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Features of Sepsis With Worse Outcomes in the ICU Admissions: a Cohort Study From Quick Diagnostic Tests

Background: Sepsis is still a global public health priority. We aimed to investigate the features of sepsis with worse outcomes in a single ICU of China.. Methods: We enrolled patients with acute critically ill with sepsis from ICU in China (Jan 1, 2018 to Nov 30, 2019). All patients underwent quick diagnostic tests before and after on admission. We collected data on the features of sepsis cases from hospital medical records and follow-up information. Outcomes were compared between patients who were survivors and those who were not. Results: Of 520 ICU admissions, 214 (41.2%) critically ill adults with sepsis were analyzed. The median age was 66 years (range 18-91 years) and 140 (65.4%) patients were males. 144 (78.3%) community-acquired pneumonia in 184 pneumonia cases were identied by quick chest CT and need mechanically ventilation in ICU. The rate of community- acquired sepsis was 73.8% (158/214) and was associated with a high risk of dynamic prole of inammatory mediators for nonsurvivors. The initial common symptoms 0f sepsis were fever (42.5%), altered mental status/delirium (41.1%), acute coma (34.1%), and cough/dyspnea (29.9%). Based on data with signicant univariate at initial 24 hours in ICU, the multivariate logistic analysis revealed a higher SIRS score (OR,4.7; 95% CI, 2.004-14.37), a higher SOFA score which mainly showed higher prevalent lungs and brain failure (OR, 1.7; 95% CI, 1.299- 2.298), and a lower GCS score (OR, 0.8; 95% CI, 0.673- 0.987) were established as early risk factors for sepsis in nonsurvivors. The mortality of sepsis was 55.6% at 28 days. Conclusions and relevance: Sepsis cases are mainly from community-acquired pneumonia. Severe SIRS and lungs/brain failure are related to the high mortality of sepsis.


Introduction
Sepsis is a life-threatening organ dysfunction that is caused by a dysregulated host response to infection [1]. However, the sepsis-met sepsis-3 criteria, also the most frequent complication of critically ill adults in the ICU, has become the leading cause of morbidity and mortality worldwide [2,3]. Moreover, the WHO estimates 30 million new cases of sepsis and approximately 6 million deaths per year in high-income countries worldwide, and recognizes sepsis as a global public health priority [4]. Unfortunately, this data may be severely underestimated because its statistics did not have the data from China and in lowincome countries worldwide. Furthermore, this sepsis has been largely ignored by clinical workers and the public because its onset is often hidden behind various critical illnesses and is unlike coronavirus disease 2019 (COVID-2019) patients with sepsis with outbreak transmission [5,6]. In the present study, we aimed to determine the features of worse outcomes of critically ill patients with sepsis in a single ICU of China, including epidemiological, clinical complications, radiological ndings, laboratory data, and treatment.
Moreover, our cohort study is from quick diagnostic tests (quick systemic CT scans and quick clinical tests). We hope that our study results will provide new evidence for the update of sepsis and achieve effective treatment.

Study setting and population
This study included critically ill adults who were admitted to a general ICU at the A liated Shuyang Hospital of Xuzhou Medical University in China. The current study recruited critically ill adults who were admitted between Jan 1, 2018, and Nov 30, 2019 (before COVID-19 outbreak), with a length of stay of more than 24 hours. We examined the electronic medical records of patients who were veri ed as having critically ill events with available records. We also excluded possible critically ill patients who did not have data in their medical records due to either death or transport out of the ICU within the rst 24 hours. The study was approved by the ethical committee on clinical research of the A liated Shuyang Hospital of Xuzhou Medical University. Because the study involved only a review of records obtained as a part of routine medical care, it did not require written information consent from all patients.

Patient identi cation
All patients underwent quick systemic CT scans (brain, thorax, and abdominal) before on admission. On quick chest CT tests, we identi ed community-acquired pneumonia (the typical pneumonia of chest CT images including bilateral multiple lobular and subsegmental areas of consolidation). The communityacquired sepsis was diagnosed by an acute change in the total Sequential Organ Function Assessment (SOFA) scores ≥ 2 points consequent to the community-acquiretherd pneumonia and/or systemic in ammatory response syndrome (SIRS).
A SIRS mainly involves massive in ammatory cytokine release [7]. More recently, this response has been called a cytokine storm or cytokine release syndrome, which is a life-threatening systemic in ammatory syndrome [8]. Furthermore, SIRS has been recognized as a clinical manifestation of the host response to suspected infection. Thus, we used SIRS criteria ≥ 2 to identify infection events within rst 0.5-1 hour in ICU. The clinical manifestations of SIRS include the following 4 points: (1) temperature > 38℃ or < 36℃; (2) heart rate > 90 beats per minute;(3) tachypnea greater than 20 respirations per minute or Pco2 less than 32mmHg; (4) white blood cell count > 12.0×10 9 /L or < 4.0×10 9 /L, or > 10% band forms. The identi ed criteria for SIRS must be at least ≥2 points/scores (≥3 points/scores= severe). In addition, this in ammatory syndrome also involves other in ammatory mediators in the blood (e.g., interleukin-6, Ddimer and C-reactive protein). Therefore, we also quick tested these in ammatory mediators. Sepsis must present one or more acute organ dysfunctions caused by infection. Acute organ dysfunction is de ned as equivalent to a sequential [sepsis-related] organ function assessment (SOFA) score ≥ 2 for a particular organ [with >4 scores indicating a multiple organ dysfunction syndrome (MODS)]. For example, a SOFA score ≥ 2 for acute respiratory failure/ARDS indicates PaO2/Fio2 <300 mmHg or SpO2<93% on minimal 2 L/min supplemental oxygen. The SOFA criteria for other organ failures are reported in document [9].

