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Comparison of Hypotonic and Isotonic Solutions Containing Sodium

Hyaluronate on the Symptomatic Treatment of Dry Eye Patients

Article in Ophthalmologica · March 2001

DOI: 10.1159/000050842 · Source: PubMed

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Originai Paper. Travail originai. Originalarbeit

OJ::ilillmnologica
" Ophthalmologica2001;215:124-127

Comparison of Hvpotonic and Isotonic

Solutions Containing Sodium Hvaluronate on
the Svmptomatic Treatment of Drv Eve Patients

Vincenzo Papaa Pasquale Aragonab Simona Russoa Alessandro Di Bellaa

Pietro Russoa Giovanni Milazzoa

"Medicai DepartmentSIFI SpA,lavinaio (Catania),and blnstituteof Ophthalmology,University of Messina,Italy

Key Words
Dry eye. Sodium hyaluronate. Osmolarity
Abstract
This study was designed to compare the efficacy of two
artificial tears both containing hyaluronic acid but differ-
ing in their osmolarity. A multicentric double-masked,
crossover clinical trial was performed in which 158 sub-
jects were randomized to receive either hypotonic or iso-
tonic artificial tears up to 6 times a davo 80th treatments
were effective in improving signs and symptoms to a
similar extent. No adverse events were reported. It was
concluded that hypotonic and isotonic eye drops are
comparable far the symptomatic treatment of patients
suffering tram dry eye syndrome.
Copyright@2001
seem to play a major Tale in the development of the ocular
surface damage [1].
In patients with dry eye, tear film osmolarity is in-
creased by up to 30-40 mosm/l [2-4]. Several studies
bave suggested that this high osmolarity may be responsi-
ble far both symptoms and signs associated to dry eye.
Moreover, high osmolarity may be toxic to the corneal
epithelium, as suggested by in vitTO studies with corneal
tissue cultures [5]. Consequently an attempt was made to
reduce tear osmolarity by applying hypotonic artificial
tear solutions in patients with dry eye. However, the
results obtained with such solutions bave been contradic-
tory [6, 7]. The aim of the present study was to assess
whether hypotonic drops would give greater symptomatic
reliefthan isotonic drops in patients with dry eye.
S. Karger AG, Basel

Patients and Methods

Introduction A total of 158patients with dry ere wereenrolled in 14 different

Dry eye symptoms anse from a senes of et1olog1esand
afe manifest with varying severity. The pathogenesis of
the ocular surface damages and symptoms afe at present
not well understood. For this reason topical therapy of dry
eye syndrome has been essentially empirical and fre-
quently unsausfactory. Th1S therapy 1Smamly based on
artificial tears in the attempt to keep the eye from drying.
However, ocular surface wetting abnormalities do not
centerslocated in Germanyduring a period of 7 months. Diagnosis
wasbasedon stringentinclusion criteria, i.e.: (l) a history of dry ere
far at least2 months; (2) tear film abnormalities (tear breakuptime,
BUT, <lO s and/or Schirmer II test<5.0 mm in one or both eyes),
and (3) ocular surfacedamage(rose bengal and/or fluoresceintest
score ~ 3 in at least~ne ere) [8]. Patients w~t4externa~ocular ?is-
ease,.gla.ucoma,we~nng.contac~ lense.sor usmg syste~lc or toplcal
medlcatlon potentlally mterfenng wlth tear productlon (such as
sleepingtablets,tranquilizers, antidepressants, monoamineoxidase
inhibitors, dopaminergics,neuroleptics,benzodiazepines,antisero-
tonergicand antiemetic agents)wereexcluded.

