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Pathophysiology of ill-health > Sepsis > Flashcards

Sepsis Flashcards

1
Q

Pyrexia - what is it?

What benefits does it have?

A

Fever

Pyrexia inhibits bacterial growth and mobilises immune defences, damaging membranes of both the body and the bacterial cells

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2
Q

Classic Symptoms of Sepsis?

A
  • Hypo or hyper-thermia
  • Elevated heart rate (>130 BPM)
  • Low blood pressure
  • Hypoxia /Hypoxaemia
  • Shadowing on chest X-ray (‘white-out’) - fluid in the lung tissue due to inflammatory mediators
  • Elevated white blood cell count - or reduced!
  • Hyperglycaemia
  • Altered mental state / consciousness
  • Decreased urine output(<0.5ml/kg/hr)
  • Coagulopathy - problems with clotting
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3
Q

2 x famous pyrogens?

what do they do?

A
  • Tumor Necrosis Factor
  • Interleukin 1

Both travel in the blood, to work directly to lower the set-point via the hypothalamus - heat conservation and generation mechanisms are initiated e.g. shivering

OR indirectly via release of prostoglandins

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4
Q

What happens when cell membranes are broken down?

A

e.g. through trauma, bacterial infection

Bigger the insult, bigger the pyrogen release

Release pyrogens (proteins)

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5
Q

What are cytokines?

A

Pro-inflammatory proteins, chemical messengers produced by damaged tissue and WBC’s

e.g. IL-1, TNF

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6
Q

What does TNF do?

A

Acts on hypothalamus directly.
Induces IL-1 and IL-6 release

Macrophage activation

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7
Q

How can you explain pyrexia?

3 ways

A
  1. Release of pyrogens
  2. Direct action of cytokines
  3. Increased metabolic rate (organs fighting infection work harder)
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8
Q

How does Pyrexia damage human tissue?

A
  • Disrupting the Golgi apparatus
  • SWELLING THE MITOCHRONDIA (inhibiting ATP production)
  • Change cellular permeability
  • Disrupt the nucleus and aggregation of chromatin (DNA + proteins in nucleus)
  • Elevating protein synthesis
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9
Q

What symptoms are explained by fever & reduced ATP production?

A
  • normal electrical activity - heart, nervous system
  • cardiac arrest
  • seizures
  • changes in level of consciousness
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10
Q

Sepsis can also cause hypothermia - why?

A

Poor oxygen delivery to tissues - organs start to shut down

Liver - under-perfused, become cold

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11
Q

Elevated heart rate - why/how?

3 x explanations

A
  1. Stress response - the Sympathetic nervous system stimulates an increased release of ADRENALINE and NORADRENALINE from the ADRENAL MEDULLA (stress response), stimulating heart rate and contractibility by acting upon ALPHA and BETA receptors in the heart
  2. In response to falling blood pressure (low circulating volume) - Baroreceptors -> Medulla Oblongata -> Vagus nerve (release the break) - > increased HR
  3. Sweating due to fever - dehydrated, this can drop BP
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12
Q

Elevated Respiratory Rate - how / why?

A
  1. Acidosis - falling pH

BP low? perfusion to tissues is low, respiration becomes anaerobic? -> lactic acid/ lactate

BP low? perfusion to kidney is low, this can impact urine output - retain hydrogen

Fast HR? More CO2 being produced - acidosis

ALL CAUSES…

Chemoreceptors -> Medulla Oblongata -> Phrenic and respiratory nerves -> stimulates lungs!

  1. Stimulation of medulla oblongata by endotoxins and other inflammatory mediators (e.g. TNF) has been proposed as a cause
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13
Q

Inflammatory Mediators:

A

Histamine
Bradykinin
Cytokines - TNF, IL-1,2,3 etc.

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14
Q

What does HISTAMINE do?

A

Makes the capillary wall and the alveoli wall increasingly permeable. A profound vasodilator. Found in MAST and BASOPHIL cells.

Water leaves capillary bed into alveoli

relevance for anaphylaxis

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15
Q

Why can you have ‘white out’ on a chest x-ray due to Sepsis?

A

Due to release of inflammatory mediators, cells become increasingly permeable, water leaves capillary bed and enters alveoli.

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16
Q

Why might someone with sepsis become hypoxic?

A

Inflammatory mediators -> permeability of cells, fluid into alveoli

Switch from aerobic to anaerobic respiration (fewer ATP’s)

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17
Q

Compare Anaerobic and anaerobic respiration

A

Aerobic - 36 ATP

Anaerobic - 2 ATP’s plus lactate and lactic acid

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18
Q

What is the difference between lactate and lactic acid?

A

Lactic acid increases in anaerobic respiration due to a lack of oxygen being delivered to cells resulting in anaerobic respiration producing large numbers of hydrogen acids.

Lactate is an alkali bicarbonate substance - it increases in your cells in an attempt to buffer lactic acid and normalise pH levels in cells.

pH reducing due to hypoxia…as pH falls, lactate increases

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19
Q

Why other than anaerobic respiration, can someone have high levels of lactate?

A

If tissues are poorly perfused, if you have kidney or liver problems.

Lactate is metabolised by liver (50%) and kidneys (20-30%)

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20
Q

Elevated WBC count- how / why?

Lymphocytes

A

Lymphocytes develop and mature as a young child

They dormant until activation - called lymphocyte proliferation

The body has only a few lymphocytes that recognise invading organisms, but hundreds of thousands are required to fight infection

Body has a ‘memory’ of previous pathogen - when phagocytosis takes place a ‘warning system’ is set up - phagocyte kills the pathogen, then retains a tiny tiny amount of pathogen DNA- in the future helper T cell can be quickly activated - WBC quickly divide and increase.

HIV destroys Helper T cells - this is why it is so devastating to immune system - normally trivial infection becomes serious

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21
Q

Hypotension - how / why?

A
  1. Dehydration can lead to hypotension (via increased respiratory rate OR fever)
  2. Widespread vasodilation and increased tissue permeability -> BP will fall

due to 4 x classic inflammatory mediators

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22
Q

What does KININS do?

e.g. BRADYKININ

A

Kinins are rapidly generated in blood plasma after tissue injury leading to VASODLATION, INCREASED VASCULAR PERMEABILITY and CELL MIGRATION

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23
Q

What does CYTOKINES do?

A

Protein, chemical messengers produced by damaged tissue and WBC

e.g. IL-1, TNF

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24
Q

What are the 4 x classic inflammatory mediators

A
  • Cytokines
  • Prostoglandin
  • Kinins
  • Histamine
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25
Q

Altered Mental State - how/ why?

Slurred speech?

A

Optimal brain funct. requires stable brain environ - pH, temp, o2, glucose delivery

Hypo-perfusion

Not entirely understood, believed t be a problem with protein/ amino-acid metabolism

= poor oxygen, poor cellular activity

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26
Q

Hyperglycaemia - how / why?

A

Stress response…

Glucagon releasing cells in the pancreas are stimulated to release glucagon into the liver, this acts on the liver, this breaks down glycogen into glucose into the bloodstream.

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27
Q

Decreased urine output - how / why?

A
  1. Poor perfusion to kidneys due to low BP

The renal system responds to hypotension by stimulating RENIN secretion from the juxtaglomerular apparatus in the bowman’s capsule of the nephron.

Renin converts ANGIOTENSIN to ANGIOTENSIN 1, which is subsequently converted to ANGIOTENSIN 2 by the lungs

ANGIOTENSION 2 has 2 x effects:

  • vasoconstriction of smooth muscle
  • stim of aldosterone by adrenal cortex
  1. Hypothalamus senses decreased blood volume / increased osmolarity

ADH is released from the posterior pituitary gland in response to a decrease in BP (detected by baroreceptors)

ADH indirectly leads to an increased reabsorption of water and salt by the distal tubule, the collecting ducts and the loop of Henle in the nephron

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28
Q

ANGIOTENSION 2 has 2 x effects:

A
  • vasoconstriction of arteriolar smooth muscle
  • stimulation of ALDOSTERONE secretion by the adrenal cortex

this increases salt and water conservation in the kidney, thereby reducing urine output

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29
Q

What does ALDOSTERONE do?

