Advances in Anesthesia 37 (2019) 207–228

ADVANCES IN ANESTHESIA

Optimal Management of
Hypotension During Cesarean
Delivery Under Spinal Anesthesia
Jennifer L. Fichter, MD*, Kenneth E. Nelson, MD
Department of Anesthesiology, Wake Forest School of Medicine, 9th Floor Janeway Tower,
1 Medical Center Boulevard, Winston-Salem, NC 27157, USA

Keywords

Obstetric anesthesia
Cesarean delivery
Spinal hypotension

Left uterine displacement
Vasopressor choice
Fluid coloading
Key points

The management of hypotension under spinal anesthesia for cesarean delivery
has evolved remarkably, with previous obstetric dogmas being questioned and
novel strategies showing success in robust clinical trials.

Ongoing investigations are showing that aortocaval compression and its clinical
ramifications are neither as ubiquitous nor as straightforward as previously
thought.

Phenylephrine administered via infusion is superior to the use of ephedrine in
terms of maternal hemodynamic control and neonatal acid-base status.

Crystalloid coloading, which can be given quickly and facilitates vasopressor
administration, is an effective method for the prevention of hypotension under
spinal anesthesia.

INTRODUCTION
Spinal anesthesia was first used for cesarean delivery in the United States in
1941 [1]. Since that time, hypotension during neuraxial anesthesia for cesarean
delivery has plagued obstetric anesthesia. Without prophylactic treatment, hy-
potension occurs in up to 80% of patients undergoing spinal anesthesia for ce-
sarean delivery [2]. Spinal hypotension results in decreased uteroplacental
blood flow, fetal acidosis, and maternal symptoms such as nausea, vomiting,

Disclosure: The authors have nothing to disclose.

*Corresponding author. E-mail address: [email protected]

https://doi.org/10.1016/j.aan.2019.08.008
0737-6146/19/ª 2019 Elsevier Inc. All rights reserved.
208 FICHTER & NELSON

and decreased consciousness [3]. If severe enough, hypotension can lead to

complete maternal cardiovascular collapse [4]. As such, finding the solution
to spinal anesthesia–induced hypotension has been likened to discovering the
Holy Grail of obstetric anesthesia [5,6].
Maternal death from spinal anesthesia is now rare; however, this was a com-
mon occurrence just 50 years ago. Holmes [7] titled his 1957 review, ‘‘Spinal
Analgesia And Caesarean Delivery; Maternal Mortality.’’ Studies around this
time focused on the detrimental effects of aortocaval compression from the su-
pine gravid uterus on maternal hemodynamics and fetal status [8,9]. As a
result, management strategies largely targeted maternal positioning to relieve
vasculature collapse [10]. Early prevention and treatment measures also
included increasing maternal blood volume and decreasing venous capacitance,
through techniques such as fluid preloading and compression stockings. As the
understanding of hypotension during spinal anesthesia has evolved, so has the
management, and what were once considered standard management tech-
niques (ie, left uterine tilt, fluid preloading, lower extremity compression) might
now be deemed outdated (Table 1).
This review provides an overview of the definition and pathophysiology of
spinal anesthesia–induced hypotension, compares strategies for the prevention
and treatment of maternal hypotension, and reviews recent literature support-
ing a conventional approach to management.

HYPOTENSION DURING SPINAL ANESTHESIA

In the absence of a neuraxial-induced sympathectomy, up to 10% of term
women experience hypotension in the supine position [11]. This condition re-
sults from compression of the inferior vena cava (IVC) by the term gravid
uterus when supine [12]. The disorder has been coined supine hypotensive syn-
drome of pregnancy. Compression of the IVC results in reduced preload and

Table 1
Chronology of selected events in the evolution of the management of spinal-induced hypoten-
sion
1935 Angiography first suggests vascular compression in supine parturients
1953 Supine hypotensive syndrome described
1968 Angiography further defines vascular compression in supine parturients
1972 Crawford wedge and concept of 15 lateral tilt developed
1974 Ephedrine shown to be superior to alpha-agonists in pregnant ewes
2002 Systematic review reports ephedrine, compared with phenylephrine, results in
decreased fetal pH
2004 Crystalloid coload shown to be superior to crystalloid preload
2010 Phenylephrine preferred vasopressor and studies show benefit of infusion compared
with bolus dosing
2015 In first controlled study, norepinephrine is used to adequately maintain maternal CO
and SBP
2015 Traditional concept of aortocaval compression challenged by MRI study
Abbreviations: CO, cardiac output; SBP, systolic blood pressure.
OPTIMAL MANAGEMENT OF HYPOTENSION 209

