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Role of Low-Molecular-Weight Heparins in the

Treatment of Sudden Hearing Loss
Wen L. Yue, MD, Pei Li, MD, Pei Y. Qi, MD, Hui J. Li, MD, and
Hong Zhou, MD
Objective: For the present, no definitive treatment is universally accepted for sudden
sensorineural hearing loss (SNHL). The goal of this study was to evaluate the role of
low-molecular-weight heparins in its therapeutic regimen.
Methods: A retrospective analysis has been taken in 100 patients with SNHL in which they
were divided into 2 groups: 50 patients received commonly therapy added with and without
low-molecular-weight heparins each. The audiogrametric data at pretreatment were compared with data at day 10 and with data collected at follow-up (average 20 days).
Results: The results showed that there was a significant improvement for early or late
audiometric outcome in group 1 when compared with group 2 (P ⬍ .05). Forty-three patients
(86%) were classified into recovery or good improvement in group 1, which was higher than
group 2 (P ⬍ .01). The improvement rate was calculated for each of the 100 patients, and
the average value was 84. Seventy percent in group 1 and 70% in group 2.
Conclusion: It is concluded that the use of low-molecular-weight heparins not only considerably improve the curative rate in the hearing improvement of sudden sensorineural
hearing loss but without such potential risk as unfractionated heparins.
(Am J Otolaryngol 2003;24:328-333. © 2003 Elsevier Inc. All rights reserved.)

Until now, various theories been proposed
from the etiology of idiopathic sudden sensorineural hearing loss (SNHL).1-3 These include blood flow disturbances, viral infections, immune disorders, membrane rupture
of the inner ear, and toxic and metabolic
causes. Because of the problematic identification of the cause, many regimens have been
used to treat SNHL. Of them, a good deal of
attention will be paid to the blood flow disturbance theory because the blood supply
within the ear is its termination and intraosseous position.4 These characteristics, together
with the sudden onset of SNHL, suggest that
impairments in microcirculation of the inner
ear might be involved in pathophysiology of
this condition. Regarding the condition as a
thromboembolic, vasospasm, or hemorrhagic
event means that plasma expanders, anticoagulants, and vasodilators are used as common medical treatment.5-8 In a prospective

From the Department of Otolaryngology.
Address correspondence to: Wen L. Yue, MD, Department of Otolaryngology, Pingdingshan People⬘s
Hospital No. 1, 117 you-yue Road, Pingdingshan City,
Henan 467000, P. R. China.
© 2003 Elsevier Inc. All rights reserved.
0196-0709/03/2405-0000$30.00/0
doi:10.1016/S0196-0709(03)00066-8
328

study by Mattox and Simmons,9 60% of patients were found to recovered with unfractionated heparins (UFHs) treatment, which is
no significant advantage independent of the
type of medical therapy, so that this method
has been almost abandoned because of its
potential risks, such as thrombocytopenia,
spontaneous hemorrhage, and so on.10-12 In
fact, the use of these agents in treatment of
sudden hearing loss patients remains a controversial subject both clinical curative rate
and complications.
Since the introduction of low–molecularweight heparins (LMWHs) in the early 1990,
its use and indications have been greatly expanded.13-15 This agent is made from general
heparin by using chemical techniques (nitrous acid, alkaline hydrolysis, or peroxidase
cleavage) or heparinase techniques. They provide some advantages over UFHs, including
better bioavailability, longer half-life, fewer
bleeding complications, and they are at least
equally efficacious.16,17 But for all that, there
was no report on this agent for the treatment
of sudden hearing loss among the world literature. In this study, we compared 2 therapeutic regimens for sudden hearing loss, our commonly used therapy added with and without
LMWHs (Livaracine, Siu-Fung USTC Pharma-

American Journal of Otolaryngology, Vol 24, No 5 (September-October), 2003: pp 328-333

intravenously infused. After informed consent was obtained. The initial hearing loss level (the arithmetic mean of 5 frequencies: 250. and any recent respiratory tract infection. alanine transaminase. 329 TABLE 1. electrolytes. China) to improve the clinical result of SNHL. Ltd.. tinnitus. units was on the first 10 days and 2. 500. Ltd. The average duration from onset to initiation of treatment was 10 days.000 Hz) ranged from 45 to 100 dBHL. 5.19 They had to meet the following criteria: (1) abrupt onset of hearing loss. from March 2002 to January 2003.000 Hz or hearing level recovers to that of the intact ear if hearing of the intact ear is judged to be sTABLE Average hearing improvement for five frequencies is more than 30 dB Average hearing improvement for 5 frequencies is between 10 and 30 dB Average hearing improvement for 5 frequencies is less than 10 dB .000.LOW-MOLECULAR-WEIGHT HEPARINS ceutical Co. steroid drug. Group I *Livaracine is a product of low–molecular-weight heparin. nausea or vomiting). Ltd.000. Group 2: they received our commonly used therapy alone.000. The therapeutic plan was as follows: 1.000 Hz). glucose. or other pathological otoscopic findings. usually in the abdomen. Audiometry was performed on admission. 2. (1987) Definition Recovery Good improvement Fair improvement No change Improvement Hearing level recovers to less than 30 dB at 250. (3) hearing loss that is unusually severe. and carbogen inhalation. making it less necessary to monitor the blood. Improvement in hearing was judged on the basis of pure-tone average (PTA) obtained before and immediately after the treatment. and (7) no cranial nerve symptoms other than from the eighth nerve.000. (6) acompanied by some symptoms (ie. 500. and serum fibrinogen measured before and at 24 and 72 hours after the initial administration of Livaracine.500 units. All patients were specifically asked a history of tinnitus. twice a day.8. 1.000. compound injection of salivae miltiorrzae. 2.. Special care was taken to exclude patients with Meniere’s disease. idiopathic perilymphatic fistula. prior sudden deafness. Coenzymi A. Hearing improvement was evaluated with 2 methods: categorical judgement (Table 2) and improvement rate (%). and at follow-up examination. Hefei City. others as above MATERIAL AND METHODS One hundred consecutive patients suffering from SNHL were presented to the Department of Otolaryngology. ATP 40 mg. twice a day. acoustic neuroma.. for 10 days on initial administration. The earliest time therapy began was on the day of hearing loss and the latest was 21 days after onset. prothrombin time/partial thromboplastin time. 30 mL. usually in the abdomen. There were 54 women and 46 men in this study. coenzymi A 200 mg. each patient was randomly assigned to 1 of 2 treatment groups.3 dB. 2. 500. No Liveracine. A battery of blood tests consisted of a complete blood count. including carbogen inhalation. aspartate aminotransferase. once each daily. This agent was made in the Siu-Fung USTC Pharmacetical Co.000 Hz and to 25 dB at 40. Their ages ranged from 32 to 60 years with a mean age of 46. Modified Low–Molecular-Weight Heparin Therapy for SNHL Groups Treatments Group I Livaracine*.19 With this method. 1. PTA was calculated with the arithmetic mean of 5 frequencies (250. vertigo. 5. (4) hearing loss was defined as a sensorineural impairment. vertigo. Henan Province. China. China) intravenously infusion. (5) the hearing deterioration had to be 30 dB or more compared with the healthy ear and at least affect 3 frequencies. chronic otological history. The left ear was involved in 44 patients and the right in 56. Pingdingshan People⬘s Hospital No. and 4. injected under the skin. and is unilateral in most cases. Hefei City. Group 1: beside from our commonly used therapeutic regimen. 1. Seventy-three patients had complained of tinnitus and 23 vertigo or some forms of unsteadiness. (2) uncertain cause of hearing loss.. hearing outcome is ranked into 4 TABLE 2. and compound injection of Salviae Miltiorrhizae (Great East Pharceyical Co. adenosine triphosphate. does not fluctuate.1. GPT. Livaracine injection. The protocol for modified LMWH therapy is shown in Table 1. was injected under the skin.000 units. The diagnostic criteria were established by the Helsinki Committee of the Chim Sheba Medical Center18 and the Ad Hoc Committee of the Japanese Ministry of Health and Welfare. lactic dehydrogenase. and the mean was 68. 2. once a day for 10 days. dexamethesone 10 mg.000. on day 10 after completion of treatment. and 4. The definition for the categorical judgement was proposed by the Ad Hoc Committee of the Japanese Ministry of Health and Welfare. Hearing Recovery as Defined by the Ad Hoc Committee of the Health and Welfare in Japan.

5). Nevertheless. and flat curve. Improvement was considered to be a minimum 15 dB change between the average hearing level evaluated at the different times mentioned. patients with an initial PTA of more than 90 dB showed significantly poor recovery (P ⬍ . and P ⬍ . Analysis of the average hearing level at 5 frequencies for all the participations in this study. 50 (69 dB). Four configurations of audiometric curves were defined: up slope. At follow-up. 43 patients (86%) belong to the recovery or good improvement groups. fair improvement. U-shape. Statistical analysis (by analysis of variance) of improvement indicated a significant difference between the 2 groups (P ⬍ . patients were divided into 2 groups. we found the early posttreatment im- provement to be 86% in group 1 and 70% in group 2. which was calculated with the opposite ear as the reference: % improvement ⫽ initial PTA ⫺ final PTA/ initial PTA ⫺PTA of opposite ear Hearing improvement for 3 patients could not be evaluated in terms of the improvement rate because PTA for the opposite ear was more than 40 dBHL. Although there was no significant difference in initial PTA between these 2 groups.01 after treatment.01). there was no significant difference among the groups of 25 (49 dB). 3 (6%) had fair improvement. Average Hearing Level at 6 Frequencies According to the Treatment and Control Groups Group Admission (dB) Day 6 (dB) Follow-up (dB) Improvement After Treatment (%) Improvement at Follow-up (%) Group I Group II 41. improvement rates were 84% and 66%. and the existence or absence of tinnitus or vertigo (Table 6). The outcome of similar audiometric configurations was evaluated and compared. Overall. It was ranged from 1% to 100%. the interval between onset and start of treatment. Patients who had vertigo at onset were evaluated as a separate group and compared with the study population that did not suffer from vertigo. 3 (6%) had good improvement. As has been reported.4 40. Statistical analysis was done with Student’s t test. RESULTS According to categorical judgement.2 45.330 YUE ET AL TABLE 3. and 4 (8%) patients showed no change (Table 3). 40 (80%) of group 1 showed a recovery.6 30. and no change.05 at follow-up). Patients were divided into groups according to the initial PTA. down slope.2 10. This result suggests that the patients who received TABLE 4. The improvement rate (%) for each of the 50 patients was calculated. this was not statistically significant (P ⬍ . 1 to 10 days and 11 to 20 days. There is a trend for the up-slope curves to improvement more and the contrary for the down-slope curves. and the average value was 84. and 70 (89 dB). The other criterion was improvement rate (%).5 36. As the interval between onset of hearing loss and start of treatment is concerned. this trend was not statistically significant.05 was considered significant. However. Overall Outcome According to the 2 Criteria of Hearing Recovery Categorical Judgement (%) Recovery Good Improvement Fair Improvement No Change Average Improvement Rate 42 (82%) 5 (10%) 1 (2%) 3 (14%) 64% categories: recovery.7%. good improvement.01). Although patients without vertigo show a trend toward better improvement than patients with vertigo. the former showed significantly better hearing recovery than the latter (P ⬍ . The correlation coefficient for the prognostic factors was calculated. respectively (Table 4). P ⬍ . Improvement evaluation of average hearing level at 5 frequencies according to the configuration of audiometric curve is shown in Table 5.2 60 36 80 40 .

