Ward 3 (Sepsis pt.1 +dementia)

Question 1

Types of dementia

Answer 1

Alzheimer’s disease
vascular dementia
mixed dementia
dementia with Lewy bodies
frontotemporal dementia
posterior cortical atrophy

Question 2

Most common types of dementia

Answer 2

• Alzheimer’s (60%)
• Vascular dementia (15%)
• Mixed dementia (Alz + Vascular) (10%)
• Dementia with Lewy bodies (10%)
• Frontotemporal dementia (2%)

Question 3

Frontomporal dementia age

Answer 3

It predominantly affects people under the age of 65 years

Question 4

What is the most important risk factor for dementia?

Answer 4

Age

Question 5

Dementia symptoms

Answer 5

Symptoms may include:
- memory loss: especially for recent events
- difficulty processing information
- difficulty finding the right word
- difficulty carrying out everyday tasks
- sleep disruption: disturbance in the sleep wake cycle
- mood changes: anxiety, apathy, depression
- hallucinations: seeing things that are not there
- change in personality or behaviour
- being confused about time or place

Question 6

What is delirium?

Answer 6

A temporary, short-term state of confusion

Question 7

Most common cause of delirium

Answer 7

most commonly infection (e.g. urinary or respiratory), drug side-effects or dehydration

Question 8

What is sepsis?

Answer 8

A dysregulated host response to infection that leads to acute organ dysfunction

Question 9

Source of sepsis

Answer 9

• Sepsis can arise from both community-acquired and hospital-acquired
  infections
• Of these infections, pneumonia is the most common source, accounting for about half of cases; next most common are intrabdominal and genitourinary infections

Question 10

Culture positivity in sepsis

Answer 10

Blood cultures are typically positive in only one-third of cases, while many cases are culture negative at all sites

Question 11

Most common organisms in sepsis

Answer 11

• Bacteria represent large majority of cases
• Staphylococcus aureus and Streptococcus pneumoniae are the most common gram-positive isolates, while Escherichia coli, Klebsiella species, and Pseudomonas aeruginosa are the most common gram-negative isolates
• About 50/50 gram neg/pos and less commonly fungi

Question 12

Risk factors of sepsis

Answer 12

• Related to both the predisposition to develop an infection and, once infection develops, the likelihood of developing acute organ dysfunction
• Common risk factors for increased risk of infection include chronic diseases (e.g., HIV infection, chronic obstructive pulmonary disease, cancers), immunosuppression, chemotherapy, on long term steroids, recent surgery/invasive procedure (less than 6 weeks), IV drug users, and with catheters/lines inserted in them.
• Risk factors for progression from infection to organ dysfunction are less well understood but may include underlying health status, preexisting organ function, and timeliness of treatment.
• Age, sex, and race/ethnicity all influence the incidence of sepsis, which is highest at the extremes of age (less than 1 and above 75), higher in males than in females, and higher in blacks than in whites.

Question 13

How common is the presence of shock in sepsis

Answer 13

Estimated around 30%

Question 14

Individual response to sepsis in patients

Answer 14

• The specific response of each patient depends on the pathogen (load and virulence) and the host (genetic composition and comorbidity), with different responses at local and systemic levels.
• The host response evolves over time with the patient’s clinical course.
• Generally, proinflammatory reactions (directed at eliminating pathogens) are responsible for “collateral” tissue damage in sepsis, whereas anti-inflammatory responses are implicated in the enhanced susceptibility to secondary infections that occurs later in the course
• These mechanisms can be characterized as an interplay between two “fitness costs”: direct damage to organs by the pathogen and damage to organs stemming from the host’s immune response. The host’s ability to resist as well as tolerate both direct and immunopathologic damage will determine whether uncomplicated infection becomes sepsis.
• Sepsis occurs when these local proinflammatory immune processes become exaggerated, resulting in a generalized immune response affecting normal tissues remote from the site of injury or infection

Question 15

Summary of initial host response to infection

Answer 15

ttern- Host response to infection is initiated when pathogens are recognized and bound by
innate immune cells, particularly macrophages.
- Pathogen recognition receptors (PRRs) (e.g. TLRs and NOD-like receptors (NLRs)) present on the surface of immune cells bind pathogen-associated molecular patterns (PAMPs). The interaction of PRRs with PAMPs results in upregulation of inflammatory gene transcription
and activation of innate immunity
- Infection also lead to release of DAMPS, reactive oxygen species, microparticles, proteolytic enzymes, and neutrophil extracellular traps, which can also influence inflammatory processes
- Concurrent to macrophage activation, polymorphonuclear leukocyte (PMN) surface receptors also bind microbial components. This interaction results in the expression of surface adhesion molecules that cause PMN aggregation and margination to the vascular endothelium. Through a multistep process of rolling, adhesion, diapedesis, and chemotaxis, PMNs migrate to the site of infection, releasing inflammatory mediators responsible for endothelial dysfunction, local vasodilation, hyperemia, coagulation activation, complement activation. and increased microvascular permeability.
- Subsequent alterations in cellular bioenergetics lead to greater glycolysis (e.g., lactate production), mitochondrial injury, release of reactive oxygen species, and greater organ dysfunction.

