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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 3  |  Page : 95-102

Heparin-binding protein as a predictive and diagnostic biomarker for severe sepsis and septic shock in patients with sepsis


1 Department of Anesthesia and Intensive Care, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Medical Biochemistry, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Submission12-Jan-2016
Date of Acceptance27-Feb-2016
Date of Web Publication4-Nov-2016

Correspondence Address:
Hala E Zanfaly
Assistant Professor of Anesthesia and Intensive Care, Department of Anesthesia and Intensive Care, Faculty of Medicine, Zagazig University, Zagazig
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2356-9115.193408

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  Abstract 

Background
Detection of impending circulatory failure in a patient with sepsis is critical for modification of the treatment. Heparin-binding protein (HBP) is an inflammatory mediator with an important role in central sepsis mechanism.
Design
This study was a prospective, randomized, comparative one.
Objective
The aim of this study was to investigate the serum levels of HBP in patients with sepsis and to assess its value in the early detection of circulatory failure compared with the currently used biomarkers of sepsis.
Patients and methods
A total of 90 patients with signs of sepsis were prospectively enrolled in this study. After a 12-h study period, 41 patients had signs of sepsis (the sepsis group), 29 patients developed severe sepsis (the severe sepsis group), and 20 patients progressed to septic shock (the septic shock group). Blood samples were collected at enrollment and after 12 h for the measurement of white blood cell count and the serum levels of HBP, procalcitonin, lactate, and C-reactive protein. Vital signs were recorded at the same predetermined times.
Results
The serum levels of HBP were elevated up to 12 h before signs of circulatory failure were detected in patients with severe sepsis and septic shock. HBP serum level with an area under the curve value of 0.95 at a cutoff point of more than 31.6 ng/ml, sensitivity of 85.7%, specificity of 87.8%, positive predictive value of 89.4%, and negative predictive value of 83.7% was better indicator of circulatory failure compared with the other investigated biomarkers. After 12 h, the mean values of serum HBP were significantly increased in the severe sepsis group (75.67±11.85 ng/ml) and in the septic shock group (92.23 ± 16.13 ng/ml) compared with patients in the sepsis group (23.20 ± 5.26 ng/ml) (P < 0.001).
Conclusion
The increase in serum levels of HBP in patients with sepsis is an early predictor and diagnostic marker for the development of circulatory failure compared with the other investigated biomarkers.

Keywords: biomarker, heparin-binding protein, sepsis, septic shock


How to cite this article:
Zanfaly HE, Shalaby SM, Elshal AS. Heparin-binding protein as a predictive and diagnostic biomarker for severe sepsis and septic shock in patients with sepsis. Res Opin Anesth Intensive Care 2016;3:95-102

How to cite this URL:
Zanfaly HE, Shalaby SM, Elshal AS. Heparin-binding protein as a predictive and diagnostic biomarker for severe sepsis and septic shock in patients with sepsis. Res Opin Anesth Intensive Care [serial online] 2016 [cited 2020 Jun 4];3:95-102. Available from: http://www.roaic.eg.net/text.asp?2016/3/3/95/193408


  Introduction Top


Sepsis is a leading cause of death in critically ill patients [1]. The early detection of patients with sepsis who are at risk of developing septic shock can reduce morbidity and mortality [2],[3].

The biomarkers such as procalcitonin (PCT), C-reactive protein (CRP), and neutrophil and lymphocyte counts are mostly used in the early diagnosis of bacterial etiology in patients with sepsis, but they have an insufficient role in prognostic scoring of critically ill patients [4],[5].

Heparin-binding protein (HBP) is an inflammatory mediator and a powerful inducer of endothelial leakage [6]. Previous studies recorded elevated plasma levels of HBP in patients with severe sepsis and septic shock [7],[8]. In addition, the value of HBP to localize patients with impending circulatory failure was suggested [9]. Therefore, this study hypothesized that the elevated serum level of HBP in patients with sepsis can be used as an early detector for circulatory failure.

The aim of this study was to investigate the serum level of HBP in patients with sepsis and to assess its value in the early detection of circulatory failure compared with the currently used biomarkers of sepsis.


  Patients and methods Top


After obtaining approval from the institutional review board and written informed consent from the patients or their relatives, this prospective randomized comparative study was carried out at the two ICUs (Surgical and Emergency) of Anesthesia Department of Zagazig University Hospital from June 2014 to July 2015. A total of 90 patients who had signs of sepsis were enrolled in this study.

Inclusion criteria

Patients with sepsis, those having an infectious disease and at least two systemic inflammatory response syndrome (SIRS) criteria, and those who had not developed an organ failure were included in the study. Signs of SIRS are as follows: body temperature ∼38°C, white blood cell (WBC) count more than 12 × 109 or less than 4 × 109 cells/l, heart rate (HR) more than 90 beats/min, and respiratory rate (RR) more than 20 breaths/min or a significant hypotension (systolic blood pressure < 90 mmHg or a decrease of >40 mmHg from baseline). These criteria were proposed by the American College of Chest Physicians/Society of Critical Care Medicine [10]. The final diagnoses of the patients were made by attending physicians who were unaware of the study results, with the use of standard microbiological tests and radiological procedures. All patients received fluids, antibiotics, and vasopressors as needed.

Exclusion criteria

Exclusion criteria were as follows: age younger than 18 years, neutropenia from malignancy, primary abnormalities of coagulation, immunosuppression due to medication or disease, and being on hemodialysis.

Data collection

Patients’ data were collected at enrollment and after 12 h. It included recording of vital signs and laboratory investigations.

Vital signs

HR, mean arterial blood pressure (MAP), RR, oxygen saturation (SpO2), and temperature were measured.

Laboratory testing

WBC count and the serum levels of HBP, PCT, lactate, and CRP were measured. The suspected source of infection was noted.

Continuous monitoring for all vital signs was carried out. All signs of organ dysfunction, including hypotension, were noted. On the basis of the presence of the SIRS criteria, the presence or absence of organ failure, and the final diagnosis, the patients were categorized into various groups according to the criteria proposed by the American College of Chest Physicians/Society of Critical Care Medicine [11]. Sepsis was defined as a systemic response to infection including the criteria for SIRS plus microbiological evidence of local infection and/or a positive culture. Severe sepsis was defined as an infectious disease, at least two SIRS criteria, and the presence or the development of hypotension and/or organ failure within 24 h after the collection of the blood samples. Septic shock was defined as severe sepsis in addition to hypotension requiring vasopressor support or a persistent hypotension for more than 1 h despite adequate fluid resuscitation. The patients were divided into the following groups:

  1. Sepsis group.
  2. Severe sepsis (without septic shock) group.
  3. Septic shock group.


Sample collection and biomarker assays

Venous blood samples for the determination of biomarkers were drawn from patients at enrollment (sample 1) and 12 h after the initial sample (sample 2). Blood was left for 30–60 min for spontaneous clotting at room temperature before being centrifuged at 3000 rpm for 10 min. Serum samples were kept frozen at −80°C for the determination of HBP, PCT, and lactate.

Levels of HBP were measured using an enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions (Human HBP ELISA Kit; MyBioSource, Minneapolis, Minnesota, USA). The plates were read at a wavelength of 450 nm with an automatic ELISA reader and the assay did not cross-react with other related proteins. The sensitivity in this assay was 1 ng/ml. PCT was measured using an electrochemiluminescence immunoassay on Elecsys and Cobas (Roche Diagnostics, Rotkreuz, Switzerland) immunoassay analyzers. WBCs, CRP, and lactate analyses were performed at the clinical chemistry laboratories.

Statistical analysis

The data were checked, entered, and analyzed using statistical package for the social sciences (version 17; SPSS Inc., Chicago, Illinois, USA). Qualitative data were represented as frequencies and relative percentages. The χ2-test was used to calculate difference between qualitative variables. Quantitative data were expressed as mean±SD. The ANOVA F-test was used to calculate difference between quantitative variables in more than two groups in normally distributed data. The post-hoc least significant difference test was used to find differences between two groups, which were compared in the ANOVA test. Pearson's correlation coefficient was used to calculate correlation between quantitative variables. A positive sign denoted direct correlation (i.e. when an increase in the frequency of independent variables led to an increase in the frequency of dependent variables) and a negative sign denoted inverse correlation (i.e. when an increase in the frequency of independent variables led to a decrease in the frequency of dependent variables). Moreover, we considered values near to 1 as strong correlation and values near to 0 as weak correlation. Reliability data were calculated using the following formulas:

Sensitivity=true positives/(true positive+false negative),

Specificity=true negatives/(true negative+false positives),

PV+=true positive/(true positive+false positive).

