Randomized, Controlled Trial Comparing Longterm Sulfonamide Therapy to Ventilation Tubes for Otitis Media With Effusion

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Randomized,

Controlled

Trial

Comparing

Long-term

Sulfonamide

Therapy

to Ventilation

Tubes

for Otitis

Media

With Effusion

Philippe AM. Bernard, MD, PhD, FRCS(C)*; Robert J. Stenstrom, BSc,

MSc*f;

William

Feldman,

MD FRCP(C)f;

and Andree

Durieux-Smith,

PhD

From the Departments of *Q/ryflg/#{231}jgy, fPediatrics, and §Audiology, Children’s Hospital of Eastern Ontario, Ottawa, Canada

ABSTRACT. Several studies have indicated that either

the surgical insertion of ventilation tubes (VTs) or

long-term treatment with sulfonamide-based antibacterials is

effective in the management of otitis media with effusion (OME; otherwise known as serous otitis media, secretory

otitis media, and glue ear) when compared with a

no-treatment control or placebo. This controlled trial is the

first to compare directly the effectiveness of these two

treatments for long-standing OME. Outcome variables are treatment success rates, hearing thresholds, recurrent acute otitis media episodes, and side effects of medication or complications of VT placement. One hundred

twenty-five children (aged 2.5 to 7 years) who met the usual indications for surgery (long-standing [>3 months] OME

and conductive hearing loss) were randomly assigned to

“medical” treatment (sulfisoxazole 75 mg/kg per day for 6 months) or “surgical” treatment (bilateral insertion of VTs). Subjects underwent pure-tone audiometry (500,

1000, 2000, 4000 Hz) and otomicroscopic examination at

2, 4, 6, 12, and 18 months. A significantly greater propor-tion of medical subjects (67%) than surgical subjects

(48%) were treatment failures at 6, 12, or 18 months (P

= .0208). Surgical subjects had significantly better

hear-ing at 2 and 4 months (P values < .01) but not at 6, 12, and 18 months (P values > .2). A significantly greater

proportion of surgical subjects (50%) experienced corn-plications of treatment than did medical subjects (9%)

(P < .001). Thirty-three percent of candidates for VT

placement did not require surgery when treated with a

6-month course of sulfisoxazole. Given these findings, to-gether with the low cost of sulfonamide, a 6-month trial

of antimicrobial therapy is recommended for children

with long-standing OME, before considering VT

place-ment. Pediatrics 1991;88:215-222; otitis media with

effu-Received for publication Jul 20, 1990; accepted Dec 12, 1990. Reprint requests to (P.A.M.B.) Chief of Otolaryngology, Chil-then’s Hospital of Eastern Ontario, 401 Smyth Rd, Ottawa, Ontario, Canada K1H 8L1.

sion, antimicrobial therapy, ventilation tubes, conductive hearing loss.

ABBREVIATIONS. AOM, acute otitis media; OME, otitis media with effusion; VT, ventilation tube; dB HL, decibel hearing level (based on the ANSI 53.6 1969 standard); MEE, middle ear effusion.

In the preantibiotic era, acute otitis media (AOM) carried with it the possibility of life-threat-ening complications such as brain abscesses and otogenic meningitis. The advent of antibiotherapy saw these complications decrease dramatically and AOM was rendered a more benign disease. How-ever, the presence of fluid in the middle ear cleft (otitis media with effusion-OME-otherwise

known as serous or secretory otitis media or glue ear) in the absence of acute signs of inflammation has been described as a sequela of AOM. Otitis media with effusion is the most common cause of hearing loss in children and represents a therapeu-tic challenge.

Since the development of ventilation tube (VT) surgery in 1954,’ its popularity has increased con-siderably, making it one of the most common pe-diatric operations, performed more than 1 million times (usually bilaterally) annually in the United States according to one estimate.2

Controlled trials of VTs in the treatment of OME have had conflicting results. One research group3

(2)

consid-erably better in the VT ear 48 hours postoperatively (8.9 and 24.7 decibel hearing level [dB HL], respec-tively). However, by 6 months and 1 year, there was no significant difference between the surgically treated and control ear in terms of hearing

thresh-olds. Sequelae (scarring, tympanosclerosis, etc)

were considerably more common in the ear with the VT. Another study4 reported similar results and drew the conclusion that “The use of VT in children with cases of primary serous otitis media is not justified. Observation has shown that only a small proportion will require surgical treatment of the middle ear.” Some investigators have gone so far as to suggest that the use of VTs has reached “epi-demic” proportions.5

Other studies have observed a beneficial effect of VTs. One report6 indicated that patients receiving VTs had less middle ear disease in the short run (1 year) than did children undergoing myringotomy alone or a no-treatment control. However, only a preliminary report was published and the incidence of long-term sequelae was not established. Simi-larly, a recent study7 reported a decrease in the amount of time spent with effusion in children treated with VTs as opposed to myringotomy alone. Additional benefit was conferred by the combina-tion of adenoidectomy and VT insertion. Another stud? also propounded the use of adenoidectomy in the treatment of OME. However, given the mor-bidity associated with this procedure, it may rep-resent an excessive adjunct.

Several studies9” have reported a significant reduction in AOM episodes in otitis-prone children using prophylactic sulfonamide-based antibacteri-als at subtherapeutic dosages. One study’2 demon-strated a beneficial effect of trimethoprim-sulfa-methoxazole (8 and 40 mg/kg per day) in the treat-ment of OME, as evidenced by improved tympanogram patterns over a 4-week period. Short-term amelioration of hearing loss associated with OME using a combination of trimethoprim-sulfa-methoxazole and prednisone has also been de-scribed.’3 A 2-week course of amoxicillin was also found to increase the likelihood of resolution of middle ear effusion (MEE) in children with OME.’4 The use of antibacterials in the treatment of OME

is predicated on the finding that MEE, in absence of acute inflammation, often contains pathogenic bacteria. Once thought of as sterile, the middle ear aspirates of a significant proportion of children with OME contain bacteria.15”6

In view of the short-term nature of the follow-up

studies showing improvement of OME with medical management and the absence of studies comparing medical and surgical treatment, we wished to eval-uate, in a randomized controlled fashion, the

effec-tiveness of sulfisoxazole given over 6 months com-pared with VTs in terms of treatment failure rates, hearing loss, recurrent AOM episodes, and side

effects, in the treatment of long-standing OME.

METHODS

Subjects

The 125 subjects in this study met all of the following criteria and were enrolled through the otolaryngology clinic at the Children’s Hospital of Eastern Ontario.

Inclusion Critera: (1) age 2.5 to 7 years; (2) long-standing (greater than 3 months) MEE as indicated by type “B” tympanogram (in at least one ear) and otoscopic evidence (fluid/air fluid levels) of MEE at least 3 months preceding entry into the trial; (3) at least two physician-documented trials of anti-bacterials for AOM or OME, of at least 10 days’ duration in the 3 months preceding entry into the trial; (4) history of hearing loss (based on parental reports) of >3 months’ duration; at the time of

entry into the trial: (5) hearing loss of at least 25

cffi HL (hearing level based on the ANSI 53.6 1969 standard) air conduction at 2 or more frequencies

0.5, 1, 2, and 4 kHz (pure-tone audiometry) in at

least one ear; (6) bone conduction thresholds within

normal limits (0 to 10 dB HL) bilaterally; (7) otom-icroscopic and tympanometric (type “B”) evidence of MEE in at least one ear; and (8) air-bone gap of >15 cm at frequencies with elevated air conduction

thresholds. These criteria (with the exception of

age limits) are those commonly considered indica-tions for VT placement.

Exclusion Criteria: (1) cervicofacial abnormality (cleft palate, Down syndrome); (2) documented im-mune insufficiency; (3) documented allergy to sul-fonamide; (4) previous insertion of VT; or (5) doc-umented speech delay.

