Background To adequately assess individual studies and synthesize quantitative research on weight loss studies, transparent reporting of data is required. The authors examined the reporting quality of randomized trials in the weight loss literature, focusing exclusively on subject characteristics as they relate to enrollment, allocation, and follow-up.
Background
To adequately assess individual studies and synthesize quantitative research on weight loss studies, transparent reporting of data is required. The authors examined the reporting quality of randomized trials in the weight loss literature, focusing exclusively on subject characteristics as they relate to enrollment, allocation, and follow-up.Methods An extensive literature review, which included a computerized search of the MEDLINE database, manual searches of bibliographic references, and cross-referencing of 92 review articles was conducted. A checklist, based on CONSORT recommendations, was used to collect information on whether or not authors reported age, gender, co-morbid disease, medication use, race/ethnicity, and postmenopausal status. Also tracked was whether or not initial and final sample size was reported and stratified by gender.
Methods
An extensive literature review, which included a computerized search of the MEDLINE database, manual searches of bibliographic references, and cross-referencing of 92 review articles was conducted. A checklist, based on CONSORT recommendations, was used to collect information on whether or not authors reported age, gender, co-morbid disease, medication use, race/ethnicity, and postmenopausal status. Also tracked was whether or not initial and final sample size was reported and stratified by gender.Results Of 604 possible articles, 231 articles met eligibility criteria. Important subject characteristics were not reported as the following breakdown indicates: age (11%), gender (4%), race/ethnicity (86%), co-morbid disease states (34%), and medication use (92%). Additionally, 21% of articles failed to report initial sample size by gender while 69% neglected to report final sample size by gender.
Results
Of 604 possible articles, 231 articles met eligibility criteria. Important subject characteristics were not reported as the following breakdown indicates: age (11%), gender (4%), race/ethnicity (86%), co-morbid disease states (34%), and medication use (92%). Additionally, 21% of articles failed to report initial sample size by gender while 69% neglected to report final sample size by gender.Conclusion Inadequate reporting can create difficulties with interpretation and can lead to biased results receiving false credibility. The quality of reporting for weight loss studies needs considerable improvement.
Conclusion
Inadequate reporting can create difficulties with interpretation and can lead to biased results receiving false credibility. The quality of reporting for weight loss studies needs considerable improvement.

Background Current statistics indicate that approximately 64.5% of US adults can be considered overweight while 30.5% can be classified as obese [ 1 ]. Obesity is also linked to a variety of chronic diseases, and is associated with approximately 300,000 deaths each year and annual economic costs of over $117 billion [ 2 ]. According to the latest Behavioral Risk Factor Surveillance Survey (BRFSS) data, obesity and overweight continue to be major pubic health concerns, and reports indicate that no state had met the Healthy People 2010 objective of reducing obesity to 15% [ 3 ]. As a result, there is need for a strong evidence base for prevention and treatment strategies. Systematic reviews can offer the most reliable sources of information on which to develop guidelines and base treatment policy. However, such reviews need to contain a high proportion of all relevant evidence, which relates both to the need to find all trials and the need to analyze data on all participants [ 4 ]. To improve the quality of reporting for randomized controlled trials (RCTs) in the overweight and obesity literature, as well as any intervention trial, investigators are encouraged to publish reports in clear and unambiguous language, accounting for all events that occurred during the conduct of the investigation, and providing an accurate and thorough description of subjects who were selected, excluded, withdrawn or did not complete the study. Failing to report essential variables, such as subject characteristics, does not allow readers to adequately judge the validity or applicability of the study results, and may influence the interpretation of findings [ 5 ]. In response to the need for quality reporting, a panel of clinical investigators, epidemiologists, biostatisticians, and journal editors published a statement called the Consolidation of the Standards of Reporting Trials (CONSORT), which is designed to improve the standard of written reports of RCTs [ 6 ]. The CONSORT statement includes a checklist of 21 items and a flow diagram that can be used by authors to mark the page of the manuscript in which each of the items is addressed. In addition, the flow chart provides a detailed description of the progression of subjects through the intervention trial, from the number of potentially eligible participants for inclusion in the study to the number of intervention subjects in each group who completed the trial [ 6 ]. Using a similar format, we adapted the CONSORT form to examine the frequency of explicit reporting of subject characteristics as they relate to enrollment, allocation, and follow-up for weight loss studies published in the diet and exercise literature.
Background
Current statistics indicate that approximately 64.5% of US adults can be considered overweight while 30.5% can be classified as obese [ 1 ]. Obesity is also linked to a variety of chronic diseases, and is associated with approximately 300,000 deaths each year and annual economic costs of over $117 billion [ 2 ]. According to the latest Behavioral Risk Factor Surveillance Survey (BRFSS) data, obesity and overweight continue to be major pubic health concerns, and reports indicate that no state had met the Healthy People 2010 objective of reducing obesity to 15% [ 3 ]. As a result, there is need for a strong evidence base for prevention and treatment strategies.Systematic reviews can offer the most reliable sources of information on which to develop guidelines and base treatment policy. However, such reviews need to contain a high proportion of all relevant evidence, which relates both to the need to find all trials and the need to analyze data on all participants [ 4 ]. To improve the quality of reporting for randomized controlled trials (RCTs) in the overweight and obesity literature, as well as any intervention trial, investigators are encouraged to publish reports in clear and unambiguous language, accounting for all events that occurred during the conduct of the investigation, and providing an accurate and thorough description of subjects who were selected, excluded, withdrawn or did not complete the study. Failing to report essential variables, such as subject characteristics, does not allow readers to adequately judge the validity or applicability of the study results, and may influence the interpretation of findings [ 5 ].In response to the need for quality reporting, a panel of clinical investigators, epidemiologists, biostatisticians, and journal editors published a statement called the Consolidation of the Standards of Reporting Trials (CONSORT), which is designed to improve the standard of written reports of RCTs [ 6 ]. The CONSORT statement includes a checklist of 21 items and a flow diagram that can be used by authors to mark the page of the manuscript in which each of the items is addressed. In addition, the flow chart provides a detailed description of the progression of subjects through the intervention trial, from the number of potentially eligible participants for inclusion in the study to the number of intervention subjects in each group who completed the trial [ 6 ]. Using a similar format, we adapted the CONSORT form to examine the frequency of explicit reporting of subject characteristics as they relate to enrollment, allocation, and follow-up for weight loss studies published in the diet and exercise literature.Methods For the present study, we used information collected from a meta-analysis of the diet and exercise literature. The primary purpose of the meta-analysis was to statistically integrate and analyze published research studies on the effects of diet restriction only, diet restriction and exercise, or exercise only on weight loss, body composition, fat distribution, metabolism, and aerobic fitness. We examined the frequency of explicit reporting of subject characteristics (i.e., age, gender, co-morbid disease states, medication use (in addition to intervention drug), race/ethnicity, and postmenopausal status). We also examined whether or not initial and final sample size was reported and if so, we recorded if the final sample size was reported by gender. Search strategy. With the assistance of a clinical medical librarian, we developed search strategies, key words, and check tags to begin our initial search for relevant articles to include in the meta-analysis. We identified studies from a computerized search of the MEDLINE database (US National Library of Medicine) from 1966 – 2003, manual searches of bibliographic references of relevant published articles, and extensive cross-referencing and manual searches of 92 review articles. Overall study inclusion criteria Subject types. We required that intervention trials must study overweight or obese (BMI ≥ 25 kg/m 2 ) adult participants (≥ 18 years old). Ambulatory patients who were kept on wards exclusively for study purposes were also included. However, studies including pregnant women, patients with serious medical conditions, military personnel, and trained or professional athletes were excluded. Intervention types. For inclusion, trials were required to meet each of the following criteria: 1) active intervention trials with one group assigned to a weight-loss program involving energy restriction, exercise (aerobic or weight training) or both energy restriction and exercise; 2) outcome measures included weight loss; however, weight loss was not required to be a primary outcome; 3) the minimum duration of the intervention for weight loss must be greater than one day; and, 4) the article must be published in the English language. Case studies, crossover trials (due to possible carryover effects of weight reduction), and exploratory studies were excluded. We did not require studies to have been conducted in the United States. Pharmacotherapy, hormonal therapy, or surgical treatment studies, which did not include a separate group receiving a weight loss intervention (i.e., diet and/or exercise) were not included in the review process. Initial screening process. We independently screened all records resulting from our MEDLINE search strategies and manual searches by examining the titles and abstracts. We rejected articles if we could determine from the title and/or abstract that the study did not meet our selection criteria. If we could not determine whether or not to reject the article or if there was disagreement among reviewers, we retrieved the full text of the article for further evaluation. Quality control measures To control for abstraction bias, we trained five graduate research assistants to extract information from articles, using sample articles. Reliability checks were completed on the first several sample articles before graduate students were allowed to code independently. On a monthly basis thereafter, inter- and intra-rater reliability checks were completed to control for drift. All research assistants were required to attend weekly meetings with the principal investigator and co-investigators to discuss coding issues and to resolve coding disagreements. To control for potential selection biases after our initial screening procedure, we selected or rejected studies based on an examination of the research design and methodology. Acceptance or rejection for inclusion in the meta-analysis was not based on the study's outcome. We required coders to list specific reasons for all excluded studies. In addition, we tried to enhance data reporting for studies with missing covariate data by contacting authors by email or letter. Data entry quality control measures included the design of screens to match the coding sheet, automatic range limits placed on items entered, and queries to check for outliers. Values greater than two standard deviations from the mean were checked against the article. In addition, a random sampling of 58 articles (~25%) was pulled to check for accuracy. Standardized coding sheet for data abstraction. A separate checklist was devised based on CONSORT recommendations and quality indicators suggested by other authors [ 6 - 10 ]. Specific subject information was extracted from the meta-analysis database to examine if investigators reported age, race/ethnicity, and gender of their study subjects. Coders also recorded whether or not investigators reported the subjects' health status and presence of co-morbidities (i.e., diabetes, cardiac problems, cancer, or hypertension). Whether or not investigators reported medication use by subjects, other than the intervention drug, was also recorded. In addition, we tracked reporting of the postmenopausal status of subjects in investigations which included women 45 years or older. When analyzing the reporting quality for initial and final sample size separated by gender, only studies that included a group(s) consisting of both men and women were selected. Statistical analysis The frequency of reporting in the journal articles for the selected variables was obtained by performing a proc frequency using SAS (Version 8.2, Cary, NC). Results are presented as totals.
