Understanding Functional Abdominal Distention

Posted on June 5, 2015 by gutsandgrowth

A recent study (Barba E, et al. Gastroenterol 2015; 148: 732-9) provides insight into why some patients develop functional abdominal distention.

In this prospective study of 45 patients (42 women), the researchers performed numerous tests to determine the reasons for abdominal distention. Most patients had CT scan (n=39), and electromyography (EMG) of the abominothoracic wall (n=32) both at baseline and during distention. In addition, 15 patients underwent EMG-guided biofeedback.

Findings:

Abdominal distention was associated with diaphragm contraction (~19% increase from baseline) and intercostal contraction (~14% increase from baseline).
There was an increase in thoracic antero-posterior diameter compared with basal values with increase in anterior abdominal wall protrusion.
Biofeedback treatment was effective in reversing these changes. This indicates that the distention is under voluntary control.

The authors use the term for the changes that cause the abdominal distention as “abdominal accommodation.” They note that “in healthy subjects, an increase in intra-abdominal contents induces relaxation and ascent of the diaphragm, which permits cephalic expansion of the abdominal cavity with minor protrusion of the anterior wall.” In this study, the distention was determined in real-life settings to be due to “a paradoxical contraction of the diaphragm, that pushed abdominal contents downward, and relaxation of the anterior abdominal wall.”

Bottomline: These experiments provide a ‘proof-of-concept’ regarding the mechanisms of abdominal distention, though these experiments are not practical for most patients with these symptoms.

pH Probe Testing: Rumors of My Death are Premature

Posted on June 4, 2015 by gutsandgrowth

Several years ago, an “obituary” was written for the pH probe (Putnam PE,J Pediatr. 2010; 157(6):878-80) due to the presumed superiority of pH-impedance (pH-MII) studies in detecting gastroesophageal reflux disease (GERD) As noted in previous blogs (see below), there have remained a number of concerns with the assumption that pH-MII is an improvement over pH studies without impedance. Several recent studies elaborate on those concerns:

Cheng F-K F, et al. Clin Gastroenterol Hepatol 2015; 13: 867-73
Patel A, et al. Clin Gastroenterol Hepatol 2015; 13: 884-91
Vaezi MF. Clin Gastroenterol Hepatol 2015; 13: 892-94 (editorial)

In the first study, the authors identified 221 patients and retrospectively reviewed GERD testing from 2006-2011. Prior to testing, 97% had received prescribed PPIs before testing; however, PPIs were discontinued for at least 1 week prior to evaluation which included upper endoscopy, esophageal manometry, and pH-MII.

21 (10%) had erosive esophagitis
61 (27%) had nonerosive reflux disease with increased pH
18 (8%) had nonerosive reflux disease with abnormal impedance
30 (14%) had hypersensitive esophagus
18 (8%) had functional heartburn
30 (14%) had other functional disorders
43 (19%) were undetermined

Thus, this retrospective study showed that the majority (roughly 2/3rds) of patients with GERD symptoms on PPI therapy did not have GERD based on objective testing. The authors chose to test off PPI therapy “because we postulated that the pretest probability of GERD diagnosis was low, primarily given their lack of response to PPI.”

In the second study, 187 subjects (≥18 years) underwent pH-MII testing in a prospective study from 2005-2010. 49.7% were tested off proton pump inhibitor therapy. Abnormal acid exposure time consistently predicted symptomatic outcome. The authors note that performing pH-MII off PPI therapy best predicts response to antireflux therapy

In the third reference, the editorial which commented on the second, there are several useful points:

“There is little doubt that pH-impedance testing provides a more sensitive means of comprehensively identifying reflux events in a given patient. However, to date, studies have failed to demonstrate that it provides any significant additional clinical benefit.”
“Caution must be exercised when incorporating the added objective data from non-acidic or weakly acidic reflux events into treatment decision-making…Studies including Patel et al have not shown that knowledge regarding continued non-acid or weakly acid reflux events alter patient outcomes.”
“Wireless pH testing is generally better tolerated and provides longer measurement duration”
The use of symptom indices are too subjective. “Recent data question the use of these indices especially in those with refractory symptoms and minimal reflux by pH or impedance testing.” SI and SAP could be altered by chance occurrences….”A colleague expert in esophageal diseases …once said: “I know the tests are no good but I don’t know what else to use.'”
“Let us simplify our approach on the basis of available data and not use measures that we know are suboptimal at best.”

