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PHYSIOLOGY OF CSF PRODUCTION AND CIRCULATION, ALTERATIONS IN VARIOUS PATHOLOGY

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Unnikrishnan Prathapadas
Unnikrishnan Prathapadas

This document discusses the physiology of cerebrospinal fluid (CSF) production and circulation, and how it can be altered in various pathologies. It covers the anatomy and function of the choroid plexus, CSF composition and circulation pathways, methods to measure CSF formation rate and resistance to absorption, effects of various drugs on CSF dynamics, and alterations seen in different diseases. Key points include how CSF is formed at the choroid plexus, circulates through the ventricles and subarachnoid space, and is reabsorbed into venous sinuses. Inhalational and intravenous anesthetics can impact CSF formation rate and resistance in different ways.

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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 spaces PRESSURES 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 . of lateral ventricle Body 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 ventricles Third ventricle Aqueduct of sylvius Fourth ventricle Central canal of spinal cord Subarachnoid spaces
MICROSCOPIC SPACES- BRAIN & SPINAL CORD ECF SPACES are small Capillary – ECF exchange is l i m i t e d Blood brain barrier Whats your diameter? ………<20 A⁰ ?
COMPOSITION Plasma CSF Na+(mM) 140 141 K+(mM) L 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 289 289 H2O-1) Protein (mg 100 g-1) 7000 28 Specific gravity 1.025 1.007
COMPOSITION Vary according to sampling site Altered during neuroendoscopy
CSF FORMATION
CSF FORMATION Rate [Vƒ] 0.35-0.40 mL/min OR 500-600 mL/day 0.25% of total vol replaced each minute Turn over time for total CSF vol  5-7 hours = 4 times / day 40%-70% enters macroscopic spaces via CP 30%-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 plasma Remains constant, unless blood glucose >270-360 Enters CSF quickly by facilitated transport Rate ∝ 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 Vƒ ↑ ICP 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 Vƒ When 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 formation Cilia of ependymal cells Respiratory variations Vascular pulsations of cerebral arteries,CP
Site of formation Choroid plexus of the lateral ventricle 1. Lateral ventricle Superiorly Interventricular foramina Superiorly 2. Third ventricle Cerebral aqueduct Absorbed Absorbed 3. Fourth ventricle 3.2 Lateral 3.2 Lateral foramina foramina (Luschka) (Luschka) 3.1 Median foramen (Magendie) 4. Subarachnoid space Inferiorly
5 Superiorly = lateral aspect Choroid plexus of of each 1 the lateral cerebral 2 ventricle hemisphere 3 Choroid plexus of 3.2 the 3rd ventricle 3.1 Choroid plexus of the 4th Inferiorly = ventricle subarachnoid 4 space around the brain & spinal cord
Circulation of CSF in subarachnoid space : Superior cistern Chiasmatic cistern Median Interpeduncular foramen of cistern 4th ventricle Pontine Cerebellomedullary cistern cistern Median sagittal section to show the subarachnoid cisterns & circulation of CSF
