Systemic inflammatory response syndrome (SIRS) is a clinical syndrome characterized by a dysregulated inflammatory response that can be caused by infectious or noninfectious processes. Sepsis is defined as SIRS caused by a confirmed or suspected infection. As sepsis progresses it can lead to severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS). Key aspects of managing sepsis include early identification of infection, administering antibiotics, and supporting vital organ function by correcting hypoxemia, hypotension, and hypoperfusion. Investigations should identify the source of infection and assess organ dysfunction, while priorities of treatment are stabilizing respiration and circulation followed by identifying and treating the underlying infection.

1. by : Heba Abusaleem
Abeer Alshare’

2. Systemic inflammatory response syndrome
(SIRS)
A clinical syndrome that is a form of dysregulated
inflammation.
Noninfectious
processes
Infectious
processes
SEPSIS
1.Autoimmune
disorder
2. Pancreatitis
3.Surgery
4.Vasculitis
5.Thromboembolism
6.burns

3. • > 90
beats /
minute
• >38°C or
<36°C.
Temperat
ure
>20breaths
/minute or
PaCO2<32mm
Hg
Heart rate
Respirator
y rate
leucocytes
<4x109/L
(<4000/mm³),
>12x109/L
(>12,000/mm³),
or 10% band

4. Infection : is the invasion of normally sterile
tissue by organisms.
Bacteremia : is the presence of viable bacteria
in the blood.
Sepsis: the clinical syndrome that results from a
dysregulated inflammatory response to an infection.
{the presence of infection together with systemic
manifestations of infection}

5. General variables :
 Temperature >38.3 or <36ºC
 Heart rate >90 beats/min.
 Tachypnea, respiratory rate >20 breaths/min
 Altered mental status
 Significant edema or positive fluid balance
(>20 mL/kg over 24 hours)
 Hyperglycemia (plasma glucose >140 mg/dL
or 7.7 mmol/L) in the absence of diabetes

6. Inflammatory variables
 Leukocytosis (WBC count >12,000 microL–1) or
leukopenia (WBC count <4000 microL–1)
 Normal WBC count with greater than 10
percent immature forms
 Plasma C-reactive protein more than two
standard deviations above the normal value
 Plasma procalcitonin more than two standard
deviations above the normal value

7. Hemodynamic variables

Arterial hypotension (systolic blood pressure SBP
<90 mmHg, MAP <70 mmHg, or an SBP decrease
>40 mmHg in adults)
Tissue perfusion variables
Hyperlactatemia (>1 mmol/L)
 Decreased capillary refill or mottling


8. Organ dysfunction variables







Arterial hypoxemia (arterial oxygen tension [PaO2]/fraction
of inspired oxygen [FiO2] <300)
Acute oliguria (urine output <0.5 mL/kg/hr for at least two
hours despite adequate fluid resuscitation)
Creatinine increase >0.5 mg/dL .
Coagulation abnormalities (international normalized ratio
[INR] >1.5 or activated partial thromboplastin time [aPTT]
>60 seconds)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count <100,000 microL–1)
Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or 70
micromol/L)

10. Severe sepsis : refers to sepsis-induced tissue hypoperfusion or
organ dysfunction with any of the following thought to be due to
the infection:

Sepsis-induced hypotension

Lactate above upper limits of laboratory normal

Urine output <0.5 mL/kg/hr for more than two
hours despite adequate fluid resuscitation

Acute lung injury with PaO2/FIO2 <250 in the
absence of pneumonia as infection source

Acute lung injury with PaO2/FIO2 <200 in the
presence of pneumonia as infection source

Creatinine >2 mg/dL (176.8 micromol/L)

Bilirubin >2 mg/dL (34.2 micromol/L)

Platelet count <100,000 microL–1

Coagulopathy (INR >1.5)
Sepsis-induced hypotension:
(SBP) <90 mmHg or
(MAP) <70 mmHg or
a SBP decrease >40 mmHg in
the absence of other causes
of hypotension.
Sepsis-induced tissue
hypoperfusion :
infection-induced
hypotension, elevated
lactate, or oliguria.

11. 
Septic shock : is defined as sepsis-induced hypotension
persisting despite adequate fluid resuscitation.
Adequate fluid resuscitation may be
defined as infusion of 30 mL/kg of
crystalloids .

Septic shock is a type of vasodilatory or distributive shock ,
it results from a marked reduction in systemic vascular
resistance, often associated with an increase in cardiac
output

13. Multiple organ dysfunction syndrome (MODS)


refers to progressive organ dysfunction in an acutely ill patient,
such that homeostasis cannot be maintained without
intervention. It is at the severe end of the severity of illness
spectrum of both SIRS and sepsis.
MODS can be classified as primary or secondary:
Primary
MODS
• is the result of a well-defined insult
in which organ dysfunction occurs
early and can be directly
attributable to the insult itself (eg,
renal failure due to rhabdomyolysis
Secondary
MODS
• is organ failure that is not in direct
response to the insult itself, but is a
consequence of the host’s response
(eg, acute respiratory distress
syndrome in patients with
pancreatitis)

14. Incidence
• racial and ethnic groups : highest among AfricanAmerican males .
• Season : winter.
• Age : patients ≥65 years of age account for nearly
60 percent of all episodes of severe sepsis .
Gram positive bacteria are most frequently identified
in patients with sepsis in the United States
•The number of cases of Gram negative sepsis remains
substantial.
•Fungal sepsis has increased over the past decade, but
remains lower than bacterial sepsis.
•
Pathogens
Disease
severity
Mortality
• The most common manifestations of
severe organ dysfunction were acute
respiratory distress syndrome, acute renal
failure, and DIC.
• Sepsis has a high mortality rate, with
estimates ranging from 12 to 50 percent.

15. Pathophysiology of sepsis
Sepsis is the result of the interaction between the
microorganism and their products and the host factors
released on response (cytokines and other mediators).
 This host response is an innate mechanism developed to
protect the organism from harm but in sepsis the response
is in excess, with negative effects, leading to organ
dysfunction and frequently to death.
 The amplitude of the host defense depends on:
1.the amount and virulence of the invading microorganism.
2.the genetic interindividual variability that governs the
extent of the inflammatory response.


16. Initiation of the systemic response
the microbial products are recognized by
soluble or cell-bound recognition molecules
or receptors, such as CD14 or the Toll-like
receptors (TLRs).
 This binding activates the nuclear factor K-B
(NF-KB) with secondary macrophage
activation and cytokine release.


17. The Inflammatory cascade

18. The inflammatory cascade

If an imbalance develops between SIRS and
CARS, homeostasis is violated. If SIRS
predominates the result may be sepsis/
severe sepsis/ septic shock. If CARS
predominates, the immune system may be
suppressed, leaving the patient susceptible
to life – threatening infections.

19. Coagulation cascade

Tissue factor (TF) exposed on the surface of endothelial cells
after stimulation by endotoxin or certain proinflammatory
mediators (including TNF, IL-1, IL-6, PAF) activates the extrinsic
coagulation pathway, resulting in the release of thrombin and the
conversion of fibrinogen to fibrin.
Here are a number of anticoagulant mechanisms that ensure the
limitation of coagulation. These mechanisms include:
a. Anticoagulation mechanisms:
• Tissue factor pathway inhibitor (TFPI);
• Antithrombin: blocks the activation of the thrombin and factor X;
• Activated Protein C blocks thrombin generation;
b. Fibrinolytic mechanism:
• Tissue plasminogen activator (t-PA): activates plaminogen to plasmin,
which realize the lysis of stable clots into soluble fibrin fragments;
• Activated Protein C: inhibits Plasminogen activator inhibitor (PAI-1) and
another inhibitor of fibrinolysis, Thrombin activatable fibrinolysis
inhibitor (TAFI).
In sepsis, these anticoagulant and profibrinolytic mechanisms are down
regulated with a resultant procoagulant state.

