On the brink

For transplant patients, the teenage years are the most precarious


Sid Marshall was trying to stay up all night. It was spring break 2007 and the 15-year-old Red Bluff, Calif., boy was reveling in bits of normalcy that had eluded him during a lifetime of heart problems. At the moment, he was focused on the rather mundane worry that he’d awaken with a glob of shaving cream adorning his face or toothpaste in his hair — pranks he and his visiting cousins had agreed to play on the first person to nod off.

Jamie Kripke

Most nights he escaped the shaving cream gauntlet unscathed, but the late nights extracted a much more serious toll. Sid slept late nearly every day that week, neglecting until early afternoon his morning handful of 11 pills necessary to keep his body from rejecting the transplanted heart he’d received the previous July.

“I wanted to be like everybody else,” says Sid. “I wanted to stay up late, and to take them later. I promised myself it was only for week, and then I’d get back on my regular schedule.” Sid didn’t know it, but he was entering the most dangerous part of his transplant journey: the period between one and three years after surgery when many teens stray from their medication regimens. 

Because Sid’s time-released medication affords only a 30-minute grace period between doses, a delay of even just a few hours has repercussions. By the end of the week, Sid was experiencing a severe rejection episode, and his life was in the balance.

It seems counterintuitive that teens who’ve overcome the hurdle of an organ transplant would jeopardize their lives over the seemingly simple matter of medication. But recent studies estimate that as many as 30 to 50 percent of U.S. adolescent organ transplant patients miss some of their anti-rejection medication, and non-adherence is the main reason for organ rejection and re-transplantation in this age group.

“This is a huge problem,” says Minnie Sarwal, MD, PhD, a pediatric nephrologist at Lucile Packard Children’s Hospital. “We need to get inside the minds of these kids and help them understand that if they don’t take their medication, they could die.”

Normal spells trouble

A journey to the center of the adolescent brain, with its cacophony of conflicting impulses and pressures, is not for the faint hearted. Often cited as part and parcel of growing up, the twin feelings of invincibility and rebellion harbored by many teens are enough to drive any parent batty. But this natural testing of the limits has deadly implications for kids with transplanted organs. Even minor, nearly unnoticeable rejection episodes can damage formerly healthy organs; repeated assaults can cause organ failure.

“Not taking your medications is normal behavior for adolescents, unfortunately,” says Packard child psychiatrist Richard Shaw, MD. “But the consequences are so much more grave for teens with organ transplants.”

The very success of the transplants feeds the problem. “Kids start feeling so good,” says Marshall’s mother, Peggy Larez, “they tend to forget. It’s like, ‘Oh yeah, I had a heart transplant.’ They don’t feel disabled anymore.”

Physicians at Lucile Packard Children’s Hospital are concocting a variety of ways to predict which patients are most at risk and how best to help them — from talking tough to parents and teens, to devising ways to pinpoint possible problems even before surgery, to contriving desperate stop-gap measures to get medication into the most reluctant of teens.

“Non-adherence is a symptom, like a fever,” says Shaw. “Our job is not to say, ‘Yes, you have a fever.’ It’s to find out why.”

The reasons teens cite for not taking their medication run the gamut. Some anti-rejection medications cause side effects like acne and weight gain that are particularly onerous to image-conscious adolescents. Some kids are reluctant to interrupt activities with peers to conform to rigorous, time-sensitive medication schedules. Others were so traumatized by the experience of having an organ transplant that they avoid anything that reminds them of the procedure. The most common reason might surprise you, however. They simply forget.

“Anti-rejection medication isn’t like antibiotics for an ear infection or painkillers for a headache,” says Becca Berquist, MD, an intern at Packard Children’s who began researching the issue after helping at the hospital’s annual Transplant Camp. “There’s no positive or negative feedback loop where you quickly feel better or worse if you miss a dose. In teen-time it takes forever to have an effect.”

