CSF and ICP Flashcards
What is the Munro Kellie Doctrine
- It is determined by the three components of the Monro-Kellie relationship, which states that an increase in the volume of one intracranial compartment will lead to a rise in ICP unless it is matched by an equal reduction in the volume of another compartment
Draw an intracranial pressure volume vurve
What is the 3 volume s of the compartments making up the Munro Kellie doctrine
◦ Brain tissue: 1400ml on average
◦ Cerebral blood volume: 150ml
◦ Cerebrospinal fluid: 150ml
What is a normal ICP? How does it vary with position?
- Normal ICP 7-15mmHg or <20mmHg
◦ On average 9mmHg across 24 hours
◦ Head down 14-19mmHg
◦ With heads lifted 20 degrees the ICP was 3-4mmHg
◦ Interestingly if someone is totally upright variation can be -2 to +2
CSF pressure = (equation)
CSF pressure = resisatnce to CSF outflow x CSF formation + pressure in sagittal sinus
What is CSF production dependent on
CPP (not ICP
How is CSF production related to ICP
It is related to CPP
What is the normal variation in the the ICP trace due to?
- percussion
- Tidal
- Dicrotic
- Respiratory
What are the names for P 1-3 on the ICP trace
- percussion
- Tidal
- Dicrotic
What does increased amplitude of all waves indicate
Increased CSF volume
Missing bone flap
What does diminished P1 indicate
Reduced CPP
Prominent P1 menas
Systolic BP too high
Prominent P2
Oedema - reduction in cerebral compliance
How does ICP change with posture
- Intracranial pressure is normally ~ 10 mmHg in the supine person, and probably 0-2 mmHg in the upright person
How is ICP regulated 3
- Displacement of venous blood out of the CNS
- Displacement of CSF out of the CNS - to the psinal cord, venting to veinous circulations
- Meningeal distension
What is the most important minute to minute ICP regulation mechanism
Displacement of veinous blood out fo CNS
◦ Displacement of venous blood out of the CNS - large and mobile component, and can shift at short notice ‣ Arterial volume is smaller and higher pressure so shfits in it are of less significance ‣ Venous displacement likely accounts for the majority of second to second changes
What are the 2 ways CSF can be displaced from the cranium due to raised ICP?
- Into spinal cord due to better compliance
- Venting to veinous circulation - low velocity
What are factors affecting ICP
- Munro Kellie doctrine assumptions - that you have an intact cranial vault - sometimes not true
- CSF volume
- CSF production
- VSF drainage - Arterial and veinous volume
- Arterial - cerebral metabolic rate, vasoactive agents, systemic
- Veinous - outflow obstruction either pressure or physical obstriction - Brain - blood, tumour
How can CSF efflux be affeted
eg. hydrocephalus, EVD, VP shunt)
‣ ability to drain the CSF –> into the spinal cord inthe case of hydrocephalus, out of the CNS in EVD, VP shunt or inadvertant dural tear or into the venous ciruclation when arachnoid granulations are occluded by meningitis or SAH
Why might CSF production be reduced
(acetazolamide, diuretics, dehydration)
‣ CSF production directly
‣ Reduced volume status
What factors affect brain volume
◦ Age (decreased mass)
◦ Space occupying lesions (eg. tumour, abscess)
◦ Cerebral oedema
What 3 factors affect arterial brain volume
◦ Arterial blood volume
‣ Cerebral metabolic rate (eg. hyper or hypthermia, seizures, sedation)
‣ Cerebral arterial vasoactive agents (CO2, hypoxia)
‣ Systemic increases in blood flow or blood pressure (eg. pain, anxiety)
What 2 factors affect veinous volume
◦ Venous volume
‣ Venous outflow obstruction (eg. raised intra-thoracic pressure (valsalva, cough, childbirth), shivering, coughing, C-spine collar, jugular or sinus venous thrombosis, poor RV compliance
‣ Venous reflux - head down
‣ Venous efflux - upright
Mechanisms of agents used to reduce ICP are 34
- Cerebral metabolic demand
- Sedation
- Seizure - Improve veinous flow - reduced cough, muscle realxant, diuretic
- Reduce brain tissue volume - osmotherpay, dexamethasone
- CSF production - Acetazolamide inhibits carbonic anydrase
What are the 2 drugs that can reduce brain volume
Dexamethasone
Osmotic therapy
5 methods of measurnig ICP
CLinical
EVD
Codman
Epidrual catheter
Lumbar puncture
What is CSF
ultrafiltrate of plasma contained within the ventricles of the brain and the subarachnoid spaces of the cranium and spine.
