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Prognostic value of SARS‐CoV‐2 on patients undergoing cardiac surgery

Abstract Objective To analyze Italian Cardiac Surgery experience during the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) identifying risk factors for overall mortality according to coronavirus disease 2019 (COVID‐19) status. Methods From February 20 to May 31, 2020, 1354 consecutive adult patients underwent cardiac surgery at 22 Italian Centers; 589 (43.5%), patients came from the red zone. Based on COVID‐19 status, 1306 (96.5%) were negative to SARS‐CoV‐2 (COVID‐N), and 48 (3.5%) were positive to SARS‐CoV‐2 (COVID‐P); among the COVID‐P 11 (22.9%) and 37 (77.1%) become positive, before and after surgery, respectively. Surgical procedures were as follows: 396 (29.2%) isolated coronary artery bypass grafting (CABG), 714 (52.7%) isolated non‐CABG procedures, 207 (15.3%) two associate procedures, and three or more procedures in 37 (2.7%). Heart failure was significantly predominant in group COVID‐N (10.4% vs. 2.5%, p = .01). Results Overall in‐hospital mortality was 1.6% (22 cases), being significantly higher in COVID‐P group (10 cases, 20.8% vs. 12, 0.9%, p < .001). Multivariable analysis identified COVID‐P condition as a predictor of in‐hospital mortality together with emergency status. In the COVID‐P subgroup, the multivariable analysis identified increasing age and low oxygen saturation at admission as risk factors for in‐hospital mortality. Conclusion As expected, SARS‐CoV‐2 infection, either before or soon after cardiac surgery significantly increases in‐hospital mortality. Moreover, among COVID‐19‐positive patients, older age and poor oxygenation upon admission seem to be associated with worse outcomes.

Cardiac surgery (CS) patients represent a particularly vulnerable population due to the fact that perioperative concomitant COVID-19 infection is burdened by adverse outcomes. 3 Moreover, when COVIDpneumonia develops early after CS, several factors (surgery-related immunomodulation, extracorporeal-circulation (ECC)-related lung dysfunction, and high inflammatory response) can rapidly exacerbate adult respiratory distress syndrome (ARDS) with a very dismal prognosis. 4 Some limited experiences of CS in COVID patients reported high incidence of perioperative mortality (ranging 20%-30%) and morbidity, especially in terms of pulmonary complications. 5,6 Nowadays, very limited data are available concerning the risk profile of patients suffering from COVID, either pre-or postoperatively, undergoing cardiac surgery. 7 Hence, the aim of the present multicenter study is to identify risk factors for in-hospital mortality in the overall and in the COVIDpositive populations.

| Population
The Italian Society of Cardiac Surgery (SICCH) sponsored a multicenter study to understand how Italian CS departments performed in the early days of the March-April 2020 lockdown, and in the first month after this was lifted. 8 From February 20 to May 31, 2020, 1354 consecutive patients undergoing cardiac surgery at 22 Italian Centers were retrospectively enrolled. Preoperative and perioperative characteristics were anonymously inserted into a dedicated data set Tables 1 and 3, and statistical analysis was performed at the central core lab.
Overall cohort was further divided in two groups depending on the SARS-CoV-2 infective status, COVID-P (48 cases positive [3.6%] to SARS-CoV-2 nasal swab and/or with chest computed tomography [CT] scan positive for interstitial pneumonia) and COVID-N (1306 cases negative to SARS-CoV-2). Patients who underwent elective surgery, urgent surgery (patients who have not been electively admitted for operation but who require intervention or surgery on the current admission for medical reasons. These patients cannot be sent home without a definitive procedure), and emergent surgery (operation before the beginning of the next working day after the decision to operate; emergency included also salvage that are patients requiring cardiopulmonary resuscitation (external cardiac massage) on route to the operating theater or before induction of anesthesia).
Under official endorsement by the SICCH task force on COVID-19, the Central Ethical Committee (EC number 1232/4/20), followed by each single-center institutional review board approved the study and waived the need for informed consent.

| Patient and public involvement
Given the retrospective nature of the study, patients were not initially involved in it during hospitalization. Nevertheless, they were contacted either through phone calls or through visits in the inpatients clinics to perform the follow-up.

| Definition of terms and end-points
All the variables collected in the data set were defined according to Euroscore II. 9 SARS-CoV-2 swab assays were performed according to the World Health Organization and based on the detection of unique viral genome sequences by real-time reverse transcriptionpolymerase chain reaction (RT-PCR). 10 According with law decrees issued by Italian Prime Minister,

