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The Effect of Ph and Osmolarity on the Ability to Tolerate Artificial Tears
THE E F F E C T OF P H AND OSMOLARITY ON THE ABILITY TO TOLERATE ARTIFICIAL TEARS MICHAEL MOTOLKO, M.D., AND CALVIN W. BRESLIN, Toronto, Canada
M.D.
Many patients with keratitis sicca complain that the commercially available artificial tears burn when they are instilled and fail to relieve their distressing symptoms. We examined the effects of altering both the pH and osmolarity of a hydroxypropyl methylcellulose tear substi tute on the tolerance of 15 patients with varying degrees of keratitis sicca. Approximately equal numbers of patients selected the neutral hypotonie tear preparations and the isotonic or near-isotonic alkaline tear substitutes. The isotonic alkaline tear preparation was preferred by the majority of our patients with moderate or severe dry eyes. A commercially available alkaline tear substitute is needed.
Keratoconjunctivitis sicca is one of the more common distressing clinical prob lems facing the ophthalmologist. The symptoms range from mild ocular irrita tion to severe, disabling ocular pain and visual loss from corneal damage. Al though artificial tears are the main thera py for the dry eye, many patients com plain that the commercially available tear substitutes burn when instilled and fail to provide relief for their discomfort. In an effort to provide our patients with a more comfortable artificial tear, we set out to determine empirically what features of an artificial tear were im portant for improved tolerance by the patient. Having confirmed that an alka line tear substitute was preferred by the majority of our patients with keratitis sicca,1 we then examined the effects of varying both the pH and osmolarity of a hydroxypropyl methylcellulose tear substitute.
SUBJECTS AND METHODS
During an 18-month period, we stud ied 15 patients (three men and 12 women, ranging in age from 27 to 76 years) with keratitis sicca. All had moderate to severe symptoms of burning, foreign-body sensation, photophobia, or dryness associated with rose bengal staining of the cornea and conjunctiva, diminished height of the precorneal tear film meniscus (less than 0.5 mm), and less than 10 mm of wetting by Schirmer strip testing. We asked each subject to grade the symptoms of burning, foreign-body sen sation, dryness, itching, photophobia, tearing, blurred vision and tired eyes as absent, mild, moderate, or severe. Conjunctival injection, conjunctival chemosis, and rose bengal staining of the cor nea, conjunctiva, or both were graded in a similar fashion. The height of the pre corneal tear film meniscus was measured with the variable slit of a slit lamp. All ocular therapy was discontinued 24 From the Department of Ophthalmology, Univer sity of Toronto, and the Toronto Western Hospital, hours before the patient entered the Toronto, Canada. study. The trial was divided into three Reprint requests to Calvin W. Breslin, M.D., 3101 parts and conducted in a randomized, Bloor St. West, Suite 311, Toronto, Ontario, M8X 2W2 Canada. double-masked, cross-over fashion. AMERICAN JOURNAL OF OPHTHALMOLOGY 91:781-784, 1981
781
782
AMERICAN JOURNAL OF OPHTHALMOLOGY
The test solutions were a hydroxypropyl methylcellulose tear substitute with a borax-boric acid buffer system. In part 1 of this study, we examined the patients' ability to tolerate tear substi tutes with a pH of 7.4 and osmolarities of 250, 200, and 150 mOsm/liter (Table 1). Each preparation was used for a twoweek period. The patients were instruct ed to instill the drops as often as neces sary but no less than four times per day. At the conclusion of each two-week peri od, we evaluated the patients' symptoms and the slit-lamp findings. The patients were asked which solution they pre ferred. Part 2 was conducted in a similar man ner and involved comparing the patients' stated preferences from part 1 with an isotonic (300 mOsm) alkaline tear substi tute with a p H of 8.4 (Table 1). Alkaline artificial tears with approximately this p H have been well tolerated by patients with dry eyes.1"3 In the final phase of this project, we compared the patients' ability to tol erate tear substitutes with a p H of 8.4 and osmolarities of 250, 200, and 150 mOsm/liter (Table 1). The patients were then asked to state their overall preference. RESULTS