A

Increases salt and water conservation in the kidneys

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30
Q

What does ADH do?

Anti-diuretic hormone

A

Hypothalamus senses decreased blood volume / increased osmolarity

ADH is released from the posterior pituitary gland in response to a decrease in BP (detected by baroreceptors)

ADH indirectly leads to an increased reabsorption of water and salt by the distal tubule, the collecting ducts and the loop of Henle in the nephron

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31
Q

Coagulopathy - how / why?

A

The ENDOTHELIUM lining of blood vessels is a major contributor to the inflammatory response and is an active metabolic organ responsible in part for both coagulation and anticoagulation

-> during inflammatory response, mediators are released into the bloodstream leading to uncontrolled intravascular inflammation.

LIVER- involved a lot in clotting, a lot of the clotting substances are metabolised by the liver

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32
Q

What does osmolarity mean?

A

The concentration of a solution expressed as the total number of particles per litre.

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33
Q

Fibrin

Dissolving fibrin clot

A

fibrin clot - coagulation part of healing

= anticoagulation part of healing, strongly suggested that ENDOTHELIAL LINING controls how long you clot for , how long you pause, and when the clot is broken down

Inappropriately clotting and bleeding - coagulopathy (explains mottled / strange skin appearance)

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34
Q

Sepsis - definition

A

A life-threatening organ dysfunction due to a dysregulated host response to infection

  • Sepsis Campaign & EICS
    (SC = offshoot of European Intensive Care Society)
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35
Q

‘Dysregulated’ ?

A

Normal responses / changes become problematic - e.g. induce a seizure

36
Q

What’s unclear?

A

Why one person may have normal

37
Q

Infection - definition:

A

Microbial phenomenon characterised by an inflammatory response to the presence of micro-organisms or the invasion of normally sterile host tissue by those organisms

e.g. bactaraemia

38
Q

bactaraemia

A

presence of viable bacteria in the blood

39
Q

Global burden of sepsis?

A

Difficult to ascertain - WHO 2018

30 million people worldwide each year

Estimated that 3 million new-borns and 1.2 million children suffer from sepsis globally each year

40
Q

3 of every 10 deaths due to neonatal sepsis are thought to be caused by what?

A

Resistant pathogens (WHO 2018)

41
Q

How often does someone die of sepsis in the UK?

A

Every 4 hours.

Sepsis Campaign (Sepsis Research 2020)

42
Q

How many deaths annually in the UK?

A

52,000 deaths in the UK each year (more than breast and bowel cancer combined)

Sepsis Campaign (Sepsis Research 2020)

43
Q

How many people die globally each year from sepsis?

A

Around 11 million people per year

That’s 1 in 5 of all deaths

Sepsis Campaign (Sepsis Research 2020)

44
Q

Where does sepsis stand in comparison to other diseases?

A

Number 1 cause of preventable death in the world

Up to 15,000 lives a year could be saved in the UK through prompt diagnosis and treatment

Sepsis Campaign (Sepsis Research 2020)

45
Q

York Health Economics Consortium (YHEC)

A

Over 14,000 lives a year could be saved in the UK through prompt diagnosis and treatment

Costs £15.6 billion per year in the UK - £2.8 billion could be saved

One in four NHS hospital trusts is failing to give antibiotics to half their patients with sepsis in the recommended timeframe

46
Q

How many deaths associated with pregnancy and childbirth is due to maternal sepsis?

A

one in ten

-WHO, 2018

47
Q

Who is at risk of sepsis?

A

Anyone, especially vulnerable populations e.g.

