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Intrathecal Therapy:Catheter Position and CSF
Dynamics
Salim Hayek, MD, PhD
Chief, Division of Pain Medicine
Professor, Dept of Anesthesiology
University Hospitals of Cleveland
Learning Objectives
Pharmacokinetics of Intrathecal Meds
Optimal Catheter placement
CSF Flow Dynamics
Clinical Correlates
Krames E. Journal of Pain and Symptom Management;1996, Vol 11, No 6: 333-352
Intrathecal Therapy for Pain: Patient Selection
Objective evidence of pathologyFailure to achieve adequate results
from oral opioid therapy Inability to tolerate the side effects
of oral opioids Psychological evaluationAgeStarting dose of opioids IT Medications (Bupivacaine)
Pharmacological Considerations
Receptors for the agents have to be at the spinal level
Drug considerationsLipid solubility
Density and baricity
Bolus vs. continuous
Location of catheter/receptors
Kroin JS. Clin.Pharmacokinet. 22:319-326, 1992 Nordberg G. Acta Anaesthesiol.Scand.Suppl 79:1-38, 1984
Mechanism of Action--IT CSF ~ ISF
Most receptors are in the substantia gelatinosa 1-2 mm from surface of dorsal horn
Synapses
OpioidsClonidineZiconotide
Bupivacaine
Hydrophilic>HydrophobicLonger ½ life
Deeper penetration
Smaller volume of distribution
Rostral spread
OpioidsClonidineZiconotide
Bupivacaine
DRGDRG
Dorsal Rootlets(sensory)
Dorsal Rootlets(sensory)
Ventral Rootlets(motor)
Ventral Rootlets(motor)
Kroin JS et al: The distribution of medication along the spinal canal after chronic intrathecal administration. Neurosurgery 33:226-230, 1993
Pharmacokinetics-lipophilicity
Moderately hydrophilic agents (such as morphine, baclofen or clonidine) concentration gradient in the CNS cisternal CSF drug concentration is 1/3
to 1/7 that in the lumbar CSF
Bupivacaine-lipohilic
Cerebrospinal Fluid Flow
Bulk Flow (Circulation) Theory CSF is produced by the choroid plexus and
absorbed by the arachnoid granulations, dural sinuses, perineural sheaths
Produces CSF movement by hydrostatic pressure gradient in cranio-caudal direction
Pulsatile Flow Theory Bidirectional cranio-caudal oscillatory
movement of CSF
Battal B, Kocaoglu M, Bulanski N et al. Cerebrospinal Fluid Flow imaging by using phase-contrast MR technique. British Journal of Radiology. 2011 (84),758-65
Pulsatile Flow Recent insights by phase contrast MR techniques have….
Validated pulsatile flow as the major locomotive for CSF flow To and fro motion has been characterized by numerous authors
Influenced by pressure volume relationships with proposed engines including cardiac cycle intrathoracic and intraabdominal pressures
Although Bulk flow likely occurs, its effects are negligible-estimates of 0.4%
P-V Relationship
Monro-Kellie Doctrine Newtonian fluid in compliant space within rigid
case
Pressure Volume Relationship
Governed by:o CSF Volume
o Arterial blood Volume
o Venous Blood Volume
o Spinal and intracranial Parenchyma
CSF Oscillatory Flow
Henry-Feugeas MC, Idy-Peretti I, Baledent O et al. Origin of Subarachnoid CerebrospinalFluid Pulsations: a phase-contrast MR analysis. Magnetic Resonance Imaging. 2000 (18) 387-395
Oscillatory CSF Flow
Henry-Feugeas MC, Idy-Peretti I, Baledent O et al. Origin of Subarachnoid CerebrospinalFluid Pulsations: a phase-contrast MR analysis. Magnetic Resonance Imaging. 2000 (18) 387-395
End of cardiac cycle R phase Early Systole Systole
Oscillatory CSF Flow
Spinal CSF pulsations mainly arterial in origin
direct transfer of spinal vascular pulsatile pressure
No continuous downward progression of the onset of CSF systole was detected from the craniocervical junction to the thoracolumbar studyVariable arterial supply of mid cord
Henry-Feugeas MC, Idy-Peretti I, Baledent O et al. Origin of Subarachnoid CerebrospinalFluid Pulsations: a phase-contrast MR analysis. Magnetic Resonance Imaging. 2000 (18) 387-395
CSF Oscillatory Flow
Influence of RespirationCSF pulsation was high in the anterior
cervical and in the thoracolumbar spine
Respiratory influence rose caudad spine19% at C1 vs. 28% at T12
The systolic flow was elevated during late expiration and the diastolic upward movement was pronounced by early expiration
Friese S, Hamhaber U, Erb M et al. The influence of Pulse and Respiration on Spinal Cerebrospinal Fluid Pulsation. Invest Radiol 2004;39:120-130.