How much CSF is produced per day
25ml/hr
400-600ml per day
How much CSF do you have at any one time
150ml
How is CSF distributed
25ml ventricles
30ml in spinal cord
remaining in subarachnodi space
What are the 3 sources of CSF production
CHoroid plexus in lateral ventricles 75%
Brain intersitial fluid - brain cpaillaruy endothelial cells
Circumventricular organ
How is CSF produced
Highly regulated ultrafiltration and secretion
How is there an ultrafiltrate when there is a BBB
- Ultrafiltrate of plasma is formed by the fenestrated choroidal capillaries
◦ The choroid plexus is the highest surface area of BBB fenestration and the largest fluid output area for CSF
◦ lack tight junctions
What determines the fluid in the intersitial space within the choroid
Starlings forces
How is the intersitial space of the choroid translated to CSF?
CHoroidal epithelium
Choroidal epithelium histological feature
Microvilli in the ventricle
How is the ionic content of the CSF regualted
- Na - actively secreted from apical membrane + Sodium co transport with Cl
- Carbonic anhydrase provides H+ to power Na/H+ exchange at basal membrane and makes HCO3 for transport into the CSF
- Cl/HCO3 exchanger
- Na/K/2Cl cotransporter
- Aquaporins then allow water to flow transcelluarly in basal and apical membrane
How is sodium transported in the CSF?
- Na - actively secreted from apical membrane + Sodium co transport with Cl
How is carbonic anhydrase involved in CSF production
- Carbonic anhydrase provides H+ to power Na/H+ exchange at basal membrane and makes HCO3 for transport into the CSF
The HCO3 is then exchanged for Cl
How does water cross into the CSF
Aquaporins then allow water to flow transcelluarly in basal and apical membrane
Flow down the gradient created by ionic transport
CSF production vs pressure
Pressure independnet unless CPP <55mmHg and then it decreases
Describe the cation content of CSF with reference to plasma?
- CSF sodium potassium and calcium are slightly lower than plasma
◦ Calcium lower due to less albumin, ionised calcium similar, tihgtly regulated
◦ Tightly regulated CSF K to be slightly lower to not interfere with transmembrane gradient, independent of blood K - 2.9 mmol/L
◦ Sodium varies with plasma levels, activity is essentially the same 135-140
Ca 1.12mmol/L
Mg 1.1mmolL
When descibring CSF content what are the 6 domains
- Cations
- Anions
- Acid base
4, Cells - Protein - total protein and specific beta 2 transferrin
- Glucose
How does sodium activity in the CNS compare with plasma for osmolality?
Similar
Level is very slightyl lower 135-140mmol/L
How does CSF anion concentration vary compared to plasma
- CSF chloride, CO2 and bicarbonate are higher than plasma
◦ Higher bicarbonate - no proteins to act as buffers, it is exactly what you’d expect from the Henderson/Hasselbach equation
◦ Chloride - main anionic proteins not present therefore maintain electroneutrality; 15-20mmol higher (124mmol/L)
What is the bicarbonate content of CSF
- CSF chloride, CO2 and bicarbonate are higher than plasma
◦ Higher bicarbonate - no proteins to act as buffers, it is exactly what you’d expect from the Henderson/Hasselbach equation
◦ Chloride - main anionic proteins not present therefore maintain electroneutrality; 15-20mmol higher
What is the protein content in CSF?