PV−=true negatives/(true negatives+false negatives).

Accuracy=(true positive+true negative)/total.

Receiver operating characteristic curve analysis was used to identify optimal cutoff values of different parameters with maximum sensitivity and specificity.

The significance level for all above-mentioned statistical tests was determined. The threshold of significance is fixed at 5% level (P-value).

A P-value of more than 0.05 indicates nonsignificant results.

A P-value of less than 0.05 indicates significant results.

The appropriate sample size and power of the study were calculated based on the published data so that the study had 80% power at the 95% confidence interval using Open Epi (www.openepi.com).


  Results Top


A total of 90 patients with sepsis were prospectively enrolled in this study. Within the 12-h study period, of these 90 patients, 41 (45.6%) patients had signs of sepsis, 29 (32.2%) patients developed severe sepsis, and 20 (22.2%) patients progressed to septic shock. There were no significant differences between the three groups with respect to demographic data, source of infection, and etiological agents (P > 0.05) [Table 1].
Table 1: Patient characteristics, source of infection, and microbiological data

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Mean values (baseline) of WBC count and serum levels of HBP, PCT, CRP, and lactate in all septic patients of the study are shown in [Table 2].
Table 2: Biomarkers in all patients (baseline values)

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As regards the vital signs at enrollment (baseline), there were no significant differences between the three groups (P > 0.05) [Table 3].
Table 3: Vital signs of the studied groups at enrollment (baseline)

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However, after 12 h, in the severe sepsis and septic shock groups, there was a significant increase in HR (P < 0.01 and < 0.001, respectively) and RR (P < 0.05 for each) and a significant decrease in MAP (P < 0.001 for each) and SpO2 (P < 0.001 for each) when compared with the sepsis group. The mean values of temperature after 12 h were comparable between the three groups (P > 0.05) [Table 4].
Table 4: Vital signs of the studied groups after 12 h

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On comparing the severe sepsis and septic shock groups after 12 h, there were no significant differences as regards the vital signs except for MAP, which was significantly decreased in the septic shock group(P < 0.001) [Table 4].

In the sepsis group, there were no significant differences between the mean values of vital signs at enrollment (baseline) and after 12 h, except for HR, which was significantly increased (P < 0.001). Meanwhile, in the severe sepsis and septic shock groups, the HR showed a significant increase (P < 0.001), whereas the MAP and SpO2 showed a significant decrease after 12 h compared with baseline values (P < 0.001 for each) [Table 5].
Table 5: Vital signs of the studied groups at enrollment (baseline) and after 12 h

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Heparin-binding protein as a predictor of risk for severe sepsis and septic shock

At enrollment (baseline), the current study found a highly significant increase in HBP serum levels in the severe sepsis group (62.86 ± 18.77 ng/ml) and in the septic shock group (65.28 ± 18 ng/ml) compared with the sepsis group (21.28 ± 5.49 ng/ml) (P < 0.001). However, the levels of PCT, WBC count, CRP, and lactate were comparable between the three groups (P > 0.05) [Table 6].
Table 6: Comparison of the parameters between the three groups at enrollment (baseline)

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Heparin-binding protein as a diagnostic marker of severe sepsis and septic shock

After 12 h, the concentrations of all biomarkers were significantly increased in patients who had severe sepsis or septic shock compared with patients in the sepsis group. The mean values of serum HBP were 75.67 ± 11.85 ng/ml in the severe sepsis group and 92.23 ± 16.13 ng/ml in the septic shock group compared with a mean value of 23.20 ± 5.26 ng/ml in the sepsis group (P < 0.001). Moreover, there was a significant increase in serum levels of HBP and PCT in the septic shock group compared with the severe sepsis group (P < 0.001 and < 0.01, respectively). However, the other biomarkers (WBC count, CRP, and lactate) showed no significant differences between the severe sepsis and septic shock groups (P > 0.05) [Table 7].
Table 7: Comparison of the parameters between the three groups after 12 h

