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SCI: Cranberry Juice and Urinary Tract Infections (2007)

Citation:

Lee BB, Haran MJ, Hunt LM, Simpson JM, Marial O, Rutkowski SB, Middleton JW, Kotsiou G, Tudehope M, Cameron ID. Spinal-injured neuropathic bladder antisepsis (SINBA) trial. Spinal Cord. 2007;45:542-550. 

PubMed ID: 17043681
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
To determine whether Methenamine Hippurate (MH) or cranberry tablets prevent urinary tract infections (UTI) in people with neuropathic bladder following spinal cord injury (SCI).
Inclusion Criteria:
  • SCI with neurogenic bladder.
  • stable bladder management with either indwelling urethral or suprapubic catheter, intermittent catheterization, or reflex voiding with or without a condom drainage device
  • absence of complex urological or serious renal or hepatic pathology
  • not being prescribed antibiotics at the time of enrollment
  • willing to stop any intercurrent urinary antiseptics before entering the trial.
Exclusion Criteria:
  • Previous allergy to any of the tested interventions
Description of Study Protocol:

Recruitment

 Subjects were sampled from the New South Wales Spinal Cord Injuries Database and related database records of the two hospitals in New South Wales, Australia between November 2000 and August 2002.

Design

Participants were randomly assigned to one of four groups using a factorial design. These groups were: MH (2g) with cranberry (1600 mg), MH (2g) with cranberry placebo, Cranberry (1600 mg) with MH placebo and MH placebo and cranberry placebo.  All four regimens were indistinguishable in appearance (size and shape) and taste (iron oxide coating).   All participants recieved the same number of tablets, split into a twice-daily regimen. 

Blinding used (if applicable)

All investigators and participants were blinded to patient allocation.  Clinicians and patients were blinded to allocation as well as the results. All staff was blinded to allocation in the assessment of symptomatic and microbiological outcomes.

Intervention (if applicable) 

Participants were randomized to one of four groups: MH (2g) with cranberry (1600 mg), MH (2g) with cranberry placebo, Cranberry (1600 mg) with MH placebo and MH placebo and cranberry placebo.  The dose of MH was 1 g twice daily and the dose of  cranberry was 800 mg twice daily. Patients continued on this regime until the primary end point was reached or 6 months elapsed.

Statistical Analysis

  •  To assess generalizability of the results, those included in the trial were compared with those who were excluded or opted not to participate. 
  • The X2-test was used to compare categorical variables and the two-sample t-test was used for continuous variables.
  • Analysis was by intention to treat.
  • Survival analysis was used to examine the effects of MH and cranberry on the time to the primary end point (UTI).
  • Logrank test statistic was used to test the significance of the unadjusted effect of a variable on UTI-free survival time.
  • The logrank test for trend was used for ordered categorical variables.
  • Kaplan-Meier life tables were used to calculate the quartiles of survival rates across the starta of the covariates.
  • Cox proportional hazards models were used to calculate unadjusted hazard ratios (HR) and HRs adjusted for important covariates.
  • Covariates collected for the trial were examined in a blind manner from all baseline information and rated.  Any variable rated weak was not used in the multivariate analysis.
  • Urinary bacterial count was also included to adjust for the clincially important difference between groups at baseline.
Data Collection Summary:

Timing of Measurements

 All participants were contacted biweekly by the research team to confirm asymptomatic status or if a symptomatic UTI had occurred.

Dependent Variables

  • Symptomatic UTI occurred to prestablished criteria.
  • Time from randomization to the first symptomatic UTI or 6 months if no UTI occurred.

Independent Variables

  • 1 g MH twice a day with cranberry placebo
  • 800 mg cranberry twice a day with MH placebo
  • 1 g MH twice a day and 800 mg cranberry twice a day
  • MH placebo and cranberry placebo

Control Variables

 Bladder management type was adjusted for in the multivariate analysis.

Description of Actual Data Sample:

 

Initial N:

543 eligible predominantly community dwelling patients were invited to participate in the study, of whom 305 (56%) agreed to participate.

Attrition (final N):

305 participants were included in the analysis.

Age:

Mean age of 43.5 ± 13.5 years; range of 16-82 years)

Ethnicity:

Not noted by author

Other relevant demographics:

83% male

55% tetraplegia

49% complete spinal injury

Medium time since SCI 12 years (range 1 month to 61 years)

Anthropometrics

There was no clinically important difference between the treatment groups at baseline in any of the characteristics measured with the exception of bladder management type and urine bacterial count in the MH compared to the placebo group.

Location:

 New South Wales, Australia

Summary of Results:

 Adjusted effects of MH and cranberry treatments and other factors on UTI-free survival

Variables

Hazard ratio

(95% CI)

P-value

MH

0.96 (0.68-1.35)

0.75

Cranberry

 0.93 (0.67-1.31)

 0.70

 

Other Findings

 Theer was no significant relationship between UTI-free survival and inpatient/outpatient status, gender, age or education at time of recruitment. Having one UTI in the preceeding 6 months increases the risk of a subsequent UTI by 25% in the following 6 month period. Having two or more UTI in the same time period increases the risk by 89%.

Author Conclusion:
MH and cranberry tablets are not effective in prolonging the UTI-free period in people with SCI.  These results could potentially be extrapolated to other population groups with supra or infrasacral neuropathic bladder dysfunction.  It is important that the lack of prophylactic effect of  current urinary antiseptic medications is brought to the attention of clinicians facilitating the care of people with SCI.
Funding Source:
Government: Motor Accidents Authority of New South Wales
Reviewer Comments:
  • Failure to balance adequately for bladder management type (with potential bias towards null)
  • Failure to recruit the targeted 350 participants
  • 16% of patients who indicated symptoms suggestive of a UTI did not have microbiological or bacteriolgical criteria supportive of this diagnosis when formal microbiological results became available.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? Yes
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? Yes
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? Yes
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? Yes
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes