Ondansetron Given Intravenously to Attenuate Hypotension ...

Ondansetron Given Intravenously to Attenuate Hypotension and Bradycardia During
Spinal Anesthesia in Cesarean Delivery: A Literature Review
Matthew Denryter, Phillip Lim, Joseph Ponik and Tyler Wilhelm
Oakland University
Abstract

Spinal Anesthesia is the most common type of anesthesia provided to the parturient for
cesarean section. An undesired side effect often seen with the administration of a spinal
anesthetic is hypotension and bradycardia. The Bezold-Jarisch reflex is the likely cause of
hypotension and bradycardia associated with spinal anesthesia. This reflex is elicited by
stimulation of peripheral serotonin receptors 5-hydroxytryptamine (5-HT3 type). Ondansetron is
a selective serotonin 5-HT3 receptor antagonist. Current research in animals, obstetric and non-
obstetric populations indicates that 5-HT3 antagonism may abolish the Bezold-Jarisch reflex.
However, further research is needed to determine the effectiveness of using ondansetron in
preventing hypotension and bradycardia post spinal anesthesia in the obstetric population.

Keywords: Ondansetron, Bezold-Jarisch reflex, obstetric, 5-HT3

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Ondansetrom and Spinal Anesthesia 2

Ondansetron Given Intravenously to Attenuate Hypotension and Bradycardia During
Spinal Anesthesia in Cesarean Delivery

Spinal Anesthesia is the most common type of anesthesia provided to the parturient for
cesarean section. An undesired side effect often seen with the administration of a spinal
anesthetic is hypotension and bradycardia. Current treatments include fluids and vasopressors,
with the latter known to have maternal and fetal side effects. The Bezold-Jarisch reflex is the
likely cause of hypotension and bradycardia associated with spinal anesthesia. This reflex is
elicited by stimulation of peripheral serotonin receptors 5-hydroxytryptamine (5-HT3
type).caused by stimulation of peripheral serotonin receptors 5-hydroxytryptamine (5-HT3 type).
Ondansetron is a selective serotonin 5-HT3 receptor antagonist.1 Current research indicates that
5-HT3 antagonism may abolish the Bezold-Jarisch reflex response to spinal anesthesia.

Existing research concerning the undesired cardiovascular effects of spinal anesthesia has
been conducted on the non-obstetric, obstetric, and neonatal patient. A knowledge gap exists,
stimulating the current literature review on the use of ondansetron to prevent undesired
cardiovascular effects of spinal anesthesia. Because spinal anesthesia is one of the most
common types of anesthesia provided to the parturient during a cesarean section, the use of a 5-
HT3 antagonist may be beneficial to prevent bradycardia and hypotension. The purpose of this
literature review is to demonstrate that further research needs to be conducted in the obstetric
population with the administration of ondansetron to address hypotension and bradycardia
caused by the Bezold-Jarisch reflex during spinal anesthesia.

Compared to general anesthesia, regional anesthesia offers reduced maternal mortality,
the ability to use fewer drugs, direct maternal and paternal experience of childbirth, and the
capability to decrease blood loss while providing excellent postoperative pain control.2 Despite

Ondansetrom and Spinal Anesthesia 3

all of its advantages, spinal anesthesia is not free from adverse effects, including potentially
harmful hypotension and bradycardia.3 The incidence of hypotension and bradycardia in the
parturient patient is 52.6% and 2.5% respectively.4 This hypotension and bradycardia causes a
decrease in systemic vascular resistance and myocardial contractility. In addition, peripheral
vasodilatation with a redistribution of central blood volume to the splanchnic circulation and
lower extremities occurs.5 Bradycardia may be due to unopposed parasympathetic activity,
increased baroreceptor activity, or the Bezold-Jarisch reflex.3

The Bezold-Jarisch Reflex is an inhibitory response usually described as a
cardioinhibitory reflex. The heart is innervated by the vagus nerve, which consists of two major
fiber types, 25% are myelinated fibers which originate in the walls of the atria and 75% are
nonmyelinated fibers found in the walls of all four cardiac chambers.5 Animal studies have
shown that the Bezold-Jarisch reflex originates in cardiac receptors with nonmyelinated type C
vagal fibers creating the afferent limb of the reflex. These receptors are both mechanosensitive
and chemosensitive and when stimulated produce bradycardia, peripheral vasodilation and
hypotension.5 These chemoreceptors are sensitive to several different chemicals including
serotonin.6

Serotonin, 5-hydroxytryptamine (5-HT), is one class of monoamine neurotransmitters
produced by enterochromaffin cells in the human body. The majority of serotonin is in the
gastrointestinal system while the remaining serotonin is located within the central nervous
system.7 Serotonin is important for many physiological roles within the human body such as,
development, cardiovascular, gastrointestinal, endocrine function, sensory perception and
behavior.7 Currently there are 14 different 5-HT receptors identified, and with the exception of 5-
HT3, which is a ligand-gated channel, all other receptors are a G-protein coupled receptor.7 The

Ondansetrom and Spinal Anesthesia 4

5-HT3 receptors are located in both the peripheral and central nervous system in humans, and are
found both pre- and postsynaptically.7 It is thought that the stimulation of these peripheral 5-HT3
receptors results in increased parasympathetic activity and decreased sympathetic activity,
resulting in bradycardia, vasodilation, and hypotension.8

Ondansetron is a selective serotonin 5-HT3 receptor antagonist, and is currently approved
by the Food and Drug Administration (FDA) for treatment of nausea and vomiting caused by
chemotherapy, radiation therapy, and surgery.9 Side effects associated with the use of
ondansetron include: diarrhea, headache, constipation, weakness tiredness, and dizziness.9 The
FDA has assigned ondansetron to pregnancy category B, which means quality studies in human
parturients receiving this medication have not yet been conducted. However, animal studies
demonstrated no harm to their offspring.10 A limited study was conducted in 176 pregnant
females which showed that ondansetron does not appear to be associated with an increased risk
for major malformations above baseline.11 Although limited human data exists, ondansetron is
frequently given to parturient patients to help prevent nausea and vomiting without any reported
maternal or fetal harm.

Many research studies have been conducted to show the correlation between 5-HT3
receptors and the cardiovascular effects via the Bezold-Jarisch reflex. A study done at the
University of Connecticut investigated whether granistron, a 5-HT3 antagonist, could alter
hypotension and bradycardia caused by the Bezold-Jarisch reflex utilizing the hemorrhagic
model.12 In this quantitative experimental study, rabbits were randomized to receive 5
micrograms (mcg) of granistron or 5 milliliters (ml) of normal saline. Rabbits were observed
and after 5 minutes of administration of granistron (n=5) or saline (n=6), hemorrhage was
induced until blood pressure reached a target low of 80 millimeters of mercury systolic blood

Ondansetrom and Spinal Anesthesia 5

pressure. Acute blood loss in hemorrhagic animals causes a biphasic response. The first phase is
characterized by an increase in heart rate and systemic vascular resistance. The second phase is
characterized by bradycardia and hypotension which has been termed the Bezold-Jarisch reflex.12
This reflex is paralleled in humans. This study showed that the administration of granistron
significantly attenuated the decline of heart rate in rabbits, suggesting that granistron does not
affect the first phase of the hemorrhagic model, but does attenuate the lowing of heart rate seen
in phase two.12 The study also concluded that the granisetron group was more resistant to
lowering of blood pressure which was shown by significantly larger amounts of blood being
removed in the granistron group when compared to the normal saline group.12

In a case study reported by Marnitek patient developed asystole after the administration
of a spinal anesthetic.8 A 50 year old healthy male presented for tibial osteotomy under spinal
anesthesia. Following intravenous volume administration with 500 ml of lactated ringers and
sedation with intravenous remifentanil 25 mcg, a spinal anesthetic was administered. Vital sign
measurements were normal at the time of spinal administration. Thirteen minutes after spinal
administration, the surgeon injected the incision site with local anesthetic containing
epinephrine. One minute later the patient’s electrocardiogram (ECG) showed a sinus
bradycardia; blood pressure and oxygen saturation remained stable. Several minutes later the
patient went into cardiovascular collapse. Atropine 0.6 milligrams (mg) was given intravenously
followed immediately by ondansetron 4 mg intravenously. Before chest compressions were
initiated, vital signs returned with no further complications.8 The asystole in this patient may be
explained by exogenous epinephrine that triggered the Bezold-Jarisch reflex, and the
administration of ondansetron may have antagonized the afferent vagal 5-HT3 receptors
sufficiently to block the reflex.8 The authors of this study stated that further research was needed

Ondansetrom and Spinal Anesthesia 6

to examine the effects of ondansetron on the Bezold-Jarisch reflex.
According to Saxena and Villalon, intravenous bolus injections of 5-HT,

phenylbiguanide, and 2-methyl-5-HT in anesthetized rats, rabbits, cats, ferrets, dogs, and guinea
pig elicit short lasting bradycardia that can be blocked by a 5-HT3 receptor antagonist.13 The
results of the study demonstrated that the bradycardia due to 5-HT injection results from an
effect on cardiac receptors, specifically 5-HT3, causing a Bezold-Jarisch reflex.

A study conducted by Owczuk et al., verified the hypothesis that blockade of type 3
serotonin receptors by intravenous ondansetron administration may reduce hypotension and
bradycardia induced by spinal anesthesia in non-obstetric patients. Seventy-one patients were
selected and randomized for the study.3 Thirty-six patients received intravascular ondansetron 8
mg and thirty-five patients received a placebo of normal saline five minutes prior to the
administration of spinal anesthesia.3 Hemodynamic measurements were recorded at designated
intervals prior to and after administration of spinal anesthesia. The authors of this study reported
higher minimal systolic and mean blood pressure values in patients who were given 8 mg
intravenous ondansetron before spinal anesthesia, compared to patients in the placebo group.3

A study in Kolkata, India conducted by the Institute of Post Graduate Education and
Research Department of Anesthesia evaluated the effect of ondansetron on the hemodynamic
response following subarachnoid block in parturients undergoing elective cesarean section. The
authors hypothesized that the use of IV ondansetron in non-laboring obstectric patients would
reduce spinal-induced hypotension and bradycardia by blocking 5-HT3 receptors and preventing
the Bezold Jarisch reflex. Fifty-two parturient patients scheduled for elective cesarean section
were randomly selected into two groups.14 The parturient patients were American Society
Anesthesiology physical status I, between 20 and 40 years of age, and undergoing an elective,

Ondansetrom and Spinal Anesthesia 7

lower segment caesarean section. Before subarachanoid block twenty-six patients in Group O
received ondansetron 4 mg diluted to 10 ml and twenty-six patients in Group S received normal
saline 10 ml.14 The spinal technique was performed in the sitting position at L3-4 or L4-5 and
0.5% hyperbaric bupivacaine 2 mL was administered after confirmation of cerebrospinal fluid
through a 25- or 26-gauge Quincke spinal needle.14 Heart rate, systolic/diastolic, mean arterial
pressure, oxygen saturation were recorded at the time of spinal administration and at 2-min
intervals up to 20 minutes, followed by 5 minute intervals until end of surgery. Results showed
decreases in mean arterial pressure were significantly less in Group O than Group S from 14 min
until 35 min. Patients in Group O required significantly less vasopressor (P = 0.009) and had
significantly fewer incidences of nausea and vomiting (P = 0.049).14

Given that spinal anesthesia is the most common type of anesthetic given for cesarean
section, it is not uncommon for parturients to experience hypotension and less commonly
bradycardia. Current management of hypotension post-spinal anesthesia in cesarean section is
fluid management and the use of vasopressors.1 The use of a crystalloid or colloid fluid bolus
prior to spinal anesthetic administration for cesarean section has been used successfully to
combat hypotension. In a study conducted by Ngan, Khaw, Lee, Ng & Wong, an experimental
group received 15 ml/kg colloid bolus just prior to spinal anesthesia for cesarean section.15 When
compared to the control group, the experimental group had higher systolic blood pressures within
the first ten minutes following spinal anesthesia. Nonetheless, participants from both study
groups still required a vasopressor infusion to maintain systolic blood pressures within 90-100%
of baseline.

Many studies have been done with the utilization of phenylephrine and ephedrine in the
obstetric population. Both vasoactive drugs successfully treat post-spinal hypotension but have

Ondansetrom and Spinal Anesthesia 8

undesired side effects. Ephedrine is a synthetic, non-selective, non-catecholamine,
sympathomimetic vasopressor.1 The side effects that coincide with the use of ephedrine include
supraventricular tachycardia, tachyphylaxis, and fetal acidosis.16 Ephedrine causes B-adrenergic
stimulation as it crosses the placenta and increases fetal catecholamine levels. Phenylephrine is a
pure alpha-agonist and is associated with maternal bradycardia.16 Although the use of vasoactive
drugs in the parturient population has been shown to be effective, their use does not come
without potential harmful fetal effects. Finding an alternative to these medications, such as
ondansetron may decrease the risks of spinal anesthesia in the cesarean section patient.

In conclusion, if ondansetron can successfully block the Bezold-Jarisch reflex it may be
used successfully to treat post-spinal hypotension without the side effects of vasoactive drugs.
Anesthesia providers may improve patient outcomes by minimizing the use of vasopressors post
spinal anesthesia with the simple intervention of prophylactic ondansetron. This literature
review highlights the use of a 5HT3 antagonist as a successful prevention of hypotension and
bradycardia caused by the Bezold-Jarisch reflex in animals, obstetric and non-obstetric patients.
Further research is needed to determine the effectiveness of using ondansetron in preventing
hypotension and bradycardia post spinal anesthesia in the obstetric populations. With a decreased
incidence of bradycardia and hypotension, anesthesia providers can provide improved outcomes
for their parturient patients and neonates. As a result, patient satisfaction will be improved and
anesthesia providers can practice with an increased margin of safety.

Ondansetrom and Spinal Anesthesia 9

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