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On comparing the mean values of all biomarkers at enrollment (baseline) and after 12 h, there were no significant differences in the sepsis group but there was a significant increase in the severe sepsis and septic shock groups (P < 0.001 for each) [Table 6] and [Table 7].{Table 6}{Table 7}

The diagnostic accuracy for the identification of patients progressing to severe sepsis and septic shock was highest for HBP, with an area under the curve (AUC) value of 0.95. At a cutoff point more than 31.6 ng/ml, HBP provided a specificity of 87.8% and sensitivity of 85.7% for identifying patients at risk of developing severe sepsis or septic shock. The present study demonstrated that HBP had an AUC (0.95) significantly higher than all other biomarkers (P < 0.001): PCT (0.58), WBC (0.57), CRP (0.55), and lactate (0.53) [Table 8] and [Figure 1].
Table 8: Sensitivity, specificity, positive predictive value, and negative predictive value of tested variables in prediction of severe sepsis with or without septic shock

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Figure 1: Receiveroperatingcharacteristiccurveisshowncomparingheparin-binding protein (HBP), procalcitonin (PCT), C-reactive protein (CRP), lactate, andwhitebloodcell(WBC)countindiscriminatingbetweensepticpatients whoprogressed to severe sepsisandseptic shockandthosewho did not.

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Correlation between heparin-binding protein and the mean arterial blood pressure and the other parameters

At enrollment (baseline) and after 12 h, a statistically significant negative correlation was elucidated between HBP level and MAP in all septic patients (R= − 0.37, P < 0.001, and R= − 0.89, P < 0.001, respectively). However, there was a statistically significant positive correlation between HBP level and CRP (R=0.27, P=0.01, and R = 0.66, P < 0.001, respectively) and lactate (R = 0.26, P = 0.02, and R = 0.49, P < 0.001, respectively) in all septic patients. There was no significant correlation between HBP and PCT or WBC count [Table 9] and [Table 10].
Table 9: Correlation between heparin-binding protein and other parameters at enrollment (baseline)

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Table 10: Correlation between heparin-binding protein and other parameters after 12 h

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  Discussion Top


Patients with sepsis are at risk of progression to severe sepsis and septic shock because of the nonspecific diagnostic criteria of sepsis [12]. Therefore, the early detection of high-risk patients facilitates resuscitation and treatment before the development of circulatory failure [2],[3]. This study hypothesized that the elevated serum level of HBP in patients with sepsis can be used as an early detector for circulatory failure. The results of this study found that the patients who had elevated serum level of HBP at enrollment developed severe sepsis and septic shock within several hours. These results are in agreement with the results of other studies [7],[13],[14], which reported increased serum levels of HBP several hours before the development of circulatory failure or organ dysfunction. Moreover, a previous single-center study showed increased plasma HBP in over 90% of patients with infection who developed severe sepsis after inclusion [12]. Linder et al.[8] concluded that patients with severe sepsis and septic shock had a significantly high plasma level of HBP at admission, and this elevation was associated with an increased risk for death. In contrast to this study, Chew et al.[15] recorded elevated levels of HBP in 53 patients with shock in the ICU without infectious etiology and did not find an association with severity and outcome. It is probable that the loss of a correlation between HBP level and infection or severity of illness in Chew et al.'s [15] study refers to the unselective nature of the patients.

In this study, no significant differences in serum levels of the other investigated biomarkers were found at enrollment between patients with sepsis and those who developed severe sepsis or septic shock. Meanwhile, the serum level of HBP was elevated in patients who developed severe sepsis or septic shock at enrollment, and this indicates that HBP levels were elevated before other investigated biomarkers.

