SYNOPSIS FOR PG DISSERTATION FOR MD/MS,

UNDER RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BENGALURU.

1. Name And DR. SWETHA.J Address of the candidate DEPT. OF GENERAL MEDICINE (in block letters) BANGALORE MEDICAL COLLEGE AND

RESEARCH INSTITUTE, BANGALORE

2. Name of the institution BANGALORE MEDICAL COLLEGE AND RESEARCH INSTITUTE, BANGALORE

3. Course of study and subject M D (General Medicine) 4. Date of admission to course 31st May, 2012 5. Title of the Topic: “ Prognostic significance of N-terminal Pro Brain Natriuretic Peptide (NT- ProBNP) in patients with SIRS and Sepsis” Prognostic significance of N- terminal Pro Brain Natriuretic eptide()

6. Brief resume of the intended work:

6.1 : Need for the study:

Sepsis is a major cause of morbidity and mortality in intensive care units (ICU) worldwide. The incidence of sepsis is increasing and it is as high as the incidence of myocardial infarctions. The mortality rate has been reported at 20 to 50 per cent, most of which are attributed to cardiovascular collapse.[2] Mortality is highest in immune- compromised patients and in those patients who have been referred late to ICU after losing advantage of initial 6 to 24 hours. A study of National Hospital Discharge Survey (NHDS) data done in USA identified organ failure in 30.2 per cent in patients with sepsis from 1990 to 2000. Though we do not have exact statistics from India, the incidence and mortality from sepsis could be worse in India.

Studies have been performed to identify biomarkers for use in the early identification of patients at risk of developing severe sepsis and septic shock. Patients with septic shock were shown to have reversible left ventricular systolic dysfunction with an associated elevation in cardiac index. Thus, a readily measurable circulating biomarker would facilitate the assessment and perhaps prevent cardiovascular dysfunction in these patients.[2] Natriuretic peptides are of importance in the diagnosis, and assessment of prognosis, in patients with congestive heart failure. Numerous studies have been undertaken to examine the significance of high levels of plasma BNP and/or NT-Pro BNP levels in the context of severe sepsis or septic shock. Variable findings have been reported. Some investigators reported a strong link between plasma BNP or NT-Pro BNP and prognosis.[4,9] Others did not find such a link.[5] Clinical utility of Brain Natriuretic Peptide(BNP) in sepsis during first 24hrs is not clear. Hence, the purpose of present study is to evaluate the utility of BNP as a prognostic marker in sepsis.

6.2 Review of literature: Prohormone BNP is released in response to hemodynamic stress from ventricular dilatation, hypertrophy, or increased wall tension. It is cleaved by a circulating endoprotease into two polypeptides: the inactive N-terminal proBNP (NT- proBNP), 76 amino acids in length, and the biologically active peptide BNP, 32 amino acids in length. BNP and NT-proBNP levels rise with increasing age and worsening renal function.[1]

YUNXIA CHEN MM, CHUNSHENG LI MD. (2008) conducted a study on Prognostic significance of brain natriuretic peptide obtained in the emergency department in patients with SIRS or sepsis and concluded that the positive rates of BNP in SIRS and septic patients were significantly higher than that of non-SIRS patients, and this is an index for unfavorable prognosis in septic patients.[3]

CHARPENTIER J, LUYT CE, FULLA Y, VINSONNEAU C et al. (2004) conducted study on Brain natriuretic peptide: A marker of myocardial dysfunction and prognosis during severe sepsis and concluded that Systolic myocardial dysfunction is present in 44% of patient with severe sepsis or septic shock. In this setting, brain natriuretic peptide seems useful to detect myocardial dysfunction, and high plasma levels appear to be associated with poor outcome of sepsis, but further studies are needed.[4]

WANG F, WU Y, TANG L, ZHU WCHEN FXU TBO LLI JDENG Xet al. (2012) conducted study on Brain natriuretic peptide for prediction of mortality in patients with sepsis: a systematic review and meta-analysis and concluded that elevated BNP or NT-proBNP level may prove to be a powerful predictor of mortality in septic patients. Future larger and more adequately powered prospective studies are warranted to clarify the assay standardization, the optimal cut-off, and the prognostic value of BNPs in conjunction with other biomarkers.[6] MICHA MAEDER, PETER AMMANN et al. (2005) conducted study on B-type natriuretic peptide in patients with sepsis and preserved left ventricular ejection fraction [7] and concluded that BNP is associated with sepsis even if LVEF>40%.

MARTINA BRUECKMANN, GUENTER HUHLE et al. (2005) conducted a study on Prognostic value of plasma N-terminal pro-brain natriuretic peptide in patients with severe sepsis and finally concluded that NT-proBNP may serve as useful laboratory marker to predict survival in patients presenting with severe sepsis.[9]

EMAD KANDIL, MD JOSHUA BURACK et al. (2008) conducted a study on B-Type Natriuretic Peptide A Biomarker for the Diagnosis and Risk Stratification of Patients With Septic Shock and concluded that the relationship between BNP level elevation and severity of sepsis independent of congestive heart failure. It also supports the utility of BNP level as a marker for mortality in septic shock. [10]

6.3 Objectives of the study: o To know the significance of N-terminal Pro Brain Natriuretic peptide(NT-proBNP) for prognosis in septic patients. 7. Materials and Methods:

7.1 Source of data: The subjects for the study will be selected from the cases admitted

in intensive care unit Victoria hospital and Bowring & Lady Curzon hospitals during

the period of November 2012 to October 2014.

