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Microsoft PowerPoint - Shock Lecture

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					Shock
Dr Maha Abdelrahman
The William Harvey Research Institute Centre for Experimental Medicine, Nephrology & Critical Care St. Bartholomew’s and the Royal London School of Medicine and Dentistry Charterhouse Square, London, EC1M 6BQ, UK

Shock
progressive failure of the circulation to provide blood and oxygen to vital organs

characterised by severe hypotension, often associated with the dysfunction/failure of several organs or systems

Causes of Shock
bacteraemia (septic shock) trauma (traumatic shock) haemorrhage (haemorrhagic shock) severe allergic reactions (anaphylactic shock) insufficient cardiac output (cardiogenic shock) burn (burn shock)

Haemorrhagic Shock
Most common causes of haemorrhagic shock are: trauma vascular gastrointestinal pregnancy-related

Treatment?
Stop bleeding Replace lost blood volume

Treatment?
Stop bleeding Replace lost blood volume

Result?
Multiple Organ Failure Death

Multiple Organ Failure (MOF)
present when two or more organs or systems can no longer support their activities spontaneously complicates primary clinical conditions such as haemorrhage, trauma and severe bacterial infections major cause of morbidity and mortality

MOF – history
Tilney and colleagues described patients who developed progressive organ system failure following rupture of an abdominal aortic aneurysm (Tilney et al., 1973). In 1975, concept that a severe physiologic insult could result in damage to distant organs was formalised in an editorial by Baue entitled ‘Multiple, Progressive, or Sequential Systems Organ Failure: A Syndrome of the 1970’s’ (Baue, 1975).

MOF – mortality rate
As the number of organs that fail increases from one to four, the mortality rate progressively increases from 30% to 100% (Fry et al., 1980)
100
100

MOF – facts
Prognosis is related more to the number of organs that have failed than to any other variable, including the precipitating event

Mortality Rate (%)

Mortality Rate (%)

75

75

50

25

50

0

Syndrome of MOF usually follows a predictable course
1 2 3 4

25

Number of failed organs

- Starts with the lungs followed by hepatic, intestinal and renal failure

0

1

2

3

4

Number of failed organs

MOF – important characteristics
1) Organs that fail are frequently not directly injured in the primary disease process 2) There is a lag phase of days to weeks between the initial insult and the development of distant organ failure

MOF – a sign of infection?

Patients suffering from MOF appear to be clinically septic

Several groups reported a relationship between an untreated septic focus and MOF

MOF is a systemic process mediated by endogenous or exogenous circulating factors, the effects of which are not directly obvious after the initiating insult

Is MOF the external expression of occult or uncontrolled infection?

MOF – a sign of infection?
Clinical Studies have shown: 1) Not all patients which appear to be clinically septic with MOF have evidence of an underlying infection or development of infection is a pre-terminal event of no prognostic importance 2) In >30% of bacteriaemic patients which appear to be clinically septic with MOF, no septic focus can be identified 3) Identification and treatment of occult septic foci in patients with MOF may not improve survival 4) Dead or injured tissues can replace bacteria as the stimulus for the septic response

MOF – a sign of infection?

NO!
Septic response can occur in the absence of infection Systemic clinical manifestations of MOF – fever, leukocytosis, hypermetabolism, hyperdynamic circulatory state – can be induced by non-infectious causes including mechanical and thermal trauma, pancreatitis and shock

MOF - predisposing factors
1) Severe physical and metabolic insult e.g. trauma, operation or both 2) Clinical or technical errors e.g. continued bleeding, inadequate wound closure, bacterial contamination 3) Infection e.g. peritonitis, pneumonia 4) Severe inflammation 5) An individual with limitations in one or more organs before injury/operation 6) Patients with vascular occlusive disease, chronic obstructive lung disease, hepatic damage, renal disease, cardiac disease, immunosuppressed

MOF - mechanisms

1) The Uncontrolled Inflammatory Response Hypothesis

2) The Gut Hypothesis

3) The Ischaemia-Reperfusion Hypothesis

Inflammation

Systemic Inflammatory Response Syndrome
Although beneficial to the host at the tissue level, inflammatory processes are intrinsically destructive and have deleterious effects if they escape the local environment Patients who suffer major injury may produce an excessive inflammatory reaction called the Systemic Inflammatory Response Syndrome (SIRS) SIRS is the clinical consequence of systemic activation of the human inflammatory cascade

is a localised protective response elicited by injury or destruction of tissues, which serves to contain and eradicate infecting organisms and to sequester damaged tissues or foreign materials characterised by the activation of cascade systems (complement, coagulation, kinins, fibrinolysis), cells (macrophages, leukocytes, endothelial cells, monocytes and mast cells) and the release of mediators (cytokines, histamine, arachidonic acid metabolites, reactive oxygen species and coagulation factors) characterised by the activation of cascade systems (complement, coagulation

SIRS
SIRS - Exaggerated Inflammatory Response Damage to host tissues/cells Defective oxygen utilisation Cell death

Uncontrolled Inflammatory Response Hypothesis
According to this hypothesis, MOF is caused by an uncontrolled systemic inflammatory response

- Supported by discovery of an association between the presence of MOF and histological evidence of organ inflammation (Nuytinck et al., 1988)

Uncontrolled Inflammatory Response Hypothesis - cytokines
Several mediators have been implicated in the development of MOF, including over-production of cytokines Excessive activation of macrophages/monocytes results in the over-production, expression and liberation of cytokines Elevated cytokine levels can result in host responses that culminate in the septic response and MOF Elevated circulating cytokine levels have been reported in the serum of patients with shock

Cytokines – TNF-α
Principal mediator in the inflammatory response Secreted by macrophages and monocytes Effects: activates macrophages and neutrophils - tissue damage due to the release of reactive oxygen species
and proteolytic enzymes

up-regulates adhesion molecules stimulates further cytokine release

Cytokines – TNF-α
TNF-α has been implicated in the development of MOF and shock.
Evidence: Administration of TNF-α into healthy experimental animals causes a syndrome indistinguishable from shock In animals treated with LPS, blocking TNF-α (using antibodies) suppressed cytokine release and improved survival Treatment with TNF-α antibodies attenuated the organ injury and improved survival in a rat model of haemorrhagic shock

Cytokines – IL-1
Produced by macrophages and monocytes Pro-inflammatory: T-cell activation, neutrophil activation, up-regulates adhesion molecules and stimulates further cytokine release Evidence: In a murine model of haemorrhagic shock, treatment with an IL-1 antagonist improved survival when compared to the control group

The Gut Hypothesis of MOF

The Gut Hypothesis of MOF
Under normal physiological conditions, intestinal mucosa functions to 1) Absorb nutrients 2) Act as a defence barrier, preventing bacteria and/or bacterial products within the intestinal lumen from reaching systemic organs

According to this hypothesis, gut-derived factors contained primarily in the mesenteric lymph potentiate the development of MOF

The Gut Hypothesis of MOF
Shock Decrease in blood flow to gut Reduction in mesenteric perfusion Intestinal damage & increased intestinal permeability Evidence:

The Gut Hypothesis of MOF
Administration of TNF-α into healthy experimental animals causes a syndrome indistinguishable from shock In animals treated with LPS, blocking TNF-α (using antibodies) suppressed cytokine release and improved survival Treatment with TNF-α antibodies attenuated the organ injury and improved survival in a rat model of haemorrhagic shock

Sepsis – Severity of disease
Sepsis -- characterised by a generalised inflammatory response, which can include abnormal clotting and bleeding, in the presence of infection Severe sepsis -- sepsis with associated acute organ dysfunction. Patients need to be actively treated in the hospital. 30-35% mortality rate Septic shock -- severe sepsis in which the cardiovascular system begins to fail, the blood pressure drops, and vital organs are deprived of adequate blood supply. Patients need rapid emergency admission to the hospital intensive care unit. Despite active treatment in the ICU, the death rate is around 50%.

