Introduction

One of the most frequently reported adverse events occurring as a result of anesthesia is postoperative nausea and vomiting (PONV).1 There are three categories for increased risk of PONV: surgery-related, anesthesia-related and patient-specific factors. Surgery-related factors include laparoscopic procedures and surgery duration greater than one hour.2 Anesthesia-related factors include the use of nitrous oxide, volatile anesthetics, higher doses of opioids and high doses of neostigmine.1,2 Patient-specific factors include female sex, age younger than 50 years, non-smoking status and a history of motion sickness or PONV.2 Up to 30% of surgical patients experience PONV, while 80% of patients with the associated risk factors experience PONV.2 For patients undergoing laparoscopic procedures, this PONV incidence increases to 72%.3 Postoperative nausea and vomiting is associated with increased risk for aspiration, surgical wound dehiscence and unexpected hospital admissions.3 The risk of PONV associated with volatile anesthetics has a direct correlation to length of exposure.4 Laparoscopic procedures are more time-consuming in comparison to other open procedures, subsequently increasing anesthesia time and exposure to volatile anesthetic.3 Patients receiving surgical care have reported PONV as being one of the most unpleasant experiences, often resulting in low satisfaction scores in the postoperative period.1 Prevention of PONV is more effective than treatment after nausea or vomiting has occurred.2 Postoperative nausea and vomiting can increase length of stay, prolong recovery time and increase healthcare costs.1

Laparoscopic surgical techniques have revolutionized patient care in urology, general surgery and gynecology.3 Laparoscopic approaches utilize smaller incisions, thereby decreasing surgical stress, which reduces postoperative pain.5 This allows patients to ambulate and resume activities of daily living sooner. Resumption of these activities leads to shorter hospital stays and decreased morbidity, creating the potential for significant cost savings.5 Creation of the pneumoperitoneum by instillation of gas under constant pressure into the peritoneum increases the visibility of intra-abdominal structures and provides increased space for surgical manipulation.3 Bowel manipulation and peritoneal insufflation are believed to be the causes of the increased risk of PONV in patients who are undergoing laparoscopic procedures.5 The use of multi-modal anti-emetics targeting different receptors has become the standard of care for laparoscopic procedures, yet emphasis should be placed on prevention whenever possible.3 The use of neuro-muscular blocking agents (NMBA) decreases the intra-abdominal pressure required for abdominal distention during creation of the pneumoperitoneum and prevents patient movement, which can displace surgical instruments leading to patient injury.5,6 After administration of NMBAs, it is not uncommon for patients to experience residual blockade. Recent studies have shown as many as two-thirds of patients receiving NMBAs show symptoms in the postoperative period.6 Residual blockade can lead to a decrease in airway patency, airway protective reflexes and respiratory function, which can increase the risk for aspiration or respiratory failure in the postoperative period.5,6 Neuromuscular recovery is enhanced by decreasing the concentration of NMBAs. This can be accomplished by increasing metabolism of the NMBA, encapsulating the NMBA, or by increasing the amount of acetylcholine available.6

Muscle depolarization and contraction is reliant upon acetylcholine release into the synaptic cleft. This occurs after an action potential makes its way across the nerve to the motor end plate. Once released, acetylcholine attaches to the muscle membrane receptor sites, leading to depolarization of the muscle and ultimately muscle contraction.7 Non-depolarizing NMBAs compete with acetylcholine at the receptor site to block nerve impulse transmission at the neuromuscular junction.8 The most commonly used non-depolarizing NMBA is rocuronium bromide due to its quick onset and intermediate duration, usually lasting around 30-60 minutes.7 The use of rocuronium itself does not increase the risk for PONV, but it can lead to residual paralysis.6 Best practice recommends that the paralytics effects of rocuronium be reversed before the patient is transferred to the recovery area.7 Sugammadex and neostigmine are two common agents used to reverse the effects of rocuronium.6,7

Acetylcholinesterase hydrolyzes approximately 5000 molecules of acetylcholine per second. Cholinesterase inhibitors bind with acetylcholinesterase, preventing the destruction of acetylcholine.6,7 This increases the amount of acetylcholine that is available at the motor end plate. Acetylcholine competes with NMBAs to occupy open receptor sites. Additionally, the life of acetylcholine will be prolonged when acetylcholinesterase is not available to hydrolyze it.7 The increase of acetylcholine is not limited to the motor end plate; it occurs throughout the body. This includes the muscarinic and nicotinic receptors that are occupied with acetylcholine, which can lead to parasympathetic side effects. Patients can experience bradycardia, bronchospasm, nausea and vomiting, increased pharyngeal secretions, miosis and increased intestinal tone.6 With the increased risk of PONV already present with laparoscopic procedures and routine use of NMBAs, the effect of reversal agents on PONV should be explored.