Data collected
The collected clinical pro le for this study performed in the ICU included patient demographics, comorbidities, time from critical illness to ICU admission, presenting symptoms, vital sign data, acute organ dysfunction, laboratory tests, cranial and thorax/ abdominal CT scans ndings, and treatment during the ICU stay. Laboratory tests included complete blood count, coagulation data (D-dimer and brinogen), liver and renal function, cytokines and other in ammatory mediators, SIRS score, SOFA score, mechanical ventilation, length of stay (LOS) in the ICU, and outcomes.
The outcome events were reviewed by two of the investigators (the rst and fourth authors). To investigate the outcomes of patients during the rst 72 hours and at 28 days, the survival results were determined from the hospital records and followed up to 28 days.
Based on the inclusion criteria for sepsis after critically ill events, the study data were divided into the sepsis survivor group and nonsurvivor group for statistical analysis.

Statistical methods
The results for each group are expressed as the mean ± standard deviation (SD) or median (IQR), and n (%) indicates qualitative values. Fisher's exact test and the Mann-Whitney U test were used to examine the relationship between baseline patient variables. Continuous variables were compared using Student's t test. Multivariate-adjusted odds ratios (ORs) and 95% con dence intervals (CIs) were estimated using a logistic regression model if they were signi cant according to the univariate analysis. Differences between patients were considered signi cant if the p-value was <0.05. Statistical calculations were performed using a proprietary, computerized statistics package (SPSS 17.0.).

Results
A total of 520 acute critically ill adult patients were recruited. After ruling out patients who did not meet the eligibility criteria for the study design, infection was con rmed by a brain-chest-abdomen CT scan before on admission. Finally, 214 (41.2%) critically ill patients with sepsis at ICU admission were identi ed by the sepsis-3 criteria ( Figure 1).
The clinical characteristics of the 214 sepsis patients are shown in Table 1. The median age was 66.7 years (range 18-91 years) and 140 (65.4%) patients were males. Of these patients, the most common comorbidity was hypertension (45.8%), followed by previous cardiac-cerebral vascular disease (33.6%), current acute traumatic brain injury events (27.1%), and current intracranial hemorrhage events (18.7%). The most common initial presenting symptoms were fever [91 (42.5%)], altered mental status/delirium   The data of the surviving or nonsurviving sepsis patients are described in Table 2. The laboratory ndings in the survivors were from the worst value during the clinical course in the ICU, but the major critical values in the nonsurvivors were tracked before death. The main dynamic ndings during sepsis progression included 6 laboratory parameters, which were from within the initial 1 days to 24 days after ICU admission at 3-day intervals. The interleukin-6 (IL-6), D-dimer, C-reactive protein (CRP), and SpO2 levels and the SIRS and SOFA scores were higher in the nonsurvivors than in the survivors (Figure 3). In addition, we found that nonsurviving sepsis patients were more likely to present with higher qSOFS scores, elevated procalcitonin, elevated creatinine, elevated blood glucose, and elevated lactic acid than survivors (all p<0.05). However, the white blood cell counts and neutrophil counts were similarly high between the nonsurvivors and survivors.  However, by logistic regression analysis, only a severe SIRS (OR, 4.7; 95% CI, 2.004-14.37), a higher SOFA score which mainly indicate lungs and brain failure (OR, 1.7; 95% CI, 1.299-2.298), and a lower GCS score (OR, 0.8; 95% CI, 0.673-0.987), were established as early risk factors for sepsis in nonsurvivors. (Table 3) Table 3 Logistic regression analysis to identify the death risk factors of sepsis patients in ICU  (Figure 4).

