A new study is shaking up the standard practice of using heparin for anticoagulation in ECMO patients.
Anticoagulation therapy during extracorporeal membrane oxygenation (ECMO) has long relied on heparin, but a groundbreaking multicenter study co-authored by Jonathan Byrnes, M.D., medical director of cardiac ECMO at Children’s of Alabama, shows the benefits of replacing heparin with bivalirudin.
Bivalirudin isn’t a new drug, but its rise in use in pediatric ECMO stems from successes in pediatric ventricular assist devices (VADs). With earlier stroke rates as high as 25–30% on VADs using heparin, the transition to bivalirudin brought about a remarkable reduction, dropping the stroke rate to 5–8%. This significant improvement in neurological outcomes sparked interest in applying bivalirudin more extensively in ECMO settings.
The study, spearheaded by Mohammed Hamzah, M.D., of Cleveland Clinic Children’s Hospital, diverged from past practices of individual center decision-making. Instead, six medical centers collaborated, aiming to analyze outcomes through a case-matched lens, minimizing variability across patients requiring ECMO. The study’s cooperative nature across multiple centers necessitated remarkable coordination.
One of the study’s key findings, according to Byrnes, is that patients on bivalirudin exhibited lower mortality rates than those on heparin. Intriguingly, despite higher PTT levels in bivalirudin patients, they experienced less bleeding and fewer thrombotic incidents in the ECMO circuit. This hints at bivalirudin’s inherent benefits, possibly enhancing biocompatibility. “It seems that there’s something intrinsic to bivalirudin that allowed for better biocompatibility of the patient’s blood to the ECMO circuit,” Byrnes said.
The impact of this study extends far beyond the academic realm. At Children’s of Alabama, the findings suggest potential benefits such as reduced bleeding, fewer transfusions and lower mortality rates for ECMO-supported patients. However, as Byrnes noted, the retrospective nature of the study necessitates a randomized controlled trial to solidify these outcomes and effectively influence the standard of care.
Plans for a prospective trial are underway, aiming for a randomized approach coordinated through the Extracorporeal Life Support Organization (ELSO). This prospective study could validate the retrospective findings, potentially reshaping protocols for anticoagulation during ECMO.
Despite the excitement surrounding the study’s outcomes, Byrnes emphasized the need for caution. While retrospective data suggests bivalirudin’s superiority, a randomized trial is crucial to establish this definitively. Prospective data will unveil any center-specific confounders that might have influenced the study’s retrospective findings.
Byrnes underscored the significance of these findings and the hope for future randomized controlled trials. The study’s retrospective nature lays a robust foundation, but prospective data will offer irrefutable evidence to guide clinical practice, leading to a potential paradigm shift in anticoagulation therapy that may result in improved patient care and outcomes.
Many patients skip follow-up visits after kidney stone surgery. A QI project aims to change that.
The incidence and prevalence of pediatric kidney stones have been rising rapidly in the United States, particularly in the South. A Children’s of Alabama study found an increase of 84.4% over 15 years, with an average increase of 16.1% every three years.1 Recurrence rates are also high, with about half of children experiencing a recurrence within five years.2
The economic costs are significant, noted Children’s of Alabama pediatric urologist Carmen Tong, D.O. One study found overall costs for 8,498 patients of $117.1 million.3 Medical costs, however, don’t take into consideration the intangible human capital loss such as lost workdays for caregivers and extra childcare costs, Tong said.
Carmen Tong, D.O.
Some of this cost is due to high recurrence rates, she said, but also to issues relating to pain and infections after intervention.
Current guidelines call for follow-up imaging four to six weeks after surgery to confirm all stones are gone and discuss preventive measures. However, Tong’s review of 130 patient charts found that nearly half didn’t return for that follow-up visit. Those findings echo other studies in larger populations.4
That prompted a new quality improvement project to identify socioeconomic factors that could predict adherence with postoperative follow-up, she said. “We’ve noted that parents come back with their patients because of pain, poor pain control or issues with infection,” but not for routine follow-up if the child is doing well, Tong said.
The project will examine barriers and boost resources and education for families. “Enhanced communication can hopefully limit complications like inadequate pain control and infections, which currently prompt some visits,” Tong said. Her team will partner with Nationwide Children’s Hospital in Columbus, Ohio, to examine the influence of a multi-institutional, incentivized study on follow-up adherence versus no incentive.
