 µg/mL norepinephrine that was started at 30 mL/h (2.5 µg/min) immediately after intrathecal injection and then manually adjusted within the range 0-60 mL/h (0-5 µg/min), according to values of systolic BP measured noninvasively at 1-minute intervals until delivery, with the objective of maintaining values near baseline. In group 2, no prophylactic vasopressor was given, and a bolus of 1 mL norepinephrine 5 µg/mL (5 µg) was given whenever systolic BP decreased to <80% of the baseline value. The study protocol was continued until delivery. The primary outcomes of the study were the incidence of hypotension and the overall stability of systolic BP control versus baseline compared using performance error calculations. In addition, the incidence and timing of hypotension were further compared using survival analysis. RESULTS: Three patients were excluded from the analysis. Nine patients (17%) in group 1 had 1 or more episodes of hypotension versus 35 (66%) in group 2 (P < .001). Performance error calculations showed that on average, systolic BP was maintained closer to baseline (P < .001) in group 1. Survival curve analysis showed a significant difference between groups (log-rank test P < .001). Four patients in each group had a recorded heart rate <60 beats/min (P = .98). Despite a much greater rate of administration of norepinephrine in group 1 (median, 61.0 [interquartile range, 47.0-72.5] µg) versus group 2 (5.0 [0-18.1] µg) (P < .001), there was no difference in neonatal outcome as assessed by Apgar scores and umbilical cord blood gas analysis. CONCLUSIONS: In patients having spinal anesthesia for elective cesarean delivery, a manually titrated infusion of 5 µg/mL of norepinephrine was effective for maintaining BP and decreasing the incidence of hypotension, with no detectable detrimental effect on neonatal outcome. Further investigation of the use of dilute norepinephrine infusions for routine use in obstetric patients is suggested.

Dose-Response Curves for Intrathecal Bupivacaine, Levobupivacaine, and Ropivacaine Given for Labor Analgesia in Nulliparous Women.

BACKGROUND AND OBJECTIVES: Bupivacaine, levobupivacaine, and ropivacaine are often given intrathecally for labor analgesia, but limited data are available for their dose-response properties in this context. The objective of this study was to describe the dose-response curves of these local anesthetics when given intrathecally for labor analgesia, to determine values for D50 (dose producing a 50% response) and to compare the calculated values of D50 for levobupivacaine and ropivacaine with those for bupivacaine. METHODS: With ethics approval and written consent, we randomized 270 nulliparous laboring patients requesting neuraxial analgesia at 5-cm cervical dilation or less to receive a single dose of intrathecal local anesthetic without opioid as part of a combined spinal-epidural technique. Patients received either bupivacaine, levobupivacaine, or ropivacaine at a dose of 0.625, 1.0, 1.5, 2.5, 4.0, or 6.25 mg (n = 15 per group). Visual analog scale pain scores were measured for 15 minutes, after which further analgesia and management were at the clinician's discretion. The primary end point was percentage reduction of pain score at 15 minutes. Logistic sigmoidal dose-response curves were fitted to the data using nonlinear regression, and D50 values were calculated for each drug. RESULTS: Data were analyzed from 270 patients. Patient characteristics were similar between groups. The calculated D50 and 95% confidence interval values were as follows: bupivacaine, 1.56 mg (1.25-1.94 mg); ropivacaine, 1.95 mg (1.57-2.43 mg); and levobupivacaine, 2.20 mg (1.76-2.73 mg). CONCLUSIONS: The results of this study support previous work showing that intrathecal levobupivacaine and ropivacaine are less potent than bupivacaine. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (identifier: ChiCTR-TRC-09000773) and Centre of Clinical Trials Clinical Registry of the Chinese University of Hong Kong (identifier: CUHK_CCT00245).

A Random-allocation Graded Dose-Response Study of Norepinephrine and Phenylephrine for Treating Hypotension during Spinal Anesthesia for Cesarean Delivery.