Question 16

What are PAMPs?

Answer 16

Structures conserved across microbial species that bind to pattern recognition receptors

Question 17

Examples of PAMPs

Answer 17

Includes, among many, viral RNAs and flagellin, a common PAMP is the lipid A moiety of lipopolysaccharide (LPS or endotoxin) found in the outer membrane of gram-negative bacteria.

Question 18

LPS binding to PAMPS

Answer 18

LPS first attaches to the LPS-binding protein on the surface of monocytes, macrophages, and neutrophils. It is then transferred to and signals via TLR4 to produce and release proinflammatory cytokines such as tumor necrosis factor and interleukin 1 (IL-1) that grow the signal and alert other cells and tissues

Question 19

Aside from PAMPS, what else can PRRs bind to and what are they? What happens when they are released?

Answer 19

• In addition to pathogen recognition, PRRs also sense endogenous molecules released from injured cells—so-called damage-associated molecular patterns (DAMPs)
• DAMPs, or “alarmins,” are nuclear, cytoplasmic, or mitochondrial structures that are released from cells as a result of infection, tissue injury, or cell necrosis
• Once released into the extracellular environment, DAMPs are recognized by PRRs on immune cells, resulting in upregulation of proinflammatory cytokine production

Question 20

Examples of DAMP

Answer 20

Examples of DAMPs include high-mobility group protein B1, uric acid, S100 proteins, and extracellular RNA, DNA, and histones.

Question 21

Pathogenic components of sepsis

Answer 21

• Initiation of inflammation
• Coagulation abnormalities
• Organ dysfunction
• Anti-inflammatory mechanisms
• Immune suppression

Question 22

Sepsis association with coagulation

Answer 22

Sepsis is commonly associated with coagulation disorders and frequently leads to disseminated intravascular coagulation

Question 23

Role of coagulation in infection

Answer 23

• Abnormalities in coagulation are thought to isolate invading microorganisms and/or to prevent the spread of infection and inflammation to other tissues and organs
• Excess fibrin deposition is driven by coagulation via tissue factor, a transmembrane glycoprotein expressed by various cell types; by impaired anticoagulant mechanisms, including the protein C system and antithrombin; and by compromised fibrin removal due to depression of the fibrinolytic system.
• Coagulation (and other) proteases further enhance inflammation via protease-activated receptors. In infections with endothelial predominance (e.g., meningococcemia), these mechanisms can be common and deadly.

Question 24

Mechanisms underlying organ failure in sepsis

Answer 24

• Both cellular and hemodynamic alterations play a key role
• Key contributing factors include aberrant inflammatory response, cellular alterations, endothelial dysfunction, circulatory abnormalities, and tissue ischemia
• Aberrant inflammation causes cellular damage, increasing the risk of organ dysfunction
• Cellular alterations, including impaired cell death pathways, mitochondrial dysfunction, and intracellular handling of reactive oxygen species, play a key role
• Endothelial dysfunction is also critical to the pathogenesis of multiple organ failure common to sepsis.
• Emerging evidence suggests the gut may also play an independent role in the development of sepsis-associated organ dysfunction.

Question 25

Cellular alterations related to mitochondrial dysfunction in infection

Answer 25

• Mitochondrial damage due to oxidative stress and other mechanisms impairs cellular oxygen utilization.
• The slowing of oxidative metabolism, in parallel with impaired oxygen delivery, reduces cellular O2 extraction.
• Yet energy (i.e., ATP) is still needed to support basal, vital cellular function, which derives from glycolysis and fermentation and thus yields H+ and lactate.
• With severe or prolonged insult, ATP levels fall beneath a critical threshold, bioenergetic failure ensues, toxic reactive oxygen species are released, and apoptosis leads to irreversible cell death and organ failure

Question 26

Endothelial dysfunction in sepsis

Answer 26

• Cell-cell connections in the vascular endothelium are disrupted in sepsis due to a number of factors, resulting in loss of barrier integrity, giving rise to subcutaneous and body-cavity edema.
• Endothelial glycocalyx disruption also contributes to endothelial permeability and
  edema formation.
• Circulatory dysfunction, both at the systemic and microcirculatory level, is also common in sepsis and contributes to the development of organ failure.
• Uncontrolled release of nitric oxide from cellular damage causes vasomotor collapse, opening of arteriovenous shunts, and pathologic shunting of oxygenated blood from susceptible tissues.
• Microcirculatory complications, including microthrombosis and decreased capillary density, also impair tissue oxygen delivery, resulting in the development of organ dysfunction.