“We want to improve our communication and education to this population so they’re better equipped to provide the follow-up care their child needs,” she said.
[1] Zhang SY, Collingwood JD, Fujihashi A, He K, Oliver LA, Dangle P. Incidence of Emergency Department Presentations of Symptomatic Stone Disease in Pediatric Patients: A Southeastern Study. Cureus. 2022;14(11):e30979. Published 2022 Nov 1. doi:10.7759/cureus.30979 ↩︎
[1] Tasian GE, Kabarriti AE, Kalmus A, Furth SL. Kidney Stone Recurrence among Children and Adolescents. J Urol. 2017;197(1):246-252 ↩︎
[1] Sturgis MR, Becerra AZ, Khusid JA, et al. The monetary costs of pediatric upper urinary tract stone disease: Analysis in a contemporary United States cohort. J Pediatr Urol. 2022;18(3):311.e1-311.e8. doi:https://doi.org/10.1016/j.jpurol.2022.02.019 [1] Ellison JS, Merguerian PA, Fu BC, et al. Postoperative Imaging Patterns of Pediatric Nephrolithiasis: Opportunities for Improvement. J Urol. 2019;201(4):794-801. doi:10.1016/j.juro.2018.10.002 ↩︎
Ellison JS, Merguerian PA, Fu BC, et al. Postoperative Imaging Patterns of Pediatric Nephrolithiasis: Opportunities for Improvement. J Urol. 2019;201(4):794-801. doi:10.1016/j.juro.2018.10.002 ↩︎
Children’s of Alabama residents practice using the urology team’s surgical robot by playing games like Hasbro’s Perfection.
When the Children’s of Alabama urology department acquired its first Da Vinci surgical robot in January 2023, Carmen Tong, D.O., pediatric urologist at Children’s of Alabama, developed a training curriculum that brings in classic children’s games to help residents develop their skills with the new technology.
“There’s a movement in urology to ‘gamify’ the robot,” Tong said. “Such training is vital to the safety of our patients.”
Surgeons are very competitive, she said. “Gamification taps into our competitive side and allows us to push and encourage each other to improve. It helps with camaraderie.”
Indeed, studies show that gamification, whether with actual games like Tong is using or embedding competitions and rewards into skill development, enhances resident engagement.[i]
The curriculum is not, however, all fun and games. Residents and any interested ancillary medical staff learn the robot from the inside out. “The surgeon who’s using that technology should be the most knowledgeable person of that technology,” Tong said. “We have to be prepared to troubleshoot to figure out what’s happening if the components of the robot are not responding the way we want.”
The residents complete online modules and practice surgeries via a video game-type simulator. Then, every two months, Tong brings in the actual games, and the residents compete against each other using the robotic arm in place of their own hands. For instance, they used the Hasbro Perfection game, designed for kids ages 5 and up, to work on wrist articulation. The fast-paced puzzle involves fitting shapes into their matching holes before time is up and the pieces pop out.
“We’re sitting at the robot using real instruments,” Tong said. “They may have perfected those simulator games. But when you’re actually holding the needle with the robotic instrument, it’s very different.” Ultimately, she said, “when they’re ready to perform those skills on an actual patient, it’s not their first time.”
Even though the gaming sessions aren’t mandatory, “almost all residents participate.” That, she said, “says a lot about the program’s success.”
The residents aren’t the only ones playing with ‘Tater Bot,’ which the surgical robot was named following a hospital-wide naming contest. Two patients, who underwent surgery with the device, have also had a chance to play the games. Tong brought in some hospital administrators to play with the new equipment, as well.
The two most challenging skills to learn are spatial awareness and manipulating tissue so it doesn’t tear. “One of the harder things to grasp with the robot is tactile feedback,” Tong said. “You just don’t know how hard you’re pulling because it isn’t the same as having your hand in there. But with practice, you learn how to be gentler. But that takes a really long time to master.”
Most residents won’t complete their first robotic surgery on a real patient until the end of the five-year program. “They have to prove that they understand the advantages and the shortcomings of the robot in order to be a safe and competent surgeon,” Tong said. “It’s essentially practice, practice, practice.”
[i] Nakamoto K, Jones DB, Adra SW. Gamification of robotic simulation to train general surgery residents. Surg Endosc. 2023 Apr;37(4):3136-3144. doi: 10.1007/s00464-022-09520-3. Epub 2022 Aug 10. PMID: 35947198.
Dr. Isabel Virella-Lowell and the pulmonology team at Children’s of Alabama are working on two clinical trials to help CF patients.
The evolution of cystic fibrosis (CF) treatment is considered one of the major success stories in medicine, with average life expectancy for patients skyrocketing from early teens in the 1970s to well over 50 years today. But Children’s of Alabama specialists continue dogged efforts to help the 5% of CF patients who don’t qualify for or respond to groundbreaking disease-modulating drugs—which Children’s faculty helped develop and test—that have transformed CF treatment over recent years.
Co-directed by Isabel Virella-Lowell, M.D., and George “Marty” Solomon, M.D., the University of Alabama at Birmingham (UAB) Cystic Fibrosis Therapeutics Development Center—a joint pediatric and adult endeavor—boasts more than 25 years of prominence in CF research. Nationally recognized as one of the top centers of its kind, it’s one of only 13 national resource centers for the more than 90 clinical trial centers that comprise the CF Clinical Trials Network.
Gene mutations in an epithelial membrane protein called CFTR trigger chloride transport defects that drive CF symptoms. Much-heralded disease-modulating drugs to target those defects—including Trikafta, a triple combination therapy approved in 2019 to treat patients with the most common CF mutation—have greatly improved both health and quality of life for the vast majority of these patients, Virella-Lowell said.
But the research team wants all CF patients—about 30,000 in the United States and 70,000 worldwide—to have those same advantages.
“About 5% of patients don’t have a life-changing medication,” Virella-Lowell explained. “The answer for them will be introducing a corrected gene or fixing the CFTR gene with gene editing techniques so the epithelia will produce its own normal chloride channels. If genetic therapies are successful, they could be extended to the entire CF population. Ultimately, the goal is to develop a genetic therapy that cures cystic fibrosis.”
Two of the team’s current clinical trials are focusing on these potential approaches. One is an mRNA-CFTR therapy, while the other is an adeno-associated virus (AAV)-based CFTR gene therapy. Both are phase 1 trials to determine safety and potential side effects. Other genetic therapy trials are in the pipeline as well.
With this research, the UAB CF Therapeutics Development Center is again setting itself apart in the region. It’s one of only four centers in the Southeast conducting the mRNA genetic therapy trial and one of only three performing the AAV gene therapy trial.
Spina bifida is the most frequently occurring permanently disabling birth defect to affect the nervous system.
Jeffrey Blount, M.D., MPH, knows the struggles of patients with spina bifida (SB). He and his colleagues in the Division of Pediatric Neurosurgery at Children’s of Alabama and the University of Alabama at Birmingham (UAB) have seen them firsthand—hydrocephalus, lower extremity paralysis, sleep apnea, pressure sores, variable incontinence, and the frequent need for multiple surgeries. Other doctors providing SB care see urologic, musculoskeletal, orthotic and ambulatory problems. A few years ago, the desire to address these issues led Blount to a big idea—one that would help not only his patients, but others around the world. In 2019, he co-founded the Global Alliance for the Prevention of Spina Bifida, or GAPSBiF, an organization dedicated to increasing awareness and advocating for the prevention of SB through large-scale food fortification with folic acid (FA). It’s already affecting change.
Blount is the medical director of the Pediatric Spina Bifida Clinic at Children’s of Alabama—one of the largest clinics of its kind in North America, following about 450 children. The medical professionals in the clinic work with those at the Adult Spina Bifida Clinic at UAB, which follows about 250 adults. In founding GAPSBiF, Blount partnered with Gail Rosseau, M.D., an international leader in global neurosurgery; Adrian Caceres, M.D., a Costa Rican neurosurgeon who accomplished widespread fortification of FA in Costa Rica; and Colombian neurosurgeon Kemel A. Ghotme, M.D., Ph.D., who had just completed a Ph.D. in Global Health Policy with a focus on FA fortification. One of the GAPSBiF’s major strategies for preventing SB was working with other neurosurgical and nutrition directed organizations in putting together a resolution that called upon all World Health Assembly (WHA) member states to embrace micronutrient fortification including FA to prevent SB. Resolution 76.19 was introduced by the Colombian government and 37 other member states and went through a rigorous process of vetting. In May, the WHA adopted it.
