1. COMPILED BY MODERATOR
Dr. Bharat Arora Dr. Abhijit Tarat
PG Trainee Associate Professor
Department Of Anesthesiology And Critical Care
Silchar medical college And Hospital, Silchar

2. • The condition characterized by signs of systemic
Inflammation(eg . fever & leucocytosis) is called
Systemic Inflammatory response syndrome (SIRS).
•When SIRS is the result of an infection, the condition is
called Sepsis.
•When sepsis is accompanied by dysfunction of
one or more vital organs, the condition is called
Severe sepsis.
•When sepsis is accompanied by hypotension that is
refractory to volume infusion, the condition is called
Septic shock.

3. Diagnostic Criteria For SIRS
 The diagnosis of SIRS requires at least 2 of the
following:
1)Temperature > 380 C or < 360 C
2)Heart rate > 90 beats/ min
3)Respiratory rate > 20 breaths/ min
or
Arterial PCO2< 32 mm of Hg
4)WBC count > 12,000/mm3 or <4000 mm3
or
>10 % immature (band ) forms

4. 1)Infections in the aged and malnourished
2)Inadequate immune response due to hepatic or renal
failure, diabetes mellitus, malignancy, HIV
infection, lymphoma.
3)Iatrogenic infections
4)Virulent gram negative and gram positive infections
5)Oppurtunistic infections (fungal, viral)following organ
transplants, HIV infections and lymphoma.
6)Fulminant tetanus
7)Disseminated haematogenous tuberculosis
8)Severe Pl. falciparum infections
9)Fulminant B. typhosus, salmonella, amoebic infection
10) Trauma , crush injuries, burns, pancreatitis.

5. Severe SEPSIS :
 Sepsis accompanied by hypo-perfusion or
organ dysfunction.
 Cardiovascular :
 SBP<90mmhg/MAP<70 for at least 1 hr
despite adequate volume resuscitation or
the use of vasopressors to achieve the
same goals.
 Renal :
 Urine output <0.5ml/kg/hr or Acute Renal
Failure.
 Pulmonary :
 PaO2/FiO2 <250if other organ dysfunction
is present or <200 if the lungs is the only
dysfunctional organ.

6.  Gastrointestinal :
 Hepatic dysfunction
(hyperbilirubinemia, Elevated
transaminases
 CNS :
 Alteration in Mental status (delirium)
 Hematologic :
 Platelet count of <80,000/mm3 or
decreased by 50% over 3 days/DIC
 Metabolic :
 PH<7.30 or base deficit >5.0mmol/L
 Plasma lactate >1.5 upper limit of
normal.

9. BASIC
PATHOPHYSIOLOGY

10. Nidus of infection
Blood stream
invasion
Release of
mediators
Peripheral
vascular
effects
Myocardial
depression Cellular Injury
Poor tissue perfusion
and metabolic acidosis
Multiple organ
dysfunction Death

11.  Classically septic shock is due to endotoxins
released by gram negative bacteria though it
can occur with fungal and protozoal infections.
Endotoxin is a lipopolysaccharide component
of the outer membrane of the bacterial cell. It
contains Lipid A which is highly antigenic and
is responsible for features of sepsis syndrome.
 Endotoxin interacts with normal host defense
system and triggers release of numerous
mediators notably cytokines like TNF from
mononuclear cells.

12.  Endotoxins also activates neutrophils with the
release of proteases and oxidants which promote
endothelial cell damage.
 Arachidonic acid in the cell wall undergoes
degradation through phospholipase leading to
formation of prostaglandins, leucotrienes and
thromboxanes.
 Phospholipase A2 release membrane bound
phospholipids which are converted to platelet
activating factor which increases vascular
permeability, produces free radicals and activates
platelets and phagocytes.

13.  Endotoxins also activates the coagulation
factors in the serum stimulating the
coagulation pathway.
 Fibrinolysis normally counters procoagulant
factors but is suppressed in sepsis due to
increased levels of plasminogen activator
inhibitor-1(PAI-1), thrombin activatable
fibrinolysis inhibitor(TAF.1a)and decreased
levels of Protein C.
 This haemostatic mechanism prevailing in
sepsis is believed to lead to micro-vascular
thrombi in various organ system.

14.  In summary, invasion by microorganisms
and their toxins elicit a strong response from
the host defenses, which is characterized by
activation of cellular elements and the
plasma protein system. The cells activated
are mononuclear cells
, macrophages, neutrophils and endothelial
cells. These activated cells produce
numerous cytokines and mediators . The
host defense system also activates the
complement , coagulation cascades and the
kallikrein-kinin system

15. • If the host defense system is disorganized
, un-orchestrated , unbalanced and
unchecked it fails to defend the host and
paradoxically enough inflicts injury on the host
.
• This injury is widespread because of the toxic
effect of numerous mediators , and also
because of endothelial cell damage and the
dominance of procoagulant factors leading to
micro vascular thrombi in various organ
systems.

16. Infection
Endotoxin
(LPS)
Cellular activation
Direct cell
injury
Plasma
protein
system
PMN Macrophage Lymphocyte Monocyte Endothelial cell
Pro inflammatory
mediators
Activation of
complement
coagulation
cascade&
kallikrein kinin
TNF IL-6,
IL-1
Leucotrienes,
Prostaglandin
Superoxide,
H2O2,OH-
G-CSF
Selectins,
ICAMS
NO
Cell injury
Organ failure

17. • The typical result is a high output hyper dynamic
circulatory state with tachycardia and
hypotension.
• Septic shock in addition is characterized by SBP≤
90 mm of Hg not responding to fluid replenishment.
It is associated with evidence of hypo perfusion
and/or organ dysfunction.
• This state may be a compensatory response to
increased tissue metabolism.

18. 1)Arterial and venous tone markedly decreases
-venous and arteriolar dilatation
- fall in peripheral vascular resistance
- fall in SBP.
Vasodialating substances :- TNF,IL-1,NO,EDRF and PAF.
Catecholamine receptor down regulation may also occur and
causes poor response to vasopressors.
2) Generalized increase in vascular permeability
- increase in interstitial fluid and
-tissue edema.
Peripheral pooling , hepatosplanchnic pooling and loss from
GIT leads to low circulatory volume.

19. 3)Combined effect of 1 & 2 leads to
hypovolemia which may mask the hyper
dynamic state.
4)Pattern of blood flow distribution changes .
Some organs receive supernormal O2 supply
and some get ischemic .Especially the
splanchnic circulation is affected .
Hepatovenous desaturation has been reported
in septic patients.

20. Myocardial depression occurs in all patients.
Decreased compliance with decreased left
ventricular diastolic function.
Left ventricular systolic dysfunction also occurs
evidenced by dilated cardiomyopathy with low
ejection fraction.
Cardiac output increases because of marked
tachycardia.
Beta receptor downgrading occurs and causes a
poor response to inotropic drugs.

21. Pulmonary hypertension due to increased
pulmonary vascular resistance can occur when septic
shock produces ARDS.
When pulmonary hypertension is significant , right
ventricular function may be markedly affected due to
an increased after load.

22. 1)Early stage:-Tachycardia , hypotension , low PCWP,
high CI , low SVR
2)With progression and deteriorating cardiac function
hypotension , high PCWP , normal or slightly low
CI , normal to rising SVR
3) Late (pre terminal stage):-hypotension , high PCWP,
low and progressively decreasing CI and increased
SVR
4) Rarely very low CI , high PCWP and high SVR is
seen at the start of fulminant septic shock.