CSF Oscillatory Flow: 2 “motors” Cranial Motor
Arterial cardiac pulsations > respirations displacing CSF
Bidirectional, with interindividual differences in magnitude and location
Lumbar Motor Arterial cardiac pulsations < respirations
Filling epidural veins displacing CSF
Bidirectional, although more heterogeneous
Friese S, Hamhaber U, Erb M et al. The influence of Pulse and Respiration on Spinal Cerebrospinal Fluid Pulsation. Invest Radiol 2004;39:120-130.
CSF Oscillatory Flow
Extent of CSF pulsation is dependent on many factors, including Age
Ambulation
CSF volume
Stoquart-ElSankari S, Baledent O, Gondry-Jouet C et al. Aging effects on cerebral blood flow and cerebrospinal fluid flows. Journal of Cerebral flow and metabolism. 2007.(27):1563-1572.
Shin BS, Kim CS, Sim WS et al. A Comparison of the Effects of Preanesthetic Administration of Crystalloid Verus Colloid on Intrathecal Spread of Isobaric Spinal Anesthetics and Cerebrospinal Fluid Movement. Anesthesia and Analgesia. 2011 (112)4: 924-30.
CSF Oscillatory Flow
CSF space is heterogeneous space: Outgoing nerve roots and
various membranous elements
Has a nonhomogenous annular volume Enhanced fluid space in
the cervical and lumbar region
Reduced cross sectional diameter in the thoracic space
Hogan Q. Gross Anatomy of the human vertebral column. In: Spinal Drug Delivery. Tony Yaksh (Ed) ©1999 Elsevier Science B.V., Amsterdam
Hansen: Netter’s Clinical Anatomy, 2nd Edition. © 2009 Saunders.
CSF Oscillatory Flow Fine structures within the
subarachnoid space offer barriers for bidirectional flow, and although do not greatly affect flow averaged over the length of the vertebra, introduce complex mixing locally
Stockman HW. Effect of Anatomic Fine Structure on the Flow of Cerebrospinal Fluid in the Spinal Subarachnoid Space. Journal of Biochemical Engineering 2006. Vol 128, 106-114
CSF Oscillatory Flow CSF may be a POORLY MIXED system
Known concentration gradients exist Homovanillic acid concentrations
o 6 x higher in cisternal CSF as compared to lumbar CSF
Uric acid concentrationso 2x higher in lumbar than cisternal CSF
CSF motion propelled in opposite directions cyclically
Areas along the spine with no measurable CSF flow
Limited circumferential flow
Degrell I, Nagy E: Concentration gradients for HVA, 5-HIAA, ascorbic acid, and uric acid in cerebrospinal fluid. Biol Psychiatry 1990; 27:891–6
Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and Bupivacaine during slow intrathecal infusion in Pigs. Anesthesiology 2006;105:169-78.
Henry-Feugeas MC, Idy-Peretti I, Baledent O et al. Origin of Subarachnoid CerebrospinalFluid Pulsations: a phase-contrast MR analysis. Magnetic Resonance Imaging. 2000 (18) 387-395
Particle Size Effect
1 = H2O
2 = intermediate group of substances such as organic acids
3 = 3H-Inulin
Bulat M, Klarica M. Recent insights into the hydrodymanics of the cerebralspinal fluid.Brain Research Reviews 65(2011):99-112
Diagram of CSF Hydrodymanics
CSF Pharmacokinetics: why so challenging?
Requires delivery of a substance and data sampling at different sites and time points
Inherently, intrathecal drug delivery has barrier associated with multiple sampling sites along the craniocaudal axis
Potential for neural toxicity of intrathecal agents
Conventional pharmacokinetics based on systemic drug delivery not correlative
Shafer SL, Shafer A. Chapter 11: Spinal Pharmacokinetics. Spinal Drug Delivery. Tony Yaksh (Ed) ©1999 Elsevier Science B.V.
Pharmacokinetic Modeling
Diffusion/Distribution Model
Shafer SL, Shafer A. Spinal Pharmacokinetics In: Spinal Drug Delivery. Tony Yaksh (Ed) ©1999 Elsevier Science B.V., Amsterdam
Pharmacokinetic Insights
Bolus drug studies may not be applicable to chronic intrathecal drug delivery
Sought to characterize the distribution of intrathecally administered drugs by slow infusion
Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and Bupivacaine during slow intrathecal infusion in Pigs. Anesthesiology 2006;105:169-78.
Pharmacokinetic Insights Vertical Pig Model (n=19) with multiple dialysis
probes (8) Anterior and Posterior placement along spine
Anesthetized, paralyzed, controlled conditions
Infusion rates of 20μL/hr (0.48mL/day)-typical IDDS delivered volume
1mL/hr (24mL/day)
1mL bolused over 5 minutes every hr (24mL/day)
Isobaric Baclofen (2mg/mL) and Bupivacaine (0.75%)
Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and Bupivacaine during slow intrathecal infusion in Pigs. Anesthesiology 2006;105:169-78.
Pharmacokinetic Insights
Pilot Study
Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and Bupivacaine during slow intrathecal infusion in Pigs. Anesthesiology 2006;105:169-78.
Posterior
Lateral
Anterior
Pharmacokinetic Insights
20 μL/hr rate 1 mL/hr rate 1mL/hr bolused
Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and Bupivacaine during slow intrathecal infusion in Pigs. Anesthesiology 2006;105:169-78.
