This document discusses sepsis and septic shock. It defines severe sepsis as acute organ dysfunction caused by infection, and septic shock as sepsis with hypotension refractory to fluid resuscitation requiring vasopressors. Common infection sites include the respiratory tract, intra-abdominal space, and urinary tract. Gram-positive and gram-negative bacteria, as well as fungi, can cause sepsis. The pathophysiology involves an initial inflammatory response that can lead to organ damage and dysfunction if not controlled. Complications include disseminated intravascular coagulation, acute respiratory distress syndrome, and acute renal failure. Treatment involves identifying and treating the infection source along with early, targeted antimicrobial therapy and organ support.

1. SEPSIS AND
SEPTIC
SHOCK
PRESENTED BY
RAVI TEJA A
13Y01T0017

2. INTRODUCTION
– Severe sepsis: refers to patients with an acute organ dysfunction such as acute renal failure or respiratory failure.
– Mortality rate is about 40% in severe sepsis
– Septic shock: sepsis patient with arterial hypotension that is refractory to adequate fluid resuscitation, thus
require vasopressor administration.
– Require intensive care and ultimately die in 50 – 80 % case.
– Infection sites and pathogens:
– Respiratory tract – 21- 68% Gram positive bacteria – 40%
– Intra abdominal space – 14 – 22 % Gram negative bacteria – 38%
– Urinary tract – 14 -18 % Fungi – 17%

3. SPECIES
– Gram positive bacterial species: predominant pathogen in sepsis and shock
– S. aureus
– S. pneumoniae – overall mortality rate is >25%
– Enterococcus species
– S. pyrogens
– Gram negative bacterial species: These are also more likely to produce septic shock in comparison to gram
positive – 50 vs 25 %.
– Highest mortality rate when compared to other group of organisms.
– E. coli Enterobacter species
– P. aeruginosa (14%) Proteus species
– Klebsiella species

4. – Fungal species: fungal infections increased more than 200% from 1979 – 2000.
– Candida species the most common.
– Candida albicans are the most dominant.
– Non- albicans species – C. glabrata; parapsilolis; tropicalis.
– Mortality rate in fungal sepsis is 41 – 71%

5. PATHOPHYSIOLOGY
Pro inflammatory mediators and microbial interaction
Anti inflammatory mediators activation
Damage to host tissue and inflammatory response
Once the control of the leukocytes over infection lost
Sepsis; severe sepsis; septic shock

6. CELLULAR COMPONENTS FOR INITIATING
INFLAMMATORY PROCESS
– Gram negative: lipopolysaccharide component of the cell wall of the bacterium releases endotoxin.
– This Endotoxin is released on bacterial lysis.
– Lipid A is highly immunoreactive present in the innermost layer of the lipopolysaccharide causes tissue damage
and trigger the inflammatory cascade.
– this causes the production to sepsis and septic shock.
– Endotoxins forms a complex with protein called lipopolysaccharide – binding protein which then engages the
CD14 receptor on surface of macrophage.

7. CELLULAR COMPONENTS FOR
INITIATING INFLAMMATORY
PROCESS
– Gram positive bacteria: Exotoxin a peptidoglycan comprises up to 40% of gram
positive call mass.
– Lipid A competes for similar binding sites on CD14 to which peptidoglycan
binds.

8. Pro and Anti – Inflammatory
mediators
– Key Pro inflammatory mediators:
– TNF ALPHA
– IL 1
– IL 6
– Other – IL 8
Platelet Activating factors
Leukotrienes
Throboxane A2

9. – TNF Alpha is increased in various diseases but there is a correlation of plasma TNF Alpha with severity of sepsis.
– TNF Alpha more elevated in sepsis causes activation of other Cytokines (IL 1 and IL 6).
– This increase in TNF Alpha stimulates the release of cyclooxygenase derived arachnoidic acid metabolites
(Thromboxane A2 and Prostoglandins).
– Thromboxane A2 and Prostoglandins contribute to vascular endothelial damage.
– Higher levels of IL 6 and 8 have reported in patients with septic shock.

10. – Anti – inflammatory mediators: IL 1 Receptor agonist
IL 4
IL 10
– Levels of IL 10; IRA have reported in patients with septic shock.
– When the balance between pro and anti – inflammatory changes the bacterial activity from local to systemic
toxicity , organ failure or death.