21.  There
is usually an abscess or nidus of infection,
which may be occult. Risk factors for developing
sepsis include the following:
1. Age - elderly and very young at risk.
2. Instrumentation or surgery (including illegal
abortion occurring in unhygienic circumstances).
3. Ethanol abuse.
4. Diabetes mellitus.
5. Burns.
6. Immunocompromise.
7. Medications, eg high dose corticosteroids,
chemotherapy

23. 
1.
2.
3.
4.

•
•
•
CLINICAL PRESENTATION / EVALUATION
Patients may present a few days earlier with a focus of infection.
Patients may then deteriorate rapidly despite having the
appropriate oral antibiotics.
Nonspecific symptoms are common, eg lethargy, nausea and
vomiting, abdominal pain and diarrhoea.
Also inquire about symptoms relating to a possible focus of
infection, eg cough, recent travel.
Cardiovascular changes are most significant physical findings in
patients with septic shock;
changes of heart rate – tachycardia / bradycardia,
changes in perfusion are seen.
Hypotension, when noted is a late finding and suggests
decompensated shock.

24. 


1.
2.
3.


• Warm / Early shock: presentation is a febrile, warm, pink, wellperfused with tachycardia and tachypnea. The initial release of
inflammatory cytokines causes a drop in systemic vascular resistance (SVR)
which leads to low diastolic blood pressures. On physical exam, this causes
a widened pulse pressure and
bounding pulses.
• Cold shock: describes a condition that resembles cardiogenic or severe
hypovolemic shock.
Pulses are poor,
extremities are cool,
and perfusion is severely diminished.
The septic patient progresses to this state once the compensatory
mechanisms are exhausted. Myocardial function is depressed and
catecholamine response may be diminished due to relative cortisol and
vasopressin deficiency.

25.  Respiratory:
Tachypnea is primarily due either to an
inciting respiratory or metabolic acidosis. Patients often
have a primary respiratory alkalosis on presentation and
develop hypoxemia and respiratory acidosis as the sepsis
progresses

 Neurologic:
Patients may present with agitation, which
often progresses, to decreased mentation due to poor end
organ perfusion.

 Renal:
Decreased urine output is noted for inpatients
and elicited on history for outpatients.


26.  Skin:
Palpable petechiae and purpura may be present if
the patient presents in DIC.
 Poor skin turgor and perfusion can also be noted.

27. Clinical features
1. Looks unwell.
2. Fever (maybe spiking) and/or rigors.
3. Tachycardia, tachypnoea and cyanosis.
4. Hyperdynamic circulation with a bounding pulse (early on).
5. Poor capillary refill and cold peripheries occur later.
6. Hypotension with a postural drop (indicates septic shock).
7. Sweating.
8. Lymphadenopathy.
9. Hepatosplenomegaly.
10. Drowsiness or impaired consciousness (common in the elderly but a
late sign in young children and young adults).
11. Features relating to actual infection, eg rash in meningococcal
sepsis, dullness to percussion in pneumonia.
These features may not be present in the very young, elderly and
immunocompromised.

28. 
1.
2.
3.
4.
5.
6.
Investigations should include:
FBC - anaemia, neutrophilia or neutropenia,thrombocytopenia may
be present (pancytopenia may indicate bone marrow involvement).
In viral infections lymphocytosis predominates.
Urine dipstick and sample for microscopy, culture and sensitivity.
Renal function - looking at extent of dehydration or organ failure.
Liver function tests - hypoalbuminaemia likely to be present.
Glucose - hyperglycaemia can be present.
Clotting screen, including D-dimer and fibrinogen testing, looking
for disseminated intravascular coagulation (DIC).

29. 7. Blood cultures - several sets from several sites are required.
Cultures for mycobacteria should also be sent. Ideally these should be
sent before antibiotics are given - but do not delay, especially if the
patient is very ill.
8. Radiology - including CXR, abdominal ultrasound looking for a
collection, and CT scan looking for source.
9. Measures of lactate and oxygen saturation of venous blood
10. Arterial blood gases - metabolic acidosis is common.
11. More invasive investigations looking for a source of infection for example, lumbar puncture, bronchoscopy, laparoscopy, lymph node
biopsy, etc.

