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On the dispersion of a drug delivered intrathecally in the spinal canal

Published online by Cambridge University Press:  27 December 2018

J. J. Lawrence
Affiliation:
Department of Mechanical and Aerospace Engineering, University of California San Diego, USA
W. Coenen
Affiliation:
Department of Mechanical and Aerospace Engineering, University of California San Diego, USA
A. L. Sánchez*
Affiliation:
Department of Mechanical and Aerospace Engineering, University of California San Diego, USA
G. Pawlak
Affiliation:
Department of Mechanical and Aerospace Engineering, University of California San Diego, USA
C. Martínez-Bazán
Affiliation:
Department of Mechanical and Mining Engineering, University of Jaén, Spain
V. Haughton
Affiliation:
Department of Radiology, University of Wisconsin, USA
J. C. Lasheras
Affiliation:
Department of Mechanical and Aerospace Engineering, University of California San Diego, USADepartment of Bioengineering, University of California San Diego, USA
*
†Email address for correspondence: als@ucsd.edu

Abstract

This paper investigates the transport of a solute carried by the cerebrospinal fluid (CSF) in the spinal canal. The analysis is motivated by the need for a better understanding of drug dispersion in connection with intrathecal drug delivery (ITDD), a medical procedure used for treatment of some cancers, infections and pain, involving the delivery of the drug to the central nervous system by direct injection into the CSF via the lumbar route. The description accounts for the CSF motion in the spinal canal, described in our recent publication (Sánchez et al., J. Fluid Mech., vol. 841, 2018, pp. 203–227). The Eulerian velocity field includes an oscillatory component with angular frequency $\unicode[STIX]{x1D714}$, equal to that of the cardiac cycle, and associated tidal volumes that are a factor $\unicode[STIX]{x1D700}\ll 1$ smaller than the total CSF volume in the spinal canal, with the small velocity corrections resulting from convective acceleration providing a steady-streaming component with characteristic residence times of order $\unicode[STIX]{x1D700}^{-2}\unicode[STIX]{x1D714}^{-1}\gg \unicode[STIX]{x1D714}^{-1}$. An asymptotic analysis for $\unicode[STIX]{x1D700}\ll 1$ accounting for the two time scales $\unicode[STIX]{x1D714}^{-1}$ and $\unicode[STIX]{x1D700}^{-2}\unicode[STIX]{x1D714}^{-1}$ is used to investigate the prevailing drug-dispersion mechanisms and their dependence on the solute diffusivity, measured by the Schmidt number $S$. Convective transport driven by the time-averaged Lagrangian velocity, obtained as the sum of the Eulerian steady-streaming velocity and the Stokes-drift velocity associated with the non-uniform pulsating flow, is found to be important for all values of $S$. By way of contrast, shear-enhanced Taylor dispersion, which is important for values of $S$ of order unity, is shown to be negligibly small for the large values $S\sim \unicode[STIX]{x1D700}^{-2}\gg 1$ corresponding to the molecular diffusivities of all ITDD drugs. Results for a model geometry indicate that a simplified equation derived in the intermediate limit $1\ll S\ll \unicode[STIX]{x1D700}^{-2}$ provides sufficient accuracy under most conditions, and therefore could constitute an attractive reduced model for future quantitative analyses of drug dispersion in the spinal canal. The results can be used to quantify dependences of the drug-dispersion rate on the frequency and amplitude of the pulsation of the intracranial pressure, the compliance and specific geometry of the spinal canal and the molecular diffusivity of the drug.

Information

Type
JFM Papers
Copyright
© 2018 Cambridge University Press 
Figure 0

Figure 1.Schematic view of the spinal canal, with indication of the curvilinear coordinates used in the analysis and the most common injection route in ITDD procedures; adapted from Sánchez et al. (2018).

Figure 1

Figure 2.A schematic view of the model geometry used in the numerical evaluations (a) and the associated distributions of Lagrangian velocity components at different sections $x$ for $\unicode[STIX]{x1D6FD}=0.5$, $\unicode[STIX]{x1D6FC}=3$, $k=0.5$ (b).

Figure 2

Figure 3.(a) Maps show the distributions of the width-averaged axial and azimuthal Lagrangian velocity components for $\unicode[STIX]{x1D6FD}=0.5$, $\unicode[STIX]{x1D6FC}=3$ and $k=0.5$, while (b) shows the parametric variation of their root-mean-square values $\Vert \!\int _{0}^{1}u_{L}\,\text{d}\unicode[STIX]{x1D702}\Vert$ and $\Vert \!\int _{0}^{1}w_{L}\,\text{d}\unicode[STIX]{x1D702}\Vert$, with the dots indicating the values corresponding to the distributions shown in (a).

Figure 3

Figure 4.The distributions of the Taylor diffusivities for $\unicode[STIX]{x1D6FD}=0.5$, $\unicode[STIX]{x1D6FC}=3$, $k=0.5$ and $S=1$.

Figure 4

Figure 5.The parametric variation of the root-mean-square values of the Taylor diffusivities, with the dots indicating the values corresponding to the distributions shown in figure 4.

Figure 5

Figure 6.Distributions of width-averaged concentration $\int _{0}^{1}c_{0}\,\text{d}\unicode[STIX]{x1D702}$ at different instants of time as obtained numerically for $\unicode[STIX]{x1D6FD}=0.5$, $\unicode[STIX]{x1D6FC}=3$ and $k=0.5$ by integration of (3.9) with $\unicode[STIX]{x1D70E}=10$ (a) and $\unicode[STIX]{x1D70E}=1$ (b), by integration of (3.13) (c) and by integration of (3.33) with $S=1$ (d). The axial distribution of the average concentration at each canal section $\int _{0}^{1}\bar{h}\int _{0}^{1}c_{0}\,\text{d}\unicode[STIX]{x1D702}\,\text{d}s$ is indicated along the right side of each panel.

Figure 6

Figure 7.The variation with time of the solute flux $\unicode[STIX]{x1D719}_{c}(\unicode[STIX]{x1D70F})$ at three different sections $x=(0,0.25,0.5)$ for $\unicode[STIX]{x1D6FD}=0.5$, $\unicode[STIX]{x1D6FC}=3$ and $k=0.5$. The value of $\unicode[STIX]{x1D719}_{c}$ for $S=1$ (thin dot-dashed curves) and $S=50$ (thick dot-dashed curves) was evaluated from (3.36), whereas that for $1\ll S\ll \unicode[STIX]{x1D700}^{-2}$ (thick solid curves) was evaluated from (4.2) and that for $\unicode[STIX]{x1D70E}=\unicode[STIX]{x1D700}^{2}S=1$ (thick dashed curves) and $\unicode[STIX]{x1D70E}=\unicode[STIX]{x1D700}^{2}S=10$ (thin dashed curves) was evaluated from (3.11).

Figure 7

Figure 8.The evolution of the solute concentration in a concentric canal ($\unicode[STIX]{x1D6FD}=0.0$) obtained for $\unicode[STIX]{x1D6FC}=6$, $k=1$ and $S=1$. (a) Instantaneous spatial distributions at six instants of time. Each panel shows on the left the concentration $c(x,\unicode[STIX]{x1D702},t)$ obtained from integration of (B 2) for $\unicode[STIX]{x1D700}=0.02$, with the corresponding width-averaged value $\int _{0}^{1}c\,\text{d}\unicode[STIX]{x1D702}$ (red solid line) compared on the right with the value of $c_{0}(x,\unicode[STIX]{x1D70F})$ obtained from the simplified transport equation (B 3) (thick dashed line). (b) Comparison of the temporal evolution of the width-averaged value $\int _{0}^{1}c\,\text{d}\unicode[STIX]{x1D702}$ at $x=0.65$ obtained from (B 2) for $\unicode[STIX]{x1D700}=0.02$ (pink) and $\unicode[STIX]{x1D700}=0.1$ (purple) with the value of $c_{0}(x=0.65,\unicode[STIX]{x1D70F})$ (black) determined from (B 3).

Figure 8

Figure 9.Results of integrations of (B 2) for $\unicode[STIX]{x1D700}=0.02$, $\unicode[STIX]{x1D6FC}=6$, $k=1$ and different values of $S$. (a) Concentration fields $c(x,\unicode[STIX]{x1D702},t)$ at $t/(2\unicode[STIX]{x03C0})=125$. (b) Time evolution of $\unicode[STIX]{x0394}c=\int _{0}^{1}\int _{0}^{1}(c-c_{i})^{2}\,\text{d}\unicode[STIX]{x1D702}\,\text{d}x/\!\int _{0}^{1}\int _{0}^{1}(c_{i})^{2}\,\text{d}\unicode[STIX]{x1D702}\,\text{d}x$.