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Little patients, big medicine

Special Report

Little patients, big medicine

Getting serious about helping without hurting

In a small dressing room at Lucile Packard Children’s Hospital, 13-year-old Aria Chimalamarri is following a familiar routine.

She changes from her jeans and sweater to a hospital gown, then carefully removes the jewelry she made herself: delicate beaded earrings and a brightly colored bracelet, one of many she has designed to hold the MedicAlert tag that warns about her epilepsy. Her wire-rimmed glasses come off last. Aria is headed for the hospital’s magnetic resonance imaging scanner, where she’ll spend the next hour lying motionless in a noisy, claustrophobic tube so a radiologist can peer into her brain.

“My biggest worry is, what if I have a seizure in the scanner?” Aria says.

Aria’s regular journeys to the radiology department — she’s had 15 to 20 MRI scans since her 2001 epilepsy diagnosis — are emblematic of the paradoxes of pediatric medicine. Kids like Aria now receive better health care than ever before, yet this care still entails discomforts and dangers that would tax even a mature individual.

Today’s pediatric physician-scientists, at Packard Children’s and elsewhere, are working to unravel this conundrum. No longer content to jerry-rig adult treatments and medical devices for small patients, they’re turning to collaborators in disciplines from stem cell research to electrical engineering to devise treatments tailor-made for children. Drawing on disparate branches of science is allowing them to invent new ways around the collateral damage that complicates pediatric care. It’s a renaissance of the core concept of medical ethics: First, do no harm.

So pediatric hospitals and physicians are looking at game changers for young patients. In a research push that has been gradually gaining steam since the early days of pediatric laparoscopic surgery in the mid-1990s, pediatricians are asking how to keep children safer and more comfortable. Their efforts focus on every stage of treatment from the hours a patient spends in the hospital for a test or an operation to the years he lives with a surgical scar or transplanted organ.

Making MRIs less scary

Before every MRI procedure, the radiology nurses reassure Aria that if she feels a seizure coming on, she should call out to them — despite the noisy bangs of the machine, they can hear her, stop the scanner and get her out. Aria has decided to accept this reassurance and adopts relaxation techniques like listening to music in the scanner. (Rhianna is a favorite.)

It’s not an ideal solution, but the alternative seems worse. Many children in Aria’s shoes undergo general anesthesia before each MRI.

“About 50 percent of our cases are being done under anesthesia,” says Packard Children’s pediatric radiologist Shreyas Vasanawala, MD, PhD. “That takes a procedure that’s otherwise very safe and turns it into a big deal.” While MRI is radiation-free and completely non-invasive, the general anesthetic lowers heart rate, breathing rate and blood pressure, and carries risks of more serious complications.

To circumvent these risks, Vasanawala is studying ways to shorten MRI scans for kids so children will be exposed to less anesthetic — or maybe none at all. The innovation is urgently needed. Many young children simply can’t hold still for an hour or more, Vasanawala explains: Three to five minutes of concentration per year of age is a realistic expectation. (Aria is unusual — even as a 5-year-old, she chose to go through 90-minute scans unanesthetized. “She has always been on the courageous side,” says her mom, Devi.)

So Vasanawala’s team is taking an approach that seems counterintuitive: Instead of collecting more data with each scan, they’re collecting less. The strategy uses the same concepts that allow a digital camera to collapse photo files down to a manageable size, but with a twist, Vasanawala explains.

A camera records over-detailed images, then throws out data in a way our eyes can’t detect. Similarly, MRI scanners collect thousands of tiny magnetic signals that are sent out by the body’s water molecules in response to the scanner’s strong magnetic field. A computer assembles the data into a 3-D image of the patient’s soft tissue. But instead of collecting and discarding extra MRI data, Vasanawala’s team is systematically gathering less information in the first place. The scientists have halved scan times, and are now investigating whether scan quality holds up in varied tissues and diagnoses.

“Right off the bat, we tried to push this technology very hard,” Vasanawala says. When he began clinical testing of the new method in 2007, he hoped to get good images from one-tenth the standard amount of data, but the scans were hopelessly compromised. “We backed off some — increased the percentage — and then it started working really well,” Vasanawala says.

But he’s still not content to stop at a 50 percent improvement in scan times. Because collecting less data won’t get him all the way to his goal, Vasanawala is studying two more approaches to speed up MRIs.

One plan calls for scaling down MRI equipment for children. Grown-ups’ scanners make it impossible for physicians to zoom in on kids’ smaller body parts, increasing the time needed to get detailed images.