- CSF contains minimal protein (~0.2g/L)
◦ With intracranial bleeding for every 100RBC you get a 0.01g/L increase in protein
◦ Reasons for raised protein
‣ Exudation – infection (menginitis, enecephalitis), malignancy through immature capillaries, mycobacterial infection
‣ Increased portein due to local synthesis - neurosyphillis, MS, sarcoidosis, infection
‣ Decreased reabsorption - hydrocephalus
Why might CSF protein be raised
- CSF contains minimal protein (~0.2g/L)
◦ With intracranial bleeding for every 100RBC you get a 0.01g/L increase in protein
◦ Reasons for raised protein
‣ Exudation – infection (menginitis, enecephalitis), malignancy through immature capillaries, mycobacterial infection
‣ Increased portein due to local synthesis - neurosyphillis, MS, sarcoidosis, infection
‣ Decreased reabsorption - hydrocephalus
CSF glucose vs plasma glucose
- CSF glucose is about 2/3rds of the plasma value
◦ 2-4mmol/L range, tracks BSL but lags by 2-4 hours
◦ Its lower value does not correspond to brain metabolism
◦ Causes of low CSF glucose
‣ Bacterial meningitis
‣ Viral meningitis - often normal
‣ IC malignancy
‣ CNS sarcoidosis
‣ SAH - RBC consume glucose
It passes across due to faciliated diffusion
Why might CSF glucose be low
- CSF glucose is about 2/3rds of the plasma value
◦ 2-4mmol/L range, tracks BSL but lags by 2-4 hours
◦ Its lower value does not correspond to brain metabolism
◦ Causes of low CSF glucose
‣ Bacterial meningitis
‣ Viral meningitis - often normal
‣ IC malignancy
‣ CNS sarcoidosis
‣ SAH - RBC consume glucose
How does pH compare between blood and brain
- pH slightly lower - but must remain similar to the blood as the pH of cerebral interstitial fluid is what central chemoreceptors sample. It will change with plasma PCO2 (pH7.33)
◦ Explains changes in ventilation in meningitis
◦ It is lower as PCO2 is higher by 4-11mmHg as there is no haemoglobin or protein to buffer (no Bohr/Haldane effect) and more closely resembles venous blood
Why is there a difference in PCO2 in the brain compared to the blood? What impact does this have?
- pH slightly lower - but must remain similar to the blood as the pH of cerebral interstitial fluid is what central chemoreceptors sample. It will change with plasma PCO2 (pH7.33)
◦ Explains changes in ventilation in meningitis
◦ It is lower as PCO2 is higher by 4-11mmHg as there is no haemoglobin or protein to buffer (no Bohr/Haldane effect) and more closely resembles venous blood
pCO2 50
What is the CSF WCC to RBC ratio allowed
1:500
What si the normal leucocyte count in the CSF
<3
CSF pleocytosis not uncommon with EVDs
4-5 RBC per mL
What are the 4 functions of CSF?
- Barrier function (the blood-CSF barrier)
◦ Shields neural tissue from unregulated exposure to substances - large proteins, bacteria and virus particles, neurotransmitters, hormones and metabolic toxins - Chemical stability and waste removal of extracellular environment inc. pH
◦ Maintains concentration gradient for removal of waste products and electrolytes and interstitial fluid transit through perivascular spaces would be inefficient - Buoyancy and mechanical cushioning of the CNS
◦ Average brain mass 1400g, net weight while suspended in fluid is 50g
◦ Ventricles are particualrly effective for this byoyancy as they are a low density bubble of variable volume quickly buffering changes in brain density - Hydraulic pressure buffering of ICP with arterial pulse and respiration
◦ Compensating for raised ICP
◦ Transient changes displace CSF into the spinal canal, and sustained changes increase reabsorption
◦ Arterial pulse causes a 1-2mmHg fluctuation in lumbar CSF pressure
4 functions of CSF
- Hydraulic pressure buffering
- Buoyancy
- Shielding from toxic substances
- Removal of waste proudcts
Describe how buoyancy of the brain is facilitated
◦ Average brain mass 1400g, net weight while suspended in fluid is 50g
◦ Ventricles are particualrly effective for this byoyancy as they are a low density bubble of variable volume quickly buffering changes in brain density
What is the path of circulation of CSF
- CHoroid plexus
- Lateral ventricle –> 3rd ventricle via foramen of munro
- 3rd ventricle
- Cerebral aqueduct (Acqueduct of Sylvius)
- 4th Ventricle
- Foramen of Magendie and Lushka
- Subarachnoid space - basilar cisterns via the Sylvian fissure to cortial regions or to the spinla subarachnoid space via central canal
What is the join between the lateral ventricles and the 3rd ventircle called
foramen of munro
WHat is the joint between the 3rd and 4th ventricle called
cerebral aqueduct of sylvius
What drives CSF reabsorption
- Arterial pulsation pressure
- Constant production
- Venous pulsatino and varation in pressure
Essentially hydrostatic pressure differences - ultrafiltration - it is pressure dependent and relies on CSF pressure 1.5mmHg greater than veinous pressure
How fast is CSF reabsorbed
25ml/hr
Where is CSF reabsorbed
85% via arachnoid granulations in dural veinous sinuses - outpouchings of arachnoid space through the dura into sagital and sigmoid sinuses. Mostly via pinocytosis and opeing of extracellualr fluid spaces, and pressure dependent
Ventricle walls
Cervical lymphatics
When does CSF reabsorption stop
CSF pressure ~7cmH20
Baseline cerebral blood flow is what % anterior and what % posterior
70/30
How much blood does the brain get in mls/min and as a % of cardiac output
15% cardiac output
750ml/min
What is the blood supply to the brain in ml/100g/min
50ml/100g/min
How much does a brain usually weigh
1400g
What si the DO2/VO2 supply to the brain at baseline
3:1
What is the equation used to describe determinants of cerebral blood flow
- It is described by the Ohm equation, Q = (Pa- Pv) / R, where
◦ (Pa- Pv) is the cerebral perfusion pressure (CPP) - use CVP or ICP whichever is higher
◦ R is the cerebral vascular resistance
◦ As Ohm’s law reflects: pressure is the product of resistance and flow
Cerebral resistance can be described using what equation? How does it compare to other areas of the body?
- Cerebral resistance (R) = (8 l η) / πr4, where
◦ l = length of the vessel
◦ η = viscosity of the blood - excess of cells or protein
◦ r = radius of the cerebral vessels, which is the main variable susceptible to regulation
◦ The cerebral resistance is very low compared to other organs
Define cerebral autoregulation
- Cerebral autoregulation is a homeostatic process that regulates and maintains cerebral blood flow (CBF) constant and matched to cerebral metabolic demand across a range of blood pressures.
What are the mechanisms by which cerebral autoregulation likely occurs
◦ Autonomic neurogenic theory - cerebral vessels have rich autonomic innervation so it must play a role in vascular control; cannot be the only mechanism as present with denervation
◦ Endothelial mechansism - pressure stretch or shear on endothelium lead to paracrine mediators producing vasodilation
◦ Myogenic autotegulation
◦ Metabolic autoregulation - CO2, pH, lactate, potassium, low oxygen, adenosine, nitric oxide
What range of MAP is CBF stable over
MAP 50 -150
Draw a graph illustrating the concept of cerebral autoregulation. Include how PaO2 and PaCO2 influence this
Illustrate on a Cerebral blood flow graph how PCO2 influences flow
At what range of PCO2 does autoregulation become severely impaired in humans
55-60 anaesthetised
What does raised PCO2 affect in autoregulation
Autoregulation plateau shrinks and the baseline cerebral blood flow increases 1-2ml/100g/min for every 1mmHg rise in CO2
How much does a rise in CO2 affect cerebral blood flow
1-2ml/100g/min for every 1mmHg rise in CO2
Such that by the time PCO2 is 80 cerebral blood flow has doubled (maximum dilation)
What si the maximal vasoconstriction that can be induced with hypocapnoea
PCO2 20 –> 40% drop in blood flow
What si the pharmacodynamcis for CO2 influencing cerebral blood flow?
‣ Reduction in pH due to high CO2 tension
‣ Nitric oxide synthase activity increases–> increases intracellular cGMP production
‣ cGMP acts as a secondary mecahnism to affect a change in intracellular calcium availability
‣ Decreased cerebral vascular resistance is the result
How does blood flow change with hypoxia?
PaO2 falling below 50 mmHg leads to exponentially increased CBF
◦ Stable linear relationship of BP in hyperoxia and normoxia, only at around 50mmHg PaO2 does cerebral vascular resistance drop and from here cerebral blood flow increases exponentially
Draw a graph to illustrate the relationship of cerebral blood flwo to oxygenation
What are the 5 factors influencing cerebral blood flow
PaO2
PaCO2
Temperature
Medications
MAP
Temperature affects cerebral metabolic rate how?
For every 1 degree fall in body temperature CMRO2 decreases by 7%
How does propofol affect CMRO2
Effects of propofol on cerebral blood flow and CMRO2:
* Propofol produces a dose-dependent decrease in CMRO2.
* As CMRO2 is closely tied to the autoregulation of blood flow, it also decreases CBF
* The relationship between CBF and CMRO2 changes is linear
* Thus, because both oxygen consumption and oxygen delivery are decreased together, the total oxygen extraction ratio remains stable, and there is no change in the SjvO2 (Oshima et al, 2002)
How does ketamine influence cerebral blood flow
- Ketamine certainly increases CBF
- Ketamine supposedly also increased CMRO2.
- The increase in CBF is said to be in excess of the increase in metabolic rate (
- Therefore, ketamine decreases SjvO2
Define BBB
- The blood brain barrier is a diffusion barrier which impedes influx of most compounds from blood to brain.
What are the layers of the BBB
Endothelial cells with tight junctions
Basement membrane
Pericytes (supportive tissue)
Perivascular fluid space
Astrocyte foot processes
How do endothelial cells function as an element of the BBB (4)
- Tight junctions - impermeable to water (occludin and adherin)
- No fenestrations - continuous lipid bilayer
- Metabolism - MAO, cholinesterase
- efflux pumps - ABC transporter, P glycoprotein
What are the signficant features of the basement membrane of basal lamina of the BBB
20-30nm wide
Collagen containing and laminins
Scaffold structure
Perivascular fluid space in BBB is also known as?
Virchow Robin sapce
Describe the anatomy of the perivascular fluid space of the BBB
◦ Fluid filled cavity separating the astrocyte foot processes from the smooth muscle of arterioles as they course into the brain tissue
◦ potentially clearage spaces fro metabolic waste
◦ There are pial fenestrations allowing communication between intersititum and CSF
What is the main supportive cell of the BBB outside the cpaillary
Astrocyte foot processes
◦ Relatively non essential from a functional BBB perspective but likely form some regulator function and assist in development of the BBB in the first place
What do the tight junctions in the BBB prevent
Passage of hydrophilic molecules
What are the non barrier mechanisms that the BBB utilises to form a further barrier
- Drug metabolism within cells e.g. dopa decarboxylase in endothelial cells
- Drug efflux pumps e.g. P glycoprotein
What are the mechanisms of transport across the BBB
- Paracellular transport - usually limited
- Passive transport of small lipophilic molecules
- active facilitated diffusion e.g. vitamins, peptides
- Specific active transport
What glucose transport proteins are present on BBB
Glut 1 and 3
What factors are actively transported at the bBB
◦ Glut1and Glut 3
◦ MCT famiyl of monocarboxylic AA transporters - Short chain fatty acid, salicylic acid, biotin, lactate and valproate
◦ AA transporters - aspartate, glutamate, lysin, arginine, L ornithine
◦ Choline transporters - choline and thiamine
◦ Peptide
◦ Nucleoside
What are ideal characteristics of a drug to penetrate the BBB
- Passive transport
◦ Small molecular weight - facilitating diffusion
◦ High lipophilicity e.g. propofol
◦ Low polarity
◦ Low volume of distribution - high blood concentration
◦ High concentration gradient (low protein binding, small volume of distribution, low potency of drug i.e. large concentration of drug) - Hydrophilic drugs
◦ Hgh concentration gradient - forces it paracellularly e.g. ethanol
◦ Low protein binding - large free fraction
How do hydrophilic drugs penetrate the BBB
- Hydrophilic drugs
◦ Hgh concentration gradient - forces it paracellularly e.g. ethanol
◦ Low protein binding - large free fraction
What are examples of drugs which utilise active transport by impersonating normal drugs?
Lithium (sodium)
Valproate (lactate)
Where is the BBB interrupted 5
- Area postraema - CTZ
- CHoroid plexus
- Pineal gland
- Posterior pituitary
- Hypothalamic centres - Preoptic recess of anterior hypothalamus, osmoreceptors within hypothalamus (lamina terminalis)
Organ vasculosum lamina terminalis
Subfornical organ
Medial eminence
What is the name of the area that acts as CTZ? Where is it located
Medulla on the floor of the 4th ventricle
What connections closely reside next to the CTZ
NTS
Motor dorsal vagal nucleus
Where is the choroid plexus primarily
◦ Several areas of CSF secreting tissue in the psoterior horns of the lateral ventricles and roof ot eh 3rd and 4th ventricles
Pineal gland does what
◦ Endocrine organ between halves of the thalamus, secretes melatonin into systemic circulation
◦ Fenstrated capillaries facilitate direct entry of melatonin
What is the OVLT
Organam, vasculosum lamina terminalis - circumventricular organ with sensory role in osmoreceptors
What are the 4 circumventricular organs? Where are they located? What do they communicate with
The vascular organ of lamina terminalis (VOLT), organum vasculosum of the lamina terminalis (OVLT), or supraoptic crest is one of the four sensory circumventricular organs of the brain, the others being the subfornical organ, the median eminence, and the area postrema in the brainstem
Communicate with the hypothlamus for sodium and osmolality control
Located around the 3rd ventricle
What is baseline cerebral blood flow?
750ml/min 14% CO
50ml/100g/min
What is the effect of CO2 and O2 on cerebral blood flow
PaCO2: in CBF linearly by 1-2ml/100g/min for every 1mmHg in PaCO2 over range 20-80mmHg
PaO2 < 50mmHg à CBF increases non-linear (exponential)
