How to protect and resuscitate the mitochondrium: Role of Metformin and Cyclosporin

(Jean-Charles Preiser)

3 post-injury phases: Early Phase attempts to protect cellular integrity at the expense of functionality

• changes in macro / microcirculation
• decreased oxygen consumption
• decreased energy expenditure
• metabolic shutdown

Hyperlactataemia closely related to severity of sepsis; in established sepsis it is defect of oxygen utilisation, rather than impaired oxygen transport

 

Mitochondria in critical illness– more than just a powerhouse – also key roles in cell signalling (ROS), calcium homeostasis, regulation of apoptosis. Stressed mitochondria release DAMPs, further increasing inflammation and systemic toxicity

 

Metformin directly decreases mitochondrial respiration and increases aerobic glycolysis

Several studies have shown improved outcomes associated with metformin use in ITU patients

Cyclosporin A inhibits opening of mitochondrial permeability transition pore (mPTP), thereby preventing cell death

Rabbit model: cardiac arrest –> resuscitation with either 1. Control or 2. Cyclosporin A or 3. Non-immunosuppressive analogue-Inhibitor of mPTP opening –> organs harvested with functional markers recorded

 

Cyclosporin A (and non-immunosuppressive analogue-Inhibitor of mPTP opening) – protective effect on liver, kidney and heart, but not lung

Clinical:

1. Cyclosporine before PCI for acute MI (800 pts): randomisation to bolus of Cyclosporine or Placebo –> disappointingly same primary outcome (death any cause / cardiac compromise) in both groups   ??dose ??timing-related
2. Out-of-hospital cardiac arrest (800pts): randomisation to bolus of cyclosporine vs placebo – No difference in SOFA scores 24 hrs post-admission   ??dose ??timing-related ??inclusion criteria

 

Late and Recovery phases post-injury: Long stayers >5 days – decreased mitochondrial biogenesis, dysregulated lipid oxidation –> weakness, muscle inflammation, impaired anabolic recovery

 

Inhibitors of mitochondrial function may prevent later organ failure if given very early post-injury BUT prolonged mitochondrial dysfunction is not desirable

 

Recommended reading: Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence

 

The role of the Glucocorticoid (GC) receptor in circulatory shock

(Sabine Vettorazzi)

 

GC production and function is required for efficient response to inflammation – abnormal GC production associated with higher sepsis mortality in animal models and humans

GC binds to Glucocorticoid receptor (GR) –> translocates to nucleus

• GR monomer –> Represses inflammation
• GR dimer –> Induces inflammation

 

GR Dimerisation-deficient mouse model (GRdim) created, to clearly discriminate effects of GR monomers from GR dimers (which are completely absent)

Mice subjected to endotoxin-mediated shock: GRdim mice died faster than wild-type mice

• more severe lactate acidosis
• higher inotropic requirement for haemodynamic stability
• impaired lung compliance
• increased osteopontin levels (with decreased levels of anti-inflammatory IL-10)

 

GR Dimer is important for survival during LPS induced toxic shock, at least during the first 6 hours of shock in GRdim mice (only observed for 6 hours with intensive care support)

 

Why and how the heart fails

(Alain Rudiger)

 

Four shock states –

• shock –> cardiac dysfunction, MOF
• combination of shock states commonly occur

 

Cardiac dysfunction during Inflammatory Shock:

• Elevated BNP and Troponin
• Arrhythmia
• Systolic and diastolic dysfunction

 

Is this myocardial injury the reason for cardiac dysfunction?

Little evidence of myocyte necrosis in pts dying of sepsis + impaired contractility is Reversible = functional impairment rather than structural damage

 

Adaptive myocardial depression when myocardium is at risk

• reprogramming of genes
• activation of fetal genes (survival program)
• decreased energy expenditure to keep cells viable

 

Complex process of gene activation / down regulation in multiple cell-types at different times

 

Rat model 6 hours post-onset of faecal peritonitis:  500+ genes up/down regulated

• –> downstream: signalling cascades e.g. blunted adrenergic cascade / blunted calcium transport
• –> further downstream: affects electromechanical coupling and decreases myocardial contractility

 

Close interactions between shock, cardiac dysfunction and MOF

The heart fails as a result of multiple factors:

• Insufficient preload
• Excessive RV afterload
• Arrhythmia, dyssynchrony
• Diastolic dysfunction and impaired contractility