Although an organ can withstand one or two forgotten doses of medication, the psychological implications are much more severe. Because nothing seems to happen, it’s common for adolescents to begin to doubt their parents’ and doctors’ insistence that — for the rest of their lives — every dose is critical.

“At this age, adolescents naturally have trouble seeing how their actions now impact them later,” says Packard psychologist Rebecca Bernard, PhD, who devises ways to combat non-adherence in teens with transplants. “I’ve had many teens tell me, ‘I took my medications late, and nothing happened. It wasn’t until I got really sick that I understood that the pills are important.’” Internet-savvy kids are also quick to do their own analysis of the medical literature and decide that they belong to the minority of patients who escape significant repercussions from non-adherence.

Pre-transplant counseling is one approach that seems to help. Bernard and Shaw have developed a questionnaire intended to highlight patients likely to struggle with non-adherence after transplant. They’ve found that lower socioeconomic status and living in a single-parent family tend to correlate with a reluctance or inability to stick to the necessary medication schedule. Kids who have struggled with a long illness and missed lots of school might also lack the developmental and academic sophistication to truly understand the consequences of their actions. Tackling those issues before transplantation, when the physician has more leverage, can decrease the chance of problems.

“If we can say, ‘We want to transplant you but we’re concerned about these issues,’ the patient and family are more likely to listen,” says Shaw. “But it’s frustrating. A teen can parrot back to you, ‘Yes, I know I need to take my medicines,’ but there is a big difference between this and a capacity to personalize possible risks of non-adherence. If we specifically ask, ‘Do you think this could happen to you?’ they often answer, ‘Well, no.’”

Peer-to-peer straight talk is one way to break through the invincibility barrier. In 2001, 15-year-old heart transplant patient Anthony Hollingsworth suffered a severe rejection episode after deciding he didn’t need to take his anti-rejection medication. When he awoke after spending nearly a month unconscious while his medical team fought for his life, he vowed to tell other teens how important it is to follow their doctors’ orders. His video, in which the outgoing, happy teen dishes about dating, friendships and family to a rapt audience of hospital staff, is required watching for many pre- and post-transplant teens at Packard Children’s.

“A lot of doctors don’t understand when you go back into the real world you’re around your friends, you’re like, ‘OK, well they don’t have to take medication, so why should I have to take medication?’” Anthony says in the video. “You get around your friends, and you don’t want to feel like an outcast.

“It’s really a mind game,” he continues. “Most teenagers have a mind to rebel against what somebody tells them to do. That’s basically me. If someone tells me I can’t do something I’ll do it just because they told me I couldn’t do it. But I’ve learned it’s not worth putting your life at risk just because you don’t want to seem different from everybody else.” 

Sid’s taken Anthony’s advice to heart. His own recent rejection episode frightened him badly. “I was so scared I was going to die,” he says. “It was a huge wake-up call.”

“Even the act of taking medication can make teenagers feel different,” says psychologist Bernard. “If they have to stop playing basketball or leave a dinner with friends to take their medication, they feel that everyone will notice.” That’s because it’s not a simple matter of ducking behind the bleachers with a glass of water and a handful of pills. Some anti-rejection medications must be swallowed as soon as they are removed from their foil packaging, and others can cause nausea or headaches. Some of this can be addressed by helping individual kids anticipate how they will react to specific school or peer situations when they leave the hospital.

Although promising, pre-transplant counseling was not an option for many of today’s transplanted teens, who received their organ as infants. “In their minds, the transplant is something that was done to them,” says Berquist. “They didn’t choose it. Of course they are happy to be alive, but they may not realize what a gift they received.”

Holding on and letting go

Not so their parents, who often remember every excruciating detail. Shepherding their child to independent adulthood is a tremendous challenge when it’s necessary to simultaneously monitor their medication intake twice a day. Knowing when to back off and when to knuckle down is like taking aim at a moving target with your child’s life on the line.