After looking at these studies and the previous pH probe obituary, I’m reminded of a story. Several religious leaders were asked what they wanted someone to say at their funeral. A few stated that they wanted their congregants/flock to comment on their values, like piety and charity. However, one said, “I hope they say, ‘Look he’s moving!'”

Bottomline: There is no reliable evidence that pH-MII testing improves outcomes over conventional pH probe testing. In fact, the use of pH-MII, by lowering the specificity for GERD, could have a detrimental effect. With either test, holding acid suppression for 1 week (with PPIs) is likely to be helpful in interpreting the results.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Zoo Atlanta

Toronto Consensus: Practice Guidelines for Nonhospitalized Ulcerative Colitis

Posted on June 3, 2015 by gutsandgrowth

A group of 23 experts followed a rigorous process over a 1-year period to assess the quality of evidence and develop consensus statements regarding the medical management of ulcerative colitis (UC) in adults (Bressler B, Marshall JK et al. Gastroenterol 2015; 148: 1035-58, editorial 877-80).

The need for updated guidelines has emerged due to practice variation related in part to a wider availability of treatments and diagnostic tools. It is recognized that early institution of effective therapy is associated with the best outcomes. In addition, due to the chronic nature of ulcerative colitis and the potential for reduced durability of biologic agents, careful decision-making can improve response.

Table 4 in the article summarizes the recommendations. I will list a few:

1. Thiopurines:

“In patients with UC, we recommend against the use of thiopurine monotherapy to induce complete remission.”
In selected patients, “we suggest thiopurine monotherapy as an option to maintain complete corticosteroid-free remission.”

2. Anti-TNF therapy:

“In patients with UC who fail to respond to thiopurines or corticosteroids, we recommend anti-TNF therapy to induce complete corticosteroid-free remission.”
“When starting anti-TNF therapy, we recommend it be combined with a thiopurine or methotrexate rather than used as monotherapy to induce complete remission.”
For UC patients with suboptimal response or for those who lose response to anti-TNF therapy, “we recommend dose intensification.” Dose optimization should be informed by therapeutic drug monitoring.

3. Vedolizumab

Vedolizumab is recommended with primary anti-TNF failure (rather than switching to an alternative anti-TNF), whereas either a 2nd anti-TNF or vedolizumab is recommended with secondary anti-TNF failure based on therapeutic drug monitoring.

4. Fecal microbial transplant (FMT)

“We recommend against FMT…outside the setting of a clinical trial.”

5. 5-ASA and Corticosteroids

Rectal 5-ASA is recommended at 1 g daily for mild-to-moderate ulcerative proctitis. 5-ASA enemas are recommended for mild-to-moderate left-sided ulcerative colitis.
In patients with moderate-to-severe UC, corticosteroids are recommended as 1st line therapy for induction of remission but not for maintaining remission. In addition, corticosteroids are recommended as 2nd-line agents for inducing remission in those with mild-to-moderate disease who do not respond to 5-ASA products.

With all of the treatments, the authors recommend followup to assure response to therapy; this followup ranges from within 2 weeks for steroids, to 4-8 weeks with 5-ASA products, to 8-14 weeks for biologic agents.

Overall, the emphasis of this consensus statement is on maximizing the response to biologic agents. By optimizing dosing and using combination therapy, the treatment guidelines aim to lower rates of antidrug antibody formation. This in turn should improve results and is in agreement with data from both the SONIC study and the UC-SUCCESS study.

