06-10-22 - Pathophysiology and Treatment of Sepsis Flashcards
Learning outcomes
- Define sepsis and septic shock
- List the causes and risk factors for sepsis
- Describe the immune and inflammatory mechanisms underlying sepsis
- Identify the signs and symptoms of sepsis
- Explain the clinical management of sepsis in adults
What is sepsis?
- Sepsis is 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.
- AKA dysregulated inflammation following infection
- Sepsis is the body’s extreme response to an infection
What is severe sepsis?
What is this term reserved for?
What are 5 characteristics of severe sepsis?
- Severe sepsis is a clinical life-threatening syndrome that complicates severe infection and arises when the body’s responses to infection injures self (host) tissues and organs
- 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.
- 5 characteristics of severe sepsis:
1) Inflammation
2) Vasodilation
3) Leucocytosis/leukopenia – increased/decreased white blood cells in blood
4) Increased microvascular permeability
5) Organ / system failure/dysfunction
What is septic shock?
What 2 factors are classified as septic shock?
- Septic shock is a life-threatening condition that happens when your blood pressure drops to a dangerously low level after an infection
- Septic shock is when there is arterial hypotension (systolic BP <90 mmHg,
MABP <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 (caused by inadequate perfusion of tissue and organs)
What is SIRS?
What 2 things can it be used for?
What are the 4 variables it can be defined by?
What does SIRS affect?
- SIRS is Systemic Inflammatory Response Syndrome (SIRS) - dysregulation of the inflammatory response.
- SIRS is a way to score sepsis (BUT is a downstream response and also a way to score severe non-infectious illness eg: severe burns, pancreatitis, severe trauma
- 4 variables that define SIRS:
1) temperature <36 or >38oC,
2) heart rate >110 bpm,
3) respiratory rate >25 bpm
4) WBC’s <4 or >11 x10^3/uL - SIRS affects distal organs and systems and manifests as multiple organ and system dysfunction
What are 6 important systems/organs to monitor to detect SIRS?
What does any type of organ dysfunction indicate?
What are we trying to prevent?
- 6 important systems/organs to monitor to detect SIRS:
1) Cardiovascular
2) Respiratory
3) Renal
4) Hepatic
5) Neurological
6) 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?
What are examples of gram negative and gram-positive bacteria?
In what % of sepsis cases is the causative organism identified?
Why is this?
- Gram positive and gram-negative bacteria are responsible for 90% of cases of sepsis
- Gram negative bacteria:
1) E. coli,
2) Klebsiella pneumonia
3) Pseudomonas aeruginosa. - Gram positive bacteria:
1) Streptococci pneumoniae
2) Staphylococcus aureus
3) coagulase negative Staphylococci
4) Enterococci
5) other Staphylococci - Causative organisms are only identified in 50 – 70% of cases
- This is because it can be difficult to culture bacteria when someone is on antibiotics
How does pathophysiology vary with sepsis?
What is the causative organism responsible for?
What is this systemic effect mediated by?
What does SIRS underpin?
- 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 localised infection that progresses to a systemic effect – SEPSIS
- Systemic effect is mediated through inflammation leading to distal pathology and organ/system failure (infection hasn’t spread, the inflammation is just dysregulated)
- SIRS underpins the classic signs and symptoms of sepsis and severe sepsis
What do normal innate immune responses provide?
What 4 ways is this characterised?
- Normal innate immune responses provide early rapid protective inflammation at the site of infection/injury
- Innate immune responses are characterised by:
1) HEAT – to inhibit pathogen growth
2) PAIN – to signal to body something is wrong
3) REDNESS – influx of cells and mediators to the site though increased blood flow
4) SWELLING – local fluid accumulation due to vasodilation, cellular influx and local coagulation to seal off site to prevent spread of infection
Regulated innate inflammation – localised.
What are TLRs?
What is the role of TLRs?
What 2 places can TLRs be found?
What do they recognise?
Where are the TLR 1-9 found, and what are the ligands that they bind to?
- Regulated innate inflammation – localised:
- 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 that are damaged.
- TLR - pattern molecule complex signals through the cell cytoplasm that something is wrong
- TLRs can be found on the cell surface or on the surface of the endosomes in most cell types e.g macrophages, neutrophiles, mast cells
- The TLRs on the cell surface respond to components of foreign bodies, such as proteins, sugars, fats from e.g bacteria or viruses
- The TLRs response to double stranded RNA, single stranded RNA and side chains of DNA, as foreign DNA/RNA can be found from viruses replicating
What occurs when TLRs are activated?
What are 6 downstream effector pathways of TLR activation and inflammation?
How does the TLR activated alter the downstream response?
- When TLRs are activated, this upregulates gene expression for pro-inflammatory mediators such as:
1) Cytokines e.g IL-1, IL-6, TNFα
2) Chemokines
3) Cytokine receptors - Downstream effector pathways of TLR activation and inflammation:
1) Increased blood flow – through vasodilation response
2) MHC expression (major histocompatibility complex) – gene up-regulation
3) Cortisol, oestrogen, adrenaline – hormonal response
4) Platelet activation – vascular modulation and coagulation
5) Metabolism – increased in response to heightened cell activity
6) Mitochondrial activity – to support response
- Depending on the TLR activated, the downstream response will be appropriate – proinflammatory pathways to fight bacterial infections (TLRs on host cell surface) or Type 1 interferons (IFNα and IFN β) to fight viral infections (TLRs on internal endosome membranes)
What are 7 systemic effects of dysregulated inflammation (SIRS)?
- 7 systemic effects of dysregulated inflammation (SIRS):
1) Systemic vasodilation and reduced blood volume –poor organ perfusion with TNF-α, IL-1, IL-6 and endothelial cell activation.
2) Impaired O2 delivery intravascular coagulation – restricted blood flow.
3) Lactic acidosis, cellular dysfunction and multi-organ dysfunction.
4) ATP levels fall Mitochondria (Mt) function and cell performance falls
5) Mt dysfunction can lead to cell death (tissue necrosis) but NOT in sepsis.
6) In sepsis Mt may adopt a low energy state (Singer, 2014).
7) May explain rapid recovery of organ function once systemic inflammation resolves.
What does mitochondria consume?
What are the 5 roles of mitochondria?
What occurs in diseases where the electron transport chain is terminated early?
What 4 things does 02 consumption lead to the formation of?
What is the role of these products?
How are these products formation affected with SIRS?
What 2 other things mitochondria is responsible for?
What can mitochondria with low levels of ATP trigger?
- Mitochondria consume 98% of body oxygen supply O2 to:
1) Produce ATP
2) Generate heat
3) Regulate extracellular calcium
4) Regulate temperature
5) Produce Reactive Oxygen Species (ROS) - Include peroxides, super oxide, hydroxyl radical and singlet oxygen – they are required for signalling, to maintain vascular tone and act as O2 sensors
- In disease, increased premature termination of the electron transport chain leads to excessive ROS formation
- Mt protects against ROS excess by producing antioxidants (Examples of ROS - superoxide dismutase, glutathione, thioredoxin)
- BUT in severe disease antioxidants can be overwhelmed by [ROS]
- O2 consumption results in endogenous gas generation (normal):
1) Carbon dioxide CO2
2) Carbon monoxide CO
3) Nitric Oxide NO
4) Hydrogen sulfide HS - These gases are Important regulators of mitochondrial signalling in health
- In inflammatory disease (SIRS) higher concentrations of CO, NO and HS exert proportionate inhibition of Mt respiration and increase in ROS generation
- Mitochondria is also responsible for:
1) Site of cortisol production and tri-iodothyronine and oestrogen action
2) Heme and Iron clusters are synthesised in Mt - Mt with ATP levels below a certain threshold can trigger cell death – therefore effects of Mt (inhibition) fundamental to cell function and survival.
What are 2 of the products of inflammation?
What do these 2 products controls?
How do they do this? What does this lead to?
- Inflammation leads to Elevated NO and superoxide (SO) production
- Normally NO and SO control protein function (post translational control)
- This is done by:
1) Oxidation
2) Nitrosylation
3) Nitration
4) Acylation - Therefore, deregulated inflammation (SIRS) affects protein function
What are 5 systemic effects of dysregulated inflammation on Mitochondria?
How does mitochondria try to compensate for reduced ATP?
What does this affect the organs?
What happens to the organs when inflammation resolves?
Is this real or a theory?
- 5 systemic effects of dysregulated inflammation on Mt:
1) Impaired perfusion, reduced 02 to tissues to fuel electron transport and ATP generation
2) NO, CO, HS and the ROS’s inhibit Mt respiration and cause direct damage to Mt proteins
3) Hormonal alterations affect Mt function
4) Genes transcribing Mt proteins are down- regulated early in septic process
5) Metabolic consequences – ATP levels fall but in sepsis cell death does not occur (as would be expected in other low ATP situations) - Mitochondria tries to compensate for reduced ATP by adopting a decreased metabolic rate
- Decrease in cell functionality within the tissue/system that is manifest as organ dysfunction.
- When inflammation resolves organs recover
- Mt Hibernation is a new hypothesis in the pathophysiology of sepsis
What is risk stratification?
What 3 levels do we consider in the triage of sepsis?
What 3 monitoring methods are used?
What 4 measurements determine high risk?
What 3 things should be considered in ICU involvement?
- Risk stratification enables providers to identify the right level of care and services for distinct subgroups of patients
- 3 levels do we consider in the triage of sepsis:
1) L1 (ward) – 1 nurse to about 6-8 patients
2) L2 (HDU – high dependency unit) – 1 nurse to about 3 patients
3) L3 (ICU – intensive care unit) – 1 nurse to 1 patient - 3 monitoring methods used:
1) Arterial line
2) Central line
3) Urinary catheter - High risk measurements:
1) Serum Lactate >4
2) Declining GCS
3) Declining urine output
4) qSOFA >2 (1pt for each criteria met) - What to consider in ICU involvement:
1) Note logistics of HDU/ICU units
2) Request to review vs request to admit to ICU
3) Use ‘SBAR’ to communicate
What 3 ways do we identify/treat sepsis/ vulnerability to sepsis early?
- How we identify/treat sepsis/ vulnerability to sepsis early:
1) EWS – early warning scores (FEWS in Fife, NEWS everywhere else)
2) CCOT – Critical Care Outreach Team – Team of doctors/nurses that identify high fevers/EWS scoring can identify sepsis/vulnerability to sepsis early
3) EGDT – Early Goal Directed Therapy - EGDT promotes prompt recognition of sepsis followed by starting up a treatment “bundle” within the first 3 to 6 hours following diagnosis
