Do Probiotics Really Help Crying Infants?

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This is the question from a recent meta-analysis (JAMA Pediatr 2013; 167: 1150-57 -thanks to Ben Gold for this reference).

Table 1 details the study designs, probiotic intervention, and outcomes.

Results: “Of the 12 eligible studies (1825 infants), 6 suggested that probiotics reduced crying and 6 did not…Meta-analysis of 3 small trials of breastfed infants with colic found that Lactobacillus reuteri markedly reduced crying time at 21 days…However, all trials had potential biases.”

In the three breastfed trials alluded to above, there were concerns regarding inadequate blinding of the intervention, unequal baseline characteristics, and use of non validated crying “diaries” which could be prone to recall bias.

More data are needed; fortunately there are several ongoing trials.

Bottomline (from the authors’ conclusion): “Although L reuteri may be effective as treatment for crying in exclusively breastfed infants with colic, there is still insufficient evidence to support probiotic use to manage colic, especially in formula-fed infants.”

Previous  related posts:

Cost of Email

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While email has been considered “cost-free,” a recent JAMA Peds letter titled “Metastasis of E-mail at an Academic Medical Center,” identifies a significant opportunity cost.  Think twice about sending that email to everybody! Here’s the link (from John Pohl’s twitter feed): http://dlvr.it/4lD22K 

“If 30 seconds were spent per e-mail, the annual cost per physician to read these mass distribution emails was $1641.”  If 90 seconds each, then $4923.

Tobacco 21 & ENDing Combustible Tobacco Use

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While “some 6 million [deaths] globally every year and 400,000 in the United States” are tobacco-related, the best way to reduce these statistics is unclear.  Currently, nearly 50 million Americans continue to use some form of tobacco. A couple important ideas are discussed in a few recent perspective articles:

  • NEJM 2014; 370: 293-4
  • NEJM 2014; 370: 295-7  bit.ly/P6LiF4 
  • NEJM 2014; 370: 297-9

In my view, the most promising idea is “Tobacco 21.”  Starting in May, in New York City, it will be illegal to sell tobacco products and electronic cigarettes to persons younger than 21 years of age.  While the FDA set a national minimum of age 18 years, states and localities can set a higher age.

Although there are those who decry the ‘nanny state’ interfering in adults who are capable of enlisting in the army, there are compelling arguments to ignore these nihilists.

  1. In 2005, Needham, Massachusetts became the first town with a Tobacco 21 statute.  What has happened?  Youth smoking rate has fallen by nearly half to 6.7% (previously 12.9%).  The surrounding communities have a rate of 12.4% (previously 14.9%). Thus, the rate of decline was nearly triple.  This counters the notion that most of these youths will purchase in adjacent areas.
  2. 80% of adult smokers began smoking daily before 20 years of age.  In addition, “90% of persons who purchase cigarettes for distribution to minors are under 21.”  Thus, Tobacco 21 could make a big dent in a minor’s ability to buy from other students/youths.  Furthermore, 90% of U.S. adults smokers have indicated that “if they had to it over again, they would not have started.”
  3. The “adolescent brain has a heightened susceptibility to the addictive qualities of nicotine.”  Also, adolescents are more impulsive and risk takers which increase the likelihood that they would discount the potential consequences of tobacco experimentation.
  4. Checking age of purchasers is already needed for anyone “who appears younger than 27.” Thus, this does not increase regulatory burdens significantly.

Even though Tobacco 21 is the most logical next step in reducing the dangers of tobacco, a much more visible and controversial measure has been ENDs or electronic nicotine delivery systems.  E-cigarettes have been widely advertised.  The opponents of e-cigarettes object because they have the potential to diminish the stigma of smoking and serve as a gateway product, leading to more smoking (JAMA 2013; 310: 685-6).

On the other hand, advocates suggest that “the majority of e-cigarette users treat them as cessation aides.” Ultimately, these products will improve health only if it helps reduce use of combustible products.

