Effects of Sodium Hyaluronate on Tympanic Membrane Perforations MP
RIVAS LACARTE\
T
CASASIN2 AND A ALONS0 3
'Department of Otorhinolaryngology, Viladecans Hospital, Barcelona, Spain; 2Department of Pharmacy, Viladecans Hospital, Barcelona, Spain; "Department of Statistics, Viladecans Hospital, Barcelona, Spain
The effects oftopically applied 1 % sodium hyaluronate as an alternative treatment to surgery for tympanic membrane perforations was studied. In an open study, the inclusion criteria were increased by accepting patients previously treated by surgery or with placebo and, compared with a previous study, the frequency at which sodium hyaluronate was applied was reduced. Reduction in the size of the perforation was detected in 12/16 (75.0%) patients, six (37.5%) of whom showed complete tympanic healing, and in the remaining four (25.0%) there was no healing. The average percentage reduction in the perforation area was 80.5%. The two factors altered in this trial, i.e. inclusion criteria and frequency of administration of treatment, had little influence on the degree of membrane healing. KEY
WORDS:
SODIUM HYALURONATE;
TYMPANIC MEMBRANE
PERFORATION; WOUND HEALING
INTRODUCTION different studies have been published supporting the topical application of healing products as an alternative to surgery.' - 6 It seems that the best results have been obtained
Tympanic membrane perforation is a common disease arising from a variety of causes and which, in some cases, may require surgical treatment. In the last 3 years, however,
353 Downloaded from imr.sagepub.com by guest on December 19, 2015
TREATMENT
following the application of hyaluronic acid.' -" Preliminary studies carried out in animals ' ° showed a significant increase in tympanic membrane healing when hyaluronic acid was used. Subsequent studies indicated that the technique had no harmful effects on the middle and inner ears,"'!' and could be employed in humans. ' - :l.5.n -lb An improvement, measured as the percentage reduction in the total perforated area of the tympanic membrane, achieved using topically applied hyaluronic acid in a double-blind study has previously been reported'" The present study concentrates on whether or not the improvement can be affected by the alteration of certain parameters.
The topical treatment consisted of a sterile aqueous solution of 1% sodium hyaluronate (pH 7.25 - 7.5) prepared by the Hospital Pharmacy Service. All the solutions were checked for the absence of bacteriological contamination by the Hospital Microbiological Service and were stored at a temperature of between 2°C and 8°C until the time of use. To facilitate the application of the solution, syringes were filled with 0.3 ml 1% sodium hyaluronate which was then administered in the operating theatre with the aid of an 01ympus OME-GA microscope equipped with a 170 OME-GWHI0X and a OME-GWH-I0XCD lens for the measurement of the area of the perforation. Patients were treated at 72-h intervals (in the previous study the interval was 48 h) for a maximum period of 1 month; however, treatment was discontinued if healing was achieved. Patients were monitored weekly for 1 month following the end of the treatment and, subsequently, at monthly intervals for a period of 6 months.
PATIENTS AND METHODS PATIENTS A total of16 patients (11 male, five female; age range 10 - 60 years) were enrolled in the study; the patients were all out-patients attending the Otorhinolaryngology Department, Viladecans Hospital, Barcelona. Inclusion criteria included: dry tympanic perforation; perforation of more than 2 months' duration; and perforation size smaller than a tympanic quadrant. Patients were excluded on the basis of changes in the perforation characteristic between enrolment and the start of treatment, and deviations from treatment protocol (> 30% of failures). Patients who had previously received medical or surgical treatment were accepted in the study (these cases would have been rejected in the previous double-blind study":"). Of these patients, three had been treated with placebo but without success in the previous study and another two patients had undergone surgery (myringoplasty or insertion of a transtympanic ventilation tube).
EFFICACY ASSESSMENT The characteristics of the perforation were assessed prior to treatment on the basis of aetiology (acute otitis media, chronic otitis media, traumatic perforation, perforation after myringotomy, perforation after myringoplasty, other), date ofthe appearance of the perforation, size of the perforation (small perforation meaning less than half a quadrant, medium perforation meaning between half a quadrant and a whole quadrant), and situation of the perforation (central or marginal quadrant). A clinical evaluation, which included an assessment of the size of the perforation area in mm' and any indications of healing, was made after treatment. The area of perforation was defined as the product of the largest and smallest diameters of the tympanic hole. The difference between areas before and after
354 Downloaded from imr.sagepub.com by guest on December 19, 2015
treatment determined the percentage improvement.
