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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 2  |  Page : 53-65

A study of Pro-brain natriuretic peptide compared with procalcitonin in critically ill patients with severe sepsis as a marker of diagnosis of sepsis


Department of Critical Care Medicine, Faculty of Medicine, University of Alexandria, Alexandria, Egypt

Date of Submission20-May-2015
Date of Acceptance20-Oct-2015
Date of Web Publication6-Sep-2016

Correspondence Address:
Sally R El-shrief
4 Tekla street, lamies Tower, Alexandria
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2356-9115.189783

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  Abstract 


Objective In this study we assessed the diagnostic value of Pro-brain natriuretic peptide (ProBNP) in severe sepsis and the relation of ProBNP and procalcitonin (PCT) as a biochemical marker of sepsis to cardiac dysfunction in severely septic patients.
Design This was a prospective screening study.
Patients and methods Twenty-four patients who were admitted to the Critical Care Medicine Department with a preliminary diagnosis of severe sepsis, defined according to the Surviving Sepsis Campaign, and 12 healthy adults as volunteers were recruited into the study. Twenty-four patients with a preliminary diagnosis of severe sepsis were divided into two groups according to echocardiography (Echo) findings. Group I included severely septic patients with normal Echo findings and group II comprised severely septic patients with abnormal Echo findings. Cultures from suspected sites of infection were obtained. Blood levels of C-reactive protein, ProBNP, and PCT were measured on admission in the case of severely septic patients. We compared ProBNP and PCT levels in severely septic patients with normal Echo findings and those with systolic and/or diastolic dysfunction and we also compared the level of ProBNP in these two groups with the control group.
Results The level of ProBNP was very high, ranging from 102 to 24 244 pg/ml in all patients compared with 20–120 pg/ml in the control group. The ProBNP level was high in both groups of patients. Severely septic patients with normal or abnormal Echo findings had no significant difference regarding age, sex, vital signs, white blood count, serum creatinine, arterial blood gases, Acute Physiologic and Chronic Health Evaluation II (APACHE II) score, C-reactive protein, PCT, and ProBNP on admission. In group I, ProBNP ranged from 102 to 3776 pg/ml compared with 361 to 24 244 pg/ml in group II, with no significant difference (P<0.603). ProBNP was significantly high in severely septic patients compared with controls (P=0.001). ProBNP was significantly higher in septic shock patients with abnormal Echo findings compared with those with normal Echo findings (P=0.014), as well as in severely septic patients with left ventricular dysfunction (LVH) (P=0.012). ProBNP was high with no significant difference regarding systolic and diastolic dysfunction and LVH in severely septic patients with abnormal Echo findings (P=0.087). ProBNP level was high but there was no significant difference (P=0.296) when correlated to culture results whether sterile or positive. The level of ProBNP in diagnosing severe sepsis in the patient group (with cutoff point>108 pg/ml as recommended by Youden’s index) had 95.83% sensitivity, 83.33% specificity, 92.0% positive predictive value (PPV), 90.91% negative predictive value (NPV), and 91.67% accuracy. To differentiate severely septic patients with normal Echo findings from those with abnormal Echo findings, ProBNP (with cutoff point>2900 pg/ml) had 41.67% sensitivity, 83.33% specificity, 71.43% PPV, and 58.82% NPV with 62.50% accuracy; PCT (with cutoff point>2 pg/ml) had 66.67% sensitivity, 50.0% specificity, 57.14% PPV, 60% NPV, and 58.33% accuracy. Therefore, ProBNP and PCT levels did not have good sensitivity or specificity in differentiating between severely septic patients with normal cardiac functions and those with abnormal cardiac functions.
Conclusion ProBNP level increased with significant difference in all severely septic and septic shock patients with no impact of sex, type of organism, and site of infection. ProBNP level increased in severely septic patients with LVH, but it could not distinguish between types of ventricular dysfunction. PCT and ProBNP levels were not specific or sensitive in differentiating severely septic patients with normal cardiac function from those with abnormal cardiac function. ProBNP level was affected by renal dysfunction.