“It’s a chicken-and-egg problem,” Vasanawala says. “You don’t have that many requests for MRI for kids because there’s such a high barrier imposed by the need for anesthesia.” Manufacturers don’t perceive a market for kid-specific equipment and don’t put much research effort toward child-sized technology.

To break this barrier, the Packard researchers are collaborating with engineers in Stanford’s Department of Electrical Engineering and at General Electric to redesign the inner circuitry of MRI scanners. They’re making child-sized radiofrequency coils, the parts of the MRI machine that receive the electromagnetic signals. Smaller coils will improve the scanners’ resolution and speed them up.

Another tactic, now in early development, aims to improve mathematical corrections that account for movement during scans. Even when a patient lies still, her internal structures still move: Blood flows through arteries and veins, for instance. Movement blurs magnetic resonance images, just as a photo of a moving car will blur if the camera’s shutter speed is too slow. A better method of correcting for these small movements would cut the total time children spend in the scanner.

Vasanawala is excited by the progress. “When these techniques are combined, we expect they’ll act synergistically,” he says. “We still haven’t fully exploited the ways of speeding things up for kids.”

Aria is excited, too. “Faster would be better, definitely,” she says. So far, she’s been fortunate enough never to have a seizure in the scanner, and she knows faster scans would help keep it that way.

Bypassing brain damage

In one sense, Aria and her family have been lucky. They could choose to avoid the dangers of anesthesia for each of her many MRI scans.

But other medical procedures are a different story. For instance, pediatric cardiac anesthesiologist Chandra Ramamoorthy, MD, monitors young patients during one of the riskiest scenarios they can face: open-heart surgery. For these children, often infants undergoing lifesaving repair of congenital heart defects, few aspects of treatment are optional. The only way to keep them safer is for physicians to innovate past the risks.

Ramamoorthy’s challenge is that, to let surgeons cut and sew, her team must stop the heart while making sure enough oxygen reaches the vital organs. Open-heart surgery requires several hours on a heart-lung bypass machine, raising the patient’s chance of brain injury from low blood oxygen or prolonged exposure to anesthesia. Fortunately, there’s one surefire method for slowing the brain’s oxygen use.

“Keeping a cool head is one of the most protective strategies for the brain,” Ramamoorthy says.

She’s not speaking figuratively. Ramamoorthy uses controlled hypothermia — cooling the patient’s blood as it passes through the bypass machine — to dampen brain metabolism. Chilling the patient’s body by nine to 16 degrees Fahrenheit effectively heads off dips in blood oxygen.

However, new research shows that what goes down must be brought back up carefully. In a 2009 study of neonatal pigs, Ramamoorthy and surgical colleagues demonstrated the brain was protected only if it was warmed up slowly and evenly after an operation.

“We found that, in our enthusiasm to come off the heart-lung machine, we might be rewarming too quickly,” she says. Temperature probes placed at two locations in the pigs’ brains showed that core brain temperatures often exceeded those at other sites in the body during rapid reheating. Hotter parts of the brain gobbled more oxygen, leaving them more prone to damage. The most vulnerable brain structures were those deep in the midbrain, positioned to get direct hits of warm blood from major arteries. The hippocampus, a midbrain structure that helps form new memories, was one of the brain parts at risk.

The cardiac team at Packard Children’s has changed its rewarming plan as a result of the pig study. Today, instead of quickly returning bypass patients to a normal body temperature of 98.6 degrees Fahrenheit, Ramamoorthy gradually rewarms them to 95 degrees, then monitors as their bodies bring themselves back to normal. If body temperature goes above 98.6 in the recovery room, the team cools patients off a bit. They can cool the blood passing through the heart-lung machine, or use cooling blankets and a lower room temperature to slow rewarming.

Even with these advances, anesthesia is still not an exact science. “Giving anesthetic isn’t like baking a cake,” Ramamoorthy says. Bakers can taste whether their creation turned out, she explains. “It’s very hard to measure how good an anesthetic was.” But despite the challenges, Ramamoorthy and her colleagues continue striving to attain the essential goals of anesthesia — blocking pain and memory of surgery — while reducing harm to the developing brain.

Big surgeries, tiny scars

While skillful administration of anesthesia leaves no traces, pediatric general surgeon Sanjeev Dutta’s results are plain as day: The tumor is gone, the hernia is fixed or the malfunctioning body part works.

Dutta, MD, can also easily observe the unwanted aftereffects of his handiwork, including pain, hospital stays and scars. While many surgeons want to reduce pain and hospital time, “they seem not to care much about scarring,” Dutta says. “They tend to say, ‘Suck it up, it had to happen.’ That’s the Calvinistic culture of surgery.”

But scars matter to young patients. Research shows children with prominent scars struggle with school performance, socialization and self-esteem. That knowledge drives Dutta’s operating-room innovations. “My goal in life is to eliminate scarring,” he says. Rather than follow the old model of surgery, in which big incision equals big surgeon, Dutta and his Packard Children’s colleagues are pioneering another way. “We can do these big operations on the inside now, so we’re still performing a maximal operation, but with minimal collateral damage.”

The transition isn’t trivial. Tiny laparoscopic incisions radically change the surgeon’s view of the operation and require mastering new tools and techniques.

“People say that looking through a laparoscopic instrument is like looking through a straw,” Dutta says. But that’s not quite accurate. Laparoscopic tools magnify the surgeon’s view by a factor of 10. On small patients, the laparoscopic view is often clearer, once the surgeon gets used to it. “You need to understand and identify anatomy from this new vantage point,” Dutta says.

Once they’ve got the technique down, though, surgeons can begin substituting small, hidden cuts for big scars.

One child who benefited from this strategy was an 8-year-old who came to Packard Children’s with torticollis, an unnatural tightening of his neck muscles. The boy was forced to hold his head tilted awkwardly toward one shoulder, which could lead to permanent disfigurement. “The brain wants to see the world level, so the skull gradually reshapes itself to compensate, leaving the patient with a crooked head,” Dutta says.

Traditional surgery to cut the problem muscles would have left a prominent neck scar, trading one deformity for another. Dutta took a different route, making three tiny incisions in the child’s armpit and tunneling under the skin to reach his neck. “Not too many people will come up and stare at your armpit,” Dutta points out. An “after” photo shows the excited boy in Dutta’s office, grinning proudly as he holds his head straight.

The next step, after hiding scars, is eliminating them completely. One approach is to put a scar inside a scar. In a first-of-its-kind 2008 surgery, Dutta removed the spleen of a 9-year-old named Ryan using only an incision in the boy’s belly button. Ryan’s mom, Elaine, guessed her son might receive a laparoscopic procedure but was surprised the surgeons could use his belly button. “I thought, Wow, that seems even better, since there are no scars at all,” she says. Elaine herself has a large scar from her own splenectomy, necessitated by the same hereditary red blood cell disorder that led to Ryan’s surgery.

“These parents don’t want the same for their kids,” Dutta says.

Dutta’s next step is figuring out how to access surgical sites via natural body orifices such as the mouth. To that end, he’s collaborating with engineers from SRI International (formerly the Stanford Research Institute) to build new tools for fixing esophageal atresia, a congenital gap in the esophagus that prevents infants from eating normally.

Figuring out how to perform a complete surgical repair of the esophagus through an infant’s mouth will take 10 to 15 years, Dutta says. But he’s optimistic the approach will eventually succeed. “We want to figure out how we can safely and reasonably use natural orifices for surgery in children.”

A crystal ball for transplant rejection

Some forms of collateral medical damage don’t occur until months or years after treatment. Packard Children’s pediatric nephrologist Minnie Sarwal, MD, PhD, is working to lessen one such problem: damage inflicted by a cumbersome method used to monitor transplanted kidneys.

Children with kidney transplants face pressing danger that their immune systems will reject the organs — about one-quarter of pediatric patients have a bout of acute rejection in the year after surgery. Sarwal, who is also a professor of pediatrics at the School of Medicine, leads a team that has developed the first-ever method for detecting acute rejection before damage sets in.

“We’re figuring out how to get transplanted organs to last longer and how to help patients live more safely with them,” Sarwal says.

The new, non-invasive test gives doctors time to stop acute rejection in its tracks. Instead of an invasive biopsy, a blood sample is tested to measure activity of five genes that switch on when a patient’s immune system starts rejecting a transplanted organ. Doctors can then respond to early signs of rejection with a prompt, moderate increase in immune-suppressing drugs, bringing the immune system under control before the transplanted kidney gets hurt. Urine samples may hold similar gene-activity clues to transplant rejection, so Sarwal’s team is studying urine now.

Sarwal hopes the method will eventually replace the current system for assessing transplant health, which can’t spot rejection until the kidney begins to malfunction. At that point, doctors use a biopsy to confirm the problem, then give big doses of immune-suppressing drugs. The drugs usually stop rejection, but not before the kidney sustains permanent damage.

In addition to predicting rejection, the new test will also show which patients could safely lower their doses of anti-rejection medication to reduce infection risk and other side effects. Until now, clinicians have had no way to tailor immune suppression to individual patients.

