Objective Recent studies have shown that blood urea nitrogen to creatinine (BUN/Cr) ratio might be an effective marker for the prognosis of patients with respiratory diseases. Herein, we aimed to assess the association between BUN/Cr ratio and the risk of in-hospital mortality in patients with trauma-related acute respiratory distress syndrome (ARDS).
Design A retrospective cohort study.
Setting and participants 1034 patients were extracted from the Medical Information Mart for Intensive Care-III (MIMIC-III) database.
Primary and secondary outcome measures The primary outcome of the study was in-hospital mortality, defined by the vital status at the time of hospital discharge (ie, survivors and non-survivors).
Results Of the total patients, 191 (18.5%) died in hospital. The median follow-up duration was 16.0 (8.3–26.6) days. The results showed that high level of BUN/Cr ratio was significantly associated with an increased risk of in-hospital mortality (15.54–21.43: HR=2.00, 95% CI: (1.18 to 3.38); >21.43: HR=1.76, 95% CI: (1.04 to 2.99)) of patients with trauma-related ARDS. In patients with trauma-related ARDS that aged ≥65 years old, male and female, Onychomycosis Severity Index (OSI)>98, Revised Trauma Score (RTS)>11, Simplified Acute Physiology Score II (SAPS-II)>37 and sequential organ failure assessment (SOFA) scores≤7, BUN/Cr ratio was also related to the increased risk of in-hospital mortality (all p<0.05). The predictive performance of BUN/Cr ratio for in-hospital mortality was superior to BUN or Cr, respectively, with the area under the curve of receiver operator characteristic curve at 0.6, and that association was observed in age, gender, OSI, RTS, SAPS-II and SOFA score subgroups.
Conclusion BUN/Cr ratio may be a potential biomarker for the risk of in-hospital mortality of trauma-related ARDS, which may help the clinicians to identify high-risk individuals and to implement clinical interventions.
- respiratory medicine (see thoracic medicine)
- respiratory infections
Data availability statement
Data are available upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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Strengths and limitations of this study
The association between blood urea nitrogen to creatinine (BUN/Cr ratio) and in-hospital mortality in patients with trauma-related acute respiratory distress syndrome, and predictive performance of BUN/Cr ratio for in-hospital mortality comparing to single BUN and Cr index were explored.
Subgroup analyses of different score systems including Revised Trauma Score, Simplified Acute Physiology Score II and sequential organ failure assessment score were performed for exploration of the relationship between BUN/Cr ratio and in-hospital mortality.
MIMIC-III (Medical Information Mart for Intensive Care-III) database is a publicly available database, and the participation is large and representative.
This study is a single-centre retrospective cohort study with selection bias inevitably.
The information regarding the fluid administration when admitting to intensive care unit and the baseline left ventricle ejection fraction were not available in the NHANES (National Health and Nutrition Examination Survey) database.
Acute respiratory distress syndrome (ARDS) is an acute diffuse lung injury.1 Various intrapulmonary and extrapulmonary pathogenic factors contribute to development and progress of ARDS and the mortality rate range is between 35% and 45% in the USA.2 Severe trauma is a common predisposing factor of ARDS, accounting for about 10% of all ARDS cases, which is associated with longer hospital stays, increased costs and worse long-term health related quality of life.3 Early identification of high-risk patients and reduction in organ dysfunction and mortality have been the strategic focuses of ARDS.4 The Simplified Acute Physiology Score II (SAPS-II) is often used to assess outcomes in patients who are critically ill and with ARDS, however, is not specific enough for the evaluation of prognosis in trauma-related ARDS.5 Thus, it is necessary to find clinical parameters as biomarkers or to construct a model for the prediction of in-hospital survival in patients with ARDS after trauma or severe surgery.
