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A Spinal Cord Model for Studying Diffusion and Enhanced Mixing of a Dye

Permanent Link: http://ufdc.ufl.edu/UFE0025071/00001

Material Information

Title: A Spinal Cord Model for Studying Diffusion and Enhanced Mixing of a Dye
Physical Description: 1 online resource (63 p.)
Language: english
Creator: Merta, Nika
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2009

Subjects

Subjects / Keywords: dye, spinal, spread
Mechanical and Aerospace Engineering -- Dissertations, Academic -- UF
Genre: Aerospace Engineering thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Currently doctors and researchers are working on finding the proper dosage and spinal injection site for baclofen, a muscle relaxant, which is commonly used in people with multiple sclerosis. This anesthetic affects the respiration of patients, and hence the dosage and drug dispersion location is critical. There has been no previous information describing the way pulsatile movement enhances anesthetic diffusion and whether the nerve rootlets have a factor in its enhanced mixing. This study specifically focuses on constructing a fluid test model as close to in-vitro conditions as possible in order to observe whether pulsatile motion could enhance a dye?s diffusion; and whether nerve rootlets could play a factor in enhanced mixing. This study is a building block for future studies to help prescribe the amount of dosage required, and the length of time required for obtaining the proper spinal level of need. In this way toxic level of anesthesia can be prevented.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Nika Merta.
Thesis: Thesis (M.S.)--University of Florida, 2009.
Local: Adviser: Tran-Son-Tay, Roger.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2009
System ID: UFE0025071:00001

Permanent Link: http://ufdc.ufl.edu/UFE0025071/00001

Material Information

Title: A Spinal Cord Model for Studying Diffusion and Enhanced Mixing of a Dye
Physical Description: 1 online resource (63 p.)
Language: english
Creator: Merta, Nika
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2009

Subjects

Subjects / Keywords: dye, spinal, spread
Mechanical and Aerospace Engineering -- Dissertations, Academic -- UF
Genre: Aerospace Engineering thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Currently doctors and researchers are working on finding the proper dosage and spinal injection site for baclofen, a muscle relaxant, which is commonly used in people with multiple sclerosis. This anesthetic affects the respiration of patients, and hence the dosage and drug dispersion location is critical. There has been no previous information describing the way pulsatile movement enhances anesthetic diffusion and whether the nerve rootlets have a factor in its enhanced mixing. This study specifically focuses on constructing a fluid test model as close to in-vitro conditions as possible in order to observe whether pulsatile motion could enhance a dye?s diffusion; and whether nerve rootlets could play a factor in enhanced mixing. This study is a building block for future studies to help prescribe the amount of dosage required, and the length of time required for obtaining the proper spinal level of need. In this way toxic level of anesthesia can be prevented.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Nika Merta.
Thesis: Thesis (M.S.)--University of Florida, 2009.
Local: Adviser: Tran-Son-Tay, Roger.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2009
System ID: UFE0025071:00001


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1 A SPINAL CORD MODEL FOR STUDYING DIFFUSION AND ENHANCED MIXING OF A DYE By NIKA JANET MERTA A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR TH E DEGREE OF MASTE R OF SCIENCE UNIVERSITY OF FLORIDA 2009

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2 2009 Nika Janet Merta

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3 To my Mom, Dad, Lindsay, Kendra and Craig for believing in me

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4 ACKNOWLEDGMENTS I would like to thank my parents and family for th e encouragement and suppor t they have given me to accomplish my goals I would also like to thank the members of my supervisory committee : Dr. Roger Tran SonTay, Dr. Malisa Sartinoranont, and Dr. David Hahn for their guidance throughout this opportunity. I would also like to thank the members of our lab who have provided me with recommendations, and advice. I thank everyone whole heartedly.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................................... 4 LIST OF TABLES ................................................................................................................................ 7 LIST OF FIGURES .............................................................................................................................. 8 LIST OF ABBREVIATIONS ............................................................................................................ 10 ABSTRACT ........................................................................................................................................ 11 INTRODUCTION .............................................................................................................................. 13 Objective ...................................................................................................................................... 13 Specific Aims .............................................................................................................................. 14 BACKGROUND ................................................................................................................................ 16 Anatomy ....................................................................................................................................... 16 Meninges .............................................................................................................................. 16 Spinal Cord ........................................................................................................................... 17 Nerve Roots .......................................................................................................................... 18 Nerve Rootlets ..................................................................................................................... 18 Cerebrospinal Fluid ............................................................................................................. 21 Spinal Cord Level vs. Functions ................................................................................................ 21 INTRATHECAL DRUG DELIVERY .............................................................................................. 23 Procedures .................................................................................................................................... 23 Cephalic Distribution .................................................................................................................. 23 Baricity of Anesthetics an d Patient Positioning ................................................................ 23 Hyperbaric solutions .................................................................................................... 24 Hypobaric solutions ..................................................................................................... 24 Isobaric solutions .......................................................................................................... 24 Anesthetic Temperature ...................................................................................................... 25 The Patient ........................................................................................................................... 25 Type of Catheters ................................................................................................................. 25 Volume, Dose and Concentration ....................................................................................... 26 Anesthetics ................................................................................................................................... 27 Distribution Factors ............................................................................................................. 27 Baclofen ................................................................................................................................ 27 Pumps ........................................................................................................................................... 28 MATERI ALS AND METHODS ...................................................................................................... 30

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6 Model System .............................................................................................................................. 30 Model Design .............................................................................................................................. 31 Spinal Cord ........................................................................................................................... 32 Subarachnoid Space ............................................................................................................. 33 Nerve Rootlets ..................................................................................................................... 34 Peristaltic Pump ........................................................................................................................... 35 Model Catheter Entrance ............................................................................................................ 36 THE EXPERIMENT AND RESULTS ............................................................................................. 38 Pulsatile Flow .............................................................................................................................. 38 Model System With Nerve Rootlets and With Pulsatile Flow ................................................. 39 Model System Without Nerve Rootlets and With Pulsatile Flow ............................................ 41 Model System With Nerve Rootlets and No Flow .................................................................... 43 Model System Without Nerve Rootlets and No Flow .............................................................. 45 DISCUSSION ..................................................................................................................................... 48 Dye ............................................................................................................................................... 48 Womersley Number .................................................................................................................... 48 Velocity ........................................................................................................................................ 51 Reynolds Number ........................................................................................................................ 51 Peclet Number ............................................................................................................................. 52 FOLLOW -UP RESEARCH AND CONCLUSIONS ...................................................................... 53 Follow -Up Research ................................................................................................................... 53 Previous Procedures ............................................................................................................ 53 Ringers Solution ................................................................................................................. 53 Follow -Up Research Experiments ...................................................................................... 54 Factors Causing Different Results ...................................................................................... 54 Conclusions ................................................................................................................................. 55 APPENDIX: TABLES OF PIXEL INTENSITY VS. TIME PER SPINAL LEVEL .................... 56 L IST OF REFERENCES ................................................................................................................... 60 BIOGRAPHICAL SKETCH ............................................................................................................. 63

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7 LIST OF TABLES Table page 4 1 List of Dis tances between each spinal level ........................................................................ 33 A 1 Average Values after 4 Trails of Pixel Intensity Values vs. Time per Spinal Level for Spinal Model With Pulsatile Flow and With Nerve Rootlets. ............................................. 56 A 2 Average Values after 4 Trails of Pixel Intensity Values vs. Time per Spinal Level for Spinal Model With Pulsatile Flow and No Nerve Rootlets. ................................................ 57 A 3 Average Values after 4 Trails of Pixel Intensity Values vs. Time per Spinal Level for Spinal Model No Flow and With Nerve Rootlets. ............................................................... 58 A 4 Average Values after 4 Trails of Pixel Intensity vs. Time per Spinal Level for Spinal Model No Flow and No Nerve Rootlets .............................................................................. 59

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8 LIST OF FIGURES Figure page 2 1 Vertebrae Regions of the Spine ............................................................................................. 16 2 2 Schematic cross -section of Spinal Cord, Nerve Roots, and Mengines ............................... 17 2 3 Schematic view of Nerve Rootlets. ....................................................................................... 19 2 4 Schematic view of lower Lumbar Spine and Sacrum. ......................................................... 19 2 5 Posterior view of the Sacral Region ...................................................................................... 20 2 6 Anterior view of the Sacral Region ...................................................................................... 20 2 7 Segmental Spinal Cord Level and Functions ....................................................................... 22 3 1 Doses and Duration for local Anesthetic Solutions in Spinal Anesthesia .......................... 28 4 1 Spinal Model and System. ..................................................................................................... 31 4 2 Level Segmen ts of Spinal Model ......................................................................................... 32 4 4 View of Subarachnoid Space between Spinal Tubing and Dura Mater Tubing. ............... 34 4 5 Series of Nerve Rootlet Views ............................................................................................. 35 4 6 Typical diameter sizes for L/S Tubing .................................................................................. 35 4 7 Performance of Peristaltic Pump ........................................................................................... 36 4 8 Series of Pulsatile Pump Views ........................................................................................... 36 4 9 Catheter Entrance Port ........................................................................................................... 37 5 1 Model System With Nerve Rootlets and With Pulsatile Flow. ........................................... 40 5 2 Average Pixel intensity as a measure of the Concentration of Dye Solution as it varied with Time for each Spinal Level for the Model System With Ner ve Roots and a Pulsatile flow motion. ......................................................................................................... 41 5 3 Model System Without Nerve Rootlets and With Pulsatile Flow ....................................... 42 5 4 Average Pixel I ntensity as a measure of the Concentration of Dye Solution as it varied with Time for each Spinal Level for the Model System Without Nerve Roots and a Pulsatile flow motion. .................................................................................................. 43 5 5 Model Syst em With Nerve Rootlets and Without Pulsatile Flow. ...................................... 44

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9 5 6 Average Pixel Intensity as a measure of the Concentraion of Dye Solution as it varied with Time for each Spinal Level for the Model Sy stem With Nerve Roots and No flow. .................................................................................................................................. 45 5 7 Model System With Nerve Rootlets and No Flow .............................................................. 46 5 8 Average Pixel Intensity as a mea sure of the Concentraion of Dye Solution as it varied with Time for each Spinal Level for the Model System Without Nerve Roots and No flow motion. .............................................................................................................. 47 6 1 Portion of Annulus where the velocity profile is taken at for Figures 6 2 and 63. ........... 49 6 2 View of velocity profile for low Womersley number (W=2.3) and a highly viscous fluid. ........................................................................................................................................ 50 6 3 View of velocity profile for a high Womersley number (W= 16) and a less viscous fluid. ........................................................................................................................................ 50 6 5 View of studys displacement vs. time. ................................................................................ 51

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10 LIST O F ABBREVIATIONS C1 C7 Cervical levels T1 T12 Thoracic levels L1 L5 Lumbar levels S1 -S5 Sacral levels CSF Cerebrospinal Fluid BPM Beats Per Minute RPM Revolutions Per Minute ID Inner Diameter OD Outer Diameter m M eters Pa Pascal s Seconds d Deca R Hydraulic radius ( 2A/r ) L 2*R V velocity dynamic viscosity density angular frequency D diffusivity

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11 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requi rements for the Degree of M aster of Science A SPINAL CORD MODEL FOR STUDYING DIFFUSION AND ENHANCED MIXING OF A DYE By Nika Janet Merta August 2009 Chair: Roger Tran -Son Tay Major: A erospace Engineering A common method for treating patients with chronic pain or muscle spasticity is through intrathecal drug delivery. Intrathecal drug delivery involves the administration of pain relieving medicines directly into the spinal cord. This can be done clinically, or thr ough a programmable drug pump. Pain relieving anesthetics including m orphine and b aclofen work within the spinal cord. Di rectly injecting the anesthetic to its specific working site requires a lower dosage when compared to taking a pain reliever orally. L arger dosage s of oral medicine saturat e the body with unneeded medicin e in the process of getting to the needed site Currently doctors and researchers are working on finding the proper dosage and injection site for baclofen, which is a muscle relaxant. This drug affects the respiration of patients and hence the dosage and anesthesia dispersion location is critical T here has been few experimental studies describing the way pulsatile movement enhances anesthetic spread, flow and diffusion around the nerve rootlets within the subarachnoid space Knowledge on this f luid flow will help prescribe the amount of dosage required, and the length of time required for obtaining t he proper spinal level of need. The objective of this study is to develop an in -vitro fluid test model of the subarachnoid space, spinal cord and nerve root le t s which mimics parameters such as geometry, size and the

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12 pulsatile motion of the cerebrospinal fluid within the spinal regions. Past researchers have modeled t he spinal cord without nerve roots within the s ubarachnoid space and observed anesthetic spread in c audal or cranial directions Factor s affecting anesthetic spread include the position of the patient or the direction, size, and rate the pain reliever delivers from the catheter None of the previous model s have modeled the nerve rootlets and observ ed the resulting anesthetic spread This study specifically focuses on constructing a model as close to in-vitro conditions as possible in order to ob serve whether pulsatile motion could e nhance a dyes diffusion ; and whether nerve rootlets could play a fa ctor in enhanced mixing This study will later enable follow up flow tests involving various anesthetics in a solution similar to the cerebrospinal fluid over the nerve rootlets

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13 CHAPTER 1 INTRODUCTION Intrathecal drug delivery involves the administra tion of pain relieving drugs directly into the spinal cord region. In sertion of a catheter for i ntrathecal drug delivery usually occurs between the L5 L4 vertebrae and the catheter is inserted up to the T12 level where the anesthetic is then distributed. Ceph alad distribution verses caudal distribution of local anesthetic is depen dent on the site of injection. A higher injection site spares the lumbar -sacral reg ion from anesthetic build up [1 ]. As the local anesthetic solution is injected, it spread s initially by the displacement of the cerebrospinal fluid and by any currents created from the catheter Anesthesia is then spread due to the interplay between the densities of both CSF and the local anesthetic solution under the influence of gravity and CSF pulsati ons Amplitude of the CSF pulsations depends on the amount of cerebral arteri al inflow and venous outflow [2]. Many factors affect the spread of local anesthetics including: anesthetic volume, dose, concentration and temperature ; position of the patient ; the catheter size and tip angle ; anesthetic injection rate and finally the solutions baricity [3 4, 5 ]. I ntrathecal local anesthetic s appear to stop spreading within 20 25 min utes after injection [3 ]. Objective There has been extensive research done on t he spinal regions to understand the spread, flow, concentration, and diffusion of anesthetics within the subarachnoid space. Previous researchers have modeled the spinal cord within the subarachnoid space, and observed anesthetic spread and concentration s in caudal or cranial directions F actors which affect this spread includ e : position of the patient or the direction, size and rate the anesthesia was d istributed from the catheter. A ll previous ly constructed experimental models have modeled the spinal cord and surrounding subarachnoid space The inner nerve root let s were left out for simplicity There has

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14 been no previou s experimental study investigating pulsatile movement that may enhance anesthetic spread around the nerve rootlets This k nowledge will he lp further prescribe the amount of dosage and the length of time required for obtaining the proper spinal level when administering anesthetics to patients An anesthetic that may benefit from improved dosage and injection site is baclofen This is a musc le relaxant commonly used for patients with multiple sclerosis. This anesthetic affects the respiration of patients and hence the dosage, and anesthesia dispersion location is critical T here is a need for an in -vitro model which can mimic the spinal regi on and its inner attaching nerve root let s in order to obtain a flow distribution of the anesthetic. A flow model provides a way to test the different dosage amounts and provide better understanding of the eddects of fluid flow on intrathecal delivery. The objective of this study is to develop an in -vitro fluid test model of the subarachnoid space, spinal cord and nerve root let s which mimics parameters such as geometry, size and the pulsatile motion of the cerebrospinal fl uid within the spinal regions. This study specif ically focuses on constructing the model and observing how the pulsatile movement of a water solution could enhance a food coloring dyes transport and spread; and whether nerve rootlets could play a factor in enhanced mixing. The dye represen ts an anesthetic, and this study will later enable the follow up flow tests of various anesthetics or dyes in a solution similar to the cerebrospinal fluid as they flow over the nerve rootlets Specific Aims There are three specific aims of this thesis. Th e first specific aim is to design and build a system which models the regions of the spinal cord, inner attaching nerve root le t s, and the subarachnoid space The second aim is to simulate cerebrospinal fluid oscillations within the subarachnoid space throu gh a pumping system. The third aim is to release a dye and observe if

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15 the pulsatile movement of the fluid enhance s the dyes diffusion; and whether nerve rootlets play a factor in enhanced mixing

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16 CHAPTER 2 BACKGROUND Anatomy Meninges The five main sectio ns of the spinal cord consist of the cervical, thoracic, lumbar, sacral, and coccygeal regions (F igure 2 1 ). A total of 24 vertebrae make up these regions and when stacked together form an inside cavity called the spinal cavity [6 ]. This cavity holds the s pinal cord, nerves, and the meninges. The meninges are group of membranes whose main objective is to protect the spinal cord. The meninges con sist of: dura ma ter; arachnoid; and pia mater. The dura mater is located between the verteb rae and the arachnoid m embrane. The arachnoid membrane is next, located between the dura mater and a space called the subarachnoid space. This space is filled with cerebrospinal fluid whose main objective is to also protect the spinal cord. The pia mater membrane is located afte r this space and dir ectly next to the spinal cord (F igure 2 2 ) [7 ]. Figure 2 1. Vertebrae Regions of the Spine (Source: Hutchinson; Mallatt; Marieb.2003. A Brief Atlas of the Human Body. San Francisco. Daryl Fox (Benjamin Cummings) Figure 17. Pg 19.)

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17 Figure 2 2: Schematic cross -sect ion of Spinal Cord, Nerve Roots, and M engines (Source: Kapit, Wynn; Lawrence Elson.2002. The Anatomy Coloring Book. San Francisco. Daryl Fox (Benjamin Cummings). Ed 3: pg 77.). Spinal Cord The spinal cord measures 41 48 cm long, and extends from the foramen magnum at the base of the skull to the fir st or second lumbar vertebrae [8 ]. The cross -sectional diameter of the spinal cord varies per region and per average adult I n the cervical region the cord is around 12 mm in diam eter with the greatest expans ion at C5 [9, 10]. It is a round 8 9 mm in the th oracic and lumbar regions [9]. The spinal cord has two sets of dorsal and ventral roots attaching to it, which connect together to form one spinal nerve at the intervertebral fora men (Figure 2 3 ). The denticulate ligament provides stability against motion for the spinal cord and is located between the dorsal and ventral roots. The s pinal cord tapers to an end (conus medullaris) at the lower end of the first lumbar vertebrae.

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18 Nerve Roots There are 31 pairs of spinal nerves: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal. The first pair of spinal nerves emerges between the atlas and the skull whereas the others emerge from the spinal cavity The C1 to C 8 nerve roots lea ve the spinal canal above the corre spondingly numbered vertebrae. All the remaining spinal nerves from T1 down leave below their corresponding vertebrae [8 ]. The anterior roots area for 15 subjects ranged between 0 .6 mm to 2 mm and the posteriors roots a rea ra nges between .4 mm to 1. 9 mm [11 ]. The length of the nerve roots from the spinal cord to its vertebrae exit varies between 5 mm in the thoracic region, 60 mm in the lumbar region to 170 mm in the sacral region [12 13]. The l umbar and sacral nerve ro ots arise from the spinal cords end, conus medullaris and form bundles of root s called the Cauda Equina. The roots of the Cauda Equina are loosely enveloped by an arachnoid membrane, from which a sleeve extends to cover each nerve root as it turns to exi t its corresponding vertebrae [14 ]. The lumbar nerve roots run obliquely downward and laterally leaving under their corresponding vertebrae (Figure 2 4). Before exiting the spinal canal, t he sacral nerves d ivide in to rami with e ach ve ntral ramus emerging through a pelvic sacral foram en and each dorsal ramus emerging th rough a dorsal sacral foramen (F igures 2 -4, 2 5, 2 6 ) [14 ]. Nerve Rootlets Within the cervical and thoracic regions of the spinal cavity, the spinal nerves are split off into 6 8 dorsal and v entral rootlets These rootlets are attach ed in a 3 mm wide array fashion to each side of the spinal cord with the diameter of each rootlet having an average dimension of 0.508 mm (F igure 2 3 ) [15, 16].

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19 Figure 2 3. Schematic view of Nerve R ootlets Fig ure 2 4. Schematic view of lower Lumbar Spine and S acrum

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20 Figure 2 5 Posterior v iew of the Sacral Region (Source: Hutchinson; Mallatt; Marieb.2003. A Brief Atlas of the Human Body. San Francisco. Daryl Fox (Benjamin Cummings). Figure 21. Pg 28.) Figu re 2 6 Anterior v iew of the Sacral Region (Source: Hutchinson; Mallatt; Marieb.2003. A Brief Atlas of the Human Body. San Francisco. Daryl Fox (Benjamin Cummings). Figure 22. Pg 29.)

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21 Cerebrospinal Fluid Cerebrospinal fluid is found within the subarachnoi d space of the spinal cavity and brain serving as a cushion against shock It is produced from the choroid plexus within the brain and is circulated into the vertebral subarachnoid space The circulation of the CSF is aided by the pulsations of the choroid plexus and by the motion of the cilia of the ependymal cells and changes in brain volume which are in sync with the pulsations of the heart [17]. Upon entering the vertebral subarachnoid space, the CSF passes downward in a pulsated fashion on the posterio r side of the cord and returns upward on the anterior side of the cord exiting the subarachnoid space into the blood stream through the arachnoid granulations [10 ]. Cerebrospinal fluid is a clear, colorless Newtonian fluid with the viscosity of 0 .7 1 .0 mP a s and density range of 1.000 to1.006 g/L at 37C similar to that of plasma [ 3 18, 19]. The solution is made up of 4080 mg/dL glucose and 15 45 mg/dL of protein with lower and higher values in children and adults respectively. The CSF solution contains less than 35 mg/dL of lactate ; no red blood cells; leukocytes ranging from 0 5 / L for adult s and children and 30/L in newborns; and finally a pressure of 100180 mm H20 (8 15mm Hg) for patients lying on the ir side and 200 300 mm H20 for patients sitting up [17, 20]. The specific gravity of CSF is usually between 1.0061.009, having a pH b etween 7.30 7.36 [ 20, 21]. There is between 125 mL to 140 ml of CSF fluid within an adult b ody with 25 mL of this fluid wi thin the ventricles of the brain. CSF is produce d at a rate of 0.2 0.7 ml per minute (600700 ml per day ) and is replaced every three hours [18, 17, 22]. The flow rate of CSF is averaged 0 .7 mL/min with the amplitude of each oscillation at 4 mm in the thoracolumbar region for an average healthy adult [10, 18]. Spinal Cord Level vs. Functions The levels of the spinal cord have multiple nerves which contribute to various functions of the body. For instance, the cervical spinal nerves deal with the head and neck, diaphragm, deltoid

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22 and biceps, wrist exten ders, triceps a nd hands. The thoracic nerves concentrate on chest muscles and abdominal muscles while the lumbar nerves concentrate on leg muscles. Finally the sacral nerves deal w ith bowel and bladder movements (Figure 27) [23 ]. Figure 2 7. Segmental S pinal Cord L evel and Functions (Source: Map of the Spinal Cord. Spinal Cord Injury and Disease Resourses. 20 Feruary 2009. 3 June 2009. http://www.makoa.org/scimap.htm ).

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23 CHAPTER 3 INTRATHECAL DRUG DEL IVERY Procedures Intrathecal drug delivery involves the administration of pain relieving medicines directly into the spinal cord region. As to not puncture the spinal cord, the lower lumbar region is a good site for injections since t he adult spinal cord ends b etween levels L1 L2 [8 ] During lumbar puncture, the catheter is inserted between the L4 L5 vertebrae and delicately pushed up towards the T12 level where the anesthesia is dis per sed [8 ]. The clinical need of the patient will determine the type of anesthe tic administered with cephalic distribution desired. Cephalic Distribution Cephalic distribution, or the distribution towards the head, is the direction that anesthetics need to flow in the subarachnoid space for absorption by the spinal cord. Many factors affect cephalic distribution. Baricity of the anesthetic; p atient positioning ; anesthetic temperature; the patient him /herself ; type of catheter used ; an anesthetics volume dose, and concentration are all factors that affect cephalic distribution [3, 1 ]. Bari city of Anesthetics and Patient Positioning Bari city is defined as the ratio of the density of anesthesia, t o the density of CSF at 37C [1 ]. Anesthetic solution with the same density as CSF is termed isobaric, a higher density termed hyperbaric, and a low er density termed hyp obaric [3 ]. Bari city plays a key role in local anesthetic distribution because gravity causes hyperbaric solutions to distribute to the most dependent areas of the subarachnoid space whereas hypobaric solutions rise upward toward the non dependent are as of the subarachnoid space [1 ]. The distribution of a hyperbaric and hypobaric solution are spread due to their i nterplay between the densities of CSF and local anesthetic solution under the influence of gravity and determined fr om the patients position [ 3 1 ].

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24 H yperbaric solutions Hyperbaric solutions are formed from a solution mixed with dextrose, and can be thought of as having a sinking action Hyperbaric solutions have a max imum dis tribution height within the mid thoraci c (T6 T7) region no matter i f the patient is in the lateral or supine position [1 ]. H ypobaric solutions A hypobaric solution is anesthesia diluted in water, and is thought as ha ving a floating action [3 ]. The position of a patient during and after injectio n of hypobaric anesthetic solutions determines the distribution in the CSF. If the patient is maintained in the head up position during and after injection, the anesthetic solution will distribute in th e cephald direction, and if head d own, it will distr ibute in the caudal direction [1] The peak cephald height achieved by a hypobaric solution is within the lower thoracic region if the patient is lying down, and wit hin the upper thoracic region if the patient is sitting up [1 ]. Hyperbaric and hypobaric solutions are able to change spinal level if patient position is varied. Therefore in order to maximize cephalic distribution to the spinal segment of need, it is desired to choose the appropriate baricity in combination wit h proper patient positioning [1 ]. I sobaric solutions An isobaric solution is ideal to use since it has the same density composition as CSF. They are formed by mixing equal volumes of tetracaine 1% solution with either CSF or sterile saline 9%. Truly isobaric solutions are not affected by a patients positioning, and tend not to distribute far from the injection site Since isobaric solutions do not distribute far from the injection site, they are useful when anesthetics are needed in the lower thoracic regions [1 ]. For this study the dye so lution is isobaric, since the dye has a similar density composition to that of water.

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25 Anesthetic Temperature Anesthetic temperature is one of the factors that affect cephalic distribution. Both CSF and anesthesia exhibit a linear decrease in densit y with i ncreasing temperature [3 ]. Isobaric solutions are affected by temperature, and this should be kept in mind and adjust ed for when preparing solutions since the solution may become hypobaric. The Patient A major factor affecting the cephald distribution of a nestheti cs is the patient him/herself. Age, weight, and pregnancy are all factors that affect the distribution. When comparing two patients with a 30 year age difference between them, the older patient ha d a more longitudinal spread of anesthetics within t he subdural space The escape of anesthetics through the intervertebral foramina is decreased in o lder patients due to calcifications [1 ]. A patients weight affects th e distribution of anesthetics. Epidural fat compressing on the dural sac results in a re duction of the CSF volume, causing a greater spread of anesthetics in obese patients as to what the normal distribution would b e in an average person [3 ]. In pregnant women, the CSF density is lower, and this can cause a difference in CSF movement [3 ]. Max imum dos age of an anesthetic is al so dependent upon the patient. Age, weight, health and type of solution used affect the concentrations that are appropriate to their toxicity and a nesthesia producing qualities. The maximum dosage for a local anesthetic is between 70 mg and 500 mg for an average 154 lb patient [24 ]. Type of Catheter s Th e type of catheter used during i ntrathecal drug delivery affects the distribution of anesthetics for cephald distribution. Factors affecting distribution are as follows : tip position, injection rate, catheter size, catheter angle of insertion, and tip configuration. The direction in which you insert the tip of the catheter will result in a higher concentration of anesthetic in that

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26 direction. For example, the CSF will be more concentrated with anesthesia in the cephalad direction if the catheter was inserted in that direction verses in the caudal direction [5 ]. A catheter positioned towards the ventral wall, has concentration movements towards the ce phalad and caudal directions [5 ]. In pas t studies when comparing cath eters inserted at the same angle a larger catheter size used (28 G) resulted in a lower anesthetic concentration A smaller catheter (18 G) had higher velocities and cause d high areas of concentration and turbulent mixing [4 ]. H igh injection flow rates in past research have not been proven to increase the bulk of the flow in the cephalad direction but in fact may produce a bulk movement o f CSF and pressure changes that keep that solution near the injection site [1 3 ]. There have been no studies done on how tip position injection rate, catheter size, catheter angle of insertion, and the tip configuration of catheters affect the flow of the anesthesia There is only information known about the areas of anesthetic concentration distributed when above catheter variables are changed. Volume, Dose and Concentration The v olume, d ose, and c oncentration of the distributed anesthesia, are important factors for achieving cephalic distribution t o the needed spinal cord level However, of the three, dose is the most important factor in determining the highest spinal level achieved by a certain anesthetic. Patients g iven a larger dose of anesthesia despite concentration and volume achieve d a higher spinal level than those give n a lower dose [1 ]. This is important in determining the proper injection site and dosage for a given anesthetic. For instance, baclofen is a muscle relaxant and affects the respiratory system of patients The given dosage could be too large and become tox ic for the patient while at the same time mov ing to an unwanted spinal level and affecting the respiratory system. Thus volume, dose and concentration are important factors w hen determining anesthetic distribution

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27 Anesthetics Distribution Factors The proper dosage and in jection site for various anesthetics are currently known for some but for others are not Previous anesthetics that have been studied already have a recommended distribution dosage and have a known peak cephalad block height The peak ceph alad block height is the highest spinal level that a given anesthetic will distribute to The d uration at the peak cephalad block height, is determined by the peak height itself. Spinal blockage with a higher cephalad block height regressed faster compared to a lower peak cephalad block distribution (F igure 3 1 ) [1 ]. Shorter duration with higher peak cephalad blockage is based on a wider distribution within the CSF resulting in lower drug concentrations throughout the CSF, as well as a larger surface area w ithin the subarachnoid space f or rapid vascular absorption [1 ]. T op up dosages are distributed after the first injection. These dosages are usually 50% of the initial dose and are distributed when the anesthesia level has receded two dermat oma l levels (F igure 3 1) Top up dosages are used to maintain the anesthesia past the expected duration time or to increas e the level of sensory block [1 ]. Local anesthetics are not metabolized in the intrathecal or epidural space. Rather, they are eliminated from the intrathecal and epidural space almost completely via vascular absorption into the systemic circulation. Thus, the duration of anesthesia is primarily determined by the rate of systemic absorption, which is influenced by the physiochemical propertied of the individual local anesthetics, as well as the site of administration, which in the case of intrathecal and epidural anesthesia also dete rmines the administered dose [1 ]. After absorption, the anesthesia is distributed throughout the body, affecting the are a of need. Baclofen Baclofen is an anesthetic used as a muscle relaxer and as an anti -spastic agent. It is used to treat muscle spasms, pain, and stiffness caused by mul tiple sclerosis [25 ]. The best method for distributing baclofen is intrathecally, as ve ry little of the oral dose reaches the spinal fluid.

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28 Currently the do se that is distributed starts 10 mg pe r day, and can increase up to 80 mg. Exact dosage is important The o verdo se side effects are as follows: vomiting, weakness, drowsiness, slow breath ing, seizures, unusual pupil size, and coma. This whi te, odorless, crystalline powder is very soluble in methanol and can easily be distributed through a pump [26 ]. Figure 3 1. Doses and Duration for local Anesthetic Solutions in Spinal A nesthesia (Sour ce: Wong, Cynthia. Spinal and Epidural Anesthesia Ed: illustrated. McGraw Hill Professional, 2006. Pg 92 19 May, 2009. http://books.google.com/books?id=4jXkqyFJEhcC ). Pumps Anesthesia can be i njected into the body clinically with a catheter, o r through a programmable pump. A programmable pump is an electronic device that is used to distributed

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29 anesthes ia. The pump is a round and metal about the size of a hockey puck, and is surgically implante d 46 inches ben eath the skin of the abdomen [27]. Compared to a constant flow rate pump, where the same amount of anesthesia is constantly delivered into the patient, the programmable pump can be adjust ed to release different amounts of medication during different times of the day depending on the c hanging needs of the patient [27]. Programmable pumps are recommended for people with multiple sclerosis or cerebral palsy The programmable pump has a battery so its longevity is limited and when emptied, it c an be refilled by inserting a needle through the skin and into the fill port on top of the reservoir [28, 27].

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30 CHAPTER 4 MATERIALS AND METHOD S Model System The model for this study was built to represent the lumbar and thoracic regions of the spinal cord, subarachnoid space, and nerve rootl ets. The lumbar and thoracic regions were chosen to be modeled since this is the site of intrathecal drug delivery. The model design included a small diameter tube, the spinal cord, within a larger diameter tube represen t ing the s urrounding subarachnoid space. The in -vitro diameters of the lumbar and thoracic regions of the spinal cord and subarachnoid space do not vary in diameter drastically, and hence tubing was utilized to represent an averaged diameter and to give the model a nonturbulent inside lining [9 ]. The spinal cord tubing wa s divided up into segments representing level s L2 to T2 of the spinal cord. At each level twelve nerve rootlets in total were attached and represented with fishing line. Three fishing line rootlets were sown in an array fashion from the right and left dorsal laterial sulcii and ventral lateral sulcii (Figure 4 3) and then were brought together at the dura mater edge (Figure 4 5) Two holes representing the intervertebral foramen were drill ed at each spinal level 180 from each other into the outter dura mater tubing using a 5/32 drill bit. The spinal tubing with attached nerve rootlets was placed inside the clear dura mater tubing, and using a small hook, was pulled through the drilled holes To prevent leaking and movement the nerve rootlets were th en pulled through a connector. One end of the connector was inserted through the clear dura mater tubing and the other end was capped with Nalgene 50 Silicone Tubing which wrapped around to cap the connector on the same spinal level (F igure 4 1 B ). Any water lea king through the connector drip ped into the N algene tubing, and for this study few drips were observed within the Nalgene tubing.

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31 A peristaltic pumping system was used to pump water wi thin the model in a pulsatile fashion. A flexible 0 .31 diameter tube ran through the pulsatile pump. This tube was attached to the capped beaker filled with water on one side and to the model by a by by brass tee secured with hose c lamps on the other The tube was filled with water. The peristaltic pump was calibrated to run at th e average heart beat of 70 bpm. A vacuum reaction occurred within the model due to the capped beaker and top end of the model remaining opened creating the pulsatile fl o w which o ccurs within the spinal cavity (F igure 4 1 A ). A B Figure 4 1. Spinal Model and System A) Model System B) View of Model with Nalgene tubing Model Design The lumbar and thoracic regions were chos en to be modeled for this study to properly replic ate the injection procedure and dye diffusion with in the subarachnoid space. A nesthetic s h ave certain peak cephalad heights (F igure 3 1 ) most occurring under the T2 level [1 ]. Consequently, the model was chosen to represent level s from L2 to T2 to get an idea of the pulsatile f low distribution around the nerve rootlets within the subarachnoid space.

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32 Spinal Cord The spinal cord was modeled using 5/32 ID by 9/32 OD Silicon flexible t u bing, cut to a length of 7.5. The tubing was divided up into spinal leve ls ranging from where the spina l cord terminates, L2, up to T3. The tube was divided into levels which were spaced according based fr om an average spinal cord (Table 4 1) [9 ]. Each spinal level was identified with twelve nerve rootlets three protruding fr om the right and left dorsal laterial sulcii and ventral lateral sulcii (F igure 4 2, 4 3 ). A second spinal model was constructed to compare the dyes diffusion and spread of concentration without rootlets to observe their effect on mixing (Figure 4 2 B). A B Figure 4 2. Level Segments of Spinal Model A) Spinal Model With Nerve Rootlets B)Spinal Model Without Nerve Rootlets.

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33 Figure 4 3. Schematic of the Right and Left Dorsolateral Sulcii and Ventrolateral Sulcii. Table 4 1. List of Distances between each spinal level Level Distance (in) L5 L4 .275 L4 L3 .314 L3 L2 .354 L2 L1 .433 L1 T12 .472 T12 T11 .51 T11 T10 .55 T10 T9 .63 T9 T8 .71 T8 T7 .775 T7 T6 .866 T6 T5 .91 T5 T4 .75 T4 T3 .70 T3 T2 .669 Ko HY, Park JH, Shin YB, Baek SY: Gross Quantitative Measurements of Spinal Cord Segments in Human. Spinal Cord 42:3540, 2004. Figure 1d. http://www.nature.com/sc/journal/v42/n1/full/3101538a.html Subarachnoid Space Th e dura mater and arachnoid membranes are represented with a clear Tygon @ Beve rage Tubing with dimensions of 5/8 ID by 7/8 OD by 1/8 wall. The spinal cord and nerve rootlets are attached inside this tubing, leaving the space between these two tubes as the subarachnoid

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34 space (F igure 4 4 ). The distance between these t wo tubes are approximately .196 inches (5 mm) which in essence is the length of the ner ve rootlets within the thoracic region [12 ]. Figure 4 4 View of Subarachnoid Space between Spinal T ubing and Dura Mater Tubing Nerve Rootlets In -vivo, there are normally 6 8 nerve rootlets total attaching to the spinal cord at each level and when combined have a width that is 3 mm (.118) wide, the average di ameter of a rootlet was 0.508 mm [11, 16]. Thus, t he nerve rootlets were represented with fishing line having a diameter of 0.508 mm [11 ]. The model rootlets were sown through the spinal tubing in an array fashion of width 3 mm (.118) with three rootlets emerging from right and left dorsal lateria l sulc ii and ventral lateral sulcii (F igure s 4 3 4 5 ) [15 ]. Three rootlets were represented within the same space on account that the more rootlets sewn through the spinal tubing created punctures, weakening the tube, resulting in a torn tube.

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35 A B Figure 4 5 Series of Nerve Rootlet Views: A) Rootlets in Array Fashion B) Nerve Rootlets forming one nerve at the Dura Mater. Peristaltic Pump A Masterflex, Easy Load 2, model 7720062 peristaltic pump was used for this studys model The pump head (F igure 4 8 A ) in a closed operating position is 4 by 4.75 by 2.75 for width, height and diameter respectively The tubing used within the pump ( F igure 4 8 ) was a Nalgene 50 silicone tube with dimensions of .312 ID by .500 OD and 25 inches in length This tubing wa s chosen for the pump since it was a similar size t o the pumps model L/S 35 tubing (Figure 4 6 ) and allowed the normal CSF pulse amplitude of 4 mm to be mimicked within the model [10 ]. Th is pump contains fo ur stainless steel rollers which move fluid through the pump by compressing the tube during the roller revolutions and spinning the fluid out the exit of the pump (F igur e 4 7 ) Figure 4 6 Typical diameter sizes for L/S Tubing [29 ]

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36 Figure 4 7 Performance of Peristaltic Pump A B C D Figure 4 8 Se ries of Pulsatil e Pump Views: A) Pulsatile Pump B) Four roller rotor C) Tube placement within pump D) Fully secured tube within pump Model Catheter Entrance In order to observe a dye or an anesthetic flowing throughout the spinal model a catheter entranc e port was installed (F igure 4 9 A ). Simulating in -vitro conditions, the port was positioned a t the L5 L4 level of the model. A black screw was inserted within the third leg of the

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37 brass tee with an inside diameter just big enough to fit the dye injector t ube inside (F igure 4 9 C). To prevent leakage, epoxy was filled between the gaps of the dye injector and the black screw The third leg of the brass tee only creates a small gap between the pump tubing and the model tubing resulting in minimal up -flow i n t he syringe d irection When inser ting a dye within the model, a syringe can be attached to the dye injector which is inserted through the black screw and pushed up into the model. Again representing in -vitro conditions, t he dye injector tip is inserted up t o the T12 level where dispersion of the dye takes place (F igure 4 9 D E ) T he syringe is kept attached to the dye injector throughout the entire process. A B C D E Figure 4 9 Catheter Entrance Port : A) Catheter Entrance Port B) Syringe, Dye Injector, Bl ack Screw C) View of Black Screws small port. D ) Dye Injector inserted into Black Screw D) Tip of Dye injector at the T12 Spinal level

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38 CHAPTER 5 THE EXPERIMENT AND RESULTS The way pulsatile motion enhances a n isobaric dyes spread; and whether nerve ro otlets play a factor in enhanced mixing is the goal of this study Four total experiments were co mpleted to determine this goal. The first one involved a model system with nerve rootlets and pulsatile flow, while the second one involved a model system without nerve rootlets while still having the pulsatile flow. The third experiment involved the model system with nerve rootlets but with no flow, while the fourth one included the model without nerve rootle ts and no flow. Pictures were taken for each experime nt for each of the following time segments: injection time, after 15 seconds, 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, and finally 10 minutes. A center line was drawn on each of the models pictures and using a computer program, th e p ixel blue intensity was noted for each experiment at the following spinal levels: L2, T12, T10, T8, T6, T4, and T2. The closer to zero the intensity number was, the darker the blue color was. In this way, the trend of dye could be noted such that the wa y pulsatile flow enhances drug distribution and the way nerve rootlets could affect m ixing could be determined. Pulsatile Flow Given that the spinal model was modeled after average adult sizes the flow rate can manually as well as experimentally be calc ulated. The model sys tem is an annulus, there for e the volume displaced in one cycle can be calculated as V=h(Ao -Ai), where h is the max height of water for o ne pulse; Ao is the outer area ( dura mater clear tubing ) ; and Ai is the ar ea of the inside spinal t ubing. Using the values of the tubing by l etting h=4 mm, Ao be 15.875 mm and Ai be 3.96 mm the volume can be calculated as 2.437mL [10]. Experimentally, the pump tubing was filled with water, and the starting height was noted. Once the pump latch was close d and the rollers compressed the tubing within the pump, t he resulting height was noted. The change in

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39 height of water from the time when the pump latch was open to the time when it was closed provided the displaced fluid volume to fill 2.5 mL in a syringe It can be known that per pulse of the pump, about 2.5 mL of fluid wa s displaced. Model System With Nerve Rootlets and With Pulsatile Flow The model system with nerve rootlets was attached to the pulsatile pump and beaker The beaker and pump tubing were completely filled with water and the beaker was capped such that little air was trapped inside. 50 mL of water was filled with in the model The pump was turned on and ra n at a rate of 70 bpm for about 3 .5 minutes This is the time it took for the water in the tubing between the beaker and the pumps head to be moved out into the model. A ft er thi s time the vacuum effect caused the pulsati le motion to be set into effect throughout the system A solution of 10 drops of blue food coloring was mixed into 10mL of water, and 1mL (1 drop/ 1mL) of this solution was injected into the model through a syringe. The blue solution was injected slowly at the T12 spinal level, and blue dye intensity levels were noted at each spinal level during the following times: the inje ction time, after 15 seconds, 30 seconds, 1 minute, 2 minutes, 3minutes, 4 minutes, 5 minutes, and finally 10 minutes. The blue dye intensity was found from a computer program using a pixel intensity sample. For each spinal level, three pixel color sample s were taken and averaged to give the blue dye intensity at that specific level. This entire test was run 4 times and the blue dye intensity found at each spinal level with varying time was averaged This information was then used to generate graphs of pix el intensity at a given spinal level as time varies In this way the effect pulsatile motion on the solutions transport was measured ; and the effect of nerve rootlets as a factor in enhanced mixing was observed. The model with nerve rootlets and pulsatile flow had dye solution seemed completely mixed throughout the system after the 10 minute marker The final solution throughout the entire model had close to the same intensity at each spinal level and was not as concentrated as it had

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40 been at the injection site (Figure 5 1.I). The solution had been injected at the T12 level, but rose to the T10 leve l during the injection process. Due to the pulsatile movement and upward pumping direction, the solution seemed to be mixed and dye spread throughout the entire model, lowering the dye intensity in the process (F igure 5 1 ). The pulsatile movement seemed to cause mixing at the lower L1 L2 spinal levels as well having minor dye spread transport back int o the pumps tubing outside of the model around the 4 minute mar ker. The model system with nerve rootlets and pulsatile flow motion had a strong blue intensity in the lower spinal levels after the initial injection, which as time went on decreased to a more uniform intensity of blue. The higher spinal levels from T5 to T2 experienced no blue dye afte r the initial injection, but eventually saw light blue intensity levels after the first minute until finally reaching a more uniform blue intensity (F igure 5 2 ), ( Appendix A 1 ). A B C D E F G H I Figure 5 1. Model System W ith Nerve Rootlets and With Pulsatile Flow: A) Injection Site B) View after 15s C) View after 30s D) View after 1 min E) View after 2 min F) View after 3 min G) View after 4 min H) View after 5 min I) View after 10 min

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41 Figure 5 2. Average Pixel intensity as a measure of t he Concentrati on of Dye Solution as it varied with Time for each Spinal Level for the Model System With Nerve Roots and a Pulsatile flow motion. Model System Without Nerve Rootlets and With Pulsatile Flow The model system without nerve r ootlets was attached to the pulsatile pump and beaker. This experiment was set up, run, and had the collection of data similar to that of the Model System With Nerve Rootlets and With Pulsatile Flow. The model without nerve rootlets and with pulsatile fl ow did not have dye solution completely mixed throughout the system at the 10 minute marker like the model with the nerve rootlets had (F igure 5 3 ). For this model, the pulsatile motion and the upward pumping direction slowly mix ed the dye solution between the L2 to T6 spinal level s unti l dye was finally spread to the T5 level lo w ering the blue intensity level to a lighter blue color At the 4 minute marker there was more solution transport back in the pumps tubing outside of the model and was noted in th e model with nerve rootlets (F igur e 5 3 G ). The model system having no nerve rootlets had dark blue intensity levels in the lower spinal levels of T12T10 after the initial injection, with solution reaching the L1 L2 levels after 15 seconds. The higher spi nal levels from T4 to T2

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42 experienced no blue dye coloring during the 10 minutes of pumping. The concentration level along this spinal model did not spread completely or dilute to the same concentration pixel intensity (Figure 5 4 ), ( Appendix A 2) A B C D E F G H I Figure 5 3 Model System Without Nerve Rootlets and With Pulsatile Flow: A) Injection Site B) View after 15s C) View after 30s D) View after 1 min E) View after 2 min F) View after 3 min G) View after 4 min solution sinking in pump tube H) Vi ew after 5 min I) View after 10 min

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43 Figure 5 4 Average Pixel Intensity as a measure of t he Concentra t ion of Dye Solution as it varied with Time for each Spinal Level for the Model System Without Nerve Roots and a Pulsatile flow motion. Model System Wit h Nerve Rootlets and No Flow The model system with nerve rootlets was attached to the pulsatile pump and beaker. However, the pump was not turned on resulting in no flow throughout the system. This experiment was set up in a similar fashion to that of the previous two experiments. A similar dye solution was injected into the model and intensity level were obtained in a similar fashion to that of the Model System With Nerve R ootlets and With Pulsatile Flow, and Model System Without Nerve Rootlets and Wit h Pulsatile Flow. The model system with nerve rootlets and without pulsatile flow had dark blue intensity levels of dye solution in the low er spinal levels with some mixing (F igure 5 -5 ). The highest spinal level where the re was dye solution color was the T8 spinal level There was no blue color in the upper spinal levels. Due to what seemed like the lack of fluid motion and gravity, there was dye solution in the pumps tubing outside of the model. Also, t h is system had con tinuously

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44 dark intensity blue leve ls in the lower spinal levels of L2 T9 after the initial injection. There seemed to be slight mixing in this spinal model due to the initial injection. The upper spinal levels showed light blue intensities (F igure 5 6 ), ( Appendix A 3 ). A B C D E F G H I Figure 5 5 Model System With Nerve Rootlets and Without Pulsatile Flow: A) Injection Site B) View after 15s C) View after 30s D) View after 1 min E) View after 2 min F) View after 3 min G) View after 4 min H) View after 5 min I) V iew after 10 min

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45 Figur e 5 6 Average Pixel Intensity as a measure of t he Concentraion of Dye Solution as it varied with Time for each Spinal Level for the Model System With Nerve Roots and No flow. Model System Without Nerve Rootlets and No Flow The model system without nerve r ootlets was attached to the pulsatile pump and beaker. However, the pump was not turned on resulting in no flow throughout the system. This experiment was set up in a similar fashion to that of the previous three experiments. A similar dye solution was in jected into the model and intensity levels were obtained in a similar fashion to that of the Model System With Nerve Rootlets and With Pulsatile Flow, and Model System Without Nerve Rootlets and With Pulsatile Flow, and Model System With Nerve Rootlet s and No Flow. The model system with nerve rootlets but without pulsatile flow had dark blue intensity levels of the dye solution in the lower spinal levels like incomplete mixing (F igure 5 7 ). The highest spinal level that showed traces of blue color was the T6 spinal level There was no soluti on in the upper spinal levels. Due to the lack of pulsatile motion and gravity, there were high intensity levels of blue in the pumps tubing outside of the model. Th is model system had

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46 continuously dark levels of b lue concentration in the lower spinal levels of T12T9 after the initial injection, with dark intensity reaching the lower L1 L2 level slowly after 30 seconds to a minute after injectio n. The highest spinal level reached during this experiment was the T6 l evel, and th is was reached after 1 minute. There seemed to be no mixing in the model system and hence a uniform intensity blue level was not reached (F igure 5 8 ), ( Appendix A 4 ). A B C D E F G H I Figure 5 7 Model System With Nerve Rootlets and No Flow : A) Injection Site B) View after 15s C) View after 30s D) View after 1 min E) View after 2 min F) View after 3 min G) View after 4 min H) View after 5 min I) View after 10 min

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47 Figure 5 8 Average Pixel Intensity as a measure of t he Concentraion of Dye Solution as it varied with Time for each Spinal Level for the Model System Without Nerve Roots and No flow motion.

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48 CHAPTER 6 DISCUSSION The way pulsatile movement could enhance dye spread ; and whether nerve rootlets play a factor in enhanced mi xing was th e goal of this study and was determined in the above experiments. Factors that can describe the transport and mixing in the above experiments include the dye, Womersley number, flow r ate, R eynolds number, and finally the Peclet Number. Dye The blue food coloring dyes main properties consisted of water and propylene glycol. The density of propylene gl ycol is 1. 036 g/cm^3. This density is close to that of water having a density of 1.00 g/cm^3. The density of the dye was taken to be 1.036 g/cm^3, which is slightly hyperbaric to the water solution it was dispersed in. Although the dye is slightly hyperbaric, the dye is still able to flow in a similar fashion to that of water i.e. it was considered to be isobaric Womersley Number The Womersley Number rel ates the pulsatile flow frequency to the viscous effects of the fluid and can be used to describe the velocity profile of the flow (Equation 6 1). (6 1) Previous studies have shown that the Womersley number depends on a patient s spinal cord diameter. The larger the outer diameter compared to the inner diameter, and hence a bigger gap for fluid to flow, the larger the Womersley number will be. Following along the length of the spinal column the Womersley number varies from 5 to 18 in the cervical to lumbar regions respectively [18 ]. For this study, the Womersley number was computed to be 4.6: given that R hydr aulic radius taken as (2*A)/r (where A =8.68 mm^2 i s the area of the tube, and r= 3.937 mm is the radius of the outer tub ing ), was 4.41mm (distance from the spinal cor d to the outer dura

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49 mater wall) given that the fluid oscillation frequency, =7.35 rad/sec; density of the dye, 1036 kg/m^3; dynamic viscosity, =.00697 kg/s*m. This number is a good match with previous stu dies. The velocity profile can be determined from the Womersley number to later estimate the Reynolds number. For an annulus, the velocity as it relates to the radius and viscosity of the fluid is shown for one side of the annulus where the fluid flows (F igure 6 1). For low Womersley numbers and a highly viscous fluid, t he velo city profile ( letting R be the hydraulic radius R= 2A/r = (2* 8.68 mm^2 )/ ( 3.937mm ); and =.00697 kg/s*m the dynamic viscosity of the fluid), is a smooth curve (Equation 6 2, Figure 6 2 ). For higher Womersley numbers and a less viscous fluid, the velocity profile becomes blunter in the center and has slight bumps at the wall edges (Figure 6 3) V=R ^2 (6 2) Figure 6 1. Portion of Annulus where the veloci ty profile is taken at for Figures 6 2 and 6 3

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50 Figure 6 2 View of velocity profil e for low Womersley number (W=2.3 ) and a highly viscous fluid (Source: Loth, Yardimci, Alperin, Hydrodynamic Modeling of Cerebrospinal Fluid Motion Within the Spinal Cavit y. Journal of Biomedical Engineering 123: 7179, 2001). Figure 6 3 View of velocity profile fo r a high Womersley number (W= 16 ) and a less viscous fluid (Source: Loth, Yardimci, Alperin, Hydrodynamic Modeling of Cerebrospinal Fluid Motion Within the Spi nal Cavity. Journal of Biomedical Engineering 123: 7179, 2001).

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51 Velocity Some information can be determined from the velocity profile found from the Womersley number. For this studys velocity profile, due to the hornlike structures at the wall edges, the velocity is not constant. However, a constant velocity was assumed in order to find a representative velocity and Reynolds number. Knowing that the fluid inside the model was p umped at 70 B PM, to a height of 4 mm (Figure 6 5) the velocity was calculated to be a constant 560 mm/ min The f low rate was then determined to be 4.8 mL/min. Figure 6 5 View of studys displacement vs. time Reynolds Number The Reynolds Number describes the ratio of inertial forces to viscous forces; or rather it describes whether the fluid flow is laminar or turbulent letting L be twice the hydraulic radius, L= ; and =.00697 kg/s*m be the dynamic viscosity (Equation 6 3 ). A Reynolds number less than 2300 describes a laminar flow. Laminar flow is a smooth, streamline flow with no disruptions. A Reynolds number greater than 4000 is considered turbulent flow. Turbulent flow is dominated by inertial forces. Past studies have shown that the Reynolds number varies between 150 and 450 depending on the s pinal cords diameter [18 ]. For this study, the nerve rootlets were blocking the smooth pulsating flow given from the pump, and can be thought of as obstacles in the laminar flow and may be regions of higher velocity flows For this study, the

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52 Reynolds numb er for average flow was determined to be 117. This value is slightly lower than what was computed in previous studies; however this could be a result of an average velocity assumed. Re=L*V / (6 3 ) Peclet Number The Peclet number is used to determine the rate of diffusion and defines the ratio of convection to diffusion by using L = 2R=8.82, for twice the hydraulic radius; V for the velocity of the fluid, V =560 mm/min; and D= diffusivity (Equations 6 4 ). Pe= L*V/D (6 4 ) The Peclet number for this study wa s not able to be determined due to the unknown diffusivity value. Diffusivity governs how the dye concentration varies with time. For this study, concentration values were not determi ned, only the pixel blue intensity. The concentration values throughout the model need to be determined for dyes with known. To just quantity the Peclet number, the smaller the diffusivity, the larger the Peclet number will be and the smaller the diffusion of the dye. Hence if Pe >>1 the transport in convection dominates.

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53 CH APTER 7 FOLLOW -UP RESEARCH AND CONC LUSIONS Follow -Up Research The way pulsatile motion affect s a intrathecal transport; and whether nerve rootlets play a factor in enhanced mixing were noted in this study This study will later enable the follow up flow te sts involving various dyes anesthetics to determine these results. Previous Procedures Various spinal models have been built to test and observe a variety of delivery procedures and measure CSF distribution. The purpose of previous model testing was to obs erve affects of different catheter sizes, injection angles, injection flow rates, and sol ution concentration build ups. These studies incl uded important factors that need to be taken into account for affecting a solutions diffusion in follow up research e xperiments. Ringers S olution Ringers solution is a mixture of sodium chloride, potassium chloride, calcium chloride and sodium bio carbonate in concentrations that they occur in body fluids. This solution is commonly used to refill blood volume s in traum a victims [3 0 ]. Ringers solution was used in past spinal models to sim ulate the cerebrospinal fluid. This solution ha s a specific gravity of 1.005. Simulated anesthesia injected in one previous model contained distilled water, 7.5% dextrose, .84% phthaloc yanine blue dye and had a specific density of 1.047 [4 ]. Another type of anesthesia injected was a mixture of 5% lidocaine hydrochloride with 7.5% glucose, and 1% methylene blue solution with a specific gravity of 1.047 [5]. In this way similar density con centrations can be ensured in an isobaric fashion such that a factor like patient positioning has no affect on the desired data. Ringers solution used throughout the model can be used to better represent CSF.

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54 Follow -Up Research Experiments The same proce dures presented in this study can be done similar in a similar fashion to follow up research experiments only now with minor changes. As previously stated, Ringers solution can be used instead of water for the working fluid and is a good representation of CSF for in -vivo conditions The syringe used in administering the anesthesia should also be taken into account since the size of the catheter, direction and injection rate may affect the dye concentration. For more realistic injection flows during injecti on in the cephalad direction, a 28 G catheter tip with an injection rate of 0 .5 mL/sec could be desirable [4, 3 1 ]. Baclofen affects the respiratory system when the drug is at level C4 or higher. The flow model for this study can only represent the flow a mong spinal regions that conduct the abdominal, and chest muscles (T2 T12). Thus, a longer model will need to be used to study the flow of baclofen. When completing experiments, a computational model can be used to better determine the rate of transport th roughout the model in that it can take into account the varying velocity profile, which in a sense affects the rate of convection Factors C ausing D ifferent R esults When comparing water to CSF (or Ringers solution), the different compound qualities of eac h could result in different data. When observing both at 37C (98.6F), water is slightly less dense, h ypobaric, when compared to CSF. Water has a viscosity of 0 .682 mPa -s, while CSF ranges from 0 .7 to 1.0 mPa -s and hence may cause the dye to spread faster than when injected in a CSF solution or Ringers solution. While completing the follow up research experiments, the pump configuration should be taken into consideration. For this study, the spinal model was only used to show the upward pumping motion a nd diffusion of the dye in order to mimic intrathecal drug delivery. To get a

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55 better representation of the CSF fluid flow, placing the pump above the model (to represent the direction the CSF flow s from the brain) would provide a more physiological set up and backflow into the pumps tubing will be removed The spinal cord was not centered exactly in the model with the nerve rootlets and clearly was not centered in the model without the nerve rootlets. The eccentric case of the spinal cord can result in different transport and flow effects. When the spinal cord is situated closer to the dura mater tube, there is a smaller space for fluid to flow through. The velocity is higher in this small region, resulting in a nonuniform flow pattern and possibly enhanced mixing The opposite effect happens on the wider part of the eccentric spinal cord. All of these factors can be compared and taken into consideration when completing the follow up research experiments. Conclusions This study was completed in order to observe whether pulsatile motion could enhance a dyes intrathecal transport and spread ; and whether nerve rootlets could play a factor in enhanced mixing From this study it was found that pulsatile motion has prospects of enhancing a dyes intrathecal based off of the pixel blue intensity found throughout the four experiments. T he nerve rootlets also seem to have the prospects of playing a factor in the enhanced mixing, based off of less spread by the dye in the model without the nerve rootlets. The n erve rootlets and CSFs pulsatile motion are factors which seem to enhance mixing and could allow the drug to transport faster up along the spinal column. The rate of diffusion of the dye solution can be used to find the Peclet number if another dye compou nd is tested. This knowledge is an important building block to later help doctors and researchers better determine the frequency of distributing dosages such that toxic levels of anesthesia or drugs are not accumulated.

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56 APPENDIX : TABLES OF PIXEL IN TENSIT Y VS. TIME PER SPINA L LEVEL Table A 1. Average Values after 4 Trails of Pixel Intensity Values vs. Time per Spinal Level for Spinal Model With Pulsatile Flow and With Nerve Rootlets (Figure 5 2) Injection 15s 30s 1min 2min 3min 4min5min 10min L2 164.0 52.0 52.0 94.0 100.0 110.0115.0 122.0 131.0 L1 174.0 60.0 77.0 133.0 134.0 140.0150.0 151.0 159.0 T12 175.0 140.0 136.0 139.0 155.0 156.0158.0 162.0 165.0 T11 150.0 65.0 120.0 130.0 146.0 138.0141.0 150.0 160.0 T10 140.0 142.0 143.0 145.0 146.0 149.0150.0 155.0 160.0 T9 195.0 184.0 142.0 143.0 192.0 190.0148.0 143.0 141.0 T8 227.0 209.0 155.0 147.0 145.0 146.0144.0 143.0 142.0 T7 234.0 222.0 166.0 149.0 204.0 211.0155.0 151.0 150.0 T6 238.0 232.0 181.0 164.0 160.0 157.0155.0 151.0 149.0 T5 241.0 241.0 174.0 165.0 222.0 224.0166.0 165.0 164.0 T4 245.0 249.0 175.0 171.0 165.0 162.0159.0 156.0 152.0 T3 252.0 255.0 177.0 174.0 232.0 235.0172.0 172.0 170.0 T2 260.0 259.0 179.0 174.0 170.0 169.0165.0 162.0 160.0

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57 Table A 2 Average Values afte r 4 Trails of Pixel Intensity Values vs. Time per Spinal Level for Spinal Model With Pulsatile Flow and No Nerve Rootlets (Figure 5 4) Injection 15s 30s 1min 2min 3min 4min 5min 10min L2 171.0 19.0 40.0 58.0 48.0 75.0 99.0 100.0 103.0 L1 178.0 42.0 51.0 74.0 91.0 96.0 105.0 106.0 111.0 T12 179.0 74.0 59.0 71.0 99.0 100.0 106.0 110.0 112.0 T11 182.0 60.0 38.0 69.0 96.0 103.0 105.0 110.0 113.0 T10 172.0 16.0 34.0 74.0 84.0 109.0 113.0 115.0 116.0 T9 25.0 25.0 41.0 72.0 102.0 103.0 106.0 110.0 116.0 T8 30.0 70.0 71.0 84.0 99.0 112.0 116.0 118.0 121.0 T7 200.0 189.0 176.0 180.0 177.0 162.0 157.0 140.0 138.0 T6 220.0 219.0 217.0 211.0 209.0 205.0 203.0 201.0 199.0 T5 240.0 234.0 228.0 225.0 221.0 219.0 215.0 210.0 200.0 T4 230.0 227.0 233.0 213.0 210.0 207.0 205.0 204.0 203.0 T3 255.0 252.0 248.0 237.0 232.0 230.0 226.0 220.0 214.0 T2 255.0 254.0 253.0 242.0 240.0 236.0 234.0 227.0 225.0

