Septic shock

Septic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome (formerly known as multiple organ failure) and death. Its most common victims are children, immunocompromised individuals, and the elderly, as their immune systems cannot deal with the infection as effectively as those of healthy adults. Frequently, patients suffering from septic shock are cared for in intensive care units. The mortality rate from septic shock is approximately 25–50%.

Definition
In humans, septic shock has a specific definition requiring several criteria for diagnosis:


 * First, SIRS (systemic inflammatory response syndrome) must be met by finding at least any two of the following:
 * Tachypnea (high respiratory rate) > 20 breaths per minute, or on blood gas, a PCO2 less than 32 mmHg signifying hyperventilation.
 * White blood cell count either significantly low, < 4000 cells/mm³ or elevated > 12000 cells/mm³.
 * Heart rate > 90 beats per minute
 * Temperature: Fever > 38.5 C or hypothermia < 35.0 C


 * Second, there must be sepsis and not an alternative form cause of SIRS. Sepsis requires evidence of infection, which may include positive blood culture, signs of pneumonia on chest x-ray, or other radiologic or laboratory evidence of infection
 * Third, signs of end-organ dysfunction are required such as renal failure, liver dysfunction, changes in mental status, or elevated serum lactate.
 * Finally, septic shock is diagnosed if there is refractory hypotension (low blood pressure that does not respond to treatment). This signifies that intravenous fluid administration alone is insufficient to maintain a patient's blood pressure from becoming hypotensive.

Types
A subclass of distributive shock, shock refers specifically to decreased tissue perfusion resulting in ischemia and organ dysfunction. Cytokines released in a large scale inflammatory response results in massive vasodilation, increased capillary permeability, decreased systemic vascular resistance, and hypotension. Hypotension reduces tissue perfusion pressure causing tissue hypoxia. Finally, in an attempt to offset decreased blood pressure, ventricular dilatation and myocardial dysfunction will occur.

Causes
When bacteria or viruses are present in the bloodstream, the condition is known as bacteremia or viremia. If the organisms are particularly virulent, or the host is immunocompromised, then the host organism may develop a condition known as systemic inflammatory response syndrome (or SIRS). Sepsis is by definition bacteremia, combined with SIRS. If sepsis worsens to the point of end-organ dysfunction (renal failure, liver dysfunction, altered mental status, or heart damage), then the condition is called severe sepsis. Once severe sepsis worsens to the point where blood pressure can no longer be maintained with intravenous fluids alone, then the criteria have been met for septic shock. The precipitating infections which may lead to septic shock if severe enough include appendicitis, pneumonia, bacteremia, diverticulitis, pyelonephritis, meningitis, pancreatitis, and necrotizing fasciitis.

Pathophysiology
Most cases of septic shock (approximately 70%) are caused by endotoxin-producing Gram-negative bacilli. Endotoxins are bacterial wall lipopolysaccharides (LPS) consisting of a toxic fatty acid (lipid A) core common to all Gram-negative bacteria, and a complex polysaccharide coat (including O antigen) unique for each species. Analogous molecules in the walls of Gram-positive bacteria and fungi can also elicit septic shock. Free LPS attaches to a circulating LPS-binding protein, and the complex then binds to a specific receptor (CD14) on monocytes, macrophages, and neutrophils. Engagement of CD14 (even at doses as minute as 10 pg/mL) results in intracellular signaling via an associated "Toll-like receptor" protein 4 (TLR-4), resulting in profound activation of mononuclear cells and production of potent effector cytokines such as IL-1 and TNF-α. These cytokines act on endothelial cells and have a variety of effects including reduced synthesis of anticoagulation factors such as tissue factor pathway inhibitor and thrombomodulin. The effects of the cytokines may be amplified by TLR-4 engagement on endothelial cells. TLR-mediated activation helps to trigger the innate immune system to efficiently eradicate invading microbes. At high levels of LPS, the syndrome of septic shock supervenes; the same cytokine and secondary mediators, now at high levels, result in systemic vasodilation (hypotension), diminished myocardial contractility, widespread endothelial injury and activation, causing systemic leukocyte adhesion and diffuse alveolar capillary damage in the lung activation of the coagulation system, culminating in disseminated intravascular coagulation (DIC). The hypoperfusion resulting from the combined effects of widespread vasodilation, myocardial pump failure, and DIC causes multiorgan system failure that affects the liver, kidneys, and central nervous system, among others. Unless the underlying infection (and LPS overload) is rapidly brought under control, the patient usually dies.

PD-1 and monocytes/macrophages activation
PD-1 was found to be up-regulated on monocytes/macrophages during sepsis in human and mice. This up-regulation was related to the up-regulation of IL-10 levels in the blood.[28] Interestingly, Said et al. showed that activated monocytes, which is the case in sepsis, express high levels of PD-1 and that triggering monocytes-expressed PD-1 by its ligand PD-L1 induces IL-10 production which inhibits CD4 T-cell function.

Treatment
Treatment primarily consists of the following.
 * 1) Volume resuscitation
 * 2) Early antibiotic administration
 * 3) Early goal directed therapy
 * 4) Rapid source identification and control.
 * 5) Support of major organ dysfunction.

Among the choices for vasopressors, norepinephrine is superior to dopamine in septic shock. Both however are still listed as first line in guidelines.

Antimediator agents may be of some limited use in severe clinical situations however are controversial:
 * Low dose steroids (hydrocortisone) for 5 – 7 days led to improved outcomes.
 * Recombinant activated protein C (drotrecogin alpha) in a 2011 Cochrane review was found not to decrease mortality and thus was not recommended for use. Other reviews however comment that it may be effective in those with very severe disease.

Epidemiology
According to the US CDC, septic shock is the 13th leading cause of death in the United States, and the #1 cause of deaths in intensive care units. There has been an increase in the rate of septic shock deaths in recent decades, which is attributed to an increases in invasive medical devices and procedures, increases in immunocompromised patients, and an overall increase in elderly patients. Tertiary care centers (such as hospice care facilities) have 2-4 times the rate of bacteremia than primary care centers, 75% of which are nosocomial infections.

The process of infection by bacteria or fungi can result in systemic signs and symptoms that are variously described. Approximately 70% of septic shock cases were once traceable to Gram staining gram-negative bacilli that produce endotoxins; however, with the emergence of MRSA and the increased use of arterial and venous catheters, Gram-positive cocci are implicated approximately as commonly as bacilli. In rough order of increasing severity, these are bacteremia or fungemic; septicemia; sepsis, severe sepsis or sepsis syndrome; septic shock; refractory septic shock; multiple organ dysfunction syndrome, and death.

35% of septic shock cases derive from urinary tract infections, 15% from the respiratory tract, 15% from skin catheters (such as IVs); over 30% of all cases are idiopathic in origin.

The mortality rate from sepsis is approximately 40% in adults, and 25% in children, and is significantly greater when left untreated for more than 7 days.

Sepsis has a worldwide incidence of more than 20 million cases a year, with mortality due to septic shock reaching up to 70 percent even in industrialized countries.