Keywords: arterial blood gases, C-reactive protein, echocardiography, left ventricular dysfunction, Pro-brain natriuretic peptide, procalcitonin


How to cite this article:
Fayed AM, Aglan AA, Abdel Mahros AA, El-shrief SR. A study of Pro-brain natriuretic peptide compared with procalcitonin in critically ill patients with severe sepsis as a marker of diagnosis of sepsis. Res Opin Anesth Intensive Care 2016;3:53-65

How to cite this URL:
Fayed AM, Aglan AA, Abdel Mahros AA, El-shrief SR. A study of Pro-brain natriuretic peptide compared with procalcitonin in critically ill patients with severe sepsis as a marker of diagnosis of sepsis. Res Opin Anesth Intensive Care [serial online] 2016 [cited 2020 Jun 4];3:53-65. Available from: http://www.roaic.eg.net/text.asp?2016/3/2/53/189783




  Introduction Top


Severe sepsis and septic shock are affecting millions of people around the world each year. They are the most common cause of morbidity and mortality in intensive care [1],[2],[3]. Severe sepsis is defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion [4].

Septic shock is defined as sepsis-induced hypotension persisting despite adequate fluid resuscitation [4].

Severe sepsis occurs as a result of both community-acquired and healthcare-associated infections. Gram-positive infections are more common than Gram-negative and fungal infections, although a more recent study showed Gram-negative bacteria to be the most common [5].

Pneumonia is the most common cause of septic shock, accounting for about half of all cases, followed by intra-abdominal and urinary tract infections [5].

There are many hypotheses on the pathophysiology of severe sepsis. Proinflammatory reactions are thought to be responsible for collateral tissue damage in severe sepsis, whereas anti-inflammatory responses enhanced susceptibility to secondary infection [5].

Early diagnosis of sepsis is the key to improving survival, and hence laboratory tests play an important role in identifying the infectious agent. Culture is the diagnostic tool but the microbiological origin of infection is demonstrated only in about two-third of cases. Therefore, biomarkers have an important place in this process because they can indicate the presence or absence of sepsis. They can differentiate bacterial from viral and fungal infection. It is also important in evaluating the response to therapy and recovery from sepsis [1],[2],[3],[4].

Procalcitonin (PCT) is the peptide precursor of calcitonin, a hormone that is synthesized by the parafollicular C cells of the thyroid under the control of the calcitonin gene-related peptide 1, and is released as an acute-phase reactant in response to inflammatory stimuli, especially those of bacterial origin. It aids in diagnosis and risk stratification of bacterial sepsis, but has limited value in diagnosing viral, fungal, and atypical infection [6].

C-reactive protein (CRP) is a protein synthesized by the liver mainly in response to interluekin-6, also produced by cells in the vascular wall, such as endothelial cells, smooth muscle cells, and adipose tissue. It has no relationship with protein C or C-peptide. Significant increase in CRP indicates clinically relevant inflammation; in contrast, the absence of a high CRP helps in exclusion of infection and inflammation. It also aids in diagnosis of sepsis, in which it appears early and falls rapidly after removal of stimuli. Its level increases in atypical bacterial, viral, and fungal infections but its value increases in autoimmune diseases and malignancy as well [7],[8].

Increased level of Pro-brain natriuretic peptide (ProBNP) in severe sepsis and septic shock is a consequence of cytokine production independent of myocardial dysfunction. Tumor necrosis factor-α and interleukin-β1 are important cytokines released during sepsis, which are associated with myocardial depression. It has been demonstrated that these proinflammatory cytokines upregulate the BNP gene expression and secretion [9],[10],[11],[12]. Cardiotrophin-1 is a member of the interleukin-6 family. It increases the BNP messenger RNA expression in vivo [13]. Bacterial endotoxins secreted from Gram-negative organisms and Staphylococcus aureus α-toxin mediate myocardial depression in septic shock by a mechanism that involves nitric oxide release. They also modulate BNP expression and secretion [14],[15]. Neutral endopeptidase 24.11 (NEP 24.11), the enzyme responsible of degradation of ProBNP, decreases its activity in septic shock rather than in sepsis [16]. Finally, ProBNP clearance decreases because of renal dysfunction accompanying severe sepsis.


