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New study examines treatment for diabetic ketoacidosis

IV Bag

Brain injuries that happen during episodes of diabetic ketoacidosis (DKA) – where the body converts fat instead of sugar into energy, and where the pancreas is unable to process insulin, such as in type 1 diabetes – are rare, and happen in less than 1 percent of DKA episodes, but these injuries can carry lasting consequences – including mild to severe neurological damage.

A new 13-center, randomized, controlled trial published on June 13, 2018, in the New England Journal of Medicine finds two variables – the speed of rehydration fluids administered to patients and the sodium concentrations in these intravenous fluids – don’t impact neurological function or brain damage.

“One medical center would never be able to study this independently because of the relatively small volume of children with DKA that present to any one site,” says Kathleen Brown, M.D., a study author, the medical director of the emergency medicine and trauma center at Children’s National Health System and a professor of pediatrics and emergency medicine at George Washington University School of Medicine. “The strength of this research lies in our ability to work with 13 medical centers to study almost 1,400 episodes of children with DKA over five years to see if these variables make a difference. The study design showcases the efficiency of the Pediatric Emergency Center Applied Research Network, or PECARN, a federally-funded initiative that powers collaboration and innovation.”

Researchers have speculated about the techniques of administering intravenous fluids, specifically speed and sodium concentrations, to patients experiencing a DKA episode, with many assuming a faster administration rate of fluids would produce brain swelling. Others argued, from previous data, that these variables may not matter – especially since higher levels of brain damage were noted among children with higher rates of dehydration before they were treated. Some thought DKA created a state of inflammation in the brain, which caused the damage, and that speed and sodium concentration wouldn’t reverse this initial event. The researchers set out to determine the answers to these questions.

The PECARN research team put the data to the test: They created a 2-by-2 factorial design to test the impact of providing 1,255 pediatric patients, ages zero to 18, with higher (.9 percent) and lower (.45 percent) concentrations of sodium chloride at rapid and slow-rate administration speeds during a DKA episode. They administered tests during the first DKA episode and again during a recurrent episode. After analyzing 1,389 episodes, they found that the four different combinations did not have a statistically significant impact on the rate of cognitive decline during the DKA episode or during the 2-month and 6-month recovery periods.

“One of the most important lessons from this study is that diabetic ketoacidosis should be avoided because it can cause harm,” says Dr. Brown. “But the best way to treat diabetic ketoacidosis is to prevent it. Parents can monitor this by checking blood sugar for insulin control and taking their children for treatment as soon as they show signs or symptoms that are concerning.”

According to the National Institute of Diabetes and Kidney Disease, symptoms of diabetic ketoacidosis include nausea and vomiting, stomach pain, fruity breath odor and rapid breathing. Untreated DKA can lead to coma and death.

An accompanying video and editorial are available online in the New England Journal of Medicine.

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the Health Resources and Services Administration. The PECARN DKA FLUID ClinicalTrials.gov number is NCT00629707.

Children’s National Health System’s Division of Pediatric Emergency Medicine has been a lead site for the PECARN network since its inception in 2001.

Improving asthma care at community emergency departments

Through partnerships with community health care facilities, children suffering from severe asthma attacks can receive the type of state-of-the-art care championed by Children’s National.

Asthma is an exceedingly common pediatric disease, affecting nearly 7 million children in the United States, particularly in urban areas. Asthma is responsible for more than 775,000 Emergency Department (EDs) visits each year. However, the vast majority of these visits are to community EDs closest to patients’ homes, rather than to medical centers that specialize in pediatric care.

This fact could potentially lead to big problems for small patients, says Theresa A. Walls, M.D., M.P.H., Director of Emergency Department Outreach at Children’s National Health System. Nearly 70 percent of EDs in the United States treat fewer than 14 children a day, leaving many without the requisite experience or resources critical to effectively treat pediatric patients. Research shows that children seen for asthma in general community EDs are less likely to receive corticosteroid medications systemically — an essential first-line therapy during an asthma attack per National Institutes of Health guidelines — compared with children seen at pediatric EDs. Additionally in these general EDs, children are also more likely to receive unnecessary testing and treatment.

“In our experience, the emergency care of children with asthma in our area mirrors what has been found in national studies: Children are not treated as aggressively in community EDs. If we partner with them and get them to treat asthma as aggressively as we do, it would be a great thing for pediatric patients.”

That’s why when a nurse educator from a local community hospital’s ED contacted them to try to improve pediatric asthma care, Dr. Walls and Children’s colleagues jumped at the opportunity. “They were motivated participants,” she says. “It was a great way to start a partnership.”

The team worked with the community hospital’s ED to implement a pediatric asthma care plan known as a “pathway,” similar to the one currently in place at Children’s National, to ensure that children in the throes of an asthma attack receive evidence-based care that significantly decreases their chances of hospital admission or transfer to a specialty center.

The treatment pathway includes elements such as assigning each patient an asthma score — a number ranging from 1 to 10 that characterizes the severity of the patient’s asthma attack. The treatment plan also includes providing corticosteroids as quickly as possible to more eligible patients.

Effectively implementing this plan requires the efforts of a multidisciplinary team of providers and experts. Beyond the physicians, nurses and respiratory therapists who care for patients directly, this includes pharmacists to ensure proper doses of medications are available in child-friendly liquid forms and information technology specialists to revamp the hospital’s electronic charting system, automatically requesting an asthma score or recommending appropriate medication orders.

To gauge whether mimicking Children’s asthma pathway made a significant difference at the community ED, Dr. Walls and colleagues launched a study that was published online December 8, 2016, in Pediatrics. Comparing data collected for 19 months after the new guidelines were put into place with data from 12 months prior, the researchers made some promising initial findings. Following the pathway implementation, 64 percent of children ages 2 to 17 who arrived at the community ED with asthma symptoms received an asthma score. About 76 percent of these patients with asthma received corticosteroids after the pathway was in place, compared with 60 percent of comparable patients prior to the switchover. The mean time to corticosteroid administration dropped by nearly half, falling from 196 to 105 minutes. Additionally, Dr. Walls says, 10 percent of patients required transfer to another hospital after pathway implementation, compared with 14 percent before — another significant drop.

Dr. Walls notes that there is significant room for improving these metrics and overall asthma care at community EDs. The research team hopes to continue working with the first community hospital and expand their partnership to form a network of other local hospitals. By working together in a large collaboration, she says, hospitals can share resources and knowledge while learning from each other’s successes and mistakes.

“The more we can deliver this state-of-the-art care to the community,” she says, “the better, because that’s where most kids go.”

Biomarkers sensitive to daily corticosteroid use

Using a mass spectrometer, Yetrib Hathout, Ph.D., is able to quantify 3,000 to 4,000 proteins from a tissue sample to identify proteins associated with cancer.

Using a Somascan proteomics assay – which simultaneously analyzes 1,129 proteins in a small volume of serum – a team led by Children’s National Health System researchers identified 21 biomarkers that respond to corticosteroids taken daily by children with Duchenne muscular dystrophy (DMD) and inflammatory bowel disease.

Corticosteroids are commonly prescribed to treat inflammatory conditions. High daily doses of corticosteroids are considered the standard of care for DMD, a type of muscular dystrophy characterized by worsening muscle weakness that affects 1 in 3,600 male infants. However, depending on the age of the child and drug dosage, chronic use is associated with such side effects as changes in bone remodeling that can lead to stunted growth, weight gain, facial puffiness caused by fat buildup, mood changes, sleep disturbances, and immune suppression. The research team sought to identify blood biomarkers that could be leveraged to create a fast, reliable way to gauge the safety and efficacy of corticosteroid use by children. The biomarkers also could guide development of a replacement therapy with fewer side effects.

“Ten pro-inflammatory proteins were elevated in untreated patients and suppressed by corticosteroids (MMP12, IL22RA2, CCL22, IGFBP2, FCER2, LY9, ITGa1/b1, LTa1/b2, ANGPT2 and FGG),” Yetrib Hathout, Ph.D., Proteomic Core Director at Children’s National, and colleagues write in the journal Scientific Reports. “These are candidate biomarkers for anti-inflammatory efficacy of corticosteroids.”

The blood biomarkers sensitive to corticosteroids fit into three broad groups, according to the authors. The children taking corticosteroids were matched with children of the same age who had never taken the medicine. Five biomarkers significantly increased in this corticosteroid-naïve group and decreased in kids prescribed corticosteroids. The biomarkers generally were inflammatory proteins and included chemokine, insulin-like growth factor binding protein 2, and integrin alpha-I/beta-1 complex.

The second group of biomarkers included nine proteins associated with macrophage and T-lymphocytes that were significantly reduced in concentration in kids taking corticosteroids. According to the study, this finding hints at corticosteroids blunting the ability of the immune system’s most able fighters to respond to infection.

In the third group were five proteins that were significantly increased by corticosteroid treatment in DMD and included matrix metalloproteinase 3, carnosine dipeptidase 1, angiotensinogen, growth hormone binding protein, insulin, and leptin, a hormone linked to appetite.

What researchers learned with this study will help them more accurately design the next phase of the work, Hathout says.

“We are the first team to report a number of novel discoveries, including that growth hormone binding protein (GHBP) levels increase with corticosteroid use. This represents a candidate biomarker for stunted growth. In order to use that new information effectively in drug development, the next studies must corroborate the role of serum GHBP levels as predictors of diminished stature,” he adds. “The study finding that four adrenal steroid hormones are depressed in kids taking corticosteroids raises additional questions about the broader impact of adrenal insufficiency, including its role in the delay of the onset of puberty.”

This work was supported by National Institutes of Health grants (R01AR062380, R01AR061875, P50AR060836, U54HD071601, K99HL130035, and R44NS095423) and Department of Defense CDMRP program grant W81XWH-15-1-0265. Additional support was provided by AFM-Telethon (18259) and the Muscular Dystrophy Association USA (MDA353094).