Bottomline: Tobacco 21 has the best potential to reduce the mortality and morbidity of smoking, but ongoing efforts with warning labels, tax increases, clean-indoor policies, cessation programs, and public-service campaigns need to continue.

From NEJM twitter feed: Listen now to audio interview w/ TobaccoFreeKids’ Matthew Myers on efforts to reduce, eliminate, prevent smoking. http://nej.md/LKTV7F 

Related blog posts:

HCV Website -No “Cat on The Roof”

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A joke I heard a long time ago:

A guy asks his friend to check up on his cat while he is away on a trip.  He calls to see how kitty is doing.  His friend says, “Sorry but she died.”  In response, he tells his friend, “you should have broken me the news a lot more gently.  Maybe you could have said she was up on the roof and the next time I called it would have been easier to accept the news.”  A few years pass and he again asks his friend for a favor, this time to check up on his grandmother while he is away on a trip.  He calls to see how granny is doing.  His friend says, “Oh, she is up on the roof.”

The AASLD and “the Infectious Diseases Society of America (IDSA), in collaboration with the International Antiviral Society-USA (IAS-USA), announced the launch of a new website,HCVguidelines.org, that offers up-to-date recommendations for testing, managing, and treating hepatitis C virus (HCV) infection.”

The website clearly dismisses the previous established breakthrough treatments of telaprevir and boceprevir “because they are markedly inferior.”

For anyone who has been confused with the onslaught of new work on HCV, the website spells out in clear detail the best regimens for HCV treatment now that both sofusbuvir and simeprevir are available.

Bottomline: The website makes it clear that both telaprevir and boceprevir are up on the roof.

Related blog posts:

MD Job Dissatisfaction –Million $ Mistake?

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A recent report indicates a high level of job dissatisfaction among physicians, leading some to conclude that it could be a million dollar mistake: http://www.cbsnews.com/news/1-million-mistake-becoming-a-doctor … (from Eric Benchimol’s twitter feed)

Here’s an excerpt:

If you are brilliant, ambitious and gifted in science, you may consider becoming a doctor. If so, think twice. According to a new survey by personal finance site NerdWallet, most doctors are dissatisfied with the job, and less than half would choose a career in medicine if they were able to do it all over again….

Worse, the cost of becoming a doctor has soared, with higher education expenses leaving the average newly minted physician with $166,750 in medical school debt, while average salaries are declining. Nearly one-third of doctors — 28 percent – saw a cut in pay last year, according to NerdWallet’s research….

To be sure, pay is still high, with of six-figure positions in the country, according to government data. But it also takes between 11 and 14 years of higher education to become a physician. That means the typical doctor doesn’t earn a full-time salary until 10 years after the typical college graduate starts making money. 

That lost decade of work costs a cool half-million dollars, if you assume this individual could have earned just $50,000 annually, and the typical medical school candidate is smart and successful enough to earn considerably more.  Add in the time and cost it takes to pay off medical school debt and a dissatisfied physician may well consider pursuing medicine a $1 million mistake.

Take-home message: Financial considerations are probably the wrong reasons to to pursue a career in medicine.

Related blog posts:

Brain Response to Physical Activity different in Obesity

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From NY Times (http://nyti.ms/1afnEyJ) review of the following article:

Int J Obes (Lond). 2013 Dec 24. doi: 10.1038/ijo.2013.245. [Epub ahead of print]

Differences in neural activation to depictions of physical exercise and sedentary activity: An fMRI study of overweight and lean chinese women. Jackson T, Gao X, Chen H.

An excerpt:

Overweight women’s brains respond differently to images of exercise than do the brains of leaner women…

The scientists asked their volunteers to complete two questionnaires, one of which probed the extent to which they considered exercise desirable; would they agree, for instance, that, “if I were to be healthy and active, it would help me make friends”? The other set of questions examined whether they expected exercise to be unpleasant; if they were to be physically active on most days, for example, would they expect to wind up feeling sore, or maybe even embarrassed by exercising in public?

The researchers next had each woman lie inside a functional magnetic resonance imaging machine, which scans blood flow to specific areas of the brain, indicating areas of increased activity. Then they started a slide show.