30. 1.
2.
3.
Disseminated intravascular coagulation
(DIC).
Adrenal failure, eg adrenal
haemorrhage secondary to
meningococcus (WaterhouseFriderichsen syndrome)***
Multiorgan failure, eg renal failure or
cardiorespiratory failure.

31. 
Therapeutic priorities for patients with severe
sepsis or septic shock include:
1- Early initiation of supportive care to correct
physiologic abnormalities, such as hypoxemia
and hypotension .
2- Distinguishing sepsis from systemic
inflammatory response syndrome (SIRS)
because, if an infection exists, it must be
identified and treated as soon as possible .This
may require a surgical procedure (eg, drainage),
as well as appropriate antibiotics.

32.  The
first priority in any patient with severe sepsis
or septic shock is stabilization of their airway and
breathing. Next, perfusion to the peripheral tissues
should be restored.
 1-Stabilize respiration — Supplemental oxygen
should be supplied to all pa tients with sepsis and
oxygenation should be monitored continuously with
pulse oximetry. Intubation and mechanical
ventilation may be required to support the
increased work of breathing that typically
accompanies sepsis, or for airway protection since
encephalopathy and a depressed level of
consciousness frequently complicate sepsis.

33. 
2-Assess perfusion — Once the patient's
respiratory status has been stabilized, the
adequacy of perfusion should be assessed.
Hypotension is the most common indicator that
perfusion is inadequate (eg, systolic blood
pressure (SBP) <90 mmHg, mean arterial
pressure <70 mmHg, decrease in SBP >40 mmHg).
Therefore, it is important that the blood
pressure be assessed early and often. An arterial
catheter may be inserted if blood pressure is
labile or restoration of arterial perfusion
pressures is expected to be a protracted process,
because a sphygmomanometer may be unreliable
in hypotensive patients.

34. Critical hypoperfusion can also occur in the
absence of hypotension, especially in:
 1- during early sepsis(Common signs of
hypoperfusion include cool, vasoconstricted skin
due to redirection of blood flow to core
organs, tachycardia >90/min, obtundation or
restlessness, and oliguria or anuria).
 2- elderly patients.
 3-diabetic patients.
 4-patients who take beta-blockers.
 5-Patients with chronic hypertension .
 ****An elevated serum lactate (eg,
>1 mmol/L) can be a manifestation of organ
hypoperfusion in the absence of hypotension and
is an important component of the initial
evaluation.


35.  3-Establish
laboratory studies that help
central
characterize the severity of
venous access:
sepsis include :
1- platelet count.
After initial assessment, a central
2- international normalized ratio.
venous catheter (CVC) should be
3-creatinine, and bilirubin.
4- serum lactate>4mmol/l
inserted in most patients with
severe sepsis or septic shock.
**** uses of CVC:
1- to infuse intravenous fluids, infuse
medications, infuse blood products, and
draw blood.
2- used for hemodynamic monitoring by
measuring the central venous pressure (CVP)
and the central venous oxyhemoglobin
saturation (ScvO2).

36. ***dynamic
hemodynamic
measures are:
1- radial artery
pulse pressure.
2-aortic blood flow
peak velocity.
3-brachial artery
blood flow velocity.
***static
hemodynamic
measures are:
1-CVC.
2- PAC(Pulmonary
artery catheter).
You have to know there are two
types of hemodynamic measures:
1-dynamic hemodynamic
measures.
2-static hemodynamic measures.
that dynamic measures are
predictors of fluid responsiveness.

37. 





Once it has been established that hypoperfusion
exists, early restoration of perfusion is necessary to
prevent or limit multiple organ dysfunction, as well
as reduce mortality.
goals during the first six hours of fluid resuscitation,
as suggested by the Surviving Sepsis Campaign
Guidelines, include the following :
1-●Central venous pressure 8 to 12 mmHg.
2-●Central venous (superior vena cava) or mixed
venous oxygen saturation 70 or 65 percent,
respectively.
3-●Mean arterial pressure ≥65 mmHg (MAP = [(2 x
diastolic) + systolic]/3).
●4-Urine output ≥0.5 mL/kg/hour.

38. The best evidence favors targeting central
venous oxygen saturation (ScVO2) ≥70 percent.
However, following any or all of these goals, as
valuable indicators of tissue perfusion, is
reasonable.
 ***** Lactate clearance — The lactate clearance
is defined by the equation [(initial lactate lactate >2 hourslater)/initial lactate] x 100. The
lactate clearance and interval change in lactate
over the first 12 hours of resuscitation has been
evaluated as a potential marker for effective
resuscitation .
 There is a trial show no difference in hospital
mortality, length of stay, ventilator-free days, or
incidence of multiorgan failure, suggesting that
lactate clearance criteria may be an acceptable
alternative to ScvO2 criteria.


39. Restoration of perfusion is predominantly
focused on administration of intravenous fluids;
additional modalities such as vasopressor
therapy, inotropic therapy, and blood transfusion
are added, depending on the response to fluid
resuscitation, evidence for myocardial
dysfunction, and presence of anemia.
 ****Intravenous fluids :
rapid, large volume infusions of intravenous fluids
are indicated as initial therapy for severe sepsis
or septic shock, unless there is coexisting clinical
or radiographic evidence of heart failure.


40. Fluid therapy should be administered in welldefined (eg, 500 mL), rapidly infused boluses
.Volume status, tissue perfusion, blood pressure,
and the presence or absence of pulmonary
edema must be assessed before and after each
bolus. Intravenous fluid challenges can be
repeated until blood pressure is acceptable,
tissue perfusion is acceptable, pulmonary edema
ensues, or fluid fails to augment perfusion.
**** In our clinical practices, we generally use a
crystalloid solution instead of albumin
solution because of the higher cost of albumin.
We believe that giving a sufficient quantity of
intravenous fluids rapidly and targeting
appropriate goals is more important than the
type of fluid chosen. We do not use hydroxyethyl
starch or pentastarch.


41.  ****
Vasopressors: Vasopressors are second
line agents in the treatment of severe sepsis
and septic shock.
However, intravenous vasopressors are useful
in patients who remain hypotensive despite
adequate fluid resuscitation or who develop
cardiogenic pulmonary edema.
****** In severe septic shock, we prefer to
use norepinephrine in most patients
.However, we findphenylephrine (a pure
alpha-adrenergic agonist) to be useful when
tachycardia or arrhythmias preclude the use
of agents with beta-adrenergic activity

42. Prompt identification and treatment of the
primary site or sites of infection are essential
.This is the primary therapeutic intervention,
with most other interventions being purely
supportive.
 *****Identification of the septic focus by:
Taken gram stain and culture from :
1- urine(should be always taken:.
2-sputum(if there is prouducive cough)
3- intraabdminal collection (post op.)
4-blood(Blood should be taken from two distinct
venipuncture sites and inoculated into standard
blood culture media (aerobic and anaerobic).


43. 
Prompt and effective treatment of the active
infection is essential to the successful treatment
of severe sepsis and septic shock .Source
control should be undertaken since undrained
foci of infection may not respond to antibiotics
alone .As examples, potentially infected foreign
bodies (eg, vascular access devices) should be
removed when possible, and abscesses should
undergo percutaneous or surgical drainage. Some
patients require extensive soft tissue
debridement or amputation; in severe cases,
fulminant Clostridium difficile-associated colitis
may necessitate colectomy.

44. **The choice of antibiotics can be complex and should
consider :
1-the patient's history(eg, recent antibiotics received ).
2-comorbidities.
3-clinical context(eg,community- or hospital-acquired).
4-Gram stain data.
5-local resistance patterns .
****When the potential pathogen or infection source is
not immediately obvious, we favor broad-spectrum
antibiotic coverage directed against both grampositive and gram-negative bacteria.