Methods
For the present study, we used information collected from a meta-analysis of the diet and exercise literature. The primary purpose of the meta-analysis was to statistically integrate and analyze published research studies on the effects of diet restriction only, diet restriction and exercise, or exercise only on weight loss, body composition, fat distribution, metabolism, and aerobic fitness. We examined the frequency of explicit reporting of subject characteristics (i.e., age, gender, co-morbid disease states, medication use (in addition to intervention drug), race/ethnicity, and postmenopausal status). We also examined whether or not initial and final sample size was reported and if so, we recorded if the final sample size was reported by gender.Search strategy. With the assistance of a clinical medical librarian, we developed search strategies, key words, and check tags to begin our initial search for relevant articles to include in the meta-analysis. We identified studies from a computerized search of the MEDLINE database (US National Library of Medicine) from 1966 – 2003, manual searches of bibliographic references of relevant published articles, and extensive cross-referencing and manual searches of 92 review articles.Overall study inclusion criteria Subject types. We required that intervention trials must study overweight or obese (BMI ≥ 25 kg/m 2 ) adult participants (≥ 18 years old). Ambulatory patients who were kept on wards exclusively for study purposes were also included. However, studies including pregnant women, patients with serious medical conditions, military personnel, and trained or professional athletes were excluded. Intervention types. For inclusion, trials were required to meet each of the following criteria: 1) active intervention trials with one group assigned to a weight-loss program involving energy restriction, exercise (aerobic or weight training) or both energy restriction and exercise; 2) outcome measures included weight loss; however, weight loss was not required to be a primary outcome; 3) the minimum duration of the intervention for weight loss must be greater than one day; and, 4) the article must be published in the English language. Case studies, crossover trials (due to possible carryover effects of weight reduction), and exploratory studies were excluded. We did not require studies to have been conducted in the United States. Pharmacotherapy, hormonal therapy, or surgical treatment studies, which did not include a separate group receiving a weight loss intervention (i.e., diet and/or exercise) were not included in the review process. Initial screening process. We independently screened all records resulting from our MEDLINE search strategies and manual searches by examining the titles and abstracts. We rejected articles if we could determine from the title and/or abstract that the study did not meet our selection criteria. If we could not determine whether or not to reject the article or if there was disagreement among reviewers, we retrieved the full text of the article for further evaluation.
Overall study inclusion criteria
Subject types. We required that intervention trials must study overweight or obese (BMI ≥ 25 kg/m 2 ) adult participants (≥ 18 years old). Ambulatory patients who were kept on wards exclusively for study purposes were also included. However, studies including pregnant women, patients with serious medical conditions, military personnel, and trained or professional athletes were excluded.Intervention types. For inclusion, trials were required to meet each of the following criteria: 1) active intervention trials with one group assigned to a weight-loss program involving energy restriction, exercise (aerobic or weight training) or both energy restriction and exercise; 2) outcome measures included weight loss; however, weight loss was not required to be a primary outcome; 3) the minimum duration of the intervention for weight loss must be greater than one day; and, 4) the article must be published in the English language. Case studies, crossover trials (due to possible carryover effects of weight reduction), and exploratory studies were excluded. We did not require studies to have been conducted in the United States. Pharmacotherapy, hormonal therapy, or surgical treatment studies, which did not include a separate group receiving a weight loss intervention (i.e., diet and/or exercise) were not included in the review process.Initial screening process. We independently screened all records resulting from our MEDLINE search strategies and manual searches by examining the titles and abstracts. We rejected articles if we could determine from the title and/or abstract that the study did not meet our selection criteria. If we could not determine whether or not to reject the article or if there was disagreement among reviewers, we retrieved the full text of the article for further evaluation.Quality control measures To control for abstraction bias, we trained five graduate research assistants to extract information from articles, using sample articles. Reliability checks were completed on the first several sample articles before graduate students were allowed to code independently. On a monthly basis thereafter, inter- and intra-rater reliability checks were completed to control for drift. All research assistants were required to attend weekly meetings with the principal investigator and co-investigators to discuss coding issues and to resolve coding disagreements. To control for potential selection biases after our initial screening procedure, we selected or rejected studies based on an examination of the research design and methodology. Acceptance or rejection for inclusion in the meta-analysis was not based on the study's outcome. We required coders to list specific reasons for all excluded studies. In addition, we tried to enhance data reporting for studies with missing covariate data by contacting authors by email or letter. Data entry quality control measures included the design of screens to match the coding sheet, automatic range limits placed on items entered, and queries to check for outliers. Values greater than two standard deviations from the mean were checked against the article. In addition, a random sampling of 58 articles (~25%) was pulled to check for accuracy. Standardized coding sheet for data abstraction. A separate checklist was devised based on CONSORT recommendations and quality indicators suggested by other authors [ 6 - 10 ]. Specific subject information was extracted from the meta-analysis database to examine if investigators reported age, race/ethnicity, and gender of their study subjects. Coders also recorded whether or not investigators reported the subjects' health status and presence of co-morbidities (i.e., diabetes, cardiac problems, cancer, or hypertension). Whether or not investigators reported medication use by subjects, other than the intervention drug, was also recorded. In addition, we tracked reporting of the postmenopausal status of subjects in investigations which included women 45 years or older. When analyzing the reporting quality for initial and final sample size separated by gender, only studies that included a group(s) consisting of both men and women were selected.
Quality control measures
To control for abstraction bias, we trained five graduate research assistants to extract information from articles, using sample articles. Reliability checks were completed on the first several sample articles before graduate students were allowed to code independently. On a monthly basis thereafter, inter- and intra-rater reliability checks were completed to control for drift. All research assistants were required to attend weekly meetings with the principal investigator and co-investigators to discuss coding issues and to resolve coding disagreements.To control for potential selection biases after our initial screening procedure, we selected or rejected studies based on an examination of the research design and methodology. Acceptance or rejection for inclusion in the meta-analysis was not based on the study's outcome. We required coders to list specific reasons for all excluded studies. In addition, we tried to enhance data reporting for studies with missing covariate data by contacting authors by email or letter.Data entry quality control measures included the design of screens to match the coding sheet, automatic range limits placed on items entered, and queries to check for outliers. Values greater than two standard deviations from the mean were checked against the article. In addition, a random sampling of 58 articles (~25%) was pulled to check for accuracy.Standardized coding sheet for data abstraction. A separate checklist was devised based on CONSORT recommendations and quality indicators suggested by other authors [ 6 - 10 ]. Specific subject information was extracted from the meta-analysis database to examine if investigators reported age, race/ethnicity, and gender of their study subjects. Coders also recorded whether or not investigators reported the subjects' health status and presence of co-morbidities (i.e., diabetes, cardiac problems, cancer, or hypertension). Whether or not investigators reported medication use by subjects, other than the intervention drug, was also recorded. In addition, we tracked reporting of the postmenopausal status of subjects in investigations which included women 45 years or older. When analyzing the reporting quality for initial and final sample size separated by gender, only studies that included a group(s) consisting of both men and women were selected.Statistical analysis The frequency of reporting in the journal articles for the selected variables was obtained by performing a proc frequency using SAS (Version 8.2, Cary, NC). Results are presented as totals.
