Spinal fusion surgical home helps kids go home sooner

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The first of its kind for pediatric patients, the Children’s National Spinal Fusion Surgical Home implements a newly developed model of care to streamline and optimize the spinal fusion process for adolescent idiopathic scoliosis patients.

Using frameworks of care used in adult models, along with best practices and literature reviews, a multidisciplinary team developed the first Spinal Fusion Surgical Home for pediatric patients. It standardizes the infection-control process, pain-management pathway, and physical-therapy program for patients undergoing spinal fusion.

“This model eliminates variability in the care process and increases the quality of care for pediatric patients,” said Matthew Oetgen, MD, MBA, Chief of Orthopaedic Surgery and Sports Medicine. “It’s just the start—by developing this model specifically for our young patients with adolescent idiopathic scoliosis, we are paving the way for a number of other kids that require different kinds of surgeries.”

Hallmarks of the spinal fusion surgical home
From pre-operative care through recovery, the Spinal Fusion Surgical Home streamlines care with an emphasis on increasing quality outcomes for patients. Children’s National provides an informational website and a single point of contact for scheduling procedures and pre-operative laboratory exams. Before surgery, patients and families attend an evening education class that features presentations from orthopaedic nurse practitioners, physical therapists, and anesthesiologists.

After surgery, a nurse follows up by phone to assess how the patient is handling pain and healing.

Increasing the quality of care
By implementing these standardized protocols, Children’s National has seen a decrease in the average length of stay for spinal fusion patients from about five days to three and a half days. The surgical home also has reduced the transfusion rate from 30 to 12 percent, and patient pain scores have decreased.  “Patients are getting better faster with less pain, and are getting to leave the hospital sooner,” says Karen Thomson, MD.

Children’s National also is creating surgical homes for sickle cell disease patients, who need a variety of different types of surgery, as well as for children who need Nissen fundoplication and heart surgery.

Javad Nazarian

Surviving pediatric diffuse intrinsic pontine glioma

Mutations in histone-encoding genes are associated with the vast majority of pediatric DIPG cases.

For more than four decades, clinicians around the nation have been giving the parents of pediatric patients diagnosed with diffuse intrinsic pontine glioma (DIPG) the same grim prognosis. In the past five years, there has been an explosion of innovative research at Children’s National Health System and elsewhere that promises to change that narrative. That’s because the black box that is DIPG is beginning to divulge its genetic secrets. The new-found research knowledge comes as a direct result of parents donating specimens, judicious shepherding of these scarce resources by researchers, development of pre-clinical models, and financing from small foundations.

From just 12 samples six years ago, Children’s National has amassed one of the nation’s largest tumor bio banks – 3,000 specimens donated by more than 900 patients with all types of pediatric brain tumors, including DIPG.

Such donated specimens have led to the identification of H3K27M mutations, a groundbreaking finding that has been described as the single-most important discovery in DIPG. Mutations in histone-encoding genes are associated with the vast majority of pediatric DIPG cases.

Histone mutations (also referred to as oncohistones) are sustained in the tumor throughout its molecular evolution, found a research team led by Javad Nazarian, Ph.D. Not only were H3K27M mutations nearly ubiquitous in all samples studied, the driver mutation maintained partnerships with other secondary mutations as DIPG tumor cells spread throughout the developing brain. Children’s National researchers have identified tumor driver mutations and obligate partner mutations in DIPG. They are examining what happens downstream from the histone mutation – changes in the genome that indicate locations they can target in their path toward personalized medicine. The value of that genomic knowledge is akin to emergency responders being told the specific house where their help is needed, rather than a ZIP code or city name, Dr. Nazarian says. While there is currently no effective treatment for DIPG, new research has identified a growing number of genomic targets for future therapeutics.“That changed the dynamic,” says Dr. Nazarian. “In DIPG clinical research, nothing had changed for 45 years. Now we know some of the genomic mutations, how the tumor was evolving – gaining new mutations, losing mutations. With precision medicine, we can target those mutations.”

Another study led by neuro-oncologist Eugene Hwang, M.D., reported the most comprehensive phenotypic analyses comparing multiple sites in a young girl’s primary and metastatic tumors. This study showed that despite being uniform, small molecules (mRNA) could be used to distinguish an evolved tumor from its primary original tumor mass.Key to this multidisciplinary work is collaboration across divisions and departments. Within the research lab, knowledge about DIPG is expanding.

Each member of the DIPG team – neurosurgery, neuro-oncology, immunology, genomics, proteomics – feeds insight back to the rest of the team, accelerating the pace of research discoveries being translated into clinical care. Among the challenges that the team will address in the coming months is outmaneuvering tumors that outsmart T-cells (immune cells).

“What is happening in the checkpoint inhibitor field is exciting,” says Catherine M. Bollard, MBChB, MD, Chief of Allergy and Immunology and Director of the Program for Cell Enhancement of Technologies for Immunotherapy. “The inhibitors work by reversing the ‘off’ switch – releasing the brake that has been placed on the T-cells so they can again attack multiple tumor proteins. The next exciting step, and novel to Children’s National, will be to combine this approach with T-cell therapies specifically designed to attack the DIPG tumors. Unlike the use of combination chemotherapy, which has had a limited impact, we hope that the novel combination of immunotherapeutic approaches will offer the hope of a potential cure.”

