Single center cross-sectional survey and prognostic risk factors analysis of sepsis complicated with ARDS based on “Berlin definition”

doi:10.21203/rs.3.rs-2751766/v1

Download PDF

Research Article

Single center cross-sectional survey and prognostic risk factors analysis of sepsis complicated with ARDS based on “Berlin definition”

https://doi.org/10.21203/rs.3.rs-2751766/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Objective:To investigate the prognostic risk factors for sepsis complicated with acute respiratory distress syndrome (ARDS) based on the Berlin definition.

Methods: A total of 152 patients with sepsis complicated with ARDS admitted to the intensive care unit of our hospital from June 2016 to August 2017 were enrolled. According to the in-hospital clinical outcome, they were divided into death group (n=113) and survival group (n=39). The general characteristics, medical history, treatment and blood biochemical indexes of the two groups were collected. Multivariate Logistic regression analysis was performed to analyze the risk factors of death in these patients. The nomogram prediction model of inpatient death was constructed, and the prediction value of this model was assessed by receiver operating characteristic (ROC) curve.

Results: There were obvious differences in the survival group and death group with regard to total hospital stay, APACHE II score, ARDS lung infection, concurrent diseases, fluid accumulation unbalance within 72 hours of admission, type of sepsis, number of organ failure, tracheotomy, blood purification, and coagulation dysfunction (P< 0.05). Prominent differences were examined in the levels of laboratory indexes of albumin and urea between the two groups (P < 0.05). Logistic regression analysis demonstrated that APACHE II score, ARDS pulmonary infection, unbalance of fluid accumulation 72 hours after admission, organ failure number and coagulation dysfunction were independent risk factors for death in sepsis patients with ARDS, and blood purification was protective factor (P < 0.05). The findings of ROC curve illustrated that the area under the curve of the nomogram for forecasting in-hospital death in patients with sepsis and ARDS was 0.822 (95% CI 0.712-0.899), with a sensitivity of 80.25% and a specificity of 75.26%.

Conclusion: The prognosis of sepsis ARDS is poor and the mortality rate is extremely high. Active prevention should be taken to improve the cure rate of ARDS. Early use of blood purification and other rescue measures can help reduce the mortality rate of patients with sepsis complicated by ARDS.

Berlin definition

Sepsis

ARDS

Prognosis

Risk factors

Acute respiratory distress syndrome (ARDS), as a familiar clinical emergency in the respiratory system, has attracted much attention due to its high morbidity and mortality. At present, the frequently explored diagnostic criteria for ARDS is the Berlin definition revised in 2012. Although the understanding of the diagnosis and etiological mechanism of ARDS has gradually deepened, the overall mortality rate of patients is still as high as 35–45% [1, 2]. ARDS is often caused by severe infection, shock, trauma and other inducing factors, and is mostly manifested as acute onset and respiratory distress. The performance of patients with quarterly hypoxia cannot be relieved by conventional oxygen therapy. In severe cases, disturbance of consciousness and even death may occur[3].

The pathogenesis and causes of ARDS are complex, and sepsis has always been regarded as a principal risk factor for the development of ARDS [4]. With the severity of sepsis, ARDS patients have worse prognosis and higher mortality [5]. At present, research has continuously improved the early diagnosis and treatment of sepsis and ARDS, but there is no specific treatment method, and the mortality rate of patients is still high, causing a huge mental and economic burden to the family and society [6]. Therefore, inchoate diagnosis and early intervention exert vital significance to improve the survival rate of patients with sepsis complicated with ARDS.

In this study, a single-center cross-sectional survey was conducted to investigate the clinical characteristics of patients with sepsis complicated with ARDS who met the "Berlin definition" in our hospital, aiming to reduce ARDS incidence and mortality.