23. • Early and evolving phase of sepsis and septic shock
is characterized by increase in DO2 and VO2.
• In spite of increased O2 consumption , tissue needs
may not be satisfied and tissue hypoxia may occur.
• In late phase of septic shock,O2 consumption may
fall even though DO2 is satisfactory resulting in a low
O2 extraction ratio causing hypoxia and acidosis.
• Critical threshold of oxygen delivery

24. • Reasons are:-
1)Damaged endothelial cells in capillaries ,get
edematous resulting in increased distance necessary
for diffusion of O2 into tissue cells.
2) Damaged tissue cells find it difficult to utilize O2
for their metabolic needs.
3)Tissue oxygenation may not be impaired at all in
sepsis as PO2 is increased in sepsis . Defect may be in
the O2 utilization in the mitochondria which
challenges aerobic metabolism. The culprit may be
endotoxin ,which blocks the enzyme pyruvate
dehydrogenase which moves pyruvate into
mitochondria . Pyruvate accumulates in the
cytoplasm where it is converted into lactate.

25.  4) There is persistent hypotension following
ischemic insult to an organ. This can be explained
due to calcium influx within the vascular smooth
muscles during hypoxia, which leads to persistent
vasoconstriction even after CO and BP are restored
to normal, leading to progressive multi-organ
dysfunction.
 5) Reperfusion Injury
 6)Oxygen debt leading to Hyper carbonic acidosis
in tissues.
 7)Assessment of Stress by Gastric tonometry .

26. General Sign and Symptoms
 Rigor – fever (sometimes hypothermia)
 Tachypnea /respiratory alkalosis
 Positive fluid balance – edema
 General inflammatory reaction
 Altered white blood cell count
 Increased CRP, IL-6, PCT concentrations
 Hemodynamic alterations
 Arterial hypotension
 Tachycardia
 Increased cardiac output/low SVR/high SvO2
 Altered skin perfusion

27.  Decreased urine output
 Hyperlactatemia – increased base deficit
 Signs of organ dysfunction
 Hypoxemia
 Coagulation abnormalities
 Altered mental status
 Hyperglycemia
 Thrombocytopenia, DIC
 Altered liver function (hyperbilirubinemia)
 Intolerance to feeding (altered GI motility)

28. MODS
 Multiple organ dysfunction syndrome (MODS)-
failure of two or more organ systems
 Homeostasis cannot be maintained without
intervention-Results from SIRS
 SIRS and MODS represent ends of a continuum
 Transition from SIRS to MODS DOES NOT
occur in a clear-cut manner
 MODS occurs late and is the most common cause
of death in patients with Sepsis.
 Lactic acidosis led investigators to think that this
is due to tissue ischemia.

29.  Recovery from Sepsis is associated with near complete
recovery of organ function, even in organs whose cells
have poor regenerative capacity.

30. PATHOPHYSIOLOGY OF MODS
 MITOCHONDRIAL DYSFUNCTION
 INCREASED CELLULAR APOPTOSIS
 ENDOTHELIAL AND EPITHILIAL DYSFUNCTION
 LATE ACTING MEDIATORS OF INFLAMMATION
like MIF.

31. MANAGEMENT

32. 1)Leucocytosis or leucopenia.
2)Deranged coagulation profile which includes
elevated PT , thrombocytopenia , decreased
fibrinogen and increased FDP .
3)Hyperglycemia is common . Hypoglycemia
may also occur in pre terminal or terminal stage
signifying hepatic dysfunction.
4)Slight rise in bilirubin , SGOT,SGPT and
alk.phosphatase.

33. 5)Increase in urinary urea or urinary nitrogen
over 24 hrs and a negative nitrogen balance.
6)Low arterial pH due to presence of metabolic
acidosis
7)Recently cytokines (esp. IL-6 and IL-8),
C-reactive proteins and Procalcitonin (PCT)
levels have been noted to rise significantly
following sepsis.PCT is reported to be superior
to other markers in the diagnosis of a bacterial
focus complicated by symptoms of severe sepsis
and septic shock ( more than 2SD above
normal values).

