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Prophylactic Norepinephrine Infusion for Preventing

Hypotension During Spinal Anesthesia for Cesarean


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

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 g/mL norepinephrine that was started at 30 mL/h (2.5 g/
min) immediately after intrathecal injection and then manually adjusted within the range 060
mL/h (05 g/min), according to values of systolic BP measured noninvasively at 1-minute inter-
vals until delivery, with the objective of maintaining values near baseline. In group 2, no prophy-
lactic vasopressor was given, and a bolus of 1 mL norepinephrine 5 g/mL (5 g) 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 [inter-
quartile range, 47.072.5] g) versus group 2 (5.0 [018.1] g) (P < .001), there was no differ-
ence 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 g/mL of norepinephrine was effective for maintaining BP and decreas-
ing 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. (Anesth Analg 2017;XXX:0000)

N
orepinephrine has been recently described as a pos- has not been described previously. This method of admin-
sible alternative to phenylephrine for maintaining istration is widely used for other vasopressors such as
blood pressure (BP) during spinal anesthesia for phenylephrine.6
cesarean delivery.13 However, it has been recommended The aim of the current study was to evaluate the
that more data on its use in this context should be obtained efficacy of a titrated, manually controlled variable-rate
before it can be considered suitable for routine clinical infusion of norepinephrine for maintaining BP and pre-
practice.4,5 venting hypotension in patients having spinal anesthesia
Previous reports on the use of norepinephrine during for elective cesarean delivery. We hypothesized that BP
spinal anesthesia for cesarean delivery have described would be more stable and that the incidence of hypo-
delivery by computer-controlled infusion, fixed-rate infu- tension would be reduced when a titrated prophylactic
sion, and intermittent boluses.13 The use of manually infusion of norepinephrine was compared with a control
titrated infusions of norepinephrine in obstetric patients group that did not receive any prophylactic vasopressor
administration.
From the *Department of Anaesthesia and Intensive Care, the Chinese
University of Hong Kong, Hong Kong, China; and Department of Health
Technology and Informatics, the Hong Kong Polytechnic University, Hong
METHODS
Kong, China. This was a randomized double-blinded 2-arm parallel
Accepted for publication April 21, 2017. controlled trial. Approval was obtained from the Joint
Funding: Supported solely by departmental and institutional funding. Chinese University of Hong KongNew Territories
The authors declare no conflicts of interest. East Cluster Clinical Research Ethics Committee, Shatin,
Reprints will not be available from the authors. Hong Kong, Chinaand the study was registered in the
Address correspondence to Warwick D. Ngan Kee, MBChB, MD, FANZCA, Chinese Clinical Trial Registry (registration No. ChiCTR-
Department of Anaesthesia and Intensive Care, the Chinese University of TRC-14004572). All participating patients gave written
Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China. Address
e-mail to wngankee@gmail.com. informed consent. The study was conducted in the oper-
Copyright 2017 International Anesthesia Research Society ating rooms in the labor ward of a university-affiliated
DOI: 10.1213/ANE.0000000000002243 teaching hospital.

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Norepinephrine Infusion for Cesarean Delivery