  • elderly
  • pregnancy
  • neonates
  • those in hospital
  • chronic health conditions
48
Q

60% of cases of sepsis are caused by?

A

Bacteria!

Can also be virus, fungi, parasites…

49
Q

Parts of bacteria?

A 
ribosome
mesosome
plasma membrane
CELL WALL
capsule
plasmid DNA
bacterial flagelium
chromosomal DNA (floating in cytoplasm)
fimbriae
50
Q

What do bacterial cells not have that humans do?

A

ER
golgi bodies
cell
nucleus

51
Q

What do antibiotics tend to do?

A

Damage the cell wall of bacteria

52
Q

How do bacteria replicate?

How fast?

A

Via binary fission - requires protein synthesis (cell division)

Can multiple 2.x every 20 minutes!

53
Q

How can you test bacteria?

A

Gram stain test

54
Q

Gram stain test - what does +/- mean

A

Gram +ve : Stains purple, thick cell wall

Gram -ve : Not coloured, thinner cell wall, have an additional lipid coat (phospholipid)

55
Q

Gram stain test (Hans Gram)

A
  • Differentiates bacteria based on whether or not stain

- respond to thickness of cell wall

56
Q

How can bacteria be classified?

A

By shape:

  • Cocci (spherical)
  • Bacili (rod-shaped)
  • Spirals
  • Strept - chains
  • Staph - bunched together

By gram stain

57
Q

Examples of bacteria which are:

  • Cocci (spherical)
  • Bacili (rod-shaped)
  • Spirals
A
  • bacili - anthrax (gram+ve)
58
Q

Example of

Gram positive bacteria

Gram negative bateria

A

Gram +ve: streptococcus pneumoniae

Gram -ve: e-coli

59
Q

Endotoxin: Definition

A

Structural components of bacterial cells - part of the cell wall (Lipopolysaccharides)

Liberated when bacteria is destroyed by the immune system

Toxic to human cells

60
Q

Endotoxin - what are the effects?

A

Stimulates:

  • TNF (cytokine protein)
  • IL-1, IL-2
  • Histamine (vasodilator -> permeability of cells fluid-> into tissues)
  • Bradykinin (vasodilator)
  • Prostaglandin
  • Activation of coagulation system

meaning dead bacteria can continue to damage cells post-death

61
Q

Exotoxin: Definition

A

Products of micro-organisms that are harmful to the host - some produce one significant toxin e.g tetanus

62
Q

Bacteria with endo and exotoxin?

A

Pseudomonas

63
Q

Examples of enzymes(?) released by bacteria and their actions:

A

STREPTOKINASE (streptococci) dissolves fibrin clots this preventing the isolation of infection by the inflammatory response

HYALURONIDASE
(pneumococci, streptococci, staphylococci) digest ell membrane permitting tissue penet

64
Q

Examples of ENZYMES released by bacteria and their actions:

A

STREPTOKINASE (streptococci) dissolves fibrin clots this preventing the isolation of infection by the inflammatory response

HYALURONIDASE
(pneumococci, streptococci, staphylococci) digest ell membrane permitting tissue penetration

LEUOCIDIN
(staphylococci, streptococci) disintegrates phagocytes

  • note - all of these are streptococci

HAEMOLYSIN
(clostridia, staphylococci) dissolves red blood cells, inducing anaemia and limiting oxygen delivery

65
Q

Inflammatory response in sepsis is:

A

exaggerated, excessive

driven by bacterial endo and exotoxins

66
Q

What do the inflammatory mediators cause?

A

Widespread vasodilation and increasing permeability of tissues

In sepsis - driven by endo/extoxins

67
Q

What does PROSTAGLANDINS do?

A

A potent hormone-like substance found in most tissues, influences:

  • vascular tone
  • platelet aggregation
  • inflammatory response
68
Q

Skin - deter bacteria, why?

