Description of fìndings

The fìndings of each subgroup of strategies are available in Table 1. Twenty seven papers were rated as moderate to high quality according to AMSTAR-2, which describe the fìndings on acetaminophen, acupuncture and acupression, 5HT3 antagonists, NKi antagonists, dexamethasone and corticosteroids, dexmedetomidine, gabapentinoids, ginger, fluids, metoclopramide, midazolam, mirtazapine, naloxone, non-disaggregated non-pharmacological measures, total intravenous anesthesia (TIVA).

Acetaminophen

The use of IV acetaminophen as a prophylactic strategy for PONV was described by Doleman et al. ²¹ with moderate quality assessment result according to AMSTAR-2. Doleman et al. obtained RR=o.5 (95 % CI [0.31-0.83]; p=o.96) for the incidence of postoperative vomiting (POV), without mentioning the exact observation time. This research focused on pain dynamics, but the analysis of the incidence of POV was secondary.

Acustimulation, acupuncture and acupression

The research conducted by Chen et al. ²² included seven meta-analyses, the results of which pointed to transcutaneous electrostimulation as a prophylactic measure for PONV versus placebo. This research showed results for nausea with a RR=0.54 (95 % CI [0.42-0.69]; p<0.001), for the prevention of vomiting RR= 0.59 (95 % CI [0.49-0.71]; p=0<0.001) and for the prevention of PONV a RR=0.46 (95 % CI [0.33-0.65]; p<0.001).

Cheong et al. ²³ assessed the effectiveness of acupuncture and acupression at different sites, with various techniques, as compared against medication, placebo or impostor operator. Different electrostimulation - acupuncture strategies were reviewed at point PC6 -, pooled in the 30 randomized clinical trials (RCT) included. The findings indicated that acupuncture at PC6 for prophylaxis of nausea during the first 6 hours is not effective (RR=0.64; 95 % CI [0.34-1.19]; p=0.150), neither for postoperative vomiting prophylaxis over the first 24 hours (RR=0.82, 95 % CI [0.48-1.38]; p=0.450). However, practicing acupuncture for early and late nausea did prove to be effective (RR=0.36; 95 % CI [0.19-0.71]; p=0.003 and RR=0.25; 95 % CI [0.10-0.61]; p=0.002, respectively).

This same paper by Cheong showed that acupression at PC6 reduces the occurrence of nausea and vomiting during the first 24 hours postop (RR=0.71; 95 % CI [0.57-0.87]; p=0.001 and RR=0.62, 95 % CI [0.49-0.80]; p<0.001, respectively). Electrostimulation at point PC6 acted as prophylaxis for nausea and vomiting in the same postoperative period (RR=0.49; 95 % CI [0.38-0.63]; p<0.001 for PON and RR=0.50, 95 % CI [0.36-0.70]; p<0.001 for POV). The simultaneous stimulation of PC6 and other acupuncture points had a prophylactic effect for PONV over 24 hours postop (RR=0.29; 95 % CI [0.17-0.49]; p<0.001). The stimulation of different acupuncture points other than PC6 was effective in the prophylaxis of PONV over the first 24 hours (RR=0.63; 95 % CI [0.49-0.81]; p<0.001). Notwithstanding the results submitted, the authors declare a low quality of the studies included with a high possibility of bias, so the recommendation is to be cautious in the interpretation of the results.

5HT3 antagonists

Ahn et al. ²⁴ summarized the evidence with respect to the use of palonosetron versus ramosetron as a strategy for PONV prophylaxis; no statistically significant differences were identified (RR=1.07; 95 % CI [0.60-1.92]; p=0.03). They argued limitations in the data of the articles included in the analysis given the nature of the studies and the low reliability of the results, because the study populations were small.

Mihara et al. ²⁵ conducted a systematic review with meta-analysis, and did not include the data reported by Fujii because of a potential bias. They assessed the impact of administering ramosetron versus ondansetron or other pharmacological strategies as comparators in the prevention of PONV, concluding superiority versus placebo (RR= 0.59; 95 % CI [0.47-0.73]; p<0.001); however, such superiority was no better than the findings in other meta-analyses. They concluded that ramosetron may be more effective than ondansetron in the prevention of POV, but its clinical significance is questionable based on the high NNT in the interventions.