For some time, scientists have known that many overweight people’s brains operate differently than the brains of thinner people when they look at images related to eating. In previous neurological studies, when heavier volunteers viewed pictures of food or food preparation, they typically developed increased activity in portions of the brain involved in reward processing, or an urge to like things, including in an area called the putamen. At the same time, their brains showed relatively blunted activity in areas that are thought to induce satiety, or the ability to know when you are full. These changes generally are reversed in the brains of thinner people shown the same images.

But no brain-scanning studies had examined whether being heavy might also affect people’s brain responses — and presumably their attitudes — toward physical activity.

So, to address that gap, the researchers now flashed a series of photographs before their volunteers. Ninety of the images showed people being joyously active by running, dancing, leaping, playing tennis and such. The women were asked to vividly imagine themselves performing the same actions, using hand gestures and limited bodily contortions, to the extent possible within the confines of the scanner.

Ninety additional images featured relaxed, sedentary behaviors, including stretching out on a sofa and sitting in a desk chair. Again, the women were directed to imagine themselves similarly lounging. The various images of activity and quiet were interspersed with photographs of landscapes.

While the women viewed the pictures, the functional M.R.I. machine monitored their brain activity.

The resulting readouts revealed that overweight women’s brains were put off by exercise. Shown images of people being active, these women developed little activation in the putamen region of the brain, suggesting that they did not enjoy what they were seeing. At the same time, a portion of the brain related to dealing with negative emotions lit up far more when they viewed images of moving than of sitting. Emotionally, the brain scans suggested, they anticipated disliking physical activity much more than they expected to disdain sitting.

Leaner women’s brain activity, by and large, was the opposite, with the putamen lighting up when they watched others work out and envisaged doing the same themselves.

Has Your Hospital Restricted Quarter-Normal Saline?

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In a previous post (What’s critical to you | gutsandgrowth), I’ve drawn attention to the problem of hyponatremia.  This particular hospital problem is often iatrogenic and often preventable.  Two recent studies provide more data to support limiting hypotonic fluids.

The first study that took place between 2009-2011, shows that this remains a common problem at Stanford’s pediatric hospital (J Pediatr 2013; 163: 1646-51).  This study was a retrospective study with data extracted from the hospital’s EMR.

From a cohort of 5498 patients receiving intravenous fluids (IVFs) on admission, 1048 were suitable for study due to the availability of serum sodium levels, not having several types of IVFs, and not being neonatal patients.  In addition, patients who had abnormal sodiums on admission (n=753) were excluded.

Hypotonic fluids included: D5W, one-quarter normal saline (1/4 NS), D5 1/4 NS, 1/2 NS, D5 1/2 NS, and total parenteral nutrition.  No patients received D5W as a maintenance fluid, but its use with medications contributed to total free water delivery.

Isotonic fluids were D5 NS, NS, and Lactated Ringer’s.

Results:

  • Hyponatremia (Na <135 mEq/L) developed in 260 of 674 (38.6%) who received hypotonic fluids and in 104 of 374 (27.8%) who received isotonic fluids. OR 1.63
  • The overall incidence of hyponatremia was 34.7% in this cohort.
  • Other factors associated with developing hyponatremia: surgical admission (adjusted OR 1.44), cardiac admitting diagnosis (aOR 2.08), and hematology/oncology admission (aOR 2.37)

The fact that hyponatremia occurred in a large number on isotonic fluids indicates that additional factors like total fluid volume and uncorrected volume deficits contribute as well. Preferential water retention can still occur in the setting of increased ADH levels. This study, like all retrospective studies, has several limitations.  However, the basic finding that hypotonic fluids increase the risk of hyponatremia remains solid.

The second study was a recent meta-analysis (Pediatrics 2014; 133: 105-113 -thanks to Seth Marcus for this reference) which included ten randomized controlled trials. It showed that hypotonic maintenance IV fluids were associated with a much higher risk of hyponatremia (RR 2.24) and severe hyponatremia (Na <130) (RR=5.29).