REABSORPTION Subarachnoid spaceArachnoid villi & granulation venous blood are protrusion of the arachnoid matter through perforations in the dura into the lumina of venous sinuses Intracranial-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 barrier Trans villous hydrostatic pressure gradient [CSF pressure-Venous sinus pressure] Pressure sensitive resistance to CSF outflow at the arachnoid villus If 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 CSF Factors 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 47g Stable 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 CBF CMR CSF CBF-AR Respiration
Control of the chemical environment
Control of the chemical environment L
Excretion Removes metabolic products,unwanted drugs BBB excludes out toxic large,polar and lipid insoluble drugs, humoral agents etc
Intracerebral transport MEDIAN CSF EMINENCE Neurohormone releasing factors formed in hypothalamus
METHODS OF DETERMINING CSF FORMATION RATE & RESISTANCE TO CSF ABSORPTION • Plasm • CSF
VENTRICULO CISTERNAL PERFUSION Heisey and colleagues & Pappenheimer and associates Cannula placed in one or both lateral ventricle and in cisterna magna Labeled mock CSF into ventricles Labeled 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 solution Va= 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 associates Manometric infusion device inserted into the spinal/supracortical SubArachnoid Space[SAS] Mock CSF into the SAS CSF pressure measured @ same site of infusion Each 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 Miller Ventricular 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 pressure Pressure 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 space Ventricular & spinal CSF pressures are closely monitored to ensure that obstructed perfusion do not ↑ CSF pressure very high Needs >1 hour Mock CSF
MANOMETRIC INFUSION Number of infusions are reduced Infusion rate 1.5-15 times Vf [.01-.1mL/sec] Infusions restricted to20-60 sec Discontinued @ CSF pressures of 60-70 cm H2O/ rapid rise Needs multiple infusions Mock CSF
VOLUME INJECTION OR WITHDRAWAL No hazard associated with mock CSF Hence more commonly used CSF withdrawal can be therapeutic Closed system- hence risk of infection less More suitable for repeated testing Calculation 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 ICP LOW [0.9% &1.8%] 0 + + HIGH [2.65 &3.5 end + 0 + expired] ENFLURANE INDUCE INCREASED CP METABOLISM
INHALED ANESTHETICS HALOTHANE Vf Ra ICP 1 MAC -- + + INCREASE GLUCOSE TRANSPORT INTO BRAIN INCREASE Na/Cl/H2O/Albumin TRANSPORT INTO CSF HALOTHANE INDUCED STIMULATION OF VASOPRESSIN RECEPTORSDECREASE Vf
INHALED ANESTHETICS ISOFLURANE Vf Ra ICP LOW[0.6] 0 0 0 LOW[1.1%] 0 + + HIGH[1.7,2.2%] 0 -- -- GLUTAMATE CONCENTRATION IN CSF IS MORE WHEN ISOFLURANE IS USED THAN IN PROPOFOL BASED ANESTHESIA
INHALED ANESTHETICS SEVOFLURANE Vf Ra ICP 1MAC -- + ?
INHALED ANESTHETICS DESFLURANE Vf Ra ICP HYPOCAPNIA & ↑CSF + + + PRESSURE OTHER SITUATIONS 0 0 0 ONLY FRUSEMIDE 2MG/KG DECREASED Vf IN THE FIRST SITUATION.
INHALED ANESTHETICS NITROUS OXIDE Vf Ra ICP 66% 0 0 0 DECREASE BRAIN GLUCOSE INFLUX AND EFFLUX
I.V. ANESTHETICS KETAMINE Vf Ra ICP 40MG/KG/HR 0 + + DECREASE TRANSPORT OF SMALL HYDROPHILIC MOLECULES ACROSS BBB
I.V. ANESTHETICS ETOMIDATE Vf Ra ICP LOW [.86MG/KG.86MG/KG/HR] 0 0 0 HIGH[2.58MG/KG/HR] -- -- --
I.V. ANESTHETICS PROPOFOL Vf Ra ICP 6MG/KG12,24 & 48 MG/KG/HR 0 0 0 PENTOBARBITAL Vf Ra ICP 40MG/KG 0 0 0 CSF CONCENTRATION OF PROPOFOL IS APPROX 60% OF THAT OF PLASMA CONCENTRATION
I.V. ANESTHETICS THIOPENTAL Vf Ra ICP LOW DOSE[6MG/KG F/B 6-12MG/KG/HR] 0 +/0 +/0 HIGH DOSE[18-24MG/KG/HR] -- -- -- INCREASE
I.V. ANESTHETICS MIDAZOLAM Vf Ra ICP LOW[1.6MG/KG.5MG/KG/HR] 0 + + INTERMEDIATE[1-1.5MG/KG/HR] 0 0 0 HIGH [2MG/KG/HR] -- + --/? FLUMAZENIL Vf Ra ICP LOW[.0025MG/KG] 0 0 0 HIGH [.16MG/KG] 0 -- -- LOW[DOGS GETTING MIDAZOLAM] 0 + HIGH[ “ ] 0 0
OPIOIDS FENTANYL Vf Ra ICP LOW DOSE 0 -- -- HIGH DOSE -- 0/+ --/? SUFENTANIL Vf Ra ICP LOW DOSE 0 -- -- HIGH DOSE 0 0/+ 0/+ ALFENTANIL Vf Ra ICP LOW DOSE 0 -- -- HIGH DOSE 0 0 0
I.V. DRUGS LIDOCAINE Vf Ra ICP .5MG/KG1μG/KG/MIN -- 0 0/-- 1.5 3 4.5 9
I.V. DRUGS IV acetaminophen permeate readily and attain peak concentration in 1 hour in CSF rapid central analgesia and antipyretic effects Ibuprofen :peak @ 30-40 mins
DIURETICS Vf MECHANISMS ACETAZOLAMIDE -- BY 50% INHIBITION OF CARBONIC ANHYDRASE METHAZOLAMIDE INDIRECT ACTION ON ION TRANSPORT [VIA HCO3] CONSTRICT CP ARTERIOLES & ↓ CPBF ACETAZOLAMIDE +OUABAIN↓Vf BY 95% = ADDITIVE
OTHERS DRUG L 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 PLASMACP OR BRAIN TISSUECSF DINITROPHENOL -- UNCOUPLE OXIDATIVE PHOSPHORYLATION DECREASE ENERGY AVAILABLE FOR MEMBRANE PUMP ANP -- ↑cGMP
DIURETICS Vf MECHANISMS FUROSEMIDE -- DECREASE Na+ OR Cl- TRANSPORT MANNITOL -- DECREASED 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/dexa Probable mechanisms postulated: Improved CSF flow in subarachnoid spaces/ A. villi Reversal of metabolically induced changes in the structure of the villi, action @ CP Dexamethasone ↓Vf by 50% [inhibition of Na-K ATPase]
REGULATION OF Vf /Ra
NEUROGENIC REGULATION Adrenergic nerves from superior and lower cervical ganglia innervate CP Lateral ventricle– U/L Midline ventricle– B/L 3rd ventricle rich in cholinergic innervation, whereas 4th ventricle devoid of it Peptidergic nerves contain VIP and substance-P : both are potent vasodilators
Adrenergic system α  constriction βdilatation Decrease carbonic anhydrase activity Norepinephrine:↓ Vf high α mediated vasoconstriction Low β1 mediated inhibitory action on CP
Cholinergic system Also ↓ Vf Receptors presumably muscarinic Act on CP epithelium, rather than on vasculature
METABOLIC REGULATION HYPOTHERMIA: ↓ Vf – By decreasing secretory and transport process and by ↓ing CBF between 41310 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 ↑osmolarity of serum ↓osmolarity of ventricular CSF ↓/↑ in Vf caused by change in serum osmolarity 4 times higher
ALTERATIONS IN VARIOUS PATHOLOGIES .
Intracranial volume change Volume of intracranial blood/gas/tissue ↑  CSF volume ↓ MECHANISM: >TRANSLOCATION INTO SPINAL SPACES >INCREASED REABSORPTION Volume of intracranial blood/gas/tissue ↓  CSF volume ↑ 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 valuesstimulate Va  Va ↑ Va = Vf here,ICP same; brain volume ↓; CSF volume↑
INTRACRANIAL MASS ANIMAL STUDY IN 3 GROUPS OF DOGS GROUP 1 HYPOCAPNIA GROUP2 I.C. MASS GROUP3 I.C.MASS + HYPOCAPNIA 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
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 Rx Methyl prednisolone ↓ed Ra to a value between control and infected
PSEUDOTUMOR CEREBRI Increased Ra , Vf ,water movement into brain, CBF & CBV increased ICP Impaired reabsorption is the principal cause Prednisone 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 brain Anesthetics induced changes in both, significantly alters Rx to reduce ICP
So…… We demand more attention from you..
