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Medicine Year 1 - Semester 2 - Part 2 > Sepsis > Flashcards

Sepsis Flashcards

1
Q

Statistics regarding sepsis

A

Accounts for 1/5 of all deaths globally

3 million deaths in children <5

85% of cases are in Low+Middle income countries

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2
Q

Sepsis in the UK

A

1 dies in the UK every 12 minutes

2 in 5 have major complications of sepsis (major disability/ limitation)

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3
Q

qSOFA score

A

Used to rapidly identify sepsis.

Features include:

Respiratory rate : 22/min or greater
Systolic blood pressure : 100 mmg Hg or less

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4
Q

What does qSOFA look at ?

A

Organ dysfunction

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5
Q

Sepsis

A

Life-threatening organ dysfunction caused by a dysregulated host response to infection.

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6
Q

Septic shock

A

A subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone.

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7
Q

Septic Shock features

A

Subset of sepsis
Organ Dysfunction

  • Persistent hypotension requiring vasopressors to maintain MAP>= 65 mmHg
  • Serum lactate >= 2mmol/L
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8
Q

SIRS

A

Systemic Inflammatory Response Syndrome

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9
Q

What does SIRS do ?

A

Reflects the usual, expected and useful host immune responses.

Typically, represent responses to infection.

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10
Q

Key features of SIRS - systematic inflammatory response syndrome

A

2 or more of:

Temperature >38 or <36

Heart rate >90/min

Resp rate >20/min

White cell count > 12,000/mm3

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11
Q

Data on SIRS

A

Now thought to lack both specificity and sensitivity

Sepsis is not an inevitable consequence of escalating inflammation.

Sepsis involves anti- and pro- inflammatory pathways.

SIRS is still useful but has limitations

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12
Q

Non-infection causes

A

Severe burns
Pancreatitis
Severe trauma
Ischaemia- reperfusion injury

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13
Q

Inflammation

A

Automated, early, rapid and protective responses

Directed at the site of infection, injury or trauma

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14
Q

Features of inflammation

A

Heat
Pain
Redness
Swelling

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15
Q

Celsus Tetrad

A

Calor
Dolor
Rubor
Tumor

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16
Q

Heat

A

Inhibiting or Mitigating pathogen expansion

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17
Q

Pain

A

Protective alert mechanism, encouraging withdrawal/action

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18
Q

Redness

A

Increased blood flow, facilitating access to site of injury

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19
Q

Swelling

A

Local fluid accumulation, cellular influx, pro-thrombotic, creating a seal

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20
Q

Localised regulated inflammation

A

Resident cells able to immediately recognise and response

Use of surface receptors, signal transduction and downstream responses to effect immediate changes

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21
Q

What are Toll-like receptors ?

A

Critical (host) cell receptors

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22
Q

Function of TLRs

A

TLRs and CLRs identify and signal downstream responses to attempt to address pathogen.

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23
Q

PRRs

A

Pattern Recognition receptors

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24
Q

Function of PRRs

A

Pattern recognition receptors are evolved to recognise abnormal patterns

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25
Q

PAMP

A

Pathogen Associated Molecular Patterns

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26
Q

Function of PAMPs

A

Pathogen Associated Molecular Patterns trigger such responses

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27
Q

NLRs

A

Nod-like receptors

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28
Q

CLRs

A

C-lectin type receptors

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29
Q

Most severe type of sepsis

A

Gram negative sepsis through TLR4

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30
Q

What is TLR4 associated with ?

A

LPS
Lipopolysaccharide

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31
Q

Function of TLR4

A

TLR4 is the major receptor for lipopolysaccharide (LPS), the major trigger for gram-negative sepsis.

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32
Q

Action of TLR4

A

TLR4 uses 2 accessory molecules in a complex

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33
Q

Function of TLR3

A

TLR3 is expressed on the endoscope inner surface - well placed to recognise PAMPs - specifically Virus associated (RNA) PAMPs

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34
Q

What is TLR5 associated with ?