##The general information

A total of 152 patients with sepsis complicated with ARDS were retrospectively collected from the intensive care unit of our hospital from June 2016 to August 2017. This single center cross-sectional study was authorized by the ethics committee of the Shanghai Jiao Tong University Affiliated Sixth People’s Hospital. The inclusion criteria were as follows: (1) All patients met the definition of sepsis as defined by the International Sepsis Conference [7]; (2) All met the definition of ARDS according to the Berlin criteria in 2011 [8]; (3) Not complicating with other serious life-threatening emergencies; (4) ICU admission time ≥ 72 hours; (5) Complete follow-up data; (6) Patients and their caregivers gave informed consent to participate in this study. Exclusion criteria: (1) Age < 18 years old; (2) Pulmonary tumor or lobectomy; (3) Hemorrhagic shock caused by trauma; (4) Patients with advanced malignant tumor receiving chemotherapy; (5) Combined immune system diseases and hematological diseases; (6) Those who take hormones or immunosuppressants. The 152 patients included 85 males and 67 females, aged from 45 to 85 years, with an average age of (63.25 ± 7.17) years, and the total hospitalization time was (13.25 ± 27.44) days. According to the outcome of the patients at discharge, they were divided into a survival group of 39 cases and a death group of 113 cases. The flow chart of the selection of general information was illustrated in Fig. 1.

##observational Index

The clinical data of 152 patients with sepsis complicated with ARDS were retrospectively analyzed. Missing data of each parameter was below 10%, and complete-case-analysis was performed for this study.

General information: age, gender, total hospital stay, APACHE II score, ARDS lung infection, fluid accumulation balance within 72 hours of admission, type of sepsis, etc.

Medical history: concurrent diseases, trauma, smoking, drinking and allergy history.

Characteristics of the present illness: onset time and symptoms, first infection site, first failure site, time of organ failure, number of organ failures, acidosis, and coagulation dysfunction.

Treatment conditions: tracheotomy, blood purification, mechanical ventilation, blood transfusion, etc.

Blood biochemical indicators: white blood cell, platelet, neutrophil ratio, hemoglobin, albumin, serum creatinin, urea.

##statistical Methods

The data in this study were analyzed using IBM SPSS24.0 software package, and the measurement data conforming to the normal distribution were expressed as (‾x ± s). The independent samples t test was used to compare the means, the count data were expressed as [n (%)], and the χ² test was used to compare the results in the survival group and death group. The survival curve was drawn by the Kaplan-Meier method for survival analysis. The multivariate Logistic regression analysis was applied to analyze the risk factors of death in patients with sepsis complicated with ARDS. A nomogram prediction model for in-hospital death of these patients, and the receiver operating characteristic (ROC) curve was used to evaluate the predictive value of the model. P < 0.05 was considered statistically significant. Sample size was calculated using PASS15.0. The prevalence of ARDS hospital mortality was set as 0.35, the proposed sensitivity and specificity were both 0.9, the dropout out rate of patients was 20%, and a total of 54 patients were need for this study at α = 0.05, β = 0.1 levels.

##Analysis of general situation of sepsis complicated with ARDS

Among the 152 patients, 152 patients (100.00%) had the first failure site in the respiratory system, with a mortality rate of 75.66%. The most common underlying disease was cardiovascular disease in 53 patients (34.87%) with a mortality rate of 81.13%. The most common site of infection was the lungs in 75 cases (49.34%), and the mortality rate was 86.67%. The rest of the clinical features are shown in Table 1.

Table 1

General analysis of patients with sepsis complicated with ARDS [n(%)]
Clinical symptoms		Cases	Mortality
Gender	Male	85 (55.92)	65 (76.47)
	Female	67 (44.08)	48 (71.64)
Site of first failure	Cardiovascular system	138 (90.79)	84 (60.87)
	Respiratory system	152 (100.00)	115 (75.66)
	Central nervous system	24 (15.79)	13 (54.17)
	Kidney	53 (34.87)	36 (67.92)
	Liver	63 (41.45)	50 (79.37)
Background disease	Endocrine disease	26 (17.11)	16 (61.54)
	Cardiovascular disease	53 (34.87)	43 (81.13)
	Respiratory disease	13 (8.55)	10 (76.92)
	Digestive system disease	3 (1.97)	1 (33.33)
	Urinary system diseases	8 (5.26)	4 (50.00)
	Autoimmune disease	7 (4.61)	6 (85.71)
	Malignant tumor	12 (7.89)	12 (100.00)
	None	18 (11.84)	9 (50.00)
Infection site	Cardiovascular	3 (1.97)	1 (33.33)
	Urinary system	4 (2.63)	2 (50.00)
	Lung	75 (49.34)	65 (86.67)
	Digestive tract	41 (26.97)	38 (92.68)
	Abdominal cavity	10 (6.58)	8 (80.00)
	Lower limbs	15 (9.87)	13 (86.67)
	Skin	2 (1.32)	2 (100.00)
	Adnexa uteri	2 (1.32)	0 (0.00)

##survival Analysis Of Sepsis Complicated With Ards

Among 152 patients with sepsis complicated with ARDS, 39 survived and 113 died at the time of discharge. The median overall survival time of the dead patients was 18 days. The patient survival curve was shown in Fig. 2.