9 idiopathic sudden hearing loss is an emergency disease that requires immediate treatment.01. and compound injection of Saliviae Miltiorrhizae) as the control comparing the patients with Li- TABLE 6.6 23. down slope.1 6 5 39.5 76 67 78. As far as the type of pure-tone audiogram is concerned.5 43/57 7. and PTA of the opposite ear also did not show a significant correlation with improvement rate (P ⬎ . Lacking a standard evaluation method for hearing recovery makes it is difficult to establish a control group with placebo tablet used for comparative study or else the proper therapy will be delayed in the control group and even leave behind a poor prognosis in the control group if they had a placebo agent. considering the medical ethics point of view.5 14 11 tion was paid to bleeding tendency during this therapy. Minor side effects occurred in 15 out of 50 patients (10%). ATP.5 47. the strongest correlation was found between the interval and improvement rate (P ⬍ . and 5 patients profound deafness. r ⫽ ⫺0. Average Age. These symptoms subsided soon after the cessation of Livaracine injection. For these reasons. but there was no such complication in our report.392).8.05).7 8 6 40. of patients) Vertigo (no. steroid.4 70. Initial PTA values. which is no therapeutic effect in my mind. Among those. and Vertigo at Onset in the Treatment Groups TABLE 5. It is believed that the onset of the disease and start of the treatment are the most crucial factors for a good prognosis.3 23/27 7. the correlation coefficients between these prognostic factors and improvement rate were calculated (Table 7).4 . the sick patients were unwilling to accept such informed consent.1 19. Configuration of Audiometric Curves in Treatment Group U shape Flat Up slope Down slope Total Group 1 Group 2 7 3 12 23 50 5 7 10 20 50 the treatment in the early stage of sudden deafness can be expected to have a better prognosis. we chose the combining therapeutic regimen (includes carbogen inhalation. no correlation was found between the total dose given to each patients and hearing recovery. and flat types. 15 patients showed an upwardsloping audiogram. up slope. The authors of this study agree with the opinion hold by Shiraishi et al11 that every patient should be treated as soon as possible. Results of other blood tests were all within the normal range. yr) Sex (male/female) Duration (d) Tinnitus (no. particulary in our country. Tinnitus. Mean concentrations of serum fibrogen before and after Livaracine administration were not considerably changed at 24 hours and 72 hours after treatment. Sex. Average Hearing Level at 5 Frequencies With Respect to Vertigo at Onset in the Total Study Population Vertigo at onset (n ⫽ 12) No vertigo (n ⫽ 13) Admission (dB) Day 6 (dB) Follow-up (dB) Improvement After Treatment (%) Improvement at Follow-up (%) 56. of patients) Group 1 (n ⫽ 50) Group 2 (n ⫽ 50) Total (n ⫽ 100) 41. Coenzymi A. 33 patients flat type. These symptoms included slight subcutaneous bleeding in the injected area. Improvement Rate. ie. the patient’s age.LOW-MOLECULAR-WEIGHT HEPARINS 331 TABLE 7. Again.4 21. Close atten- Terms Age (average. At the same time. Duration From Onset to Initiation of Treatment. and so results in a series of medical or legal problems.4 23. Further statistical analyses were performed on the prognostic factors. 10 patients downward slopes.6 20/30 6. The profound deafness type showed significantly poorer recovery than the other 3. DISCUSSION As generally accepted.

