Definitions

Systemic Inflammatory Response Syndrome (SIRS)
Two or more of the following:

• T⁰C >38⁰C or <36⁰C

• Heart rate >90 beats/min

• Respiratory Rate >20 breaths per min or PaCO2 <4.3 kPa

• White Cell Count >12,000 cells/mm³ , <4000 cells/mm³ or >10% immature forms.

Sepsis
SIRS resulting from documented infection.

Severe sepsis
Sepsis associated with organ dysfunction, hypoperfusion or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria or an acute alteration in mental state.

Refractory shock
Shock refractory to conventional therapy (intravenous fluids and inotropic/vasoactive agents) within one hour.

S.I.R.S. (pathophysiology)

Systemic activation of leucocytes leads to the release of a variety of mediators

Dissemination of this response:

• Haemodynamic changes
• Microvascular abnormalities
• Intracellular defects

Toxins

• Gram +ve organisms (staph & strep) liberate exotoxin
• Gram -ve organisms produce endotoxin
• Pseudomonas produces both endotoxin and exotoxin
• Endotoxin is a heat stable polysaccharide derived from the cell wall of gram negative bacteria.

Endotoxin - Lipid moiety - Lipid A = active part

Core oligosaccharide and polysaccharide are probably inert.

Lipopolysaccharide + lipopolysaccharide binding protein bind to macrophages then inflammatory cascade stimulated by TNF.

1. Activation of the complement cascade leads to activation of leucocytes, release of inflammatory mediators such as proteases and oxygen free radicals. This leads to localised tissue damage and increased capillary permeability.

2. Tumour necrosis factor (TNF) plays a pivotal role via the cyclooxygenase pathway.

3. Interleukin 1 (IL1) - stimulates T helper cells to produce IL2 which stimulates Cytotoxic T cells.

4. IL1 & TNF act synergistically

Induction of cyclooxygenase
Platelet Activation Factor (PAF)
Nitric Oxide Synthetase

5. IL6 and IL8 are involved in the reparitive proccess they cause down regulation of TNF & IL1 production.

Prostacyclin (PGI2) = vasodilator, inhibits platelet activity.

Thromboxane A2 = vasoconstrictor & platelet agregator.

• Hypotension
• Increased Vascular permeability
• Platelet aggregation

Lead to release of lysosomal enzymes

• Directly cytotoxic
• Myocardial depression
• Coronary vasoconstriction
• Activation of kininogens and kinins

Vasodilatation
Increased Capillary refill
Myocardial depression
Activation of clotting systems

The vascular endothelium is an organ which regulates:

• Blood vessel tone
• Vascular permeability
• Coagulation
• Angiogenesis
• White blood cell and platelet activity
• Phagocytosis of bacteria

The endothelium produces a number of vasoactive substances

• Nitric Oxide (EDRF)
• Prostacyclin
• Endothelin-1

• Produced from l-arginine by nitric oxide synthetase (NOS).
• Activity is via cGMP

Effects

1. Vasodilatation
2. Inhibition of platelet aggregation

1. Constitutive NO

involved in physiological regulation of vascular tone.

2. Inducible NOS

exists in sepsis: induced in the vascular smooth muscle and monocytes within 4 -18 hours of stimulation with TNF and endotoxin

causing sustained release of NO
causing Vasodilation
causing Hypotension
causing Hyporeactivity to adrenergic agents.

……………………………………………in septic shock

Endothelin-1 = Potent vasoconstrictor

Increased circulating levels in cardiogenic shock and following severe trauma.

The dominant haemodynamic feature in septic shock is peripheral vascular failure.

Leading to persistent hypotension resistant to vasoconstrictors

Usually high output due to low SVR / increased HR

Nevertheless, there usually is a myocardial depressant factor present

decreased SV decreased left ventricular stroke work : tx = volume loading

Ventricular dilatation occurs due to decreased compliance

Cardiac dysfunction may also be afected by

• Acidosis
• Hypoxaemia
• Mocardial Oedema

Microcirculatory Changes = Capillary leak syndrome

• Vasodilatation

• Maldistribution of flow

• A-V shunting

• increased Capillary permeability + interstitial oedema

• decreased Oxygen extraction

• Primary defect of oxygen utilisation at cellular level

Process of microcirculatory failure in shock:

The pre capillary arterioles and post capillary venules vasoconstrict: this helps maintain systemic blood pressure

increased hydrostatic pressure in the capillaries

consequently fluid is "sucked" / sequestered from the interstitium

This is known as "transcapillary refill"

This leads to restoration of circulating volume, along with the renin-angiotensin-aldosterone axis.

