Transcript Catheter Position and CSF Dynamics

Intrathecal Therapy:
Catheter Position and CSF Dynamics
Salim Hayek, MD, PhD
Chief, Division of Pain Medicine
Professor, Dept of Anesthesiology
University Hospitals of Cleveland
Relevant Conflicts of Interest
 Research/Fellowship Support
Medtronic
Learning Objectives
 Pharmacokinetics of Intrathecal Meds
 Optimal Catheter placement
 CSF Flow Dynamics
 Clinical Correlates
Intrathecal Therapy for Pain:
Patient Selection
 Objective evidence of pathology
 Failure to achieve adequate results
from oral opioid therapy
 Inability to tolerate the side effects
of oral opioids
 Psychological evaluation
 Age
 Starting dose of opioids
 IT Medications (Bupivacaine)
Krames E. Journal of Pain and Symptom Management;1996, Vol 11, No 6: 333-352
Pharmacological Considerations
 Receptors for the agents have to be at
the spinal level
 Drug considerations
Lipid solubility
Density and baricity
Bolus vs. continuous
Location of catheter/receptors
Mechanism of Action--IT
 CSF ~ ISF
 Most receptors are in the
substantia gelatinosa 1-2
mm from surface of dorsal
horn
Opioids
Clonidine
Bupivacaine
Synapses Ziconotide
 Hydrophilic>Hydrophobic
 Longer ½ life
 Deeper penetration
 Smaller volume of distribution
 Rostral spread
Kroin JS. Clin.Pharmacokinet. 22:319-326, 1992
Nordberg G. Acta Anaesthesiol.Scand.Suppl 79:1-38, 1984
Bupivacaine
Opioids
Clonidine
Ziconotide
Dorsal Rootlets
(sensory)
Bupivacaine
Opioids
Clonidine
Dorsal Rootlets
(sensory)
Ziconotide
Ventral Rootlets
(motor)
Ventral Rootlets
(motor)
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
Kroin JS et al: The distribution of medication along the spinal canal after chronic
intrathecal administration. Neurosurgery 33:226-230, 1993
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
Hansen: Netter’s Clinical Anatomy, 2nd Edition. © 2009 Saunders.
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 negligibleestimates 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 Cerebrospinal
Fluid Pulsations: a phase-contrast MR analysis. Magnetic Resonance Imaging. 2000 (18) 387-395
Oscillatory CSF Flow
End of cardiac cycle
R phase
Early Systole
Systole
Henry-Feugeas MC, Idy-Peretti I, Baledent O et al. Origin of Subarachnoid Cerebrospinal
Fluid Pulsations: a phase-contrast MR analysis. Magnetic Resonance Imaging. 2000 (18) 387-395
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 study
 Variable arterial supply of mid cord
Henry-Feugeas MC, Idy-Peretti I, Baledent O et al. Origin of Subarachnoid Cerebrospinal
Fluid Pulsations: a phase-contrast MR analysis. Magnetic Resonance Imaging. 2000 (18) 387-395
CSF Oscillatory Flow
 Influence of Respiration
CSF pulsation was high in the anterior
cervical and in the thoracolumbar spine
Respiratory influence rose  caudad spine
19% 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
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.
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.
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
Hansen: Netter’s Clinical Anatomy, 2nd Edition. © 2009 Saunders.
Hogan Q. Gross Anatomy of the human vertebral column. In: Spinal Drug Delivery.
Tony Yaksh (Ed) ©1999 Elsevier Science B.V., Amsterdam
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 concentrations
o 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
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
Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and Bupivacaine during slow intrathecal
infusion in Pigs. Anesthesiology 2006;105:169-78.
Degrell I, Nagy E: Concentration gradients for HVA, 5-HIAA, ascorbic acid, and uric acid in cerebrospinal fluid. Biol
Particle Size Effect
1 = H 2O
2 = intermediate
group of
substances such
as organic acids
3 = 3H-Inulin
Diagram of CSF Hydrodymanics
Bulat M, Klarica M. Recent insights into the hydrodymanics of the cerebralspinal fluid.
Brain Research Reviews 65(2011):99-112
CSF Oscillatory Flow
>
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
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
Posterior
Lateral
Anterior
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
Bupivacaine Concentration
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.
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
Vertical Position
 Baricity Effect
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.
2 mg/ml
7.5 mg/ml
Baricity Effect?
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.
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, Benards CM. Cerebrospinal Fluid and Spinal Cord Distribution of Hyperbaric Bupivacaine and Baclofen during
Slow Intrathecal Infusion in Pigs. Anesthesiology 2010 112 165-75.
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.
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
14 patients with CRPS-Dystonia
Randomized DB: 0.75mg/ml or 3mg/ml
 4x Infusion Rate
No 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.
IT FLOW RATE EFFECT
20 patients with stable IDDS
Randomized DB: 1x, 2x or 4x the flow rate
 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.
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?
 Granuloma Formation
saline
morphine
hydromorphone
Allen JW, Horais KA, Tozier NA et al. Opiate Pharmacology of Intrathecal Granulomas.
Anesthesiology 2006; 105:590-598.
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