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March 4, 2010

Research Notes

End-of-life care compared

Patients admitted to hospitals with higher-intensity end-of-life care live longer than those admitted to hospitals with low-intensity approaches, according to a University study published in the February issue of the journal Medical Care.

The study, led by Amber E. Barnato, a faculty member in medicine, clinical and translational science and health policy, examined admission records of more than 1 million patients 65 and older in Pennsylvania hospitals between 2001 and 2005.

The researchers found a survival benefit in hospitals with more intensive treatment styles, but this benefit lessened with time. After 30 days, patients treated at high-intensity hospitals had a 7 percent risk of dying compared to 9 percent at low-intensity hospitals. By six months’ post-admission, the risk of dying increased to 18 percent compared to 19.5 percent, respectively. Risk of dying was the same for higher-intensity hospitals as average-intensity hospitals six months after admission.

Higher-intensity care refers to greater use of life-sustaining measures such as ICU admission, intubation or mechanical ventilation, kidney dialysis and feeding tubes.

Unlike previous studies that assessed records of people who died having received life-sustaining measures, Barnato and colleagues looked at all seniors admitted to hospitals to determine the impact of intensity style on survival.

“Looking solely at people who received life support and died will not give you a true indication of how these measures impact survival,” said Barnato. “That’s akin to being a Monday morning quarterback. Instead, we looked at a hospital’s approach to people who were sick enough to die.”

The study did not address questions about the cost effectiveness of greater end-of-life treatment intensity or the quality of life experienced by the patients who lived longer because they went to a more intensive hospital.

“Ongoing controversies about the utility and cost effectiveness of life-sustaining treatment for individual patients will not be solved by this study. However, our findings support the strategy of hospitals ‘moving toward the middle,’ when it comes to life-sustaining interventions,” said Barnato.

Co-authors included Chung-Chou Chang and Mark S. Roberts of medicine, Judith R. Lave of health policy and management and Derek Angus of critical care medicine.

The study was funded by the National Institute on Aging. The article is available online at

Heart pump for kids proceeding

Pitt researchers and their collaborators have been awarded a $5.6 million federal contract to continue developing an implanted ventricular assist heart pump for infants and small children with heart disease. The project aims to provide access to the technologies that have saved the lives of older heart failure patients.

Harvey Borovetz, Distinguished Professor and chair of the Department of Bioengineering and a deputy director of the McGowan Institute for Regenerative Medicine, is the principal investigator of one of four projects that comprise the Pumps for Kids, Infants and Neonates (PumpKIN) preclinical program, a $23.6 million effort sponsored by the National Heart, Lung and Blood Institute (NHLBI). Borovetz and his colleagues at Pitt, Children’s Hospital, Carnegie Mellon University, California-based LaunchPoint Technologies and Salt Lake City-based WorldHeart began designing and building their device, called PediaFlow, more than five years ago.

“We now have the opportunity to put PediaFlow through the necessary development and testing needed to proceed to clinical trials,” Borovetz explained. “The aim is to begin human studies in three to four years.”

PediaFlow is made of a titanium alloy and is about the size of an AA battery. Blood is drawn through it by means of a high-speed rotor that essentially floats within its housing due to magnetic levitating forces. Oxygenated blood is pulled from the left ventricle through the device, returning the blood to the aorta and patient circulation.

Pediatrician Susan B. Shurin, acting director of NHLBI, said, “This research seeks to develop technologies to expand life-saving options for infants and children born with congenital heart defects or those who develop heart failure. Similar devices are in use in adults. Well-designed circulatory support could dramatically improve the outcomes of these young patients as they seek to recover or wait to receive a heart transplant.”

Peter Wearden, a cardiothoracic surgeon at Children’s Hospital who leads the clinical work of the project, said, “We believe the PediaFlow will be capable of replacing the heart function of our smallest patients. Left ventricular assist devices (LVADs) have been very successful in supporting older children and adults as a bridge to eventual heart transplantation or, in some cases, as a temporary measure that allows the heart to rest and recover. But there currently are no FDA-approved LVADs for babies and toddlers.”

Extracorporeal membrane oxygenation currently is the only form of support for these smallest of children, but it requires that patients be fully anesthetized, and only can be used for a few weeks before severe complications develop. “This creates a ‘race against time’ while we and the family wait for an appropriate donor organ to become available,” Wearden noted.

“To meet the NHLBI’s requirements, PediaFlow must support patients for up to six months, and our preclinical research has already shown that it works flawlessly for at least 70 days,” he said.

Bipolar parents raise ADHD risk

Preschool children of parents with bipolar disorder have an eight-fold increase in the risk for attention deficit hyperactivity disorder (ADHD) and significantly higher rates of multiple psychiatric disorders, compared with children of parents who don’t have the mental illness, according to a study by School of Medicine researchers to be published in the March issue of the American Journal of Psychiatry.

