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

Ngan Kee, Warwick D. MD, FANZCA, FHKCA*; Lee, Shara W. Y. PhD; Ng, Floria F. RN, BASc*; Khaw, Kim S. MD, FRCA, FHKCA*

doi: 10.1213/ANE.0000000000002243
Obstetric Anesthesiology: Original Clinical Research Report
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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.

From the *Department of Anaesthesia and Intensive Care, the Chinese University of Hong Kong, Hong Kong, China

Department of Health Technology and Informatics, the Hong Kong Polytechnic University, Hong Kong, China.

Published ahead of print July 1, 2017.

Accepted for publication April 21, 2017.

Funding: Departmental and Institutional.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Warwick D. Ngan Kee, MBChB, MD, FANZCA, Department of Anaesthesia and Intensive Care, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China. Address e-mail to wngankee@gmail.com.

Norepinephrine has been recently described as a possible alternative to phenylephrine for maintaining blood pressure (BP) during spinal anesthesia for cesarean delivery.1–3 However, it has been recommended that more data on its use in this context should be obtained before it can be considered suitable for routine clinical practice.4,5

Previous reports on the use of norepinephrine during spinal anesthesia for cesarean delivery have described delivery by computer-controlled infusion, fixed-rate infusion, and intermittent boluses.1–3 The use of manually titrated infusions of norepinephrine in obstetric patients has not been described previously. This method of administration is widely used for other vasopressors such as phenylephrine.6

The aim of the current study was to evaluate the efficacy of a titrated, manually controlled variable-rate infusion of norepinephrine for maintaining BP and preventing hypotension in patients having spinal anesthesia for elective cesarean delivery. We hypothesized that BP would be more stable and that the incidence of hypotension would be reduced when a titrated prophylactic infusion of norepinephrine was compared with a control group that did not receive any prophylactic vasopressor administration.

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METHODS

This was a randomized double-blinded 2-arm parallel controlled trial. Approval was obtained from the Joint Chinese University of Hong Kong—New Territories East Cluster Clinical Research Ethics Committee, Shatin, Hong Kong, China—and the study was registered in the Chinese Clinical Trial Registry (registration No. ChiCTR-TRC-14004572). All participating patients gave written informed consent. The study was conducted in the operating rooms in the labor ward of a university-affiliated teaching hospital.

Inclusion criteria were as follows: American Society of Anesthesiologists physical status <3, nonlaboring, normotensive, term singleton pregnancy, elective cesarean delivery under spinal anesthesia, and baseline systolic BP 90–140 mm Hg. Exclusion criteria were as follows: known fetal abnormality, preexisting or pregnancy-induced hypertension, known cardiovascular or cerebrovascular disease, thrombocytopenia, coagulopathy, or any medical contraindication to spinal anesthesia, weight <50 or >100 kg, height <140 or >180 cm, inability or refusal to give informed consent, and age <18 years.

Standardized anesthetic care was provided according to institutional standards, which included fasting, antacid premedication, and noninvasive hemodynamic monitoring. After arrival in the operating room, patients were positioned supine with left lateral tilt, and baseline BP and heart rate (HR) were measured after a brief resting period by averaging 3 consecutive measurements for which systolic BP varied by <10%. Baseline cardiac output (CO) was then measured noninvasively by one of the investigators (S.W.Y.L.) using a suprasternal Doppler technique (USCOM 1A cardiac output monitor; USCOM, Ltd, Sydney, Australia) as previously described.1,7 A wide-bore intravenous (IV) catheter (default size 16-gauge) was then inserted into an upper limb vein under local anesthesia, but no prehydration was given. Patients were then placed in the right lateral position. After skin disinfection and skin infiltration with lidocaine 1% w/v, spinal anesthesia was performed. A 25-gauge Whitacre spinal needle (Becton Dickinson, Madrid, Spain) was inserted via an introducer at the estimated L3–4 or L4–5 vertebral interspace. After confirming free flow of cerebrospinal fluid, 2.2 mL of hyperbaric bupivacaine 0.5% w/v (11 mg) and fentanyl (15 µg) were injected intrathecally. The patient was then returned to the left-tilted supine position. Rapid IV prehydration was commenced up to a total of 2 L, after which the infusion rate was slowed to a maintenance rate. Block height was assessed using ice; for the purposes of comparison, the upper dermatomal level of block 5 minutes after intrathecal injection was recorded for each patient. However, the decision to allow surgery to start was based on clinical judgment of the attending anesthesiologist.