The editorial comments that methotrexate “may be an attractive option for young male patients;” however, “the absence of data on risk of malignancy with methotrexate in IBD may reflect lower frequency of use for this indication.”

While these guidelines will be useful, there are many unanswered questions (discussed in editorial).

In patients on combination therapy, what is the optimal dose of the immunomodulator?
When or Should the immunomodulator be withdrawn?
For secondary failure, should a 2nd anti-TNF be used prior to vedolizumab?
How should these guidelines be tailored for the pediatric population (or the elderly)?
What is the optimal monitoring for UC patients with regard to biomarkers and endoscopy?
What is the appropriate role of therapeutic drug monitoring?

Bottomline: These guidelines are likely to promote the use of more combination therapy and help define the current role of vedolizumab.

Related blog posts:

FDA Approves Rifaximin and Eluxadoline for IBS-D

Posted on June 2, 2015 by gutsandgrowth

From FDA (5/27/15): Two New FDA-Approved Treatments for adults with IBS-D

Excerpt:

The U.S. Food and Drug Administration today approved Viberzi (eluxadoline) and Xifaxan (rifaximin), two new treatments, manufactured by two different companies, for irritable bowel syndrome with diarrhea (IBS-D) in adult men and women….

“For some people, IBS can be quite disabling, and no one medication works for all patients suffering from this gastrointestinal disorder,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research. “The approval of two new therapies underscores the FDA’s commitment to providing additional treatment options for IBS patients and their doctors.”

Viberzi, which contains a new active ingredient, is taken orally twice daily with food. Viberzi activates receptors in the nervous system that can lessen bowel contractions. Viberzi is intended to treat adults with IBS-D.

Xifaxan can be taken orally three times a day for 14 days, for the treatment of abdominal pain and diarrhea in patients with IBS-D. Patients who experience a recurrence of symptoms can be retreated with a 14 day treatment course, up to two times. Xifaxan, an antibiotic derived from rifampin, was previously approved as treatment for travelers’ diarrhea caused by E. coli and for reduction of the risk in adult patients of recurring overt hepatic encephalopathy, the changes in brain function that occur when the liver is unable to remove toxins from the blood. The exact mechanism of action of Xifaxan for treatment of IBS-D is not known, but is thought to be related to changes in the bacterial content in the gastrointestinal tract.

The safety and effectiveness of Viberzi for treatment of IBS-D were established in two double-blind, placebo-controlled clinical trials…Results showed Viberzi was more effective in simultaneously reducing abdominal pain and improving stool consistency than placebo over 26 weeks of treatment.

The safety and effectiveness of Xifaxan for treatment of IBS-D were established in three double-blind, placebo-controlled trials.

Related blog posts:

How to Incorporate Budesonide Foam into UC Treatment Algorithm

Posted on June 1, 2015 by gutsandgrowth

A recent study (Sandborn WJ, et al. Gastroenterol 2015; 148: 740-50, editorial 701-4) shows that budesonide foam can be helpful for patients with ulcerative proctitis and ulcerative proctosigmoiditis.

Design: Two identical randomized, double-blind, placebo-controlled trials examined the use of budesonide foam in 546 patients with mild to moderate ulcerative proctitis or ulcerative proctosigmoiditis. Patients had at least 5 cm of involved mucosa but no more than 40 cm. Dosing: 2 mg/25 mL twice daily for 2 weeks, then once daily for 4 weeks. The primary endpoint of remission was defined as an endoscopy subscore of ≤1, rectal bleeding subscore of 0, and improvement or no change from baseline in stool frequency subscore of the Mayo score. It is noted that about 90% of patients had moderate Mayo endoscopy subscore at baseline.

Key findings:

Combining the results of the studies, 41.2% achieved the primary end point of remission at the end of 6 weeks, compared with 24.0% of placebo patients.
There were 10 patients (3.7%) with low morning cortisol (compared with 0.7% of placebo-treated patients) and 14% who had abnormal ACTH testing at 6 weeks (compared with 4% of placebo-treated patients), though there no reported signs/symptoms of adrenal suppression present.

