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Norepinephrine Intermittent Intravenous Boluses to Prevent Hypotension During Spinal Anesthesia for Cesarean Delivery

A Sequential Allocation Dose-Finding Study

Onwochei, Desire N., MBBS BSc (Hons), FRCA*; Ngan Kee, Warwick D., MBChB, MD, FANZCA, FHKCA; Fung, Lillia, MD, FRCPC*; Downey, Kristi, MSc*; Ye, Xiang Y., MSc; Carvalho, Jose C. A., MD, PhD, FANZCA, FRCPC*

doi: 10.1213/ANE.0000000000001846
Obstetric Anesthesiology: Original Clinical Research Report
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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 β-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.

Published ahead of print February 28, 2017.

From the *Department of Anesthesia and Pain Management, Mount Sinai Hospital, University of Toronto, Canada; Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, Hong Kong; and Maternal-Infant Care Research Centre (MiCare), Mount Sinai Hospital, University of Toronto, Canada.

Published ahead of print February 28, 2017.

Accepted for publication November 23, 2016.

Funding: None.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

IRB: Research Ethics Board, 700 University Avenue, 8th floor, Suite 8–600, Toronto, Ontario, Canada, M5G 1Z5. Clinical Trial Number at clinicaltrials. gov: NCT02654847.

Reprints will not be available from the authors.

Address correspondence to Desire N. Onwochei, MBBS BSc (Hons), FRCA, Department of Anesthesia and Pain Management, Mount Sinai Hospital, 600 University Ave, Room 19–103, Toronto, ON M5G 1X5. Address e-mail to desire@doctors.org.uk.

Phenylephrine is currently the first-choice vasopressor for prevention and treatment of maternal hypotension during spinal anesthesia for cesarean delivery (CD). It is easy to titrate and can be used either as an intravenous (IV) bolus or as an infusion.1–3 Recently, the use of phenylephrine in this context has been questioned, owing to its propensity to increase afterload, reduce maternal heart rate, and reduce cardiac output.1,4,5 Although the healthy parturient and healthy fetus seem to tolerate these hemodynamic changes well, the effect on a fetus that is already compromised has not been fully elucidated, and a concern exists.4,5 The negative chronotropic response to phenylephrine has been shown to be dose related,5 with higher doses reducing the cardiac output to a greater extent than lower ones. Further, these effects are seen with bolus doses and also when phenylephrine is given as an infusion.3

Norepinephrine has been suggested as a potential alternative to phenylephrine, because it is a potent α-adrenergic agonist with some β-adrenergic effect and, therefore, should not have a tendency to reduce heart rate and cardiac output as much as phenylephrine.4 The use of norepinephrine to prevent and treat hypotension during CD is new and data in the literature are scarce. Continuous infusions of norepinephrine and phenylephrine to prevent hypotension during CD have been studied,4 with norepinephrine being effective at maintaining blood pressure, alongside greater cardiac output and heart rate compared with phenylephrine. However, the use of norepinephrine 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 IV boluses, to prevent postspinal hypotension in 90% of women undergoing elective CD (ED90). A potency ratio for norepinephrine to phenylephrine of approximately 16:1 has been suggested,4 hence, because the effective phenylephrine bolus dose is approximately 100 µg,6 we hypothesized that the ED90 of norepinephrine would be approximately 6 µg.

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METHODS

After receiving institutional Research Ethics Board approval from Mount Sinai Hospital, Toronto, Ontario, Canada (REB 15-0305-A; January 22, 2016) and Health Canada (January 20, 2016), we conducted a prospective, double-blind sequential allocation dose-finding study, using the biased coin up-and-down (BCUD) design targeting ED90.7 We recruited nonlaboring women at term undergoing elective CD, from January 26, 2016 to March 29, 2016. Written informed consent was obtained from each participant. The trial was registered at clinicaltrials.gov under number NCT02654847, principal investigator Jose C. A. Carvalho, on January 5, 2016. We followed the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidance in conducting and reporting our investigation.

