Pathophysiology and Treatment of Sepsis

Question 1

Define sepsis.

Answer 1

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

Question 2

Define septic shock.

Answer 2

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

Question 3

Describe the incidence of sepsis.

Answer 3

44,000 deaths in the UK

Globally: 20 million cases annually with mortality around 35% - second leading cause of death after vascular disease

Question 4

How much does sepsis cost the NHS annually ?

Answer 4

Costs the NHS £2.5 billion per year

Question 5

Where is sepsis generally acquired ?

Answer 5

Can be both community and hospital acquired

Question 6

Describe the epidemiology of sepsis. Any populations at a greater risk ?

Answer 6

• Very young (< 1 year) and older adults (>75 years) or the very frail (although it affects all ages)
• Those with impaired immune system due to illness or medication (cancer, diabetes, spleen removed, rheumatic disease)
• Those who have had surgery/invasive procedure in last 6 weeks
• Anyone with breach of skin integrity (cuts, burns, blisters, skin infection
• People who misuse drugs intravenously
• People with indwelling lines or catheters
• Women who are pregnant, have given birth or had a termination of pregnancy or miscarriage in last 6 weeks
• Neonates
• Possibley a genetic factor

Question 7

Describe the aetiology of sepsis.

Answer 7

• Vary significantly depending on region, hospital, season, type of unit
• Pathogenic organisms identified in only around half of cases of sepsis
• Source: (pretty much anything)
– Respiratory Tract (around 60%)
 – Abdomen (26%)
– Bloodstream (20%)
– Skin (14%)
– Urinary system (12%)
– Unknown source (20-30%)

Question 8

Identify some key causative pathogens of sepsis.

Answer 8

GRAM NEGATIVE SEPSIS (most common, 60%)
• Enterobacteriaceae (e.g. E Coli, Klebsiella pneumoniae)
• Pseudomonas aeruginosa
• Neisseria meningitidis
• Salmonella typhimurium

GRAM POSITIVE SEPSIS
• Staphylococcus aureus (including MRSA)
• Coagulase negative Staph, Enterococci and Streptococci (e.g. Strep Pneumonia, Strep pyogenes)

FUNGAL INFECTIONS
Candida

Question 9

Which organisms are especially involved in post-splenectomy sepsis.

Answer 9

Encaspulated organisms

Question 10

What barriers are breached in sepsis ?

Answer 10

Physical barriers (skin, mucous membranes, can also be more subtle like epithelial cell damage)

Question 11

How may barriers be breached, in sepsis ?

Answer 11

– Catheters
– Wounds
– Burns
– Thorn pricks
– Insect bites

Question 12

Identify the main factors affecting infection, in sepsis.

Answer 12

• Virulence of pathogen
• Bioburden
• Portal of entry
• Host susceptibility
• Temporal evolution

Question 13

Explain how virulence of the pathogen affects infection in sepsis, using a specific pathogen as an example.

Answer 13

STREPTOCOCCUS PYOGENES

Before release of endotoxins:
• Cellulitis/impetigo
• Local pain

After release of endotoxins: 
• Cellulitis
• Toxic shock
• Hypotension
• Altered mental state

Question 14

Define bioburden, and explain how bioburden affects infection in sepsis, using a specific pathogen as an example.

Answer 14

Bioburden = Number of viable bacterial cells

SALMONELLA TYPHIMURUIUM

10^3 CFUs:
• Gurgling tummy
• Loose stools

10^5 CFUs:
• Haemorrhagic colitis
• Fever
• Abdominal pain

Question 15

Explain how portal of entry affects infection in sepsis, using a specific pathogen as an example.

Answer 15

KLEBSIELLE PNEUMONIAE

Renal: 
• Tachycardia 
• Fever
• UTI
(may still end up with a chest infection) 

Chest:
• Tachycardia
• Fever
• Hypotension

Question 16

Explain how host susceptibility affects infection in sepsis, using a specific pathogen as an example.

Answer 16

STREPTOCOCCUS PNEUMONIAE

Fit Adult:
• Fever
• Pneumonia

Elderly (more comorbidities, possibly immunosupressed):
• Fever
• Pneumonia
• Physical unsteadiness 
• Confusion
• Altered mental state

State of nourishment (malnourished ?) can also affect state of the immune system (thereby making host more susceptible).

Question 17

Explain how temporal evolution affects infection in sepsis, using a specific pathogen as an example.

Answer 17

NEISSERIA MENINGITIDIS

Early: 
• Rash
• Fever
• Malaise
• Headache
• Myalgia
• Arthralgia

Late:
• Septic shock
• Altered mental state
• Hypotension

The nature of the pathogen (does the pathogen work acutely i.e. is it going to resolve quickly, or does it have slow growth i.e. is it going to cause more chronic problems). For instance Hep A has shorter incubation period than Hep B (people feel better relatively quickly). Hep B on the other hand is a chronic problem.
Other example, Lyme disease, may only show symptoms after 2 months.

