We will review pathophysiology of sepsis according to the CHAOS scheme. This covers Cardiovascular shock, Homeostasis impairment, Apoptosis, Organ dysfunction and Suppression of the immune system.
Before proceeding, a few terms need to be defined. These terms are from the human's ACCP/SCCM Consensus Conference Definitions, including 2016 the most recent iteration (Sepsis 3 definitions):
SIRS—Systemic inflammatory response syndrome. Initially, it was defined as a condition where local inflammation becomes systemic and affects the entire body. It can be due to various causes, for example pancreatitis, heat stroke or trauma (including surgical trauma). It is based on 4 criteria such as temperature, heart rate, respiratory rate, and white blood cell count or percentage of bands.
Sepsis—Initially, it was defined as SIRS+infection. This was a specific term used when SIRS is secondary to an infection (viral, bacteria, fungal, protozoal, etc.). It is not the same as bacteremia or septicemia. However, the Sepsis 3 guidelines now defines it as life-threatening organ dysfunction caused by a dysregulated host response to infection. This new definition emphasizes the primacy of the non-homeostatic host response to infection, the potential lethality that is considerably in excess of a straightforward infection, and the need for urgent recognition, effectively moving the new sepsis definition into the slot previously held by severe sepsis (see below).
Septic shock—The classic definition clinically uses hypotension requiring use of vasopressors to maintain MAP ≥65 mm Hg and having a serum lactate >2 mmol/l persisting despite adequate fluid resuscitation.
Cardiovascular collapse in septic shock is multifactorial, a combination of multiple shock categories such as maldistributive, hypoxemic, anemic, cardiogenic, hypovolemic and metabolic. Traditionally considered a vasodilatory shock due to nitric oxide production and endothelial glycocalyx impairment, it is common that dogs and especially cats with septic shock are presented with clinical signs consistent with vasoconstriction. It is after fluid resuscitation and intravascular volume replacement that the vasodilation can be uncovered.
Cellular dysfunction and disruption of homeostasis is a hallmark of sepsis. The underlying pathophysiology is complex with both pathogenic and host factors such as PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) playing a significant role in the development and subsequent outcome. Pro- and anti-inflammatory cytokines may balance each other, resulting in complex scenario where SIRS and its counter regulatory pathways are neutralizing each other, and can progress to syndrome resolution or worsening of organ dysfunction.
Apoptosis is defined as programmed cell death and should be compared and contrasted with necrosis. Intensive efforts have been made to explore the molecular mechanisms of the apoptotic signaling pathways, called "death signals," including the initiation, mediation, execution and regulation of apoptosis. Caspases are central effectors of apoptosis. Cells undergo apoptosis through two major pathways, the extrinsic pathway (death receptor pathway) or the intrinsic pathway (the mitochondrial pathway). There are many triggers for apoptosis, including reactive oxygen species (ROS). Apoptosis, as well as necrosis, participates to organ dysfunction.
In sepsis, the presence of multiple organ dysfunction and MODS is a very bad prognostic indicator. Many organs can be damaged and failed, including the kidney (AKI), the lungs (ARDS), the endothelial and hemostasis (DIC), the immune system (CARS), and/or the adrenal glands (CIRCI). The more organs are failing, the higher the mortality rate. In fact, in veterinary medicine, it is commonly reported that each failing system typically corresponds to a 20% increase in the mortality rate (i.e., an animal with 3 failing organ systems has an approximate mortality rate of 60%). However, that depends on the type of organs and the therapy available. MODS is a multifactorial syndrome that is a result of many insults and injuries that have occurred throughout the body secondary to sepsis. The damaged organ can be at a distant site of the initial injury, for example respiratory failure in a severe necrotizing pancreatitis dog or kidney failure in a cat with pyothorax. There are multiple reasons for a distant or local organ to fail due to SIRS/sepsis. Overwhelming pro-inflammatory cytokines are thought to be the starting point and then the following can occur:
1. Endothelial activation causing activation of the clotting cascade and microthrombosis (causing ischemia and tissue hypoxia), i.e., progression to disseminated intravascular coagulation (DIC). Remember that everything pro-inflammatory is pro-coagulant!
2. Direct injury by ROS and complement (membrane attack complex) resulting in further loss of functional tissue.
3. Direct tissue damage from initial injury (burn, heat stroke, trauma).
4. Edema formation by modification of Starling forces (albumin leaves and endothelial gaps increase) resulting in increased distance for oxygen diffusion.
5. Microvascular dysfunction and blood vessels shunting causing loss of tissue perfusion and decrease utilization of oxygen.
6. Apoptosis, or programmed cell death, triggered by multiple pathways including pro-inflammatory cytokines.
7. Impaired oxygen delivery to the tissues from hypoperfusion, anemia and/or hypoxemia.
Immune suppression, or anergia, due to compensatory anti-inflammatory response syndrome (CARS), is commonly described in people, although the description of such syndrome is lacking in veterinary medicine. CARS is a complex pattern of immunologic responses to severe infection or injury. The difference is that while SIRS is a proinflammatory response tasked with killing infectious organisms through activation of the immune system, CARS is a global deactivation of the immune system tasked with restoring homeostasis. This immune system response is believed to be a protective response based on the balance between the innate and adaptive immune systems. The timely arrival of CARS seeks to limit the damage while not interfering with the pathogen elimination; however, the response can be dangerous is poorly timed or its effects go unchecked, leaving the host vulnerable to excessive immunosuppression and the next set of pathogens. The CARS response includes reduction of lymphocytes by means of apoptosis, decreased cytokines response of monocyte to stimulation, and expression of cytokines such as IL-10 that suppresses TNF expression.
References
References are available upon request.