Inclusion criteria were elective CD under spinal anesthesia, age over 18 years, healthy singleton pregnancy beyond 36 weeks’ gestation, American Society of Anesthesiologists (ASA) physical status II/III, weight 50 to 100 kg, and height 150 to 180 cm. Exclusion criteria were allergy or hypersensitivity to norepinephrine or sulfite, preexisting or pregnancy-induced hypertension, cardiovascular or cerebrovascular disease, fetal abnormalities, history of diabetes mellitus (excluding gestational diabetes), use of monoamine oxidase inhibitors, triptyline or imipramine antidepressants, and patient refusal.

At the holding area, an IV line was established with an 18-gauge IV cannula in the forearm, and an infusion of lactated Ringer’s (LR) solution was started at a minimal rate to keep the vein open. A baseline systolic blood pressure (SBP) was measured in the sitting position by averaging 3 readings taken 1 minute apart using an automated device for noninvasive blood pressure assessment.

In the operating room, standard monitoring, including 5-lead electrocardiography, noninvasive blood pressure, and pulse oximetry were attached. Immediately preceding the intrathecal injection, 10 mL/kg LR was commenced as a bolus infusion (maximum 1000 mL) using a pressure bag (250 mm Hg). The rate of administration was then reduced to keep the vein open until the delivery of the infant. Spinal anesthesia was performed with the patient in the sitting position, using a 27-gauge Whitacre needle. Surgical anesthesia was achieved using 0.75% hyperbaric bupivacaine 13.5 mg mixed with preservative-free fentanyl 10 µg and morphine 100 μg, injected over 30 seconds, as per our standard practice. The patient was then positioned supine, with left uterine displacement using a wedge under the right hip. Oxygen 3 L/min was administered via nasal prongs if the oxygen saturation fell below 95%.

The norepinephrine doses to be investigated were 3, 4, 5, 6, 7, and 8 µg. Before each case, the research assistant prepared the study solution by adding a measured volume of norepinephrine (Sandoz Canada Inc, Quebec City, Canada) to a 100-mL bag of 5% dextrose to produce a concentration ranging from 3 to 8 µg/mL (Supplemental Digital Content, Appendix 1, http://links.lww.com/AA/B609). Hence, 1-mL doses of the solution were used for each case, to ensure blinding of the clinician. The norepinephrine doses were based on the infusion dose ranges from a recent study by Ngan Kee et al4 In this study, the mean rates of vasopressor infusion were norepinephrine 2.4 µg/min and phenylephrine 39.1 µg/min, with the 90th percentile norepinephrine infusion rate being 3.29 µg/min (from unpublished data). This suggests a potency ratio of approximately 16:1. Considering that the usual effective phenylephrine bolus dose is 100 µg, the range of 3 to 8 µg norepinephrine was chosen, allowing for variation above and below our ED90 estimate of 6 µg.

The norepinephrine dose of 3 µg was used for the first patient. The dose administered to subsequent patients varied by increments or decrements of 1 µg, and was determined by the response of the previous patient. If the patient did not respond adequately to the current dose (SBP decreased to < 80% of baseline), the dose was considered to have failed and the subsequent dose for the following patient was increased to the next higher dose level. If the current patient responded to the current dose, this was considered a success and the next patient was randomly assigned with a probability of 1/9 to the next lower dose or with a probability of 8/9 to the same dose. The dose of 3 µg was the floor dose and 8 µg was the ceiling dose. If a success was observed for the current patient with floor dose (3 µg), the same dose level (3 µg) would be assigned to the subsequent patient. Similarly, if a failure was observed for the current patient with the ceiling dose (8 µg), the same dose level (8 µg) would be assigned to the subsequent patient. In an up-down study, the floor and the ceiling must be established ahead of time, as a reasonable dose range has to be assumed. This was implemented using the BCUD allocation scheme7 prepared by the study biostatistician in Microsoft Excel 2016 (Microsoft Corp, Redmond, WA), for use by the research assistant, who was the only person with access to this software, maintaining blinding. The patient’s study number was allocated and recorded in the Excel spreadsheet. Hence, doses for subsequent patients were determined from this spreadsheet and the next study number assigned.