A total offour (25.0%) patients had small tympanic membrane perforations; two of them healed and in the other two there was a reduction in the area of the perforation. The remaining 12 patients had medium-sized perforations; of these, four healed completely, four healed partially, and four cases did not at all. Central perforations were observed in nine patients; of these four healed, two had a partial reduction in the size of the perforation and in three cases treatment failed. Marginal perforations were found in seven patients: treatment was successful in two of them; four had a partial healing; and one did not change.
STA TIS TICAL ANALYSIS Results were analysed using the Student's itest (quantitative variables) and the x'-test (quantitative variables).
RESULTS Patient characteristics, including details of the tympanic perforations, are shown in Table 1. The results of treatment are shown in Table 2. In 12/16 (75.0%) patients, a reduction in the size of the perforation was achieved with complete healing being evident in the six (37.5%) patients treated with 1% sodium hyaluronate; there was no change in the size of the perforation in four (25.0%) patients. The average percentage reduction in area was 80.5%. Only partial healing was obtained in the three patients who had been previously treated; in previously placebo-treated patients the mean reduction of the area was 54%. The patient (No.7) who had previously undergone myringoplasty showed 100% reduction in the size of the perforation and the perforation was, therefore, considered healed. This was not the case for the patient with a previous transtympanic ventilation tube, in whom there was no evidence of reduction in the size of the perforation. As far as aetiology was concerned, tympanic perforation was due to acute otitis media in six patients and in this treatment group total healing was achieved in four (66.6%) patients, whereas in the other two (33.3%) patients there was no change. Of the group of eight patients suffering from chronic otitis media, one (12.5%) patient was healed, six (75.0%) patients had some degree of reduction and in one (12.5%) patient there was no change.
DISCUSSION The hyaluronic acid-treated perforations closed better than did untreated controls,'? with the formation of hyperplastic stratified squamous epithelium supported by granulation ti ssue.I''-" Application of hyaluronic acid results in the formation of a bridge to bring about these mechanisms and greatly accelerates the rate of healing. The variation in the concentration of the solution and hence the viscosity appears to be important in the structural quality of the healed perforation. ' 5 . 17 The application of rice paper has been shown to have a beneficial effect in only 20% of patients, resulting in a thicker tympanic membrane,' and the application of fibronectin has been found to have no stimulatory effect on percentage healing." The present study provides additional support for the use of topically applied sodiurn hyaluronate as an alternative to surgery for selected patients with tympanic membrane perforations, i.e. those with small perforations, dry perforations, and acute or traumatic perforations. Criteria for inclusion in the study were modified in the present study compared with a previous double-blind 'study; treatment
355 Downloaded from imr.sagepub.com by guest on December 19, 2015
Downloaded from imr.sagepub.com by guest on December 19, 2015
Q-r O'l
"-l
49 32 36 47 17 13 54 28 60 54 13
11
53 38 60 38
Age (years) M M M M M M F M M M M F F M F F
Sex L R R R R R R L L L R L L L R R
Side COM COM COM COM AOM AOM MYR AOM COM AOM TVT AOM AOM COM COM AOM
Cause Small Medium Medium Medium Medium Medium Small Small Medium Medium Medium Medium Medium Small Medium Medium
Size 0.04 0.28 0.15 0.84 0.48 0.48 0.06 0.09 0.20 0.35 0.48 1.69 0.30 0.04 0.88 0.48
Area (rnm-) C-SA M-2A M-SP M-2A M-SA C-SA C-SP C-IP M-SA M-SP C-SP C-SP C-SP M-SP C-IP C-SP
Situation
40 years Unknown Unknown Unknown 14 months 3 months 2 years 4 months 7 years 6 months 4 years 10 years 3 months 20 years 2 years 20 months
Duration
M, marginal; S, superior; I, inferior; A, anterior; P, posterior.
M, male; F, female; L, left; R, right; COM, chronic otitis media; AOM, acute otitis media; MYR, myringoplasty; TVT, transtympanic ventilation tube; C, central;
12 13 14 15 16
11
1 2 3 4 5 6 7 8 9 10
Patient No.