Sugammadex is a selective cyclodextrin that binds to NMBAs such as vecuronium, pancuronium and rocuronium. The NMBA is encapsulated by sugammadex, leaving it unable to bind to acetylcholine receptors.6 Once encapsulated, the complex is excreted in the urine.6,7 Even deep blockades can be reversed with sugammadex when the dosage is accurate.7 Since sugammadex does not increase the level of acetylcholine, it also does not produce the muscarinic and nicotinic effects seen with neostigmine.7

The proposed systematic review intends to determine the effectiveness of sugammadex as a reversal agent on PONV, compared to neostigmine. Since laparoscopic procedures increase the risk of PONV, the findings of this review could drastically improve patient outcomes. The results will assist healthcare providers in determining if there is sufficient evidence to support using sugammadex instead of neostigmine for the reversal of rocuronium in patients undergoing laparoscopic procedures.

Prior to the development of this protocol, a preliminary search was conducted in PROSPERO, JBI Database of Systematic Reviews and Implementation Reports, the Cochrane Library and PubMed. One systematic review comparing sugammadex to neostigmine was found in PubMed. In the review, 15 out of 17 clinical trials included reported results on PONV. The studies did not include any demographic information for patients experiencing PONV in each of the groups. Because age and sex can influence the occurrence of PONV, this lack of information could affect the quality of the results. Additionally, the results did not report on the presence or absence of the any of the risk factors for PONV in each of the compared groups, which could also influence the results. None of the clinical trials that were included in the systematic review were designed or powered to address PONV and the related use of sugammadex or neostigmine.9 The authors of the systematic review stated that it would be difficult to interpret any of the side effects included due to the varied events pooled from each of the studies. The systematic review also stated that the sample size was not large enough to analyze any of the drug-related side effects.9

A meta-analysis on the efficacy and safety of sugammadex compared to neostigmine was also found during the preliminary search.10 The authors stated that an analysis was conducted on nausea and vomiting, but it was limited and lacked data, so conclusions could not be drawn.10

Another meta-analysis on sugammadex and neostigmine as reversal agents was located.11 While some of the randomized control trials (RCTs) included in this meta-analysis included results for PONV, the results were conflicting, and the authors were unable to draw any conclusions.11

Several studies designed to explore the occurrence of PONV and use of neostigmine and sugammadex have been conducted, including a randomized study by Tas Tuna et al.12 and a clinical trial by Mathur.13 This proposed systematic review will focus on studies that were designed to test for PONV.

Review question

What is the effect of sugammadex versus neostigmine on PONV in adult patients undergoing laparoscopic procedures, paralyzed with rocuronium bromide?

Inclusion criteria

Participants

This review will consider studies that include adult surgical patients, 18 years and over, who underwent general anesthesia for laparoscopic surgeries and were paralyzed with rocuronium. This review will not consider studies in which the patient's procedure began laparoscopically but, for any reason, was not completed in the same way.

Intervention

This review will consider all studies that use any dosage of sugammadex as a reversal agent for rocuronium in adult patients undergoing laparoscopic procedures.

Comparator

This review will consider studies that use any dose of neostigmine to reverse the paralytic effects of rocuronium, following laparoscopic surgery, to compare with the intervention.

Outcomes

This review will consider studies that include the following primary outcomes: presence of PONV, severity of PONV and need for rescue anti-emetics. Symptom severity outcome measures may include descriptive reports, standardized nausea vomiting scoring tools and documented administration of any anti-emetics used to treat the presence of PONV. No other adverse effects or secondary outcomes will be considered.