As per our standard practice, SBP, heart rate, and pulse oximetry were assessed every minute, commencing immediately after intrathecal injection until delivery. The study drug, norepinephrine, was administered manually by the attending anesthesiologist every time the SBP was lower than the baseline SBP, to maintain SBP at 100% of the baseline value. Study drug was administered IV through a port positioned approximately 5 cm from the IV cannula. All fluids were running at a rate of approximately 15 to 30 mL/min. The time interval between blood pressure readings was 1 minute, therefore the maximum frequency of administration of norepinephrine was every minute. Hypotension was defined as a SBP < 80% of the baseline value, in which case the treatment was deemed a failure, and the anesthesiologist in charge would revert to the standard practice of phenylephrine 100 µg/mL or ephedrine 5 mg/mL, as appropriate. Hypertension was defined as a SBP > 120% of the baseline value, in which case the study solution was held until the SBP was less than baseline and a vasodilator (nitroglycerin) could be given if necessary. Bradycardia was defined as a heart rate < 50 bpm and could be treated with anticholinergics if necessary. Decision to treat was at the discretion of the anesthesiologist. All patients with sensory block levels lower than T6 at 20 minutes were to be considered a dropout. The study protocol ended at delivery of the fetus. Use of norepinephrine after completion of the study period was at the discretion of the attending anesthesiologist, otherwise phenylephrine 100 µg/mL was used, as per standard practice.

As per standard practice, upon delivery, a segment of the umbilical cord was collected for assessment of blood gases in both the umbilical artery and umbilical vein.

The primary outcome was the success of intermittent boluses of the assigned dose of norepinephrine to maintain the SBP at or above 80% of baseline, from induction of spinal anesthesia to delivery of the fetus. Secondary outcomes were nausea (spontaneous complaints recorded only to maintain consistency across anesthesia providers), vomiting, hypertension, bradycardia, upper sensory level of anesthesia to ice cold upon delivery, and umbilical artery and vein blood gases. Additional data collection included maternal demographics: age, weight, height; time of intrathecal injection, skin incision, uterine incision, and delivery. Time of fetal exposure to anesthesia and to surgical procedures were evaluated as induction-delivery interval (time from intrathecal injection to delivery of the fetus) and uterine incision-delivery interval (time from uterine incision to delivery of the fetus).

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Statistical Analysis and Sample Size Calculation

For a dose-finding study based on the BCUD design, the distribution of data is unknown and nonindependent. This prevents the development of theoretical rules to estimate the sample size for a prespecified precision of the estimation of the effective interval ED90. However, simulation studies suggest that the stopping rule of enrolling 20 to 40 patients will provide stable estimates of the target dose for most realistic cases.8 In this study, a sample size based on the stopping rule of 40 patients was used.

Descriptive statistical methods were used to summarize the study population. The ED90, defined as the dose of norepinephrine at which the primary outcome of success was observed in 90% of the patients in the study population, was estimated using 2 commonly used methods: the truncated Dixon and Mood (DM) method8–10 and isotonic regression method.8,9 Let Ω={x(1)< x(2)<… <x(k)} be the k doses investigated and p(i) be the observed rate of the primary outcome of success at dose x(i), i=1,2,3,…,k. Under the BCUD design targeting ED90, the allocated doses cluster unimodally around the ED90. As a nonparametric estimator of ED90, the DM estimator is the truncated simple average of the doses administered, for example,

, where X(j) is the dose assigned to jpatient, s=max{j: the first j patients having the same response}. The isotonic regression estimator of ED90 is the linear interpolated dose between p*(r) and