Dr. Hwang, another member of the multidisciplinary team, adds: “When you’re looking at the landscape – for me, at least – it starts and ends with how my patients are doing. There are kids for whom we have had great successes in improving survival rates in some cancers, like leukemia, and some where the needle has moved nowhere, like DIPG. We’re still trying to figure out the whole picture of who responds. The immune system is present in all kids. Its ability to attack is present in all kids.”

Children’s National is one of the few hospitals in the nation that conducts brainstem biopsies for DIPG and does so with very little chance of complications. The pons is like a superhighway through which nerves pass, making it instrumental in smooth operation of such vital functions as breathing, heart rate, sleeping, and consciousness. The ability of neurosurgeon Suresh Magge, MD, to perform such sensitive biopsies upends conventional wisdom that these procedures were inherently too dangerous. Within two weeks of diagnosis, genomics analyses are run to better understand the biology of that specific tumor. Within the following weeks, the tumor board occurs, and patients with DIPG are placed on therapy that best targets their tumor’s mutations.

The black box that is diffuse intrinsic pontine glioma is beginning to divulge its genetic secrets.

Despite an increasing number of experimental therapies tested via clinical trials, more than 95 percent of children with DIPG die within two years of diagnoses. Biomarkers that point to DIPG – like the copies of DNA that tumors shed and leave behind in the bloodstream – could enable creation of liquid biopsies, compared with today’s surgical approach.

Children’s also is making a concerted effort to create preclinical models of DIPG. Preclinical models will be used to winnow the field of potential therapeutics to the candidates most likely to help children survive DIPG. The preclinical tumor cells will be labeled with luciferase – enzymes that, like photoproteins, produce bioluminescence – permitting the researcher to visually see the formation, progression, and response of DIPG tumors to treatment in preclinical settings.

These preclinical models could be used to test multiple drug combinations in conjunction with radiation therapy. Molecular signatures and response to treatment could then be assessed to learn how the tumor resists therapy. Due to the obligate partnerships between driver mutations and secondary mutations, the research team already knows that effective DIPG medicines will need more than one target. If there were a single mutation, that would be like having a single master key to open many locks. Multiple mutations imply that more than one key will be needed. Thus, the search for cures for DIPG will necessitate taking a multi-pronged approach.

Combined drug regimens, including those created with proprietary technology, with or without radiation, will be keys to targeting myriad mutations in order to kill tumors where they are. Those drug combinations that demonstrate they can do their jobs – slowing tumor growth, increasing chances of survival, taming toxicity – will be selected for clinical application.

Immunotherapy leverages T-cells, the immune system’s most able fighters, to help in the overall goal of extending patients’ survival. One of the most challenging aspects of pediatric brain tumors is the body does a very good job of shielding the brain from potential pathogens. Precise drug delivery means finding innovative ways for therapeutics to cross the blood-brain barrier in order to reach the tumor. The team has identified one such potential target, the protein NG2, which may represent a good target for immune therapy. The protein is expressed in primitive cells that have not become specialized – meaning there may be an opportunity to intervene before it is driven to become a tumor cell.

Related resources
Research at a Glance: Clinicopathology of diffuse intrinsic pontine glioma and its redefined genomic and epigenomic landscape
Research at a Glance: The role of NG2 proteoglycan in glioma
Research at a Glance: Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma
Research at a Glance: Histological and molecular analysis of a progressive diffuse intrinsic pontine glioma: a case report

Rheumatic heart disease is a family affair

Parasternal long axis echocardiographic still frames in early systole in black and white and color Doppler of RHD-positive index case, sibling, and mother.

Parasternal long axis echocardiographic still frames in early systole in black and white and color Doppler of RHD-positive index case, sibling, and mother.

Siblings of children in Northern Uganda with latent rheumatic heart disease (RHD) are more likely to have the disease and would benefit from targeted echocardiographic screening to detect RHD before it causes permanent damage to their heart valves, according to an unprecedented family screening study.

RHD results from a cascade of health conditions that begin with untreated group A β-hemolytic streptococcal infection. In 3 percent to 6 percent of cases, repeat strep throat can lead to acute rheumatic fever. Almost half of children who experience acute rheumatic fever later develop chronic scarring of the heart valves, RHD.  RHD affects around 33 million people and occurs most commonly in low-resource environments, thriving in conditions of poverty, poor sanitation, and limited primary healthcare. Treating streptococcal infections can prevent a large percentage of children from developing RHD, but these infections are difficult to diagnose in low-resource settings.

Right now, kids with RHD often are not identified until they reach adolescence, when the damage to their heart valves is advanced and severe cardiac symptoms or complications develop. In such countries, cardiac specialists are rare, and intervention at an advanced stage is typically too expensive or unavailable.  Echocardiographic screening can “see” RHD before symptoms develop and allow for earlier, more affordable, and more practical intervention. A team led by Children’s National Health System clinicians and researchers conducted the first-ever family echocardiographic screening study over three months to help identify optimal strategies to pinpoint the families in Northern Uganda at highest RHD risk.

“Echocardiographic screening has the potential to be a powerful public health strategy to lower the burden of RHD around the world,” says Andrea Beaton, M.D., a cardiologist at Children’s National and the study’s senior author. “Finding the 1 percent of vulnerable children who live in regions where RHD is endemic is a challenge. But detecting these silent illnesses would open the possibility of providing these children monthly penicillin shots – which cost pennies and prevent recurrent streptococcal infections, rheumatic fever, and further valve damage.”

The research team leveraged existing school-based screening data in Northern Uganda’s Gulu District and recruited 60 RHD-positive children and matched them with 67 kids attending the same schools who were similar in age and gender but did not have RHD. After screening more than 1,000 parents, guardians, and first-degree family members, they found that children with RHD were 4.5 times as likely to have a sibling who definitely had RHD.

“Definite RHD was more likely to be found in mothers, with 9.3 percent (10/107 screened) having echocardiographic evidence of definite RHD, compared to fathers 0 percent (0/48 screened, p = 0.03), and siblings 3.3 percent (10/300 screened, p = 0.02),” writes lead author Twalib Aliku, School of Medicine, Gulu University, and colleagues. “There was no increased familial, or sibling risk of RHD in the first-degree relatives of RHD-positive cases (borderline & definite RHD) versus RHD-negative cases. However, RHD-positive cases had a 4.5 times greater chance of having a sibling with definite RHD (p = 0.05) and this risk increased to 5.6 times greater chance if you limited the comparison to RHD-positive cases with definite RHD (n = 30, p = 0.03.”

The paper, “Targeted Echocardiographic Screening for Latent Rheumatic Heart Disease in Northern Uganda,” was published recently by PLoS and is among a dozen papers published this year about the group’s work in Africa, done under the aegis of the Children’s Research Institute global health initiative.

The World Health Organization previously has prioritized screening household contacts when an index case of tuberculosis (TB) is identified, the authors note. Like TB, RHD has a strong environmental component in that family members are exposed to the same poverty, overcrowding, and circulating streptococcal strains. In a country where the median age is 15.5, it is not practical to screen youths without a detailed plan, Dr. Beaton says. Additional work would need to be done to determine which tasks to shift to nurses, who are more plentiful, and how to best leverage portable, hand-held screening machines.

“Optimal implementation strategies, the who, when, in what setting, and how often to screen, have received little study to date, yet these details are critical to developing cost-effective and sustainable screening programs,” Aliku and co-authors write. “Our study suggests that siblings of children identified with latent RHD are a high-risk group, and should be prioritized for screening.”

Related resources:  Research at a Glance

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).

In Brief- Fetal Medicine

Cognitive training exercises at home help kids with sickle cell boost visuospatial working memory

A team led by Children’s National Health System clinicians and research scientists attempted to identify novel approaches to boost working memory in children who suffer from sickle cell disease.

A team led by Children’s National Health System clinicians and research scientists attempted to identify novel approaches to boost working memory in children who suffer from sickle cell disease.

Youths with sickle cell disease who used hand-held computers to play game-like exercises that get harder as a user’s skill level rises improved their visuospatial working memory (WM). Children with sickle cell disease, however, completed fewer training sessions during an initial study compared with children with other disease-related WM deficits.

A team led by Children’s National Health System clinicians and research scientists attempted to identify novel approaches to boost WM in children who suffer from sickle cell disease. Kids who have this red blood cell disorder inherit abnormal hemoglobin genes from each parent. Rather than slipping through large and small vessels to ferry oxygen throughout the body, their stiff, sickle-shaped red blood cells stick to vessel walls, impeding blood supply and triggering sudden pain. Children with sickle cell disease have more difficulty completing tasks that place demands on one’s WM, the brain function responsible for temporarily remembering information and manipulating that information to facilitate learning and reasoning. As a result, they’re more likely to repeat a grade, require special academic services, and to have difficulty maintaining employment as adults.

Because computerized cognitive training programs have been used with success to boost WM for children with other health conditions, such as childhood cancer, the research team sought to examine the feasibility of using the technique for kids with sickle cell disease. “This small study highlights the challenges and opportunities of implementing a home-based cognitive training intervention with youths who have sickle cell disease,” says Steven J. Hardy, PhD, a pediatric psychologist in the Divisions of Hematology, Oncology, and Blood and Marrow Transplantation at Children’s National. “While a larger, randomized controlled clinical trial is needed to better characterize efficacy, our initial work indicates that Cogmed is acceptable and moderately feasible in this population.”

Children’s National is home to the Sickle Cell Disease (SCD) Program, one of the nation’s largest, most comprehensive pediatric programs that cares for 1,350 patients younger than 21 annually. Over 15 months, the team recruited youths aged 7 to 16 participating in the program who had an intelligence quotient of at least 70 and an absolute or relative memory deficit. Those who lacked access to a tablet computer were loaned an iPad Mini 2 loaded with Cogmed RM, an interactive audiovisual cognitive training program that consists of exercises that get progressively more challenging. A clinical psychologist provided coaching and moral support through weekly telephone calls to review progress and challenges, and to offer tips on how to optimize the youths’ progress.

Six of 12 eligible participants – all girls – completed by finishing at least 20 sessions of the program. The mean number of sessions completed was 15.83, and the kids spent a median of 725 minutes working actively on Cogmed exercises. “Participants who completed Cogmed indicated that they perceived greater levels of social support from teachers,” Hardy and colleagues write in the study, published by Pediatric Blood & Cancer. “[T]here was not a statistical difference in perceived parent support.”

