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A double-blind, randomized, placebo-controlled trial of cranberry supplements in multiple sclerosis.

Abstract: Cranberry cocktail has been reported to reduce bacteriuria and pyuria in elderly women and self-reported urinary tract infection (UTI) in young female undergraduates, but commercially prepared cranberry concentrate supplements have never been evaluated in multiple sclerosis (MS) patients with neurogenic bladder. The purpose of this study was to determine whether one 8,000-mg cranberry concentrate supplement daily could prevent UTI in MS participants with bladder symptoms. We conducted a double-blind, randomized, placebo-controlled longitudinal trial of cranberry supplement versus placebo with participants who have MS. After informed consent had been obtained from the participants, baseline data were collected and participants were randomized to receive either one cranberry supplement or placebo daily for 6 months. The sample consisted of 135 participants. In the cranberry group 34.6% of participants failed (i.e., developed a UTI) versus 32.4% in the control group (p = .849). Not all cranberry supplements have been found to contain proanthocyanidins, the active ingredient of cranberries. Because there is no way for the consumer to distinguish supplements that contain proanthocyanidins from those that do not, taking juice or whole cranberries may be preferable.

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The reported prevalence of urinary tract infection (UTI) in people with multiple sclerosis (MS) varies from 20% to 74% depending on the sample selected for study, and some 12% to 25% are recurrently infected (Edich, Westwater, Lambordi, Watson, & Howards, 1990; Gonor, Carroll, & Metcalfe, 1985; Koldewijn, Hommes, Lemmens, Debruyne, & Van Kerrebroeck, 1995; Surls, Zimmern, & Leach, 1994). Incomplete bladder emptying with urinary stasis is probably the leading cause of UTI in people with MS. Spinal cord lesions, interrupting spinal pathways between the pontine micturition center and the sacral spinal cord, are the most common cause of disordered bladder function and result in detrusor hyperreflexia. The loss of normal inhibitory pathways also results in unsustained detrusor contractions, detrusor-sphincter dyssynergia, or both. In this population, UTI is associated with significant morbidity. UTI temporarily worsens neurologic impairment, and there is some evidence to suggest that UTI might trigger MS relapses (Edich et al., 1990; Metz, McGuinness, & Harris, 1998). In the only randomized trial reported in the literature, cranberry cocktail reduced bacteriuria and pyuria in a sample of 153 elderly women who consumed at least 300 ml daily (Avorn et al., 1994). Foxman, Gieger, Plain, Gillespie, and Koopman (1995) found that cranberry cocktail reduced the risk of self-reported UTI in young female undergraduates. However, the efficacy of cranberry cocktail has never been studied in MS patients with neurogenic bladder.

Recent studies (Howell, Vorsa, Marderosian & Foo, 1999; Sobota, 1984) have isolated the active ingredient from cranberries as proanthocyanidins. Proanthocyanidins have been isolated from pure cranberry juice, cranberry cocktail, and fresh cranberries and found to prevent the adhesion of uropathogenic strains of Escherichia coli (E. coli) to the urinary tract. Bacterial adherence is a prerequisite for the development of infection. Cranberry cocktail is frequently recommended prophylactically in persons with recurrent UTI. However, the concentration of pure cranberry juice in cranberry cocktail ranges from only 15% to 30% depending on the brand, and cranberry cocktail is high in sugar and calories. In addition, many persons with MS do not like the taste of cranberry cocktail. Cranberry supplements in capsule form are now available from health food stores, but their efficacy has never been evaluated. Therefore, the purpose of this study was to determine whether cranberry concentrate supplements prevent UTI in participants with MS.

Design

This was a double-blind, randomized, placebo-controlled, 6-month trial of 8,000 mg of cranberry supplements versus placebo ingested daily by MS participants with urinary tract symptoms. Urinary tract symptoms were classified as irritative (urgency, frequency, nocturia, pain), obstructive (hesitation, double voiding, residual, weak flow), or incontinence. The primary outcome variable was diagnosed UTI. Participants were considered to have completed the study if they were randomized and reached the primary outcome or completed 6 months of treatment. Those who developed UTI during the 6-month study were considered failures and were withdrawn. Urinary tract infection was defined as positive urinary culture (>[10.sup.6] CFU/ml) with presence of leukocytes, blood, or nitrites on microscopy. Symptoms of UTI were not required for diagnosis, because these symptoms are commonly masked in persons with MS. Cranberry supplement and placebo were supplied by NOW Natural Foods at a dose of 8,000 mg for cranberry. That particular amount of cranberry supplement was selected because it was the highest available dose. Placebo comprised beetroot powder in a gelcap and appeared identical. This study was approved by the Conjoint Health Research Ethics Board at the University of Calgary, and the rights of all participants were protected at all times.

Sample Selection

Participants were recruited from an outpatient MS clinic and its affiliated outpatient rehabilitation program. Eligibility criteria were that the participant

* had clinically or laboratory-supported definite MS according to the Poser criteria (Poser et al., 1983)

* had an Expanded Disability Status Scale score between 0 and 8.0 (Kurtzke, 1983)

* was able and willing to provide informed consent to participate and to refrain from consuming other cranberry products for the duration of the trial

* had no indwelling or condom catheters

* if using intermittent self-catheterization (ISC), used standard technique and catheterized no more than six times daily

* had some symptoms of neurogenic bladder

* had no current UTI.

Because differential UTI rates may exist in patients using ISC versus those voiding normally, the sample was stratified by use of ISC.

Procedure

After informed consent had been obtained from the patient, a sterile catheter or midstream urine was collected for routine microscopy and culture. Baseline data including MS course and duration, age, gender, number of UTIs in past year (self-report), postvoid residual, presence of urinary tract symptoms, management strategies, and medication use (for urinary symptoms only) were collected. Eligible participants were then randomized to receive either cranberry supplement or placebo and were instructed to take one capsule with food each morning. Participants were provided with information about the common symptoms of UTI (e.g., pyrexia, flank pain, dysuria, hematuria) and were instructed to call the MS clinic immediately if they thought they might have a UTI. In addition, a research assistant contacted every participant once a month to review compliance and to ensure the study endpoint was not missed. Participants suspected of having a UTI provided an immediate urine sample for microscopy, culture, and sensitivity. Standard clinical practice was followed to treat UTI. Data on date of onset and symptoms, prescribed treatment, and results of urine culture were collected. Participants who did not develop a UTI within 6 months provided a urine sample for microscopy, culture, and sensitivity at the end of 6 months to rule out undetected UTI.

All outcome data were analyzed by using an intent-to-treat approach wherein participants remained in their originally assigned treatment groups regardless of whether or not they completed the study. The primary outcome was analyzed by using Fisher's exact test (FET). We also conducted an exploratory analysis stratifying the primary outcome by baseline variables such as gender, use of medication for bladder symptoms, presence of retention (defined as PVR [greater than or equal to] 100 ml), presence of obstructive symptoms, history of recurrent UTI ([greater than or equal to] 3 UTIs in the past year), and infection with E. coli.

Results

The sample consisted of 135 participants, 63 using ISC and 72 voiding naturally. Nine participants withdrew from the study before completion for a variety of reasons, including wanting to drink cranberry juice, family reasons (i.e., illness in the family), and urinary frequency (UTI ruled out). Three participants were lost to follow-up. There was no difference in any baseline characteristics between those completing the study and those who withdrew or were lost to follow-up, and there was no difference between treatment groups. Demographic and disease characteristics are presented in Table 1. No difference in any baseline variables between treatment groups was evident. As expected, participants using ISC had significantly higher postvoid residuals than those voiding normally (mean postvoid residual in ISC subjects was 253 ml versus 41 ml in non-ISC subjects).

Baseline urinary tract symptoms and management strategies are presented in Table 2. Again, no differences between the two treatment groups were detected. Participants in the ISC group reported more obstructive symptoms such as double voiding, hesitancy, or weak flow (n = 59, 93.7%) than those in the non-ISC group (n = 25, 34.7%), and more ISC subjects reported medication use to control bladder symptoms (n = 47, 74.6%) than non-ISC subjects (n = 16, 22.2%). The most commonly used medication was oxybutynin chloride (Ditropan), which was taken by 31 (83.8%) of placebo subjects and 23 (85.2%) of cranberry subjects. Other medications, used by less than 5% of the sample, were flavoxate hydrochloride (Urispas), ascorbic acid (vitamin C), and imipramine hydrochloride (Tofranil).

In the cranberry group 34.6% failed (i.e., developed a UTI) versus 32.4% in the control group (p = .849). When we stratified the sample according to use of ISC, 57.7% of cranberry subjects using ISC failed versus 48.5% of placebo subjects (p = .601). In the non-ISC group, 13.8% of cranberry participants failed versus 17.1% of placebo participants (p = .745). There were no statistically significant findings on any of the exploratory analyses, and no trend favoring treatment with cranberry supplements was found.

Discussion

Our results differ from those reported by Avorn et al. (1994), who found that drinking at least 300 ml of cranberry cocktail daily reduced bacteriuria and pyuria in elderly women. However, Avorn et al. did not measure diagnosed UTI. The population in this study had neurogenic bladder, and diagnosed UTI was used as the outcome measure. Although the dose of cranberry supplement may have been too low, this seems unlikely given that data from the Avorn et al. study showed an effect with only 300 ml of cranberry cocktail.

Our original power calculation was based on a failure rate of 75% in 6 months. However, overall only 32.4% of participants in the placebo group failed in 6 months. Therefore, the sample may have been too small to show a statistically significant difference. However, if cranberry supplement showed any effect, there would have been a trend favoring cranberry treatment. There was no such trend in the data. In fact, in the primary analysis more subjects on cranberry (34.6%) failed than those on placebo (32.4%). We also analyzed time to failure but found no difference between treatment groups, indicating that cranberry supplement neither prevented nor delayed UTI.

Howell et al. (1999) identified the active ingredient in cranberries as proanthocyanidins. Proanthocyanidins are found in cranberry cocktail and juice, as well as in fresh cranberries and blueberries. Proanthocyanidins prevent adhesion of fimbriated E. coli to uroepithelial cells. In a secondary analysis we tested the hypothesis that participants may have been infected by bacteria other than E. coli. However, there was no difference in E. coli infection rates between the two treatment groups (61.1% in the cranberry group versus 50% in the placebo group, FET = 0.532). Of crucial importance is the fact that proanthocyanidins are not found in all commercially produced supplements; presumably they are destroyed in some manufacturing processes (A. Howell, personal communication, September 29, 1999). We did not have laboratory facilities available to test for anti-adhesion properties and may have used a supplement that did not contain proanthocyanidins. This raises serious concerns for the consumer, because there is no way of knowing which supplements actually contain the active ingredient.

In light of our results, we are not confident that all commercially available cranberry supplements are effective in preventing UTI. Consumers may be better served by drinking either pure juice or cranberry cocktail or eating cranberries or blueberries, but this requires further study. There may also be an incubation period in which urine must be stored in the bladder for the anti-adhesion effect to occur. Therefore, cranberry products in any form will be ineffective in persons with indwelling catheters.

Study Limitations

Given the lower-than-expected rate of developing a UTI in the study (actual rate of 32.4% versus expected rate of 75%), the study may have been underpowered and a type II error may have resulted. A second limitation of the study is that we were unable to secure sufficient funding to have independent laboratory tests conducted on the cranberry supplements to verify the presence of proanthocyanidins. Therefore, the supplement the participants took may actually have been inactive. Also, 8,000 mg once per day may have been too low a dose to have any therapeutic effect.

Recommendations for Future Study

The study should be repeated with a larger sample and with a supplement that has been proven in the laboratory to contain proanthocyanidins. In addition, a head-to-head comparison study of cranberry supplement against traditional cranberry cocktail and placebo may demonstrate which preparation, if any, has superior efficacy.

Summary

In a sample of 153 participants with MS, we were unable to show that oral treatment with 8,000 mg of cranberry supplement daily prevented or delayed the onset of urinary tract infection when compared to placebo. The study may have been underpowered or the cranberry supplement may not have contained the active ingredient, proanthocyanidins. Alternatively, patients with neurogenic bladder may not benefit from the ingestion of cranberry products.
Table 1. Baseline Sample Characteristics by Treatment Group

 Treatment Group

 Cranberry
Characteristics Supplement Placebo

Age
 Mean 44.8 45.4
 Standard deviation 9.9 9.8
 95% confidence interval 42.3-47.3 43.2-47.7
Female
 Number 49 57
 Percentage 79.0% 78.1%
 Binomial 95% confidence interval 66.8%-88.3% 66.9%-86.9%
Duration of Multiple Sclerosis (years)
 Mean 11.9 13.4
 95% confidence interval 10.0-14.2 11.2-16.0
Postvoid Residual (ml)
 Mean 134.5 159.7
 95% confidence interval 90.1-200.9 99.6-256.1
Median Number of Urinary 1 1
 Tract infections in Past Year

Table 2. Baseline Urinary Tract Symptoms and Management Strategies by
Treatment Group

 Treatment Group

 Cranberry
Symptom or Management Strategy Supplement Placebo

Irritative (1) Symptoms
 Number 53 66
 Percentage 85.5% 90.4%
 Binomial 95% confidence interval 74.2%-93.1% 81.2%-96.1%
Obstructive (2) Symptoms
 Number 38 46
 Percentage 61.3% 63.0%
 Binomial 95% confidence interval 48.1%-73.4% 50.9%-74.0%
Incontinence
 Number 38 49
 Percentage 61.3% 67.1%
 Binomial 95% confidence interval 48.1%-73.4% 55.1%-77.7%
Incontinence Pads
 Number 13 32
 Percentage 21.0% 43.8%
 Binomial 95% confidence interval 11.7%-33.2% 32.2%-56.0%
Limit Fluid Intake
 Number 23 30
 Percentage 37.1% 41.1%
 Binomial 95% confidence interval 25.2%-50.3% 29.7%-53.2%
Stay Near Bathroom
 Number 24 37
 Percentage 38.7% 50.7%
 Binomial 95% confidence interval 26.6%-51.9% 38.7%-62.6%
Use Medications
 Number 26 37
 Percentage 41.9% 50.7%
 Binomial 95% confidence interval 29.5%-55.2% 38.7%-62.6%

(1) Urgency, frequency, nocturia, pain

(2) Hesitation, double voiding, residual, weak flow


Acknowledgments

This research was supported by grants from the Alberta Association of Registered Nurses and the American Association of Neuroscience Nurses. Cranberry supplement and placebo were provided by NOW Natural Foods. Catheters were provided by Mentor Medical Systems, Inc. We gratefully acknowledge the assistance of Colleen Harris, Sharon Peters, Angela Moore, and Amanda Mills.

Questions or comments about this article may be directed to: Sandra McGuinness, MN MS, Multiple Sclerosis Clinic, AC137A, Foothills Medical Centre, 1403 29 Street, NW, Calgary, Alberta T2N 2T9 Canada, or by e-mail to Sandra.mcguinness@calgaryhealthregion.ca. She is a research program coordinator at the Multiple Sclerosis Clinic.

References

Avorn, J., Monane, M., Gurwitz, J.H., Glynn, R.J., Choodnovskiy, I., & Lipsitz, L.A. (1994). Reduction of bacteriuria and pyuria after ingestion of cranberry juice. Journal of the American Medical Association, 271, 751-754.

Edich, R.F., Westwater, J.J., Lambordi, S.A., Watson, L.R., & Howards, S.S. (1990). Multiple sclerosis and asymptomatic urinary tract infection. The Journal of Emergency Medicine, 8, 25-28.

Foxman, B., Geiger, A.M., Palin, K., Gillespie, B., & Koopman, J.S. (1995). First-time UTI and sexual behavior. Epidemiology, 6, 162-168.

Gonor, S.E., Carroll, D.J., & Metcalfe, J.B. (1985). Vesical dysfunction in multiple sclerosis. Urology, 25, 429-431.

Howell, A.B., Vorsa, N., Marderosian, A.D., & Foo, L.Y. (1999). Inhibition of adherence of p-fimbriated Escherichia coli to uroepithelial-cell surfaces by proanthocyanidin extracts from cranberries. New England Journal of Medicine, 339, 1085-1086.

Koldewijn, E.L., Hommes, O.R., Lemmens, W.A.J.G., Debruyne, F.M.J., & Van Kerrebroeck, P.E.V. (1995). Relationship between lower urinary tract abnormalities and disease-related parameters in multiple sclerosis. The Journal of Urology, 154, 169-173.

Kurtzke, J.F. (1983). Rating neurologic impairment in multiple sclerosis: An Expanded Disability Status Scale. Neurology, 33, 1444-1452.

Metz, L.M., McGuinness, S.D., & Harris, C. (1998). Urinary tract infections may trigger relapse in multiple sclerosis. Axon, 19(4), 67-70.

Poser, C.M., Paty, D.W., Scheinberg, L., McDonald, W.I., Davis, F.A., Ebers, G.C., Johnson, K.P., Sibley, W.A., Silberberg, D.H., & Tourtellotte, W.W. (1983). New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Annals of Neurology, 13, 227-231.

Sobota, A.E. (1984). Inhibition of bacterial adherence by cranberry juice: Potential use for the treatment of urinary tract infections. The Journal of Urology, 131, 1013-1016.

Surls, L.T., Zimmern, P.E., & Leach, G.E. (1994). Role of limited evaluation and aggressive medical management in multiple sclerosis: A review of 113 patients. The Journal of Urology, 151, 946-950.

Ruth Krone, BN, was an outpatient nurse at the Multiple Sclerosis Clinic.

Luanne M. Metz, MD FRCPC, is the director of the Multiple Sclerosis Clinic.
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Author:McGuinness, Sandra D.; Krone, Ruth; Metz, Luanne M.
Publication:Journal of Neuroscience Nursing
Geographic Code:1USA
Date:Feb 1, 2002
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