34. Principles of Therapy
1)To find out and eradicate the infection or sepsis
responsible for the state of septic shock.
2)To reverse shock using volume infusion and
inotropic support.
3)Ventilator support to all critically ill patients
4)To use recombinant human activated protein C in
selected patients with severe sepsis.
5)Provide support to other organ systems
6)Provide nutritional support
7)Provide metabolic support
8)Prophylaxis for DVT and stress ulcers.

35. • Both eradication of infection and shock reversal
are set into motion together . In severe shock
, resuscitation takes place of prime , yet
resuscitation would come to a standstill if prompt
use and continuation of antibiotics are delayed , or
if a pocket of pus remains undetected and not
drained.
• Septic shock needs to be urgently treated and
reversed . Though the patient should be urgently
shifted to ICU , treatment should commence
wherever the patient is at the time of diagnosis(in
the ambulance , emergency dep't. or ward)

36. SEPSIS RESUSCITATION BUNDLE
TO BE COMPLETED WITHIN 3 HOURS:
 1) Measure lactate level
 2) Obtain blood cultures prior to administration of
antibiotics
 3) Administer broad spectrum antibiotics
 4) Administer 30 mL/kg crystalloid for hypotension or
lactate 4mmol/L

37.  TO BE COMPLETED WITHIN 6 HOURS:
 5) Apply vasopressors (for hypotension that does
not respond to initial fluid resuscitation)
 to maintain a mean arterial pressure (MAP) 65
mm Hg
 6) In the event of persistent arterial hypotension
despite volume resuscitation (septic shock) or
initial lactate 4 mmol/L (36 mg/dL):
 - Measure central venous pressure (CVP)
 - Measure central venous oxygen saturation
(ScvO2)
 7) Re measure lactate if initial lactate was elevated

38. 1)Management of severe sepsis(EGDT)
A) Initial Resuscitation(first 6 hours)
 Begin resuscitation immediately in pts with
hypotension and elevated lactate(>4 mmol/l).Do not
delay pending ICU admission.
 Resuscitation goals
CVP 8-12 mm of Hg
MAP≥65 mm of Hg
Urine output ≥ 0.5 ml/kg/hr
Central venous(superior vena cava)oxygen saturation ≥
70% or mixed venous saturation ≥ 65%

39. If venous oxygen saturation target is not achieved:-
Consider further fluid
Transfuse packed red blood cells if required to a
haematocrit of ≥ 30%
Start dobutamine infusion , maximum 20 mcg/kg/min
B)Diagnosis
 Obtain appropriate cultures before starting antibiotics
provided it does not significantly delay antibiotic
administration.
 Obtain two or more blood cultures
1) One or more blood cultures may be percutaneous
2) One blood culture from each vascular access device
 in place > 48 hrs.
 Culture other sites as clinically indicated like urine CSF
, wounds, respiratory secretions etc.
 Perform imaging studies if safe to do so

40.  Use of 1,3 beta D glucan assay , mannan and anti-
mannan antibodies for diagnosis of invasive
candidiasis and fungal infections.(If Available)
C)Antibiotic Therapy
 Begin i.v. antibiotic therapy as early as possible and always
within the first hour of recognizing severe sepsis and septic
shock.
 Broad spectrum: one or more agents active against likely
bacterial/fungal pathogens and with good penetration in the
presumed source.
Reassess antimicrobial regimen daily to optimize efficacy
, prevent resistance , avoid toxicity and minimize costs.
• Consider combination therapy in Pseudomonas
infection.

41. • Consider combination empiric therapy in
neutropenic patients
• Combination therapy ≤ 3-5 days and de-escalation
following susceptibilities.
Duration of therapy typically limited to 7-10 days,
longer if response is slow or there are an un-drainable
foci of infection or immunologic deficiencies.