Among those children who completed Cogmed, standard scores increased an average of 5.05 on a measure of visuospatial short-term memory, 19.72 on a measure of verbal WM, 27.53 on a measure of visuospatial short-term memory, and 23.82 on a measure of visuospatial WM. The researchers also observed a normalizing of memory functioning for those who finished Cogmed, as a significant portion of participants scored below the average range before using Cogmed and most scored in the average range or higher on memory tests after finishing the program.

“In this initial feasibility trial, adherence to Cogmed was lower than expected (50 percent completion) compared to adherence rates of other samples of children with medical histories, including patients with symptomatic epilepsy and youth treated for cancer,” Hardy and co-authors write. “Thus, additional modifications may be needed to achieve consistent delivery of the intervention to youth with SCD.”

Related Resources: Research at a Glance

Sharp images key to spotting the earliest signs of compromised pregnancies

Fetuses wiggle. They waggle. Some pirouette within the womb, amniotic fluid easing their spins. Pregnant mothers’ meals and beverages from hours earlier wend their way through their digestive systems. On top of that, mother and offspring may breathe out of sync and their hearts may beat in time to different drummers.

In short, there’s a whole lot of movement going on in the womb.

As anyone trying to capture a photograph with a digital camera knows, sudden movements are the enemy of a sharp image. The challenge is the same for fetal researchers aiming to capture crisp functional magnetic resonance imaging (fMRI) of the developing brains of fetuses who are always on the move.

Over two years, a Children’s National Health System research team led by Wonsang You, a research associate in the Developing Brain Research Laboratory, worked out complex mathematical algorithms to account for independent fetal and placental motions, to erase those noise artifacts, and to validate the accuracy of the technique.

“[M]otion correction is optimized to the experimental paradigm, and it is performed separately in each phase as well as in each region of interest (ROI), recognizing that each phase and organ experiences different types of motion. To obtain the averaged [blood oxygen level-dependent] BOLD signals for each ROI, both misaligned volumes and noisy voxels are automatically detected and excluded, and the missing data are then imputed by statistical estimation based on local polynomial smoothing,” You and colleagues wrote in a technical article published recently by the Journal of Medical Imaging and spotlighted on the journal’s website as a featured article.

To underscore the work’s clinical utility, they analyzed differences in fetal motion by acquiring BOLD fMRI data from eight pregnant women with healthy fetuses and comparing them with eight women whose fetuses had been diagnosed with congenital heart disease (CHD) between 25 to 40 weeks of gestational age. The team focused on changes in oxygenation of the fetal brain and placenta during maternal hyperoxia, an oxygen challenge test during which both groups of pregnant women received 100 percent oxygen via face mask for four to six minutes. Measurements were then taken to determine whether there were differences in how the fetuses and the placentas responded to the oxygen challenge test.

Recognizing compromised fetuses in utero – and understanding the subtle but important ways they deviate from the trajectory of normal fetuses – opens a critical window of opportunity to intervene through nutritional, pharmaceutical, or surgical means – before brain injury is consolidated, says Catherine Limperopoulos, PhD, Director, MRI Research of the Developing Brain at Children’s National, and the paper’s senior author.“

Our goal is to exploit the power of MRI, a non-invasive imaging technique, to detect the earliest signs of the fetus getting into trouble before it runs into serious problems,” Limperopoulos says. “We needed the technical development described in this foundational work to allow us to reliably measure the fMRI BOLD response in the fetal brain and placenta.”

The BOLD signal can be degraded by the independent and collective movements of the mother and fetus. Traditional motion correction makes assumptions, such as treating all moving objects like the fetal brain, which is solid, rigid, and has a high range of motion. The traditional approach also fails to account for such subtleties as the placenta’s low range of motion and its flexing in response to maternal and fetal movements.

The research team employed four-step pre-processing – which included correcting bias magnetic field, correcting for global and local motion, and rejecting outliers – and followed with data imputation, an alphabet soup of letters and Latin symbols that mathematically accounts for objects (placenta and fetal brain) that move independently.“

We showed that the proposed preprocessing pipeline can be effectively employed to characterize fetal motion in healthy controls and CHD fetuses. Our preliminary data suggest that the degree of fetal motion tends to increase during hyperoxia in CHD fetuses (but not significantly). In addition, the motion of the fetal brain in CHD cases showed higher variance during hyperoxia compare[d] to controls,” You and colleagues write. “These observations suggest that the CHD fetus may be more responsive to maternal hyperoxia. However, these pilot data need to be validated on a larger cohort of healthy and high-risk CHD fetuses.”

Related resources: Research at a Glance

Patient-centered family conferences can boost satisfaction with care

Malone Brand Shoot January 2015 CICU Cardio Patient Baby Boy African American Dailen Miles Staff
The medical team typically speaks for nearly three-quarters of the time allotted to family conferences in the pediatric intensive care unit (PICU). Clinicians can transform those one-sided conversations into patient-centered interactions by ensuring that they show empathy, ask questions, and speak from the heart as well as from their clinical experience, according to a cross-sectional study published June 17 by Pediatric Critical Care Medicine.