KARG ER @2001 S. Karger AG, Basel Giovanni Milazzo, MD

.0030-3755/01/2152-0124$17.50/0 SIFlSpA,MedicaiDivision
Fax+4161 306 1234 ViaErcolePatti,36
E-Mail karger@karger.ch Accessible online al: Lavinaio 95020, Catania (Italy)
www.karger.com www.karger.com/joumals/oph Tel. + 39095 7922111, Fax + 390957893451, E-Mail Giovanni_Milazzo@sifiit
 The trial was perforrned under complete double-blind conditions.
This study was designed as a crossover, in which each patient
received two different artificial tear solutions (isotonic or hypotonic).
Patients were randomly assigned to one of two possible treatment
sequences. 84 patients received the treatment according to the
sequence isotonic -t hypotonic and 74 received the treatment
according to the sequence hypotonic -t isotonic. Treatment (up to E
6 drops/day per eye according to the severity of symptoms) was car- ~
ried out for 28 consecutive days. A saline solution (0.9% w/v sodium ~
chloride, pH 7.4) was used for 7 days (washout) between the 2 treat- :>

ment periods.
The two solutions used (one hypotonic and the other isotonic)
were similar in terrns of a viscoelastic agent (hyaluronic acid) and
viscosity but different in terrns of osmolarity (215 and 305 mosmn,

respectively). 1 2 3
A complete ophthalmologic examination was perforrned by the Groups 4

same ophthalmologist before the beginning oftreatment (visit 1), at

the end ofthe first treatment period (visit 2 = day 28 :t 3), the end of
the washout period (visit 3 = day 35 :t 3) and at the end ofthe second Fig. 1. Effect ofhypotonic (groups 1 and 2) or isotonic (groups 3 and
treatment period (visit 4 = day 63 :t 3). The examination took pIace 4) solutions on symptoms of dry eye. Posttreatment values (groups 2

after at least 6 h from the last instillation and included tear BUT and 4) were compared to baseline values (groups 1 and 3). Data afe
(mean of2 different measurements), fluorescein staining, rose bengal expressed as means :t SEM.
staining (at least 5 min after fluorescein staining) and a Schirrner II
test with anesthetic (Jones test). Fluorescein staining was graded
using a standardized grading system [8]. Rose bengal staining was
graded according to Lemp [8] for 6 areas of each eye. The scores
obtained in each area were summed up. In addition, subjective
t
symp oms
( '.
stmgmg,
b .
ummg,
ti .
orelgn-
b d
o y sensatlon,
. h
eavmess
. o
f R esu It 5

the lids and photophobia) and global ocular symptoms were assessed
ateachstudyvisitbymeansofavisualanalogueratingscale(VARS) Nineteen out of the 158 patients withdrew or were
on which sens~tions were to be indicat~d by a line placed between the withdrawn because of adverse events (AE; n = 14), being
left and the nght end of a 100-mm lme. Values could range from 10st to f01low-up (n = 2) fai1ure to keep to schedule (n = 2)
O mm ('none') to 100 mm ('severe'). For the V ARS scales ofvisits 2 ...'
and 4, a mean value of the left and right eyes was calculated per or uthe patle~t dld not coope:ate (n =.1). Therefor~ data

patient for each symptom. from 139 patlents were used m the pnmary analysls. Of

The primary objective of this study was to obtain in patients these, 78 were in the isotonic ~ hypotonic treatment
treated with the hypotonic eyedrop an improvement of dry eye symp- sequence and 61 in the hypotonic ~ isotonic treatment
toms at least clinically equivalent (within a therapeutic range of sequence The efficacy ana1ysis was based on pooled
:t 1.0%) to that obtained with the isotonic solution. .

The primary efficacy variables of the study were the global symp- results from ~oth ~reatment arrns far each of the two com-

tom score ([maximum obtainable cumulative V ARS score -cumula- pounds used m thlS crossover study.

tive symptom V ARS scores]/[maximum obtainable cumulative

V ARS score]) and the signs of ocular surface damage (evaluated by Symploms
either rose bengal or fluorescein stains). Tear BUT and Schirrner test Five individua1 V ARS scales were used far ocular
were Anconsider~d
analysis ofvariance
secondary was
efficacy
perforrned
variables. for the primary variables. symptoms .(st~ngmg, .bummg, forelgn-body sensatlon,

A 5% level of significance was used for within-patient comparisons photophobla, lld heavmess). Each value could range from
(i.e. for the period and treatment effects) and a 10% level of signifi- O to 10 (lower va1ue = lower subjective discomfort). At the

cance for between-patient comparisons (i.e. for the carryover effect). start of treatment, average ratings ranged from 3.1 (lid
For th~ ocular surface damage (rose bengal s~ore) a nonparametr~c heaviness) to 5.7 (buming sensation), indicating a marked
analysis
analyses was
were perforrned.
applied to the
The other
same variables.
parametnc The and
sample
nonparametnc
size deter- subjectlve dlscomfort fe1t ~y the patlents. The posttreat-

mination was based on the'rose bengal score'. Since the two drugs afe ment symptom scores obtamed after the first and the sec-

very similar in terrns of composition, the differences in terrns of effi- ond 28-day treatment periods were of comparable magni-
cacy can be expected to be quite small. However, recent studies [7] tude suggesting that both compounds induced most ofthe
have sh~wn that the coefficient of variation for this parameter is maxima11y obtainable relief within 1 month of treatment
rather high. Therefore, both treatment groups can be regarded as .
therapeutically equivalent if their mean rose bengal scores do not (fig. 1). The global l~prove~ent of symptom.s (g10ba1

differ by more than 35 %. The sample size calculation (72 patients per symptom score) obtamed wlth the two s01utlons was

group) was adapted to the current two-way crossover designo almost identical (fig. 2).

Sodium Hyaluronate and Dry Eye Ophthalmo10gica 2001;215:124-127 125

 meni with hypotonic and from 5.1 :t 0.3 to 6.7 :t 0.4 mm
100 fì . h h o o
-Baseline a ter treatment wlt t e Isotomc drops.
-End oftreatment
xla
E 80 C o o
OnjUnctlvaIS ymptoms
~
~ The number of patients with conjunctiva1 rednesswas
~ 60 reduced after both treatments to a similar extent (from
g 78.3 to 41.7% in the group treated with hypotonic solu-
~ 40 tion and from 71.2 to 37.7% in the group treated with the
~la isotonic solution).
.g 20
a TreatmentTolerability/Adverse
Events
o Patients were asked to rate the tolerability to the
Isotonic .Hypotonic respective drug after each treatment period (visits 2 and
Solutlon
4). Pooled results (both eyes, both treatment sequences,
alI patients) revealed that the two solutions were well tol-
Fig. 2. Global symptomscore([maximumobtainablecumulative erated by the majority of patients (>90%) to a similar
v ARSscore-cumulative symptomVARS scores]/[maximum ob- extent.
tainable cumulative V ARS score]) at the start of treatment and the A total of 38 AE (20 in the h otonic ou and 18 in
end of treatmento A value of 100% means no ocular symptoms; a o .yp gr .p
valueof 0%meansmaximumintensityof alIsymptoms
assessed
by the Isotomc grOUp)were reported far 32 patlents. Of the
VARSo Dataafeexpressed
asmeans:t SEMo 38 AE, 23 were classified as related to the study treatment
(mostly blepharitis or allergic reactions) with no differ-
ences between the treatment groups. On1y 2 treatment-
related AE were described as severe, 1 far each group of
treatment. Both AE were associated to a local allergic
Ocular SurfaceDamage reaction and required corticosteroids. Finally, 2 serious
The mean rose bengal score per patient (mean ofboth AE requiring hospitalization were reported (1 far each
eyes)decreasedfrom 5.6 :t 0.3 (mean :t SEM) at baseline group of treatment) and both were classified as noi treat-
to 3.0 :t 0.3 after treatment with hypotonic and from 4.9 meni related.
:t 0.3 at baseline to 3.0 :t 0.3 after treatment with the
isotonic solution, suggestinga marked reduction of con-
junctival surface damage with both treatments. Discussion
The mean fluorescein score per patient (mean of both
eyes)decreasedfrom 4.6 :t 0.2 (mean :t SEM) at base1ine Dry ere syndrome is essentially a symptomatic prob-
to 2.2 :t 0.2 after treatment with hypotonic and from 4.3 lem far which there is stilI no completely satisfactory
:t 0.3 to 2.3 :t 0.2 after treatment with the isotonic com- treatment. Replacementofthe missing fluid from the out-
pound, suggestinga normalization of the corneal epithe- er ere would seem a simple matter, bui no universally
lia1 surface. acceptabletear substitute exists and no single formulation
has been shown to be superior far relief of symptoms. In
Tear Film Parameters fact the symptom complex causedby tear deficiency is noi
While BUT did noi normalize during the study, there specific, and many other external ere disorders, such as
was an impressive improvement in tear film stability aver blepharitis and primary ocular surface disorders, may
lime, with BUT increasing from 4.8 :t 0.2 s (mean:t produce identica1 symptoms. It follows that the large
SEM) at base1ineto 7.2 :t 0.4 s after treatment with hypo- number of prescriptions far artificial tear drops therefore
tonic, and slightly less (from 4.6 :t 0.2 to 6.6 :t 0.3 s) after on1ypartia1ly represent replacement therapy far dry eyes,
treatment with the isotonic compound. This difference and probably the greater use is a placebo. This more than
was statistically significànt (p = 0.021). other factors explains the conflicting reports oftheir effi-
A Schirmer test value below 5 mm is considered abnor- cacy, and it was considered essential in this study to try
mal. Again, a significant improvement was observed aver the drops in those patients with well-established dry ere
lime: the mean test value increased from 4.8 :t 0.3 mm who were dependent on tear substitute drops.
(mean :t SEM) at baseline to 6.8 :t 0.4 mm after treat-