The present study confirms the opinions of other investigators that patients seen and treated early in the course of their illness enjoy a significantly better prognosis than those seen later. but it is not possible to identify the pathogenesis of each patients at present. On other hand. the hearing improvement rate was significantly increased in patients with SNHL who were administered Livaracine treatment (86%) than that in UFH (77%).05. it greatly decreased the side reactions associated with general heparin. an encouraging finding is that hearing measured immediately after treatment continues to improve over time. which is more than the control group. Heparin as a treatment for sudden hearing loss was described by Fisch et al3. It experimentally showed that the advantages of LMWHs over UFH is in its safely is higher than the later through a series of purification and fraction of UFH.9 In the current study. and vascular disturbances in microcirculation within the ears. Viral infection and circulatory disturbance are the most common etiological mechanisms of idiopathic sudden deafness. there was no significant difference between the patients with and without general heparin therapy (60.1%) so this treatment was abandoned because of its potential risk (ie. Many hypotheses have been advanced to explain its etiology.20-22 Compared with classic heparin. From our data. LMWH is a purified product from general heparin that has been widely used. and so on). the Livaracine group showed better results than the control group.3. and at follow-up it was 84%. it has a anticoagulant effect on intracranial blood vessels. The results indicate superiority of this method compared with the control group with Saliviae Miltiorrhazae alone. up to about 50%. However. however. On one hand. As measured at a later follow-up. atypical viral infections. The overall improvement in all the patients in our study at the end of treatment was 86%. and 5 of them had down slope audiometric curves. local endogamous histamine production. The present study. This uneven distribution is probably because of the rather small number of participants in our study.332 varacine so as to evaluate the role of LMWHs in the improvement of combing therapeutic regimen for sudden hearing loss. Six of the 11 patients in the Livaracine group had vertigo at onset. It has been suggested that decreased hearing in the opposite ear may indicate fragility of the bilateral inner ears and poor recovery potential. r ⫽ ⫺2. As is evident from the results for the whole patient population. Mattox and Simmons9 have reported the great possibility of spontaneous recovery from sudden deafness. which is of great current interest.3 There ought to be a suitable therapy for each. The finding is not in accordance with the 65% spontaneous recovery rate reported by Mattox and Simmons. It has also been reported that the hearing level in the opposite ear is important for predicting a good prognosis. no advantage was found for the group 2 in this aspect. including allergies. it is capable of preventing the venous thrombosis. spontaneous hemorrhage. Garcia Callejo et al23 have shown that the presence of disturbances in the microcirculation are linked in some way to the onset of sudden deafness. liver impairment. It should be born in mind that in our study there appears to be to be 2 tendencies in some cases for the disease-received Livaracine therapy. The aim of the study described here was to compare 2 common therapeutic modalities for treatment of SNHL: the commonly used regimen with and without LMWHs. those with vertigo or down-slope audiometric curves did not have a worse prognosis at the after treatment examination and at follow-up. thrombocytopenia. suggestive of differencing it from UFH in the pharmacological field with regard to sudden hearing loss. chiefly characterized by . It seems quite clear that there were therapeutic advantages for Livaracine injection in treating idiopathic sudden hearing loss when compared with the traditionally used regimen with Saliviae Miltiorrhazae. It is believed that the extent of hearing loss and the interval between the onset of the disease and start of treatment are the most crucial factors for good prognosis. Firstly. it revealed that the hearing improvement is significantly higher in patients added with Livaracine than that reported in the group with the commonly used therapeutic regimen alone (reach as high as 86%). showed only a weak correlation (P ⬍ .4 By using whole-blood filterability as an index of blood flow in microcirculation.02) between YUE ET AL PTA of the opposite ear and the improvement rate.

