Sepsis

1. MODERATOR: DR.SHREE KRISHNA SHRESTHA
PRESENTER: DR.OMPRAKASH PATEL
MS GENERAL SURGERY RESIDENT (2ST YR)
2078-04-21
Sepsis in surgical patients and its
biomarkers

2. Sepsis
• Schottmuller,in 1914 defines sepsis as a state which is caused
by microbial invasion from a local infectious source into the
blood stream which leads to sign of systemic illness in remote
organ.
 Major cause of illness and death .
 Early diagnosis and treatment influence the morbidity and
mortality

3. • SIRS was diagnosed clinically by the presence of at least two
features;
-Temp >380C or 360C
-HR > 90bpm
-RR>20 breaths/m or PaCO2 <32 mmHg
-WBC >12000/mm3 or <4000/mm3 or immature(band) forms
>10%
• This defination was neither sensitive nor specific for sepsis.
• These features can be seen in postoperative patient , many non
infectious conditions like burns , pancreatitis , trauma ,
ischemia-reperfusion.

4.  However, presence or absence of infection is difficult to prove
in these patient.
 Many patient with SIRS plus infection has excellent outcome
thus SIRS plus infection did not identify the patient at high risk
of death.
 Sepsis is defined as life threatening organ dysfunction caused
by dysregulated host response to infection.

5.  Now the focus has been shifted from inflammation to organ
dysfunction in presence of infection.
 Organ dysfunction is defined in term of sequential organ
failure assessment (SOFA) score increase in two or more from
baseline in the presence of infections.

6. SOFA Score

7. Pathophysiology

9. qSOFA score
Use three criteria;
 An alteration in mental status
 Systolic BP <100 mm Hg
 RR> 22 breaths/min
Significance
 Presence of at least 2 qSOFA criteria is predictor of both
increased mortality and ICU stays of >3 days for non ICU
patients.

11. Septic Shock:
A subset of sepsis in which underlying circulatory and cellular/
metabolic abnormalities are profound enough to increase
mortality.
Clinical criteria identifying such condition include:
• Persisting hypotension requiring vasopressors to maintain
MAP≥65 mm Hg
• Blood lactate >2 mmol/L despite adequate volume resuscitation

13. SSC 2016 Recommendations

14. Surviving Sepsis Campaign guidelines
 Initial resuscitation:
Begin resuscitation immediately in patients with hypotension or
elevated serum lactate with resuscitation goal of at least 30 mL / kg IV
crystalloid given in the first 3 hours.
Fluid administration should be guided by physiologic response as
measured by clinical variables (e.g., heart rate, blood
pressure, urine output) and/or other invasive or noninvasive
monitoring.
Resuscitation goals include mean arterial pressure >65 mmHg, urine
output >0.5 mL/kg per h, and mixed venous oxygen saturation>65%.
Target resuscitation to normalize lactate in patients with elevated
lactate level .

15.  Diagnosis:
Obtain appropriate cultures prior to antibiotics, but do not
delay antibiotic therapy.
Imaging studies should be performed promptly to confirm a
source of infection.
Antibiotic therapy:
Begin IV antibiotic therapy as early as possible and within the
first hour after recognition of sepsis/septic shock.
Use broad spectrum antibiotic regimen.
Reassess regimen daily with de-escalation as appropriate ,
continue antibiotics for 7 to 10 days for most infections.

16. Source control:
Establish anatomic site of infection as rapidly as possible.
Implement source control measures after initial resuscitation.
Remove intravascular access devices if potentially infected.

17.  Hemodynamic Support and Adjunctive Therapy
Fluid therapy:
Fluid resuscitate using crystalloid, with continued fluid
challenges as long as hemodynamic parameters continue to
improve.
Albumin may be used as an adjunct if large volumes of
crystalloid are required but hydroxyethyl starch and gelatin-
based fluids should not be used.

18.  Vasopressors/Inotropic Therapy:
Maintain MAP of >65 mmHg.
Centrally-administered norepinephrine is the first-line choice.
Add vasopressin if needed to raise MAP or to reduce
norepinephrine requirement.
Epinephrine is an alternative to vasopressin but has greater
risk of reduced splanchnic blood flow.
Dopamine is an appropriate alternative only in select patients
(bradycardia, low risk of arrhythmia).

20.  Steroids:
Consider intravenous hydrocortisone (dose <300 mg/day)
for adult septic shock when hypotension responds poorly to
fluids and vasopressors.