Bottomline from both studies: Isotonic fluids are safer than hypotonic fluids in hospitalized children for maintenance IV fluids in terms of decreasing the risk of hyponatremia.

 

In PURSUIT of Better Treatment for Ulcerative Colitis

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Patient education materials:

#1  Ulcerative Colitis For Dummies | UC Patient Resource This link connects to a free educational book promoted by Salix pharmaceuticals.  In order to receive a free download, you have to register and include your email.  I have not read this book but other similar books (eg. Colonoscopy for Dummies) by Salix have been well-written.

#2 This link, ow.ly/sPX95, is to the ImproveCareNow visit planner website.  It poses of ~ 8 questions and a text box  for “my list of things I’m concerned about and questions that I have.”  Families that use this planner may help themselves achieve more comprehensive care.

Anyone who follows this blog knows that I really enjoy a good study acronym.  The Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment (PURSUIT) is responsible for two papers in the most recent Gastroenterology issue:

  • Gastroenterol 2014; 146: 85-95
  • Gastroenterol 2014; 146: 96-109

PURSUIT is composed of >200 sites from around the world.  The first study was a combined phase 2 and phase 3 study. It enrolled 1064 adults with moderate to severe ulcerative colitis (UC) who were randomly assigned to either placebo, 200/100 mg or 400/200 mg of SC golimumab at 0 and 2 weeks.  All patients were naive to previous anti-TNF therapies. The average duration of disease was 6 years among the participants. The primary endpoint of the phase 3 part of this study was the clinical response at 6 weeks.  Clinical response was at least a 30% improvement and a ≥3-point improvement in the Mayo score. At baseline, the average Mayo score was 8.

  • The golimumab groups had response rates of 51.8% and 55.0% respectively compared to 29.7% for placebo.
  • Approximately 18% of patients achieved a clinical remission with treatment compared with 6% of placebo patients.
  • Approximately 10% had healed mucosa compared with ~4% in the placebo group.
  • Adverse events: Rates of serious infection were 1.8% for the active treatment group compared with 0.5% for placebo-treated patients.  In the 400/200 mg dosing group, there was 1 death attributed to peritonitis and sepsis after multiple procedures for ischiorectal abscess repair.  In addition, a single case of demyelination was noted in this group.

The second study, a phase 3 double-blind trial, evaluated the efficacy of maintenance treatment of 50 mg or 100 mg SC every 4 weeks in those with a successful induction (n=464).  This study took place at 251 centers between 2007-2011. At 54 weeks, the actively-treated gourds had maintained a clinical response, using the Mayo score, in 47.1% and 50.6% respectively compared to 31.4% for placebo.  Antibodies to golimumab developed in 2.9%, two-thirds of these antibodies were neutralizing.  Antibody formation was lower in those receiving concomitant immunomodulators. 4 cases of tuberculosis were noted from endemic regions despite previous screening.  Overall, infections occurred in 28% of those treated with placebo compared with 39% of those treated with golimumab.

During the course of the study, three deaths were reported, all in the 100 mg golimumab maintenance group.  The causes were malnutrition/sepsis, cardiac failure/thrombosis, and disseminated tuberculosis (patient was receiving isoniazid). After the study, another 6 deaths were reported, including two in the placebo group.  Three malignancies were reported through week 54 in patients receiving golimumab maintenance, two of these presented in the induction period while receiving placebo rectal cancer and thyroid cancer) and one (lung adenocarcinoma) occurred in a patient with a 40-year smoking history who received golimumab for induction and maintenance.

Taken together, about 25% of patients randomized to and maintained on golimumab achieved a clinical response lasting >1 year; similarly, about 17% had clinical remission at 1 year.

In the commentary (page 13-15), Stephen Hanauer notes that better response was noted with higher serum levels and there remains “a strong possibility that optimal dosing was not achieved.”  He and the authors comment on the observation that less-severe patients had a better response, indicating that  “greater disease severity may be correlated with more rapid clearance.”

