Providence, RI ““ While it has been widely reported that older children, teens and adults aren’t getting enough sleep, it turns out that younger children might be sleep deprived as well. A study by researchers at Bradley Hospital and Brown Medical School finds that children 5 and under get less than the recommended amount of sleep.

“We were very surprised to find how little preschool aged children actually sleep at night, which we could measure with our activity monitors. Children in our sample slept only about 8.7 hours at night and less than 9.5 hours per 24 hours when naps were included. This contrasts with the 12 to 15 hours usually recommended for children this age,” says lead author Christine Acebo, PhD, of the Bradley Hospital Sleep and Chronobiology Research Laboratory.

Other studies show that decreased sleep in older children, teenagers, and adults may lead to physical and cognitive problems including ““ decreased physical performance, lower academic performance and reduced cognitive and other daytime functioning. Several studies in adults also link lack of sleep to neuroendocrine abnormalities that may lead to overeating and obesity.

“We are concerned that the problem of too little sleep extends even to the youngest members of families, though we do not know if this puts them at risk for problems down the line,” says Acebo.

The research paper, published in the December issue of the journal Sleep, corroborates the results of a recent survey of parents, funded by the National Sleep Foundation (NSF) and Pampers Baby-Dry, showing that many children from newborn to age four do not get the minimum 12 to 15 hours of sleep per day recommended by the NSF and pediatric sleep experts.

Acebo and colleagues studied 169 children between 1 and 5 years old, once a week in their homes. The children wore activity monitors on their ankles or wrists to record their sleep, and mothers also chronicled their children’s sleep habits in detailed diaries.

“We wanted to study sleep in preschool aged children because most of the research in this area is more than 25 years old — this is one of the first studies to describe sleep patterns in this age group with objective measures in recent years,” explains Acebo.

The authors also found an interesting difference between families of differing socioeconomic status (SES).

“Children in families with lower SES spent more time in bed at night with more night waking and more variable bedtimes than those in higher SES families who were in bed for fewer hours, but had more regular schedules,” says Acebo.

In addition, the researchers found that the children in the study awoke more often during the night than is usually described in the scientific literature, but which is consistent with concerns that many parents bring to their pediatricians.

Finally, they report that 82 percent of children older than 18 months were not taking naps on some or all days.

Acebo says that she was surprised to find that kids are sleeping less than the recommendations that have been in place for the past 50 years.

“I think based on what we know in older children, teens and adults, it’s fair to speculate that insufficient sleep in children would be related to difficulties — although this is an area that’s been little studied for decades,” says Acebo.

The results of this study are important because they indicate that all members of American families may be getting insufficient sleep in our fast paced, 24-hour society, Acebo and colleagues say. Their results also reveal that more data is needed to determine how much sleep small children really need and the effects of insufficient sleep on later development

On the World Wide Web:

Lifespan

ZURICH (Reuters) – Novartis has warned doctors not to use
its hormone-based breast cancer drug Femara to help women
become pregnant after reports of adverse events following such
off-label use.

Novartis had found 13 reports of cases where individual
doctors had prescribed Femara for ovulation induction in its
safety data base, a spokeswoman said.

This lead to birth defects in two cases and two spontaneous
miscarriages in two others. There were four normal births,
while there was a lack of information in the five remaining
cases.

“Novartis simply encouraged physicians and patients to
stick to the prescribed information,” the spokeswoman said.

“This indication is not approved and Novartis never did
anything to promote it.”

Femara is for use in post-menopausal women only, she said,
but some doctors across the world had prescribed the drug to
treat infertility in women, leading to the reports.

Novartis shares were 0.8 percent lower at 68.80 Swiss
francs by 1500 GMT, having hit a low of 68.10 francs earlier.

Novartis is seeking wider indications for Femara. U.S.
regulators in August agreed to speed up their review process on
whether to allow it to be used by women with breast cancer
immediately following surgery to remove a tumour.

Femara is the second in a new class of hormone-based
breast-cancer treatments called aromatase inhibitors to have
demonstrated an advantage over tamoxifen, currently standard
treatment for women with breast cancer.

INDIANAPOLIS, Nov. 30 /PRNewswire/ — A new blood test helps physicians manage their patients’ postmenopausal osteoporosis. The Roche Diagnostics’ Elecsys N-MID Osteocalcin test has now received clearance from the U.S. Food and Drug Administration (FDA) and determines the amount of osteocalcin, a protein found in the bone and in blood serum, which is an indicator of bone formation.

For women with Osteoporosis like Cherrie Burch, a 49-year old woman diagnosed six years ago with low bone mass and taking a weekly biphosphonate, a blood test that can help her and her physician manage her osteoporosis more closely is key.

“Right now, I can only get a bone scan once every two years because of the insurance reimbursement and because it takes that long for the scan to see changes in bone formation through that type of test. I’m diligent about taking my biphosphonate, but it would be nice to see results more frequently,” she said. “Osteoporosis is very prevalent in my family, and I want to do what I can now in order to avoid fracturing a bone in the future.”

“Osteoporosis is a serious, widespread and growing public health threat. The National Osteoporosis Foundation welcomes any new FDA cleared diagnostic options that will help patients address this all too prevalent disease,” said Judith Cranford, Executive Director of the National Osteoporosis Foundation.

Regular monitoring has shown that it can improve a patient’s compliance with their therapy. A recent study on the impact of monitoring on adherence and persistence with treatment for postmenopausal osteoporosis, showed that the group that was tested at 3-month intervals increased their adherence to therapy by 57 percent and stayed on their therapy for 25 percent longer compared to the group with no monitoring.(1)

According to the National Osteoporosis Foundation, osteoporosis and low bone mass currently affects approximately 44 million women and men in the United States, which is 55 percent of all people aged 50 and over. By 2010, the number could increase by another 7 million people.(2)

The U.S. Department of Health and Human Services estimates that 1.5 million people suffer from an osteoporotic-related fracture each year and that one out of every two women over 50 will have an osteoporosis-related fracture in their lifetime.

To test patients with the Roche Diagnostics Elecsys N-MID Osteocalcin test they need to have their blood drawn in the physician’s office or on-site at a laboratory, and it typically takes one to two days for the results.

Roche Diagnostics and Osteoporosis

As part of its market leading bone marker portfolio, Roche Diagnostics also offers the Elecsys Beta-CrossLaps test, a bone resorption marker, which monitors the efficacy of medications that slow or stop the natural process that dissolves bone tissue given to postmenopausal osteoporatic women. Using

the Elecsys Beta-CrossLaps test, physicians can check the efficacy of treatment as early as three months after its introduction. Roche Diagnostics also has the Elecsys PTH test, which determines intact parathyroid hormone in human serum and plasma for the differential diagnosis of hypercalcemia and hypocalcemia.

The Elecsys Osteocalcin N-MID test will be available for laboratories in November and should be available for testing of postmenopausal women with osteoporosis by the end of 2005.

About Roche and the Roche Diagnostics Division

Headquartered in Basel, Switzerland, Roche is one of the world’s leading research-intensive healthcare groups. Its core businesses are pharmaceuticals and diagnostics. As a supplier of innovative products and services for the prevention, diagnosis and treatment of disease, the Group contributes on a broad range of fronts to improving people’s health and quality of life. Roche is a world leader in Diagnostics, the leading supplier of medicines for cancer and transplantation and a market leader in virology. In 2004, the Pharmaceuticals Division generated 21.7 billion Swiss francs in prescription drug sales, while the Diagnostics Division posted sales of 7.8 billion Swiss francs. Roche employs roughly 65,000 people in 150 countries and has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai. Roche’s Diagnostics Division, with a uniquely broad product portfolio, supplies a wide array of innovative testing products and services to researchers, physicians, patients, hospitals and laboratories world-wide.

Roche Diagnostics’ North American headquarters is located in Indianapolis, Ind. (http://www.roche-diagnostics.us/ ). For further information, please visit our websites http://www.roche.us/ and http://www.roche-diagnostics.com/

   ELECSYS is a trademark of Roche.    For more information contact:   Lori LeRoy   Roche Diagnostics   317-521-7159   [email protected]   

1. Clowes et al, Journal of Clinical Endocrinology & Metabolism 89 (3): 1117-1123, 2004.

2. America’s Bone Health: The State of Osteoporosis and Low Bone Mass in Our Nation: The National Osteoporosis Foundation; February 2002.

Roche Diagnostics

CONTACT: Lori LeRoy of Roche Diagnostics, +1-317-521-7159,[email protected]

Web site: http://www.roche-diagnostics.us/http://www.roche.us/http://www.roche-diagnostics.com/

TUESDAY, Nov. 29 (HealthDay News) — Long-term research has found that laser surgery using magnetic resonance guidance is effective in treating cancerous liver tumors in some patients, German researchers report.

In this 12-year study, 839 patients at the University of Frankfurt received magnetic-resonance-guided, laser-induced thermotherapy for the treatment of liver tumors resulting from colorectal cancer. Under the procedure, laser light is used to destroy tumor tissue.

The report was to be presented Tuesday at the Radiological Society of North America’s annual meeting, in Chicago.

In the trial, lead researcher Dr. Martin Mack, an associate professor in the university’s department of diagnostic and interventional radiology, and colleagues treated 2,506 liver tumors and tracked patient survival to evaluate the long-term results of the procedure.

Using the laser technology, the average survival rate from the date of diagnosis was 3.8 years, which compared well with survival rates after traditional surgery, which are usually 1.5 to 5.0 years, the researchers reported.

According to Mack, laser ablation has many advantages over other treatments.

“Traditional surgical resection has higher morbidity and mortality rates than laser ablation,” Mack said in a prepared statement. “Laser treatment can be done on an outpatient basis under local anesthesia. Typically, the patient stays only a couple of hours, instead of a couple of weeks in the hospital after surgical liver resection [surgery],” he added.

In addition, laser surgery can be used to treat tumors in both halves of the liver — often during the same procedure. This is practically impossible in a traditional surgery where only the left or right lobe is surgically excised, the researchers note.

Moreover, if new tumors are found during follow-up exams, it is easier to do another laser treatment than to subject the patient to another invasive surgery.

“Many surgeons are already performing local ablation instead of resection, because they have already recognized the positive effect of local ablation,” Mack said. “I believe that minimally invasive tumor ablation together with chemotherapy will play the most important role in the treatment of tumors in the years to come.”

One expert, however, doesn’t think this method is as good as standard surgery for the treatment of liver cancer.

“I would be wary of making too much out of this new technology,” said Dr. Charles Cha, an assistant professor of gastrointestinal surgery and surgical oncology at Yale University School of Medicine.

“The long-term survival presented by Mack’s group is impressive and does demonstrate some promise for this new and experimental technology,” Cha added.

But, he noted, “the five-year survival after resection for metastatic colon cancer is around 40 percent, much higher than the 24 percent reported. In addition, there was no surgical arm to compare to, and the conclusion that this technology is better than resection is a bit of a stretch.”

The results with either cold (cryotherapy) or heat (radiofrequency ablation) for the treatment of metastatic colorectal cancer have not yet matched the results of surgery, which remains the gold standard, Cha said.

“Until more definitive evidence is available, patients should not consider this technology as a replacement for standard surgical therapy, but rather as an alternative if surgery is not possible,” he said.

Another expert agreed.

“This is the only group that has really done this procedure,” said Dr. Ronald W. Busuttil, chief of the division of liver and pancreas transplant at the University of California, Los Angeles School of Medicine. “It has not been duplicated.”

Busuttil said he thought that there are a lot of other methods that can be used to treat liver tumors caused by colorectal cancer that do not include surgery.

“For this technique to really come to the fore, it needs to be compared against surgery and radiofrequency ablation,” he said.

“It’s interesting,” Busuttil said, “but I don’t know if it’s ready for prime time.”

More information

The National Cancer Institute can tell you more about liver cancer.

SOURCES: Ronald W. Busuttil, M.D., Dumont Professor of Transplantation Surgery, and chief, Division of Liver and Pancreas Transplant, UCLA School of Medicine; Charles Cha, M.D, assistant professor, gastrointestinal surgery and surgical oncology, Yale University School of Medicine, New Haven, Conn.; Nov. 29, 2005, presentation, Radiological Society of North America annual meeting, Chicago~-GEN~~-LIV~~-COL~

By Anne Harding

NEW YORK (Reuters Health) – Teen motherhood does not always
ruin a young woman’s life, but instead may drive her to greater
maturity and ambition, according to the results of a small,
long-term study.

“For some of them it’s a turning point experience,” Dr. Lee
SmithBattle of St. Louis University Doisy College of Health
Sciences, the study’s author, told Reuters Health. “They now
have more educational aspirations and want to do better and
turn their lives around because they have this child to care
for.”

SmithBattle has been following a group of former teen moms
for 17 years, interviewing them every four years and also
talking with the women’s parents, partners and children. In the
study, published in the November issue of the Western Journal
of Nursing Research, she reports on the moms at the 12-year
point, when the women were in their early 30s.

The study included 11 adolescent girls, who were an average
of 17 years old when they delivered an infant. About half of
the subjects had dropped out of high school.

Women fell into three groups, SmithBattle notes, those for
whom motherhood helped provide a coherent structure or
“narrative spine” for their lives, and who fared well in their
adult love relationships and work; those who also drew meaning
and structure from motherhood, but did not fare as well in
their adult relationships and work; and those for whom
mothering did not provide structure or meaning. The study
includes the stories of three young women, each representing
one of these groups.

Support from family and community is essential for helping
teen moms to find their way successfully, SmithBattle notes.

Previous research exaggerated the difficulties teen moms
face, she adds, by comparing women who gave birth in their
teens with women who first became mothers in their 20s.

“That’s a very unfair comparison because teen mothers tend
to have lots of adverse childhood experiences and they tend to
be more disadvantaged than women who wait (to) have children,”
SmithBattle said. Newer studies that have controlled for such
factors have found teen moms actually fare as well as or even
better than women from similar socioeconomic backgrounds who
did not have children early, she added.

Research has also shown that many teen moms do better over
time, eventually achieving independent, stable lives. “For some
teen moms becoming a parent can turn around their lives in
really positive ways, they want to do better for themselves
because of the child; they want to do better in school because
of the child,” SmithBattle said.

Motherhood, she added, can be a rite of passage into
adulthood, similar to what going to college may be for more
advantaged teens.

But if teen moms don’t receive adequate support, they may
fall prey to the factors that contributed to their becoming
pregnant as teens in the first place, SmithBattle’s study
shows.

One way society can help young women avoid teen pregnancy
in the first place is to give them a sense of a real, positive
future, she said. In addition to providing support for young
women who do become mothers, efforts should be made to wipe out
stereotypes and stigmas many hold about these women.

“The kinds of stereotypes we hold about teen mothers are
not very helpful, because teen mothers feel very stigmatized by
the assumption that they’re failures,” she said. People should
understand, she added, that teen motherhood isn’t “an
unmitigated disaster.”

SOURCE: Western Journal of Nursing Research, November 2005.

By Patricia Reaney

LONDON (Reuters) – Pre-school children can show early signs
of a mental disorder which can be diagnosed and treated to
prevent problems later in life, a leading psychologist said on
Monday.

Children as young as 2 or 3 years may suffer from
depression, anxiety, disruptive behavior and attention deficit
hyperactivity disorder (ADHD).

“A lot of substantial psychiatric problems are actually
starting and are identifiable much earlier than we ever
thought,” said Adrian Angold of Duke University in North
Carolina.

“Early-onset depression is thought to begin in the teenage
years but in fact it is turning out to be as early as we can
begin to measure it. We ought to be thinking much more about
who are the children who already have these disorders.”

In a study of 307 pre-school children based on interviews
with parents in the United States, Angold found that about 17
percent met standard criteria for having a mental disorder.

“About one in 10 have symptoms that meet criteria for a
disorder plus also have some significant impairment to leading
a normal life,” said Angold, who presented the research at a
meeting of the Institute of Psychiatry in London.

Early signs of problems include hyperactivity, difficulty
concentrating, aggressiveness, disruptiveness, difficulty
playing with other children and social and separation anxiety.

“We are talking about patterns of behavior,” said Angold.
“What is striking about this is that it suggests that the rate
(of disorders) in these much younger children, aged 2-5, are
not very different from what they will be in children of 9 or
14.”

He admitted that some children will grow out of the
problems but added that others would benefit from treatment
such as behavioral therapy, psychotherapy and medication.

The diagnosis of a disorder in young children is based
mainly on information from parents and teachers. Angold said
there is little medical evidence for treating anxiety and
depression in young children but youngsters with disturbed
behavioral problems could benefit from treatment.