Of the 15 patients, 14 expressed a preference after completing part 1 of this
JUNE, 1981
study. Six selected the 250-mOsm solu tion, four chose the 200-mOsm solution, and four preferred the 150-mOsm solu tion. We then correlated these preferences with the clinical severity of the symptoms as determined by the patients' subjec tive responses. The results are shown in Table 2. Each patient's preferred osmolarity so lution at p H 7.4 was then compared with an isotonic (300 mOsm) alkaline tear sub stitute with a p H of 8.4. Seven of 14 patients selected the alkaline artificial tear as the most comfortable. Of these, five had originally selected the 250mOsm solution and two the 200-mOsm solution. Of the seven other patients who chose the neutral (pH 7.4) tear substitute, one selected the 250-mOsm solution, two chose the 200-mOsm solution, and four preferred the 150-mOsm solution. These results and the relationship between clin ical severity and osmolarity preference are shown in Table 2. Interestingly, the four patients who had preferred the 150mOsm solution at p H 7.4 in part 1 made the same choice in part 2. The final phase of this project com pared the patients' ability to tolerate arti ficial tears with a p H of 8.4 and varying osmolarities. Twelve of 14 patients ex pressed a preference in this part of the study. Seven of 12 patients selected the 250-mOsm solution, three chose the 200-
TABLE 1 COMPOSITION OF TEAR SUBSTITUTES
At pH 7.4 Constituents
250
Sodium chloride Potassium chloride Borax Boric acid Hydroxypropyl methylcellulose Benzalkonium chloride Purified water
4.18 g 2.23 g 0.2 g 3.0 g 3.0 g 0.2 ml
200 3.2 1.48 0.2 3.0 3.0 0.2
Osmolarity (mOsm/liter) At pH 8.4 150
g 2.49 g g 0.53 g g 0.2 g g 3.0 g g 3.0 g ml 0.2 ml Eno ugh to reach
300 4.5 g 3.7 g 2.0 g 2.5 g 3.0 g 0.2 ml a volume
250
200
3.0 g 2.31 g 2.5 g 1.46 g 2.5 g 2.5 g 2.5 g 2.5 g 3.0 g 3.0 f 0.2 ml 0.2 ml of 1,000 ml
150 1.57 g 0.53 g 2.5 g 2.5 g 3.0 g 0.2
VOL. 9 1 , NO. 6
ARTIFICIAL TEAR TOLERANCE
783
TABLE 2 CLINICAL SEVERITY OF SYMPTOMS AND OSMOLARITY PREFERENCES
Preferred Osmolarity (mOsm/liter)
PH
Mild
Moderate
Severe
150 200 250
7.4 7.4 7.4
Part 1 of Study 2 1 1
1 2 3
1 1 2
150 200 250 300
7.4 7.4 7.4 8.4
Part 2 of Study 2 0 0 2
1 2 1 2
1 0 0 3
150 200 250
8.4 8.4 8.4
Part 3 of Study 1 1 1
1 0 4
0 2 2
No. of Patients With Keratitis Sicca
mOsm solution, and two preferred the 150-mOsm solution (Table 2). DISCUSSION
The search for the ideal artificial tear has led to an emphasis on the develop ment of tear substitutes that mimic the composition of normal tears. Normal tears are iso-osmotic with a mean pH value of 7.0.4,5 Commercial tear substi tutes vary in their polymer content and viscosity, but tend to be isotonic with a pH ranging from neutral to acid (Table 3). Unfortunately, many patients with kerati tis sicca complain that these tear preparaTABLE3 OSMOLARITY AND P H O F COMMERCIAL TEAR SUBSTITUTES
Product
PH
Osmolarity
Adsorbotear Isopto-Tears 0.5% Isopto-Tears 1.0% Tears Naturale Liquifilm Tears Liquifilm Forte Lyteers Hypotears
7.23 7.45 7.50 6.91 4.66 5.41 7.34 7.00
Isotonic Isotonic Isotonic Isotonic Isotonic Isotonic Isotonic Hypotonie
