Sepsis and septic shock

Dr. Heba Abdella

Prof. of Tropical medicine, Ain Shams university

Extended Modular Program

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Describe pathogenesis, diagnosis and treatment of sepsis and
septic shock

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 • Sepsis is defined as a life-
threatening organ dysfunction
Definition caused by a dysregulated host
response to infection.

An appropriate physiologic
reaction in association with a
confirmed or strongly
suspected infection or any
• Systemic inflammatory
other stimulus that activates response.
inflammation is
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 This inflammatory
response is • A core body temperature>38ºC or
commonly referred <36ºC.
• A heart rate>90 bpm or >2SD from the
to as the systemic age-appropriate normal.
inflammatory • A respiratory rate > 20 bpm or
response syndrome hyperventilation (as evidenced by a
(SIRS) and is defined PaCO2<32 mmHg).
clinically by two or • 4. A measured peripheral WBC count>
more of the 12,000 cells/mm3 or <4,000 cells/mm3
following
manifestations:
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• Sepsis, however, is no longer simply defined as
infection or suspected infection plus two or
more SIRS criteria alone.
• The most recent established criteria for sepsis
include the following:
I- Quick Sepsis Organ-Failure Assessment (qSOFA).
II- Sepsis Organ-Failure Assessment (SOFA).
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I- Quick Sepsis Organ-Failure Assessment
(qSOFA).
• This is defined by two of the following three variables:
• Altered mentation,
• Respiratory rate > 22 bpm, and/or
• Systolic blood pressure < 100 mmHg.
• This quick assessment tool is best applied to the
identification of patients with sepsis outside the
intensive care setting.
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II- Sepsis Organ-Failure Assessment (SOFA).

• This is defined by a score of 2 or greater of the following variables from

baseline:
• Alteration of PaO2/FiO2 ratio,
• Worsening thrombocytopenia,
• Escalating total bilirubin level,
• Hypotension with or without the use of vasopressors,
• Escalating serum creatinine and declining urinary output, and/or
• Declining Glasgow coma scale score.
• This assessment tool is best applied to the identification of patients with
sepsis within the intensive care setting.

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8
 The most recent established criteria for this subset of
sepsis are

The need for vasopressors Elevated serum lactate >2

to maintain MAP > 65 mmol/L despite adequate
mmHg fluid resuscitation
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Defined as a subset of sepsis Septic shock
in which profound
Circulatory abnormalities
are associated
with a greater
Cellular risk of mortality
than with sepsis
alone
Metabolic

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PATHOGENESIS OF SEPSIS.
 Hyperinflammation and Hypo-inflammation
Shift toward and immune
hypercoagulation in the
early stages a condition of suppression as sepsis
persists.

The pathogenesis of sepsis is complex and multifactorial;

however, sepsis is generally considered a condition of Some
key components to the pathogenesis of sepsis include:
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 C. Hypercoagulation and
A. Pattern Recognition
Impaired Anticoagulation.
Receptors. B. Reactive Oxygen Species.
While this is most likely
Innate immune cells (e.g., produced as part of the innate
complex and multifactorial,
dendritic cells) recognize immune response to
human activated protein C
certain pathogen-associated microorganisms but also have
(APC) is relatively deficient
molecular patterns  deleterious effects as they
during sepsis and may
activation of a series of contribute to CVS instability
contribute to hypercoagulation
intracellular signaling and organ dysfunction in
and hyperinflammatory state.
pathways  an inflammatory sepsis.
(APC has anti-inflammatory
state.
properties.)

D. Vascular endothelial E. Mitochondrial F. Apoptosis.

Dysfunction. Dysfunction. Sepsis leads to
abnormal oxygen utilization Sepsis apoptosis of innate
Due to reduced nitric oxide
by mitochondria that may immune cells  an
abnormal leukocyte response
further contribute to CVS immunosuppressed state and
as well as both a
instability and organ reduced clearance of
hypercoagulation and a
dysfunction. pathogenic microorganisms.
hyperinflammatory state.
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MICROBIOLOGY OF
SEPSIS
A. Gram-Positive Bacteria. 1. Staphylococcus aureus
• Predisposing factors for these pathogens 2. Streptococcus pyogenes (group A)
usually include a normal or
3. Streptococcus agalactiae (group
immunosuppressed host.
B)
• Asplenia patients are particularly
susceptible to encapsulated gram- 4. Streptococcus pneumoniae
positive bacteria such as Streptococcus 5. Listeria monocytogenes
pneumoniae.
• These pathogens are usually community-
acquired (Staphylococcus aureus can also
be hospital-acquired) and associated with
skin and soft-tissue infections,
pneumonia, or meningitis.
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B. Gram-Negative Bacteria.
• Predisposing factors for these pathogens
usually include immunosuppression,
chronic medical conditions (e.g.,
hemodialysis, diabetes, cirrhosis), or
indwelling catheters.
• These pathogens are usually nosocomial
in origin (e.g., hospital-acquired) and may
be associated with multidrug resistance.
• Asplenia patients are particularly
susceptible to encapsulated gram negative
bacteria such as Neisseria spp and
Haemophilus spp.
1. Escherichia coli
2. Klebsiella spp (K. pneumonia, K.
oxytoca)
3. Enterobacter spp (E. aerogenes, E.
cloacae)
4. Pseudomonas aeruginosa
5. Acinetobacter spp (A. baumannii)
6. Salmonella spp (S. enterica)
7. Vibrio spp (V. vulnifi cus)
8. Yersinia enterocolitica
9. Neisseria spp (N. gonorrhoeae, N.
meningitidis)
10. Haemophilus spp (H. influenzae)
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C. Anaerobic Bacteria. 1. Clostridium spp. C. difficile is a
• Although uncommon, pathogen strongly associated with
predisposing factors for these recent antimicrobial use and recent
pathogens usually include history of diarrhea.
traumatic injuries or invasive
disease to cause necrotizing skin
and soft-tissue infections.

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D. Fungi. 1. Candida spp.
• Predisposing factors for these 2. 2. Aspergillus spp.
pathogens usually include 3. Pneumocystis jirovecii.
immunosuppression, chronic 4. Cryptococcus neoformans
medical conditions (e.g.,
hemodialysis, diabetes), or
indwelling catheters.

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E. Viruses. 1. Cytomegalovirus
Predisposing factors for these 2. Herpes simplex virus
pathogens usually include 3. Varicella-zoster virus
immunosuppression. 4. Epstein–Barr virus

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CAUSES OF SEPSIS
I- Noninfectious Causes of Sepsis
• 1. Trauma, surgery, or burns
• 2. Myocardial infarction or acute coronary syndrome
• 3. Severe pancreatitis
• 4. Thyroid storm or acute adrenal insufficiency
• 5. Acute leukemia or tumor lysis syndrome
• 6. Malignant hyperthermia (e.g., anesthetic-related halothane)
• 7. Malignant neuroleptic syndrome (e.g., haloperidol)
• 8. Pulmonary or deep venous thrombosis
• 9. Intracranial or subarachnoid hemorrhage (or any hematoma)
• 10. Solid-organ transplantation rejection

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II- Infectious Causes of Sepsis.
• 1. Bacteremia (the major sources of bacteremia are intravascular devices, pulmonary
infections, intra-abdominal infections, endovascular infections, or UTI)
• 2. Vascular access or intravascular device associated infection
• 3. Lower respiratory tract infection (e.g., pneumonia or empyema)
• 4. Intra-abdominal infection (e.g., peritonitis, cholecystitis, diverticulitis/ abscess,
pancreatic abscess, septic abortion or Clostridium difficile colitis)
• 5. Urinary tract infections (e.g., cystitis, pyelonephritis, renal abscess or Foley
catheter–related infection)
• 6. Endovascular infections (e.g., endocarditis or vascular graft infections)
• 7. Skin and soft-tissue infections (e.g., necrotizing fasciitis, soft-tissue abscess, or
surgical site infection)

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CLINICAL
MANIFESTATIONS OF
SEPSIS
• While the clinical manifestations associated with sepsis
vary, manifestations typically reflect the underlying source
of infection.
• Common nonspecific clinical manifestations include:
1) Fevers, chills, and/or rigors
2) Irritability, confusion, or lethargy
3) Tachypnea, hypoxia, acute respiratory distress, or
respiratory failure
4) Hepatic and/or renal failure
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APPROACH TO THE
PATIENT WITH SEPSIS
A- History
The most important initial approach to the
patient with sepsis is a complete, accurate,
and comprehensive history.