126 Ophthalmologica
2001;215:124-127 Papa/Aragona/Russo/Di
Bella/Russo/
Milazzo
 In the presentstudy we found no significant differ-
encesbetweenan isotonic and a hypotonic solution. In
fact both were effective in the treatmentof dry ere syn-
drome.The efficacyof the two solutionswascomparable
in respectto all the parametersanalyzedwith the excep-
tion of the BUT, whichwasbetterimproved by the hypo-
tonic solution (p = 0.021).Theseresultsafe in agreement
with thoseofWright et al. [7] who reportedno significant
differencesin the relief of symptomsobtained with iso-
tonic and hypotonic solutions in a selectedgroup of
patients with dry ere. Interestingly, during the l-week
saline washoutphase,symptomsworsenedmarkedly in
both treatment arms, suggestingthat the improvement
could indeedbe relatedto the viscoelasticagent,sodium
hyaluronate.An improvementof ocularsymptomsafter
treatment of dry ere patients with sodium hyaluronate
hasbeenreportedin severalclinical'llStudies [9-12]. Early
reports showedthat sodium hyaluronate,an important
constituentofthe extracellularmatrix, may play a role in
inflammation and wound healingand may promotecor-
neal epithelial cell proliferation [13-15]. However,none
oftheseclinical trials haveprovideda clearstatementthat
ere drops containing sodium hyaluronateafe effective
treatmentsfar dry ere patients.However,a recentstudy
reporteda clearbenefit of hyaluronanaversalinein both
the subjectiveand objective assessment of dry ere syn-
drome[12].
Althoughdamageto rabbit cornealepithelium in vivo
and in vitro has been demonstratedafter exposureto
hyperosmolarsolutionsin the samerangeas is found in
dry ere, and evidenceof epithelialdamagewas found at
the ultrastructurallevel,our studyshowedthat no signifi-
cant difference at the level of ocular surfacediseaseis
reportedaftertreatmentwith hypotonicand isotonicsolu-
tions. Bothtreatmentsreducefluoresceinand rosebengal
scoresin the samerangeof magnitudeindicatingthat the
improvementcould not be ascribedto the osmolarityof
the solution,but to otherfactors.
In conclusion,althoughan increasedtear osmolarity
hasbeenfound in dry ere patientsand it hasbeenconsid-
eredtoxic far the cornealepithelium,the useofhypotonic
eyedropsasa remedyfar hyperosmolaritydoesnot offer a
significantadvantagewith respectto anisotonicsolution.
Oneofthe reasonsis that the reductionoftear osmolarity
after the application of hypotonic ere drops is of short
duration and that far the sameperiod tear osmolarityis
lowered,within the normal range,also by isotonic solu-
tions [7]. Our study suggeststhat in designingnew tear
substitutes,attention should not be focusedon tear di-
luents to compensatethe hypertonicity associatedwith
the dry ere status.Onepossibleattemptshouldduplicate
the tearfilm.

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Sodium Hyaluronate and Dry Eye OphthaImologica2001;215:124-127 127

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