NK1 receptor antagonists

Liu et al. ²⁶ systematically described the reviewed evidence up to 2014 with regards to the use of aprepitant and other NK1 receptor antagonists in terms of their impact on PONV. They concluded that the use of this group of medicines, aprepitant in particular - with the most available evidence in the medical literature so far -, were effective in controlling PONV as compared to placebo (for nausea RR=0.6; 95 % CI [0.470.75]; p<0.001; and for vomiting RR=0.13; 95 % CI [0.04-0.37]; p<0.001).

Singh et al. ²⁷, in the assessment of aprepitant for PONV prophylaxis, found that it reduces the incidence of vomiting during the first postoperative day (OR=0.48; 95 % CI [0.34-0.67]; in the absence of a p value report), though such finding involves a heterogeneity which is difficult to explain according the statement of the authors; this reduces the strength of the evidence. They also reported that its use reduces the need for rescue medication and that the oral administration of the drug is equivalent to the parenteral administration.

Dexamethasone and corticosteroids

Chen et al. ²⁸ summarized the results of five trials assessing the use of dexamethasone for PONV prophylaxis in patients undergoing thyroidectomy. They found that the drug reduced the incidence of PONV (RR=0.38; 95 % CI [0.30-0.49]; with no p value report) and the need for postoperative analgesia.

Fan et al. ²⁹ collected information about the postoperative outcomes of dexamethasone in patients undergoing total knee arthroplasty, assessing pain and PONV outcomes. They found a lower incidence of PONV (OR=0.33; 95 % CI [0.23-0.47]; p<0.001). The investigators recommend expanding the number of studies to improve the confidence of the results.

Li and Wang ³⁰ conducted a meta-analysis on the available evidence in 2014 with regards to the use of dexamethasone for the prevention of PONV in thyroid surgery patients. They included the Fujii trials and they even found that one of them may have a confounding factor due to its poorer quality as compared to other trials. The conclusion was that the use of one dose of preoperative dexamethasone reduces the incidence and the severity of PONV in patients undergoing thyroidectomy (SMD=0.23; 95 % CI [0.130.41]; p<0.001).

Yang et al. ³¹ summarized the scientific evidence available on the use of corticoids -dexamethasone, methylprednisolone or hydrocortisone, taking equivalent doses with dexamethasone as the benchmark- versus controls for the prevention of PONV and postoperative pain. The conclusion was that the incidence of PONV and pain is significantly reduced during the postoperative period following total hip arthroplasty with the use of corticoids (RR=0.41; 95 % CI [0.30-0.57]; p<0.001); however, they recommend caution when considering these results because of dose variations, the methodological quality, and the strength of the trials in terms on the number of patients included.

Zou et al. ³² conducted a meta-analysis on the use of dexamethasone in the pre-operative period for patients undergoing thyroidectomy, in order to reduce the incidence of PONV. They found that administering a dose of between 8 to 10 mg before the induction of anesthesia is a safe and effective strategy for reducing the incidence of PONV (RR=0.52; 95 % CI [0.43-0.63]; p<0.001), reducing the use of rescue antiemetics, postoperative pain and the need to use rescue analgesia.

Dexmedetomidine

Fifteen prior studies were used by Wang et al. ³³ to determine the effectiveness of the prophylactic use of dexmedetomidine for PONV (for nausea, RR=0.43; 95 % CI [0.280.66]; p<0.001; and for vomiting RR=0.36; 95 % CI [0.18-0.72]; p=0.004), as well as to reduce postoperative tremor and the need for rescue antiemetics in patients under-going laparoscopic surgery.

Gabapentinoids

Notwithstanding the availability of another primary outcome for the assessment of gabapentin in perioperative medicine, Alayed et al. ³⁴ found that the administration of gabapentin versus placebo is effective as prophylaxis for nausea (RR= 0.76; 95 % CI [0.66-0.88]; with no p-value report).

Ginger

Chaiyakunapruk et al. ³⁵ conducted a meta-analysis of five studies assessing the use of ginger for PONV prophylaxis. They argued that the administration of 1 gr of ginger proved to be effective as compared to placebo (for nausea RR=0.69; 95 % CI [0.54-0.89]; without a p-value report. For vomiting RR=0.61; 95 % CI [0.45-0.84]; without p-value report). In contrast, Tóth et al. ³⁶ reviewed 10 research papers on the use of ginger as PONV prophylaxis versus placebo and failed to find any statistically significant differences, mainly because of the high heterogeneity of the original research projects.

Fluids

Jewer et al. ³⁷ conducted a statistical analysis of the information from 41 original papers assessing the use of crystalloids and found that their use in elective surgeries reduced the incidence of PONV, but there was no clarity about the outcomes in emergency surgeries because of the variability of the measurements of the primary studies.

Lee et al. ³⁸ reviewed the available evidence of nine clinical trials assessing the incidence of PONV on groups receiving colloids, versus crystalloids. They found that the perioperative administration of colloids does not reduce the incidence of PONV (RR=0.8; 95 % CI [0.56- 1.15]; p=0.224) as compared to crystalloids in surgeries, regardless of the surgical time; but there was a difference for surgical procedures exceeding 3 hours in which colloid infusion was used (RR=0.63; 95 % CI [0.44- 0.89]; p=0.009) as compared to the group receiving crystalloids infusion (RR=1.24; 95 % CI [0.4-2.09]; p=0.408). Despite this statistical finding, the authors state the need for improved methodological models with a larger number of patients to prove this association.

Yokohama et al. ³⁹ analyzed the information from 11 prior research papers and found that the administration of dextrose decreases the incidence of nausea, as compared to placebo (for early nausea RR=0.76; 95 % CI [0.59-0.99]; with no p-value report. For late nausea RR=0.65; 95 % CI [0.48-0.89]; with no p-value report), but they found no differences in the incidence of vomiting.

Metoclopramide

De Oliveira et al. ⁴⁰ reviewed 30 original articles on the use of metoclopramide in PONV prophylaxis. They found that the 10 mg IV dose is effective for the prevention of PONV as compared to placebo (RR=0.58; 95 % CI [0.43-0.78], with no p-value report). They also conducted sub-analyses of three articles published by Fujii, because of the risk of bias involved, but did not find any alterations in the final results.

Midazolam

Ahn et al. ⁴¹ summarized the available evidence for the use of IV midazolam as a prophylactic strategy for PONV. They found that a dose between 0.04 and 5 mg is effective in reducing postoperative events (RR= 0.45; 95 % CI [0.36-0.57]; p<0.001).

Grant et al. ⁴² assessed the efficacy of midazolam during the pre or intra-operative period to prevent the incidence of PONV and it proved to be effective (RR=0.55; 95 % CI [0.43-0.70]; with no p-value report) for up to 24 hours, as compared to the use of placebo.

Mirtazapine

Since mirtazapine is an antidepressant with various mechanisms of action including serotonin 5HT3 receptor antagonist, it has been described as an agent for PONV prophylaxis. The study by Bhattacharjee et al. ⁴³ identified in three out of seven studies included in their review, that the oral administration of 30 mg of mirtazapine 1 to 2 hours before surgery, significantly reduced PONV, with a RR=0.44 95 % CI [0.32-0.62], I2 0 %), and these results were confirmed with a trial sequential analysis (TSA). In a single low quality trial, a comparison against the drug ondansetron was identified with findings of equi-effectiveness. Based on low-quality studies, the advantages of the drug include a reduction in preoperative anxiety; however, increased sedation during the postoperative period was also identified.

Naloxone

The only study on this drug conducted by Barrons et al. ⁴⁴ and published in 2017 highlighted the importance of perioperative opioid administration as a source of PONV. They suggested the administration of low doses of naloxone which could have a dose-dependent effect with regards to specific outcomes, particularly PONV. The paper described a benefit in the perioperative administration of naloxone, in studies with minimum 24 hours of observation for PON with a RR=0.80 (95 % CI [0.67-0.95]; p=0.01). However, such benefit did not materialize in the case of postoperative vomiting, reporting a RR=0.83 (95 % CI [0.63-1.09]; p=0.18).