“There is good evidence that if you intervene relatively
early on with parent-training programs it could be very
helpful,” he added.

“These are kids who deserve to be taken notice of by the
mental health system. The vast majority of them have not been
identified and receive no treatment.”

DALLAS, Nov. 28 /PRNewswire/ — Presbyterian Hospital of Dallas (PHD) has unveiled an innovative surgical option — available for the first time in North Texas — to correct a life-threatening abnormal heart rhythm known as atrial fibrillation (AF). The new Epicor(TM) Cardiac Ablation System (St. Jude Medical, MN) uses high intensity focused ultrasound (HIFU) — a unique energy source — allowing surgeons to treat AF from outside a patient’s beating heart without invading the heart muscle or using a heart-lung bypass machine during surgery. PHD joins such centers as Northwestern Memorial Hospital, Chicago and Jewish Hospital, Louisville where the technology is available.

Atrial fibrillation is a widespread cardiac rhythm disorder in which the upper chambers of the heart do not beat effectively because of abnormal electrical activity. AF results in reduced cardiac output, exacerbates heart failure and can result in the pooling and clotting of blood in the heart, leading to stroke or other neurological problems. According to the American Heart Association, about 2.2 million people in the United States have AF, making it the most common chronic heart-rhythm disturbance.

“Ultrasound provides a safer energy source for restoring heart rhythm,” said William H. Ryan, III, MD, cardiovascular surgeon on the medical staff at Presbyterian Hospital of Dallas where he performs the procedure. “Unlike radiofrequency and microwave energy — used in other ablation techniques — HIFU avoids the potential for damage to structures around the heart,” he explained. The device allows surgeons to avoid use of the heart-lung bypass machine, which can introduce new complications. Epicor also holds potential to perform the procedure minimally invasively, enabling a broader population of patients to be considered.

Many AF patients have been treated with medications to slow the heart and prevent blood clots. These powerful medications, which some patients will need for the rest of their lives, have a number of side effects. Catheter-based treatments have also been performed; however, the procedure time can be long and may not always be successful.

Currently, the Cox-Maze procedure is considered one of the most effective surgical treatments for AF, eliminating arrhythmia in nearly 97 percent of patients treated. However, only a handful of surgeons — including Dr. Ryan — perform the Cox-Maze procedure, due to the technically challenging and invasive nature. Additionally, it requires patients to go on a heart-lung bypass machine, so it has been reserved mostly for those needing additional heart procedures, such as a coronary artery bypass graft or valve repair.

Using Epicor, surgeons complete a “simplified Maze” pattern by delivering HIFU energy to the surface of the heart muscle — a process that takes about 10 minutes. HIFU causes scar tissue to appear along the “maze” patterned on the heart’s surface. The scar tissue serves to guide the heart’s electrical current along the appropriate path — much as a river flows through two embankments — thus correcting the AF.

PHD is a regional cardiovascular referral center, with more than 30 cardiologists and cardiothoracic surgeons — including Dr. Ryan — on the medical staff, who perform some of medicine’s most challenging heart-related procedures. Dr. Ryan is one of only 13 surgeons in the world who has performed more than 200 Ross procedures — a complex surgery to replace a damaged aortic valve with a patient’s own pulmonary valve; and subsequently replace the pulmonary valve with a human donor valve. For more information on Presbyterian Hospital of Dallas heart programs and other services, visit http://www.phscare.org/ or call 1-800-4-Presby (1-800-477-3729). For more information on St. Jude Medical, Inc. visit http://www.sjm.com/ .

About Presbyterian Hospital of Dallas

Established in 1966, Presbyterian Hospital of Dallas (PHD) has provided nearly 40 years of service and is the flagship hospital of Presbyterian Healthcare System, a part of the faith-based, non-profit Texas Health Resources system. PHD is a recognized clinical program leader, providing technologically advanced care to patients in Women and Infants, Cardiovascular, Orthopedic, Neuroscience, Digestive/Surgery, Oncology, and Ambulatory Care services. PHD is a regional referral hospital for North Texas and beyond. The 866-bed facility maintains approximately 4,000 employees and an active medical staff of more than 1,000 physicians.

Presbyterian Hospital of Dallas

CONTACT: Linda Goelzer of Presbyterian Hospital of Dallas,+1-214-345-4960, or pager, +1-214-759-5535, or [email protected]

Web site: http://www.texashealth.org/http://www.phscare.org/http://www.sjm.com/

By Maureen Maratita

HAGATNA, Guam (Reuters) – Can wartime suffering have a
price? According to a bill making its way through the U.S.
Congress, losing a spouse or a parent is worth $25,000.

The figure is part of an act intended to compensate the
Chamorro people of the Pacific island of Guam for atrocities
during the Japanese occupation from December 1941 to July 1945.
The island is now a U.S. territory and first came under U.S.
control in the 19th century.

About $85 million has been earmarked for survivors and
remaining family members through the Guam World War Two Loyalty
Recognition Act introduced in Congress earlier this year.

The list of reparations is stark: For rape, paralysis or
loss of a limb, $15,000; for forced labor, scarring or
disfigurement, $12,000; for internment or forced march,

$10,000.

Marian Johnston Taitano is 86, the daughter of a Chamorro
mother and an American father from Tennessee who was working on
Guam in the civil service in 1941.

When the Japanese invaded, Taitano was 21 and engaged to a
U.S. Navy ensign, a gunnery officer. His ship, the USS Penguin,
was returning from patrol when the Japanese attacked.

“He happened to be the first American that shed his blood,”
Taitano said. “When the Japanese came, the fire (from the
planes) cut him across the chest.”

His shipmates put the body on a raft and pushed it to
shore.

DISPLACED AND IMPRISONED

Taitano’s father, William Johnston, was taken prisoner and
then shifted to Japan in 1942 with about 500 American military
personnel and civilians. She never saw him again.

“Can you imagine what it was like to watch your father on
one of those trucks?” she said.

Taitano has kept everything of her family’s documents from
the war years.

“My father was the second one who died in the concentration
camp in Japan,” she said. “I have a portion of my father’s
diary, from the day Guam was bombed until the day he died. I
haven’t been able to read it through completely.”

Taitano’s family was displaced throughout the occupation
and she was part of a group of Chamorros forced to march to a
prison camp in Manenggon in June 1945, a journey many did not
complete.

“I saw them fall by the wayside,” said Taitano, who was at
the camp for about a month before the war ended. “It seemed
like eternity. Whatever food we had we held off from eating it
to give it to the babies.”

Taitano remembers seeing the liberating U.S. troops arrive.

“When I looked up toward the mountain, they looked like
Greek gods,” she said. “They didn’t look like GIs to me.”

One of Taitano’s brothers developed tuberculosis during
confinement and later died.

The act is not the first attempt to compensate indigenous
islanders for wartime suffering or recognize the territory’s
long-standing loyalty to the United States.

In 1945, the Guam Meritorious Claims Act offered
compensation to surviving Chamorros but many were unaware of
its existence.

In 1946, Guam’s Chamorro population was 22,628. A year
later, only 711 death and injury claims were submitted to the
U.S. Congress.

The U.S. Navy Department, which governed the island after
the war, set a limit of $4,000 on death claims, making only one
such award. Some other claims paid upwards of $3,000 and

$1,000.

TIME RUNNING OUT

Since then, a variety of bills and commissions have
maintained the issue of reparations for Guam, culminating in
2002 with an act signed by President George W. Bush to create
the Guam War Claims Review Commission.

On December 8 and 9, 2003 — 62 years after the Japanese
occupation began — a five-member commission heard testimony in
Guam from survivors, including Taitano.

“I remember a lot of things. I just started to speak out
recently. It took a long time,” she said. “Coming close to home
again, it hurts.”

The 2005 act measure gathered the support of 98 co-sponsors
from both sides of the U.S. House of Representatives and has
one more committee to clear before debate starts on the floor.

Support from the Senate is expected to be equally firm.

Though the Bush administration has offered no overt backing
for the act, Guam’s Democratic delegate to Congress, Madeleine
Bordallo, remains optimistic it will become law.

But time is marching. Most of the Chamorro survivors are
elderly and infirm.

In 1979, 11,370 people testified before a government of
Guam reparations committee. In 2003, fewer than 200 testified.

“I can probably do without it but there are other people
that have been waiting and waiting,” Taitano said. “Poor Guam.
After 60 years, I think we should be recognized.”

By Paul Hoskins

KNOCKVICAR (Reuters) – As an autumn gale assails his
hilltop cottage, Pepijn Martius sits beside a peat-fired stove,
savoring the earthy smell and glowing warmth that has cost him
little more than a sore back.

“For my pocket it’s much better,” said the 27-year-old
Dutchman. “If I would heat with oil or gas I would spend
probably quadruple the amount of money that I spend on peat.”

“And it keeps me warm twice,” he adds, referring to the
physical labor involved in harvesting the dark, carbon-rich
earth which is the first stage in the formation of coal.

The clumps of peat, or turf, are dug from Ireland’s bogs —
waterlogged land formed after the last Ice Age. They must be
turned regularly and stacked to dry before hauling them home.

It’s a time-consuming task but soaring oil prices mean a
new generation is rediscovering the tradition.

Irish-born Martius reckons 150 euros buys enough peat to
run his central heating and provide hot water for a year — a
fraction of Ireland’s average annual domestic gas bill which,
after a recent 25 percent price hike, is set to hit 946 euros.

A short, bumpy ride from his home in County Roscommon is
the source of his energy: a blustery bog where the only respite
for chilled bones comes from a black, 8-foot wall of earth
dividing the original field from years of peat digging below.

Here, despite using mechanical cutters, owner Jimmy
McLoughlin is struggling to meet demand.

“Up to about five years ago it was down to nearly nil but
the oil price changed all that,” said McLoughlin. “I didn’t
have enough turf this year for people.”

“SQUELCH AND SLAP”

The 52-year-old farmer charges 12 euros for cutting a row
which contains about 1,000 peat bricks. For an extra fee he’ll
turn, dry and deliver but Martius prefers to do that himself.

“It adds a kind of quality to your life,” says the hotel
worker. “It’s the outdoors and you’re working for your fuel.”

Those with memories of a less affluent island have a
different, but no less romantic, view of what Irish poet Seamus
Heaney called “the squelch and slap of soggy peat.”

The Nobel Laureate often exploits the discovery of human
remains in “the display-case peat” to delve into Ireland’s
troubled past and history’s cruel, cyclical nature.

John P. Flanagan, 80, is one of thousands of workers who
spent World War Two, or “The Emergency” as it is known in
Ireland, digging peat by hand to keep trains running and
bakers’ ovens alight after coal imports dried up.

“There’d be 40 men working on this bank here and another 30
… over there,” he says, pointing across the deserted field,
near McLoughlin’s plot, with a turf spade known as a “slean.”

Peat has been used for fuel since prehistoric times but it
wasn’t until the 18th century that deforestation, spurred by
British shipbuilding, made it Ireland’s major source of fuel.
By the 1840s, when the Great Famine killed an estimated 1
million people, peat was often the only source of heat.

OIL CRISIS

Small wonder that Heaney’s “kind, black butter” plays such
an important part in the national consciousness.

“I was quite impressed with the way people talk about it,”
said Martius. “It’s part of their lives.”

In the nearby midland town of Lanesborough sits a more
modern manifestation of peat’s significance and of a postwar
policy to reduce Ireland’s dependence on imported energy.

Opened in 2004, the 100-megawatt Lough Ree power station is
one of two new peat-fired plants belonging to the state-owned
Electricity Supply Board (ESB), which has been generating power
from peat since the 1950s.

“Strategically, of course, they worked out very well and
the 1970s proved that with the oil crisis when peat power
stations came into their own,” said station manager Pat
Treanor.

A 15-year contract with state peat producer Bord Na Mona
that caps price rises gives ESB customers some protection from
oil prices that have roughly doubled since 2003.

From the roof of Lough Ree it’s easy to see why there’s
little chance of a breakdown in the supply chain that feeds its
furnaces with 800,000 tons of peat annually. No pipelines or
oil tankers, just a small train ferrying fuel from the bogs.

Such large-scale exploitation has forced Bord na Mona to
diversify into renewable energy to secure its future.

“There’s a finite amount of peat on the bogs that’s viably
harvestable — 15 years is all these stations have,” said
Treanor. “At night, with the weather like this now, wind energy
probably already meets 20, 30 percent of the whole
requirement.”

For environmentalists, it’s too little, too late.

“Bogs are a huge store of carbon dioxide so if you do start
cutting and burning them you’re actually releasing a lot of
greenhouse gas into the atmosphere,” says Caroline Hurley of
the Irish Peatland Conservation Council (IPCC).

The bogs also provide a haven for vulnerable birds,
particularly waders and ground nesters like the golden plover
and red grouse, and to plants like butterworts and bladderworts
which have adapted to the poor soil by becoming carnivores.

But peat’s economic importance to the traditionally
depressed midlands means Hurley faces an uphill battle: “I
don’t think people are worried about burning peat to be honest
… they are only too happy to use a cheaper substitute.”

Given that Ireland is 17 percent bog land — a proportion
only exceeded by Finland, Canada and Indonesia — it is not
easy to persuade small-scale farmers of the environmental
urgency.

“I depend on it at certain times of the year when there
isn’t any other income,” says McLoughlin.

Or, in the words of one Irish proverb: “He who has water
and peat on his own farm has the world his own way.”

By Joe Fahy, Pittsburgh Post-Gazette

Nov. 24–The Pittsburgh Mercy Health System has sold its psychiatric hospital on the North Side to a Louisville, Ky., company and will transfer those services, with a reduced number of beds, to its Uptown flagship early next year.

Officials said yesterday that Mercy’s North Shore campus, at 1004 Arch St., was sold for $5.4 million to Kindred Healthcare, which plans to convert the facility into a 110-bed hospital for patients needing long-term acute care and subacute skilled nursing care.

After renovations, Kindred plans to open the new hospital by the fourth quarter of 2006, said Mary Pat Stroia, Kindred’s director of business development.

Kindred already offers long-term acute care hospital services in Oakdale and Beaver, and also operates hospitals, nursing centers, institutional pharmacies and a contract rehabilitation services business in many other states.

Inpatient behavioral health services and evaluation and referral of behavioral health emergencies will continue at the North Shore campus until March, Ken Eshak, Mercy Health System’s president, said in a statement. Those services, pending regulatory approval, will then be provided at Mercy Hospital of Pittsburgh, Uptown.

Mercy’s North Shore facility currently has 126 full-time equivalent employees. “We expect a majority of those people will move with the programs and services,” though other employees might fill other positions within Mercy’s health system, said Mercy spokeswoman Linda Ross.

Some might be offered jobs at Kindred’s new facility, Ms. Stroia said.

Mercy Hospital of Pittsburgh will expand its emergency department to include a 24-hour evaluation and referral center for behavioral health emergencies.

Two unoccupied medical-surgical units will be converted into a 24-bed adult behavioral unit and a 10-bed unit for substance abusers who have mental illnesses or mental retardation.

Due to limited space, those units will offer fewer beds than the existing North Shore facility, which has 31 beds for adults and 20 for people with mental health and substance abuse problems, Ms. Ross said.

Mercy is still working to find space to relocate a unit that serves the psychiatric needs of geriatric patients. Ms. Ross said the current unit has 12 beds for those patients.

The Arch Street building was erected in 1953 by the Sisters of Divine Providence, who operated it for four decades as Divine Providence Hospital. It was sold in July 1993 to Pittsburgh Mercy Health System and was renamed Mercy Providence Hospital. It operated as a general services hospital until January 2004, when it became an inpatient behavioral health facility.

Mercy Behavioral Health, which provides outpatient mental health and substance abuse services, will not be affected by the consolidation of inpatient behavioral health services, Mercy officials said. Those services and medical offices will continue at the Arch Street site and will not be affected by the renovations, Ms. Stroia said.

—–

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Copyright (c) 2005, Pittsburgh Post-Gazette

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Families gathered around the Thanksgiving dinner table might consider giving thanks for the bacteria-busting ability of cranberry juice, say dental researchers who have discovered that the beverage holds important clues for preventing cavities.

A team led by oral biologist Hyun (Michel) Koo, D.D.S., Ph.D., at the University of Rochester Medical Center has discovered that the same traits that make cranberry juice a powerful weapon against bladder infections also hold promise for protecting teeth against cavities. Koo found that cranberry juice acts like Teflon® for teeth, making it difficult for the bacteria that causes cavities to cling to tooth surfaces. Stickiness is everything for the microbe Streptococcus mutans, which creates most cavities by eating sugars and then excreting acids that cause dental decay.

“Scientists believe that one of the main ways that cranberries prevent urinary tract infections is by inhibiting the adherence of pathogens on the surface of the bladder. Perhaps the same is true in the mouth, where bacteria use adhesion molecules to hold onto teeth,” Koo said.

Koo’s team also found evidence that cranberry juice disrupts the formation of the building block of plaque, known as a glucan. Like a mason using cement to build a wall brick by brick, bacteria use enzymes known as glucosyltransferases to build dental plaque piece by piece, quickly forming a gunky fortress that covers the tooth and gives bacteria a safe haven to munch on sugar, thrive, and churn out acid. Koo’s team found that cranberry juice prevents bacteria from forming plaque by inhibiting those enzymes and by stopping additional bacteria from glomming on to the ever-growing goo.

“Something in the cranberry juice disarms the pathogens that cause tooth decay,” Koo said.

But don’t even think about running to the juice aisle in the grocery store to prevent tooth decay, Koo said. The sugar that is usually added to cranberry juice can cause cavities, and the natural acidity of the substance may contribute directly to tooth decay.

Instead of advocating mass consumption of cranberry juice, Koo hopes to isolate the compounds within the juice that pack an anti-cavity punch. The substances could then be added to toothpaste or mouth rinse directly. He is working closely with Nicholi Vorsa, Ph.D., a plant pathologist and director of the Blueberry and Cranberry Research and Extension Center at Rutgers, to isolate the compounds in juice that are most protective.

A food scientist turned dentist, Koo became fascinated with research and is an expert on natural substances that can improve oral health. Currently, as an assistant professor in the Eastman Department of Dentistry and a researcher in the Center for Oral Biology, he is focusing on ways to stop the bacteria that ultimately causes cavities. Such research, if successful, would improve the oral health of millions of people worldwide.

Koo’s work with cranberry juice is one of nine projects funded through a special program by the National Institutes of Health to test the berry’s reputed health-enhancing effects. The other projects focus on topics such as urinary tract infections and how the body processes cranberry juice.

“There is a massive number of publications about the effect of cranberries on urinary tract infections,” said Koo, “but there are only few studies on the dental side.”

The cranberry research will be published in the January 2006 issue of Caries Research. Other authors include dentist Patricia Nino de Guzman, dental student Brian Schobel, and microbiologist Anne Vacca Smith, Ph.D., and dental researcher William Bowen, D.D.S., Ph.D.

As Thanksgiving approaches, Koo said that only cranberry juice is under study, so diners shouldn’t reach for the cranberry sauce just to stop the tooth decay brought on by carbohydrate-laden foods like mashed potatoes, rolls, and pumpkin pie. He recommends traditional measures to avoid cavities: Brush your teeth after dinner, don’t snack often, stay away from sugary foods, use a mouth rinse, and get regular dental checkups.

On the World Wide Web:

University of Rochester Medical Center

By Gasper, Mason C; Gilchrist, James M

Measurement of serum enzymes is a widely used screening diagnostic test for suspected muscle disease. Creatine kinase (CK), otherwise known as creatine phosphokinase (CPK), is the preferred screening tool because, unlike other enzymes found in skeletal muscle (e.g., lactate dehydrogenase, aldolase, and transaminases), CK has relative predominance in skeletal muscle, is not falsely elevated by hemolysis, and being unbound in cell cytoplasm is readily released in cellular injury.1,2 Despite these advantages, CK may create diagnostic uncertainty when an elevated level is found in a mildly symptomatic or asymptomatic patient. Not only are myopathy and cardiac disease among possible causes of the elevated CK, but a false positive CK elevation must be considered, such as in transient non-pathological situations (e.g., cramps, post-exercise) or in those with normally high baseline CK levels. To address diagnostic uncertainty in the use of serum CK levels, this paper will describe the structure and function of CK, summarize common reasons for elevated CK levels in normal individuals as well as those with myopathy or neuropathy, and finally develop a diagnostic strategy for mildly symptomatic or asymptomatic patients suspected to have myopathy. Additionally, a strategy for suspected myopathy in statin- treated patients will be addressed.

STRUCTURE AND FUNCTION OF CK

Cytoplasmic CK, a protein-product of chromosome 19, is an 86,000 molecular weight dimer molecule that produces adenosine triphosphate for use in muscle cells by catalyzing the transfer of a high energy phosphate bond from creatine phosphate, the major storage reservoir of energy during muscle at rest, to adenosine diphosphate.3 CK exists in relatively tissue-specific forms called isoenzymes, allowing for greater diagnostic precision. CK-MM makes up over 95% of total CK in skeletal muscle, whereas CK-BB comprises most of the total CK in brain tissue.4,5 Although CK-MB is a useful measure of cardiac muscle infarction, CK-MM is the most abundant isoenzyme (over 60%) in the myocardium.4,5 Total CK content is largely contained in skeletal muscle, exceeding the myocardial concentration by as much as twofold.4 Consequently, serum normally contains CK provided predominantly from skeletal muscle, almost exclusively as the CK-MM isoform.5

Aldolase, present in skeletal muscle, liver, and erythrocytes, is not considered a particularly good screening test for myopathy because the enzyme is not released readily with muscle injury and is often technically compromised by serum sample hemolysis.1,2 However, approximately 10% of active inflammatory myopathies may have normal CKs and elevated aldolase.6 We have had a case in which a patient with isolated persistent elevated serum aldolase levels was found to have florid vasculitis and myositis on muscle biopsy in the face of a normal examination and electromyography, and near-normal CK levels. Therefore, aldolase may be useful in those situations with a high clinical suspicion of myopathy and normal CK levels.

ELEVATED SERUM CK LEVELS IN THE NORMAL POPULATION

Normal values of CK are difficult to estimate due to individual and population variation in serum levels. Persistent high levels of CK may be seen in blacks compared with other races, males compared with females, and in those with large muscle mass.7,8 In one study of normal adults, reported mean total CK was 147 U/L (range of 7 to 284 U/L) for 57 black males, 61 U/L (range 35 to 87 U/L) for 44 white males, 66 U/L (range 16 to 116 U/L) for 90 black females, and 37 U/L (range 19 to 55 U/L) for 99 white females.7 This study highlighted a lack of specificity when laboratory reference values for serum CK do not consider race.

Transient elevations in CK levels are common after reversible causes of muscle injury such as trauma (including injections or needle electromyography), vigorous exertion, or even muscle cramping. A serum sample drawn after electromyography (EMG) in a normal patient will increase up to three fold within the next 24 hours and may show a false positive CK result suggesting myopathy. Therefore, it is important to draw CK levels before EMG studies. In one report, CK levels rose from a mean baseline of 53 U/L in 10 patients to a maximum mean CK of 91 U/L 12 to 24 hours after an EMG; a return to baseline occurred after 48 to 72 hours.9

Vigorous exertion may increase serum CK levels transiently. After a marathon, CK levels in 7 runners were reported to maximally increase 24 hours after the race to a mean of 1404 U/L (range 683 to 2261 U/L).10 In this study, mean CK levels approached baseline after about 1 week. In general, one week of avoidance of exertional activity should be sufficient to ensure accurate measurement of CK levels in a frequently exercising patient. Excessive skeletal muscle exertion resulting in CK elevations can also be seen in certain non- neuromuscular pathological events such as neuroleptic malignant syndrome, convulsive seizures, acute psychosis and violent behavior.2

A single non-pathological cramp can also cause a substantial rise in CK levels. In one published case,11 after a single severe cramp in a gastrocnemius muscle lasting several minutes, serum CK elevated from 117 IU/L (normal

SERUM CK LEVELS IN MUSCLE DISEASE

The degree of CK elevation in muscle disease largely reflects the underlying disease process, and is predominantly due to myonecrosis or membrane defects2, 5 (Figure 1: Serum CK level and time course of various myopathies and Table 1: Expected serum CK levels amongst common myopathies). Highest elevations of CK are seen with conditions causing muscle fiber necrosis as in dystrophinopathies (e.g., Duchenne and Becker muscular dystrophy), rhabdomyolysis, malignant hyperthermia, neuroleptic malignant syndrome, and severe polymyositis. More indolent myopathies, such as fascioscapulohumeral muscular dystrophy, myotonic dystrophy, and inclusion body myositis usually have lesser degrees of CK elevation. Disorders causing muscle atrophy without cell membrane damage often have normal CK levels, as in steroid-induced myopathy, hyperthyroidism, channelopathies and mitochondrial myopathies.

Table 1: Expected serum CK levels amongst common myopathies

Most inflammatory myopathies (i.e., polymyositis, dermatomyositis) will have abnormal CK levels during the disease course, although the extent of CK level elevation can be quite variable.12 In polymyositis and dermatomyositis, CK levels improve on steroids, usually regardless of whether weakness improves and are not particularly useful to monitor success or failure of treatment.12 An acute increase in CK levels in these disorders, however, may be a harbinger of relapse. As patients with chronic myopathies lose muscle mass and strength, CK levels will drop and may approach normal in later stages of muscular dystrophy2, 12 (Figure 2: CK values in a large population of autosomal recessive Limb-girdle muscular dystrophy by duration of disease).

Diagnostic confusion sometimes occurs in destructive myopathies as regenerating fibers may release a larger proportion of the CK-MB fraction compared with mature muscle cells, which primarily release CK-MM when injured.1, 5, 13 In these cases, higher serum levels of CK-MB do not necessarily indicate coexisting cardiac disease in the presence of destructive myopathies.

SERUM CK LEVELS IN NERVE DISEASE

Serum CK levels are not commonly thought to be elevated in neurogenic disease such as mononeurpathy or polyneuropathy, and for the most part, this is true. However, in certain neurogenic diseases, such as amyotrophic lateral sclerosis14, spinal muscular atrophy and Guillan Barre syndrome,15 there may be an elevation of CK, though usually no more than five times normal. One proposed mechanism is damage due to increased work requirement on muscle fibers in weakened muscle,2 though this seems doubtful given that other causes of weakness do not cause elevations of CK. These neuropathies cause denervation of muscle fibers and the ongoing entrophic changes to the muscle fiber membrane may result in leakage of CK. Another possibility would be elevation of CK secondary to frequent cramping, a common symptom in acute neurogenic diseases such as amyotrophic lateral sclerosis and Guillain-Barre syndrome.11

Figure 1: Serum CK level and time course of various myopathies.

COMMONLY ENCOUNTERED PRIMARY CARE SITUATIONS INVOLVING ELEVATED CKs

Three situations commonly confront primary care providers: the patient complaining of myalgias (muscle pain or tenderness) without weakness, the asymptomatic patient found to have elevated CK levels, and suspected myopathy in a patient taking cholesterol-lowering medications. A proposed diagnostic algorithm is presented in Figures 3 and 4.

SITUATION 1: MYALGIAS

Muscle pain is common in normal individuals. One-third to 80% of the population reports muscle pain at some point and many of these patients will have no abnormal test findings.16 Since few cases of myalgia will likely be due to myopathy, screening tests with high specificity are useful to select those few patients in whom more sensitive (and more invasive) testing will be necessary.17 Common screening tests for myopathy include serum CK and erythrocyte \sedimentation rate (ESR), which have been shown to be highly specific (81% and 93%, respectively) for suspected myopathy.17 ESR, while less sensitive than CK in diagnosing myopathy,17 is helpful in evaluating common causes of myalgias that do not cause elevated CKs, e.g., polymyalgia rheumatica. Other potentially useful initial serum testing includes aldolase and thyroid stimulating hormone (TSH). Patients with thyroid disease may show myopathic clinical manifestations that may or may not result in elevated CK levels.

Figure 2: CK values in a large population of autosomal recessive Limb-girdle muscular dystrophy by duration of disease (shows reduced serum CK levels with reduction in muscle mass in limb girdle muscular dystrophy).

If these screening blood tests are abnormal, further investigation should then proceed to EMG testing and possibly, to muscle biopsy as well as other tests (e.g., ischemic exercise testing and DNA evaluation). EMG and muscle biopsy are more invasive tests and typically the second and third line diagnostic tests in screening and confirming muscle disease. Muscle biopsy is the most sensitive diagnostic test for myopathy (81%17) and should be employed in patients with a positive screening test (e.g., confirmed weakness, elevated CK or ESR, abnormal EMG). With normal screening tests, the yield for a significant finding on muscle biopsy is low. One study reported that among 20 patients with modest elevations of CK, a normal neurologic examination and nondiagnostic EMG, only one was found to have a diagnostic muscle biopsy.18

Other tests may also be helpful, including genetic testing for those with a significant family history of myopathy (to test for dystrophinopathy or carrier state, for example) or ischemic exercise testing for those with exercise-related myalgias or weakness, suggesting a possible metabolic myopathy.

SITUATION 2: ASYMPTOMATIC INCREASED LEVELS OF CK

Mild CK elevations are often detected during evaluation of heart disease or routine testing for other medical conditions. Out of 100 consecutive patients seen with elevated CKs after admission to an Austrian medical service,19 the diagnosis was acute myocardial infarction (32%), drug-related (32%), trauma after a fall (24%), hematoma (17%), intramuscular injection (16%), and malignancy (11%). Only 2% of the CK elevations were explainable by neuromuscular disease. Gender, race, age and recent exercise must also be considered in the situation of mildly elevated CK.

A persistent unexplained elevated CK level, usually three- to 10- times above normal, in an otherwise strong healthy asymptomatic individual with a normal EMG and muscle biopsy is termed idiopathic hyperCKemia.2 Numerous studies report the results of detailed neuromuscular evaluation in patients with suspected idiopathic hyperCKemia. After considering common causes of asymptomatic elevated CK levels, such as exertion, thyroid disease or other nonpathological reasons of raised CK levels, identifiable causes for suspected idiopathic hyperCKemia are found in approximately one out of every six cases after extensive testing, including EMG and muscle biopsy.20,21 Neuromuscular diseases subsequently diagnosed in patients with idiopathic hyperCKemia included inflammatory, mitochondrial, and metabolic myopathy among other causes.20,21 The prognosis of idiopathic hyperCKemia is good: a long-term (mean 7 years, range 4-18 years) follow-up study of 31 patients diagnosed with idiopathic hyperCKemia reported no clinical deterioration in 74% of the patients who had a final evaluation.22

For unexplained elevations in CK, we generally perform an EMG. If this is normal, and the patient remains without weakness or significant symptoms, a muscle biopsy is best deferred. The diagnostic yield of muscle biopsy in this setting is low, and even if a diagnosis were made, it would be difficult to make an asymptomatic patient feel better than they already are, thus providing little benefit to the patient. Uncommonly, elevated CK in an asymptomatic individual may be an indicator of either pre- symptomatic or carrier status for an inherited muscle disease, such as muscular dystrophy. The same ethical considerations come into play in this situation as for any asymptomatic patient seeking genetic testing, as for example, Huntington’s disease23 and referral to a center with genetic counseling is appropriate before any genetic testing is done. Continued follow-up of the patient for the development of symptoms or signs suggestive of myopathy is important, though regular testing for CK levels is uncommonly useful as further testing will be predicated not on the already known elevation of CK, but rather on the history and exam.

