Intrathecal Therapy: Catheter Position and CSF Dynamics Salim Hayek, MD, PhD Chief, Division of Pain Medicine Professor, Dept of Anesthesiology University

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 InterestResearch/Fellowship Support

Medtronic

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


Bupivacaine


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

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 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


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



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.


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 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.


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


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%)



Pilot Study


Posterior

Lateral

Anterior


20 μL/hr rate 1 mL/hr rate 1mL/hr bolused


Bupivacaine Concentration


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


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


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


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.


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


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

Documents

Intrathecal Therapy: Catheter Position and CSF Dynamics Salim Hayek, MD, PhD Chief, Division of Pain Medicine Professor, Dept of Anesthesiology University