Enrollment, Randomization, and Treatment

Ad-ministration. Following informed parental consent, subjects were randomized to “medical” treatment consisting of sulfisoxazole, 75 mg/kg, divided in two daily doses for 6 months or to “surgical” treatment in which they underwent bilateral myringotomy and insertion of VTs at the anterior-inferior quad-rant of the tympanic membrane by the same

(3)

respec-tively, were lost to follow-up for reasons such as

subjects moving out of town or parental refusal to

attend follow-up appointments. A summary of sub-ject characteristics is available in Table 1.

Subjects were seen at 2, 4, 6, 12, and 18 months

following entry into the study. In both groups fewer than 6% of follow-up appointments were missed. At each assessment subjects underwent pure-tone audiometric testing (0.5, 1, 2, and 4 kHz) conducted by the same audiologist. Tympanometry was con-ducted only at 18 months to keep the audiologist “blind” to treatment group. Subjects also had a bilateral otomicroscopic examination performed by the same otolaryngologist at all appointments and medical subjects had remaining suspension meas-ured at 2, 4, and 6 months to determine compliance.

Acute Otitis Media Episodes and Superinfection

In the event of acute-onset ear pain or otorrhea, parents were asked to bring their child immediately to see the study otolaryngologist. For subjects in both groups an episode of AOM was included if it was diagnosed, documented, and treated by a

phy-sician when the subject could not see the study otolaryngologist. Otherwise, information on middle ear status based on physician reports was not used. In medical subjects, AOM was diagnosed based on otomicroscopic findings (redness of the tympanic membrane, absence of landmarks) and acute-onset ear pair with or without fever or otorrhea. For surgical subjects, the diagnosis of AOM was contin-gent on discharge from the ear and presence of pathogens commonly associated with AOM. If the

diagnosis of AOM was made, an oral,

non-sulfa-based antibiotic (usually amoxicillin) was given for

10 days. Medical subjects were required to continue

sulfisoxazole over this time.

Superinfection in surgical subjects was defined

as tube otorrhea and presence of Gram-negative

bacteria (except for Haemophilus influenzae and

Branhamella catarrhalis) and was treated with otic

drops (aminoglycoside and cortisone) for 7 days. In

TABLE 1. Group Characteristics of Medically Treated

(M) and Surgically Treated (5) Subjects*

Characteristics M Group S Group

(n=65) (n=60)

Mean age, y 5.0 4.7

% Male 52.3 56.7

% Female 47.7 43.3

Mean hearing loss (PTA) at 29.6 30.7

entry into study, dB HL

Mean no. of AOM episodes in 3.0 2.9

6 mo preceding study

* Abbreviations: PTA, pure-tone average; dB HL, decibel

hearing level; AOM, acute otitis media.

absence of culture results, tube otorrhea was on several occasions classified as an AOM episode by the child’s primary care physician. These episodes were counted as AOM and not as side effects of surgical treatment.

Treatment Success/Failure Criteria

Medical subjects remained on the medical regi-men for 6 months unless they experienced a skin rash due to possible allergy to sulfonamide (four

subjects). At 6 months, 12 months, and 18 months

each subject was classified as a treatment success or failure. At each time point, a treatment failure was defined as 1 of the following: (1) persistent/ recurrent MEE and associated hearing loss (>25

dB HL at 2 or more frequences 0.5, 1, 2, and 4 kHz, in at least one ear); (2) allergic reaction to sulfon-amide (for medical group only); or (3) three or more AOM episodes over a 6-month period of the study.

All treatment failures in the surgical group were related to number 1 (above) because of extrusion or blockage of VTs.

Unfortunately, the original study protocol did not provide for the rerandomization of treatment fail-ures, and the type of retreatment administered was based on parental concerns and the opinion of the otolaryngologist. Usually, medical subjects who did well with 6 months of medical treatment, but had a recurrence of hearing loss at 12 months, were retreated with sulfonamide. Medical subjects who still showed evidence of MEE and hearing loss at 6 months and did not respond to sulfonamide in the first place were retreated with VTs. Treatment failures in the surgical group were usually retreated with VTs. A breakdown of how treatment failures were retreated is available in Table 3.

Sample Size Calculation

The sample size calculation for this trial is based on the proportion of subjects who were expected to be treatment successes at 18 months. A chart review of the last 200 patients with OME who were treated with VTs indicated that approximately 55% re-quired no further treatment for OME over the

ensuing 18 months. Therefore, with an estimated

success rate of 55% for VT subjects, the following assumptions were made: (1) A clinically important difference in success rates at 18 months between the two treatment groups is 25% (higher or lower for medical or surgical subjects). (2) Accept a 3 (type II) error rate of 0.2 (power = 80%). (3) Accept

an a error rate of 0.05 (two-tailed).

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RESULTS

Sensitivity and Specificity of Otolaryngologist for Diagnosing OME

The sensitivity and specificity of the study

oto-laryngologist for diagnosing OME using

otomicro-scopic examination, hearing test results, and tym-panometry was based on tympanocentesis results (as the gold standard) in surgical subjects. These subjects required tympanocentesis as part of VT placement and it was deemed unethical to perform tympanocentesis on medical subjects unnecessarily. However, it should be borne in mind that subjects were randomly assigned to treatment.

Using tympanocentesis as the gold standard, the study otolaryngologist’s sensitivity in diagnosing OME was 96.9% (93 of96 ears with effusion present correctly identified) and specificity was 87.5% (21 of 24 ears with no effusion present correctly iden-tified).

Baseline

Characteristics

A summary of patient characteristics is avail-able in Table 1.

Separate t tests indicated that the medical and

surgical groups did not differ significantly (P values

> .20) with regard to number of AOM episodes in the 6 months preceding entry into the study or hearing thresholds at entry. Eighty-four percent of our subject had a bilateral hearing loss according to our criteria (>25 dB HL at 2 or more frequencies, 0.5, 1, 2, and 4 kHz) and the remaining 16% had unilateral hearing loss. The proportion of subjects with unilateral/bilateral hearing loss was similar for both groups

(x2

= 1.47, P = .774). Similarly, separate

x2

analyses showed no difference between

groups in the proportion of male and female

sub-jects, the proportion of subjects having a family history of ear infections, or the proportion of sub-jects having seasonal/perennial allergies, based on parental reports (P values > .20).

Treatment

Failure

The outcome of primary interest in the present study was the proportion of “treatment successes in each group.

Subjects meeting any of the treatment failure criteria were declared treatment failures at 6 months, 12 months, or 18 months. Inasmuch as there were three different time points at which subjects would be deemed treatment failures, an overall comparison of the success experience for both groups was performed using a modification of the

x2

technique proposed by Mantel’9 and this

manipulation compares the success rates of two groups over several time points. This analysis in-dicated that a significantly greater proportion of surgical subjects than medical subjects were treat-ment successes (as defined by not meeting one or more of the above criteria) over the three time points simultaneously (6, 12, and 18 months)

(x2

Mantel-Haenzel = 5.34; P = .0208). A summary of

treatment successes and failures is available in Table 2. Retreatment of subject failures is described in Table 3.

Hearing

Thresholds

Hearing results were analyzed based on a pure-tone average for 0.5, 1, 2, and 4 kHz averaged for both ears. Data from all subjects were analyzed according to the group to which they were originally randomized.

A repeated-measures analysis of variance was conducted to establish the effect of treatment over time (2, 4, 6, 12, and 18 months) on hearing

thresh-olds. A significant interaction between treatment

and time was noted (F = 5.07, P < .001),

necessi-tating a simple main-effects analysis of variance, as described by Kirk.2#{176}This procedure looks at each time point separately and indicated that surgical subjects were hearing significantly better than med-ical subjects at 2 months (F = 12.38, P < .001) and

at 4 months (F = 6.16, P = .0132) but not at 6, 12,

and 18 months (P values > .25). Hearing threshold data are summarized in the Figure.

When hearing thresholds were dichotomized (>25 dB HL at 2 or more frequencies in the worst ear = abnormal hearing), there was a significantly

greater proportion of medical than surgical subjects with abnormal hearing at 2 months

(x2

= 22.43, P < .001) and at 4 months

(x2

= 10.32, P = .001) but

not at 6 months

(x2

= 0.59, P .44), 12 months

(x2

= 0.001, P = .983), or 18 months

(x2

0.06, P

.81).

Acute Otitis Media

The diagnosis of AOM was based on the criteria outlined earlier. Subjects’ data were analyzed ac-cording to original group allocation.

The incidence of AOM episodes was very low over the first 6 months of the study and the mean number of AOM episodes per subject was 0.21 for the medical group and 0.36 for surgical subjects (t

= 1.36, P = .178). Between 6 and 12 months, rates

were 0.56 and 0.33 for medical and surgical subjects, respectively (t = 1.61, P = .109). Between 12 and

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TABLE 3. Retreatment of Subjects* TABLE 4. Frequency of Side Effects of Medication

* Allergic reaction to sulfonamide was defined as a rash appearing within 7 days of starting treatment. In these subjects, sulfonamide was discontinued and ventilation tube inserted.

* Percentages of group totals are given in parentheses.

M, medically treated subjects; 5, surgically treated

sub-jects; VT, ventilation tube.

dBHL (PTA)

40 MEDICATION

SURGERY

10Ih

Ih

i Ih

i

2MONTHS #{149}4MONTHS 6 MONTHS 12 MONTHS 18 MONTHS

Figure. Mean (+SE) hearing thresholds (pure tone av-erage (PTA): 0.5, 1, 2, 4 kHz) dBHL at 2, 4, 6, 12, and 18 months. * Simple main effects analysis of variance

sig-nificant at P < .05.

TABLE 2. Treatment Successes for Each Group at 6, 12, and 18 Months*

Month edical Treatment S urgical Treatment

N at Start Failures

(F)

Successes

(N-F)

N at Start Failures

(F)

Successes (N-F)

6

12 18

65

43 26

22 (34)

17 (26) 5 (6)

43 (66)

26 (40) 21 (33)

60

48 36

12 (20)

12 (20) 5 (8)

48 (80)

36 (60) 31 (52)

* Percentages of group totals are given in parentheses.

Group Retreated With VT

Retreated With Sulfonamide

for 6 mo

Not Re-treated

M (n = 65) 31 (47.7) 13 (20) 21 (32.3)

S (n = 60) 23 (38.3) 6 (10) 31 (51.7)

Side-Effects of Treatment

Side effects of medical treatment were relatively uncommon, and only 9.2% of medical subjects re-ported those complaints. No serious side effects were observed. Four subjects experienced rash due to possible allergy to sulfonamide and two subjects reported nausea. One or more complication(s) of

surgery such as tube otorrhea, superinfection, for-eign body reaction, and myringosclerosis (limited tympanosclerosis without involvement of middle ear structures) occurred in 50% of surgical subjects. There was a significantly greater proportion of sur-gical subjects experiencing complications of surgery than medical subjects experiencing side effects of sulfonamide

(x2

= 23.3, P < .001). Tables 4 and 5

summarize side effects of medication and compli-cations of surgery, including diagnostic definitions.

Compliance with Medical Regimen

Compliance (according to the amount of suspen-sion returned) was, on average, 94% over the

6-Side Effect No. (%)

Affected

Allergic reaction* 4 (6.2)

Nausea 2 (3.1)

Vomiting 0 (0)

TABLE 5. Frequency of Complications of Ventilation Tube (VT) Placement

Complication of VT No. (%)

Affected

Tube otorrhea* Myringosclerosist Superinfectiont

Foreign body reactions Chronic tympanic membrane

perforation

8 (13.3) 17 (28.3) 18 (30.0) 2 (3.3) 0 (0)

* Tube otorrhea and no evidence of Gram-negative

bac-teria on culture or culture results unavailable (four sub-jects).

t Localized myringosclerosis without the involvement of

middle ear structures. Four medically treated subjects showed evidence of myringosclerosis.

:1:Tube otorrhea with presence of Gram-negative bacteria

on culture.

