Прогноз исхода у пациентов с абдоминальной и легочной бактериальной инфекцией по уровню ароматических микробных метаболитов в сыворотке крови

Резюме

Введение. Согласно рабочей гипотезе авторов, сывороточный уровень ароматических микробных метаболитов (AMM), таких как фенилмолочная (PhLA), п-гидроксифенилуксусная (p-HPhAA) и п-гидроксифенилмолочная (p-HPhLA) кислоты, могут иметь прогностическое значение у пациентов с тяжелой бактериальной инфекцией.

Материал и методы. Клинические и лабораторные данные пациентов с инфекцией были зарегистрированы в день поступления в отделение интенсивной терапии, дополнительно определены уровни AMM (PhLA, p-HPhLA и p-HPhAA) в крови методом газовой хроматографии- масс-спектрометрии (ГХ-МС). Спустя 28 дней от начала исследования проведено сравнение показателей в двух подгруппах: у выживших и невыживших пациентов. Рассчитаны корреляции между AMM и клинико-лабораторными данными, оценена прогностическая значимость AMM, используя метод логистической регрессии и ROC-анализа.

Результаты. В исследование включены 112 пациентов высокого риска c бактериальной инфекцией разной локализации: группа 1 (n=58) с хирургической абдоминальной инфекцией на фоне непроходимости или перфорации кишечника; группа 2 (n=54) с тяжелой пневмонией. Анализ клинико-лабораторных данных показал, что выжившие и не выжившие пациенты достоверно различались не только по шкалам APACHE II, SOFA, но и по исходным концентрациям AMM в сыворотке крови. Доказана высокая прогностическая ценность AMM: выявлена прямая тесная корреляция между концентрацией AMM и APACHE II, АММ и SOFA; прямая тесная корреляция между концентрацией AMM и риском смерти; обратная корреляция между p-HPhAA, суммой трех метаболитов (Σ3PhCA) и продолжительностью жизни до смерти. Используя метод логистической регрессии, было подтверждено, что модели монопараметрического прогнозирования, основанные на концентрациях PhLA или p-HPhLA, сопоставимы по значимости с многопараметрическими шкалами APACHE II и SOFA.

Выводы. Высокие концентрации АММ в крови критических пациентов, поступающих в реанимационное отделение, связаны с риском неблагоприятного исхода. Сывороточные концентрации AMM могут быть использованы в качестве независимых и практических критериев для оценки прогноза у пациентов с тяжелой бактериальной инфекцией.

Ключевые слова:пациенты в критическом состоянии, хирургическая инфекция, абдоминальный сепсис, пневмония, биомаркеры прогноза, ароматические микробные метаболиты, фенилмолочная кислота, п-гидроксифенилуксусная кислота, п-гидроксифенилмолочная кислота

Конфликт интересов. Авторы заявляют об отсутствии конфликта интересов.
Для цитирования: Белобородова Н.В., Саршор Ю.Н., Осипов А.А. Прогноз исхода у пациентов с абдоминальной и легочной бактериальной инфекцией по уровню ароматических микробных метаболитов в сыворотке крови // Клин. и эксперимент. хир. Журн. им. акад. Б.В. Петровского. 2020. Т. 8, No 2. С. 96-104. DOI: 10.33029/2308-1198-2020-8-2-96-104 Статья поступила в редакцию 20.12.2019. Принята в печать 26.03.2020.

Assessing the severity of the condition of patients is an integral part of the diagnostic process in surgical and intensive care units., extremely important. Among the clinical scales, the most widely used scales are Acute Physiology and Chronic Health Evaluation (APACHE) and the Sequential Organ Failure Assessment (SOFA) to determine the severity of critical conditions and to identify a high risk of death [1-4].

Prediction scales usually include a large number of variables and are characterized by complex calculation of the final score. In order to improve the quality of the prognosis, there is a continuous improvement in the systems for assessing the patient’s condition. At the same time, a reasonable compromise must be reached between the degree of accuracy of the scale and its complexity. Scales proposed several decades ago continue to improve today; especially often using SOFA-based models [5-8].

Along with the development and improvement of multi-parameter scales, the search for individual biochemical markers continues, on the basis of which simpler methods can be developed for assessing the severity of the condition and predicting the result, up to one-parameter, for example lactat, proadrenomodullin, procalcitonin etc. [9-11].