The study drug regimen was started immediately after intrathecal injection. Patients were randomized to 1 of 2 groups. Before the commencement of the study, 110 randomization codes were generated using an online random number generator (http://www.psychicscience.org/random.aspx). A closed-sequence generator was used to ensure equal numbers in each group. One code for each patient was placed into a sealed, opaque, consecutively numbered envelope by one of the secretarial staff who had no involvement with the conduct of the study. A research nurse (F.F.N.) opened the envelope for each patient shortly before commencement of the study and prepared two 60-mL syringes labeled either “bolus” or “infusion” for each patient. The research nurse had no role in patient management or data collection. In group 1, the infusion syringe contained 60 mL of norepinephrine (5 µg/mL) diluted with saline and the bolus syringe contained 60 mL of saline. In group 2, the infusion syringe contained 60 mL of saline and the bolus syringe contained 60 mL of norepinephrine (5 µg/mL) diluted with saline. The norepinephrine concentration used was the same as that used in our previous study.1

The study drugs were administered by the principal investigator (W.D.N.K.), who was blinded to the group assignment. The infusion syringe was placed in a syringe pump (Graseby 3500 Anaesthesia Pump; Graseby Medical, Ltd, Watford, UK) that was connected to a 3-way stopcock attached directly to the patient’s IV cannula using low-volume tubing. Solution from the bolus syringe was drawn up into 10-mL syringes for ease of administration. Immediately after intrathecal injection, infusion of the study drug was started at 30 mL/h. Noninvasive BP monitoring was started 1 minute after intrathecal injection and cycled at 1-minute intervals until delivery. After the completion of each BP measurement, the infusion was adjusted according to the regimen shown in Table 1. This regimen was based on our previous experience of using phenylephrine infusions. The infusion regimen was continued until the time of delivery, after which the study was terminated. For the purposes of the study, hypotension was defined as systolic BP <80% of the baseline value. Whenever hypotension occurred, a 1-mL bolus of the solution from the bolus syringe was immediately administered IV. The time of the first episode of hypotension, if it occurred, was recorded. The total volume of study solutions given by infusion and bolus until the time of uterine incision was recorded. The total volume of IV fluid given until the time of uterine incision was estimated by inspection of the infusion bag.

Table 1.

Table 1.

Values for systolic BP and HR were recorded at the end of each BP measurement cycle. In addition, CO was monitored at 5-minute intervals after intrathecal injection. Oxygen was not routinely administered. The attending anesthesiologist was at liberty to override the protocol and administer alternative or additional drugs at any time if it was deemed clinically indicated according to clinical discretion. This could include administration of IV ephedrine for the treatment of bradycardia associated with hypotension. Treatment of bradycardia not associated with hypotension was managed expectantly by stopping all study medications.

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Statistical Analysis

The primary outcomes of the study were the incidence of hypotension and the overall stability of systolic BP control versus baseline. The latter was assessed using performance error (PE) calculations as previously described8,9 and included calculation of percentage PE, median performance error (MDPE; the median of all values of PE for each patient), median absolute performance error (MDAPE; the median of the absolute values of PE for each patient), and wobble (a measure of the variability of PE around MDPE for each patient, calculated as the median value of the differences between each value of PE and MDPE) for each patient. The primary outcome of stability of systolic BP control was assessed by MDAPE.

Sample size was calculated based on changes in MDAPE. Reanalysis of data from a previous study10 showed that when hypotension was treated with intermittent boluses of vasopressor, MDAPE was 15.46% with SD 4.76%. Based on this, we estimated that a sample size of 50 patients per group would have 90% power, to show a 20% difference in MDAPE between groups, based on a 2-sample t test (PASS 6.0; NCSS, LLC, Kaysville, UT). Allowing for possible dropouts, the sample size was increased by 10% to 55 patients per group.

Continuous data were assessed for normal distribution using the Kolmogorov–Smirnov test followed by intergroup comparisons using the Student t test or the Mann-Whitney U test as appropriate. Nominal data were compared using the χ2 test. The incidence and timing of hypotension was analyzed using Kaplan–Meier survival analysis, with differences between groups compared using the log-rank test. For serial hemodynamic data, the area under the curve (AUC) for values plotted against time was calculated using the trapezium rule; because the number of data points recorded varied among patients because of varying surgical times, standardized values were derived by dividing the values for AUC by the number of data points recorded for each patient.11 Values for AUC were then compared between groups using the Mann-Whitney U test.

Data were analyzed using Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA) and IBM SPSS Statistics version 21 (IBM SPSS, Inc, Chicago, IL). Statistical significance was determined at the .05 level. For the 2 primary outcomes, a Bonferroni correction was applied to maintain α at .05 such that the significance criterion was P < .025 (.05/2). Secondary outcomes were considered exploratory, so adjustments for multiple comparisons were not made.

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RESULTS

Patient recruitment was conducted between May 2014 and December 2016. A total of 110 patients entered the trial. Two patients in group 1 and 1 patient in group 2 were excluded because spinal anesthesia was inadequate and had to be repeated. Because the investigator tasked to perform CO measurements changed employment during the study period, CO measurement was only made for 80 patients (43 patients in group 1 and 37 patients in group 2). Patient recruitment and flow is shown in Figure 1. Data were analyzed for 53 patients in group 1 and 54 patients in group 2. Patient and surgical characteristics are shown in Table 2. Serial changes in systolic BP are shown in Figure 2, and serial changes in HR are shown in Figure 3. Results of PE calculations are shown in Table 3.

Table 2.

Table 2.

Table 3.

Table 3.

Figure 1.

Figure 1.

Figure 2.

Figure 2.

Figure 3.

Figure 3.

The primary outcomes were significantly different between groups. Nine (17%) patients in group 1 versus 35 (66%) patients in group 2 had 1 or more episode of hypotension (uncorrected P < .001). MPAPE was significantly smaller in group 1 versus group 2, indicating maintenance of systolic BP on average was closer to baseline in group 1 (uncorrected P < .001).

Comparison of standardized values for AUC showed that systolic BP was greater over time and HR was lower over time in group 1 versus group 2 (both P < .001). MDPE was negative in both groups, indicating a bias for systolic BP on average to be below baseline in both groups, although the magnitude of this difference was greater in group 2 than in group 1 (P < .001).

A survival curve showing occurrences and timing of hypotension is shown in Figure 4; analysis using the log-rank test showed a significant difference in the survival distributions between groups (P < .001). A recorded HR <60 beats/min occurred in 4 patients in group 1 and 4 patients in group 2 (P = .98).

Figure 4.

Figure 4.

CO changes are shown in Figure 5. Comparison of standardized values for AUC showed no difference between groups.

Figure 5.

Figure 5.

The median total dose of norepinephrine given until the time of uterine incision was greater in group 1 (61.0 [interquartile range {IQR}, 47.0–72.5]) µg versus group 2 (5.0 [IQR, 0–18.1] µg) (P < .001). The overall median rate (dose divided by time to uterine incision) of norepinephrine administration was 2.22 (IQR, 1.87–2.57) µg/min in group 1 versus 0.28 [0–0.63] µg/min in group 2 (P < .001). The total volume of IV fluid given until delivery was not different between group 1 (median, 1950 [IQR, 1700–2020] mL) and group 2 (1975 [IQR, 1500–2038] mL). No patient received an alternative vasopressor or an anticholinergic drug. Five patients in each group had nausea or vomiting.

Table 4.

Table 4.

Neonatal outcome is shown in Table 4. No Apgar score was <7 at 1 minute or <8 at 5 minutes in either group. Umbilical arterial blood gases could not be obtained from 1 patient in group 1 and 2 patients in group 2. Umbilical venous blood gases could not be obtained from 1 patient in group 1 and 3 patients in group 2. The umbilical arterial PO2 was less than the lower limit of detection of the blood gas analyzer (10 mm Hg) in 2 patients in group 1 and 7 patients in the group 2; for these analyses, the data values were entered as constant values equal to the lower limit of detection divided by √2,12 and the values were then analyzed by ranks. There was no difference between groups in any of the parameters.

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DISCUSSION

The results of this study showed that in patients having spinal anesthesia for cesarean delivery, a manually controlled infusion of norepinephrine titrated in the range 0–5 µg/min was effective for decreasing the incidence of hypotension and resulted in more stable BP control compared with a control group that received rescue boluses of 5 µg norepinephrine to treat hypotension when it occurred. Despite a much greater dose of norepinephrine given to patients who received norepinephrine by infusion, no adverse effect on neonatal outcome was detected.

The current study follows on from a previous study in which we compared norepinephrine with phenylephrine during cesarean delivery and found that norepinephrine had advantages of causing less depression of HR, which was associated with greater CO compared with phenylephrine.1 In that study, the vasopressors were administered by closed-loop feedback computer-controlled infusions because this is a useful research tool for comparing drugs objectively and without bias. However, in an accompanying editorial, Carvalho and Dyer4 commented that this technology is currently not recommended for clinical practice. In comparison, in the current study, we used a manually controlled infusion using a simple algorithm that can be easily implemented. The senior author recently reported on the routine use of norepinephrine during cesarean delivery over a 1-year period, during which infusions based on this algorithm were used in most cases.13 Of note, for routine practice that does not have the restrictions of a controlled trial, we have found that satisfactory control of BP is easily achievable with simplified infusion regimens using fewer rate adjustments than in the current report.

