physiology of csf production and circulation, alterations in various pathology
DESCRIPTION
Physiology of CSF dynamics with an anaesthesia eye!TRANSCRIPT
PHYSIOLOGY OF CSF PRODUCTION AND CIRCULATION, ALTERATIONS
IN VARIOUS PATHOLOGY
Dr Unnikrishnan P
First few drops…
Emanuel Swedenborg who discovered CSF, referred to it as “highly gifted juice” that is dispensed from the roof of the fourth ventricle to the medulla oblongata, and the spinal cord.Albrecht von Haller found that that the “water” in the brain, in case of excess secretion, descends to the base of the skull resulting in hydrocephalus
OUTLINE
CSF SPACES
CSF FORMATION-CIRCULATION-REABSORPTION
METHODS OF DETERMINING Vf and Ra
EFFECTS OF DRUGS
REGULATION
ALTERATION IN CSF DYNAMICS IN PATHOLOGIES
Introduction
CSF flows via macroscopic & ECF spacesPRESSURES AND VOLUMES
CSF PRESSURE [mm of Hg]
CHILDREN 3.0-7.5
ADULTS 4.5-13.5
CSF VOLUME [mL]
INFANTS 40-60
YOUNG CHILDREN 60-100
OLDER CHILDREN 80-120
ADULTS 100-160
CHOROID PLEXUS
Invagination of blood vessels & leptomeninges
covered by a layer of modified ependyma
Epithelium is the blood-CSF barrier
Carbonic anhydrase present in the epithelium
& Na-K pump in luminal plasma membrane
play major role in CSF formation
Anatomy
• Choroid plexus projects into• The temporal horn of each lateral ventricle,• the posterior portion of the third ventricle &• the roof of the fourth ventricle.
CHOROID PLEXUS BLOOD SUPPLY
. Body of lateral ventricle Posterior choroidal artery
Body of third ventricle Anterior choroidal artery
Temporal horns Superior cerebellar artery
Fourth ventricles Posterior inferior cerebellar artery
NERVE SUPPLY:IX,X, Sympathetic nerves
MACROSCOPIC SPACES
Two lateral ventriclesThird ventricleAqueduct of sylviusFourth ventricleCentral canal of spinal cordSubarachnoid spaces
MICROSCOPIC SPACES- BRAIN &SPINAL CORD ECF SPACES
are smallCapillary – ECF exchange is l i m i t e dBlood brain barrier Whats your diameter?
………<20 A⁰ ?
COMPOSITION
L
Plasma CSF
Na+(mM) 140 141
K+(mM) 4.6 2.9
Mg2+(mM) 1.7 2.4
Ca2+(mM) 5.0 2.5
Cl-(mM) 101 124
HCO3-(mM) 23 21
Glucose (mM) 92 61
Amino acids (mM) 2.3 0.8
pH 7.41 7.31
Osmolality (mosmol.Kg H2O-1) 289 289
Protein (mg 100 g-1) 7000 28
Specific gravity 1.025 1.007
COMPOSITION
Na,Cl,Mg
Glucose,Protein,AA,K,HCO3,Ca,P
Vary according to sampling site
Altered during neuroendoscopy
CSF FORMATION
CSF FORMATION
Rate [Vƒ] 0.35-0.40 mL/min OR 500-600 mL/day0.25% of total vol replaced each minuteTurn over time for total CSF vol 5-7 hours= 4 times / day40%-70% enters macroscopic spaces via CP30%-60% enters across ependyma and pia
@ CHOROID PLEXUS
L
@ CHOROID PLEXUS
Blood filtered protein rich fluid similar to ISF
Hydrostatic pressure & bulk flow-> enter cleft between cells
Ultra filtration & secretion
@EXTRA CHOROIDAL SITES
Oxidation of glucose by brain [60%]Ultra filtration from cerebral capillaries [40%]
TIGHT JUNCTIONS
Glucose/electrolyte/water
Large polar/protein
MOVEMENT OF GLUCOSE
Glucose concentration is 60% that of plasmaRemains constant, unless blood glucose >270-360Enters CSF quickly by facilitated transportRate ∝ Serum glucose [not on gradient]
MOVEMENT OF PROTEIN
CSF protein concentrations are 0.5% or less than that of plasma protein concentration [60% @ CP / 40%@ extrachoroidal sites]If structural barrier between ECF & CSF spaces are not intact, it enters, but then also cleared from CSF spaces into dural sinuses - because of the sink effect of flowing CSF
VENTRICLES 26MG/100ML
CISTERNA MAGNA 32MG/100ML
LUMBAR SAC 42MG/100ML
Vƒ & ICP/CPP
↑ ICP
Vƒ
Vƒ
↓CPP
Vƒ and ICP/CPP
