Efficacy and safety of enhanced recovery after surgery protocol on minimally invasive bariatric surgery: a meta-analysis

Background: Enhanced recovery after surgery (ERAS), a multidisciplinary and multimodal perioperative care protocol, has been widely used in several surgical fields. However, the effect of this care protocol on patients receiving minimally invasive bariatric surgery remains unclear. This meta-analysis compared the clinical outcomes of the ERAS protocol and standard care (SC) in patients who underwent minimally invasive bariatric surgery. Material and methods: PubMed, Web of Science, Cochrane Library, and Embase databases were systematically searched to identify literature reporting the effects of the ERAS protocol on clinical outcomes in patients undergoing minimally invasive bariatric surgery. All the articles published until 01 October 2022, were searched, followed by data extraction of the included literature and independent quality assessment. Then, pooled mean difference (MD) and odds ratio with a 95% CI were calculated by either a random-effects or fixed-effects model. Results: Overall, 21 studies involving 10 764 patients were included in the final analysis. With the ERAS protocol, the length of hospitalization (MD: −1.02, 95% CI: −1.41 to −0.64, P<0.00001), hospitalization costs (MD: −678.50, 95% CI: −1196.39 to −160.60, P=0.01), and the incidence of 30-day readmission (odds ratio =0.78, 95% CI: 0.63–0.97, P=0.02) were significantly reduced. The incidences of overall complications, major complications (Clavien–Dindo grade ≥3), postoperative nausea and vomiting, intra-abdominal bleeding, anastomotic leak, incisional infection, reoperation, and mortality did not differ significantly between the ERAS and SC groups. Conclusions: The current meta-analysis indicated that the ERAS protocol could be safely and feasibly implemented in the perioperative management of patients receiving minimally invasive bariatric surgery. Compared with SC, this protocol leads to significantly shorter hospitalization lengths, lower 30-day readmission rate, and hospitalization costs. However, no differences were observed in postoperative complications and mortality.


Introduction
Obesity, a global epidemic, is closely associated with many chronic diseases, such as type 2 diabetes mellitus, dyslipidemia, hypertension, and obstructive sleep apnea, posing a severe threat to public health [1] . Bariatric surgery is considered a conventional treatment for morbid obesity, improving obesity-related comorbidities and, weight loss outcomes better than intensive medical therapy [2] . Therefore, over 1.6 million bariatric surgeries have been performed globally in the past decade. Of them, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) are the two most standard and prevalent surgical approaches, accounting for greater than 80% of all procedures [3,4] . Minimally invasive technology offers the advantages of reduced intraoperative bleeding, reduced postoperative complications, and a shortened hospital stay, thus making bariatric surgery more popular [5,6] .

HIGHLIGHTS
• Enhanced recovery after surgery (ERAS) is a multimodal and multidisciplinary perioperative care protocol and has been widely implemented in several surgical fields. • The effect of the ERAS protocol on patients receiving minimally invasive bariatric surgery remains unclear. • This is the first meta-analysis of the ERAS protocol versus standard care in patients undergoing minimally invasive bariatric surgery, and the results indicate that this protocol is feasible and safe.
Nevertheless, the incidence of serious adverse events (such as deep-incisional surgical site infection, pulmonary embolism, pneumonia, stroke/cerebral vascular accident, etc.) remained high during minimally invasive SG (3.53%) and RYGB (7.23%) in super-obese patients [7] . Enhanced recovery after surgery (ERAS) was first described as an interdisciplinary, standardized, and multimodal care protocol in the late 1990s. This protocol minimizes the surgical stress response and improves postoperative outcomes through perioperative interventions [8] . Compared with conventional perioperative care, the ERAS protocol significantly improves overall morbidity, shortens hospital stay, and reduces hospitalization costs in patients enduring most surgeries, such as gastrointestinal surgery, hepatobiliary surgery, and cardiothoracic surgery [9][10][11] . Patients with morbid obesity commonly experience respiratory, metabolic, and circulatory problems, significantly increasing the difficulty of perioperative care. Simultaneously, these problems challenge the feasibility of implementing the ERAS protocol in the bariatric procedure [12] . In 2016, the ERAS Society reported the first version of evidence-based guidelines for perioperative management in bariatric surgery, updated in 2021. However, many recommendations for this implementation are extrapolated from other surgery types, with relatively low quality of evidence [13,14] . Several studies  have yielded inconsistent outcomes after assessing the effectiveness of this multimodal care protocol in minimally invasive bariatric surgery. Therefore, the safety and usefulness of the ERAS protocol in a bariatric setting are unclear. Thus, a meta-analysis was conducted to evaluate the overall clinical outcomes associated with the ERAS protocol compared with standard care (SC) in patients who underwent a minimally invasive bariatric procedure and to provide a foundation for evidence-based clinical decision-making.

Protocol and registration
This systematic review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [36] and Assessing the Methodological Quality of Systematic Reviews (AMSTAR) standards [37] . Moreover, the prospective study protocol was registered in PROSPERO (CRD42022308886).

Search strategy
PubMed, Web of Science, Cochrane Library, and Embase databases were systematically searched from inception to 01 October 2022, to identify all studies reporting the effects of the ERAS protocol on overall clinical outcomes of minimally invasive bariatric surgery. The following search keywords or medical subject heading terms were used in all possible combinations: 'ERAS,' 'ERABS,' 'enhanced recovery after surgery,' 'enhanced recovery after bariatric surgery,' 'fast track,' 'laparoscopic,' 'robotic,' 'minimally invasive,' 'bariatric surgery,' 'metabolic surgery,' 'weight loss surgery,' 'diabetes surgery,' 'sleeve gastrectomy,' and 'Roux-en-Y gastric bypass.' Furthermore, reference lists of the selected articles were manually examined to identify other relevant articles. Only studies presented in the English language were included in the study.

Inclusion and exclusion criteria
Three authors (J.C., Y.L., and S.H.) independently determined the eligibility of the articles, and any disagreements were resolved through group discussion. The inclusion criteria were: published randomized controlled trials (RCTs) and retrospective cohort studies; ERAS protocols including at least eight items from the recommended guidelines; a study comparing the influence of the ERAS protocol with that of SC on surgical outcomes in patients after minimally invasive bariatric surgery; and studies whose full texts were available. The latest and most comprehensive data were included if the same institution replicated studies. The exclusion criteria were: abstracts, reviews, case reports, and conference reports; studies without a control group; and studies without a clear description of ERAS protocol elements.

Data extraction and quality assessment
The full-text screening of the eligible studies was independently conducted by two authors (R.W. and F.P.), followed by data extraction based on the predefined criteria. Consistently, disagreements were resolved through a plenum consensus. The extracted data had details on study characteristics (region, study design, sample size in each arm, and follow-up time), patient baseline features [age, sex, BMI, comorbidity, and type of surgery], ERAS protocol elements, and the clinical outcome indicators [such as hospital length of stay, overall complications, major complications, postoperative nausea and vomiting (PONV), anastomotic leak, intra-abdominal bleeding, incisional infection, reoperation, 30-day readmission, hospitalization costs, and mortality]. The Clavien-Dindo classification was used to assess the severity of complications, with major complications being grade ≥ 3 [38] .
Using the Cochrane Risk of Bias, two authors (C.F., Y.G.) assessed the quality of the included RCTs tool based on seven criteria [39] . Besides, the selected nonrandomized comparative studies were evaluated for risk of bias using the Newcastle-Ottawa scale (NOS), and a score of greater than 6 was considered high-quality [40] .

Statistical analysis
Pooled estimates for continuous and categorical variables were described as mean difference (MD) and odds ratio (OR), respectively, with a 95% CI. Moreover, heterogeneity between trials was assessed by the χ 2 -test and was expressed using the I 2 index. Significant heterogeneity was indicated when P less than 0.1 or I 2 greater than 50%. In case of significant heterogeneity, pooled data were calculated with the random-effects model. Otherwise, the fixed-effects model was adopted. Sensitivity analyses were conducted to evaluate the stability of results by removing each study in a single turn and determining the pooled effect size. Further subgroup analyses were performed to determine potential sources of significant heterogeneity, if necessary. The potential publication bias of the included studies was evaluated using contour-enhanced funnel plots. Statistical data analysis was performed using the Cochrane Review Manager software (RevMan, version 5.3), with P less than 0.05 being statistically significant.
In contrast, the pooled data from the three RCTs [17,25,28] displayed that the ERAS group patients had a lower PONV rate than those in the SC group (OR = 0.42; 95% CI: 0.19-0.95; P = 0.04).