##comparison Of Clinical Features

The results of univariate analysis displayed that the total hospitalization time, APACHE II score, ARDS lung infection, underlying diseases, fluid accumulation balance within 72 hours of admission, type of sepsis, number of organ failure, tracheotomy, blood purification, and coagulation dysfunction between the two groups were markedly improved. The difference was memorably significant (P < 0.05). See Table 2.

Table 2

Comparison of clinical characteristics of the two groups of patients (‾x ± s ),[n(%)]
Factors		Survival group (n = 39)	Death group (n = 113)	χ²/t	P
Gender	Male	20 (51.28)	65(57.52)	0.458	0.500
	Female	19 (48.72)	48(42.48)
Age (years)		60.21 ± 6.34	62.55 ± 8.10	1.638	0.104
Total hospital stay (d)		43.25 ± 22.19	31.04 ± 25.46	2.665	0.009*
APACHE II score		13.25 ± 4.71	24.26 ± 4.08	6.672	༜0.001*
ARDS pulmonary infection	Intrapulmonary	19 (48.72)	78 (69.03)	5.179	0.023*
ARDS pulmonary infection	Extrapulmonary	20 (51.28)	35 (30.97)
Combined underlying disease	YES	28 (71.79)	103 (91.15)	9.122	0.003*
	NO	11 (28.21)	10 (8.85)
Fluid accumulation balance within 72 h of admission	Positive balance	13 (33.33)	60 (53.10)	4.537	0.033*
Fluid accumulation balance within 72 h of admission	Negative balance	26 (66.67)	53 (46.90)
Type of sepsis	Sepsis	21 (53.85)	22 (19.47)	20.939	༜0.001*
	Severe sepsis	13 (33.33)	38 (31.93)
	Septic shock	5 (12.82)	53 (46.90)
Number of organ failures		2.13 ± 0.59	4.22 ± 1.05	11.788	༜0.001*
Tracheotomy	YES	21 (53.85)	81 (71.68)	4.178	0.041*
	NO	18 (46.15)	32 (28.32)
Blood purification	YES	15 (38.46)	11 (9.73)	16.874	༜0.001*
	NO	24 (61.54)	102 (90.27)
Mechanical ventilation	YES	33 (84.62)	105 (92.92)	2.391	0.122
Mechanical ventilation	NO	6 (15.38)	8 (7.089)
Acidosis	YES	20 (51.28)	40 (35.40)	3.062	0.080
	NO	19 (48.72)	73 (64.60)
Blood transfusion	YES	14 (35.90)	42 (37.17)	0.020	0.887
	NO	25 (64.10)	71(62.83)
Coagulation disorders	YES	10 (25.64)	67(59.29)	13.135	༜0.001*
Coagulation disorders	NO	29 (74.36)	46(40.71)
Note: *P < 0.05 is considered to have a statistically significant difference.

##comparison Of Laboratory Indicators

There were significant differences in the levels of laboratory indexes of albumin and urea between the two groups (P < 0.05). See Table 3.

Table 3

Comparison of laboratory indicators between the two groups of patients (‾x ± s )
Laboratory metrics	Survival group (n = 39)	Death group (n = 113)	t	P
Leukocyte (×10⁹/L)	11.64 ± 2.22	11.98 ± 1.03	1.282	0.202
Platelets (×10⁹/L)	172.32 ± 20.40	165.12 ± 37.07	1.153	0.251
Neutral ratio	82.17 ± 5.06	82.85 ± 4.83	0.750	0.455
Hemoglobin (g/L)	110.25 ± 11.52	107.69 ± 11.47	1.201	0.232
Albumin (g/L)	27.15 ± 5.32	24.01 ± 4.16	3.772	0.001*
Creatinine	123.25 ± 31.56	132.25 ± 34.87	1.423	0.157
Urea	11.13 ± 0.79	12.05 ± 1.16	4.594	༜0.001*
Note: *P < 0.05 is considered to have a statistically significant difference.