tions burn when they are instilled and tend to aggravate rather than relieve their ocular discomfort. Jones and Coop2 were the first to dem onstrate the value of an alkaline artificial tear in the treatment of patients with dry eyes. Their preparation was a carboxymethylcellulose tear substitute with a bicarbonate buffer system. A major prob lem with this product was that the bicar bonate buffer was heat-labile, creating problems with heat sterilization. This led to the development of a hydroxypropyl methylcellulose tear substitute with a borax-boric acid buffer system.3 This preparation has a pH of 8.5 and is mar keted in the United Kingdom under the trade name of Hypromellose. Unfortunately, a comparable tear sub stitute is not yet commercially available in North America. This study, based sole ly on the patients' subjective responses, confirmed the value of an alkaline iso tonic tear substitute in treating keratitis sicca, especially in patients with moder ately severe complaints. Hypotonie saline has been used in con junction with hydrophilic bandage lenses to treat severe dry eyes with excellent
784
AMERICAN JOURNAL OF OPHTHALMOLOGY
results. 6 We have also successfully used half-normal saline solutions to control the symptoms of dry eye in our patients who wear cosmetic hydrogel contact lenses. One possible explanation of the success of hypotonie saline in these situations is that patients with keratitis sicca have hypertonic tears. 7 Furthermore, Gilbard and Farris 8 found that four of five patients with severe keratitis sicca preferred a half-normal saline tear substitute to an isotonic neutral tear substitute. 8 Our results supported the view that a hypotonie tear substitute is a valuable therapeutic alternative in treating dry eyes. The majority of our patients with moderately severe dry eyes, however, preferred the isotonic or near-isotonic alkaline tear substitute to the half-normal saline, pH-neutral artificial tear. Part of this difference may be explained by the different methods used to determine clin ical severity. In our series, clinical severi ty was determined by the patients' sub jective responses rather than by rose bengal staining of the cornea and con junctiva. We have found that objective slit-lamp findings correlate poorly with the severity of the patients' complaints. It is clear that no one tear preparation is consistently better tolerated. The pref erences of the patients may change, prob
JUNE, 1981
ably reflecting the fluctuating nature of keratoconjunctivitis sicca. We have, how ever, demonstrated the value of a hypotonic neutral artificial tear and an isotonic alkaline tear substitute in treating pa tients with dry eyes. The isotonic alkaline tear substitute is especially valuable in those patients with moderately severe disease. A hypotonie tear substitute is now commercially available, and there is a need for an isotonic alkaline tear substi tute as well. REFERENCES 1. Raber, I., and Breslin, C. W.: Toleration of artificial tears. The effect of pH. Can. J. Ophthalmol. 13:247, 1978. 2. Jones, B. R., and Coop, H. V.: The manage ment of keratoconjunctivitis sicca. Trans. Ophthal mol. Soc. U.K. 85:379, 1965. 3. Wright, P.: Diagnosis and treatment of dry eyes. Trans. Ophthalmol. Soc. U.K. 91:119, 1971. 4. Carney, L. G., and Hill, R. M.: Human tear pH. Diurnal variations. Arch. Ophthalmol. 94:821, 1976. 5. Abelson, M. B., Udell, I. J., and Weston, J. H.: Normal human tear pH by direct measure ment. Arch. Ophthalmol. 99:301, 1981. 6. Gasset, A. R., and Kaufman, H. E.: Hydrophilic lens therapy of severe keratoconjunctivitis sicca and'eonjunctival scarring. Am. J. Ophthalmol. 61:1185, 1971. 7. Gilbard, J. P., Earris, R. L., and Santamaria, J.: Osmolarity of tear microvolumes in keratocon junctivitis sicca. Arch. Ophthalmol. 96:677, 1978. 8. Gilbard, J. P., and Farris, R. L.: Tear osmolar ity and ocular surface disease in keratoconjunctivitis sicca. Arch. Ophthalmol. 97:1642, 1979.
M.D.
Many patients with keratitis sicca complain that the commercially available artificial tears burn when they are instilled and fail to relieve their distressing symptoms. We examined the effects of altering both the pH and osmolarity of a hydroxypropyl methylcellulose tear substi tute on the tolerance of 15 patients with varying degrees of keratitis sicca. Approximately equal numbers of patients selected the neutral hypotonie tear preparations and the isotonic or near-isotonic alkaline tear substitutes. The isotonic alkaline tear preparation was preferred by the majority of our patients with moderate or severe dry eyes. A commercially available alkaline tear substitute is needed.
Keratoconjunctivitis sicca is one of the more common distressing clinical prob lems facing the ophthalmologist. The symptoms range from mild ocular irrita tion to severe, disabling ocular pain and visual loss from corneal damage. Al though artificial tears are the main thera py for the dry eye, many patients com plain that the commercially available tear substitutes burn when instilled and fail to provide relief for their discomfort. In an effort to provide our patients with a more comfortable artificial tear, we set out to determine empirically what features of an artificial tear were im portant for improved tolerance by the patient. Having confirmed that an alka line tear substitute was preferred by the majority of our patients with keratitis sicca,1 we then examined the effects of varying both the pH and osmolarity of a hydroxypropyl methylcellulose tear substitute.
SUBJECTS AND METHODS
During an 18-month period, we stud ied 15 patients (three men and 12 women, ranging in age from 27 to 76 years) with keratitis sicca. All had moderate to severe symptoms of burning, foreign-body sensation, photophobia, or dryness associated with rose bengal staining of the cornea and conjunctiva, diminished height of the precorneal tear film meniscus (less than 0.5 mm), and less than 10 mm of wetting by Schirmer strip testing. We asked each subject to grade the symptoms of burning, foreign-body sen sation, dryness, itching, photophobia, tearing, blurred vision and tired eyes as absent, mild, moderate, or severe. Conjunctival injection, conjunctival chemosis, and rose bengal staining of the cor nea, conjunctiva, or both were graded in a similar fashion. The height of the pre corneal tear film meniscus was measured with the variable slit of a slit lamp. All ocular therapy was discontinued 24 From the Department of Ophthalmology, Univer sity of Toronto, and the Toronto Western Hospital, hours before the patient entered the Toronto, Canada. study. The trial was divided into three Reprint requests to Calvin W. Breslin, M.D., 3101 parts and conducted in a randomized, Bloor St. West, Suite 311, Toronto, Ontario, M8X 2W2 Canada. double-masked, cross-over fashion. AMERICAN JOURNAL OF OPHTHALMOLOGY 91:781-784, 1981
781
782
AMERICAN JOURNAL OF OPHTHALMOLOGY
The test solutions were a hydroxypropyl methylcellulose tear substitute with a borax-boric acid buffer system. In part 1 of this study, we examined the patients' ability to tolerate tear substi tutes with a pH of 7.4 and osmolarities of 250, 200, and 150 mOsm/liter (Table 1). Each preparation was used for a twoweek period. The patients were instruct ed to instill the drops as often as neces sary but no less than four times per day. At the conclusion of each two-week peri od, we evaluated the patients' symptoms and the slit-lamp findings. The patients were asked which solution they pre ferred. Part 2 was conducted in a similar man ner and involved comparing the patients' stated preferences from part 1 with an isotonic (300 mOsm) alkaline tear substi tute with a p H of 8.4 (Table 1). Alkaline artificial tears with approximately this p H have been well tolerated by patients with dry eyes.1"3 In the final phase of this project, we compared the patients' ability to tol erate tear substitutes with a p H of 8.4 and osmolarities of 250, 200, and 150 mOsm/liter (Table 1). The patients were then asked to state their overall preference. RESULTS
Of the 15 patients, 14 expressed a preference after completing part 1 of this
JUNE, 1981
study. Six selected the 250-mOsm solu tion, four chose the 200-mOsm solution, and four preferred the 150-mOsm solu tion. We then correlated these preferences with the clinical severity of the symptoms as determined by the patients' subjec tive responses. The results are shown in Table 2. Each patient's preferred osmolarity so lution at p H 7.4 was then compared with an isotonic (300 mOsm) alkaline tear sub stitute with a p H of 8.4. Seven of 14 patients selected the alkaline artificial tear as the most comfortable. Of these, five had originally selected the 250mOsm solution and two the 200-mOsm solution. Of the seven other patients who chose the neutral (pH 7.4) tear substitute, one selected the 250-mOsm solution, two chose the 200-mOsm solution, and four preferred the 150-mOsm solution. These results and the relationship between clin ical severity and osmolarity preference are shown in Table 2. Interestingly, the four patients who had preferred the 150mOsm solution at p H 7.4 in part 1 made the same choice in part 2. The final phase of this project com pared the patients' ability to tolerate arti ficial tears with a p H of 8.4 and varying osmolarities. Twelve of 14 patients ex pressed a preference in this part of the study. Seven of 12 patients selected the 250-mOsm solution, three chose the 200-
TABLE 1 COMPOSITION OF TEAR SUBSTITUTES
At pH 7.4 Constituents
250
Sodium chloride Potassium chloride Borax Boric acid Hydroxypropyl methylcellulose Benzalkonium chloride Purified water
4.18 g 2.23 g 0.2 g 3.0 g 3.0 g 0.2 ml
200 3.2 1.48 0.2 3.0 3.0 0.2
Osmolarity (mOsm/liter) At pH 8.4 150
g 2.49 g g 0.53 g g 0.2 g g 3.0 g g 3.0 g ml 0.2 ml Eno ugh to reach
300 4.5 g 3.7 g 2.0 g 2.5 g 3.0 g 0.2 ml a volume
250
200
3.0 g 2.31 g 2.5 g 1.46 g 2.5 g 2.5 g 2.5 g 2.5 g 3.0 g 3.0 f 0.2 ml 0.2 ml of 1,000 ml
150 1.57 g 0.53 g 2.5 g 2.5 g 3.0 g 0.2
VOL. 9 1 , NO. 6
ARTIFICIAL TEAR TOLERANCE
783
TABLE 2 CLINICAL SEVERITY OF SYMPTOMS AND OSMOLARITY PREFERENCES
Preferred Osmolarity (mOsm/liter)
PH
Mild
Moderate
Severe
150 200 250
7.4 7.4 7.4
Part 1 of Study 2 1 1
1 2 3
1 1 2
150 200 250 300
7.4 7.4 7.4 8.4
Part 2 of Study 2 0 0 2
1 2 1 2
1 0 0 3
150 200 250
8.4 8.4 8.4
Part 3 of Study 1 1 1
1 0 4
0 2 2
No. of Patients With Keratitis Sicca
mOsm solution, and two preferred the 150-mOsm solution (Table 2). DISCUSSION
The search for the ideal artificial tear has led to an emphasis on the develop ment of tear substitutes that mimic the composition of normal tears. Normal tears are iso-osmotic with a mean pH value of 7.0.4,5 Commercial tear substi tutes vary in their polymer content and viscosity, but tend to be isotonic with a pH ranging from neutral to acid (Table 3). Unfortunately, many patients with kerati tis sicca complain that these tear preparaTABLE3 OSMOLARITY AND P H O F COMMERCIAL TEAR SUBSTITUTES
Product
PH
Osmolarity
Adsorbotear Isopto-Tears 0.5% Isopto-Tears 1.0% Tears Naturale Liquifilm Tears Liquifilm Forte Lyteers Hypotears
7.23 7.45 7.50 6.91 4.66 5.41 7.34 7.00
Isotonic Isotonic Isotonic Isotonic Isotonic Isotonic Isotonic Hypotonie