A
  • low pH
  • fatty acids in sebaceous secretions
  • presence of lysozymes
  • loads of resident bacteria
69
Q

What if bacteria gets in a cut?

process

A

They can release enzymes which can;

  • dissolve fibrin clots
  • dissolve cell membranes

Allowing travel into the circulatory system - 5 l per minute! ‘super-highway’

= bacteraemia (blood poisoning)

70
Q

Big WBC?

A

Macrophages

Monocytes

71
Q

What happens during bacteraemia?

A

Macrophages/monocytes hunting bacteria, bacteria ‘hunting’ WBC’s

  • Bacteria gains entry
  • Bacterial ENDOTOXIN binds to CD14 MACROPHAGE receptor
  • This stimulates release of TNF
  • TNF acts on numerous WBC, stimulating further cytokine release

AKA - CYTOKINE STORM

72
Q

Clinical Effect of TUMOUR NECROSIS FACTOR

pro-inflammatory mediator

A

Activation of inflammatory cascade

-> fever, hypotension, tachycardia, tachypnoea, hyperglycaemia, metabolic acidosis, third spacing (fluid shift)

73
Q

Clinical Effect of IL-1

pro-inflammatory mediator

A

Pyrogen

-> fever, increasing WBC, release amino acids from skeletal muscle, decreasing systemic vascular resistance AKA vasodilation (lower BP)

74
Q

Clinical Effect of IL-6

pro-inflammatory mediator

A

Fever, antibody secretion, neutrophil production

75
Q

Clinical Effect of IL-8

pro-inflammatory mediator

A

Stimulates neutrophil function and attracts inflammatory cells to the site of infection / injury

76
Q

Clinical Effect of TISSUE FACTOR

pro-inflammatory mediator

A

Initiates blood clotting

77
Q

Clinical Effect of INTERFERON - Y

pro-inflammatory mediator

A

‘interferes’ with the activity of virus’

  • Macrophage activation
78
Q

What is ‘third spacing’?

A

Fluid shift in circulatory system

79
Q

cytokine storm?

A

sudden, dramatic release of inflammatory mediators following bacterial stimulation of endotoxin of CD14 receptors (found on white macrophage cells)

80
Q

Sequential Organ Failure Assessment (qSOFA) HAT i.1. 2 or more of the following:

A

HAT

H - hypotension SBP less than or equal to 100 mmHg (mm mercury) - but, consider baseline
A - Altered mental state
T - Tachypnoea RR greater or equal to 22

*Critique - BTS - RR above 30

NICE / RCUK - 25 and above

81
Q

Assessment for Sepsis?

A

qSOFA (Sequential Organ Failure Assessment):

82
Q

Respiratory rates - when to worry?

A

NICE / RCUK - 25 and above

BTS- 30 and above

qSOFA - 22 and above

83
Q

Respiratory rate - what do you assess?

A

Rate, depth, pattern

84
Q

Classic sepsis symptoms:

A
  • Fast HR over 90 BPM
  • High or low WBC (under 4,000 /mml or over 12,000 mmL)
  • High lactate over 4
  • Temperature over 38 or under 36
  • Hypoxaemia
  • Decreased urine output (0.5/kg/hr minimum)
  • Hyperglycaemia
  • Coagulopathy
85
Q

NICE Risk stratification tool for suspected sepsis - what

A
  • Altered level of consciousness
  • Raised RR, 25 p/m or more
  • Low systolic BP, or a drop
  • Sig increased HR
  • Poor urine output
  • Mottled or ashen appearance
  • Rash?
  • Cyanosis
  • BUT - only mention of temperature is BELOW 36 degrees
86
Q

NICE ‘red flag’ tool

A

ONE:

Unresponsive / pain / voice
Fast HR
Fast RR
Cyanosis
Poor urine output
Elevated
87
Q

Parliamentary and Health Service Ombudsman (2013)

S E P S I S

A 
S - Slurred speech
E - Extreme muscle pain
P - Passing no urine
S - Severe breathlessness
I - I feel I might die
S - Skin mottled / discoloured

Pathophysiology of ill-health (16 decks)

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