Sepsis Hysteria: Part II

A practical approach to getting it right

Ed Palmer

ST8 in Anaesthesia & Intensive Care Medicine

2025-01-28

Part 1…

  • We reviewed the “sepsis-six” and its (lack) of evidence.
  • Sepsis is a complex and unsolved problem.
  • We should be warey of simple answers to complex problems.
  • Objectives for today:
    • Define sepsis and understand its historical context.
    • Consider sepsis as a hetrogenous syndrome.
    • Understand the gap between infection and sepsis and what fills it.
    • Review management and best practices in “early” sepsis.

Disclaimer: any presented cases are entirely fictional.

History & Definitions

  • Sepsis (1992) Bone et al.(1)
    • Consensus definition for: SIRS, sepsis, severe sepsis, septic shock.
    • \(\text{Sepsis} = \text{SIRS} + \text{Infection}\)
  • Sepsis 2 (2001) Levy et al.(2)
    • Consensus defintion: unchanged. Expanded some diagnostic criteria.
    • Noted: SIRS insensitive and non-specific.
  • Sepsis 3 (2016) Singer et al.(3)
    • Empiric defintiion
    • \(\text{Sepsis} = \text{SOFA} + \text{Infection}\)
    • “Sepsis” retired. “Severe sepsis” = “sepsis”.
    • Sepsis: 10% mortality. Organ dysfunction
    • Septic shock: 40% mortality; Organ failure.

Definitions

Sepsis is a life threatenin organ dysfunction caused by a dysregulated host response to infection

Singer et al.(3)

  1. Infection
  2. Dysregulated host response
  3. Organ dysfunction (and failure)
  4. Life threatening

Organ Failure

Pathophysiology

  • It’s… complicated
  • DAMPS and PAMPS
  • Vasoplegia and mitochondrial failure

Immune and Cellular

  • Pathogen associated molecular patterns (PAMPs): well conserved foreign cellular apparatus e.g. endotoxin (lipopolysaccharide).
  • Identification of PAMPs by: dendritic cells, macrophages etc.
  • Pattern recognition receptors (PRRs); toll-like receptors
  • Inflammatory mediators are released: TNF-alpha, IL-1 and IL-6.
  • These recruit and activate polymorphonuclear leukocytes (PMNLs).
  • PMNLs arrive at the site of infection to release inflammatory mediators designed to kill foreign microbes.
  • Damage associated molecular patterns (DAMPs): host material like mitochondrial DNA released during cellular injury (“friendly fire”).
  • PRRs assemble into molecular complexes: inflammasomes
  • Inflammasomes involved in secretion of the highly potent cytokines IL-1\(\beta\) and IL-18 (triggering cellular apoptosis)

Immune and Cellular

  • The net effect:
    • Increase number, lifespan and activation of innate immune cells.
    • Induce hepatic acute phase proteins: complement and fibrinogen
    • Trigger neutrophils to release extracellular traps (NETs)
    • Upregulate tissue factor expression by blood monocytes (immune mediated thrombosis)
  • So far… this is all perfectly normal…

Early Damage Pathway

  • Reactive Oxygen Species (ROS) damage cellular proteins and DNA.
  • Mitochondrial function impaired; bioenergenic failure.
  • Widespread thrombosis: microvascular flow dysfunction with organ failure.
  • A number of negative feedback loops begin to amplify:
    • Cellular ischaemia
    • Intracellular/mitochondrial dysfunction
    • Lactataemia
    • Self sustained cytokine production and inflammatory dysregulation.

Downstream Sequelae

  • Cardiovascular:
    • Myocardial dysfunction
    • Vasoplegia
    • Increased vascular permeability
  • Respiratory:
    • V/Q mismatch
    • ARDS
  • Renal:
    • reduction in filtration rate regardless of haemodynamics.
    • AKI
  • Neurological:
    • Sepsis encephalopathy
  • Gut:
    • Oedema and bacterial translocation.
    • Impaired hepatic microbial clearance of the portal system.
    • Pancreatic autodigestion.
  • Liver:
    • Impaired hepatocyte clearance of bilirubin and cholestasis
  • Haematological:
    • DIC
    • Pancytopaenia
  • Musculocutaneous:
    • Sarcopenia and ICU-Acquired Weakness

Is it sepsis?

Is it sepsis?

An 85 year old patient presenting to the A&E with 3 days history of myalgia and non-specifc deterioration; “off legs”.

Initial observations: SpO2 not-recordable as patient moving too much. BP 110/75. HR 95 sinus. RR 20. Patient confused and agitated, temp 36.4.

Initial labs: WCC 10.5, Plts 33, CRP 208, INR 3.1, Fibrinogen 85.

Is it sepsis?

A 35 year old with a 3 day history of cough productive of green sputum. Now feels SOB so took self to A&E. Otherwise well.

Initial observations: SpO2 78% RA. RR 35. Febrile 38. HR 110. BP 135/85.

Initial labs: WCC 14, CRP 85

VBG: Lactate 0.8

Is it sepsis?

A 17 year old with a 36 hour history of migratory RIF pain. Parents brought to A&E.

Initial observations: SpO2 99% RA. RR 20. Febrile 38. HR 110. BP 135/85.

Initial labs: WCC 14, CRP 85

VBG: Lactate 0.8

Sepsis as a Syndrome

  • Not always immediately clear if a severe infection is sepsis
  • Sepsis is not a single disease
  • Extremely heterogeneous
  • Unified by common themes
  • The microbial zoo:
    • Predators: Group A Strep, Staphylococcus Aureus, Neisseria meningitidis
    • Cohabitants: Lot’s of others

Paradox of Early Treatment

  • Sepsis was necessarily redefined: SOFA
  • But this creates a vacuum:
    • What do we do before they become septic?
    • Can we prevent it?
    • When does someone “become” septic?
  • Proper sepsis, especially if vulnerable, is an emergency
  • If everything is an emergency, nothing is.

How the void was filled

  • “Red flag sepsis”
  • Sepsis screening
  • Identify different populations
  • Criticisms of “missed sepsis” often totally unfounded
    • Asking for “pre-sepsis” not “early sepsis”.

Practical Advice

  • Clarify potential source of infection:
    • Different for new admissions vs. inpatients
    • “Septic screen”?… “Infection Inquest”
  • Clarify organ dysfunction:
    • Which organs are effected and how?
  • Culture before ABx wherever possible.
    • Sputum, urine, CSF, pus etc.
    • Blood cultures: Aerobic first, 10 mL each.

Practical Advice

  • Source control, source control, source control.

Practical Advice

  • Source control, source control, source control.
  • Give ABx considering the likely source.
  • Investigations (including imaging) directed to find source.
  • 20-30 mL/Kg: fluids for hypotension
    • Call the ICU
    • Accept when patients are no longer fluid responsive
    • Refractory lactataemia likely doesn’t reflect hypovolaemia
  • Review your patient often. Get help and escalate.

Our Turn

  • Organ support: buys time
  • Don’t cause harm: Lung protective ventilation. Catheter care etc.
  • Some potential treatments:
    • Albumin
    • NorAdrenaline, Vasopressin
    • Methylene Blue
    • Steroids

Sepsis Mimics

  • Autoimmune: Vasculitis.
  • Traumatic: SIRS following polytrauma.
  • Vascular
    • Pulmonary Embolus
    • Intestinal Ischaemia.
    • Hypovolaemia.
    • Cardiogenic Shock: MI etc.
  • Endocrine and Metabolic
    • Hyperthermic Toxidrome
    • Diabetic Ketoacidosis
    • Addisons
    • Thyrotoxicosis
  • Inflammatory
    • Pancreatitis
    • Bowel obstruction
    • Anaphylaxis
    • Hemophagocytic lymphohistiocytosis (HLH)1
  • Neoplastic
    • Lymphoma and Haematological Malignancy
    • Disease progression
    • Tumour Lysis Syndrome
  • Drug induced: Stevens-Johnson Syndrome and TEN