As long as CPP remains >70 mm of Hg, increase of ICP [upto 20 mm of Hg] has no major impact on VƒWhen CPP is significantly lowered CBF↓ CPBF↓, Vƒ↓But Rate of reabsorption(Va); @ ICPs > 7 cms of H2O, Va ↑ directly as ICP ↑[relation linear upto ICP of 30 cms of H2O]
CIRCULATION OF CSF
Hydrostatic pressure of CSF formationCilia of ependymal cellsRespiratory variationsVascular pulsations of cerebral arteries,CP
15 cm H2O @ formation
9 cm H2O @SSS
Choroid plexus of the lateral ventricle
Site of formation
1. Lateral ventricle
2. Third ventricle
Interventricular foramina
3. Fourth ventricle
Cerebral aqueduct
3.2 Lateral foramina (Luschka)
3.1 Median foramen (Magendie)
3.2 Lateral foramina (Luschka)
4. Subarachnoid space
Inferiorly
Superiorly
Absorbed
Superiorly
Absorbed
Choroid plexus of the 4th ventricle
Choroid plexus of the 3rd ventricle
12
3
5
3.2
3.1
4
Superiorly = lateral aspect of each cerebral hemisphere
Inferiorly = subarachnoid space around the brain & spinal cord
Choroid plexus of the lateral ventricle
Median sagittal section to show the subarachnoid cisterns & circulation of CSF
Superior cistern
Interpeduncular cistern
Cerebellomedullary cistern
Chiasmatic cistern
Pontine cistern
Circulation of CSF in subarachnoid space :
Median foramen of 4th ventricle
REABSORPTION
Subarachnoid spaceArachnoid villi & granulation venous bloodare protrusion of the arachnoid matter through perforations in the dura into the lumina of venous sinusesIntracranial-Superior sagittal sinus[85%-90%]Spinal-dural sinusoids on dorsal nerve roots[15%]
Reabsorption
High velocity of blood flow through the fixed diameter of the sinuses & the low intraluminal pressure that develops @ the circumference of the sinus wall where the arachnoid villi enter, cause a suction –pump action circulation continues over a wide range of postural pressures…
Arachnoid villus
L
‘Traced’ journey Radio labelled CSF enters
Low Cx-High Tx @ 10-20’
Tx-lumbar @ 30-40’
L-S cul de sac @60-90’
Basal cisterns @ 2-2.5 hrs
SSS @12-24 hrs
Determinants of reabsorption
Endothelium covering the villus acts as a CSF-blood barrierTrans villous hydrostatic pressure gradient
[CSF pressure-Venous sinus pressure]Pressure sensitive resistance to CSF outflow at the arachnoid villusIf through endothelium:(1)pinocytic vesicles
(2)transcellular openings
Determinants of reabsorption
Rate of rebsorption of CSF (Va)Resistance to reabsorption (Ra)
(Va) increase as the pressure gradient increase(Ra) remains normal upto a CSF pressure of 30 cm of H2O; above this it decreases
CSF drainage & cerebral edema
vasogenic edema resolves partly by drainage of fluid into ventricular CSFFactors influencing:
(1) pressure gradient between brain tissue and CSF (2) sink action of CSF
Brain ECF proteins cleared by glial uptake
FUNCTIONS OF CSF-support,nutrition
The low specific gravity of CSF (1.007) relative to that of the brain(1.040) reduces the effective mass of a 1400g brain to only 47gStable supply of nutrients ,primarily glucose; also vitamins /eicosanoids/monosaccharides/neutral & basic Amino acids
Control of the chemical environment
Exchange between neural tissue & CSF is easy diffusion distance 15mm (max) & ISF space and CSF spaces are continuous
CSF
CBF
CBF-AR
Respiration
CMR
Control of the chemical environment
CSF Ca/K/Mg
HR
BP
VASOMOTOR
RESPIRATION
MUSCLE TONE
EMOTIONAL
Control of the chemical environment
L •K/HCO3•Ca/Mg
PRIMARY PUMPS
•H+•Cl-
SECONDARYPUMPS
Excretion
Removes metabolic products,unwanted drugsBBB excludes out toxic large,polar and lipid insoluble drugs, humoral agents etc
Intracerebral transport
CSF
Neurohormone releasing factors formed in hypothalamus
neuron.