Bupivacaine Concentration
Pharmacokinetic Insights
Limited drug distribution from the posterior site of administration, most pronounced with low volume infusions
Circumferential spread can be increased with larger infusion volumes and appears to be dependent on physiochemical properties of the drug
Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and Bupivacaine during slow intrathecal infusion in Pigs. Anesthesiology 2006;105:169-78.
Vertical vs. Horizontal Pig IT Infusion
Flack SH, Benards CM. Cerebrospinal Fluid and Spinal Cord Distribution of Hyperbaric Bupivacaine and Baclofen during Slow Intrathecal Infusion in Pigs. Anesthesiology 2010 112 165-75.
Vertical Position
Baricity Effect
7.5 mg/ml2 mg/ml
Flack SH, Benards CM. Cerebrospinal Fluid and Spinal Cord Distribution of Hyperbaric Bupivacaine and Baclofen during Slow Intrathecal Infusion in Pigs. Anesthesiology 2010 112 165-75.
Baricity Effect?
Flack SH, Anderson CM, Bernards C., Morphine distribution in the spinal cord after chronic infusion in pigs. Anesth Analg. 2011 Feb;112(2):460-4
Pharmacokinetic Insights
Recent animal studies suggest: Limited drug distribution following intrathecal
administration at slow infusion
Drug distribution at very low continuous rates is affected by baricity
Drug distribution in ambulatory animals result in limited spread and there are significant concentration gradients at the point of infusion
Flack SH, Anderson CM, Bernards CM. Morphine Distribution in the Spinal Cord After Chronic Infusion in Pigs. Anesthesia and Analgesia. 2011 Vol 112 no 2 460-464.
Flack SH, Benards CM. Cerebrospinal Fluid and Spinal Cord Distribution of Hyperbaric Bupivacaine and Baclofen during Slow Intrathecal Infusion in Pigs. Anesthesiology 2010 112 165-75.
Lipid Solubility
Resident time within the CSF dramatically affects drug distribution within the CSF and exposure to the spinal cord
Competing active site vs. extraspinal sites
hydrophobicity exposure to the spinal cord
Ummenhofer WC, Arends RH, Shen DD et al. Comparative Spinal Distribution and Clearance of Intrathecally Administered Morphine, Fentanyl, Alfentanil, and Sufentanil. Anesthesiology 2000;92: 739-53.
Pharmacokinetic Insights What Drives Intrathecal Drug Distribution?
Diffusion (Brownian movement) Very slow
CSF Bidirectional Motion Kinetic Energy of Injectate
Volume and rate of injection
Resident times within the CSF Physiochemical properties
Redistribution out of CSF
Amount of medication deposited
ITB FLOW RATE CRPS
4x Infusion RateNo improvement in NRS or Dystonia
frequency of Adverse Events
van der Plas AA, Marinus J, Eldabe S, Buchser E, van Hilten JJ. The lack of efficacy of different infusion rates of intrathecal baclofen in complex regional pain syndrome: a randomized, double-blind, crossover study. Pain Med. 2011;12(3):459-465.
14 patients with CRPS-Dystonia Randomized DB: 0.75mg/ml or 3mg/ml
IT FLOW RATE EFFECT
VAS did not significantly change
QOL with ’g flow rate (EQ-5D) Due to pain and anxiety dimension of EQ-5D
Perruchoud C, Eldabe S, Durrer A, et al. Effects of flow rate modifications on reported analgesia and quality of life in chronic pain patients treated with continuous intrathecal drug therapy. Pain Med. 2011;12(4):571-576.
20 patients with stable IDDS Randomized DB: 1x, 2x or 4x the flow
rate
Pharmacokinetic Summary
Volume
Concentration
Dose
Speed of Delivery
Site of Injection
Baricity
Lipid Solubility
Pharmacokinetic Insights
Conclusion: Studies suggest placement of the
Intrathecal Catheter tip at the anatomic level concordant with desired effect
Posterior location may be more desirable than anterior location to treat pain
Consideration of the drug’s physiochemical properties may be important
Increased dose (or concentration) may increase spread
Pharmacokinetic Failure?
Anecdotal evidence of desired effect after drug delivery by bolus (trial) with less efficacy following slow intrathecal delivery
40% of patients failed to demonstrate clinical improvement with intrathecal infusion despite doses of 1mg/day
Walker RH, Danisl FO, Swope DM, et al. Intrathecal baclofen for Dystonia: Benefits and complications during six years of experience. Mov Disord 2000;15: 1242-7.
Pharmacokinetic Failure?
saline morphine hydromorphone
Allen JW, Horais KA, Tozier NA et al. Opiate Pharmacology of Intrathecal Granulomas. Anesthesiology 2006; 105:590-598.
Granuloma Formation
Conclusions
CSF moves in bidirectional pattern via cranial and lumbar engines with very limited bulk flow
Intrathecal space is poorly mixed environment
Increased resident times within the CSF improve ability to distribute within the CSF
Despite pharmacokinetic knowledge inadequacies, IT therapy is efficacious