The rapid increase in HBP can be attributed to its location within the secretory granules, which are the first to be mobilized upon neutrophil activation. After release, HBP contributes to the neutrophil-mediated permeability changes of the endothelium, leading to vascular leakage [6],[16]. Linder et al. [7],[14] reported the same results and concluded that HBP was the best detector of circulatory failure when compared with the other investigated biomarkers [7]. The biomarkers such as PCT, CRP, and WBC count are mainly used in the early diagnosis of bacterial causes in critically ill patients and they have limited roles in the detection of circulatory failure [5],[17]. In the present study, HBP was significantly more efficient in identifying patients who developed septic shock compared with the other investigated markers as the diagnostic accuracy for the identification of patients progressing to severe sepsis and septic shock was highest for HBP, with an AUC value of 0.95 compared with the other investigated biomarkers. This is in accordance with the results of Linder et al. [14], who reported that HBP had an AUC of 0.85 (95% confidence interval: 0.82–0.88), which was significantly higher than all other biomarkers. HBP was reported to have a higher sensitivity and specificity compared with PCT and CRP in identifying patients with severe sepsis in the emergency department [7]. A statistically significant correlation was elucidated between HBP level and MAP in all patients in the present study at the enrollment and after 12 h. There was a close correlation between the elevated HBP plasma levels and the occurrence of hypotension and septic shock [7]. In this study, there was a statistically significant positive correlation between HPB level and CRP and lactate, but there was no significant correlation between HBP and PCT or WBC count. Previous studies reported that the elevated levels of lactate, cortisol, and interleukin-6 in the blood of patients with different etiologies of shock had significant predictive values [10],[18]. However, these biomarkers have some limitations: lactate levels are less influenced by arterial sampling; endogenous cortisol levels are downregulated by corticosteroids used in the treatment of septic shock, or by relative adrenal insufficiency; and interleukin-6 analysis is not generally available in regular hospital laboratories [19].

A lot of clinicians recommended that the early introduction of adequate antibiotic therapy and resuscitation fluid decreases the mortality rate among patients with septic shock [20]. The mortality rate increases up to 7.5% for every hour that proper treatment is delayed [21]. In the present study, as the increased plasma HBP level preceded the clinical development of circulatory failure by several hours in patients with sepsis, the measurement of plasma HBP may enable an early treatment and prevent the progression to severe sepsis or septic shock. The evident suggestion of these results is that the detection of an increased plasma HBP level in a febrile patient should immediately alert the clinician to intensify and start a proper treatment with antibiotic and resuscitation fluid. This study had some limitations such as the limited number of patients in the study nd the lack of data on long-term mortality. Moreover, patients receiving immunosuppressive therapy or those with neutropenia due to hematological malignancy were excluded from this study. Therefore, further investigations are necessary to evaluate the use of HBP measurements in these patient groups.


  Conclusion Top


The increase in serum level of HBP in patients with sepsis is an early predictor and diagnostic marker for circulatory failure. Moreover, HBP is considered to be the best predictor of circulatory failure compared with the other investigated biomarkers.

Recommendations

The repeated measurements of HBP serum levels of critically ill septic patients can be a good aid for close monitoring of treatment and can predict the outcome. However, further studies on a large and more heterogenous population is needed to confirm the findings of our study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Pierrakos C, Vincent J-L. Sepsis biomarkers: a review. Crit Care 2010; 14:R15.  Back to cited text no. 1
    
2.
Rivers EP, Katranji M, Jaehne KA, Brown S, Abou Dagher G, Cannon C, Coba V. Early interventions in severe sepsis and septic shock: a review of the evidence one decade later. Minerva Anestesiol 2012; 78:712–724.  Back to cited text no. 2
    
3.
Bastani A, Galens S, Rocchini A, Walch R, Shaqiri B, Palomba K et al. ED identification of patients with severe sepsis/septic shock decreases mortality in a community hospital. Am J Emerg Med 2012; 30:1561–1566.  Back to cited text no. 3
    
4.
Gibot S, Cravoisy A, Kolopp-Sarda MN, Béné MC, Faure G, Bollaert PE, Levy B. Time-course of STREM (soluble triggering receptor expressed on myeloid cells)-1, procalcitonin, and C-reactive protein plasma concentrations during sepsis. Crit Care Med 2005; 33:792–796.  Back to cited text no. 4
    