Blood urea nitrogen (BUN) and creatinine (Cr) are recognised indicators of renal insufficiency.6 Studies by Varmudy et al7 and Komara et al8 showed that high BUN level was associated with poor outcomes in patients with ARDS. Cr is a biochemical signature of persistent critical illness and a potential indicator of ongoing muscle catabolism. Prowle et al9 indicated that soon after major trauma, there was a rapid, sustained fall in serum Cr during the first 4 days. The BUN/Cr ratio is a laboratory biomarker frequently used for determination of dehydration, and has been reported as the independent predictor for the prognosis of many diseases, such as stroke, gastrointestinal bleeding, heart failure and hip fracture.10–13 Research by Tang et al5 found that the BUN/Cr ratio between the survival group and the death group in ICU patients was greater than 10:1, suggesting that patients with trauma-related ARDS have predominantly prerenal azotaemia. In addition, Ok et al14 considered that the BUN/Cr ratio may function as a predictive factor for the severity and survival of COVID-19. Therefore, we speculated the BUN/Cr ratio might be an effective predictor for the in-hospital mortality of patients with respiratory diseases.
Herein, this study aims to explore the association between BUN/Cr ratio and the risk of in-hospital mortality in patients with trauma-related ARDS, and further explored this relationship in age, gender and different scoring systems of disease severity subgroups. In order to early identify high-risk populations and provide some clinical reference for further exploration of biomarkers for mortality prediction accurately in trauma-related ARDS.
Patient and public involvement statement
The Medical Information Mart for Intensive Care-III Clinical (MIMIC-III) database is a publicly available database, and participation is voluntary and informed consent was obtained from all participants.
Study design and data source
In this single-centre retrospective cohort study, data of adults diagnosed with trauma-related ARDS were extracted from the MIMIC-III database. The MIMIC-III database was jointly published by the Computational Physiology Laboratory of Massachusetts Institute of Technology, Beth Israel Deaconess Medical Center and Philips Medical. It collected and sorted out the clinical diagnosis and treatment information on more than 40 000 real patients who are predominantly white people living in the ICU of the Beacon Israel Dikang Medical Center from 2001 to 2012.15 The data are publicly available at https://physionet.org/content/mimiciii/1.4/, and the information data of relevant patients of this study mainly from the MIMIC-III.16
A total of 1776 adult patients with trauma-related ARDS were initially included. We excluded those who stayed in the ICU for less than 24 hours, had a heart failure and advanced kidney dysfunction (serum Cr >354 µmol/L or estimated glomerular filtration rate<15 mL/min/1.73 m2) on ICU admission, with Onychomycosis Severity Index (OSI) >315 mm Hg (OSI=SPO2/FIO2) and missed information of BUN and Cr. Finally, 1034 patients were eligible.
We extracted variables including age, gender, ethnicity, length of stay in ICU, vasopressor use, comorbidities (hypertension, diabetes mellitus, atrial fibrillation, lung cancer, heart disease) (identified using ICD-9 codes), Elixhauser Comorbidity Index (ECI), systolic blood pressure (SBP), diastolic blood pressure, respiration rate, heart rate, temperature, PO2, FiO2, SpO2, OSI, white blood cell, neutrophil count (NEUT), lymphocyte count, platelet, haemoglobin (HB), red blood cell distribution width (RDW), Cr, albumin (ALB), BUN, bicarbonate, glucose, lactate, neutrophil to lymphocyte ratio, Glasgow Coma Scale score, SAPS-II, sequential organ failure assessment (SOFA) score and Revised Trauma Score (RTS).
The BUN/Cr ratio was calculated from serum BUN and Cr according to the MIMIC-III. The information of PaO2 is unavailable in MIMIC-III, and we used OSI instead of oxygen index (OI) to assess ARDS: OSI=64+0.84×OI. The laboratory data of patients were obtained during their ﬁrst 24 hours after ICU admission.
Outcomes and follow-up
The study outcome is in-hospital mortality, defined as the vital status at the time of hospital discharge. The patients were divided into survival group and in-hospital mortality group. The follow-up was started at the ICU admission and ended until patients’ death or 30 days after ICU admission, and the median follow-up duration was 16 (8.3–26.6) days.
Mean and SD (mean±SD) was used to represent continuous data. Analysis of variance among three groups was used to reflect the differences between groups. N (%) was used to represent categorical data, and Χ2 test was used to analyse the differences between groups. Univariate Cox regression analysis was used for screening of confounding factors (online supplemental table S1). Univariate and multivariate Cox regression analyses were used to explore the association between BUN/Cr ratio and the risk of in-hospital mortality in patients with trauma-related ARDS. Subgroups analyses of age, gender, OSI, RTS, SAPS-II and SOFA score were also performed. Additionally, we drew receiver operator characteristic curves (ROCs) with area under the curves (AUCs) to evaluate the predictive performance of BUN/Cr ratio for the in-hospital mortality.
The BUN/Cr ratio (<15.54, 15.54–21.43 and >21.43), BUN (<14, 14–21 and >21 mg/dL) and Cr (<0.8, 0.8–1.1 and >1.1 mg/dL) were divided into three levels according to the tertiles, respectively. Model 1 was the crude model, and Model 2 adjusted for confounding factors including gender, ethnicity, length of stay in ICU, vasopressor use, ECI, NEUT, HB, RDW, lactate, SAPS-II, SOFA score and RTS. The evaluation indexes were the HRs (ORs) with 95% CIs, and statistical tests of two-sided p<0.05 considered significant. Statistical analyses were performed using R V.4.2.2 (Institute for Statistics and Mathematics, Vienna, Austria). Missing data are shown in online supplemental table S2, and dealt using multiple interpolation according to Rubin’s rules and combine the results across the imputed data sets.
Characteristics of patients with trauma-related ARDS
Figure 1 is the flow diagram of the screening of the study population. A total of 1776 individuals with trauma-related ARDS were initially included. Then those who aged <18 years old (n=8), missing information of BUN and Cr (n=13), diagnosed of heart failure (n=576) and advanced kidney dysfunction (n=53) at ICU admission, with OSI >315 mm Hg or missing OSI information (n=3), and stayed in the ICU less than 24 hours (n=59) were excluded. Finally, 1034 patients were eligible.
Table 1 shows the characteristics of patients with trauma-related ARDS. Of the eligible patients, 191 (18.5%) died in-hospital. We divided the participants into three groups according to the BUN/Cr level, BUN/Cr <15.6 (n=341), BUN/Cr: 15.6–21.4 (n=340) and BUN/Cr >21.4 (n=353). Among the patients, 583 (56.38%) were men. The average age among three groups were, respectively, 53.2, 63.7 and 71.4 years old. The average serum BUN levels among three groups were, respectively, 14.2, 18.7 and 27.8 mg/dL. Average BUN/Cr ratios were 12.4, 18.2 and 29.9, and the average SAPS-II were 36.7, 37.6 and 42.2 in the three groups. Besides, ethnicity, length of stay in ICU, comorbidities, SBP, SpO2, HB, RDW, ALB, pH, bicarbonate, lactate and SOFA score were also significantly different among three BUN/Cr level groups (all p<0.05).
Association between BUN/Cr ratio and BUN and Cr and in-hospital mortality in patients with trauma-related ARDS
Table 2 shows the relationship between BUN/Cr ratio and BUN and Cr, and in-hospital mortality, respectively. After adjusted for the confounding variables including gender, ethnicity, length of stay in ICU, vasopressor use, ECI, NEUT, HB, RDW, lactate, SAPS-II, SOFA score and RTS, we found that comparing to low level of BUN/Cr ratio, high level of BUN/Cr ratios were significantly related to the increased risk of in-hospital mortality (15.54–21.43: HR=2.00, 95% CI: (1.18 to 3.38); >21.43: HR=1.76, 95% CI: (1.04 to 2.99)). At the same time, no association between BUN or Cr and in-hospital mortality was discovered (all p>0.05).