The accumulation of hydrogen ions, lactic acid, increased PaCO2 & vasoactive substances, occurs.

- precapillary sphincters relax

but, the post capillary venules become unresponsive and vasoconstrict.

- blood "sieves" out of the capillary bed (remember, above, increased capillary permeability in sepsis).

- interstitial oedema / haemoconcentration / increased blood viscosity

Intravascular dehydration results

- procoagulant effects:

ADP + thrombin + increased viscosity + decreased flow

- platelet activation + clot formation in the capillary bed

- in addition: antigen-antibody complexes are laid down + endotoxin = cell damage

- release of tissue thromboplastin

- triggering of intrinsic pathway

- DIC

- cell damage due to thrombosis and ischaemia and cell compression by interstitial oedema.

- ultimately, there is consumption of clotting factors and abnormal bleeding

• DIC
• Microemboli
• Release of vasoactive components
• Complement activation
• Extravascular migration of leucocytes

Capillary permeability is increased so that fluid is lost into the interstitial space leading to hypovolaemia / interstitial oedema / organ dysfunction.

Reperfusion of the microcirculation leads to the generation of large quantities of oxygen free radicals leading to tissue damage, particularly to the gut mucosa.

Organ dysfunction:

The brain and kidneys are normally protected from swings in blood pressure by autoregulation:

In early sepsis - autoregulation curve shifts rightwards (due to and increase in sympathetic tone).

In late sepsis - vasoparesis occurs

- autoregulation fails

"steal phenomena" may occur (areas of ischaemia may have their blood stolen by areas with good perfusion).

Myocardial O2 supply is dependent on diastolic blood pressure

Circulating myocardial depressant factor.

Ventilation / perfusion mismatches

Initially due to increased dead space

Subsequently due to shunt

Acidosis - tachypnoea decreased PaCO2

Nosocomial pneumonia approx 70%

Oliguria

• -pre renal (by a long way most common)

• -renal

• -post renal

Pre-renal failure due to intravascular dehydration, circulating nephrotoxins, drugs.

Uncontrolled production of inflammatory cytokines by the kuppfer cells (of the liver), primed by ischaemia and stimulated by endotoxin (derived from the gut), leads to cholestasis and hyperbilirubinaemia.

GUT mucosa is usually protected from injury by autoregulation.

Hypotension and hypovolaemia leads superficial mucosal injury

Which leads to atrophy and translocation of bacteria into the portal circulation and stimulate liver macrophages causing cytokine release and amplification of SIRS.

• Confusion / stupor / coma secondary to:
• Hypoperfusion injury
• Septic encephalopathy
• Metabolic encephalopathy
• Drugs

• Hyperglycaemia due to sepsis & catecholamines (both cause insulin resistance)
• Lactic acidosis
• Muscular breakdown
• Generalised catabolic state

Signs and Symptoms of Sepsis

Investigation of sepsis of unknown origin:

Management of a septic patient:

1. Ensure a patent airway and that the patient is breathing spontaneously

O2 then CPAP then PSV + PEEP then SIMV + PSV + PEEP then NO / prostacyclin, prone positioniong

Oral airway then et tube then tracheostomy

2. Ensure and adequate pulse and blood pressure:

Intravenous canulation: volume loading then inotropes then inoconstrictors

3. Look for source of sepsis (cultures); assess background issues that may have

contributed.

4. Start antimicrobial therapy, guided by cultures, or "best guess"

5. ICU staff personal hygeine, to prevent transmission of resistant microbes.

6. Enteral nutrition to pevent bacterial translocation.

7. Rigorous screening for newly emerging sources of sepsis (particularly pneumonia).

Controversies: