ORIGINAL RESEARCH
Plasma Endothelin-1 Levels in Septic Patients Mariusz Piechota, MD, PhD* Maciej Banach, MD, PhD† Robert Irzmanski, MD, PhD‡ Marcin Barylski, MD‡ Magdalena Piechota-Urbanska, MD§ Jan Kowalski, MD, PhD‡ Lucjan Pawlicki, MD, PhD‡ Dysfunction of the vascular endothelium (ET) causes an increase in serum ET-1 concentration, as observed in septic patients. It was assumed that in this patient population the ET-1 level correlates with the degree of sepsis severity, including the level of organ dysfunction and, in particular, the level of circulatory dysfunction. The aim of the present study was to assess the relationship between levels of ET-1 and levels of N-terminal brain natriuretic propeptide (NTproBNP), procalcitonin (PCT), and C-reactive protein (CRP), as well as the Sepsis-related Organ Failure Assessment (SOFA) score in septic patients. PCT and CRP were used to estimate the level of sepsis severity; the SOFA score was used to estimate multiorgan dysfunction; and NT-proBNP was used as a marker of cardiac dysfunction. Twenty patients with sepsis and severe sepsis were included in the study. Blood serum ET-1, NT-proBNP, PCT, and CRP concentrations were determined at specific time intervals, and the SOFA score was calculated. Mean ET-1, NT-proBNP, PCT, and CRP concentrations were 8.39 pg/ml ± 6.39 pg/mL, 140.80 pg/mL ± 84.65 pg/mL, 22.32 ng/mL ± 97.41 ng/mL, and 128.51 mg/L ± 79.05 mg/L, respectively. Correlation between ET-1 levels and levels of NT-proBNP, PCT, and CRP was .3879 (P < .001), .358 (P < .001), and .225 (P = .011), respectively. Mean SOFA score was 6.31 pts ± 3.75 pts. Correlation between the ET-1 levels and SOFA score was .470 (P < .001). Six patients (30%) died during the observation period of 28 days. ET-1 levels correlate with levels of NT-proBNP, PCT, and CRP, as well as the SOFA score in septic patients.
From the *Department of Anaesthesiology and Intensive Care Unit, and the Departments of †Cardiology, ‡Internal Diseases and Cardiological Rehabilitation, and §Pharmacy, Medical University of Lodz, Poland. Received Aug 8, 2006, and in revised form Sep 22, 2006. Accepted for publication Oct 11, 2006. Financial support for this study provided by Boleslaw Szarecki University Hospital, Lodz, Poland. Address correspondence to Maciej Banach, MD, PhD, Department of Cardiology, Medical University of Lodz, Poland 91-425, or e-mail:
[email protected]. Piechota M, Banach M, Irzmanski R, et al. Plasma endothelin-1 levels in septic patients. J Intensive Care Med. 2007; 22:232-239 DOI: 10.1177/0885066607301444
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Key words: Endothelin-1; Sepsis-related Organ Failure Assessment score; N-terminal brain natriuretic propeptide; procalcitonin; C-reactive protein; sepsis; severe sepsis
Introduction Septic patients constitute the majority of intensive care unit (ICU) patients in Poland, with 31.5% hospitalized for sepsis, 14.6% for severe sepsis, and 6% for septic shock [1]. Septic shock is characterized by massive vasodilatation with low systemic vascular resistance and severe hypotension [2]. Endothelin-1 (ET-1) is one of the peptides that plays a significant role in maintaining vascular wall tone. ET-1 is a 21amino-acid vasoactive peptide synthesized by many cell types [3,4]. ET-1 is formed from its biological precursor, big ET-1, a 38-amino-acid-long peptide that, after its synthesis in the cytoplasm, is cleaved by ET conversion enzyme to yield active ET-1 (amino acids 1–21) and a C-terminal fragment (amino acids 22–38) [3]. The vasoconstrictive power of ET-1 is 140-fold greater than that of big ET-1 [5]. In the normal, uninjured vasculature, endothelial cells synthesize ET; however, injury to the endothelial cells during disease states leads to an increase in levels of ET-1. This peptide is also synthesized by cardiac myocytes and cardiac fibroblasts [6,7]. ET-1 has been associated with vasospasm, vascular damage, cardiovascular remodeling. and inflammation [7–9]. ET-1 also plays an important role in regulating cardiac function and renal perfusion. In patients with severe sepsis, ET-1 plasma levels are markedly increased [10–13] and correlate significantly with renal function [10]. Clinical manifestations of sepsis in newborns are accompanied by increased concentrations of ET-1 [12,13]. Myocardial dysfunction often accompanies severe sepsis and septic shock [14–16]. In order to
Copyright © 2007 Sage Publications
Endothelin-1 Levels In Septic Patients
evaluate this dysfunction, specific markers are used in clinical practice, including brain natriuretic peptide (BNP), which is now recognized as an excellent marker of ventricular dysfunction. BNP is mainly synthesized in the heart as a prohormone (proBNP), which is hydrolyzed to produce the biologically active form BNP plus an N-terminal fragment (NTproBNP). The mean half-life and blood values of NT-proBNP are greater than those of BNP, and the molecule is highly specific for the diagnosis of heart failure. NT-proBNP may serve as a useful laboratory marker to indicate myocardial dysfunction [17] and may help to differentiate between survivors and nonsurvivors of severe sepsis [17,18]. Procalcitonin (PCT) and C-reactive protein (CRP) are also accepted sepsis markers. PCT is a protein formed from 116 amino acids [19]. In physiological conditions in thyroid C-cells, PCT is a precursor, among others, of calcitonin. PCT is generated as the result of proteolysis of the pre-PCT precursor protein formed from 141 amino acids. In acute inflammatory reaction, an increase in PCT release to blood is observed, which, in this case, probably does not originate from thyroid C-cells. It is assumed that PCT is synthesized in liver macrophages and monocytes [20], as well as in pulmonary and intestinal neuroendocrine cells [19,21]. The latest studies have also suggested that various types of blood leucocytes may be the site of PCT production [22]. PCT is a sensitive and specific marker of generalized bacterial, fungal, or parasitic infection. With few exceptions, the PCT level is generally not affected by an injury, including surgery, chronic inflammatory process, autoimmune diseases, or the applied drugs. Serum levels of CRP, an acute-phase protein synthesized by the liver following stimulus by various cytokines, markedly increase within hours after the onset of infection or inflammation [23]. Numerous studies have demonstrated increased CRP levels in patients with sepsis [24–29], and some studies have suggested that CRP may be an indicator of organ failure [30–34]. The Sepsis-related Organ Failure Assessment (SOFA) score is successfully used for the evaluation of organ dysfunction in septic patients [35–40]. Worked out during numerous coordinating conferences, the SOFA score is designed to estimate multiorgan dysfunction. We assumed that in septic patients, the ET-1 level correlates with the level of sepsis severity (with the level of PCT and CRP), with the severity of organ dysfunction (the SOFA score), and, in particular, with the level of cardiac dysfunction (NTproBNP level). To our knowledge, such relationships have not previously been described in septic patients.
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We investigated the relationships between ET-1 concentrations and concentrations of NT-proBNP, PCT, and CRP, as well as the severity of organ dysfunction as assessed by the SOFA score in septic patients.
Material and Methods Having obtained approval from the Bioethics Committee of the Medical University of Lodz, we recruited 20 consecutive patients for the study (15 men, 5 women) based on the criteria for sepsis as defined by the American College of Chest Physicians/ Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference (modified by Polish Working Group for Sepsis [41]) [42,43]. Investigations were carried out in each patient until he or she either no longer met the criteria for sepsis or died. All patients were given verbal and written information about the potential risks and benefits of participation in the study and gave written consent prior to study enrolment. Subjects were recruited consecutively from patients admitted to the ICU between July 1, 2003, and July 31, 2004. All patients were treated by the same team of physicians, and patient care was administered according to existing protocols. Standard treatment included administration of adequate antibiotics, control of the source of infection, and supportive therapy, including intravenous fluids, vasopressors, and medication to aid the circulatory system and failing organs. Two patients were given recombinant human activated protein C (rhAPC). Blood serum ET-1, NT-proBNP, PCT, and CRP concentrations were measured at 12, 24, 36, 60, and 108 hours after study enrolment, and the SOFA score was calculated to describe the severity of organ dysfunction. The quantitative determination of ET-1 (in pg/mL) and NT-proBNP (in pg/mL) was based on the immunoenzymatic (EIA) method. The reading was performed on ETI-Max3000 analyzer (DiaSorin) using BioMedica reagents. A panel of 70 blood donors had a median ET-1 concentration of .65 pg/mL (.26 fmol/mL) (according to the manufacturer, each laboratory should establish its own reference data); reference values for NT-proBNP are below 600 pg/mL (250 fmol/mL) in healthy persons, according to the manufacturer. The quantitative measurement of PCT (in ng/mL) was performed using the immunoluminometric method, with two monoclonal antigen-specific antibodies binding PCT. The luminescence was read in a BERLUX 250 luminator with LUMI test PCT 233
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reagent (Brahms Diagnostica GmbH); according to the manufacturer, reference values for PCT are below .5 ng/mL in healthy persons. To measure CRP concentration (in mg/L) the immunoprecipitation method was applied with the use of specific immunoglobulins. The measurements were performed with KonePro (Konelab) with Biomerieux reagents; according to the manufacturer, reference values for CRP are below 5 mg/L in healthy persons. Statistical analysis was performed with Statistica 5.1 PL (StatSoft, Poland) and Microsoft Office 97. The correlation between the SOFA score and NTproBNP, PCT, and CRP concentrations was calculated using Pearson’s correlation coefficient (in case of normal distribution) or Spearman’s correlation coefficient (when at least one sample had a different distribution). The result was given in the form of P < max (eg, P < .05), such that the correlation was statistically significant at the determined level.
Results Twenty consecutive patients (15 men, 5 women) were qualified for the study (mean age 52.2 years ± 18.24 years). Twelve patients required mechanical ventilation and eighteen were given catecholamines during their stay in the ICU. Baseline characteristics are presented in Table 1. A total of 128 measurements (mean 6.4 in each patient) were performed in the investigated group. Mean ET-1, NT-proBNP, PCT, and CRP concentrations were 8.39 pg/mL ± 6.39 pg/mL, 140.80 pg/mL ± 84.65 pg/mL, 22.32 ng/mL ± 97.41 ng/mL, and 128.51 mg/L ± 79.05 mg/L, respectively. Correlation of the ET-1 levels and NT-proBNP, PCT, and CRP levels was .3879 (P < .001) (Fig. 1), .358 (P < .001) (Fig. 2), and .225 (P = .011) (Fig. 3), respectively. Mean Acute Physiology And Chronic Health Evaluation (APACHE) II score was 12.29 pts ± 4.97 pts. Mean SOFA score was 6.31 pts ± 3.75 pts. Correlation between the ET-1 levels and SOFA score was .470 (P < .001) (Fig. 4). Mean length of stay in the ICU was 12.85 days ± 13.53 days. Six patients (30%) died due to their underlying diseases during the observation period of 28 days.
Discussion ET-1 is a strong mediator of the cardiovascular system. Elevated concentrations of ET-1 and its precursor, big ET-1, provide an important, independent indicator 234
of heart failure in congestive heart disease [44] and, in patients with this condition, are related to pulmonary hypertension [44,45], the severity of their overall condition, and their prognosis. During the course of sepsis, an excessive and maladjusted inflammatory reaction is observed. The increased secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-1 causes inflammation, which damages and impairs tissues and numerous capillary vessels, leading to multiple organ failure. In patients with sepsis, the excessive expression of tissue factor on the surface of endothelial cells and monocytes is observed as a result of the pro-inflammatory functions of cytokines (IL-1a, IL-1b, TNF-α) that activate the coagulation cascade. Endothelial dysfunction causes an increase in ET-1 concentration in blood serum, which is thought to play a key role in the pathogenesis of sepsis; therefore, the increase in ET-1 concentration observed in septic patients is understandable. Weitzberg et al observed that in septic patients, plasma ET-like immunoreactivity was 5-fold higher (11.3 ± 2.8 pmol/L) than that of subjects who did not have sepsis (2.4 ± .07 pmol/L) (P < .01) [46]. Similarly, Pittet et al found that plasma immunoreactive ET-1 concentration was significantly (P < .001) increased in septic patients (19.9 ± 2.2 pg/ml) compared with the concentration found in healthy volunteers (6.1 ± .3 pg/ml) [47]. The ET-1 concentration obtained in our study is consistent with the results reported by other authors. In our opinion, the increase of ET-1 in blood serum is, among other things, a consequence of endothelial damage. The variety of cell types secreting ET-1 and the complex pathophysiology of severe sepsis limit the possibility of pinpointing a single source. ET-1 plays an essential role in regulation of the muscular tonus of capillary vessels, both during the course of severe sepsis associated with increased vascular resistance and in septic shock. The final effect in terms of muscular tonus of capillary vessels is the result of many different factors, which often oppose one another. Although the mechanism of their interactions is not completely clear, ET-1 is an essential regulator of muscular tonus of capillary vessels and should not be treated simply as a marker of severe sepsis [48,49]. According to BioMedica, reference values for NTproBNP are below 600 pg/ml (250 fmol/mL) in healthy persons. In our study, the mean NT-proBNP concentration was below 200 pg/ml, suggesting that cardiac failure was not significant in our septic patients. This multicenter study shows the correlation between plasma big ET-1 and NT-proBNP levels in a group of patients with heart failure [48]. Increased
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Female Female
Male Male
Female Male Male
Female
Male Male Male
Female Male
Male
Male Male Male
Male
3 4
5 6
7 8 9
10
11 12 13
14 15
16
17 18 19
20
55
59 41 30
51
88 67
47 51 71
50
53 22 70
33 49
90 29
49 39
5/5
6/31 19/54 14/15
3/3
5/6 8/14
7/16 3/11 4/18
16/18
5/11 14/14 11/11
13/88 55/55
7/31 14/14
4/59 44/44
Severe sepsis
Severe sepsis Severe sepsis Severe sepsis
Severe sepsis
Severe sepsis Severe sepsis
Severe sepsis Severe sepsis Severe sepsis
Severe sepsis
Sepsis Sepsis Severe sepsis
Severe sepsis Severe sepsis
Severe sepsis Sepsis
Sepsis Sepsis
Basis for Inclusion Into the Study
Lungs
Abdominal cavity Abdominal cavity Abdominal cavity
Lungs
Abdominal cavity Abdominal cavity
CNS Abdominal cavity Abdominal cavity
Abdominal cavity
Abdominal cavity Lungs Lungs
Abdominal cavity Lungs / Abdominal cavity
Abdominal cavity Abdominal cavity
Abdominal cavity Abdominal cavity
Infection Site
MRSA MRSA Escherichia coli, Enterococcus faecium -
-
MRSA
Pseudomonas aeruginosa Enterobacter aerogenes MRSA, Stenotrophomonas maltophilia MRSA Pseudomonas aeruginosa Enterobacter cloacae, MRSA Pseudomonas aeruginosa
Microbial Etiology
17
7 4 11
24
10 13
11 8 12
17
3 12 14
10 19
17 9
7 14
Number of Scores in APACHE II at Study Initiation
4
2 2 2
4
1 3
2 1 3
4
1 1 1
2 4
1 5
0 3
Highest Number of Organ Failures
Yes
No No No
Yes
No Yes
No No Yes
Yes
No No No
No No
No Yes
No No
Death During the Course of the Study
Respiratory– circulatory failure
Respiratory– circulatory failure Respiratory– circulatory failure Respiratory– circulatory failure -
MODS
-
-
MODS, DIC
-
Cause of Death
ICU = intensive care unit; APACHE = acute physiology and chronic health evaluation; MODS = multiple organ dysfunction syndrome; DIC = disseminated intravascular coagulopathy; MRSA = methicillin-resistant staphylococcus aureus; CNS = central nervous system.
Male Male
Sex
Age (yrs)
ICU/ Hospital Stay (days)
Basic Data on the Studied Group
1 2
Patient Number (N)
Table 1.
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450 y = 5.195x + 92.273 r = .3879 P < .05
NT-proBNP (pg/ml)
400 350 300 250 200 150 100 50 0 0
5
10
15
20
25
30
35
ET-1 (pg/ml) Fig 1. The correlation between ET-1 concentrations and NT-proBNP concentrations. ET-1, Endothelin-1; NT-proBNP, N-terminal brain natriuretic propeptide.
800 700
PCT (ng/ml)
600 y = 5.4586x - 23.454
500
r = .358
400
P < .05
300 200 100 0 -100
0
5
10
15
20
25
30
35
ET-1 (pg/ml) Fig 2. The correlation between ET-1 concentrations and PCT concentrations. ET-1, Endothelin-1; PCT, procalcitonin.
big ET-1 concentrations are associated with increased ventricular dysfunction [48]. In patients with acute myocardial infarction, ET-1 showed a significant positive correlation with BNP (r = 0.48, P < .0001) [49]. In the present study, ET-1 levels correlated with NT-proBNP levels in septic patients (r = .3879, P < .001). To our knowledge, the correlation between ET-1 concentrations and NT-proBNP concentrations in septic patients has not previously been described. In acute generalized inflammatory reaction, an increase in PCT release to blood is observed. There are little data assessing the relationship between PCT levels in septic patients and the estimation of their clinical state using appropriate measurement
236
scales. Serum PCT concentration correlates with sepsis severity and is a reliable method of determining the prognosis and response to treatment. Studies estimating the correlation between PCT concentration and severity of sepsis were first carried out by Zeni et al [50]. They demonstrated that in cases of severe sepsis, the serum PCT concentration is elevated, an observation that was confirmed by later studies. It was also determined that PCT is the only serum marker other than neopterin that enables sepsis and severe sepsis differentiation [51–54]. An attempt was made to determine the concentration of PCT that would be the point of differentiation between sepsis, severe sepsis, and septic shock.
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Endothelin-1 Levels In Septic Patients
400 y = 2.7833x + 105.17 r = .225 P < .05
350
CRP (mg/L)
300 250 200 150 100 50 0 0
5
10
15
20
25
30
35
ET-1 (pg/ml) Fig 3. The correlation between ET-1 concentrations and CRP concentrations. ET-1, Endothelin-1; CRP, C-reactive protein.
18 16
SOFA (pts)
14 12 10 y = .2774x + 3.9863 r = .470 P < .05
8 6 4 2 0 0
5
10
15
20
25
30
35
ET-1 (pg/ml) Fig 4. The correlation between ET-1 concentrations and the severity of organ dysfunction assessed by the SOFA score. ET-1, Endothelin-1; SOFA, Sepsis-related Organ Failure Assessment; pts, points.
Gramm et al and Barylski et al suggested the concentration of 5.5 ng/mL as the limiting value between sepsis and severe sepsis, determining the sensitivity of the method to be 81% and specificity to be 94% [51,55,56]. According to the majority of researchers, a PCT concentration exceeding 10 ng/mL is associated with the development of severe infection and poor prognosis [52,57]. In studies carried out by Castelli et al, mean serum concentration of PCT in patients with systemic inflammatory response syndrome (SIRS) was .38 ng/mL, whereas in those with sepsis (including severe sepsis and septic shock) it was 1.58 ng/mL [58]. In the studies of
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Tugrul et al, in patients with severe sepsis and septic shock mean PCT concentration was 19.25 ng/mL and 37.15 ng/mL, respectively, whereas in SIRS patients it was .73 ng/mL [59]. In our study, mean PCT concentration was 22.32 ng/mL ± 97.41 ng/mL. In the available literature, we have not found any reports on the relationship between ET-1 concentration and PCT concentration in septic patients. According to our data, correlation between the ET-1 levels and PCT levels was .358 (P < .001). Because PCT is a very sensitive and specific marker of sepsis, it may be assumed that higher serum PCT concentrations accompany major epithelial dysfunction. 237
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CRP is a recognized marker of sepsis; however, it is significantly less specific than PCT. To our knowledge, in the available literature the correlation between ET-1 and CRP concentration in septic patients has not previously been described. Few reports investigating the relationship between ET-1 and CRP concentrations concern patients with heart diseases. In patients with acute myocardial infarction, ET-1 showed a significant positive correlation with CRP (r = .43, P < .001) [48]. In patients with unstable angina, ET-1 levels did not significantly correlate with levels of CRP [60]. In our study, ET-1 levels correlated with CRP levels (r = .225, P = .011); however, this correlation was weak. In the case of CRP, the positive correlation obtained in our study between ET-1 and CRP and the relationship between the severity of sepsis and the level of epithelial dysfunction is difficult to account for. First of all, CRP does not differentiate sepsis, severe sepsis, and septic shock. Second, it is a protein that, when increased, is observed in many disease entities in which epithelial dysfunction is insignificant or limited to a small area. Third, CRP is a well-known activator of ET-1 release by endothelial cells, and this peptide mediates the pro-inflammatory effects of CRP [61]. For these reasons, it is difficult to explain the obtained correlation between ET-1 and CRP. This correlation is probably the result of many complex reactions. In the study of Pittet et al, ET-1 concentration was correlated with the severity of disease as documented by APACHE II score (r = .74, P < .01) [47]. To our knowledge, the correlation between ET-1 concentration and SOFA score in septic patients has not previously been described. As observed in the present study, the greater the SOFA score, the faster the patient’s clinical condition deteriorates. In the case of septic patients, it is associated with more pronounced epithelial dysfunction, which results in an increase in ET-1 concentration. On the basis of statistical analysis, we have observed that none of the parameters measured strongly correlate (r > .5). One explanation for this result is that the patients included in the study were not in critical condition (the SOFA score and median PCT were low, and many patients had sepsis [as opposed to severe sepsis with potential cardiovascular dysfunction]). In our opinion, ET-1 measurements may be a more useful marker in septic patients than NT-proBNP or CRP measurements. In conclusion, ET-1 levels correlate with NT-proBNP, PCT, and CRP levels, as well as with the SOFA score in septic patients.
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