Sepsis - MODS
The progression of sepsis to multiple organ failure (or multiple organ dysfunction syndrome; MODS) is associated with an increase in mortality proportional to the number of organs failing Mortality progressively increases from 30% (in the absence of MODS) to virtually 100% in those with 4 or more failed organs

Sepsis - Symptoms
Presence of an infection, plus any two of these four criteria: Heart rate greater than 90 beats per minute Increased respiratory rate High or low white blood cell count Fever or low body temperature

Sepsis - Symptoms
Visible symptoms of sepsis include in the presence of an infection: reduced mental alertness, confusion shaking chills, fever nausea, vomiting diarrhea

Sepsis – Diagnosis
Tricky: some of its symptoms very general, and can mimic many other disorders. First line of treatment: to identify and eliminate the underlying infection with anti-infection agents. NO TREATMENT for severe sepsis !

Sepsis – Treatment
First line of treatment: to identify and eliminate the underlying infection with anti-infection agents. NOTE: Certain antibiotics may worsen sepsis * increase the breakdown of bacteria and the release of toxins into the bloodstream

Sepsis – Supportive care
Depending on the patient's clinical status, other supportive care methods are used: fluid resuscitation vasopressors, inotropes mechanical ventilation kidney dialysis None of these measures specifically treats severe sepsis!

Sepsis – Risk groups
Sepsis is most likely to develop in people who: Are very young (e.g. premature babies) or very old Have a weakened immune system, often because of treatments such as chemotherapy for cancer, steroids (e.g. cortisone) for inflammatory conditions, etc. Have wounds or injuries, such as those from burns, a car crash, or a bullet Are receiving certain treatments or examinations (e.g., intravenous catheters, wound drainage, urinary catheters Are more prone to develop sepsis than others because of genetic factors

Sepsis – Risk Groups
Patients who are admitted to the hospital with serious diseases are at the highest risk of developing sepsis because of: Their underlying disease Their previous use of antibiotics The presence of drug-resistant bacteria in the hospital The fact that they often require an intravenous tube, urinary catheter, or wound drainage

Sepsis – Risk Groups
Sepsis is becoming more common, especially in the hospital, as a result of: Medical and technological advances associated with treatments The increasing number of elderly or debilitated people, and patients with underlying diseases such as cancer, who require therapy The widespread use of antibiotics, which encourages the growth of drug-resistant microorganisms

Sepsis - Statistics
Annually 135,000 European and 215,000 American deaths, over 18 million cases worldwide Kills approximately 1,400 people worldwide every day Incidence of severe sepsis expected to rise to 1 million by the end of the decade as the population ages The leading cause of death in the non-coronary ICU Each year sepsis costs €7.6 billion in Europe and €17.4 billion in the US

Sepsis - Statistics
Annually 135,000 European and 215,000 American deaths, over 18 million cases worldwide Kills approximately 1,400 people worldwide every day Incidence of severe sepsis expected to rise to 1 million by the end of the decade as the population ages The leading cause of death in the non-coronary ICU Each year sepsis costs €7.6 billion in Europe and €17.4 billion in the US Sepsis takes more lives than myocardial infarction Sepsis takes more lives than breast, colon/rectal, pancreatic, and prostate cancer combined

Sepsis - Future
Improvements can be made by *identifying patients earlier through the use of globally accepted definitions *treating with the most appropriate medication *adopting agreed standards of care All these initiatives will assist in reducing mortality Hope with the introduction of more new exciting therapies

Sepsis - Summary
overwhelming systemic response to infection, which can rapidly lead to organ injury and dysfunction, and ultimately death widespread inflammation, coagulation, and suppression of fibrinolysis mediated through systemic release of pro-inflammatory cytokines (TNF-α, IL-1, IL-6) and, secondarily, anti-inflammatory molecules (IL-10) bimodal nature: pro-inflammatory SIRS followed by antiinflammatory CARS becoming more common, especially in the hospital limited treatment, only supportive care – early diagnosis pivotal


				
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