Question 18

Describe the role of the immune system in sepsis.

Answer 18

Sepsis is immune cell driven, mainly by cells of the innate immune system. Whereas most immune responses are very local, sepsis is rather disseminated. Receptors in the innate immune system such as Toll-like receptors (surface receptors, notably present on dendritic cells) and NOD-like receptors (intracellular, involved in recognition of pathogens i.e. PAMPS and recognition of damage i.e. DAMPS) detect the presence of pathogens and result in the overproduction of inflammatory markers including cytokines (e.g. Interleukins (ILs) and Tumour Necrosis Factor Alpha (TNFα)) and Reactive oxygen species (ROS).

Question 19

Identify the main components (molecules / cells / receptors) of innate immunity.

Answer 19

– Complement
– Mannose-binding lectin (MBL)
– Phagocytes
– Toll-like receptors (TLRs)
– Nucleotide-binding oligomerisation domain receptors (NLRs)

Question 20

Identify components of pathogens recognized by Toll-like receptors.

Answer 20

Flagellin, double stranded RNA

Question 21

What cells are interleukins produced by ?

Answer 21

Immune cells and damaged endothelial cells

Question 22

What are the main cytokines involved with sepsis ? What is their role ?

Answer 22

Interleukin 1 and Tumor Necrosis Factor α.

Involved in acute phase response:
• Fever (over 38, or possibly below 36)
• Hypotension
• Increased HR (usually above 100)
• Corticosteroid and ACTH release 
• Release of neutrophils
• Generalized vasodilation (NO.)
• Increased vascular permeability (activated leukocytes) (exudate leaks out, as do serum proteins)
• Intravascular fluid loss
• Myocardial depression (tissue hypoxia)
• Circulatory shock

Question 23

What kind of treatment can we target IL-1 and/or TNFα with ?

Answer 23

Monoclonal antibody therapy (e.g. infliximab against TNFα)

Question 24

What were the main findings from the Third International Consensus Definitions for Sepsis and Septic Shock ?

Answer 24

• Excessive focus on inflammation
• Misleading model of sepsis continuum (idea that patients travelled along continuum of sepsis, then severe sepsis, then septic shock is misleading, leading to imperfect management)
• Inadequate specificity and sensitivity of the SIRS criteria (missing cases)
• Multiple definitions and terminology currently in use (sepsis alone, septic shock alone)
• Conclusion that term severe sepsis was redundant

Question 25

What are the clinical criteria to identify patients with sepsis and septic shock, in critical care ?

Answer 25

1) SOFA and qSOFA (Sepsis-related organ failure assessment score):
- Patient with a suspected infection need to be examined using qSOFA (three variables: elevated respiratory rate above 22, drop in mental status, drop in systolic BP)
- if qSOFA suggests possible sepsis, assess for evidence of organ dysfucntion through SOFA (variables: PaO2/FiO2 ratio, GCS, MABP, serum creatinine or urine output, billirubin, platelet count, administration of vasopressors with type and dose rate of infusion)
- If so, treat for sepsis (MAY BE sepsis)

Question 26

What is SOFA graded out of ? At which point does it start getting bad ?

Answer 26

Each category out of 4, from 0 to 4.

2 is bad.

Question 27

How to we decide who to screen for sepsis ?

Answer 27

Consider Screening Patient For Sepsis if they:

1. Present with unexplained illness
2. Clearly look unwell and have a likely infective cause OR presents with (or subsequently deteriorate to) an individual parameter score of 3 or aggregate score of 4 or higher on NEWS/ locally derived equivalent

Once again, binary decision: this patient could have sepsis OR this patient does not have sepsis

Question 28

What is the problem with qSOFA ?

Answer 28

It is a pragmatic approach. How do we know who to screen ?

Question 29

What are other methods used to identify patients with sepsis and septic shock, in clinical care ?

