Blood urea nitrogen (BUN) independently predicts mortality in critically ill patients admitted to ICU: A multicenter study

BACKGROUND AND PURPOSE: The Microcirculatory Shock Occurrence in Acutely Ill Patients (micro-SOAP) study investigated associations of microcirculation and mortality. Risk stratification in critically ill patients is of utmost interest. Established score such as APACHE2 (Acute Physiology And Chronic Health Evaluation 2) are relatively complex and might therefore be of limited use. Blood urea nitrogen (BUN) was described to be associated with mortality in various diseases. We therefore aimed (i) to evaluate BUN for prediction of mortality in a cohort of critically ill patients and (ii) to investigate associations of BUN with microcirculation. METHODS: 412 patients were included in our post-hoc analysis of the prospective multicenter microSOAP study. Assesment of the sublingual microcirculation (Sidestream Dark Field (SDF) imaging) and collection of laboratory values were performed on the same day in this point prevalence study. Evaluation of associations with mortality was done by logistic regression analysis. An optimal BUN cut-off was calculated by means of the Youden Index. RESULTS: Median BUN was 9.0 mmol/L. BUN was associated with in-hospital-mortality in a logistic regression analysis (HR 1.03; 95% CI 1.01–1.05; p < 0.001). Per quartile (BUN 0–5.4 mmol/L, 5.4–9.0 mmol/L, 9.0–15.9 mmol/L and above 15.9 mmol/L) in-hospital mortality increased by as much as 51% (HR 1.51; 95% CI 1.23–1.85; p < 0.001). ROC analysis was done (AUC 0.63 95% CI 0.58–0.67) and the statistically optimal cut-off calculated by means of the Youden Index: 9.7 mmol/L. This cut-off was associated with a significant 3-fold increase in mortality (HR 2.97 95% CI 1.88–4.70; p < 0.001) and remained robustly associated with adverse outcome after correction for APACHE2 (HR 2.71 95% CI 1.61–4.59; p < 0.001), renal function as expressed by creatinine (HR 2.63 95% CI 1.59–4.33; p = 0.001), as well in an integrative model (MAP<60 mmHg, tachycardia (heart rate >90/min), lactate above 1.5 mmol/L, age above 80 years; HR 2.43 95% CI 1.50–3.92; p < 0.001). Parameters of microvascular perfusion were associated neither with BUN nor mortality. CONCLUSIONS: BUN is associated with hospital mortality and a combination of BUN and clinical signs might constitute a powerful but easy-to-use tool for risk stratification in critically ill patients and help improve their outcome. BUN was not associated with parameters of microcirculation which were not associated with mortality.

Critically ill; BUN; ICU; risk stratification; risk score; microcirculation

Risk stratification in critically ill patients remains challenging as these represent a heterogenous collective. Elaborate scores like APACHE2 score might be unpractical for an initial early assessment and quick risk stratification, as they are complex to calculate and base on volatile parameters such as heart and respiratory rate [[1] ]. Simple but reliable tools are needed and might improve our patients’ outcome.

Blood urea nitrogen (BUN) was shown to be useful for risk stratification in various diseases such as heart failure, aortic dissection, pancreatitis and peripheral artery disease [[4] ]. BUN is considered to constitute a marker not only for renal function but for neurohumoral activity too, due to its reabsorption from the tubules and its role in physiological fluid balance [[8] ].

The Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP) study constituted a multi-center study to investigate associations of microcirculation and mortality in a prospective manner and impaired microcirculation was shown to be associated with mortality in a high-risk sub-group suffering from tachycardia, but not in the overall cohort [[9] ]. The microSOAP study constituted the first prospective multicenter study on microcirculation and constitutes the largest investigation in this field. Microcirculatory alterations were assessed by sublingual microscopy directly in vivo and in real time, a method which is well established [[10] ]. Laboratory and clinical values were obtained on the same day of sublingual microscopy in this point prevalence study [[9] ].

Before, impaired microcirculation has been reported to be associated with mortality in the critically ill. Interestingly, microcirculation is not associated with parameters of macrocirculation such as mean arterial pressure, heart rate and cardiac output [[13] ]. Further, microcirculation stays impaired even after therapeutically normalization of macrocirculation [[22] ]. Microcirculation was therefore discussed to be an independent treatment target especially in patients in shock and suffering from sepsis in which both macro- and microcirculation are severely impaired [[23] ].

In our post-hoc retrospective study we aimed to investigate associations of mortality with BUN and further possible associations of BUN with microcirculation.