HEAD INJURY THANK YOU

More Related Content

PHYSIOLOGY OF CSF PRODUCTION AND CIRCULATION, ALTERATIONS IN VARIOUS PATHOLOGY

  • 1. PHYSIOLOGY OF CSF PRODUCTION AND CIRCULATION, ALTERATIONS IN VARIOUS PATHOLOGY Dr Unnikrishnan P
  • 2. 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
  • 3. OUTLINE CSF SPACES CSF FORMATION-CIRCULATION-REABSORPTION METHODS OF DETERMINING Vf and Ra EFFECTS OF DRUGS REGULATION ALTERATION IN CSF DYNAMICS IN PATHOLOGIES
  • 4. Introduction CSF  flows via macroscopic & ECF spaces PRESSURES 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
  • 5. 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
  • 6. 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.
  • 7. CHOROID PLEXUS BLOOD SUPPLY . of lateral ventricle Body 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
  • 8. MACROSCOPIC SPACES  Two lateral ventricles Third ventricle Aqueduct of sylvius Fourth ventricle Central canal of spinal cord Subarachnoid spaces
  • 9. MICROSCOPIC SPACES- BRAIN & SPINAL CORD ECF SPACES are small Capillary – ECF exchange is l i m i t e d Blood brain barrier Whats your diameter? ………<20 A⁰ ?
  • 10. COMPOSITION Plasma CSF Na+(mM) 140 141 K+(mM) L 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 289 289 H2O-1) Protein (mg 100 g-1) 7000 28 Specific gravity 1.025 1.007
  • 11. COMPOSITION Vary according to sampling site Altered during neuroendoscopy
  • 13. CSF FORMATION Rate [Vƒ] 0.35-0.40 mL/min OR 500-600 mL/day 0.25% of total vol replaced each minute Turn over time for total CSF vol  5-7 hours = 4 times / day 40%-70% enters macroscopic spaces via CP 30%-60% enters across ependyma and pia
  • 15. @ CHOROID PLEXUS Blood filtered protein rich fluid similar to ISF Hydrostatic pressure & bulk flow-> enter cleft between cells Ultra filtration & secretion
  • 16. @EXTRA CHOROIDAL SITES Oxidation of glucose by brain [60%] Ultra filtration from cerebral capillaries [40%] TIGHT JUNCTIONS  Glucose/electrolyte/water Large polar/protein
  • 17. MOVEMENT OF GLUCOSE Glucose concentration is 60% that of plasma Remains constant, unless blood glucose >270-360 Enters CSF quickly by facilitated transport Rate ∝ Serum glucose [not on gradient]
  • 18. 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
  • 19. Vƒ & ICP/CPP Vƒ ↑ ICP Vƒ ↓CPP
  • 20. 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 Vƒ When 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]
  • 21. CIRCULATION OF CSF Hydrostatic pressure of CSF formation Cilia of ependymal cells Respiratory variations Vascular pulsations of cerebral arteries,CP
  • 22. Site of formation Choroid plexus of the lateral ventricle 1. Lateral ventricle Superiorly Interventricular foramina Superiorly 2. Third ventricle Cerebral aqueduct Absorbed Absorbed 3. Fourth ventricle 3.2 Lateral 3.2 Lateral foramina foramina (Luschka) (Luschka) 3.1 Median foramen (Magendie) 4. Subarachnoid space Inferiorly
  • 23. 5 Superiorly = lateral aspect Choroid plexus of of each 1 the lateral cerebral 2 ventricle hemisphere 3 Choroid plexus of 3.2 the 3rd ventricle 3.1 Choroid plexus of the 4th Inferiorly = ventricle subarachnoid 4 space around the brain & spinal cord
  • 24. Circulation of CSF in subarachnoid space : Superior cistern Chiasmatic cistern Median Interpeduncular foramen of cistern 4th ventricle Pontine Cerebellomedullary cistern cistern Median sagittal section to show the subarachnoid cisterns & circulation of CSF
  • 25. REABSORPTION Subarachnoid spaceArachnoid villi & granulation venous blood are protrusion of the arachnoid matter through perforations in the dura into the lumina of venous sinuses Intracranial-Superior sagittal sinus[85%-90%] Spinal-dural sinusoids on dorsal nerve roots[15%]
  • 26. 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…
  • 28. ‘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
  • 29. Determinants of reabsorption Endothelium covering the villus acts as a CSF- blood barrier Trans villous hydrostatic pressure gradient [CSF pressure-Venous sinus pressure] Pressure sensitive resistance to CSF outflow at the arachnoid villus If through endothelium:(1)pinocytic vesicles (2)transcellular openings
  • 30. 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
  • 31. CSF drainage & cerebral edema vasogenic edema resolves partly by drainage of fluid into ventricular CSF Factors influencing: (1) pressure gradient between brain tissue and CSF (2) sink action of CSF Brain ECF proteins cleared by glial uptake
  • 32. 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 47g Stable supply of nutrients ,primarily glucose; also vitamins /eicosanoids/monosaccharides/neutral & basic Amino acids
  • 33. Control of the chemical environment Exchange between neural tissue & CSF is easy diffusion distance 15mm (max) & ISF space and CSF spaces are continuous CBF CMR CSF CBF-AR Respiration
  • 34. Control of the chemical environment
  • 35. Control of the chemical environment L
  • 36. Excretion Removes metabolic products,unwanted drugs BBB excludes out toxic large,polar and lipid insoluble drugs, humoral agents etc
  • 37. Intracerebral transport MEDIAN CSF EMINENCE Neurohormone releasing factors formed in hypothalamus
  • 38. METHODS OF DETERMINING CSF FORMATION RATE & RESISTANCE TO CSF ABSORPTION • Plasm • CSF
  • 39. VENTRICULO CISTERNAL PERFUSION Heisey and colleagues & Pappenheimer and associates Cannula placed in one or both lateral ventricle and in cisterna magna Labeled mock CSF into ventricles Labeled mock + Native CSF collected from cisternal cannula & volume determined
  • 40. 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
  • 41. 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 Va= ViCi - V0C0/C0 V0=outflow rate of CSF from cisternal cannula Ra= reciprocal measure of the slope relating Va to CSF pressure
  • 42. MANOMETRIC INFUSION Maffeo and colleagues & Mann and associates Manometric infusion device inserted into the spinal/supracortical SubArachnoid Space[SAS] Mock CSF into the SAS CSF pressure measured @ same site of infusion Each 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
  • 43. VOLUME INJECTION OR WITHDRAWAL Marmarou and colleagues and Miller Ventricular 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 pressure Pressure Volume Index[PVI] calculated & Vf and Ra from it.
  • 44. METHODS OF DETERMINING CSF FORMATION RATE & RESISTANCE TO CSF ABSORPTION • Plasm • CSF
  • 45. VENTRICULOCISTERNAL PERFUSION Outflow catheter in lumbar subarachnoid space Ventricular & spinal CSF pressures are closely monitored to ensure that obstructed perfusion do not ↑ CSF pressure very high Needs >1 hour Mock CSF
  • 46. MANOMETRIC INFUSION Number of infusions are reduced Infusion rate 1.5-15 times Vf [.01-.1mL/sec] Infusions restricted to20-60 sec Discontinued @ CSF pressures of 60-70 cm H2O/ rapid rise Needs multiple infusions Mock CSF
  • 47. VOLUME INJECTION OR WITHDRAWAL No hazard associated with mock CSF Hence more commonly used CSF withdrawal can be therapeutic Closed system- hence risk of infection less More suitable for repeated testing Calculation needs only a single change of CSF volume and pressure lasting for minutes
  • 48. . ANESTHETIC AND DRUG INDUCED CHANGES IN CSF FORMATION RATE AND RESISTANCE TO CSF ABSORPTION AND TRANSPORT OF VARIOUS MOLECULES INTO CSF AND THE CNS
  • 49. INHALED ANESTHETICS ENFLURANE Vf Ra ICP LOW [0.9% &1.8%] 0 + + HIGH [2.65 &3.5 end + 0 + expired] ENFLURANE INDUCE INCREASED CP METABOLISM
  • 50. INHALED ANESTHETICS HALOTHANE Vf Ra ICP 1 MAC -- + + INCREASE GLUCOSE TRANSPORT INTO BRAIN INCREASE Na/Cl/H2O/Albumin TRANSPORT INTO CSF HALOTHANE INDUCED STIMULATION OF VASOPRESSIN RECEPTORSDECREASE Vf
  • 51. INHALED ANESTHETICS ISOFLURANE Vf Ra ICP LOW[0.6] 0 0 0 LOW[1.1%] 0 + + HIGH[1.7,2.2%] 0 -- -- GLUTAMATE CONCENTRATION IN CSF IS MORE WHEN ISOFLURANE IS USED THAN IN PROPOFOL BASED ANESTHESIA
  • 52. INHALED ANESTHETICS SEVOFLURANE Vf Ra ICP 1MAC -- + ?
