Risk factors for developing acute respiratory distress syndrome in sepsis patients: a retrospective study from a tertiary hospital in China

Abstract

Purpose: To investigate the risk factors for ARDS as well as for the severity of ARDS in patients with sepsis.

Methods: We retrospectively collected the characteristics of septic patients from the intensive care unit of the First Affiliated Hospital of China Medical University from January 2017 to September 2018. Logistic regression was used in determining the risk factors.

Results: 529 patients with sepsis were enrolled and 179 developed ARDS. The most common infection sites were acute abdomen (n=304) and pneumonia (n=117). Multivariate analysis showed that patients with pancreatitis and peripancreatic infection (odds ratio [OR], 3.601; 95% confidence interval [CI], 1.429 to 9.073, P =0.007), pneumonia (OR, 3.486; 95% CI, 1.890 to 6.430, P<0.001 ), septic shock (OR, 2.163; 95% CI, 1.429 to 3.275, P <0.001), a higher sequential organ failure assessment (SOFA) score (OR, 1.241; 95% CI, 1.155 to 1.333, P <0.001) and non-pulmonary SOFA score (OR, 2.849; 95% CI, 2.113 to 3.841, P <0.001) were independent risk factors for ARDS. Moreover, pneumonia is associated with increased severity of ARDS (OR, 2.512; 95% CI, 1.039 to 6.067, P =0.041).

Conclusions: We determined five risk factors for ARDS development in sepsis patients. Moreover, pneumonia is significantly associated with an increased severity of ARDS.

Introduction

Acute respiratory distress syndrome (ARDS) remains a major syndrome in the intensive care unit (ICU). It has been reported that 10.4% of total ICU-admitted patients develop ARDS [1]. Moreover, nearly 40% of ARDS patients are underdiagnosed [1]. Sepsis, defined as organ dysfunction induced by either pneumonia or non-pulmonary infection, is a common risk factor for the development of ARDS. Patients with sepsis-induced ARDS are reported to have a poorer prognosis than those without ARDS [2, 3] due to the lack of effective treatment strategies [4–8]. In accordance with the rapid deterioration of such clinical conditions, clinicians have shifted the management paradigm to prevent ARDS [9]. Potential risk factors for ARDS have been reported in previous studies [10–14], but there is still a lack of large-sample studies on risk factors for ARDS in ICU-admitted septic patients under the background of updated sepsis 3.0 criteria [15]. Moreover, to our knowledge, the risk factors related to the severity of ARDS in ICU sepsis patients diagnosed according to sepsis 3.0 criteria have not been reported to date.

In this study, we evaluated risk factors for ARDS and those associated with ARDS severity in patients with sepsis in ICU who were diagnosed according to sepsis 3.0 criteria.

Methods

Results

Discussion

ARDS remains a difficult clinical syndrome with high morbidity and mortality in the ICU. Risk factors for ARDS have long been discussed by clinicians, but there is no consensus yet. Moreover, little is known about the direct risk factors correlating with the severity of ARDS in ICU-admitted septic patients diagnosed according to sepsis 3.0 criteria. Our study reported the incidence of ARDS in septic patients was 34%, ranking as the highest incidence rate in the literature worldwide [10–14]. Possible reasons include: (1) the increased severity of sepsis in our cohort, as 46% patients developed septic shock, which is also a higher rate than that in previous studies [17]; (2). the improved clinical recognition of ARDS at our center. We believe that our data were convincing because the 28-day mortality rate agreed with that in a previous study [13].

Our study found a younger median age in patients with sepsis-induced ARDS. Ageing is a strong risk factor for adverse outcomes in the processes of many diseases. Studies on severe sepsis or septic shock patients have shown that older (> 65), critically ill surgical patients have a higher incidence of organ dysfunction and adverse outcomes [18]. According to our results, the median age was 66 years in ARDS patients and 70 years in non-ARDS patients. There was a significant difference between the two groups. We noticed that the results of 3 studies, including ours, showed that septic patients who developed ARDS were younger than those who did not (P < 0.05), although age was not an independent factor for developing ARDS [10, 11]. This divergence may be due to none of the 3 studies dividing patients according to age. Instead, we compared the median ages of patients from the ARDS group and non-ARDS group. Another possible reason is that ARDS is a clinical condition characterized by severe inflammatory responses accompanied by immune activation [19]. A set of functional and structural alterations in the immune system has been considered a crucial component of aging, such as a diminished response to vaccination and decreased inflammation grade [20]. This diminished response might be the underlying reason why ARDS patients had a younger median age than non-ARDS patients. Further studies may focus on this interesting clinical phenomenon in critically ill patients.

Our study reported a significantly worse prognosis of patients with sepsis-induced ARDS compared with those without ARDS, regarding to the length of mechanical ventilation, length of ICU stays, and 28-day mortality, which is in consistent with the data in the literature. Researchers reported that sepsis-associated ARDS leads to a prolonged recovery of patients from lung injury and a slower rate of extubating [21, 22] Moreover, the progression to ARDS is associated with an increased risk of in-hospital mortality in patients with sepsis. [23, 24] That’s why it is at urgent need in determining risk factors for sepsis patients who develop ARDS.

We confirmed five independent risk factors for developing ARDS in patients with sepsis, including septic shock, pneumonia, pancreatitis with local infection, increased SOFA score and extrapulmonary SOFA score. Septic shock is a severe form of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are profound enough to substantially increase the risk of mortality. Septic shock has long been recognized as a trigger of acute lung injury (ALI) and ARDS [14]. Iscimen et al reported that 44% of septic shock patients developed ALI in their ICU [14], which is almost the same as the rate in our ICU (48.6%). The results from our cohort showed that septic shock is an independent risk factor for developing ARDS in septic patients, which is in agreement with a previous study [10, 11].

Apart from septic shock, we confirmed two sites of infection including pneumonia and local pancreatic infection were associated with the occurrence of ARDS. Pneumonia has been reported as the most common source of infection in patients with ARDS and a risk factor in developing ARDS [25, 26]. The direct lung damage caused by pneumonia and the indirect lung damage caused by the systemic inflammatory response of sepsis together lead to the occurrence of ARDS. Acute severe pancreatitis may be caused by hyperlipidemia, alcohol consumption or cholelithiasis. The early stage of pancreatitis is considered as an asepsis condition. We carefully reviewed the medical records and confirmed that the 25 patients with local pancreatic infection enrolled in our study developed peripancreatic infection before ARDS occurred. It has been reported that 29%-39% of pancreatitis patients developed fatal lung complications, including ARDS [27, 28]. In pancreatitis patients, the development of ARDS is believed as a consequence of severe systemic inflammatory response with increased endothelial and epithelial barrier permeability, with leakage of a protein-rich exudate into the alveolar space and interstitial tissues, thus compromising oxygenation and gas exchange [29–31]. The result of our study contributes to the literature the strong relationship between infection site and ARDS development in patients with sepsis.

The lung injury prediction score (LIPS), early acute lung injury (EALI) score, APACHE II score and SOFA score are all considered to be related to the occurrence and development of ARDS in some studies. Research targeting patients in the emergency department consistently showed that the APACHE II score is an independent risk factor for ARDS in patients with sepsis [10, 23], while our results presented a significant difference in only the APACHE II score between the 2 groups of patients, but it was not an independent risk factor for ARDS development. Conversely, the SOFA score and non-pulmonary SOFA score were calculated as risk modifiers for ARDS. As the SOFA score increases, the risk of developing ARDS in sepsis patients is higher. This result is consistent with another study in ICU-admitted bacteremia patients [12]. This phenomenon may be explained by the fact that patients admitted to the emergency department are at their early stage of the disease process, and most of them have not yet been complicated with organ failure, while ICU patients have already developed complex organ dysfunction. This point may remind clinicians to pay more attention to respiratory function in patients with other organ dysfunction, such as acute kidney injury and dysfunction of the coagulation system.