42. D)Source identification and control
A specific anatomic site of infection must be must be
established within first 6 hrs of presentation.
Formally evaluate a patient for a focus of infection
amenable to source control measures(eg. abscess drainage
, tissue debridement)
Implement source control measure soon after
resuscitation.(except infected pancreatic necrosis).
Choose source control measure with maximum efficacy
and minimum physiological upset
Remove i.v. access devices if potentially infected.
Infection prevention by oral decontamination using
chlorhexidine gluconate solution.

43. E)Fluid Therapy
Fluid resuscitation using crystalloid, the fluid of choice.
Target a CVP of 8mm of Hg( ≥12 mm of Hg if
mechanically ventilated)
Give fluid challenges of 1000 ml of crystalloids or
30 ml/ kg. More rapid and larger volumes needed in
sepsis induced tissue hypo perfusion
Rate of fluid administration should be reduced if cardiac
filling pressures increase without concurrent hemodynamic
improvement.
Against the use of heta starch for resuscitation.
Albumin can be used if patient require substantial
amount of crystalloids.

44. F)Vasopressors:
Maintain MAP ≥ 65 mm of Hg
Nor epinephrine and dopamine administered centrally are
the initial vasopressors of choice.
Vasopressin (0.03 units/min) may be subsequently
administered with the anticipation of an effect equivalent to
nor epinephrine alone.
Use epinephrine as the first alternative agent when blood
pressure is poorly responsive to nor epinephrine or
dopamine
Do not use low dose dopamine for renal protection
Insert an arterial line as soon as practical

45. G)Inotropic therapy:
Use dobutamine in patients with myocardial dysfunction
as supported by elevated cardiac filling pressures and low
cardiac output.
Do not increase cardiac index to predetermined
supernormal levels
H)Steroids:
 i.v. hydrocortisone to be considered in hypotension not
responding to fluids and vasopressors.
ACTH stimulation is not recommended for identifying which
patients should receive hydrocortisone.
Hydrocortisone is preferred to dexamethasone
Fludrocortisone (50μg orally OD)may be used if an alternative to
hydrocortisone is used lacking mineralocorticoid activity.
Hydrocortisone dose should be ≤ 300 mg/day
Should not be used in absence of shock unless the endocrine or
corticosteroid history warrants it

46. I)Recombinant human activated protein C
Once Considered the use of rh -APC in adult patients
with sepsis induced organ dysfunction with high risk of
death(APACHE II ≥25 or MODS) if there are no
contraindications.
Adult patients with severe sepsis and low risk of
death(APACHE II ≤ 20 or one organ failure) should not
receive rhAPC
PROWESS SHOCK Trail in 2011 shows no benefit of
rhAPC in patients with septic shock, following which it
was withdrawn from the market.

47. Supportive Therapy Of
Severe Sepsis

48. J)Blood Product Administration:
RBC’s to be administered when Hb<7 gm/dl to target Hb at
7-9gm/dl . A higher level may be required in conditions like
MI , severe hypoxemia , hemorrhage, cyanotic heart diseases
or lactic acidosis.
Do not use erythropoietin
Do not use FFP to correct clotting defects unless there is
bleeding or planned invasive procedures
Do not use antithrombin therapy
Administer platelets when:
• Counts < 10000/mm3
• Counts <20000 and there is significant bleeding risk
• Higher platelet counts(>50000) are required for surgery or
invasive procedures

49. K) Mechanical ventilation of sepsis induced ALI/ARDS
Target a tidal volume of 6ml/kg body weight
Target an initial upper limit plateau pressure ≤ 30 cm
H2O.Chest wall compliance to be considered.
Allow PACO2 to rise above normal , if needed to
minimize plateau pressures and tidal volume.
Set PEEP to avoid excessive lung collapse.
Consider prone position for patients requiring potentially
injurious levels of FIO2
Maintain mechanically ventilated patients in semi-
recumbent position between 30o-45o
Noninvasive ventilation may be considered in minority of
patients with ALI/ARDS.
Recruitment maneuvers, beta agonists only if required.

