Urografin in the Treatment of Sudden Sensorineural Hearing Loss
Javad S. Totonchi,
Seyed Esmail Ayat
Shabnam R. Rad
The present study was conducted to find out whether
combined treatment of intravenous urografin and corticosteroid has a therapeutic
advantage over oral corticosteroid therapy in the treatment of Sudden
Sensorineural Hearing Loss (SSNHL). The design of the study was an interventional
and controlled clinical trial. Between 2003 and 2005, patients with SSNHL
were treated in our center in Tabriz, Iran. Patients were selected if
they had a hearing loss of at least 30 dB in at least 3 frequencies on
audiometric testing. Audiograms were performed before admission, 1 and
2 weeks and 1 and 2 months after treatment. Patients who were put on bed
rest and received intravenous urografin and hydrocortisone were compared
with outpatients treated with oral steroid alone. Various descriptive
analytical calculations and both Chi-square and t-test were used to analyze
the data. Sixty patients were included in this study. Fifty-one patients
referred to the otological clinics for the appropriate treatment within
the first two weeks after the onset of hearing loss. The overall improvement
of both groups was 53.3%. Seventeen (56.6%) of 30 patients treated in
the inpatient group who received intravenous urografin and intravenous
corticosteroid had hearing improvement, while half of the outpatient group
received oral corticosteroid responded positively to the treatment (p>0.05).
This study revealed no significant difference in hearing improvement between
the hospitalized patients who received intravenous urografin and corticosteroid
and the patients who received oral corticosteroid alone.
Sudden Sensorineural Hearing Loss (SSNHL) is an uncommon otologic condition
that is thought to affect 10 persons per 100,000 annually (Zadeh et
al., 2003). SSNHL, which accounts for about 1% of all cases of Sensorineural
Hearing Loss (SNHL), is defined as hearing loss greater than 30 dB in
at least three subsequent frequencies of sudden onset on audiometric testing
or within maximum of 72 h (Penido Nde et al., 2005; Chandrasekhar,
2003). Although extensive evaluations have been done, an etiology can
only be found in 10 to 15% of patients (Zadeh et al., 2003). Viral
infection of the labyrinth or cochlear nerve, vascular insult, intralabyrinthine
membrane rupture, perilymphatic fistula and autoimmunity are a few entities
known to cause SSNHL (Yeo et al., 2007). Apart from the high spontaneous
recovery rate within two weeks after the onset (30 to 60% of patients),
an unknown pathophysiology and the low incidence make the selection of
treatment options difficult (Uri et al., 2003).
Therefore, a cocktail therapy (combination therapy) including systemic
corticosteroids, vasodilators, Hyper-Baric Oxygen therapy (HBO), diuretics,
anticoagulants, carbogen inhalation and vitamins has been frequently used
for two or more probable mechanisms, such as cochlear blood flow insufficiency
(Kanzaki et al., 2003; Psifidis et al., 2006; Narozny et
al., 2004). Nowadays, the confirmed gold standard of treatment of
SSNHL is steroid therapy (Chandrasekhar, 2003). However, vasodilator drugs
such as urografin (Natrium-Meglumine-diatrizoat) which was first reported
in 1976 as a treatment of SSNHL is still used as a therapeutic agent for
the treatment of SSNHL in some otological clinics (Noi and Makimoto, 1998).
Not recently performed studies have shown controversial results regarding
the therapeutic effects of urografin in the treatment of SSNHL. Therefore,
we aimed to find out whether combined treatment of intravenous urografin
and corticosteroid has a therapeutic advantage over oral corticosteroid
MATERIALS AND METHODS
The design of the study was an interventional and controlled clinical
trial. Between 2003 and 2005, 60 patients with SSNHL were treated for
SSNHL in the Department of Otolaryngology-Head and Neck Surgery at Imam
Khomeini Hospital in Tabriz, Iran. Hearing loss was defined as a sensory
hearing impairment of at least 30 dB in at least 3 frequencies on audiometric
testing. Patients were selected if they were aged over 12 years and had
a hearing loss of at least 30 dB in at least 3 frequencies on audiometric
testing. Excluded from the study were patients with general medical condition
necessitating a specific therapy as well as incompliance to the medications.
