INTRATHECAL THERAPY CATHETER POSITION AND CSF DYNAMICS Salim

INTRATHECAL THERAPY: CATHETER POSITION AND CSF DYNAMICS Salim Hayek, MD, Ph. D Chief, Division of Pain Medicine Professor, Dept of Anesthesiology University Hospitals of Cleveland

RELEVANT CONFLICTS OF INTEREST Ø Research/Fellowship Support v. Medtronic

LEARNING OBJECTIVES Ø Pharmacokinetics of Intrathecal Meds Ø Optimal Catheter placement Ø CSF Flow Dynamics Ø Clinical Correlates

PAIN: PATIENT SELECTION Ø Objective evidence of pathology Ø Failure to achieve adequate results from oral opioid therapy Ø Inability to tolerate the side effects of oral opioids Ø Psychological evaluation Ø Age Ø Starting dose of opioids Ø IT Medications (Bupivacaine) Krames E. Journal of Pain and Symptom Management; 1996, Vol 11, No 6: 333 -352

PHARMACOLOGICAL CONSIDERATIONS Ø Receptors for the agents have to be at the spinal level Ø Drug considerations v. Lipid solubility v. Density and baricity v. Bolus vs. continuous v. Location of catheter/receptors

MECHANISM OF ACTION-IT Ø CSF ~ ISF Ø Most receptors are in the substantia gelatinosa 1 -2 mm from surface of dorsal horn Opioids Clonidine Bupivacaine Synapses Ziconotide Ø Hydrophilic>Hydrophobic v Longer ½ life v Deeper penetration v Smaller volume of distribution v 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 RG D Ventral Rootlets (motor) Ziconotide Dorsal Rootlets (sensory) DR G Ventral Rootlets (motor)

PHARMACOKINETICSLIPOPHILICITY Ø Moderately hydrophilic agents (such as morphine, baclofen or clonidine) concentration gradient in the CNS vcisternal CSF drug concentration is 1/3 to 1/7 that in the lumbar CSF Ø 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 Ø Bulk Flow (Circulation) Theory v CSF is produced by the choroid plexus and absorbed by the arachnoid granulations, dural sinuses, perineural sheaths v Produces CSF movement by hydrostatic pressure gradient in cranio-caudal direction Ø Pulsatile Flow Theory v 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, 2 nd Edition. © 2009 Saunders.

PULSATILE FLOW Ø Recent insights by phase contrast MR techniques have…. v Validated pulsatile flow as the major locomotive for CSF flow v To and fro motion has been characterized by numerous authors Ø Influenced by pressure volume relationships with proposed engines including v v cardiac cycle intrathoracic and intraabdominal pressures Ø Although Bulk flow likely occurs, its effects are negligibleestimates of 0. 4%

P-V RELATIONSHIP v Monro-Kellie Doctrine q Newtonian fluid in compliant space within rigid case q Pressure Volume Relationship q 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 Cerebrospin Fluid Pulsations: a phase-contrast MR analysis. Magnetic Resonance Imaging. 2000 (1

OSCILLATORY CSF FLOW End of cardiac cycle R phase Early Systole Henry-Feugeas MC, Idy-Peretti I, Baledent O et al. Origin of Subarachnoid Cerebrospin Fluid Pulsations: a phase-contrast MR analysis. Magnetic Resonance Imaging. 2000 (1

OSCILLATORY CSF FLOW Ø Spinal CSF pulsations v mainly arterial in origin v direct transfer of spinal vascular pulsatile pressure Ø No continuous downward progression of the onset of CSF systole was detected from the craniocervical junction to the thoracolumbar study v Variable arterial supply of mid cord Henry-Feugeas MC, Idy-Peretti I, Baledent O et al. Origin of Subarachnoid Cerebrospin Fluid Pulsations: a phase-contrast MR analysis. Magnetic Resonance Imaging. 2000 (1

CSF OSCILLATORY FLOW Ø Influence of Respiration v. CSF pulsation was high in the anterior cervical and in the thoracolumbar spine v. Respiratory influence rose caudad spine q 19% at C 1 vs. 28% at T 12 v. 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” Ø Cranial Motor v Arterial cardiac pulsations > respirations displacing CSF v Bidirectional, with interindividual differences in magnitude and location Ø Lumbar Motor v Arterial cardiac pulsations < respirations Filling epidural veins displacing CSF v 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 Ø Extent of CSF pulsation is dependent on many factors, including v Age v Ambulation v CSF volume Shin BS, Kim CS, Sim WS et al. A Comparison of the Effects of Preanesthetic Administra of Crystalloid Verus Colloid on Intrathecal Spread of Isobaric Spinal Anesthetics and Cerebrospinal Fluid Movement. Anesthesia and Analgesia. 2011 (112)4: 924 -30. Stoquart-El. Sankari S, Baledent O, Gondry-Jouet C et al. Aging effects on cerebral blood f and cerebrospinal fluid flows. Journal of Cerebral flow and metabolism. 2007. (27): 1563 -1