| Overall cohort
The general preoperative characteristics of patients are listed in
In COVID-P cohort, the variables initially included in the multivariable analysis for in-hospital mortality, after univariate analysis, were age (both as continuous or as dummy variables, and oxygen saturation that was confirmed also at multivariable analysis Table 2. Using ROC curve (Figure 1) analysis, cut-offs were also identified: In Table 4, a model with cut-offs was also reported. The leading cause of death in this subgroup was a respiratory failure (70% vs. 30% for other causes, p < .001).
Interestingly, we recorded a trend towards higher mortality rates in patients who had a positive swab upon admission (4/11, 36%) with respect to patients who became COVID-19 positive in the postoperative period (6/37 16%), although no statistical significance was found, due to the small sample size (p = .126).  Despite the very limited sample of COVID-P group, in this series we can confirm how advanced age (>75 years) and low O 2 saturation levels at admission (<88%) were an independent risk factors for inhospital mortality in the COVID-P population. Age indeed, in multiple large epidemiological analyses, has proven as the single independent risk factor for mortality in COVID-19 patients. 13  if we consider that only 0.38% of the overall population was found positive on the day the survey was closed. Thus, it has to be considered that infection incidence at the worst of the first wave was 10-fold higher in-hospital admitted patients compared with the general population. Several explanations can justify this observation, including the following: the overall penetration of the SARS-CoV-2 in the Italian population was much higher than officially reported; the saturation screening that occurred for surgery patients uncovered reallife data, or hospitals and healthcare facilities have worked as incubators and disease spreader.
Indeed it is evident how the medical community was found unprepared, and this was especially harsh in the setting where the aerial diffusion of the virus is facilitated by invasive procedure on the airways (intubation, bronchial aspiration, transesophageal echocardiography, and respiratory therapy); in this setting, the accurate management of aerosol and air-spraying is mandatory for this very contagious disease. 17 Furthermore, considering that a molecular swab was performed in every patient before surgery, and only 11 over 48 patients were operated on with a pre-operatory positive sample, we assume that most patients workers. Furthermore, the fear of being infected during hospitalization for elective diagnostic or interventional procedures, prevents many patients, even with acute symptoms, to access the local or tertiary centers. This fact is reflected by a dramatic reduction worldwide of planned surgical activities (as evident also in the present report) but, unfortunately, determined a steep increase in mortality for acute pathology due to underreferral and treatment. 18 The overall pattern of surgical procedures performed within the monitored period is within the regular activities generally performed.
Indeed, none of the cardiac pathologies appeared to prevail over the others. Furthermore, the preoperative clinical profile of the present study population appeared not significantly different from the average profile of the CS population and none of the standard risk factors recorded prevailed above the others.
Another fundamental issue emerging from the present report is the high mortality of patients with COVID pneumonia submitted to CS. In the COVID population, in-hospital mortality peaked to 20% | 171 reasonable to suppose that pulmonary function could be more impaired in valvular disease than in CABG or aortic patients with preserved EF.
Anyway, none of the cardiac conditions or the type of surgical procedures seemed to play a prognostic role.
As we recall the only prognostic marker we could recognize is age and saturation upon admission. Accordingly, we should consider very carefully undergoing cardiac surgery with a 75-year or older patient in case of clinical evident COVID pneumonia or even a simple positive swab and try to delay the procedure as long as possible through medical or palliative approaches. Furthermore is important to recover the most efficient pulmonary function, reaching a nearnormal saturation to mostly minimize procedure-related risk.
In this viewpoint, is useful to recall how infections are one of the A positive remark can be finally derived: despite the high level of hospital rearrangement and the probable delayed patient presentation, the mortality in the COVID-N population (0.9%) resulted significantly lower than the benchmark mortality set by national survey of the ministry of health. 22 As this mortality was achieved in a group of nondeferrable, somehow urgent, procedures, we believe that, despite all the limitations ascribable to the initial pandemic outbreak, the hub-andspoke healthcare reorganization model was able to guarantee a successful safety net for acute cardiac and oncological pathology to offer the best patient care ever.

| STUDY LIMITATION
The main limitation of this report is, despite involving a nationwide database, the limited amount of surgical cases that were performed during this 3-months period: an average of less than 50 cases per center were performed during the 84 days span of monitoring. Consequently, it is very hard to perform any reliable statistical evaluation; furthermore, noticeable events were sporadic and conclusions on case-related effects can only be anecdotal. Moreover, some information regarding preoperative and postoperative data, such as type of previous surgery, renal clearance, and re-intubation rate are missing.
The two groups are too much different in terms of size and this makes a possible matching unreliable, even if data reported in Table 1 show as they are statistically similar for all the variables but the history of heart failure. Finally, we failed, very likely due to the small sample size to identify other technic predictors for early mortality.

| CONCLUSIONS
The SARS-CoV-2 pandemic highly affected cardiac surgery service in Italy. In this Italian Society of Cardiac Surgery sponsored database were collected data from 1354 surgical cases performed during the first wave: roughly 3.5% of patients (n = 48 pts)) were affected by COVID-19, 22% (11 pts) of these presenting with the infection before surgery, but the remaining 78% became COVID-19 positive during the hospital stay, showing how important is to identify and isolate hospital-based hotspots. In cardiac surgery, COVID-19 claimed almost 20% mortality, comparable with other surgery, especially in elderly (>75 years) patients.