May 2013, Vol. 3, No. 3

Clinical Update
& Research News
May, 2013 Vol. 3, No. 3
IN THIS ISSUE
VibeX Rapid Clinical Update
Update from the Field/Lab
Dr. Rechichi’s
VibeX Rapid Protocol
For corneas 325 microns
or greater, after epithelial
removal
1. After epithelial removal,
apply VibeX Rapid. Soak
for up to 10 minutes,
reapplying every 1-2
minutes.
2. Following completion of
the soak, rinse VibeX Rapid
from the eye with BSS.
3. Treat with 7.2 J/cm2,
using an irradiance of
30mW/cm2 with pulsed
illumination [1,1].
1
VibeX Rapid Clinical Update
In the October, 2012 Vol. 2, No. 4 issue of Avedro’s Clinical Update and Research News,
Avedro introduced its VibeX Rapid riboflavin formulation as an alternative to VibeX
with dextran. VibeX Rapid contains 0.1% riboflavin with hydroxypropyl methylcellulose.
Unlike dextran, hydroxypropyl methylcellulose does not dehydrate and thin the cornea,
making VibeX Rapid the ideal choice for all epithelium-off cross-linking procedures.
The response from our physicians who have switched from VibeX to VibeX Rapid has
been extremely positive and therefore Avedro will be phasing out VibeX during the
next six months. Below, we review the laboratory basis for VibeX Rapid and share a
KXL user’s clinical experience.
VibeX Rapid Advantages:
• Suitable for thin corneas
• Stable intraoperative corneal thickness
• Faster diffusion; soaking time reduced by half
Update from the Field
Accelerated cross-linking with Vibex Rapid and pulsed illumination:
early in-vivo clinical results
Contributed by Miguel Rechichi, MD Magna Graecia University, Catanzaro, Italy
Dr. Miguel Rechichi of Catanzaro, Italy has shared early clinical results from his study of
the first 10 patients affected by keratoconus that he has treated with VibeX Rapid and
epithelium-off cross-linking with pulsed illumination. The aim of this ongoing study is
to demonstrate the safety of the procedure in human corneas and evaluate the postoperative morphological changes observed in treated eyes.
Corneal cross-linking has been demonstrated to slow or halt the progression of corneal
ectasia due to keratoconus or post-refractive surgery. While complications are rare,
transitory or permanent complications, including corneal haze or scarring, do sometimes occur. Possible risk factors for development of complications include pre-operative keratometry values > 58 D and the treatment of ultra-thin corneas with unmodified
protocols.1 Excessive intraoperative corneal thinning may also occur when a riboflavin
solution that contains dextran is used during longer treatment times (Figure 1). Theoretically, limitation of intraoperative thinning through modification of the riboflavin
solution2-3 may reduce the risk of persistent complications, such as stromal opacity. 4-6
The KXL® System is a CE Marked product and is not for sale in the United States. MA-00237, Rev. A
Clinical Update
& Research News
To analyze pachymetric variations in real time, Dr.
Rechichi used a handheld HD-OCT device to perform
in-vivo intraoperative OCT imaging of the corneas.
Several corneal thickness maps were obtained during the
procedure. Measurements centered on the cornea were
obtained pre-operatively (PREOP), after epithelial removal
(Epi-R), after 10 min riboflavin soaking with VibeX Rapid
(RS), and after a 6 min procedure utilizing a 30mW/cm2,
7.2 J, pulsed protocol (IR). The primary endpoint of this
study was the central corneal thickness (CCT).
homogeneous hyperreflective band that was equal from
center to the periphery (Figure 4).
To improve overall safety of epi-off procedures, the use
of VibeX Rapid and accelerated protocols may reduce
corneal dehydration and preserve original corneal
thickness. Preoperative pachymetry may not be sufficient
to confirm endothelial safety with standard protocols.
Intraoperative pachymetry should be obtained following
riboflavin soak, prior to irradiation, particularly if a dextrancontaining riboflavin formulation is utilized.
Corneal soaking with VibeX Rapid following epithelial
removal did not substantially alter the CCT. After irradiation,
a mild decrease of 5.8 micron in CCT was observed
(Graph 1). This behavior was observed in all sectors of the
pachymetric maps and confirmed by analysis of corneal
tomographic sections obtained in-vivo (Figures 2,3).
The early results of this clinical study are supported
by the Avedro laboratory findings shown in the article
below, demonstrating that the absence of dextran and
the addition of HPMC limit evaporation. Preliminary
clinical data shows that after epithelial removal, the
corneal thickness remained stable until the end of the
procedure, independent of preoperative pachymetry.
HD-OCT imaging of early postoperative pediod showed a
Graph 1. CCT changes during pulsed CXL
Procedure
FIGURE 1. Intraoperative corneal thinning (> 250 micron) in a patient
treated by traditional epi-off procedure (Riboflavin plus dextran, 30
min irradiation at 3 mw/cm2).
2
The KXL® System and VibeX Rapid™ are CE Marked products and are not for sale in the United States. MA-00237, Rev. A
Clinical Update
& Research News
Figure 2. Immediate pre-operative pachymetric map prior to epithelial removal.