Figure 3: Diagnostic Algorythm for incidental high CK and myalgias

SITUATION 3: ELEVATED CK WHILE ON A CHOLESTEROL-LOWERING AND OTHER DRUGS

Various medications have been associated with elevated CK levels24, 25 (Table 2: Commonly used medications associated with elevated CK levels). Although most medications that lower cholesterol have been associated with muscle disease, the statins, being the most common cause of cholesterol-lowering agent myopathy (CLAM), will be our primary concern. Statins (HMG CoA reductase inhibitors) are considered first line therapy in reducing low density lipoprotein levels, 26 however, concerns about adverse effects, including CLAM, may be behind reports of underutilization of statins in populations that would benefit from such medications.27 Moreover, concerns of myopathy have led to extensive monitoring of asymptomatic statin-users, leading to increased costs and discontinuation of a medically important therapy.27

CLAM is clinically variable, manifesting in its most acute state as rhabdomyolyisis, or in a more indolent manner as isolated elevations in serum CK levels or subjective complaints of myalgias. The mechanism of statin-induced muscle injury is not completely understood, although a leading theory proposes that statins may create unstable myocytes by reducing the cholesterol content in muscle cell membranes.28

Statin-induced rhabdomyolysis was highlighted by the recent withdrawal of Baycol (cerivastatin) after an association with deaths due to rhabdomyolysis.29 Rhabdomyolysis is a syndrome of myalgias, weakness and muscle swelling associated with acute elevation of CK greater than 10 times the upper limit of normal, usually accompanied by myoglobinuria, hyperkalemia and potentially, acute renal failure.30 The risk of rhabdomyolysis from statins has been extensively studied retrospectively, through voluntary reporting data as well as clinical trials, and is real, although the absolute risk is rare.28,29,30

Table 2: Commonly used medications associated with elevated CK levels

A widely cited analysis summarizing reported adverse events found the incidence of fatal statin-related rhabdomyolysis to be only 0.15 deaths per 1 million prescriptions, although voluntary reports likely underestimate actual occurrences.29 In a review of randomized clinical trials of statin therapy, only 49 cases of myopathy and 7 cases of rhabdomyolysis were noted among the 42,323 patients on statins, numbers virtually identical to the 41,535 control patients.28 One retrospective study of approximately 250,000 patients treated with lipid-lowering medications reported that only 24 required hospitalization for rhabdomyolysis, a risk of 1 in 10,000.31

Statins may also cause low-grade myopathie symptoms, characterized by muscle pain (myalgias) with or without elevated CK levels.32 However, other than individual cases showing a temporal relationship between statins and muscle pain, statin-induced myalgias have been difficult to prove as many studies have shown quite low rates of myalgias in statin-treated patients (in many studies only as high as about 5%) and not significantly different than controls.28,33 Statins do appear to have a real pathological effect on muscle in some cases, however. One report recently documented myopathy by biopsy in four patients with myaglias and normal CK levels while on statin therapy.34

Figure 4: Diagnostic Algorythm for Suspected CLAM

Isolated asymptomatic elevated serum CK associated with statin- use, generally less than 10 times normal, is usually detected incidentally.28 Here again, the incidence has been difficult to determine formally with extremely low rates (

General recommendations30, 33 regarding the use of statins reflect the increased risk of myopathy associated with certain patients and elevated statin serum concentrations. These recommendations include: starting statins at a low dose, especially when used with concomitant medications that affect liver metabolism and using the lowest dose possible to meet cholesterol goals; using statins more cautiously in high risk groups such as the elderly, those with renal insufficiency, liver disease, alcoholism or hypothyroidism, and those on multiple medications; and, possibly withholding statins prior to expected stressful periods such as major surgery. Medications that may be associated with increased risk of CLAM when used concomitantly with a statin include fibrates, cyclosporine, azole antifungals, macrolide antibiotics, protease inhibitors, nefazadone, verapamil, diltiazem, and amiodarone.33 When combination therapy is required, a new inhibitor of intestinal cholesterol absorption, ezetimibe, can be considered which appears to be safe to use in combination with statins without an increased risk of myopathy.28

Routine measurements of CK levels in asymptomatic patients are not required although a baseline CK level is helpful in evaluating subsequent muscle complaints.33 CK levels should be checked for any new muscle complaint while on statins and considerations made to discontinue or lower the dose if myaglias progres\s or CK levels are found to be over 10 times normal.33 Once statins are discontinued, improvement may occur as early as a few days to a week,36 or recovery may be prolonged. In one report, CK returned to normal after 12 days but weakness persisted for over two months.37 Therefore, if myalgias continue to worsen or persist off statins for one to two months, another cause of myopathy is possible.

CONCLUSION

Serum CK is a useful screening test for suspected myopathy. Diagnostic challenges occur when symptoms are mild (isolated myalgia) or there are no symptoms (isolated rise in serum CK levels). Additionally, statin medications offer many neuromuscular diagnostic challenges. We have briefly reviewed the structure and function of CK, and developed a treatment algorithm for common situations in which CK, as well as follow-up neuromuscular testing, are useful.

REFERENCES

1. Coodley EL (editor). Diagnostic Enzymology. Lea & Febiger. Philadephia, PA 1970:257-72.

2. Katirji B, Kaminski HJ, et al (editors). Neuromuscular Disorders. Butterworth-Heinemann, Boston 2002:39-47.

3. Bessman SP, Carpenter CL. Ann Rev Biochem 1985;54:831-62.

4. Lang H (editor). Creatine Kinase Isoenzymes: Pathophysiology and Clinical Application. Springer-Verlag: New York 1981:85-109.

5. Layzer RB. Contemporary Neurology Series: Neuromuscular Manifestations of Systemic Disease. FA Davis Co, Philadelphia 1985: 23-7.

6. Carter JD, Valeriano J, Vasey FB. [Letter]. J Rheum 2003;30:2078.

7. Black HR, Quallich IT, Garaleck CD. Am J Med 1986;61:479-92.

8. Garcia W. JAMA 1974;28:1395-6.

9. Levin R, Pascuzzi RM, et al. Muscle Nerve 1987;10:242-5.

10. Apple FS. Rogers MA. et al. Clinica Chimica Acta 1984;138:111- 8.

11. Gilchrist JM. Muscle Nerve 2003;27:766.

12. Bohan A, Peter JB, et al. Medicine 1977;56:255-86.

13. Silverman LM, Lubahn DB, et al. Clin Chem 1986;32:1137-8.

14. Felice KJ, North WA. J Neurol Sci 1998;160: S30-2.

15. Satoh J. Okada K. et al. Eur J Neurol 2000;7:107-9

16. Eriksen HR, Ihlebaek C. Scand J Psychol 2002;43:101-3.

17. Mills KR, Edwards RH. J Neurol Sci 1983;58:73-8.

18. Simmons Z, Peterlin BL, et al. Muscle Nerve 2003;27:242-4.

19. Kodatsch I, Finsterer J, Stollberger C. Acta Medica Austria 2001;28:11-5.

20. Kleppe B, Reimers CD, et al. Med Klin 1995;90:623-7.

21. Prelle A, Tancredi L, Sciacco M. J Neurol 2002, 249:1432-59.

22. Reijneveld JC, Notermans NC, et al. Muscle Nerve 2000;23:575- 9.

23. Pulst SM (editor). Neurogenetics. Oxford University Press, New York 2000:433-42.

24. Engel AG, Franzini-Armstrong C. (editors). Myology, 2nd Edition. McGraw-Hill, New York 1994: 1697-725.

25. Meltzer HY, Cola PA, Parsa M. Neuropsychopharmacology 1996; 15:395-405.

26. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-97.

27. Smith CC. Bernstein LI. et al. Arch Int Med 2003;163:688-92.

28. Thompson PD, Clarkson P, Karas RH. JAMA 2003;289:1681-90.

29. Staffa JA. Chang J. Green E. [Letter] NEJM 2002;346:539-40.

30. Ballantyne CM. Corsini A, et al. Arch Int Med 2003;163:553- 564.

31. Graham DJ, Staffa JA, Shatin D, et al. JAMA 2004;292;285- 2590.

32. Grundy SM. Ann Int Med 2002;137:617-8.

33. Pasternak RC, Smith SC, et al. J Am Coll Cardiol 2002;40:567- 72.

34. Phillips PS, Haas RH, et al. Ann Intern Med 2002;137:581-5.

35. MRC/BHF Heart Protection Study. Lancet 2002;360:7-22.

36. Bottorff M, Hanstern P. Arch Int Med 2000;160:2273-80.

37. Deslypere JP, Vermeulen A. Ann Int Med 1991;114:342.

MASON C. GASPER, DO, MPH, AND JAMES M. GILCHRIST, MD

Mason C. Gasper, DO, MPH, formerly a fellow in clinical neurophysiology at Rhode Island Hospital, Brown Medical School, is in practice at the Fallon Clinic in Worcester, Massachusetts.

James M. Gilchrist, MD, is Professor of Neurology, Brown Medical School, and Vice-Chair of Neurology, Rhode Island Hospital.

CORRESPONDENCE:

James M. Gilchrist, MD

593 Eddy Street, APC 689

Providence, RI 02903

Phone: (401) 444-8761

Fax: (401) 444-5929

e-mail: [email protected]

Copyright Rhode Island Medical Society Nov 2005

By Megan Rauscher

NEW YORK — Children who are spanked when they misbehave are more likely to be anxious and aggressive than children who are disciplined in nonphysical ways, research shows. This is true even if spanking is the “cultural norm.”

Whether parents should spank their children or use other forms of physical discipline is controversial. Some experts argue that children should not be spanked when they act out citing evidence that it leads to more, rather than fewer, behavior problems and it could escalate into physical abuse. There are data to support this argument.

Other experts, however, argue that the effects of spanking and physical discipline might depend on the characteristics of the child and family and the circumstances in which it is used.

To investigate the latter theory, researchers from questioned 336 mothers and their children in China, India, Italy, Kenya, the Philippines, and Thailand about cultural norms surrounding use of physical discipline and how it affected their children’s behavior.

Jennifer Lansford, a research scientist from the Center for Child and Family Policy at Duke University spearheaded the survey. She told Reuters Health that “across the six countries studied, children who were physically disciplined more frequently were more aggressive and anxious than were children who were physically disciplined less frequently.”

“However, in countries where the use of physical discipline was more common, being physically disciplined more frequently was not related as strongly to aggression and anxiety as it was in countries where physical discipline was less frequently used,” she said.

Not surprisingly, in Thailand, a country where peace-promoting Buddhist teachings predominant, moms were least likely to spank their children or use other forms of physical discipline.

In Kenya, on the other hand, where use of physical discipline is common and considered normal for the most part, moms were most likely to spank or engage in similar disciplinary tactics. In a study conducted in Kenya in 2003, 57 percent of grandmothers reported caning, pinching, slapping, tying with a rope, hitting, beating, and kicking as forms of discipline they had used on their grandchildren.

One question the findings raise, according to Lansford, is whether being physically disciplined more frequently causes an increase in aggression and anxiety or whether children who are already aggressive and anxious are simply physically disciplined more often. “On the basis of other work conducted in the United States, the answer is probably some of each,” Lansford said.

“Another question is whether physical discipline is appropriate in this day and age, regardless of how accepted it may be,” she added.

SOURCE: Child Development, November/December 2005.

By Peta Bee

6pm ONE UNIT

It’s been a long day…

BRAIN: From the first sip, alcohol is absorbed into the bloodstream and reaches the brain. Although you won’t be aware of it, there is an impairment of brain function, which deteriorates further the more you drink. Cognitive abilities that are acquired later in life, such as conduct and behaviour, are the first to go. Early on you will experience mild euphoria and loss of inhibition, as alcohol impairs regions of the brain controlling behaviour and emotion. Most vulnerable are the brain cells associated with memory, attention, sleep and coordination. Sheer lack of mass means that people who weigh less become intoxicated more quickly, and women will feel the effects faster than men. This is also because their bodies have lower levels of water.

HEART: Your pulse quickens after just one unit. Alcohol is a vasodilator ” it makes the peripheral blood vessels relax to allow more blood to flow through the skin and tissues, which results in a drop in blood pressure. In order to maintain sufficient blood flow to the organs, the heart rate increases. Your breathing rate may also speed up.

8pm FIVE UNITS

Whose round is it then?

DIGESTIVE SYSTEM: The Government advises men to drink no more than three to four units a day and women no more than two to three, so after two pints of normal-strength beer (four units) or a large glass of red wine (3.5 units) we have already exceeded our healthy guidelines. The alcohol is absorbed through the stomach and small intestine and if you are not used to it, even small amounts of alcohol can irritate the stomach lining. This volume of alcohol also begins to block absorption of essential vitamins and minerals.

SKIN: Alcohol increases bloodflow to the skin, making you feel warm and look flushed. It also dehydrates, increasing the appearance of fine lines. According to Dr Nicholas Perricone, a dermatologist, even five units will lead to an unhealthy appearance for days.

11pm 10 UNITS

Sorry, what was your name again?

LUNGS: A small amount of alcohol speeds up the breathing rate. But at this level of intoxication, the stimulating effects of alcohol are replaced by an anaesthetic effect that acts as a depressant on the central nervous system. The heart rate lowers, as does blood pressure and respiration rates, possibly to risky levels ” in extreme cases the effect could be fatal. During exhalation, the lungs excrete about 5 per cent of the alcohol you have consumed ” it is this effect that forms the basis for the breathalyser test.

1am 15 UNITS

Let me tell you about my ex…

LIVER: Alcohol is metabolised in the liver and excessive alcohol use can lead to acute and chronic liver disease. As the liver breaks down alcohol, by-products such as acetaldehyde are formed, some of which are more toxic to the body than alcohol itself. It is these that can eventually attack the liver and cause cirrhosis. A heavy night of drinking upsets both the delicate balance of enzymes in the liver and fat metabolism. Over time, this can lead to the development of fatty globules that cause the organ to swell. It is generally accepted that drinking more than seven units (men) and five units (women) a day will raise the risk of liver cirrhosis.

3am 20 UNITS

Where am I? I need to lie down

HEART: More than 35 units a week, or a large number in one sitting, can cause ‘holiday heart syndrome’. This is atrial fibrillation – a rapid, irregular heartbeat that happens when the heart’s upper chambers contract too quickly. As a result, the heartbeat is less effective at pumping blood from the heart, and blood may pool and form clots. These can travel to the brain and cause a stroke. Atrial fibrillation gives a person nearly a fivefold increased risk of stroke. The effect is temporary, provided heavy drinking is stopped.

BLOOD: By this stage, alcohol has been carried to all parts of the body, including the brain, where it dissolves into the water inside cells. The effect of alcohol on the body is similar to that of an anaesthetic ” by this stage, inhibitions are lost and feelings of aggression will surge.

The morning after

Can you please just shut up…

BRAIN: Alcohol dehydrates virtually every part of the body, and is also a neurotoxin that causes brain cells to become damaged and swell. This causes the hangover and, combined with low blood-sugar levels, can leave you feeling awful. Cognitive abilities such as concentration, coordination and memory may be affected for several days.

DIGESTION: Generally, it takes as many hours as the number of drinks you have consumed to burn up all the alcohol. Feelings of nausea result from dehydration, which also causes your thumping headache.

KIDNEYS: Alcohol promotes the making of urine in excess of the volume you have drunk and this can cause dehydration unless extra fluid is taken. Alcohol causes no damage or harm to the kidneys in the short term, but your kidneys will be working hard.

One year on

Where did it all go wrong?

REPRODUCTIVE ORGANS: Heavy drinking causes a drop in testosterone levels in men, and causes testicular shrinkage and impotence. In females, menstrual cycles can be disrupted and fertility is affected. Studies have shown that women who drink up to five units of alcohol a week are twice as likely to conceive as those who drink 10 or more. It is thought it may affect the ability of the fertilised egg to implant.

BRAIN: Over time, alcohol can cause permanent damage to the connection between nerve cells. As it is a depressant, alcohol can trigger episodes of depression, anxiety and lethargy.

HEART: Small amounts of alcohol (no more than a unit a day) can protect the heart, but heavy drinking leads to chronic high blood pressure and other heart irregularities.

BLOOD: Alcohol kills the oxygen-carrying red blood cells, which can lead to anaemia.

CANCER: Excessive alcohol consumption is linked to an increase in the risk of most cancers. Last week, Cancer Research UK warned how growing alcohol use is causing a steep rise in mouth cancer cases.

PANCREAS: Just a few weeks of heavy drinking can result in painful inflammation of the pancreas, known as pancreatitis. It results in a swollen abdominal area and can cause nausea and vomiting.

By Alverzo, Joan P

Predictors of temporal disorientation among brain injury and stroke patients undergoing rehabilitation were explored in this descriptive study. Cognitive orientation is a construct of consciousness, and the Parallel Distributed Processing model provided a framework for conceptualizing consciousness in this study. Data were collected by a retrospective chart review of a convenience sample of stroke and brain injury patients admitted to an acute rehabilitation hospital over 4 months. The dependent variable in the study was the Temporal Orientation Test used as a daily measure in the study hospital. A total of 167 patients were admitted during the time frame, and of those, 114 patients met the study criteria and were included in the data analysis. The independent variables were defined as age, gender, years of education, number of comorbidities, patient diagnosis, orientation status on admission, and use of narcotic/sedative medications. A logistical regression was performed using SPSS Release 11.01. Only one of the six variables-orientation status on admission-reliably predicted the onset of disorientation during the rehabilitation stay with an odds ratio of 0.217, p

KEY WORDS

cognition

cognitive assessment

consciousness

neurologic assessment

temporal orientation

Impaired consciousness is one of the earliest and most reliable indicators of neurological compromise. During the period immediately following neurological injury, level of consciousness (LOC) may fluctuate (Crosby & Parsons, 1989; Neatherlin, 1999). Any change in LOC, both immediately after the injury and in the hours, days, or weeks that follow, is often clinically important (Feske, 1998; McNair, 1999; Plum & Posner, 1980). Early determination that a patient’s LOC is deteriorating affords an opportunity for clinicians to intervene with treatment and potentially avert further brain damage. Orientation as an indicator of a change in LOC fluctuating in either a positive or negative direction or a pattern of change in orientation has not been investigated.