Physicians must be meticulous and

systematic when obtaining information for
the following key elements:

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 • e.g., urinary tract infections, pneumonia,
and intra-abdominal abscess may be more

Age:
likely in persons>50).
• Additionally, it is important to determine
any attempted abortions in women of
childbearing age.

• It is important to establish in chronologic

fashion the onset of symptoms and events

HPI
that may be related to the sepsis syndrome.

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 Past medical • Recent infection or chronic medical illness
(e.g., IBD, biliary tract disease, or underlying
history: This heart disease),
• Prior diagnosis of malignancy or
area should chemotherapy,
focus on any • Indwelling venous catheter.

• OTC and herbal medications or antimicrobial

therapy–related allergies.
Medications and • Beta-blockers may falsely indicate relative
bradycardia.
allergies: • Corticosteroids and NSAIDs may mask the
signs and symptoms of infection.

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 • Patient’s country of origin,
• Immigration status,
• Travel history (with relevant exposure,
vaccination, and prophylaxis history),
• Vaccination status,
Social • Occupation and occupational risks,
• Smoking status,

history: • Alcohol and drug exposure,

• Hobbies or leisure activities,
• Pet or animal exposure,
• Sexual activity that may place the
patient at particular risk for infection.

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B- Physical Examination.
All body systems
Meticulous and conduct the examination in a systematic approach
Repeat examinations
1-Vital signs:?? nonspecific -
• Fever may be the first indication of sepsis.
• Pulse should increase 15 to 20 beats/min for each 1 degree
increase in core body temperature >39°C.
• A lower than normal increase (or no increase) is termed relative
bradycardia.
• The diastolic blood pressure (DBP) usually decreases as a result
of a sepsis-induced decrease in systemic vascular resistance.
• Impaired oxygenation and tachypnea may also be present but is
generally nonspecific.
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2- Dermatologic examination.

• Surgical sites, traumatic wounds,

• Pressure ulcers,
• Vascular access sites (e.g., erythema, edema, warmth, tenderness, and purulent drainage). Greater than 4
mm of erythema surrounding a vascular access site has been associated with infection.
• Petechiae and bleeding from vascular access sites may suggest disseminated intravascular coagulation
(DIC).
• Candidiasis may be associated with diffuse erythematous nodules.
3- Head, eyes, ears, nose, and throat (HEENT) examination.
• A funduscopic examination may reveal Roth spots suggestive of systemic candidiasis.
• While jaundice is nonspecific in sepsis, its presence may suggest a biliary tract infection (e.g.,
ascending cholangitis).
• Conjunctiva petechial lesions may suggest endocarditis.
• Findings of gingival inflammation and poor dentition may suggest a head and neck infection (e.g.,
odontogenic infection) or a necrotizing pneumonia (especially with a history of aspiration and
respiratory symptoms).
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4- Cardiovascular examination.

• A new diastolic murmur or change with existing murmur may suggest endocarditis.

5- Pulmonary examination.

• Impaired oxygenation, tachypnea, and signs of pulmonary consolidation may suggest

pneumonia, complicated parapneumonic effusion, or empyema.

6- Abdominal, pelvic, and rectal examination.

• Inspection for prior surgical scars.

• Abdominal tenderness, guarding, rebound, and absent bowel sounds may for peritonitis.
• Internal and external rectal examination may reveal a perirectal abscess, or swollen and
tender prostate on internal examination may suggest prostatitis.
• A bimanual pelvic examination should be performed in women for PID.
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7- Neurologic examination.

• An altered mental status is commonly observed in elderly patients with infection but is
nonspecific; however, findings of a stiff neck (e.g., Kernig sign and Brudzinski sign) may
suggest meningitis.

8- Musculoskeletal examination.

• Bone tenderness on palpation may suggest osteomyelitis.

• Warm, tender joint with an effusion and decreased range of motion may suggest septic
arthritis.
• A prior joint-space surgical scar should also be sought that may indicate a prosthetic joint
infection.
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C. Laboratory Studies.
 No diagnostic gold standard workup for the etiology of sepsis.
 Laboratory testing or imaging should be guided by findings from a complete
history and physical examination.
1. Complete blood count (CBC) with differential cell count.
• Leukocytosis may suggest infection; however, an elevated
neutrophil count (e.g., left shift) lacks sufficient sensitivity to
differentiate infectious from noninfectious etiologies for
sepsis.
• Thrombocytosis (>600,000 mm³) may be associated with
infections due to yeast or molds.
2. Basic metabolic panel.
• Routinely ordered but nonspecific; however, results of the
serum creatinine level may affect antimicrobial dosing.
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3. Liver enzymes and coagulation tests ([PT/PTT/INR]).
• Biliary tract infections may be associated with elevated ALP
and total bilirubin levels.
• Coagulation studies can be abnormal with sepsis but
nonspecific with elevated values suggesting DIC (especially
with a decreased fibrinogen level).
4. Serum lactate.
Levels >2 mmol/L may suggest tissue hypoperfusion and the need
for fluid resuscitation; however, sepsis is associated with increased
glycolysis and increased serum lactate production.
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5. Urine microscopy and urine culture.
Fever and/or UTI symptoms (e.g., urinary frequency, dysuria,
urgency, or costovertebral angle tenderness) in association with
hematuria, significant pyuria (at least 10 WBCs/m3), and
bacteriuria (traditionally defined as 105 colony-forming units/m3)
may suggest cystitis, pyelonephritis, or renal abscess.
6. Stool studies.
A stool sample should be evaluated for Clostridium difficile colitis.

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7. Blood cultures.
• Routinely ordered as 2 sets of blood cultures (10 mL of blood
per blood culture bottle) prior to the initiation of antimicrobial
therapy.
• One set should be obtained through a percutaneous site (using
standard skin preparation methods) and one set should be
obtained through each vascular access site that has been in
place for greater than 48 hours.
8. Sputum Gram stain and culture.
In patients with sepsis and purulent respiratory secretions.
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9. Wound or abscess cultures.
• Superficial swab cultures are not recommended.
• Needle-aspirated contents from intact bullae or vesicles as well as deep cultures from
abscesses, surgical wounds, or pressure ulcers are most helpful to identify a causative
pathogen.
10. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and procalcitonin
(PCT).
• Nonspecific tests that are elevated with infections or inflammation.
• PCT levels between 0.5 and 2.0 ng/mL make sepsis possible as these levels are also
associated with noninfectious conditions (e.g., trauma, postsurgical, burns, heat stroke,
mesenteric infarction, and pancreatitis).
• Levels between 2.0 and 10.0 ng/mL are suggestive of sepsis.
• Alternatively, a serum PCT value <0.5 ng/mL may serve best to identify those patients
without sepsis rather than identify those for whom infection has actually been detected.
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D. Radiography Studies.
The need for transportation to the radiology suite for certain diagnostic imaging
methods should be balanced by the clinical status and safety of the patient.
1. Plain-film abdominal and chest imaging.
These imaging modalities rarely yield a diagnosis; however, a single-view chest image
may be helpful to identify pneumonia.
Additionally, plain films of the abdomen may indicate free air (suggesting bowel
perforation with peritonitis) or the presence of gas within an abscess cavity.
2. CT scan.
Imaging of the abdomen and chest with contrast is more sensitive than plain films or
ultrasonography and of importance early in the evaluation as two of the most common
causes of sepsis include pneumonia and intraabdominal abscesses.
3. Echocardiography.
Transthoracic or transesophageal imaging in association with the review of Duke
criteria is important for the evaluation of endocarditis.
4. Ultrasonography.
A noninvasive imaging study that may be helpful to evaluate biliary tract or pelvic
etiologies for sepsis.
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TREATMENT.
1- Immediate efforts to stabilize the patient
2- Identifying the underlying cause
3- Formulating a treatment plan for that particular condition.
Guidelines have been developed for the treatment of sepsis that involves three main components:
A. Early Goal-Directed Therapy and Initial Resuscitation.

