Largest group hospitalized for sepsis?
Individuals over 65 years of age, males
Mortality rates?
Sepsis - 28.6 - 30%; severe sepsis - 39.4%
Risk factors for sepsis mortality?
Old age, co-morbidities (diabetes, cancer, etc.), females, sepsis occurring after hospitalization
Trend in sepsis hospitalization rates?
Sepsis - same, but increasing in US; severe sepsis - increasing
What detects sepsis invaders?
Toll-like receptors (TLRs); TLR4 - lipopolysaccharides (endotoxins, Gm -); TLR3 - ds RNA (viral)
Describe the TLR pathway
- PAMPS (pathogen associated molecular patterns) bind TLRs
- PAMPS may activate nuclear factor kappa B (NFκB), a transcription factor
- Signalling cascade (from PAMPS, NFκB) results in expression of inflammatory mediators (e.g. cytokines)
- Vasodilation, increased capillary permeability, endothelial damage, fibrin clots (via coagulation cascade)
Criteria for SIRS diagnosis
At least two the following symptoms:
- Body temperature: >38° C or 90 beats/minute (i.e. increased)
- Respiratory rate: > 20/minute (i.e. increased) (or a PaC02 of 12,000 mm3 or < 4,000 mm3 (i.e. high or low WBCs)
- Bands (immature WBCs): >10% (indicates body-wide inflammation)
Severe sepsis diagnosis
defined as deterioration/progression of the condition such that organ systems start to fail (i.e. organ dysfunction) due to lack of perfusion
Signs of organ dysfunction
Altered mentation (confusion, agitation), oliguria (i.e. decreased urine production), or increased lactate levels (insufficient oxygen delivery to cells)
Third spacing
When H2O moving from extracellular space (or interstitum) and into cells (to dilute Na/Cl) causes water to flow out of the vasculature to replace it
Cause of septic shock
- Leakage of fluids into extravascular space = low BV
- Heart compensates for low BV
- Increased cardiac O2 demand
- Cardiovascular dysfunction
- Refractory hypotension
Pathophysiology of septic shock
- Refractory hypotension
- Poor O2 tissue perfusion due to decreased systemic vascular resistance
- Anaerobic metabolism = decreased ATP and lactic acidosis
- Decreased ATP affects pumps/gradients; Na/Cl accumulate in cell causing swelling
- Third spacing results in lower intravascular volume, worsening organ/tissue perfusion
How to measure metabolic acidosis?
Blood lactate levels
Most common organ system failures?
1 - Respiratory/pulmonary
2 - Kidneys
3 - Cardiovascular system (septic shock)
Least common - liver (highest mortality)
Pathophysiology of pulmonary system failure
- Endothelial dysfunction in capillaries/extravation of fluid = pulmonary edema/impaired gas exchange
- Less surfactant is produced and immune cells infiltrate lung tissue causing further damage.
- Loss of aeration leads to hypoxia and impaired perfusion in other organs, as well as the lungs causing ARDS
ARDS?
- Acute respiratory distress syndrome
- Impaired pulmonary perfusion
- Mechanical ventilation
DAMPS?
- Damage associated molecular patterns refer to:
1. pathogen-associated molecular patterns from invading microorganisms or parasites
2. molecules released by injured tissues
Component that recognizes DAMPS?
Pattern recognition receptors (PRR)
Binding to PRR results in
- Over expression of pro-inflammatory mediators - Activation of the complement and coagulation systems
- Cytokines recruit innate immune cells; release ROS and enzymes
- Damage to endothelium causes coagulation
- Inhibition of fibrinolysis causes disseminated intravascular coagulation (DIC)
- Immune cell dysfunction - immunosuppression (CAIRS)
CAIRS?
- Compensatory anti-inflammatory response system
- Reduced expression of pro inflammatory cytokines
- Increased level of anti inflammatory cytokines and cytokine inhibitors
- High rate of apoptosis of lymphocytes, dendritic cells and epithelial cells
- Late stage sepsis - immune paralysis - opportunistic infections
Most effective way to treat sepsis
- Early recognition, early treatment
The golden hours?
The period when recognition of sepsis and intervention with fluids and antibiotics can save the life of a patient
Early goal directed therapy?
- Treatment for severe sepsis within 6 hours of recognition
- Fluids, antibiotics, and culture within an hours
- Crystalloid/colloids to increase CVP
- Vasoactive agents to increase MAP
- Inotropes to increase SvO2
Approved pharmacological treatment for sepsis?
- Recombinant Human Activated Protein C (rhAPC, also known as Drotecogin alpha and Xigris)
- Natural inhibitor of Factors 5a and 8a of coagulation cascade
- Inhibits antifibrinolytic effects, cytokines, selectins
- Anti-inflammatory, anti-apotitic
- IV over 96 hours
rhAPC reduction in mortality?
6%
Disadvantages of rhAPC?
- $10, 000 per dose
- Increased bleeding
What other pathologies lead to the development of shock?
- Cardiogenic
- Hypovolemic
- Neurogenic → distributive shock (no fluid loss; rather there is a redistribution of fluid that impairs tissue perfusion)
- Anaphylaxis → distributive shock
Symptoms of all types of shock?
- Low blood pressure
- Decreased urine production
- Poor perfusion leading to acidosis
- Body temperature and heart rate vary depending on type of shock
Body temperature effects for each type of shock
- Most = low body temperature
- Neurogenic = high body temperature
- Early septic shock = high body temperature
Heart rate effects for each type of shock
- Most - increased HR
- Neurogenic - decreased HR
Symptoms of anaphylactic shock
- Apprehension
- Abdominal cramping
- Coughing
- Wheezing
- Hives
Pathophysiology of cardiogenic shock
- RAAS: fluid retention and vasoconstriction
- ADH: increased BV
- Catecholamines: increased HR and vasoconstriction
- Pulmonary/peripheral edema
- Increased myocardial O2 demand
- Decreased BP
- Insufficient O2 = cardiac/organ system dysfunction
Causes of cardiogenic shock
- Consequence of MI
- Severe myocardial ischemia
- Late stage result of coronary artery disease
Causes of hypovolemic shock
- Hemorrhage
- Plasma loss (e.g. burns)
- Shift in fluid from the vascular compartment to the extra-vascular space to replace lost fluids (e.g. vomiting or diuresis)
Amount of blood loss affecting CO
- 10%: CO and perfusion
- 35-45%: CO and MAP
Pathophysiology of hypovolemic shock
- RAAS/ADH: fluid retention
- Increased HR
- Increased contractility, vasoconstriction
- Hepatic blood released into circulation
- Hypothalamus stimulates thirst
Causes of neurogenic shock
- Imbalance between PNS and SNS
- Trauma to spinal cord or brain
- Depressant drugs, anesthetics, insufficient delivery of glucose to the brain (e.g. excess insulin)
Pathophysiology of neurogenic shock
- Loss of vascular tone
- Prolonged vasodilation
- Drop in BP
- SNS suppressed: HR slows, increased temp.
Rarest form of shock?
Neurogenic
Causes of anaphylactic shock
Systemic allergic response due to exposure to an antigen (e.g. shellfish, bee stings, nuts, drugs)
Pathophysiology of anaphylactic shock
- Vasodilatory substances (e.g. histamine) are released = vasodilation, increased capillary permeability
- Drop in BP = reduced tissues perfusion, altered mentation
- Constriction of extravascular SM (e.g. broncoconstriction, laryngospasm, GI cramps)
- Death within minutes
Treatment of anaphylactic shock
- EpiPen (IV, IM)
- Vasoconstriction, reverse SM constriction, minimizes release of histamine
- Short half life; may require multiple doses
Effect of pH on O2
- Drop in pH reduces hemoglobin’s affinity for O2
Effects of shock on glucose?
- Hypoperfusion reduces glucose delivery
- Uptake reduced (via hormones, vasoactive substances, and steroids)
- lipolysis, gluconeogenesis, and glycogenolysis
Effects of lypolysis
- Increased FFAs and TGs
- Cytotoxicity (esp. pancreatic B cells)
- Cell death
Effects of gluconeogenesis
- Uses protein
- Increases urea and toxic ammonia
- Low protein = fluid movement from vasculature
- Alanine generation, converted to pyruvate = lactic acidosis
- Muscle wasting, impaired immune function, organ failure
Initial treatment for neurogenic shock?
- Stabilization of the spine
How is BV increased?
- Colloids (albumin) and crystalloids (5% dextrose) - Whole blood
Causes of pancreatitis?
- Gallstones
- Alcohol abuse (75%)
- Endoscopic Retrograde Cholangiopancreatography (ERCP)
- Drug reactions
- Abdominal trauma
- Hypertriglycridemia
- Idiopathic
Roles of pancreas?
- Endocrine: insulin, glucagon
- Exocrine: acinar cells produce digestive enzymes (e.g. proteolytic enzymes, amylase, lipases, trypsin inhibitors) deliver to duodenum
Pathophysiology of pancreatitis?
- Acinar cell injury
- Activation of trypsin
- Premature activation of other enzymes
- Auto-digestion of the pancreatic tissues
Role of trypsin (pancreas)?
- Activates proteolytic enzymes, amylase, lipases in SI
- Enzymes are released from acinar cells with trypsin inhibitors to prevent premature activation
Consequences of pancreatitis?
- Inflammation with release of pro-inflammatory cytokines
- Complement system activation
- Systemic inflammation
- SIRS
- Organ dysfunction (such as ARDS or ATN)
- Possible fluid accumulation in abdomen = reduced BV and hypoperfusion
- Gut lining dysfunction = intestinal bacteria enter blood stream causing sepsis
Symptoms of pancreatitis?
- Severe epigastric or mid-abdominal pain (radiation to back)
Indicators of pancreatitis?
- Elevated serum lipase level (best indicator)
- Serum amylase
- C-reactive protein (CRP) (inflammation; indicates severity)
Pain relief for pancreatitis?
- Meperidine hydrochloride (Demerol)
- Prescribe over morphine due to reduced incidence of spasm in the pancreatic ducts’ sphincter
- Also fentanyl for mild cases (less damaging to kidneys)
Pancreas rest?
- No food or fluids by mouth
- Nasogastric tube to remove gastric fluids
- Somatostatin (IV/SC) to limit secretions
Other precautions for pancreatitis
- IV fluids
- Ultrasound: gallstones
- CT scan: fluid accumulation, necrosis
- Cholecystectomy (gall bladder removal) for necrosis, gall stones
- Nutritional support
Nutrition for pancreatitis
- Mild pancreatitis: soft-food, low-fat diet once as pain has subsided
- NPO for first 7 days
- Enteral feeding after 7 days
- TPN if enteral feeding is not tolerated