CSF OSCILLATORY FLOW Ø CSF space is heterogeneous space: v Outgoing nerve roots and various membranous elements v Has a nonhomogenous annular volume q Enhanced fluid space in the cervical and lumbar region q Reduced cross sectional diameter in the thoracic space Hansen: Netter’s Clinical Anatomy, 2 nd 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 Ø 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 Spinal Subarachnoid Space. Journal of Biochemical Engineering 2006. Vol 128, 106 -1

CSF OSCILLATORY FLOW Ø CSF may be a POORLY MIXED system v Known concentration gradients exist q Homovanillic acid concentrations o 6 x higher in cisternal CSF as compared to lumbar CSF q Uric acid concentrations o 2 x higher in lumbar than cisternal CSF v CSF motion propelled in opposite directions cyclically v Areas along the spine with no measurable CSF flow v Limited circumferential 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 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 2 O 2 = intermediate group of substances such as organic acids 3 = 3 H-Inulin Diagram of CSF Hydrodymanics Bulat M, Klarica M. Recent insights into the hydrodymanics of the cerebralspinal flui Brain Research Reviews 65(2011): 99 -112

CSF OSCILLATORY FLOW >

CSF PHARMACOKINETICS: WHY SO CHALLENGING? Ø Requires delivery of a substance and data sampling at different sites and time points Ø Inherently, intrathecal drug delivery has barrier associated with multiple sampling sites along the craniocaudal axis Ø Potential for neural toxicity of intrathecal agents Ø 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 Ø 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 Ø Bolus drug studies may not be applicable to chronic intrathecal drug delivery Ø 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 -7

PHARMACOKINETIC INSIGHTS Ø Vertical Pig Model (n=19) with multiple dialysis probes (8) v Anterior and Posterior placement along spine v Anesthetized, paralyzed, controlled conditions Ø Infusion rates of v 20μL/hr (0. 48 m. L/day)-typical IDDS delivered volume v 1 m. L/hr (24 m. L/day) v 1 m. L bolused over 5 minutes every hr (24 m. L/day) Ø Isobaric Baclofen (2 mg/m. L) 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 -7

PHARMACOKINETIC INSIGHTS Ø 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 -7

PHARMACOKINETIC INSIGHTS Bupivacaine Concentration 20 μL/hr rate 1 m. L/hr rate 1 m. L/hr bolused Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and Bupivacaine during slow intrathecal infusion in Pigs. Anesthesiology 2006; 105: 169 -

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 -

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 Ø Recent animal studies suggest: v Limited drug distribution following intrathecal administration at slow infusion v Drug distribution at very low continuous rates is affected by baricity v 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 Ø Resident time within the CSF dramatically affects drug distribution within the CSF and exposure to the spinal cord Ø Competing active site vs. extraspinal sites Ø hydrophobicity exposure to the spinal cord Ummenhofer WC, Arends RH, Shen DD et al. Comparative Spinal Distribution and Cle of Intrathecally Administered Morphine, Fentanyl, Alfentanil, and Sufentanil. Anesthesiology 2000; 92: 739 -53.

PHARMACOKINETIC INSIGHTS Ø What Drives Intrathecal Drug Distribution? v Diffusion (Brownian movement) q Very slow v CSF Bidirectional Motion v Kinetic Energy of Injectate q Volume and rate of injection v Resident times within the CSF q Physiochemical properties q Redistribution out of CSF q Amount of medication deposited

ITB FLOW RATE CRPS ø 14 patients with CRPS-Dystonia øRandomized DB: 0. 75 mg/ml or 3 mg/ml Ø 4 x Infusion Rate v. No improvement in NRS or Dystonia v 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 ø 20 patients with stable IDDS øRandomized DB: 1 x, 2 x or 4 x the flow rate Ø VAS did not significantly change Ø QOL with ’g flow rate (EQ-5 D) v Due to pain and anxiety dimension of EQ-5 D 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 Ø Volume Ø Concentration Ø Dose Ø Speed of Delivery Ø Site of Injection Ø Baricity Ø Lipid Solubility

PHARMACOKINETIC INSIGHTS Ø Conclusion: v Studies suggest placement of the Intrathecal Catheter tip at the anatomic level concordant with desired effect v Posterior location may be more desirable than anterior location to treat pain v Consideration of the drug’s physiochemical properties may be important v Increased dose (or concentration) may increase spread

PHARMACOKINETIC FAILURE? Ø Anecdotal evidence of desired effect after drug delivery by bolus (trial) with less efficacy following slow intrathecal delivery Ø 40% of patients failed to demonstrate clinical improvement with intrathecal infusion despite doses of 1 mg/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? Ø Granuloma Formation saline morphine hydromorphone Allen JW, Horais KA, Tozier NA et al. Opiate Pharmacology of Intrathecal Granuloma Anesthesiology 2006; 105: 590 -598.

CONCLUSIONS Ø CSF moves in bidirectional pattern via cranial and lumbar engines with very limited bulk flow Ø Intrathecal space is poorly mixed environment Ø Increased resident times within the CSF improve ability to distribute within the CSF Ø Despite pharmacokinetic knowledge inadequacies, IT therapy is efficacious