Sensitivity and subgroup analyses
According to sensitivity analyses, the significant heterogeneity among studies reporting overall and major complications was significantly reduced (P = 0.55, I 2 = 0%; P = 0.15, I 2 = 31%, respectively) by excluding the trial of Mannaerts et al. [23] . This indicated that heterogeneity might have mainly come from this study. However, the recalculated results revealed no significant change in the outcomes. Furthermore, subgroup analyses were conducted based on surgical types, such as SG, RYGB, and SG + RYGB. The results of the subgroup analyses ( Table 2) were similar to those of the primary analyses. However, the hospital stay of RYGB and the 30-day readmission rate of SG and RYGB did not differ significantly between the two groups (MD = − 0.65; 95% CI: − 1.39 to 0.88; P = 0.08).

Publication bias
Funnel plots helped determine the potential publication bias. No significant publication bias was observed through a visual indication of the funnel plots for PONV, intra-abdominal bleeding, reoperation, and 30-day readmission (Fig. 13).

Discussion
Minimally invasive technology and the ERAS protocol are the two major approaches that could facilitate surgeons in reducing the surgical stress response and accelerating postoperative functional recovery. Since Kehlet first proposed ERAS in patients receiving major surgery, it has been translated into many surgical fields. Moreover, the corresponding evidence-based guidelines for perioperative care have been established to manage patients undergoing surgery [42,43] . However, the ERAS protocol was implemented relatively late in bariatric surgery. Several metaanalyses have concluded that the ERAS protocol significantly decreases the length of hospitalization in patients undergoing bariatric surgery [41,44,45] . Nonetheless, these studies failed to clarify the importance of ERAS in minimally invasive bariatric surgery, even though this surgical approach is strongly recommended [14] . This is the first meta-analysis comparing the ERAS program with SC in patients undergoing minimally invasive bariatric surgery, wherein more recently published studies have been included. Our results revealed that the ERAS protocol, compared with the SC, significantly decreased the length of hospitalization. The ERAS interventions are carried out throughout the perioperative period to ensure postoperative functional recovery and early discharge. Preoperative education and counseling are strongly recommended as essential ERAS protocol components to ensure  realistic expectations and reduce anxiety. All the included studies adopted these recommendations, leading to a shorter hospital stay [14,46] . Lam et al. [22] reported that the ERAS protocol successfully helped discharge 83.1% of patients on the first postoperative day without any increase in complications and readmissions. Furthermore, some medical centers explored that ERAS-based bariatric surgery could be performed as an outpatient procedure, and same-day discharge seemed feasible and safe in the selected patients [47,48] . High-quality evidence is available regarding the advantage of the ERAS protocol in reducing the length of hospitalization in bariatric surgery, as further confirmed by our results in patients undergoing minimally invasive approaches.
Regarding perioperative safety, the ERAS and SC groups had comparable incidences of postoperative complications, including overall complications, major complications, PONV, anastomotic leak, intra-abdominal bleeding, incisional infection, and reoperation. In the stratified analysis, pooled data from three RCTs [17,25,28] revealed that the ERAS group had a significantly lower PONV incidence than the SC group. Morbid obesity, gastric surgery, and gastric volume reduction are all risk factors for PONV. Therefore, multimodal PONV prophylaxis should be used in all patients before bariatric surgery based on the ERAS guidelines [14,49] . In all the included studies, antiseptic agents, opioid-free total intravenous anesthesia, or multimodal anesthesia were explicitly used as precautionary measures for PONV in the ERAS group, which may have contributed to the lower incidence. Moreover, PONV is the leading cause of delayed discharge and readmission after bariatric surgery [50,51] . The 30-day readmission rate was significantly lower in the ERAS group, which differs from that observed in previous studies [41,44,45] . This may be due to the larger sample size. Besides, PONV and longer hospital stays are predictors of readmission. Another study revealed that patients with a hospital stay of greater than 3 days were 2.57 times more likely to be readmitted than