Tympanic perforation
Demographic data for 16 patients with tympanic perforation treated with 0.3 m11% sodium hyaluronate at intervals of 72 h for
up to 1 month
Downloaded from imr.sagepub.com by guest on December 19, 2015
'1
"-l
QJ
8 8
6 9 6 9 9
8 8
5
8
7 9
8 8
6
No. of applications
TVT, transtympanic ventilation tube.
9 10 11 12 13 14 15 16
8
1 2 3 4 5 6 7
Patient No. Closed Reduction Reduction Same Closed Closed Closed Reduction Reduction Closed Same Closed Same Reduction Reduction Same
Evaluation
100 36 73 0 100 100 100 63 90 100 0 100 0 50 54 0
Reduction (%)
Tympanic perforation
Normal Normal Tympanosclerosis Normal Normal Normal Normal Normal Tympanosclerosis Normal Normal Fragile tissue Same Tympanosclerosis Normal Normal
Status of tympanic membrane
TVT
Placebo
Myringoplasty
Placebo Placebo
Previous treatment
Effects of 0.3 m11% sodium hyaluronate applied topically at 72 h intervals for up to 1 month on tympanic perforation in 16 patients.
intervals of 72 h instead of 48 h were used and inclusion of patients who had previously received surgical or medical treatment was permitted. The results of the present study indicate that neither of these variables appeared to have any influence on the results. A total of 74% of patients benefited from treatment with sodium hyaluronate in that a reduction or com plete healing of the tympanic perforation was detected. The average percentage reduction in the perforation area
was 80.5%. This is comparable to a previous double-blind study carried out, in which a reduction in the perforation area of 83 ± 26% (P < 0.001) was recorded compared with placebo-treated patients.' '" The fact that the reduction in the frequency of application of the treatment from 48 h to 72 h did not lead to any decline in efficacy means a reduction in the use of hospital facilities and less inconvenience to the patient.
REFERENCES 1 Stenfors LE:Repair of tympanic membrane perforations using hyaluronic acid: an alternative to myringoplasty. J Laryngol Oto11989; 103: 39 - 40. 2 Stenfors LE: Treatment of tympanic membrane perforations with hyaluronan in an open pilot study of unselected patients. Acta Otolaryngol (Stockh) 1987; 442: 81 - 87. 3 Soderberg 0, Laurent C, Anniko M, et al: Hyaluronan versus rice paper: a clinical study on the healing of persistent tympanic membrane perforations. XIV World Congress ofOtorhinolaryngology, Madrid, 10 - 15 September 1989. 4 Laurent C, Soderberg 0, Anniko M, et al: Repair of chronic tympanic membrane perforations using application of hyaluronan or rice paper prothesis. ORL 1991; 53: 37 - 40. 5 Rivas MP, Casasin T, Pumarola F, et al: An alternative treatment for the reduction of the tympanic membrane perforations: sodium hyaluronate: a double-blind study. Acta Otolaryngol (Stockh) 1990; 110: 110
- 114. 6 Hellstrom S, Bloom GD, Berghem L, et al: Comparison between hyaluronan and fibronectin in the repair of tympanic membrane perforations. Eur Arch Otorhinolaryngol1991; 248: 231 - 236. 7 Gibbs DA, Merill EW, Smith KA, et al: Rheology of hyaluronic acid. Biopolymers 1968; 6: 777 - 791. 8 Hakansson L, Hallagren R, Venge P: Regulation of granulocyte function by hyaluronic acid: in vivo and in vitro effects of phagocytosis, locomotion and metabolism. J Clin Invest 1980; 66: 298 305. 9 Morris ER, Ress DA, Wels EJ: Conformation and dynamic interactions in hyaluronate solutions. J Mol BioI 1980; 138: 383 - 400. 10 Stenfors LE, Berghem L, Bloom GD, et al: Exogenous hyaluronic acid (Heal on) acclerates the healing of experimental myringotomies. Auris-Nasus-Larynx (Tokyo) 1985; 12(suppl): 217 - 218. 11 Laurent C, Hellstrom S, Appelgren LE, et
358 Downloaded from imr.sagepub.com by guest on December 19, 2015
M P Rivas Lacorte. T Cososin, A Alcmso Sodium hyaluronate and ty.mpani~ perforation
12
13
14
15