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58 Table A 3 Average Values after 4 Trails of Pixel Intensity Values vs. Time per Sp inal Level for Spinal Model No Flow and With Nerve Rootlets (Figure 5 6) Injection 15s 30s 1min 2min 3min 4min 5min 10min L2 139.0 39.0 21.0 25.0 29.0 33.0 35.0 38.0 40.0 L1 198.0 50.0 25.0 20.0 36.0 43.0 44.0 49.0 50.0 T12 50.0 34.0 76.0 110.0 111.0 130.0 143.0 143.0 162.0 T11 78.0 60.0 78.0 131.0 139.0 191.0 208.0 212.0 211.0 T10 95.0 101.0 110.0 119.0 124.0 219.0 226.0 227.0 231.0 T9 59.0 102.0 114.0 220.0 224.0 226.0 228.0 229.0 230.0 T8 262.0 260.0 257.0 254.0 252.0 249.0 247.0 234.0 230.0 T7 270.0 252.0 251.0 250.0 250.0 249.0 248.0 244.0 236.0 T6 257.0 256.0 255.0 255.0 254.0 253.0 253.0 252.0 231.0 T5 275.0 273.0 272.0 271.0 269.0 264.0 257.0 254.0 245.0 T4 278.0 275.0 276.0 274.0 272.0 270.0 269.0 263.0 250.0 T3 294.0 291.0 290.0 289.0 288.0 286.0 285.0 280.0 250.0 T2 299.0 296.0 294.0 293.0 292.0 290.0 289.0 286.0 255.0

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59 Table A 4 Average Values after 4 Trails of Pixel Intensity vs. Time per Sp inal Leve l for Spinal Model No Flow and No Nerve Rootlets (Figure 5 8) Injection 15s 30s 1min 2min 3min 4min 5min 10min L2 178.0 136.0 54.0 49.0 97.0 100.0 103.0 123.0 125.0 L1 187.0 179.0 56.0 89.0 91.0 97.0 115.0 126.0 130.0 T12 58.0 60.0 70.0 94.0 105.0 123.0 125.0 130.0 134.0 T11 119.0 127.0 86.0 76.0 99.0 104.0 105.0 115.0 136.0 T10 208.0 162.0 78.0 92.0 93.0 86.0 106.0 128.0 135.0 T9 210.0 44.0 77.0 66.0 76.0 102.0 127.0 132.0 144.0 T8 125.0 47.0 51.0 80.0 108.0 116.0 153.0 175.0 179.0 T7 86.0 67.0 77.0 120.0 124.0 218.0 223.0 225.0 226.0 T6 73.0 91.0 106.0 136.0 154.0 226.0 227.0 230.0 233.0 T5 254.0 250.0 248.0 246.0 240.0 237.0 234.0 233.0 230.0 T4 270.0 266.0 265.0 260.0 257.0 253.0 244.0 240.0 237.0 T3 275.0 261.0 260.0 259.0 257.0 256.0 256.0 245.0 241.0 T2 280.0 264.0 263.0 259.0 253.0 251.0 249.0 243.0 240.0

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60 LIST OF REFERENCES 1 Wong, C., Spinal and Epidural Anesthesia. Ed: illustrated. McGraw Hill Professional, 2006. 9095, 2006. 19 May 2009. http://books.google.com/books?id=4jXkqyFJEhc C 2 Bhadelia, Bogdan. Kaplan, Cerebrospinal fluid pulsation amplitude and its quantitative relationship to cerebral blood flow pulsations: a phase -contrast MR flow imaging study. Diagnostic Neuroradiology 39 (4):258264,1997. 3 Hocking, G., and Wildsmith, J. A.W., Intrathecal Drug Spread. British J. of Anaesthesia 93:568578, 2004. 4 Robinson, R. A., In Vitro Modeling of Spinal Anesthesia. Anesthesiology 81: 10531060, 1994. 5 Rigler, M. L., Drasner, K. D., Distribution of Catheter injected Local Anesthetic in a model of the Subarachnoid Space, Anesthesiology 75: 684 692, 1991. 6 Hutchinson, Mallatt, Marieb, A Brief Atlas of the Human Body. San Francisco. Daryl Fox (Benjamin Cummings).1829, 66 69, 2003. 7 Kapit, W., Lawrence E., The Anatomy Coloring Book. San Francis co. Daryl Fox (Benjamin Cummings). 3: p. 77, 2002. 8 ORahilly, Muller, Carpenter, Swenson, Chapter 41: The Spinal Cord Meninges. Basic Human Anatomy 2008. 11 Dec 2008. 9 Ko H.Y., Park J.H., Shin Y.B., Baek S.Y., Gross Quantitative Measurements of Spinal Cord Segments in Human. Spinal Cord. 42:3540, 2004. 5 Dec 2008. http://www.nature.com/sc/journal/v42/n1/full/3101538a.html 10. Yaksh, T., Spinal Drug Delivery. Amsterdam, The Netherlands: Elsevier Science B.V.1999. 1:106111. 1999. 11. Sunderland S., Bradley K.C., Stress -strain phenomena in human spinal nerve roots. Brain 84: 120124, 1961. 12. Tarlov I. M., Structure of nerve roots: Nature of the junction between the central and peripheral nervou s system. Arch Neurol Psychiat 37: 555853, 1937. 13. Rydevik, B., Brown, M.D., Lundborg, G., Pathoanatomy and pathophysiology of nerve root compression. Spine 9: 715 1984. 14. Stewart, J., Focal Peripheral Neuropathies. New York, New York: Raven Press, Ltd. 2: 2 61263, 1993. 15. Parke, W.W & Watanabe, R., The intrinsic vascular supply of the lumbaosacral spinal nerve roots. Spine 10: 508515, 1985.

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61 16. Spinal Cord. 2009. AbsoluteAstronomy.com. 11 June 2009. http://www.absoluteastronomy.com/topics/Spinal_cord. 17. Agamanolis, D.,Chapter 14 The Normal CSF. December 2008. Neuropathology. 8 June 2009. http://www.neuropathologyweb.org/chap ter14/chapter14CSF.html 18. Loth, Yardimci, Alperin, Hydrodynamic Modeling of Cerebrospinal Fluid Motion Within the Spinal Cavity. Journal of Biomedical Engineering 123: 7179, 2001. 19. Bilston, L., Effects of Proteins, Blood Cells and Glucose on the Viscosity of Cerebrospinal Fluid. Pediatric Neurosurgery 28:246251, 1998. 20. Cerebrospinal Fluid (CSF) Analysis. Surgery Encyclopedia. 2009. Answers Corporation. 1 June 2009. http://www.answe rs.com/topic/cerebrospinal -fluid -csf analysis 21. Mitchell, R.A., Carman, C.T., Severinghaus, J.W., Richardson, B.W., Singer, M.M., Shnider, S., Stability of cerebrospinal fluid pH in chronic acid -base disturbances in blood. J Appl Physiol. 20:443452, 1965. http://jap.physiology.org/cgi/content/abstract/20/3/443. 22. Carlson, N., Cerebrospinal Fluid. Physiology of Behavior 6:1998. 8 June 2009. http://everything2.com/title/cerebrospinal%2520fluid 23. Spinal Cord Injury and Disease Resourses, Map of the Spinal Cord. 20 Feruary 2009. 3 June 2009. http://www.makoa.org/scimap.htm 24. Spil ler, M., Toxicity, How Much is too Much?. 2000. 16 June, 2009. http://www.doctorspiller.com/local_anesthetics 3.htm 25. Baclofen. 20002009. Drugs.com. 2 June 2009. http://www.drugs.com/baclofen.html 26. Kemstro. 2009. RxList Inc. 3 June 2009. http://www.rxlist.com/kemstro -drug.htm 27. Intrathecial Drug Pump. April 2009. Mayfield Clinic. 5 June 2009. http://www.mayfieldclinic.com/PEPUMP.htm 28. Advantages of programmable Pumps. 1 April 2009. ChronicPainConnection.com. 2 June 2009. http://www.healthcentral.com/chronic -pain/neurostimulation andpain pumps 13009109.html 29. Masterflex FAQ. Cole-Parmer Technical Library.4 June 2009. http://www.coleparmer.com/techinfo/techinfo.asp?htmlfile=Tubing_LS Options.htm&ID=772. 30. Bhadelia, Bogdan, Kaplan, Wolpert. Cerebrospinal fluid pulsation amplitude and its quantitative relationship to cerebral blood pulsations: a phase contrast MR flow imaging study. Neuroradiology 39: 258264, 1997 http://www.springerlink.com/content/rarpcvcuac1r27n1/fulltext.pdf?page=1

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62 31. Ringers Solution. Encyclopedia Britannica. 2009. 16 June 2009. http://www.britannica.com/EBchecked/topic/504086/Ringers -solution 32. Atchison S., Wedel D., Wilson P., Effect of Injecti on rate on level and duration of hypobaric spinal anesthesia. Anesth Analg. 69:496 500, 1989.

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63 BIOGRAPHICAL SKETCH The author was born in Jacksonville North Carolina in the year 1985 as the second daughter in her family Living there briefly, she and her family moved to Denver Colorado where her second sister was born. Three years later at the age of 5, she moved to Virginia and stayed there until the age of 11 where she and her family then moved to Jacksonville Beach, Florida. It was here that the author grew up spending her time in her stud ies and athletics, havi ng a strong interest in the National Aeronautics and Space Administration In May of 2007 she obtain ed a Bachelor of Science degree in p hysi cs at the Universi ty of Florida Shortly thereafter she began working on a masters d egree in the Mechan ical and Aerospace Engineering D epartment. The author enjoys marathons with her family, swimming, and biking. She has hopes of hiking th e Appalachian Trail with her pare nts completing an Iron Man, and will always be reaching for the moon.