INTRODUCTION:

Septic Shock Also called:

1. bacteremic shock

2. septicemic shock ²

Septic shock is a serious condition caused by an infection in the bloodstream (sepsis) that results in low blood pressure and low blood flow to vital organs. During an infection, some types of bacteria make and release substances called toxins (endotoxins) that trigger an immune response. When endotoxins are released into the bloodstream they cause:

· large blood vessels to become wider (dilate)

· small blood vessels (capillaries) to leak, which allows fluid to seep from the bloodstream into tissues ¹

INCIDENCE:

Septic shock is an increasingly common problem. The incidence of sepsis is increasing every year. The reason being that the people are living longer as there is advanced technology to sustain life and this aged population are the most vulnerable to sepsis. There has been a rise in the number of immunocom promised patients due to aggressive cancer therapy and the increased prevalence of HIV makes them vulnerable to shock .³

PATHOPHYSIOLOGY:

STEP 1 : PAMPs LPS , LTA , PGN , Flagellin

DAMPs intracellular proteins - heat shock proteins , HMGB1 ; extracellular proteins - hyaluron fragment ; non - proteins - DNA anywhere outside the cell nucleus or mitochondria

STEP 2 : Pattern recognition receptors - TLRs , NOD-LRRS , RLHS , C-Type lecitin receptors

STEP 3 : Intracellular signal transduction

STEP 4 : Synthesis and release of cytokine and non cytokine mediators

STEP 5 : Potential imbalances in the functioning of cytokines and non cytokine mediators

CYTOKINE NON CYTOKINE

inflammation anti inflammation

coagulation anti coagulation

oxidation anti oxidation

apoptosis anti apoptosis⁴

PATHOGENESIS:

Microbial triggers of disease:

A. gram-negative bacteria= endotoxin, formyl peptides, exotoxins, and proteases

B. gram-positive bacteria = exotoxins, superantigens (toxic shock syndrome toxin (TSST), streptococcal pyrogenic exotoxin A (SpeA)), enterotoxins, hemolysins, peptidoglycans, and lipotechoic acid

C. fungal cell wall material. ⁵

Sequence of events:

This is a very complex sequence of events . Patients with septic shock have a biphasic immunological response. Initially they manifest an overwhelming inflammatory response to the infection. This is due to the pro-inflammatory cytokines Tumor Necrosis Factor (TNF), IL-1, IL-12, Interferon gamma (IFNgamma), and IL-6.

The body then regulates this response by producing anti-inflammatory cytokines (IL-10), soluble inhibitors TNF receptors, IL-1 receptor type II, and IL-1RA (an inactive form of IL-1). Which is manifested in the patient by a period of immunodepression. Persistence of this hyporesponsiveness is associated with increased risk of nosocomial infection and death.

This systemic inflammatory cascade is initiated by various bacterial products. These bacterial products (gram-negative bacteria= endotoxin, formyl peptides, exotoxins, and proteases, gram-positive bacteria= exotoxins, superantigens (toxic shock syndrome toxin (TSST), streptococcal pyrogenic exotoxin A (SpeA)), enterotoxins, hemolysins, peptidoglycans, and lipotechoic acid, and fungal cell wall material) bind to cell receptors on the host's macrophages and activate regulatory proteins Nuclear Factor Kappa B (NFkB). Endotoxin activates the regulatory proteins by interacting with several receptors. The CD receptors pool the LPS-LPS binding protein complex on the surface of the cell and then the TLR receptors translate the signal into the cells. ⁶

The pro-inflammatory cytokines produced are tumor necrosis factor (TNF), Interleukins 1, 6 and 12 and Interferon gamma (IFNgamma). These cytokines can act directly to affect organ function or they may act indirectly through secondary mediators. The secondary mediators include nitric oxide, thromboxanes, leukotrienes, platelet-activating factor, prostaglandins, and complement. TNF and IL-1 (as well as endotoxin) can also cause the release of tissue-factor by endothelial cells leading to fibrin deposition and disseminated intravascular coagulation (DIC).

Then these primary and secondary mediators cause the activation of the coagulation cascade, the complement cascade and the production of prostaglandins and leukotrienes. Clots lodge in the blood vessels which lowers profusion of the organs and can lead to multiple organ system failure. In time this activation of the coagulation cascade depletes the patient's ability to make clot resulting in DIC and ARDS.

The cumulative effect of this cascade is an unbalanced state, with inflammation dominant over antiinflammation and coagulation dominant over fibrinolysis. Microvascular thrombosis, hypoperfusion, ischemia, and tissue injury result. Severe sepsis, shock, and multiple organ dysfunction may occur, leading to death.

DIAGNOSIS:

Making an early, accurate diagnosis of septic shock is a key to increasing survival rates. The signs and symptoms of severe sepsis may be subtle thus making the diagnosis difficult . The components of SIRS are non specific, the combination of suspected infection and the presence of SIRS ( systemic inflammatory response )may help alert the clinician to a possible diagnosis of sepsis and hypotension is another clinical sign that may signal the onset of septic shock. The patient either presents with severe sepsis or global tissue hypoxia . Metabolic marker such as serum lactate, arterial base deficit may help to identify the severe cases. A single lactate measurement of 4mmol/l or more at initial presentation is associated with an increased rate of mortality . There may well be signs of altered mentation and abnormalities of renal and liver function test, as well as coagulation abnormalities. At least two blood cultures and cultures of other sites as indicated before commencement of antibiotic therapy. Diagnostic studies such as Ultra sound and CT scan should be performed promptly.

D dimers are grossly elevated in sepsis. Levels of Protein C are lowered which has therapeutic implications. The potential role of biomarkers for diagnosis of infection in patients presenting with severe sepsis remains undefined. Perhaps the most common considerations as diagnostic biomarkers for sepsis have been C-reactive protein and procalcitonin. Despite initial enthusiasm for their potential diagnostic strengths, they have more recently been related to the growing heap of biomarkers that have failed to accurately differentiate sepsis from similar critical illnesses.⁷

TREATMENT:

USUALLY DONE IN INTENSIVE CARE UNIT ⁸

TREATMENT INCLUDES:

1. frequent monitoring of blood pressure, heart rate and breathing⁹

2. intravenous fluids to increase blood pressure

3. medications to increase blood pressure and blood flow to the brain, heart, and other vital organs

4. intravenous antibiotics to kill the bacteria or other organisms causing infection

a. the choice of antibiotics depends on the type of bacteria present

b. 2 or more antibiotics may be used until the infecting organism is identified ¹⁰

5. oxygen therapy

6. mechanical ventilation for severe breathing problems

7. removal of any cathers that could have started the infection ¹¹

8. surgery to drain an abscess or remove dead tissue that could have started the infection ¹²

NOTE:

Infections can rapidly progress and be life-threatening in some cancer patients if they are not successfully treated. ¹³

REFERENCES:

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Received on 13.08.2014 Modified on 22.08.2014

Research J. Pharm. and Tech. 7(11): Nov. 2014 Page 1345-1347