Inclusion criteria were as follows: American Society of diluted with saline. The norepinephrine concentration used
Anesthesiologists physical status <3, nonlaboring, nor- was the same as that used in our previous study.1
motensive, term singleton pregnancy, elective cesarean The study drugs were administered by the principal
delivery under spinal anesthesia, and baseline systolic BP investigator (W.D.N.K.), who was blinded to the group
90140 mm Hg. Exclusion criteria were as follows: known assignment. The infusion syringe was placed in a syringe
fetal abnormality, preexisting or pregnancy-induced hyper- pump (Graseby 3500 Anaesthesia Pump; Graseby Medical
tension, known cardiovascular or cerebrovascular disease, Ltd, Watford, UK) that was connected to a 3-way stopcock
thrombocytopenia, coagulopathy, or any medical contrain- attached directly to the patients IV cannula using low-vol-
dication to spinal anesthesia, weight <50 or >100 kg, height ume tubing. Solution from the bolus syringe was drawn up
<140 or >180 cm, inability or refusal to give informed con- into 10-mL syringes for ease of administration. Immediately
sent, and age <18 years. after intrathecal injection, infusion of the study drug was
Standardized anesthetic care was provided according started at 30 mL/h. Noninvasive BP monitoring was started
to institutional standards, which included fasting, antacid 1 minute after intrathecal injection and cycled at 1-minute
premedication, and noninvasive hemodynamic monitor- intervals until delivery. After the completion of each BP
ing. After arrival in the operating room, patients were measurement, the infusion was adjusted according to the
positioned supine with left lateral tilt, and baseline BP and regimen shown in Table1. This regimen was based on our
heart rate (HR) were measured after a brief resting period previous experience of using phenylephrine infusions. The
by averaging 3 consecutive measurements for which sys- infusion regimen was continued until the time of delivery,
tolic BP varied by <10%. Baseline cardiac output (CO) was after which the study was terminated. For the purposes of
then measured noninvasively by one of the investigators the study, hypotension was defined as systolic BP <80% of
(S.W.Y.L.) using a suprasternal Doppler technique (USCOM the baseline value. Whenever hypotension occurred, a 1-mL
1A cardiac output monitor; USCOM Ltd, Sydney, Australia) bolus of the solution from the bolus syringe was immedi-
as previously described.1,7 A wide-bore intravenous (IV) ately administered IV. The time of the first episode of hypo-
catheter (default size 16-gauge) was then inserted into an tension, if it occurred, was recorded. The total volume of
upper limb vein under local anesthesia, but no prehydra- study solutions given by infusion and bolus until the time
tion was given. Patients were then placed in the right lat- of uterine incision was recorded. The total volume of IV
eral position. After skin disinfection and skin infiltration fluid given until the time of uterine incision was estimated
with lidocaine 1% w/v, spinal anesthesia was performed. by inspection of the infusion bag.
A 25-gauge Whitacre spinal needle (Becton Dickinson, Values for systolic BP and HR were recorded at the end of
Madrid, Spain) was inserted via an introducer at the esti- each BP measurement cycle. In addition, CO was monitored
mated L34 or L45 vertebral interspace. After confirming at 5-minute intervals after intrathecal injection. Oxygen was
free flow of cerebrospinal fluid, 2.2 mL of hyperbaric bupi- not routinely administered. The attending anesthesiologist
vacaine 0.5% w/v (11 mg) and fentanyl (15 g) were injected was at liberty to override the protocol and administer alter-
intrathecally. The patient was then returned to the left-tilted native or additional drugs at any time if it was deemed clin-
supine position. Rapid IV prehydration was commenced up ically indicated according to clinical discretion. This could
to a total of 2 L, after which the infusion rate was slowed to include administration of IV ephedrine for the treatment
a maintenance rate. Block height was assessed using ice; for of bradycardia associated with hypotension. Treatment of
the purposes of comparison, the upper dermatomal level bradycardia not associated with hypotension was managed
of block 5 minutes after intrathecal injection was recorded expectantly by stopping all study medications.
for each patient. However, the decision to allow surgery
to start was based on clinical judgment of the attending Statistical Analysis
anesthesiologist. The primary outcomes of the study were the incidence of
The study drug regimen was started immediately after hypotension and the overall stability of systolic BP con-
intrathecal injection. Patients were randomized to 1 of 2 trol versus baseline. The latter was assessed using perfor-
groups. Before the commencement of the study, 110 ran- mance error (PE) calculations as previously described8,9
domization codes were generated using an online random and included calculation of percentage PE, median perfor-
number generator (http://www.psychicscience.org/ran- mance error (MDPE; the median of all values of PE for each
dom.aspx). A closed-sequence generator was used to ensure patient), median absolute performance error (MDAPE; the
equal numbers in each group. One code for each patient median of the absolute values of PE for each patient), and
was placed into a sealed, opaque, consecutively numbered wobble (a measure of the variability of PE around MDPE
envelope by one of the secretarial staff who had no involve- for each patient, calculated as the median value of the
ment with the conduct of the study. A research nurse (F.F.N.)
opened the envelope for each patient shortly before com-
mencement of the study and prepared two 60-mL syringes Table 1.Infusion Regimen
Norepinephrine Delivery
labeled either bolus or infusion for each patient. The Systolic Blood Pressure Infusion Rate Rate in Infusion Group
research nurse had no role in patient management or data (% of Baseline) (mL/h) (g/min)
collection. In group 1, the infusion syringe contained 60 >110 0 0
mL of norepinephrine (5 g/mL) diluted with saline and 100110 15 1.25
the bolus syringe contained 60 mL of saline. In group 2, the 9099 30 2.5
infusion syringe contained 60 mL of saline and the bolus 8089 45 3.75
<80 60 5
syringe contained 60 mL of norepinephrine (5 g/mL)

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differences between each value of PE and MDPE) for each primary outcomes, a Bonferroni correction was applied to
patient. The primary outcome of stability of systolic BP con- maintain at .05 such that the significance criterion was P
trol was assessed by MDAPE. < .025 (.05/2). Secondary outcomes were considered explor-
Sample size was calculated based on changes in MDAPE. atory, so adjustments for multiple comparisons were not
Reanalysis of data from a previous study10 showed that made.
when hypotension was treated with intermittent boluses
of vasopressor, MDAPE was 15.46% with SD 4.76%. Based RESULTS
on this, we estimated that a sample size of 50 patients per Patient recruitment was conducted between May 2014 and
group would have 90% power, to show a 20% difference in December 2016. A total of 110 patients entered the trial. Two
MDAPE between groups, based on a 2-sample t test (PASS patients in group 1 and 1 patient in group 2 were excluded
6.0; NCSS, LLC, Kaysville, UT). Allowing for possible drop- because spinal anesthesia was inadequate and had to be
outs, the sample size was increased by 10% to 55 patients repeated. Because the investigator tasked to perform CO
per group. measurements changed employment during the study
Continuous data were assessed for normal distribution period, CO measurement was only made for 80 patients
using the KolmogorovSmirnov test followed by intergroup (43 patients in group 1 and 37 patients in group 2). Patient
comparisons using the Student t test or the Mann-Whitney recruitment and flow is shown in Figure1. Data were ana-
U test as appropriate. Nominal data were compared using lyzed for 53 patients in group 1 and 54 patients in group
the 2 test. The incidence and timing of hypotension was 2. Patient and surgical characteristics are shown in Table2.
analyzed using KaplanMeier survival analysis, with differ- Serial changes in systolic BP are shown in Figure 2, and
ences between groups compared using the log-rank test. For serial changes in HR are shown in Figure3. Results of PE
serial hemodynamic data, the area under the curve (AUC) calculations are shown in Table3.
for values plotted against time was calculated using the tra- The primary outcomes were significantly different
pezium rule; because the number of data points recorded between groups. Nine (17%) patients in group 1 versus 35
varied among patients because of varying surgical times, (66%) patients in group 2 had 1 or more episode of hypo-
standardized values were derived by dividing the values tension (uncorrected P < .001). MPAPE was significantly
for AUC by the number of data points recorded for each smaller in group 1 versus group 2, indicating maintenance
patient.11 Values for AUC were then compared between of systolic BP on average was closer to baseline in group 1
groups using the Mann-Whitney U test. (uncorrected P < .001).
Data were analyzed using Microsoft Excel 2010 Comparison of standardized values for AUC showed
(Microsoft Corporation, Redmond, WA) and IBM SPSS that systolic BP was greater over time and HR was lower
Statistics version 21 (IBM SPSS Inc, Chicago, IL). Statistical over time in group 1 versus group 2 (both P < .001). MDPE
significance was determined at the .05 level. For the 2 was negative in both groups, indicating a bias for systolic

Figure 1. CONSORT diagram showing


patient recruitment and flow.

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Norepinephrine Infusion for Cesarean Delivery

Table 2.Patient Characteristics and Surgical


Times
Group 1 Group 2
(n = 53) (n = 54)
Age (y) 33.2 (3.5) 33.1 (4.4)
Weight (kg) 68.2 (8.2) 68.8 (8.8)
Height (m) 158.3 (5.5) 157.8 (5.5)
Block height at 5 min (dermatome) T5 (T3.5T6.5) T4.5 (T4T6)
Spinal anesthesia to delivery interval 30.1 (6.1) 32.7 (10.5)
(min)
Uterine incision to delivery interval(s) 100 (45) 114 (43)
Values are represented as mean (standard deviation) or median (interquartile
range).

Figure 3. Serial changes in heart rate. Data are represented as


mean (standard deviation) and are shown for the first 30 minutes
only. Values on the x-axis correspond to the number of each con-
secutive blood pressure measurement made with the monitor set
to record at 1-minute intervals; because the noninvasive blood
pressure monitor takes a variable time to complete each measure-
ment, these values are not exactly equal to chronological time.
Comparison between groups showed that heart rate was lower over
time in group 1 (standardized area under the curve 82.2 [SD, 10.4]
beats/min) versus group 2 (standardized area under the curve 88.2
[SD, 12.1] beats/min) P = .007).

Table 3.Performance Error Calculations


Group 1 Group 2 P Value
Median performance 2.99 11.15 <.001
Figure 2. Serial changes in systolic blood pressure. Data are rep- error (MDPE) (%) (6.36 to 0.29) (14.77 to 7.65)
resented as mean (standard deviation) and are shown for the first Median absolute 4.97 11.33 <.001
30 minutes only. Values on the x-axis correspond to the number performance error (3.81 to 6.74) (7.86 to 14.99)
of each consecutive blood pressure measurement made with the (MDAPE) (%)
monitor set to record at 1-minute intervals; because the noninvasive Wobble (%) 3.13 3.32 .77
blood pressure monitor takes a variable time to complete each mea-
(2.51 to 3.76) (2.45 to 5.00)
surement, these values are not exactly equal to chronological time.
Comparison between groups showed that systolic blood pressure Data are represented as median (interquartile range). Uncorrected P values
was greater over time in group 1 (standardized area under the curve are shown. For MDAPE, which was 1 of the 2 defined primary outcomes,
110.9 [SD, 8.3] mm Hg) versus group 2 (standardized area under the P value should be interpreted using a Bonferroni-corrected significance
the curve 101.9 [SD, 9.4] mm Hg; P < .001). criterion of .025.

BP on average to be below baseline in both groups, although vasopressor or an anticholinergic drug. Five patients in each
the magnitude of this difference was greater in group 2 than group had nausea or vomiting.
in group 1 (P < .001). Neonatal outcome is shown in Table4. No Apgar score was
A survival curve showing occurrences and timing of <7 at 1 minute or <8 at 5 minutes in either group. Umbilical
hypotension is shown in Figure 4; analysis using the log- arterial blood gases could not be obtained from 1 patient in
rank test showed a significant difference in the survival dis- group 1 and 2 patients in group 2. Umbilical venous blood
tributions between groups (P < .001). A recorded HR <60 gases could not be obtained from 1 patient in group 1 and 3
beats/min occurred in 4 patients in group 1 and 4 patients patients in group 2. The umbilical arterial PO2 was less than
in group 2 (P = .98). the lower limit of detection of the blood gas analyzer (10 mm
CO changes are shown in Figure5. Comparison of stan- Hg) in 2 patients in group 1 and 7 patients in the group 2;
dardized values for AUC showed no difference between for these analyses, the data values were entered as constant
groups. values equal to the lower limit of detection divided by 2,12
The median total dose of norepinephrine given until the and the values were then analyzed by ranks. There was no
time of uterine incision was greater in group 1 (61.0 [inter- difference between groups in any of the parameters.
quartile range {IQR}, 47.072.5]) g versus group 2 (5.0 [IQR,
018.1] g) (P < .001). The overall median rate (dose divided DISCUSSION
by time to uterine incision) of norepinephrine administra- The results of this study showed that in patients having
tion was 2.22 (IQR, 1.872.57) g/min in group 1 versus 0.28 spinal anesthesia for cesarean delivery, a manually con-
[00.63] g/min in group 2 (P < .001). The total volume of IV trolled infusion of norepinephrine titrated in the range
fluid given until delivery was not different between group 05 g/min was effective for decreasing the incidence of
1 (median, 1950 [IQR, 17002020] mL) and group 2 (1975 hypotension and resulted in more stable BP control com-
[IQR, 15002038] mL). No patient received an alternative pared with a control group that received rescue boluses of

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5 g 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 phenyl-
ephrine.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 accompany-
ing editorial, Carvalho and Dyer4 commented that this tech-
nology 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
Figure 4. Serial changes in cardiac output. Data are represented algorithm were used in most cases.13 Of note, for routine
as mean (standard deviation) and are shown for the first 30 minutes practice that does not have the restrictions of a controlled
only. Comparison between groups showed that cardiac output was
trial, we have found that satisfactory control of BP is easily
not different over time in group 1 (standardized area under the curve
6.85 [SD, 1.37] L/min) versus group 2 (standardized area under the achievable with simplified infusion regimens using fewer
curve 6.42 [SD, 1.31] L/min; P = .14). 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 ver-
sus 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 hypo-
tension 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
Figure 5. Cardiac output changes. who had an episode of HR <60 beats/min was small and

Table 4.Neonatal Outcome


Group 1 Group 2 P
Birthweight (kg) 3.20 (0.38) 3.32 (0.55) .20
Umbilical arterial blood gases
pH 7.31 (7.28 to 7.33) 7.30 (7.28 to 7.32) .64
Pco2 (mm Hg) 47 (42 to 49) 48 (43 to 52) .11
Po2 (mm Hg) 16 (14 to 18) 14 (12 to 17) .08
Base excess (mmol/L) 3.8 (5.9 to 2.7) 4.0 (5.7 to 2.0) .75
Umbilical venous blood gases
pH 7.36 (7.34 to 7.37) 7.35 (7.33 to 7.38) 1.0
Pco2 (mm Hg) 40 (36 to 43) 40 (37 to 43) .73
PO2 (mm Hg) 26 (23 to 30) 25 (22 to 29) .28
Base excess (mmol/L) 3.0 (4.6 to 2.0) 4.2 (5.3 to 2.1) .43
1 min Apgar score <7 0 0
5 min Apgar score <8 0 0
Values are represented as mean (standard deviation), median (interquartile range), or n (%).

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Norepinephrine Infusion for Cesarean Delivery

similar between groups, and no difference in CO averaged Name: Shara W.Y. Lee, PhD.
over time was observed between groups. The small inci- Contribution: This author helped design the study, collect the data,
and prepare the manuscript.
dence of bradycardia contrasts with the use of phenyleph- Name: Floria F. Ng, RN, BASc.
rine and most likely reflects the mild -adrenergic agonist Contribution: This author helped collect the data and prepare the
properties of norepinephrine. manuscript.
In the current study, the concentration of norepinephrine Name: Kim S. Khaw, MD, FRCA, FHKCA.
used was 5 g/mL, which was the same as that used in our pre- Contribution: This author helped design the study and prepare the
manuscript.
vious study,1 and was based on the assumption that this would This manuscript was handled by: Jill M. Mhyre, MD.
be approximately equivalent in potency to 100 g/mL of phen-
ylephrine; this equates to a potency ratio of 20:1. Our initial REFERENCES
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