Sepsis and inflammation: battle of waterloo

Question 1

What changes are there during inflammation which leads to multi-organ failure during sepsis?

Answer 1

• neural and endothelial activation
• coagulation activation
• immune dysfunction
• epithelial dusfunction
• disordered micro-circulation
• metabolic changes
• hormone alterations
• disordered macrocirculation
• mitochondrial dysfunnction

Question 2

Definition of sepsis

Answer 2

• life-threatening organ dysfunction due to a dysregulated host response to infection
• rise in SOFA score >2

Question 3

How could we explain sepsis multi-organ failure?

Answer 3

• Despite MOF, when look at autopsies, organs look fairly normal
• tissue PO2 is maintained or elevated but affected organs are functionally inactive
• this may be a metabolic shutdown due to lack of ATP (those patients which went on to die of sepsis had much lower ATP)
• mitochondrial dysfunction may be adaptation to prolonged stress, but may push over the edge to maladaptation (could be influenced by drugs given too?)
• studies have found that survival in critical illness is associated with early activation of mitochondrial biogenesis, and early sepsis and recovery is associated with increased oxygen consumption and RMR

Question 4

Roles of the mitochondria in sepsis: thermogenesis

Answer 4

• using uncouplers such as UCP1
• thermogenesis bactericidal
• can see in sepsis patients much higher concentrations of brown adipose tissue

Question 5

Role of the mitochondria during sepsis: fuel choice

Answer 5

• survivors of sepsis typically metabolise CHO, non-survivors move towards fat and ketone bodies
• fatty acids can increase mitochondrial stress
• in septic non-surviving rats can see a higher rate of lipolytic hormones released vs septic rats which survived

Question 6

Role of the mitochondria during sepsis: what leads to decreased mitochondrial activity?

Answer 6

• prolonged inflammation leads to ROS and RNS, tissue hypoxia and endocrine effects (such as low T3, sex hormones), reduced gene transcription which all lead to reduced mitochondrial function
• decreased mitochondrial activity reduces ATP turnover and leads to metabolic shutdown
• eventually leading to MOF

Question 7

Potential strategies to enhance mitochondrial function during MOF

Answer 7

• enhance substrate delivery and utilisation
• replete reducing equivalents (NADH, through substrate/cofactor supply)
• restore/protect mitochondrial activity (antioxidants)
• improve bioenergetic efficiency (biogenesis stimulation)
• prevent apoptosis in immune cells (hormone manipulation)
• ‘switch on’ mitochondria (‘resuscitation promoting factor’)

BUT need to make sure dose and time is right

Question 8

Strategies to enhance mitochondrial function: NO inhibitors/scavengers, insulin, antioxidants (MnSOD), coenzyme Q, succinate/TAG, PGC1a stimulation, GH/thyroxin

Answer 8

• NO inhibitor/scavenger: NO produces endogenously can inhibit complex I and IV, could inhibit but puts BP up and increased mortality in a trial
• insulin: may increase the efficiency of the mitochondria, in critically ill patients keeping a toght glycemic control with insulin and glucose gave better complex I activity
• MnSOD: should reduce ROS, and when give this to patients who have hyperglycaemia could normalise damage caused, and protects against organ damage
• coenzyme Q: found that supplementation has improved survival, and case studies have shown that helped in acute cardiac events (ie overdose of beta blockers, statins and calcium channel blockers)
• succinate: could be supplemented to bypass blockage of complex I by peroxynitrite. High TAG diet also shown to bypass the complex I and feed straight into CII (as produces FADH in first step of beta oxidation)
• PGC1a stimulation: stimulates mitochondrial biogenesis. Can stimulate PGC1a through oestrogen, cold, exercise, CO (need to avoid giving too much though)
• thyroxin and GH supplementation have been found to increase mortality in sepsis patients