tions burn when they are instilled and tend to aggravate rather than relieve their ocular discomfort. Jones and Coop2 were the first to dem onstrate the value of an alkaline artificial tear in the treatment of patients with dry eyes. Their preparation was a carboxymethylcellulose tear substitute with a bicarbonate buffer system. A major prob lem with this product was that the bicar bonate buffer was heat-labile, creating problems with heat sterilization. This led to the development of a hydroxypropyl methylcellulose tear substitute with a borax-boric acid buffer system.3 This preparation has a pH of 8.5 and is mar keted in the United Kingdom under the trade name of Hypromellose. Unfortunately, a comparable tear sub stitute is not yet commercially available in North America. This study, based sole ly on the patients' subjective responses, confirmed the value of an alkaline iso tonic tear substitute in treating keratitis sicca, especially in patients with moder ately severe complaints. Hypotonie saline has been used in con junction with hydrophilic bandage lenses to treat severe dry eyes with excellent
784
AMERICAN JOURNAL OF OPHTHALMOLOGY
results. 6 We have also successfully used half-normal saline solutions to control the symptoms of dry eye in our patients who wear cosmetic hydrogel contact lenses. One possible explanation of the success of hypotonie saline in these situations is that patients with keratitis sicca have hypertonic tears. 7 Furthermore, Gilbard and Farris 8 found that four of five patients with severe keratitis sicca preferred a half-normal saline tear substitute to an isotonic neutral tear substitute. 8 Our results supported the view that a hypotonie tear substitute is a valuable therapeutic alternative in treating dry eyes. The majority of our patients with moderately severe dry eyes, however, preferred the isotonic or near-isotonic alkaline tear substitute to the half-normal saline, pH-neutral artificial tear. Part of this difference may be explained by the different methods used to determine clin ical severity. In our series, clinical severi ty was determined by the patients' sub jective responses rather than by rose bengal staining of the cornea and con junctiva. We have found that objective slit-lamp findings correlate poorly with the severity of the patients' complaints. It is clear that no one tear preparation is consistently better tolerated. The pref erences of the patients may change, prob
JUNE, 1981
ably reflecting the fluctuating nature of keratoconjunctivitis sicca. We have, how ever, demonstrated the value of a hypotonic neutral artificial tear and an isotonic alkaline tear substitute in treating pa tients with dry eyes. The isotonic alkaline tear substitute is especially valuable in those patients with moderately severe disease. A hypotonie tear substitute is now commercially available, and there is a need for an isotonic alkaline tear substi tute as well. REFERENCES 1. Raber, I., and Breslin, C. W.: Toleration of artificial tears. The effect of pH. Can. J. Ophthalmol. 13:247, 1978. 2. Jones, B. R., and Coop, H. V.: The manage ment of keratoconjunctivitis sicca. Trans. Ophthal mol. Soc. U.K. 85:379, 1965. 3. Wright, P.: Diagnosis and treatment of dry eyes. Trans. Ophthalmol. Soc. U.K. 91:119, 1971. 4. Carney, L. G., and Hill, R. M.: Human tear pH. Diurnal variations. Arch. Ophthalmol. 94:821, 1976. 5. Abelson, M. B., Udell, I. J., and Weston, J. H.: Normal human tear pH by direct measure ment. Arch. Ophthalmol. 99:301, 1981. 6. Gasset, A. R., and Kaufman, H. E.: Hydrophilic lens therapy of severe keratoconjunctivitis sicca and'eonjunctival scarring. Am. J. Ophthalmol. 61:1185, 1971. 7. Gilbard, J. P., Earris, R. L., and Santamaria, J.: Osmolarity of tear microvolumes in keratocon junctivitis sicca. Arch. Ophthalmol. 96:677, 1978. 8. Gilbard, J. P., and Farris, R. L.: Tear osmolar ity and ocular surface disease in keratoconjunctivitis sicca. Arch. Ophthalmol. 97:1642, 1979.