“This has real potential to favorably and fundamentally impact the global prevalence of SB and other micronutrient dependent diseases,” Blount said. “It is an essential step toward overcoming the stalled progress on the prevention of spina bifida.”
Spina bifida and folic acid
SB is the most frequently occurring permanently disabling birth defect to affect the nervous system. It results from the spine’s failure to close properly during the first month of pregnancy. The cause of SB is not fully understood, but it is thought to be associated with both genetic and environmental factors. The most important environmental factor is maternal intake of dietary FA, a B vitamin that is critically important in development and has long been known to reduce the risk of neural tube defects (NTDs), such as SB.
Nutritional shortage of FA in women of childbearing age is the most important contributor to SB prevalence worldwide. Many women supplement FA in their diet by taking 400 micrograms of FA while pregnant. But, in some cases, that’s not soon enough. “This problem of spina bifida occurs so early on in development that it has already occurred before most women even realize they’re pregnant,” Blount said. “So, it’s not like they can realize they’re pregnant, change their nutritional strategy and put up an effective barrier for this problem. Once they realize they’re pregnant, if they have the problem, it’s already occurred.” Fortifying widely consumed foods such as corn, grain or rice is more effective, which is why GAPSBiF works so hard to promote this strategy.
Evidence that fortification helps
In the U.S., mandatory fortification of enriched cereal grain products with FA was authorized in 1996 and fully implemented in 1998. Here, NTDs, including SB, affect approximately seven out of every 10,000 births. The rates in other regions that fortify are similar. In regions that don’t fortify, NTDs affect up to 150 births per 10,000.
But some countries—even advanced Western European nations—still are not practicing fortification, and, in many cases, are focused more on detection. But that approach can be problematic, Blount says. “Some places are very aggressive at terminating those pregnancies, which of course is a very difficult, very challenging, whole approach to problems. But it’s surprisingly widespread.”
GAPSBiF’s approach is centered around prevention. “Let’s keep these little children from getting this terribly difficult disease,” Blount said, “because it’s lifelong.”
The role of GAPSBiF
When Blount and his colleagues were forming GAPSBiF, they spoke with neurosurgeons from around the world. Even in North America, where fortification is already commonplace, SB takes an exhausting toll on patients, families, the health care system and the neurosurgical infrastructure. In many other countries, it’s much worse—due not only to the lack of fortification, but also because there are far fewer neurosurgeons per person. “A big part of their life and their world is taken up caring for these children,” Blount said. “And it prevents them from being able to do other things, such as taking care of people with strokes, taking care of people with trauma, things like that. So, it overloads an already challenged workforce.
“We saw this, we came together as a group, and we said, ‘Neurosurgery sees this. Neurosurgery knows this disease. We have a front-row seat to all these problems. So, why don’t we try to organize in such a way that we work with other agencies to try and attain this goal of universal fortification?’ ” Blount said.
“We know that if we can get folic acid into population food supplies, that up to 90% [of the SB cases worldwide] can be profoundly reduced,” Blount said. “Right now, the best studies suggest that we are collectively preventing less than one quarter of the global burden of SB.”
Fortification is not perfect, though. Blount emphasizes that while it can markedly reduce the prevalence rate of SB, it cannot completely eliminate the disease. That’s why he says that women and families who live in regions that fortify should not blame themselves for their child’s SB due to insufficient FA intake. “No woman should ever say to herself, ‘If only I had taken more folic acid, my child would not be affected,’ ” he said. Regulations for mandatory fortification of wheat flour with FA are currently in place in 60 countries, although in many cases, these regulations have not been implemented. Moving forward, Blount and his colleagues with GAPSBiF will remain active and invested in monitoring the resolution’s progress and working one-on-one with countries, guiding them in their national and regional implementation plans.
New XR technology is enabling Children’s of Alabama orthopedic specialists to evaluate injuries more effectively.
Children’s of Alabama has new XR technology in its sports medicine clinic, and orthopedic specialist Kevin Williams, M.D., says it’s a game-changer, enabling specialists to quickly determine the best treatments to get young patients back to their chosen game.
About 5,000 children and adolescents visit the clinic each year—some as repeat patients—seeking help for injuries and congenital bone malformations that include strains and sprains, fractures, torn ligaments and more. Until recently, decades-old X-ray equipment challenged clinicians’ ability to assess and treat these common musculoskeletal problems.
The new XR equipment, which is useful in about 75% of pediatric cases, includes an easily positioned moveable arm with a 135-degree range. The equipment has larger plates that can capture wider images of patients’ bones and soft tissue while “taking into account features of the joints above and below, allowing more comprehensive images while using less radiation,” Williams said.
“There’s also a dynamic mode that allows us to take live, fluoroscopic images or continuous X-ray to evaluate a bone or joint dynamically,” he explained. “This is crucial when we’re trying to inject a joint or aspirate it to get fluid out. The whole system is smaller and more modern, which improves ease of use dramatically.”
Children with ankle injuries have perhaps benefited most from the XR equipment so far, Williams said. “Sometimes, to avoid the need for CT or MRI images, we can use X-ray to determine which ligaments are loose and potentially need to be repaired or reconstructed around the ankle,” he said.
The system’s longer plates also help Williams and his colleagues evaluate leg alignment in patients who seek care for rotational injuries, congenital knock knees or bowed legs. This assessment can dictate if a patient needs bracing, physical therapy or even surgery in which bones may need to be broken and put back into place to align them better for the future and to prevent degenerative problems.
“The XR equipment has been incredibly helpful in terms of allowing us to make appropriate treatment decisions, and it’s much easier to use,” he said. “It speeds up our ability to get patients into the clinic and get an X-ray that’s more valuable to us while decreasing clinic wait times. It really affects almost every patient who comes in needing an X-ray, so it makes us more effective in treating pediatric sports patients.”
Children’s of Alabama pediatric neurologists Dr. Amitha Ananth (left) and Dr. Alan Percy
In March, the U.S. Food and Drug Administration approved the first treatment for Rett syndrome, a rare neurological disease. Considered a major breakthrough, the new drug, called trofinetide, or Daybue, may never have made it to market without the groundbreaking work of Children’s of Alabama pediatric neurologist Alan Percy, M.D.
Percy is one of the leading Rett syndrome experts in the world. He diagnosed the first patient with the disease in the U.S. and led a multicenter, National Institutes of Health-funded study on its natural history. He now co-leads, with Amitha Ananth, M.D., the Children’s of Alabama/University of Alabama at Birmingham (UAB) Child Neurology Rett Syndrome Clinic, one of the largest in the country and one of just 15 centers of excellence in Rett syndrome in the country.
“The availability of this medication is a game-changer in our efforts to treat this disorder directly, rather than only treating the specific problems that may arise,” Percy said. “It is remarkable that this treatment emerged less than 40 years after Rett syndrome first became known throughout the world.”
Rett syndrome affects about one in 10,000 babies, nearly all female. Infants with the condition develop normally until about 18 months of age, when they start missing developmental milestones and even regressing in some areas. The most classic feature, according to Ananth, a pediatric neurologist at Children’s, is loss of ability to use their hands in a meaningful way. Instead, they make repetitive, purposeless movements like handwringing, squeezing, clapping, tapping or rubbing. They also can’t communicate verbally.
Ananth has begun prescribing the new treatment to her patients. Prior to its approval, physicians prescribed physical, speech and occupational therapy; medications to treat symptoms like seizures and anxiety; and monitored growth and nutrition. “But there are a lot of aspects of this condition for which we really don’t have great drug treatment,” Ananth said. For instance, many patients with the disease will hold their breath or breathe very rapidly. “That can be quite disruptive to their daily life, but we don’t have great tools to deal with it.”
The Department of Defense initially developed trofinetide to treat traumatic brain injury. It’s a novel synthetic version of a tripeptide within the insulin-like growth factor 1 molecule (IGF-1). People with Rett syndrome have altered levels of IGF-1. Data suggests trofinetide helps brain neurons grow and communicate, while potentially reducing inflammation in the brain.
Children’s and UAB hosted clinical trials for the drug which involved 187 female patients with Rett syndrome ages 5 to 20. Those who received the drug demonstrated significant improvements on caregiver and physician assessments compared to those who received a placebo.
“To actually see a statistically significant difference between the two groups in just 12 weeks is pretty remarkable,” Ananth said. However, she stressed, “this isn’t a cure. But it is different from other medications we’ve been using because it targets the overall well-being of the person as opposed to specific symptoms.”
Anecdotally, Ananth has heard from parents of patients who received the drug that their daughters are more alert and engaged, both of which are important to the success of the various therapies the girls receive. For instance, some patients can be taught to use eye-gaze communication devices since most are nonverbal and can’t use their hands to communicate. “Parents said their daughters who received the drug were using [the devices] better,” she said. One girl who, prior to the trial, spoke only two or three words has now expanded her vocabulary exponentially, Ananth said.
The drug is a liquid administered by mouth or through a gastrostomy tube. The major side effects are vomiting and diarrhea, although clinicians are finding ways to reduce their severity and better manage them.
Another clinical trial is testing the drug in children ages 2 to 5. In addition, two companies have submitted applications to the FDA to start gene therapy trials, Ananth said, and one woman in Canada has received the first such treatment. Other investigational therapies are also under way. “We may very quickly move from an era with no treatments to one with multiple treatments and combination therapies,” she said. “It’s very exciting.”
Dr. Michael Lopez is a co-investigator of a clinical trial involving a new drug for spinal muscular atrophy.
A new drug is in late-stage clinical trials at Children’s of Alabama for spinal muscular atrophy (SMA), a rare genetic disease marked by progressive muscle deterioration and atrophy. The drug, apitegromab, has a different mechanism of action than other SMA treatments and is being studied in patients already taking others.
Apitegromab is a human monoclonal antibody that targets the myostatin pathway, which affects muscle cell mass. “The thought is that if you can inhibit this pathway, then you could increase the muscle cell mass,” said Michael Lopez, M.D., Ph.D., co-investigator with Han Phan, M.D., at Children’s. Numerous animal studies show that inhibiting the myostatin pathway increases muscle mass, while overactivation reduces muscle mass.
Apitegromab binds to the precursor (pro/latent) myostatin, preventing its conversion into the active, mature form of the protein. This prevents the muscle cells from receiving the signals to reduce their mass. Because it works differently from the gene-based therapies already available, it’s being investigated as an adjunctive therapy, ideally providing another avenue to building muscle and reversing the weakness and atrophy SMA patients experience. “Muscle is regenerative; it can repair and renew itself,” Lopez said.
Apitegromab is the latest encouraging investigational drug in SMA treatment. In 2016, the FDA approved the first disease-modifying treatment for SMA, nusinersen, which works by increasing the amount of spinal motor neuron (SMN) protein produced by the SMN2 gene. SMA patients have nonfunctional SMN1 genes but several copies of SMN2 genes.
Since then, two other treatments, the gene therapy onasemnogene abeparvovec—which is administered just once to those less than 2 years of age—and the oral therapy, risdiplam—which also alters how effectively the SMN2 gene makes the SMN protein—have been approved.
In the latest clinical trial, called SAPPHIRE, participants must already be taking nusinersen or risdiplam. The trial will evaluate the drug in patients ages 2 to 12 who have SMA type 2 or 3 and can no longer walk. They will be randomized to receive one of two doses of apitegromab or placebo by IV infusion every 4 weeks for a year. Children’s is one of several participating centers in the U.S.
Previously, a phase 2 trial called TOPAZ showed improved motor function, even in patients who couldn’t walk. “The preliminary data was encouraging, but additional study is required,” Lopez said.
The progress that’s been made in SMA in the last few years, which Lopez called “revolutionary and game changing,” would not have been possible without the support of the families enrolling in clinical trials for the currently approved drugs, he said. “And they didn’t know if there would be a benefit, or even if they were in the investigational arm or placebo arm.” He also praised the Muscular Dystrophy Association Clinic at Children’s for the “superb care provided.”
“Every day, I’m in awe of the progress that has been made in treating this disease,” Lopez said. “We have gone from not having any treatment options at all and watching patients succumb to the disease to knowing that every patient now has a different life ahead of them—something that wasn’t imaginable when I started med school.”
Children’s of Alabama researchers are using an NIH grant to study the link between childhood adversity and adult heart disease.
Children’s of Alabama pediatric nephrologist Michael Seifert, M.D., and cardiorenal physiologist Jennifer Pollock, Ph.D., have received a five-year, National Institutes of Health-funded grant to explore the link between stressful childhood experiences and increased risk for cardiovascular disease in adulthood.
“We’re trying to study how exposure to early life stress (ELS) starts to have an effect in childhood on your cardiovascular system,” Seifert said. ELS includes adverse experiences such as physical and emotional abuse or neglect before age 18.
Studies over the last 20 years have linked ELS to adult-onset heart disease and other poor health outcomes like diabetes, mental illness, cancer and high-risk health behaviors. “But despite that, we still know relatively little about the mechanisms connecting the two,” Seifert said.