45. Staphylococcus aureus is associated with
significant morbidity if not treated early in the
course of infection .There is growing recognition
that methicillin-resistant S. aureus (MRSA) is a
cause of sepsis not only in hospitalized patients,
but also in community dwelling individuals
without recent hospitalization . For these
reasons, we recommend that severely ill patients
presenting with sepsis of unclear etiology be
treated with intravenous vancomycin (adjusted
for renal function) until the possibility of MRSA
sepsis has been excluded.
 ***Potential alternative agents to vancomycin
should be considered for patients with:1refractory or virulent MRSA, or 2-a
contraindication to vancomycin.. Are:
 1- daptomycin for non-pulmonary MRSA.
 2- linezolid.
 3- ceftaroline.


46.  In
our practice, if Pseudomonas is an unlikely
pathogen, we favor
combining vancomycin with one of the
following:
 1-●Cephalosporin, 3rd generation
(eg, ceftriaxone or cefotaxime).
 2-●Beta-lactam/beta-lactamase inhibitor
(eg, piperacillin-tazobactam, ticarcillinclavulanate).
 3-●Carbapenem
(eg, imipenem or meropenem).

47. ***Alternatively, if Pseudomonas is a possible
pathogen, we favor combining vancomycin with
two of the following (see "Principles of
In patients who are
antimicrobial therapy of Pseudomonas
neutropenic,
aeruginosa infections"):
antibiotic
treatment should
 1-●Antipseudomonal cephalosporin
continue until the
(eg, ceftazidime, cefepime).
neutropenia has
 2-●Antipseudomonal carbapenem
resolved or the
planned antibiotic
(eg, imipenem, meropenem).
course is complete,
 3-●Antipseudomonal beta-lactam/betawhichever is
lactamase inhibitor (eg, piperacillinlonger.
tazobactam, ticarcillin-clavulanate).
 4-●Fluoroquinolone with good anti-pseudomonal
activity (eg, ciprofloxacin).
 5-●Aminoglycoside (eg, gentamicin, amikacin).
 ●6-Monobactam (eg, aztreonam).


48. CLINICAL
SCENARIO
ANTIMICROBIAL
RATIONALE
Meningitis – GPC
on gram stain
Meningitis – gram
neg diplococci
Neutropenia
Vanco + 3rd gen
cephalosporin
3rd gen cephalosporin
Cover for resistant
S.pneumo
Likely N. meningitides
Vanco + Double-coverage
for GNR
Pts are susceptible to
Pseudomonas and other
SPACE organisms
Toxic shock
Indwelling central
venous catheters
Clinda + Vanco
Vanco + 3rd gen
cephalosporin
Deterioration
despite broadspectrum
antibiotics.
Antifungals; also
consider what possible
resistant organisms
may be involved
Cover for MRSA/Strep
Vanco is needed for Gram +
organisms, most notably
S.epi.
Loss of normal bacterial
flora increases susceptibility
to fungus, particularly in
patients on steroids, with
hyperglycemia, or who are
immunosuppressed

49.  1-Glucocorticoids.
 2-Nutrition.
 3-Intensive
insulin therapy.
 4-External cooling( External cooling consists
of using either an automatic cooling blanket,
or ice-cold bed sheets and ice packs, to
achieve a core body temperature of 36.5 to
37°C for 48 hours. It decreases the time to
fever control without exposing the patient to
potential adverse effects of antipyretic
drug).
 5-protocols.

50.  http://www.uptodate.com/contents/evaluat
ion-and-management-of-severe-sepsis-andseptic-shock-inadults?source=search_result&search=septice
mia&selectedTitle=2~150
 http://www.uptodate.com/contents/sepsisand-the-systemic-inflammatory-responsesyndrome-definitions-epidemiology-andprognosis?source=search_result&search=risk+
factors+of+sepsis&selectedTitle=1~150