  • 53. INHALED ANESTHETICS DESFLURANE Vf Ra ICP HYPOCAPNIA & ↑CSF + + + PRESSURE OTHER SITUATIONS 0 0 0 ONLY FRUSEMIDE 2MG/KG DECREASED Vf IN THE FIRST SITUATION.
  • 54. INHALED ANESTHETICS NITROUS OXIDE Vf Ra ICP 66% 0 0 0 DECREASE BRAIN GLUCOSE INFLUX AND EFFLUX
  • 55. I.V. ANESTHETICS KETAMINE Vf Ra ICP 40MG/KG/HR 0 + + DECREASE TRANSPORT OF SMALL HYDROPHILIC MOLECULES ACROSS BBB
  • 56. I.V. ANESTHETICS ETOMIDATE Vf Ra ICP LOW [.86MG/KG.86MG/KG/HR] 0 0 0 HIGH[2.58MG/KG/HR] -- -- --
  • 57. I.V. ANESTHETICS PROPOFOL Vf Ra ICP 6MG/KG12,24 & 48 MG/KG/HR 0 0 0 PENTOBARBITAL Vf Ra ICP 40MG/KG 0 0 0 CSF CONCENTRATION OF PROPOFOL IS APPROX 60% OF THAT OF PLASMA CONCENTRATION
  • 58. I.V. ANESTHETICS THIOPENTAL Vf Ra ICP LOW DOSE[6MG/KG F/B 6-12MG/KG/HR] 0 +/0 +/0 HIGH DOSE[18-24MG/KG/HR] -- -- -- INCREASE
  • 59. I.V. ANESTHETICS MIDAZOLAM Vf Ra ICP LOW[1.6MG/KG.5MG/KG/HR] 0 + + INTERMEDIATE[1-1.5MG/KG/HR] 0 0 0 HIGH [2MG/KG/HR] -- + --/? FLUMAZENIL Vf Ra ICP LOW[.0025MG/KG] 0 0 0 HIGH [.16MG/KG] 0 -- -- LOW[DOGS GETTING MIDAZOLAM] 0 + HIGH[ “ ] 0 0
  • 60. OPIOIDS FENTANYL Vf Ra ICP LOW DOSE 0 -- -- HIGH DOSE -- 0/+ --/? SUFENTANIL Vf Ra ICP LOW DOSE 0 -- -- HIGH DOSE 0 0/+ 0/+ ALFENTANIL Vf Ra ICP LOW DOSE 0 -- -- HIGH DOSE 0 0 0
  • 61. I.V. DRUGS LIDOCAINE Vf Ra ICP .5MG/KG1μG/KG/MIN -- 0 0/-- 1.5 3 4.5 9
  • 62. I.V. DRUGS IV acetaminophen permeate readily and attain peak concentration in 1 hour in CSF rapid central analgesia and antipyretic effects Ibuprofen :peak @ 30-40 mins
  • 63. DIURETICS Vf MECHANISMS ACETAZOLAMIDE -- BY 50% INHIBITION OF CARBONIC ANHYDRASE METHAZOLAMIDE INDIRECT ACTION ON ION TRANSPORT [VIA HCO3] CONSTRICT CP ARTERIOLES & ↓ CPBF ACETAZOLAMIDE +OUABAIN↓Vf BY 95% = ADDITIVE
  • 64. OTHERS DRUG L 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 PLASMACP OR BRAIN TISSUECSF DINITROPHENOL -- UNCOUPLE OXIDATIVE PHOSPHORYLATION DECREASE ENERGY AVAILABLE FOR MEMBRANE PUMP ANP -- ↑cGMP
  • 65. DIURETICS Vf MECHANISMS FUROSEMIDE -- DECREASE Na+ OR Cl- TRANSPORT MANNITOL -- DECREASED CP OUTPUT AND ECF FLOW FROM BRAIN TO CSF COMPARTMENT
  • 66. MUSCLE RELAXANTS RELAXANTS Vf Ra SCOLINE, VECURONIUM INFUSIONS 0 0
  • 67. STEROIDS Decrease Ra M.prednisolone/prednisone/cortisone/dexa Probable mechanisms postulated: Improved CSF flow in subarachnoid spaces/ A. villi Reversal of metabolically induced changes in the structure of the villi, action @ CP Dexamethasone ↓Vf by 50% [inhibition of Na-K ATPase]
  • 69. NEUROGENIC REGULATION Adrenergic nerves from superior and lower cervical ganglia innervate CP Lateral ventricle– U/L Midline ventricle– B/L 3rd ventricle rich in cholinergic innervation, whereas 4th ventricle devoid of it Peptidergic nerves contain VIP and substance-P : both are potent vasodilators
  • 70. Adrenergic system α  constriction βdilatation Decrease carbonic anhydrase activity Norepinephrine:↓ Vf high α mediated vasoconstriction Low β1 mediated inhibitory action on CP
  • 71. Cholinergic system Also ↓ Vf Receptors presumably muscarinic Act on CP epithelium, rather than on vasculature
  • 72. METABOLIC REGULATION HYPOTHERMIA: ↓ Vf – By decreasing secretory and transport process and by ↓ing CBF between 41310 C: each 10 C↓in temperature, ↓ Vf by 11% HYPOCAPNIA: acutely ↓ Vf [mechanism : ↓ CBF, ↓ H+ for exchange with Na]
  • 73. METABOLIC REGULATION Metabolic alkalosis ↓ Vf due to pH effect Metabolic acidosis: no change
  • 74. ↓ Vf in change of osmolarity/ Wald & associates ↑osmolarity of serum ↓osmolarity of ventricular CSF ↓/↑ in Vf caused by change in serum osmolarity 4 times higher
  • 75. ALTERATIONS IN VARIOUS PATHOLOGIES .
  • 76. Intracranial volume change Volume of intracranial blood/gas/tissue ↑  CSF volume ↓ MECHANISM: >TRANSLOCATION INTO SPINAL SPACES >INCREASED REABSORPTION Volume of intracranial blood/gas/tissue ↓  CSF volume ↑ MECHANISM: >CEPHALAD TRANSLOCATION >DECREASED REABSORPTION
  • 77. 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
  • 78. 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 valuesstimulate Va  Va ↑ Va = Vf here,ICP same; brain volume ↓; CSF volume↑
  • 79. INTRACRANIAL MASS ANIMAL STUDY IN 3 GROUPS OF DOGS GROUP 1 HYPOCAPNIA GROUP2 I.C. MASS GROUP3 I.C.MASS + HYPOCAPNIA 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
  • 80. 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
  • 81. 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
  • 82. C/C CHANGES AFTER SAH Extensive fibrosis leptomeningeal scarring functional narrowing or blockage of CSF outflow tracts [Ra is increased] hydrocephalus
  • 83. Bacterial meningitis Animal study with 1.S pneumoniae 2.E coli ↓ is increased Even with antibiotics it remained high for 2 weeks post Rx Methyl prednisolone ↓ed Ra to a value between control and infected
  • 84. PSEUDOTUMOR CEREBRI Increased Ra , Vf ,water movement into brain, CBF & CBV increased ICP Impaired reabsorption is the principal cause Prednisone decreased Ra
  • 85. Head Injury 20% of the raised ICP derived from changes in Ra &Vf
  • 86. It means… Vf changes: changes ICP Ra changes: changes ICP, alters pressure buffering capacity of brain Anesthetics induced changes in both, significantly alters Rx to reduce ICP
  • 87. So…… We demand more attention from you..