Bendet E. Kayser SR: Therapeutic equivalency of low-molecular-weight heparins. Sai H: Eeeficacy of defibrinogenation and steroid therapies on sudden deafness. Ltd. Arch Otolaryngol Head Neck Surg 116:820-823. 1975 22. Eur Arch Otorhinolaryngol 258:477480.. Kleinschmidt K. Japan 4:169-172. China. Nagahara K. 1990 7. Emerg Med Clin North Am 19:1025-1049. et al: Hearing recovery in sudden deafness patients using a modified defibrinogenation therapy. Haberkamp TJ. 1999 6. 2001 333 9. Arch Otolaryngol Head Neck Surg 114:649-652. and so on. McKay GA. 2002 18. 2001 (suppl) 16. 1981 23. Kubo T. Kubo T. 1991 12. 2001 15. Jackson IT. 1984 3. Matsunaga T: Chronological study of sudden deafness treated with defibrinogenation and steroid therapies. et al: Hearing recovery and vestibular symptoms in patients with sudden deafness and profound hearing loss. Byl FM: Sudden hearing loss research clinic. Plast Reconstr Surg 109:19941999. Collet JP. et al: Blood viscosity and sensorineural hearing loss. Donaldson JA: Heparin therapy for sudden sensorineural hearing loss. Simmons FB: Natural history of sudden sensorineural hearing loss. Kronenberg J: Steroid. Yamamoto M. Almagor M. Am J Otol 20:587-595. Bloch F. Holland WB. Montalescot G: Review and future perspectives on low-molecular-weight heparin. McCormick JG. Ann Otol 86:463-480. 1978 2. Byl FM: Sudden hearing loss: Eight years experience and suggested prognostic table. Miyake H. Shiraishi T. Am J Otolaryngol 2:69-72. Am J Otol 20:488-491. Pollak A: Sudden hearing loss: Circulatory. Garcia Callejo FJ. 1977 10. Laryngoscope 94: 647-661. Ann Pharmacother 36: 1042-1057. Acta Otolaryngol (Stock) Suppl 514:41-44. Martinez Beneyto MP. 2002 17. Nomura Y: Diagnostic criteria for sudden deafness. et al: Vasoactive therapy versus placebo in the treatment of sudden hearing loss: A double blind clinical study. Kanzaki J. 501:46-50. for her help in manuscript preparation. 2001 14. Yanagita N: Annual report of perceptive deafness research team of the ministry of health and welfare. Acta Otolaryngol (Stock) 111:867871. REFERENCES 1. Paterson KR: Low molecular weight heparins—A safer option than unfractionated heparin? Adverse Drug React Toxicol Rev 20:256-276. Okumura S. 1993 (suppl) 13. 1988 5. Bendet E. Elmazar H. Tanyeri HM: Management of idiopathic sudden hearing loss. Muchnik C. Shiraishi T. Cinamon U. rarefaction of bone. 1984 4. Choussat R.) administration except for mild purpura of the injected skin in 6 patients. et al: Sudden hearing loss due to diving and its prevention with heparin. et al: The effect of low-molecular-weight heparin in the survival of a rabbit congested skin flap. Otolaryngol Clin North Am 8:417-430. Platero Zamarreno A. Acta Otorrinolaringol Esp 2001 52:556564. 1988 11. Donaldson JA: Priapism: An unusual complication of heparin therapy for sudden deafness. 1981 20. carbongen or placebo for sudden hearing loss: A prospective double-blind study. 2001 . thrombocytopenia. Laryngoscope 102:6568. mumps deafness and perilymphatic fistula. Arch Mal Coeur Vaiss 94:1233-1242. Acta Otolaryngol Suppl (Stock) 456:7-8. From evidence from some cases suffering from SNHL. Kronenberg J. Arch Otolaryngol 105:351-354. 1994 19. McCart GM. Miyawaki T. Matsunaga T. 1992 8. Mattox DE. Fisch U. Kubo T. Brauer RW. et al: Non-interventional study on blood filterability changes in the clinical onset of sensorineural sudden deafness. 1979 21. Hildesheimer M.LOW-MOLECULAR-WEIGHT HEPARINS lowering the tendency of spontaneous hemorrhages. the business deputy of the Siu-Fung USTC Pharmacetical Co. Charles R: Pharmacology of low molecular weight heparins. ACKNOWLEDGMENT The authors thank Mrs Win Lee. Ltd. Ogawa K. Otolaryngol Clin North Am 11:71-78. we also found that there was no serious complication to be encountered in the patients with SNHL receiving the Livaracine (Siu-Fung USTC Pharmaceutical Co. Nakajima Y.