Non-pharmacological measures

Lee and Done ⁴⁵, in 1999, documented a moderate quality meta-analysis and systematic review summarizing the scientific evidence on non-pharmacological approaches for PONV, including acupuncture, electroacupuncture, transcutaneous electrical nerve stimulation, acupoints stimulation and acupression. They concluded that these techniques are effective for the prevention of early nausea, but not of early or late vomiting. They failed to assess the compounded PONV outcome. This article is described separate from the previously mentioned acupuncture articles because there was no separation among the groups of intervention, as was the case with acustimulation, acupuncture and acupression.

Total intravenous anesthesia (TIVA)

According to the findings by Schaefer et al. ⁴⁶ in 2016, total intravenous anesthesia as compared against balanced general anesthesia plus a single pharmacological intervention (anti 5HT3 or droperidol) are equally effective to prevent PONV episodes with a RR=1.06 (95 % CI [0.85-1.32]) for PONV and a RR=1.17 95 % CI [0.78-1.76] for nausea. The quality of the evidence in this trial was moderate as compared with the critically low evaluation of the study by Tramer ⁴⁷, and so the results were not taken into account.

Qualitative analysis

Table 2 lists the NNT for the studies included as moderate to high quality using the treat-as-one-trial methodology and the corrected NNT (NNTc) according to the methodology described in the Cochrane Manual of systematic reviews of interventions version 6.3 of 2022. The results for PON, POV and PONV are described in accordance with the original report of the referred authors.

Quantitative analysis

Keeping in mind that the populations were comparable, as well as the interventions assessed in the studies, a meta-analysis of three scientific articles was then conducted:

Chen (2012), Li (2014) and Zou (2014). Table 3 depicts the information of the articles included.

Postoperative nausea and vomiting prophylactically managed with dexamethasone

The tree chart on Figure 2 shows a RR=0.48 (95% CI [0.41-0.57]; p<0.001), with 63 % heterogeneity (p=0.07). The overlap analysis of the three trials assessing dexamethasone are shown on Table 4, the estimate for the corrected covered area (CCA) was 50 %, which according to Pieper et al. ⁴⁸ corresponds to a very high overlap, indicating that the source for the analysis of the studies had several clinical trials in common, a situation that could result in overestimating the RR. The study with the largest number of original papers was Zou et al. (2014). Table 4 depicts the overlap matrix for the visual assessment thereof. Using this matrix, the corrected covered area (CCA) was then estimated. The CCA for the dexamethasone studies was 50 %. This number, according to the cutoff points suggested by Pieper et al. ⁴⁸, is interpreted as a very high overlap.

Source: Authors.

Figure 2 Evaluation by items of the articles included in the study using the AMSTAR-2 tool. 

In view of the risk of bias based on the heterogeneity data and the nature of the studies, the sensitivity-based adjustment was implemented disaggregating one by one the reviews included in this study, with no differences identified in the results.

No meta-regression was conducted based on the findings in one single type of results, without subgroup analysis or covariables. ^49,50

Endorsement of the ethics committee

The research protocol registered under Prospero CRD42021251999 was submitted for approval by the Curricular Committee of the School of Health and Sports Sciences of Fundación Universitaria del Área Andina. Based on the nature ofstudy, it was classified as "no risk", pursuant to Resolution 8430 of 1993 of the Ministry of Health of Colombia (11). Therefore the approval of the ethics in research committee was not required.

Protection of humans and animals

The authors declare that no experiments in humans or in animals were conducted for this research. The authors declare that the procedures followed were consistent with the ethical standards of the committee for responsible human experimentation and pursuant to the World Medical Association and the Declaration of Helsinki.

Confidentiality of the data

The authors declare that the protocols of their work center on the publication of patient data have been followed.

Right to privacy and informed consent

The authors declare that no patient data are disclosed in this article. The authors were not required to obtain an informed consent from patients and/or subjects mentioned in the article.

Contribution by the authors

All of the authors significantly contributed to the conception or design of the study, and to the collection, analysis or interpretation of the data. They produced the design or the critical review of the document for a significant intellectual content and have approved the final version for publication.