5.
de Jager CP, van Wijk PT, Mathoera RB, de Jongh-Leuvenink J, van der Poll T, Wever PC. Lymphocytopenia and neutrophil–lymphocyte count ratio predict bacteremia better than conventional infection markers in an emergency care unit. Crit Care 2010; 14:R192.  Back to cited text no. 5
    
6.
Gautam N, Olofsson AM, Herwald H, Iversen LF, Lundgren-Akerlund E, Hedqvist P et al. Heparin-binding protein (HBP/CAP37): a missing link in neutrophil-evoked alteration of vascular permeability. Nat Med 2001; 7:1123–1127.  Back to cited text no. 6
    
7.
Linder A, Christensson B, Herwald H, Björck L, Akesson P. Heparin-binding protein: an early marker of circulatory failure in sepsis. Clin Infect Dis 2009; 49:1044–1050.  Back to cited text no. 7
    
8.
Linder A, Akesson P, Inghammar P, Treutiger CJ, Linnér A, Sundén-Cullberg J. Elevated plasma levels of heparin-binding protein in intensive care unit patients with severe sepsis and septic shock. Crit Care 2012; 16:R90.  Back to cited text no. 8
    
9.
Dankiewicz J, Linderb A, Annborn M, Rundgrena M, Friberg H. Heparin binding protein: an early indicator of critical illness and predictor of outcome in cardiac arrest. Resuscitation 2013; 84:935–939.  Back to cited text no. 9
    
10.
Hack CE, De Groot ER, Felt-Bersma RJ, Nuijens JH, Strack Van Schijndel RJ, Eerenberg-Belmer AJ et al. Increased plasma levels of interleukin-6 in sepsis. Blood 1989; 74:1704–1710.  Back to cited text no. 10
    
11.
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992; 101:1644–1655.  Back to cited text no. 11
    
12.
Glickman SW, Cairns CB, Otero RM, Woods CW, Tsalik EL, Langley RJ et al. Disease progression in hemodynamically stable patients presenting to the emergency department with sepsis. Acad Emerg Med 2010; 17:383–390.  Back to cited text no. 12
    
13.
Shapiro NI, Trzeciak S, Hollander JE, Birkhahn R, Otero R, Moretti E et al. A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis. Crit Care Med 2009; 37:96–104.  Back to cited text no. 13
    
14.
Linder A, Arnold R, Boyed JH, Zindovic M, Zindovic L, Lange A et al. Heparin-binding protein measurement improves the prediction of severe infection with organ dysfunction in the emergency department. Crit Care Med 2015; 43:2378–2386.  Back to cited text no. 14
    
15.
Chew MS, Linder A, Santen S, Ersson A, Herwald H, Thorlacius H. Increased plasma levels of heparin-binding protein in patients with shock: a prospective, cohort study. Inflamm Res 2012; 61:375–379.  Back to cited text no. 15
    
16.
McNamara C, Zinkernagel AS, Macheboeuf P, Cunningham MW, Nizet V, Ghosh P. Coiled-coil irregularities and instabilities in group A Streptococcus M1 are required for virulence. Science 2008; 319:1405–1408.  Back to cited text no. 16
    
17.
Oberhoffer M, Vogelsang H, Russwurm S, Hartung T, Reinhart K. Outcome prediction by traditional and new markers of inflammation in patients with sepsis. Clin Chem Lab Med 1999; 37:363–368.  Back to cited text no. 17
    
18.
Mavrić Z, Zaputović L, Zagar D, Matana A, Smokvina D. Usefulness of blood lactate as a predictor of shock development in acute myocardial infarction. Am J Cardiol 1991; 67:565–568.  Back to cited text no. 18
    
19.
Moran JL, Chapman MJ, O’Fathartaigh MS, Peisach AR, Pannall PR, Leppard P. Hypocortisolaemia and adrenocortical responsiveness at onset of septic shock. Intensive Care Med 1994; 20:489–495.  Back to cited text no. 19
    
20.
Rivers E, Nguyen B, Havstad S. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368–1377.  Back to cited text no. 20
    
21.
Kumar A, Roberts D, Wood KE. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34:1589–1596.  Back to cited text no. 21
    


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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

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