Seifert and Pollock will test their central hypothesis: ELS causes immune cell activation and inflammation, leading to vascular dysfunction and increasing the risk for hypertension and cardiovascular disease (CVD) later in life.
The investigators will follow a group of 300 adolescents from racially diverse backgrounds to identify critical clinical features and molecular pathways in ELS-associated CVD risk. Early research shows that this population has increased vascular stiffness and ambulatory diastolic blood pressure as well as pro-inflammatory metabolite and gene methylation patterns in plasma and circulating monocytes, respectively.
Seifert and Pollock will use comprehensive profiling to measure vascular stiffness and blood pressure and analyze the metabolome and epigenome—chemical signatures in blood and genes. The goal is to identify inflammatory and molecular pathways linked to cardiovascular changes. The grant also includes two basic science studies that will further inform the clinical trial and a similar study in young adults who had early-life stress exposure.
While it might seem counterintuitive to have nephrology specialists working on a cardiovascular health study, the two are closely linked. “We expect the same things increasing cardiovascular risk probably also increase chronic kidney disease risk,” Seifert said. “There is a lot of cross-talk between the cardiovascular system and the kidneys.” Findings may reveal new therapeutic targets. “This study has important translational potential,” Seifert said. “If we identify something in adolescence that’s driving this, maybe we can mitigate some effects of early-life stress.”
A baby in a Neonatal Intensive Care Unit (Stock photo)
A new effort led by Children’s of Alabama pediatric nephrologist Lindsey Gordon, D.O., is taking aim at fluid overload and its harmful offshoots—including acute kidney injury, prolonged ventilation and hospital stays—in hopes of smoothing the path for infants in the NICU toward a healthier future. The initiative, dubbed CAN-U-P-LOTS, encapsulates a 10-step clinical practice bundle that will be tested over the coming year in collaboration with Children’s NICU clinicians.
Babies in the NICU face many grave health challenges, not least of which is fluid overload from IV medications and nutrition intended to keep them alive and help them thrive.
“New evidence shows how fluid overload in these neonates can cause a lot of problems in the long run, and many times, this can lead to a poor outcome,” Gordon, a third year fellow at Children’s and the University of Alabama at Birmingham (UAB), explained. “We’re trying to recognize the problem early to prevent some of these negative outcomes.”
Elements of the CAN-U-P-LOTS practice bundle include:
C: Evaluating the cause of fluid overload
A: Assessing albumin level and replenishing as needed
N: Limiting nephrotoxic medications that can hurt the kidneys
U: Assessing and treating high levels of uric acid and using dialysis for ultra-filtration to remove extra fluid
P: Perfusion to the kidneys by increasing blood pressure to ensure adequate blood flow
L: Lasix stress test and attempting diuretic use to assess if the kidneys respond
O: Monitoring urine output/obstruction carefully and considering placing a Foley catheter or doing a renal ultrasound to ensure no blockage
T: Monitoring total fluid intake with an eye toward reducing fluid amounts without sacrificing nutrition
S: Considering steroid use if a patient is on several vasopressors to further support blood pressure
Some NICU neonates have risk factors that confer a high risk for fluid imbalance, including patients:
with sepsis or acute kidney injury
receiving multiple antibiotics
being prepared for major surgery
requiring blood pressure support with multiple medications
“Preliminary data suggest that the vast majority of neonates admitted to the Children’s of Alabama NICU meet the criteria at least once for fluid overload problems,” Gordon said.
The CAN-U-P-LOTS effort “will produce valuable data that will help us understand whether and how this practice bundle can be implemented on a widespread basis,” said David Askenazi, M.D., director of the Children’s Pediatric and Infant Center for Acute Nephrology (PICAN).
“The idea started with a collaborative approach to help standardize care of these children and educate providers in an effort to equip the NICU team with these systematic tools, so babies don’t ever have to develop fluid overload—the soggy lungs or wet heart that will keep them sicker longer,” Askenazi said. “It takes a village because a project like this takes multiple people, conversations and opportunities to learn from one another.”
“Our hunch is it’s going to work,” he added. “If we can show clinical improvements in these vulnerable babies, we can communicate this to our colleagues to help babies around the country and world. We’re giving them 10 things to think about that can help them maximize medical management before these babies need dialysis.”
