Mechanisms of Septic Shock
I. Changing evolution of bacterial infection- In the past, infections tended to be in HEALTHY, UNHOSPITALIZED people. Now, they tend to be in debilitated, hospitalized people. G (-) sepsis is the leading cause of death in I. C. Units in the U.S. Associated changes that may have caused this:
- Antibiotic therapy
- Catheters and foreign bodies
- Chemo for malignancy, cytotoxic drugs, and corticosteroids
- Improved longevity
II. Factors important in systemic bacterial infection-
- Breach of anatomic barriers (burns, endotracheal tubes, catheter, surgery)
- Immunosupression (AIDS, chemo)
- Advanced age
- Selection of antimicrobial resistance
III. Settings for life threatening bacterial infection
- 2 things set healthy people up for sepsis:
1) highly virulent organism (N. meningitidis, Staph. aureus, and Strep. pyogenes TSS)
2) High inoculum
- Pt. with no spleen can’t make Ab to Strep. pneumoniae or H. flu capsule (no opsonization) and so is prone to infection. (check for a splenectomy scar)
- Bacteria like to stow-away on foreign bodies, so if your pt. has an artificial heat valve, catheter, artificial joints, etc., s/he is at risk. Foreign body may need to be removed.
- Pt. with low polymorphonuclear leukocytes (<500) is prone to infection because the polys should move to an infection and keep it contained. Neutropenia (<1000) = Bacteremia. Infection is often with G(-) bacteria like Pseudomonas aeruginosa.
- Pt. with low T cells is more likely to get intracellular pathogens
- Diabetes mellitus
- Superinfection (common in the immunosuppressed.)
IV. Clinical aspects of the Septic patient-
- Bacteremia- blood culture is (+). Dx is microbiologic.
- Septicemia (Sepsis)- Dx is based on clinical evidence. (Remember that blood cultures of a septic pt. may often be (-) due to the intermittent nature of bacteremia.)
- Tachypnea- resp. >20/min.
- Tachycardia- HR >90/min.
- Hyperthermia- body temp. > 38.4 C (101 F)
- Hypothermia- body temp.<35.6 C (96.1 F)
- Systemic toxicity (labored breathing, tachypnea, altered senses)
- Cardio, renal, pulmonary, and metabolic complications (acidosis) caused by underperfusion.
- Shock has 2 parts
1) Hypotension for more than one hour, which can be:
a. BP <90/60 or a >40 mmHg drop in a normal person
b. >70 mmHg drop in a stable hypertensive pt.
2) Decreased tissue perfusion, manifested by:
a. oliguria- decreased urine output
b. ARDS- white line on chest film
c. EKG changes
d. Altered sensorium
e. GI manifestations- ischemic colitis
- Outcome: Mortality is 30%…. 70% if shock complicates.
V. Pathogenesis of self-limiting bacterial infection- A local inflammatory response should be elicited by infection, and the body should respond appropriately and then reinstate homeostasis.
Nidus of infection (abscess, pyelonephritis, peritonitis, pneumonia, cellulitis, etc.)
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Local infection
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Biologic products released in microenvironment (endotoxins, leukocyte chemotaxic factors)
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Endogenous mediators produced (cytokines- local defenses)
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Tissue modeling and repair
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Down regulation of immune factors
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Clinical cure (homeostasis)
VI. Pathogenesis of the sepsis Cascade- Normal processes are turned on to excess, and down-regulation doesn’t happen.
Nidus of infection is either extensive or the local defenses are unable to localize it.
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Intravascular or extensive perivascular infection
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Systemic release of exogenous toxins (endotoxins, exotoxins (TSST-1or toxin A), techoic acid antigens)
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Endogenous mediators produced in excess:
- Cytotoxins (IL 1, 2, &6 and TNF)
- Nitrous Oxide
- Platelet activating factor
- endothelial derived relaxing factor (EDRF)
- Arachadonic acid metabolites
- Hageman factor (XII)
- Humoral defense system (complement…especially C3a and C5a, kinins, and coagulation)
- Myocardial depressant substance
- Endorphins
- Histamine
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Myocardial dysfunction and depressed ventricular function due to decreased contractility. Notice this doesn’t show up right at first. CO may actually increase early in sepsis but then declines. Vascular changes such as:
- endothelial damage which causes arterial plugging
- increased permeability
- Release of endothelium derived relaxing factor (NO & endothelin-1), which produces vasodilation AND vasoconstriction leading to maldistribution of blood flow. So the guts may get lots of blood while the vital tissues starve.)
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Hypotension (various tissues underperfused)
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Organ failure, anaerobic metabolism, systemic acidosis, ARDS, oliguria, renal failure, DIC
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Death
Alternatively, the sepsis cascade may be viewed as having four parts:
1) initial event- endotoxin release
2) intermediary events-
- cytokine release
- complement activation
- release of platelet activating factor (PAF)
3) downstream events
- arachadonic acid metabolite formation
- damaged vascular endothelium
- increased blood coagulability
- myocardial depression
4) resultant Dz
- Systemic inflammatory Response Syndrome (SIRS) = clinical sepsis
- Adult respiratory distress syndrome (ARDS) = sludging of blood in capillaries of lungs
- Disseminated intravascular coagulation (DIC)
- Shock
- Renal failure (ARF)
- Death
Some of the mediators released during infection which don’t get down-regulated in the sepsis cascade preferentially damage certain body tissues:
- Lungs (ARDS)- TNF, IL1
- Kidney (ARF) -endothelin-1
- GI tract (ulceration)- PAF
VII. Diagnosis of bacteremia, septicemia, and septic shock- you want to do this quickly so that Tx can be started right away.
- Clinical suspicion- keep it in the back of your mind with any febrile pt, especially one who just looks sick or gives any indication of systemic toxicity. Watch for BP changes, oliguria, and ARDS on chest films.
- Blood cultures x 3
- Lab values- you might see leukocytosis, azotemia, acidosis, or hypoxemia.
VIII. Treatment of sepsis and bacteremia- find the primary problem and get rid of it. Note that the blood stream itself is the site of the primary infection only in intravascular infections such as endocarditis.
- Tx the primary infection, drain any purulence, and remove intravascular devices.
- Monitor vital functions
- Empiric antimicrobial therapy- use a broad spectrum antibiotic against G(+), G(-), and anaerobic bacteria. If you suspect:
1) Staph. aureus, give Vancomycin + G(-) drug (ex. aminoglycoside, 3rd gen. cephalosporin, quinolone, or imepenem). This organism is likely to infect if the pt has a foreign body present, recent surgery, or HIV.
2) Pseudomonas or G(-) organism, give Ceftazidime + G (-) drug (ex. quinolone) + Vancomycin.
3) Other organisms, give Piperacillin/tazobactam (Zosyn) + gentamycin.
- Manage septic shock
1) prompt, aggressive monitoring and therapy in the ICU
2) indwelling arterial catheters to monitor BP and arterial blood gasses
3) hemodynamic, respiratory, and acid-bases changes
4) pulmonary artery catheter for assessment of intravascular volume and to help differentiate shock from sepsis from other forms
5) Rapid therapeutic intervention with:
- Fluids- until pulmonary wedge pressure (PWP) rises to 15-18 mmHg.
- Vasoactive agents- if pt remains hypotensive in spite of a PWP >15. Dopamine is given to raise mean BP to => 60 mmHg. This preserves renal perfusion. If the Dopamine dose >20 g/kg/min, you might give norepinepherine instead.
6) Immunotherapy- this is still in the experimental stages, but the goal is to curb the effects of the sepsis cascade through the use of immunologic mechanisms.
- Prevention of activation of inflammatory cells- anti-endotoxin (LPS) Ab or TNF Ab would help the body to dump these substances.
- Inhibition of secondary mediators- anti-cytokines, inhibitors of arachadonate metabolism, NO, and coagulation.
- Limitation of end organ damage from secondary inhibitors- steroids, inhibition of neutrophil chemotaxis, activation and adherence, antioxidants and protease inhibitors.
Tags: Adult respiratory distress syndrome, anaerobic metabolism, Bacteremia, Cytokines, Diabetes mellitus, Endorphins, endothelial damage, Hageman factor, Histamine, Hypotension, infection, Mycobacterial infections, Opsonization, renal failure, sepsis, Tachycardia, toxicity