The associated editorial suggests that budesonide could be implemented in patients who did not respond to 5-ASA topical therapy (suppository for proctitis and enema for proctosigmoiditis). In addition, the editorial questions whether a single night-time administration may be more effective by maximizing adherence.

Bottomline: Budesonide foam was superior to placebo in this study and may eliminate the need for systemic steroid use. As the editorial suggests, 5-ASA topical therapy likely should be considered as first-line treatment.

Related blog post: Budesonide for Ulcerative Colitis

Healthcare Transition: Why Being the Best May Not Work

Posted on May 31, 2015 by gutsandgrowth

According to a commentary, “Why Strategy Matters Now,” (NEJM 2015; 372: 1681-4), successful health care organizations are going to need to develop a strategy to provide better value as the key goal.

They note that previous approaches to develop scale and market presence will be trumped by patients choosing insurance products with narrowed provider networks and high deductibles. With reimbursement decreases and resistance from private insurance companies to ‘cross-subsidize care’ for publicly-insured or noninsured patients, that change is inevitable. Key points:

“Having a good brand is no longer enough: patients and payers are looking for good value, service by service.”
“Providers that organize themselves to improve outcomes and become more efficient in doing so will be rewarded.”

The authors then detail several questions that healthcare organizations need to answer to develop their strategy for being successful.

My take: While there is an effort to transform health care, a big stumbling block is the ability to measure value and quality. Until this becomes easier, this transformation will be slow-going.

Early Look At Entyvio (Vedolizumab) in Pediatrics

Posted on May 30, 2015 by gutsandgrowth

From DDW 2015 and HealioGastro: Entyvio shows promise in pediatric patients

First study, abstract 321:

Namita Singh, MD, of Cedars Sinai Medical Center in New York, … presented results of a prospective observational study in which they initiated Entyvio (vedolizumab, Takeda; 6 mg/kg, maximum 300 mg) — off label — via intravenous infusion in pediatric patients…The primary clinical outcomes was clinical remission at week 6 (PUCAI ≤ 10; PCDAI ≤ 10).

The study looked at 23 patients (15 with Crohn’s; eight with ulcerative colitis) enrolled between June 2014 and October 2014; median age of vedolizumab initiation was 14 years.

At 88%, the patients with ulcerative colitis had a higher rate of remission than those with Crohn’s who were at 40% [at week 6]. This trend sustained at week 14 and Singh said all patients with ulcerative colitis were in remission at week 14.

Week 6 and week 14 remission rates overall were 46.6% and 54.5%, respectively, and week 6 remission predicted week 14 remission (P < .05).

“Week 6 remission is associated with week 14 remission,” Singh said. “This suggests that we can determine early in therapy whether a patient will be a primary responder to therapy. If not, then perhaps we should move on to another therapy.”

“Longer duration from last anti-TNF exposure is associated with higher remission rates,” Singh said.

Second study, abstract 322:

Ronen Stein, MD, from the Perelman School of Medicine at the University of Pennsylvania, also presented data on vedolizumab therapy in patients with severe pediatric IBD…In this single center, prospective observational cohort study, the primary endpoint was a decrease in PCDAI/PUCAI from baseline to weeks 6, 14 and 22 and secondary endpoints were changes in albumin, hematocrit and CRP as well as remission at the same time points.

Patients received vedolizumab infusions (300 mg) at weeks 0, 2 and 6 for induction and maintenance through week 22.

The researchers included children aged 13 years to 21 years (n = 17) with IBD who weighed 40 kg or more and had a past failure on TNF-alpha inhibitor therapy. Of these patients, 15 had Crohn’s disease and two had unclassified IBD (IBD-U).

More than three-quarters started on systemic corticosteroids at baseline; more than one quarter were on immunomodulators. Seven patients had previous abdominal surgery and 59% of patients had failed more than one biologic therapy…

At each time point in question, this study saw improvement of PCDAI (P < .001 at week 6; P < .05 at week 14; P < .0001 at week 22).

“Starting at week 6, there was a significant decrease in PCDAI that was sustained for weeks 14 and 22.”

Five patients reached remission at week 6.

“There really is no pattern to tell us which patients will be in remission at week 6. They have pretty different characteristics,” Stein said.

Briefly noted:

Link: Case description/images of 9 year old with gastric Crohn’s

Related blog posts:

I love Ria’s Bluebird –the best pancakes ever!

Do You Know How Long to Use Antibiotics for Intraabdominal Infections?

Posted on May 29, 2015 by gutsandgrowth

Since 2010, there have been published guidelines for complicated intraabdominal infections which recommend a treatment course of 4 to 7 days. These include guidelines from the Surgical Infection Society (SIS) and the Infectious Diseases Society of America (IDSA). Now, a new study (Sawyer RG et al. NEJM 2015; 372: 1996-2005, editorial 2062-63) provides additional support for a short course of antibiotics when there is adequate source control. The study termed “Study to Optimize Peritoneal Infection Therapy” or STOP-IT included 23 institutions from the U.S. and Canada.

Video Summary (1:33): Trial of Short-Course Antimicrobials

Rationale: While traditional therapy of 10-14 days has been based on the premise that ongoing fever and leukocytosis indicate ongoing infection, “more recent experimental data, however, suggest that a prolonged SIRS [systemic inflammatory response syndrome] may be more a reflection of host immune activity than an indication of the presence of viable microorganisms.”

Design: 518 patients were randomly assigned to either a fixed 4-day course of antibiotics or to a control group that received antibiotics for 2 days after resolution of fever, leukocytosis, and ileus (max of 10 days). The median number of days in the control group was 8 days.

Study characteristics:

Mean age 52 years
34% of the infections originated in colon/rectum, 14% in small bowel, and 14% in the appendix
11% had cancer, 10% had inflammatory bowel disease

Source-control procedures: “defined as procedures that eliminate infectious foci, control factors that promote ongoing infection, and correct or control anatomical derangements to restore normal physiological function”

Percutaneous drainage 33.1%
Resection and anastomosis or closure 26.5%
Surgical drainage alone 21.2%
Resection and proximal diversion 10.4%
Simple closure 7.7%
Surgical drainage and diversion 1.2%

Results:

Surgical site infection, recurrent intraabdominal infection, or death occurred in 21.8% of the experimental 4-day group compared with 22.3% of the control group. Death occurred in 3 experimental patients and 2 control patients.
No significant differences were found between the two groups in terms of primary or secondary outcomes.

Limitations:

18% of the experimental group and 27% of the control group deviated from the protocol. In the control group, this included 26 patients who received less than 10 days of therapy but more than 2 days longer than the resolution of the physiological findings.
Patients without adequate source control were excluded

The editorial notes that if these findings are incorporated into clinical practice, more than $97 million would be saved on antibiotic costs alone; in addition, there would be less diarrhea and phlebitis. The editorial suggests that the reason why more than 20% of both groups had complications is likely related to source control. If inadequate course of antibiotics was the culprit, “we would have expected still more complications after treatment in the short-course therapy group.”

(From editorial): “We have encouraging data from the STOP-IT trial that suggest cost savings and improved safety.”

Take-home message Because of years of practice patterns, it is going to be difficult to stop antibiotics at 4 days when patients are still having fevers, especially since 20% will not have resolution of their infection. These data should, however, make it easier to shorten antibiotic courses.

Related blog posts:

Zoo Atlanta

Something Bad is Going to Happen

Posted on May 28, 2015 by gutsandgrowth

A recent commentary (Sonnenberg A, Clin Gastroenterol Hepatol 2015; 13: 820-23) discusses the statistical inevitability of adverse events. As such, despite our efforts to provide the best care, we should consider how we look at bad outcomes. This article highlights a few common issues in adult gastroenterology, failing to identify colorectal cancer and adverse events at the time of endoscopy. Using statistical models, the author notes that avoiding all adverse events is nearly impossible.

The broader points for pediatric gastroenterologists/all physicians:

Using simple statistics, “adverse events can be expected to occur with a high probability. Their occurrence is a function of the number of patient encounters and the probability of making mistakes.”
“It is a statistical misconception to believe that their rare occurrence would make it possible for an individual gastroenterologist to dodge the bullet.”
“It is another statistical misconception to assume that by exerting extreme caution a gastroenterologist also could avert adverse events. The only means to truly reduce adverse events is to avoid patient encounters.”
“The physician rarely is given credit for innumerous other patient encounters with good outcomes. The bad outcome is considered potentially reflective of professional failure or flawed performance. The process ultimately is geared toward showing avoidable mistakes and assigning guilt. The occurrence of an error, even at its lowest rate, generally is not accepted as a viable reason, although under different circumstances the same reviewers would be willing to accept the less-than-perfect sensitivity or specificity of all diagnostic tests.”
“We have to …free ourselves from the illusion that perfection will become achievable through limitless quality assurance.”
“Highlighting the statistical nature of adverse events is not meant to belittle the need for continued efforts at improving patient safety and increasing the quality of health care delivery…In a ‘just culture’ of safety and accountability, the occurrence of any error would become an opportunity for learning and improvement rather than retribution or punishment.”

As a personal aside, I took some solace in reading this article and previously in reading the book “Complications: A Surgeon’s Notes on an Imperfect Science” (Complications | Atul Gawande). I clearly remember a few terrible situations that from time to time still fill me with sadness and regret. I feel better knowing that the mistakes that I have made were not due to a lack of effort or due to a lack of caring.

Take-home message: If you practice medicine, something bad is going to happen. Can we forgive ourselves if our judgement contributed to an adverse event?

Zoo Atlanta

Does it really cost $2.6 billion to bring a new drug to market?

Posted on May 27, 2015 by gutsandgrowth

A recent editorial (Avorn J. NEJM 2015; 372: 1877-79) helps provide some perspective on a recent unpublished study that “it costs pharmaceutical companies $2.6 billion to develop a new drug.” (http://csdd.tufts.edu/files/uploads/cost_study_backgrounder.pdf)

Dr. Avorn notes that when this study is published scrutiny over the methods is needed; however, the authors of the study note that their methods are unchanged from a previous 2003 study (NEJM 2015; 372: 1972). Apparently the analysis was based on data from 10 drug makers regarding compounds that they had ‘self-originated.’

Some preliminary criticisms:

Nearly half the costs were attributed to the cost of capitol rather than direct spending. This cost indicates that the money being used for drug development was not available for other purposes (“opportunity costs”); however, the capital costs were assessed at a very generous 10.6% per year, compounded.
The analysis did not include the large public subsidies provided to pharmaceutical companies in the form of research-and-development tax credits.
Pharmaceutical companies remain highly profitable and only spend a small fraction of their revenues on truly innovative research.
Many of the drugs brought to market are not “self-originated.”
Many drug costs are borne by the public via research at university-affiliated centers with the pharmaceutical companies taking the new discovery the last mile. “Gilead Sciences did not invent its blockbuster treatment for hepatitis C, sofosbuvir (Sovaldi)…it acquired the product from a small company founded by the drug’s inventor, a faculty member at Emory University, much of whose work on the usefulness of nucleoside viral inhibitors was federally-funded.”

Bottomline: While pharmaceutical companies invest heavily in new drug development, the huge numbers often attributed to research costs may be overestimates; these type of analysis likely underestimate how much taxpayers have paid in subsidizing the foundation for new treatments.

Related blog post: The Difficulty with Drug Development | gutsandgrowth