STUDY OF SERUM HDL-CHOLESTEROL

LEVELS IN SEPSIS PATIENTS AND ITS

PROGNOSTIC SIGNIFICANCE

DR.– BHARGAV KIRAN GADDAMREG . NO: 1601091001 | JUNE/2016O | APRIL/2019

MD, GENERAL MEDICINE, MGMCRI

GUIDEDR.M.NARAYANAN

PROFESSOR

DEPARTMENT OF GENERAL MEDICINE, MGMCRI

Co-GUIDEDR. E. DEYAGARASAN

ASSISTANT PROFESSOR

DEPARTMENT OF MGMCRI

MAHATMA GANDHI MEDICAL COLLEGE & RESEARCH

INSTITUTE

CANDIDATE

Candidate Name : DR.BHARGAV KIRAN .G

Course of Study : MD GENERAL MEDICINE

University Identity No : 1601091001

Mobile Phone No : +919866051150

E-mail Address : kiransmiles21@gmail.com

Month/Yr of Admission : JUNE2016

Month/Yr of Examination : APRIL 2019

GUIDES

GUIDE:DR.M.NARAYANAN

Professor

Department of GENERAL MEDICINE

Contact Number:9444024606

Email: narayananm@mgmcri.ac.in

CO GUIDE:

Dr. E.DEYAGARASAN

Department of General Medicine

Contact Number: 9894250451

Email:drdeyagu@gmail.com

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PART II – THE PROTOCOL

1 INTRODUCTION

Sepsis is defined as the presence (probable or documented) of infection

together with systemic manifestations

It is the fourth most common admitting diagnosis to the ICU and is the

second leading cause of mortality in the ICU after multi-organ failure.(16)Despite

advances in aggressive management, a diagnosis of sepsis continues to have a high

mortality rate, which increases with sepsis severity from 20.8% in patients with

sepsis and as high as 48.8% in patients with septic shock.

The incidence of severe sepsis in India was 16.45% of all admissions. Mean

age of the population was 58.17 years (SD 18.66), of which 57.71% were male. The

median APACHE II score was 13 (IQR 13 to 14) with predominant (90.93%)

medical admission. Median duration of stay in the ICU for the severe sepsis cohort

who survived was 13 days (IQR 11 to 17). The lung was the predominant source of

sepsis (57.45 %). [4]

Currently there are few reliable therapeutic strategies for the management of

sepsis including empiric antibiotic therapy, aggressive volume repletion, and tight

insulin control. Given that the reversibility of severe sepsis is poor, the need for an

“early prognostic marker” to identify those at highest risk for mortality in order to

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optimize therapeutic options is critical in order to reduce the ICU mortality

secondary to sepsis.

Recent evidence [7] suggests that serum High density lipoprotein cholesterol

(HDL-C) may be a useful prognostic marker of sepsis given that cholesterol

metabolism has been shown to be markedly influenced by a state of widespread

inflammation secondary to bacteremia. Additional studies (5) have demonstrated that

patients diagnosed with severe sepsis in the ICU have a measured decrease in

circulating level of lipoproteins and an increase in triglycerides independent of

comorbidities. These changes have been noted to occur early (within hours) in the

inflammatory cascade associated with sepsis. A reduction in serum cholesterol was

also negatively correlated to clinical outcome

A low HDL-C cholesterol level on day 1 of severe sepsis is significantly

associated with an increase in mortality and adverse clinical outcomes.(2)

Although the reduction in lipid and lipoprotein levels is well known in

critically ill patients (12) their prognostic implications in patients with sepsis remain

controversial. The aim of this study was to investigate the association between HDL-

C and clinical outcome in patients with sepsis

HDL-C value can be used as a biomarker of septicaemia:

It is easily available

Cheap

Septicaemia biomarker due to the wide range of HDL-C normal value

(40 – 60 mg/dl) compared with other biomarkers, also wide range

4

from normal value to HDL-C value in septicaemia(from 40 mg/dl to

15 mg/dl).

During septicaemia HDL-C level decreases to low levels accompanied with

hypertriglyceridemia.

The levels of both HDL-C and triglyceride will get increased again when

sepsis is cured until reach to the normal value.

5

2 AIMS AND OBJECTIVES

Aim: To evaluate the correlation between septicemia and high density Lipoproteins–

Cholesterol (HDL-C-) level in Sepsis patients. To further correlate with prognostic

outcome of patients with abnormal HDL-C levels.