ependyma
MEDIAN EMINENCE
METHODS OF DETERMINING CSF FORMATION RATE & RESISTANCE TO CSF ABSORPTION
• Plasm• CSF
VENTRICULO CISTERNAL PERFUSION
Heisey and colleagues & Pappenheimer and associatesCannula placed in one or both lateral ventricle and in cisterna magnaLabeled mock CSF into ventriclesLabeled mock + Native CSF collected from cisternal cannula & volume determined
VENTRICULO CISTERNAL PERFUSION
Vf = Vi {Ci –C0/C0}
Vi= mock CSF inflow rate
Ci= concentration of label in mock CSF
C0=concentration of label in the mixed outflow solution
VENTRICULO CISTERNAL PERFUSION
Vf = Vi {Ci –C0/C0}
Vi= mock CSF inflow rate
Ci= concentration of label in mock CSF
C0=concentration of label in the mixed outflow solutionVa= ViCi - V0C0/C0
V0=outflow rate of CSF from cisternal cannula
Ra= reciprocal measure of the slope relating Va to CSF pressure
MANOMETRIC INFUSION
Maffeo and colleagues & Mann and associatesManometric infusion device inserted into the spinal/supracortical SubArachnoid Space[SAS]Mock CSF into the SASCSF pressure measured @ same site of infusionEach steady state CSF pressure[Ps] is paired with its associated Vi
Vi vs Ps semilog plot is made; Vf and Ra are derived from this plot; compliance also can be derived
VOLUME INJECTION OR WITHDRAWAL
Marmarou and colleagues and MillerVentricular or spinal subarachnoid catheter for injection or withdrawal of CSF and for measurement of accompanying CSF pressure change Resting CSF pressure [P0] is determined and a known volume of CSF is injected/withdrawn with timed recording of CSF pressurePressure Volume Index[PVI] calculated & Vf and Ra from it.
METHODS OF DETERMINING CSF FORMATION RATE & RESISTANCE TO CSF ABSORPTION
• Plasm• CSF
VENTRICULOCISTERNAL PERFUSION
Outflow catheter in lumbar subarachnoid spaceVentricular & spinal CSF pressures are closely monitored to ensure that obstructed perfusion do not ↑ CSF pressure very highNeeds >1 hourMock CSF
MANOMETRIC INFUSION
Number of infusions are reducedInfusion rate 1.5-15 times Vf [.01-.1mL/sec]
Infusions restricted to20-60 secDiscontinued @ CSF pressures of 60-70 cm H2O/ rapid riseNeeds multiple infusionsMock CSF
VOLUME INJECTION OR WITHDRAWAL
No hazard associated with mock CSFHence more commonly usedCSF withdrawal can be therapeuticClosed system- hence risk of infection lessMore suitable for repeated testingCalculation needs only a single change of CSF volume and pressure lasting for minutes
.
ANESTHETIC AND DRUG INDUCED CHANGES IN CSF FORMATION RATE AND RESISTANCE TO CSF ABSORPTION AND TRANSPORT OF VARIOUS MOLECULES INTO CSF AND THE CNS
INHALED ANESTHETICS
ENFLURANE Vf Ra ICPLOW [0.9% &1.8%] 0 + +
HIGH [2.65 &3.5 end expired]
+ 0 +
ENFLURANE INDUCE INCREASED CP METABOLISM
INHALED ANESTHETICS
HALOTHANE Vf Ra ICP1 MAC -- + +
INCREASE GLUCOSE TRANSPORT INTO BRAININCREASE Na/Cl/H2O/Albumin TRANSPORT INTO CSFHALOTHANE INDUCED STIMULATION OF VASOPRESSIN RECEPTORSDECREASE Vf
INHALED ANESTHETICS
ISOFLURANE Vf Ra ICPLOW[0.6]LOW[1.1%]HIGH[1.7,2.2%]
000
0+--
0+--
GLUTAMATE CONCENTRATION IN CSF IS MORE WHEN ISOFLURANE IS USED THAN IN PROPOFOL BASED ANESTHESIA
INHALED ANESTHETICS
SEVOFLURANE Vf Ra ICP1MAC -- + ?
INHALED ANESTHETICS
DESFLURANE Vf Ra ICPHYPOCAPNIA & ↑CSF PRESSUREOTHER SITUATIONS
+
0
+
0
+
0
ONLY FRUSEMIDE 2MG/KG DECREASED Vf IN THE FIRST SITUATION.