As for clinical and prognostic factors of ARDS at different severity, our results showed patients with pneumonia and higher SOFA score were more likely to have severe ARDS. Moreover, they have significant worse 28-day and 90-day mortality rate. This result is in consistent with the mortality rate reported when ARDS Berlin Definition was published, which again illustrates the credibility of the patients enrolled in this study.[16] In addition, to the best of our knowledge, we determined for the first time that pneumonia has a significant correlation with increased severity of ARDS in patients with sepsis. Moreover, patients with pneumonia-induced ARDS showed significant worse PaO₂/FiO₂ index, longer duration of mechanical ventilation, and higher mortality rate. As we mentioned before, our results were consistent with previous studies that reported pneumonia as a risk factor in ARDS development in sepsis patients. When conquering infection, pulmonary defense system can trigger immune responses to microbes resulting in profound local and systematic inflammation, thus might develop ARDS.[32, 33] Nam H et al reported a significant higher proportion of pneumonia patients in 28-day non-survivors who diagnosed with ARDS caused by bacteremia-induced sepsis in Korea.[11] However, other studies showed that there is no relationship between pneumonia and increased mortality. [25, 34, 35]. Indeed, these results may not be directly comparable because of different inclusion criteria. Moreover, this might be due to the different populations between the studies, e.g., Asian, and non-Asian. We hypothesize that beneficial measurements and interventions should be implemented more aggressively in pneumonia patients to reduce the progression to severe ARDS, which may enhance the prognosis of ARDS caused by pulmonary sepsis.

ARDS is a clinical syndrome with a high rate of under-diagnosis. Up to 40% of ARDS patients cannot be clinically recognized quickly enough [1]. A better understanding of risk factors for ARDS in sepsis patients can help improve the ability of clinicians to recognize ARDS as early as possible. Moreover, several studies have shifted the emphasis from clinical risk factors to biomarkers for ARDS incidence, which is also a strategy for better precision medicine in ARDS. [36–38] Larger sample studies should be carried out to provide appropriate interventions to specific patients.

The limitations of this study are the following. 1. Our study is a retrospective study, and the homogeneity of the data is not guaranteed, which may affect the study results. 2. The severity of the disease in the selected population is high, and it cannot represent the clinical characteristics of all patients with sepsis and ARDS. 3. This study is a single-center study, and the research results cannot be extended to all patients with sepsis and ARDS or all severe patients.

Conclusion

Our study in the northeastern region of China showed that pneumonia, pancreatitis with local infection, septic shock, SOFA score and non-pulmonary SOFA score are independent risk factors for sepsis patients developing ARDS. In addition, pneumonia is significantly related to an increased severity of ARDS and increased mortality. Multicenter, prospective studies are needed to better recognize this severe clinical syndrome with high heterogeneity.

Declarations

Ethics approval and consent to participate

The study was approved by Ethics Committee of the First Affiliated Hospital of China Medical University. All the patients or their family who enrolled in this study have signed an informed consent. All methods were carried out in accordance with relevant guidelines and regulations.

Consent for publication

Not applicable.

Availability of data and material

The data could be shared if readers contact the authors and explain why they would like to access the data and material. Corresponding author should be contacted if someone wants to request the data from this study.

Competing interests

The authors declare that they have no competing interests.

Funding

None.

Authors’ contributions

Y Shi and X Li contributed the conception of the study, data collection and they drafted the manuscript together; L Wang contributed significantly to statistical analysis; S Yu helped to collect data. X Ma also contributed the conception of the study.

Acknowledgements

We acknowledge all the patients who enrolled in this study.

References

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Tables

Table 1. Comparisons of baseline characteristics between ARDS and non-ARDS patients.

Values are presented as median (interquartile range) or number (%).

ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease; HTN, hypertension; CHD, coronary heart disease; DM, Diabetes mellitus; CKD, chronic kidney disease; CRBSI, catheter related bloodstream infection; APACHE II, acute physiology and chronic health evaluation; SOFA, sequential organ failure assessment. 

Table 2. Prognostic analysis between ARDS and non-ARDS patients

ARDS, acute respiratory distress syndrome; ICU, department of intensive care unit;

Table 3. Univariate analysis of risk factors for ARDS

ARDS, acute respiratory distress syndrome; OR, odds ratio; CI, confidence interval; APACHEII, acute physiology and chronic health evaluation; SOFA, sequential organ failure assessment;

Table 4. Multivariate analysis of risk factors for ARDS

Table 5. Comparisons of characteristics between mild, moderate, and severe ARDS patients

Table 6. Prognostic factors between mild, moderate and severe ARDS patients

Table 7. Baseline characteristics and outcome between pulmonary and non-pulmonary groups in sepsis‐associated ARDS