7.2 Method of collection of data :

A. Study design: 28 day Observational study. 28 follow up will be performed, and the survival or death of the patients within 28days was considered as the end point and will be documented

B. Study period: November 2012 to October 2014.

C. Place of study: Cases admitted in intensive care unit Victoria hospital and Bowring & Lady Curzon hospitals

D. Sample size: 30

E. Inclusion criteria: o Patients admitted in Intensive Care Unit with sepsis or SIRS

o Control group will include patients who did not satisfy the criteria for SIRS, but needed treatment and monitor immediately including patients with coma, shock, toxicosis, acute abdomen, stroke, trauma, and others.

o After taking informed consent F. Exclusion criteria:  Patients with Congestive heart disease

 Patients with myocardial infarction

 Renal and hepatic failure G. Methodology:  Patients will be classified into 3 groups-

1. Systemic inflammatory response (SIRS) group, 2. Non SIRS group, and 3. Sepsis group  BNP level and positive detection rates of BNP will be examined  BNP level of 100pg/ml or more will be considered positive, and then positive detection rates in these groups will be compared  The prognostic values of BNP and APACHE (Acute physiology and chronic health evaluation) II score for the 28-day mortality will be investigated and their cutt off value for death will be determined

7.3 Investigation to be conducted on patients Routine investigations: o Haemoglobin percentage

o Total count

o Differential count

o Random blood sugar

o Blood urea

o Serum creatinine

o Urine routine

o Liver function tests

o SpO2 monitoring

 Specific investigations:

o Plasma NT-ProBNP levels

Any other investigation whenever required:

Culture of blood/ urine / indwelling catheter/ sputum 7.4 Has ethical clearance been obtained from your institution in case of 7.3? Yes. 8. List of references: 1) Greenberg B, Kahn A, Clinical assessment of heart failure, Chapter-26. Libby. P, Braunwald. E, Braunwalds heart disease. Text book of cardiovascular Medicine; 9th Edn. Chapter 26 ;p : 509-510

2) Rivers E et al. Improving Outcomes for Severe Sepsis and Septic Shock: Tools for Early Identification of At-Risk Patients and Treatment Protocol Implementation. Crit Care Clin 23 (2008) S1–S47

3) Yunxia chen MM, Chunsheng Li MD et al. prognostic significance of BNP obtained in the ED in patients with SIRS or sepsis. American J of EM (2009) 27, 701- 706. 4) Charpentier J, Luyt CE, Fulla Y, et al. Brain natriuretic peptide: A marker of myocardial dysfunction and prognosis during severe sepsis. Crit Care Med. 2004;32:660–5.

5) McLean AS, Huang SJ, Hyams S, Poh G, Nalos M, Rahul P, Tang B, Seppelt IM. The prognostic values of B-type natriuretic peptide in severe sepsis and septic shock. Crit Care Med 2007; 35:1019-1026.

6) Wang F, Wu Y, Tang L, Zhu W, Chen F, Xu T, Bo L, Li J, Deng X. Brain natriuretic peptide for prediction of mortality in patients with sepsis: a systematic review and meta-analysis. Crit Care Med. 2012 May 6;16(3):R74.

7) Maeder, Micha; Ammann, Peter; Kiowski, Wolfgang; Rickli, Hans. B-type natriuretic peptide in patients with sepsis and preserved left ventricular ejection fraction. The European J of Heart Failure 7.2005;1164 – 1167

8) Hoffmann U, Brueckmann M, Bertsch T, et al. Increased plasma levels of NTproANP and NT-proBNP as markers of cardiac dysfunction in septic patients. Clin Lab. 2005;51(7-8):373-379.

9) Brueckmann M, Huhle G, Lang S, et al. Prognostic value of plasma N-terminal pro-brain natriuretic peptide in patients with severe sepsis. Circulation. 2005; 112(4):527-534.

10) Kandil E, Burack J, Sawas A, Bibawy H, Schwartzman A, Zenilman ME. B-type naturetic peptide (BNP): a biomarker for the diagnosis and risk stratification of patients with septic shock. Arch Surg, 143(3): 242-6, 2008. 9. Signature of the candidate Dr. Swetha. J

10. Remark of the guide This study is undertaken to know the prognosis in patients with sepsis and SIRS. There are no studies done in India. Hence this study is done to evaluate the utility of BNP as a prognostic marker in sepsis.

11. 11.1 Name and DR. PRABHAKAR.B designation of Guide PROFESSOR AND HEAD OF DEPARTMENT OF GENERAL MEDICINE, BANGALORE MEDICAL COLLEGE AND RESEARCH INSTITUTE, BANGALORE 11.2 Signature

11.3 Head of the DR.PRABHAKAR.B Department PROFESSOR AND HEAD OF DEPARTMENT OF GENERAL MEDICINE, BANGALORE MEDICAL COLLEGE AND RESEARCH INSTITUTE, BANGALORE 11.4 Signature 12 12.1 Remarks of the Principal

12.2 Signature