Bottomline: These studies demonstrate that golimumab is an effective treatment for UC with a similar risk of adverse reactions as other anti-TNF agents.  The published studies are complicated and take some time to analyze.

Plus more references:

Gastroenterol 2014; 146: 110-18. “Adalimumab therapy is associated with reduced risk of hospitalization in patients with ulcerative colitis.” Data for this studies was derived from ULTRA1 and ULTRA2 trials with 963 patients.  Risk for hospitalization, whether due to UC or all-causes, was reduced between 40-50% compared to placebo within the first 8 weeks of adalimumab administration.

Clin Gastroenterol Hepatol 2013; 11: 1538-49.  Excellent review on pouchitis. Figure 5 (pg 1545) provides a nice treatment algorithm.  Initial approach is antibiotics (metronidazole or ciprofloxacin); in those responsive, either prn therapy or chronic treatment.  In those not responsive, look for pathogens (eg. CMV and C difficile) or determine it is immune-mediated (PSC-associated, IgG4-associated, or autoimmune).  The immune-mediated may respond to 5-ASA/budesonide or immunomodulators.

Clin Gastroenterol Hepatol 2013; 11: 1601-08. This case-control study with 141 UC controls and 59 patients who developed colorectal neoplasia found that increased inflammation was associated with colorectal neoplasia.  Use of immune modulators reduced the risk of colorectal neoplasia.

Related blog post:

Simponi (Golimumab) Approved for Ulcerative Colitis | gutsandgrowth

Pre-PEG UGIs -Low Yield If No Major Malformations or Cystic Fibrosis

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From JPGN online and NASPGHAN twitter feed, bit.ly/19q99Y8 :

Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0000000000000282

Abstract: “We studied the utility of a preoperative upper gastrointestinal series in children with and without major congenital anomalies undergoing gastrostomy tube (G-tube) placement. Of 1163 children evaluated, 743 had major anomalies and a total of 39 episodes of malrotation were found. All of the children with malrotation either had major congenital anomalies or cystic fibrosis. Our study suggests that an upper gastrointestinal series may be unnecessary prior to G-tube placement in children without other congenital anomalies or cystic fibrosis.”

Comment: while I agree with the conclusions of the abstract, it is worth noting that upper gastrointestinal series will pick up other abnormalities as well, including duodenal stenosis (which I have seen picked up on two separate occasions).

Variation in Practice -The Influence of Money

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A recent study highlights the problem of bundling and shows how financial incentives distort care in some gastroenterology practices (Clin Gastroenterol Hepatol 2014; 12: 58-63).

Background: When needed, patients can undergo both colonoscopy and esophagogastroduodenoscopy (EGD) at the same time; when combined, the procedures are considered bundled.  It is more convenient for patients and less costly to do the two procedures during the same sedation.  However, Medicare reimbursement to physicians for bundled procedures is less than the sum of the two procedures when charged separately. This creates an incentive for physicians to unbundle these procedures.

Study design: The authors examined Medicare claims from 2007-2009 in a national, random sample (patients ≥66 years) –part of the Surveillance Epidemiology and End Results Program.

Results:

  • 12,982 had colonoscopy and EGD within 180 days.  ~35% of these were not bundled.  This included 2359 (18%) unbundled procedures which were performed within 30 days of each other.
  • Geographic differences were noted: bundling occurred less often in the Northeast (55%) and most often in the West (68%)

What does this study indicate about bundling (& human nature)?  This study indicates that physicians respond to underlying financial incentives to separate these procedures.  In our pediatric practice, we do not unbundle procedures.  The additional facility costs, use of anesthesia, costs to families from missing work, and convenience are compelling reasons to combine procedures if feasible.  However, this data indicates that unless physicians are paid the same value for each EGD and colonoscopy, there will continue to be many patients who have their procedures scheduled on separate dates.

Bottomline: Medicare and other insurance companies will save money by not paying less for combined procedures.

Another example of financial incentive influencing care with regard to ambulance and EMS care:  How Perverse Incentives Drive Up Health Care Costs / ideastream …