SYSTEMIC INFLAMMATORY RESPONSE SYNDROME

Introduction:

y talk today is on SIRS. This is a relatively unchartered territory in medicine. I believe that it is an extremely challenging topic as there is a lot of controversies and uncertainities in this area. My hope is that I can layout some guidelines to help understand this clinical entity. It is not my intention to expound on the complete spectra of the development of infection to multi-organ failure, but rather to introduce the concept of Systemic Inflammatory Response Syndrome and hope that by the end of this talk you will be able to:

I will divide this talk under the following headings:

Epidemiology

Definitions

Pathophysiology

Old Paradigm

Cytokine Cascade

New Paradigm

Approach to a patient with SIRS/Sepsis

Risk Assessment Stratification

Severity of illness scoring system

Proposed treatment modalities

Neutralizing Adhesion molecules

Modifications of Cytokine mediators and their receptors

Conclusion

Epidemiology:

fig 1: Graph

Definitions:

Results of clinical trials to evaluate the conventional and innovative therapies were extremely difficult to interpret as they were obscured by the use of varying definition for infections, bacteremia, sepsis, septicemia, "septic syndrome", and septic shock.

Therefore in August '91 an ACCP/SCCM Concensus conference was held with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and it's sequelae.

Standardization of terminologies led to

a) elimination of confusion in communication for both clinicians and researchers

b) ability to compare protocols and evaluate therapeutic interventions

Infection: Microbial phenomenon characterized by an inflammatory response to the presence of microorganism or the invasion of normally sterile host tissue by those organisms.

Bacteremia: Presence of viable bacteria in the blood

Sepsis: The systemic inflammatory response to infection. i.e. temperature above 38C or below 36C,

heart rate greater than 90bpm, respiratory rate greater than 20/min or PaCO2 less than 32mmHg and WBC count greater than 12,000/mm3 or less than 4000/mm3 or greater than 10% immature (band) forms.

Severe Sepsis: Sepsis associated with organ dysfunction, hypoperfusion, or hypotension..

Septic Shock: a subset of severe sepsis and defined as sepsis induced hypotention despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients receiving inotropic or vasopressor agents may no longer be hypotensive by the time they manifest hypoperfusion abnormalities or organ dysfuncion, yet they would still be considered to have septic shock.

 

 

 

 

Pathophysiology:

The ability of the body to defend itself is based on three elements: external barrier against invasion and tissue injury, non-specific systems against foreign pathogens and debris, and antigen specific response to foreign pathogens.

 

Insult

(mechanical, chemical, microbial)

Inflammation

(Initial non-specific response to

Body tissue injury)

Cytokines

Macrophages Endothelial cells

 

Paracrine / autocrine Activation

---------------------------------------------------------------------------------------------------------------------------------

Amplification/loss of homeostasis

Sepsis/SIRS

shock and multiorgan dysfuction

and possible death

(Fig). 2

 

Systemic inflammatory response syndrome:

Definition:

It is a characteristic clinical response manifested by two or more of the following:

Temperature above 38C or below 36C (rectal)

Heart rate above 90 bpm

Respiratory rate above 20 breaths per min or PaCO2 less than 32mmHg

WBC count above 12,000 cells/mm3 or 10% immature (bands) forms

What are the common causes of SIRS?

Pie Chart

 

Pathophysiology of systemic inflammatory response syndrome:

" patient die not of their disease, they die of the physiological

abnormalities of their disease."

-Osler

It was as recently as 1996, that Bone proposed that there were three main stages in the development of SIRS. This was later revised more recently as having five stages.

It must be understood that localized inflammation is a physiological protective response which is generally tightly controlled by the body at the site of injury. Loss of this local control or an overly activated response results in an exaggerated systemic response which is clinically identified as SIRS. SIRS may be initiated by infection (viruses, bacteria, protozoa and fungi) or by non-infectious cause such as trauma, autoimmune reactions, cirrhosis and pancreatitis

(fig.) 4

Stage 1: In response to an insult, the local environment produces cytokines which are primarily intended to evoke an inflammatory response, promote wound repair and recruit the cells of the reticuloendothelial system.

Stage 11: Small quantities of cytokines are released into the systemic circulation enhance the local response. Macrophages and platelets are recruited and growth factor production is stimulated. An acute-phase response is initiated and is tightly controlled by a simultaneous decrease in proinflammatory mediators and release of endogenous antagonists. These mediators keep the initial inflammation response in check both by down regulating cytokine production and by counteracting the effects of cytokines already released. This continues until the wound is healed, the infection resolved and homeostasis is restored.

Stage 111: Loss of regulation of the proinflammatory response results in a massive systemic reaction manifest as the clinical findings of SIRS. Underlying the clinical findings are pathophysiologic changes that include the following:

Progressive endothelial dysfunction, leading to increased microvascular permeability

platelet sludging that blocks the microcirculation, causing maldistribution of blood flow and possibly ischemia, which in turn may cause reperfusion injury and induction of heat shock proteins

activation of the coagulation system and impairment of the protein C-protein S inhibitory pathway

profound vasodilation, fluid transudation and maldistribution of blood flow may result in profound shock

With the failure of homeostasis a massive systemic reaction begins. The predominant effects of cytokines become destructive rather than protective. The flood of inflammatory mediators triggers numerous humoral cascades and results in sustained activation of the reticular endothelial system with loss of microcirculatory integrity and insults to various distant end organs. Coupled to these events there is depression of myocardial contractility which may be due to the effect of paracrine nitric oxide production and coronary non-occlusive microvascular damage and myocyte injury.

These phenomena make it difficult to volume resuscitate a hypotensive patient adequately. In combination, the loss of peripheral vascular tone and the loss of volume into extravascular spaces negate the normal homeostatic response necessary to maintain oxygen delivery and correct the abnormal arteriovenous difference in oxygen content. The inability physiologically to correct these adverse responses results in end organ hypoperfusion, edema, initiation of anaerobic metabolism and end-organ dysfunction.

 

 

 

Cytokine Cascade:

"Only by fully understanding how these extraordinarily complex proteins work will we be able to develop effective agents that combat their destructive effects while preserving their protective function."

-Roger Bone.

Orchestration of immune and inflammatory responses depends upon communication between cells by soluble molecules given the generic term cytokines. The inflammatory response to infection or injury is a highly conserved and regulated reaction of the organism. After recognition that a response is required, the organism (eg. human being) produces soluble protein and lipid proinflammatory molecules that activate cellular defenses, then produces similar anti-inflammatory molecules to attenuate and halt the proinflammatory response. Molecules known or presumed at this time to be proinflammatory and anti-inflammatory are listed.

 

 

 

 

 

 

 

Partial list of Proinflammatory and Anti-inflammatory Molecules

Proinflammatory

Molecules

Anti-inflammatory

TNF-a

Thromboxane

IL-1

IL-1b

Platelet activating factor

IL-4

IL-2

Soluble adhesion molecules

IL-10

IL-6

Vasoactive neuropeptides

IL-13

IL-8

Phospholipase A2

Type 11 IL-1 receptor

Il-15

Tyrosine kinase

Transforming GF-b

Neutrophil elastase

PAI-1

Epinephrine

IFN-g

Free radical generation

Soluble TNF-a receptor

Protein kinase

Neopterin

Leukotriene b 4 receptor antagonist

Mcp-1

CD14

Soluble recombinantCD14

MCP-2

Prostacyclin

LPS binding protein

Leukemia inhibitory factor

Prostaglandins

LPS binding protein

 

Cytokines are the physiological messengers of the inflammatory response and the principal molecules involved are tumor necrosis factor (TNF) a, interleukins (IL-1 and IL-6), interferons and colony stimulating factors (CSF). Polymorphonucleocytes (PMN), monocytes/macrophages and endothelial cells are the cellular effectors of the inflammatory response.

