The Impact of New-onset Atrial Fibrillation on Short-term and Long-term Mortality of Critically ill Patients with Candidemia

Both new-onset atrial brillation (NOAF) and candidemia occurred frequently in critically ill patients, which are associated with poor outcomes. But, the association between NOAF and critically ill patients with candidemia is still uncertain. This study is try to identify the impact of NOAF on short-term and long-term mortality of critically ill patients with candidemia. We retrospectively identied NOAF in all patients with candidemia admitted to a non-cardiac intensive care unit (ICU) from January 2011 to March 2018 in a teaching hospital. We categorized these patients into 3 groups (NOAF, Prior AF, No AF) and compared clinical information between groups. Risk factors for these patients’ short-term and long-term mortality were also analyzed. regression analysis indicated that anemia, Sequential Organ Failure Assessment year


Introduction
Atrial brillation (AF) is the most common arrhythmia found in postoperative and critically ill patients [1][2][3][4]. Several critical medical or surgical conditions have been proved to be associated with this cardiac arrhythmia. In intensive care unit, the development of atrial brillation can be triggered by uid shift, neurohormonal disturbances, systemic in ammatory responses and sometimes be viewed as a response to physiological stress [5]. NOAF is both a marker of disease severity as well as a likely contributor to poor outcomes [6,7].
Patients with fungal infections are a representative category of critically ill. Invasive fungal infection is a leading cause of ICU-associated infection and also a signi cantly predictor to mortality and morbidity in the critically ill [7][8][9][10]. Candida species has been reported as the most common cause of fungal disease, and the incidence rate of candidemia in ICU is nearly 10 to 20 times more than non-ICU patients [11,12].
Although available evidence provides enough information regarding a relationship between candidemia or NOAF and mortality, separately. But no previous study has determined the epidemiology and outcome of NOAF in candidemia patients. Therefore, the clinical importance of candidemia-associated NOAF is a matter of ongoing uncertainty. Therefore, we retrospectively identi ed NOAF in all patients admitted to our ICU with candidemia and analyzed its effect on patients' outcome.

Study population
We retrospectively identi ed and analyzed all patients admitted to a non-cardiac ICU with candidemia reported by the microbiological department of Peking University People's Hospital in China from January 2011 to March 2018. We investigated NOAF following candidemia hospitalization and categorized patients into 3 groups: 1) NOAF; 2) Prior AF; 3) No AF. The medical records of all patients were reviewed and the following information was collected: age, sex, height, weight, BMI, patient source (medical/surgical ward), underlying conditions (diabetes, hypertension, vascular disease, cerebral stroke, pneumonia, chronic renal dysfunction, solid tumor), the worst laboratory data within 3 days after admission to the ICU ( hemoglobin level, temperature, serum total protein level, serum albumin level) and the worst SOFA score within 3 days after admission to the ICU and CHA 2 DS 2 -VASc score, complications including heart failure and stroke, short-term outcome data including death in hospital, length of ICU stay, length of hospital stay, and duration of mechanical ventilation, long-term outcome including death within 3 years after hospital discharge.

De nitions
We de ned candidemia as the isolation of Candida species from at least one blood culture in patients with symptoms or signs of a systemic infection. NOAF was categorized if rst detected by bedside telemetry and con rmed by 12-lead ECG during hospitalization or initiated pharmacologic therapy without previous AF. Anemia was de ned as a hemoglobin level < 70 g/l. Hypoproteinemia was de ned as a total protein level < 60 g/dl or serum albumin level < 25 g/dl.

Statistical analysis
Data were analyzed with SPSS software version 21.0. For continuous variables, we used means with SDs. We compared independent groups using the t test, and paired groups using paired sample t test; One-way analysis of variance was used for comparison between multiple groups, and LSD method was used for post-hoc comparison. For categorical variables, we used percents and counts. The count data were described by case number (n), and the difference between groups was tested by the Chi-square test. Factors with a p < 0.05 in univariate tests were analyzed with a binary logistic regression model to identify the independent risk factors. The difference was statistically signi cant when p < 0.05.

Results
Incidence of new-onset atrial brillation and baseline characteristics Ninety-two patients with candidemia were identi ed over a 7-year period from 2011 to 2018. Among these patients with candidemia, 26 (28.3%) developed NOAF during their hospital stay and 7 (7.6%) had AF history before hospital admission. Baseline characteristics of these patients are shown in

Distribution of Candida species
Distribution of Candida spp. of these patients was shown in Figure 1. Candida albicans was the most prevalent fungal species in patients with or without AF, followed by Candida parapsilosis,Candida glabrata and Candida tropicalis.
Risk factors for short-term and long-term outcomes Compared with patients never developed AF, patients with NOAF or prior AF had a longer mechanical ventilation time (33.69±34.46 days and 15.43±12.87 days vs. 13.71±26.22 days) and higher in-hospital death rate (73.1% and 85.7% vs. 39%). And 85.7% of these patients with POAF and all patients with prior AF who survived when discharged from hospital died within 1 year, which is extremely higher than survivors with no AF.
In univariate analysis, in-hospital mortality was associated with cerebral stroke, heart failure, stroke, anemia, CHA 2 DS 2 -VASc score, SOFA Score, new-onset AF and total mechanical ventilation days as shown in Table 2. In logistic regression analysis, stroke, anemia, SOFA score and NOAF were independent risk factors for in-hospital mortality (Table 3).
For long-term outcome, the univariate analysis showed that NOAF, hypertension, solid tumor and stroke were associated with 1 year mortality after discharge (Table 4). And the logistic regression analysis indicated that NOAF was the independent risk factor for 1 year mortality (Table 5).

Discussion
Identi cation of prognostic factors associated with the outcomes of critically ill patients can be helpful to physicians in making treatment plan and discussing goals of care with patients and their relatives. Inhospital mortality is high in critically ill patients with candidemia, and its incidence rise when these patients complicated with NOAF. Although much remains to be understood, heightened awareness and early intervention may help reduce the burden among these patients. Compared with patients who never developed AF, the mechanical ventilation time in patients with POAF was signi cantly prolonged, which translated into more resource utilization and higher costs. Patients with NOAF also had an extremely high in-hospital mortality rate (73.1%) and 1 year mortality rate after discharge from hospital (85.7%). In multivatiable logistic regression analysis, NOAF was signi cantly associated with higher in-hospital mortality and 1 year mortality in patients with candidemia, which indicated that NOAF could be a predictor for poor outcomes of these patients.
According to previous study, Patients with NOAF had an increased risk of embolic stroke [36]. In our study, NOAF in patients with candidemia is associated with an increased risk of stroke compared with patients without AF. In multivariable analysis, stroke is also associated with in-hospital mortality. The possible explanations are that AF could cause embolic and ischaemic stroke which could be attributable to haemodynamic instability and biochemical disturbances and lead to clinical deterioration and death[37-39].
The CHA2DS2-VASc score which include congestive heart failure; hypertension; age (65-74 years, ≥75 years [doubled]); diabetes; previous stroke or TIA (doubled); vascular disease; and sex has been widely used for the assessment of thromboembolic risk and guiding antithrombotic therapy in patients with AF. Several studies have demonstrated that the higher CHA 2 DS 2 -VASc score is an independent predictor for mortality in patients with AF[40-44]. In our study, CHA 2 DS 2 -VASc score was higher in patients with AF than those without AF and also a risk factor for in-hospital mortality even following a multivariate analysis, suggesting that CHA 2 DS 2 -VASc score may be a prognostic factor associated with the poor outcome in critically ill patients with candidemia.
Unsurprisingly, SOFA score as a organ dysfunction or failure evaluating system was closely related to inhospital mortality[45, 46]. Anemia is a common clinical situation which could due to many factors including blood loss, nutritional de ciency, renal dysfunction, in ammation and so on. Same as previous studies, patients with anemia had an increased in-hospital mortality in our study. This result reminded us that we should correct anemia appropriately according to the cause.

Strengths And Limitations
To our knowledge, this study is the rst to demonstrate that NOAF was associated with in-hospital mortality and 1 year mortality in critically ill patients with candidemia, which suggested that NOAF maybe considered an important predictor of deterioration among these patients. There are several limitations in our study. Firstly, these data was retrospectively collected, and it is possible that the number of prior-AF cases may be inaccurate as many patients may have asymptomatic AF. Secondly, this is a single center study. The number of cases is relatively small making our conclusion not su cient. Thirdly, majority of patients with NOAF died within 1 year after discharge from hospital, so there is insu cient data to assess long-term outcome. Therefore, the result of our study might not be fully generalizable, so a multicenter prospective, randomized controlled trial should be conducted to overcome these limitations.

Conclusions
Our study identi ed an important novel association between NOAF and poor outcomes including shortterm and long-term mortality in critically ill patients with candidemia. Further studies should involve larger, multicenter, prospective studies to get more accurate result and help the clinicians to adjust the treatment plan and communicate with patients and their relatives.