A

Flagellin

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35
Q

Downstream effects of TLRs

A

Inflammatory cytokines response

36
Q

Function of activated TLRs

A

Regulate genes responsible for:

  • Cardiovascular regulation
  • Immune regulation
  • Hormonal control
  • Coagulation
  • Metabolism
  • Bio-energetic systems
37
Q

What is implicated in downstream drivers of inflammation by TLR activation ?

A

Mitochondrial function

38
Q

What is found in activated TLRs ?

A

Pro-inflammatory cytokines, chemokine and cytokine receptor genes found in cells with activated TLR are up-regulated

e.g. TNFalpha, IL-1, IL6

39
Q

Results of activated TLRs

A

Increased blood flow
MHC expression

Cortisol, oestrogen, adrenaline
Platelet activation

Metabolism - increased
Mitochondrial - varied responses

40
Q

Results of dysregulated inflammation

A

SIRS / Sepsis

41
Q

Describe dysregulated inflammation

A

Systemic vasodilation and reduced blood volume.

Impaired O2 delivery, intravascular coagulation - reduced blood flow

Lactic acidosis, cellular dysfunction and multi-organ dysfunction.

ATP levels fall, mitochondria function and cell performance falls

Mitochondria dysfunction can lead to cell death (tissue necrosis) but NOT in sepsis.

In sepsis, Mitochondria may adopt a low energy state.

This may explain recovery of organ function once systemic inflammation resolves.

42
Q

Systemic vasodilation and reduced blood volume

A

Poor organ perfusion with TNF-alpha, IL-1, IL-6 and endothelial cell activation

43
Q

Describe mitochondria in sepsis

A

IN sepsis, the mitochondria may adopt a low energy state.

44
Q

Key feature of dysregulated inflammation

A

Lactic acidosis
Cellular dysfunction
ATP levels fall
Mt (mitochondria) function falls

45
Q

State the major role of mitochondria

A

Generation of ATP

Production of reactive oxygen species (ROS)

Note: Mitochondria consume >95% of the body’s oxygen supply

46
Q

Functions of mitochondria

A

Generation of heat, thermoregulation

Cell signalling
Intracellular calcium regulation

Inflammasome assembly

Initiation of cell death

47
Q

What is the mitochondria the site of ?

A

Site of production (e.g. cortisol) OR action (e.g. oestrogen) of several hormones

Synthesis of heme and iron-sulfur clusters (cofactors in the electron transport chain)

48
Q

How is the electrochemical gradient generated ?

A

An electrochemical gradient is generated across the inner mitochondrial membrane.

The result proton gradient in complex V (ATP synthase) drives ADP to ATP.

49
Q

ROS

A

Reactive oxygen species

50
Q

Describe mitochondrial dysfunction in sepsis

A

Impaired ATP generation

Micro- and Macrovascular (endothelial) complications

Increased ROS, in response to PAMPs, DAMPs

Pro-inflammatory cytokine release
Hyper-inflammatory release

51
Q

Mitochondrial dysfunction

A

Electron transport chain complex dysfunction (I, III, IV)

52
Q

What does mitochondrial dysfunction lead to ?

A

Compromised immune function

Compromised metabolic function of end-organisms : multi-organ dysfunction

Hyper-inflammatory state, loss of haemostasis

53
Q

Impact of dysregualted inflammation on Mt

A

Impaired perfusion, reduced O2 to tissues to fuel electron transport and ATP generation.

Hormonal alterations affect Mt function.

54
Q

What damages Mitochondria (Mt) ?

A

NO, CO, HS and the ROS inhibit Mt respiration and damage Mt proteins

55
Q

What is down-regulated in early septic processes ?

A

Genes transcribing Mt proteins are down-regulated early in septic processes.

56
Q

Metabolic consequences of dysregulated inflammation ?

A

ATP levels fall, but in sepsis cell death does not occur (as would be expected in other low ATP situations)

This may lead to dysfunction and ‘damaging’ mitochondrial biogenesis, aggravating pro-inflammatory responses.