We retrospectively evaluated a sub-group of the microSOAP (Microcirculatory Shock Occurrence in Acutely ill Patients [microSOAP]; ClinicalTrials.gov identifier NCT01179243; registered on August 3, 2010) study group [[9] ]. Patient inclusion and data collection was as described before, from September 5th to 9th 2011 heterogenous ICU patients above 18 years of age were included in 36 international ICUs, [[9] ]. In this point prevalence study, patient characteristics and laboratory values and sublingual sidestream dark-field (SDF) imaging were collected simultaneously on a single day for all patients in a given ICU or ICU subunit. This post-hoc analysis included all patients with a BUN level reported and not undergoing renal replacement therapy (412 of 501 patients).

Normally distributed data points are expressed as mean (±standard error of the mean). Differences between independent groups were calculated using ANOVA. Chi-square test was applied to calculate differences between groups. Both univariate and multivariate logistic regression analysis to adjust for confounding factors for mortality were done. A p-value of <0.05 was considered statistically significant. We report several multivariate regression models and one integrated model which adjusts for several confounders. SPSS version 22.0 (IBM, USA) and MedCalc version 14.8 (MedCalc Software, USA) were used for statistical analysis. Correlation analysis was done using Spearman’s rank coefficient.

Evaluation of the sublingual microcirculation was done as described before by in-vivo microscopy using Sidestream Dark Field Imaging [[9] ]. Offline analysis yields the semiquantitative microvascular flow index (MFI), ranging from 0 (no flow) to 3 (continuous flow), and percentage of perfused vessels (PPV), total vessel density (TVD) and perfused vessel density (PVD, both expressed in mm/mm2), providing information on diffusion (TVD and PVD) and convexity (PPV and MFI)[[30] ]. A small vessel (<20μm) MFI below 2.6 is considered abnormal being the minimum reported value for the lower bound of the 95% CI of MFI in healthy volunteers [[32] ].

This study was conducted in accordance with the ethical guidelines of Clinical Hemorheology and Microcirculation [[35] ]. A study protocol was provided to participating centers. Every participating center obtained ethics approval according to local legislation. A copy of the ethics approval was sent to the study coordinator before start of the study. The study was registered at http://www.clinicaltrials.gov/(NCT01179243). Written informed consent was obtained of all included subjects, unless the local ethics committee specifically allowed a waiver in this respect.

412 patients were included in our post-hoc analysis, a subgroup of microSOAP. The median BUN levels were 9 mmol/L (inter-quartile range 5.4 mmol/L –15.9 mmol/L). We split our cohort in two subgroups at this median BUN concentration of 9 mmol/L. Patients with higher BUN levels were older (64±1 years vs 57±1 years; p < 0.001), clinically sicker as expressed by higher APACHE2 scores (17±1 points vs 14±1 points, p < 0.001) and had higher creatinine levels (creatinine 133±8 micromol/L vs 68±2 micromol/L; p < 0.001). Markers of microcirculation did not differ between patients with high and low BUN levels as shown in [NaN] .

Table 1 Baseline demographics

BUN was associated with in-hospital-mortality in a logistic regression analysis (HR 1.03; 95% CI 1.01–1.05; p < 0.001). Per quartile (BUN 0–5.4 mmol/L, 5.4–9.0 mmol/L, 9.0–15.9 mmol/L and above 15.9 mmol/L) in-hospital mortality increased by as much as 51% (HR 1.51; 95% CI 1.23–1.85; p < 0.001).

ROC analysis was done (AUC 0.63 95% CI 0.58–0.67) and the statistically optimal cut-off calculated by means of the Youden Index: 9.7 mmol/L. This cut-off was associated with a significant 3-fold increase in mortality (HR 2.97 95% CI 1.88–4.70; p < 0.001; [NaN] ) and remained robustly associated with adverse outcome after correction for APACHE2 (HR 2.71 95% CI 1.61–4.59; p < 0.001), renal function as expressed by creatinine (HR 2.63 95% CI 1.59–4.33; p = 0.001), as well in an integrative model (MAP<60 mmHg, tachycardia (heart rate >90/min), lactate above 1.5 mmol/L, age above 80 years; HR 2.43 95% CI 1.50–3.92; p < 0.001).

Of note, in our sub-group of the microSOAP study cohort, abnormal microcirculation (MFI <2.6) was not associated with mortality (HR 1.27 95% CI 0.72–2.25; p = 0.40). Whereas abnormal microcirculation was not associated with mortality neither in the BUN>9.7 mmol/L (HR 1.46 95% CI 0.67–3.15; p = 0.33) nor in the BUN<9.7 mmol/L (HR 1.14 95% CI 0.46–2.85; p = 0.78) subgroup, a BUN cut-off of 9.7 mmol/L was associated with mortality in both the normal (HR 2.78 95% CI 1.68–4.60; p < 0.001) as well in the abnormal (4.27 95% CI 1.43–12.76; p = 0.009) microcirculation group.

