Pathophysiology and Treatment of Sepsis Flashcards
Lecture objectives
• Define Sepsis and explain the differences between Sepsis, Septic Shock and Systemic Inflammatory Response Syndrome (SIRS).
• List the infections that can lead to Sepsis.
• Describe the characteristics and function of normal Innate
Immunity.
• What is the role of Toll-like receptors in inflammation?
• Compare and contrast regulated and dysregulated inflammation.
• Briefly describe the role of mitochondrial function.
• Discuss how mitochondrial dysfunction may impact the downstream pathophysiology of Sepsis.
• Understand the rationale behind the treatment of Sepsis and SIRS.
• List the risk factors of Sepsis.
What is sepsis?
A syndrome that complicates severe infection and arises when the body’s responses to infection also cause serious injury to distal host tissues and organs.
Dis-regulated inflammation following infection
What is severe sepsis?
• A clinical life-threatening syndrome that complicates severe infection and arises when the body’s responses to infection injures self (host) tissues and organs.
NB: the term severe sepsis is reserved for patients with infection who look bad (have vital organ failure) and are ill enough to be admitted to ICU.
- Severe sepsis is characterised by
- 1) inflammation
2) vasodilation
3) leukocytaemia
4) microvascular permeability
5) organ / system failure/dysfunction
When does a patient ‘look bad’ with signs for sepsis
- A degree of associated organ / system dysfunction
- Arterial hypotension
- Bloodlactate>2
- Gas exchange impaired – PaO2 down; PaCO2 (can be low or high depending compensation)
- Patient obtund (diminished responsiveness) or confused.
- This calls for a systematic review of 6 organs/systems
What is septic shock
Arterial hypotension (systolic BP <90 mmHg, MAP <65 mmHg, or reduction in systolic BP >40 mmHg from baseline) persisting for at least 1 hour, despite adequate fluid resuscitation, or
Serum lactate >4mmol/L after adequate fluid resuscitation
What is SIRS?
• Systemic Inflammatory Response Syndrome (SIRS) - deregulation of the inflammatory response.
• SIRS is a way to score sepsis (BUT is a down stream response and also a way to score severe non-infectious illness eg: severe burns, pancreatitis, severe trauma)
• SIRS simply can be defined by measuring 4 variables: temperature <36 or >38oC, heart rate >110 bpm,
respiratory rate >25 bpm & WBC’s <4 or >11 x103/uL
SIRS affects distal organs and systems and is manifest in multiple organ and system dysfunction.
What are six important systems/organs to monitor to detect SIRS
• Cardiovascular • Respiratory • Renal • Hepatic • Neurological • Coagulation Any type of organ dysfunction indicates that an acute potentially life-threatening disorder is present and must be treated rapidly to prevent Multiple Organ Dysfunction Syndrome (MODS ) and optimise outcome.
What infections lead to sepsis?
- Gram positive and gram negative bacteria are responsible for 90% of cases.
- Gm negatives include E. coli, Klebsiella pneumonia, Pseudomonas aeruginosa.
- Gm positives include Streptococci pneumoniae Staphylococcus aureus, coagulase negative Staphylococci, Enterococci, other Staphylococci) Note: causative organisms are only identified in 50 – 70% of cases
Discuss the pathophysiology of sepsis
• Pathophysiology variable depending on primary causative infecting organism and efficiency of the host response to infection (influenced by wellness).
• Generally, the causative organism is responsible for a localalised infection that progresses to a systemic effect - SEPSIS .
• Systemic effect is mediated through inflammation leading to distal pathology and organ/system failure.
SIRS underpins the classic signs and symptoms of
SEPSIS and SEVERE SEPSIS
Discuss innate immunity in inflammatory response
Normal INNATE immune responses provide early rapid protective inflammation at the site of infection/injury.
Characterised by:
HEAT – to inhibit pathogen growth PAIN – to signal to body something
is wrong
REDNESS – influx of cells and
mediators to the site though increased blood flow
SWELLING – local fluid accumulation due to vasodilation,
cellular influx and local coagulation to seal off site to
prevent spread of infection
Describe localised regulated innate inflammation
- Most tissues and organs have resident cells with surface receptors to immediately recognise and respond to abnormal change and provide protection
- Toll-like receptors (TLR’s) are important surface receptors in INNATE Inflammation
- TLRs recognise non-host molecular patterns (pathogen proteins and molecules) or host patterns that are normally compartmentalized (hidden) or damaged.
- TLR - pattern molecule complex signals through the cell cytoplasm that something is wrong
TLR’s recognize patterns of common foreign molecules
TLR’s represent INNATE immunity that helps alert the body that there is an infection or tissue tissue damage.
Discuss recognition by common well-characterized TLRs
TLR = Toll-like receptor
Cellular location = where the TLR is located on the mammalian cell
Ligands = the foreign/altered molecules that are recognised by each TLR
eg. TLR4 recognises bacterial lipopolysaccharide
TLR5 recognizes flagellin on bacteria that have flagella
Discuss TLR action and it’s multiple actions through regulation of gene expression
Pro-inflammatory cytokine, chemokine and cytokine receptor genes in cells with activated TLR’s are up-regulated – eg TNFα, IL-1, IL-6
Activated TLR’s regulate genes responsible for:
Cardiovascular regulation Immune regulation
Hormonal control Coagulation Metabolism Bio-energetic systems
-Mitochondrial function is strongly implicated in these down stream drivers of inflammation by TLR activation
Functional outcomes:
Increased blood flow MHC expression
Cortisol, estrogen, adrenaline Platelet activation Metabolism - increased Mitochondrial response
-Mitochondrial function is strongly implicated in these down stream drivers of inflammation by TLR activation
Discuss downstream effector pathways of TLR activation and inflammation
• Increased blood flow – through vasodilation response
• MHC expression – gene up-regulation
• Cortisol, estrogen, adrenaline – hormonal
response
• Platelet activation – vascular modulation and coagulation
• Metabolism – increased in response to heightened cell activity
• Mitochondrial activity – to support response
Discuss dysregulated inflammation (SIRS)
• Systemic vasodilation and reduced blood volume –poor organ perfusion with TNF-α, IL-1, IL-6 and endothelial cell activation.
• Impaired O2 delivery intravascular coagulation – restricted blood flow.
• Lactic acidosis, cellular dysfunction and multi-organ dysfunction.
• ATP levels fall Mitochondria (Mt) function and cell performance falls
• Mt dysfunction can lead to cell death (tissue necrosis) but NOT in sepsis.
• In sepsis Mt may adopt a low energy state (Singer, 2014).
• May explain rapid recovery of organ function once systemic
inflammation resolves.