Figure 3. Intra-operative pachymetric map after irradiation with 7.2 J pulsed illumination
Figure 4. Figure 4. One month Post-Op in-vivo OCT imaging of the same patient. Anterior hyper reflective
band was clearly visible with a demarcation line at approximately 218 micron depth
3
The KXL® System and VibeX Rapid™ are CE Marked products and are not for sale in the United States. MA-00237, Rev. A
Clinical Update
& Research News
From the Lab
Corneal Cross-linking with VibeX Rapid
The early work on corneal cross-linking by Wollensak,
Spoerl and Seiler was performed using a 0.1% riboflavin
formulation containing 20% dextran. Dextran was chosen
in part for its viscosity, which allowed the riboflavin to
remain in place on the eye for delivery during an extended
soak time. Avedro’s original VibeX formulation was
derived from this work. Much research has been done
since that time, and as scientists and physicians continue
to deepen our knowledge in this area of medicine, it is
useful to understand the effects of including or omitting
dextran from riboflavin formulations.
When applied to the cornea, the use of dextran results
in dehydration and subsequent thinning of the cornea
(Figure 5). As the water is drawn out of the cornea, a
concentration gradient is created that slows the diffusion
of riboflavin into the stroma. Avedro scientists have
studied the diffusion characteristics of various riboflavin
formulations through corneal flaps using fluorimetry
and have demonstrated the slower rate of diffusion of
formulations containing dextran (Figure 6).
As an alternative to riboflavin formulations containing
dextran, Avedro suggests the use of its VibeX Rapid™
for epithelium-off procedures. VibeX Rapid contains
0.1% riboflavin with hydroxypropyl methylcellulose.
Methylcellulose has approximately the same viscosity as
dextran and therefore is able to achieve the desired effect,
delivering riboflavin into the stroma, without dehydration
and thinning of the cornea. This makes VibeX Rapid the
ideal choice for all epithelium-off cross-linking procedures,
especially for thinner than average ectatic corneas.
“To improve overall safety of
epi-off procedures, the use of
VibeX Rapid and accelerated
protocols may reduce corneal
dehydration and preserve
original corneal thickness.”
Miguel Rechichi, MD
Based on theoretical models derived from finite element
analysis, Avedro’s standard protocol recommendations
allow corneas as thin as 325 microns after epithelial
removal to be treated with VibeX Rapid without exceeding
the safety thresholds at the endothelium that have been
outlined in the published literature and have given rise
to the widely cited 400 micron limit for the Dresden
protocol.7,8 Figure 7 illustrates the activation of VibeX
Rapid in a 325 micron, epithelium-off cornea. Comparing
the blue bar to the Dresden protocol (grey, 0.1% riboflavin
and 20% dextran) at the anterior stroma, one can see that
the modeled riboflavin activation with the VibeX Rapid
protocol exceeds the Dresden protocol. At a depth of
300-325 microns, the blue bar falls below the established
endothelial safety limit (red).
Figure 5: Relative corneal shrinkage of rabbit cornea for 3
different solutions at 35°C. Due to its low viscosity, distilled
water evaporates quickly when applied at 3 minute intervals and
results in dehydration. The higher viscosity of Vibex Rapid limits
evaporation.
4
In corneas thinner than 325 microns, one clinical approach
is to swell the cornea prior to cross-linking using distilled
water.
Hypotonic solutions evaporate more quickly,
necessitating a frequent drop interval. It is recommended
that hypotonic saline be applied at 30 second intervals
following epithelial debridement.
Once the desired
The KXL® System and VibeX Rapid™ are CE Marked products and are not for sale in the United States. MA-00237, Rev. A
Clinical Update
& Research News
corneal thickness is reached, the methylcellulose contained
in VibeX Rapid provides the desired viscosity for soaking
without excessive evaporation or additional thinning. VibeX
Rapid may then be applied at 2 minute intervals for the
remainder of the 10 minute soaking time.
References
1. Koller T, Mrochen M, Seiler T. Complication and failure
rates after corneal crosslinking. J Cataract Refract Surg.
2009 Aug;35(8):1358-62. doi: 10.1016/j.jcrs.2009.03.035.
PubMed PMID: 19631120.
2. Hafezi F. Limitation of collagen cross-linking with
hypoosmolar riboflavin solution: failure in an extremely
thin
cornea. Cornea. 2011;30(8):917-919.
3. Raiskup F, Spoerl E. Corneal cross-linking with hypoosmolar riboflavin solution in thin keratoconic corneas.
Am J Ophthalmol.
4. Spoerl E, Hoyer A, Pillunat LE, Raiskup F. Corneal
cross-linking and safety issues. Open Ophthalmol J.
2011;5:14-16.2011;152(1):28-32.
Figure 6: Mean diffusivities of VibeX, VibeX Xtra and VibeX
Rapid.
5. Raiskup F, Hoyer A, Spoerl E. Permanent corneal
haze after riboflavin-UVA-induced cross-linking in
keratoconus. J Refract Surg. 2009 Sep;25(9):S824-8.
doi: 10.3928/1081597X-20090813-12. Epub 2009 Sep 11.
PubMed PMID: 19772259
6. Vinciguerra P, Albé E, Romano MR, et al. Stromal
opacity after cross-linking. J Refract Surg. 2012;28(3):165.
7. Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T. Safety
of UVA-riboflavin cross-linking of the cornea.
Cornea. 2007 May;26(4):385-9
8.
Wollensak G, Spörl E, Reber F, et al. Corneal
endothelial cytotoxicity of riboflavin/UVA treatment in
vitro. Ophthalmic Res. 2003;35:324-328.
Figure 7: Theoretical model of riboflavin activation in a 325 micron cornea, with
equivalence to the Dresden protocol at the anterior cornea. Activation falls
below the Dresden safety threshold at the level of the endothelium.
5
The KXL® System and VibeX Rapid™ are CE Marked products and are not for sale in the United States. MA-00237, Rev. A
Clinical Update
& Research News