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2. Factors Affecting Drug Distribution Through Infusion
by The Infusion Physics Study Group*
05-18-09
Convection Enhanced Delivery (CED) is a technique used to distribute drugs inside the
brain parenchyma using pressure to cause the movement of infused fluid.1 While this
technique does distribute large molecules much further than diffusion alone could do, its
application has been limited because the extent and shape of distribution are variable.
Understanding and reducing the causes of such variability was the purpose of this study.
Previous in vivo experience has shown that the most common departure from ideal
infusion distribution was backflow along the outer surface cannula. (Figure 1a shows an
image of a good infusion and Figure 1b shows an image of an infusion with significant
backflow.) Backflow takes place whenever it is easier for the fluid to travel along an
annular space created between the outer surface of the catheter and the surrounding
medium than out through the pores of the media.
We systematically studied the physics of infusion in gels and attempted to determine the
conditions that contributed to variability. We then tested the applicability of these
findings in vivo. Each experiment was performed at least three times, maintaining the
same conditions, in order to evaluate reproducibility. In total, over 300 experiments were
performed.
This study was based on the hypotheses that
1. Infusion into a uniform and isotropic medium leads to a spherical infusate
distribution,
and
2. Whenever the medium is either non-uniform or non-isotropic, the infusion will
depart from the spherical distribution, often in unpredictable ways.
No single technique ensures reproducibility. Instead some of the techniques increased the
margin for error in the system.
The experiments focused on five key subjects:
(1) Effect of cannula insertion techniques
(2) Effect of using a stepped cannula design
(3) Effect of a prior cannula track in the surrounding medium
(4) Effect of using pulsatile flow
(5) Infusion pressure as a real-time monitor
Experimental methods are described in the Appendix.
Effect of cannula placement technique:
The method of insertion itself can have a significant effect on variability of the infusion
due to the seal of the gel around the catheter. We evaluated various techniques that have
been used in prior work. Figure 2 shows the three insertion modes that were evaluated.
Figure 2a shows the results obtained when the catheter was inserted into the gel while it
was still in liquid form and then allowed to solidify around the catheter. Good spherical
distribution with no backflow was observed in 5 or 6 experiments. In contrast, if after
allowing the gel to solidify around the catheter, and then lifting the catheter 3mm and
then “re seating” it to its original position (to break the seal between the gel and the
catheter), we observed backflow of approximately 17 mm every time. (see Figure 2B)
The third method used to insert the catheter consisted of first allowing the gel to solidify
and then inserting the catheter into the solidified gel. As can be seen in Figure 2c, this
method provided the most variability. Nevertheless, this mode was chosen for most
experiments since it is the most realistic insertion mode for in vivo experiments.
Smooth insertion was an important factor in minimizing backflow. Even a slight lateral
movement of the catheter could provide a low resistance path for backflow. Sometimes
these movements were too small to be visible by the naked eye, necessitating the use of a
video monitor for observation. For most experiments, a mechanical introducer was used
to insert the catheter in a consistent manner.
Inserting the catheter into the gel often causes small cracks to from around the catheter.
Figure 3a shows the typical backflow at room temperature when the gel is constrained in
a plastic cube. This problem can be minimized by raising the temperature of the gel to
body temperature by suspending it in a heated bath and removing the gel from the plastic
cube. This set up is called “unconstrained gel at temperature”. Backflow in such cases is
more typical of backflow in tissue and is shown in Figure 3b.
Effect of using a stepped design: A catheter disturbs the surrounding medium by displacing some of it while being
inserted. Catheters with a smaller outside diameter will cause less displacement than
those with a larger gauge.
A cannula has to be rigid enough to allow successful in vivo insertion. A step design can
give most of the catheter sufficient structural rigidity to allow it to be inserted into a gel
or the brain tissue while minimizing the displacement of the material in the target region
by the use of a step. The step can also help hinder any backflow starting at the cannula
tip. Such a step is illustrated in Figure 4.
