Page 834 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 64: Sepsis, Severe Sepsis, and Septic Shock 565

Cytokines: Many cytokines serve as messengers to the host immune Additionally, coronary blood flow did not change between septic shock
system, promoting an increased inflammatory response. Pro- patients who developed myocardial depression and those who did not. 26
7
inflammatory cytokines (eg, interleukin-1 [IL-1], IL-2, IL-6, IL-8, There are multiple mechanisms contributing to myocardial dysfunction
IL-10, interferon gamma [INF-γ], and platelet-activating factor [PAF]) in sepsis. The proinflammatory mediators already discussed such as tumor
conduct a myriad of biological pathways that are known as the systemic necrosis factor-alpha (TNF-α), interleukin (IL), and nitric oxide (NO)
inflammatory response syndrome (SIRS). Chemokines are a family of depress cardiac myocyte contractility. Excess NO production by vascular
27
17
27
cytokines that has the capacity to regulate leukocyte migration and endothelial cells causes myocardial depression. Changes in volume status,
are crucial to the organization and structure of cell distribution in downregulated β receptors, reduced calcium from the sarcoplasmic reticu-
17
the inflammatory response. During inflammation, neutrophils and lum, and downregulated signaling pathways all contribute to septic cardiac
macrophages produce large amounts of reactive oxygen species (ROS) dysfunction. Dysfunction can be seen early in sepsis and an echocar-
27
and reactive nitrogen species (RNS), which allows the neutrophils and diogram may reveal systolic, diastolic, and/or biventricular dysfunction.
macrophages to kill microorganisms. ROS can also cause oxygen cell Myocardial depression can also exist in a hyperdynamic state. Cardiac
damage of the endothelium. The imbalance between production and function usually recovers between 7 and 10 days after onset. 28
18
changes in vascular tone and vascular permeability. ROS and RNS can ■ VASCULAR DYSFUNCTION
adequate removal of ROS can result in leukocyte and platelet adhesion,
also contribute to mitochondrial dysfunction. Oxygen delivery is In contrast to cardiogenic or hypovolemic shock, septic shock is a dis-
18
impaired in sepsis as is the cell’s ability to utilize oxygen coining the tributive shock state resulting in vessel dilatation instead of vasoconstric-
phrase “cytopathic hypoxia.” Depletion of mitochondrial ATP and tion during hypotension. NO is overproduced by inducible nitric oxide
19
impaired oxidative phosphorylation has been demonstrated in animal synthase (iNOS) found in arterial smooth muscle cells and endothe-
models. Mitochondrial dysfunction in skeletal muscle and liver has lium. NO is released into circulation bound to hemoglobin. Overactive
29
been associated with poor outcomes in septic patients. Mitochondria substances like NO decrease vascular tone by activating potassium
are the main cellular oxygen consumers and their dysfunction in sepsis channels and hyperpolarizing smooth muscle plasma membranes. This
30
related to multiorgan dysfunction is an area of research interest. leads to the most common presentation of a septic patient with hyperdy-
The early inflammatory response is followed by an anti-inflammatory namic cardiac output, hypotension, and low systemic vascular resistance.
response by mediators such as IL-10, IL-1 receptor antagonist (IL-1ra), ■
and soluble tumor necrosis factor (TNF) receptor in order to estab- RESPIRATORY DYSFUNCTION
lish homeostasis. In addition, T-helper cells are able to change their Sepsis is a major risk factor foracute respiratory distress syndrome
20
production of type 1 proinflammatory to type 2 anti-inflammatory (ARDS), which is characterized by neutrophilic inflammation and
cytokines. Organ dysfunction and mortality often occur during this increased pulmonary vascular permeability. Development of ARDS is
period of hypoimmunity. This hypoimmune state can also prolong the associated with a high rate of morbidity and mortality in the range of
host ability to recover. 30% to 50%. ARDS can progress into a more fatal form known as acute
Complement: Complement activation includes three major pathways respiratory distress syndrome (ARDS), which carries an even higher rate
31
as part of the innate immune system. All three pathways lead to C3, of fatality. The pooled mortality rate for ALI/ARDS in several locations
which starts the cascade of cleavage products like C3a, C3b, C5a, around the world exceeds 40%. 32
C5b, and C5b-C9 lytic membrane attack complex where complement There are two barriers that make up the alveolar-capillary barrier: the
molecules create a pathway for fluid to shift from the extracellular to microvascular endothelium and the alveolar epithelium. In the acute
intracellular space resulting in cell wall lysis of the pathogen. 7,21 phase, there is denudation of the basement membrane and sloughing off
of the bronchial and epithelial cells. Neutrophils adhere to the injured
Coagulation Imbalance: In recent years, it has been discovered that the capillary endothelium and marginate into the air space interstitium. In
coagulation system acts in concert with the inflammatory cascade in the air space, alveolar macrophages attack by secreting TNF-α, IL-1,
the pathophysiology of sepsis. The endothelium is the protective IL-6, IL-8, and IL-10, which signal chemotaxin and neutrophils to attack.
22
barrier for the blood vessel. In sepsis, their integrity is compromised. Neutrophils bombard the pathogen by releasing proteases, leukotri-
Damage to the endothelium causes hemorrhage and increases perme- enes, and platelet-activating factor (PAF). Many research groups are
33
ability, which is a key factor to the pathogenesis of severe sepsis. actively seeking accurate biomarkers for both diagnosis and prognosis in
23
Endothelial cells maintain systemic blood pressure and flow to organs. patients with ARDS. Investigators have identified certain inflammatory
The human body contains about 10 endothelial cells, an area of 4000 to mediators such as IL-1β and TNF-α, which have been found in the distal
13
7000 m . Damage to the endothelial cells cause tissue edema by increas- airways in ARDS patients. 34-36 IL-8, plasminogen activator inhibitor-1,
2 18
ing microvascular permeability resulting in fluid loss into the interstitial and protein C of the coagulation system have also been suggested to be
space, which can lead to hypovolemia, arterial hypoxemia, impaired gas predictive of clinical outcomes in this patient population. Markers of
37
exchange, and impaired tissue oxygen distribution. Endothelial damage both endothelial lung injury, such as Von Willebrand factor, and epithe-
24
ignites the coagulation tissue factor cascade as well. The protein C lial lung injury, such as receptor for advanced glycation end products
25
pathway serves as an anticoagulant system, promoting fibrinolysis (RAGE) and surfactant protein-D (SP-D), are being studied as potential
by inhibiting thrombosis and inflammation. Thrombin binds to markers for disease severity. 38
25
thrombomodulin at the endothelial protein C receptor (EPCR) on the
endothelium, resulting in a complex that rapidly activates protein C, ■ GASTROINTESTINAL DYSFUNCTION
which binds to protein S, ultimately inactivating factors Va and VIIIa. In sepsis, the gastrointestinal track becomes hypoperfused, which
Activated protein C (APC) is decreased in sepsis by impaired synthesis, can result in gut ischemia, but in addition reperfusion of the gut can
consumption, and degradation. 25
ignite proinflammatory mediators, which can cause intestinal perme-
ability, ileus, and bacterial translocation. Bacterial translocation is the
39
ORGAN DYSFUNCTION IN SEPSIS passage of endogenous bacterial flora endotoxins across mucosal barriers.
■ CARDIOVASCULAR DYSFUNCTION Ileus, defined as intestinal dysmotility, causes an accumulation of bac-
teria of the stomach and small intestine that predisposes to bacterial
Septic patients often have an elevated troponin level and it was unclear translocation and aspiration pneumonia. The pathogen can also sense
at first if this represented irreversible myocardial injury or reversible the alteration in the host and enhance their virulence phenotype.
40
myocardial depression. However, previous studies found that coronary Therefore, ileus perpetuates the infectious and proinflammatory state of
26
blood flow did not differ between septic shock and healthy patients. sepsis contributing to multiorgan failure. 39

section05_c61-73.indd 565 1/23/2015 12:47:49 PM