##Logistic regression analysis of factors influencing the risk factors of death in patients with sepsis complicated with ARDS

Multivariate Logistic regression analysis showed that APACHE II score, ARDS pulmonary infection, positive balance of fluid accumulation 72 hours after admission, organ failure number and coagulation dysfunction were independent risk factors for death in sepsis patients with ARDS (P < 0.05), and blood purification was protective factor (P < 0.05). Shown in Table 4.

Table 4

Multivariate logistic regression analysis of risk factors for death in patients with sepsis complicated with ARDS
Factors	B	SE	Wald	P	OR	95%CI
Total hospital stay (d)	0.925	0.425	4.211	0.089	1.400	1.152 ~ 2.658
APACHEⅡ score	2.206	0.690	10.261	0.001	9.175	2.254 ~ 12.546
ARDS pulmonary infection	1.647	0.725	5.239	0.021	5.137	1.245 ~ 10.687
Fluid accumulation balance within 72 h of admission	1.725	0.892	4.521	0.028	5.758	1.152 ~ 25.369
Septic shock	1.358	0.472	7.930	0.120	3.821	1.504 ~ 10.152
Number of organ failures	0.320	0.124	5.252	0.012	1.352	1.025 ~ 1.792
Tracheotomy	2.619	0.502	2.052	0.068	1.267	1.102 ~ 2.067
Blood purification	-2.752	0.718	13.325	༜0.001	0.068	0.015 ~ 0.258
Coagulation disorders	1.302	0.630	4.251	0.028	3.524	1.070 ~ 12.528
Albumin	2.651	1.254	3.884	0.069	1.070	1.256 ~ 5.212
Urea	1.254	0.351	5.125	0.095	3.425	1.610 ~ 5.849

##nomogram Drawing And Verification

Based on the above results, a nomogram prediction model for in-hospital death in patients with sepsis and ARDS was constructed, and the corresponding scores of each prediction index were obtained (Fig. 3). The ROC curve was also drawn, and the results showed that the area under the curve of the nomogram for predicting in-hospital death in patients with sepsis complicated with ARDS was 0.822 (95% CI, 0.712–0.899), with a sensitivity of 80.25% and a specificity of 75.26% (Fig. 4).

ARDS is a common clinical type of respiratory failure. The main clinical features are progressive respiratory distress and intractable hypoxemia. The onset of this disease is acute and the condition is dangerous. According to statistics, sepsis can cause 10 million deaths worldwide every year, 40% of ARDS patients are caused by sepsis, and the mortality rate is significantly higher than that of patients without sepsis[9, 10]. With the improvement of clinical treatment level, the overall mortality rate of sepsis complicated with ARDS has dropped to 32%-50%, but it is still an important cause of death in ICU patients [11]. At present, the pathogenesis and treatment of ARDS are still difficult medical problems. Accurate identification of patients with high risk of death will help to formulate more active treatment and nursing strategies in time, reduce the incidence and mortality, and improve the treatment rate [12].

In this study, multiple Logistic regression analysis showed that APACHE II score, ARDS pulmonary infection, positive balance of fluid accumulation 72 hours after admission, organ failure number and coagulation dysfunction were independent risk factors for death in patients with SEPSIS complicated with ARDS, and blood purification was a protective factor. APACHE II score is a widely used evaluation index for severity and prognosis of critical illness at present. The higher the patient score is, the more severe the disease is and the worse the prognosis is. Relevant data show that the fatality rate of patients with APACHE II score above 20 is over 80%. In this study, the APACHE II score of the death group was above 20 on average, so APACHE II score can be used as a reliable indicator of the prognosis of patients with sepsis complicated with ARDS [13]. Pathogens infected with ARDS in the lung can secrete endotoxin to damage the function and structure of lung tissue, aggravate refractory hypoxemia and respiratory distress, and the prognosis of ARDS patients with intrapulmonary infection is dramatically inferior to that of ARDS patients with extrapulmonary infection [14].

At present, restricted fluid replacement is advocated for ARDS patients in shock to avoid pulmonary edema and severe hypoxia caused by excessive fluid infusion. In this study, positive fluid balance within 72 hours of admission was regarded as a prognostic risk factor for patients, suggesting that negative fluid balance within 72 hours of clinical treatment of sepsis complicated with ARDS was beneficial to patients. Some scholars have found through research that patients with sepsis, especially those with septic shock, were more likely to receive active fluid resuscitation, and achieving negative fluid balance within 48 hours of continuous renal replacement therapy may help improve prognosis [15]. Patients with sepsis complicated with ARDS have pulmonary insufficiency, circulatory dysfunction and other organ failures. When the dysfunction of various systems occurs, it can aggravate systemic organ hypoxia and worsen the disease, thus forming a vicious circle. Therefore, the greater the number of organ failures, the worse the prognosis and the significantly increased risk of death [16]. During the progression of sepsis complicated with ARDS, various inflammatory mediators are released, which activate the coagulation system while inhibiting the anticoagulation system. During the coagulation process, a large number of inflammatory factors are released, causing coagulation dysfunction and multiple organ dysfunction in sepsis, which seriously affects the prognosis[17, 18]. At present, blood purification has become one of the treatment methods for critical diseases, such as ARDS and multiple organ dysfunction syndrome. The blood of the patient's body is drawn out of the body through a purification device to remove some of the pathogenic substances and maintain the balance of the internal environment. Relevant data show that the filtration and adsorption of blood purification can protect the endothelial function of patients with sepsis, reduce tissue damage and inflammatory response, and reduce the mortality rate [19, 20].

In conclusion, the prognosis of SEPSIS ARDS is poor and the mortality rate is very severe. Relevant risk factors should be actively prevented to improve the cure rate of ARDS. Early application of blood purification and other rescue measures can help reduce the mortality of sepsis complicated with ARDS. However, the study is limited for its retrospective nature, few events per predictor, and undefined bacterial etiology for sepsis, and further studies are needed for evaluating this prognostic model.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

The project is supported by the Clinical Research Planky-012 of SHDC（SHDC2020CR6030）and Clinic Scientific Research inside Hospital （ynhg202107）

Authors' contributions

Yiqing Tong confirmed the authenticity of all the raw data and edited the manuscript, Lulu Shen and Jianming Zhang collected data and processed the data. Yiqing Tong and Yimu Fu conducted the statistics.Wei Wu reviewed and revised the article. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

Ethics approval and consent to participate

Informed consent was obtained from participants and/or their legal guardian for

the participation in the study and all methods were carried out in accordance with

relevant guidelines and regulations.The study was approved by the Ethics Committee of TheShanghai Jiao Tong University Affiliated Sixth People’s Hospital.

Consent for publication

All authors read and approved the final manuscript. All authors agree to publish the article.

Gorman E, Millar J, McAuley D, O'Kane C. Mesenchymal stromal cells for acute respiratory distress syndrome (ARDS), sepsis, and COVID-19 infection: optimizing the therapeutic potential. Expert Rev Respir Med. 2021;15:301–24.
Meyer NJ, Gattinoni L, Calfee CS. Acute respiratory distress syndrome. Lancet. 2021;398:622–37.
Wick KD, McAuley DF, Levitt JE, Beitler JR, Annane D, Riviello ED, et al. Promises and challenges of personalized medicine to guide ARDS therapy. Crit Care. 2021;25:404.
Villar J, Herran-Monge R, Gonzalez-Higueras E, Prieto-Gonzalez M, Ambros A, Rodriguez-Perez A, et al. Clinical and biological markers for predicting ARDS and outcome in septic patients. Sci Rep. 2021;11:22702.
Carlet J, Payen D, Opal SM. Steroids for sepsis and ARDS: this eternal controversy remains with COVID-19. Lancet. 2020;396:e61–e2.
Schmitt FCF, Lipinski A, Hofer S, Uhle F, Nusshag C, Hackert T et al. Pulmonary microbiome patterns correlate with the course of the disease in patients with sepsis-induced ARDS following major abdominal surgery.J Hosp Infect. 2020.
Briegel J. High-dose vitamin C administration in patients with sepsis and acute respiratory distress syndrome: comments on the CITRIS-ALI study. Anaesthesist. 2019;68:852–3.
Riviello ED, Kiviri W, Twagirumugabe T, Mueller A, Banner-Goodspeed VM, Officer L, et al. Hospital Incidence and Outcomes of the Acute Respiratory Distress Syndrome Using the Kigali Modification of the Berlin Definition. Am J Respir Crit Care Med. 2016;193:52–9.
Chen D, Wu X, Yang J, Yu L. Serum plasminogen activator urokinase receptor predicts elevated risk of acute respiratory distress syndrome in patients with sepsis and is positively associated with disease severity, inflammation and mortality. Exp Ther Med. 2019;18:2984–92.
Shah A, Ma K, Bhanot N, AlhajHusain A, Cheema T. Acute Respiratory Distress Syndrome From an Infectious Disease Perspective. Crit Care Nurs Q. 2019;42:431–47.
Yehya N, Thomas NJ, Wong HR. Evidence of Endotypes in Pediatric Acute Hypoxemic Respiratory Failure Caused by Sepsis. Pediatr Crit Care Med. 2019;20:110–2.
Nilsson B, Persson B, Eriksson O, Fromell K, Hultstrom M, Frithiof R, et al. How the Innate Immune System of the Blood Contributes to Systemic Pathology in COVID-19-Induced ARDS and Provides Potential Targets for Treatment. Front Immunol. 2022;13:840137.
DiSilvio B, Young M, Gordon A, Malik K, Singh A, Cheema T. Complications and Outcomes of Acute Respiratory Distress Syndrome. Crit Care Nurs Q. 2019;42:349–61.
Leligdowicz A. The Challenge and the Promise of Identifying More Homogeneous Subgroups in Acute Respiratory Distress Syndrome. Crit Care Med. 2019;47:1806–8.
Roca O, Penuelas O, Muriel A, Garcia-de-Acilu M, Laborda C, Sacanell J, et al. Driving Pressure Is a Risk Factor for ARDS in Mechanically Ventilated Subjects Without ARDS. Respir Care. 2021;66:1505–13.
Villar J, Gonzalez-Martin JM, Ambros A, Mosteiro F, Martinez D, Fernandez L, et al. Stratification for Identification of Prognostic Categories In the Acute RESpiratory Distress Syndrome (SPIRES) Score. Crit Care Med. 2021;49:e920–e30.
Popadic V, Klasnja S, Milic N, Rajovic N, Aleksic A, Milenkovic M, et al. Predictors of Mortality in Critically Ill COVID-19 Patients Demanding High Oxygen Flow: A Thin Line between Inflammation, Cytokine Storm, and Coagulopathy. Oxid Med Cell Longev. 2021;2021:6648199.
Morrissey SM, Geller AE, Hu X, Tieri D, Ding C, Klaes CK et al. A specific low-density neutrophil population correlates with hypercoagulation and disease severity in hospitalized COVID-19 patients.JCI Insight. 2021;6.
Ramirez-Sandoval JC, Gaytan-Arocha JE, Xolalpa-Chavez P, Mejia-Vilet JM, Arvizu-Hernandez M, Rivero-Sigarroa E, et al. Prolonged Intermittent Renal Replacement Therapy for Acute Kidney Injury in COVID-19 Patients with Acute Respiratory Distress Syndrome. Blood Purif. 2021;50:355–63.
Popescu M, Dima S, David C, Tudor A, Simionescu M, Tomescu D. Standard renal replacement therapy combined with hemoadsorption in the treatment of critically ill septic patients. Ther Apher Dial. 2021;25:663–70.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Single center cross-sectional survey and prognostic risk factors analysis of sepsis complicated with ARDS based on “Berlin definition”

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

##The general information

##observational Index

##statistical Methods

Results

##Analysis of general situation of sepsis complicated with ARDS

##survival Analysis Of Sepsis Complicated With Ards

##comparison Of Clinical Features

##comparison Of Laboratory Indicators

##nomogram Drawing And Verification

Discussion

Declarations

References

Additional Declarations

Status:

Version 1