a1: Fate of exogenous hyaluronic acid in the middle ear. Am J Oto1aryngo11986; 7: 334 - 340. Laurent C, Hellstrom S, Anniko M: Inner ear effects of exogenous hyaluronan in the middle ear of the rat. Acta Oto1aryngo1 (Stockh) 1988; 105: 273 - 280. Stenfors LE: Repair of traumatically ruptured tympanic membrane using hyaluronan. Acta Oto1aryngo1 [Supp1} (Stockh) 1987; 442: 88 - 91. Rivas MP, Casasin T, Pumarola F, et a1: Tratamiento de las perforaci ones timpani cas con hiarluronato sodico. I. Relacion con la etiologia de la perforacion. II. Audiometria antes y despues del tratamiento. ORL-DIPS Internaciona11989; 5: 229 - 234. Hellstrom S, Laurent C: Hyaluronan and healing of tympanic membrane perforations: an experimental study. Acta
Oto1aryngo1 [Supp1} (Stockh) 1987; 442: 54 - 61. 16 Casasin T, Rivas MP, Noguera MM: Treatment of small tympanic membrane perforation with sodium hyaluronate. Pharm Weekb1 [Sci} 1990; 12: G21. 17 Laurent C, Hellstrom S, Fellenius E: Hyaluronan improves the healing of experimental membrane perforations. Arch Oto1aryngo1 Head Neck Surg 1988; 1435 - 1441.
M P Rivas Lacarte, T Casasin and A Alonso Effects of Sodium Hyaluronate on Tympanic Membrane Perforations The Journal of International Medical Research 1992; 20: 353 - 359 Received for publication 12 December 1991 Accepted 13 March 1992 © Copyright 1992 Cambridge Medical Publications
Address for correspondence DR M P RIVAS LACARTE Department of Otorhinolaryngology, Viladecans Hospital, Avenida Gava 38, Viladecans, 08840 Barcelona, Spain.
359 Downloaded from imr.sagepub.com by guest on December 19, 2015
RIVAS LACARTE\
T
CASASIN2 AND A ALONS0 3
'Department of Otorhinolaryngology, Viladecans Hospital, Barcelona, Spain; 2Department of Pharmacy, Viladecans Hospital, Barcelona, Spain; "Department of Statistics, Viladecans Hospital, Barcelona, Spain
The effects oftopically applied 1 % sodium hyaluronate as an alternative treatment to surgery for tympanic membrane perforations was studied. In an open study, the inclusion criteria were increased by accepting patients previously treated by surgery or with placebo and, compared with a previous study, the frequency at which sodium hyaluronate was applied was reduced. Reduction in the size of the perforation was detected in 12/16 (75.0%) patients, six (37.5%) of whom showed complete tympanic healing, and in the remaining four (25.0%) there was no healing. The average percentage reduction in the perforation area was 80.5%. The two factors altered in this trial, i.e. inclusion criteria and frequency of administration of treatment, had little influence on the degree of membrane healing. KEY
WORDS:
SODIUM HYALURONATE;
TYMPANIC MEMBRANE
PERFORATION; WOUND HEALING
INTRODUCTION different studies have been published supporting the topical application of healing products as an alternative to surgery.' - 6 It seems that the best results have been obtained
Tympanic membrane perforation is a common disease arising from a variety of causes and which, in some cases, may require surgical treatment. In the last 3 years, however,
353 Downloaded from imr.sagepub.com by guest on December 19, 2015
TREATMENT
following the application of hyaluronic acid.' -" Preliminary studies carried out in animals ' ° showed a significant increase in tympanic membrane healing when hyaluronic acid was used. Subsequent studies indicated that the technique had no harmful effects on the middle and inner ears,"'!' and could be employed in humans. ' - :l.5.n -lb An improvement, measured as the percentage reduction in the total perforated area of the tympanic membrane, achieved using topically applied hyaluronic acid in a double-blind study has previously been reported'" The present study concentrates on whether or not the improvement can be affected by the alteration of certain parameters.