The study was approved by the Institutional Board Review and Ethics Committee,
a section of Research Deputy of Faculty of Medicine at Tabriz University
of Medical Sciences, Iran. Audiograms were performed before admission,
1 and 2 weeks and 1 and 2 months after treatment. The Pure-Tone Average
(PTA) was calculated as the average of thresholds at 250, 500, 1000, 2000,
4000 and 8000 Hz. The initial pretreatment audiogram was classified into
5 categories depending on the degree of SSNHL: mild (25 to 50 dB), moderate
(51 to 70 dB), severe (71 to 90 dB), profound (91 to 110 dB) and total
SSNHL (over 110 dB). The definition of a significant hearing improvement
was a decrease in pure tone average of 20 dB, regardless of the degree
of the initial hearing loss.
A blood sample was obtained to determine the complete blood cell count,
the level of glucose, creatinine, electrolytes, cholesterol, triglycerides
and thyroid hormones (T3, T4 and thyroid-stimulating
hormone). In addition, all the patients both outpatients and inpatients
were sent for Magnetic Resonance Imaging (MRI) with gadolinium to detect
any pathological finding in cerebellopontine angle such as acoustic neuroma.
Concurrent systemic diseases including hypertension and diabetes mellitus
were evaluated. The examined parameters included age, time to initial
treatment, type of SSNHL (bilateral or unilateral), history of upper respiratory
tract infection, history of trauma, family history, severity of hearing
loss, previous treatments and presence of associated symptoms with hearing
loss such as tinnitus, vertigo and aural fullness.
Patients were assigned into 2 groups. Group U, the study group, included
30 patients who willingly put on bed rest and treated with intravenous
urografin 2 mL four times a day (qid) and hydrocortisone 1 mg/kg/day three
times a day (tid) on the first day of treatment. The dosage of urografin
increased to 5 mL qid by the 2nd day for the maximum of 5 days. Hydrocortisone
with the same dosage continued to be administered for ten days. Group
H, the control group, consisted of 30 outpatients who didn`t accept to
be hospitalized, treated with oral hydrocortisone (1 mg/kg/day tid) for
a course of 10 days followed by a slow taper. In addition, oral acyclovir,
1000 mg tid for ten days, was administered to both groups.
Statistical analyses were performed using SPSS version 12. We used various
descriptive analytical calculations and both Chi-square and t-test to
analyze the data. A two-tailed p-value less than 0.05 was considered statistically
Of the 60 patients, 28 (46.7%) were male and 32 (53.3%) were female.
The average age was 36.95 years (range, 18 to 66). No differences were
found between groups H and U with regard to the age, gender and severity
of hearing loss at the onset of treatment (t-test and Chi-square; p>0.05).
The right ear was involved in 50% and the left ear in 43.3% and bilateral
involvement was in 6.7% of the patients. Gender and laterality of the
affected ear were not statistically significant in recovery (Chi-square,
According to the pretreatment audiogram, a significant proportion of
our sample had mild (20 cases, 32.8%), moderate (16 cases, 26.5%) and
severe (13 cases, 21.8%) SSNHL. In contrast, patients with total and profound
SSNHL constituted 12.5 and 6.25% of patients, respectively.
Fifty-one (85%) of patients referred to the otological clinics for the
appropriate treatment within the first two weeks after the onset of hearing
loss, compared to 9 (15%) patients referred after 2 weeks. The duration
of onset of hearing loss to the time of treatment varied from one day
to 60 days. The average time from onset of symptoms to beginning of therapy
was 9 days. A significant association was found between a positive response
to the treatment and the early medical consultation (Chi-square, p<0.05).
No hearing improvement was observed at the age of 55 and more (Table
1). However, the age group and the response to the treatment were
not significantly associated (Chi-square, p>0.05).
||Percentage of patients with hearing improvement according
to the age group distributions
||Prevalence of the associated pathological conditions
in SSNHL at the time of insult
|SSNHL: Sudden Sensorineural Hearing Loss
Approximately 81.6% of patients declared the presence of the associated
symptoms. The most frequent associated symptom was tinnitus, which was
present in 90% of patients. Aural fullness and vertigo were far less common
and were present in 43 and 42% of patients, respectively. It appeared
that patients with vertigo, tinnitus and aural fullness significantly
have better possibilities to be improved in hearing (Chi-square, p<0.05).
Hypertension was the most prevalent concurrent pathologic condition (Table
2). Hypertension was associated commonly with SSNHL. Hypercholesterolemia,
Diabetes mellitus and depression were also reported in association with
SSNHL. The findings revealed no significant association between the associated
pathologic conditions and the positive response to the treatment (Chi-square,
Recent upper respiratory infection and smoking were the most common findings
of past medical history and social history, respectively (Table
3). Findings revealed that no significant association was found between
the trauma to the ear, ototoxic drugs, ear surgery and the positive response
to the treatment (Chi-square, p>0.05). On the contrary, the patients
having recent upper respiratory tract infection showed better possibilities
of hearing improvement rather than the patients having no such history
The assessment of the routine paraclinical tests demonstrated abnormal
findings in nearly 12% of the patients. The analysis of the patients`
complete blood cell count revealed an increase in the number of White
Blood Cells (WBC) in one-tenth of the patients. According to the findings
of MRI, only two patients (3.3%) were diagnosed as having an acoustic
In summary, with regard to the improvement of more than 20 dB as a hearing
improvement, the overall improvement of both groups was 53.3% (32 of a
total of 60 patients). Seventeen (56.6%) of 30 patients treated in the
inpatient group who received intravenous urografin and corticosteroid
(Group U) had hearing improvement, while half of the outpatient patients
received oral corticosteroid (Group H) responded positively to the treatment.
The patients of group U did not show significantly positive response to
the treatment rather than the patients in group H (Chi-square, p>0.05).
||Past medical and social history of the patients with
The most appropriate therapy for the treatment of SSNHL still remains
a matter of controversy due to the unproven origins of sudden sensorineural
hearing loss and empirical treatment (Huang et al., 1989). However,
most physicians agree that steroid therapy, which is associated with significant
complications and side effects, is an accepted treatment choice of SSNHL
(Roebuck and Chang, 2006). Hence, a cocktail therapy (combination therapy)
aimed at several probable mechanisms of hearing loss has been frequently
used including systemic corticosteroids, vasodilators, diuretics, HBO,
anticoagulants, carbogen inhalation and vitamins (Kanzaki et al.,
2003; Psifidis et al., 2006; Narozny et al., 2004).
In an experimental study by Noi and Makimoto (1998) on the healthy guinea
pig inner ear, measurement of cochlear blood flow was performed before
and after an infusion of urografin. They found an increased cochlear blood
flow following the urografin infusion considering a mechanism of osmolarity
gradient (Noi and Makimoto, 1998). This may clarify the mechanism by which
urografin leads to the hearing improvement in the patients suffering from
An intravenous administration of urografin leading to hearing improvement
was first reported by Morimitsu in 1976 (Yanagihara and Asai, 1993). Nonetheless,
the true efficacy of urografin therapy for SSNHL is still unclear. In
a study by Strohm (1980), only 16% of patients had a hearing improvement
after urografin therapy revealing no particular clinical criteria which
indicating a favorable prognosis with urografin-therapy. Unlike this finding,
Emmett and Shea (1979) reported 80% of hearing improvement after the administration
of urografin. Redleaf et al. (1995) reviewed the efficacy of intravenous
infusion of the radiopaque contrast for the treatment of SSNHL in the
University of Iowa for the last 10 years. It is reported that sixty-four
percent of 39 cases showed audiometric improvement in their pure-tone
averages after the therapy (Redleaf et al., 1995). Huang et
al. (1989) analyzed the outcomes of administration of diatrizoate
meglumine (urografin), steroids and a vasodilator for the treatment of
SSNHL suggesting that none of the above mentioned regimens produced consistently
better results than the spontaneous recovery rate of 65%. Likewise, Wilkins
et al. (1987) treated 109 SSNHL patients with such a cocktail therapy
consisting of dextran, histamine, Hypaque meglumine (urografin), diuretics,
steroids, vasodilators and carbogen inhalation. They concluded that there
was no difference between the cocktail therapy and spontaneous recovery.
The overall hearing improvement rate in the current study was found to
be 53.3%. This improvement rate seems to be similar to the high spontaneous
recovery rate of 30% to 60% known in the literature (Uri et al.,
2003). In the current trial, there was no significant difference in hearing
improvement between the hospitalized patients who received intravenous
urografin and corticosteroid and the patients managed on outpatient who
received oral corticosteroid.
Present findings demonstrated that right ear involved slightly more than
the left ear which was incomparable with the prior reports in which left
ear was more affected than the right ear (Zadeh et al., 2003; Psifidis
et al., 2006; Tiong, 2007). Although the bilateral occurrence is
reported rare in SSNHL, bilateral hearing loss was detected in more than
one-twentieth of the patients in this study (Oh et al., 2007).
The presence of associated symptoms, such as tinnitus and vertigo, was
related with worse prognosis by many authors (Psifidis et al.,
2006; Roebuck and Chang, 2006; Stokroos et al., 1998). On the contrary,
Uri et al. (2003) mentioned tinnitus as an indicator of better
prognosis, while no association was found between the incidence of accompanying
symptoms and the prognosis in other studies (Zadeh et al., 2003;
Penido Nde et al., 2005; Oh et al., 2007). Likewise the
prior reports (Uri et al., 2003; Roebuck and Chang, 2006), tinnitus
and vertigo were the commonest accompanying symptoms in present study.
In addition, all the three associated symptoms (tinnitus, vertigo and
aural fullness) presented significant association with better prognosis
in present study.
In this study, it is found that acoustic neuroma in 3.3% of the cases
which is much less compared with the 13.9% reported by Pensak et al.
(1985) and the 19% by others (Berg et al., 1986; Yanagihara and
Asai, 1993). Furthermore, Chaimoff et al. (1999) declared the high
rate of acoustic neuroma (47.5%) among the Israeli patients suffering
from SSNHL. However, present finding is well compared to the acoustic
neuroma prevalence of 0.8-3% among the general population (Art, 2005).
Present data suggest that the sooner treatment is started; the better
is the chance for recovery. The overall hearing improvement in pure tone
is higher when treatment was started within the first two weeks after
the onset of hearing loss compared with the patients referred after 2
weeks from onset of hearing loss. Similar finding has been reported in
other studies (Penido Nde et al., 2005; Redleaf et al.,
1995; Tiong, 2007).
Severity of hearing loss is one of the main prognostic indicators of
hearing improvement in SSNHL (Stokroos et al., 1998). Better prognosis
has been found in patients with mild and moderate SSNHL by Psifidis et
al. (2006), Tiong (2007) and Kanzaki et al. (1988). The same
observations were found in the results of this study.
Numerous factors such as hypertension, hypercholesterolemia and diabetes
mellitus have been considered to be implicated in the pathogenesis of
SSNHL (Psifidis et al., 2006). Approximately a quarter of the patients,
14 of 60 patients, had these risk factors in this trial, compared well
with 17 to 28% in the report by Hirano et al. (1999). However,
these were not statistically significant prognostic factors in the current
The true efficacy of intravenous urografin therapy for SSNHL is still
unclear. This study was a cohort study and was not randomized, so there
is a significant possibility of bias. However, the patients in this study
were evenly matched in reference to age, sex and pretreatment severity
of hearing loss. Furthermore, large sample sizes seem to be needed to
achieve statistically significant results in rigorous clinical trials.