Types of studies

Randomized control trials have been conducted that focus on the occurrence of PONV after the reversal of rocuronium in patients undergoing laparoscopic procedures. This review will be limited to RCTs. This review will only include studies that are available in English. If studies are found that are not available in English, they will be noted in the final review. There will be no date restriction on studies.

Methods

This systematic review will be conducted in accordance with the JBI methodology for systematic reviews of effectiveness evidence.14 The title for this protocol has been registered with JBI.

Search strategy

The search strategy aims to find both published and unpublished studies. An initial limited search of MEDLINE (PubMed) has been undertaken followed by an analysis of text words contained in the title and abstract, and of index terms used to describe the articles. This informed the development of a search strategy which will be tailored for each information source. A full search strategy for MEDLINE (PubMed) is detailed in Appendix I. The reference list of all studies selected for critical appraisal will be screened for additional studies.

Information sources

The databases to be searched will include: CINAHL, Embase, MEDLINE (PubMed) and Scopus.

The trial registers to be searched will include: Cochrane Central Register of Controlled Trials and ClinicalTrials.gov. The search for unpublished studies will include OpenGrey and ProQuest Dissertations and Theses.

Study selection

Following the search, all identified citations will be collated and uploaded into RefWorks (ProQuest LLC, Ann Arbor, USA) and duplicates removed. Titles and abstracts will then be screened by two independent reviewers for assessment against the inclusion criteria for the review. Studies that may meet the inclusion criteria will be retrieved in full and their details imported into JBI System for the Unified Management Assessment and Review of Information (JBI SUMARI; Joanna Briggs Institute, Adelaide, Australia). The full text of selected studies will be retrieved and assessed in detail against the inclusion criteria. Full-text studies that do not meet the inclusion criteria will be excluded and reasons for exclusion will be provided in an appendix in the final systematic review report. Included studies will undergo a process of critical appraisal. The results of the search will be reported in full in the final report and presented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.15 Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer.

Assessment of methodological quality

Selected studies will be critically appraised by two independent reviewers at the study level for methodological quality in the review using the JBI standardized critical appraisal instrument for RCTs.14 Any disagreements that arise will be resolved through discussion or with a third reviewer. All studies regardless of methodological quality will be included in the review. Critical appraisal results will be included in tabular and narrative formats.

Data extraction

Quantitative data will be extracted from papers included in the review using the standardized data extraction tool available in JBI SUMARI by two independent reviewers, AF and MA.16 The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. Authors of papers will be contacted to request missing or additional data, where required.

Data synthesis

Quantitative data will, where possible, be pooled in statistical meta-analysis using JBI SUMARI. Effect sizes will be expressed as either odds ratios (for dichotomous data) or weighted or standardized mean differences (for continuous data), and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-squared and I-squared tests. The choice of model (random or fixed effects) and method for meta-analysis will be based on the guidance by Tufanaru et al.17 Subgroup analyses will be conducted where there are sufficient data to investigate. Subgroups may include sex, race and duration of surgery. Sensitivity analyses will be conducted to test decisions made regarding pre-existing conditions, such as cholecystitis, gastroesophageal reflux and hiatal hernias, which may affect the presence of PONV. 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. A funnel plot will be generated to assess publication bias if there are 10 or more studies included in a meta-analysis. Statistical tests for funnel plot asymmetry (Egger test, Begg test, Harbord test) will be performed, where appropriate.

Assessing certainty in the findings

A Summary of Findings will be created using GRADEpro software (McMaster University, ON, Canada). The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for grading the quality of evidence will be followed. The Summary of Findings will present the following information, where appropriate: absolute risks for treatment and control, estimates of relative risk, and a ranking of the quality of the evidence based on study limitations (risk of bias), indirectness, inconsistency, imprecision and publication bias. The following outcomes will be included in the Summary of Findings: presence of PONV, severity of PONV, and administration of rescue anti-emetics.

Acknowledgments

This review will contribute to a Doctor of Nursing degree for AF.

The authors would like to thank Dr. Marsha Bennett, Director of The Louisiana Centre for Promotion of Optimal Health Outcomes: a Joanna Briggs Institute Centre of Excellence.

Appendix I: Search strategy for PubMed

PubMed via National Center for Biotechnology Information (NCBI)

References