2.6 Sepsis and fever Flashcards
The human body can only tolerate temperatures (core temperature) between ___________ (above which results in core protein destruction and death):
• Temperature is generated by biochemical reactions in all living cells (mitochondria)
• More than 50% of body heat is generated by inefficient biochemical processes converting food energy into free energy
• Body temperature is regulated by the nervous system → nervous input causes physiological adaptation
Physiological response to heat*
- Sweating (evaporation of water in sweat produces a cooling effect)
- Increased blood flow to the skin surface (allows increased heat loss)
- Thermal set point: ______________ before any heat loss response is triggered
Physiological response to cold
- Shivering/non-shivering thermogenesis (_____________ is main source of non-shivering form)
- Diversion of blood from non-vital organs (e.g. skin) to the heart and brain
28°C - 41°C;
maximum temperature tolerated;
brown adipose tissue
THERMOREGULATION
The body detects core temperature via the thermoregulatory area (hypothalamus + limbic system + lower brainstem + reticular formation + stem cord + sympathetic ganglia):
• ___________ is the most important (situated near the rostral hypothalamus)
• Detects thermal input signals from the skin and core organs (including CNS)
Fever
- Elevated core temperature in response to invading microorganisms or inanimate objects recognised as pathogenic/alien
- ________ in early morning and ________ at any other time*
Hyperthermia
- Unregulated rise in body temperature due to failure of _______________
- Standard antipyretics (e.g. paracetamol) are generally ineffective
- Diurnal variation in body temperature must be considered (lowest at 6am; highest at 4 – 6pm)
Pre-optic area (POA);
≥ 37.2°C; ≥ 37.8°C;
thermoregulatory homeostasis (not due to pyrogenic cytokines)
FEBRILE RESPONSE The febrile response is a complex physiological reaction to disease, accounting for concurrent physiological responses and components of the acute phase response:
• Exogenous pyrogens enter the body and activate __________, which produce various cytokines (e.g. IL-6, IL-1, TNF-α, IFN-γ) that act on the __________________
• Induces _________________, which mediates the febrile response (negative feedback loop induced to control core body temperature → reduce temperature-induced cell damage)
Exogenous pyrogens
- Originate from outside the body
- May be infectious agents/products or non-infectious agents (e.g. foreign products)
- Usually microorganisms, toxins, other products (antigens)
- Induce host cells (mainly ____________) to produce endogenous pyrogens
- Bacterial liposaccharide (LPS) has a direct pyrogenic effect (binds ________ on macrophages)
Endogenous pyrogens
- Originate from within host cells)
- 4 main host cell-derived cytokines (____________________)
- Produced in response to exogenous pyrogens or certain endogenous molecules (e.g. Ab-Ag complexes with complement, certain androgenic steroid metabolites, various lymphocyte-derived molecules)
Cryogens
- Helps the body to lose heat (opposite effect to pyrogens):
- α-MSH, glucocorticoids, GIP, __________ (stimulates gastric release), glucocorticoid inducers (CRH, corticotrophin → inhibit_______________, arginine vasopressin, TRH, NO, CO
leukocytes;
organum vasculosum of the lamina terminalis (OVLT);
prostaglandin E2 synthesis
macrophages;
TLR-4;
IL-1, TNF-α, IL-6, IFN;
bombesin ;
IL-6 & TNF-α
ACUTE PHASE RESPONSE
The acute phase response is a complex interplay between systems in response to a clinical insult (inflammatory response involving many changes):
• Patients develop a fever and other physiologic changes (severity is variable; depends on other factors like the pathogen and state of immunocompromise)
Neuroendocrine:
- Fever, malaise, sleepiness (somnolence), loss of appetite (anorexia)
- Rise in _____, _________, ____
- Decrease in ______________
Haematopoietic
- Increased WCC (predominantly neutrophilia; sometimes increased platelets → may decrease instead in very septic patients due to DIC)
- Anaemia of chronic disease (not blood loss)
Metabolic
- Muscle breakdown, fat breakdown, reduced _____________________ → cachexia (wasting of the body; may occur in other syndromes like AIDS/malignancies)
Hepatic
- Changes in concentrations of various hepatic proteins
Non-protein plasma constituents
- Decreased total ___________, increased ______
catecholamines, cortisol, arginine vasopressin;
IGF-1 (insulin-like growth factor 1) ;
gluconeogenesis;
iron and zinc; copper
There are various proteins which are affected by the acute phase response (ceruloplasmin, haptoglobin, C-reactive protein, serum amyloid A, albumin, transferrin):
• Haptoglobin is useful in measuring the presence of haemolysis (decreased haptoglobin in ___________; increased haptoglobin ______________)
- C-reactive protein (CRP) & Serum amyloid A: _______________
- Haptoglobin & Fibrinogen: Rise gradually and falls gradually
- _______________: Decrease during the acute phase response
- Procalcitonin is another marker of inflammation which is more specific for sepsis (inflammation due to severe infection) and is generally used in the critical setting.