Objectives:

a. To measure HDL-C values in all patients in sepsis.

b. To assess and compare the prognosis and response to treatment in

correlation with values of HDL-C.

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3 REVIEW OF LITERATURE

The word “sepsis” was derived from the ancient Greek for rotten flesh and

putrefaction. Without using the term, the Greek physician Hippocrates (460 to 370

BC) was probably the first to describe the clinical course of septic shock (“when

continuing fever is present, it is dangerous if the outer parts are cold, but the inner

parts are burning hot”)(17).

In 1914, Hugo Schottmüller provided the first scientific definition of sepsis:

“sepsis is a State caused by microbial invasion from a local infectious source into the

bloodstream which leads to signs of systemic illness in remote organs” (18).

According to this definition, bacteremia was a conditio sine qua non to the

diagnosis of sepsis. This notion did not change significantly over the years

SYSTEMIC INFLAMMATORY RESPONSE SYNDROME (SIRS)

The presence of two or more of the following criteria, one of which must be

abnormal temperature or leukocyte count:

• Corea temperature of >38.5°C or <36°C

• Tachycardia, defined as a mean heart rate >2 SD above normal for age in the

absence of external stimulus, chronic drugs, or painful stimuli; or otherwise

unexplained persistent elevation over a 0.5- to 4-hour time period or for children

<1 year old: Bradycardia, defined as a mean heart rate <10th percentile for age in

the absence of external vagal stimulus, beta-blocker drugs, or congenital heart

disease;

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• Mean respiratory rate >2 SD above normal for age or mechanical ventilation for an

acute process not related to underlying neuromuscular disease or the receipt of

general anesthesia

• Leukocyte count elevated or depressed for age (not secondary to chemotherapy-

induced leukopenia) or >10% immature neutrophils

SEPSIS

SIRS in the presence of or as a result of suspected or proven infection

SEVERE SEPSIS

Sepsis plus the following: cardiovascular organ dysfunction, acute respiratory

distress syndrome (ARDS), or two or more other organ dysfunctions

SEPTIC SHOCK

Sepsis and cardiovascular organ dysfunction

In 1993 Levine DM et al(19) was the first to explain the protective effect of

HDL-C against bacterial endotoxin. They showed, transgenic mice with high HDL-C

had high levels of endotoxin bound to HDL-C, low levels of cytokine response and

improved survival compared with mice having low HDL-C level.

Hudgins et al,(11) in a study evaluating the systemic inflammatory response in both

septicpatients and healthy volunteers injected with a low dose of endotoxin, found

that there is a major disruption in the normal metabolism of lipids, including lower

levels of circulating HDL-C and the loss of one of the most abundant HDL

apolipoproteins, Apo-A1.(14) Changes in plasma lipids have been demonstrated to

8

occur very early in systemic inflammation, with evidence that HDL-C decreases

within hours of systemic cytokine stimulation,8 suggesting that plasma lipids,

specifically HDL-C and Apo-A1 levels, may have significant promise as a sensitive

prognostic markers of mortality in patients admitted to the ICU with sepsis.,

Windleret al13 suggest that the convenience of total cholesterol is its non-

specificity for any particular disease, which make low serum cholesterol a potential

universal marker of mortality for a spectrum of diagnoses in the ICU.

Shor R et al(20) retrospective analysis of 204 patients showed low HDL (≤20

mg/dl) was associated with a 17.5-fold increase in odds for death compared to HDL

≥ 65 mg/dl (OR 17.5 95% CI, 5.2–59.04, P < 0.0001)

Van Leeuwen HJ et al (9) and Dunham CM et al (10) observed finding of

rapidly changing HDL levels in severe sepsis patients,

SH Lee et al (16) concluded from his study that Non-survivors showed

significantly higher SOFA scores than survivors (p = 0.008). Non-survivors had low

levels of cholesterol, TG, HDL, LDL, and apo A-I levels on days 0, 1, 3, and 7.

NareshMonigari*,et al (1) concluded that t here is significant association of

low HDL value on day 1 with mortality. HDL value of 9 mg/dl at admission had

sensitivity of 89% and specificity of 73% predicting the overall mortality in patients

with severe sepsis. Risk of death in patients with day 1 HDL value <10mg/dl is 7.01

times the risk of death in patients with day 1 HDL value ≥10mg/dl . Trend of HDL

correlated with clinical outcome of patients. Raising trend favours improvement in

clinical condition and decreasing trend implied worsening of the clinical condition.