A research team led by Tessie W. October, MD, MPH, a critical care specialist at Children’s National Health System, sought to clarify the association between the patient-centered nature of physicians’ communication patterns and the degree to which parents were satisfied with decision-making during family conferences in the PICU. In order to dissect the dynamics of those conversations, the team recorded 39 family conferences, which averaged 45 minutes in length. The medical team spoke 73 percent of the time. Physicians contributed 89 percent of the dialogue and spent 79 percent of their time speaking about medically focused topics. Parents’ contribution amounted to 27 percent of the conversation, according to the study, “Parent Satisfaction With Communication is Associated With Physician’s Patient-Centered Communication Patterns During Family Conferences.”

“These conferences cover some of the toughest decisions that families of critically ill children will ever make: Whether to start life support, place a tracheostomy, repeat bone marrow transplantation, or to withdraw life-sustaining interventions,” Dr. October says. “Rather than essential decisions about the child’s care being made in partnership with families, the conferences are akin to monologues with the medical team deciding the pace and content of the conversation.”

A few subtle changes can shift more of the balance of the conversation to the parents and, when clinicians use these skills, parents are more satisfied with the decision-making, she says. Simple changes include maintaining eye contact, smiling when appropriate, and acknowledging the parents’ emotions by saying “I can’t imagine how difficult this must be for you” or “I wish I had better news” ­–  rather than simply informing the parents of the child’s prognosis. When these social niceties are skipped, parents can perceive their medical team to be uncaring, she says. Slowing the pace of the conversation is helpful, as are including open-ended questions and moments of silence, which both tease out opportunities for parents and family members to offer their thoughts.

“There is an art to it,” October says. “From the outset, clinicians can ask about the family’s understanding of their child’s medical condition and follow up with questions about their family’s goals, such as ‘What does a meaningful life look like? Has anyone ever spoken with you about that?’ ”

The parents who were involved in the study completed satisfaction surveys within 24 hours of the family conference. “The median parent satisfaction score was significantly higher (82.5) when the patient-centeredness score was greater than or equal to 0.75, compared to a median satisfaction score of 70.0 when the patient-centeredness score was less than 0.75,” October and co-authors write.

“We do not know the optimal balance of discussing psychosocial elements compared to medical talk, but our results reveal that the amount of psychosocial elements does impact[the degree of parent satisfaction with communication. It is clear that parents want their fears and concerns to be understood and addressed, and they want to feel cared for and about. Making our interactions with parents more patient-centered can likely improve the communication experience for parents and also improve the grieving process should their child not survive their illness,” the authors continue.

In the next phase of research, the team will explore how parents’ perceptions change when additional members of the medical team speak during family conferences. In the current study, case managers and bedside nurses each spoke 2 percent of the time while social workers spoke 7 percent of the time.

Related Resources: Patient centered family conferences can boost satisfaction with pediatric ICU care

Treating injured adolescents at pediatric trauma centers associated with lower mortality

Swanson Russell photo shoot trauma emergency department Brand Photos FY13

As children mature into adolescence, they also transition from being cared for by pediatric healthcare providers to being cared for by health professionals who primarily treat adults. Controversy remains about whether a primarily pediatric or adult treatment location is optimal to meet the needs of injured adolescents. For this reason, the cutoff age for triaging children to pediatric versus adult trauma hospitals varies in different settings. A research team led by Randall S. Burd, MD, PhD, Chief of the Children’s National Health System Division of Trauma and Burn Surgery, found that injured adolescents treated at pediatric trauma centers (PTCs) had a lower mortality rate than injured adolescents treated at adult trauma centers (ATCs) or mixed trauma centers (MTCs), facilities that treat both adults and children, even when controlling for differences in patients.Trauma is a leading cause of death and acquired disability among adolescents. To determine any potential association between the type of trauma center and mortality rates, the research team examined 29,613  records for patients aged 15 to 19 years old drawn from the 2010 National Trauma Data Bank.“Trauma centers dedicated to the treatment of pediatric patients see a different adolescent population than do ATCs and MTCs,” Dr. Burd and colleagues write in an article published June 27 by JAMA Pediatrics. “After controlling for these differences, we observed that adolescent trauma patients have lower overall and in-hospital mortality when treated at PTCs.”

These findings, bolstered by additional research, have the potential to change the approach for triaging injured adolescents, says Dr. Burd, the paper’s senior author. The study findings suggest that commonly used age thresholds of 14 or 15 years might be safely adjusted higher.

Because the data were obtained from a large dataset, making that case will require closer examination – perhaps chart-by-chart analysis for each patient – to tease out nuances that differentiate care adolescents receive at different types of trauma hospitals, Dr. Burd says. “Are there differences in the process of care – or availability of specific resources – that account for the differences in outcome? Or, do the patients treated at each hospital type have differences in their injuries that we have not yet identified?”

Most adolescents (68.9 percent) included in the study were treated at an adult trauma center. In addition to being older, these youths were more likely to be severely injured and more frequently suffered severe injuries to the head, chest, and upper extremities. The most common traumatic injuries seen at adult centers resulted from children being passengers in motor vehicles (32.6 percent). Penetrating injuries from firearms (12 percent) and cutting or piercing (7.1 percent) were more common at adult centers.

Some 1,636 patients (5.5 percent) were treated at a pediatric trauma center, with many being transferred there from another hospital. Adolescents treated at pediatric trauma centers were more likely to be injured by a blunt rather than penetrating mechanism. The most common injuries seen at pediatric centers were injuries from a fall (25.9 percent) or injuries that resulted from being struck (26.1 percent).

“Because adolescents straddle the gap between pediatric and adult medicine, identifying differences in care among PTCs, ATCs, and MTCs will help determine the most appropriate triage strategies or identify practice strategies that can optimize the outcome for patients in this age group,” the authors conclude.

Related resources: Research at a Glance 

Training developing immune systems to prevent wheezing early in life

Stephen Teach does an asthma exam

Extensively engaging stakeholders such as parents, families and local service providers in the actual study design transformed a planned research project into a more patient-centered study.

For the small number of U.S. children who grow up on working farms, activities such as feeding the cows and clearing spent hay from the barn are little changed from a thousand years ago. Through such close contact with dirt and farm animals, rural kids’ immune systems develop more normally and better distinguish common bacteria from household allergens like dust, molds, pets, and pests. Rates of allergy and asthma continue to be lower in children who grow up in those conditions.

By contrast, rates of asthma have spiked among urban and disadvantaged kids, who have far less exposure to dirt and animals early in life. Today, leading pediatric institutions, such as Children’s National Health System, are “awash in emergency department (ED) visits for asthma” with each ED visit associated with 10 to 15 missed school days annually on a population basis, says Stephen J. Teach, MD, MPH, Director and Principal Investigator of IMPACT DC , a care, research, and advocacy program focused on under-resourced and largely minority children with asthma.

A paradigm-shifting multicenter clinical trial aims to reverse that trend by going old school and safely exposing very young infants to the type of immune system training they would have experienced if they grew up closer to the earth.

The five-year study, named “Oral Bacterial Extracts (ORBEX): Primary Prevention of Asthma and Wheezing in Children,” is funded by a $27 million cooperative agreement grant from the National Heart, Lung, and Blood Institute, which is part of the National Institutes of Health. Children’s National, one of eight participating sites across the nation, will enroll an estimated 150 children in the study and will receive at least $2.5 million of that grant.

“It is currently thought by many, including me, that asthma and allergic diseases are a result of disordered development of the immune system very early in life,” says Dr. Teach, who is also Chair of the Department of Pediatrics at George Washington University. The immune system development process begins to unfold in the last few months of pregnancy and continues through infancy, meaning “the die is cast, we think, at a very young age.”

According to the Centers for Disease Control and Prevention, 8.6 percent of children across the nation have asthma, but in the District of Columbia, a disproportionately higher number of children suffer from the respiratory ailment. Once children experience early wheezing, changes begin to occur in the architecture of their lungs, causing a thicker basement membrane, a thickening of the lining of the lungs, and resulting in a heightened tendency for the airways in the lungs to become inflamed and to excrete more mucous. As a result, the children’s poorly trained immune system becomes hyper vigilant, ready to recognize a multitude of things as potentially allergenic.

“We’ve got to do something to change the course of the disease and to make it less common and less severe,” Dr. Teach says.

The study will identify 1,000 babies who range in age from 6 months to 18 months who are the highest risk for asthma, either through family history, being diagnosed with eczema, or both. The infants will receive safe doses of the inactivated bacteria, which is marketed under the name Broncho-Vaxom®. The therapy comes in capsule form, which for two years will be sprinkled into bottles or onto food. The children will be followed to gauge whether infants randomly assigned to receive treatment suffer fewer respiratory symptoms than infants randomly assigned to receive placebo.

“The rationale if we can expose these very young children to the benefits, but not the risks, of early life bacterial exposure, they may reap the benefits of developing a more properly functioning and less allergic immune system,” Dr. Teach says.

He says the Children’s National research team has had “remarkable success” engaging young children and their parents in such long-term studies, losing few to attrition.

“Going for five years will be breaking new ground. But all of our experience suggests that we will succeed if we show the families we care, we stay in touch with them, and we form these therapeutic partnerships by saying: ‘We want to partner with you. We can do this safely with mutual benefit.’ Families will get on board,” he says.

Related resources: Learn more about the clinical trial | Research at a Glance

Drs. DeBiasi and du Plessis

Suspected domestic zika virus infection in Florida underscores the importance of ongoing vigilance

Drs. DeBiasi and du Plessis

Federal health officials continue to investigate the first possible cases of domestic Zika virus transmission in Florida. In light of the growing number of Zika infections, the vast majority of which have been associated with foreign travel, vigilance for additional cases is warranted – particularly as summer heat intensifies and mosquito populations grow. The Centers for Disease Control and Prevention (CDC) now advises that all pregnant women in the continental United States and U.S. territories be evaluated for Zika infection at each prenatal care visit. The CDC also recognizes that Zika-exposed infants will require long-term, multidisciplinary care.