Patients who sustain brain injuries because of trauma or stroke are at risk for altered consciousness because of both the initial area of brain damage and extended areas of damage from secondary changes, such as increased intracranial pressure (Feske, 1998; McNair, 1999; Neatherlin, 1999; Yamamoto, Bogousslavsky, & van Melle, 1998). For this reason, nurses continue to monitor for neurological changes by assessing LOC of patients throughout their acute hospitalization as well as during rehabilitation (Le, Vend, & Levin, 1994). However, there is no consistent practice for how a nurse evaluates changes in LOC that can be subtle in nature (Alverzo & Galski, 1999; Crosby & Parsons, 1989; Way & Segatore, 1994). The purpose of this study was to determine whether the onset of disorientation during the rehabilitation stay of stroke and brain injury patients was associated with any predictive factors.

Significance of the Study

Traumatic brain injury (TBI) and stroke are significant Healthcare issues in the United States. TBIs affect a total of 7 million adults a year (McNair, 1999) and are credited with about one- third of all traumatic deaths in the United States (Thurman & Guerrero, 1999). The highest incidence is among young men and older adults. Stroke is the third leading cause of death in the United States (Rhys, Jiang, Matchar, David, & Samsa, 1999), affecting a total of 730,000 persons each year (Williams, Yilmaz, & Lopez- Yunez, 2000).

Because of improvements in medical technology over the past 20 years, more patients are surviving brain injuries and strokes (Hock, 1999; McNair, 1999). Mortality associated with TBI declined by 22% between 1979 and 1992 (Sosin, Sniezek, & Waxweiler, 1995). From 1980 to 1991, stroke mortality declined between 10.5% and 27.1% based on gender and age (Derby, Lapane, Feldman, & Carleton, 2000). The improved survival rates from both TBI and stroke have increased the need for reliable assessment methods to monitor a patient’s neurological status and potential neurological deterioration more closely. Early detection of a worsening neurological status can lead to earlier interventions, decreased morbidity, decreased resource consumption, and a shortened hospital stay (Feske, 1998). The management of patients who sustain a TBI or stroke has evolved both in the accuracy of diagnostic testing (Stein, Spettell, Young, & Ross, 1993) and in treatment options. Although diagnostic testing of TBI and stroke patients is standard practice in most emergency rooms (Feske, 1998), follow-up testing is generally performed only when there are observable changes in a patient’s neurological status (Ross, Pitts, & Kobayashi, 1992; Yamamoto et al., 1998). The most important indicator of neurological deterioration is a change in LOC (Feske, 1998; Neatherlin, 1999). In spite of the importance of a change in LOC, recognizing it remains a largely subjective process (Benner & Tanner, 1987; Ingram, 1994; Yamamoto et al). Review of the Literature

Consciousness and orientation are interwoven. In general, research on consciousness, including scales that are designed to measure LOCs, uses some measure of orientation. The same, however, cannot be said of the research and literature on orientation. Persons are known to be disoriented, from both diminished consciousness and conditions with no associated loss of consciousness, such as dementia or psychiatric illness. This review focuses on both research on consciousness and research on orientation, identifying areas of overlap and areas in which the concepts digress.

Nurses in hospital settings assess altered LOC for several days, weeks, or months to screen for potential neurological deficits. In some cases, a change in LOC determined by repeated assessments of a patient’s neurological status may be the first indication of neurological complications (Neatherlin, 1999; Plum & Posner, 1980). Healthcare providers use the Glasgow Coma Scale (GCS) to evaluate patients in a coma (Teasdale & Jennett, 1974), which is considered the international standard for determining coma level (Way & Segatore, 1992).

There is no standardized test for determining changes in LOC for patients who are not in a coma. Descriptors such as confused, obtunded, stuporous, lethargic, or delirious are common (Feske, 1998), but these terms are confusing and tend to be unreliable. Nurses have frequently monitored orientation as an indicator of altered LOC (Grant & Kinney, 1990; Johnson, Maas, & Moorhead, 2000); however, there is no standardized method for its measurement (Alverzo & Galski, 1999; Williams et al., 2000) nor any research to support the value of such testing.

A number of nursing scholars have investigated LOC. Several qualitative studies have explored the concept of LOC (Lusardi & Schwartz-Barcott, 1996; Schorr, 1983; Tosch, 1988), focused on the meaning of altered consciousness following coma, and concluded that a patients’ awareness of the state of altered consciousness varies with their LOC and acuity and is associated with themes of death and imprisonment. Ingram (1994) reviewed nurses’ knowledge of LOC from both empirical and aesthetic frameworks and determined that nurses use intuition when assessing altered consciousness rather than relying only on tests such as the GCS.

Several quantitative studies in the nursing literature have focused on the measurement of LOC, proposing new instruments to replace the GCS with more sensitive brain stem indicators (Crosby & Parsons, 1989; Segatore & Way, 1992; Way & Segatore, 1994). One study investigated what indicators nurses report they rely on to assess altered LOC, concluding that orientation is the most frequent and important indicator of altered LOC in a patient who is awake (Grant & Kinney, 1990). Although this study demonstrated that orientation is thought to be an important indicator of altered LOC among nurses, there has been no research to determine whether there is a relationship between orientation and a change in neurological status.

Orientation can be measured alone or in combination with other related cognitive constructs. A wide range of instruments that have been designed to measure phenomena such as cognition, delirium, and dementia include orientation among their critical elements. One study concluded that a single measure of orientation does not capture the scope of cognition problems following TBI (Nakase- Thompson, Sherer, Yablon, Nick, & Trzepacz, 2004). Benton, Van Alien, and Fogel (1964) developed the Temporal Orientation Test (TOT) as one of the first standardized tests for time orientation. Over the past 35 years, the TOT has been used in the formulation of a number of instruments including the Galveston Orientation and Amnesia Test (GOAT; Levin, O’Donnell, & Grossman, 1979), and the Orientation Log (O-Log; Jackson, Novack, & Dowler, 1998). The TOT is designed to measure only one sphere of orientation-orientation to time. Several studies have det\ermined that time or temporal orientation is the most fragile of the three categories of orientation-person, place, and time (Benton, Van Alien, & Fogel, 1964; Daniel, Crovitz, & Weiner, 1987; High, Levin, & Gary, 1989). It is the first category of orientation to show error when a patient is deteriorating, and it is the last category of orientation to return when a patient is improving.

Nursing practice evolves based on both traditions and research. To date, the practice of assessing orientation changes to determine whether a patient’s neurological status is altered has been a tradition that has not been validated by scientific inquiry. This study contributes to nursing scholarship by exploring changes in orientation and the predictive factors associated with those changes, thus contributing to the body of evidence-based practice. The study does not, however, provide sufficient evidence to determine whether testing patient’s orientation is useful as a means of determining a change in LOC. Further research is needed.

Theoretical Rationale-Parallel Distributed Processing

Plum and Posner (1980) performed some of the early theoretical work on coma and altered consciousness. They differentiated various coma states including clouding of consciousness, delirium, obtundation, and stupor. In the early 1970s, Plum and Posner proposed a continuum model of consciousness, with the lower end of the continuum being a person’s state of arousal and the upper end being content of thought. This model has been used by a number of researchers and has served as the basis for several scales to measure LOC (Crosby & Parsons, 1989; Way & Segatore, 1994).

Building on the framework proposed by Plum and Posner, a number of researchers have pursued a model for consciousness. Attempts to identify a focal region for consciousness have largely been unsuccessful (Anderson & Rosenfeld, 1998). Devinsky (1988) suggested that a model for consciousness requires a unification between various cortical and subcortical regions beyond simple association. The Parallel Distributed Processing (PDP) model developed by Rumelhart and McClelland with the PDP Research Group (1986) builds on artificial intelligence research and basic science research on neural networks and provides a framework for information processing in the brain, including consciousness.

Consciousness in this model is the result of many different modules at the cortical and the subcortical levels of the brain that are linked through a parallel structure (Rumelhart & McClelland, 1986). Alterations in consciousness can result from failure of individual modules or the connections between modules. This supports the early work of Plum and Posner (1980) that consciousness reflects whole brain function rather than the function of any specific region of the brain. Using the same model, orientation to time, place, and person requires the integration of current sensory input with memory in a dynamic manner.

Both alterations in consciousness and disruptions in orientation are the result of an inability to integrate information from various neural networks in the brain into a steady state of awareness or arousal (Devinsky, 1988). Conversely, full consciousness and orientation rely, at a minimum, on the activation of the reticular activation system, creating a wakeful state. Further research is needed to test the relationship between orientation as an indicator of consciousness and changes in a patient’s neurological status. Establishing the relationship between these constructs will validate orientation as a key component of consciousness within this integrated model. Further, it will determine the usefulness of orientation as a clinical measure of altered consciousness and support more objective assessment of patients’ neurological status.

Method

The purpose of this descriptive research was to determine the factors associated with a change in temporal orientation among stroke and brain injury patients during rehabilitation. A change in orientation was defined in this study as a score of 4 or more error points following a period of 3 days when the patient scored within the normal range of 0-3 error points on the total TOT (Levin & Benton, 1975; Natelson, Haupt, Fleischer, & Grey, 1979) and is a dichotomous variable. This instrument has been adopted as part of the standard assessment of stroke and brain injury patients at the facility where the research was conducted ( see Figure 1). A nurse administers the test verbally and records the results on a daily neurological assessment flowsheet. The test requires 5 minutes or less to administer and assigns a negative numerical value to errors in the day, month, year, day of week, and present clock time.

The independent variables that were examined included several demographic variables such as age, years of education, gender, number of comorbidities, traumatic versus nontraumatic diagnoses, orientation on admission to rehabilitation, and sedative/narcotic medications. The research question was “What are the variables associated with temporal disorientation among stroke and brain injury patients during their stay in rehabilitation?” A logistic regression analysis was performed on temporal orientation (oriented or disoriented during the stay) as the outcome measure. Analysis was performed using SPSS Release 11.01.

Sample

Sample inclusion criteria involved first the assignment of patients on admission to the rehabilitation impairment categories of stroke, TBI, or nontraumatic brain injury (NTBI). In addition, the sample patients needed to have a rehabilitation stay of 4 days or longer to have baseline scores on the TOT. Sample patients also were required to have a score on the TOT of 3 or less error points on admission, or for 3 days or longer before the development of a neurological complication. This allowed a normal baseline score on the TOT to be established so that a change could be detected.

Exclusion criteria were as follows: (a) persons with a history of dementia or mental illness based on the confounding effect of these diagnoses and (b) patients who were unable to respond correctly to yes-no questions because this would interfere with reliable testing. The convenience sample was chosen by retrospective chart review of consecutively admitted stroke and brain injury patients who met the study criteria. The sample for this study comprised patients with either a diagnosis of brain injury or stroke.

Figure 1. Worksheet to Serially Test Temporal Orientation (Benton, 1964)

Results

The final study sample was drawn from 177 consecutively admitted brain injury and stroke patients. A total of 114 patients met the inclusion criteria, with an average age of 59.96 years (range, 19- 87). Out of the 114 patients in the sample, 55 (48%) were older than 65 years. The gender distribution was 51% male (n = 58) and 49% female (n = 56). The rehabilitation admission diagnoses of the study patients, otherwise known as rehabilitation impairment categories (RIC), were 66 strokes, 22 TBI, and 26 NTBI. The gender varied in relation to the patients’ RICs (see Table 1). The incidence of TBI by gender was 19% of the males and 19.6% of the females. The incidence of NTBI by gender was 32.8% of the males and 12.5% of the females.

Age groupings were used to analyze differences in discharge disposition, orientation status on admission, and disorientation during the stay. Orientation status differed by age group, with those 66 years and older having a higher percentage of disorientation on admission, during the stay, and on discharge (see Table 2). In the sample, a total of 56% of patients had 12 years of education, and 19.3% had 16 years of education. The sample varied in the number of comorbidities that existed at the time of admission (Table 3). The greatest number of comorbidities were present among stroke patients, with 58% of all the comorbidities for the three groups.

At the time of admission to rehabilitation a total of 76 (66.7%) of patients were oriented to time. Of the other 38 (33.3%) patients not oriented on admission, the range of the number of days before they achieved orientation was 1-33, with a mean of 8.11 days. The group with the highest percentage of disorientation on admission was the TBI group (n = 9), representing 40.9% of those who were disoriented.

Medications were tracked in three categories for the study: narcotic medications, hypnotic/sedative medications, and anticholinergk medications. The frequency of use for each medication group in the study group is listed in Table 4.

A logistic regression analysis was performed on temporal orientation (oriented or disoriented during the stay) as the outcome measure. The variables in the model were age, gender, years of education, number of comorbidities, traumatic or nontraumatic diagnosis, orientation status on admission to rehabilitation, and use of sedative/hypnotic medications. Analysis was performed using SPSS Release 11.01.

A test of the full model with all seven variables loaded as a block against a constant only model was statistically reliable; likelihood ratio χ^sup 2^ (7, N = 114) = 17. 509, p

The model appeared to be well-calibrated. The Hosmer-Lemeshow test was performed and the results were nonsignificant; χ^sup 2^ (8, N = 114) = 2.319, p

Table 5 \contains the parameter estimates, WaId test, odds ratios, and associated 95% confidence intervals for each of the six predictors. Only one of the seven predictors, orientation status on admission, reliably predicted the onset of disorientation during the rehabilitation stay. This variable had an odds ratio of 0.217. The odds ratio indicates that the risk of becoming disoriented is 78% higher in persons having a history of disorientation at admission to rehabilitation.

The residuals were examined for outliers and influential points. There were no extreme outliers, with a range of standardized residuals of -1.73, f = 2.11, with a mean of -0.01. There did not appear to be any overly influential points. No Cook’s Ds exceeded 1, and no leverage values exceeded .35. All these tests indicate that the data were not affected by outliers or by any data points that were overly influential, supporting the validity of the results. Multicollinearity was assessed to determine whether there was any overlap between the variables that might be measuring the same thing. If the square root of the VIF is equal to or greater than 2, then multicollinearity may be a problem. In this case, all the VIFs were well below 2. Therefore, each variable measured a unique aspect of the total model.

Discussion

Research on the variability of temporal orientation is quite limited (Desmond et al., 1994; Sweet et al., 1999). This study was unique in its exploration of the longitudinal changes in temporal orientation among brain injury and stroke patients. The degree to which temporal orientation varied among the sample patients was surprising given the assumptions of other studies on orientation that often stopped once a period of orientation was achieved. The single predictor variable of a patient becoming disoriented during his or her stay was the presence of disorientation at the time of admission to rehabilitation. Out of 38 patients who were disoriented on admission and achieved 3 days of orientation during their stays, 22 (57.8%) became disoriented once again during their stay, and 4 (10%) remained disoriented at discharge. The preponderance of literature on posttraumatic amnesia (FTA) following TBI is predicated on the assumption that once a patient has achieved 3 days of orientation, the period of PTA is over. Further testing of orientation has not extended beyond the end of PTA in most studies (Ellenberg, Levin, & Saydjari, 1996; Wilson et al., 1994).

The method by which clinicians measure orientation over time is not standardized. In a study of 52 rehabilitation nurses, there was no consistency in how orientation was measured during a patient’s rehabilitation stay, and one of the more commonly reported methods to determine whether a patient was oriented was general conversation (Alverzo & Galski, 1999). This is consistent with other studies (Benton, Van Alien, & Fogel, 1964; Natelson et al., 1979), identifying the same variability among neurologists testing orientation. Jackson, Novack, and Dowler (1998) proposed a brief bedside orientation instrument for this very reason. To date, however, methods for tracking orientation change over time and are not well established in the hospital setting nor in rehabilitation. The two methods that are reported to be consistently used are the Mini-Mental Status Examination (Folstein, Folstein, & McHugh, 1975) by psychologists, physicians, nurses, and other therapists generally limited to a baseline test of new patients in the in- and outpatient settings (Smith, Breitbart, & Platt, 1995), and the use of GOAT (Levin, O’Donnell, & Grossman, 1979) among TBI patients only during the period of PTA (Schacter & Crovitz, 1977).

Sample patients included those who had sustained strokes, TBIs, and NTBIs, but for the purpose of the data analysis, these three categories were collapsed into two-TBIs and NTBIs including stroke. The groups included many more patients with NTBIs (80.7%) than TBIs (19.3%). Although the bulk of patients fit into the NTBI group, this cluster did not undermine the data analysis of the diagnostic group as a predictor in the study. Unequal group numbers is not an assumption in logistical regression.