Question 27

Gut role in sepsis

Answer 27

Proposed hypotheses include bacterial translocation through impaired mucosal integrity, release of toxic mediators by injured gut mucosa, and even alteration in gut microbiome due to critical illness.

Question 28

Morphological changes in sepsis induced organ failure

Answer 28

• The resulting morphologic changes in sepsis-induced organ failure are complex
• Generally, organs such as the lung undergo extensive microscopic changes, while other organs may undergo rather few histologic changes.
• In fact, some organs (e.g., the kidney) may lack significant structural damage while still having significant tubular-cell changes that impair function

Question 29

Anti-inflammatory mechanisms in the body against inflammation

Answer 29

• Phagocytes can switch to an anti-inflammatory phenotype (e.g. M2 macrophages) that promotes tissue repair, while regulatory T cells and myeloid-derived suppressor cells further reduce inflammation
• The so-called neuroinflammatory
  reflex may also contribute. Disruption of this neural-based system by vagotomy renders animals more vulnerable to endotoxin shock, while stimulation of the efferent vagus nerve or α7 cholinergic receptors attenuates systemic inflammation in experimental sepsis.

Question 30

Describe the neuroinflammatory reflex

Answer 30

• Sensory input is relayed through the afferent vagus nerve to the brainstem, from which the efferent vagus nerve activates the splenic nerve in the celiac plexus, with consequent
  norepinephrine release in the spleen and acetylcholine secretion by a
  subset of CD4+ T cells
• The acetylcholine release targets α7 cholinergic receptors on macrophages, reducing proinflammatory cytokine release.

Question 31

Immune supression in sepsis

Answer 31

• Patients who survive early sepsis but remain dependent on intensive care occasionally demonstrate evidence of a suppressed immune system.
• These patients may have ongoing infectious foci despite antimicrobial therapy or may experience the reactivation of latent viruses.
• Multiple investigations have documented reduced responsiveness of blood leukocytes to pathogens in patients with sepsis; these findings were recently corroborated by postmortem
  studies revealing strong functional impairments of splenocytes harvested from ICU patients who died of sepsis
• Immunosuppression was evident in the lungs as well as the spleen
• Enhanced apoptotic cell death, especially of B cells, CD4+ T cells, and follicular dendritic cells, has been implicated in sepsis associated immune suppression and death.

Question 32

Percentage of sepsis patients that develop secondary infections

Answer 32

In a cohort of >1000 ICU admissions for sepsis, secondary infections developed in 14% of
patients, and the associated genomic response at the time of infection was consistent with immune suppression, including impaired glycolysis and cellular gluconeogenesis.

Question 33

Most common secondary infections in sepsis patients

Answer 33

The most common secondary infections included catheter-related bloodstream infections, ventilator-associated infections, and abdominal infections.

Question 34

Proinflammatory mediators

Answer 34

• Important proinflammatory cytokines include TNFa and interleukin-1 (IL-1), which share a remarkable array of biological effects
• The release of TNFa is self-sustaining (ie, autocrine secretion), while non-TNF cytokines and mediators (eg, IL-1, IL-2, IL-6, IL-8, IL-10, platelet activating factor, interferon, and eicosanoids) increase the levels of other mediators (ie, paracrine secretion).
• The proinflammatory milieu leads to the recruitment of more PMNs and macrophages

Question 35

Anti-inflammatory mediators

Answer 35

• Cytokines that inhibit the production of TNFa and IL-1 are considered anti-inflammatory cytokines.
• Such anti-inflammatory mediators suppress the immune system by inhibiting cytokine production by mononuclear cells and monocyte-dependent T helper cells.
• However, their effects may not be universally anti-inflammatory. As examples, IL-10 and IL-6 both enhance B cell function (proliferation, immunoglobulin secretion) and encourage the development of cytotoxic T cells

Question 36

What can sepsis be conceptualized as?

Answer 36

Sepsis can be conceptualized as malignant intravascular inflammation:
- Malignant because it is uncontrolled, unregulated, and self-sustaining
- Intravascular because the blood spreads mediators that are usually confined to cell-to-cell interactions within the interstitial space
- Inflammatory because all characteristics of the septic response are exaggerations of the normal inflammatory response