BACKGROUND: Norepinephrine has been investigated as a potential alterative to phenylephrine for maintaining blood pressure during spinal anesthesia for cesarean delivery with the advantage of less depression of maternal heart rate and cardiac output. However, the relative potencies of these two vasopressors have not been fully determined in this context. METHODS: In a random-allocation, graded dose-response study, 180 healthy patients undergoing spinal anesthesia for elective cesarean delivery received a single bolus of norepinephrine in one of six different doses ranging from 4 to 12 µg or phenylephrine in one of six different doses ranging from 60 to 200 µg to treat the first episode of hypotension. The magnitude of response was measured as the percentage of full restoration of systolic blood pressure to the baseline value. Dose-response analysis was performed using nonlinear regression to derive four-parameter logistic dose-response curves, which were compared to determine relative potency. RESULTS: Data were analyzed for 180 patients. The estimated ED50 values (dose giving a 50% response) were norepinephrine 10 µg (95% CI, 6 to 17 µg) and phenylephrine 137 µg (95% CI, 79 to 236 µg). The estimated relative potency ratio for the two drugs was 13.1 µg (95% CI, 10.4 to 15.8 µg). CONCLUSIONS: Comparative dose-response analysis was completed for norepinephrine and phenylephrine given as a bolus to treat the first episode of hypotension in patients undergoing spinal anesthesia for cesarean delivery. The estimated dose equivalent to phenylephrine 100 µg was norepinephrine 8 µg (95% CI, 6 to 10 µg). These results may be useful to inform the design of future comparative studies.

Closed-Loop Feedback Computer-Controlled Phenylephrine for Maintenance of Blood Pressure During Spinal Anesthesia for Cesarean Delivery: A Randomized Trial Comparing Automated Boluses Versus Infusion.

BACKGROUND: We previously described the use of closed-loop feedback computer-controlled infusion of phenylephrine for maintaining blood pressure (BP) during spinal anesthesia for cesarean delivery. In this study, we report a modified system in which phenylephrine is delivered by intermittent boluses rather than infusion. We hypothesized that the use of computer-controlled boluses would result in more precise control of BP compared with infusions. METHODS: Two hundred fourteen healthy patients having spinal anesthesia for elective cesarean delivery were randomized to have their systolic BP maintained by phenylephrine administered by computer-controlled continuous infusion or computer-controlled intermittent boluses. From induction of anesthesia until the time of uterine incision, a noninvasive BP monitor was set to cycle at 1-minute intervals. In the infusion group, the infusion rate was automatically adjusted after each BP measurement using a previously described algorithm. In the bolus group, the algorithm was modified so that the mass of drug that would have been delivered over 1 minute was instead injected as a rapid intravenous bolus after each BP measurement. The precision of BP control was assessed using performance error calculations and compared between groups, with the primary outcome defined as median absolute performance error, and the latter being a measure of inaccuracy showing an average of the magnitudes of the differences of measured BP values above or below the target values. RESULTS: The precision of BP control was greater, as shown by smaller values for median absolute performance error, in the bolus group (median 4.38 [quartiles 3.22, 6.25] %) versus the infusion group (5.39 [4.12, 7.04] %, P = .008). In the bolus group, phenylephrine consumption was smaller; this was associated with smaller values for median performance error compared with the continuous infusion group (P < .001), which indicates that values for systolic BP, averaged over time, were slightly lower in the bolus group. There were no differences in cardiac output, nausea or vomiting, or neonatal outcome between groups. CONCLUSIONS: We confirmed the hypothesis that BP control was more precise when computer-controlled phenylephrine was delivered using intermittent boluses rather than continuous infusion. However, the difference between groups was small and was not associated with any difference in clinical outcomes. In the infusion group, greater doses of phenylephrine were delivered, which was related to the time taken for the noninvasive BP monitor to complete measurements. The use of intermittent boluses may be a useful alternative in the design of closed-loop vasopressor systems.

The use of vasopressors during spinal anaesthesia for caesarean section.

PURPOSE OF REVIEW: Hypotension remains one of the most researched subjects in obstetric anaesthesia. The purpose of this study is to review the most recent published articles on the use of vasopressors during spinal anaesthesia for caesarean section. RECENT FINDINGS: Despite continued research indicating advantages of phenylephrine over ephedrine, practitioners in some countries continue to favour ephedrine. Recent research has continued to compare the two drugs with some work emerging on high-risk patients. Concern about reflexive bradycardia during phenylephrine use has led to consideration of alternatives. Norepinephrine which has mild ß-adrenergic activity has been shown to have equivalent pressor activity but with less depressant effect on heart rate and cardiac output versus phenylephrine. Research continues to focus on methods of vasopressor administration. Prophylactic infusions of phenylephrine have been shown to be effective and may require less physician intervention compared with intermittent boluses. Automated computer-controlled systems have been further investigated using multiple agents and continuous noninvasive blood pressure monitoring. SUMMARY: Evidence continues to support phenylephrine as the first-line vasopressor in obstetrics. However, recent research is emerging to suggest that low-dose norepinephrine may be a better alternative. Prophylactic infusions are effective and automated systems have potential for the future.

Norepinephrine Intermittent Intravenous Boluses to Prevent Hypotension During Spinal Anesthesia for Cesarean Delivery: A Sequential Allocation Dose-Finding Study.

BACKGROUND: The use of phenylephrine as the first-line agent for prevention and treatment of maternal hypotension during cesarean delivery (CD) may reduce cardiac output, posing a theoretical risk to mother and fetus. Norepinephrine has been suggested as a potential alternative, because its ß-adrenergic effects might result in greater heart rate and cardiac output than phenylephrine. The use of norepinephrine to prevent and treat hypotension during CD is new, and its use as a bolus has not been fully determined in this context. The purpose of this study was to determine the effective norepinephrine dose, when given as intermittent intravenous (IV) boluses, to prevent postspinal hypotension in 90% of women undergoing elective CD (ED90). METHODS: This was a prospective, double-blind sequential allocation dose-finding study, using the biased coin up-and-down design. Forty-term pregnant women undergoing elective CD under spinal anesthesia received a set intermittent norepinephrine bolus of either 3, 4, 5, 6, 7, or 8 µg every time their systolic blood pressure (SBP) fell to below 100% of baseline. The primary outcome was the success of the norepinephrine regimen to maintain SBP at or above 80% of baseline, from induction of spinal anesthesia to delivery of the fetus. Secondary outcomes included nausea, vomiting, hypertension (SBP > 120% of baseline), bradycardia (<50 bpm), upper sensory level of anesthesia to ice cold and umbilical artery and vein blood gases. The ED90 and 95% confidence intervals (CIs) were estimated using both truncated Dixon and Mood and isotonic regression methods. RESULTS: The estimated ED90 of norepinephrine was 5.49 µg (95% CI, 5.15-5.83) using the truncated Dixon and Mood method and 5.80 µg (95% CI, 5.01-6.59) using the isotonic regression method. CONCLUSIONS: The use of intermittent IV norepinephrine boluses to prevent spinal-induced hypotension in elective CD seems feasible and was not observed to be associated with adverse outcomes. Practically, we suggest an ED90 dose of 6 µg. Further work is warranted to elucidate the comparative effects of intermittent IV bolus doses of phenylephrine and norepinephrine, in terms of efficacy and safety.

Performance of a closed-loop feedback computer-controlled infusion system for maintaining blood pressure during spinal anaesthesia for caesarean section: a randomized controlled comparison of norepinephrine versus phenylephrine.

Closed-loop feedback computer-controlled vasopressor infusion has been previously described for maintaining blood pressure during spinal anaesthesia for caesarean section but there are limited data available comparing the relative performance of different vasopressors. The aim of this study was to compare the performance of norepinephrine versus phenylephrine in this system. Data from a randomized, two-arm parallel group, double-blinded controlled trial were reanalyzed. 104 patients scheduled for elective caesarean section under spinal anaesthesia were randomized to receive computer-controlled closed-loop infusion of either norepinephrine 5 µg ml-1 or phenylephrine 100 µg ml-1. This was started immediately after induction of spinal anaesthesia and used an algorithm designed to maintain systolic blood pressure near baseline until fetal delivery. Performance error calculations were used to compare the performance of the two vasopressors. The primary outcome was defined as the median absolute performance error. Median performance error, wobble and divergence were also compared. Median absolute performance error was smaller in the norepinephrine group (median 3.79 [interquartile range 2.82-5.17] %) versus the phenylephrine group (4.70 [3.23-6.57] %, P = 0.028). In addition, median performance error was smaller (0.75 [-1.56-2.52] %) versus 2.61 [0.83-4.57] %, P = 0.002) and wobble was smaller (2.85 [2.07-5.17] %) versus 3.39 [2.62-4.90] %, P = 0.028) in the norepinephrine group versus the phenylephrine group. Divergence was similar between groups. The precision of the control of blood pressure was greater with norepinephrine compared with phenylephrine at the drug concentrations used.