, where x(r)=max(x(i):p*(i)≤0.9) and p*(i) the adjusted rate of the primary outcome of success at dose x(i), i = 1,2,3,…,k, estimated by the pooled-adjacent-violators algorithm (PAVA).8 Because the observed rate of p = {p(1),p(2),…,p(k)} may not be increased with respect to the dose level, the implicit assumption of the dose-finding study, the PAVA algorithm was first used in isotonic regression to obtain an increase adjusted rate p* = {p*(1) ≤ p*(2)≤,…,≤p*(k)} based on p. The 95% confidence interval (CI) of isotonic regression estimator of ED90 was obtained by a bias-corrected percentile method11,12 using 2000 bootstrap replications of Û3. Each replication was obtained by drawing a bootstrap data set with sample size of 40 and BCUD design, assuming that the true dose-response rate at each dose is p*(i), i=1,2,3,…,k estimated based on the original data. We then estimated Û3*, the isotonic regression estimator of ED90 based on the bootstrap data.

The DM estimator is more intuitive and simple. In the case that the observed response rates for all administered dose levels are less than the target percentile, ie, 90%, DM methods may provide more information if the true targeted dose falls within the dose sequence investigated,13 as per the hypothesis. However, generally speaking, the estimate based on the isotonic regression method has smaller bias and mean square error8 compared with the DM estimator, although a wider CI is expected, and therefore it was recommended to be used as the primary result.

The demographic variables and secondary outcomes were analyzed descriptively. A post hoc analysis to examine the association between norepinephrine doses and umbilical artery base excess/deficit was conducted using the Student t test. The data management and all the statistical analyses were performed using SAS 9.3 (SAS Institute, Inc, Cary, NC) and R version 3.1.3. (www.r-project.org).

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RESULTS

One hundred five women presenting for elective CD under spinal anesthesia were assessed for eligibility. Figure 1 shows the flow chart detailing patient recruitment. Forty patients were included in the final data analysis. The maternal demographics are shown in Table 1.

Table 1

Table 1

Figure 1

Figure 1

The sequence of effective and ineffective responses at each norepinephrine dose level for successive patients is shown in Figure 2. The doses used were 3, 4, 5, 6, and 7 µg. The dose of 8 µg was never used, as determined by the adequate responses and the biased coin method. Table 2 shows the observed and PAVA-adjusted response rates for each norepinephrine dose level. The bolus ED90 of norepinephrine to prevent hypotension was estimated as 5.49 µg (95% CI, 5.15–5.83) using the truncated DM method. The isotonic regression estimator of ED90 was 5.80 µg (95% CI, 5.01–6.59). The primary outcome was achieved in the majority of patients at a dose of 6 µg. In the successful cases at this dose level, the number of boluses needed varied from 1 to 13, corresponding to a total cumulative norepinephrine dose range of 6 to 78 µg from intrathecal injection to delivery of the fetus.

Table 2

Table 2

Figure 2

Figure 2

The maternal outcomes are shown in Table 3. Of the 6 patients (15%) who developed hypotension, 5 received bolus norepinephrine doses of <6 µg. Of the 11 patients reporting nausea, 4 and 7 received bolus norepinephrine doses of <6 µg and 6 µg, respectively. The rate of nausea in patients with hypotension was 66.7%, while it was 20.6% in those without hypotension.

Table 3

Table 3

Table 4

Table 4

Fetal outcomes are shown in Table 4. Umbilical arterial blood was not obtained in 7 cases, 2 because of technical difficulties and 5 because of the obstetrician’s practice. Umbilical artery base excess values ranged from –8.4 to 0.8 mEq/L. A post hoc analysis showed that umbilical artery base excess for patients with allocated doses of less than 6 µg was higher compared with those with a dose of 6 µg (–2.56 vs –4.94, P = .01). The pH values ranged from 7.13 to 7.35. Six patients had an umbilical artery pH <7.2. Of these, 1 had a norepinephrine dose <6 µg, and 5 had a 6 µg dose. Apgar scores were 9 and 9 for these 6 cases. Apgar scores at 1 minute and 5 minutes were 8 or above for all cases.

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DISCUSSION

The ED90 of norepinephrine was found to be 5.49 µg (95% CI, 5.15–5.83) or 5.8 µg (95% CI, 5.01–6.59) using the truncated DM and isotonic regression methods, respectively. The difference between the 2 ED90 values was not statistically significant because the CI of the ED90 using the truncated DM method included the ED90 based on isotonic regression. In practical terms, a dose of 6 µg would be easier to draw up and administer and would include the calculated ED90 figures with 95% confidence. As such, a bolus of 6 µg norepinephrine was effective at preventing hypotension in 19 of the 20 patients receiving this dose. The potency ratio of norepinephrine to phenylephrine has been suggested as 16:1 based on comparative infusion doses.4 Therefore, an ED90 around 6 µg seems logical given that the ED90 of phenylephrine has been suggested as 100 µg,6 which is the standard bolus dose given at our institution. However, this ratio is a suggestion, because it is not possible to verify a potency ratio from our study, since we did not have a comparison group. Furthermore, unmeasured factors may impact potency, so this value should be interpreted with caution.

The unwanted effects of nausea, bradycardia, and hypertension occurred at low incidences, 27.5%, 7.5%, and 10%, respectively. Data from a previous study at our institution3 showed higher incidences of nausea (36.7%), bradycardia (30%), and hypertension (40%) with bolus phenylephrine doses for the management of postspinal hypotension in elective CD, compared with what was found in this study with norepinephrine.

The safety profile of norepinephrine for the fetus and neonate is a potential concern. However, norepinephrine is not thought to readily cross the placenta into the fetus, because of the ability of the placenta to break down catecholamines.14 The use of norepinephrine may actually reduce fetal catecholamine levels, which have been shown to increase during fetal stress.4,14 Although the 6 µg norepinephrine dose was associated with a more negative base excess than the lower doses, the values still fell within the normal range, except one case with –8.4 mEq/L. Furthermore, this pattern was not observed with the 7 µg dose. We cannot comment further on the safety of norepinephrine boluses, because our study was not powered to assess this. Further research is needed to compare bolus doses of norepinephrine with phenylephrine and establish their safety profiles and therapeutic indices.

Phenylephrine, an α-adrenergic agonist, is currently the first-line drug for the management of hypotension in this context, but its propensity to induce bradycardia and decrease cardiac output has led to theoretical concerns with its use, especially when fetal compromise already exists.1,4,5 Norepinephrine, however, has a weak β-adrenergic effect in addition to its α-adrenergic action, making it less likely to induce decreases in heart rate and cardiac output.4 The lower incidence of bradycardia in the current study suggests that the β activity of norepinephrine may be beneficial over phenylephrine. Debate exists as to whether or not the β effect of norepinephrine actually bears clinical relevance.15 Studies using minimally invasive cardiac output monitors in CD have shown reductions in systemic vascular resistance but increases, not decreases, in heart rate, stroke volume, and cardiac output after spinal anesthesia is induced.16,17 In 1 study, this meant that any decrease in cardiac output caused by phenylephrine was still above baseline cardiac output, because spinal anesthesia caused an increase before phenylephrine was given.16 However, heart rate appeared to be the best marker for cardiac output in this context, and doses of phenylephrine large enough to cause a reflex bradycardia were associated with reductions in cardiac output to below baseline levels. The significance of this in a compromised mother or fetus is likely to be more marked than in healthy subjects, although this assumption remains exploratory.

Our study suggests that the use of norepinephrine in intermittent bolus doses for the prevention of postspinal hypotension in elective CD is feasible. Norepinephrine is currently a novel option for prevention and treatment of postspinal hypotension in elective CD, and as far as we are aware, this is the first study to determine the ED90 of norepinephrine as an intermittent bolus. The use of norepinephrine in any format to manage hypotension during CD is new and data in the literature are scarce. Hoyme et al18 compared a 5 µg bolus of norepinephrine with a mixture of cafedrine 20 mg/theodrenaline 1 mg and found no difference in neonatal blood pH, suggesting that norepinephrine could be a safe vasopressor in obstetric anesthesia. However, this was not a randomized comparison, but a study using retrospective controls. A double-blind randomized study by Ngan Kee et al4 compared continuous infusions of norepinephrine and phenylephrine to prevent hypotension during CD. Infusion doses of norepinephrine varied from 0 to 5 µg/min and those of phenylephrine from 0 to 100 µg/min. The infusion was administered using a closed-loop computer-controlled system aimed at maintaining SBP at baseline. They showed that norepinephrine was effective at maintaining blood pressure, with a greater cardiac output and heart rate compared with phenylephrine. Neither of these studies determined the effective bolus dose of norepinephrine needed to prevent maternal hypotension.

Concerns exist with the use of norepinephrine via peripheral veins, including tissue ischemia. However, significant morbidity was not demonstrated in a recent study19 where norepinephrine infusions were given in hypotensive patients for an average of 32 hours at a maximal rate of 30 µg/min via 18-gauge and 20-gauge cannulae in the antecubital fossa, dorsum of the hand, and forearm flexor veins. Minor complications (extravasation) occurred at a rate of 5.45% with no serious complications demonstrated. In older case reports in the literature,20,21 extravasation was seen in veins distal to the antecubital fossa or in the feet, and recent reports suggest that placement within a large proximal vein may be preferred.19,22 Moreover, the drug manufacturer (Levophed) does not specify that norepinephrine needs to be given centrally, rather via a large vein, preferably antecubital, and avoiding the lower extremities.23 Furthermore, in this study, small intermittent doses of norepinephrine (3–7 µg/mL) were used and thoroughly flushed with running IV crystalloid, rather than the concentrated infusions of 80 to 320 µg/mL commonly used in intensive care. Hence, the risk of any local tissue injury was minimal, and we did not observe any adverse effects associated with peripheral administration in our study.

Our study has some important limitations. We focused on SBP as the target for the primary outcome; however, the issue that led to the questioning of phenylephrine use in the first place relates to cardiac output. Although heart rate correlates well with cardiac output16 in this setting, the use of cardiac output monitoring to compare the efficacies of phenylephrine with norepinephrine would be highly useful and potentially more informative. Another potential limitation is that the dilutions to prepare the desired norepinephrine concentrations in 1 mL were made by injecting the set volume of norepinephrine into commercial 100 mL bags of 5% dextrose. One may argue that the volumes in these bags can be variable and often a little >100 mL. Manually measuring the diluent volume may have been more accurate; however, we wanted to conduct a pragmatic study and our phenylephrine solutions are prepared in a similar way.

In conclusion, we have determined the ED90 of intermittent boluses of norepinephrine to prevent postspinal hypotension in elective CD to be 5.49 µg (95% CI, 5.15–5.83) or 5.8 µg (95% CI, 5.01–6.59) using the truncated DM and isotonic regression methods, respectively. In practical terms, the use of a 6 µg bolus seems reasonable. Further studies are warranted to elucidate the comparative effects of intermittent bolus doses of phenylephrine and norepinephrine, in terms of efficacy and safety.

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ACKNOWLEDGMENTS

The authors thank Catherine Angotti, registered nurse in charge of elective cesarean deliveries at Mount Sinai Hospital, Toronto, Ontario, Canada for her help in mixing the study solutions to maintain blinding.

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DISCLOSURES

Name: Desire N. Onwochei, MBBS BSc (Hons), FRCA.

Contribution: This author helped design the study, collect, analyze and interpret the data, and prepare the manuscript.

Name: Warwick D. Ngan Kee, MBChB, MD, FANZCA, FHKCA.

Contribution: This author helped design the study, and revise the manuscript.

Name: Lillia Fung, MD, FRCPC.

Contribution: This author helped collect the data, and revise the manuscript.

Name: Kristi Downey, MSc.

Contribution: This author helped design the study, and collect, analyze and interpret the data.

Name: Xiang Y. Ye, MSc.

Contribution: This author helped design the study, analyze and interpret the data, and revise the manuscript.

Name: Jose C. A. Carvalho, MD, PhD, FANZCA, FRCPC.

Contribution: This author helped design the study, collect, analyze and interpret the data, and revise the manuscript.

This manuscript was handled by: Jill M. Mhyre, MD.

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REFERENCES

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