On the other hand, the efficacy of urografin therapy was assessed in combination
with the steroid therapy which is declared to be the first treatment choice.
It is obvious that if the intravenous urografin therapy was performed
without combination of any other treatments, the findings would be more
valuable. However, due to the proven efficacy of steroid therapy as well
as research ethics the urografin therapy was not performed solely in present
Based on this study, despite the probable ineffectiveness of intravenous
urografin injection in the treatment of SSNHL, the urografin administration
would be beneficial in patients who have already failed other common and
proven therapies such as steroid therapy. Practitioners who use this treatment
modality will need to counsel patients of the limited benefit of any treatment
available today when initial steroid treatment fails.
This study showed no significant indication that intravenous urografin
infusion likely provides more benefit compared with oral steroids. We,
therefore, can not support a possible role of the intravenous urografin
injection as a therapeutic advantage in the treatment of SSNHL.
This research was supported by Vice Chancellor for Research, Tabriz University
of Medical Sciences, Iran. The authors would like to express their gratitude
to Dr. Mohammadali M. Shoja for his assistance in the registration of
the current clinical trial as well as the statistical analysis.
1: Art, H.A., 2005. Sensorineural Hearing Loss: Evaluation and Management in Adults. In: Cummings Otolaryngology Head and Neck Surgery, Cummings, C.W., (Ed.). Mosby, London, ISBN: 0-323-01985-4, pp: 3550-3557.
2: Berg, H.M., N.L. Cohen, P.E. Hammerschlag and S.B. Waltzman, 1986. Acoustic neuroma presenting as sudden hearing loss with recovery. Otolaryngol. Head. Neck. Surg., 94: 15-22.
3: Chaimoff, M., B.I. Nageris, J. Sulkes, T. Spitzer and M. Kalmanowitz, 1999. Sudden hearing loss as a presenting symptom of acoustic neuroma. Am. J. Otolaryngol., 20: 157-160.
CrossRef | PubMed |
4: Chandrasekhar, S.S., 2003. Updates on methods to treat sudden hearing loss. Operat. Tech. Otolaryngol. Head. Neck. Surg., 14: 288-292.
CrossRef | Direct Link |
5: Emmett, J.R. and J.J. Shea, 1979. Diatrizoate meglumine (Hypaque) treatment for sudden hearing loss. Laryngoscope, 89: 1229-1238.
6: Hirano, K., K. Ikeda, T. Kawase, T. Oshima, S. Kekehata, S. Takahashi, T. Sato, T. Kobayashi and T. Takasaka, 1999. Prognosis of sudden deafness with special reference to risk factors of microvascular pathology. Auris. Nasus. Larynx., 26: 111-115.
CrossRef | PubMed |
7: Huang, T.S., S.T. Chan, T.L. Ho, J.L. Su and F.P. Lee, 1989. Hypaque and steroids in the treatment of sudden sensorineural hearing loss. Clin. Otolaryngol. Allied. Sci., 14: 45-51.
CrossRef | PubMed |
8: Kanzaki, J., H. Taiji and K. Ogawa, 1988. Evaluation of hearing recovery and efficacy of steroid treatment in sudden deafness. Acta Otolaryngol. Suppl., 456: 31-36.
9: Kanzaki, J., Y. Inoue, K. Ogawa, S. Fukuda, K. Fukushima, K. Gyo, N. Yanagihara, T. Hoshino, J. Ishitoya, M. Toriyama, K. Kitamura, K. Murai, T. Nakashima, H. Niwa, Y. Nomura, H. Kobayashi, M. Oda, M. Okamoto, T. Shitara, M. Sakagami, T. Tono and S. Usami, 2003. Effect of single-drug treatment on idiopathic sudden sensorineural hearing loss. Auris. Nasus. Larynx., 30: 123-127.
CrossRef | PubMed |
10: Narozny, W., Z. Sicko, T. Przewozny, C. Stankiewicz, J. Kot and J. Kuczkowski, 2004. Usefulness of high doses of glucocorticoids and hyperbaric oxygen therapy in sudden sensorineural hearing loss treatment. Otol. Neurotol., 25: 916-923.
11: Noi, O. and K. Makimoto, 1998. Comparative effects of glycerol and Urografin on cochlear blood flow and serum osmolarity. Hear. Res., 123: 55-60.
CrossRef | PubMed |
12: Oh, J.H., K. Park, S.J. Lee, Y.R. Shin and Y.H. Choung, 2007. Bilateral versus unilateral sudden sensorineural hearing loss. Otolaryngol. Head. Neck. Surg., 136: 87-91.
CrossRef | PubMed |
13: Penido Nde, O., H.V. Ramos, F.A. Barros, O.L. Cruz and R.N. Toledo, 2005. Clinical, etiological and progression factors of hearing in sudden deafness. Rev. Bras. Otorrinolaringol., 71: 633-638.
CrossRef | PubMed |
14: Pensak, M.L., M.E. Glasscock, A.F. Josey, C.G. Jackson and A.J. Gulya, 1985. Sudden hearing loss and cerebellopontine angle tumors. Laryngoscope, 95: 1188-1193.
15: Psifidis, A.D., G.K. Psillas and J.C. Daniilidis, 2006. Sudden sensorineural hearing loss: Long-term follow-up results. Otolaryngol. Head. Neck. Surg., 134: 809-815.
CrossRef | PubMed |
16: Redleaf, M.I., C.A. Bauer, B.J. Gantz, H.T. Hoffman and B.F. McCabe, 1995. Diatrizoate and dextran treatment of sudden sensorineural hearing loss. Am. J. Otol., 16: 295-303.
17: Roebuck, J. and C.Y. Chang, 2006. Efficacy of steroid injection on idiopathic sudden sensorineural hearing loss. Otolaryngol. Head. Neck. Surg., 135: 276-279.
CrossRef | PubMed |
18: Stokroos, R.J., F.W. Albers and E.M. Tenvergert, 1998. Antiviral treatment of idiopathic sudden sensorineural hearing loss: A prospective, randomized, double-blind clinical trial. Acta Otolaryngol., 118: 488-495.
CrossRef | PubMed |
19: Strohm, M., 1980. The effect of Urografin on sensorineural deafness. A clinical study. Laryngol. Rhinol. Otol. (Stuttg)., 59: 159-162 (In German).
20: Tiong, T.S., 2007. Prognostic indicators of management of sudden sensorineural hearing loss in an Asian hospital. Singapore. Med. J., 48: 45-49.
PubMed | Direct Link |
21: Uri, N., I. Doweck, R. Cohen-Kerem and E. Greenberg, 2003. Acyclovir in the treatment of idiopathic sudden sensorineural hearing loss. Otolaryngol. Head. Neck. Surg., 128: 544-549.
CrossRef | PubMed |
22: Wilkins, S.A., D.E. Mattox and A. Lyles, 1987. Evaluation of a shotgun regimen for sudden hearing loss. Otolaryngol. Head. Neck. Surg., 97: 474-480.
23: Yanagihara, N. and M. Asai, 1993. Sudden hearing loss induced by acoustic neuroma: Significance of small tumors. Laryngoscope, 103: 308-311.
24: Yeo, S.W., D.H. Lee, B.C. Jun, S.Y. Park and Y.S. Park, 2007. Hearing outcome of sudden sensorineural hearing loss: Long-term follow-up. Otolaryngol. Head. Neck. Surg., 136: 221-224.
CrossRef | PubMed |
25: Zadeh, M.H., I.S. Storper and J.B. Spitzer, 2003. Diagnosis and treatment of sudden-onset sensorineural hearing loss: A study of 51 patients. Otolaryngol. Head. Neck. Surg., 128: 92-98.
CrossRef | PubMed |