increased maternal heart rate via the baroreceptor-mediated reflex. Symptoms

commonly include maternal lightheadedness, dizziness, nausea, and general
discomfort [13]. At the extreme, maternal and neonatal death have been attrib-
uted to supine hypotensive syndrome of pregnancy [14]. Parturients normally
have a well-developed collateral venous system, which enables adequate
venous return through the azygous, hemiazygos, and ascending lumbar veins
in the event of IVC occlusion [15]. However, in patients with supine hypoten-
sive syndrome, venous collateralization and compensatory mechanisms are
apparently less effective.
Hypotension during spinal anesthesia may be exaggerated in patients with
supine hypotensive syndrome. Such patients experience baseline symptoms
from inadequate preload, which can worsen following neuraxial anesthesia.
Spinally administered local anesthetics induce a vasomotor sympathectomy, re-
sulting in decreased systemic vascular resistance (SVR) and redistributed blood
volume to the splanchnic and lower extremity circulations [16,17]. The degree
of hypotension seems proportional to block height and some investigators have
used low-dose bupivacaine spinal anesthesia to reduce hemodynamic alter-
ations [18,19]. For example, Van de Velde and colleagues [20] showed that
the mean lowest systolic blood pressure (SBP) was higher in patients receiving
6.5 mg of hyperbaric intrathecal bupivacaine compared with 9.5 mg
(102  16 mm Hg vs 88  16 mm Hg; P<.05). In addition to causing less vaso-
dilation, a lower block level is less likely to affect cardioaccelerator fibers orig-
inating from thoracic spinal levels 1 to 4 [21]. Once cardioaccelerator fibers are
blocked, vagal stimulation predominates, potentially resulting in bradycardia.
Cardiac output (CO) is directly related to heart rate and so any reduction in
heart rate results in a decrease in CO, presuming stroke volume remains
constant.
Recent advances in minimally invasive cardiac monitoring have provided
additional insight into the hemodynamic effects of spinal anesthesia. Multiple
recent trials have made use of continuous CO monitoring and suprasternal ul-
trasonography to monitor CO under spinal anesthesia. Langesaeter and col-
leagues [22] were the first to use the LiDCOplus, a minimally invasive
hemodynamic monitor, to measure CO, SVR, and SBP in pregnant women un-
dergoing spinal anesthesia for cesarean delivery. The device uses an arterial
line to detect arterial waveform changes based on injected lithium concentra-
tions [22,23]. Women were randomized to low-dose or higher-dose (7 mg vs
10 mg, respectively) isobaric bupivacaine (with sufentanil 4 lg) spinal anes-
thesia and a prophylactic phenylephrine infusion (0.25 lg/kg/min) versus pla-
cebo. They showed significantly lower mean differences in SBP and CO
changes from baseline after spinal anesthesia within the group receiving low-
dose bupivacaine and prophylactic phenylephrine compared with higher-dose
bupivacaine and placebo, which is expected given the increased vasodilatory
effects from greater amounts of local anesthetic. What was perhaps a more sig-
nificant finding from this study was the immediate increase in CO and decrease
in SVR associated with spinal anesthesia; this effect was present in all patients,
210 FICHTER & NELSON

regardless of randomization. No significant differences in stroke volume were

found between groups, indicating that CO changes were primarily heart rate
driven. In patients without minimally invasive monitoring, heart rate is re-
garded as the best surrogate marker of CO under spinal anesthesia [23].
Because placental circulation and fetal oxygenation depend more on the main-
tenance of maternal CO than SBP, an anesthetic plan should optimize all hemo-
dynamic variables, not solely SBP [24,25].
Invasive, even minimally invasive, monitoring is rarely required in the obstet-
ric population and is typically reserved for the highest-risk parturients. As a result,
most studies on the cardiovascular response to spinal anesthesia focus on the pre-
vention and treatment of hypotension. Hypotension has multiple definitions in
the obstetric anesthesia literature. Definitions have included (1) SBP less than
90 mm Hg or less than 100 mm Hg, (2) SBP less than 80% of baseline, and (3)
greater than a 25% decrease in SBP from baseline [26–30]. In practice, surveyed
anesthesiologists use different SBP thresholds for vasopressor use, with most us-
ing a decrease in SBP greater than 20% [31]. This article does not specifically state
the definition for hypotension used for each study discussed; however, it is impor-
tant to note that such heterogeneity can confound study comparisons.

MATERNAL POSITIONING
In the supine position, the gravid uterus completely occludes the IVC. Bieniarz
and colleagues [32] used angiography in the 1960s to determine the degree of
vasculature collapse and found that both the IVC and the aorta are compressed
when a parturient lies supine (see Table 1). Nonanesthetized parturients typically
tolerate aortocaval compression well without significant cardiovascular effects as
the result of collateral blood flow. However, during neuraxial anesthesia the
induced sympathectomy may result in fetal compromise. Crawford and col-
leagues [33]were among the first anesthesiologists to draw attention to this matter
(see Table 1). They examined 150 women undergoing elective cesarean delivery
with general anesthesia, tilting 63 of those patients to the right with the use of a 15
rubber wedge. The remaining 87 women were supine. They found a statistically
significant difference in mean umbilical artery pH of newborns from the tilted
group, 7.31 versus 7.27 in the nontilted group (P<.001). Their study conditions
are hardly generalizable to contemporary obstetric anesthesia practice. All women
had general anesthesia, there was no mention of vasopressor use, and most pa-
tients were tilted to the right, per obstetrician preference. However, tilting mothers
laterally 15 has essentially remained obstetric anesthesia dogma for decades.
So, should clinicians still be tilting? The 2016 ‘‘Practice Guidelines of Obstet-
ric Anesthesia,’’ established by the American Society of Anesthesiologists and
the Society for Obstetric Anesthesia and Perinatology, recommends maintain-
ing left lateral tilt until time of delivery [34]. A Cochrane Review performed
just 3 years prior showed that, overall, positioning does not affect the incidence
of maternal hypotension [35]. Work by Higuchi and colleagues [36] showed the
potential reason for this lack of association (see Table 1). They performed
abdominal MRI of 10 healthy pregnant and nonpregnant women in 4 different
OPTIMAL MANAGEMENT OF HYPOTENSION 211