Documenting your Review

  • Write the diagnosis in terms of the definition: Infection + Organ Dysfunction
  • Consider other differentials/sepsis mimics using a surgical sieve
  • Avoid terms like “urosepsis”, “chest sepsis” etc.
  • Avoid one-liners: “impression sepsis”
  • It’s ok to write: simple infection and doesn’t have sepsis.
  • It’s ok to describe uncertainty: Possible, probable, confirmed etc.

Documenting your Review

Probable sepsis from a pneumonic (lung) source manifesting as cardiovascular (hypotension), respiratory (oxygen requirement) and renal (AKI) organ dysfunctions.

Microbial source as yet undefined.

Main differentials include: cardiogenic pulmonary oedema and PE.

PLAN

  1. Obtain sputum
  2. Blood cultures followed by immediate ABx to cover for community respiratory organisms.
  3. Fluid resuscitation directed by capillary refil with 2 hourly VBGs to check for lactate clearance.
  4. C-XR
  5. Consider CT-PA

Plan initiated with senior review to follow.

Guidelines

NICE

Think ‘could this be sepsis?’ if a person presents with symptoms or signs that indicate possible infection.

  • Troubling that this is the first recommendation in their guideline
  • But…
    • Take a proper history and examine. Be systematic.
    • Create a differential diagnosis
    • Sepsis should be part of any differential in at risk populations or non-specific presentations.
  • Know the groups at high risk of developing sepsis
  • Pregnancy, children, neutropaenia, the predators.
  • Perform a full secondary survey if someone hasn’t previously
  • Use and apply NEWS-2

NICE

take microbiological and blood samples before giving an antimicrobial.

give a broad-spectrum antimicrobial at the maximum recommended dose, without delay (within 1 hour of identifying that they meet any high risk criteria), if antibiotics have not already been given for this episode of sepsis

discuss with a consultant.

[Clinician \(\geq\)FY2] think about alternative diagnoses to sepsis

SSC(4)

  • Recommends against qSOFA for screening (prefer NEWS)1

For patients with sepsis induced hypoperfusion or septic shock we suggest that at least 30 mL/kg of intravenous (IV) crystalloid fluid should be given within the first 3 h of resuscitation

  • Guide resuscitation with “dynamic parameters”
  • Target lactate clearance, but also capillary refil.(5)

Question Your Assumptions

Patient Getting Better Patient Getting Worse
I know whats going on Great! No Change Are you missing something? Second opinion. Check your biases.
I don’t know whats going on Seek education The bad place. Get help immediately.
  • Almost all my referrals are the right column by definition.
  • Most patients come to hospital, get the right diagnosis, and get better.
  • Some patients come to hospital and despite treatment get worse.
    • Did we get it wrong?

Lacking evidence

  • IVIG. Maybe. Specific predators.
  • Vitamin C. Lol Nope.
  • Anti-coagulation. Nope.
  • Extra-corporeal absorption: High flux CVVH. Nope.

Thank you

References

1.
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RMH, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644–55.
2.
Levy MM, Fink MP, Marshall JC, Abraham E, Angus DC, Cook D, Cohen J, Opal SM, Vincent J-L, Ramsay G, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Critical care medicine 2003;31:1250–1256.
3.
Singer M, Deutschman CS, Seymour C, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA - Journal of the American Medical Association 2016;315:801–810.
4.
Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, Mcintyre L, Ostermann M, Prescott HC, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Medicine 2021;47:1181–1247.
5.
Hernández G, Ospina-Tascón GA, Damiani LP, Estenssoro E, Dubin A, Hurtado J, Friedman G, Castro R, Alegría L, Teboul J-L, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA 2019;321:654.