Not only does the biopsy method do a poor job of spotting early signs of rejection, it strains patients and their families. Carla Combi, mom to 11-year-old kidney recipient Cole, knows the burden well: Her son received his first transplant at age 1, and got another kidney last March after the original transplant failed. Cole has had at least one biopsy a year throughout his childhood. Every procedure requires a long day at the hospital, general anesthesia and a week of bed rest afterward.

“It disrupts his life,” Carla says. Her son, a very social fifth-grader who loves basketball and his family’s two golden retrievers, struggles with the feeling that he’s different. A week alone in bed certainly doesn’t help.

“Telling Cole he can’t be with his friends, he can’t do what they’re doing — that’s the hardest thing,” Carla says. The possibility of a more normal life for Cole, an easier balance between his medical needs and his desire to be ordinary, is tantalizing.

Letting kids be kids

In the end, inventing better pediatric medicine goes beyond developing technological firepower or physiologic knowledge. It’s also about a search for ways to help sick children feel normal.

“This is really a culture change,” says surgeon Dutta. “It’s a difference in how we look at our patients.” Instead of expecting patients to tough it out, he says, more physicians are moving beyond a narrow focus on immediate medical problems to treat the child as a whole.

For patients and their families, the change is welcome. Describing her son’s lifetime of medical scrutiny, Carla Combi says, “He’s OK with being in the hospital. Needles don’t scare him, all that stuff does not scare him.” She’s effusive in her praise for the care Cole has received.

Yet she also acknowledges, a bit wistfully, that Cole’s lifesaving treatments can leave him feeling isolated, “different.”

That’s why parents like Combi appreciate the advances that allow pediatric medicine to surge ahead without leaving trouble in its wake. Yes, they care about the measureable benefits of innovating for children’s health. But they’re also excited about the intangible satisfaction of seeing their young ones be regular kids — the best possible side effect of safer, more comfortable treatments for seriously ill children.

E-mail Erin Digitale


Heart valves from stem cellsGrowing long-lasting replacement parts

Repeated open-heart surgeries are risky. Yet for infants born with severe heart defects, multiple surgeries may be the only shot at life.

Heart surgeon Frank Hanley, MD, is working to change that. Hanley, Packard Children’s chief of pediatric cardiothoracic surgery and co-director of the hospital’s Children’s Heart Center, has spent years perfecting a technique that condenses the usual two or three surgeries for mis-plumbed hearts into one long operation. So far, he’s saved more than 500 children from extra trips to the OR.

But lately, Hanley has hit a roadblock: Patients born with missing heart valves must receive prosthetic valves, which don’t last forever.

“Little Johnny outgrows his T-shirts and shoes — kids also outgrow the valves we use, or the valves wear out,” Hanley says. “The patients have to come back and get their valves replaced.”

So Hanley is partnering with colleagues in regenerative medicine to learn how to make fully functional heart valves that grow and repair themselves. The scientists are now studying what goes on inside normal valves, the paper-thin leaves of tissue that prevent blood from backwashing on its trip through the heart.

“The heart contracts 40 million times a year,” says senior research scientist Kirk Riemer, PhD, who leads the lab work. “The valves are very busy pieces of tissue. They flap like flags in a continuous windstorm.”

That continuous turbulence wears out prosthetic valves in a few years, but doesn’t cause problems for natural valve tissue until old age, if then. “The tissue must be a master at repairing itself,” Riemer says. Understanding self-repair is essential to build effective replacement valves, he adds.

But first the researchers needed a way to study valves in action. Plopping a valve in a dish wouldn’t expose the tissue to the fluid forces thought to prompt self-repair. So Riemer spent a year rigging a “bioreactor” that pumps body-temperature fluid through rat heart valves at just the right speed and pressure.

Now, the team is ready to examine how individual cells within the valve signal damage and initiate repairs.

“We think if the valve starts to lose cells, a small breach can bring about a series of reactions that materialize as a big problem, like the tiles on the space shuttle,” Riemer says. To catch the earliest hints of a problem, the team will have to detect miniscule changes in chemical signals sent out by valve cells — and figure out how such signals work in an environment as turbulent as a washing machine.

Ultimately, the researchers hope to program a patient’s own stem cells to fashion functioning heart valves that last a lifetime.

“If we could form a heart valve with a patient’s own tissue that would grow and heal itself, that would be a huge advance,” Hanley says. “Then, we could operate on little Johnny at 1 year and say, ‘He’s cured.’”






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