§ Purulent discharge and pyogenic granuloma formation.

month treatment period. In three medical subjects, treatment failure at 6 months could possibly be linked to noncompliance, in that less than 40% of the prescribed amount of sulfisoxazole was taken. These subject’s data are included in the analyses.

DISCUSSION

The results of our trial suggest that the success rate of the surgical treatment is superior to that of the medical treatment of long-standing OME, in subjects followed up for a period of 18 months. Hearing thresholds were significantly better for surgical subjects at 2 and 4 months but not at 6,

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were retreated with VTs (Table 2), and data were analyzed according to how subjects were originally randomized. The success-over-time (survival)

analysis previously mentioned does not suffer this

failing, as once subjects were designated as

“fail-ures” their data from subsequent time points were

not considered. Therefore, the treatment-success-over-time analysis better reflects the true efficacy of the two treatments.

However, our data do suggest that 33% of subjects with indications for VT surgery treated with sulfi-soxazole for 6 months required no further interven-tion by 18 months after entry into the study. This finding raises two important considerations: First, the management of OME with VTs is costly-approximately $700 in Canada (including the cost of VTs, surgeons and anesthetists’ fees, and day-care surgery costs), whereas a 6-month course of sulfisoxazole (75 mg/kg per day, based on a weight of 20 kg) costs about $85. This cost difference is likely more pronounced in the United States, and one estimate21 has put the price of treating otitis media at $2 billion annually in the United States, a significant proportion of which is likely accounted for by the insertion of VTs. At this point, it should be borne in mind that, although 67% of medical

subjects required retreatment, so did 48% of

sur-gical subjects by 18-month follow-up. A second pertinent observation is that complications with VT placement were considerably more common than side effects of medical treatment. Superinfec-tion and tube otorrhea are not regarded as serious complications; however, they do represent some degree of inconvenience to the child and parents, and precautions (such as wearing earplugs) should be taken during bathing and swimming activities. Limited tympanosclerosis (myringoscierosis) is an-other side effect of VT placement that is relatively common and generally regarded as innocuous in

the short-term. However, the long-term outcome of

myringosclerosis is unknown. One study,3

compar-ing the efficacy of VT placement in one ear but not the contralateral ear for the treatment of bilateral OME, showed slightly better hearing in the control ear at 5-year follow-up (14 dB HL and 17 dB HL, respectively) and myringosclerosis was consider-ably more common in the VT ears. Another study22 documented myringosclerosis in almost every ear in which VT had been placed 7 to 10 years prior for the treatment of recurrent OME. A recent retro-spective stud?3 reported the incidence of

myrin-gosclerosis was 6.5% in children given antibiotics

for OME or recurrent AOM compared with 52.3%

in children undergoing three or more VT

place-ments for the same disorders. Furthermore,

audio-logic sequelae were more common in VT-treated

ears; between 9.3% and 18.7% of VT ears had a

threshold of >20 dB (depending on frequency

tested: 0.5 to 8 kHz) while the range for medically

managed ears was 3.7% to 9%. Our data support this observation that it is the VT and not otitis media that causes sclerosis of the tympanic mem-brane inasmuch as only 6.2% of medical subjects and 28.3 percent of surgical subjects showed evi-dence of myringosclerosis.

Certainly, the treatment of OME with sulfisoxa-zole is not without its disadvantages as well. Com-pliance (which is not an issue for surgically treated

subjects) is a prerequisite to the success of this

regimen, although it did not seem to be a problem

in this trial. Sulfonamide-induced photosensitivity

and other possible side effects should also be con-sidered.

The surgical management of OME has also been justified on the findings of several cohort and case-control studies indicating that long-standing MEE can lead to possible language and cognitive delays (eg, Refs 24 and 25). However, these studies have been criticized on the basis of various methodolog-ical flaws26 and some authorities believe that the case for language and cognitive delays caused by OME has been overstated.27 Recent evidence

sug-gests that early OME and associated conductive

hearing loss can act synergistically with preexisting language delay to make matters worse.28

Accord-ingly, we believed that patients with documented

speech-language delay and conductive hearing loss associated with OME were candidates for VT in-sertion and were not included in our study.

Another contraindication for antimicrobial

ther-apy in OME is the situation in which a child has a bilateral hearing loss of greater than 40 dB HL. In this study four medical subjects had a bilateral loss of this magnitude and it was observed that (1) they were unresponsive to the medical regimen, and (2) because of the degree of their hearing loss, they had to be fitted with a hearing aid. However, OME is

not usually associated with a bilateral hearing loss

of this magnitude and an average of 25 to 30 dB HL is the rule.29

The prophylaxis of recurrent AOM was approx-imately equal in both groups over the study period. This finding was consistent with other studies in-dicating a significant reduction in recurrent AOM

episodes using VT vs placebo3#{176} or sulfisoxazole vs

(7)

pro-tection from AOM once therapy has been discon-tinued. However, this supposition is confounded by the fact that a significant proportion of medical and surgical subjects received VTs or a second course of sulfisoxazole for recurrent hearing loss and it is likely that these retreatments were, in part, responsible for the amelioration of AOM at-tack rates between 6 and 18 months in both groups. Another contributing factor would be the natural

history of recurrent AOM, which shows lower

at-tack rates with increasing age (after 2 years old). The possibility also exists that some of the AOM

episodes occurring in the 6 months preceding entry

into the trial were misdiagnosed and were not true

AOM episodes.

The only real cure for long-standing OME is “the tincture of time” and neither of these treatments is a panacea; 67% of medical subjects and 48% of surgical subjects required some form of retreatment over the 18-month study period. This difference between the groups is both statistically and

clini-cally significant. There is a small but real risk of

anesthesia morbidity and mortality and almost 40%

of surgical subjects required more than one opera-tion over the 18 months. In addition, there was a higher complication rate in the surgically treated group, the long-term seriousness ofwhich is unclear at this point. These findings, together with the low

cost, limited side effects, and effectiveness in a

significant proportion of children who otherwise require surgery, lead us to recommend a 6-month

trial of antimicrobial therapy before considering

VT placement.

Additional research is required to determine whether more potent antimicrobials and second

courses of antimicrobials might further decrease

the number of children requiring surgery for

long-standing OME. The usefulness of other regimens

such as initial therapeutic dosages followed by

pro-phylactic dosage for some time should also be

in-vestigated.

ACKNOWLEDGMENTS

This work was funded by the National Health and

Welfare Research and Development Program, Ottawa,

Canada (grant 6606-2944-42).

The sulfisoxazole was kindly provided by

Hoffmann-Laroche Canada Ltd.

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RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF

METHOTREXATE IN STEROID-DEPENDENT ASTHMA

Abstract

69 patients with steroid-dependent asthma (mean daily prednisolone dose 14.2 [SD 6.1] mg) took part in a randomised, double-blind, placebo-controlled

study of 24 weeks’ treatment with methotrexate 15 mg weekly. The patients

were seen every 4 weeks by the same physician, who reduced the daily pred-nisolone dose by 2.5 mg if the daily diary card variables and measurements of lung function were unchanged or improved. All other treatment remained unchanged. After 24 weeks of treatment the prednisolone dose had been reduced by a significantly greater proportion in the methotrexate than in the placebo group (50% vs 14%) and the reduction was not sustained after the study treatment stopped. There were substantial abnormalities in liver function tests in 5 of the 38 patients taking methotrexate.

Shiner R4J, Nunn AJ, Fan-Chung K, Geddes DM. Randomised, double-blind, placebo-controlled trial of methotrexate in steroid-dependent asthma. The Lancet. 1990;336:137-140.

NOTED BY J.F.L., MD

at Viet Nam:AAP Sponsored on September 1, 2020

www.aappublications.org/news

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1991;88;215

Pediatrics

Philippe A.M. Bernard, Robert J. Stenstrom, William Feldman and Andree Durieux-Smith

Ventilation Tubes for Otitis Media With Effusion

Randomized, Controlled Trial Comparing Longterm Sulfonamide Therapy to

Services

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