those with a hospital stay of less than or equal to 3 days [52] . In contrast, subgroup analysis from six RCTs revealed that the two groups had no significant difference in the incidence of 30-day readmission. Admittedly, this conclusion should be interpreted cautiously and verified through large-scale RCTs. Our analysis also failed to perceive any statistically significant difference in mortality between the two groups. Venous thromboembolism (VTE) is the primary cause of morbidity and mortality in morbidly obese patients undergoing bariatric surgery [53] . Among all the included studies, only Papasavas et al. [35] reported the complications of portal vein thrombosis. Therefore, we did not pool VTE for analysis in our study. The incomplete data could be attributed to the relatively low incidence of VTE in bariatric surgery (< 1%) [54] . Moreover, the ERAS protocol implementation is conducive to reducing VTE incidence. In the study of Meunier et al. [24] , all the patients wore compression stockings during the operation. However, others with a BMI > 50 kg/m 2 or a history of International Journal of Surgery deep venous thrombosis wore pneumatic stockings. Moreover, the combination of mechanical prophylaxis and chemoprophylaxis with unfractionated heparin were also used to prevent the occurrence of VTE as part of the ERAS protocol [27] . Overall, the safety of the ERAS protocol was corroborated in minimally invasive bariatric surgery, which is consistent with most of the included studies. Previous meta-analyses of the ERAS protocol implementation in bariatric surgery did not determine hospitalization costs. Our study revealed that hospitalization costs were significantly reduced in the ERAS group, indicating the cost-effectiveness of the perioperative interventions. A retrospective study had a significant decline in the median costs by 19.2%, from $11,739.03 to $9482.18, after implementing the ERAS program [55] . Generally, the reduction in length of stay causes a significant decrease in overall hospitalization costs, although the costs of surgical and anesthesia services associated with ERAS will increase accordingly [20] . Stone et al. [56] reported that a length of stay reduction by 0.7 days led to a net institutional savings of nearly $400,000 annually.
Postoperative pain can lead to severe suffering in patients and delay functional recovery. Therefore, effective analgesia is a  critical component of the ERAS protocol. The ERAS guidelines support using multimodal, opioid-sparing analgesia approaches, including local anesthetics, to advance postoperative recovery for bariatric surgery patients [14] . Lidocaine, dexmedetomidine, ketamine, and nonsteroidal anti-inflammatory drugs possibly have better anti-inflammatory effects and are preferred [57] . In a recent meta-analysis including eight RCTs [58] , applying the transversus abdominis plane block in laparoscopic bariatric surgery could decrease pain intensity, morphine requirement, and ambulation time, thereby facilitating faster patient recovery. In our meta-analysis, multimodal analgesia protocols were adopted in all the included studies to promote recovery. However, these approaches were very heterogeneous regarding local anesthetic infiltration and drugs. Four studies [20,27,28,32]    reported transversus abdominis plane block application in multimodal analgesia projects, improving efficacy and significantly reducing postoperative opioid use. Moreover, most included studies assessed postoperative pain, but data were not pooled for quantitative analysis due to heterogeneity. Nonetheless, our meta-analysis has several limitations. First, the number and compliance of ERAS protocol elements varied among the included studies. This could have affected the ERAS efficacy evaluation. Second, heterogeneity could be exacerbated by various baseline characteristics and surgical procedures. Although subgroup analyses were performed, the influence of heterogeneity could not have been eliminated. Finally, only articles published in English were included, leaving out relevant articles in other languages.

Conclusions
Our study indicated that the ERAS protocol is feasible and safe for patients undergoing minimally invasive bariatric surgery. The protocol significantly reduced the length of hospitalization, hospitalization costs, and 30-day readmission rate without any increase in postoperative complications and mortality. These data can have crucial clinical implications for elevating the quality of evidence, thereby supporting the protocol implementation in patients undergoing minimally invasive bariatric surgery.

Ethical approval
Ethical approval was not required.