11. CASCADE OF SEPSIS
– When injured, endothelial cells allow circulatory cells such as granulocytes and plasma constituents to enter
inflamed tissues, which can result in organ damage.
– Micro circulation is affected by sepsis induced inflammation.
– The capillaries are less perfused even at early phases of septic shock and there is neutrophil infiltration and
protein leakage into the venules.
– The inflammatory system also directly linked with coagulation system.
– Levels of protein C is reduced in patients with sepsis.

12. COMPLICATIONS
– Disseminated intravascular coagulation:
– It is the inappropriate activation of the clotting cascade that causes formation of microthrombi, resulting in
consumption of coagulating factors, organ dysfunction and bleeding.
– Sepsis is the most common cause f DIC.
– Occurs in 50% gram negative sepsis.
– Activation and production of pro- inflammatory cytokines such as TNF, IL 1, IL 6.
– The combination of excessive fibrin formation . Inhibited fibrin removal from depressed fibrinolytic system and
endothelial injury result in microvascular thrombosis and DIC.

13. – Complications of DIC depend on targeted organ effected and severity of coagulopathy.
– DIC complications:
– Acute renal failure
– Necrosis of GI mucosa
– Liver failure
– Acute pancreatitis
– Acute Respiratory Distress Syndrome
– Pulmonary failure

14. – Acute Respiratory Distress Syndrome: Most common organ dysfunction in Sepsis
Activated neutrophils and platelets adhere to the pulmonary
endothelium
Initiates multiple inflammatory cascade with a release of variety of
toxic substances
Diffuse pulmonary endothelial cells injury, increased capillary
permeability, alveolar epithelial cell injury
Interstitial pulmonary edema leading to alveolar flooding and
collapse
Loss of functional volume ; impaired pulmonary compliance;
hypoxemia

15. Fibrnolytic activity is depressed
This favours the alveolar fibrin deposition
Fibrin deposition in the injured lung and
abnormalities of coagulation and fibrinolysis are
integral to the pathogenesis of ARD

16. – Hemodynamic effects:
– Hallmark in sepsis – High cardiac output and abnormally low systemic vascular resistance (SVR).
– TNF Alpha and Endotoxin depress cardiovascular function.
– Endotoxin depress left ventricular function independent of changes in LV volume or vascular resistance.
– Myocardial dysfunction is common in severe sepsis and septic shock – 64% patients.
Impaired left ventricular function caused hypotension
Decreased oxygen delivery (DO2)
Decreased oxygen consumption by the tissues (VO2)

17. Sepsis Distributive shock
Inappropriately
increased blood flow
to particular tissue at
the expense of other
tissue
Increased precapillary
arterioventricular
shunt
If tissue perfusion
decreases, oxygen
extraction increases
Arteriovenous
oxygen gradient
widens
Metabolic
acidosis and
organ dysfunction
Cellular oxygen distribution is decreased but volume of distribution to the blood is unaffected

18. – Acute renal failure: occurs to 42 – 64% of patients.
Decreased urine
output
Fluid overload in the
extravascular space
including lungs
Impairment of
pulmonary gas
exchange
Severe hypoxemiaOrgan damage

19. CLINICAL PRESENTATION
– Early sepsis is the one that occurs in the first 6 hours.
– Uncontrolled sepsis leads to clinical evidence of organ system dysfunction is
Late sepsis.
– The hypoventilation causes the elevated lactate levels which further causes
metabolic acidosis.
– The metabolic acidosis leads to impaired gluconeogenesis, Altered glucose
metabolism, Excessive insulin release.

20. TREATMENT
– Primary goals
1. Timely diagnosis and identification of pathogen
2. Rapid elimination of infection source
3. Early aggressive antimicrobial therapy
4. Interruption of pathogen sequence leading to septic shock
5. Avoid organ failure

21. – Elimination of source of infection:
– If the infection is by catheter it is to be removed.
– Any intraabdominal pathology should prompt surgical intervention.
– Anti microbial therapy:
– Empirical regimen should be based on suspected site of infection, pathogen nature, acquisition of organism from
community or hospital, patients immune status, resistance profile for the institute.
– Treatment to be started with parenteral anti microbials.
– Empirical therapy to be broad for the immunocompromised patients.
– Once the pathogens and its susceptibility is known regimen to be modified accordingly.
– Pathophysiological changes can affect the drug distribution and different dosing regimens are required in
critically ill with sepsis.

