Accepted Manuscript

Spinal induced hypotension: incidence, mechanisms, prophylaxis and management:

summarizing 20 years of research

Jennifer Lee, MD, MPH, Ronald B. George, MD, FRCPC, Ashraf S. Habib, MBBCh,
MSc, MHSc, FRCA

PII: S1521-6896(17)30001-0
DOI: 10.1016/j.bpa.2017.01.001
Reference: YBEAN 927

To appear in: Best Practice & Research Clinical Anaesthesiology

Received Date: 14 November 2016

Revised Date: 20 December 2016
Accepted Date: 2 January 2017

Please cite this article as: Lee J, George RB, Habib AS, Spinal induced hypotension: incidence,
mechanisms, prophylaxis and management: summarizing 20 years of research, Best Practice &
Research Clinical Anaesthesiology (2017), doi: 10.1016/j.bpa.2017.01.001.

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 ACCEPTED MANUSCRIPT

Spinal induced hypotension: incidence, mechanisms, prophylaxis and management:

summarizing 20 years of research

Jennifer Lee,1 MD, MPH

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1
Duke University Medical Center, Durham, NC, USA

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Ronald B George,2 MD, FRCPC

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2
Dalhousie University, IWK Health Centre, Halifax, NS, Canada

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Ashraf S Habib,1 MBBCh, MSc, MHSc, FRCA
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Duke University Medical Center, Durham, NC, USA
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Corresponding Author
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Ashraf S Habib, MBBCh, MSc, MHSc, FRCA

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Duke University Medical Center,

Box 3094
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Durham, NC 27710
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Tel: 919 668 2024

Fax: 919 681 4698

Email: habib001@dm.duke.edu

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Abstract

Hypotension occurs commonly in parturients undergoing cesarean delivery under spinal

anesthesia. This leads to maternal and neonatal adverse outcomes, including maternal nausea and

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vomiting, fetal acidosis and might even lead to cardiovascular collapse if untreated. Arterial

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dilatation and reduction in systemic vascular resistance are the major contributors to spinal

induced hypotension. Therefore, strategies aimed at expanding the intravascular volume with

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fluid loading, or increasing venous return with lower extremities mechanical compression and

lateral tilt, have had limited effectiveness in the management of spinal induced hypotension.

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Vasopressors are therefore the mainstay for the prophylaxis and treatment of spinal induced
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hypotension. Phenylephrine is associated with improved neonatal acid base status and a lower

risk of maternal nausea and vomiting, and is now considered the vasopressor of choice in
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obstetric patients. This review discusses the various strategies for managing spinal induced
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hypotension with a particular emphasis on the optimal use of vasopressors.

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Keywords: Spinal anesthesia, hypotension, vasopressors, fluid therapy.

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Spinal anesthesia is often the modality of choice for cesarean delivery. It is an effective

anesthetic that avoids the risks of general anesthesia in parturients with potentially difficult

airways. However, a reliable spinal block has predictable undesirable consequences including

maternal hypotension leading to nausea and vomiting, decreased uteroplacental blood flow, and

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fetal acidosis. In South Africa, more than half of the anesthetic deaths in 2011-2013 were related

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to spinal hypotension.1 Much research over the last twenty years has improved the management

of these adverse sequelae of spinal anesthesia, and yet they remain a persistent challenge to the

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anesthesia provider. The incidence of hypotension depends on the definition used,2 and on the

dose of intrathecal local anesthetics administered.3 Klohr and colleagues reported that 15

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different definitions of hypotension were used in the literature.2 With the most commonly used
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definition of a 20% drop from baseline blood pressure, an incidence of 70-80% is reported.4
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Over the last two decades, significant changes have occurred in the management of spinal
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induced hypotension in the parturient. This review will summarize various strategies that have
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been investigated over the years including fluid loading, vasopressors, and other methods such as

mechanical lower extremity compression, positioning and 5HT3 receptor antagonists. We will
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also discuss the mechanisms of hypotension and suggest areas for further study.
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Mechanisms of Spinal-Induced Hypotension

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Aortocaval compression was first indicted as a cause for maternal hypotension over fifty

years ago. Described in 1957, the theory poses that the gravid uterus compressing the great

vessels against the lumbar vertebral bodies impedes the return of blood from the vena cava

resulting in decreased cardiac output.5 Compression of the aorta also impedes perfusion to the

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uteroplacental unit. Alternately, an early study from the 1940s suggested that 16 to 20% of

blood volume can be redistributed after spinal blockade to the lower extremities contributing to

its hypotensive effect.6 Both mechanisms were thought to result in a reduction in central venous

pressure, leading to a reduction in cardiac output and resulting in hypotension. Therefore, the

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mainstay of therapy included increasing venous pressure with fluid loading, enhancing venous

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return with leg wrapping and avoiding aortocaval compression with left uterine displacement.