Answer 29

1) NICE Guidelines (aims to identify which patients should immediately be commenced on life saving therapy)
- Is physiology abnormal (i.e. NEWS ≥ 3) and/or does the patient look very sick (because some patients e.g. dementia patient, patient under suppressant drugs may not trigger the NEWS variables) ?
- If so, is the history suggestive of infection ? (could be of unknown source, UTI, pneumonia, meningitis…)
- If so, is one red flag present ? (responds only to voice/unresponsive, systolic BP ≤ 90 mmHg, HR ≥ 130, respiratory rate ≥ 25, needs oxygen to keep Sp02 ≥ 92%, cyanotic/ashen, no urine output in last 18 hours/less than 0.5 ml/kg/hr)
- Any patient with presumed sepsis with ONE or more red flag should be assumed to have sepsis or septic shock and immediately commenced on SEPSIS SIX Care Pathway
- If no red flag, any Amber flag criteria ? (relatives concerned about mental status, acute deterioration in functional ability, immunosuppressed, systolic BP 91 to 100, HR 91-130 or new arrythmia, no urine output in last 12 hours, respiratory rate 21-24 or breathing hard, trauma/surgery in last 6 weeks)
- If Amber flag, start thinking it may be sepsis (start treatment and ask for senior clinician input)
- Once sepsis 6 pathway is underway, check for signs of organ dysfunction (using SOFA). If so, sepsis, continue treatment.

OVERALL, BINARY PROCESS: NO SEPSIS or MAY HAVE SEPSIS (in which case, start treating for sepsis)

2) SIGN Guidelines
- FEWS ≥ 3
- Assess for SIRS (Systemic inflammatory response syndrome)
- Any 2 of the following signs and symptoms of SIRS present ? (Temperature over 38 or under 36, HR over 90, WCC > 12 or < 4 x 10^9/l, or respiratory rate > 20)
- If so, patient has SIRS
- If so, is there history or sign suggestive of infection ? (cough, sputum, abdo pain, endocarditis, dysuria, headache with neck stifness)
- Treat as sepsis and start sepsis six (do not wait for confirmation of the pathogens)
- Once sepsis 6 pathway is underway, check for signs of organ dysfunction (using SOFA). If so, sepsis, continue treatment.

Question 30

Define sepsis 6.

Answer 30

The Sepsis Six is an initial resuscitation bundle designed to offer basic
intervention within the first hour. Should begin pre-hospital (ambulance)

• Give IV antibiotics
• Give IV fluids
• Give supplemental oxygen
• Take blood cultures
• Measure serum lactate
• Measure urine output

Question 31

What factors must we take into consideration when prescribing antimicrobials in sepsis ?

Answer 31

1) Where is the infection ?
2) What’s the likely micro-organism?
3) What effect is it having on the organs ?

Question 32

What bacteria do we have to cover for with our antimicrobials if it’s a respiratory infection ?

Answer 32

Cover with broad spectrum antibiotics, consider pseudomonas and MRSA

Question 33

What bacteria do we have to cover for with our antimicrobials if it’s a UTI ?

Answer 33

Cover for G-ve and Pseudomonas

Question 34

What bacteria do we have to cover for with our antimicrobials if it’s an abdo infection ?

Answer 34

Cover for G-ve/+ve/ anaerobes

Question 35

What bacteria do we have to cover for with our antimicrobials if it’s a soft tissue/joint infection ?

Answer 35

Cover for G-ve/+ve/anaerobes

Question 36

What does SUO stand for in the context of sepsis ?

Answer 36

Sepsis of unknown origin

Question 37

Identify the general prescribing principles in sepsis.

Answer 37

• Take blood cultures before prescribing but don’t delay prescribing
• Review once microbiology results available
• administer antibiotics within 60 minutes of
recognition of sepsis using IV route
• if thought to be viral, still give antibiotics
• Add in IV fluids, oxygen and possible vasopressors if BP low.

Question 38

What kinds of bacteria do we need to cover for in SUO ?

Answer 38

Need a broad spectrum of cover, including G (+ve) and G (–ve) plus anaerobes.

Question 39

Describe the specific treatment used for SUO, including specific antibiotics’ names and the kinds of bacteria they cover for.

Answer 39

FIRST LINE
Amoxicillin (broad spectrum, not so good for Staph Aureus / G-ve (e.g. E.Coli))
+ Gentamicin (-good against some G+ve, many G-ve, including pseudomonas. Not useful versus anaerobes)

IF MRSA SUSPECTED OR SEVERE SEPSIS
Piperacillin-tazobactam (broader spectrum, anti-pseudomonal, G+ve (but not versus MRSA ) and G –ve, anaerobes.)
+ Vancomycin (-good against G+ve including MRSA, some G-ve)

IF TRUE PENICILIN ALLERGY
Vancomycin (as above)
+ Ciprofloxacin (broad spectrum including pseudomonas)
+ Metronidazole (good versus anaerobes)

Question 40

Describe the management required if a meningococcal disease is suspected in the context of sepsis.

Answer 40

• Transfer to hospital immediately
• Want to cover Strep. pneumoniae and N. meningitidis (responsible in ~80% of bacterial meningitis and high mortality/morbidity)
• Want drug which penetrates blood brain barrier well:
-Community setting- V/IM Benzylpenicillin or Cefotaxime
-Hospital setting - IV Ceftriaxone (less likely to cause allergic reactions)