9

Baseline HDL value correlated with APACHE 2 score in predicting mortality in ICU

Patients

Emerging evidence suggests that serum total cholesterol may be a useful and

superior prognostic marker of mortality for patients admitted to the ICU with sepsis

secondary to infection compared to its CRP and PCT counterparts(6). With larger,

more comprehensive studies, it is likely that evidence will indicate that serum

cholesterol levels will provide ICU clinicians a more sensitive screening tool for

identifying those patients at highest risk for morbidity and mortality irrespective to

other underlying comorbidities, whereas CRP may be more useful for monitoring

response to therapy.

Monitoring serum cholesterol levels on hospital admission could provide a

very novel, inexpensive tool that has the potential to start early and aggressive

therapy in patients most at risk for death, thus decreasing the mortality rate

secondary to sepsis.

Understanding the patho-physiology of lipid metabolism in the event of systemic

inflammation also opens the door to additional experimental therapy including the

use of statin medications in septic patients.(6)

4 RESEARCH QUESTION OR HYPOTHESIS

Whether there is correlation between the levels of HDL-C and the severity

and prognosis of sepsis?

10

5 SUBJECTS AND METHODS

5.1 STUDY SUBJECTS

HUMANS

5.2 TYPE OF STUDY

The Study InvolvesProspective study

5.3 PLACE OF STUDY

MAHATMA GANDHI MEDICAL COLLEGE AND RESEARCH

INSTITUTE AND HOSPITAL

5.4 SELECTION PROCESS

5.4.1 STUDY POPULATION

This study will be conducted in patients who are proven to be in sepsis

according to to International guidelines for management of severe sepsis and septic

shock 2016

5.4.2 VOLUNTEERS RECRUITEMENT PROCESS

NIL

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5.4.3 INCLUSION CRITERIA

Patients with age greater than 18 years and satisfying the criteria for sepsis

according to International guidelines for management of severe sepsis and

septic shock 2016 [ ]

5.4.4 EXCLUSION CRITERIA

1. Patients on treatment with statins

2. Patients with Chronic liver disease, chronic kidney disease, thyroid

dysfunction, diabetes.

3. Patients with known chronic inflammatory conditions like Human

immunodeficiency virus disease, SLE (Systemic lupus erythematous) and RA

(Rheumatoid arthritis)

4. Patients diagnosed to have malabsorbption disorders

5.4.5 SAMPLING PROCEDURE

Patients admitted with sepsis.

5.4.6 STUDY GROUPS

The number of group is one

5.4.7 SAMPLE SIZE

100

5.5 METHODOLOGY / PROCEDURES:

This study is being conducted in MGMC&RI. Those patients diagnosed to be

in Sepsis will be the study participants. Whenever patient is diagnosed to be in

sepsis, those patients will be contacted immediately. Details of the study will be

explained in detail. Permission is sought in the form of written consent and the study

is conducted. After ethical committee approval all the patients diagnosed to have

12

sepsis in High dependency units/wards of Mahatma Gandhi Medical College and

research institute will be recruited for the study. 

Blood samples from each patient will be taken for HDL-C-cholesterol levels,

creatinine, bilirubin levels, and platelet levels at the time of admission and on the day

5 after admission and SOFA scores will be calculated accordingly on day of

admission and day 5

5.5.1 INTERVENTIONS/DRUGS USED

NO

5.5.2 PROCUREMENT OF INVESTIGATIONAL DRUGS, STORAGE,

DISPENSING, ETC.

NIL

5.6 STUDY TERMINATION

After completion period of study [18 months]

6 STUDY VARIABLES

Serial No : Study Variable Statistics

1 Age Quantitative

2 Gender Qualitative

3 Length of ICU stay (days) Quantitative

4 HDL-C levels Quantitative

5 SOFA score Quantitative

6 Liver function tests Quantitative

7 Blood sugar levels Quantitative

13

8 Creatinine levels Quantitative

9 Platelet levels Quantitative

10 PaO2/fi02 (mmhg) Quantitative

11 Glasgow coma scale Quantitative

12 Mean arterial pressure Quantitative

13 CRP Quantitative

6.1 DATA COLLECTION

All data will be entered into a Data Collection Proforma Sheet (Appendix 1)

and entered into Excel (MS Excel 2011). Privacy and Confidentiality to be

maintained.