haemolysis;
in acute phase response;
Rapid rise (persists for a few days) before rapidly dropping;
Albumin &Transferrin
SEPSIS
Sepsis is the systemic response to severe infection, which is one form of systemic inflammatory response syndrome (SIRS) (severe inflammatory response to a wide variety of severe clinical insults):
• Occurs on a spectrum: _________ → _________ → __________ (if unchecked) → _______ → death
• Rate of progression depends on the nature of the pathogen and presence of any underlying comorbidities
infection → acute phase response → sepsis (if unchecked) → septic shock → death
INFECTION
Infection is the microbial phenomenon characterised by an _____________________ to the presence of microorganisms or invasion of normally sterile host tissues:
• Microorganisms are usually pathogenic (different from commensals) → commensals may become pathogenic occasionally when the immune system is compromised
• Inflammatory response in infection is initially localised, but may disseminate/invade
• Bacteraemia is the presence of ______________ in the blood (detected by blood cultures) → similar to fungaemia and parasitaemia
DIAGNOSIS
SIRS is diagnosed by at least 2 of the following parameters:
1. Temperature______________*
2. Heart rate > 90 beats/min
3. Respiratory rate > 20/min or PaCO2 < 32 mmHg
4. WBC count _______________ * or > 10% immature band forms
*The low temperature and WCC are paradoxical findings used as markers in certain situations (e.g. elderly).
inflammatory response;
viable bacteria;
> 38°C or < 36°C;
> 12000/mm3 or < 4000/mm3
COMPLICATIONS
If sepsis is not managed properly, it may lead to organ dysfunction, hypotension and hypoperfusion (inadequate blood supply to organ usually due to hypotension/thrombosis):
• Measurement of hypoperfusion:____________ (product of anaerobic metabolism) or urine output (oliguria: ___________)
• Cerebral hypoperfusion: causes altered mental states (e.g. delirium, drowsiness, agitation)
Septic shock is a type of severe sepsis which occurs when the patient remains hypotensive due to sepsis ___________________ (with signs of organ dysfunction):
• Sepsis-induced hypotension occurs before septic shock (defined as ______________________) → absence of other causes of hypotension
• If the low blood pressure responds to fluid resuscitation and there are no signs of organ dysfunction manifesting afterwards, it is unlikely to be septic shock
- Multi-organ dysfunction syndrome (MODS) is on the spectrum of sepsis and refers to when _______________________.
lactic acid levels;
< 400 mL/day;
despite fluid resuscitation;
systolic < 90 mmHg or reduction of ≥ 40 mmHg from baseline;
1 or more organs are compromised due to severe sepsis
Diseases caused by Group A strep (S. ? pyogenes)
Streptococcal pharyngitis, erysipelas (large raised patches on skin), necrotising fasciitis, streptococcal toxic shock syndrome, impetigo (blisters/sores), scarlet fever, myositis
Virulence factors associated with Group A strep?
M-protein (associated with invasive infections), haemolysins (e.g. streptolysin O/S), exotoxins (e.g. pyrogenic toxin → scarlet fever, STSS), antiphagocytic properties of M-protein and hyaluronic acid capsule, serum opacity factor, adhesins
Host factors associated with Group A strep?
Poorly controlled diabetes
Excess alcohol
Renal failure
Disease caused by staphylococcus
Benign/deep infections, bacteraemia, endocarditis, necrotising fasciitis (in association with GAS), osteomyelitis
Virulence factors associated with staphylococcus?
Superantigens (TSST-1, enterotoxins), haemolysis, Panton-Valentine leukocidin (PVL), surface adhesins, protein A, biofilm (protects from immune system and antibiotic penetration)
Host factors associated with staphylococcus?
Diabetes IV drug use Solid organ transplantation Dialysis SLE
Diseases caused by clostridium perfringens?
Enteric disease (food poisoning, enteritis necroticans), gas gangrene (tissue necrosis, sepsis)
Virulence factors associated with Clostridium perfringens?
Exotoxins (e.g. phospholipase C, haemolysin, β-toxins)