Randomized double-blinded comparison of norepinephrine and phenylephrine for maintenance of blood pressure during spinal anesthesia for cesarean delivery.

BACKGROUND: During spinal anesthesia for cesarean delivery, phenylephrine can cause reflexive decreases in maternal heart rate and cardiac output. Norepinephrine has weak ß-adrenergic receptor agonist activity in addition to potent α-adrenergic receptor activity and therefore may be suitable for maintaining blood pressure with less negative effects on heart rate and cardiac output compared with phenylephrine. METHODS: In a randomized, double-blinded study, 104 healthy patients having cesarean delivery under spinal anesthesia were randomized to have systolic blood pressure maintained with a computer-controlled infusion of norepinephrine 5 µg/ml or phenylephrine 100 µg/ml. The primary outcome compared was cardiac output. Blood pressure heart rate and neonatal outcome were also compared. RESULTS: Normalized cardiac output 5 min after induction was greater in the norepinephrine group versus the phenylephrine group (median 102.7% [interquartile range, 94.3 to 116.7%] versus 93.8% [85.0 to 103.1%], P = 0.004, median difference 9.8%, 95% CI of difference between medians 2.8 to 16.1%). From induction until uterine incision, for norepinephrine versus phenylephrine, systolic blood pressure and stroke volume were similar, heart rate and cardiac output were greater, systemic vascular resistance was lower, and the incidence of bradycardia was smaller. Neonatal outcome was similar between groups. CONCLUSIONS: When given by computer-controlled infusion during spinal anesthesia for cesarean delivery, norepinephrine was effective for maintaining blood pressure and was associated with greater heart rate and cardiac output compared with phenylephrine. Further work would be of interest to confirm the safety and efficacy of norepinephrine as a vasopressor in obstetric patients.

Synergistic interaction between fentanyl and bupivacaine given intrathecally for labor analgesia.

BACKGROUND: Lipophilic opioids and local anesthetics are often given intrathecally in combination for labor analgesia. However, the nature of the pharmacologic interaction between these drugs has not been clearly elucidated in humans. METHODS: Three hundred nulliparous women randomly received 1 of 30 different combinations of fentanyl and bupivacaine intrathecally using a combined spinal-epidural technique for analgesia in the first stage of labor. Visual analogue scale pain scores were recorded for 30 min. Response was defined by percentage decrease in pain score from baseline at 15 and 30 min. Dose-response curves for individual drugs were fitted to a hyperbolic dose-response model using nonlinear regression. The nature of the drug interaction was determined using dose equivalence methodology to compare observed effects of drug combinations with effects predicted by additivity. RESULTS: The derived dose-response models for individual drugs (doses in micrograms) at 15 min were: Effect = 100 × dose / (13.82 + dose) for fentanyl, and Effect = 100 × dose / (1,590 + dose) for bupivacaine. Combinations of fentanyl and bupivacaine produced greater effects than those predicted by additivity at 15 min (P < 0.001) and 30 min (P = 0.015) (mean differences, 9.1 [95% CI, 4.1-14.1] and 6.4 [95% CI, 1.2-11.5] units of the normalized response, respectively), indicating a synergistic interaction. CONCLUSIONS: The pharmacologic interaction between intrathecal fentanyl and bupivacaine is synergistic. Characterization and quantification of this interaction provide a theoretical basis and support for the clinical practice of combining intrathecal opioids and local anesthetics.