Candidate markers for assessing the severity of the condition and the prognosis of the surgical infection may be low molecular weight phenyl carboxylic acids (PhCA), which for short we call aromatic microbial metabolites (AMM) [12]. The diagnostic significance of AMM have already been shown by Russian investigators [13-15]. It was shown that in patients with a complicated postoperative period after planned cardiosurgical operations in the blood serum the concentration of the so-called sepsis-associated AMM (phenyllactic (PhLA), p-hydroxyphenyllactic (p-HPhLA) and p-hydroxyphenylacetic (p-HPhAA) acids) was increased. It was found that the surviving patients and non-surviving patients differ in the level of PhLA and p-HPhLA in the blood serum. The highest concentrations of AMM are recorded in patients with sepsis and septic shock [16-18]. Nevertheless, the question of the reliability of AMM for assessing the condition and prognosis in patients with surgical infection of the abdomen or with severe bacterial pneumonia remains poorly understood.

The aim of the study: to determine the prognostic value of the serum level of AMM in severe patients with acute abdominal or pulmonary infection upon admission to ICU.

Material and methods

The examination and treatment of patients was performed in ICUs of two State Clinical Hospitals, using the standard protocol, which was approved by the Local Ethics Committee of Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology 12.07.2017, Number 04/17. All clinical and laboratory data were collected and recorded prospectively.

Study population. We enrolled consecutive adult patients (>18 years) admitted to ICU with abdominal infection (Group 1 “abdominal infection”) and also non-surgical patients with suspected community-acquired pneumonia (Group 2 “pneumonia”). All patients in Group 1 were admitted after emergency surgery the cause of which was acute intestinal obstruction or intestinal perforation. The diagnosis of community-acquired pneumonia was made according to guidelines published by the British Thoracic Society [19]. If the diagnosis of “pneumonia” was not confirmed during the initial examination, the pa- tient was excluded from the study.

The study did not include patients with acute cardiovascular pathology, severe chronic cardiovascular insufficiency by the NYHA (New York Heart Associ tion) above grade III, patients with terminal stage of chronic renal failure, chronic hepatic failure.

Data collection. The analysis of demographic data, admission diagnoses, comorbidities, analysis of treatment methods using vasopressor support, mechanical ventilation, analysis of hospital mortality and lethality in ICU, and analysis of other clinical and laboratory data required for the calculation of scales were performed. Assessment of the severity of the clinical state was performed at the day of admis- sion to ICU using the APACHE II scale [1], the severity of pneumonia on admission was assessed also using the CURB-65 scale [20]. For a dynamic assessment of the patients’ state, a Sepsis-related Organ Failure Assessments Score/Sequential Organ Failure Assessment (SOFA) scale was used for both groups [3].

Laboratory analysis. All routine laboratory tests (white blood cells, creatinine, bilirubin, acid-base blood parameters, lactate level, etc.) were performed at the hospitals.

Aromatic microbial metabolites (AMM) were measured in blood serum using gas chromatography with a flame ionization detector (Kristall 5000.2 “Chromatek, Russia”) and verified on chromatograph - mass spectrometer Trace GC 1310, ISQ LT (Thermo Scientific, Thermo Electron Corporation, USA). Previously, a normal level in serum of healthy people was established for three so-called “sepsis-associated” metabolites: below are the median and interquartile range (IQR): PhLA 0.63 (0.46-0.82) μМ, p-HPhLA 1.47 (1.09-1.78) μМ, p-HPhAA 0.98 (0.68-1.48) μМ [21]. Samples of residual serum (0.2-0.3 ml), which were taken from patients for routine clinical laboratory studies, were frozen and then used to analyze the aromatic metabolites.

Statistical analysis. For the storage and statistical processing of data the programs “Statistica 10” (TIBCO Software Inc., Palo Alto, CA, USA) and “IBM SPSS Statistics 17” (SPSS: An IBM Company, Armonk, New York, USA) were used. The data was processed using nonparametric statistical methods. Descriptive statistics in the text are presented in the form of a median (Me) and interquartile range (IQR) - 25-75%. To assess the differences between small independent groups, the Mann-Whitney U test was applied. To evaluate the differences between dependent variables, the Wilcoxon test was used. In determining the correlation relationship, the Spearman correlation coefficient (r) was calculated. For the development of predictive models based on the level of PhCAs the method of logistic regression and ROC analysis (Receiver Operator Characteristic) were applied. For all listed statistical criteria, p<0.05 was assumed to be statistically significant.

Results

There were examined 152 patients upon admission to ICU. Among them, 40 patients were excluded from the study: due to mortality within 24 h of study (n=10), diagnosed end-stage renal disease (n=11), unconfirmed pneumonia (n=8), diagnosed end-stage liver disease (n=5), or diagnosed acute coronary syndrome (n=6). Finally, 112 patients were included in the analysis; 58 in Group 1 with abdominal infection and 54 in Group 2 with pneumonia. To assess prognostic significance, the AMM profile in both Groups was studied depending on the outcome (hospital mortality was taken into account) in subgroups: surviving and non-surviving patients.

1. Group 1: patients with abdominal infection

Patients with abdominal infection (n=58) were examined in two subgroups: with acute surgical diseases complicated by intestinal perforation (n=35), and with acute surgical diseases complicated by acute intestinal obstruction (n=23). Mortality rate in patients after intestinal perforation was 43% (15 from 35), mortality in patients with intestinal obstruction - was 39% (9 from 23).

1.1. Patients with intestinal perforation complicated by abdominal infection

Upon admission to ICU, the surviving patients (n=20) and non-surviving subsequently (n=15) patients differed in the severity of the state and concentration of Σ3PhCA in the blood serum (p<0.01) (tab. 1).

In non-surviving patients the concentration of Σ3PhCA on the day of admission was on average 9 times higher than in surviving patients (p<0.001), and exceeded dramatically the physiological level by an average of 15 times (p<0.001). In surviving patients, the baseline level of Σ3PhCA was also higher than physiological (p=0.01), but on average it exceeded only 1.7 times. Upon admission to the ICU, surviving patients were characterized by a lower degree of severity of the condition (APACHE II and SOFA scales) compared with non-surviving subsequently patients (p<0.05).

1.2. Patients with acute intestinal obstruction complicated by abdominal infection

Already on the day of admission to the intensive care unit, there were significant differences between survivors (n=14) and non-survivors (n=9) subsequently patients in the serum concentration of all three AMM, (p<0.05) (tab. 1). In non-surviving patients the concentration of Σ3PhCA was 4 times higher than in surviving patients (p=0,017). Non-surviving subsequently patients showed a 7-fold higher level of Σ3PhCA compared to physiological (p<0.001). Thus, not only their sum (Σ3PhCA) but the level of each AMM (PhLA, p-HPhAA, p-HPhLA), were statistically significantly higher in patients with lethal outcome. A correlation analysis of clinical and laboratory data upon admission revealed significant correlations of AMM with severity of condition, pH, BE, and lactate (tab. 2).

Additional statistical analysis in all patients with abdominal infection (in both subgroups) showed that in surviving patients (n=34) the duration of treatment in ICU (days) correlated with the concentration of p-HPhAA and Σ3PhCA on admission: 0.39 (p=0.02) and 0.40 (p=0.02), respectively. In non-surviving patients (n=24), the concentration of PhLA and p-HPhLA had a inverse correlation with life expectancy before death (number of days before death): -0.57 (p=0.004) and -0.583 (p=0.003), respectively. In other words, in surgical patients with abdominal infection, the higher the level of AMM, the less time remains until the end of life.

1.3. Prognostic value of AMM in patients with abdominal infection

Assessing the significance of some AMM as a prognostic markers was performed on the results of logistic regression and ROC analysis (n=58). Significant regression equations were obtained for all estimated prognostic parameters (p<0.001) with significant coefficients (p<0.001) (tab. 3). The APACHE II scale as a prognostic model had better accuracy and calibration (-2log 44,451, the significance of the Hosmer-Lemeshev test - p>0.05) compared with the SOFA scale (-2log 53,181; the significance of the Hosmer-Lemeshev test - p<0.05). The best sta- tistical characteristics had prognostic models based on the serum concentrations of aromatic metabolites PhLA and p-HPhLA.

2. Group 2. Patients with pneumonia

Demographic and basic clinical characteristics of the included patients with pneumonia (n=53) are shown in table 4. Subgroups surviving (n=35) and non-surviving patients (n=19) were comparable in age, sex and frequency of concomitant diseases, but they differed not only in clinical severity scales (APACHE II and SOFA score) and severe pneumonia (CURB-65 score), but also in the level of aromatic metabolites. So, already on the day of admission to ICU the level of Σ3PhCA and PhLA was more than 3 times, p-HPhAA more than 2,5 times, p-HPhLA more than 2 times higher in non-surviving compared with surviv- ing patients (p<0.05) (tab. 5).

Correlation analysis revealed significant correlations of aromatic metabolites with the severity of the condition, with PCT, pH, BE, lactate, presence of shock and lethal outcome (tab. 6). The closest correlations with a confidence level of p<0.001 were revealed between the level of AMM and the severity of the condition, shock, lactate and death. In non-surviving patients the level of p-HPhAA and Σ3PhCA had an inverse correlation with the life-span before death (the amount of days before death): r = -0.63 (p<0.05) and r = -0.65 (p<0.05), respectively.

2.1. Prognostic value of A MM in patients with pneumonia

The analysis of the clinical significance of aromatic metabolites in predicting the outcome was carried out in comparison with multi parameter scales of severity of condition (APACHE II and SOFA) and the severity scale of community-acquired pneumonia CURB-65. Prognostic significance was evaluated according to the results of logistic regression and ROC analysis (figure). For all prognostic parameters, significant regression equations were obtained (p<0.001) with significant coefficients (p<0.001) (tab. 7). For PhLA as a prognostic model there were revealed better statistical characteristics compared to other acids and similar characteristics compared to APACHE II, SOFA and CURB-65 (tab. 7).

Discussion

it is noteworthy that the clinical and laboratory data of patients included in the study meet the criteria for sepsis, which explains the high mortality in both Groups. The authors intentionally do not indicate the diagnosis of sepsis in the title of the article, so as not to be distracted by the inevitable discussions about the criteria for septic shock, the degree of organ dysfunction, the choice of classification of sepsis, etc.

In patients with severe infection upon admission to ICU it was found that concentrations of PhLA, p-HPhAA, p-HPhLA and Σ3PhCA in blood serum were much higher in non-surviving patients than in surviving (p<0.05) regardless of the location severe bacterial infection (abdominal sepsis or pneumonia). Aromatic microbial metabolites reflect the severity of a patient’s condition and can act as markers of severity. Direct correlations of AMM with clinical and laboratory parameters, in particular, the functions of the cardiovascular system (presence of shock), kidneys (creatinine, urea), liver (direct bilirubin, ALT), acid-base state (pH, BE, lactate) were revealed, which confirms the participation of AMM in the development of organ dysfunction.

Impaired function of vital organs and systems is usually associated with mortality in critically ill patients. The high predictive value is also shown by: 1) direct correlation between the concentration of AMM and APACHE II, SOFA; 2) direct correlation be- tween the concentration of AMM and risk of death; 3) inverse correlation between p-HPhAA, Σ3PhCA and life-span before death.

What are the underlying causes of increased levels of aromatic metabolites in the blood? The level of aromatic metabolites may increase in the blood due to excessive bacterial production in the locus of infection [12-14], or have an endogenous origin and accumulate in the blood due to impaired renal excretion [22]. We suppose that the most significant mechanism that facilitates the accumulation of PhLA and p-HPhLA in blood of critically ill patients is a tyrosine metabolism disorder, which is accompanied by the lack of biodegradation of these metabolites due to the reducing of the biodiversity of gut microbiota [23].

Numerous researchers prove the presence of own biological activity of aromatic metabolites, what is presented in detail in the review [24]. For example, the ability of some AMM to inhibit dihydropteridine reductase [25], and the activity of neutrophils [26] has been studied. The effect of some AMM on the production of reactive oxygen species [27] and the ability to participate in mechanisms of mitochondrial dysfunction [28] has been proved. Excessive accumulation of AMM in blood can promote the development of organ dysfunction, manifested by an increase in the severity of the condition. One of the important function of AMM is to ensure the balance of metabolic processes between the microbiota and the host organism, that is, maintaining the homeostasis of a human [29]. In critically ill patients with surgical abdominal infection or severe pneumonia, the association of AMM with a fatal outcome can also be explained by the fact that aromatic metabolites are involved in the pathogenesis of septic shock [18].

ROC-curves of the lethal outcome predictors based on the scales SOFA, CURB-65, aromatic metabolites (PhLA, p-HPhAA, p-HPhLA) 254×166 mm (96×96 DPI)

So, the results of our study confirm that аromatic metabolites (PhLA, p-HPhAA, p-HPhLA or Σ3PhCA) can be used as prognostic markers. Using the method of logistic regression, it was confirmed, that mono- parametric forecasting models based on the concentrations of PhLA or p-HPhLA are comparable in informative with APACHE II and SOFA scales. There is no need to prove that using one or two parameters (metabolites) to assess the risk for patients with severe infection would be faster and more convenient for a doctor than multi-parameter scales. Unfortunately, the measurement of low molecular weight aromatic metabolites is not widely available in clinical practice for now, since special equipment such as GH-MS or NMR is required. As confirmation of our data, we can cite the results of research team led by Roger et al. [30], that measured metabolites, in a multicenter study also found that elevated p-HPhLA levels were associated with mortality in critically ill patients.

Conclusion

High serum concentrations of aromatic microbial metabolites are associated with lethal outcome in critically ill patients. Serum concentrations of PhLA and p-HPhLA can be used as independent and practical criteria for the severity of the condition and for the assessing the prognosis in patients with abdominal or pulmonary infections.

Acknowledgements. The authors thank the heads of intensive care units of city hospitals Alexey V. Vlasenko (Municipal Clinical Hospital named after S.P. Botkin, Moscow) and Andrey N. Nikiforov (Moscow State Clinical Hospital named after V.V. Veresaev) for their help in recruiting clinical material and conducting the study.

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