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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 6
| Issue : 4 | Page : 201-209 |
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Pulmonary complications and 30-day mortality rate in COVID-19 patients undergoing surgery: A systematic review and meta-analysis
I Made Gede Widnyana, Tjokorda Gde Agung Senapathi, Marilaeta Cindryani, Nova Juwita, Bianca Jeanne
Department of Anesthesiology and Intensive Care, Faculty of Medicine, University of Udayana, Bali, Indonesia
| Date of Submission | 06-Jul-2022 |
| Date of Decision | 02-Oct-2022 |
| Date of Acceptance | 05-Oct-2022 |
| Date of Web Publication | 31-Oct-2022 |
Correspondence Address:
Nova Juwita
Department of Anesthesiology and Intensive Care, Faculty of Medicine, University of Udayana, Jl. PB Sudirman, Denpasar 80232, Bali
Indonesia
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/bjoa.bjoa_182_22
Hundreds of surgeries are postponed every day during the global COVID -19 pandemic. The hospital and clinicians are in dilemma scheduling elective procedures during the pandemic. The current study was designed to evaluate postoperative pulmonary complications and mortality in COVID-19 patients in a systematic review and meta-analysis of globally published peer-reviewed literatures. A systematic literature search was conducted using the selection criteria in five databases. A quality assessment was made with a validated Newcastle-Ottawa Scale. The meta-analysis worked as a generic inverse variance meta-analysis. A total of 308 articles were identified from different databases and 5 articles with a total 1408 participants were selected for evaluation after successive screenings. The meta-analysis revealed a high global rate of postoperative mortality among COVID-19 patients, as high as 23% (95% CI: 15 to 26), and high postoperative pulmonary complications including pneumonia and acute respiratory distress syndrome. The 30-days mortality rate and prevalence of pulmonary complications were high. There was one death for every five COVID-19 patients undergoing surgical procedures, indicating the need for mitigating strategies to decrease perioperative mortality, transmission to healthcare workers, and non-COVID-19 patients. Larger samples and/or multicenter trials are needed to explore the perioperative mortality dan morbidity rate of patients with COVID-19 undergoing surgeries, and in particular, factors with the highest impact on perioperative mortality. There should be a clinical guideline to determine when to operate or not to operate on patients with COVID-19 for elective and emergency surgeries. Keywords: 30-day mortality, ARDS, COVID-19, perioperative, pneumonia, pulmonary complication, surgery
How to cite this article:
Widnyana I M, Senapathi TG, Cindryani M, Juwita N, Jeanne B. Pulmonary complications and 30-day mortality rate in COVID-19 patients undergoing surgery: A systematic review and meta-analysis. Bali J Anaesthesiol 2022;6:201-9 |
How to cite this URL:
Widnyana I M, Senapathi TG, Cindryani M, Juwita N, Jeanne B. Pulmonary complications and 30-day mortality rate in COVID-19 patients undergoing surgery: A systematic review and meta-analysis. Bali J Anaesthesiol [serial online] 2022 [cited 2023 Mar 22];6:201-9. Available from: https://www.bjoaonline.com/text.asp?2022/6/4/201/359930 |
| Introduction | |  |
Hundreds of surgeries are postponed every day during the global COVID -19 pandemic. Hospitals and clinicians alike are in dilemma scheduling elective procedures during the pandemic. Safety protocol to decide whether to continue or delay surgery is urgently needed and formulated from real data, not only from expert opinions.[1]
The main concern to address is whether continuing surgery will cause more harm to the patient than delaying it. It is much easier to make decisions on life-saving procedures such as emergency surgeries or small procedures such as benign small tumor excision or cosmetic surgery that won’t cause problems when delayed. But in some grey areas and time-limited procedures such as cancer or orthopedic surgeries, which decrease the patient’s quality of life, clinicians should wisely consider the risks and benefits for the patients.[1],[2]
The incubation period of COVID-19 infection is approximately 2 to 14 days, with most of the symptoms appearing 4–5 days after exposure.[3] However, the cytokine storm period and severity vary greatly between patients and play a key role in determining morbidity and mortality. The stress caused by surgery could increase the release of the pro-inflammatory cytokines and worsen the underlying cytokine storm caused by COVID-19. Cytokine storm acts as a chemoattractant for neutrophils, CD4 helper T cells, and CD8 cytotoxic T cells that are sequestered in the lung.[4] These cells are supposed to fight the virus but are also responsible for the subsequent inflammation and lung injury. The clinical features in this phase include shortness of breath, increased respiratory rate, decreased oxygen saturation, hypoxemia, acute respiratory distress syndrome (ARDS), shock, coagulation defects, inflammation of the vascular system, and multiorgan failure.[3] The pathological feature of the lung shows bilateral diffuse alveolar damages, cellular fibromyxoid infiltrates, and interstitial mononuclear infiltrates. Involvement of the lower respiratory tract and progression to ARDS are responsible for pulmonary infiltrates and severe symptoms.[3],[4] The virus attaches itself to and enters the type 2 alveolar epithelial cells via the ACE-2 receptor and starts replicating. Subsequently, alveolar epithelial cells, macrophages, and monocyte are activated by the viral products and release many different cytokines and inflammatory markers such as interleukins (IL-1, IL-6, IL-8, IL-120, and IL-12), tumor necrosis factor-α (TNF-α), IFN-λ and IFN-β, CXCL-10, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1α (MIP-1α). In this phase, severe manifestations appear and are dictated as a cytokine release syndrome (CRS), which is a disorder induced by cytokine storms. Impaired immune response caused by suppression of the immune system by some anesthesia drugs could also worsen the patients’ clinical outcomes. Mechanical ventilation during intraoperative and postoperative care can also deteriorate an already-declining pulmonary function.[4],[5]
Some asymptomatic patients who are later confirmed for COVID-19 infection and underwent either major or minor surgery have been shown to have higher morbidities (especially in pulmonary complications), higher ICU admission rate, and higher mortality rate compared to normal pre-pandemic rate. These facts raise the question of whether or not we should delay some elective and non-emergency procedures in confirmed COVID-19 patients with none or mild symptoms until the patient passes the vulnerable infection period.[6]
This study aims to identify the association between the time of COVID-19 diagnosis and time of surgery and their effect on pulmonary complications and mortality rate among patients with COVID-19 undergoing elective surgery.
| Materials and Methods | | |
Search strategy
We conducted searches through five databases including Medline, Proquest, EBSCO, Science Direct, and EMBASE from January 1 to November 30, 2020. The following terms were used in our search for relevant studies to be analyzed in this systematic review: “CORONA VIRUS” AND “SURGERY” AND “COMPLICATIONS” AND “MORTALITY RATE”. We modified and used the appropriate MeSH terms in the database with the help of the health librarian at the University of Newcastle.
Selection of included study
We included studies fulfilling the following criteria: (1) Studies using clinical trial, cohort study, or observational study as their study design; (2) Published only in English; (3) Studies conducted between January – November 2020; (4) Reported pulmonary complications or 30-day mortality rate or postoperative outcomes; (5) Age, gender, ASA physical state, and the type of elective surgery were described clearly in the research. We excluded case reports, case series, letters to the editor, conference proceedings or recommendations, and studies with inadequate data regarding control group. Reviewers did this independently with the 2009 PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) checklist and any disagreements were discussed with other reviewers and resolved as per protocol.[7] The PRISMA flow diagram in this research can be found in [Figure 1].
Data extraction
The authors extracted all data from each relevant study and obtained the information on the population, intervention, results, study design, statistical methods, and outcomes, and used the Cochrane Public Health Group’s Data Extraction and Assessment Template to tabulate the findings of the included articles. We assessed the risk bias and the quality of each study using the Newcastle-Ottawa Scale considering that the studies were cohort studies rather than non-randomized control studies. Three assessment factors for assessing the quality of the study were included: (1) selection, including the representation of the exposed group, the unexposed group, the certainty of exposure, and that at the start of the study, the results of interest were not presented; (2) comparability, based on study designs and analyses, and whether any confounding variables are uncontrollable; and (3) outcomes, based on follow-up periods and cohort retention, and ascertained by independent blind orders, association records, or self-reports. We assessed the quality of the studies (good, moderate, and bad) as indicated with stars in each of the most recent Newcastle - Ottawa Scale domains.[8] A “good” quality requires 3 or 4 stars in the selection domain, 1 or 2 stars in the comparison domain, and 2 or 3 stars for outcome domain. A “fair” quality requires 2 stars in the selection domain, 1 or 2 stars in the comparison domain, and 2 or 3 stars in the outcome domain. A “poor” quality score reflects 0 or 1 star in the selection domain, 0 stars in the comparison domain, or 0 or 1 star in the outcome domain. The details of the study quality analysis can be seen in [Table 1] below.
Statistical analysis
Data analysis was performed in R statistical software version 4.0.2 and STATA 16. The pooled global prevalence of mortality and pulmonary complication among surgical patients with COVID-19 was determined with a random effect model as there was substantial heterogeneity. Heterogeneity among the included studies was checked with forest plot, χ2 test, I2 test, and the p-values. Substantial heterogeneity among the included studies was investigated with subgroup analysis. Publication bias was checked by a modified Robin-I tool. A modified Robin-I tool for a non-randomized controlled study that identifies possible sources of bias in the selection of participants, confounding factors, classification of interventions, deviations from intended interventions, measurement of outcomes, and selection of the reported result guided cohort or follow-up study.[9] For this tool, responses for each item were divided into low risk of bias (“definitely yes” or “probably yes”), and high risk of bias (“probably not” or “definitely no”). We marked the overall risk of bias for each outcome in each study as “low risk” if the study is comparable to a well-performed randomized trial considering that all domains were rated as low risk of bias; as a moderate risk if the study is sound for a non-randomized study concerning this domain but cannot be considered comparable to a well-performed randomized trial; and as high risk or serious risk if the study has some important problems. In this review, we included studies with moderate and low risks for bias.[9]
| Results | | |
We conducted searches through the databases and found 308 works of literature that matched the search term. After removing duplications, we obtained about 208 works of literature. Due to the limitation of language, we removed some works of literature that did not use the English language. We screened titles and abstracts and excluded 60 research that didn’t match any inclusion criteria and proceed with the full-text review. We identified 5 studies that matched our study with a good and fair quality score based on the Newcastle - Ottawa Scale (NOS).[8]
Through the PRISMA checklist, we extracted the following relevant data: (1) Title of study; (2) Lead author and year of publication; (3) Country or scope of the region of the population studied; (3) Study design; (4) Sample size; (5) Characteristics of the sample, including age, gender, ASA physical state, classification or description of the surgery, and timing of surgery; (6) Methods used to confirm COVID-19 infection; (7) Associated comorbidities; (8) Pulmonary complications and 30-days post-operative mortality rate. Characteristics of the studies are summarized in [Table 2]. All of the studies were retrospective cohort studies, published in 2020, with a total sample of 1408 patients confirmed positive for COVID-19 using laboratory testing including RT-PCR, radiological findings of ground-glass opacity, and pre-operative and post-operative clinical findings indicative of COVID-19. Four studies were conducted in Europe and one in China. The cutoffs used to differentiate between the shortest and tallest categories varied among the studies.
COVID-19 status
According to the 5 studies, COVID-19 was diagnosed pre-operatively and post-operatively. All patients were confirmed by laboratory testing, radiography, and clinical examinations. Some studies included only cases confirmed by RT-PCR, and some included cases confirmed with thoracic CT scan.[4],[5] Some positive patients admitted to the hospital were asymptomatic and subsequently developed respiratory symptoms during their inpatient stay. Specimens used for RT-PCR included nasopharyngeal and oropharyngeal swabs, sputum, tracheal tube tip, and bronchoalveolar lavage. Although not fully reported in all studies, RT-PCR tests (and in some cases, symptoms) were negative in some cases despite CT findings consistent with COVID-19. Symptoms highly indicative of SARS-CoV-2 infection included cough, fever, and myalgia. According to Jonker et al., in the case of pre-operative diagnosis, the median time from SARS-CoV-2 diagnosis was 8 days, and the median time from the operation to a post-operative diagnosis was 8 days.
Preoperative management
Overall, most patients underwent preoperative testing. The tests performed include swab test only, thoracic CT scan only, or both a swab test and a thoracic CT scan. There were several differences between groups with different preoperative testing strategies. Clinical symptoms at the time of hospital admission were recorded for emergency admissions. Demographic variables recorded included age, sex, and American Society of Anesthesiologists’ (ASA) physical status classification. All patients who underwent elective or emergency surgery were tested. The indication of surgery depends on the diagnosis and most studies categorized it as major or minor surgery. Operative variables included urgency (elective or emergency surgery), primary procedure completed, and anesthesia used like local, regional, or general anesthesia.[5],[6]
According to COVIDSurg Collaborative, a patient undergoing elective surgery was tested for SARS-CoV-2 on preoperative day 4–7, either with a single test or repeated tests. The groups undergoing CT either alone or with a swab test more commonly underwent thoracic or thoracoabdominal surgery or had advanced disease.[6] For anesthesia technique, either general anesthesia, regional anesthesia, or local anesthesia were recorded.
Patient outcomes
Patient outcomes analyzed in this review are 30-day mortality rate and pulmonary complications, i.e. pneumonia and ARDS [Table 2]. (All of the studies included reported 30-day mortality rate and the rate of pneumonia, while only four studies reported the rate of ARDS. One study reported a 100% pneumonia rate and was excluded from the analysis.
The 30-day mortality rate reported varies from 16% in the 2020 study by Pascal et al.,[10] to 30.5% in the 2020 study by Kayani et al.[11] The difference in mortality rate might be due to a difference in patient demographics, where the study by Kayani et al. only reported patients with hip fractures with a mean age of 71.9 years.[11] Bangu et al.’s[6] study had the largest cohort with 1128 patients, with various types of surgery and comorbidities, and a 30-day mortality rate of 23.8%. This study also reported mortality rate by age groups, where the mortality rate in patients aged ≥ 70 years is 34.1%, similar to the study by Kayani et al.[11] Meta-analysis of the five relevant studies showed an overall 30-day mortality rate of 23.08% (95% CI = 20.83 – 25.33) in COVID-19 patients undergoing surgery.
Pneumonia rate was included in all studies. A study by Lei et al.[12] reported pneumonia in all subjects (100%). The criteria for diagnosing pneumonia were not mentioned, and thus the study were excluded from our analysis. The rate of pneumonia reported in the other four studies varied from 13.4% in the study by Kayani et al.[11] to 43.9% in the 2020 study by Doglietto et al.[13] Meta-analysis of the four studies resulted in a pneumonia rate of 35.39% (95% CI = 32.86 – 37.92).
Four studies included ARDS as respiratory complication. ARDS rate varied from 9.8% in the 2020 study by Kayani et al., to 32.4% in the 2020 study by Lei et al.[12] ARDS is a severe complication and was associated with mortality, with a 30-day mortality rate of patients who developed ARDS being as high as 63%, as reported in Bhangu et al..[6] Meta-analysis of the four studies resulted in an ARDS rate of 14.3% (95% CI = 12.34 – 16.26).
Three of the five studies in this review provided data relating to risk factors that can increase the 30-day postoperative mortality in patients suffering from COVID-19. Each of these studies includes Bhangu et al., Pascal et al., and Kayani et al.’s studies in their analyses.
Meta-analysis result
Five studies reported the prevalence of perioperative mortality among surgical patients with COVID-19. The pooled prevalence of perioperative mortality was 23.08% (95% CI = 20.83 – 25.33 with 323 participants) [Figure 2]. The pooled prevalence of perioperative complications was estimated by taking the most common reported complication. The meta-analysis showed that the pooled prevalence of perioperative complications among surgical patients with COVID-19 was 35.39% (95% CI = 32.86 – 37.92) for pneumonia [Figure 3] and 14.3% (95% CI = 12.34 – 16.26) [Figure 4] for ARDS. Subgroup analysis revealed that pulmonary complications were the most common perioperative complications among surgical patients with COVID-19. | Figure 2: Meta-analysis of the studies examining 30-day mortality rate chi-squared heterogeneity = 6.73 (d.f. = 4) with P = 0.151; I-squared heterogeneity (variation in ES attributable to heterogeneity) = 40.5%. The midpoint of each line shows the prevalence; the horizontal line indicates the confidence interval, and the diamond shows the pooled prevalence
Click here to view |
 | Figure 3: Meta-analysis of the studies examining incidence of pneumonia chi-squared heterogeneity = 58.48 (d.f. = 3) with P = 0.000; I-squared heterogeneity (variation in ES attributable to heterogeneity) = 94.9%. The midpoint of each line shows the prevalence; the horizontal line indicates the confidence interval, and the diamond shows the pooled prevalence
Click here to view |
 | Figure 4: Meta-analysis of the studies examining incidence of ards chi-squared heterogeneity = 6.18 (d.f. = 3) with P = 0.103; I-squared heterogeneity (variation in ES attributable to heterogeneity) = 51.5%. The midpoint of each line shows the prevalence; the horizontal line indicates the confidence interval, and the diamond shows the pooled prevalence
Click here to view |
| Discussion | | |
All studies analyzed were retrospective cohort studies comparing morbidity and mortality rates between patients with and without SARS-CoV-2 infection undergoing emergency or elective surgery. In this meta-analysis, we found that preoperative or postoperative confirmation of COVID-19 was associated with increased mortality rate due to the pulmonary complications, especially pneumonia dan acute respiratory distress syndrome (ARDS). Both of these pulmonary complications are the most frequent COVID-19-related pulmonary complications in medical patients undergoing surgery.[14]
Meta-analysis of the five studies in this review showed an overall 30-day mortality rate of 23.08% (95% CI = 20.83 – 25.33) in COVID-19 patients undergoing surgery. The results were stable as shown by the stratified and sensitivity analyses and were independent of the study design and study area. The increased mortality rate in patients confirmed COVID-19 in this age category who underwent surgery might be attributed to a synergistic effect of SARS-CoV-2 and surgery. The underlying pathophysiological mechanisms behind the increased mortality rate in COVID-19 patients undergoing surgery remain unknown. Mechanical ventilation, anesthesia itself, or tissue damage caused by the operation may each provoke a proinflammatory cytokine and immunosuppressive response, potentially worsening the presentation of a pre- or postoperative SARS-CoV-2 infection.[4],[6]
Not all studies presented here necessarily distinguish between patients who may have had an active COVID-19 infection when they were operated on and patients whose airway were colonized, or patients who simply acquired the infection immediately postoperatively, at the hospital. It is postulated that a colonized airway at the time of intubation may lead to significant dissemination of the virus in the lungs, resulting in much more severe pulmonary complications. All these complications were more likely associated with low immunity and prolonged immobility while patients were on a mechanical ventilator after the surgery.[4]
In the UK, guidelines have been produced and implemented in response to NHS England (Worcestershire, UK) advice to restrict surgical practice during the pandemic for 3 months. These guidelines are intended to reduce pressure on healthcare systems, intensive care units (ICUs), and ventilators, and to reduce the risk of nosocomial COVID-19 infection and the postoperative sequelae that may ensue, including the increase in pulmonary complications and post-operative mortality.[2],[6]
In Indonesia, IUA, an organization accommodating all Indonesian urologists, has published recommendations for urologists stating that during the COVID-19 pandemic, all elective surgeries should be postponed to increase the availability of healthcare workers, and ICU beds, and inpatient rooms, in addition to preventing transmission of SARS-CoV-2. However, according to a study by Nur Rasyid in 2020, only one-third of respondents that were urologists stopped elective surgery, while most urologists reduced their elective surgery activity by more than two-thirds of cases. In line with IUA recommendations, most urologists conducted COVID-19 screening for patients undergoing elective surgery. Moreover, more than two-thirds of urologists canceled elective surgery requiring post-operative ICU care and about 30% continued with planned elective surgery only if there was a risk of disease progression. The IUA guidance recommends that it should be assumed that all patients undergoing surgery have COVID-19 unless proven otherwise. On the other hand, in contrast to elective surgeries, all emergency surgeries in Indonesia must be continued.[15]
Moreover, Indonesia have had a few cases of surgery in COVID-19 patients during the pandemic. One of them was a case in Bali, a patient with ruptured ectopic pregnancy. The patient came with a primary complaint of lower right abdominal pain for at least an hour before she was admitted to a secondary hospital with no vaginal bleeding and suspected acute appendicitis with post-uterine curettage (day 15) history. The patient was suspected of COVID-19 infection due to the reactive results of SARS-CoV-2 IgG and IgM rapid tests, and was therefore required to be treated in an isolation room. The patient had no COVID-19 symptoms and consulted to the obstetric department due to her positive pregnancy test. The patient didn’t have any COVID-19 symptoms but had a positive result from the RT-PCR test. The patient underwent the surgery on the same day when she was admitted, with a level 3 PPE requirement. Postoperatively, the patient was in good condition, isolated for ten days in an isolation room, and discharged on the 10th postoperative day for self-isolation at her home for 14 days.[16]
Surgeries in COVID-19 patients were also reported from Cipto Mangunkusumo national tertiary hospital in Jakarta. The subjects were patients who underwent emergency orthopedic surgeries at the institution from April to May 2020. The patients also underwent COVID-19 screening using SARS CoV-2 IgG and IgM tests. Patients with reactive rapid immunoglobulin test then underwent the surgery where all surgical team members used the highest level of PPE. For emergency cases, all of the guidelines agree that all acute patients who come to the emergency department are considered COVID-19 positive until proven otherwise.[17]
Our meta-analysis has several limitations. First, our analysis was based on a small number of cases. Second, it should be noted that some articles did not clearly provide information regarding the type of surgery and the types of post-operative complications, nor did they describe the detailed symptoms of COVID-19, and were also not suitable for the correlation analysis concerning the severity of COVID symptoms. Lastly, among the 5 studies included in this meta-analysis, there is just a single article from China while the others were conducted in Europe or globally, so this imbalance of sources increased the possibility of publication bias. Therefore, large sample and/or multicenter trials are needed to further explore the perioperative mortality dan morbidity rate of operative patients with COVID-19 and in particular the factors that have the highest impact on perioperative mortality. To date, we did not find any discussion or case report related to mortality rate and pulmonary complications for patients with COVID-19 infection who underwent elective surgery in Indonesia, so we could not conduct a balanced analysis of the current situation in Indonesia.
| Conclusion | | |
The meta-analysis revealed that the prevalence of the 30-day mortality and pulmonary complications was high. It also showed that there was one death for every five COVID-19 patients undergoing surgical procedures which entails mitigation strategies to decrease perioperative mortality, infection transmission to health care workers and non-COVID-19 patients, as well as to provide less risky anesthetic techniques and alternative management other than surgical procedures. Additionally, there should be guidelines on when to operate or not to operate on high-risk patients with COVID-19 for elective and urgent surgeries.
Financial support and sponsorship
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 it for publication.
Conflicts of interest
There are no conflicts of interest.
| References | | |
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]
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