The 2019 novel coronavirus disease (COVID-19) pandemic continues to infect a large number of patients, with fever, dry cough, fatigue, and shortness of breath, acute respiratory distress syndrome (ARDS) as major symptoms. These symptoms are also the risk factors for ventilator dependence [1] . As of October 5, 2020, over 36,600,000 cases and 1,000,000 deaths related to COVID-19 have been reported in at least 200 countries [2] . COVID-19 is caused by SARS-CoV-2, which belongs to the Betacoronavirus genus such as SARS-CoV, and MERS-CoV [3] . SARS-CoV-2 has a lower pathogenicity as compared with SARS-CoV, but has higher pandemic potential [4] [5] [6] [7] . Respiratory droplets, close contact transmission, and aerosol transmission in a relatively closed environment are the major routes of transmission [8] .
Thus, surgical procedures may place clinicians at particularly high risk when caring for infected patients.
Surgical stress may impair cell-mediated immunity to reduce the resistance to viruses. Meanwhile, COVID-19 may complicate the postoperative course to increase the mortality of operative patients [9, 10] , while the major factors contributing to the increased postoperative mortality in patients with COVID-19 remain unelucidated. At present, little is known about the clinical characteristics and outcomes of operative patients with COVID-19 during the perioperative period.
COVID-19 brought serious threats to the safety of medical staff in addition to the general public [11] . Among medical staff, surgeons, anesthesiologists and operating nursing staff are at the highest risk of infection due to the exposure to respiratory droplets or aerosol from infected patients during airway manipulations and surgery [12] . An early report showed that fifteen hospital staff members in Wuhan Union Hospital (China) who had closed contact with infected patients, were confirmed as being infected with COVID-19 [13] . Thus, effective personal protective procedures and cautions should be taken to prevent medical staff from COVID-19 infection. Our knowledge of the protective measures of COVID-19 during the perioperative period is inadequate and limited.
Thus, the present analysis aimed to describe the clinical outcomes of operative patients with COVID-19, and the safety of medical staff during the perioperative period to take appropriate protective measures to avoid cross-infection. It is out hope that our findings of the COVID-19 associated postoperative mortality and reasonable advises will benefit the global community in the battle against COVID-19 infection.
This meta-analysis was accomplished in agreement with the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement [14] .
We systematically searched PubMed, Cochrane Library, Embase and Chinese database National Knowledge Infrastructure (CNKI) with the search terms "COVID-19 00 or "SARS-CoV-2 00 and "Surgery" or "Operation" for all published articles on COVID-19 from December 1, 2019 to October 5, 2020. Only full articles involving humans were considered. Duplicate results were removed. The remaining articles were screened for relevance by its abstracts independently by two authors (Changshuai Wu and Kun Wang). The remaining investigators (Zhenglian Gao and Xiaowang Zhang) read full selected articles that met the requirements. In addition, closely relevant references to the current research topic were also manually searched. These articles were thoroughly read, and those that fulfilled our criteria were included in the study.
The inclusion criteria were as follows: (1) research types: randomised controlled trials (RCT), case report and case series; (2) research subjects: patients with COVID-19 underwent surgery and (3) data items: including clinical characteristics, outcomes, or medical staff safety. Exclusion criteria were as follows: (1) repeated research, and (2) lack of data.
Data extraction was performed independently by two authors (Changshuai Wu and Jian Xu), and we used standardized forms that include first author, publication date, country, number of patients, age, gender, comorbidities, surgery intervention, anesthetic method, surgical difficulty category, medical staff infection, study design, and clinical outcome, and so on. If there was any ambiguity in the search process, the decision was made by a third investigator (Zhengyuan Xia).
The primary outcome was the mortality rate of operative patients with COVID-19 and the secondary outcome was medical staff safety (i.e., the number of medical staff being infected with COVID-19 in the hospital).
Statistical analyses were performed using RStudio meta R package (version 3.6.2). Arcsine differences (ASD) were used as the measure of risk differences. The main advantages of using ASD are that the variance of the point estimate is determined solely by the sample size and that it handles occurrences of 0 counts, allowing for incorporation of trials with 0 events in both control and treatment groups into meta analyses [15] .The combined prevalence and 95% confidence interval (CI) were calculated using a random effects model or fixed effects model. The selection of the model was determined according to Q statistics. When Q statistics (p < 0.10) indicated heterogeneity, the random effect model was utilized for meta-analysis. When Q statistics (p 0.10) indicated the lack of heterogeneity, then a fixedeffect model was utilized for meta-analysis. Spearman's rank
Evidence before this study COVID-19 complicated the postoperative course to increase the mortality of operative patients, and brought serious threats to the safety of medical staff serving operative patients. We searched PubMed for all articles describing the clinical characteristics and outcomes of operative patients with COVID-19 up to October 5 2020, we found only some case reports, however, no studies performed a systematic review and meta-analysis on the perioperative mortality of operative patients with COVID-19 and no data related the risk factors for poor outcome.
We searched PubMed, Cochrane Library, Embase and CNKI with the search terms "COVID-19 00 or "SARS-CoV-2 00 and "Surgery" or "Operation" for all published articles on COVID-19 from December 1, 2019 to October 5, 2020. A total of 269 patients from 47 studies were included in our meta-analysis. The mean age of operative patients with COVID-19 was 50.91 years, and 49% were female. A total of 28 patients were deceased, with the overall mortality of 6%. The operative patients who had respiratory complications or COVID-19 typical symptoms may have higher mortality. Twenty studies reported the information of medical staff infection, and a total of 38 medical staff were infected, and medical staff who used biosafety level 3 (BSL-3) protective equipment did not get infected.
COVID-19 patients may have high postoperative mortality, and postoperative respiratory complications and COVID-19 typical symptoms may be the higher risk factors for poor outcome after operation. Medical staff serving operative patients is at high risks of cross-infection, and effective personal protective procedures can reduce the risk of COVID-19 infection of medical staff.
correlation was used to analyze the correlations among preoperative comorbidities, age, postoperative complications and the mortality rate.
Sensitivity analysis by leave-one-out was performed to single out heterogeneity. Heterogeneity was assessed with the Q statistic test and the I 2 test. The I 2 statistic measured the percentage of total variation across the studies aroused from clinical or methodological heterogeneity rather than by chance. The Egger test was performed to assess publication bias in all literature works, and p < 0.05 was considered as the exist of publication bias, and the funnel plot showed the publication bias intuitively.
The funding agencies had no role in study design, data collection and analysis. The corresponding authors have full access to all data in the study and are fully responsible for the decision of submitting for publication.
Using the above selection criteria, we identified a total of 1426 records, and 574 papers remained after exclusion of irrelevant topics and duplicates. Of those, a total of 66 citations met the inclusion criteria and remained for title and abstract screening. Four of these 66 items did not have a full text. After assessing 62 full-text articles for eligibility, we further excluded 15 full-text articles due to the exist of one of the following reasons: 1) no operative patients (8 articles) or relevant data (5 articles), and 2) review articles (2 articles). Eventually, 47 studies were included in this meta-analysis, and the trial selection process was shown in Fig. 1 .
The characteristics of included trials were presented in Table 1 Patients who presented any or more of the symptoms of respiratory failure, ARDS, short of breath and dyspnea after operation were associated with significantly higher mortality (r = 0.891, p < 0.001), while patients whose symptoms were presented as fever, cough, fatigue or myalgia only demonstrated marginally significant association with postoperative mortality (r = 0.675, p = 0.023). Preoperative comorbidities, the age of patients, and other postoperative complications were not significantly associated with increased risk of mortality. This suggests that postoperative respiratory complications and COVID-19 typical symptoms may be the major risk factors for poor outcome after operation. staff were infected, and medical staff who used biosafety level 3 (BSL-3) protective equipment during the perioperative period did not get infected.
We carried out Egger's regression test and confirmed the absence of publication bias (Egger, p = 0.06) for the final articles included for analysis, and the funnel plot was symmetrical, which indicate that publication bias did not exist.
The main focus of this study was to investigate the mortality rate of patients with COVID-19 undergoing surgery, and the related risk factors of the death during the perioperative period. We found that operative patients with COVID-19 infection had higher rate of mortality and the occurrence of postoperative complications. In particular, respiratory failure/ARDS/short of breath/ dyspnea or fever/ cough/fatigue or myalgia were significantly associated with postoperative death in patients with COVID-19. Twenty-eight of the 269 operative patients died of operation or COVID-19 associated complications, the overall mortality rate was 6%, with a mortality rate much higher than the 1.8À4.5% postoperative mortality in ASA-III patients as reported [63] . Most of the deceased patients had complications associated with COVID-19 symptom and respiratory syndrome. The patient's immune function is a major determinant of the disease severity, and surgical stress may not only impair immune function [64] , but also induce systemic inflammatory response [65] . The immune suppression after surgery should have exacerbated the progression and severity of COVID-19 infection. Most of those patients quickly present with typical symptoms such as fever, dry cough, fatigue or myalgia. COVID-19 can cause quick deterioration of lung function because the lung is the main target organ of the virus. In our study, the majority of patients rapidly developed respiratory failure/ARDS/short of breath/ dyspnea, which rendered them vulnerable to death. This is consistent with the findings of Chen et al.'s study who showed that 17% patients developed ARDS and, among them, 11% patients' condition worsened in a short period of time and died of MOF [66] . In addition to cause the progression to respiratory syndrome, COVID-19 disease also impairs other organ functions (e.g. heart, kidneys, liver) [67] . In our study, patients developed cardiac injury/cardiopulmonary arrest/arrhythmia/palpitation, acute kidney injury, diarrhea and even MOF. Furthermore, several patients rapidly progressed to shock/coma/secondary infection/sepsis that were concomitant with severe lymphopenia and electrolyte disturbance. This is consistent with the findings of Lei et al.'s study who showed that the most common complications of patients in non-survivors included shock, hyperleukocytemia, and lymphopenia [19] . Thus, operative patients with COVID-19 infection have higher perioperative mortality [68, 69] . Medical staff serving operative patients is at high risks of the cross-infection. The availability and especially proper utilization of valuable personal protective equipment (PPE) are of utmost importance. Clinicians have to balance a possible delay in cancer treatment against the risk for a potential COVID-19 exposure [70, 71] . Alternative therapeutic approaches should be pursued, especially in very early -or very advanced-stage diseases. Turaga et al.'s study found that most cancer surgeries can be safely delayed beyond the current waiting time for at least 4 weeks without having a significant impact on patient survival or cancer progression [72] . Timely treatment of urgent cases with COVID-19 infection and the optimal of the protection of medical staff should both be taken into serious consideration. During a pandemic, it is essential to ensure emergency surgery care. If non-operative management failed and surgery is deemed necessary, appropriate PPE and precautions should be adopted, and surgery should not be delayed whilst waiting for the swab results [73, 74] . The decision and plan to recognize whether surgery is required should be conducted by a senior clinician with the experienced surgeon, anaesthetist and infection control experts [75] .
The protection level of the surgical gowns depends on the type of procedure [76] . An filtering face pieces (FFP) 2 mask filters 94% of all particles that are 0.3 mm in diameter or larger; while N95 masks block 95% and FFP3 masks block 99% [77] . A class 2 or 3 FFP face mask should be worn when working in close contact with patients with suspected or confirmed COVID-19, and only to use surgical face masks in a crisis scenario of shortage of FFP 2 and 3 respirators [78] . Airborne transmission risks are high during aerosol generating procedures such as laparoscopy, endoscopy and tracheal incubation to exposure patients' oropharynx and airway secretions with a high viral load [79] . We suggest that surgical team members, including anesthesiologists, surgeons and operating nursing staff should ware highly protective levels of PPE when treating patients known to have been infected with COVID-19 [77] . Most recent information from Italy reported that 12% of healthcare workers were infected at the beginning of COVID-19 pandemic [67] , and this incidence was greatly reduced when PPE was used properly and infection control measures were followed [80] . In our analysis, 38 medical staff were infected as reported in 20 studies, while medical staff who used biosafety level 3 (BSL-3) protective equipment did not get infected. Thus, implementation of strict protections for medical staff is essential to decrease the cross-infection risks. Additionally, the choice between laparoscopy and laparotomy as a surgical approach needs to be cautious. Laparoscopy is an option but a potential risk of aerosol exposure must be considered for SARS-CoV-2 even though there is not current demonstration of SARS-CoV-2 RNA presence in the surgical smoke [81, 82] , but aerosolization of blood born viruses has been previously detected in surgical smoke during laparoscopy [83, 84] . For critically ill patients with lung dysfunction, sepsis or shock, open surgery is advised [67] . Special care must be taken to reduce smoke formation (e.g., lowering electrocautery power settings, using bipolar electrocautery, using electrocautery or ultrasonic scalpels parsimoniously), and to limit smoke dispersal or spillage from trocars (e.g., lowering the pneumoperitoneum pressure) in the OR [85] . Pneumoperitoneum and surgical smoke should be evacuated only using a direct suction connected to a vacuum suction unit [86] . To minimize infectious risk to medical staff during the perioperative period, detailed protective strategies have been proposed as briefly outlined below. Based on clinical information and expert recommendation, all elective cases are suggested to be canceled, with the focus to maintain only emergency operations and elective cancer surgeries [87, 88] . A negative pressure isolation transfer cabin is recommended for staff wearing BSL-3 protective medical equipment to transport patients [89] . Ideally, it seems necessary to create specific transfer pathways, and patients be transferred directly to the operating room (OR), without stopping at the pre-operation or post-anesthesia care unit (PACU) areas. It is also suggested that BSL-3 protective medical equipment should be worn, including N95 masks, goggles, protective suits, face shields, caps, shoe covers, and gloves [45] . Furthermore, all staff should take a training course on PPE use [67] . A negative pressure (below -4.7 Pa) OR must be established, preferably isolated from the main surgical theaters and with a separate ventilation system [85] . A checklist should be used for preparation and incubation, and enough time should be allocated for the preparation of airway equipment. It is recommended that one experienced anesthetist to deliver 100% O 2 manually for 3À5 min and videolaryngoscopy be used to perform rapid sequence induction [90, 91] . It is further recommended to use a high-quality HMEF (Heat and Moisture Exchange Filter) between the face mask and breathing circuit. Medical staff should use fast-drying hand antiseptics and change gloves immediately after contacting a patient, body fluids or contaminated materials [92] . Anesthetic equipment must be used by one person only and the anesthesia machine be strictly disinfected [93] . All protective gear should be disposed of properly. When using electrocautery devices during surgery, it is necessary to adjust to the lowest effective power in order to reduce the amount of surgical smoke [86, 94] . Surgical smoke and pneumoperitoneum should be evacuated only using a direct suction connected to a vacuum suction unit [86] .
Smoke evacuation electrosurgical devices should be used to minimize medical staff's exposure to surgical smoke. Postoperative patients should preferably recover in an isolation room with negative pressure when resources permitting in the PACU or intensive care unit (ICU). If negative pressure isolation rooms are unavailable, it is recommended to let the patients to recover in the OR prior to being transfer to a single patient room. Postoperatively, the anesthesia workstation needs to be disinfected for 2 h with an anesthesia circuit sterilizer (containing 12% hydrogen peroxide) [45] , and the next operation must be performed beyond 2 h after the completion of the disinfection [89, 95] . In particular, COVID-19 patients' specimens should be clearly labeled and handled as infectious specimens for treatment by the pathology department [90] .
Our meta-analysis has several limitations. First, our analysis was based on a small number of cases and the data availability for several parameters, such as medical staff infection. Second, it should be noted that some articles did not clearly provide information regarding the type of surgery and the kinds of post-operative complications, nor did they describe the detailed symptoms of COVID-19, and thus the number of patients in these studies could not be used for the calculation of the total number or percentage of patients included in each of the 4°of surgical difficulties, and also not suitable for the correlation analysis in relation to the severity of COVID symptoms. Lastly, among of 47 studies in this meta-analysis, 26 articles were mainly from China, and the other 21 articles were from the United States and Europe. This imbalance of sources increased the possibility of publication bias. Most of the included studies were case reports or case series, which may affect the representativeness of the results. Therefore, large sample and/or multicenter trials are needed to further explore the perioperative mortality rate of operative patients with COVID-19 and in particular the factors that have highest impact on the perioperative mortality or medical staff infection.
In summary, we found that operative patients with COVID-19 have high mortality rate, and that postoperative COVID-19 symptom and related respiratory complications were significantly associated with the death of operative patients. Medical staff who have closed contact with infected patients are at the highest potential risk of infection. Thus, it is urgently needed to apply standard measures to actively deal with postoperative complications of patients with COVID-19 in order to reduce the mortality rate, and to provide effective protection and safe environment to avoid the cross-infection during the perioperative period.
We declare no competing interests associated with this work. 