Septic shock


Septic shock is a potentially fatal medical condition that occurs when sepsis, which is defined as an abnormal immune response to infection that leads to life threatening organ dysfunction, leads to dangerously low blood pressure and abnormalities in cellular and metabolic dysfunction. The Third International Consensus Definitions for Sepsis and Septic Shock defines septic shock as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock are cared for in the emergency department and intensive care units.

Causes

Septic shock is a result of a systemic response to infection or multiple infectious causes. Sepsis always precedes septic shock; therefore, the causes of sepsis are also the causes of septic shock.
More than 80 percent of sepsis cases are caused by respiratory, genitourinary, skin and soft tissue, and gastrointestinal infections. Interestingly, pneumonia is the most common cause of sepsis. Indwelling devices, such as pacemakers or knee replacements can also lead to sepsis. Severe infections, such as meningitis, encephalitis, and endocarditis are also causes of sepsis. All together indwelling devices and severe infections make up 1 percent of sepsis cases. Bacteria are the microorganisms responsible for a majority of cases of sepsis. About 62 percent are caused by gram negative bacteria and 47 percent are caused by gram positive bacteria. A small number of patients can have sepsis brought on by fungi, parasites, or viral infections. It is also possible that sepsis can be caused by multiple simultaneously occurring infections.

Pathophysiology

The pathophysiology of septic shock is not entirely understood, but it is known that a key role in the development of severe sepsis is played by an immune and coagulation response to an infection. Both pro-inflammatory and anti-inflammatory responses play a role in septic shock. Septic shock involves a widespread inflammatory response that produces a hypermetabolic effect. This is manifested by increased cellular respiration, protein catabolism, and metabolic acidosis with a compensatory respiratory response.
Both gram positive and gram negative bacteria are the most common causes of septic shock. Toxins produced by pathogens cause an immune response; in gram-negative bacteria these are endotoxins, which are bacterial membrane lipopolysaccharides.
Cytokines released in a large-scale inflammatory response result in massive vasodilation, increased capillary permeability, decreased systemic vascular resistance, and low blood pressure. Finally, in an attempt to offset decreased blood pressure, myocardial dysfunction occurs with both systolic and diastolic dysfunction.

Gram-positive

In gram-positive bacteria, these are exotoxins or enterotoxins, which may vary depending on the species of bacteria. These are divided into three types. Type I, cell surface-active toxins, disrupt cells without entering, and include superantigens and heat-stable enterotoxins. Type II, membrane-damaging toxins, destroy cell membranes to enter and include hemolysins and phospholipases. Type III, intracellular toxins or A/B toxins interfere with internal cell function and include toxins secreted by streptococcus pyogenes or staphylococcus aureus.

Gram-negative

In gram-negative sepsis, a free LPS attaches to a circulating LPS-binding protein, and the complex then binds to the CD14 receptor on monocytes, macrophages, and neutrophils. Engagement of CD14 results in intracellular signaling via an associated "Toll-like receptor" protein 4. This signaling activates nuclear factor kappaB, which leads to transcription of several genes that trigger a proinflammatory response. This results in significant activation of mononuclear cells and synthesis of effector cytokines such as IL-1, IL-6, and TNF-α. TLR-mediated activation helps to trigger the innate immune system to efficiently eradicate invading microbes, but the cytokines they produce also act on endothelial cells. There, they 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.
In response to inflammation, a compensatory reaction of production of anti-inflammatory substances such as IL-4, IL-10 antagonists, IL-1 receptor, and cortisol occurs. This is called compensatory anti-inflammatory response syndrome.
Both the inflammatory and anti-inflammatory reactions are responsible for the course of sepsis and are described as MARS. The aim of these processes is to keep inflammation at an appropriate level. CARS often leads to suppression of the immune system, which leaves patients vulnerable to secondary infection. It was once thought that SIRS or CARS could predominate in a septic individual, and it was proposed that CARS follows SIRS in a two-wave process. It is now believed that the systemic inflammatory response and the compensatory anti-inflammatory response occur simultaneously.
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, diminished myocardial contractility, widespread endothelial injury, activation causing systemic leukocyte adhesion and diffuse alveolar capillary damage in the lung, and activation of the coagulation system culminating in disseminated intravascular coagulation.
The hypoperfusion 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 other organ systems. Recently, severe damage to liver ultrastructure has been noticed from treatment with cell-free toxins of Salmonella.
The ability of TLR4 to respond to a distinct LPS species is clinically important. Pathogenic bacteria may employ LPS with low biological activity to evade proper recognition by the TLR4/MD-2 system, dampening the host immune response and increasing the risk of bacterial dissemination. On the other hand, such LPS would not be able to induce septic shock in susceptible patients, rendering septic complications more manageable. Yet, defining and understanding how even the smallest structural differences between the very similar LPS species may affect the activation of the immune response may provide the mechanism for the fine tuning of the latter and new insights to immunomodulatory processes.