Statistical analysis
The frequency of reporting in the journal articles for the selected variables was obtained by performing a proc frequency using SAS (Version 8.2, Cary, NC). Results are presented as totals.Results Of the 604 randomized clinical trial articles that were reviewed, 231 (38%) met eligibility criteria for the present study. Figure  1  displays the frequency of articles included in the analysis by year of publication. Of these, 123 (53%) articles were randomized studies without a control group and 108 (47%) were randomized controlled trials. Seventy-six articles (33%) were dietary intervention only, 60 (26%) were exercise intervention only, and the remaining 95 articles (41%) included both exercise and dietary intervention for weight loss. Figure 1 Frequency of randomized trials published by year. Contribution of journals For this analysis, the  American Journal of Clinical Nutrition  contributed the most articles that met the eligibility criteria (47), followed by the  International Journal of Obesity  (32),  Medicine & Science in Sports & Exercise  (24),  Journal of the American Medical Association  (11),  Metabolism  (11),  New England Journal of Medicine  (7),  Archives of Internal Medicine  (6), and  Journal of the American Dietetics Association  (6). In addition, 52 journals had 5 or fewer articles in this analysis. Subject characteristics Of the 231 articles that met eligibility criteria for the present study, subjects' age was not reported in 25 (11%) articles. Investigators of ten (4%) different studies failed to report the gender of their study participants. Race and/or ethnicity of study subjects were not reported in 199 (86%) studies. In addition, 78 (34%) studies failed to report the health status (i.e., presence or absence of co-morbidities) of their study subjects at baseline. Further, medication use was not reported in 213 (92%) of the articles (Figure  2 ). For postmenopausal status, 89 articles were included in the overall analysis with only 7 (8%) studies that did not report the postmenopausal status of their female subjects. Figure 2 Proportion of selected subject characteristics not reported in randomized trials. Values reported are means. Co-morbid disease status included the reporting of diabetes, cardiac diseases, cancer, hypertension, or any other metabolic disease. Sample size and attrition Initial sample size was not reported in 14 (6%) studies while final sample size was not reported in 133 (58%) of the 231 eligible articles. When reporting initial and final sample size by gender, 68 articles were included in the analysis. Of the eligible articles, 14 (21%) did not report initial sample size by gender while 47 (69%) failed to report final sample size by gender (Figure  3 ). Figure 3 Proportion of articles that did not report initial and final sample size by group or gender in randomized trials. Values reported are means.
Results
Of the 604 randomized clinical trial articles that were reviewed, 231 (38%) met eligibility criteria for the present study. Figure  1  displays the frequency of articles included in the analysis by year of publication. Of these, 123 (53%) articles were randomized studies without a control group and 108 (47%) were randomized controlled trials. Seventy-six articles (33%) were dietary intervention only, 60 (26%) were exercise intervention only, and the remaining 95 articles (41%) included both exercise and dietary intervention for weight loss.Contribution of journals For this analysis, the  American Journal of Clinical Nutrition  contributed the most articles that met the eligibility criteria (47), followed by the  International Journal of Obesity  (32),  Medicine & Science in Sports & Exercise  (24),  Journal of the American Medical Association  (11),  Metabolism  (11),  New England Journal of Medicine  (7),  Archives of Internal Medicine  (6), and  Journal of the American Dietetics Association  (6). In addition, 52 journals had 5 or fewer articles in this analysis.
Contribution of journals
For this analysis, the  American Journal of Clinical Nutrition  contributed the most articles that met the eligibility criteria (47), followed by the  International Journal of Obesity  (32),  Medicine & Science in Sports & Exercise  (24),  Journal of the American Medical Association  (11),  Metabolism  (11),  New England Journal of Medicine  (7),  Archives of Internal Medicine  (6), and  Journal of the American Dietetics Association  (6). In addition, 52 journals had 5 or fewer articles in this analysis.Subject characteristics Of the 231 articles that met eligibility criteria for the present study, subjects' age was not reported in 25 (11%) articles. Investigators of ten (4%) different studies failed to report the gender of their study participants. Race and/or ethnicity of study subjects were not reported in 199 (86%) studies. In addition, 78 (34%) studies failed to report the health status (i.e., presence or absence of co-morbidities) of their study subjects at baseline. Further, medication use was not reported in 213 (92%) of the articles (Figure  2 ). For postmenopausal status, 89 articles were included in the overall analysis with only 7 (8%) studies that did not report the postmenopausal status of their female subjects. Figure 2 Proportion of selected subject characteristics not reported in randomized trials. Values reported are means. Co-morbid disease status included the reporting of diabetes, cardiac diseases, cancer, hypertension, or any other metabolic disease.
Subject characteristics
Of the 231 articles that met eligibility criteria for the present study, subjects' age was not reported in 25 (11%) articles. Investigators of ten (4%) different studies failed to report the gender of their study participants. Race and/or ethnicity of study subjects were not reported in 199 (86%) studies. In addition, 78 (34%) studies failed to report the health status (i.e., presence or absence of co-morbidities) of their study subjects at baseline. Further, medication use was not reported in 213 (92%) of the articles (Figure  2 ). For postmenopausal status, 89 articles were included in the overall analysis with only 7 (8%) studies that did not report the postmenopausal status of their female subjects.Sample size and attrition Initial sample size was not reported in 14 (6%) studies while final sample size was not reported in 133 (58%) of the 231 eligible articles. When reporting initial and final sample size by gender, 68 articles were included in the analysis. Of the eligible articles, 14 (21%) did not report initial sample size by gender while 47 (69%) failed to report final sample size by gender (Figure  3 ). Figure 3 Proportion of articles that did not report initial and final sample size by group or gender in randomized trials. Values reported are means.
Sample size and attrition
Initial sample size was not reported in 14 (6%) studies while final sample size was not reported in 133 (58%) of the 231 eligible articles. When reporting initial and final sample size by gender, 68 articles were included in the analysis. Of the eligible articles, 14 (21%) did not report initial sample size by gender while 47 (69%) failed to report final sample size by gender (Figure  3 ).Discussion The present study evaluated the quality of reporting of RTs and RCTs in the diet and exercise literature for weight loss, focusing exclusively on subject characteristics, including age, gender, race, health status, medication use, postmenopausal status, and attrition. Transparent reporting of subject data is important in the scientific literature so that readers can efficiently evaluate outcomes in RTs and RCTs. Inadequate reporting creates numerous difficulties with interpretation and can lead to biased conclusions. For example, the effects of diet and/or exercise can vary based upon an individual's age. Schwartz et al. 1991[ 11 ] compared the effects of 6 months of endurance exercise (4 days/wk, 45 minutes/day, 85% of heart rate reserve) in older (Mean = 67.5 yrs, SD = 5.8 yrs) versus younger (Mean = 28.2 yrs, SD = 2.4 yrs) on body weight and composition. They found that older men had a 2.5 kg reduction in body weight, a 2.3% decrease in percent body fat, and a 2.4 kg decline in fat mass compared to no changes in the younger individuals. The findings suggest that subjects' age is an important determinant in the response to exercise. However, despite the difference in response to exercise based on the age of subjects, we found that 11% of authors failed to report their subjects' ages within their published report. Reporting gender of the study participants is also important as men and women respond differently to diet and/or exercise treatments. For example, Donnelly et al. [ 12 ] reported that following 16 months of verified, supervised aerobic exercise at 45 minutes per day, 5 days per week resulted in a decrease in body weight of 6% for the men compared to no change in the women. It also has been shown that individuals from different races and/or ethnic background may respond differently to diet and/or exercise. Jakicic et al. [ 13 ] reported that resting energy expenditure was lower in African-American women (Mean = 7279 kJ/d, SD = 825 kJ/d) compared to Caucasian women (Mean = 7807 kJ/d, SD = 854 kJ/d) even after correcting for body weight and lean body mass. The authors concluded that such differences might partially explain the smaller weight losses typically seen in African-American women when compared to Caucasian women enrolled in a weight loss program. In a recent meta-analysis on walking and resting blood pressure in adults, the investigators reported that only 13% of their included studies reported information on race [ 5 ]. In the current investigation 86% of authors failed to report the race/ethnicity of the subjects, which highlights the need for caution when extrapolating findings from one population to another. In the present study, co-morbid health conditions of study subjects were only marginally reported (66%) in the literature. It is well known that certain disease states, such as diabetes and cancer, affect metabolism [ 14 - 17 ], which can influence the effect of diet and exercise on body composition. Closely related to the need for reporting health conditions of study participants is the issue of medication use. Davis et al. [ 18 ] determined the effects of taking an antihypertensive medication (i.e., atenolol or chlorthalidone) compared to a placebo group combined with weight loss. They found that at 6 months those taking chlorthalidone lost (6.9 kg) the most weight compared to either the placebo (4.4 kg) or atenolol (3.0 kg) groups. They speculated that the group taking chlorthalidone might have reduced appetite or increased fat mobilization due to the volume depletion and increases in serum and urinary catecholamines. However, despite the profound effects that medication may have on body weight and composition 92% of authors failed to report medication use in our study. Without an adequate description of subject characteristics, readers are unable to judge the comparability of study groups. Menopause is associated with decreases in lean mass and increases in fat-mass [ 19 - 22 ]. Therefore, post-menopausal status and the associated decline in estrogens, androgens, and other hormones may significantly influence the effects of dietary/exercise interventions on body composition. It appears from the present study the majority of investigators (92%) of dietary/exercise studies report post-menopausal status of their subjects. Attrition may threaten the internal and external validity of the scientific literature as well as the efficacy of a specific dietary/exercise intervention [ 23 , 24 ]. For example, failure to report the number of dropouts and completers prevents the reader from calculating attrition rates for different experimental conditions, which can result in an overestimate of treatment effectiveness. In the present study, we found that end of study sample size was not reported in the majority (58%) of studies. Without knowledge of the number of subjects who were lost to follow-up, readers are unable to judge the effectiveness of a clinical treatment or ascertain whether or not a research finding has practical significance.