The topical treatment consisted of a sterile aqueous solution of 1% sodium hyaluronate (pH 7.25 - 7.5) prepared by the Hospital Pharmacy Service. All the solutions were checked for the absence of bacteriological contamination by the Hospital Microbiological Service and were stored at a temperature of between 2°C and 8°C until the time of use. To facilitate the application of the solution, syringes were filled with 0.3 ml 1% sodium hyaluronate which was then administered in the operating theatre with the aid of an 01ympus OME-GA microscope equipped with a 170 OME-GWHI0X and a OME-GWH-I0XCD lens for the measurement of the area of the perforation. Patients were treated at 72-h intervals (in the previous study the interval was 48 h) for a maximum period of 1 month; however, treatment was discontinued if healing was achieved. Patients were monitored weekly for 1 month following the end of the treatment and, subsequently, at monthly intervals for a period of 6 months.
PATIENTS AND METHODS PATIENTS A total of16 patients (11 male, five female; age range 10 - 60 years) were enrolled in the study; the patients were all out-patients attending the Otorhinolaryngology Department, Viladecans Hospital, Barcelona. Inclusion criteria included: dry tympanic perforation; perforation of more than 2 months' duration; and perforation size smaller than a tympanic quadrant. Patients were excluded on the basis of changes in the perforation characteristic between enrolment and the start of treatment, and deviations from treatment protocol (> 30% of failures). Patients who had previously received medical or surgical treatment were accepted in the study (these cases would have been rejected in the previous double-blind study":"). Of these patients, three had been treated with placebo but without success in the previous study and another two patients had undergone surgery (myringoplasty or insertion of a transtympanic ventilation tube).
EFFICACY ASSESSMENT The characteristics of the perforation were assessed prior to treatment on the basis of aetiology (acute otitis media, chronic otitis media, traumatic perforation, perforation after myringotomy, perforation after myringoplasty, other), date ofthe appearance of the perforation, size of the perforation (small perforation meaning less than half a quadrant, medium perforation meaning between half a quadrant and a whole quadrant), and situation of the perforation (central or marginal quadrant). A clinical evaluation, which included an assessment of the size of the perforation area in mm' and any indications of healing, was made after treatment. The area of perforation was defined as the product of the largest and smallest diameters of the tympanic hole. The difference between areas before and after
354 Downloaded from imr.sagepub.com by guest on December 19, 2015
treatment determined the percentage improvement.
A total offour (25.0%) patients had small tympanic membrane perforations; two of them healed and in the other two there was a reduction in the area of the perforation. The remaining 12 patients had medium-sized perforations; of these, four healed completely, four healed partially, and four cases did not at all. Central perforations were observed in nine patients; of these four healed, two had a partial reduction in the size of the perforation and in three cases treatment failed. Marginal perforations were found in seven patients: treatment was successful in two of them; four had a partial healing; and one did not change.
STA TIS TICAL ANALYSIS Results were analysed using the Student's itest (quantitative variables) and the x'-test (quantitative variables).
RESULTS Patient characteristics, including details of the tympanic perforations, are shown in Table 1. The results of treatment are shown in Table 2. In 12/16 (75.0%) patients, a reduction in the size of the perforation was achieved with complete healing being evident in the six (37.5%) patients treated with 1% sodium hyaluronate; there was no change in the size of the perforation in four (25.0%) patients. The average percentage reduction in area was 80.5%. Only partial healing was obtained in the three patients who had been previously treated; in previously placebo-treated patients the mean reduction of the area was 54%. The patient (No.7) who had previously undergone myringoplasty showed 100% reduction in the size of the perforation and the perforation was, therefore, considered healed. This was not the case for the patient with a previous transtympanic ventilation tube, in whom there was no evidence of reduction in the size of the perforation. As far as aetiology was concerned, tympanic perforation was due to acute otitis media in six patients and in this treatment group total healing was achieved in four (66.6%) patients, whereas in the other two (33.3%) patients there was no change. Of the group of eight patients suffering from chronic otitis media, one (12.5%) patient was healed, six (75.0%) patients had some degree of reduction and in one (12.5%) patient there was no change.
DISCUSSION The hyaluronic acid-treated perforations closed better than did untreated controls,'? with the formation of hyperplastic stratified squamous epithelium supported by granulation ti ssue.I''-" Application of hyaluronic acid results in the formation of a bridge to bring about these mechanisms and greatly accelerates the rate of healing. The variation in the concentration of the solution and hence the viscosity appears to be important in the structural quality of the healed perforation. ' 5 . 17 The application of rice paper has been shown to have a beneficial effect in only 20% of patients, resulting in a thicker tympanic membrane,' and the application of fibronectin has been found to have no stimulatory effect on percentage healing." The present study provides additional support for the use of topically applied sodiurn hyaluronate as an alternative to surgery for selected patients with tympanic membrane perforations, i.e. those with small perforations, dry perforations, and acute or traumatic perforations. Criteria for inclusion in the study were modified in the present study compared with a previous double-blind 'study; treatment
355 Downloaded from imr.sagepub.com by guest on December 19, 2015
Downloaded from imr.sagepub.com by guest on December 19, 2015
Q-r O'l
"-l
49 32 36 47 17 13 54 28 60 54 13
11
53 38 60 38
Age (years) M M M M M M F M M M M F F M F F
Sex L R R R R R R L L L R L L L R R
Side COM COM COM COM AOM AOM MYR AOM COM AOM TVT AOM AOM COM COM AOM
Cause Small Medium Medium Medium Medium Medium Small Small Medium Medium Medium Medium Medium Small Medium Medium
Size 0.04 0.28 0.15 0.84 0.48 0.48 0.06 0.09 0.20 0.35 0.48 1.69 0.30 0.04 0.88 0.48
Area (rnm-) C-SA M-2A M-SP M-2A M-SA C-SA C-SP C-IP M-SA M-SP C-SP C-SP C-SP M-SP C-IP C-SP
Situation
40 years Unknown Unknown Unknown 14 months 3 months 2 years 4 months 7 years 6 months 4 years 10 years 3 months 20 years 2 years 20 months
Duration
M, marginal; S, superior; I, inferior; A, anterior; P, posterior.
M, male; F, female; L, left; R, right; COM, chronic otitis media; AOM, acute otitis media; MYR, myringoplasty; TVT, transtympanic ventilation tube; C, central;
12 13 14 15 16
11
1 2 3 4 5 6 7 8 9 10
Patient No.
Tympanic perforation
Demographic data for 16 patients with tympanic perforation treated with 0.3 m11% sodium hyaluronate at intervals of 72 h for
up to 1 month
Downloaded from imr.sagepub.com by guest on December 19, 2015
'1
"-l
QJ
8 8
6 9 6 9 9
8 8
5
8
7 9
8 8
6
No. of applications
TVT, transtympanic ventilation tube.
9 10 11 12 13 14 15 16
8
1 2 3 4 5 6 7
Patient No. Closed Reduction Reduction Same Closed Closed Closed Reduction Reduction Closed Same Closed Same Reduction Reduction Same
Evaluation
100 36 73 0 100 100 100 63 90 100 0 100 0 50 54 0
Reduction (%)
Tympanic perforation
Normal Normal Tympanosclerosis Normal Normal Normal Normal Normal Tympanosclerosis Normal Normal Fragile tissue Same Tympanosclerosis Normal Normal
Status of tympanic membrane
TVT
Placebo
Myringoplasty
Placebo Placebo
Previous treatment
Effects of 0.3 m11% sodium hyaluronate applied topically at 72 h intervals for up to 1 month on tympanic perforation in 16 patients.
intervals of 72 h instead of 48 h were used and inclusion of patients who had previously received surgical or medical treatment was permitted. The results of the present study indicate that neither of these variables appeared to have any influence on the results. A total of 74% of patients benefited from treatment with sodium hyaluronate in that a reduction or com plete healing of the tympanic perforation was detected. The average percentage reduction in the perforation area
was 80.5%. This is comparable to a previous double-blind study carried out, in which a reduction in the perforation area of 83 ± 26% (P < 0.001) was recorded compared with placebo-treated patients.' '" The fact that the reduction in the frequency of application of the treatment from 48 h to 72 h did not lead to any decline in efficacy means a reduction in the use of hospital facilities and less inconvenience to the patient.