57
Q

Mitochondria as ‘quality control’ in sepsis

A

Critical roles in:

Supplying energy and metabolic intermediated for immune cell activation

Influencing inflammatory and cell death pathways

58
Q

Mitophagy

A

Destruction of dysfunctional mitochondria to limit associated damage cascades

59
Q

DAMPS

A

Damage associated molecular patterns

60
Q

Describe proposed mitochondrial / cell hibernation

A

Mt adopt decreased metabolic rate to compensate for reduced ATP concentration.

Decrease in cell functionality within tissue/ system - organ dysfunction

So, when inflammation resolves, the organ can recover

61
Q

Function of mitochondrial research

A

Better understand fundamental processes relevant to many diseases.

62
Q

What does sepsis lead to ?

A

Sepsis is the result of infection that leads to tissue damage - distal to the site of infection

Dys-regulated inflammation following infection

63
Q

Key risk factors for sepsis

A

Elderly >75
Very young <1

Impaired immune systems - due to illness/treatments

Post-operative (6 weeks)

64
Q

Impaired immune system

A

Cancer, Chemotherapy, DM, Splenectomy, Sickle cell, Steroids

65
Q

State some other risk factors for sepsis

A

Loss of skin integrity: cuts, burns, IV drug users

Women - pregnancy/ postnatal

Neonatal - GBS (group B strep), PROM (prem rupture of membranes)

66
Q

Pathogens causing sepsis

A

Neisseria meningitidis

Strep pneumoniae
Strep pyogenes

Staph aureus

Salmonella typhimurium
Aspergillus fumigatus

67
Q

Types of sepsis

A

Bacterial
Viral
Fungal

68
Q

Presentation of sepsis

A

Wide range of symptoms and signs

May include source of infection / trigger

Usually reflects broad systemic response of sepsis

69
Q

Things to consider in the presentation of sepsis

A

Localising symptoms/signs that point to the underlying cause

General symptoms or signs that reflect the severity of sepsis

70
Q

Localising symptoms/signs that point to the underlying cause

A

Dysuria
Red hot knee

Inflamed site around cannula

Diarrhoea

71
Q

General symptoms or signs that reflect the severity of sepsis

A

Reduced consciousness

Tachypneoa
Light-headedness

Low BP

72
Q

Clinical findings - CNS

A

Headache
Photophobia
Confusion
Seizure

73
Q

Clinical findings - Respiratory

A

Productive cough
Haemoptysis
Breathlessness

74
Q

Clinical findings - Cardiovascular

A

Murmur
Chest pain

75
Q

Clinical findings - GI

A

Diarrhoea
Abdominal pain

76
Q

Clinical Findings - renal

A

Loin pain
Dysuria
Anuria

77
Q

Clinical Findings - Joints/Skin

A

Erythema
Swelling
Tenderness
Cyanotic / Mottled

78
Q

Clinical findings - other

A

Fever
Migrane

Severe myalgia

79
Q

SOFA

A

Sequential organ failure assessment score

80
Q

qSOFA - memory aid

A

15 22 00

<15 altered mental state GCS
>22 respiratory rate
<100 blood pressure - low

81
Q

ROC curve values - diagnostic

A

0.7-0.8 OK
0.8-0.9 Very good

> 0.9 excellent

82
Q

qSOFA diagnostic score

A

0.81

Very good diagnostic tool

83
Q

Early immune response

A

TLRs

Release of IL-1, IL-6, IL-8 etc

Activation of complement, coagulation and phagocytes

84
Q

Cellular immune response

A

Activation of B cells, neutrophils, myeloid derived suppressor cells

85
Q

Humoral immune response

A

Production of immunoglobulins (IgM, IgG)

86
Q

Anti-inflammatory events

A

Decrease of HLA-DR expression

T-cell exhaustion

Apoptosis of immune cells (lymphocytes, monocytes and antigen presenting cells )

87
Q

Describe sepsis

A

System-wide release of cytokines, mediators and pathogen related molecules

Activation of coagulation ad complement pathways

Widespread inflammation, tissue damage, multi-organ dysfunction.

Medicine Year 1 - Semester 2 - Part 2 (53 decks)

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