Discussion
The prevalence of sepsis in the last 30 years has been reported to range from 21.7-51.5% of all patients admitted to the ICU [10,11], about 30-42.8% community-acquired pneumonia associated sepsis [2,3,11,12], with a mortality rate of 23-48.2% in the ICU [2,3,11], 81.7% of septic patients with delirium in the ICU develop acute respiratory distress syndrome (ARDS), requiring intubation and mechanical ventilation [13]. Although sepsis has been frequently studied, its clinical features and risk factors of patients who were non-survivors still need clari cation. Undoubtedly, early diagnosis and treatment can reduce the mortality of sepsis. In the present study, so we used quick diagnosis tests, including early systemic CT scans and quick clinical tests to screen infection and sepsis. We found that the features of sepsis were mainly from community-acquired sepsis (73.8%), and most of them with community-pneumonia (78.3%). These data are higher than previous study [14], and the features are similar to the current outbreak of COVID-19 sepsis [9,15].
More importantly, we found that acute respiratory failure/ARDS (93.5%) and acute brain failure (94.4%) were the most common life-threatening organ dysfunctions in most of the sepsis cases, with a 55.6% risk of death within the initial 28 days in the ICU.
It should be noted, however, that critically ill ICU patients with sepsis with a high risk of death in our study were more likely to present with a higher SIRS score, a higher SOFA score, a higher qSOFA score, elevated interleukin-6, elevated D-dimer, lower GCS score and lower SpO2, elevated CRP and procalcitonin, elevated creatinine, elevated blood glucose, and elevated lactic acid. Notably, by multivariate regression analysis, only higher SIRS scores and higher SOFA scores (MODS) were related to high mortality in critically ill patients with sepsis.
Several possible interpretations of the results for sepsis with high mortality are as follows. First, MODS due to sepsis resulting in high mortality has been recognized [4,14,[16][17][18][19], and previous studies have shown that sepsis patients with MODS are more likely to exhibit ARDS [4,[17][18][19] and acute brain dysfunction [13,[20][21][22], which is related to their vulnerability to hypoxia/SIRS [7,13,[19][20][21][22]. Our data showed that current sepsis had MODS and that over 90.0% of patients with sepsis had acute respiratory failure/ARDS. The features of ARDS are mainly acute pneumonia/pulmonary infection due to a dysregulated immune response leading to higher in ammation in the lungs, followed by the development of pulmonary edema, hyaline membrane formation, and respiratory failure [19,23]. Moreover, acute respiratory failure/ARDS plays a pivotal role in the development of MODS in septic events [7,13,14,18]; epithelial damage and SIRS are the main pathophysiological features of ARDS and play an important role in distinguishing the hyperin ammatory subtypes of ARDS [19] .
Another possibility is that acute brain failure is also ranked as the leading organ dysfunction and for the host response to hyperin ammation, which is more likely to be due to hypoxic/SIRS [13,14,16,[20][21][22], especially with a cause of acute pneumonia/pulmonary infection [14,17,18]. Similar to the current outbreak of COVID-19 pneumonia, the mechanisms of bacterial pneumonia are also related to angiotensin conversion enzyme 2 (ACE2)-involved in ammatory response/cascade [24,25]. Furthermore, blood-brain barrier (BBB) leakage is also due to an overwhelming release of proin ammatory cytokines and anti-in ammatory factors [26][27][28]. SIRS is responsible for extensive BBB leakage and even brain edema and cerebral ischemic injury as well as cell death [26][27][28][29]. Our current study con rmed that SIRS is a very high risk factor for dying from sepsis, supporting that it is a life-threatening systemic in ammatory syndrome [8,30].
Strengths in this study, we are a rst to report that a brain-chest-abdomen CT scan before arriving at the hospital to identify early infection site which is a visible really infection. Severe SIRS and severe lungs/brain failure could use to predict the risk of sepsis with worse outcomes, However, some limitations of our design must be addressed. One limitation is the single central design, which may present a selection bias. However, this hospital is responsible for the medical care of the prefecture's population of approximately 1.8 million people, including an urban center and 38 villages and towns. This hospital ICU is a unique regional ICU (open 21-bed) with an emergency center (a total of 10 ambulances) that is responsible for all critically ill referrals in this prefecture. Thus, we believe that this sample does not lead to a large bias. The second limitation of this study is that organ dysfunction meeting the SOFA criteria was evaluated only according to old criteria. Although we made some changes, the observed SOFA scores may still be underestimated. In addition, although the prognosis for sepsis was related to SIRS and MODS, further prospective multicenter studies are needed for some of the intermediary links.

Conclusion
The vast majority of sepsis cases are from highly prevalent community-acquired pneumonia and with high risk of death. Severe SIRS and high prevalent lungs/brain failure are related to the high mortality of sepsis, suggesting that rapid antibiotic IV within the initial 1.0 hours in the ICU may improve patients' outcomes.

Consent for publication
Because the study involved only a review of records obtained as a part of routine medical care, it did not require written information consent from all patients for publication of this article and any accompanying images. Informed consent was waived by ethics committee of Shuyang Hospital.

Figure 1
Study pro le. Acute critically ill adult patients who were undergone a brain-chest-abdomen computed tomograph(CT) scans before arriving at the ICU were selected as an eligibility criteria.

Figure 2
The features of the chest computed tomographic (CT) images. Figure 2 A is from a patient with bacterial sepsis and ARDS. On days 2, 7, and 17 after symptom onset, chest CT showed progressive bilateral pneumonia deterioration with a large area of ground glass opacities in the left lobe, and due to resistance to antibiotics, the patient died. Figure 2 B is from a patient with sudden delirium who was admitted to the ICU. On day 2 and day 7 after symptom onset, chest CT showed bilateral pneumonia in the lungs. On day 3, the patient was in coma and respiratory failure requiring respiratory intubation, and bacterial sepsis was diagnosed. On day 10, chest CT showed that the bilateral lesions had improved by using antibiotics for treatment, and the patient nally recovered.