21.  Other Supportive Therapy
Blood product administration:
Transfuse red blood cells when hemoglobin decreases to <7.0
g/dL.
It is not necessary to use fresh frozen plasma to correct INR
abnormalities in the absence of bleeding.
Consider prophylactic transfusion of platelets :
-when count <10,000/ml in the absence of bleeding.
-<20,000/mL if there is a risk of bleeding.
-<50,000 in the setting of active bleeding or need for
procedure.

22.  Mechanical ventilation:
Target an initial tidal volume of 6 mL/kg body weight and
plateau pressure of <30 cm H2O in patients with acute lung
injury.
Use PEEP to avoid lung collapse.
Adopt a conservative fluid strategy.

23. In sepsis-induced ARDS with PaO2/FiO2 ratio <150.
Use prone ventilation over continued supine position or high
frequency oscillatory ventilation.
Use a weaning protocol to evaluate the potential for
discontinuing mechanical ventilation.
Pulmonary artery catheter placement is not indicated for
routine monitoring

24. Sedation:
Minimize sedation .
Glucose control:
Use protocolized approach to blood glucose management
targeting upper blood glucose target of 180 mg/dL.
Prophylaxis:
Use stress ulcer (proton pump inhibitor or H2 blocker) and
deep venous thrombosis (low-dose unfractionated or
fractionated heparin) prophylaxis.
Limitation of support: Discuss advance care planning with
patients and families and set realistic expectations .

27.  For identifications of pathogen such as blood culture my take
time ,while early and rapid recognition may lead to early
institution of therapy , reduce mortality and morbidity and
improve outcome.
 Hence ,there is role of biomarker in recognization of sepsis.

28. Biomarkers
 Biomarkers are naturally occurring molecules , genes or other
characteristics by which physiological and pathological
processes can be identified.
 Characteristics of ideal biomarker are;
-it should be an objective parameter
-easy to measure
-reproducible
-inexpensive

29. -have fast kinetics
-high sensitivity and specificity
-have a short turn around time
-show appropriate response to therapy
 Clinical biomarker can be divided into two groups.
- Diagnostic and prognostic biomarkers.

30.  Diagnostic biomarkers help to differentiate infectious cause
from noninfectious cause as well as possible causative
organisms.
 Hence , it can be used in prevention of unnecessary use of
antibiotics.
 Prognostic biomarkers help in stratifying patients into risk
groups and predict the outcome.

31.  Differentiate local infection, disseminated infection and sepsis.
 Differentiate viral and fungal infection from bacterial infection.
 Determine the response of antibiotics , response to therapy ,
prediction of organ dysfunction and complications.

32.  Initial biomarkers investigated in sepsis were WBC count ,
lactate , ESR,C-reactive protein ,pro calcitonin .
 WBC : leucocytosis can be seen in both noninfectious and
infectious cause hence it is not specific.
 Lactate: a byproduct of glycolysis is a marker of sepsis,
hypoperfusion leading to anaerobic glycolysis causes
hyperlactatemia .

33.  Lactate level is high in hypovolemia and haemorrhage during
trauma and surgery.
 Thus lactates are not a good marker of sepsis but a important
indicators of the severity of shock , hypoperfusion and
adequacy of resuscitation.
 ESR is an indicator of inflammation and its utility in sepsis is
limited as it can be influenced in presence of anemia ,
immunoglobulins , change in erythrocyte size , shape and
number ,malignancy , tissue injury.

34.  C-reactive protein is an acute phage reactant which is
synthesized in liver(hepatocytes) in response to inflammation
or tissue injury and upregulated by interleukin 6.
 Normal level:less then 0.3 to 0.5 mg/dl.
 Level can rise upto 1000times in response to acute phase
stimulus.
 It starts to rise after 6 hours and peak at about 48 hours with
half life of 20 hours.

35.  Elevated in both infectious and noninfectious conditions ,
modest elevation can be seen in low grade inflammatory
conditions such as atherosclerosis, obesity , hypertension,
diabetes and obstructive sleep apnea.
 Marked elevation is associated with bacterial infections.
 It has good sensitivity but poor specificity.
 It is a good marker of inflammation rather then infection.

36.  Procalcitonin a precursor of calcitonin , produced by C –cells of
thyroid under the control of calcitonin gene related peptides
(CALC-1) gene.
 During infection there is increase of CALC-1 gene expression in
various extrathyroid tissue like parenchymal tissue such as
lungs , liver , kidney which is mediated by proinflammatory
cytokines such as TNF-a and IL-6.

37.  Both microbial toxins and host response by humoral or cell
mediated can lead to release of PCT.
 PCT starts rising by 2 hours after stimulus , peaks at 6 hours ,
plateau at 8-24 hours and decrease to base line by 2 days.
 Half life is around 20 hours.
 Low or negligible amount is seen in healthy individuals
however it can be increased to 1000 folds during active
infection and sepsis.

38.  Interferon gamma released during the viral infections
suppress PCT.
 High level of Pct is seen in systemic infections therefore local
bacterial colonization , encapsulated abscess , localised and
limited infections may shows normal level of PCT.

39.  Some condition where PCT can be elevated are :neonate less
then 48 hours of age , first day after major surgery , trauma,
burns , pancreatitis, treatment with OKT3,interleukins,TNF-a ,
invasive fungal infections , malaria , severe cardiogenic shock ,
malignancies eg . Medullary carcinoma of thyroid ,small cell
carcinoma of lungs.

40. Interpretation of procalcitonin level
Procalcitonin values(ng/ml) interpretation
Less then 0.05 normal
0.05-0.5 Localized infection possible.
Retest after 6-24 hours.
0.5 -2.0 Systemic bacterial infection possible.
Retest after 6-24 hours.
2.0-10 Systemic bacterial infection highly likely.
High risk of severe sepsis
Greater then 10 Severe sepsis

41. Diagnosis of bacterial infection and sepsis
 Biomarker of infection and sepsis.
 Many studies shows PCT as a reliable diagnostic and
prognostic marker in patient with septic shock.
 A systemic review and meta analysis on PCT as a diagnostic
marker of sepsis found the sensitivity of 89% and specificity
of 95% .
 However , they warned that the results of the test must be
interpreted carefully in context of medical history , physical
examination and microbiological assessment.

42.  PCT is produced in response to endotoxin or few inflammatory
mediators released by human body through humoral and cell
mediated response such as ILs and TNF.This sorts of a response
is seen in bacterial infections.
 In viral infection there is a release of interferon and cytokine
which attenuates PCT production.Hence PCT level rarely
increase in viral infections.

43. De-escalation of antibiotics
 Due to rampant use of antibiotics in past few decades , there is
emergence of antibiotics resistance.
 The concept of optimal use of antibiotics and de-escalation of
antibiotics is accepted and encouraged.
 This help prevent unnecessary usage of antibiotics and
development of drug resistance.
 PCT starts rising by 2 hours after stmulus ,peaks at 6 hours
,plateau at 8-24 hours and decrease to base line by 2 days.

44. PRORATA Trial
 A RCT-PROcalcitonin to Reduce Antibiotics Treatments in
Acutely ill patients(PRORATA) trial was done in 621 adult
patients with suspected bacterial infectionand ultilised an
algoritham in which an initial PCT was used to assess whether
to start antibiotics.
 Subsequent daily level of PCT was used with cut –off level of
less then 0.5ug/L or decreased from peak value by greater then
80% to stop the antibiotics.

45.  They found that PCT group has significant few days antibiotics
use with noninferior in mortality with the control group with
no significant complications.

46. ProGUARD Trial
 RCT trial done in 11 austrialian icu centre with 400 patients
using algoritham in which antibiotics was stopped if PCT level
were below 0.1ug/L or level decrease by 90% from baseline.
 They found no reduction in antibiotics use in PCT group ,the
negative results was due to too low cut off value .

47. SAPS Trial
 RCT –Stop Antibiotics on Procalcitonin guidance study –was
done in Netherland using similar algoritham like ProRATA
Shows significant reduction in antibiotics requirement with
no increased rates of complications and mortality.
 However there was slight increase in reinfection.
 The study provides strong evidance for use of PCT based
algoritham in sepsis.

49.  Infectious Disease Society of America (IDSA) and Surviving
Sepsis Campaign (SSC) suggest utilization of PCT for
cessation of antibiotics.

50. PCT in postoperative period
 Following surgery there is a cell disruption,hemorrhage, and
ischemia-reperfusion injury which leads to the activation of
innate proinflammatory response and adaptive anti-inflammary
response.
 The proinflammatory response helps in destruction of harmful
molecules where as the anti-inflammatory response promotes
healing by restricting inflammatory process.

51.  Some usual mediators which are increases following tissue
injury like
-oxygen reactive species,
-cytokines , nitric oxide,
-molecules like high mobility group B1,
-mitochondrial DNA,
-glycosaminoglycans,
-heat shock protein,
-adenosine triphosphate , protein s100, and uric acid .
collectively called damage associated molecular
patterns(DAMPs).