REFERENCES 1 Stenfors LE:Repair of tympanic membrane perforations using hyaluronic acid: an alternative to myringoplasty. J Laryngol Oto11989; 103: 39 - 40. 2 Stenfors LE: Treatment of tympanic membrane perforations with hyaluronan in an open pilot study of unselected patients. Acta Otolaryngol (Stockh) 1987; 442: 81 - 87. 3 Soderberg 0, Laurent C, Anniko M, et al: Hyaluronan versus rice paper: a clinical study on the healing of persistent tympanic membrane perforations. XIV World Congress ofOtorhinolaryngology, Madrid, 10 - 15 September 1989. 4 Laurent C, Soderberg 0, Anniko M, et al: Repair of chronic tympanic membrane perforations using application of hyaluronan or rice paper prothesis. ORL 1991; 53: 37 - 40. 5 Rivas MP, Casasin T, Pumarola F, et al: An alternative treatment for the reduction of the tympanic membrane perforations: sodium hyaluronate: a double-blind study. Acta Otolaryngol (Stockh) 1990; 110: 110
- 114. 6 Hellstrom S, Bloom GD, Berghem L, et al: Comparison between hyaluronan and fibronectin in the repair of tympanic membrane perforations. Eur Arch Otorhinolaryngol1991; 248: 231 - 236. 7 Gibbs DA, Merill EW, Smith KA, et al: Rheology of hyaluronic acid. Biopolymers 1968; 6: 777 - 791. 8 Hakansson L, Hallagren R, Venge P: Regulation of granulocyte function by hyaluronic acid: in vivo and in vitro effects of phagocytosis, locomotion and metabolism. J Clin Invest 1980; 66: 298 305. 9 Morris ER, Ress DA, Wels EJ: Conformation and dynamic interactions in hyaluronate solutions. J Mol BioI 1980; 138: 383 - 400. 10 Stenfors LE, Berghem L, Bloom GD, et al: Exogenous hyaluronic acid (Heal on) acclerates the healing of experimental myringotomies. Auris-Nasus-Larynx (Tokyo) 1985; 12(suppl): 217 - 218. 11 Laurent C, Hellstrom S, Appelgren LE, et
358 Downloaded from imr.sagepub.com by guest on December 19, 2015
M P Rivas Lacorte. T Cososin, A Alcmso Sodium hyaluronate and ty.mpani~ perforation
12
13
14
15
a1: Fate of exogenous hyaluronic acid in the middle ear. Am J Oto1aryngo11986; 7: 334 - 340. Laurent C, Hellstrom S, Anniko M: Inner ear effects of exogenous hyaluronan in the middle ear of the rat. Acta Oto1aryngo1 (Stockh) 1988; 105: 273 - 280. Stenfors LE: Repair of traumatically ruptured tympanic membrane using hyaluronan. Acta Oto1aryngo1 [Supp1} (Stockh) 1987; 442: 88 - 91. Rivas MP, Casasin T, Pumarola F, et a1: Tratamiento de las perforaci ones timpani cas con hiarluronato sodico. I. Relacion con la etiologia de la perforacion. II. Audiometria antes y despues del tratamiento. ORL-DIPS Internaciona11989; 5: 229 - 234. Hellstrom S, Laurent C: Hyaluronan and healing of tympanic membrane perforations: an experimental study. Acta
Oto1aryngo1 [Supp1} (Stockh) 1987; 442: 54 - 61. 16 Casasin T, Rivas MP, Noguera MM: Treatment of small tympanic membrane perforation with sodium hyaluronate. Pharm Weekb1 [Sci} 1990; 12: G21. 17 Laurent C, Hellstrom S, Fellenius E: Hyaluronan improves the healing of experimental membrane perforations. Arch Oto1aryngo1 Head Neck Surg 1988; 1435 - 1441.
M P Rivas Lacarte, T Casasin and A Alonso Effects of Sodium Hyaluronate on Tympanic Membrane Perforations The Journal of International Medical Research 1992; 20: 353 - 359 Received for publication 12 December 1991 Accepted 13 March 1992 © Copyright 1992 Cambridge Medical Publications
Address for correspondence DR M P RIVAS LACARTE Department of Otorhinolaryngology, Viladecans Hospital, Avenida Gava 38, Viladecans, 08840 Barcelona, Spain.
359 Downloaded from imr.sagepub.com by guest on December 19, 2015