“How am I ever going to be able to go to bed at night and not ask Miranda if she’s taken her medicines?” says Michele Ashland, whose now 12-year-old daughter had a liver transplant at Packard Children’s when she was just 6 months old. “I regulate it all for her right now, but I have to start teaching her to remember to take her medications, to plan ahead and order refills, and to maintain a schedule when her life gets more complicated.”

But the natural learning cycle of practice and failure isn’t an option for teens with transplants. They have to learn to do it all without failing. Not even once. Packard Children’s newly instituted teen clinic for liver transplant recipients is meant to smooth the transition from the solicitous atmosphere of a pediatric hospital to the fend-for-yourself milieu of adult care. Appointments without parents and free-form support groups about life after transplant are just some of the clinic’s plans.  

Parents need lessons too, says Shaw. “You don’t want to become really punitive when your child messes up. It’s more effective to reward good behavior than to over-react when they don’t do well.”

Tough love

Although forgetfulness, procrastination or a reluctance to appear anything but completely normal are the most common reasons teens lapse on their anti-rejection medications, a subset of adolescents actively refuse to take their pills. Some dump them down the drain, some don’t even pretend to take them. They might be reacting to a difficult family situation or feeling depressed or traumatized by their experience. A recent study by Shaw, Sarwal and others indicates that about 30 percent of non-adherent teens with kidney transplants lapsed because of psychiatric illnesses such as major depression and adjustment disorders, and about 35 percent due to conflict between the child and his or her parents.

“Depressed kids sometimes decide they don’t want to take their medications, perhaps because they have a passive wish not to survive,” says Shaw. “Others, who have developed post-traumatic stress disorder related to their treatment, may avoid anything that reminds them of their surgery, including their pills and clinic appointments. Alcohol and drug use can also make them not want to take their medications.”

As the numbers indicate, positive interactions within a child’s family can also be very important. An atmosphere of conflict can overwhelm parents and leave a teen less-well supervised. “A child may act out to distract parents from arguing,” says Shaw. “Or if they’re divorced, it’s possible the only time they are ever in the same place is when they show up in the emergency room together for their child.”  

Parents and physicians have the best luck when they team up on particularly hard-headed cases.

“Parents can take away their teen’s privileges, for example, watching TV, playing video games or getting their allowance,” says Shaw. “They have a lot of power, although they may not know it.” In extreme cases, Sarwal and her colleagues have turned to a few last-ditch efforts to save the kids, including infusing long-lasting immunosuppressants during their monthly appointments.

“We’re trying to rescue them during this period of craziness when they don’t take their meds,” says Sarwal, pointing out that even the most reluctant teen usually comes around after a year or two.

Sarwal and her colleagues are pursuing new, steroid-free transplant protocols to reduce the burden of the medications on kids. They are also testing whether it might one day be possible to wean at least some transplant recipients off immunosuppressants entirely.

“Of course we want to reach the stage where everybody’s transplant lasts a lifetime with the least amount of medication,” says Sarwal. “But in the meantime we have an obligation to help these kids.”

Good intentions can’t save everyone, though. Although Sid has recovered well, and in July celebrated his first anniversary after his transplant with a heart-shaped red velvet cake with red frosting, Anthony wasn’t so lucky. After years of struggling with ongoing rejection, the 19-year-old died at Kaiser Santa Teresa Hospital in San Jose on Aug. 22, 2005.

“It’s easy to look at this problem and think ‘Why are they doing this’,” says Berquist. “But there’s a more important flip side. ‘How are we failing them? What can we do better?’”

Sid doesn’t completely accept this premise. “In the end it was just me getting lazy,” he says. “There’s not much the transplant team can do about that when they’re five hours away.” Asked what he’d like to share with other transplant teams, he pauses.

“I would tell other kids to keep taking their meds no matter how good they feel. I was warned, and it still happened to me. I was just like Anthony.”

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