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Obstetric Anesthesia

Controversies: Vasopressor
Choice for Postspinal Hypotension
During Cesarean Delivery
Alison Macarthur, MD*
Mount Sinai Hospital
Toronto, Ontario, Canada

Edward T. Riley, MDw


Stanford University School of Medicine
Stanford, California

The use of spinal anesthesia for cesarean delivery has increased with
the introduction of small-gauge, noncutting spinal needles. Most women
in Canada, the United States, Australia, and Europe requiring elective
cesarean delivery receive some variation of a spinal anesthetic technique
owing to the perceived advantages of a clear end point in locating the
subarachnoid space, fast onset of local anesthetic effect, and reduced risk
of local anesthetic toxicity. To successfully administer spinal anesthesia
for cesarean delivery, however, requires consistent attention to details to
minimize side effects, the predominant one being maternal hypotension.
Maternal hypotension is an unwanted consequence of the physiologic onset of spinal blockade, and causes both maternal and fetal effects.
Maternal symptoms include nausea, vomiting, and a sense of impending doom from inadequate cerebral perfusion. Inadequate treatment
of hypotension can ultimately end with the loss of consciousness and
cardiovascular collapse. The fetus is indirectly affected by the development of hypotension, because of its dependency on maternal uterine
artery pressure for adequate uterine blood flow. With a persistent
reduction in uterine blood flow, fetal acidosis will occur; uterine blood
flow reductions of 65% led to acidosis in 10 minutes in the fetal lamb
model.1 Although anesthesiologists do not allow hypotension to persist,
successful treatment can occasionally take longer than desired.
The incidence of maternal hypotension is reported to be 50% to
80% depending upon the definition of hypotension used, the position of
FROM THE *DEPARTMENT OF ANESTHESIOLOGY AND PAIN MANAGEMENT, UNIVERSITY HEALTH NETWORK; AND THE
wDEPARTMENT OF ANESTHESIOLOGY
REPRINTS: DR ALISON MACARTHUR, DEPARTMENT OF ANESTHESIA, ROOM 1514, MOUNT SINAI HOSPITAL, TORONTO,
ONTARIO, CANADA, M5G 1X5, E-MAIL: ALISON.MACARTHUR@UHN.ON.CA

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the patient, the rate of spinal anesthetic agent injection, intravenous


fluid loading, and whether the women is laboring or has associated
morbidity such as pregnancy induced hypertension. Regardless of the
definition and associated factors that change the incidence of hypotension, this phenomenon is common enough that all anesthesiologists
must be vigilant during cesarean delivery performed under spinal
anesthesia.

Physiology of Postspinal Hypotension

The recommended dose of hyperbaric bupivacaine to achieve


predictable anesthetic effect for cesarean delivery appears to be between
12.5 to 15 mg, depending upon whether lipophilic narcotics are added.2
With this dose, a block extends above the thoracic upper limit of the
autonomic nervous system, and effectively removes sympathetic control
of the cardiovascular system. The induced sympathectomy causes
vasodilation with a subsequent decrease in systemic vascular resistance
(SVR). The decrease in SVR will compound the parturients predisposition to hypotension in the supine position.
The supine hypotensive syndrome was first reported in the 1930s
by a Swedish obstetrician, Gideon Ahltorp, who perceptively observed
the event and identified mechanical treatments including the prone
position, manual displacement of the uterus to the left, and immersion
of the body in water to the neck.3 Approximately 2.5% to 20.6% (mean
of 8%) of pregnant women, evaluated during the second and third
trimester, will develop the syndrome when positioned supine. Frank
Holmes, a consultant anesthetist in Edinburgh, Scotland described the
implications of supine hypotension when combined with anesthesia,
particularly regional anesthesia.4 He noted spinal anesthesias ability to
reduce cardiac output to a dangerous degree and that accompanying
hypotension likely contributed to maternal deaths occurring during
cesarean delivery. An electronic search of a medical database using terms
spinal anesthesia+ maternal death led to more than 10 website pages of
publications. In light of this predictable event, anesthesiologists must be
prepared to prevent maternal hypotension, and to treat it quickly if it
does occur.

Vasopressor Therapy

Despite maneuvers such as slow injection of spinal local anesthetics,


administration of colloid intravenous fluid bolus, and the use of
compressive leg devices, anesthesiologists will have to treat with
vasopressor medications 40% to 60% of women undergoing cesarean
delivery. The choice of vasopressors in North America includes

Obstetric Anesthesia Controversies: Vasopressor Choice for Spinal-induced Hypotension

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ephedrine, phenylephrine, and epinephrine. Other sympathomimetics


are available, such as methoxamine, mephentermine, dopamine, and
norepinephrine; however, their use is uncommon with obstetric regional
anesthesia. One sympathomimetic not used in North America but used
widely elsewhere is metaraminol. The ideal vasopressor is inexpensive,
easily available, quick in onset, reliable, favorably affects maternal heart
rate and minimizes detrimental effects upon the fetus and placental
perfusion. The choice between ephedrine and phenylephrine has
provoked much debate. The advantages and disadvantages of each will
be discussed in the next sections.

Vasopressor Basic Science


Structure and Metabolism

The key element common to all vasopressors is their ability to mimic


some of the sympathetic nervous system activities. The differences
between them depend upon each drugs ability to lead to a and breceptor stimulation. The pharmacologic activity of each vasopressor is
dependent upon its structural configuration.5 The basic structure of all
sympathomimetics is the benzene-ring based b-phenylethylamine (Fig. 1).
a and b-receptor activity is maximized if hydroxyl groups are
attached at the third and fourth carbons of the benzene ring.
Compounds without hydroxyl groups on the third and fourth carbon
are synthetic noncatecholamines. Included in this group are ephedrine
and phenylephrine.
The metabolism of phenylephrine is by the same process as the
natural and synthetic catecholamines, which is rapid inactivation by
catchol-O-methyltranserease and monamine oxidase. Because of its
short duration of action, it can be administered by intravenous boluses
of 50 to 200 mcg, or by intravenous infusion of 20 to 50 mcg/min.
Ephedrine is not metabolized by catchol-O-methyltranserease enzymes
because it lacks hydroxyl groups, and monamine oxidase enzyme
deamination does not occur because of its a-methyl group. Thus,
ephedrine is excreted almost unchanged in urine. Its actions are
primarily ended by reuptake in terminal nerve endings. This difference
in metabolism explains the relatively long duration of action of
ephedrine compared to phenylephrine. The routes of administration
of ephedrine include oral, intramuscular and intravenous bolus.
Mechanism of Action

Ephedrine has both indirect and direct actions on the sympathetic


nervous system. Its indirect effects are due to the stimulation of
postganglionic sympathetic nerve endings to release norepinephrine.

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Figure 1. Biochemical structure of basic vasopressors.

As norepinephrine is a weak b-2-receptor agonist, these effects are


primarily a and b-1-receptor mediated. Ephedrines direct effects are
less potent than natural catecholamines, but do provide some b-2receptor activation.
Phenylephrine, although structurally a synthetic noncatecholamine,
functions similarly to norepinephrine with direct action at the a-1receptor. However, it is less potent, and longer acting than norepinephrine. Unlike other synthetic noncatecholamines, phenylephrines
indirect actions are minimal. Thus, phenylephrine will result in
venoconstriction, which is greater than its arterial constriction, and
predictably increases blood pressure by increasing both SVR and
preload. Because of minimal b-2-receptor activity, phenylephrine does
not cause tachycardia, but instead can cause reflex bradycardia with
increasing blood pressure.

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Ephedrine

Ephedrine has become the standard vasopressor in obstetric


anesthesia as a result of animal studies of the 1970s. Sol Shniders
groups investigations, using the instrumented sheep model, demonstrated that ephedrine did not cause uterine artery vasoconstriction
despite releasing norepinephrine at the preganglion.6 The result was
maintenance of uterine artery blood flow and fetal pH, whereas
methoxamine, mephentermine, and metaraminol tended to decrease
uterine blood flow and pH.
More recent evaluations have elucidated the mechanisms contributing to the preservation of uterine blood flow by ephedrine. Eisenach
initially identified a differential effect upon vascular beds of the
pregnant ewe model. Ephedrine causes substantial femoral artery
vasoconstriction but relatively little uterine artery vasoconstriction in
the pregnant ewe compared with the nonpregnant ewe.7 Later studies
identified that nitric oxide synthase was increased in uterine artery
endothelium of pregnant ewes compared with nonpregnant ewes.8 This
localized increase would mediate increased local nitric oxide production,
a potent vasodilator. Given these effects, ephedrine preferentially shunts
blood to the uterus during pregnancy.
With the support of these findings, ephedrine quickly became the
vasopressor of choice in obstetrics. Two recent quantitative reviews
summarized ephedrines effectiveness in preventing hypotension
compared with fluid boluses or expectant management.9,10 Both
reviews identified randomized clinical trials which administered
intramuscular or intravenous ephedrine before or immediately after
spinal anesthesia, compared with control groups receiving placebo, no
intervention, or intravenous fluid boluses. The individual studies did
not show a benefit with the use of ephedrine; however, the meta-analysis
of their findings was significant. Ephedrine was more effective than
controls in preventing maternal hypotension by almost 30% (relative
risk 0.73: 95% 0.63, 0.86). However, the incidence of hypotension in the
ephedrine group was still 32% to 55%.
Ephedrine Dosing

Perhaps the explanation of ephedrines failure in up to half of the


study patients was a result of inadequate dose. The minimum effective
dose of ephedrine was reviewed in a paper by Lee et al,11 which
attempted to determine the dose-response from studies evaluating
various doses of ephedrine. Four randomized trials compared the effect
of 0, 5, 10, 15, 20, 30 mg IV ephedrine boluses given simultaneously
with or immediately after spinal anesthesia for elective cesarean
delivery.1215 The dose of spinal hyperbaric local anesthesia varied
slightly with one study using 10 mg of tetracaine and the rest using

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bupivacaine 10 to 12.5 mg. A dose-response effect was identified with


reduced risk of hypotension with increasing dose of ephedrine. This
benefit was balanced against the risk of maternal hypertension (usually
defined as a maternal blood pressure >20% above baseline). The dose
at which the authors felt the likelihood of benefit outweighed the risk
of harm was 12 mg of ephedrine. This recommended dose contrasts
with the commonly described dose in obstetric anesthesia texts, which
recommend doses of 5 to 10 mg IV. Ephedrines ineffectiveness at
preventing hypotension in the other studies may have been the result of
inadequate doses.
Another reason for ephedrines ineffectiveness may be that the
timing of administration does not coincide with the onset of anesthesiainduced hypotension. Studies administering ephedrine intramuscularly
gave the medication at unspecified times prior to spinal anesthesia, 5 to
25 minutes before the spinal, or after the administration of spinal
anesthesia. None of the studies confirmed pharmacologic activity of the
drug before the administration of spinal anesthesia and its associated
sympathectomy and hypotension. Ephedrine was administered either as
a bolus or as an infusion. Intravenous infusion rates ranged between 0.5
and 5 mg/min, and bolus doses were between 5 and 30 mg preceding
or after spinal anesthesia. Again, the activity of ephedrine likely lagged
behind the onset of those physiologic changes leading to hypotension. It
is possible that the timing of ephedrine administration has not been
optimized. I have not identified any study, which attempted to increase
maternal blood pressure with ephedrine before spinal anesthesia.
Obviously concerns over this methodology would have to be considered,
but spinal-induced hypotension and its consequences are not inconsequential.
Ephedrine and Umbilical Arterial Acidosis

Ephedrine has been associated with lower umbilical artery (UA) pH


when compared with other vasopressors, such as phenylephrine, or to
controls.13,16,17 The difference in mean umbilical arterial pH values
was approximately 0.03, with the range of mean pH in ephedrine
groups between 7.18 (SD 0.13) and 7.27 (SD 0.04). Although the
difference is statistically significant, the clinical relevance has yet
to be determined. No study has shown a difference in long-term
neonatal outcome. Only surrogate outcomes have been measured.
However, 2 important predictors of poor outcomes for the neonate
are UA pH below 7.2 and UA negative base deficit lower than 12.
Cooper et al18 found a greater number of neonates with an UA pH of
less than 7.2 and NganKee et al19 found that ephedrine use was
associated with a lower negative base excess compared with phenylephrine.

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Riley20 hypothesized the pathophysiology of ephedrines association


with lower UA pH in 2004. He was concerned by accumulating
evidence that doses of ephedrine large enough to maintain homeostasis
after the induction of spinal anesthesia may be detrimental to the fetus.
He suggested that ephedrine, which crosses the placenta, led to
increased fetal metabolic activity and subsequent reductions in fetal
arterial pH. Presuming that much of the argument against
ephedrine is based upon its effect on UA pH or umbilical base
deficit, we must define a deleterious pH and base deficit. What are
the implications of an UA pH of 7.20, 7.10, or 7.00, and when
should we be concerned that acidotic intrapartum conditions are
responsible for long-term, deleterious neonatal outcomes? In 1999, a
consensus paper of the American, Canadian, and Australian obstetric
societies defined the evidence required to identify a significant
intrapartum asphyxial event severe enough to be cause neonatal
neurologic injury.21 The committee concluded that an intrapartum
asphyxial event was associated with a significant metabolic acidosis,
defined as an UA pH <7.00 and base deficit >12 mmol/L. In the
studies to date, which have been carried out on healthy, uncomplicated
elective cesareans, ephedrine use has caused a reduction in umbilical
arterial pH primarily because of elevated fetal CO2 levels, indicating a
respiratory acidosis. Numerous pediatric and obstetric papers have
identified that respiratory acidosis alone is not associated with newborn
complications.22,23 It seems that ephedrine is not deleterious to the
uncompromised fetus. Ephedrines effect on the compromised fetus is
unknown.
If maternal ephedrine increases fetal catecholamines and
metabolic activity, similar to the effect of labor, might this be beneficial?
The incidence of transient tachypnea of the newborn (TTN) is
significantly reduced amongst babies born following a labor
compared with babies born at elective cesarean delivery. This
concept was tested in a blinded, randomized clinical trial evaluating
the effectiveness of terbutaline administered to mothers 2 hours
before an elective cesarean delivery.24 The authors hypothesized
that the b-adrenergic stimulation of terbutaline would simulate labor
and improve respiratory function and glucose homeostasis in the
newborn. Twenty-five babies were studied, after 13 mothers
received terbutaline and 12 received saline placebo. Initial respiratory rates of the babies in the terbutaline group were significantly lower
than the placebo group, and serum glucose levels were maintained over
the first 2 hours at a higher level in the terbutaline group. Babies of
mothers who received terbutaline also had significantly lower airway
resistance and higher lung compliance than controls, as measured by
pneumotachometer. Two babies in the control group were diagnosed
with TTN. However, the UA base deficit was significantly higher for the

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treatment group, with a BE of 5.2 compared with 2.7 for the control
group.
The last issue to address is what is the relative importance of
ephedrines contribution to UA pH changes compared with other
variables. A retrospective study of all elective cesarean deliveries
performed under hyperbaric bupivacaine spinal anesthesia identified
12 explanatory variables and assessed their contribution towards
the prediction of final UA pH.25 The explanatory variables included
patient demographics (age, weight, height, neonatal birth weight),
anesthesia-related information (block height, use of prehydration,
vasopressor used, maximum decrease in systolic pressure, and
length of hypotension) and relevant obstetric information (induction
to delivery time, skin incision to delivery time, uterine incision to
delivery time). Each variable was evaluated in a multivariate linear
regression model, a statistical technique that allows for evaluation of
each variables effect adjusting for the other variables effect on the
outcome, UA pH. The final predictive model concluded that the
important variables to predict the UA pH were whether ephedrine was
used, the length of uterine incision to delivery time, the maximum
decrease in systolic pressure in mm Hg, and the duration of hypotension
in minutes. An interaction term was identified in the model, between
ephedrine use and duration of hypotension, indicating that the women
receiving ephedrine had a further deleterious effect depending upon
the duration of hypotension.
The final mathematical model to predict UA pH in this population
of healthy women under spinal anesthesia was:
UA pH = 7.413 to 0.042 (if ephedrine used) 0.014  duration
of hypotension in minutes (if ephedrine used) 0.001  maximum
decrease in systolic arterial pressure in mm Hg 0.0002  uterine
incision to delivery time+ 0.0002  duration of hypotension in
minutes.
Although this formula seems overwhelming, its applicability can be
seen using a case of extreme pathophysiology: a woman for elective
cesarean delivery under spinal anesthesia has a significant reduction of
systolic arterial pressure of 40 mm Hg, who then receives ephedrine and
has a hypotensive episode of 5 minutes and then experiences a longer
than usual uterine incision to delivery time of 32 seconds. In this case,
the above formula predicts the resulting UA pH to be 7.25. This
demonstrates that there is a large reserve for protecting the fetus from
acidosis.2628
Ephedrine, with its longer duration of action, still has a role in
obstetric anesthesia to prevent or treat spinal-induced hypotension
when given in an appropriate dose. The optimal method to administer
ephedrine, whether combined with other vasopressor therapy or
nonmedication therapy, awaits future study.

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Phenylephrine
Concerns With Using a-1-agonist Agents

Standard obstetric anesthesia textbooks up until the 1990s condemned the use of a-1-agonists in the treatment or prevention of
maternal hypotension. These recommendations were based on sheep
studies, which detailed drastic reductions in uterine blood flow after the
administration of methoxamine, metaraminol, or phenylephrine.29
However, in the 1990s clinical researchers reported on the effectiveness
of phenylephrine in treating spinal anesthesia-induced hypotension.30
The incentive to evaluate this vasopressor arose from the failure of
ephedrine when used in the recommended 5 to 10 mg IV bolus doses,
and a desire to reduce the tachycardia elicited by ephedrine that was
undesirable in some parturients.
Between 1991 and 2001, 7 studies compared ephedrine with
phenylephrine among women undergoing elective cesarean delivery
under spinal anesthesia.3137 These studies were summarized by Lee
et al38 in a quantitative review. The summary concluded that ephedrine
and phenylephrine were not different in preventing or treating
hypotension (refer to Table 1). The only difference identified in the
studies was that women given phenylephrine had neonates with higher
umbilical arterial pH values, by 0.03 pH units. Umbilical arterial base
excess was greatest amongst neonates born to mothers receiving
phenylephrine (weighted mean difference = 1.41; 95% confidence
interval, 0.812.02).
This unexpected finding of improved neonatal parameters with
phenylephrine may be explained by the lack of fetal metabolic effect as
compared with ephedrine. Although UA resistance may be increased
with phenylephrine, the oxygen consumption by the fetus is not, and
therefore the net oxygen balance is more favorable than ephedrine.
Phenylephrine has been incorporated into the clinical practice of North
American obstetric anesthesiologists as the evidence grows that it is not
more harmful than ephedrine.
Table 1.

Maternal and Fetal OutcomesComparing Ephedrine to Phenylephrine

Outcome (Ephedrine Control Group)


Trials preventing maternal hypotension
Trials treating maternal hypotension
Overall effect in management of maternal hypotension
Umbilical arterial pH values
Fetal acidosis

Relative Risk
1.09 (95% CI, 0.71-1.69)
1.00 (95% CI, 0.95-1.05)
1.00 (95% CI, 0.96-1.06)
WMD
0.03 (95% CI, 0.02-0.04)
0.78 (95% CI, 0.16-3.92)

CI indicates confidence interval; WMD, weighted mean difference.

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Phenylephrine has proven to be a useful, immediate remedy to


maternal hypotension, and may in fact reduce the incidence of maternal
intraoperative nausea and vomiting better than ephedrine. Two studies
of a-agonists (metaraminol and phenylephrine) compared with ephedrine in double-blind randomized trials documented the incidence
of maternal nausea and vomiting.18,19 The studies compared both
vasopressors given as infusions with maintain systemic blood pressure at
baseline values immediately after the administration of 10 to 12.5 mg
spinal hyperbaric bupivacaine. Patients were repeatedly asked during
the intraoperative period about nausea and the number of vomiting
episodes was documented. Combining these results using a metaanalytic technique, the risk of nausea or vomiting was reduced by almost
80% in the women receiving a-agonists (refer to Fig. 2).
Optimal Method of Phenylephrine Administration

The evolution of vasopressor therapy in obstetrics has moved from


the avoidance of vasoactive agents except when maternal blood pressure
dropped significantly, to a philosophy that any reduction in maternal
blood pressure is undesirable. Ngan Kee et al39 compared the use of
prophylactic phenylephrine with phenylephrine used only when systolic
arterial blood pressure dropped Z20% from baseline. A prophylactic
infusion of 100 mcg/min of phenylephrine was started immediately after
the administration of 10 mg hyperbaric bupivacaine in half the study
population and adjusted according to 1-minute blood pressure evaluations. The control group only received 100 mcg boluses of phenylephrine when the blood pressure dropped to r80% of baseline. The
primary outcome was the UA pH, to indirectly assess fetal acid-base
status. Despite almost tripling the dose of phenylephrine in the
prophylactic group (median 1260 mcg; first/third quartiles 1010,
1640 mcg) compared with the treatment-only group (median 450 mcg;
first/third quartiles 300, 750 mcg) fetal arterial blood gas results were no
different, and only 1 neonate in each group had UA pH <7.20. The
prophylactic group, however, had fewer women with hypotensive
episodes (23%) compared with the treatment group (88%). The
number of hypotensive episodes was greater and the minimum systolic
arterial pressure was lower amongst women in the treatment-only
group. Phenylephrine was shown to have beneficial effects when given
before the development of hypotension without compromising the
balance of fetal oxygen demand/delivery.
A recent randomized clinical trial examined the maternal and
neonatal effects of maintaining maternal blood pressure within 80%,
90%, or 100% of baseline levels using a phenylephrine infusion.40
Using phenylephrine 100 mcg/mL infused at initial rates of 100 mcg/
min, the investigators adjusted the dose depending upon whether

Figure 2. Random effects meta-analysis of nausea and vomiting risk.

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blood pressure was kept within the assigned groups range. The primary
outcome was the difference in UA pH between the 3 groups, and
secondary outcomes of the incidence of hypotension, reactive hypertension, nausea, and vomiting. Despite an almost 2-fold increase in the
mean phenylephrine dose administered, women in the 100% baseline
group had fewer episodes of nausea or vomiting (4% vs. 16%, 40%) and
their neonatal mean umbilical arterial pH was higher (7.32 0.04 vs.
7.30 0.03 for both other groups). The unpleasant symptoms of
hypotension are better controlled with tight control of blood pressure
using aggressive vasopressor administration. Maximizing uterine artery
perfusion after the sympathectomy of spinal anesthesia may be more
important in maintaining uterine blood flow and fetal well being than
previously understood.
Our concern with a-1-agonists vasoconstrictive effects on the
uterine artery has distracted us from their effects across different
vascular beds. In an elegant study of pregnant and nonpregnant sheep,
Magness et al41 demonstrated that the pregnant uterine artery was less
responsive to a-1-agonist stimulation than the nonpregnant uterine
artery. Figure 3 illustrates the relative changes in pregnant and
nonpregnant uterine vascular resistance, SVR, mean arterial pressure,

Figure 3. Relationship between the percent change in uterine vascular resistance (*) and blood
flow (D) with mean arterial pressure (&) and SVR (^) during systemic infusions of phenylephrine
in nonpregnant sheep.

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and uterine blood flow over the various administered doses of


phenylephrine. At 12.89 mcg/min of phenylephrine, uterine blood flow
declined approximately 50% less in pregnant sheep compared with the
nonpregnant sheep. The pregnant uterine vasculature seems to have a
protective adaptation to preserve blood flow to the placenta above other
vasculatures.
Phenylephrine appears to have survived the period of intense
suspicion and concern over its use in obstetric anesthesia. It is reliable in
its effect, although short-acting, and its effect on the fetus appears to be
even less than that of ephedrine.
Combination Therapy

There are 3 recent publications which examined the use of


combination vasopressor therapy,18,42,43 and one which examined the
use of intravenous fluid administration with vasopressor therapy.44
Combination Vasopressor Therapy

The 3 studies evaluating combined vasopressor therapy used


ephedrine and phenylephrine, but compared slightly different regimes.
Mercier et al42 compared the prophylactic capabilities of an ephedrine
and phenylephrine infusion (2 mg/min+ 10 mcg/min) to an ephedrine
infusion (2 mg/min) alone. The vasopressor infusion was begun at
40 mL/h following a spinal bupivacaine dose of 11 mg (with sufentanil
and morphine) and adjusted up or down depending upon maternal
blood pressure measured every minute. Their primary outcome of
interest was the incidence of maternal hypotension defined as a systolic
blood pressure less than 100 mm Hg or <80% of the baseline
measurement. The incidence of hypotension was halved in the
phenylephrine/ephedrine group (37%) compared with the ephedrine
group (75%). One would expect these findings given the combination
group received larger doses of vasopressor therapy. A criticism of
this study was that patients in the ephedrine only group should
have received a larger, equipotent dose.
Loughrey et al43 compared intravenous boluses of ephedrine and
phenylephrine (10 mg+ 40 mcg) to an ephedrine bolus alone (10 mg)
given simultaneously during spinal administration of 12 mg of bupivacaine with fentanyl and morphine. Again the patients in the control
group did not receive an equipotent dose of vasopressor as the patients
in the combination therapy group. The primary outcome was maternal
hypotension, defined as a drop in systolic blood pressure of >20% from
baseline or below 100 mm Hg occurring during 1-minute interval
measurements. The incidence of hypotension in this study did not differ
between the 2 groups with a 95% incidence in the combination group

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and an 80% incidence in the ephedrine only group. The authors


concluded that the initial bolus doses were inadequate in both groups,
and that perhaps an infusion method may have been more efficient in
preventing hypotension.
Cooper et al18 compared 3 different infusion regimes of vasopressors; phenylephrine 100 mcg/mL, ephedrine 3 mg/mL, and combination
of 50 mcg/mL phenylephrine with 1.5 mg/mL ephedrine started at
20 mL/h after the administration of spinal anesthesia. The bupivacaine dose was 12.5 mg with added fentanyl. This studys primary
outcome was different, in that the authors were interested in the
incidence of fetal acidosis (defined as UA pH <7.20). There was a
greater incidence of fetal acidosis amongst the ephedrine only group
(21/50; 42%) compared with either the phenylephrine only group (1/48;
2%) or the combination therapy group (1/47; 2%). However, the
incidence of maternal hypotension (defined as systolic pressure <80%
of baseline) was not different between the groups: 48% for phenylephrine only group, 68% for ephedrine group, and 57% for the
combination therapy group.
Reflecting upon these studies, the administration of vasopressor
drugs by infusion as close to the time of spinal anesthesia administration
as possible appears to be helpful in reducing the incidence of
hypotension. However, significant maternal hypotension still occurs in
almost half of the women receiving combined ephedrine and phenylephrine infusions. An alternative solution investigated has been
combining vasopressor therapy with other modalities used to reduce
the incidence of hypotension.
Combination Vasopressor Therapy and
Intravenous Hydration

In 2005, Ngan Kee et al44 examined the benefits of simultaneous


administration of intravenous fluids with vasopressor administration.
Patients were randomized to receive either a rapid infusion of 2.0 L of
warmed Ringers lactate solution or an infusion rate of Ringers lactate
to keep the vein open following 10 mg spinal bupivacaine and fentanyl.
All women in the study received a phenylephrine infusion starting at a
dose of 100 mcg/min after the administration of the spinal anesthetic.
The studys primary outcome was the incidence of maternal hypotension. Maternal systolic blood pressure was measured every minute after
spinal anesthesia and the phenylephrine infusion was altered depending
upon effect. With the technique of high dose phenylephrine infusion
combined with a rapid intravenous cohydration, the authors reduced
the incidence of hypotension to less than 2% (1/53) compared with an
incidence of 28% amongst those receiving the phenylephrine infusion
alone (15/53).

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Conclusions

With adequate dosages of bupivacaine for spinal anesthesia,


pregnant women will develop significant, unpleasant hypotension if
anesthesia vigilance and appropriate response are lacking. Nonpharmacologic methods can reduce the incidence of hypotension; however,
the incidence of hypotension is still substantial, requiring vasopressor
rescue.
Ephedrine has been recommended in the past as the most
appropriate vasopressor agent for pregnant patients. However, human
research has identified its association with lower UA pH values, likely
due to increased fetal metabolic activity. The benefits of ephedrine
include its longer length of action compared to phenylephrine, and its
chronotropic effect. However, the reliability of effect requires using a
dose of ephedrine between 10 to 15 mg by intravenous bolus, or
infusion of >2 mg/min. Among academic obstetric anesthetists, ephedrines use has declined and has often been relegated to a second line
agent. Phenylephrine, on the other hand, has entered a renaissance
period with the recognition that the vasoconstriction it causes does not
have a detrimental effect on placental perfusion, and instead is a reliable
and fast agent to prevent or treat maternal hypotension. Its only
drawbacks are its short duration of action, necessitating infusion
therapy, and its predictable carotid sinus reflex effect resulting
occasionally in profound maternal bradycardia. The combination of
phenylephrine with ephedrine to take advantage of both agents effects
at reduced dosages appears to work best when administered as an
infusion. What is left to determine is whether phenylephrines potent
vasoconstricting effects are significant when given to a woman with a
compromised fetal-placental unit.
Perhaps the most interesting study to date identified the original
concept of intravenous fluid preloading has a place when administered
rapidly at the same time as the spinal anesthetic and with a prophylactic
vasopressor infusion. Future development of sophisticated computerdriven devices will reduce the difficulties of attempting to administer
these therapies with spinal anesthesia.

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