  Patients and methods Top


Patients

This prospective comparative screening study was carried out on 24 patients who were admitted to the Critical Care Medicine Department with a preliminary diagnosis of severe sepsis, defined according to the Surviving Sepsis Campaign, and on 12 healthy adults as volunteers [4].

The approval of the Medical Ethics Committee of Alexandria Faculty of Medicine was taken. Informed consent from the patients’ next of kin was obtained before conducting the study.

In addition to the control group, patients fulfilling the criteria of severe sepsis were categorized according to echocardiography (Echo) findings into two groups, each comprising 12 patients:

  1. Group I: This group comprised severely septic patients with normal systolic and diastolic function.
  2. Group II: This group comprised severely septic patients with impaired systolic function alone and or impaired diastolic function during severe sepsis.
  3. Control group: This group comprised normal healthy adults who were volunteers from the medical institute (residents at Alexandria Main University Hospital).


Inclusion criteria

  1. Presence of severe sepsis and age greater than 18 years for inclusion into the patient group.
  2. Being a normal healthy adult for inclusion into the control group.


Exclusion criteria

  1. Age less than 18 years.
  2. Known heart failure or left ventricular hypertrophy.
  3. Known right heart failure or pulmonary hypertension.
  4. End-stage renal disease with the patient on permanent hemodialysis.
  5. BMI>35.


Methods

All patients included in the study were subjected on admission to the following:

  1. Demographic data including age and sex.
  2. Complete history taking, including the etiology of sepsis.
  3. Complete physical examination.
  4. Routine laboratory investigations.
  5. Sampling of arterial blood gases using a heparinized syringe using GEM premiere 3500 machine.
  6. Administration of the Acute Physiologic and Chronic Health Evaluation II scoring system (APACHE II), which ranged from 12.0 to 24.
  7. Chest radiography on admission (care stream health x-ray machine).
  8. Sepsis workup by taking cultures from suspected sites of infection (blood, urine, and sputum).
  9. Evaluation of the level of CRP in the blood as a marker of sepsis for patients with severe sepsis analyzed by immunodiffusion assay (normal level, up to 3 mg/l) [7].
  10. Evaluation of ProBNP level in the blood for patients with severe sepsis and for the control group using serum of the patient collected in a serum bottle and analyzed by chemiluminescence immunoassay (normal level, up to 108 pg/ml) [9].
  11. Evaluation of PCT level in the blood for patients with severe sepsis by using serum of the patient collected in a serum bottle and analyzed by chemiluminescence immunoassay (normal, <0.5 ng/ml) [6].
  12. Echo on admission by using a GE Vivid 3 ultrasound machine. Echo parameters that were measured included the following:





    1. left ventricular end diastolic diameter,
    2. left ventricular end systolic diameter, and
    3. ejection fraction (EF%).




Systolic dysfunction is defined as an left ventricular ejection fraction less than 40% [17].

Diastolic dysfunction referred to cardiac dysfunction in which left ventricular filling was abnormal and was accompanied by elevated filling pressures [17].

Main outcome

  1. The diagnostic value of ProBNP in the diagnosis of severe sepsis by ascertaining its sensitivity, specificity, and diagnostic cutoff value.
  2. To compare between ProBNP and PCT as a biochemical marker of sepsis at the time of diagnosis in severely septic patients with normal systolic and diastolic function and those with impaired systolic and/or diastolic functions.