positions: supine and left lateral tilt at 15 , 30 , and 45 . Imaging showed that
the IVC was almost completely collapsed by the gravid uterus in supine partu-
rients. Among the parturient group, IVC volume was only significantly
different between the supine and 30 and 45 tilt positions, with no difference
found between supine and 15 tilt. Imaging also showed no significant differ-
ence in aortic volumes in either group, regardless of amount of tilt. This finding
suggests that, in nonanesthetized parturients, CO remains stable, whereas car-
diac preload may only start to improve when a 30 to 45 angle is assumed.
Thoracic bioimpedance cardiography has been used to continuously
monitor CO, stroke volume, and heart rate with position changes in term, non-
anesthetized patients with singleton pregnancies [37]. Bamber and colleagues
showed that the full left lateral position resulted in the greatest CO. However,
the difference compared with other left tilt positions, including 5 and 12.5 ,
were nonsignificant. Even supine positioning did not result in a significant
mean difference in CO [36]. Rees and colleagues [38] similarly studied the ef-
fects of extreme positioning on CO, but with patients under spinal anesthesia.
However, they did not monitor CO directly but used signs and symptoms sug-
gestive of low CO, such as maternal nausea, vomiting, and bradycardia.
Comparing women in complete left lateral position versus 15 of left tilt
following spinal anesthesia, they found no significant presumed changes in CO.
Lateral tilt and left uterine displacement are unlikely to independently solve
hypotension during spinal anesthesia. Studies show that not only is it ineffec-
tive but it is usually applied inaccurately, as shown by Jones and colleagues
[39]. They asked anesthetists to estimate the amount of lateral tilt they had
applied during elective cesarean deliveries. Estimated tilt ranged from 7 to
35 , whereas measured tilt did not exceed 15 . If the goal is to prevent IVC
obstruction and improve cardiac preload, anesthesia providers would have to
tilt parturients to at least 30 (Fig. 1). Such a position would be uncomfortable
for the patient and inconvenient for the obstetrician (Fig. 2); however, there are
case reports of cesarean deliveries performed in the complete lateral position
[37,40,41]. For patients with supine hypotensive syndrome of pregnancy, tilt

A B

Gravid
uterus
Gravid
uterus
IVC
L R L R
Aorta IVC

Aorta

Fig. 1. (A) Near-complete IVC occlusion by the gravid uterus in the supine position. (B) Relief of
IVC occlusion observed at 30 tilt, an angle impractical for cesarean delivery. L, left; R, right.
212 FICHTER & NELSON

Fig. 2. Maternal positioning during cesarean delivery under spinal anesthesia. (A) When
positioning the parturient for cesarean delivery following a neuraxial anesthetic, even experi-
enced anesthesia providers typically apply far less than the traditionally recommended 15 .
(B) The operating room table pictured is maximally tilted with a resulting inclinometer reading
of slightly less than 30 . In order to effectively relieve compression of the vena cava, more than
30 of tilt is required, which is poorly tolerated by both patients and surgeons.

should be used. For otherwise asymptomatic parturients, a mild degree of tilt,

at the discretion of the anesthesia provider and the obstetrician, may not help
but it does not hurt.

EPHEDRINE VERSUS PHENYLEPHRINE

Until a decade or two ago, ephedrine was the preferred vasopressor for the pre-
vention and treatment of spinal-induced hypotension [42]. Early work in preg-
nant ewes showed improved fetal acidosis when ephedrine was used for
hypotension following spinal anesthesia [43]. Compared with pure alpha-
agonists, ephedrine caused less vasoconstriction of the uteroplacental circula-
tion, resulting in improved fetal oxygenation [44]. Ephedrine, through indirect
beta-agonism, was thought to increase maternal CO and augment uteroplacen-
tal blood flow. The use of ephedrine for hypotension was considered gold
standard, as shown by surveys of the time. In 1999, 95% of obstetric anesthe-
siologists in the United Kingdom preferred ephedrine as their sole vasopressor
[45]. However, ephedrine’s ubiquitous use started to come into question as sys-
tematic reviews and later randomized controlled trials unveiled effects on hu-
man fetal pH.
In 2002, Lee and colleagues [46] performed a quantitative, systematic review
of 7 randomized controlled trials of ephedrine versus phenylephrine given for
hypotension for spinal anesthesia during cesarean delivery. When given for the
prevention and treatment of hypotension, they found no difference in the inci-
dence of hypotension with the use of ephedrine or phenylephrine (relative risk
[RR], 1.0; 95% confidence interval [CI], 0.96–1.06). Limiting analysis to trials
specifically of the treatment of hypotension, again, there was no difference be-
tween groups. However, they did find statistical significance when comparing
umbilical artery pH. Neonates born to mothers receiving phenylephrine had
higher umbilical artery pH values (weighted mean difference, 0.03; 95% CI,
0.02–0.04), implying improved uteroplacental perfusion with phenylephrine.
OPTIMAL MANAGEMENT OF HYPOTENSION 213

Subsequent prospective studies investigated the effects of phenylephrine,

ephedrine, or a combination of the two on maternal cardiovascular and fetal
acid-base status. Based on an equipotency ratio of approximately 80:1, phenyl-
ephrine 100 lg and ephedrine 5 to 8 mg are typically used for both bolus and
infusion dosing [2,47–49]. When administered as a prophylactic bolus dose,
ephedrine and phenylephrine show similar efficacy in effectively treating
maternal hypotension [47,48]. When used as an infusion, phenylephrine shows
superiority over ephedrine. Not only is phenylephrine as an infusion associated
with significantly less nausea and vomiting but it more effectively prevents
hypotension [49]. More importantly, fewer fetuses are acidotic (pH<7.2)
following exposure to phenylephrine versus ephedrine for the management
of hypotension following spinal anesthesia.
What this suggests, and what has been supported by additional studies, is
that fetal acidosis in the setting of ephedrine use is related to a direct ephedrine
effect [50]. Ephedrine stimulates fetal beta-adrenergic receptors, increasing fetal
oxygen demand and anaerobic metabolism [51,52]. More often than not, a
mixed respiratory and metabolic acidosis results [50]. Although neonatal Apgar
scores do not seem to differ between ephedrine and phenylephrine use, studies
show increased neonatal complications, such as intraventricular hemorrhage,
gastrointestinal dysfunction, and death, in those with metabolic acidosis at birth
[53]. As a result, the fetal acidosis observed with ephedrine use has been
convincing enough to shift practice to the use of phenylephrine for the preven-
tion and treatment of hypotension following neuraxial anesthesia [47,49–52].