Diagnosis

Definitions

Sepsis is the precipitating condition to septic shock, hence the diagnostic criteria for sepsis are pertinent to the diagnosis of septic shock.
There are three different systems to diagnosis sepsis. These are the systemic inflammatory response syndrome criteria, the full Sequential Organ Failure Assessment, and the quick version of SOFA. The most recent gathering of professionals to discuss the topic of sepsis was called "sepsis-3" and set forth the latest guidelines for the diagnosis and management of sepsis.

SIRS

The SIRS criteria were recently excluded from sepsis-3, but are still the most used diagnostic tool for identifying sepsis. A patient that meets SIRS criteria has a possible, or documented, source of infection plus at least two or more of the criteria listed below.
Documented evidence of infection may include positive blood culture, signs of pneumonia on chest x-ray, or other radiologic or laboratory evidence of infection. Signs of end-organ dysfunction are present in septic shock, including kidney failure, liver dysfunction, changes in mental status, or elevated serum lactate. One limitation of the SIRS criteria is that it can be present in many non-infectious conditions, such as autoimmune conditions, pancreatitis, recent surgery, or vasculitis.

qSOFA and SOFA

qSOFA is another set of criteria used to diagnose sepsis and help clinicians identify sepsis in settings other than the ICU. It's counterpart SOFA is used exclusively in the ICU.
In the SOFA criteria, there are three criteria, which are listed below.
Patients meet SOFA criteria, and therefore have sepsis, when they fulfill 2 or more of the above criteria. qSOFA is typically limited as it is known mainly identify patients who present late in the course of sepsis.
SOFA criteria is used in critically ill patients and assesses the severity of dysfunction in the 6 organ systems. At the time of ICU admission the score is calculated as the baseline. After this the score is calculated every 48 hours. Baseline is a score of zero which indicates no sepsis. An increase in score by 2 or more points indicates sepsis and an increased mortality of 20%.

Septic shock

Septic shock is a subclass of distributive shock, a condition in which abnormal distribution of blood flow in the smallest blood vessels results in inadequate blood supply to the body tissues, resulting in ischemia and organ dysfunction. Septic shock refers specifically to distributive shock due to sepsis as a result of infection.
Originally, septic shock was identified in patients based only on the presence of hypotension. However, in recent years, it has been found that hypotension is a later manifestation of septic shock. Specifically, lack of blood flow to the tissue has been found to occur well before hypotension in cases of septic shock. Therefore, a lactate measurement has become an integral part to the diagnosis of septic shock. This is because lactate is a marker of tissue hypoperfusion as this metabolic product is only produced by metabolic processes that occur in the absence of adequete oxygen supply to the tissue. A lactate level of 18 mg/dL is diagnostic for septic shock according to sepsis-3. Another diagnostic criterion for septic shock is vasopressor therapy required to maintain a mean arterial pressure of 65 mmHg.