Association between BUN/Cr ratio and BUN and Cr and in-hospital mortality in age, gender, OSI, RTS, SAPS-II and SOFA score subgroups
Table 3 is the subgroup analyses of the relationship between BUN/Cr ratio and BUN and Cr and in-hospital mortality. The results showed that BUN/Cr ratio at 15.54–21.43 was associated with the increased risk of in-hospital morality in patients aged ≥65 years old (HR=2.54, 95% CI: (1.21 to 5.30)), were men (HR=2.41, 95% CI: (1.00 to 5.78)) and women (HR=2.21, 95% CI: (1.07 to 4.60)), with OSI >98 (HR=2.63, 95% CI: (1.09 to 6.32)), RTS >11 (HR=2.33, 95% CI: (1.23 to 4.45)), SOFA score ≤7 (HR=2.54, 95% CI: (1.07 to 6.03)). Additionally, both BUN/Cr ratio at 15.54–21.43 and >21.43 were linked to the increased risk of in-hospital morality in patients with SAPS-II >37 (all p<0.001).
Predictive performance of BUN/Cr ratio for in-hospital mortality and that in different subgroups
Figure 2 was the ROC curve of predictive performance of BUN/Cr ratio, BUN and Cr for in-hospital mortality, respectively. It was obvious that the predictive performance of BUN/Cr ratio for in-hospital mortality was significantly superior to single BUN or Cr, with an AUC of 0.60.
We further explored their predictive ability in age, gender, OSI, RTS, SAPS-II and SOFA score subgroups (figure 3). The results showed that in patients with trauma-related ARDS who aged <65 years old, male and female, with different OSI, RTS and SAPS-II, and SOFA score ≤7, BUN/Cr ratio had a super predictive performance for in-hospital mortality to single index of BUN or Cr.
High level of BUN/Cr ratios were significantly correlated with the increased risk of in-hospital mortality in patients of trauma-related ARDS. However, no association between BUN or Cr and in-hospital mortality was discovered. The relationship between BUN/Cr and in-hospital mortality of patients with trauma-related ARDS was also found in the subgroups of age ≥65 years old, male and female, OSI >98, RTS >11 and SAPS-II >37. The predictive performance of BUN/Cr ratio for in-hospital mortality was significantly superior to single BUN or Cr, with an AUC of 0.60. And in patients with trauma-related ARDS who aged <65 years old, male and female, with different OSI, RTS and SAPS-II, and SOFA score ≤7, BUN/Cr ratio also had a super predictive performance for in-hospital mortality to single index of BUN or Cr.
ARDS is the most frequent manifestation of multiple organ failure after trauma,17 18 and injured patients with ARDS have mortality rates as high as 35–45%.19 Previous study suggested there had the possibility of unique underlying clinical risk factors and causal biological mechanisms.20 Tang et al5 found BUN was independently associated with the prognoses of patients with trauma-related ARDS, and the BUN/Cr ratio was elevated. Komara et al8 also suggested that high BUN level is associated with poor outcomes in patients with ARDS. BUN/Cr ratio is a biomarker used to predict the prognosis of many diseases, and study has demonstrated that BUN/Cr ratio was more valuable than BUN or Cr alone in predicting the progression of patients with acute heart failure.21 However, there are few studies on BUN/Cr ratio as a predictor to evaluate the prognosis of trauma-related ARDS. Ok et al14 believed BUN/Cr would be beneficial in assessing the severity and survival of those with COVID-19 disease since that multisystem inflammation can occur in severe and critical groups of COVID-19 patients which increase BUN reabsorption and the BUN/Cr ratio. Li et al22 provided the evidence that BUN/Cr ≥15 as a marker of dehydration may be a predictor of long-term outcome of patients with acute ischaemic stroke. Analogously, our findings showed that BUN/Cr ratio was associated with in-hospital mortality of patients with trauma-related ARDS which indicated that BUN/Cr ratio might be a possible predictor of the prognosis of trauma-related ARDS. Additionally, the predictive performance of BUN/Cr ratio for in-hospital mortality was superior to single BUN or Cr index with an AUC of 0.6, indicating it may be a potential indicator for trauma-related ARDS.