6.2 STATISTICAL METHODS

Mean , Standard Deviation, Pearson Coefficient test

14

7 REFERENCES

[1] NareshMonigari. Study of Serum HDL Levels in Severe Sepsis Patients in

Medical Intensive Care Unit. International Journal of Scientific and Research

Publications, Volume 5, Issue 7, July 2015

(2) Thomas, Whitney, "Serum cholesterol: A Superior Prognostic Marker of Sepsis

Mortality in the ICU Compared to Procalcitonin or Creactive Protein" (2015). School

of Physician Assistant Studies. Paper528

(3) Lee et al. Intensive Care Medicine Experimental 2015, 3(Suppl 1):A226

(4) Todi S, Chatterjee S, Sahu S, Bhattacharyya M. Epidemiology of severe sepsis in

India: an update. Critical Care. 2010;14 (Suppl 1):P382

[5] Herzum I, Renz H. Inflammatory markers in SIRS, sepsis and septic shock. Curr

Med Chem. 2008;15:581-587.

(6) Jung-YienChien, MD; Jih-ShuinJerng, Low serum level of high-density

lipoprotein cholesterol is a poor prognostic factor for severe sepsis .Crit Care Med

2005 Vol. 33, No. 8 :1688-1693

[7] Murch O, Collin M, Hinds CJ, Thiemermann C. Lipoproteins in inflammation

and sepsis. I. Basic science. Intensive Care Med. 2007;33:13-24.

15

[8] Wendel M, Paul R, Heller AR. Lipoproteins in inflammation and sepsis. II.

Clinical aspects. Intensive Care Med. 2007;33:25-35.

(9) van Leeuwen HJ, Heezius EC, Dallinga GM, van Strijp JA, Verhoef J, van

Kessel KP. Lipoprotein metabolism in patients with severe sepsis. Critical care

medicine. 2003;31(5):1359-66.

(10) Dunham CM, Fealk MH, Sever WE, 3rd. Following severe injury,

hypocholesterolemia improves with convalescence but persists with organ failure or

onset of infection. Critical care (London, England). 2003; 7(6):R145-53.

11. Hudgins LC, Parker TS, Levine DM, et al. A single intravenous dose of

endotoxin rapidly alters serum lipoproteins and lipid transfer proteins in normal

volunteers. J Lipid Res. 2003;44:1489-1498.

(12)Gordon BR, Parker TS, Levine DM, et al: Low lipid concentrations in critical

illness: Implications for preventing and treating endotoxemia. Crit Care Med 1996;

24:584–589

13. Windler E, Ewers-Grabow U, Thiery J, Walli A, Seidel D,Greten H. The

prognostic value of hypocholesterolemia in hospitalized patients.

ClinInvestig1994;72:939-943

14. Chien JY, Jerng JS, Yu CJ, Yang PC. Low serum level of high-density

lipoprotein cholesterol is a poor prognostic factor for severe sepsis. Crit Care Med.

2005;33:1688-1693.

.

16

(15) Judith A. Guzman-Cottrill .The Systemic Inflammatory Response Syndrome

(SIRS), Sepsis, and Septic Shock

(16) US Department of Health and Human Services, Health Resources and Services

Administration Report to Congress. The Critical Care Workforce: A Study of the

Supply and Demand for Critical Care Physicians. May 2006. Available at

http://bhpr.hrsa.gov/healthworkforce/reports/studycriticalcarephys.pdf

(17) Gruithuisen VPF (ed).1814. Hippocrates des

ZweytenächtemedizinischeSchriften, ins Deutsche übersetzt. Ignaz Josef Lentner,

Munich, Germany.

(18) Schottmueller H. 1914. Wesen und Behandlung der Sepsis. Inn. Med.31:257–

280.

( 19 ) Levine DM, Parker TS, Donnelly TM, Walsh A, Rubin AL. In vivo protection

against endotoxin by plasma high density lipoprotein. Proceedings of the National

Academy of Sciences of the United States of America. 1993;90(24):12040-4.

(20) Shor R, Wainstein J, Oz D, Boaz M, Matas Z, Fux A, et al. Low HDL levels

and the risk of death, sepsis and malignancy. Clinical research in cardiology : official

journal of the German Cardiac Society. 2008;97(4):227-33

8 PRELIMINARY WORK DONE ALREADY

Proforma has been made

9 ETHICAL ISSUES

NIL

17

18

10 INFORMED CONSENT PROCEDURE

The study involves patient admitted in ward of MGMCRI with diagnosed

septicaemia and no radiation is used during the study

Patient will be explained in detail about the study in their own language and

an informed consent will be obtained.