Discussion
The present study evaluated the quality of reporting of RTs and RCTs in the diet and exercise literature for weight loss, focusing exclusively on subject characteristics, including age, gender, race, health status, medication use, postmenopausal status, and attrition. Transparent reporting of subject data is important in the scientific literature so that readers can efficiently evaluate outcomes in RTs and RCTs. Inadequate reporting creates numerous difficulties with interpretation and can lead to biased conclusions. For example, the effects of diet and/or exercise can vary based upon an individual's age. Schwartz et al. 1991[ 11 ] compared the effects of 6 months of endurance exercise (4 days/wk, 45 minutes/day, 85% of heart rate reserve) in older (Mean = 67.5 yrs, SD = 5.8 yrs) versus younger (Mean = 28.2 yrs, SD = 2.4 yrs) on body weight and composition. They found that older men had a 2.5 kg reduction in body weight, a 2.3% decrease in percent body fat, and a 2.4 kg decline in fat mass compared to no changes in the younger individuals. The findings suggest that subjects' age is an important determinant in the response to exercise. However, despite the difference in response to exercise based on the age of subjects, we found that 11% of authors failed to report their subjects' ages within their published report.Reporting gender of the study participants is also important as men and women respond differently to diet and/or exercise treatments. For example, Donnelly et al. [ 12 ] reported that following 16 months of verified, supervised aerobic exercise at 45 minutes per day, 5 days per week resulted in a decrease in body weight of 6% for the men compared to no change in the women.It also has been shown that individuals from different races and/or ethnic background may respond differently to diet and/or exercise. Jakicic et al. [ 13 ] reported that resting energy expenditure was lower in African-American women (Mean = 7279 kJ/d, SD = 825 kJ/d) compared to Caucasian women (Mean = 7807 kJ/d, SD = 854 kJ/d) even after correcting for body weight and lean body mass. The authors concluded that such differences might partially explain the smaller weight losses typically seen in African-American women when compared to Caucasian women enrolled in a weight loss program. In a recent meta-analysis on walking and resting blood pressure in adults, the investigators reported that only 13% of their included studies reported information on race [ 5 ]. In the current investigation 86% of authors failed to report the race/ethnicity of the subjects, which highlights the need for caution when extrapolating findings from one population to another.In the present study, co-morbid health conditions of study subjects were only marginally reported (66%) in the literature. It is well known that certain disease states, such as diabetes and cancer, affect metabolism [ 14 - 17 ], which can influence the effect of diet and exercise on body composition. Closely related to the need for reporting health conditions of study participants is the issue of medication use. Davis et al. [ 18 ] determined the effects of taking an antihypertensive medication (i.e., atenolol or chlorthalidone) compared to a placebo group combined with weight loss. They found that at 6 months those taking chlorthalidone lost (6.9 kg) the most weight compared to either the placebo (4.4 kg) or atenolol (3.0 kg) groups. They speculated that the group taking chlorthalidone might have reduced appetite or increased fat mobilization due to the volume depletion and increases in serum and urinary catecholamines. However, despite the profound effects that medication may have on body weight and composition 92% of authors failed to report medication use in our study. Without an adequate description of subject characteristics, readers are unable to judge the comparability of study groups.Menopause is associated with decreases in lean mass and increases in fat-mass [ 19 - 22 ]. Therefore, post-menopausal status and the associated decline in estrogens, androgens, and other hormones may significantly influence the effects of dietary/exercise interventions on body composition. It appears from the present study the majority of investigators (92%) of dietary/exercise studies report post-menopausal status of their subjects.Attrition may threaten the internal and external validity of the scientific literature as well as the efficacy of a specific dietary/exercise intervention [ 23 , 24 ]. For example, failure to report the number of dropouts and completers prevents the reader from calculating attrition rates for different experimental conditions, which can result in an overestimate of treatment effectiveness. In the present study, we found that end of study sample size was not reported in the majority (58%) of studies. Without knowledge of the number of subjects who were lost to follow-up, readers are unable to judge the effectiveness of a clinical treatment or ascertain whether or not a research finding has practical significance.Conclusion In the present critical appraisal of the methodological quality of weight loss studies, we found major shortcomings in the reporting of subject characteristics as they relate to enrollment, allocation, and follow-up in trials that evaluated diet and exercise interventions. Many studies did not report variables that may explain some of the variance in outcomes. These findings are consistent with those of similar studies, which indicate inadequate reporting of subject characteristics [ 5 , 25 ] and reveal that poor adherence to published standards of reporting is common [ 26 ]. Clearly, additional attention should be paid to ensure compliance with reporting standards for diet and exercise intervention studies.
Conclusion
In the present critical appraisal of the methodological quality of weight loss studies, we found major shortcomings in the reporting of subject characteristics as they relate to enrollment, allocation, and follow-up in trials that evaluated diet and exercise interventions. Many studies did not report variables that may explain some of the variance in outcomes. These findings are consistent with those of similar studies, which indicate inadequate reporting of subject characteristics [ 5 , 25 ] and reveal that poor adherence to published standards of reporting is common [ 26 ]. Clearly, additional attention should be paid to ensure compliance with reporting standards for diet and exercise intervention studies.List of abbreviations Consolidation of the Standards of Reporting Trials (CONSORT), randomized controlled trials (RCTs), randomized trials (RTs), kilojoules per day (kJ/d), standard deviation (SD), kilograms (kg), years (yrs)
List of abbreviations
Consolidation of the Standards of Reporting Trials (CONSORT), randomized controlled trials (RCTs), randomized trials (RTs), kilojoules per day (kJ/d), standard deviation (SD), kilograms (kg), years (yrs)Competing interests The author(s) declare that they have no competing interests.
Competing interests
The author(s) declare that they have no competing interests.Authors' contributions CAG  made substantial contributions to the conception and design, acquisition of data, analysis and interpretation of data, and drafting and revising the manuscript for important intellectual content.  EPK, JDL, BWB  and  GH  made substantial contributions to the submitted manuscript by assisting with the acquisition of data, analysis and interpretation of data, drafting of the manuscript, statistical analyses, and critical revisions.  JED  made substantial contributions to the manuscript by helping with the conception and design, critical revisions of the manuscript, and obtaining funding. All authors read and approved the final manuscript.
Authors' contributions
CAG  made substantial contributions to the conception and design, acquisition of data, analysis and interpretation of data, and drafting and revising the manuscript for important intellectual content.  EPK, JDL, BWB  and  GH  made substantial contributions to the submitted manuscript by assisting with the acquisition of data, analysis and interpretation of data, drafting of the manuscript, statistical analyses, and critical revisions.  JED  made substantial contributions to the manuscript by helping with the conception and design, critical revisions of the manuscript, and obtaining funding. All authors read and approved the final manuscript.CAGEPK, JDL, BWBGHJEDFunding source Supported by National Institutes of Health NIH DK56303, Joseph E. Donnelly, Ed.D., principal investigator
Funding source
Supported by National Institutes of Health NIH DK56303, Joseph E. Donnelly, Ed.D., principal investigatorPre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here:


There is little in biology that compares in beauty and limpidity to the development of a zebrafish embryo as viewed through a light microscope. The transparent eggshell and embryo tissues expose the minutest details of cell migrations and organ assembly to the curious viewer. Within a day, distinct vertebrate features emerge: a distinct head with the outlines of two large eyes, a quickly pumping heart, a notochord, and a growing array of somites—the bone and muscle precursors—stretching from trunk into tapering tail.The transparent zebrafish embryo has allowed geneticists to discover a large number of mutants with anomalies in the development of external and internal organs. Seven mutations, collectively known as “You-class,” turn the pointed, chevron-like somites into shallow, rounded arcs (“You” stands for “U-shaped”). Ian Woods and William Talbot now show that the You mutation disrupts a new modulator of Hedgehog signaling.Hedgehog is an extracellular signaling protein that can impose various fates on target cells at close proximity or over longer distances. Much research is focused on understanding the factors that promote or limit Hedgehog's activity and range. Woods and Talbot propose that the You protein acts in the extracellular environment to promote Hedgehog signaling.Hedgehog was originally named for mutations that cause excess brush-like denticles to grow on the surface of fruitfly embryos, but it is now known to direct countless developmental decisions in invertebrates and vertebrates alike. In addition, several cancers are known to result from inappropriate Hedgehog signaling. In fish, Hedgehog's best-documented role is in muscle development. In the absence of Hedgehog signaling, cells destined to become slow muscle fibers fail to differentiate properly. A subset of these slow muscle cells—the muscle pioneers—congregate near the dorso-ventral midline of the embryo, where the dorsal and ventral halves of somites converge. When these specialized cells are absent, abnormal somite assembly leads to the U-shaped phenotype.The authors found that You mutants showed many telltale signs of reduced Hedgehog signaling. Proteins that are normally expressed at certain times during the development of slow muscle cells were not activated in You mutants, indicating that these cells did not form. Mutant embryos also displayed reduced expression of the Hedgehog receptor Patched, a universal reporter of Hedgehog signaling activity. In addition, You mutants had specific ventral spinal chord defects that are shared by known Hedgehog pathway mutants. Yet You mutants expressed Hedgehog normally. Moreover, Hedgehog targets could still be activated in You mutants in response to excess Hedgehog signaling, suggesting that the signaling cascade is left intact. The authors concluded that the You protein was a facilitator rather than a crucial transmitter in Hedgehog signaling, likely acting at a step upstream of a cell's response to Hedgehog. Normal muscle pioneers could form in chimeric embryos (embryos made of wild-type and You mutant cells) regardless of which cells—the Hedgehog-producing cells or Hedgehog-responding muscle precursors—expressed You. This made it most likely that the You protein acted outside the cells, perhaps as a cell matrix component.The authors mapped the You mutation and found that it disrupted the coding region of a gene encoding a putative secreted protein. The predicted You protein is closely related to members of the mouse SCUBE family, a group of proteins that are defined by characteristic extracellular motifs (although these proteins have not yet been linked to Hedgehog signaling). This observation strengthens the hypothesis that the You protein has extracellular functions, and the researchers' experimental evidence supports a role for You in transport or stabilization of Hedgehog. At later stages You could also participate in other signaling pathways, as its expression does not always coincide with that of Hedgehog during zebrafish development.


Background Intrathecal baclofen pump has been used effectively with increasing frequency in patients with severe spasticity, particularly for those patients who are unresponsive to conservative pharmacotherapy or develop intolerable side effects at therapeutic doses of oral baclofen. Drowsiness, nausea, headache, muscle weakness, light-headedness and return of pretreatment spasticity can be caused by intrathecal pump delivering an incorrect dose of baclofen. Intrathecal baclofen withdrawal syndrome is a very rare, potentially life-threatening complication of baclofen pump caused by an abrupt cessation of intrathecal baclofen.
Background
Intrathecal baclofen pump has been used effectively with increasing frequency in patients with severe spasticity, particularly for those patients who are unresponsive to conservative pharmacotherapy or develop intolerable side effects at therapeutic doses of oral baclofen. Drowsiness, nausea, headache, muscle weakness, light-headedness and return of pretreatment spasticity can be caused by intrathecal pump delivering an incorrect dose of baclofen. Intrathecal baclofen withdrawal syndrome is a very rare, potentially life-threatening complication of baclofen pump caused by an abrupt cessation of intrathecal baclofen.Case presentation A 24-year-old man with a past medical history of cerebral palsy and spastic quadriparesis developed hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, acute renal failure and multisystem organ failure leading to a full-blown intrathecal baclofen withdrawal syndrome. Intrathecal baclofen pump analysis revealed that it was stopped due to some programming error. He was treated effectively with supportive care, high-dose benzodiazepines and reinstitution of baclofen pump.
Case presentation
A 24-year-old man with a past medical history of cerebral palsy and spastic quadriparesis developed hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, acute renal failure and multisystem organ failure leading to a full-blown intrathecal baclofen withdrawal syndrome. Intrathecal baclofen pump analysis revealed that it was stopped due to some programming error. He was treated effectively with supportive care, high-dose benzodiazepines and reinstitution of baclofen pump.Conclusion The episodes of intrathecal baclofen withdrawal syndrome are mostly caused by preventable human errors or pump malfunction. Educating patients and their caregivers about the syndrome, and regular check-up of baclofen pump may decrease the incidence of intrathecal baclofen withdrawal syndrome. Oral baclofen replacement may not be an effective method to treat or prevent intrathecal baclofen withdrawal syndrome. Management includes an early recognition of syndrome, proper intensive care management, high-dose benzodiazepines and prompt analysis of intrathecal pump with reinstitution of baclofen.
Conclusion
The episodes of intrathecal baclofen withdrawal syndrome are mostly caused by preventable human errors or pump malfunction. Educating patients and their caregivers about the syndrome, and regular check-up of baclofen pump may decrease the incidence of intrathecal baclofen withdrawal syndrome. Oral baclofen replacement may not be an effective method to treat or prevent intrathecal baclofen withdrawal syndrome. Management includes an early recognition of syndrome, proper intensive care management, high-dose benzodiazepines and prompt analysis of intrathecal pump with reinstitution of baclofen.

Background Baclofen is a gamma-aminobutyric acid (GABA) analog that has inhibitory effects on spinal cord reflexes and brain. Intrathecal baclofen (ITB) therapy consists of long-term delivery of baclofen to the intrathecal space. Intrathecal baclofen has been used to treat spasticity due to cerebral palsy, brain or spinal cord injury, multiple sclerosis, dystonia, stroke and stiff-man syndrome, particularly for those patients who are unresponsive to conservative pharmacotherapy or develop intolerable side effects at therapeutic doses of oral baclofen [ 1 ]. Side effects such as drowsiness, nausea, headache, muscle weakness and light-headedness can occur as a result of the pump delivering an incorrect dose of baclofen. Sudden cessation of ITB administration can cause mild symptoms like reappearance of baseline level of spasticity associated with pruritis, anxiety and disorientation [ 2 ]. These mild symptoms represent "loss of drug effect". All patients experience "loss of drug effect" when ITB is discontinued, only a small (but unknown) proportion of patients develop a full-blown potentially life-threatening withdrawal syndrome. We report a case of ITB withdrawal syndrome developing hyperthermia, severe spasticity, disseminated intravascular coagulation, rhabdomyolysis, acute renal failure and multisystem organ failure.