PHENYLEPHRINE INFUSION VERSUS BOLUS

Although phenylephrine is now considered the vasopressor of choice for spinal-
induced hypotension during cesarean delivery, the ideal dose and mode of de-
livery have been debated. Double-blinded studies randomizing patients to
either prophylactic phenylephrine infusions or rescue bolus doses have shown
conflicting results. In a double-blind, randomized controlled trial of infusion
versus the bolus technique, Doherty and colleagues [54] showed improved
SBP control in parturients administered phenylephrine boluses. However,
this effect was only present within the first 6 minutes after spinal injection
and was not deemed clinically significant. The lack of significance may have
been the result of the high phenylephrine infusion rate used in the study
(120 lg/min). When phenylephrine is delivered at lower infusion rates, this
technique may be superior to bolus administration. Siddik-Sayyid and col-
leagues [55] randomized patients to variable-rate phenylephrine infusions
with as-needed boluses versus rescue phenylephrine bolus only. The primary
outcome measure was the number of physician interventions to maintain
SBP within 20% of baseline. The infusion was initiated at a rate of
0.75 lg/kg/min (equating to 50 lg/min in a 70-kg parturient) immediately after
spinal injection and was titrated to maintain goal SBP parameters. The inci-
dence of hypotension was significantly lower in the infusion group, as was
the median number of required physician interventions, defined as needing
214 FICHTER & NELSON

to make any change to the infusion versus giving additional boluses. It must be
appreciated that phenylephrine bolus dosing in these studies was performed as
treatment of hypotension rather than prophylaxis. In practice, clinicians
frequently administer phenylephrine boluses in response to an increase in
maternal heart rate, preceding the expected decrease in SBP. Had the infusions
been started only after an observed hypotensive episode, the results may have
differed significantly.
As a result of ease of delivery and potential hemodynamic benefit, prophy-
lactic phenylephrine infusions have gained favor. The recommended infusion
rate ranges from 25 to 50 lg/min, as shown by multiple randomized trials as
well as a recently published international consensus statement on the manage-
ment of hypotension with vasopressors during cesarean section under spinal
anesthesia [56]. Compared with higher-dose infusions, with rates reaching 75
to 100 lg/min, low-dose rates equally maintain maternal SBP [57,58]. High-
dose infusions may be detrimental to hemodynamic homeostasis. Phenyleph-
rine at fixed rates of 100 lg/min often results in reactive hypertension with
additional physician involvement required to reduce blood pressure [58,59].
Such reactive hypertension can precipitate a baroreceptor-mediated brady-
cardia, which in turn may result in reduced maternal CO.
Investigators have recently used noninvasive monitoring to study specifically
the effects of phenylephrine on maternal CO and other hemodynamic param-
eters. Stewart and colleagues [57] used a handheld suprasternal ultrasonogra-
phy device to obtain CO measurements in women receiving different rates
of phenylephrine (25 lg/min, 50 lg/min, and 100 lg/min) after spinal anes-
thesia. CO decreased significantly with increasing phenylephrine rate, with a
maximum 22% reduction in CO in the group receiving 100 lg/min. Stroke vol-
ume remained unchanged in each group. This finding indicates that heart rate
changes provide the best indication of CO changes during cesarean delivery
under spinal anesthesia [23]. It is important to highlight that most cesarean de-
liveries during neuraxial anesthesia are performed with the use of noninvasive
blood pressure monitoring, and vasopressor choices are based on information
obtained from such routine monitors.
SBP is the hemodynamic variable most commonly used as an indicator of
adequate hemodynamic control. However, adequate SBP does not necessarily
correlate with adequate maternal CO, placental blood flow, and fetal oxygen-
ation. As shown by Stewart and colleagues [57], variable phenylephrine infu-
sion rates provide satisfactory SBP control, but higher rates result in reduced
CO. In healthy women with healthy fetuses, a small resultant decrease in
CO is unlikely to cause clinically significant effects. However, fetuses with
already compromised uteroplacental blood flow may not tolerate additional de-
creases in perfusion.
It can be concluded that although phenylephrine infusions are effective for
maintaining maternal blood pressure and provide an efficient method of vaso-
pressor administration for anesthesia providers, parturient-specific and fetal-
specific conditions must be taken into account [60]. In addition, a so-called
OPTIMAL MANAGEMENT OF HYPOTENSION 215

Goldilocks approach should be taken when using infusions, using an algorithm

as suggested in Fig. 3. A dose high enough to counteract sympathectomy-
induced vasodilation, but low enough to avoid excessive vasoconstriction
and reduced CO, should be chosen.

OTHER VASOPRESSORS
Ephedrine and phenylephrine are the dominant vasopressors in obstetric anes-
thesia. At a time when ephedrine was preferred, there was some investigation
into infusions of angiotensin II, which seemed promising because it did not
result in the tachycardia and fetal acidosis seen with ephedrine use [61].
Although angiotensin II did not gain favor, it showed the benefits of a potential
vasopressor that does not affect maternal heart rate and fetal acid-base status.
Recently, norepinephrine has shown similar promise [62,63]. Norepinephrine
exerts a strong alpha-agonist effect, helping to counteract the decrease in
SVR that accompanies spinal anesthesia. Unlike phenylephrine, it has weak
beta-adrenergic activity, which promotes positive chronotropy and maintains
maternal heart rate and CO. In the treatment of septic shock, norepinephrine
is a first-line vasopressor because of evidence showing improved regional and
global perfusion, lower lactate concentrations, and improved urine output
compared with other vasopressors, including phenylephrine [64]. Although hy-
potension induced by septic shock and spinal anesthesia differ in pathophysi-
ology, it is worth noting the potential for improved perfusion with
norepinephrine use.

Spinal block placed

Monitor SBP q1 min

Phenylephrine Infusion

Start at 25 –50 mcg/min

SBP< 80% BL, HR≥ 50 SBP Between 80 –120% BL SBP > 120% BL

PE bolus 80 – 100 mcg Con nue current rate Stop infusion. When SBP≤
120% BL, restart at rate
Increase by 20 mcg/min reduced by 20 mcg/min

SBP Remains< 80% BL If Bradycardic (HR < 50) If Bradycardic (HR< 50)

PE bolus 80 – 100 mcg and Give glycopyrrolate 0.2 – Stop infusion. When HR≥
0.4 mg IV. Con nue 50, restart at rate reduced
Increase by 20 mcg/min infusion at same rate by 20 mcg/min

Consider ephedrine 5 mg,

fluid bolus, increasing lt

Fig. 3. Phenylephrine infusion titration. Interventions based on changes in SBP every 1 minute.
Titration based on work from Refs. [55] and [104]. BL, baseline; HR, heart rate; IV, intrave-
nous; PE, phenylephrine; q, every.
216 FICHTER & NELSON

Ngan Kee and colleagues [63] first pioneered work with norepinephrine use
in the obstetric population in 2015. Using a norepinephrine to phenylephrine
potency ratio of 20:1, they randomized parturients to receive a norepinephrine
infusion, rates ranging from 0 to 5 lg/min, or a phenylephrine infusion, rates
ranging from 0 to 100 lg/min. At the time of spinal anesthesia for cesarean de-
livery, patients received a fluid coload and infusion initiation. The infusion was
regulated by a computer-controlled, closed-loop feedback system. Although no
difference in SBP control was found, patients receiving norepinephrine had
significantly greater CO over time (median 102.7% [interquartile ratio (IQR])
94.3%–116.7%] for norepinephrine vs 93.8% [85.0%–103.1%] for phenyleph-
rine, P ¼ .004, median difference 9.8%, 95% CI of difference between medians
2.8%–16.1%). In addition to providing insight into the hemodynamic benefits
of norepinephrine, this study suggested that the norepinephrine to phenyleph-
rine potency ratio is lower than 20:1, as previously thought. A potency ratio
closer to 13:1 to 16:1 has been suggested by additional work with norepineph-
rine in the obstetric population [65,66]. In comparison, administering a 100-lg
phenylephrine bolus would equate to administering a 6-lg to 8-lg norepineph-
rine bolus [66].
Subsequent work by Ngan Kee and colleagues [67] showed the efficacy of
a manually controlled variable-rate norepinephrine infusion, comparing
infusion with bolus norepinephrine use. Parturients receiving norepinephrine
via infusion had fewer episodes of hypotension (P<.001) compared
with those receiving norepinephrine via bolus technique. CO was the same
between groups; however, CO values were not available for all study partic-
ipants. Those receiving norepinephrine as an infusion received an overall
higher median rate (dose divided by time to uterine incision) of vasopressor
(2.22 lg/min vs 0.28 lg/min) compared with the bolus group. This
finding shows that, at low concentrations, at rates much lower than typically
used in the intensive care setting, norepinephrine has the potential to effec-
tively decrease the incidence of maternal hypotension during spinal
anesthesia.
Obstetric anesthesia providers have expressed some concern regarding
norepinephrine use in the obstetric population [62]. This concern arises from
systematic reviews and case reports documenting varying degrees of tissue
injury following peripheral administration of norepinephrine [68]. However,
patients included in these reviews are often septic, have coexisting vascular dis-
ease, and require high doses of vasopressor to maintain perfusion. As such,
norepinephrine use in healthy parturients is hardly comparable with use in crit-
ically ill patients. In addition, norepinephrine used in obstetric studies is formu-
lated in dilute concentrations (5 lg/mL) and is administered at rates much
lower than those typically given in the intensive care setting [65,67]. As Car-
valho and Dyer [62] suggest, norepinephrine is a promising vasopressor for
the management of hypotension during spinal anesthesia. However, before cli-
nicians undergo another paradigm shift in the choice of vasopressor use for
OPTIMAL MANAGEMENT OF HYPOTENSION 217

cesarean delivery, additional studies will need to confirm norepinephrine’s

maternal and fetal safety.

FLUID MANAGEMENT
There has been a paradigm shift from ephedrine to phenylephrine use and
bolus phenylephrine to infusion phenylephrine use. Fluid type and timing of
delivery has also been subject to shifting practice, based on studies of crystal-
loid versus colloid and fluid preload versus coload. A fluid preload has typi-
cally been defined as a bolus of intravenous fluid, ranging from 1 to 2 L,
delivered 10 to 20 minutes before spinal anesthesia [69]. A coload is a fluid vol-
ume administered immediately after induction of neuraxial anesthesia, and
typically completed within 5 minutes [70–72].

PRELOAD VERSUS COLOAD: CRYSTALLOID

Traditional prevention of hypotension during spinal anesthesia supported the
use of crystalloid preloading, but studies have failed to show any benefit
from this practice [29]. The reason behind this is likely 2-fold. First, crystalloid
solutions redistribute from the intravascular to interstitial space within a short
period of time. Following a 10-minute infusion of lactated Ringer, less than 50%
of the solution is retained with the central compartment at 30 minutes postin-
fusion [73]. Using indocyanine green concentration to measure blood volume,
Ueyama and colleagues [74] showed that only 28% of a lactated Ringer preload
infused over 30 minutes remained intravascularly at the end of this half hour. If
a preload crystalloid volume is given, by the time a patient experiences
sympathectomy-mediated spinal hypotension, most of the crystalloid has
already left the intravascular space. Crystalloid preload thus fails to provide
additional intravascular volume at the time when it is required to prevent hy-
potension. Second, any volume load results in atrial stretch, stimulating release
of atrial natriuretic peptide (ANP). When a preload is administered, the result-
ing ANP release induces peripheral vasodilatation and fluid excretion, leading
to decreased available intravascular volume coinciding with hypotension from
an evolving spinal block [75]. In contrast, coloading provides additional intra-
vascular volume at the time of maximal vasodilatation. When administered
concurrently with vasopressors, such as a phenylephrine infusion, a crystalloid
coload results in a significantly lower incidence of hypotension (incidence 1.9%
[95% CI, 0.3%–9.9%] in phenylephrine/coload group vs 28.3% [95% CI,
18.0%–41.6%] in phenylephrine/minimal fluid maintenance group,
P ¼ .0001) [59].

PRELOAD VERSUS COLOAD: COLLOID

Colloid coloading has failed to show the benefits found from crystalloid coload-
ing [76]. Colloid preloading has been proposed to increase intravascular vol-
ume at a time coinciding with spinal sympathectomy and hypotension better
than coloading. Hydroxyethyl starch 6% (HES) has been the most commonly
studied colloid in obstetric literature [27,70–72,77–79]. HES and other colloids,
218 FICHTER & NELSON

such as dextrans, gelatins, and albumin, are large molecules that increase intra-
vascular oncotic pressure and effectively retain plasma volume longer than
crystalloid solutions. At 30 minutes after preload with 1.0 L of HES, 100%
of colloid has been found to remain within circulation [74]. In a study of 26
parturients undergoing spinal anesthesia for elective cesarean delivery, a 1.0-
L HES preload resulted in a significantly lower incidence of hypotension
compared with administration of 0.5 L-HES and 1.5-L lactated Ringer preload
[74]. When giving HES as a coload, investigators have shown no benefit
compared with preloading [70,71]. Other than a significant increase in cardiac
output 5 minutes after spinal following an HES preload, Teoh and Sia [70]
found no difference in CO at further time points and no difference in SBP at
any time. Siddik-Sayyid and colleagues [71] confirmed these results, finding
no difference in the incidence of hypotension, severe hypotension (defined as
SBP<80 mm Hg), or total amount of vasopressor required following spinal
anesthesia. The lack of observed hemodynamic benefit from preloaded HES
may be explained again by the release of ANP. Any potential increase in
plasma volume from colloid administration may be offset by resultant vasodi-
lation and natriuresis.

VARIED FLUID PRELOADING VERSUS COLOADING

COMBINATIONS
Additional studies have investigated the effects of various combinations of fluid
type and timing. Tamilselvan and colleagues [78] conducted a double-blind,
randomized controlled study of the hemodynamic impact of fluid type given
before spinal anesthesia for elective cesarean delivery. A crystalloid solution
(Hartmann solution) 1.5 L or 6% HES 0.5 or 1.0 L were delivered 30 minutes
before combined spinal-epidural anesthesia. Cardiac parameters were
measured with the use of suprasternal ultrasonography throughout this period.
Although there was no significant difference in the incidence of hypotension be-
tween fluid groups, the study was underpowered for this specific outcome.
However, CO remained significantly higher than baseline in the 20 minutes
postspinal only in the group receiving HES 1.0 L [78]. For elective cesarean de-
liveries, clinicians potentially have time to preload patients a half hour before
anesthesia. However, this approach is impractical for the large percentage of
cesarean deliveries that are unplanned. Coloading can be given quickly and
can help deliver concurrently administered vasopressors. McDonald and col-
leagues [72] randomized patients to a coload of HES 1.0 L or Hartmann solu-
tion in addition to a phenylephrine infusion set at 100 lg/min, initiated at the
time of spinal injection. Postspinal, the incidence of hypotension was the same
between groups and there were no between-group differences in CO. When
given as a coload, colloid likely has no advantage over crystalloid.
When given as a preload, colloids may confer some benefit over crystalloid.
However, HES 6% (hetastarch), the colloid most researched in the obstetric
literature, is no longer routinely available and so future research endeavors
will need to study the potential benefits of colloid alternatives. For example,
OPTIMAL MANAGEMENT OF HYPOTENSION 219

human albumin has not been extensively studied in the obstetric population
but may be a viable colloid option for hypotension management and an area
for future research. In the interim, hypotension during spinal anesthesia can
be efficiently and effectively managed with a 1-L to 2-L crystalloid coload, initi-
ated at the time of spinal block placement and administered over approxi-
mately 5 minutes. Not only does this increase intravascular volume at the
time of maximal sympathectomy but it facilitates the delivery of concurrently
given vasopressors.

SEROTONIN ANTAGONISTS
Although the major cause of hypotension following spinal anesthesia is sec-
ondary to sympathetic blockade, the Bezold-Jarisch reflex (BJR) may also
contribute to cardiovascular instability. This reflex causes a triad of vasodila-
tion, bradycardia, and hypotension [79]. Stimulation of receptors in the ven-
tricular walls (mechanoreceptors and chemoreceptors) has been implicated in
the BJR. In response to decreased venous return, intracardiac mechanorecep-
tors are stimulated, resulting in cardiac afferent fiber activation and brady-
cardia. Such bradycardia may be protective, enabling increased diastolic
filling time during a period of reduced preload [80]. Chemoreceptors re-
sponding to 5-hydroxytryptamine3 (5-HT3 [serotonin]) also contribute to
the BJR, as shown by inhibition of the reflex with the use of 5-HT3 antago-
nists in animal models [81,82]. Animal model results have subsequently been
replicated in humans. Results from 2 recent meta-analyses suggest that the
use of prophylactic 5-HT3 receptor antagonists reduces the incidence of hy-
potension during spinal anesthesia [83,84]. Both meta-analyses included ran-
domized controlled trials from the obstetric and nonobstetric populations.
Subgroup analyses on the obstetric populations showed significantly lower in-
cidences of hypotension, bradycardia, and nausea/vomiting. For the preven-
tion of hypotension and bradycardia, the number needed to treat was 5.3 and
7.6, respectively [83]. Ondansetron was the most frequently used 5-HT3
antagonist; however, granisetron was given in one obstetric randomized
controlled trial.
Although it seems that 5-HT3 antagonists play a role in the prevention of
spinal-induced hypotension, there is a large amount of heterogeneity and
some degree of publication bias within these analyses [84]. The high heteroge-
neity was related to the differences in spinal medication, vasopressor use, and
fluid management. Half of the obstetric trials included in the Heesen and col-
leagues[83] analysis used ephedrine as the pressor of choice, making such re-
sults less applicable to recommended practice with phenylephrine use. A
recent study by Karacaer and colleagues [85] investigated the effect of ondan-
setron as part of an anesthetic that more fully embraces current accepted prac-
tice. Patients scheduled for elective cesarean delivery received a crystalloid
coload and norepinephrine 5-lg boluses for refractory hypotension. A prophy-
lactic 8-mg dose of ondansetron compared with saline placebo did not reduce
220 FICHTER & NELSON

the incidence of hypotension. However, it did result in a significantly lower

requirement for norepinephrine (P ¼ .009).
Should all parturients undergoing spinal anesthesia for cesarean delivery
receive 5-HT3 antagonists? There are not enough prospective data to conclude
that higher doses (eg, 8 mg of ondansetron) of 5-HT3 antagonists prevent hy-
potension during spinal anesthesia for cesarean delivery. With regard to
administering 4 mg of ondansetron, providing such low doses is unlikely to
cause harm and may help prevent maternal nausea and vomiting during spinal
anesthesia for cesarean delivery [83,84].

LOWER EXTREMITY MANIPULATION

The goal of lower extremity manipulation, via leg compression or elevation, is
to increase venous return to the central circulation following spinal-induced
sympathectomy [86]. Studies have investigated lower extremity elevation and
various methods of mechanical compression, including elastic bandages,
sequential compression devices, and thromboembolic deterrent stockings, to
prevent hypotension following spinal anesthesia [87–91]. Of these studies,
Rout and colleagues [91] enrolled one of the largest groups of parturients.
They randomized 97 parturients undergoing elective cesarean delivery with
spinal anesthesia to 1 of 3 interventions: leg elevation to 30 , leg elevation
plus wrapping with elastic bandages, or no elevation with sham bandages
(control). Compared with the control group, the leg-wrapped group showed
a 5-fold decrease in the incidence of hypotension (odds ratio [OR], 5.3; 95%
CI, 1.7–16.3). Leg elevation seemed to have no influence on hypotension.
Although other investigators have shown similar moderate success with
lower extremity manipulation, the benefit remains controversial. A recent Co-
chrane Review analyzed 11 studies with a total of 705 women, comparing
lower limb compression with control. Compression prevented hypotension af-
ter spinal anesthesia with an average RR of 0.61 (95% CI, 0.47–0.78;
I2 ¼ 65%); however, the review deemed the evidence as overall very low qual-
ity [92]. In addition, many of the included studies used fluid preloading and
ephedrine as the primary vasopressor, making them less comparable with rec-
ommended practice. Kuhn and colleagues [93] addressed this issue by perform-
ing a randomized, double-blinded, placebo-controlled study in which women
undergoing elective cesarean delivery received phenylephrine, leg wrapping,
or no treatment under spinal anesthesia. Every patient received a 1-L coload
and those randomized to phenylephrine received a 0.25-lg/kg bolus followed
by 0.25-lg/kg/min infusion at the time of spinal block. Study design included
the LiDCOplus monitor, enabling continuous hemodynamic monitoring of
CO and SVR. The phenylephrine group experienced significantly less hypo-
tension compared with the leg-wrapping and control groups. Although contin-
uous CO was reduced in those receiving phenylephrine, SVR was significantly
higher in this group. In addition, a rapid and profound reduction in SVR pre-
ceded a decrease in blood pressure in all 3 groups, confirming that a sudden
and marked arterial vasodilatation is the main hemodynamic effect of spinal
OPTIMAL MANAGEMENT OF HYPOTENSION 221

anesthesia. The decrease in SVR was only attenuated by phenylephrine, which

highlights that leg wrapping does not counteract arterial dilatation. Thus, the
prophylactic alpha-1 agonist action of phenylephrine is the more physiologic
approach to prevention of spinal-induced hypotension.
For elective, low-risk cesarean deliveries in which this is no time constraint,
lower extremity compression devices can be considered. Although they are
unlikely to significantly prevent hypotension during spinal anesthesia, leg wrap-
ping may provide some additional preload. For urgent or emergent deliveries,
leg compression is an unnecessary component of hypotension management,
given the availability of vasopressors and fluid coloading, which are more likely
to effectively and efficiently prevent and treat hemodynamic instability.

HYPOTENSION MANAGEMENT IN NONELECTIVE, HIGH-RISK

PREGNANCIES
Most studies investigating hypotension following spinal anesthesia have been
performed in low-risk parturients undergoing elective, primary cesarean deliv-
eries. As such, obstetric anesthesia has developed gold standards of hypotension
management based on healthy mothers and fetuses. It is important to question
whether such standards of care are appropriate, for example, for parturients
with cardiac disease or with growth-restricted fetuses. In a retrospective obser-
vational study of 385 parturients having spinal anesthesia for high-risk cesarean
deliveries, there was no statistical difference in fetal pH between patients
receiving ephedrine, phenylephrine, or no vasopressor for prophylaxis and
treatment of hypotension [51]. High-risk deliveries were defined as cesarean de-
liveries for pregnancy-induced hypertension, prolonged rupture of membranes,
cord prolapse, dystocia, and nonreassuring fetal heart tracings. This lack of dif-
ference in fetal pH may be caused by the lower median dose of ephedrine
administered, 12 mg (IQR, 6–18 mg) before delivery, compared with doses
given in studies of low-risk, elective cesarean deliveries [49,51,94]. Prospective,
randomized controlled trials have shown similar findings. In a study of emer-
gency cesarean deliveries under spinal anesthesia performed for acute fetal
compromise, Jain and colleagues [95] showed no difference in fetal acidosis be-
tween women receiving ephedrine or phenylephrine (umbilical artery pH <7.2,
31.1% in ephedrine group and 20% in phenylephrine group; P ¼ .22).
The lack of difference in fetal acidosis between parturients receiving ephed-
rine and phenylephrine may also be explained by the fact that many women
undergoing nonelective cesarean deliveries are laboring. The earliest study
describing this effect was performed by Clark and colleagues [96]. They found
that healthy women in early labor undergoing cesarean delivery with spinal
anesthesia had a significantly lower rate of hypotension compared with nonla-
boring women (P<.05). It was proposed that uterine contractions delivering
additional blood volume to the central compartment contributed to this effect.
Patients with hypertensive disorders of pregnancy have also been shown to
require less vasopressor for the treatment of hypotension from spinal anesthesia
[97]. Studies within this patient population are limited, but evidence from
222 FICHTER & NELSON

prospective trials shows this association. Aya and colleagues [98] performed the
first study of the incidence of spinal-induced hypotension in preeclamptic
compared with healthy parturients. They showed a significantly lower risk of hy-
potension in patients with preeclampsia with severe features undergoing spinal
anesthesia for scheduled cesarean delivery compared with normotensive parturi-
ents (OR, 0.17; 95% CI, 0.05–0.58; P ¼ .006) and proposed that this is caused by
the underlying pathophysiology of the disease. Preeclampsia results in altered
vascular endothelium, decreased vascular tone regulation, and increased sympa-
thetic activity [99,100]. As a result, preeclamptic patients may be less susceptible to
the sudden decrease in sympathetic tone related to spinal anesthesia.
For preeclamptic patients, clinicians can expect to see less hypotension dur-
ing spinal anesthesia and potentially a greater effect from vasopressor use. As
Sharwood and colleagues[101] also proposed, preeclamptic patients are less
dependent on sympathetic output and are potentially more sensitive to sympa-
thomimetic medications. Should preeclamptic patients require vasopressor sup-
port, either phenylephrine or ephedrine can be considered, with care taken to
carefully titrate so as not to cause iatrogenic hypertension. Fluid delivery in this
patient population should also be conservative. Preeclamptic patients are less
likely to require a 1-L to 2-L crystalloid coload and delivery of such fluid
may potentially lead to volume overload.

SUMMARY AND FUTURE DIRECTIONS

Over the past several decades, the subspecialty of obstetric anesthesia has wit-
nessed a progressive evolution in the management of hypotension with spinal
anesthesia during cesarean delivery. The work of dedicated researchers has
provided insight into the pathophysiology, the consequences, and the optimal
prevention and treatment of maternal hypotension. Current recommended
practices for the prevention of hypotension during spinal anesthesia are out-
lined in Fig. 4. Such practices include administration of 1 to 2 L of crystalloid

Fig. 4. Management techniques for prevention of hypotension under spinal anesthesia. Code
color represents level of recommended implementation: red, high; green, moderate; blue, low.
LE, lower extremity; SCD, sequential compression device.
OPTIMAL MANAGEMENT OF HYPOTENSION 223

as a coload (or 500 mL of 0.5-L to 1.0-L colloid preload, time permitting) and
initiation of a phenylephrine infusion of 25 to 50 lg/min at the time of spinal
block placement. Lateral tilt may or may not be used, depending on the pres-
ence of preexisting supine hypotension of pregnancy and the response to the
measures discussed earlier, keeping in mind that there are few disadvantages
to continuing the practice of routinely tilting parturients [102–104]. The treat-
ment of hypotension should include vasopressor infusion titration to maintain
SBP near baseline, while ensuring that reactive hypertension does not occur.
Although conventional management prevents and treats hypotension in
most patients, clinicians should continue to strive for successful management
in every patient. Future work will help to fine tune the current standard prac-
tice. Such fine-tuning is likely to include methods to maintain maternal CO
rather than SBP, given evidence that placental blood flow depends more on
CO than systolic pressure [23]. The advent of minimally invasive and nonin-
vasive cardiac monitoring, such as LiDCOplus, thoracic bioimpedance, and
suprasternal cardiac ultrasonography, and their validation in the obstetric pop-
ulation, have provided the opportunity to continuously monitor maternal CO.
The growth of point-of-care ultrasonography will also make it possible to titrate
fluids and vasopressors based on cardiac filling and function. Perhaps 5-HT3
antagonists will be shown to provide consistent additional benefit, particularly
in patients who may be susceptible to the BJR following spinal anesthesia.
Norepinephrine infusions might become routinely adopted as concerns
regarding the safety of peripheral intravenous administration are fully ad-
dressed. Obstetric anesthesia is entering an era in which delivery of care
will not only be further optimized but individualized for each mother and
her baby.

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