Statistical analysis of the data

Data were fed into the computer and analyzed using IBM SPSS software package version 20.0. Qualitative data were described using number and percentage. Quantitative data were described using range (minimum and maximum), mean, SD, and median. Comparison between different groups regarding categorical variables was made using the χ2-test. When more than 20% of the cells have an expected count less than 5, correction for χ2 was conducted using Fisher’s exact test or Monte Carlo correction. The distributions of quantitative variables were tested for normality using the Kolmogorov–Smirnov test, the Shapiro–Wilk test, and the D’Agostino test. Histograms and QQ plots were used for the vision test. Parametric tests were applied for normal data and nonparametric tests for non-normally distributed data. For normally distributed data, comparison between two independent populations was made using the independent t-test, whereas the F-test (analysis of variance) and the post-hoc test (Scheffe) were used for comparison between more than two populations. For abnormally distributed data, comparison between two independent populations was made using the Mann–Whitney test, whereas the Kruskal–Wallis test was used to compare more than two populations. Correlations between two quantitative variables were assessed using Spearman’s coefficient. Agreement of the different predictives with the outcome was expressed as sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. Receiver operating characteristic (ROC) curve was plotted to analyze a recommended cutoff. The area under the ROC curve denotes the diagnostic performance of the test. Area more than 50% gives acceptable performance and area about 100% is the best performance for the test. Significance of the obtained results was judged at the 5% level.


  Results Top


Baseline characteristic data were compared between severely septic patients with normal cardiac function and those with cardiac dysfunction with regard to age, sex, vital signs, laboratory investigations, arterial blood gases, APACHE II score, vasopressor usage (noradrenalin), Echo findings, CRP, PCT, and ProBNP levels [Table 1].
Table 1 Comparison of clinical data between severely septic patients with normal Echo findings and those with abnormal Echo findings

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There were no statistically significant differences between the two groups regarding age, sex, vital signs, laboratory investigations, vasopressor usage, arterial blood gas, APACHE II score, CRP, PCT and ProBNP levels.

There was significant difference between the two groups regarding Echo findings left ventricular dysfunction [(LVH), diastolic dysfunction, and systolic dysfunction] (P<0.001).

Cultures were taken from sputum, blood, urine, and swabs from other tissues (diabetic foot infection, gluteal abscess, and bed sores).Gram-positive organisms appeared in the cultures of two of 12 patients in group I and in the same number of patients in group II, with no significant difference. Gram-negative organisms appeared in cultures of nine of 12 patients in group I compared with seven patients of 12 patients in group II, with no significant difference. Sterile cultures (negative) appeared in five of 12 patients in group I and eight of 12 patients in group II, with no significant difference [Table 2].
Table 2 Comparison between the two groups on the basis of culture results on admission or on the second day

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ProBNP level was measured within 6 h of admission in both severely septic patients and controls. We found that the level of ProBNP was very high in all patients, ranging from 102 to 24 244 pg/ml (mean=3733.92±5468.97 pg/ml), compared with 20–120 pg/ml in controls (mean=86.42±27.14 pg/ml), revealing significant difference (P<0.001) [Table 3].
Table 3 Comparison between severely septic patients and the controls on the basis of ProBNP within 6 h of admission

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Regarding ProBNP levels [Table 4], the ProBNP level in the control group ranged from 20 to 120 pg/ml, with a mean of 86.42±27.14 pg/ml. The ProBNP level was high in the two studied groups (group I and II) with no significant difference (P<0.603). In group I the ProBNP level ranged from 102 to 3776 pg/ml, with a mean of 2065.7±1174.6 pg/ml, compared with 361–24 244 pg/ml in group II, with a mean of 5402.2±7422 pg/ml. However, each group had higher significant difference compared with the control group (P<0.001).
Table 4 Comparison between the different groups according to ProBNP

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We had two patients with atrial fibrillation (AF) in group II, whose ProBNP values were 16 791 and 24 244 pg/ml. We excluded them from the study to avoid performance bias, and then we repeated the comparison as in [Table 5]. We found that ProBNP levels in group II ranged from 361 to 6942 pg/ml with a mean of 2379.1±1820.9 pg/ml compared with group I, in which the ProBNP level also was still high, with no significant difference between the two groups (P=0.603), and each of them also had higher significant difference compared with controls (P<0.001).
Table 5 Comparison between the groups with respect to ProBNP in patients without AF

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When we correlated the level of ProBNP to the level of PCT, APACHE II score, creatinine, CRP, and EF% between the two studied groups and with total patients [Table 6], we found that there was a good correlation between ProBNP, CRP, and PCT but with no significant difference.
Table 6 Correlation between ProBNP and procalcitonin, APACHE II score, creatinine, CRP, and EF in each group and in all patients

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When we correlated ProBNP level to EF%, we found good correlation between ProBNP and EF less than 40% in severely septic patients in group II compared with group I.