The repeated measure design was an important component of this study, tracking disorientation across time. Patient tolerance for testing once per day was relatively high, based on anecdotal evidence. An increase in frequency of testing to more than once a day may have not been tolerated as well. There also may have been more interference with the validity of the test, given possible contamination of one test upon another. That being said, there remain many unanswered questions regarding how orientation varies over a 24-hour cycle. This study was limited to the inpatient stay and did not test patients after discharge. Variability of orientation as the patient gets further from the initial injury or illness event is also an open question.

Table 1. Rehabilitation Impairment Code by Gender

Table 2. Age Groups by Orientation Status on Admission, During the Stay, and on Discharge

Table 3. Comorbidities of the Sample Group

Table 4. Frequency of Medication Use

The model for predicting the onset of disorientation during the rehabilitation stay identified only one predictor for disorientation: disorientation on admission to rehabilitation. This finding is important because it confirms that orientation is unstable during the period following a stroke or brain injury. Further, the result that TBI versus NTBI was not predictive of the onset of disorientation during the patient stay was also important. The pattern of disorientation among TBI patients raises many questions about the assumptions in previous research.

Disorientation is a persistent phenomenon during rehabilitation for both TBI and NTBI patients. In the stroke population, a few studies have explored orientation changes over time. Desmond et al. (1994) looked at orientation at two intervals following stroke, concluding that orientation is both common and persistent following stroke. Hochstenback (2003) looked at the cognitive effect of stroke and noted that, of all the cognitive domains, improvements in attention including orientation were the most significant at 2 years after stroke. Predictors for disorientation based on previous research, including age, years of education, and medications, were not found to be statistically significant in this study. The incidence of disorientation that occurred following 3 days of orientation was much higher than anticipated, and disorientation on admission to rehabilitation was a statistically significant predictor of a patient becoming disoriented during his or her stay. These findings suggest that disorientation among patients with brain injuries is a persistent issue, and longitudinal testing of orientation may provide important assessment information to assist in tracking a patient’s recovery.

Table 5. Variables in the Logistical Regression Model

Conclusion

Given the paucity of research on orientation, the opportunity for further inquiry into this important concept is wide open (Desmond et al., 1994; Schneider, von Daniken, & Gutbrod, K., 1996). The frequent use of orientation in clinical assessment emphasizes the need for a greater understanding regarding its measurement (Grant & Kinney, 1990). Exploring the meaning and usefulness of testing a patient for orientation is also important so that it can be properly understood and interpreted within a clinical context. Trending data on changes in orientation are missing in many patient populations, with the greater majority of research focusing on “snapshots” of orientation at various time intervals. In addition, the need for a better understanding of orientation within theoretical frameworks of brain function is evident, since there are very few hypotheses regarding how the brain synthesizes information to arrive at the correct answers to orientation questions.

Nursing research on orientation is in its infancy. This study was one of the first to methodically test temporal orientation over time in hospitalized patients. A previous nursing study on orientation (Alverzo & Galski, 1999) laid important groundwork to confirm that the measurement of orientation by nurses in a rehabilitation hospital varies tremendously, further concluding that the interpretation of whether a patient is oriented based on their testing is equally variable. Without a standard method for nurses to test orientation, it is difficult to draw any conclusions about changes in orientation.

Further research into the phenomena of orientation is needed, both from a clinical perspective to create an empirical foundation for practice, and from a theoretical perspective to establish a working model based on brain function. Descriptive nursing research that focuses on clinical studies of varying patient populations and trends in orientation related to patient outcomes is needed first. The next step would be experimental nursing research directed at establishing nursing interventions that either directly affect disorientation or complement the recovery of disoriented patients, mitigating adverse outcomes. Research focusing on links between changes in patient orientation and a nurse’s aesthetic knowledge of a patient would provide an important insight into how intuition can complement empirical knowledge. Finally, research that explores orientation within a theoretical model of brain function is needed to further illuminate the role of orientation in consciousness.

Acknowledgment

This research was funded by the Rehabilitation Nursing Foundation New Investigator Grant (2001).

The author extends special thanks to nurse data collectors Nadia Bogovic, Virginia Dizon, Terrence Englis, Maria Levy, and Aud Lynch from the Kessler Institute for Rehabilitation.

Onentation can be measured alone or in combination with other related cognitive constructs.

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Nakase-Thompson, R., Sherer, M., Yablon, S. A., Nick, T. G., & Trzepacz, P. T. (2004). Acute confusion following traumatic brain injury. Brain Injury, 18(2), 131-142

Natelson, B. H., Haupt, E. J., Fleischer, E. J., & Grey, L. (1979). Temporal orientation and education. Archives of Neurology, 36, 444-446.

Neatherlin, J. S. (1999). Foundation for practice: Neuroassessment for neuroscience nurses. Neuroscience Nursing for a New Millennium, 34(3), 573-592.

Plum, F., & Posner, J. (1980). Diagnosis of stupor and coma (3rd ed. ). Philadelphia: F. A. Davis.

Rhys, W. G., Jiang, J. G., Matchar, D. B., & Samsa, G. P. (1999). Incidence and occurrence of total (first ever and recurrent) stroke. Stroke, 30(12), 2523-2528.

Ross, A. M., Pitts, L. H., & Kobayashi, S. (1992). Prognosticators of outcome after major head injury in the elderly. Journal of Neuroscience Nursing, 24(2), 88-93.

Rumelhart, D. E., McClelland, J. L., & PDP Research Group. (1986). Parallel Distributed Processing: Explorations in the microstructures of cognition. Cambridge: MIT Press.

Schacter, D. L., & Crovitz, H. F. (1977). Memory function after closed head injury: A review of the quantitative research. Cortex, 13,150-176.

Schneider, A., von Daniken, C., & Gutbrod, K. (1996). Disorientation in amnesia: A confusion of memory traces. Brain, 119,1627-1632.

Schorr, J. A. (1983). Manifestations of consciousness and the developmental phenomenon of death. Advances in Nursing Science, October, 26-35.

Segatore, M., & Way, C. (1992). The Glasgow coma scale: Time for change. Heart and Lung, 21(6), 548-557.

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Sosin, D. M., Sniezek, J. E., & Waxweiler, R. J. (1995). Trends in death associated with traumatic brain injury. 1979-1992. Journal of the American Medical Association, 273,1778-1780.

Stein, S. C., SpetteU, C., Young, G., & Ross, S. E. (1993). Limitations of neurological assessment in mild head injury. Brain Injury, 7(5), 425-430.

Sweet, J. J, Such, Y, Leahy, B., Abramowitz, C., & Nowinski, C. J. (1999). Normative clinical relationships between orientation and memory: Age as an important moderator variable. The Clinical Neuropsychologist, 33(4), 495-508.

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Way, C., & Segatore, M. (1994). Development and preliminary testing of the neurological assessment instrument. Journal of Neuroscience Nursing, 26(5), 278-287.

Williams, L. S., Yilmaz, E. Y, & Lopez-Yunez, A. M. (2000). Retrospective assessment of initial stroke severity with the NIH stroke scale. 2000 American Heart Association, 33(4), 858-862.

Wilson, J. T., Teasdale, G. M., Hadley, D. M., Wiedman, K. D., & Lang, D. (1994). Post-traumatic amnesia: Still a valuable yardstick. Journal of Neurology, Neurosurgery, and Psychiatry, 57,198-201.

Yamamoto, H., Bogousslavsky, }., & van Melle, G. (1998). Different predictors of neurological worsening in different causes of stroke. American Medical Association, 55(4), 481-486.

Joan P. Alverzo, PhD RN CRRN

About the Author

Joan P. Alverzo, PhD RN CRRN, is chief clinical officer at the Kessler Institute for Rehabilitation in West Orange, NJ.

Direct correspondence to Joan P. Alverzo, PhD RN CRRN, 1199 Pleasant Valley Way, West Orange, NJ 07052, or via e-mail to [email protected]

Copyright Association of Rehabilitation Nurses Nov/Dec 2005

By Gunderson, Anne; Tomkowiak, John

Situation: M.J. is a 32-year-old female currently in an inpatient rehabilitation program. She was admitted 5 weeks ago S/P Motor Vehicle Accident, with a diagnosis of traumatic brain injury (TBI). The patient was engaged in the rehabilitation program and had progressed well until 2 weeks ago. Since that time, her appetite has decreased and she has lost 5 pounds. She reported feeling more tired and taking multiple naps during the day. She has been voicing more concerns about the hopelessness of her situation, has refused to go to therapy, and has denied that she is feeling sad. Nurses report that she has required more PRN pain control.

Consultation: Anne Gnnderson, GNP CRRN-A, an assistant professor at the University of Illinois Chicago College of Medicine, Department of Medical Education, and John Tomkounak, MD, associate dean of curriculum at Rosalind Franklin University Chicago Medical School, reply:

Major depressive disorder (MDD), referred to as simply depression, is a primary mood disorder. For many rehabilitation patients, depression is a common medical problem that affects the patient’s recovery. MDD, however, is often overlooked by healthcare providers and inappropriately (or inadequately) diagnosed for many patients who present with depressive symptoms. Numerous studies cite lack of time, lack of knowledge and skill, and the stigma associated with psychiatric illness as causes of this deficit.

In inpatient rehabilitation programs, depressed patients tend to use the program less effectively, make less progress, and have an increased length of stay. After discharge, depressed patients leave the house less often, do not become involved in recreational pursuits, and report having less contact socially (Wu, 1995). Patients and families often tend to minimize the depressive symptoms or treat the symptoms as something that is “expected” after a traumatic injury. With MJ., it could be easy for her family, and even healthcare providers, to brush off the symptoms as part of an appropriate response to a TBI. Depressed individuals are also less likely to be referred for, seek out, or successfully complete rehabilitation programs or to use adaptive devices (Horowitz, 2003). Rehabilitation providers must recognize the symptoms of depression and provide the necessary treatment for these patients as part of the overall treatment plan.

No clear anatomic or physiologic cause can directly explain depression. Most experts agree that it can be diagnosed on the presentation of clinical symptoms outlined in the Diagnostic and Statistical Manual for Mental Disorders, fourth edition revised (DSM- IV; American Psychological Association, 1994). DSM-IV criteria for MDD require the presence of five of nine symptoms for a 2-week period or more (see Figure 1) and one of the nine symptoms must be a loss of interest in usual activities or a persistent depressed mood. Although MJ. denies feeling sad, she began experiencing the symptoms approximately 2 weeks ago, and they have presented daily.

Other mental health disorders that are similar in presentation to MDD and that should be considered when making a diagnosis are dysthymia, bipolar disorder, bereavement, anxiety disorders, and depression secondary to exogenous medications or substance abuse. These disorders often coexist and compound the difficulty in correctly diagnosing and treating MDD. MJ.’s medical history prior to the MVA could also help determine whether MDD is an appropriate diagnosis.

Standard treatment interventions include the use of antidepressant medications and psychotherapy; however, there is also a growing trend in the use of alternative medicine techniques such as massage, guided imagery, and bright-light therapy. Management plans for rehabilitation patients with MDD should be driven by medical and psychological assessment findings. Symptoms are important because they guide treatment (Cole, 1996). Although short- term psychotherapy is designed to assist patients with MDD in developing effective coping mechanisms, they have to have at least a minimal set of cognitive and memory function for this therapy to be effective. In the case of M.J., it is important to correctly assess her cognitive abilities before psychotherapy is started.

Figure 1. Major Depression Symptoms

In the inpatient setting, medication adjustments can be made more rapidly because side effects can be monitored more closely than in the outpatient setting. The patient with MDD will probably not feel that he or she has significantly improved within the 2-week timeframe. Regular follow-up is very important. Although follow-up may occur on a 3-month basis, treatment should continue for a minimum of 6 months and could easily extend to years (Rakel, 1999).

In the outpatient rehabilitation setting, patients who have been diagnosed with MDD and have been started on medication, psychotherapy, or both should be seen again within 2 weeks of starting the medications and should be evaluated for side effects and effectiveness of the treatment plan. This evaluation should include whether and how much progress has been achieved toward therapy goals, and documentation of the resolution of depressive symptoms.

Indications that interventions have been successful for the patient include a restoration of a euthymic mood; sleeping, eating and activity patterns that return to normal; and resolution of other depressive symptoms (noted upon assessment). For M.J., appropriate diagnosis and treatment would include an increased appetite, weight gain, elevated mood, participation in therapy, improved sleep patterns, and continued progress toward her therapy goals. Without recognition of the depressive symptoms and the development of an appropriate treatment plan, it is likely that the progress MJ. will make in her recovery will be much less.

References

American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th e.). Washington, DC: American Psychiatric Press, 1994.

Cole, S. A. (1996). Mood disorders. In J. Noble (ed.). Primary care medicine (pp. 1738-1747). St. Louis: Mosby-Year Book.

Horowitz, A. (2003). Depression and vision and hearing impairments in later life. Generations: Journal of the American Society on Aging, 27(1), 32-38.

Rakel, R. E. (1999). Depression. Primary care. Clinics in Office Practice, 26(2), 211-223.

Wu, P. B. J. (1995). Poststroke depression. Spinal Medicine. Retrieved on September 13, 2005, from http://www. spinalmedicine.com/ articles/post_stroke_depression. html

Awne Gunderson, GNP CRRN-A, John Tomkowiak, MD

About the Authors

Anne Gunderson, GNP CRRN-A, is an assistant professor at the University of Illinois Chicago College of Medicine, Department of Medical Education. She can be reached at [email protected].

John Tomkowiak is associate dean for curriculum at Rosalind Franklin University Chicago Medical School.

Copyright Association of Rehabilitation Nurses Nov/Dec 2005

By Elizabeth Jardina, STAFF WRITER

AROVING COLD around the office has left you, roughly, feeling like crap.

So you head to the drug store to find a sticky-sweet liquid to soothe your ragged tonsils, your hacking cough, your feverish forehead — only to be faced with a million options.

Do you need the orange Triaminic or the Vicks NyQuil multisymptom? The $2 store brand or the name-brand $5 cough syrup? And if you’re feeling sick, are you doomed to have to drink a couple of spoonfuls of fake-cherry, nasty stuff?

There are two important considerations here: What will make you feel better, and what can you stand to swallow?

The medicine

You’ve read it before, you’ll read it again, but we’ve gotta write it one more time: Read the label. Of any medicine you take. Read the label and see what it does and how to take it.

Larry Alejandre, a pharmacist at Kaiser Oakland Medical Center, says consumers tend to pick familiar brands and don’t figure out what the medicines do.

“They’re basing their selections

on what they see on the TV, ads in

the magazines, and oftentimes they’re throwing their money down the

drain. They need to know what

they’re treating.”

Pick a formula that treats the symptoms you have. Don’t have a fever? You don’t need a medication that has a fever-reliever. Don’t have a cough? Don’t take a cough-suppressant.

Once you find the right medicine

for your symptoms, follow the directions on how to take it.

“People tend to think a little’s good, a lot’s better and that’s not often the case,” Alejandre says. “The amount they gain is not measurable. Theywon’t feel that much better than if they took the recommended amount.”

Dr. Peter Grossman, an internist in San Mateo, says cold medicines are not silver bullets. “They have some effect on some people,” he says cautiously. A doctor can prescribe a stronger medicine if your OTC one isn’t working.

Pay attention to how the drug makes you feel. In nighttime cold medicines (like NyQuil and Tylenol PM), the thing that makes many people sleep is some combination of alcohol and antihistamines, which for many people have sedative effects.

One tricky thing in buying cold medication this year is that cold medicines that contain the decongestant pseudoephedrine (best known as the active ingredient in Sudafed) have been largely moved behind pharmacy counters. You don’t need a prescription, but you do need to ask for them. Stores that don’t have pharmacies may not carry them at all.

This doesn’t have anything to do with the drug itself; it will clear up your stuffy nose beautifully. But it’s also an ingredient in making the illegal drug methamphetamine.

Alejandre warns that people with high blood pressure should avoid drugs with pseudoephedrine altogether because it can make hypertension worse.

People usually don’t think too much about how medicine tastes, but there actually are differences, our staff members discovered, after doing an unscientific taste test.

We tasted six cold medicines: three multisymptom syrups and three cough syrups. (Because these are drugs, afterall, we tasted only small amounts and spit them out after we’d sufficiently determined the merits — or demerits — of their flavors.)

Our conclusions weren’t that surprising but may dishearten the cheapskates among us: Name brands really did taste better than store brands. Even though the Target Cough Formula DM is $3.08 cheaper than the Robitussin DM, all of our tasters said they would fork over the extra three bucks so they wouldn’t have to grimace so much as the medicine went down.