Psychiatry professor Boris Birmaher, lead author of the study, said, “Studies already have shown that the children of bipolar parents are far more likely to develop the disease, although typically not in the preschool years. By identifying ADHD and other developmental issues in this group, we can treat them early and potentially prevent full-blown development of bipolar disorder.”

According to previously published results from the Pittsburgh Bipolar Offspring Study (BIOS), having parents with bipolar disorder is the best predictor of whether their children will go on to develop the condition. However, until now, little has been known about the effects of having bipolar parents on preschool-aged children.

Study researchers compared 121 children, ages 2-5, of 83 parents with bipolar disorder to 102 offspring of 65 parents without bipolar disorder in a demographically matched control group.

Compared with the offspring of parents in the control groups, children with bipolar parents had an eight-fold increase in the risk of having ADHD, as well as a six-fold increase in the risk of having two or more other psychiatric disorders. Although only three children had clinically certified full-blown mood disorders, children of bipolar parents, particularly those with ADHD or oppositional defiant disorder, had more subclinical manic and depressive symptoms than did children in the control group.

“Because BIOS is prospectively following all of these children, we will be able to address their developmental issues and delineate the types and severity of symptoms that may predict a possible conversion to bipolar disorder,” said Birmaher, who also is the endowed chair in Early Onset Bipolar Disease and co-director of the Child and Adolescent Bipolar Services at Western Psychiatric Institute and Clinic.

“Also, because almost 70 percent of the children of parents with bipolar disorder in our study did not have any diagnosable psychiatric illnesses and very few appeared to be on the cusp of developing mood disorders, we believe there is a window of opportunity for prevention in the high-risk group of kids.”

The researchers note that these findings have important implications. “Clinicians who treat adults with bipolar disorder should question them about their children’s psychopathology to offer prompt identification and early interventions for any psychiatric problems that may be affecting the children’s functioning,” noted Birmaher. “Further studies are needed to help determine the clinical, biological and genetic risk factors that may be modified to prevent the development of psychiatric disorders in the children of those with bipolar disorder.”

Co-authors included David Axelson, David Brent, Rasim Diler, Mary Ehmann, Benjamin Goldstein, Mary Beth Hickey, Satish Iyengar, Catherine Kalas, David Kupfer, Kelly Monk, Mihaela Obreja and Wael Shamseddeen, all from the Department of Psychiatry and WPIC.

IPF blood test possible

A simple blood test could predict which patients with the lung-scarring disease known as idiopathic pulmonary fibrosis (IPF) soon will get far worse, an indicator that could one day influence their treatment, according to researchers at the School of Medicine. Their findings, published online in PLoS One, indicate that the body’s immune cells attack healthy lung tissue, suggesting that IPF is in fact an immunologic disease.

In IPF, lung tissue gets progressively more scarred, making it hard for patients to breathe, explained Steven R. Duncan, a faculty member in the Division of Pulmonary, Allergy and Critical Care Medicine. The prognosis is grim; median survival is three years after diagnosis.

“If we knew who was in the gravest danger from this illness, we could direct them to lung transplantation or experimental therapy immediately,” he said. “Also, we could possibly avoid prescribing grueling treatments for people whose disease is fairly stable.”

Duncan and his colleagues may have found a way to test for that information. They collected blood samples from 89 IPF patients at various stages of disease severity, as well as 32 healthy individuals for comparison, and examined certain immune cells called CD4 T-cells. The cells, which typically respond to infectious threats, normally carry a surface protein called CD28.

The researchers found that as a patient’s disease got worse, the CD4 T-cells lost their CD28 protein markers and the cells were unusually “revved up,” as Duncan put it.

The greater the proportion of these distinctly abnormal cells in the blood, the greater the likelihood that the patient would become gravely ill quickly. In the study group, these patients were the ones who were most likely to require a lung transplant or to die within 12 months.

“We suspect that as these CD4 cells repeatedly multiply, subsequent generations become abnormal,” Duncan said. “The altered cells send out signals that promote inflammatory processes, which perhaps could lead to the fibrosis of the lung tissue that characterizes IPF.”

Mark T. Gladwin, chief of the Division of Pulmonary, Allergy and Critical Care Medicine, added, “We may be able to develop a screening test for patients with idiopathic pulmonary fibrosis, much like cholesterol levels in the case of atherosclerosis, that identifies the patients at greatest need for referral for life-saving lung transplantation.”

The findings also hint that a low-level, chronic infection or a chronic immune response to a normal protein (an auto-antigen) might be a triggering event for the abnormal immune response, and Duncan now is looking for genetic missteps that might lead to this autoimmune-like reaction.

Lead author Syed R. Gilani of critical care medicine and Kevin Gibson and Naftali Kaminski of medicine were among the research team members, as were researchers from the University of Texas Medical Branch and the University of Alabama-Birmingham.

Caregivers also suffer post-ICU

Intensive care unit patients are not the only ones likely to be severely depressed in the aftermath of hospitalization. Family and friends who care for them often suffer emotional and social hardship, too, according to a prospective study from the School of Medicine monitoring patients and caregivers during a one-year period for predictors of depression and lifestyle disruption.

The findings, published this month in Chest, indicate that the informal caregivers of ICU survivors endure even more stress than those caring for Alzheimer’s disease patients, noted senior author Michael R. Pinsky, vice chair for academic affairs, Department of Critical Care Medicine.

“Caregiver depression is the collateral damage of these stressful ICU admissions,” he noted. “This research reveals that loved ones of critically ill patients have profound and unmet needs for assistance even after hospital discharge. The emotional and economic burden is enormous, and these issues must be addressed.”

Pinsky said, “Our previous studies indicate that caregivers often change their lives to care for recovering patients, including quitting work, taking lower-paying jobs or leaving college in order to spend more time at home. These are highly stressful choices, and it is imperative that we develop interventions to help families cope with the burden of critical illness even after they have left the hospital.”

Co-authors of the Chest paper included critical medicine fellow David C. Van Pelt, Richard Schulz of psychiatry and Lakshmipathi Chelluri of critical care medicine.

Teen brain responses studied

Pitt researchers have taken a significant step toward unraveling the brain activity that can drive adolescents to engage in impulsive, self-indulgent or self-destructive behavior. Published in the current edition of Behavioral Neuroscience, the study demonstrates that adolescent brains are more sensitive to internal and environmental factors than adult brains and suggests that the teenage tendency to experiment with drugs and develop psychological disorders could stem from this susceptibility.

Lead researcher Bita Moghaddam, a faculty member in the Department of Neuroscience, said that although the exact mechanics need further investigation, the current study is a starting point in mapping the neural path from stimuli to behavior in the adolescent brain.

“Adolescence is a period of volatility and vulnerability with tendencies toward interpersonal conflict, emotional reactivity and risk behavior, but we know very little about the brain mechanisms that promote this state,” Moghaddam said. “We want to know how the adolescent brain interacts with the environment at the brain-cell level, when the neural signals are firing. Once we identify how certain factors trigger teenage behavior, we might better understand — and possibly address — the origin of the risk-taking and psychological disorders such as depression and schizophrenia that occur during this period,” Moghaddam said.

The researchers trained adolescent and adult rats to respond to a visual light cue by rewarding them with sugar pellets. Previous research has shown that adolescent rats and mice exhibit behavioral differences from adults similar to those of adolescent humans, including greater impulsiveness, impatience and vulnerability to psychological problems, the authors wrote. The rats were placed in front of three holes with the light behind the middle hole. If a rat poked its nose into the center hole when the light was activated, it received a pellet; if it explored the right or left hole, it got nothing.

The researchers found that the adolescents responded to the light cue at least as readily as adult rats, suggesting a similar or slightly better capacity for learning.

After six days, the rats no longer received a reward for choosing the center hole. They were divided into four test groups, each with an equal number of adults and adolescents: rats that were given 20 percent less food between sessions and received the light cue; rats that received the light cue but could eat as much as they liked between sessions; a group that received less food and no light cue, and a group that could eat between sessions but was not shown the light cue during the experiments.

Moghaddam and her team found that adolescents tended to return to the center hole far more often than the adults although they received no reward and continued going to the hole long after the adult rats stopped altogether.

Such doggedness was even more prominent in adolescents who received the light cue and had a restricted diet before the experiment. This group nosed the center hole twice as often as adults under the same circumstances and as adolescents with less food and no light cue. Adolescents that received the cue and had free access to food chose the center hole only a third as often.

Thus, rats experiencing internal and external stimuli — hunger and the light cue — compulsively sought the earlier reward long after the other rats realized it no longer existed.

These results suggest that human teenagers can similarly behave irrationally and compulsively when faced with certain feelings and settings, Moghaddam said. “A scenario could range from the relatively mundane, such as hungry teenagers being more likely than adults to buy fast food immediately after seeing an advertisement, to despair and relationship problems eliciting thoughts of suicide,” she said.

For the project’s next phase, the Pitt group will repeat the experiments while monitoring activity in the emotion and cognition centers of the adolescent and adult rats’ brains, Moghaddam said. This information will help Moghaddam and her colleagues grasp how brain cells encode the behavioral signals sent in response to stimuli.

Neuroscience doctoral student David Sturman was the report’s lead author, conducting the study with Moghaddam and research assistant Daniel Mandell.

The project was supported by the National Institute of Mental Health.


The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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