11 QUALITY CONTROL

Name : DR.JAYASINGH

Designation: PROFESSOR ,HOD

DEPARTMENT OF GENERAL MEDICINE , MGMCRI

Telephone No: 919360231933

E-mail:jayasinghavmc@gmail.com

11 SPONSORSHIPS

Not applicable

19

12 INVESTIGATORS DECLARATION

This is to certify that the protocol entitled “STUDY OF SERUM HDL-

CHOLESTEROL LEVELS IN SEPSIS PATIENTS AND ITS PROGNOSTIC

SIGNIFICANCE” was reviewed by us for submission to the SBV Institutional

Ethics Committee and certified that this protocol represents an accurate and complete

description of the proposed research. We have read the ICMR guidelines, ICP-GCP

guidelines/CPCSEA guidelines/and other applicable guidelines and undertake to

ensure that the rights and welfare of the study subjects are protected.

The study will be performed as per the approved protocol only. If any

deviation is warranted, the same will be presented to the ethical committee and

permission will be sought. We assure that the study will be terminated immediately

in case of any unforeseen adverse consequences and we will inform the same to the

ethical committee immediately.

20

INFORMATION SHEET FOR THOSE WHO PLAN TO PARTICIPATE IN THE RESEARCH PROJECT

NAME OF THE RESEARCH PROJECT:

STUDY OF SERUM HDL – CHOLESTEROL LEVEL SIN SEPSIS

PATIENTS AND ITS PROGNOSTIC SIGNIFICANCE

We welcome you and thank you for having accepted our request to consider whether

you can participate in our study. This sheet contains the details of the study; the

possible risks, discomfort and benefits for the participants are also given.

You can read and understand by yourself; if you wish, we are ready to read and

explain the same to you.

If you do not understand anything or if you want any more details we are ready to

provide the details.

Information to the participants:

What is the purpose of the study?

To evaluate the correlation between septicaemia and high density

Lipoproteins- Cholesterol (HDL-C-) level in Sepsis patients. To further correlate

with prognostic outcome of patients with abnormal HDL- C Levels.

Who / where this study is being conducted?

This study is being conducted by Dr. Bhargav Kiran Gaddam Post Graduate

Medical Student belonging to General Medicine under the guidance of Dr. M.

Narayanan

21

Why I am being considered as one of the participant?

Since you have been diagnosed to be in sepsis therefore you are included in

the study.

Should I definitely have to take part in this study?

No. If you do not wish to participate you will not be included in this study.

Also you will continue to get the medical treatment without any prejudice.

If I am participating in this study, what are my responsibilities?

You should provide us with permission to access your case sheet and collect

data from it.

Are there any benefits for me / public?

Yes. If the results of the study are found to be favourable, then this method

can be used as prognostic marker of sepsis.

Will there be any discomfort / risks to me?

No there will not be any risks or discomfort to you.

Will I be paid for the study?

No. You will not be paid.

Will my participating in this study, my personal details will be kept confidentially?

Yes, confidentiality will be maintained.

Will I be informed of this study’s results and findings?

Yes, if you want you can get the details from us.

Can I withdraw from this study at any time during the study period?

22

Yes. You can withdraw at any time during the study period.

23

MAHATMA GANDHI MEDICAL COLLEGE AND RESEARCH

INSTITUTE, PUDUCHERRY

FORM FOR GETTING INFORMED CONSENT FOR THOSE PARTICIPATING IN THE RESEARCH PROJECT

NAME OF THE RESEARCH PROJECT: STUDY OF SERUM HDL –

CHOLESTEROL LEVEL SIN SEPSIS PATIENTS AND ITS

PROGNOSTIC SIGNIFICANCE

I _______________________ have been informed about the details of the study in own language.

I have understood the details about the study.

I know the possible risks and benefits for me, by taking part in the study.

I understand that I can withdraw from the study at any point of time and even then, I will continue to get the medical treatment as usual.

I understand that I will not get any payment for taking part in this study.

I will not object if the results of this study is getting published in any medical journals, provided my personal identity is not reviewed.

I know what I am suppose to do by taking part in this study and I assure that I will give my full co-operation for this study.

Signature/Thumb impression of the participant (Name/Address)__________________________________ ____________________________________________________________________

Signature/Thumb impression of the witness (Name/Address)____________________________________________________________________ __________________________________

Name & Signature of the investigator____________________________________________________________________

24

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