22. – Pharmacokinetics of the antimicrobials in severely ill patients:
– Initially high creatinine clearance is seen in patients with normal serum creatinine due to increased renal
preload.
– There is altered protein binding observed in the patients due to fluid accumulation.
– Hydrophilic antimicrobials like Aminoglycosides, beta- lactams, Carbapenems can show low peak serum
concentration with usual dose.
– Due to the myocardial depression in sepsis there is less organ perfusion in patients which increase clearance time
of antimicrobials.
– If no proper dose tailoring is done in the patients
1. Antibiotic resistance
2. Toxicity
3. Inadequate efficiency despite of appropriate antibiotic selection

23. – Selection of Anti- microbial agents:
– Non – neutropenic UTI: Ceftriaxone, Fluoroquinolones
– P. aeruginosa- either by sepsis or hospital acquired infections: Anti pseudomonal antibiotics like Ceftazidime.
– S. pneumoniae- Causing community acquired pneumonia: Respiratory Fluoroquinolones like Levofloxacin or
Moxifloxacin. The addition of beta lactams help in severe pneumonia.
– Clarithromycin and Azithromycin are effective against atypical bacteria causing pneumonia.
– Nosocomial pneumonia: gram negative bacteria like Enterobacter
Klebsiella species
P. aeruginosa
S. aureus

24. – P. aeruginosa: Beta lactam anti Pseudomonal agents like Ceftazidime and Cefepime.
– S. aureus: Linezolid is preferred over Vancomycin due to its poor penetration into lungs.
– Secondary Peritonitis: It is a consequence of perforation of GIT.
– Usually polymicrobial involving enteric aerobes and anaerobes and as many as five organisms are isolated per
patient in this condition.
– Ampicillin/ sulbactam is recommended in in E. coli due to wide spread resistance.
– Bacteroides fragilis: Major pathogen in secondary peritonitis
– Show susceptibility to Metronidazole, Carbapenems, beta lactamase inhibitors.
– This organism has high resistance for Clindamycin and Moxifloxacin.
– Low resistance for Tigecycline

25. – Intra abdominal infections:
– Needs surgical intervention and beta lactamase agents and Tigecycline.
– Carbapenems like Meropenem, Imipenem, Doripenem are used in treatment of resistant pathogens like
Enterobacteriaceae, P. aeruginosa.
– Skin and soft tissue infections:
– Mainly by: Staphylococci and Streptococci
– Early initiation of broad antimicrobial therapy is necessary in such cases.
– Therapy should include coverage against MRSA (methicillin resistance staphylococcus aureus).
– Vancomycin, Dapthomycin, Linezolid have comparable clinical efficacy and safety data.
– Organ failure and mortality: Monotherapy is most effective than combination therapy.
– The anti microbial regimen to be reassessed based on microbiological and clinical data after 48-72 hours.

26. – Anti Fungal therapy: most frequent pathogen is Candida species
– Invasive candidiasis: Amphotericin B based preparations or
Azole anti fungal agents or
Echinocandin anti fungal agents
– Suspected Nosocomial blood stream infections: Fluconazole
– Exposure to Fluconazole and antibiotics causes the emergence of Fluconazole resistance Candida species
emergence.
– C. glabrata: Exhibit resistance to both azoles and echinocandins.
– Caspofungin: Echinocandin anti fungal agent : potent against all the candida species including C. glabrata.
– Suspected systemic mycotic infection leading to sepsis in non neutropenic patients to be treated empirically with
parenteral Fluconazole, Caspofungin, Anidulafungin, Micafungin.
– Echinocandins are preferred in azole resistant fungal species.

27. – In neutropenia condition lipid formulation lipid formulation of Amphotercin, Caspofungin or Voriconazole is
recommended.
– Duration of therapy:
– Average duration: 7 – 10 days
– Fungal therapy duration: 10 – 14 days
– Longer therapy duration is required in slower clinical response and neutropenia conditions.
– In Neutropenia condition the therapy to be continued until the patient is no longer neutropenic and afebrile for
at least 72 hours.
– If the patient is afebrile and if there is a normalized WBC : stepdown therapy from parenteral to oral antibiotics.

28. – Hemodynamic Therapy:
– Septic shock – High cardiac output and low SVR.
– Low SVR, hypotension, low tissue perfusion – multiple organ failure.
– Aggressive hemodynamic support to be initiated.
– Hemodynamic therapy:
1. Fluid therapy
2. Vasopressor therapy and Inotropic therapy
– Fluid therapy:
– Patients require enormous fluid as a result of peripheral vasodilation and capillary leakage.
– Goal: Maximise cardiac output and restore tissue perforation.
– Isotonic crystalloids: 0.9% NaCl, Ringer lactate.

29. – Among the given fluids 25% remain in the intra vascular space whereas the balance distribute to the extra
vascular space.
– Commonly used crystalloid: 5% albumin and 6% hetastarch.
– The combination of crystalloids and blood products are to be given only if the patient had severe pre existing
anaemia.
– Initial target in fluid therapy: 8 & 12 mm hg on CVP for first 6 hrs.
– Resuscitation typically includes IV normal saline 500ml every 15 min. until the target CVP is reached.
– Close monitoring to be done as it cause Pulmonary edema.

30. – Vasopressor and Inotropic therapy:
– Inotropic agents such as Dopamine and Dobutamine have been effective in improving cardiac output by
increasing cardiac contractility.
– Norepinephrine to be given when systolic B.P is <90mmHg.
– These inotropes and vasopressors may be life saving but can cause potent ADR like tachycardia and myocardial
ischemia.
– Norepinephrine is first choice in septic shock after failure to restore adequate blood pressure and organ
perfusion with appropriate fluid resuscitation.
– Norepinephrine is potent alpha adrenergic agent with less beta adrenergic activity.
– Dose – 0.01 – 3 mcg/ kg/ min.

31. – Dopamine: exhibit dose dependent pharmacological effect.
– With the dose of >5mcg/kg/min: causes stimulation of beta adrenergic receptors
At this doses mean arterial pressure and cardiac output is increased.
– At higher doses: causes alpha adrenergic effect – Arterial vasoconstriction.
– It is more useful in patients with hypotension and compromised systolic function.
– Phenylephrine: Selective alpha agonist
– rapid onset, short duration, primary vascular effects.
– Epinephrine: Non specific alpha and beta adrenergic agonist.
– 0.1 – 0.5 mcg/kg/min: increase cardiac output in lower doses
vasoconstriction at higher doses

32. – Dobutamine: beta adrenergic inotropic agent
– Helps in improvement of cardiac output and oxygen delivery.
– Dose: 2 – 20 mcg/kg/min
– Norepinephrine preferred in significant hypotension, unresponsive to aggressive fluid therapy, increasing the
mean arterial pressure.
– Epinephrine helps in refractory hypotension.
– Dopamine and Epinephrine induce exacerbate Tacchycardia.

33. EARLY GOAL DIRECTED THERAPY
– Resuscitation of the patient in severe sepsis or sepsis induced tissue hypoperfusion should began as soon as
syndrome is recognised.
– Goal in first 6 hours:
1. Central Venous Pressure: 8-12 mmofHg
2. MAP: >65mmofHg
3. Urine output: >0.5ml/kg/hr
4. Saturation: >70%
5. Central venous catheter with more fluid than traditional therapy(5vs3.5)
6. Dobutamine therapy: maximum of 20mcg/kg/min
7. RBC transfusion

34. ADJUNCTIVE THERAPIES
– ARDS & hypoxia are common in sepsis.
– Oxygen therapy: oxygen saturation to be maintained >90%
– Hyperglycaemia and insulin resistance are frequently associated with sepsis regardless of presence of
diabetes.
– Intensive insulin therapy is no more a standard therapy.
– A glucose range of less than 150mg/dl is recommended in critically ill patients.
– Cortisol levels vary widely in septic shock.
– Adrenocorticotropic hormone simulation test helps to identify the adrenal insufficiency.
– Corticosteroids recommended as adjuvant therapy.
– Fludrocortisone – 200 mcg – po – for 7 days in 3 to 4 divided doses
– Hydrocortisone – 200mg/ day – continuous IV infusion

35. – Immunotherapy: disappointing results
– drotrecogin: first anti inflammatory to be approved for sepsis.
– Promotes fibrinolysis, inhibition of coagulation and inflammation.
– But causing severe ADR of bleeding, intra cranial haemorrhage, life threatening bleeding episodes.