However, as will be discussed in this review, those strategies were only minimally effective,

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which challenged the notion that a reduction in cardiac output secondary to those mechanisms is

the major factor leading to spinal induced hypotension. In fact, recent studies assessing

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hemodynamic parameters have shown that cardiac output, heart rate and stroke volume increase
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in the first 15 minutes following initiation of spinal anesthesia.7,8 Concomitantly, a significant

decrease in systemic vascular resistance occurs,7 highlighting the fact that loss of arteriolar tone
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is likely the main mechanism leading to hypotension.9 Therefore, vasopressors are currently
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identified as the mainstay for the management of spinal induced hypotension.

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Management Strategies
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Low dose spinal anesthesia

The risk of hypotension is related to the dose of intrathecal bupivacaine. Several authors
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have described that low dose spinal anesthesia for cesarean delivery, using doses of 5-7 mg
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intrathecal bupivacaine, results in in a smaller degree of sympathectomy, vasodilation, and

hemodynamic changes, including hypotension.10 While a smaller dose of intrathecal bupivacaine

reduces the risk of hypotension and the ensuing nausea and vomiting, it increases the need for

intraoperative analgesic supplementation.3 It also results in a shorter duration of block and a

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slower speed of onset.11 The combined-spinal epidural technique (CSE), which provides the

option to augment the block with the epidural catheter if needed, should therefore be used if a

low dose spinal anesthesia is planned. This allows the administration of epidural local anesthetics

to supplement or prolong a block produced by a low intrathecal bupivacaine dose if needed.

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Roofthooft and Van de Velde recommend prophylactic epidural top-ups if uterus is not closed at

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45 minutes after low dose spinal injection to prevent breakthrough pain.10 Some also deliberately

administer a low spinal dose with the expectation of extending the block with epidural local

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anesthetics, a technique that is often described as low dose sequential CSE.12 Alternatively, the

level of the block after low dose spinal anesthesia can be extended in a cephalad direction with

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normal saline administered epidurally shortly after spinal injection, a technique that has been
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labeled epidural volume extension or epidural volume expansion.13 The mechanism of this action

is most likely from the compression of the subarachnoid space, which results in rostral spread of
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the local anesthetic in the intrathecal space. The reliability of this technique has however been
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challenged. Furthermore, the optimal intrathecal dose, epidural solution volume and timing for
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supplementation remain unclear.11

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Positioning
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Numerous studies investigated the impact of patient position on the risk of spinal induced
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hypotension. A Cochrane review14 found no difference in the risk of hypotension between left

lateral tilt, right lateral tilt, a right lumbar pelvic wedge and head down tilt when compared with

the supine position. The review also found no impact of the degree of lateral tilt on the risk of

hypotension. However, the risk of hypotension was lower with left lateral tilt compared with

right lateral tilt, and with manual displacement compared with left lateral tilt. There were no

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statistically significant differences in maternal heart rate, Apgar scores, or neonatal acid base

status when comparing different positions. The risk of hypotension remains however high with

all positions, and additional measures are clearly needed.

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Mechanical Lower Extremity Compression/Elevation

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Mechanical compression of the lower extremities has been studied as a mechanism to

improve the venous return to central circulation. Various mechanical compression devices or

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strategies including leg elevation, hip flexion, elastic compression bandages, thromboembolic

deterrent stockings, and sequential compression devices have had mixed results.15-17 A Cochrane

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review including 7 trials with 399 women reported that lower limb compression was more
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effective than control (RR 0.69, 95% CI 0.53 to 0.90) in the prevention of hypotension, but the

studies were small with methodological limitations.18 Most recently, a study in Norway sought to
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compare the effect of low-dose phenylephrine infusion (0.25 µg/kg bolus followed by an
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infusion at 0.25µg/kg/min) with lower extremity compression and with placebo on blood
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pressure in women undergoing cesarean delivery under spinal anesthesia.19 They found that

phenylephrine was superior to compression, however, compared with no intervention,

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compression of the lower extremities was associated with a smaller decrease in mean arterial

pressure. Interestingly, the reduction in systemic vascular resistance was only countered by
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phenylephrine and not leg wrapping, suggesting that arterial vasodilation played the predominant
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role in spinal-induced hypotension, while enhancing venous return was only minimally effective.

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Fluid therapy

Historically, fluid therapy has been the traditional approach for managing spinal-induced

hypotension with the goal of expanding the intravascular volume. Studies have examined type of

fluid (crystalloid versus colloid), timing of fluid administration (preload prior to block versus co-

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load during and after block replacement), and optimal fluid volumes. For several decades,

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preloading with a crystalloid bolus was the mainstay of therapy. However, several studies have

demonstrated that preloading is not an efficacious strategy.20,21 It is thought that due to short

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intravascular half-life, the fluid is quickly redistributed out of the intravascular space before any

spinal induced hemodynamic changes occur. Furthermore, atrial natriuretic peptide release with

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subsequent vasodilatation may contribute to the limited effectiveness of this approach.22 It was
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therefore theorized that it may be more effective to co-load with crystalloid fluid during and

immediately following spinal block, effectively increasing intravascular volume at the time of
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vasodilation following sympathetic block.23 This co-loading technique was examined by Dyer et
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al. in 2004, who found that it resulted in a significant reduction in ephedrine requirements when
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compared with preloading.24 However, a meta-analysis completed in 2010 by Banerjee et al. that

included eight randomized controlled trials (518 total patients) comparing pre-loading to co-
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loading, including the previously mentioned trial by Dyer et al., found that there was no

statistically significant difference in the incidence of hypotension between the two fluid loading
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strategies.25
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Studies have shown that colloid solutions may offer advantages over crystalloid solutions

in reducing spinal induced hypotension.26,27 In a recent meta-analysis, Ripolles et al. found that

the use of colloids, given either as a preload or a coload, is associated with significantly reduced

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rates of hypotension when compared with crystalloids.28 It is thought that colloids are better

retained within the intravascular space, allowing for increased and sustained intravascular

volume expansion compared to crystalloids.29 As expected, there is no difference between

preloading and coloading strategies with regards to their efficacy in reducing the risk of spinal

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induced hypotension.25 The use of dextran and gelatin containing colloid solutions is however

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associated with a risk of allergic reaction, though the risk is greatly reduced with the use of

hydroxyethyl starch (HES).30 Still, there are safety concerns with the use of hydroxyethyl starch

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due to previous studies linking colloids to renal failure and mortality in the critically ill,31,32

however, there is little evidence of similar adverse events in cesarean delivery patients.

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To date, no studies have found that fluid administration alone eliminates hypotension, despite

demonstrating increases in cardiac output with fluid loading.33 While fluid loading expands the
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intravascular space, the incidence of hypotension remains high. This is further evidence that
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arterial dilation may contribute more significantly to hypotension, and thus a need for
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vasopressor therapy is evident.

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Vasopressors

Given the limited efficacy of fluid loading strategies, vasopressors have emerged as the
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preferred therapy for spinal-induced hypotension. After spinal anesthesia, there is a fall in mean
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arterial pressure and a marked reduction in systemic vascular resistance, despite increase in

cardiac output, heart rate and stroke volume in the first 15 minutes after induction of spinal

anesthesia,7,8 even after fluid therapy.33 Constriction of the arterial vessels is therefore the

optimal strategy to manage spinal induced hypotension.

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Animal Studies:

For several decades, ephedrine was the drug of choice to treat spinal-induced

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hypotension. This preference was based on several animal studies that investigated the effect of

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ephedrine, an indirect α and β agonist, and pure α agonists such as phenylephrine on the

vasoconstriction of the uterine vascular bed. For instance, Greiss reported that while

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phenylephrine and norepinephrine corrected hypotension associated with spinal anesthesia in

pregnant sheep, they caused significant uterine vessel vasoconstriction to negate the impact of

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increased blood pressure on uterine blood flow.34 James also investigated the impact of
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administration of ephedrine and mephentermine (α and β agonists) and methoxamine (pure α

agonist) in 14 pregnant ewes who received a general anesthetic followed by a spinal anesthetic.
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They reported that while all three vasopressors were effective in correcting hypotension induced
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by spinal anesthesia, uterine blood flow was significantly higher with ephedrine and
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mephentermine compared with methoxamine.35 Ralston administered ephedrine, mephentermine,

methoxamine and metaraminol to 16 non-anesthetized ewes, and reported no reduction in uterine

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blood flow with ephedrine when the blood pressure was increased by 50%, whereas it was

reduced by 45% and 62% with methoxamine and metaraminol respectively.35

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Human studies:

Based on data from animal studies, ephedrine was considered the vasopressor of choice

in obstetric patients. There are however some limitations associated with the use of ephedrine. It

has a relatively slow onset of action and repeated administration can be associated with

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tachyphylaxis.36 Furthermore, because the response to spinal anesthesia includes an initial

increased heart rate and cardiac output, a beta-adrenergic agonist may not be the ideal

therapeutic choice. The efficacy of IV ephedrine for prophylaxis against hypotension is also

limited. Ngan Kee found that while a 30 mg dose of ephedrine given 1 minute after spinal

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anesthesia was more effective than the 10 or 20 mg doses (incidence of hypotension 35%, 95%

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and 85% respectively), it was associated with a high incidence of reactive hypertension (45%),

with no difference in the incidence of maternal nausea, vomiting, or neonatal acid-base status

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between the groups.37

Neonatal Outcomes:
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In the 1980’s and 1990’s, researchers revisited the use of direct α agonists, mainly

phenylephrine, for the management of spinal induced hypotension in humans. Those studies
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focused on neonatal outcomes, mainly neonatal acid-base status and Apgar scores. Multiple
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studies reported that phenylephrine and other α agonists could be used safely in this patient
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population. Interestingly, neonatal acid-base status was better with phenylephrine when

compared with ephedrine. A meta-analysis of seven of those studies published in 2002 reported
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no difference between the two vasopressors in the incidence of hypotension, but found lower

umbilical artery pH with ephedrine compared to phenylephrine [mean difference (95% CI)= 0.03
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(0.02-0.04)].38 A more recent meta-analysis also reported a five-fold increase in the risk of fetal
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acidosis (defined as pH<7.2) and larger base deficit [mean difference (95% CI)= -1.17 (-2.01, -

0.33) with ephedrine compared to phenylephrine.39 Notably however, Apgar scores were not

different with ephedrine compared to phenylephrine. Ngan Kee investigated the etiology of fetal

acidosis associated with ephedrine administration.40 Women undergoing elective cesarean

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delivery were randomized to receive a prophylactic ephedrine or phenylephrine infusion, titrated

to maintain blood pressure at baseline. The authors found that ephedrine crossed the placenta to a

much greater extent than phenylephrine, as indicated by a higher median umbilical

venous/maternal arterial plasma concentration (1.13 vs. 0.17). Both arterial and venous umbilical

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pH were lower with ephedrine, PCO2 was higher, and concentrations of lactate, glucose,

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epinephrine and norepinephrine were greater compared with phenylephrine, secondary to

metabolic effects of fetal β adrenergic stimulation. Similar findings were also reported in

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previous studies.41,42

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Ultrasound evaluation of uteroplacental perfusion:
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Due to concerns about uteroplacental vasoconstriction with α agonists, a few studies

evaluated changes in uterine artery pulsatility index, a measure of vascular resistance, associated
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with the administration of ephedrine and α agonists. Alahuhta et al. reported an increase in
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uterine and arcuate artery pulsatility index with phenylephrine compared with ephedrine. There
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was no change in fetal umbilical artery pulsatility in either group, and a decrease in fetal renal

arteries pulsatility index with phenylephrine.43 On the other hand, Ngan Kee found no difference
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in uterine artery pulsatility index measured for 10 minutes after spinal anesthesia in women

receiving ephedrine or metaraminol infusions titrated for hemodynamic management during

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cesarean delivery.44 Similar findings were reported by Hall and colleagues who measured uterine
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artery pulsatility index for 15 minutes after spinal placement and treated spinal induced

hypotension with boluses of ephedrine 5 mg or phenylephrine 100 µg.45

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Intraoperative Nausea and Vomiting:

Studies comparing phenylephrine with ephedrine have also reported a lower incidence of

intraoperative nausea and vomiting with phenylephrine administration compared with ephedrine.

This was the case when the vasopressors were used to treat established hypotension,46,47 as well

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as in studies where the vasopressor infusion was initiated prophylactically.40,41,48 This could be

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related to the more rapid onset of action of a phenylephrine bolus compared to an ephedrine

bolus, leading to quicker correction of hypotension.4 When using a prophylactic infusion, the

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increased risk of intraoperative nausea and vomiting with ephedrine might be related to the reflex

increase in vagal tone following reduction of preload in the presence of β adrenergic stimulation,

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whereas phenylephrine might reduce this risk by producing more effective venoconstriction and
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therefore better maintaining preload.41
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Optimization of phenylephrine administration:

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Since phenylephrine was associated with improved neonatal acid base status and
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increased intraoperative maternal comfort compared with ephedrine, research started to focus on

optimizing the administration of this vasopressor for the management of spinal induced
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hypotension. Due to its rapid onset and short half-life, phenylephrine seemed to be an ideal agent

for titration of treatment and prophylaxis of spinal-induced hypotension.

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Prophylactic versus rescue administration of phenylephrine:

Ngan Kee compared a fixed-rate prophylactic phenylephrine infusion regimen (100 µg

/min initiated after spinal placement and maintained for 3 minutes, then switched off for systolic

blood pressure > 100 % of baseline) to a 100 µg phenylephrine bolus given for the treatment of

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hypotension defined as a systolic blood pressure < 80 % of baseline.49 The incidence (23% vs.

88%), frequency and magnitude of hypotension were significantly lower in the phenylephrine

infusion group. Intraoperative nausea and vomiting were also numerically less frequent with the

prophylactic phenylephrine infusion (4% vs. 21%), with no difference in umbilical cord gases or

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Apgar scores between the groups. Similarly, Das Neves reported a lower incidence of

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hypotension (18% vs. 85%) and intraoperative nausea (10% vs. 40%) when comparing a

prophylactic phenylephrine infusion (0.15 µg/kg/min) with 50 µg phenylephrine boluses to treat

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a 20% drop in blood pressure.50 Allen also found a higher incidence of predelivery hypotension

in patients who received 100 µg phenylephrine boluses for the treatment of established

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hypotension, compared to those who received a fixed-rate phenylephrine infusion of 25, 50, 75
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or 100 µg/min (80% vs. 30%, 15%, 11% and 0% respectively). There was however no difference

in the incidence of intraoperative nausea and vomiting, umbilical cord gases, or Apgar scores.51
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Using a variable-rate phenylephrine infusion initiated at 0.75 µg/kg/min, Siddik-Sayyid found a

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lower incidence of hypotension (20% vs. 90%), and of intraoperative nausea and vomiting (10%
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vs. 44%) compared to treatment of established hypotension with 100 µg phenylephrine boluses,

with no difference in umbilical cord gases or Apgar scores between the groups.52 The incidence
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of reactive hypertension was however higher with prophylactic infusions in all those studies.
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Optimum dosing of phenylephrine boluses:

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Very few studies investigated dosing of phenylephrine boluses for the management of

spinal induced hypotension. Using an up-down sequential allocation study design, Tanaka et. al

found that the ED95 (95% CI) of a prophylactic phenylephrine bolus to prevent hypotension or

nausea following spinal anesthesia with 12 mg bupivacaine was 159 (122, 371) µg.53 On the

other hand, George and colleagues determined that the ED90 (95% CI) of a phenylephrine bolus

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for treating established hypotension following spinal anesthesia with 12 mg hyperbaric

bupivacaine was 147 (98, 222) µg.54 While the two studies reported doses that are generally

higher than those used in previous studies, it is worth noting that they investigated the first dose

needed following spinal injection while the sympathectomy is evolving, and did not investigate

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doses needed to manage hypotension after this initial stage.

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Optimization of phenylephrine infusion regimens:

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With the improved outcomes reported with prophylactic phenylephrine infusions

compared with the use of phenylephrine boluses for the treatment of established hypotension,

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researchers looked at optimizing those prophylactic regimens. Ngan Kee investigated the impact
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of adding a fluid coload to the fixed rate phenylephrine infusion regimen of 100 µg/min

(described above), and reported a reduction in the incidence of hypotension from 28% in the
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group receiving fluids at maintenance rate to 2 % in the group receiving a 2 L lactated Ringer’s

coload, with a concomitant decrease in phenylephrine consumption.55 The same group

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investigated the optimal blood pressure target when using their fixed rate 100 µg/min
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prophylactic phenylephrine infusion regimen.56 After running the infusion for 2 minutes

following spinal placement, the infusion was maintained if systolic blood pressure was below
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100%, 90% or 80% of baseline but stopped if it exceeded those targets. There was a significant
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reduction in the incidence of intraoperative nausea or vomiting when blood pressure was
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maintained at 100% of baseline, compared to the 90% and 80 % targets (40% vs. 16% vs. 4%).

Umbilical artery pH was also higher in the 100% group compared to the other two groups,

however the difference was small and likely not clinically relevant.

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Closed-loop feed back control:

A number of researchers investigated the use of closed loop feed back computer

controlled systems for vasopressor administration in the management of spinal induced

hypotension. Ngan Kee initially described the use of a simple on-off algorithm using a

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phenylephrine infusion of 100 µg/min.57 Subsequently, this group investigated a variable rate

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phenylephrine infusion regimen using a proportional algorithm that administered phenylephrine

at rates ranging from 0 to100 µg/min using a computer controlled feed back system, and

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compared it with their previously described on-off fixed regimen of 100 µg/min. A non-invasive

blood pressure measurement was obtained every minute. The computer controlled variable rate

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system was associated with fewer physician interventions needed to maintain blood pressure in
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the target range, and resulted in slightly better blood pressure control, but without difference in

hypotension, reactive hypertension, or nausea and vomiting.58

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Sng et al. investigated a closed-loop automated system for the treatment of established
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hypotension using continuous non-invasive blood pressure monitoring59,60 and compared it with

manual boluses. Their algorithm involved treating hypotension with either phenylephrine or
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ephedrine based on maternal heart rate: phenylephrine was used if the heart rate was > 60 bpm

(50 µg every 30 sec in the automated group or 100 µg every minute in the manual group), and
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ephedrine if heart rate was < 60 bpm (8 mg every 30 sec in the automated group and 4 mg every
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minute in the manual group). The incidence of hypotension (35% vs. 59%) and of intraoperative

nausea (1% vs. 10 %) was significantly lower in the automated group. Furthermore, the close-

loop feed back control group was associated with more accurate blood pressure control

compared with the manual boluses group.59

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Dose response studies and impact on maternal hemodynamics:

Allen and colleagues evaluated the number of physician interventions needed to maintain

systolic blood pressure within 20% of baseline associated with the use of fixed rate

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phenylephrine infusion regimens of 25, 50, 75 and 100 µg/min.51 The number of physician

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interventions was lower in the 25 and 50 µg/min groups compared with the 100 µg/min group.

Reactive hypertension occurred less commonly with the lower infusion rates. The median

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absolute performance error, a measure of inaccuracy of blood pressure control, was also lowest

in the 50 µg/min group.

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Phenylephrine is often associated with a reflex bradycardia attributed to the baroreceptor-
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mediated response to the increased afterload. Bradycardia occurring in the setting of a

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phenylephrine infusion should not be treated with an anticholinergic agent or with ephedrine,
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unless it is accompanied by hypotension, otherwise significant hypertension may occur.51,61

Reducing the rate or stopping the phenylephrine infusion best manages such bradycardia.4
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Reactive hypertension also commonly occurs when using prophylactic phenylephrine

infusions.49,51 Since phenylephrine has a short half-life, reducing the rate or stopping the
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phenylephrine infusion quickly eliminates this increase in blood pressure. Often the increase in
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cardiac afterload combined with bradycardia results in decreased cardiac output. Some

investigators have however demonstrated that, immediately following neuraxial placement, there

is an increase in cardiac output. 7,8 So while phenylephrine can decrease cardiac output, it

typically remains higher than baseline levels. Dyer examined the changes in heart rate and

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cardiac output for 150 sec following the administration of an 80 µg phenylephrine bolus or a 10

mg ephedrine bolus for the treatment of spinal induced hypotension.8 Peak blood pressure values

were achieved significantly quicker following phenylephrine administration. There was a

decrease in heart rate and cardiac output following phenylephrine administration with values that

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were significantly lower than following ephedrine administration. Cardiac output was still

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however numerically higher than baseline cardiac output, which increased by 35 % following

spinal anesthesia and before vasopressor administration. The study suggested that heart rate

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changes could be used as a surrogate for cardiac output changes, since changes in both of those

parameters were significantly correlated.

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Stewart and colleagues investigated three fixed rate prophylactic phenylephrine infusion

regimens (25, 50 and 100 µg/min), and reported time dependent and dose dependent reductions
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in heart rate and cardiac output with greater depression of heart rate and cardiac output with the
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higher phenylephrine infusion regimen of 100 µg/min. 62 The maximum decrease in cardiac
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output was 22%, 15% and 8% in the 100 µg/min, 50 µg/min and 25 µg/min groups respectively.

Stroke volume remained stable indicating that cardiac output changes are secondary to changes
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in heart rate.
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Some have suggested that uteroplacental blood flow is better correlated with cardiac
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output than with upper arm blood pressure measurements.63 Therefore, while studies in healthy

parturients did not report any negative impact of this reduction in cardiac output with

phenylephrine infusions on neonatal acid base status or Apgar scores, concern has been

expressed that this reduction in cardiac output might have detrimental effects on an already

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compromised fetus such as in emergency situations with pre-existing fetal acidosis.62 Stewart

and colleagues therefore suggested caution with the use of high dose phenylephrine infusions

sufficient to cause a reduction in heart rate.62

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A number of strategies have been investigated in an attempt to reduce the bradycardia

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associated with the use of phenylephrine infusions. Ngan Kee and colleagues randomized

women undergoing cesarean delivery under spinal anesthesia to receive pretreatment with

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glycopyrrolate 4 µg/kg or saline placebo, and maintained blood pressure in both groups with a

prophylactic phenylephrine infusion.64 They reported higher heart rate and cardiac output and

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lower phenylephrine consumption with glycopyrrolate pretreatment, with no difference in
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hypotension and an increased risk of reactive hypertension, greater inaccuracy of blood pressure

control and an increased risk of dry mouth. There was also no difference between the groups in
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neonatal outcomes or in the incidence of maternal nausea and vomiting. The same group of
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investigators examined the impact of mixing phenylephrine with ephedrine on neonatal and
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maternal outcomes. The study included prophylactic infusions of phenylephrine, ephedrine or

combinations of ephedrine and phenylephrine in a ratio of 25%, 50%, or 75% of either agent.
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The authors found that as the proportion of phenylephrine decreased and that of ephedrine

increased, there was a faster hear rate but more hypotension, greater inaccuracy of blood pressure
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control, more maternal nausea and vomiting and lower neonatal umbilical artery pH.48 Those
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studies suggest that in healthy parturients with non-compromised fetuses, strategies to increase

heart rate when using a prophylactic phenylephrine infusion did not translate into improved

outcomes.

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A more recent study however investigated the use of norepinephrine, which possesses a weak β

adrenergic effect in addition to the potent α agonistic effect, compared with phenylephrine, with

the thought that the β activity would promote less bradycardia with improvement in cardiac

output. A computer-controlled infusion was used to maintain blood pressure using either

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phenylephrine starting at 100 µg/min or norepinephrine initiated at 5 µg/min.65 There was no

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difference in blood pressure or stroke volume between the groups, but cardiac output and heart

rate were greater and systemic vascular resistance was lower in the norepinephrine group. The

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precision of blood pressure control was greater with norepinephrine, as suggested by the lower

median absolute performance error.66 The authors suggested that the increase in cardiac output

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coupled with lower systemic vascular resistance might promote uteroplacental perfusion to a
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greater extent compared with phenylephrine. Interestingly, while there was no difference

between the groups in umbilical artery pH, umbilical vein pH and umbilical vein oxygen content
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were greater with norpepinephrine, suggesting possible improved placental blood flow and
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oxygen delivery. The differences however were very small and might not be clinically relevant.
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Data from non-elective and high-risk pregnancies:

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Most of the studies investigating spinal-induced hypotension have been performed in

elective cesarean deliveries in healthy parturients, and it is not clear if results from those studies
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are also applicable to non-elective cases and high-risk pregnancies. In a study in women
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undergoing non-elective cesarean deliveries, and receiving either ephedrine 10 mg or

phenylephrine 100 µg boluses for the treatment of hypotension, there was no difference in

neonatal acid base status between the groups, but umbilical venous and arterial lactate

concentrations, and the incidence of nausea and/or vomiting were higher with ephedrine.46

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Similarly, in a retrospective study of pre-eclamptic women receiving either ephedrine or

phenylephrine for the treatment of spinal-induced hypotension, there was no difference in

umbilical artery pH between the two groups.67 Two recent randomized controlled studies

compared phenylephrine and ephedrine in women undergoing emergency cesarean delivery for

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fetal indications.68,69 One study administered the two agents as a prophylactic infusion,68 while

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the other study used rescue boluses for the treatment of established hypotension.69 There was no

difference in neonatal acid-base status between those who received ephedrine or phenylephrine