In mid-May, Children’s National Health System Fetal Medicine Institute and Division of Pediatric Infectious Disease announced the formation of a Congenital Zika Virus Program to serve as a dedicated resource for referring clinicians and for pregnant women to receive counseling and science-driven answers about the impact of the Zika virus on pregnancies and newborns. Children’s clinicians have consulted on 30 pregnancies or births with potential Zika virus exposure and/or infection. As of Aug. 31, eight were Zika-positive or probable. One of the pregnancies was the subject of an article published by The New England Journal of Medicine.

”While we’re hopeful there are few local cases, the Congenital Zika Virus Program has been developing emergency response plans in collaboration with local departments of health to prepare for any eventuality,” says Roberta DeBiasi, MD, MS, Chief of the Division of Infectious Disease and Congenital Zika Virus Program co-leader.

Over the years, Children’s National has invested in equipment and highly trained personnel, building world-class expertise in infectious diseases, pediatric neurology, pediatric cardiology, genetics, neurodevelopment, and other specialties. Children’s clinicians are recognized leaders in next-generation imaging techniques, such as fetal MRI, which detects more subtle and earlier indications of impaired brain growth. A variety of divisions work together to offer multidisciplinary support and coordinated care to infants born with special needs. As the nation braces for the possible expansion of Zika virus infection to other states, Children’s National is facilitating the multi-step process of testing blood, urine, and tissue with state health departments, helping to ensure timely and precise information. Children’s National specialists guide Zika-affected pregnancies through the fetal period and are able to oversee and coordinate the care of Zika-affected infants after delivery. Care and clinical support is provided by a multidisciplinary team of pediatric neurologists, ophthalmologists, audiologists, physical and occupational therapists, infectious disease experts, and neurodevelopmental physicians.

The Children’s National multidisciplinary team includes:

  • Adre du Plessis, M.B.Ch.B., Director of the Fetal Medicine Institute, Chief of the Fetal and Transitional Medicine Division, and Congenital Zika Virus Program co-leader;
  • Roberta DeBiasi, M.D., M.S., Chief of the Division of Infectious Disease and Congenital Zika Virus Program co-leader;
  • Cara Biddle, M.D., M.P.H., Medical Director, Children’s Health Center, and a bilingual expert on complex care;
  • Dorothy Bulas, M.D., Radiologist in the Division of Diagnostic Imaging and Radiology;
  • Taeun Chang, M.D., Director, Neonatal Neurology Program in the Division of Neurophysiology, Epilepsy and Critical Care Neurology;
  • Sarah Mulkey, M.D., Ph.D., Fetal-Neonatal Neurologist, Fetal Medicine Institute;
  • Lindsay Pesacreta, M.S., F.N.P.-B.C., Board-Certified Family Nurse Practitioner; and
  • Gilbert Vezina, M.D., attending Radiologist in the Division of Diagnostic Imaging and Radiology and Director of the Neuroradiology Program.

Related Resources: Research at a Glance | Guidelines for Referring Clinicians
[Updated Sept. 13, 2016]

Smart Tissue Autonomous Robot

Supervised autonomous in vivo robotic surgery on soft tissues is feasible

invivo_robotic_sugery

Surgeons and scientists from Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Health System are the first to demonstrate that supervised, autonomous robotic soft tissue surgery on a live subject (in vivo) in an open surgical setting is feasible and outperforms standard clinical techniques in a dynamic clinical environment.

The study, published May 4, 2016 in Science Translational Medicine, reports the results of soft tissue surgeries conducted on both inanimate porcine tissue and living pigs using proprietary robotic surgical technology, Smart Tissue Autonomous Robot (STAR). This technology removes the surgeon’s hands from the procedure and, instead, utilizes the surgeon as a supervisor, with soft tissue suturing autonomously planned and performed by the STAR robotic system.

Soft tissues are the tissues that connect, support, or surround other structures and organs of the body such as tendons, ligaments, fascia, skin, fibrous tissues, fat, synovial membranes, muscles, nerves, and blood vessels. Currently, more than 44.5 million soft tissue surgeries are performed in the United States each year.

“Our results demonstrate the potential for autonomous robots to improve the efficacy, consistency, functional outcome, and accessibility of surgical techniques,” says Peter C.W. Kim, MD, CM, PhD, Vice President and Associate Surgeon-in-Chief, Sheikh Zayed Institute for Pediatric Surgical Innovation. “The intent of this demonstration is not to replace surgeons, but to expand human capacity and capability through enhanced vision, dexterity, and complementary machine intelligence for improved surgical outcomes.”

While robot-assisted surgery (RAS) has increased in adoption in healthcare settings, the execution of soft tissue surgery has remained entirely manual, largely because unpredictable, elastic, and plastic changes in soft tissues occur during surgery, requiring the surgeon to make constant adjustments.

To overcome this challenge, STAR uses a tracking system that integrates near infrared florescent (NIRF) markers and 3D plenoptic vision, which captures light field information to provide images of a scene in three dimensions. This system enables accurate, uninhibited tracking of tissue motion and change throughout the surgical procedure. This tracking is combined with another STAR innovation, an intelligent algorithm that guides the surgical plan and autonomously makes adjustments to the plan in real time as tissue moves and other changes occur.  The STAR system also employs force sensing, submillimeter positioning, and actuated surgical tools. It has a bedside lightweight robot arm extended with an articulated laparoscopic suturing tool for a combined 8 degrees-of-freedom robot.