INHALED ANESTHETICS
NITROUS OXIDE Vf Ra ICP66% 0 0 0
DECREASE BRAIN GLUCOSE INFLUX AND EFFLUX
I.V. ANESTHETICS
KETAMINE Vf Ra ICP40MG/KG/HR 0 + +
DECREASE TRANSPORT OF SMALL HYDROPHILIC MOLECULES ACROSS BBB
I.V. ANESTHETICS
ETOMIDATE Vf Ra ICPLOW [.86MG/KG.86MG/KG/HR]HIGH[2.58MG/KG/HR]
0--
0--
0--
I.V. ANESTHETICS
PROPOFOL Vf Ra ICP6MG/KG12,24 & 48 MG/KG/HR 0 0 0
PENTOBARBITAL Vf Ra ICP40MG/KG 0 0 0
CSF CONCENTRATION OF PROPOFOL IS APPROX 60% OF THAT OF PLASMA CONCENTRATION
I.V. ANESTHETICS
THIOPENTAL Vf Ra ICPLOW DOSE[6MG/KG F/B 6-12MG/KG/HR]HIGH DOSE[18-24MG/KG/HR]
0--
+/0--
+/0--
INCREASE
I.V. ANESTHETICS
MIDAZOLAM Vf Ra ICPLOW[1.6MG/KG.5MG/KG/HR]INTERMEDIATE[1-1.5MG/KG/HR]HIGH [2MG/KG/HR]
00--
+0+
+0--/?
FLUMAZENIL Vf Ra ICPLOW[.0025MG/KG]HIGH [.16MG/KG]LOW[DOGS GETTING MIDAZOLAM]HIGH[ “ ]
0000
0--+0
0--
OPIOIDS
FENTANYL Vf Ra ICPLOW DOSEHIGH DOSE
0--
--0/+
----/?
SUFENTANIL Vf Ra ICPLOW DOSEHIGH DOSE
00
--0/+
--0/+
ALFENTANIL Vf Ra ICPLOW DOSEHIGH DOSE
00
--0
--0
I.V. DRUGS
LIDOCAINE Vf Ra ICP.5MG/KG1μG/KG/MIN1.5 34.5 9
-- 0 0/--
I.V. DRUGS
IV acetaminophen permeate readily and attain peak concentration in 1 hour in CSF rapid central analgesia and antipyretic effectsIbuprofen :peak @ 30-40 mins
DIURETICS
Vf MECHANISMS
ACETAZOLAMIDEMETHAZOLAMIDE
-- BY 50% INHIBITION OF CARBONIC ANHYDRASEINDIRECT ACTION ON ION TRANSPORT [VIA HCO3]CONSTRICT CP ARTERIOLES & ↓ CPBF
ACETAZOLAMIDE +OUABAIN↓Vf BY 95% = ADDITIVE
OTHERS
L DRUG Vf MECHANISM
DIGOXIN , OUABAIN -- INHIBIT Na-K PUMP OF CP
THEOPHYLLIN + PHOSPHODIESTERASE INHIBITION↑cAMP STIMULATE CP Na-K PUMP
VASOPRESSIN -- CONSTRICT CP BLOOD VESSELS
3% HYPERTONIC SALINE -- ↓OSMOLALITY GRADIENT FOR MOVEMENT OF FLUID PLASMACP OR BRAIN TISSUECSF
DINITROPHENOL -- UNCOUPLE OXIDATIVE PHOSPHORYLATION DECREASE ENERGY AVAILABLE FOR MEMBRANE PUMP
ANP -- ↑cGMP
DIURETICS
Vf MECHANISMS
FUROSEMIDEMANNITOL
----
DECREASE Na+ OR Cl- TRANSPORTDECREASED CP OUTPUT AND ECF FLOW FROM BRAIN TO CSF COMPARTMENT
MUSCLE RELAXANTS
RELAXANTS Vf Ra
SCOLINE, VECURONIUM INFUSIONS 0 0
STEROIDS
Decrease Ra
M.prednisolone/prednisone/cortisone/dexaProbable mechanisms postulated:Improved CSF flow in subarachnoid spaces/ A. villiReversal of metabolically induced changes in the structure of the villi, action @ CPDexamethasone ↓Vf by 50% [inhibition of Na-K ATPase]
REGULATION OF Vf /Ra
NEUROGENIC REGULATION
Adrenergic nerves from superior and lower cervical ganglia innervate CPLateral ventricle– U/LMidline ventricle– B/L3rd ventricle rich in cholinergic innervation, whereas 4th ventricle devoid of itPeptidergic nerves contain VIP and substance-P : both are potent vasodilators
Adrenergic system
α constriction βdilatationDecrease carbonic anhydrase activityNorepinephrine:↓ Vf
high α mediated vasoconstrictionLow β1 mediated inhibitory action on CP
Cholinergic system
Also ↓ Vf
Receptors presumably muscarinicAct on CP epithelium, rather than on vasculature
METABOLIC REGULATION
HYPOTHERMIA: ↓ Vf – By decreasing secretory and transport process and by ↓ing CBF between 41310 C: each 10 C↓in temperature, ↓ Vf by 11%
HYPOCAPNIA: acutely ↓ Vf [mechanism : ↓ CBF, ↓ H+ for exchange with Na]
METABOLIC REGULATION
Metabolic alkalosis ↓ Vf due to pH effect
Metabolic acidosis: no change
↓ Vf in change of osmolarity/ Wald & associates
↓/↑ in Vf caused by change in serum osmolarity 4 times higher
↑osmolarity of serum
↓osmolarity of ventricular CSF
ALTERATIONS IN VARIOUS PATHOLOGIES
.
Intracranial volume change
Volume of intracranial blood/gas/tissue ↑ CSF volume ↓
Volume of intracranial blood/gas/tissue ↓ CSF volume ↑
MECHANISM: >TRANSLOCATION INTO SPINAL SPACES >INCREASED REABSORPTION
MECHANISM: >CEPHALAD TRANSLOCATION >DECREASED REABSORPTION
SUBDURAL HEMATOMA
Adds volume ↑ ICP driving force for reabsorption Va > Vf CSF volume contracts ICP↓ Va starts returning to normal Va & Vf in a new equillibrium–
Here ICP & total intracranial volume are same as before SDH, but CBV is ↑ed and CSF volume ↓ed
SURGICAL REMOVAL OF TUMOR
Sx ↓ intracranial volume ↓ed ICP a weak driving force for reabsorption Va ↓, Vf same CSF accumulates and volume expand ICP↑ and reach pre surgical valuesstimulate Va Va
↑ Va = Vf
here,ICP same; brain volume ↓;
CSF volume↑
INTRACRANIAL MASS
ANIMAL STUDY IN 3 GROUPS OF DOGS
Hypocapnia ↓ed an increased ICP initially by decreasing CBV but with sustained hypocapnia,CBV reexpanded but H.C. improved access of I.C CSF to spinal sites of reabsorption so CSF vol ↓ed ICP remained lower than initial values
GROUP 1 HYPOCAPNIA
GROUP2 I.C. MASS
GROUP3 I.C.MASS + HYPOCAPNIA
EFFECT OF ANESTHETICS
FIVE GROUP OF DOGS
Vf Ra ICP REASON
ENFLURANE ↑ ↑ ↑ CSF VOL DIDN’T↓TO THE EXTENT OF CBV REEXPANSION
HALOTHANE ↑ ↑ ↑
ISOFLURANE N N N CSF VOL CONTRACTION= CBV REEXPANSION
FENTANYL N N N REEXPANSION MINIMAL
THIOPENTAL N N N CSF VOL CONTRACTION= CBV REEXPANSION
ACUTE SAH
Itrathecal injection: W.Blood / plasma /dialysate of plasma/serum/saline
Whole blood and plasma raised ICP and caused a 3 to 10 fold rise in Ra respectively
C/C CHANGES AFTER SAH
Extensive fibrosis leptomeningeal scarring functional narrowing or blockage of CSF outflow tracts [Ra is increased] hydrocephalus
Bacterial meningitis
Animal study with 1.S pneumoniae 2.E coli↓ is increased
Even with antibiotics it remained high for 2 weeks post RxMethyl prednisolone ↓ed Ra to a value between control and infected
PSEUDOTUMOR CEREBRI
Increased Ra , Vf ,water movement into brain, CBF & CBVincreased ICPImpaired reabsorption is the principal causePrednisone decreased Ra
Head Injury
20% of the raised ICP derived from changes in Ra &Vf
It means…
Vf changes: changes ICP
Ra changes: changes ICP, alters pressure buffering capacity of brainAnesthetics induced changes in both, significantly alters Rx to reduce ICP
So……
We demand more attention from you..
HEAD INJURY
THANK YOU