Here’s what we found:

– Tylenol Cough & Sore Throat ($4.84 for 8 fluid ounces), contains acetaminophen for fever and sore throat, dextromethorphan to ease coughing and doxylamine succinate to clear sinuses: We plucked this product off the shelf — new for this year’s cold season — because of its flavor. Rather than being fruity and dark, it’s bright blue and minty. The tasters who enjoy mint flavors were enthusiastic about this multisymptom formula’s taste. Those who can’t drink their Listerine straight complained about a menthol sensation and too much mintiness. Recommended.

– Vick’s NyQuil Cough, cherry flavor, ($4.79 for 6 ounces), contains dextromethorphan for coughing and doxylamine succinate to clear sinuses: The granddaddy of cough syrup, tasters noted that this one didn’t taste that much like cough syrup. It wasn’t especially thick, the cherry flavor didn’t taste outrageously fake, and it had almost no aftertaste. Recommended.

– Walgreens’ Rest Easy NightTime, cherry flavor ($3.49 for 6 ounces), same ingredients as NyQuil: Not bad, but after tasting the real deal, this one tasted fake, thick and sweet. And it has a bad, bitter aftertaste.

– Robitussin DM ($5.14 for 4 ounces): The strictly cough- suppressant formulas, for some reason, didn’t taste as good as the NyQuil. But of these, the Robitussin was best. One taster conjectured that perhaps she was just used to the flavor of Robitussin and therefore didn’t mind it.

– Tasters were torn about which was worse: the Walgreens Wal- Tussin Cough ($4.99 for 4 ounces) or the Target Cough Formula DM ($2.09 for 4 ounces). Both were extremely bitter.

The October 2005 issue of The Journal of Alternative and Complementary Medicine, which commemorates the 250th anniversary of the birth of Samuel Hahnemann, the founding father of homeopathy, makes it very clear that homeopathy works and is far from dead. Presenting very clear evidence from leading scientists and clinicians, JACM shows that there is something very real going on in homeopathic medicine. The issue contains provocative letters, commentaries, and an editorial censuring The Lancet for publishing an error-filled, data-deficient study used erroneously to attack the credibility of practitioners of homeopathy. This issue of The Journal of Alternative and Complementary Medicine, a MEDLINE, peer-reviewed journal published by Mary Ann Liebert, Inc., presents the state-of-the-art of homeopathy, with all the scientific papers and editorial perspectives available free online at www.liebertpub.com/acm.

Dr. Kim A. Jobst, MA, DM, MRCP, MFHom, Editor-in-Chief of the JACM and Visiting Professor in Healthcare & Integrated Medicine at Oxford Brookes University, U.K., not only criticizes The Lancet for lending credence to “a manuscript (by Shang et al.) that fails totally to provide the information necessary for full independent replication or analysis,” but also reproaches the esteemed journal for heralding “its damning judgment of homeopathic practice with extensive international press fanfare and the full seal of approval that is implicit in its editorial opinion.” Jobst further questions The Lancet’s decision to ignore or reject numerous letters critical of the Shang paper.

JACM devotes a substantial portion of the content of the current issue to the commemoration of Hahnemann’s contributions to the field of medicine and to the evolving impact of homeopathic methods and hypotheses on clinical practice. Jobst writes, “That every molecule has its own energetic signature is beyond doubt. Indeed it is the unique electromagnetic and more subtle energy signature, or biofield, that is increasingly believed to be responsible for intra- and intercellular signaling.” Noting that these concepts are currently being explored to understand the mechanism of smell, Jobst continues, “It may well be that as long as attention is directed to an explanatory model focused on erstwhile molecular chemical models of interaction, there will continue to be incredulity and irrational reaction to the effects of ultra-high dilution, i.e., homeopathic therapy and science.”

The issue includes a seminal paper by Spence et al. entitled “Homeopathic Treatment for Chronic Disease: A 6-Year University Hospital Outpatient Observational Study,” the largest study of its kind ever published, which presents the results of the six-year study involving more than 6,500 consecutive patients, in which more than 70% reported significant positive health changes associated with homeopathic intervention and consultation.

The issue also includes letters, editorials, and other submissions which encompass the full intensity and scope of the ongoing debate and highlight the key issues that necessitate continued discussion and study. Luminaries in the field such as Dr. Alex Hankey, Dr. Mikel Aickin, Professor David Peters, Professor David Reilly, and Professor George Lewith, in separate reports, explore the profound scientific, moral, and ethical implications of the current controversy, while Professor Iris Bell, Dr. Helmut Kiene, and Professor Michael Frass each document critical flaws in the design and execution of the negative paper published by The Lancet. Dr. Lionel Milgrom explores how randomized controlled trial methodology may inadvertently be destroying the very interactions that make for effective therapeutic outcomes of the kind so clearly demonstrated in the work by Spence et al. Professor Harald Walach, and Dr Wayne Jonas (Director of the Samueli Institute in the USA) and colleagues explore in over 200 studies the current anomalies and methodological inconsistencies and suggest experimental solutions to them.

Two other papers demonstrate specific homeopathic cellular effects: Biswas et al. report on objective changes in mouse hepatocarcinoma cells; and Baars’ group in Holland presents evidence to support the effects of injected homeopathic preparations on the symptoms of hay fever.

“Paradoxically, in this era of ever-increasing technological and biomolecular sophistication and complexity, especially in medicine, there are more people than ever before suffering with and from chronic diseases, for which allopathic medicine has demonstrated limited effectiveness, and for which psychological and psychiatric interventions are rarely curative,” writes Jobst. “In this area, homeopathic medicine and the homeopathic method not only offers a safe way forward, but one which appears to be remarkably effective in routine practice, especially for such chronic conditions, and arguably more importantly, it offers and provides a profound reawakening of the importance of doctor-patient rapport and to the taking of the clinical history.”

The Journal of Alternative and Complementary Medicine is a peer-reviewed journal published monthly (beginning in 2006) in print and online that includes observational, clinical, and scientific reports and commentary, and features clinical case reports intended to help healthcare professionals and scientists evaluate and integrate therapies into patient care protocols and research strategies. The Journal facilitates data collection and analysis, explores research methodologies and results, and stimulates inquiry and dialogue. A complete table of contents and free sample issue may be viewed online at www.liebertpub.com/acm.

Mary Ann Liebert, Inc., is a privately held, fully integrated media company known for establishing authoritative peer-reviewed journals in many promising areas of science and biomedical research, including Alternative & Complementary Therapies, Disease Management, and Journal of Palliative Medicine. Its biotechnology trade magazine, Genetic Engineering News (GEN), was the first in its field and is today the industry’s most widely read publication worldwide. A complete list of the firm’s 60 journals, books, and newsmagazines is available at www.liebertpub.com.

By Tan Ee Lyn

HONG KONG (Reuters) – Fanny Fong contracted SARS in 2003 while caring for patients at the hospital where she worked. But while she has recovered, it has left her so weak she needs to carry an oxygen tank whenever she leaves home.

Not only did the disease leave her lungs scarred, the former hospital attendant also feels constant pain in her bones.

Her doctors say her skeletal system is degenerating very quickly — a condition called avascular necrosis and which was caused by the heavy use of steroids when she was treated for Severe Acute Respiratory Syndrome.

“I am living in constant suffering,” said the 48-year-old who now walks with a cane and takes morphine regularly to help her cope with her pain. Next to her is an oxygen tank, which she takes with her in a carrier on wheels when she goes to hospital — the only time she leaves home.

Fong spent two months in hospital fighting for her life when she came down with SARS. She winces whenever she hears about a looming pandemic that might be triggered by the deadly H5N1 bird flu virus, which health experts say might kill millions of people.

When SARS broke out and spread to 30 countries in 2003, hospitals in affected nations were quickly overwhelmed and their economies came to a standstill. The virus infected more than 8,400 people in all, killing about 800 of them.

“SARS killed only 800 people and already it caused so much chaos. How can the world cope with H5N1?” Fong said. The Hong Kong government’s repeated assurances that the city was well prepared for a pandemic are hardly convincing for her.

“We now have the same number of hospitals as we did in 2003. Can they cope with a sudden increase in the number of sick people?” said Fong, who was working at the Caritas Medical Center when she fell ill with SARS in late April 2003.

During the 1968 Hong Kong flu pandemic, 15 percent of Hong Kong’s population was infected.

Working from that percentage, top health officials have said that as many as a million people in Hong Kong could be sickened by the next pandemic. Many people in the city fear health services would be overwhelmed and thousands could die.

INUNDATED

When SARS began spreading in Hong Kong in early 2003, it quickly overwhelmed two public hospitals that were initially handling such patients. Fong’s hospital was then ordered to take in suspect cases and soon, practically anyone with a fever was admitted and her ward filled up in no time.

“There was no isolation whatsoever. Everyone was in one big room and we took care of just anyone not knowing what they were suffering from,” she said, adding that the hospital provided no protective gear except for a flimsy surgical mask.

She remembers helping to bathe more than 10 patients in her ward just a day before she herself was admitted to hospital when x-rays showed “shadows” in her lungs — tell-tale signs of pneumonia, one of the classic symptoms of SARS.

“Five days later, I was in ICU where they punched holes in the sides of my body so they could insert tubes directly into my lungs to help me breathe,” she said, adding she was by that time so weak she could not even suck from a straw.

In Hong Kong, 1,755 people were infected by SARS, and 299 of them died. Of those infected, 386 were healthcare workers and of these, 6 died.

Hong Kong’s government came under heavy criticism in the aftermath of SARS for its many blunders, which included not providing enough protective gear for hospital staff.

“I was a very normal person. Now I have lost everything, even my freedom to work,” Fong said, as she stared into empty space.

She now survives on social welfare and has to depend on volunteers to bring her three meals each day as she does not even have the strength to do any shopping or cook.

Like other SARS survivors, Fong has to live with the stigma attached to the disease. She has not seen her only son, who is in his 20s, since she walked out of hospital in late June 2003. None of her relatives or friends keep in touch with her.

“I just hope the government can educate the public not to discriminate against us,” Fong said, as she reached again for the oxygen tube to help her breathe.

By Young, David W

“What’s the use of running if you are not on the right road?”

So says a German proverb, and it’s a question that healthcare organizations should be asking themselves. During the next two decades, they will confront a variety of new environmental and competitive demands requiring serious strategic thinking. For example, the leading edge of baby boomers is approaching age 60, suggesting that, without some significant changes in lifestyles, public health programs, or healthcare delivery patterns, inpatient costs will increase exponentially.

THE MARKET PROBLEM

EXAMPLE OF NEW INPATIENT UTILIZATION PATTERN

These new demands are occurring in a marketplace decidedly unlike those described in economics textbooks. There are four actors in this market: a consumer, who receives services from or at the behest of aprovider, whose fees are paid (or costs reimbursed) by a health plan or other insurer, who receives insurance premiums from an employer.

Each of the resulting “submarkets” has a different pricing unit. Moreover, in each submarket, the seller’s price will have an impact on the purchaser’s buying behavior, resulting in decisions that interact with other aspects of the healthcare system.

Some of these interactions have been known for decades. For example, 30 years ago, the introduction of a $1 copayment for California’s MediCal (indigent) patients led to a substantial reduction in their use of primary care. Unfortunately, some of these same patients were hospitalized several months later with conditions that could have been avoided had they received timely primary care. The result was an increase in total MediCal expenditures (see “Copayments for Ambulatory Care: Penny-Wise and Pound-Foolish,” by Milton Roemer, et al., inMedical Care, June 1975).

The mixture of environmental demands, market forces, and system interactions means that all healthcare organizations should be thinking more carefully about the challenges and opportunities they face, and couple that assessment with an analysis of their capacity to develop appropriate strategic responses.

SWOT Analysis: Perceived Versus Real

Strategy formulation frequently includes a SWOT analysis, or an assessment of internal strengths and weaknesses (SW) combined with environmental opportunities and threats (OT). However, a SWOT analysis rarely identifies real organizational strengths and weaknesses or real environmental opportunities and threats. Instead, senior managers act only onperceived strengths, weaknesses, opportunities, and threats as filtered through their own lenses and those of middle managers, physicians, nurses, and others in the organization. These filtered perspectives prevent senior management from seeing the real SWOT, thereby creating a potential for suboptimal strategic decisions.

There are four techniques that senior managers can use to close the gap between their perceived environment and the real one. In some industrial organizations, these techniques are essential aspects of the strategy formulation process; they can be equally valuable for a healthcare organization.

STRATEGIC POSITIONING IN THE HEALTHCARE INDUSTRY

Generate conflict. Properly managed, conflict can provide considerable information about an organization’s environment. For example, a hospital concerned about the impact of a proposed musculoskeletal center on its overall operations might dedicate an afternoon or longer to a discussion among the leaders of several departments about ways the proposed center will affect matters such as operating room demand, nursing and other staffing needs, purchasing, transport, housekeeping logistics, and the like. A variety of contrasting views no doubt would arise and need to be resolved, all of which can contribute to a more successful implementation effort.

Encourage employees to question existing rules and assumptions. When a hospital includes a member of the housekeeping staff or a transport worker on a process redesign task force, the results can be both surprising and dramatic. In some hospitals, these lower- level workers have a deeper understanding than their superiors of the environment that affects their jobs, and can suggest effective ways to address those issues.

Develop a learning culture. An off-site workshop to discuss the difficulties one department encountered in developing and implementing a clinical pathway no doubt would be immensely useful to other departments faced with a similar task. For this to happen, the culture needs to encourage it, and the organization needs to institute a process for the sharing of problems, solutions, and other matters by which one department or program can learn from the experience of another.

Distinguish between available resources and patient needs. In one hospital where a study was under way to improve the efficiency of the admissions office, a member of the task force questioned whether the office was needed at all. After some weeks of study and analysis, the hospital decided to eliminate its admissions office entirely-it found that the admissions process could take place without the presence of an admissions office.

This experience suggests that hospitals need to think carefully about the mix of supportive services they provide to patients, their cost, and whether a less expensive approach could achieve the same results.

The Strategic Value of Trade-Offs

Once an organization believes it has a good understanding of its real strengths and weaknesses, and its real environmental threats and opportunities, it can formulate its strategy. In part, this strategy’s quality can be assessed in terms of trade-offs. That is, a high-quality strategy is one in which an organization has decided what it is not going to be as well as what it intends to be.

There are three broad trade-off dimensions: service or program variety, customer needs, and customer access. Two well-known industrial organizations are illustrative. Ikea, a company that sells unassembled furniture, focuses on many customer needs, but offers limited access and has a limited range of products. Jiffy Lube, by contrast, has made its trade-offs by focusing on broad access to some very limited services, meeting very few customer needs.

Most healthcare organizations have not made these sorts of trade- offs, preferring instead to attempt to be all things to all patients. Nothing could be more strategically misguided. To thrive in the 21st century, healthcare organizations should consider which services and programs they wish to emphasize, for which kinds of patients, and in which localities-and then eliminate programs and other activities that do not fit that focus.

Making strategic trade-offs does not require hospitals to become what Regina Herzlinger called “focused factories”-institutions offering only one service to many patients (Market-Driven Health Care, 1997). Shouldice Hospital, in Ontario, Canada, is an example. Its only service is hernia surgery. It draws patients from long distances for its cost-effective and high-quality care, and thus has become the epitome of the focused factory. By focusing on patients with particular disease conditions or characteristics, or on particular organs or surgical procedures, organizations such as M.D. Anderson Cancer Center, Cincinnati Children’s Hospital, Massachusetts Eye and Ear Infirmary, and New England Baptist Hospital have made similar trade-off decisions, although none quite as specific as Shouldice.

A Framework for Strategic Trade-Offs

Strategic trade-offs also can be assessed in terms of competitive scope (broad versus narrow) and pricing policy (low price versus premium price). The goal of organizations with a low-price strategy is to deliver a product of acceptable quality at a price below that of its competitors. By contrast, organizations with a premium-price strategy select narrow market segments with unusual needs, and offer products and/or services that are widely acknowledged as superior on at least one dimension. The distinction between Bic and Mont Blanc pens illustrates the contrast.

In addition to Shouldice Hospital, Mayo Clinic is an example of an organization that has made trade-offs along these two dimensions. Mayo focuses on patients (especially international patients) who are not constrained by insurance limits on payments, and it offers what most observers consider to be a superior, well-coordinated set of services.