Goals to therapy should include the following:

a. Maintain CVP of 8 to 12 mmHg. For patients with CVS history
(e.g., diastolic heart failure) or mechanical ventilation, the CVP should
be maintained at 12 to 15 mmHg.
b. Maintain an MAP >65 mmHg. For patients with sepsis induced
hypoperfusion, infuse 30 mL/kg of IV crystalloid within 3 hours with
additional fluid replacement based on frequent reassessments.
c. Maintain central venous oxygenation >70% (mixed venous
oxygenation greater than 65%).
Extended Modular Program
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Persistent hypotension:
 Absolute systolic blood pressure <90 mmHg or
 A relative systolic blood pressure <40 mmHg of the baseline

Extended Modular Program

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 1. Initial fluid • Persistent hypotension and/or serum lactate level
resuscitation
>2 mmol/L in order to improve CVS support and
should be
perfusion.
initiated with

2. Vasopressor
and inotropic
support to • Norepinephrine followed by dopamine are the
further improve preferred agents.
CVS status and
perfusion.

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 • Some data suggest that patients with persistent hypotension
despite initial fluid resuscitation and vasopressor and
inotropic support may benefit from corticosteroid therapy
3. Corticosteroid for functional adrenal insufficiency.
therapy. • hydrocortisone 50 mg IV q6 or
• fludrocortisone 50 mcg PO daily.
• Corticosteroid therapy should be weaned off following
the discontinuation of vasopressor and inotropic support.

• Transfuse packed RBCs if the hemoglobin < 7.0 g/dL.

4. Blood product
• Platelets should be transfused for any significant bleeding
administration
episode or if the platelet count < 5,000 cells/mm3.
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 • Insulin therapy should be initiated to maintain
5. Glucose
glucose levels between 140 and 180 mg/dL
control.
(this improves neutrophil function).

• Renal replacement therapy (continuous veno-

venous hemofiltration [CVVH] or intermittent
6. Other hemodialysis can both be considered),
supportive • Mechanical ventilation support
measures
• DVT prophylaxis,
include:
• Stress ulcer prophylaxis (either an H2-blocker
or proton-pump inhibitor can be used).

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 B. Antimicrobial Therapy. (renal function.)
• Prompt initiation of broad spectrum antimicrobial therapy (e.g., a combination
regimen that covers both gram-positive and gram-negative pathogens) within the
first hour of sepsis recognition is paramount to patient survival.
• Obtain anatomical infection source control as rapidly as clinically practical.
• Assess patients daily for de-escalation of antimicrobial therapy and/or narrow
therapy based on culture data and/or clinical improvement.
• While guidelines suggest an estimated duration of antimicrobial therapy for sepsis
be 7 to 10 days, therapy should be monitored daily and adjusted for renal function
and comorbid conditions, drug intolerances or interactions, susceptibility pattern
of isolated pathogens, and the underlying infectious disease process.
• No standard empirical regimen exists but suggested combination regimens.

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1. Ceftazidime 2 g IV q8 or
Cefepime 2 g IV q8 or
Doripenem 500 mg IV q8 or
Meropenem 500 mg IV q8 or
Piperacillin tazobactam 3.375 to 4.5 g IV q6.
Metronidazole 15 mg/kg IV loading dose followed by 7.5 mg/kg IV
q6-8 maintenance dosing should be used with regimens containing
ceftazidime or cefepime; however, the addition of metronidazole is
NOT required for doripenem, meropenem, or piperacillin–
tazobactam; plus

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2. Daptomycin 6 mg/kg IV q24 (daptomycin should
NOT be used if the infection is suspected from CNS or
pulmonary source due to inadequate penetration) or
Linezolid 600 mg IV q12 or
Vancomycin 15 mg/kg IV q12–24 (dosing for
vancomycin should be adjusted to a goal serum level
between 15 and 20 mcg/mL).

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 C. Source Identification and Control.
Within the first 6 hours of sepsis the source should be identified if
possible in order to identify patients who may benefit from a timely
and effective intervention (e.g., percutaneous or surgical drainage).
Conditions that may benefit from early intervention include:
1. Prompt removal of an infected vascular access device (e.g., central
venous catheter, urinary Foley catheter).
2. Percutaneous or surgical drainage of deep space infection (e.g.,
intra-abdominal, intrathoracic, or intracranial abscess, joint-space
infection, or necrotizing skin and soft-tissue infection).

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Thank you