Background
Baclofen is a gamma-aminobutyric acid (GABA) analog that has inhibitory effects on spinal cord reflexes and brain. Intrathecal baclofen (ITB) therapy consists of long-term delivery of baclofen to the intrathecal space. Intrathecal baclofen has been used to treat spasticity due to cerebral palsy, brain or spinal cord injury, multiple sclerosis, dystonia, stroke and stiff-man syndrome, particularly for those patients who are unresponsive to conservative pharmacotherapy or develop intolerable side effects at therapeutic doses of oral baclofen [ 1 ]. Side effects such as drowsiness, nausea, headache, muscle weakness and light-headedness can occur as a result of the pump delivering an incorrect dose of baclofen. Sudden cessation of ITB administration can cause mild symptoms like reappearance of baseline level of spasticity associated with pruritis, anxiety and disorientation [ 2 ]. These mild symptoms represent "loss of drug effect". All patients experience "loss of drug effect" when ITB is discontinued, only a small (but unknown) proportion of patients develop a full-blown potentially life-threatening withdrawal syndrome. We report a case of ITB withdrawal syndrome developing hyperthermia, severe spasticity, disseminated intravascular coagulation, rhabdomyolysis, acute renal failure and multisystem organ failure.Case presentation A 24-year-old man was admitted to our intensive care unit (ICU) with a possible diagnosis of seizure disorder and sepsis. He had a past medical history of cerebral palsy and spastic quadriparesis. Three years ago, he had an ITB pump implanted for spasticity refractory to the high doses of oral baclofen. He had a significant improvement in spasticity, social and functional capacity in the past three years. Later, he developed some disorientation and increased spasticity. He was taken to a local physician who prescribed oral baclofen (120 mg daily in four divided doses) for his increased spasticity. He also advised him to have his ITB pump checked immediately. The following day, his spasticity increased even after taking oral baclofen. He developed multiple seizures and respiratory distress in the next 24-hour period. Subsequently, he was admitted in a local hospital where he was orally intubated and transferred to our ICU for aggressive management. On presentation, his temperature was 104.6°F (40.3°C), heart rate 127 beats per minute, and the blood pressure was 85/45 mm/Hg. His ventilator settings were: assist-control ventilation mode; respiratory rate, 15 breaths per minute; tidal volume, 650 mL; positive end expiratory pressure (PEEP), 5 cm H 2 O; and FiO 2 , 60%. His spontaneous respiratory rate was 18 breaths per minute and an oxygen saturation of 100% was noted on pulse oximetry. In the local hospital, he was documented to have a high fever of 107°F (41.6°C) and he had received intravenous lorazepam, phenytoin, pantoprazole, piperacillin/tazobactem and dopamine. On physical examination, neurologically he was unconscious with decerebrate posturing and his Glasgow coma scale was 6. He had an absent corneal and gag reflexes. He was moving all four limbs in response to noxious stimuli. He was also noted to have an extreme spasticity in all four limbs. Lung examination revealed decreased breath sounds in the left lower base. Cardiac examination was unremarkable. He had a palpable baclofen pump on abdominal wall and bowel sounds were heard. The differential diagnoses were septic shock, meningitis, neuroleptic malignant syndrome and malignant hyperthermia. The initial laboratory results showed serum creatinine phosphokinase (CPK) 5250 U/L (Normal, 25–235 U/L) and CPK-MB fraction 12.1 ng/ml (Normal, 0.5–6.3 U/L). Serum chemistry revealed sodium 142 mmol/L, potassium 5.1 mmol/L, chloride 120 mmol/L, bicarbonate 13 mmol/L, and creatinine 2.1 mg/dl. Hemogram showed white blood cell count 12.2 K/UL, hemoglobin 16.5 g/dl and platelet count 9 K/UL (Normal, 130–400 K/UL). Liver function test showed aspartate aminotransferase (ALT) 1128 U/L, alanine aminotransferase (AST) 1140 U/L, alkaline phophatase 90 U/L, total bilirubin 1.2 mg/dl, conjugated bilirubin 0.7 mg/dl, prothrombin time 20.2 seconds (Normal, 10–12.5 seconds), and INR 2.0 (Normal, 0.9–1.1). Blood and urine cultures were obtained. Chest radiograph was normal. A computed tomography (CT) scan of the chest revealed atelectasis of the left lung base. His CT scan of head did not show any acute infarct or bleeding. His initial management included intravenous fluids, norepinephrine, platelet transfusion, phenytoin, propofol and broad-spectrum antibiotics (vancomycin, ceftriaxone) for suspected meningitis and septic shock. He received intravenous lorazepam (4–8 mg every four hours) for his spasticity. Next day, his spasticity improved and an ITB specialist investigated his baclofen pump. His baclofen pump analysis revealed that it was stopped due to some programming error, which was restarted at a previously prescribed baclofen rate (260 μg/day). On third hospital day, his serum CPK was 15,878 U/L, AST was 2566 U/L, ALT was 2993 U/L, while CPK-MB fraction came down to 3.4 ng/ml. His urine output decreased (<400 ml/ day) and serum creatinine increased in the range of 5–6 mg/dl. Later, he was hemodialyzed few times during the course of hospitalization due to acute renal failure. His echocardiogram showed left ventricular ejection fraction of 20–25% and severe global hypokinesis. His electroencephalogram did not reveal any epileptogenic activity. He developed full-blown multisystem organ failure with an evidence of shock liver, renal failure, respiratory failure, disseminated intravascular coagulation and myocardial depression. His nutrition was started on nasogastric tube feedings, and proper ventilator care was taken through a tracheostomy tube. His serum baclofen obtained at the time of admission was less than 0.02 μg/ml (Expected values, 0.08–0.4 μg/ml). After a three-week course of aggressive management in ICU, he was weaned off from the ventilator and his multiple organ shock resolved. At a six-month follow-up, he was observed in a nursing home with his baseline functional, social, and family activities.
Case presentation
A 24-year-old man was admitted to our intensive care unit (ICU) with a possible diagnosis of seizure disorder and sepsis. He had a past medical history of cerebral palsy and spastic quadriparesis. Three years ago, he had an ITB pump implanted for spasticity refractory to the high doses of oral baclofen. He had a significant improvement in spasticity, social and functional capacity in the past three years.Later, he developed some disorientation and increased spasticity. He was taken to a local physician who prescribed oral baclofen (120 mg daily in four divided doses) for his increased spasticity. He also advised him to have his ITB pump checked immediately. The following day, his spasticity increased even after taking oral baclofen. He developed multiple seizures and respiratory distress in the next 24-hour period. Subsequently, he was admitted in a local hospital where he was orally intubated and transferred to our ICU for aggressive management.On presentation, his temperature was 104.6°F (40.3°C), heart rate 127 beats per minute, and the blood pressure was 85/45 mm/Hg. His ventilator settings were: assist-control ventilation mode; respiratory rate, 15 breaths per minute; tidal volume, 650 mL; positive end expiratory pressure (PEEP), 5 cm H 2 O; and FiO 2 , 60%. His spontaneous respiratory rate was 18 breaths per minute and an oxygen saturation of 100% was noted on pulse oximetry. In the local hospital, he was documented to have a high fever of 107°F (41.6°C) and he had received intravenous lorazepam, phenytoin, pantoprazole, piperacillin/tazobactem and dopamine. On physical examination, neurologically he was unconscious with decerebrate posturing and his Glasgow coma scale was 6. He had an absent corneal and gag reflexes. He was moving all four limbs in response to noxious stimuli. He was also noted to have an extreme spasticity in all four limbs. Lung examination revealed decreased breath sounds in the left lower base. Cardiac examination was unremarkable. He had a palpable baclofen pump on abdominal wall and bowel sounds were heard. The differential diagnoses were septic shock, meningitis, neuroleptic malignant syndrome and malignant hyperthermia.The initial laboratory results showed serum creatinine phosphokinase (CPK) 5250 U/L (Normal, 25–235 U/L) and CPK-MB fraction 12.1 ng/ml (Normal, 0.5–6.3 U/L). Serum chemistry revealed sodium 142 mmol/L, potassium 5.1 mmol/L, chloride 120 mmol/L, bicarbonate 13 mmol/L, and creatinine 2.1 mg/dl. Hemogram showed white blood cell count 12.2 K/UL, hemoglobin 16.5 g/dl and platelet count 9 K/UL (Normal, 130–400 K/UL). Liver function test showed aspartate aminotransferase (ALT) 1128 U/L, alanine aminotransferase (AST) 1140 U/L, alkaline phophatase 90 U/L, total bilirubin 1.2 mg/dl, conjugated bilirubin 0.7 mg/dl, prothrombin time 20.2 seconds (Normal, 10–12.5 seconds), and INR 2.0 (Normal, 0.9–1.1). Blood and urine cultures were obtained. Chest radiograph was normal. A computed tomography (CT) scan of the chest revealed atelectasis of the left lung base. His CT scan of head did not show any acute infarct or bleeding. His initial management included intravenous fluids, norepinephrine, platelet transfusion, phenytoin, propofol and broad-spectrum antibiotics (vancomycin, ceftriaxone) for suspected meningitis and septic shock. He received intravenous lorazepam (4–8 mg every four hours) for his spasticity. Next day, his spasticity improved and an ITB specialist investigated his baclofen pump. His baclofen pump analysis revealed that it was stopped due to some programming error, which was restarted at a previously prescribed baclofen rate (260 μg/day).On third hospital day, his serum CPK was 15,878 U/L, AST was 2566 U/L, ALT was 2993 U/L, while CPK-MB fraction came down to 3.4 ng/ml. His urine output decreased (<400 ml/ day) and serum creatinine increased in the range of 5–6 mg/dl. Later, he was hemodialyzed few times during the course of hospitalization due to acute renal failure. His echocardiogram showed left ventricular ejection fraction of 20–25% and severe global hypokinesis. His electroencephalogram did not reveal any epileptogenic activity. He developed full-blown multisystem organ failure with an evidence of shock liver, renal failure, respiratory failure, disseminated intravascular coagulation and myocardial depression. His nutrition was started on nasogastric tube feedings, and proper ventilator care was taken through a tracheostomy tube. His serum baclofen obtained at the time of admission was less than 0.02 μg/ml (Expected values, 0.08–0.4 μg/ml). After a three-week course of aggressive management in ICU, he was weaned off from the ventilator and his multiple organ shock resolved. At a six-month follow-up, he was observed in a nursing home with his baseline functional, social, and family activities.Discussion Intrathecal baclofen provides an effective improvement in the spasticity of patients whose spasticity is not sufficiently managed by oral baclofen or other oral anti-spastic medications [ 1 ]. Regardless of the cause of spasticity (cerebral or spinal), anti-spastic effects of baclofen occur at spinal level. Poor response of oral baclofen in many patients can be explained by the fact that the spinal cord represents only about 2% mass of the brain, and receives proportionately a lower blood flow as a fraction of cardiac output. Therefore, cerebral side effects often occur before therapeutic anti-spastic effects of oral baclofen are observed. A programmable ITB pump provides a direct, pattern-controlled delivery of baclofen to the spinal cord. Precise delivery of the ITB pump yields better spasticity reduction at 1000 times lower than the doses of oral baclofen. In addition, the adverse effects are minimized as compared with oral baclofen. ITB provides reduced tone, spasms and pain, improves speech, mobility, sleep quality and bladder control, with a response rate up to 97% in adults and children [ 3 , 4 ]. The ITB pump is approximately 3 inches wide and 1 inch thick. It is surgically implanted in the subcutaneous tissue of anterior abdominal wall. Baclofen is delivered via a silicone rubber catheter into the lumbar subarachanoid space. The ITB pump delivers approximately 100–900 μg/day of baclofen, and it is titrated for the desired clinical response. It is also equipped with an alarm that signals low volume, low battery, or malfunction. Nine years ago, catheter or pump-related malfunction that leads to an overdose or withdrawal has been reported in 40 % of the patients with ITB pump [ 5 ]. Catheter system, operative techniques and programming system of the ITB pump have now been improved significantly to reduce the incidence of an overdose or withdrawal. The precise mechanism of action of baclofen as a muscle relaxant and anti-spasticity agent is not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal cord level [ 6 ], possibly by decreasing excitatory neurotransmitter release from primary afferent terminals, although actions at supraspinal sites may also contribute to its clinical effects. Baclofen also causes enhancement of vagal tone and inhibition of mesolimbic and nigrostriatal dopamine neurons (directly or via inhibiting substance P) [ 7 ]. Baclofen is a structural analog of the inhibitory neurotransmitter GABA, and may exert its effects by stimulation of the GABA B  receptor to cause muscle relaxation. Baclofen reduces increased muscle tone, Babinski sign, tendon reflexes, ankle clonus and sometimes decreases muscle force. Long-term ITB infusion causes down-regulation of GABA B  receptors in the CNS and spinal cord. Down-regulation of GABA B  receptors accounts for the decreased sensitivity to the baclofen over time. Although GABA B  receptors are down-regulated, it is the baclofen itself that causes increased inhibitory tone in the CNS and spinal cord [ 8 ]. Therefore, abrupt ITB withdrawal results in a predominance of excitatory effects and simulates other conditions that are associated with CNS hyperexcitability and severe spasticity. Sudden cessation of ITB administration can cause mild symptoms like reappearance of baseline level of spasticity associated with pruritis, anxiety and disorientation. These mild symptoms represent "loss of drug effect". All patients experience "loss of drug effect" when ITB is discontinued. However, more severe symptoms like hyperthermia (109.4°F), myoclonus, seizures [ 9 - 12 ], rhabdomyolysis, disseminated intravascular coagulation, multisystem organ failure [ 10 ], cardiac arrest, coma and death [ 9 , 12 , 13 ] have been well reported, and represents a full-blown life-threatening ITB withdrawal syndrome. Food and drug administration (FDA) of USA has included a drug label warning for baclofen withdrawal syndrome in April 2002 [ 1 , 13 ]. Differential diagnoses include malignant hyperthermia, neuroleptic-malignant syndrome, autonomic dysreflexia, sepsis and meningitis. ITB withdrawal syndrome has been fatal in some cases. Six patients have died out of 27 cases reported to FDA [ 13 ]. Most reported episodes of ITB withdrawal were caused by preventable human errors or oversights. However, catheter dislodgement, catheter migration and kinks, and other catheter-related issues might be more common than pump-related malfunctions [ 1 , 14 ]. Close attention to pump refilling and programming procedures may reduce the incidence of ITB withdrawal syndrome. Benzodiazepines are helpful in controlling spasticity and seizures during ITB withdrawal syndrome [ 1 , 10 ]. Benzodiazepines activate central receptors and GABA A  receptors of spinal cord by different mechanisms [ 1 ]. Therefore, ITB induced down-regulation of GABA B  receptors do not interfere with benzodiazepine's mechanism of action. During a planned removal of ITB pump due to infection or other causes, premedication with high doses of benzodiazepines and augmented oral baclofen is usually administered in the hospitals to prevent spasticity. Similarly, high doses of oral baclofen is also tried in some cases of ITB withdrawal syndrome [ 15 , 16 ]. But failure of high doses of oral baclofen (80 mg three times daily) have been reported recently [ 17 ]. High doses of oral baclofen may not be adequate to treat or prevent ITB withdrawal because of down-regulation of central GABA B  receptors due to chronic ITB administration. Moreover, it has been suggested that it may take many hundreds of grams of oral baclofen to achieve a therapeutic baclofen level in the cerebrospinal fluid, compared to the patients who had effective spasticity control with an ITB pump [ 17 ]. Although, our patient received oral baclofen (120 mg daily in four divided doses) initially but these doses may be low enough to prevent ITB withdrawal syndrome. Failure of high doses of oral baclofen suggests that resumption of GABA B  receptor agonist by prompt restoration of ITB pump and proper supportive care might be the best treatment. Similarly, high-dose benzodiazepines may be effective because of similar mechanism of action on widespread CNS GABA A  receptors. High-dose benzodiazepines could be an initial life saving strategy even before analysis and restoration of ITB pump is achieved, or in cases, where resumption of ITB administration is not as simple as correcting a programming error. Intrathecal baclofen bolus is appropriate, but due to the risk of inadvertent overdose, an experienced physician should immediately perform reinstitution of ITB pump. We had restarted ITB in our patient at a previously prescribed dose. However, a much higher dose of baclofen could have safely been given to overcome the spasticity since the patient was in an ICU. High-dose dantrolene (a direct muscle relaxant that acts on sarcoplasmic reticulum of skeletal muscle) has been tried to reduce spasticity and fever in ITB withdrawal syndrome [ 18 ]. Reduction in fever may be due to cessation of repetitive and thermogenic contractions of muscle fibers. It is unlikely that dantrolene has any GABA agonistic effects, and administration of dantrolene may not be accompanied by any correction in anomalies of CNS functions. Therefore, seizures, autonomic instability and death may occur in ITB withdrawal syndrome even after controlling spasticity with dantrolene. Cyproheptadine (a non-selective serotonin antagonist) has also been used postulating that ITB withdrawal may be a form of serotonergic syndrome that occurs from the loss of GABA B  receptor-mediated presynaptic inhibition of serotonin [ 19 ]. We did not consider dantrolene or cyproheptadine in our patient due to lack of sufficient clinical support in the treatment of ITB withdrawal syndrome. There was a three-day period of delay in diagnosing the ITB withdrawal syndrome leading to deterioration and multisystem organ failure. However, our patient had a successful recovery in response to restoration of baclofen pump and adequate intensive care management.
Discussion
Intrathecal baclofen provides an effective improvement in the spasticity of patients whose spasticity is not sufficiently managed by oral baclofen or other oral anti-spastic medications [ 1 ]. Regardless of the cause of spasticity (cerebral or spinal), anti-spastic effects of baclofen occur at spinal level. Poor response of oral baclofen in many patients can be explained by the fact that the spinal cord represents only about 2% mass of the brain, and receives proportionately a lower blood flow as a fraction of cardiac output. Therefore, cerebral side effects often occur before therapeutic anti-spastic effects of oral baclofen are observed. A programmable ITB pump provides a direct, pattern-controlled delivery of baclofen to the spinal cord. Precise delivery of the ITB pump yields better spasticity reduction at 1000 times lower than the doses of oral baclofen. In addition, the adverse effects are minimized as compared with oral baclofen. ITB provides reduced tone, spasms and pain, improves speech, mobility, sleep quality and bladder control, with a response rate up to 97% in adults and children [ 3 , 4 ]. The ITB pump is approximately 3 inches wide and 1 inch thick. It is surgically implanted in the subcutaneous tissue of anterior abdominal wall. Baclofen is delivered via a silicone rubber catheter into the lumbar subarachanoid space. The ITB pump delivers approximately 100–900 μg/day of baclofen, and it is titrated for the desired clinical response. It is also equipped with an alarm that signals low volume, low battery, or malfunction. Nine years ago, catheter or pump-related malfunction that leads to an overdose or withdrawal has been reported in 40 % of the patients with ITB pump [ 5 ]. Catheter system, operative techniques and programming system of the ITB pump have now been improved significantly to reduce the incidence of an overdose or withdrawal.The precise mechanism of action of baclofen as a muscle relaxant and anti-spasticity agent is not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal cord level [ 6 ], possibly by decreasing excitatory neurotransmitter release from primary afferent terminals, although actions at supraspinal sites may also contribute to its clinical effects. Baclofen also causes enhancement of vagal tone and inhibition of mesolimbic and nigrostriatal dopamine neurons (directly or via inhibiting substance P) [ 7 ]. Baclofen is a structural analog of the inhibitory neurotransmitter GABA, and may exert its effects by stimulation of the GABA B  receptor to cause muscle relaxation. Baclofen reduces increased muscle tone, Babinski sign, tendon reflexes, ankle clonus and sometimes decreases muscle force.Long-term ITB infusion causes down-regulation of GABA B  receptors in the CNS and spinal cord. Down-regulation of GABA B  receptors accounts for the decreased sensitivity to the baclofen over time. Although GABA B  receptors are down-regulated, it is the baclofen itself that causes increased inhibitory tone in the CNS and spinal cord [ 8 ]. Therefore, abrupt ITB withdrawal results in a predominance of excitatory effects and simulates other conditions that are associated with CNS hyperexcitability and severe spasticity. Sudden cessation of ITB administration can cause mild symptoms like reappearance of baseline level of spasticity associated with pruritis, anxiety and disorientation. These mild symptoms represent "loss of drug effect". All patients experience "loss of drug effect" when ITB is discontinued. However, more severe symptoms like hyperthermia (109.4°F), myoclonus, seizures [ 9 - 12 ], rhabdomyolysis, disseminated intravascular coagulation, multisystem organ failure [ 10 ], cardiac arrest, coma and death [ 9 , 12 , 13 ] have been well reported, and represents a full-blown life-threatening ITB withdrawal syndrome. Food and drug administration (FDA) of USA has included a drug label warning for baclofen withdrawal syndrome in April 2002 [ 1 , 13 ]. Differential diagnoses include malignant hyperthermia, neuroleptic-malignant syndrome, autonomic dysreflexia, sepsis and meningitis. ITB withdrawal syndrome has been fatal in some cases. Six patients have died out of 27 cases reported to FDA [ 13 ]. Most reported episodes of ITB withdrawal were caused by preventable human errors or oversights. However, catheter dislodgement, catheter migration and kinks, and other catheter-related issues might be more common than pump-related malfunctions [ 1 , 14 ]. Close attention to pump refilling and programming procedures may reduce the incidence of ITB withdrawal syndrome.Benzodiazepines are helpful in controlling spasticity and seizures during ITB withdrawal syndrome [ 1 , 10 ]. Benzodiazepines activate central receptors and GABA A  receptors of spinal cord by different mechanisms [ 1 ]. Therefore, ITB induced down-regulation of GABA B  receptors do not interfere with benzodiazepine's mechanism of action. During a planned removal of ITB pump due to infection or other causes, premedication with high doses of benzodiazepines and augmented oral baclofen is usually administered in the hospitals to prevent spasticity. Similarly, high doses of oral baclofen is also tried in some cases of ITB withdrawal syndrome [ 15 , 16 ]. But failure of high doses of oral baclofen (80 mg three times daily) have been reported recently [ 17 ]. High doses of oral baclofen may not be adequate to treat or prevent ITB withdrawal because of down-regulation of central GABA B  receptors due to chronic ITB administration. Moreover, it has been suggested that it may take many hundreds of grams of oral baclofen to achieve a therapeutic baclofen level in the cerebrospinal fluid, compared to the patients who had effective spasticity control with an ITB pump [ 17 ]. Although, our patient received oral baclofen (120 mg daily in four divided doses) initially but these doses may be low enough to prevent ITB withdrawal syndrome. Failure of high doses of oral baclofen suggests that resumption of GABA B  receptor agonist by prompt restoration of ITB pump and proper supportive care might be the best treatment. Similarly, high-dose benzodiazepines may be effective because of similar mechanism of action on widespread CNS GABA A  receptors. High-dose benzodiazepines could be an initial life saving strategy even before analysis and restoration of ITB pump is achieved, or in cases, where resumption of ITB administration is not as simple as correcting a programming error.Intrathecal baclofen bolus is appropriate, but due to the risk of inadvertent overdose, an experienced physician should immediately perform reinstitution of ITB pump. We had restarted ITB in our patient at a previously prescribed dose. However, a much higher dose of baclofen could have safely been given to overcome the spasticity since the patient was in an ICU. High-dose dantrolene (a direct muscle relaxant that acts on sarcoplasmic reticulum of skeletal muscle) has been tried to reduce spasticity and fever in ITB withdrawal syndrome [ 18 ]. Reduction in fever may be due to cessation of repetitive and thermogenic contractions of muscle fibers. It is unlikely that dantrolene has any GABA agonistic effects, and administration of dantrolene may not be accompanied by any correction in anomalies of CNS functions. Therefore, seizures, autonomic instability and death may occur in ITB withdrawal syndrome even after controlling spasticity with dantrolene. Cyproheptadine (a non-selective serotonin antagonist) has also been used postulating that ITB withdrawal may be a form of serotonergic syndrome that occurs from the loss of GABA B  receptor-mediated presynaptic inhibition of serotonin [ 19 ]. We did not consider dantrolene or cyproheptadine in our patient due to lack of sufficient clinical support in the treatment of ITB withdrawal syndrome. There was a three-day period of delay in diagnosing the ITB withdrawal syndrome leading to deterioration and multisystem organ failure. However, our patient had a successful recovery in response to restoration of baclofen pump and adequate intensive care management.Conclusions Baclofen withdrawal syndrome is a potentially life-threatening complication of intrathecal baclofen pump. Empty pump reservoir, catheter leaks or displacement, pump malfunction, programming error and refill of pump with improper drug concentration are the possible mechanisms which could lead to an ITB withdrawal syndrome. Regular check-up of the ITB pump by a specialist, educating patients and their caregivers may decrease the incidence of ITB withdrawal syndrome. Oral baclofen replacement may not be an effective method to treat or prevent ITB withdrawal syndrome. Early recognition of syndrome, high-dose benzodiazepines, prompt analysis of the ITB pump with reinstitution of baclofen, and proper intensive care management are mainstays for the management of ITB withdrawal syndrome.
Conclusions
Baclofen withdrawal syndrome is a potentially life-threatening complication of intrathecal baclofen pump. Empty pump reservoir, catheter leaks or displacement, pump malfunction, programming error and refill of pump with improper drug concentration are the possible mechanisms which could lead to an ITB withdrawal syndrome. Regular check-up of the ITB pump by a specialist, educating patients and their caregivers may decrease the incidence of ITB withdrawal syndrome. Oral baclofen replacement may not be an effective method to treat or prevent ITB withdrawal syndrome. Early recognition of syndrome, high-dose benzodiazepines, prompt analysis of the ITB pump with reinstitution of baclofen, and proper intensive care management are mainstays for the management of ITB withdrawal syndrome.List of abbreviations GABA -gamma amino butyric acid, ITB – intrathecal baclofen, CPK – creatinine phosphokinase, ALT – aspartate aminotransferase, AST – alanine aminotransferase, CT – computed tomography.
List of abbreviations
GABA -gamma amino butyric acid, ITB – intrathecal baclofen, CPK – creatinine phosphokinase, ALT – aspartate aminotransferase, AST – alanine aminotransferase, CT – computed tomography.Competing interests None declared.
Competing interests
None declared.Authors' contributions IM: Direct patient care, article conception, critical and extensive revision of article for important intellectual content, review and drafting of the original article. AH: Literature search, case review and summary, drafting of the original article. Both authors read and approved the final manuscript and contributed equally to the manuscript.
Authors' contributions
IM: Direct patient care, article conception, critical and extensive revision of article for important intellectual content, review and drafting of the original article. AH: Literature search, case review and summary, drafting of the original article. Both authors read and approved the final manuscript and contributed equally to the manuscript.Pre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here: