Review question/objective

The objective of this review is to synthesize the best available evidence on the effectiveness of ondansetron given prophylactically prior to spinal anesthesia on attenuating hypotension in women undergoing elective cesarean section.

The specific review question is as follows:

In women undergoing spinal anesthesia for elective cesarean section, what is the effectiveness of prophylactic ondansetron on preventing hypotension, compared to placebo?

Background

The anesthetic technique of choice for the majority of elective cesarean sections worldwide is spinal anesthesia (SA).1,2 In recent decades the rate of cesarean deliveries has risen because of the greater awareness of fetal and maternal complications and more advanced technology to monitor them, as well as a shift in emphasis on the neonate's well-being.3 In fact, cesarean deliveries accounted for approximately 33% of all births in the United States in 2009 its 13th year with a consecutive increase4, and 15% worldwide in 2007 with a disproportionate distribution across countries.5 Spinal anesthesia is easy to perform, reliable, safe, and avoids the depressant effects of anesthetic drugs, allowing the mother to be awake during and immediately after delivery.2,6,7 The procedure consists of a fine needle placed in the subarachnoid (spinal or intrathecal) space in the spinal canal located in the lower back region. The needle passes beyond the epidural space where medication can also be infused and must puncture the dura to enter the subarachnoid space where cerebral spinal fluid and spinal nerves are located. Drainage of cerebral spinal fluid through the needle allows the anesthesia provider to confirm accurate placement of the needle; a small dose of local anesthetic can then be administered and at completion the needle is removed. The local anesthetic provides analgesia by acting directly on the nerves that supply the abdominal wall and uterus. In general anesthesia (GA) the mother is made unconscious for the birth most commonly by inhalation of volatile anesthetics that affect the whole body and ability to perceive pain. Recovery from the inhaled anesthetic after GA takes time, which might have impact on mother-child relationship, bonding, breast-feeding, and perhaps time before mother feels well enough to care for the newborn.8 Spinal anesthesia is preferable since GA is associated with a higher incidence of hemorrhage, the leading cause of maternal death worldwide.9 Also, GA requires securing the parturient's airway by tracheal intubation, which has an increased failure rate that is eight times higher (one in 274) than the general population.10 Both problems contribute to an increase in mortality. Despite the popularity of SA, maternal hypotension (MH) is a well-known complication with several studies reporting the incidence as high as 80-100%2,6,11-13 and is associated with other adverse effects such as bradycardia, nausea and vomiting. If severe, MH can result in detrimental consequences to the mother such as dyspnea, loss of consciousness, aspiration and cardiac arrest, and potentially cause harm to the baby as a result of fetal acidosis, and uteroplacental hypoperfusion.2,6,14,15 These complications can significantly impact outcomes; therefore, identification of effective prevention or minimization of hypotension is imperative for improved safety.

Profound physiological changes accompany pregnancy and clinicians must have a sound knowledge of these processes to avoid adverse events. Parturients become increasingly dependent on sympathetic tone to maintain hemodynamics as pregnancy progresses. During cesarean delivery, adequate SA must occur at the T4 dermatome level in order to provide a suitable sensory block.2,3 At this level, a blockade of sympathetic outflow occurs, causing peripheral and central vasodilation, which decreases return of blood to the heart. In addition to this loss of important sympathetic tone, the high incidence of MH after SA administration can be attributed to many other inherent risk factors for undergoing an elective cesarean section at full term. First, the utero-placental vessels are maximally dilated at term which results in low resistance and lack of significant autoregulation in response to low blood pressure.15 Also, when in the supine position, aorto-caval compression by the enlarged uterus leads to additional decrease in venous return to the heart.2,16 Lastly, patients scheduled for an elective procedure are required to fast for a prolonged period leading to dehydration and low preoperative blood volumes. All of these factors combined with the pathophysiological mechanisms following SA contribute to the severity and frequency of MH.

To date, numerous studies have been conducted to identify a reliable means of prophylaxis of MH following SA.2,17 Aside from any other treatment or prevention modalities, the American Society of Anesthesiologists in current practice guidelines recommends an intravenous infusion prior to and to be maintained throughout the duration of the anesthetic.18 Moreover, research on prevention and treatment has mainly focused on the efficacy of leg wrapping, patient positioning using reverse Trendelenburg and/or left-tilt, fluid preloading or co-loading, and administration of vasopressors such as ephedrine and phenylephrine.2,13,19 Interventions such as colloids, ephedrine and lower leg compression have been linked to a slight reduction in incidence of MH, but no single or combined intervention listed has proven to eliminate the need for treatment of MH following SA during an elective cesarean section.2,11,15,20 Furthermore, severe adverse effects from many of these interventions have been identified. Administration of colloids and/or vasopressors may lead to anaphylaxis, increased coagulation, cardiac dysrhythmias, impaired utero-placental perfusion and fetal acidosis specifically with ephedrine and phenylephrine.2,15,20 Leg wrapping may cause lower extremity ischemia as well as intense discomfort for the mother.2 Thus, the use of these methods may not be favorable and the search continues for the most efficient and low-risk strategy to achieve hemodynamic stability with SA during an elective cesarean section.

In recent years, many studies have linked MH following SA to a physiological mechanism called the Bezold-Jarish Reflex (BJR), a form of vaso-vagal syncope triggered by the sympathetic blockade and resulting decreased peripheral vascular resistance.14,19,21,22 The sudden decrease in left ventricle preload activates mechano- and chemoreceptors within the heart to produce a cardioinhibitory reflex: the BJR.23 Activation of the BJR causes further inhibition of sympathetic outflow and shifts the cardiac autonomic balance towards parasympathetic dominance, inducing bradycardia while further exacerbating hypotension and vasodilation.23,24 Research cites 5-Hydroxytryptamine-3 (5-HT3 or serotonin) as a potential factor which contributes to induction of the BJR by activating serotonin-sensitive chemoreceptors, especially in the presence of decreased blood volume.6,14,22,25 Therefore, current studies focus on investigating the ability of prophylactic intravenous 5-HT3 receptor blockers to attenuate MH after SA during elective cesarean delivery.

In particular, the prophylactic administration of a 5-HT3 antagonist, ondansetron, is of interest because it is widely available, economical, already commonly given to parturients to prevent nausea and vomiting with minimal side effects for the mother and has been shown to be safe with no harmful effects to the baby if given at term.1,26,27 Although there have been multiple randomized controlled trials conducted on the effect of 5-HT3 antagonists on hypotension following spinal anesthesia6,12,13,14,19,22,24,25, there is no systematic review that specifically investigates the effect of prophylactic ondansetron for the prevention of maternal hypotension following SA in women undergoing elective cesarean section. An initial search of EMBASE, PubMed, Joanna Briggs Database of Systematic Reviews and Implementation Reports and Cochrane Library of Systematic Reviews was conducted to locate any published systematic review on the proposed topic. A Cochrane systematic review published in 2006 reviewed prophylactic techniques for prevention of hypotension during SA for cesarean section2, but it does not include outcomes for use of 5-HT3 blockers. The most heavily researched techniques included intravenous fluids, drugs other than ondansetron, and physical methods like patient positioning. Given the frequency and severity of MH following SA during an elective cesarean delivery, a comprehensive systematic review on prophylactic ondansetron's effectiveness in preventing MH will provide valuable information that could improve the overall safety of SA and satisfaction for both provider and patient.

Inclusion criteria

Types of participants

The review will consider all quantitative studies that include parturients, of any ethnicity, undergoing spinal anesthesia for elective cesarean delivery. Studies that focus on any other surgeries other than cesarean section and anesthesia modes other than spinal anesthesia (general anesthesia or epidural anesthesia) will be excluded. Furthermore, any study with parturients not undergoing cesarean section or undergoing emergent cesarean section will also be omitted. Lastly, it is important to exclude studies that include subjects with hypertensive disorders of pregnancy, because this population may meet hypotension criteria less frequently.15

Types of intervention(s)/phenomena of interest

This review will only consider studies of ondansetron administered intravenously for the prevention of hypotension in subjects requiring spinal anesthesia for elective cesarean section. More precisely, the goal of this review is to identify if prophylactic administration of ondansetron is more effective than a placebo in preventing hypotension after spinal anesthesia. All variations of ondansetron dosages and their duration of administration will be included. Differences in anesthetic technique across studies, including the variations in armamentarium and dosing strategies are beyond the goal of the review question under inquiry, and will not be compared - this would be a topic for a separate review. More importantly, anesthetic standardization among comparison groups in any study included for analysis must exist. Any study that uses ondansetron for the treatment of hypotension will also be excluded; prophylactic administration is the only acceptable period. Finally, if a study's definition of hypotension lacks clarity it will also be this will also be excluded.

Types of outcomes

This review will consider studies that include the following outcomes: systolic, diastolic or mean arterial blood pressure - used alone or in combinations. The definition of hypotension usually varies among studies and providers, but the most commonly reported definition in the literature is a drop in blood pressure of less than 80% of baseline, which is actually in contrast with most clinicians preference in treating absolute values compared to a percentage of the patient's baseline number.28 Therefore, for the purpose of this review and data synthesis hypotension is defined as a decrease in systolic, diastolic or mean arterial blood pressure more than 20% compared to baseline, or a systolic measurement less than 90 mmHg or diastolic less than 60 mmHg.

Types of studies

This review will consider all published or unpublished well-designed controlled trials, randomized controlled trials, prospective and retrospective cohort studies that compare the use of ondansetron with placebo.

Search strategy

The comprehensive search strategy aims to find both published and unpublished studies. In this review a three-step search strategy will be utilized. An initial limited search of MEDLINE and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe the article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of identified reports and articles will be hand-searched for additional studies as Studies published from 1980 to July 2015 will be considered for inclusion in this review. Ondansetron was first developed in the 1980s.29 Only studies published in the English language will be considered for this review.

Additional databases to be searched:

Cochrane Central Trials Register

EMBASE

Web of Science

Wiley Online Library

PubMed

TRIP (Turning Research Into Practice)

mailto:Nursing@OVID

ScienceDirect

Clinical Key

The search for unpublished studies will include:

New York Academy of Medicine Grey Literature Report

AHRQ (Agency for Healthcare Research and Quality)

ProQuest Dissertations and Theses

Initial keywords to be used will include:

Ondansetron, Spinal anesthesia, Hypotension OR Low Blood Pressure, Cesarean section OR Cesarean delivery OR Abdominal delivery, Parturient, Prevention OR prophylaxis

Assessment of methodological quality

Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer.

Data extraction

Data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Authors of primary studies will be contacted for missing information or to clarify unclear data.

Data synthesis

Quantitative data will, where possible be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square and also explored using subgroup analyses based on the different study designs included in this review. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.

Conflicts of interest

The authors have no potential conflicts of interest to declare.

Acknowledgements

This systematic review is being conducted in partial fulfillment of the requirements for a Doctor of Nursing Practice (DNP) degree as established by the Texas Christian University School of Nurse Anesthesia.

References