key: cord-0848890-p8ckcvyj
authors: nan
title: Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study
date: 2020-05-29
journal: Lancet
DOI: 10.1016/s0140-6736(20)31182-x
sha: 7a482ec2ed1256a05e559efb9766c39c24beb87d
doc_id: 848890
cord_uid: p8ckcvyj

BACKGROUND: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. METHODS: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. FINDINGS: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 82·6% (219 of 265) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p<0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p<0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p<0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). INTERPRETATION: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. FUNDING: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread to most countries, with WHO declaring a COVID-19 pandemic on March 11, 2020 . 1 The pandemic has tested the resilience of health-care systems, including hospitals, which were largely unprepared for the scale of the pandemic. 2 Patients having surgery are a vulnerable group at risk of SARS-CoV-2 exposure in hospital and might be particularly susceptible to subsequent pulmonary complications, due to the pro-inflammatory cytokine and immunosuppressive responses to surgery and mechanical ventilation. 3, 4 Evidence of the safety of performing surgery in SARS-CoV-2exposed hospitals is urgently needed.

Before the SARS-CoV-2 pandemic, high-quality, multinational observational studies established overall baseline rates of postoperative pulmonary complications (up to 10%) and subsequent mortality (up to 3%) after surgery. [5] [6] [7] With initiatives such as the UK's National Emergency Laparotomy Audit (NELA), mortality was improving even in high-risk groups. 8 Guidelines have been published for the management of surgical patients during the SARS-CoV-2 pandemic, [9] [10] [11] but they are based solely on expert opinion. The impact of SARS-CoV-2 on postoperative pulmonary complications and mortality needs to be established in order to enable surgeons and patients to make evidence-based decisions during the pandemic. This study reports the clinical outcomes of patients who had surgery with perioperative SARS-CoV-2 infection, including the impact of pulmonary complications.

We did an international, multicentre, observational cohort study in patients with SARS-CoV-2 infection who had surgery at 235 hospitals in 24 countries (appendix p 10). Data release and ethical considerations were discussed with an independent data monitoring and ethics committee. We collected only routine, anonymised data with no change to clinical care pathways. In the UK, the study was registered at each site as either a clinical audit or service evaluation; at the lead centre (University Hospital Birmingham) it was approved as clinical audit, with registration CARMS-15986. In other countries, local principal investigators were responsible for contacting competent research ethics committees to obtain local or national approvals in line with applicable regulations, as well as seeking approvals from data protection officers. In some participating hospitals, informed patient consent was taken, whereas in other countries the requirement for patient consent was waived by local research ethics committees.

Each participating hospital included all patients undergoing surgery who had SARS-CoV-2 infection diagnosed within 7 days before or 30 days after surgery. Surgery was defined as any procedure done by a surgeon in an operating theatre under general, regional, or local anaesthesia. Patients undergoing surgery for any indication were eligible, including benign disease, cancer, trauma, and obstetrics. The study included children and adults, but individual hospitals had the option to apply local age cutoffs, if appropriate. If patients with SARS-CoV-2 infection had multiple operations, the procedure closest to the time of confirmation of SARS-CoV-2 infection was defined as the index procedure.

Participating hospitals prospectively screened patients for eligibility to ensure that all patients fulfilling eligibility criteria were captured. However, the study was initiated after the SARS-CoV-2 pandemic had peaked in some regions, so retrospective data collection was permitted if collaborators were able to identify and include all eligible patients. The importance of working across surgical specialties to identify all eligible patients was highlighted in site training, because incomplete case ascertainment could introduce bias, if patients with less severe disease were missed. Site inves tigators were provided with a range of written materials setting out possible strategies to capture consecutive eligible patients. In addition, investigators were invited to join social media groups and teleconferences for the purpose of troubleshooting site-specific recruitment issues and shared learning.

Laboratory testing for SARS-CoV-2 infection was based on viral RNA detection by quantitative RT-PCR. Sampling, including nasal swabs or bronchoalveolar lavage, and analyses were done according to individual hospital protocols.

As quantitative RT-PCR testing was not available at all participating hospitals, patients were also included based on either clinical or radiological findings. Clinical

Evidence before this study We searched PubMed and Embase on March 15, 2020, for studies reporting on surgical patients during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. We used the search terms "COVID-19", "SARS-CoV-2", "coronavirus", and "pandemic", in combination with "surgery", and applied no language or date restrictions. We identified 13 articles (12 from China and one from Singapore), all of which provided clinical guidance, with none reporting patientlevel outcomes.

This international, observational, cohort study provides crossspecialty, patient-level outcomes data for patients who had surgery and acquired perioperative SARS-CoV-2 infection. 1128 patients were included across 24 countries. Overall 30-day mortality was 23·8% (268 of 1128 patients). Pulmonary complications occurred in 577 (51·2%) patients; these patients accounted for 82·6% (219 of 265) of all deaths. Independent risk factors for mortality were male sex, age 70 years or older, American Society of Anesthesiologists grades 3-5, surgery for malignant disease, emergency surgery, and major surgery.

Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. These pulmonary complication and mortality rates are greater than those reported for even the highest-risk patients before the pandemic. Thresholds for surgery during the SARS-CoV-2 pandemic should be higher than during normal practice; men aged 70 years and older who have emergency or major elective surgery are at particularly high risk of mortality. Consideration should be given for postponing non-critical procedures and promoting non-operative treatment to delay or avoid the need for surgery. When hospitals recommence routine surgery, this will be in hospital environments that remain exposed to SARS-CoV-2, so strategies should be developed to reduce in-hospital SARS-CoV-2 transmission and mitigate the risk of postoperative complications. diagnosis consistent with SARS-CoV-2 infection was made by a senior physician and based on clinical presentation of symptoms highly indicative of SARS-CoV-2 infec tion, including cough, fever, and myalgia. 12 Radiological diagnosis was based on thorax CT, in keeping with locally implemented protocols. All patients included initially based on clinical or radiological criteria who subsequently had laboratory testing for SARS-CoV-2 infection and returned a negative result were excluded from the study. Data were collected online using the Research Electronic Data Capture web application. Demographic variables recorded included age, sex, and American Society of Anesthesiologists (ASA) physical status classification. Age was collected as a categorical variable by deciles of age. ASA at the time of surgery was analysed as grades 1-2 versus grades 3-5. The timing of SARS-CoV-2 diagnosis was recorded as either preoperative or postoperative. Clinical symptoms present at the time of hospital admission were recorded for emergency admissions. Physiological variables recorded (respiratory rate, heart rate, and blood pressure) were based on readings taken immediately before surgery. The quick sequential organ failure assessment score 13 was calculated on the basis of individual variables recorded immediately before surgery. Operative variables included urgency (elective or emergency surgery), primary procedure completed, and anaesthesia used (local, . Before locking of the dataset for analysis, the senior local principal investigator for each hospital was asked to confirm data completeness and that all eligible patients had been entered into the database.

The primary outcome was 30-day mortality, with the day of surgery defined as day 0. The key secondary outcome measure was the rate of pulmonary complications, a composite outcome adapted from the Prevention of Respiratory Insufficiency after Surgical Management trial. 15, 16 Pulmonary complications were defined as pneumonia, acute respiratory distress syndrome (ARDS), or unexpected postoperative ventilation; these are the most frequent COVID-19-related pulmonary complications in medical patients. 12 Unexpected postoperative ventilation was defined as either any episode of non-invasive ventilation, invasive ventilation, or extracorporeal membrane oxygenation after initial extubation after surgery; or patient could not be extubated as planned after surgery. Additional secondary outcomes included pulmonary embolism, intensive care unit admission, reoperation, 7-day mortality, and length of hospital stay. 

The study was done according to STROBE guidelines for observational studies. 17 Continuous data were tested for distribution, with normally distributed data presented as mean and 95% CI, and differences between groups were tested using the unpaired t test. The χ² and Fisher's exact tests were used for categorical data.

Missing data were included in flowcharts and descriptive analyses, allowing denominators to remain consistent in calculations. Multilevel logistic regression was used to calculate odds ratios (ORs) and 95% CIs. Models included factors that occurred before the outcome of interest. Country was included as a random effect with hospital nested within country, in both the unadjusted and adjusted models. The primary adjusted model included preoperative variables to identify predictors of 30-day mortality. Secondary models identified predictors of 7-day mortality and pulmonary complications. Sensitivity analyses were done, including only patients with laboratory-confirmed SARS-CoV-2 infection; and only patients with preoperatively confirmed SARS-CoV-2 infection. Analyses were done using Stata, version 15.1 for Mac.

The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author and analysis group had full access to all the data in the study and the corresponding author and the writing committee had final responsibility for the decision to submit for publication.

At the time of analysis (May 2, 2020), 30-day follow-up had been reached for 1128 patients who had surgery between Jan 1 and March 31, 2020. 605 (53·6%) of 1128 patients were men and 523 (46·4%) were women, 214 (19·0%) were younger than 50 years, 353 (31·3%) were aged 50-69 years, and 558 (49·5%) were aged 70 years or older, with age missing for three patients (table 1) . 

Odds ratio (log 10 ) figure 1 ). Men had higher mortality rates than women, and men and women aged 70 years or older In a sensitivity analysis including only patients with laboratory-confirmed SARS-CoV-2, the overall 30-day mortality rate was 23·7% (230 of 969), and pulmonary complications occurred in 493 (50·9%) of 969 patients. In adjusted analyses (appendix p 18), predictors of 30-day mortality were consistent with the main analysis: male sex, age 70 years or older, ASA grades 3-5, cancer surgery, and emergency surgery. The only independent predictor for 30-day pulmonary complications was ASA grades 3-5.

In a sensitivity analysis including only patients with preoperatively diagnosed SARS-CoV-2, the overall 30-day mortality rate was 21·1% (62 of 294), and pulmonary complications occurred in 142 (48·3%) of 294 patients. In adjusted analyses (appendix p 19), predictors of 30-day mortality were male sex and ASA grades 3-5. The only independent predictor for 30-day pulmonary complications was ASA grades 3-5.

This study identified that postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. This has direct implications for clinical practice around the world. The increased risks associated with SARS-CoV-2 infection should be balanced against the risks of delaying surgery in individual patients; this study identified men, people aged 70 years or older, those with comorbidities (ASA grades 3-5), those having cancer surgery, and those needing emergency or major surgery as being most vulnerable to adverse outcomes.

Thresholds for surgery during the SARS-CoV-2 pandemic should be higher than during normal practice. Men aged 70 years and over who have emergency or major elective surgery are at particularly high risk of mortality, although minor elective surgery is also associated with higher-than-usual mortality. During SARS-CoV-2 outbreaks, consideration should be given for postponing non-critical procedures and promoting nonoperative treatment to delay or avoid the need for surgery. 18 Postoperative outcomes in SARS-CoV-2-infected patients are substantially worse than pre-pandemic baseline rates of pulmonary complications and mortality. The overall 30-day mortality in this study was 23·8%, and was high across all patient subgroups; all-cause mortality rates were 18·9% in elective patients, 25·6% in emergency patients, 16·3% in patients who had minor surgery, and 26·9% in patients who had major surgery. SARS-CoV-2-infected patients had greater mortality than even the highest-risk subgroups of the UK's NELA. The 2019 NELA report presented 30-day mortality rates of 16·9% in patients with a high preoperative risk of death, 16·8% in patients with an unexpected critical care admission, and 23·4% in frail patients older than 70 years. 19 The mortality rates identified in this study are also higher than those previously reported across international settings; a study across 58 countries, including low-income and middle-income countries, reported a 30-day mortality of 14·9% in the high-risk subgroup who had emergency midline laparotomy. 20 Postoperative mortality rates in SARS-CoV-2-infected patients with postoperative pulmonary complications approach those of the sickest patients with community-acquired COVID-19 who are admitted to intensive care. 21 Mortality in patients with SARS-CoV-2 was mainly in those who had postoperative pulmonary complications, which was about 50% of patients. This rate is far higher than the pre-pandemic baseline; in the POPULAR multicentre, prospective, observational study of 211 hospitals from 28 European countries in 2014-15, the pulmonary complication rate was 8%. 5 In our study, ARDS had the highest mortality rate of the different complications (mortality 63·0%) and occurred much more frequently (20%) than reported in the pre-pandemic African Surgical Outcomes Study (0·05%). 22 In another study of high-risk ASA grade 3 patients undergoing noncardiac surgery in seven US centres, 0·2% developed ARDS, with an overall mortality related to postoperative pulmonary complications of 2·3%. 23 Even considering differences in the case-mix, the incidence of and mortality associated with pulmonary complications in SARS-CoV-2infected patients is disproportionately high.

This study has limitations. Protocols for laboratory testing and radiological interpretation were not standardised across participating centres. We describe outcomes in the early phases of the pandemic when routine testing was not available across all sites; setting study inclusion criteria requiring laboratory-confirmed SARS-CoV-2 would have excluded some infected patients. Therefore, patients who did not have a laboratory test or CT scan were eligible for inclusion on the basis of clinical diagnosis. Only a minority of patients (6·0%) were included on the basis of a clinical diagnosis and these patients had similar clinical outcomes to patients with laboratory-confirmed SARS-CoV-2. The limitations of laboratory testing mean that some infected patients were excluded from the study based on false negative laboratory test results. Future studies need to make recommendations on the role of preoperative testing in patient selection for surgery.

The study included patients having any type of surgery and although this has produced generalisable results, it is possible that in large hospitals investigators might have not identified all patients. To mitigate this, the importance of identifying and enrolling all eligible patients was highlighted in training packages for local site investigators and strategies to support comprehensive patient identification were shared regu larly with all sites. Final case ascertainment and data completeness were confirmed with local principal investigators, creating as robust a dataset as possible. As far as we are aware, this is the first international study assessing mortality rates after surgery in patients with SARS-CoV-2 infection, and the first that reaches across all surgical specialties. [24] [25] [26] [27] It was not feasible for all participating hospitals, many of which were experiencing significant stress, to collect data on all patients who had surgery during the pandemic period. Consequently, this study's findings should be interpreted with caution because they have been benchmarked against pulmonary complication and mortality rates from high-quality pre-pandemic studies, rather than against contemporaneous non-SARS-CoV-2infected comparators.

Data were collected in hospitals with ongoing SARS-CoV-2 infection outbreaks, which were predominantly in Europe and North America at the time of this study. As the pandemic continues, the evidence this study provides will be relevant to countries where large-scale outbreaks might take place in the future. To facilitate rapid study approvals, this study has focused on key outcomes (mortality and pulmonary complications) that can be collected using routine data. To support decision making by patients and surgeons, future studies should collect longer-term and patient-centred outcomes.

When hospitals resume routine surgery, it is likely to be in environments that remain exposed to SARS-CoV-2. In the future, routine preoperative screening for SARS-CoV-2 might be possible with rapid tests that have low false positive rates, but hospital-acquired infection would remain a challenge. 12, 28 Strategies are urgently required to minimise in-hospital SARS-CoV-2 transmission and mitigate the risk of postoperative pulmonary complications in SARS-CoV-2-infected patients whose surgery cannot be delayed.

The writing group (appendix p 1) contributed to study conception, protocol development, data collection, data interpretation, and critical revision of the manuscript. AB is the guarantor.

We declare no competing interests.

Data sharing requests will be considered by the management group upon written request to the corresponding author. Deidentified participant data or other prespecified data will be available subject to a written proposal and a signed data sharing agreement.

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