We also found good correlation between APACHE II score and ProBNP level in group I and total patients compared with group II.

As regards serum creatinine, we found good correlation between ProBNP level and serum creatinine, with significant difference in total patients.

There was no significant difference as regards the relation between sex and ProBNP level in all patients, as seen in [Table 7]. The ProBNP level ranged in seven male patients from 621.0 to 3600 pg/ml (mean=1872.7±1002.6 pg/ml) and in 16 female patients from 102.0 to 24 244 pg/ml (mean=4500.3±6362.3 pg/ml) (P=0.325).
Table 7 Relation between ProBNP and sex in all patients

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As regards the relation of ProBNP in septic shock patients with normal and abnormal Echo findings, we found significant difference (P=0.014). We had four patients with normal Echo findings with ProBNP level 102–1818 pg/ml (mean=808.25±722.72 pg/ml) compared with five patients with abnormal Echo findings with ProBNP level 3000.0–24 244 (mean=10 855.40±9335.31), as shown in [Table 8].
Table 8 Relation between ProBNP level and septic shock in patients with normal and those with abnormal Echo findings

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As regards the relation between ProBNP level and LVH [Table 9], seven of 24 patients had LVH with or without other Echo abnormalities. Their mean ProBNP level was 8315.29±8770.78 pg/ml, compared with a mean ProBNP level of 1847.47±1088.03 pg/ml among 17 patients with no LVH; this showed significant difference (P=0.012).
Table 9 Relation between ProBNP and LVH in the patient group

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An analysis of the ProBNP level in patients with abnormal Echo findings [Table 10] revealed the following: three patients had only systolic dysfunction and their mean ProBNP level was 1277.33±885.77 pg/ml; four patients had diastolic dysfunction and LVH and their mean ProBNP level was 12 444.25±10 028.35 pg/ml; four patients had systolic dysfunction with LVH and their mean ProBNP level was 2271.75±1059.29 pg/ml. All of them had a high level of ProBNP with no significant difference because of high SDs (P=0.087).
Table 10 Relation between ProBNP and patients with abnormal Echo

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Regarding the relation of ProBNP level to culture results [Table 11], we found that all cultures, whether positive or sterile, had a high level of ProBNP, but with no significant difference (P=0.297).
Table 11 Relation between ProBNP and culture results

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We had nine patients with sterile cultures, whose ProBNP level ranged from 1342 to 24 244 pg/ml (mean=7095.33±7997.88 pg/ml), and 15 patients with positive cultures, whose ProBNP level ranged from 102.0 to 16 791.0 pg/ml (mean=4243.0±5008.4 pg/ml).

After the exclusion of two patients with AF [Table 12], we found significant difference between ProBNP level and culture results (P=0.045). We had seven patients with sterile cultures, whose ProBNP levels ranged from 342.0 to 6942 pg/ml (mean=3260.43±1857.43 pg/ml), and 15 patients with positive cultures, whose ProBNP levels ranged from 102.0 to 3300 pg/ml (mean=1717.07±981.43 pg/ml).
Table 12 Relation between ProBNP and culture results in patients without atrial fibrillation

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After the exclusion of patients with AF and differentiation [Table 13], we found no significant difference between ProBNP level and culture results. We had 12 patients with Gram-negative cultures, whose ProBNP levels ranged from 361.0 to 3776.0 pg/ml (mean=2450.4±1122.12 pg/ml), and three patients with Gram-positive cultures, whose ProBNP levels ranged from 102.0 to 2129 pg/ml (mean=974.3±1042.6 pg/ml).
Table 13 Relation between ProBNP and culture results in patients without atrial fibrillation

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We also had 12 patients with negative cultures, whose ProBNP levels ranged from 361.0 to 6942 pg/ml (mean=2287.7±1609 pg/ml). All culture results showed high ProBNP levels, with no significant difference (P=0.081).

[Table 14] and [Figure 1] show the sensitivity, specificity, and accuracy of ProBNP for the diagnosis of severe sepsis in the patient group.
Table 14 Agreement (sensitivity, specificity, and accuracy) for ProBNP in the diagnosis of severe sepsis

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Figure 1 Receiver operating characteristic (ROC) curve for Pro-brain natriuretic peptide (ProBNP) in the diagnosis of severe sepsis.

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We used the ROC curve for the best cutoff point greater than 108 pg/ml as recommended by Youden’s index. ProBNP level had 95.83% sensitivity, 83.33% specificity, 92.0% PPV, 90.91% NPV, and 91.67% accuracy, which indicated that the level of ProBNP greater than 108 had a high sensitivity and specificity for detection of severe sepsis.

[Table 15] and [Figure 2] show the sensitivity, specificity, and accuracy of ProBNP in diagnosing patients with normal Echo findings and those with abnormal Echo findings.
Table 15 Agreement (sensitivity, specificity, and accuracy) for ProBNP and procalcitonin in the diagnosis of cardiac dysfunction in severely septic patients

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Figure 2 Receiver operating characteristic (ROC) curve for procalcitonin (PCT) and Pro-brain natriuretic peptide (ProBNP) to differentiate between severely septic patients with normal cardiac function and those with abnormal cardiac function.

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We used the ROC curve for the best cutoff point greater than 2900 pg/ml as recommended by Youden’s index. It had 41.67% sensitivity, 83.33% specificity, 71.43% PPV, 58.82% NPV, and 62.50% accuracy, which indicated that ProBNP level was less sensitive and specific in differentiating between severely septic patients with normal cardiac functions and those with abnormal cardiac functions.

As regards PCT levels to differentiate patients with normal Echo findings from those with abnormal Echo findings, we used ROC for the best cutoff point greater than 2 as recommended by Youden’s index. It had 66.67% sensitivity, 50.0% specificity, 57.14% PPV, 60.0% NPV, and 58.33% accuracy, which also indicated that PCT level was less sensitive and specific in differentiating severely septic patients with normal cardiac functions from those with abnormal cardiac functions.


  Discussion Top


The aim of the present study was to evaluate the diagnostic value of ProBNP in terms of its sensitivity, specificity, and cutoff point value in severe sepsis and the relation of ProBNP and PCT to cardiac dysfunction in severely septic patients.

Regarding demographic data there was no significant difference in the distribution of male and female participants in the three groups.

Regarding age, there was no significant difference between group I and group II (mean age=60 years) but there was a highly significant difference compared with controls (mean age=27 years).

Regarding the source of sepsis, pneumonia was the most common cause of severe sepsis in the present study (15 patients), followed by urinary tract infection in six patients and intra-abdominal sepsis in four patients. Several epidemiological studies had the same results and showed that the lung is the primary source of infection both in severe sepsis and in septic shock, followed by the abdomen and the urinary tract [1],[2].

Pro-brain natriuretic peptide level

ProBNP had been documented to be increased significantly in patients with heart failure and LVH [18].

The current study showed that the level of ProBNP was very high in severely septic patients compared with controls.

We had two patients with AF in group II with a very high level of ProBNP, and ProBNP level was proven to be high in patients with AF, as in studies conducted by Patton et al. [19] and Knudsen et al. [20].

We excluded them from this comparison to avoid performance bias and repeated the comparison. We also found no significant difference between the two groups.

The same findings were proven by the following studies:

Early in 2004 Chua and Kang-Hoe [21] studied six patients with septic shock to find marked elevation in ProBNP in all of them.

Li et al. [22] came to the conclusion that ProBNP level, CRP, and lactic acid increased significantly in patients with severe sepsis and septic shock than in patients with sepsis alone (P<0.05).

Kandil et al. [23] studied ProBNP levels in septic and septic shock patients and in a control group on admission. They found a highly significant correlation of ProBNP in septic shock patients compared with controls, but patients with early sepsis had no significant difference compared with controls.

PiEchota et al. [24] found that the level of ProBNP was not too high because they considered patients with early sepsis and severe sepsis together in the statistics.

However, Fried et al. [25] compared patients with sepsis and patients with acute LVH and found that the ProBNP level was elevated in patients with sepsis but was significantly higher in patients with acute LVH. When they compared ProBNP level between septic patients with impaired systolic function and septic patients with normal systolic function, they found no significant difference.

In the present study, the level of ProBNP was very high in severely septic patients regardless of whether they had cardiac abnormalities, with no significant difference. Similar results were found when we correlated the level of ProBNP in male and female patients. We found higher ProBNP levels in patients with septic shock with abnormal Echo findings compared with those with normal Echo findings.

Rudiger et al. [26] derived the same conclusions. They compared severely septic and septic shock patients with cardiac patients. They found that the level of ProBNP was high with no significant difference between patients with severe sepsis and patients with cardiac abnormalities. This indicated that severe sepsis induced high levels of ProBNP as in cardiac failure. In our study the ProBNP level was high in severely septic patients with or without cardiac abnormalities, which indicated that cardiac abnormalities in septic cases cannot be considered an additional factor that increases the ProBNP level. Rudiger and colleagues also proved that the relation between sex and the level of ProBNP was not significantly different between patients with severe sepsis and those with heart failure.

Fried et al. [25] compared ProBNP levels between septic patients with impaired systolic function and septic patients with normal systolic function and found no significant difference.

In our present study, we constructed an ROC curve to evaluate the diagnostic value of ProBNP in severely septic patients.

We found that the best cutoff point was greater than 108 pg/ml, as recommended by Youden’s index. It had 95.83% sensitivity, 83.33% specificity, 92.0% PPV, 90.91% NPV, and 91.67% accuracy, which meant that the level of ProBNP greater than 108 pg/ml had high sensitivity and specificity for the detection of severe sepsis.

Correlation of Pro-brain natriuretic peptide level with Acute Physiologic and Chronic Health Evaluation II

This study showed that the APACHE II score was high in the two groups (mean of 19), with no significant difference.

These findings agreed with those of Chua and Kang-Hoe [21] and PiEchota et al. [24], who enrolled severely septic patients with high APACHE II score.

When we correlated the APACHE II score with ProBNP level, we found that it was significantly higher in group I compared with group II.

These findings agreed with the study of Brueckmann et al. [27], who enrolled patients with severe sepsis and found good correlation between APACHE II score and ProBNP, with highly significant difference. Our findings were in agreement with the results of Li et al. [22], who found a positive correlation between ProBNP level and APACHE II score in severely septic and septic shock patients.

Culture results

Cultures were from different sites (sputum, blood, urine, and swabs). In the present study some cultures were taken after starting antibiotics, which affected the culture results. Patients were deemed to have sterile cultures as per the Surviving Sepsis Campaign and positive CRP and PCT results, which is why there was a mildly significant difference between sterile and positive cultures in relation to ProBNP level (P=0.045). However, when we differentiated cultures into Gram-positive, Gram-negative, and sterile cultures, there was no significant difference, which indicated that bacterial infection and myocardial depression contributed to increasing ProBNP levels in cases of severe sepsis.

Arampatzi et al. [28] found high ProBNP, PCT, and CRP levels in septic patients, with no significant difference between them. There was no correlation between positive cultures and ProBNP level either, except for respiratory tract infection cultures.

Vila et al. [29] measured ProBNP levels in healthy individuals who agreed to take Escherichia coli endotoxin (LPS) in an experimental model of systemic infection and inflammation and found high ProBNP levels with E. coli infection.

All these studies agreed with the notion that ProBNP levels increase with infection without the presence of cardiac disease.

Echo findings

Elevated natriuretic peptide level was found to be an indicator of myocardial dysfunction in septic patients [21],[24],[29].

As for the relation between ProBNP level and EF in the present study, ProBNP level was high in severely septic patients with low EF of less than 40%, with highly significant difference compared with those with EF of at least 40%.

The correlation of ProBNP level in severely septic patients with LVH and with the level in those who did not have LVH showed a highly significant difference.

Charpentier et al. [30] assessed myocardial systolic performance by fractional area contraction and found that ProBNP levels were high in patients with severe sepsis and fractional area contraction greater than 50%. They found that systolic myocardial dysfunction was present in 44% of patients with severe sepsis or septic shock.

Our results were in agreement with those of Ignatios et al. [31], who used tissue Doppler Echo to diagnose diastolic dysfunction in patients with sepsis. They found that the level of ProBNP increased in septic patients with diastolic dysfunction. When they used ROC to assess the diagnostic performance of ProBNP in diastolic dysfunction, they found that a cutoff point greater than 941 pg/ml had 73% sensitivity and 70% specificity to diagnose patients with left ventricular diastolic dysfunction.

In our present study when we used ROC to evaluate the efficacy of ProBNP in diagnosing patients with normal Echo findings and abnormal Echo findings, we found that ProBNP level with a cutoff greater than 2900 pg/ml had 41.67% sensitivity, 83.33% specificity, 71.43% PPV, 58.82% NPV, and 62.50% accuracy. It means that ProBNP level was less sensitive and specific to differentiate between patients with normal and those with abnormal cardiac functions in cases of severe sepsis.

C-reactive protein and procalcitonin

In the present study, CRP, PCT, and ProBNP levels were high but with no significant difference between CRP and PCT when it was correlated to ProBNP.

These findings were similar to those of PiEchota et al. [32], who found high CRP, PCT, and ProBNP levels but with no significant difference.

In contrast to our study, Arampatzi et al. [28] found significant correlation between CRP and ProBNP level in septic patients, but there was no significant correlation between them and PCT. This difference might be because the authors used only septic patients with positive cultures and we used sterile and positive cultures from different sources of infection.

All these findings conclude that sepsis is a powerful stimulant for CRP, ProBNP, and PCT.

In the present study when we used ROC to evaluate the efficacy of PCT in diagnosing patients with normal Echo findings and abnormal Echo findings, we found that cutoff point greater than 2 pg/ml had 66.67% sensitivity, 50.0% specificity, 57.14% PPV, 60% NPV, and 58.33% accuracy. It means that PCT level was less sensitive and specific to differentiate severely septic patients with normal cardiac function from those with abnormal cardiac function.

Correlation between Pro-brain natriuretic peptide level and serum creatinine

In the present study when we correlated serum creatinine with ProBNP level, we found high levels in both, but with no significant difference between severely septic patients with normal Echo findings and those with abnormal Echo findings; however, there was significant difference in total patients because of the large sample size.

Similar findings were gained by Varpula et al. [33], who correlated plasma creatinine clearance with ProBNP level at admission in patients with severe sepsis and septic shock. They found increasing creatinine clearance with increased level of ProBNP with significant difference, which agreed with the hypothesis of increasing ProBNP level in patients with severe sepsis because of decreased clearance.

Limitations of the study

The study was limited by its small size; the results should be validated in larger trials for better definition of the role of natriuretic peptides in critically ill patients with severe sepsis and septic shock.

The delay in culture sampling after starting antibiotics affected our culture results.


  Conclusion Top


In the light of our results, ProBNP could be used in diagnosing severe septic and septic shock patients. ProBNP level was a good marker for septic shock, systolic dysfunction, and LVH. ProBNP had good correlation with CRP and PCT, but increased significantly with high APACHE II score and serum creatinine. Sex distribution and type of organisms had no impact on ProBNP level. PCT had a good correlation with ProBNP, but ProBNP and PCT levels could not differentiate between severely septic patients with cardiac dysfunction and those without. Further studies with large sample sizes are needed, using different modalities of Echo such as tissue Doppler to better define different stages of cardiac abnormalities in septic patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13], [Table 14], [Table 15]



 

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