 

 

 

 

 

Stage 1V: It is possible that a compensatory anti-inflammatory reaction can be inappropriate, with a resulting immunosuppression. This has been termed "immune paralysis", "window of immunodeficiency", and more recently compensatory anti-inflammatory response syndrome" (CARS), by Bone et al.. CARS is the body's response to inflammation and is more than just immune-paralysis. CARS may explain such anomalies as the burn patient's increased susceptibility to infection and even the anergy of the pancreatitis patient. Recently it has been shown that treatment of patients with sepsis with IFN-g-1B could effect up-regulation of monocyte surface HLA-DR expression, restoration of monocyte function and secretion of IL-6 and TNF-a. The resultant state rebalances CARS-SIRS immunophysiologic homeostasis.

Stage V: The final stage of MODS is what is also been termed "immunologic dissonance", by Bone et al.. It is an inappropriate, out-of-balance response of the immunomodulatory system. In patients with persistent immune suppression, the cause of organ failure may be inhibition of the synthesis of the proinflammatory agents needed to allow the organs to recover.

 

 

 

 

 

 

 

 

 

 

 

 

 

In summary, the pathogenesis of sepsis has 3 main stages, each of which has a pro-inflammatory and an anti-inflammatory component. At a site of local injury or infection, pro-inflammatory mediators combat infection, remove damaged tissue, and promote wound repair. Anti-inflammatory mediators then dampen the pro-inflammatory response. If homeostasis is not restored, mediators will spill out into the systemic circulation. This may occur because the original insult was massive, a secondary insult intervened, or the local site produced inappropriately high or low levels of 1 type of mediator. If balance is not restored systemically, persistent levels of pro-inflammatory mediators will produce clinical signs of sepsis and, eventually, shock and organ dysfunction. Persistent levels of anti-inflammatory mediators will cause anergy and/or immune dysfunction. Some patients may have a mixed reaction, in which pro-inflammatory and anti-inflammatory reactions fluctuate.

Proposed definitions for Sepsis and Organ Failure:

CARS: HLA-DR on monocytes <30% and diminished ability of monocytes to produce inflammatory cytokines, such as TNFalpha or IL-6

MARS: Features of SIRS in a patient with CARS.

Conclusion:

Sepsis as a leading cause of death has increased massively just as we were searching for the magic bullet. The challenge for intensive care medicine is to develop cost-effective methods for improving survival rates, while reducing expenditure on those who ultimately will die. Efforts to identify patients who cannot benefit from continued support have not been successful, primarily because group probabilities cannot be used to predict outcome for individual patients. A different approach is needed which links the pathogenesis of multiple organ failure with its prevention and with techniques to restore cellular and organ function.

Anti-inflammatory agents, such as monoclonal antibodies to tumor necrosis factor (anti-TNF), recombinant human interleukin-1 receptor antagonist, and anti-platelet activating factor are likely to be effective only in patients with a massive or persistent pro-inflammatory response. Agents that stimulate the immune system, such as granulocyte colony-stimulating factor and interferon, may help those with a massive or persistent anti-inflammatory reaction. Patients with a mixed response may benefit from agents such as ibuprofen, which has both anti-inflammatory and immune-stimulating properties (atleast in vitro) because it blocks PGE2.

If this hypothesis is true, it is tempting to speculate that the sepsis trials failed because many of the patients to whom these new drugs were given already had a predominantly anti-inflammatory or mixed state. Because the trials of new therapies did not take these states into account, they were unable to improve outcome and, in a few cases, may actually have increased mortality. Therefore, we must develop ways of quickly determining in each patient whether the inflammatory or anti-inflammatory reaction predominates and its duration. Rapid assays for pro-inflammatory mediators are being developed; measurement of IL-6 may be the most helpful of these. We need similar assays for anti-inflammatory mediators, although we do not know yet which of these will be the most useful in predicting outcome. therapies can then be targeted to the patient's condition. For eg: monoclonal Ab to TNF or receptor antagonists to IL-1 may be beneficial in patients with a persistently pro-inflammatory response. Those with a persistently anti-inflammatory reaction may be helped by immune system stimulators, such as GCSF or interferon-gamma.