Figure 2b shows 15-17mm of backflow which was consistently observed using a
standard straight catheter. Figure 5 shows results obtained using the step catheter. The
step completely stops the backflow in 3 of the 4 cases and impedes the backflow in the
other case at this flow rate.
Figure 6 shows the effect of the step at different flow rates. At low flow rates the
backflow does not reach the step. At intermediate flow rates the step impedes backflow,
but if the flow rate is high enough, the backflow overcomes the step.
Figure 7 shows the effect of the step in vivo with no backflow observed above the step,
either early on or later in the course of the infusion.
The effect of a prior catheter track in the surrounding medium:
In-vivo experiments had shown that tissue damage from a previous cannula track can
provide a low resistance path for the infusate. The top image in Figure 8 shows the
previous catheter track as well as the current catheter. The bottom of Figure 8 shows the
infusion cloud as it is diverted by the prior catheter track.
This condition was replicated in a gel experiment by inserting and then removing a
cannula adjacent to the current catheter. As shown in Figure 9, the irregularity in the
medium presents less resistance to flow and results in a preferential flow path for the
infusate.
Effect of Pulsatile Flow:
Backflow may be looked at as a result of competition between two paths for the fluid
flow: one, through the pores of the surrounding medium, and the other, along an annulus
surrounding the catheter. If these two paths had different elastic behaviors, they would
respond differently to pulsed flow: one path may open more rapidly than the other when
the fluid pressure is increased in a step-wise manner.
We tested the dynamic (time-dependent) characteristics of the two paths by employing
periodic pulsing of the pressure. Typically, the pressure was on for 1-2 seconds and off
for 8- 9, and this cycle was repeated every 10 seconds.
Gel results are shown in Figure 10 where the average flow rate of the pulsed flow is the
same as in the case of steady flow (i.e. 20% duty cycle with a peak flow of 100uL/min is
the same average rate as a steady flow of 20uL/min).. In the steady infusion, backflow
begins at a total infused volume of 50mL, while in the pulsed case, it does not appear
even at 190mL. This suggests that the annulus opens up more slowly in response to a
step increase in pressure than do the pores. Consequently, we are likely to encounter less
backflow.
Figure 11 shows the affect of increasing the duty cycle while keeping the flow rate
constant. In each case, the total Vi is 50uL, but the average flow rate is different. The
10% duty cycle results in a perfect sphere; 20% duty cycle results in backflow at 10uL
and an elliptical shape at 50uL; 50% duty cycle results in backflow at 10uL and an
oblong shape at 50uL. As the pulsed flow approaches steady flow, the backflow tends
toward the behavior expected in steady flow.
Figure 12 shows an indication of this phenomenon in vivo. The infusion on left side of
the putamen was performed at 1uL/min steady flow; the right side used pulsatile flow 1
second on/9 off with with a peak flow of 10uL/min. The right side has a more spherical
distribution and is distributed further into the tissue.
More experiments are planned to evaluate this phenomena in vivo under inter-operative
MRI
Infusion pressure as a real-time indicator:
The pressure required to maintain a given flow rate is a potentially valuable external
indicator of what is happening within the cannula and in the surrounding medium.
Figure 13 shows a typical pressure profile. The pressure rises to the required level and
then remains stable until the infusion is completed. We often saw a similar pressure
profile even in the presence of backflow, as seen in Figure 14.
However, Figure 15 shows a markedly different pressure profile. The pressure rises to a
peak of 43mm Hg and then drops to approximately 25mm Hg in about 30 seconds before
decaying to a steady state pressure of 18mm Hg. Examination of the video of the
infusion showed that an occlusion had initially blocked the flow. As the pressure was
rising, the occlusion was forced out of the catheter, followed by the pressure dropping.
Figure 16 shows a somewhat lower peak of 37mm Hg and a longer decay to about 25mm
Hg. Examination of the video indicated a partial occlusion which was gradually
removed.2
Pressure profiles corresponding to both complete and partial occlusion have been
observed in vivo as well. Figure 17 shows an in vivo example.