50. Use a weaning protocol and an SBT to evaluate the
potential for discontinuing mechanical ventilation.
SBT options include a low level of pressure support with
continuous CPAP of 5 cm of H2O or a T-piece.
Before SBT patients should be:-
•Be arousable
•Be haemodynamically stable without vasopressors
•Have no new potentially serious conditions
•Have low ventilatory and end expiratory requirements
•Require FIO2 levels that can be safely delivered through face
mask or nasal cannula.
Use a conservative fluid management strategy for patients
who do not have evidence of tissue hypoperfusion

51. Sedation , analgesia and neuromuscular blockade in sepsis.
Use either intermittent bolus sedation or continuous infusion
sedation to predetermined end points(sedation scales) with daily
interruptions/ lightening to produce awakening . Re-titrate if
necessary.
Avoid neuromuscular blockade whenever possible. Monitor
depth of blockade whenever with TOF when using continuous
infusions.

52. Glucose Control
Use intravenous insulin to control hyperglycemia in
patients with severe sepsis following stabilization in ICU.
Aim to keep blood glucose levels < 180 mg/dl using a
validated protocol for insulin dose adjustment.
Provide a glucose calorie source and monitor blood glucose
values every 1-2 hours(4 hours when stable) in patients
receiving i.v. insulin.

53. Renal replacement
Intermittent hemodialysis and CRRT are considered
equivalent.
CRRT offers easier management in haemodynamically
unstable patients.
Bicarbonate Therapy
Do not use bicarbonate therapy to improve
haemodynamics or reduce vasopressor requirements when
treating hypoperfusion induced lactic acidemia with pH ≥
7.15

54. Deep vein thrombosis prophylaxis
 Use either low dose UFH or LMWH , unless
contraindicated.
Use either a mechanical prophylactic device , such as
compression stockings or an intermittent compression
device , when heparin is contraindicated.
Use a combination of pharmacologic and mechanical
therapy for patients at very high risk for developing DVT.
In patients at very high risk , use LMWH rather than UFH.
Stress ulcer prophylaxis
Provide stress ulcer prophylaxis using H2 blocker or proton
pump inhibitor . Benefits of prevention of upper gastrointestinal
bleeding must be weighed against the potential for development
of ventilator-acquired pneumonia.

55. NUTRITION:
•Administer oral/ enteral feed ,amount as tolerated.
•Avoid mandatory full caloric feeds, suggesting low
caloric feeds, advancing only as tolerated.
•Combine i.v glucose/ enteral nutrition/ par-enteral
nutrition as required during 1st week of diagnosis.
•No immunomodulating supplementation required.
Consideration for limitation of support
Discuss advance care planning with patients and
families . Describe likely outcomes and set realistic
expectations.

56. 1)Central venous pressure monitoring is done through a
central venous line.
2)Arterial pressure to be monitored through a catheter
inserted preferably in the radial artery-so that beat to beat
pressures are displayed.
3)Septic shock is a prime indicator for use of a Swan- Ganz
catheter . The parameters which can be recorded are:-
-PvO2 -CI
-Svo2 -PAP
-CO -PVR
-PCWP

57. •Arrhythmias can occur in septic hypotensive patients
who are on inotropic support and who have indwelling
intracardiac catheters . Electrolyte disturbances
contribute to or often causes dangerous ventricular
arrhythmias . So constant monitoring of the cardiac
rhythm with ECG is mandatory to recognize and correct
these abnormalities.

58.  THOUGH THESE GUIDELINES ARE HELPFUL,
RECOMMENDATIONS FROM THESE
GUIDELINES CANNOT REPLACE THE CLINICIAN
DECISION MAKING CAPACITY , WHEN HE OR
SHE IS PRESENTED WITH PATIENTS UNIQUE SET
OF CLINICAL VARIABLES.

59. Thank
You