We also explored the association between BUN/Cr ratio and BUN and Cr and in-hospital mortality in age, gender, OSI, RTS, SAPS-II and SOFA score subgroups. The RTS, SAPS-II and SOFA score were common scoring systems for ARDS or trauma. In the current study, we found that a high BUN/Cr ratio was associated with the increased risk of in-hospital mortality in patients with RTS >11, SOFA score ≤7 and SAPS-II >37. The results indicate that clinical attention should be paid to monitor the BUN/Cr ratio of critically injured patients with ARDS at the time of admission to the ICU and in real time, so that countermeasures can be adjusted to reduce the risk of in-hospital mortality. SAPS-II is one of the traditional score systems used to assess the severity and prognosis of trauma or ARDS commonly.23 24 Grassner et al25 revealed that SAPS-II counts were independent predictors of neonatal intensive care unit mortality of patients with non-traumatic spinal cord injuries. However, SAPS-II is complicated and time consuming to calculate, and trauma-related ARDS is a heterogeneous disease, the existing score systems did not have high accuracy for the prediction.26 27 Our study population was divided into three BUN/Cr level groups, and the serum BUN were, respectively, 14.2, 18.7 and 27.8 mg/dL, the serum Cr were 1.2, 1 and 1 mg/dL. It seems that the higher BUN level may represent a higher BUN/Cr ratio that means the patients with trauma-related ARDS were more critical. RTS can assess and guide the treatment of patients with trauma, and it is typically used to determine physiological risk, guide referral patterns in a prehospital setting and as a prognostic tool.28 The RTS requires few data to calculate and has been previously validated in adults.29 However, it has not been reported to be applied in the prediction of the mortality in trauma-related ARDS. Our results partly provide some reference for the clinical indicators that should be focused in patients with severe trauma-induced ARDS. In patients with trauma-related ARDS with SOFA score ≤7, BUN/Cr ratio was also linked to the increased risk of in-hospital mortality. SOFA score is considered an excellent score to predict short-term mortality in sepsis and other life-threatening conditions.30 In our study, patients with trauma-related ARDS with high SOFA score (>7) may have already consumed the haemodynamic and neurohormonal compensatory mechanisms, with subsequent severe systemic hypoperfusion, that impairs the function of the major components of the SOFA score; such as brain, kidney, liver and haematopoietic systems31 and contribute to the BUN/Cr ratio has not been remarkable.
This study is a single-centre retrospective cohort study with selection bias inevitably. The BUN/Cr ratio closely links to volume status and cardiac function, but the information regarding the fluid administration when admitted to ICU and the baseline left ventricle ejection fraction were not available in the NHANES (National Health and Nutrition Examination Survey) database. It is difficult to calculate OI because PaO2 information is largely missing from the MIMIC-III database. However, OI was converted into OSI by a validated formula in this study to help judge the diagnostic criteria and severity of ARDS. In this study, patients with advanced kidney dysfunction were excluded to reduce its effect on BUN and Cr. As a matter of fact, it is necessary to further explore the effect of BUN/Cr level on the in-hospital mortality in patients with trauma-related ARDS with severe renal injury.
BUN/Cr ratio may be a potentially biochemical signature that predicts the risk of in-hospital mortality in trauma-related ARDS. The BUN/Cr ratio is readily available from routine clinical data and the results of our study partly aid the timely identification of high-risk patients and the development of intervention strategies.
Data availability statement
Data are available upon reasonable request.
Patient consent for publication
The requirement of ethical approval for this was waived by the Institutional Review Board of the Fourth Affiliated Hospital of Guangxi Medical University, because the data was accessed from MIMIC-III (a publicly available database). All individuals provided written informed consent before participating in the study.
HM and SL are joint first authors.
HM and SL contributed equally.
Contributors HM, SLin and DZ designed the study. HM and SLin wrote the manuscript. YX, SM, QH, HG, ZS and SLi collected, analysed and interpreted the data. DZ and SLi critically reviewed, edited and approved the manuscript. All authors read and approved the final manuscript. DZ is responsible for the overall content as the guarantor.
Funding This work was supported by Guangxi Zhuang Autonomous Region Health Committee Self-financing Research Project (grant No. Z20190700), Guangxi Science and Technology Bureau planned project key R&D plan (grant No. AB17129001) and the Project of Improving the Basic Scientific Research Ability of Young and Middle-aged Teachers in Guangxi Universities (2022KY0111).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.