Samenvatting
Samenvatting PAC
- Instelling
- Universiteit Leiden (UL)
Samenvatting van het vak physiology advanced concepts (Sepsis & Heart Failure) gebaseerd op alle colleges inclusief leerdoelen.
[Meer zien]Voorbeeld 4 van de 38 pagina's
Voorbeeld 4 van de 38 pagina's
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Voorbeeld van de inhoud
🩺Physiology Advanced Concepts
SEPSIS
LT 2 Sepsis
Background: A disease usually has a defining cause, distinguishing symptoms and treatments. A syndrome, on the other
hand, is a group of symptoms that might not always have a definite cause
Types of sepsis
sepsis: uncontrolled immune response to an infectious agent (bacteria and funghi) —> clinical syndrome
Life threatening organ dysfunction caused by a dysrefulated host response to infection
Severe sepsis: organ dysfunction
Septic shock: decreased delivery of oxygen to the tissue —> vasopresser requirement and lactate above 2
Cellular immune pathway
Activation of Toll like receptors on immune cell > intercystoplasmatic pathway > induction of pro-inflammatory cytokines >
activate the immune system > recruitment of other immune cells.
sepsis —> uncontrolled amplification of the immune response throught the whole body.
Severity
Analysed with SOFA score:
Hypotension systolic BP < 100 mmHg
Altered mental status
Tachypnea RR > 22
—> Score of >2 criteria suggest a greater risk of a poor outcome (>admitted)
Sepsis bundle
1. measure lactate
2. obtain blood culture before administering antibiotics (Culture + resistant results)
3. Administer broadspectrum antibiotics
4. begin rapid administration of crystalloid (=fluid) for hypotension or lactate (because of dialated and leaky arteries)
5. Aplly vasopressors if hypotensive during or after fluid resuscitation to maintain a mean arterial pressure (> 65 mmHg)
Medication
Norepinephrin
increases SVR and BP via vasoconstriction (alpha 1)
protects blood flow to organs due to vasodilation (beta 2)
increased HR and CO (beta 1)
Vasopressin (ADH)
increased SVR and BP via vasoconstriction: increase volume (V1)—> ischemia in fingers and toes
Increases H2O reabsorption in the kidney —> increasing BP
Dobutamine
Physiology Advanced Concepts 1
, Increased contractility which increases HR and CO (beta 1) —> tachacardia, dilatation of blood vessels
Decreases SVR and afterload via vasodilation (beta 2)
Milrinone: b.ocks PDE3
increased contractility
decreased SVR and afterload due to vasodilation
Phenylephrine
increases SVR and BP via vasoconstricton (alpha 1)
Steroids: dampen the host response against infection
(source control)
📗 Literature
LT 3 Kidney
Objectives
Know the microscopic anatomy of the nephron, in particular of the arteries and capillaries.
why the kidney is particularly susceptible to ischemic injury and know the concepts of ischemia, mitochondrial dysfunction
and tubular dysfunction
Understand how glomerular autoregulation works.
the pathophysiology of TMA
the molecular biology that underlies a number of causes of TMA
How a factor H mutation causes aHUS and TMA
Understand the pathophysiology of mitochondrial
dysfunction in AKI.
the role of heparan sulphate as determining pathogenic factor in complement factor H-associated diseases
Shock: a state in which diminished cardiac output or reduced effective circulating blood volume impairs tissue perfusion and leads to
cellular hypoxia and organ dysfunction.
Effective circulating volume: part of the ECF that is in the circulation (plasma) and that effectively perfuses tissue.
RBF - RPF - GFR
CO = HR *SV = 5L/min
RBF = 1000 ml/min
RPF = 600 ml/min (Blood consists of circa 40% red blood cells and 60% water
with electrolytes, proteins and fat)
GFR = The sum of the amount of pre-urine per unit of time that is filtrated into Bowman’s space in all nephrons (180L per 24
hours)
FF = GFR/RPF (1/5)
Filtration is caused by: Electro-chemical grdient, crystalloid osmotic pressure, colloid osmotic pressure (oncotic pressure),
and hydrostatic pressure
Net filtration pressure = Hydrostatic pressure GC - Oncotic pressure GC - Hydrostatic pressure BC
Autoregulation
Maintenance of blood flow and glomerular filtration rate when arterial pressure changes. This is done by dilating and
constricting the afferent arteriole
myogenic autoregulation
Physiology Advanced Concepts 2
, The reduced perfusion pressure in the afferent arteriole causes the transmural pressure on the afferent arteriole to
decrease.
This reduces the activation of stretch activated receptors.
This causes the afferent arteriole to dilate.
tubulo-golmerular feedback
Due to low flow, GFR decreases and less NaCl reaches the macula densa.
Via tubuloglomerular feedback this causes the afferent glomerular arteriole to dilate.
The macula densa also reacts by producing more renin, which ultimately leads to more ANGII, which causes the
efferent glomerular arteriole to constrict.
The combination of afferent arteriole dilation and efferent arteriole constriction increases the flow and glomerular
filtration pressure in the glomerular capillary. In this way, the glomerular filtration pressure is kept fairly constant and
prevented from becoming too low
Circulatory effect: Renin production ultimatly leads to an increase ANG II and aldosteron production. This leads to: (1)
vasocontristriction of the systemic circulation to increase blood pressure and (2) increase the reabsorption of the filtered
load via the tubular cells back into the PTCs and into the circulation.
Despite the autoregulation mechanisms the RPF will reduce due to the low blood pressure which leads to a decrease in GFR, a
decrease in clearance and an increase in FF
Acute renal failure/injury
Acute kidney injury (AKI), also known as acute renal failure (ARF), is a sudden episode of kidney failure or kidney damage
that happens within a few hours or a few days. In most cases caused by reduced blood flow to the kidneys
AKI: Generalized or localized reduction in renal blood flow
prerenal: result of hypoperfusion in which the renal structure and microstructure are perserved (low sodium concentration in
the urine)
renal: due to parenchymal injury of the blood vessels, glomeruli, tubules, or interstitium (high sodium concentration in the
urine)
Ischemic renal injury (sepsis): tubular injury due to oxygen depletion of inflammation > tubular casts > acute tubular
necrosis
Tubular injury is a direct consequence of metabolic pathways activated by ischemia but is potentiated by inflammation
compromise
Post renal: obstruction of the urinary tract
Mitochondria
In acute kidney injury mitochondria show signs of damage
Mitochondria: Generate energy by breaking high energy bonds in NADH and FADH2 which come from the TCA cycle.
Mitochondria use this energy to create a membrane potential over the intter mitochondrial membrane by shutteling H+. When
H+ re-shuttles back over the membrane ATP is synthesised.
Visualising membrane potential by multiphoton imaging. Oxygen depletion will have an effect of mitochondria.
Susceptibility to damage in oxygen deprived situation is based on the amount of energy needed in particular parts of the
nephron (PT, TAL). PT are not able to switch over to anaerobic glycolysis —> susceptible to damage in ischemia
LT 4 Micro-angiopathy
TMA is another cause of acute kidney injury (next to sepsis = ischemia)
Objectives
Understand the pathophysiology of thrombotic microangiopathy (TMA).
Physiology Advanced Concepts 3
, Understand the molecular biology that underlies a number of causes of TMA.
Understand how a factor H mutation causes atypical HUS (aHUS) and TMA.
Understand the role of heparan sulfphate as a determining pathogenic factor in complement factor H
related aHUS.
Symptoms TAM
Microvascular damage —> thrombotic micro Angiopathy (TMA). Small vessels start to develop thrombosis in major organs.
Symptoms are:
Low Hb and thrombocyte: microtrombi lead to break up of erythrocytes
schistocytes = fragmentocytes
Enzymes in the RBC will leak into the blood: LDH and bilirubin
haptoglobin decreases: enzym that transports fragmented RBC to the spleen
Hemolytic uremic syndrome (HUS)
Syndrome: a number of symptomps that often occur together
HUS: syndrome consisting of the symptoms hemolysis and kidney failure
Thrombotic micro-angiopathy: is a pattern of injury to the microvasculature that may be induced by a number of causes
Causes of TAM
1. Malignant hypertension: Increased RBF beyond boundries of autoregulation leads to increased flow through arteries and
micro circulation > turbulent flow > shear stress > unrolling of adhesion monomer > increase coagulation in micro circulation
= TMA > kidney failure
2. TTP (thrombotic thrombocytopenic purpura): ADAMTS13 abnormalities: enzyme cleaves van willenbrand factor on
endothelial cells to prevent thrombosis from occuring. In these patients neurological symptoms are very prominant. Low
activity due to:
a. genetic abnormality
b. autoantibodies against ADAMTS13
—> treatment: infuse donor plasma including ADAMTS13 in combination with inhibiting antibody production with
immunosurpressions (retuximap). Or performing plasma phoresis = replacing due to which antibodies are also removed.
3. Disregulation of the complement system (atypical HUS):
Complement system
three routes of activation of the complement system:
Classical pathway: antigen-antibody reaction leads to the activation of C1 >>> C3 convertase.
lectin pathway: mannose binding lectin binds mannose-containing carbohydrates in pathogens including MASP
that cleaves C4 >>> C3 convertase
alternative pathway: certain constituents of the bacterial cells surface change the physicochemical environment
leading to spontaneous hydrolysis of C3 causing the formation of soluble C3 convertase
all pathways result in the production of C3 convertase which converts C3 into c3a and c3b.
amplifying loop leading to the production of C5 convertase —> MAC
This leads to the production of (1) inflammatory mediators (c3a, c5a), (2) opsonization (c3b) and (3) production of
membrane-attack complexes (c5b, c6, c7, c8, c9)
Inhibitory factors will prevent the activation of the complement system on endothelial
1. genetic mutation (in e.g. disfunction of regulatory protein H)/polymorphisims
2. acquired defect in e.g. antibodies
Physiology Advanced Concepts 4
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