Due to the probable important role in causing variability of infusion results, further
studies of occlusion in gels and in vivo will be the subject of another report by the
Infusion Physics Study Group.
*The Infusion Physics Study Group:
Research Contributor
Senior investigators and in
vivo/ex vivo experiments Dr. Krystof Bankiewicz, University of
California at San Francisco
Dr. Marina E. Emborg, University of
Wisconsin, Madison
Fluid physics Dr. Raghu Ragavan, Therataxis
Dr. Martin Brady, Therataxis
Simulations/engineering Chris Ross, Engineering Resources
Group, Inc.
MRI physics Dr. Andrew Alexander, University of
Wisconsin, Madison
Dr. Tracy McKnight, University of
California at San Francisco
Technical contributors
(in alphabetical order) Janine Beyer, University of California at
San Francisco
John Bringas, University of California at
San Francisco
Dr. Kevin Brunner, University of
Wisconsin, Madison
Michael Dobbert, University of
Wisconsin, Madison
Ronald Fisher, University of Wisconsin,
Madison
Valerie Joers, University of Wisconsin,
Madison
Philip Pivirotto, University of California
at San Francisco
James J. Raschke, University of
Wisconsin, Madison
Dr. Dali Yin, University of California at
San Francisco
Elizabeth Zakszewski, University of
Wisconsin, Madison
Project management Ken Kubota, Kinetics Foundation
Tom Dunlap, Kinetics Foundation
References:
1. Convection Enhanced Delivery is described in the companion report, “What is CED?”
by the Infusion Study Group, May, 2009
2. This phenomenon was observed in “Convection-enhanced delivery of macromolecules
in the brain”, R. Hunt Bobo, Douglas W. Laske, Aytac Akbasak, Paul F. Morrison,
Robert L. Dedrick, and Edward H. Oldfield, Proc. Natl. Acad. Sci. USA, Vol. 91, pp.
2076-2080, 1994
3. Krauze MT, Saito R, Noble C, Bringas J, Forsayeth J, McKnight TR, Park J,
Bankiewicz KS. Effects of the perivascular space on convection-enhanced delivery of
liposomes in primate putamen. Exp Neurol. 2005 Nov;196(1):104-11
APPENDIX
05-18-09
Gel experiments:
Initially, experiments were performed at room temperature with the gel (normally 0.2%
or 0.6% agarose) “constrained” in a 2 ¼ x 2 ¼ x 3 inch clear plastic container. Later
experiments were performed in a heated water bath and the gel was removed from the
plastic container and placed in the bath. This set up is called “unconstrained” gel at
temperature and provides an experimental set up that is closer to the in vivo set up. The
water is heated with a recirculator/heater system and the temperature is measured with
a digital pyrometer with its probe in a sacrificial gel in the bath. The combination of
unconstrained gel and body temperature reduces the cracking of the gel that occurs
during insertion into gels. A key component of this system is a custom built computer
which controls the pump, monitors the volume infused and the infusion line pressure.
The pressure data are presented graphically and digitally in real time. The purpose of this
subsystem was to measure the variations in pressure while keeping a constant flow rate.
A high definition video camera was set up to monitor the flow of the infusate into the gel
and it was synchronized with the pressure data acquisition. Still images were selected at
time intervals of interest to correlate the infusion cloud with the pressure trace.
Most experiments used a single port catheter with the port at the tip of the catheter. The
catheter was constructed using fused silica or stainless steel for the main body and
polyimide for the stepped tip in various sizes dictated by the requirements of the
experiment.
The infusion line is a fused silica tube that connects to a transition line through the ‘Zero
Air Chamber’. The ‘Zero Air Chamber’ allows an in-dwelling stylet to be manipulated
without the risk of introducing air into the infusion stream. The transition line is flexible
and guides the stylet through the catheter. It is attached to the catheter. The infusion
system is shown in
Figure A
In Vivo:
Comparisons between infusions require that the parameters are sufficiently controlled
allowing replication of an experiment. This includes the ability to perform accurate
targeting of the desired structure to allow controlling for anatomical variation.
In vivo experiments needed to be coordinated between the gel lab (that tests the delivery
system pre and post infusion), the surgical suite, and the MRI facility. During the surgical
and MRI procedures, vital signs are constantly monitored. Previous research has found
that changes in blood pressure may affect infusate distribution. 3
The in vivo infusion system includes the following equipment:
Pressure monitoring and infusion pump controller system (Engineering Resources
Group)
MRI-compatible syringe pump (Harvard)
step catheter
Silica infusion lines and disposable syringes
Catheter targeting system (Navigus® , a MRI-compatible trajectory guide for
intracerebral biopsies and placement of electrodes for deep brain stimulation that is
part of the Medtronic StealthStation® Navigation system, was modified for catheter
placement.)
MRI compatible stereotactic frame. The frame ensures that the animals’ head is
secured (minimizing movement during MRI and surgery), placed in a similar position
during all imaging recordings and surgical placement, and facilitates positioning of
the navigus base
Solution of Gadolinium DTPA using degassed-sterile-distilled water for in vivo
(MRI) visualization of the infusate
3.0T MRI scanner
Targeting Method:
The placement of the Navigus system is performed in sterile surgical conditions. Using
stereotaxic methods and guided by baseline T1 MRI in the coronal, axial and sagittal
planes, an entry burr hole in the skull is created and the Navigus system is anchored on
top of it. Multiple T1 MRIs are performed before and during the cannula insertion to
ensure that the tip of the canula reaches the target at the desired angle and depth in one
single tissue pass. When this is achieved, the infusion is started.
Figure A
Figures
5-18-09
Figure 1a In vivo coronal MRI; “good infusion
”.
Figure 1b In vivo coronal MRI; with backflow.
Figure 2 The effect of cannula insertion techniques.
a. Gel grown around catheter
b. Same, with gel-to-catheter seal broken
c. Insertion into a solidified gel
All at 5μL/min
a. Grow gel around catheter
b. Grow gel around catheter and re-seat
c. Insert catheter into solidified gel
• March 2008• Room temp• Constrained
• February 2009• 37 degrees C• Un-constrained
a. b.
Figure 3 Effect of ambient temperature and constraint on the flow
Figure 4 Stepped catheter design;10mm long polyimide catheter with 1.5mm step
Figure 5 The effect of the step on the flow; 5μL/min; 0.5mm; polyimide catheters
Figure 6 The effect of the step at different flow rates. Flow rates varied
from 0.1, to 10 uL/min at different time periods.
Figure 7 Step catheter inhibits backflow in vivo, at an early and later point
in the infusion.
Figure 8 The infusion cloud is diverted by a cannula track left from a previous
infusion.
Figure 9 The infusion cloud reaches a channel which had been formed earlier in
the gel. The channel diverts the flow. Steady infusion at 10 uL/min.
Run H03 20µl/m Steady Run Ho5 100µl/m Pulses 2s
ON, 8s Off
0.5minutes, 10µl
2.5minutes, 50µl
5.5minutes, 110µl
9.5minutes, 190µl
Figure 10 The effect of pulsatile flow: no backflow appears even at Vi=190 uL/min;
in an equivalent steady infusion, backflow appears at Vi=50 uL/min. Average flow rate
is the same in both cases.
Figure 11 The effect of duty cycle: as the duty cycle is increased, the effect of
pulsed flow begins to resemble the effect of steady flow.
Figure 12 The effect of pulsatile flow in vivo. Left: steady flow, Right: pulsatile flow.
The average flow rate is the same in the two cases
Figure 13 Pressure profile for a steady infusion at 20μL/min.
Figure 14 Pressure profile in the presence of backflow.
Figure 15 Pressure profile in the case of an occluded catheter; complete occlusion.
Occlusion visually verified.
Figure 16 Pressure profile in the case of a partially occluded catheter.
Occlusion visually verified.
Figure 17 Pressure profile in the case of an occluded catheter, in vivo.