“Until now, autonomous robot surgery has been limited to applications with rigid anatomy, such as bone cutting, because they are more predictable,” says Axel Krieger, PhD, technical lead for Smart Tools at Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National. “By using novel tissue tracking and applied force measurement, coupled with suture automation software, our robotic system can detect arbitrary tissue motions in real time and automatically adjust.”

To compare the effectiveness of STAR to other available surgical procedures, the study included two different surgeries performed on inanimate porcine tissue (ex vivo), linear suturing, and an end-to-end intestinal anastomosis, which involves connecting the tubular loops of the intestine. The results of each surgery were compared with the same surgical procedure conducted manually by an experienced surgeon, by laparoscopy, and by RAS with the daVinci Surgical System.

Intestinal anastomosis was the surgical procedure conducted on the living subjects (in vivo) in the study.  The Children’s research team conducted four anastomosis surgeries on living pigs using STAR technology, and all subjects survived with no complications. The study compared these results with the same procedure conducted manually by an experienced surgeon using standard surgical tools.

“We chose the complex task of anastomosis as proof of concept because this soft tissue surgery is performed over one million times in the U.S. annually,” says Dr. Kim.

All surgeries were compared based on the metrics of anastomosis including the consistency of suturing based on average suture spacing, the pressure at which the anastomosis leaked, the number of mistakes that required removing the needle from the tissue, completion time, and lumen reduction, which measures any constriction in the size of the tubular opening.

The comparison showed that supervised autonomous robotic procedures using STAR proved superior to surgery performed by experienced surgeons and RAS techniques, whether on static porcine tissues or on living specimens, in areas such as consistent suture spacing, which helps to promote healing, and in withstanding higher leak pressures, as leakage can be a significant complication from anastomosis surgery. Mistakes requiring needle removal were minimal and lumen reduction for the STAR surgeries was within the acceptable range.

In the comparison using living subjects, the manual control surgery took less time, 8 minutes vs. 35 minutes for the fastest STAR procedure, however researchers noted that the duration of the STAR surgery was comparable to the average for clinical laparoscopic anastomosis, which ranges from 30 minutes to 90 minutes, depending on complexity of the procedure.

Dr. Kim says that since supervised, autonomous robotic surgery for soft tissue procedures has been proven effective, a next step in the development cycle would be further miniaturization of tools and improved sensors to allow for wider use of the STAR system.

He adds that, with the right partner, some or all of the technology can be brought into the clinical space and bedside within the next two years.

Catherine Limperopoulos

Connection between abnormal placenta and impaired growth of fetuses discovered

CLimperopoulous

A team of researchers used 3-D volumetric magnetic resonance imaging (MRI) in an innovative study that reported that when the placenta fails to grow adequately in a fetus with congenital heart disease (CHD), it contributes to impaired fetal growth and premature birth. Fetal CHD involves an abnormality of the heart and is associated with increased risk for neurodevelopmental morbidity.Until now, CHD in the fetus and its relationship to placental function has been unknown. But the advanced fetal imaging study has shown for the first time that abnormal growth in the fetus with CHD relates to impaired placental growth over the third trimester of pregnancy. Catherine Limperopoulos, PhD, Director of Children’s National Developing Brain Research Laboratory in the Division of Diagnostic Imaging and Radiology, is the senior author of the study published in the September 2015 issue of the journal Placenta, “3-D Volumetric MRI Evaluation of the Placenta in Fetuses With Complex Heart Disease.”

Specifically, the decreased 3-D volumetric MRI measurements of pregnant women reported in this study suggest placental insufficiency related to CHD. The placenta nourishes and maintains the fetus, through the delivery of food and oxygen. Its volume and weight can determine fetal growth and birth weight.

Abnormality in placental development may contribute to significant morbidity in this high risk-population. This study shows impaired placental growth in CHD fetuses is associated with the length of the pregnancy and weight at birth. Nearly 1 in every 100 babies is born in the United States with a congenital heart defect.

Developing the capacity to examine the placenta non-invasively using advanced MRI is needed to identify early markers of impaired placental structure and function in the high-risk pregnancy. This is a critical first step towards developing strategies for improved fetal monitoring and management, Dr. Limperopoulos says.

“We are trying to develop the earliest and most reliable indicators of placental health and disease in high-risk pregnancies. Our goal is to bring these early biomarkers into clinical practice and improve our ability to identify placental dysfunction,” Dr. Limperopoulos says. “If we can develop the capacity to reliably identify when things begin to veer off course, we then have a window of opportunity to develop therapies to restore function.”

The study used in-vivo 3-D MRI studies and explored placental development and its relationship to neonatal outcomes by comparing placental volumetric growth in healthy pregnancies and pregnancies complicated by CHD.

While mortality rates continue to decrease steadily in newborns diagnosed with complex CHD, long-term neurodevelopmental impairments are recognized with increasing frequency in surviving infants, Dr. Limperopoulos says.

“Our goal is to better support the developing fetus with CHD. We can best accomplish this if we develop technology that can allow us to safely and effectively monitor the fetal-placental unit as a whole throughout pregnancy,” Dr. Limperopoulos says.

“This is the new frontier, not only to ensure survival but to safeguard the fetus and to ensure the best possible quality of life,” she says.