Biomaterials 22 (2001) 3305–3310

The clinical use of viscoelastic artificial tears and sodium chloride

in dry-eye syndrome
Johannes Nepp*, Joerg Schauersberger, Gebtraud Schild, Kerstin Jandrasits,
Jinus Haslinger-Akramian, Agnes Derbolav, Andreas Wedrich
Department of Ophthalmology and Optometry, University of Vienna, Medical School, Waehringer Guertel 18-20, A 1090 Vienna AKH, Austria

Abstract

This study was performed to test viscoelastic artificial tears (VAT) based on both subjective and clinical parameters in patients
with keratoconjunctivitis sicca (KCS). Twenty-eight patients were evaluated in a randomized double-blind study. Sodium
hyaluronate was used in two different concentrations (0.4%, 0.25%) and in combination with chondroitin sulfate. Each preparation
was used for one week preceded by another weekly cycle using a sodium chloride solution. Before and after each cycle, clinical
examinations were performed: tear film break-up time, Schirmer’s test, lipid-layer thickness and fluorescein staining. Patients kept a
record of the drop-frequency, subjective response and side effects. After the study, they were asked to give a rating of the various
preparations. The severity of KCS was expressed based on a sicca score and correlated with response to viscoelastic treatment. Both
the subjective and the clinical parameters revealed no statistically significant differences between the various viscoelastic agents or
between the viscoelastics and the sodium chloride solutions. Severe side effects did not occur. There was a positive correlation
of response to viscoelastic treatment with severe KCS (+0.36) but not with mild KCS (
0.07). The VAT seems to be indicated
in severe cases of dry-eye syndrome. Sodium chloride solutions may be a useful short-term alternative to other tear formulations.
r 2001 Elsevier Science Ltd. All rights reserved.

Keywords: Dry-eye syndrome; Viscoelastic artificial tears; Sodium chloride; Sicca score

1. Introduction various viscoelastic tear formulations. Side effects were

Artificial tears are a heterogeneous group of sub-
stances whose physical and chemical composition is
optimized for maximum compatibility with the tear film.
They include water solutions, oils, gels and ointments
[1]. Viscoelastics are highly viscous substances that are
present in all body fluids. Their main application in
ophthalmology has been to create and maintain space
during intraocular surgery [2].
For their use as tear formulations, viscoelastics are
diluted. Previous studies have failed to establish
significant differences in tolerance between substances
of different viscosity, and there was no difference
between viscoelastic agents and aqueous artificial tears
[3,4]. In the present study, we used a double-blind cross-
over design to identify, based on both subjective and
clinical parameters, any differences in tolerance between
*Corresponding author. Tel.: +43-1-404-00-7940; fax: +43-1-404-
00-7932.
E-mail address: johannes.nepp@akh-wien.ac.at (J. Nepp).
also documented.
2. Materials and methods
A total of 28 patients were included in a randomized
double-blind study for treatment with artificial tears
over a 6-week period. The study was approved by the
medical ethics committee of the University of Vienna
(No. 260/96 of December 2, 1996).
As viscoelastic artificial tear (VAT) formulations we
used (a) 40% chondroitin sulfate combined with 30%
sodium hyaluronate 0.1% (Viskoats, Alcon) (molecular
weight (Mw) of sodium hyaluronate: 500,000 Da,
chondroitin sulfate 22,500 Da); (b) sodium hyaluronate
0.25% (Hyalodrops, Croma) (molecular weight
1,000,000 Da); and (c) sodium hyaluronate 0.4% (Hea-
lons, Pharmacia) molecular weight 5,000,000 Da.
All drops were filled up in neutral bottles under sterile
condition by a person/assistant in pharmaceutical
laboratory of the hospital, not involved in this study.

