ICM Experimental 1: Concepts of Critical Illness

Immune-system-photo-1-1170x780

Inflammatory balance and imbalance

(Peter Pickkers)

 

Originally thought that pro-inflammatory phase occurs first, followed by anti-inflammatory phase

Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy

 

Initial inflammatory response NOT predictive of which patients become immunoparalysed later

 

Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis.

Acute phase of infection- Warburg effect is seen in immune cells

This is absent in immunoparalysis, but can be reversed by IFN-gamma –> pharmacological intervention possibilities

Mounting overwhelming pro-inflammatory and anti-inflammatory responses early on = poorer outcome (refractory shock, immunoparalysis, late secondary infections and death)

 

To Attack or Tolerate: Novel concepts in host response

(Michael Bauer)

 

Innate immune system has memory, related to Warburg metabolism

Tiny doses of beta-glucan / LPS induce state of trained immunity; higher doses can cause immunoparalysis

Central role of Haem / Fe:

  • in the presence of free haem, a benign response turns into profound infection independent of pathogen dose
  • Hemopexin / haem oxygenase binds / removes extracellular free haem, uncontrolled sepsis can be controlled

 

Potential to manipulate haem response in addition to antimicrobials and anti-inflammatory drugs

 

Host Stress and Strain

(Mervyn Singer)

Critical illness strain on body analogous to that seen in Hooke’s Law of elasticity

  • within reversible zone –> acute illness and organ dysfunction –> recovery
  • beyond a ‘point of no return’, enters irreversible zone –> death

IMG_0169

Less resilient pt: ‘point of no return’ shifts to left à tolerate less strain

Hardy pt: ‘point of no return’ shifts to right à more resistant to death

IMG_0170

Intervention strategy to target specific phase of illness

IMG_0172

 

Cardiac Troponin T (NOT as a marker of cardiac event) as an independent predictor of in-hospital mortality in emergency dept pts with suspected infection (de Groot et al., Emerg Med J 2014; 31:882-8)

 

Pathophysiological responses shouldn’t be simply viewed as disturbances of physiology, but as factors that accommodate the body to the insult

Is ‘shutting down’ an evolutionary mechanism?

–> Permissive hypercapnoea, hypoxaemia, hypotension, oliguria, anaemia etc could be beneficially targeted to help organs reach recovery phase, e.g.

  • ? avoid stressors (catecholamines, pain, severe cardioresp upset)
  • ? avoid arterial hyperoxia or even normoxia
  • ? induce hibernation or suspended animation
  • ? vagal stimulation of anti-inflammatory cholinergic pathway
  • ? beta-blockade +/- alpha-2-agonism
  • ? chill out psychologically
  • Acceptable patient-specific ranges need to be identified; timing, dosing and duration of intervention are Critical

Further reading:

The stress response and critical illness: A review (Cuesta et al., Crit Care Med 2012; 40:3283-9)

 

Stressing the obvious? An allostatic look at critical illness (Brame et al., Crit Care Med 2010; 38[Suppl.]: S600-7)