BUN concentration correlated with markers of renal (creatinine, r = 0.57; p < 0.001) and liver (ALAT r = 0.14; p = 0.01; ASAT r = 0.17; p = 0.02) function, but neither with parameters of microcirculation nor of macrocirculation ([NaN] ).

Table 2 Correlation analysis by Spearmen rank correlation of BUN

In our post-hoc sub-group analysis of the microSOAP study, BUN levels but not microcirculation was associated with mortality. The microSOAP study collective represents a very heterogenous patient collective reflecting everyday clinical practice and these finding might therefore be of high clinical interest.

In neither the high nor the low BUN group, abnormal microcirculation was associated with mortality. In the first analysis of the microSOAP study impaired microcirculation was shown to be associated with mortality only in a high-risk subgroup suffering from tachycardia [[9] ]. BUN remained associated with mortality in a multivariate analysis even after correction for tachycardia, indicating predictive value independent of macro- and microcirculation, most probably due to its role in neurohumoral pathways. The absence of an association of microcirculation with mortality might be due to the facts that patients included in this study were less severely ill than in other studies investigating microcirculation and that – consequently – microcirculation abnormalities were less frequent. Furthermore, as measurements of the microcirculation were limited to the sublingual mucosa, microcirculatory abnormalities in other tissues might have been missed.

This association of BUN concentration with mortality remained robust even in several multivariate models correcting for clinically relevant cofounders. We calculated an optimal cut-off for prediction of hospital mortality of 9.7 mmol/L. This cut-off was associated with a 3-fold increase in in-hospital mortality and this predictive value remained after several corrections in multivariate models. With 9.7 mmol/L this cut-off was relatively low, but comparable to cut-offs used in other tools for risk stratification incorporating BUN such as the CURB criteria for pneumonia severity which is well established in daily clinical practice [[36] ]. Further, in literature even subtle BUN changes e.g. BUN levels above 8.9 mmol/L against BUN levels between 7.1 to 8.9 mmol/L mg/dl were reported to be associated with adverse outcome [[37] ]. Therefore, our results fit into existing literature in this aspect and further support the notion that BUN might constitute an independent predictor of mortality in critically ill patients.

Though BUN is considered to be a marker of neurohumoral activity, it certainly is primarily considered as marker of renal failure. Still, in our study, BUN levels were independently of creatinine levels associated with mortality. Of note, in patients undergoing renal replacement therapy BUN is known to be altered artificially and might therefore not be useful for risk stratification – therefore, in this analysis we included only patients not on renal replacement therapy. In those 43 patients in the microSOAP study on renal replacement therapy with known BUN concentrations, BUN was not associated with mortality (data not shown).

Certainly, there are complex and well-investigated scoring tools for risk stratification such as APACHE score which might be superior to BUN for risk stratification. Still, a simple BUN cut-off of about 9.7 mmol/L might help clinicians for initial patient assessment and even play a role in an emergency department setting. One could speculate about combining a simple and robust biomarker with clinical signs such as heart rate, blood pressure, jugular venous pressure or respiratory rate to obtain an easy but powerful tool for risk stratification which might help clinicians in assessing the critically ill and consequently improve our patients’ outcome.

Besides its post-hoc design, this study has limitations. Due to missing values or the use of renal replacement therapy, BUN could only be evaluated in 412 of 501 patients, which could prone our investigation to selection bias. As this study was not originally designed to compare BUN with parameters of micro- and macrocirculation, measurements are not necessarily at the exact same timepoint albeit on the same day.

The authors declare that they have no competing interests.

BW and CJ and analyzed the data and wrote the first draft of the manuscript. ML and NV and CB contributed to statistical analysis and improved the paper. MK and CI and CJ contributed materials and analysis tools and gave guidance. All authors read and approved the final manuscript.

No (industry) sponsorship has been received for this investigator-initiated study, with the exception of a local hospital fund.

A study protocol was provided to participating centers. Every participating center obtained ethics approval according to local legislation. A copy of the ethics approval was sent to the study coordinator before start of the study.

Written informed consent was obtained of all included subjects, unless the local ethics committee specifically allowed a waiver in this respect. The study was registered at http://www.clinicaltrials.gov/(NCT01179243)).

All data relevant for this study will be given by the authors upon specific request without restriction.

We acknowledge the support of all investigators of the micro-SOAP study group.

Graph: Fig.1 The statistically optimal cut-off was 9.7 mmol/L. This cut-off was associated with a significant increase in mortality (17% vs 42; p < 0.001).