In our study, we included a control group that did not receive prophylactic vasopressor administration. In this group, rescue boluses of norepinephrine were given as required to treat any episodes of hypotension that occurred. The purpose of inclusion of the control group was to provide a baseline comparator to facilitate evaluation of the efficacy of prophylactic norepinephrine infusion. Of note, the study was not designed to compare the efficacy of infusion versus boluses of norepinephrine. In clinical practice, when an intermittent bolus technique is used, boluses may be given earlier or more frequently and as prophylaxis rather than treatment of hypotension; thus, a lower incidence of hypotension may be achieved than that observed in the control group in our study. Further work is required to compare optimized intermittent bolus and infusion techniques for the administration of norepinephrine in obstetric patients.

Although HR on average was lower in patients who received norepinephrine by infusion, the number of patients who had an episode of HR <60 beats/min was small and similar between groups, and no difference in CO averaged over time was observed between groups. The small incidence of bradycardia contrasts with the use of phenylephrine and most likely reflects the mild β-adrenergic agonist properties of norepinephrine.

In the current study, the concentration of norepinephrine used was 5 µg/mL, which was the same as that used in our previous study,1 and was based on the assumption that this would be approximately equivalent in potency to 100 µg/mL of phenylephrine; this equates to a potency ratio of 20:1. Our initial estimate of potency was based on a study of human saphenous vein.14 However, subsequent evidence has arisen that suggests that the true potency ratio in the context of obstetric spinal anesthesia is probably lower. In a recent sequential allocation dose-finding study, Onwochei et al2 suggested that when using bolus doses of norepinephrine for preventing hypotension in obstetric patients, a dose of 6 µg was close to the ED90 (dose effective in 90% of subjects) value and approximately equivalent to 100 µg of phenylephrine; this would imply a potency ratio of approximately 16:1. The senior author is currently using 6 µg/mL of norepinephrine in his routine practice.13

Finally, some concern has been expressed about the potential risk of administering norepinephrine via peripheral veins.5 However, when norepinephrine is administered in dilute concentrations of 5–6 µg/mL, given the similarity in vasoconstrictor potency, the risk should be no different to that posed by administration of phenylephrine in the commonly used concentration of 100 µg/mL. Provided it is infused via a large-bore IV catheter into which IV fluid is constantly infusing the risk of peripheral administration of phenylephrine is likely minimal, and we contend that infusion into a central venous catheter and placement of an arterial line are not routinely necessary.15 The authors consider that identical considerations should apply to the use of dilute solutions of norepinephrine.

In conclusion, this study showed that a manually titrated infusion of 5 µg/mL of norepinephrine was effective for decreasing the incidence of hypotension during spinal anesthesia for elective cesarean delivery. This was associated with a low incidence of bradycardia and no evidence of any adverse effect on neonatal outcome. We suggest further investigation of the use of dilute norepinephrine infusions for routine use in obstetric patients.

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ACKNOWLEDGMENTS

The authors thank the midwives of the Labour Ward, Prince of Wales Hospital, Shatin, Hong Kong, China, for their assistance and cooperation.

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DISCLOSURES

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

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

Name: Shara W. Y. Lee, PhD.

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

Name: Floria F. Ng, RN, BASc.

Contribution: This author helped collect the data and prepare the manuscript.

Name: Kim S. Khaw, MD, FRCA, FHKCA.

Contribution: This author helped design the study and prepare the manuscript.

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

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REFERENCES

1. Ngan Kee WD, Lee SW, Ng FF, Tan PE, Khaw KS. Randomized double-blinded comparison of norepinephrine and phenylephrine for maintenance of blood pressure during spinal anesthesia for cesarean delivery. Anesthesiology. 2015;122:736–745.
2. Onwochei DN, Ngan Kee WD, Fung L, Downey K, Ye XY, Carvalho JC. Norepinephrine intermittent intravenous boluses to prevent hypotension during spinal anesthesia for cesarean delivery: a sequential allocation dose-finding study. Anesth Analg. 2017;125:212–218.
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13. Ngan Kee WD. Norepinephrine for preventing hypotension during spinal anaesthesia for caesarean section: a 12-month review of individual use. Int J Obstet Anesth. 2017;30:73–74.
14. Sjöberg T, Norgren L, Andersson KE, Steen S. Comparative effects of the alpha-adrenoceptor agonists noradrenaline, phenylephrine and clonidine in the human saphenous vein in vivo and in vitro. Acta Physiol Scand. 1989;136:463–471.
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