52.  The activation of innate immunity leads to release of cytokines
like IL-6,IL-1b,IL-8,TNF etc.
 IL-6 stimulates the production of PCT , rise of PCT upto 9ng/L
in post operative period is considered normal.
 Level greater then 10ng/L in non transplant patient considered
abnormal.

53.  PCT elevation are greatest with abdominal and retroperitoneal
surgery while thoracotomies leads to minor rise in PCT level.
 It has been found more useful in detection of postoperative
complications them CRP,WBC and IL-6.

54.  Trasy et al used Delta PCT in postoperative patient to identify
infection .Delta PCT (PCT level from preceding day minus PCT
level on the day of suspected infection) is significantly high in
infection.
 Tsangaris et al ,concluded that a twofold increase in PCT within
24 hours period together with fever was useful to detect
infection.

55. Newer Biomarker
 Several newer biomarker has been investigated for sepsis like
TREM-1(Triggering Receptor Expressed in Myeloid cells-
1),interleukin-27,presepsin,cell free DNA , mi RNA.
 Biomarker related to symptoms of sepsis rather then
mechanism of inflammation have been tested such as CT-pro-
AVP (C-terminal segment of pro-arginine vesopressin),which
help in regulation of blood pressure.

56.  TREM-1 , is an immunoglobulin which induces inflammatory
process by production of chemokines ,cytokines and oxygen
species.
 Its level can be detected by enzyme linked immunosorbent
assay (ELISA) showed that elevated TREM-1,is highly
predictive of bacterial infection.
 IL-27 , is a cytokines produced on exposure to microbial
products and inflammatory stimuli .It has good specificity and
positive predictive value in children but similar result in adult
is not produced.

57.  CD64,an immunoglobulin which when activated by
proinflammatory cytokines leads to phagocytosis of bacteria.
 Study have shown the sensitivity and specificity of 79% and
91% respectively.
 Presepsin is a soluble form of CD14 which is expressed in
monocytes and macrophage leading to activation of toll like
receptors and TNF alpha.
 Study shows that presepsin level is high in severe sepsis which
conclude to be a good diagnostic biomarker.

58.  Cell free plasma DNA are fragments of DNA that are
released because of cell necrosis or apoptosis.
 This is being explored as prognostic biomarker of sepsis
and usually associted with cell death.
 mi RNA are short segment of endogenous RNAs that are
involve in translational gene regulation.
 This biomarker may serve in various diagnostic and
prognostic role in human pathologic conditions including
sepsis.

59.  Sepsis is often thought as an exaggerated proinflammatory
state but there may be significant antiinflammatory and
immunosuprressive components especially in late sepsis or
sepsis occuring in elderly patients.
 New biomarkers to estimate the degree of immunosupression
include circulating blood monocytes expression of HLA-DR ,
monocytes expression and low absolute lymphocytes counts.

60.  This helps in identify the patient who require
immunostimulating or immunomodulating therapy rather than
anti-inflammatory therapies in immunosuppressed stages.
 However, this is still experimental.

61. Conclusion
 Sepsis is defined as life threatening organ dysfunction caused
by dysregulated host response to infection.
 Septic shock is identified as persisting hypotension requiring
vasopressors to maintain MAP≥65 mm Hg and blood lactate
>2 mmol/L despite adequate volume resuscitation in presence
of infection.

62.  Biomarkers are naturally occuring molecules,genes,or
other characterisctics by particular pathological and
physiological process.
 Several biomarkers such as WBC , ESR ,CRP ,lactate and
procalcitonin has been investigated.
 CRP has been found to have high sensitivity but poor
specificity for infection.It is a better indicator of
inflammation then infection.

63.  PCT has been found increase in several fold in sepsis and
is used in diagnosis of sepsis, de-escalation of antibiotics
and differentiation of bacterial and viral infections.
 Several newer biomarker of has been investigated for sepsis
like TREM-1(Triggering Receptor Expressed in Myeloid
cells-1,interleukin-27,presepsin,cell free DNA , miRNA ,

64. Referrences
 Sabiston textbook of surgery -20th edition
 Bailey & Love’s short practice of surgery- 27th edition
 Schwartz’s Princles of Surgery,11thEdition
 Roshan Lall Gupta’s Recent Advances in SURGERY,
Volume 17.
 The Third International Consensus Definitions for
Sepsis and Septic Shock (Sepsis-3)
 Surviving Sepsis Campaign: International Guidelines
for Management of Sepsis and Septic Shock: 2016
 The Surviving Sepsis Campaign Bundle: 2018 update

65.  THANK YOU