0142-9612/01/$ - see front matter r 2001 Elsevier Science Ltd. All rights reserved.
PII: S 0 1 4 2 - 9 6 1 2 ( 0 1 ) 0 0 1 6 7 - 3
3306 J. Nepp et al. / Biomaterials 22 (2001) 3305–3310
The bottles were labeled as A, C, E for NaCl, B for
Viscoat, D for Hyalodrop and F for Healon, masked by
the same person.
Masking was performed across six groups using Latin
square randomization. The viscoelastic preparations
were used in weeks 2, 4 and 6. Sodium chloride (NaCl)
solutions were applied in weeks 1, 3 and 5 both to clean
the ocular surface before applying the viscoelastics and
as a ‘‘placebo’’ for control purposes.
The surface tension and angle of contact of the
viscoelastics was compared to that of polyvinylpyrroli-
done. (Table 1) Examinations at study entry included a
medical history, slit-lamp microscopy of the lid (espe-
cially the orifices of meibomian glands) and an analysis
of foam formation and detritus.
Analysis of the tear film included a Schirmer’s test (II,
modified by Henderson and Brough), break-up time
(BUT), lipid interference test (LIT) and fluorescein
staining of the corneal surface. Normal values were
Schirmer>10 mm/5 min; BUT>10 s; LIT if red lipids
were seen with the palpebral fissure being reduced by
>50% [5], negative fluorescein staining, detritus and
foam.
These examinations were performed before treatment
to obtain baseline values and were repeated every week.
Patients recorded any symptoms they experienced as
well as the frequency of usage and tolerance. Symptom
scores were compiled by the patients classifying their
complaints as 1=none/minimal, 2=mild, 3=moderate,
4=marked and 5=severe. After the study, patients were
asked to give a rating of the six agents (1=best;
6=worst). Patients were also asked about dryness,
foreign-body and burning sensations, or any other
symptoms they experienced during the study.
Patients were included in the study if they had had dry
eyes for more than one year. An informed consent was
obtained from all patients. Exclusion criteria were scars,
lid irregularities, blepharitis, lagophthalmus, use of
contact lenses, any concomitant topical therapy, da-
cryocystitis, corneal disease or substance intolerance.
Table 1
Osmolarity, contact angel, surface tension, shear rate and adhesiveness, molecular weight of VAT
SoHyaluronat 0.4
Surface tension (181C) Gamma (mN/m) 73.3
Contact-angle on PE–LD (theta) 911
Adhesiveness (At: gamma*cos theta)
4
Osmolarity (mOSm/kg H2O) 281
pH 7.37
Content (%) 40 SoHy
Molecular weight (Da) 4.0 million Daa
Zero-shear viscosity (mPs) 230 K
a
SoHyFSodium hyaluronate.
b
Chondroitinsulfate.
Treatment was discontinued in patients who lacked
compliance, if the efficacy of VAT application was
inadequate, or if signs and symptoms of substance
intolerance occurred. Patients who prematurely termi-
nated the study were replaced by extending the
randomization.
Analyzed parameters included tolerability, symptom
scores, the patients’ rating of the agents, and the results
obtained at the clinical examinations. Based on these
parameters, the various VAT were compared to each
other as well as to NaCl.
To analyze whether there was a correlation between
severity of KCS and response to VAT treatment, we
calculated a sicca score. This sicca score is based on a
comprehensive list of sicca variables to which values
between 0 (no pathology) and 1 (maximum pathology)
are assigned. The results are then added up and divided
by the number of variables used. Thus the sicca score
defines the severity of dry-eye syndrome (1=maximum
severity). The method is described in detail elsewhere [6].
The correlation between severity of dry eyes and
response to VAT treatment was expressed along the
range of +1 (maximum positive correlation) through 0
(absence of correlation) down to
1 (maximum negative
correlation).
Response to VAT treatment was expressed based on
the patients’ rating of the six agents (1=best, 6=worst),
summation of the VAT-rating divided by the number of
agents used. Thus the maximum response based on the
three viscoelastic formulations was 1+2+3=6/6. In
this way a score of 6–10/6 were considered to a good
response to VAT treatment. Correlation was again
expressed as +1 (maximum positive correlation)
through 0 (absence of correlation) down to
1 (max-
imum negative correlation).
2.1. Statistics
The artificial tears were randomized in Latin squares.
Measurements were calculated using variant analysis,
SoHyaluronat 0.5 Chondroitin sulfate
64.9 55.8
931 931

1
3
314 290
6.98 7.22
50 SoHy 30 SoHy
1.0 million Daa 22,500 Daa
5,00,000 Dab
n.A 41 K
 J. Nepp et al. / Biomaterials 22 (2001) 3305–3310 3307

repeated measurement and t-test (level of significance
po0:05). The correlation between severity of dry eyes
and response to VAT was expressed along the range of
+1 (maximum positive correlation) through 0 (absence
of correlation) to
1 (maximum negative correlation).
3. Results
Twenty-eight (25 women and 3 men) completed the
study after six weeks and could be evaluated. Their
mean age was 56 (29–77) yr. The results for Viscoats are
given as B, for Hyalodrops as D and for Healons as F.
The results of the patients’ rating of the six agents are
summarized in Figs. 1 and 2 (mean values: F:3.15,
D:3.5, B:3.64). The bar charts show us how often each
preparation was ranked with the various categories
(RANKA, RANKB, etc.). Based on viscoelastic pre-
parations, symptoms were seen with F–D–B in descend-
ing order. Significant differences in sensation and
tolerance parameters were observed neither between
any of the VAT nor in comparison with NaCl ðp > 0:05Þ:
Although the viscoelastic preparations were applied less
frequently than the NaCl, an analysis of usage
frequencies based on a generalized linear design with
fixed treatment variables (SAS Proc GLM) yielded no
significant differences ðp > 0:88Þ:
The symptom scores (1=none to 5=severe) showed
marked differences at baseline (before study entry) and
after the initial NaCl cycle. Another striking finding was
the small p-values for dryness and foreign-body sensa-
tion obtained with Hyalodrops and Healons. A total

Fig. 1. Classification of VAT.

Fig. 2. Clinical observation: mean values of both eyes (Schirmer, break up time of tear film, lipid layer thickness).
3308 J. Nepp et al. / Biomaterials 22 (2001) 3305–3310
of 258 episodes of subjective discomfort were reported.
They included scratching, itching and stinging sensa-
tions, photophobia, sticky crusty lids, mild pain,
sensations of pressure, thermal paresthesia and blurred
vision. Five patients reported no side effects with
viscoelastics.
The break-up time was improved from baseline after
Hyalodrops (D). Improvements in LlT and Schirmer’s
test were observed for all viscoelastic preparations but
fell short of statistical significance ðp > 0:05Þ:
There were no severe side effects among our patients.
The mean sicca score was 0.5670.09 SD (range: 0.22–
0.8). There was a good correlation between response to
viscoelastic treatment and severe KCS (sicca score
>0.6). There was no correlation between response to
viscoelastics and mild KCS (c:
0.07), and lack of
response correlated neither with severe nor with mild
KCS (c: +0.25/+0.22). (Figs. 3 and 4).
Fig. 3. Correlation of responder on VAT and NaCl in mild KCS.
Fig. 4. Correlation of responder on VAT and NaCl in severe KCS.
4. Discussion
Viscoelastic agents are mainly used in intraocular
surgery [2,7,8]. Their good tolerance and strong adhe-
sion to the endothelium make them excellent candidates
for use as artificial tears [4,9–16]. The treatment regimen
in the present study included two types of viscoelastics
in three different formulations, using sodium hyalur-
onate either alone (Healons 0.4%, Pharmacia and
Hyalodrops 0.25%, Croma) or in combination with
chondroitin sulfate (Viskoats 0.1%, Alcon).
In a previous study, it was demonstrated that the
three viscoelastic formulations show higher values for
osmolarity, contact angle and surface tension than
polyvinylpyrrolidone. Therefore these physical factors
do not suggest themselves as an explanation for the
subjective response to viscoelastics [14  ]. We speculate
that the type of basis used in that study (LD PE: low
density polyethylene) may have been too dissimilar from
an organic surface, although there exist other physical
and chemical factors such as osmolarity (which in the
present study was not analyzed) and adhesiveness that
might help to explain this finding.
The three cycles of NaCl (weeks 1, 3 and 5) were
technically identical but yielded different data. We
therefore treat the initial (A), intermediate (C) and
final (E) NaCl cycles as separate entities. The best
results were obtained with the initial NaCl cycle,
presumably due to a wash-out effect, as most of the
patients had used specific artificial tear preparations
for a long time. It is thus conceivable that a substance
or preservative had accumulated and irritated the
tissue. Apparently the NaCl could no longer afford
adequate lubrication in the later cycles once treat-
ment with a stronger viscoelastic substance had been
resumed.
All formulations used in our study were free of
preservatives. Toxic side effects were therefore excluded.
To avoid contamination, the preparations were made
under sterile conditions and used for a single week only.
Compared to other artificial tear substances, chondroi-
tin sulfate has a lower shear rate and higher adhesive-
ness. This property does not, however, seem to be
relevant except in severe cases of dryness.
The fact that nine patients prematurely withdrew
from the study because they experienced the initial NaCl
cycle as inadequate emphasizes the importance of
alternative tear substitutes. None of these cases was in
any way related to clinical changes in Schirmer values,
break-up time or lipid-layer thickness. Most patients
reported that the viscoelastic preparations gave them an
oily sensation, which was experienced as positive by
some and as negative by others. Only one patient
thought this sensation unpleasant enough to withdraw
from the study. There were, however, no allergic
reactions to any of the preparations.
 J. Nepp et al. / Biomaterials 22 (2001) 3305–3310
Reported paresthetic events included visual impair-
ment, itching, foreign-body sensations, redness of the
conjunctiva, thermal sensations, dryness, psychological
effects, spasmastics and general discomfort. None of
these events were severe. Out of 258 events, 137 were
associated with the viscoelastics and 121 were associated
with NaCl. General discomfort topped the list, with 79
events with viscoelastics and 76 with the NaCl. There
was no statistically significant difference between the
viscoelastic and NaCl preparations ðp > 0:01Þ:
In a similar double-blind design to ours, Limberg et al.
[3] reported that acceptance of chondroitin sulfate was
better in patients with low Schirmer values. Our own
data do not support this result, but they do confirm
Limberg’s more general finding that no specific for-
mulation emerged as significantly preferable to all
others. Viscoelastics have been shown to protect the
corneal and conjunctival surface [17–22], which may
also have implications for adhesion properties. Visco-
elastics have been shown to increase the break-up time
[23] and chemical reactions to stabilize the tear film
[24–26]. There was a correlation between response to
viscoelastics and severe dry-eye syndrome (c:+0.36).
Recently a study by Condon [28] showed that sodium
hyaluronate solution was effective improving schirmer
test and Bengal Rose staining. The majority of their
patients although had a substancial decrease of symp-
toms [27]. There was a correlation between response to
viscoelastics and severe dry-eye syndrome (c:+0.36).
To summarize, the decision on specific tear substitutes
continues to be based on maximal effect while minimiz-
ing unpleasant sensations. Both the clinical and the
subjective parameters in our study gave no indication of
a statistically significant difference between any of the
various VAT. Side effects were frequent but not serious.
Short-term substitution of NaCl may be useful in any
kind of artificial tear regimen to allow accumulated
substances to be washed out. While viscoelastics may be
useful in some patients, the success of treatment depends
mainly on subjective parameters. The present study also
suggests that viscoelastic tear substitutes may be
particularly useful in severe cases of dry-eye syndrome.
Acknowledgements
We thank H. Fendt of the Vienna General Hospital
Pharmacy, R. Amon of the ophthalmologic lab,
University Vienna, and Gerhard Svolba of the Institute
of Medical Statistics, University Vienna, for the
contributions they made to this study. The preceding
observation of surface tension on LDPE was done by
Pohle E. of the Austrian Institute of synthetic material.
The viscoelastic formulations were kindly sponsored by
Alkon (Fort Worth, Texas), Croma (Leobendorf,
Austria) and Pharmacia UpJohn (Bridgewater, USA/
3309
ErlangenFBRD). The NaCl solutions were provided by
the Vienna General Hospital Pharmacy. This study was
financed in part by the Vienna Municipal Research
Fund, Croma and ‘‘Amtsforschung’’. Translation was
performed by translation service (M.P) and corrected by
native speakers (C.A).
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