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for blood pressure support,68,69 but the incidence of intraoperative nausea and vomiting 68 and

tachycardia68,69 were higher with ephedrine, whereas bradycardia was more common with

phenylephrine.68,69
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AN
The role of Genetic polymorphisms
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Because of wide variability in the incidence and severity of hypotension after spinal
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anesthesia, there has been growing interest in the possible impact of genetic predisposition.
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Landau et al. looked at 170 healthy women with two different polymorphisms of β2

adrenoreceptors (ADRB2). All their study patients received the same spinal dose and found no
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difference in the incidence of hypotension. However, those patients with certain variant

genotypes of ADRB2 had a significantly smaller requirement of ephedrine to maintain blood

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pressure.70 The same group followed up this study on variant ADRB2 and response to
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phenylephrine, with the hypothesis that a significant difference should not exist for

phenylephrine dose, which has a different mechanism of action. They looked at 96 women and

found that there was a statistically significant difference of 200 µg, which may not be as

clinically relevant.71 Their work demonstrated that a genetic component of the ADRB2 genotype

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may contribute to a more severe hypotensive response after spinal anesthesia as well as varying

responses to sympathomimetics.

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Serotonin Receptor antagonists:

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Several recent studies investigated the use of 5 hydroxytryptamine subtype 3 (5HT3)

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receptor antagonists for prophylaxis against spinal induced hypotension. The rationale for this

approach is that the Bezold-Jarisch reflex is mediated by 5HT3 receptors located on the vagus

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nerve and within the wall of the cardiac ventricles. Serotonin is released in response to systemic
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hypotension and can cause an increase in efferent vagal signaling, and through binding of to the

5HT3 receptors activates the Bezold-Jarisch reflex, leading to bradycardia and hypotension.72,73
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A number of meta-analyses pooling studies that investigated the efficacy of 5HT3

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receptor antagonists in preventing spinal induced hypotension have recently been published.74-76
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Ondansetron was the most commonly investigated 5HT3 receptor antagonist. The meta-analyses

by Gao et al. and Heesen et al. suggested that those agents reduced the incidence of hypotension,
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bradycardia and need for vasopressors following spinal anesthesia in obstetric patients, but there

was evidence of publication bias.74,75 Terkawi et al. however, used the GRADE system, and
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suggested that the quality of the evidence was low to very low. Furthermore, by using recently
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developed statistical techniques including small trial bias assessments, selection models, and trial

sequential analyses, they failed to confirm that ondansetron reduced spinal induced hypotension

and bradycardia.76

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Conclusion:

The spinal anesthetic block is an excellent choice for cesarean delivery due to its rapid

onset and dense sensory block. However, hypotension that ensues immediately after placement is

common and can negatively impact the mother and fetus if left untreated. There are various

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mechanisms that contribute to hypotension in the parturient, but arterial dilatation appears to be

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the major factor leading to hypotension. Therefore, vasopressors are the mainstay for managing

spinal induced hypotension, whereas fluid loading strategies, left uterine displacement and

SC
mechanical lower extremity compression have limited effectiveness. In elective cesarean

deliveries, the use of phenylephrine is associated with improved neonatal acid base status and

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reduced risk of maternal nausea and vomiting compared with ephedrine, but data is limited in
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high risk pregnancies. Prophylactic phenylephrine infusion can maintain stable blood pressure

and effectively eliminate hypotension when titrated accurately. As the obstetric population
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becomes increasingly more complex, further research must focus on implementing strategies for
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the higher risk population.

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Practice Points:
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• Every patient should have blood pressure closely monitored after administration of spinal

anesthesia
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• Despite limited supporting evidence, left lateral displacement of gravid uterus to prevent
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aortocaval compression may be considered, as this is a very low risk strategy.

• Initiate prophylactic phenylephrine infusion at 25-50 µg/min immediately after spinal

placement.

• Administer a crystalloid coload in conjunction with the phenylephrine infusion.

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• Titrate the phenylephrine infusion to maintain baseline blood pressure and titrate down if

bradycardia and reactive hypertension occurs or if bradycardia occurs with normal blood

pressure.

• Consider a vagolytic or ephedrine if parturient is both hypotensive and bradycardic.

PT
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Research Agenda:

• Further research in unplanned, non-elective cesarean deliveries and high risk pregnancies

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• Further evaluation of norepinephrine as vasopressor therapy for spinal-induced

hypotension

•
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Methodologically sound research to guide the future consideration of 5HT3 receptor
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antagonists for prophylaxis of spinal anesthesia-induced hypotension.
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Conflict of Interest:
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None
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Funding:
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This research did not receive any specific grant from funding agencies in the public, commercial,
or not-for-profit sectors.
C
AC

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