Unfortunately, examples like this are difficult to find. Yet these sorts of trade-offs are essential for healthcare organizations that wish to ensure their long-term financial viability. Although some hospitals have moved slightly in this direction by offering supplemental services for which patients pay out of pocket, such as private rooms or gourmet meal service, most are stuck in the middle. They are constrained by third-party or governmental payment rates (which make them low-price providers), and yet they must contend with medical staffs that demand premium-priced resources.

As an example, some orthopedic surgeons, largely due to personal preference, use comparatively expensive joint replacement devices when less expensive devices would suffice. Some hospitals al\low physicians to admit their patients with little or no advance notice, even when the need for hospitalization is not urgent. One result is nursing coverage demands that require the use of expensive agency nurses. Other hospitals remain at low occupancy during weekends and holidays because physicians do not want to work during these time periods, or because potential patients wish to be at home with their families. Still others succumb to physician demands for cutting- edge technology when less expensive technology would do an acceptable job without compromising quality.

Assessing the Quality of an Organization’s Strategy

Three criteria can be used to assess a strategy’s quality. First, it must be consistent with the factors that are critical to success in the organization’s environment. These factors will differ from one state to the next, depending on a variety of legal and payment requirements and constraints. There also will be different factors for different hospitals in a given state. Certainly, the environment of a large urban teaching hospital in New York is considerably different from that of a small rural community hospital in the Finger Lakes region.

Second, the organization’s strategy must be capable of adapting to unanticipated circumstances or changes in its environment. Here, an organization must tread carefully between being capricious and whimsical, on the one hand, and rigid despite overwhelming evidence of a need for change, on the other. For example, despite overwhelming evidence of an aging population and the demands those patients will bring, many hospitals have not even begun to invest in geriatric programs or other infrastructure needed to care for the elderly. Denying the imminent impact of this demographic “bubble” portends the same sort of calamity that befell Polaroid and Kodak when they denied the impending effect of digital photography.

Finally, and most important, the strategy must be accompanied by a robust and internally consistent set of operational activities. An “activity set” should not only fit with the organization’s critical success factors, but also be difficult for competitors to imitate. This combination assists the organization to sustain its programs and services against competitors’ efforts to capture some of its market share.

Creating an Activity Set

An activity set comprises those structures, systems, and processes that are consistent with the organization’s strategy and that assist it to attain superior performance. An activity set includes operational policies and procedures, information systems, incentive and reward systems, conflict management processes, lines of authority, capital budgeting activities, and operational budgeting and reporting systems.

Although it may be possible to copy one or a few elements of an organization’s activity set, a good activity set is so tightly linked that it is all but impossible to copy all of it. As Michael Porter discussed in his now-classic article “What is Strategy?” (Harvard Business Review, November-December, 1996), an airline wishing to compete with Southwest Airlines would need an activity set that included limited baggage handling; use of secondary airports; a fleet of identical aircraft; and an absence of first- class travel, meal service, and assigned seats.

Without the entire collection of activities for all of its flights, an airline cannot achieve the rapid gate turnaround time that allows Southwest to keep its planes in the air more of the time than its competitors and hence use fewer aircraft for the same number of passenger miles. Southwest’s industry-beating return on assets is due in no small way to its need for fewer fixed assets (airplanes) per dollar of revenue than its competitors.

It would appear that many hospitals could make better strategic trade-offs than they have to date by recognizing that their pricing policy reflects a low-price strategy, and therefore, like Southwest, they need to design an activity set that is appropriate for a low- cost organization. Imagine the competitive advantage that a hospital could have, for example, if it:

* Linked its strategy of low-cost inpatient care services with an activity set comprising a capital budgeting process that ensured investments in assets that lowered operating costs, rather than increasing the supply of cutting-edge technology

* Used operational budgeting and procurement processes that ensured the use of standardized surgical devices

* Had an information system that included an electronic medical record permitting the rapid retrieval of diagnostic and treatment information

* Instituted an operating policy that required nonurgent care admissions to be scheduled several weeks in advance

* Adopted a policy that required patients scheduled for orthopedic surgery to begin their rehabilitation care several weeks prior to admission so as to shorten their lengths of stay

* Implemented a home care program that minimized the number of readmissions following earlier-than- average discharges

The Future

Many healthcare organizations have used their not-for-profit status and the importance of their missions as excuses to avoid making difficult strategic trade-offs. Indeed, some of them have even been highly critical of organizations that have made such trade- offs. For-profit hospitals that are selective in the patients they serve, or entities such as cosmetic surgery centers, boutique physician practices, freestanding dialysis clinics, and the like, all have been looked on with disdain. Yet the essence of strategy rests in these sorts of trade-offs.

Strategic trade-offs do not need to be mercenary, however. Nor do they imply lower-quality care or compromising the not-for-profit mission. Rather, they address the reality that no organization can be all things to all people. In short, by thinking more creatively in the future than they have in the past, healthcare organizations can begin to make the sorts of trade-offs that will allow them to choose a strategic position. They then can design an activity set to support that position-one that will allow them to be financially viable while simultaneously achieving and sustaining superior programmatic performance.

AT A GLANCE

* To get serious about its strategic decision making, a healthcare organization needs to know what it does not intend to be.

* Organizations make trade-offs along three dimensions: service or program variety, customer needs, and customer access.

* Strategic trade-offs also should be assessed in terms of competitive scope and pricing policy.

“If you don’t know where you are going, any road will get you there.”

-attributed to Lewis Carroll, British author

The patient is a 48-year-old male presenting with atypical chest pain, positive smoking and family history, and normal EKG. A review of an alternative emergency department treatment approach showed this hospital that by avoiding unneeded resources (an inpatient admission in this case), it could achieve the desired result (the effective treatment of a patient) at a much lower cost. At an incidence rate of 5/1,000, the purchaser would save $3.5 million annually.

These Healthcare organizations have made tradeoffs along the dimensions of competitive scope and pricing policy. Relatively few healthcare organizations have made comparable trade-offs.

“There is a slightly odd notion in business today that things are moving so fast that strategy becomes an obsolete idea. This is a mistake. If you do not develop a strategy of your own, you become part of someone else’s strategy.”

-Alvin Toffler, American writer and futurist

“Strategy is about setting yourself apart from the competition. It’s not a matter of being better at what you do-it’s a matter of being different at what you do.”

-Michael E. Porter, PhD, professor, Harvard Business School

About the author

David W. Young, DBA, is professor of management, Healthcare Management Program, Boston University School of Management, Boston, and a principal in The Crimson Group, Inc. (www.davidyoung.org).

Copyright Healthcare Financial Management Association Nov 2005

By Masi, Mar; Gutirrez, Flix; Shum, Conrado; Padilla, Sergio; Et al

Study objectives: To evaluate the usefulness of procalcitonin serum levels as a predictor of etiology and prognosis in adult patients with community-acquired pneumonia (CAP) when they are stratified according to severity.

Design: One-year, population-based, prospective study.

Setting: University teaching hospital.

Patients: All adult patients who received a diagnosis of CAP throughout the study period.

Interventions and measurements: An extensive noninvasive microbiological workup was performed. In patients who gave informed consent, a blood sample was collected at the time the diagnosis of CAP was established to measure biological markers. Procalcitonin levels were measured by a commercially available monoclonal immunoluminometric assay (limit of detection, 0.1 g/L). Patients were classified according to microbial diagnosis, Patients Outcome Research Team pneumonia severity index (PSI), and outcome measures, and procalcitonin levels were compared among groups.

Results: Of 240 patients who received a diagnosis of CAP during the study period, procalcitonin concentrations were measured in 185 patients (77.1%). Levels were higher in patients with high-severity risk classes (PSI classes III-V) [p = 0.01] and in those with complications (p = 0.03) or death (p

Conclusions: Procalcitonin contribution to the evaluation of CAP varies according to severity. While procalcitonin may have a role to predict the microbial etiology in patients with a low PSI score, in patients classified within high PSI risk classes, it is a prognostic marker rather than a predictor of etiology. (CHEST 2005; 128:2223- 2229)

Key words: biological markers; biomarkers; community-acquired pneumonia; etiology; outcome; pneumonia severity index; predictive scoring system; procalcitonin; prognosis

Abbreviations: CAP = community-acquired pneumonia; PORT = Patients Outcome Research Team; PSI = pneumonia severity index

The utility of serum markers of systemic infection such as C- reactive protein, lipopolysaccharide-binding protein, or procalcitonin for the differential diagnosis of various infectious conditions has become a matter of interest in the last few years. Of all, procalcitonin stands out as one of the most accurate sepsis markers.1,2 It has shown a superior diagnostic utility in sepsis when compared with C-reactive protein, interleukin-6, and lactate, and has been largely evaluated in multiple polymorbid situations, including lower respiratory tract infections, to discriminate bacterial infection from other causal mechanisms.2

Identifying clinically the etiology of community-acquired pneumonia (CAP) is difficult because single clinical, radiologic, or laboratory parameters have limited value to predict the infectious organism,3 and no rapid test has been standardized for the diagnosis of “atypical” or viral pathogens. As a result, broadspectrum initial antibiotic therapy is usually empirically chosen.4,5 Procalcitonin serum levels or other biological markers of bacterial infection might help clinicians to choose targeted antibiotic therapy in patients with CAP by differentiating between classic bacterial and atypical or viral etiology.

At present, there are few data addressing the usefulness of procalcitonin to predict etiology in patients with CAP,6 and most clinical studies have been performed in children. Investigation in adult patients has mainly focused on lower respiratory tract infections.7,8 While some studies6,7,9 have found higher levels of procalcitonin in bacterial infections, there is no general agreement about the value of procalcitonin as a predictor of etiology. Recently, Christ-Grain et al7 found that a procalcitonin-based therapeutic strategy was useful to reduce antibiotic use in lower respiratory tract infections, based on the ability of procalcitonin to discriminate between patients with or without clinically relevant bacterial infection. Similarly, procalcitonin serum levels were found to be higher in bacterial vs viral or atypical etiologies in two studies6,9 of CAP, one of them performed in children. In contrast, in other studies,8,10,11 differences were found in procalcitonin levels between bacterial and nonbacterial etiologies.

Procalcitonin has been mainly associated with severe systemic infection.12,13 A correlation between increased serum concentration and the severity of infection, clinical course, and mortality has been previously reported.12-14 Most studies6,8,15 of lower respiratory tract infections have also disclosed an association between procalcitonin levels and prognosis. The usefulness of procalcitonin to predict etiology of CAP when patients are stratified by severity according to the Patients Outcome Research Team (PORT) pneumonia severity index (PSI) has not been previously assessed. Since CAP caused by “classic” bacteria usually implicates a higher severity of disease,16 high levels of procalcitonin in this setting might also indicate a worse prognosis rather than any specific microbial etiology. In addition, it is not known if procalcitonin maintains its prognostic value when patients are classified by severity risk classes. To determine the usefulness of procalcitonin as a predictor of etiology and prognosis in adult patients with CAP when they are stratified according to PSI score, we analyzed data from a population-based study in which patients were prospectively evaluated and an extensive microbiological investigation was carried out.

MATERIALS AND METHODS

Setting and Population Studied

A prospective, population-based investigation of CAP was conducted over a 24-month period (October 15, 1999, through October 14, 2001) at Hospital Universitario de Elche, a 430-bed teaching hospital covering a population of 239,335 people living in three municipalities of the “Health Authority of Bajo Vinalop.” on the Mediterranean coitst of Spain. All adult patients (≥ 15 years old) from this health authority with signs and symptoms compatible with pneumonia over the 24-month study period were eligible for inclusion in the study. The study was approved by the local ethical committee. Attending clinicians were asked to consider pneumonia in any patient with an acute illness and symptoms suggesting lower respiratory tract infection, including new cough with high fever or chills, pleuritic chest pain, dyspnea, or prolonged fever. Patients were evaluated clinically and roentgenographically, and those with a provisional diagnosis of CAP were seen by a study investigator to confirm the diagnosis. CAP was defined as an acute illness associated with at least one of the following signs or symptoms: fever, new cough with or without sputum production, pleuritic chest pain, dyspnea, or altered breath sound on auscultation, plus a chest radiograph showing an opacity compatible with the presence of acute pneumonia. Patients with a prior hospitalization within 2 weeks of a current diagnosis of pneumonia were excluded. Demographic and clinical data were collected by a study investigator using a written standardized questionnaire.

To calculate the severity of pneumonia we used the PORT predictive PSI scoring system,17 which classifies patients according to outcome in five risk classes (class I includes patients with the most favorable prognosis, and class V includes those with the poorest prognosis). The score of classes I and II is ≤ 70 points; class III, 71 to 90 points; class IV, 91 to 130 points, and class V, > 130 points. All patients were followed up for at least 4 weeks or until death. A repeat chest radiograph and blood sample were obtained from 2 to 4 weeks after the initial diagnosis of CAP.

During the first 12-month study period from October 15, 1999, to October 14, 2000, patients enrolled in the investigation who gave their informed consent had a blood sample collected within the first 24 h after fulfilling the pneumonia criteria, for measuring biological markers. Subjects recruited through that time period comprised the cohort included in this study.

Microbiological Investigations

The laboratory workup for a patient with CAP has been previously described in detail.18 Briefly, it included sputum samples for Cram stain and culture, two blood samples for culture, urine sample for detection of Legionella pneumophila and Streptococcus pneumoniae antigens, and serum samples for serologic testing drawn during the acute stage of the illness and at least 2 weeks later.

Criteria for Etiologic Diagnosis

The following criteria were used to classify a pneumonia as being of known etiology: (1) for Mycoplanma pneunioniae, Chlamydia psittaci, Coxiella burnetii, influenza viruses A and B, parainfluenza virus, respiratory syncytial virus, and adenovirus: a fourf\old or greater antibody rise by complement fixation test; (2) for Chlamydia pneumoniae: a fourfold rise in microimmunofluorescence antibody titters to ≥ 1/128, or the presence of IgM antibodies (≥ 1/20); (3) for L pneumophila: isolation of organism from respiratory samples or Legionella antigen detected in urine, or fourfold or greater rise in immunofluorescence antibody titer; (4) for S pneumoniae: isolation from blood or from pleural fluid or the predominant organism isolated from a qualified sputum, or antigen detected in urine; (5) for Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and other bacteria, including Gram-negative enterobacteria: isolation from blood or from pleural fluid or the predominant organism isolated from a qualified sputum. Organisms included in the definition of “bacterial” pneumonia and pneumonia caused by atypical pathogens are shown in Table 1. Cases that fulfilled the etiologic diagnostic criteria described above for more than one pathogen were considered mixed pneumonia. Mixed pneumonia included the following combinations of two or more pathogens: classic bacteria plus atypical organisms, atypical organisms plus viruses, two or more classic bacteria, two or more atypical organisms, and two or mores viruses. cases that did not fulfil the etiologic diagnostic criteria described above were considered “pneumonia of unknown etiology.”

Table 1-Distribution of the Causative Microorganisms in Patients Admitted to the Hospital and in Outpatients*

Detection of Procalcitonin

Samples were centrifuged, decanted, aliquoted, and frozen at – 80C until analyzed in May 2003. Procalcitonin levels were measured by monoclonal immunoluminometric assay (Liaison Brahms PCT; Brahms Diagnostics GMBH; Berlin, Germany; limit of detection, 0.1 g/L).19 Biochemical testing was performed in a blinded fashion, without knowing the results of other microbiological investigations.

Data Analysis

Patients were classified according to microbial diagnosis and outcomes measures. Procalcitonin levels in etiologic groups were compared in the whole sample of patients, in patients with PSI- defined low-risk classes (I-II), and in patients with PSI-defined high-risk classes (III-V). A cutoff point of procalcitonin was established to separate bacterial from nonbacterial CAP after obtaining the results of the analysis. Using receiver operating characteristic curves, a cutoff point of 0.15 g/L showed the best discriminatory power. Serum levels of procalcitonin were also compared between patients with PSI-risk classes I-II and III-V, those who had or did not have complications, and those who died or survived. Since a cutoff point of 0.5 g/L has also been found to have discriminatory power in previous studies,8,13,15 a comparison of patients according to this value was also made. Statistical analysis was performed using software (SPSS Version 11; SPSS; Chicago, IL). Descriptive statistics were computed by standard methods. To detect differences between specified groups, we used the Mann-Whitney U test for continuous variables, as they were not normally distributed according to the Kolmogorov-Smirnov test. For categorical variables, we used the χ^sup 2^ test or Fisher Exact Test where appropriate. A two-tailed p value of 0.05 was considered significant.

RESULTS

Of 251 patients evaluated from October 15, 1999, to October 14, 2000, 11 patients were subsequently found not to have CAP, leaving 240 patients in the study cohort. The mean age was 59 years (range, 15 to 93 years), and 62.5% were male. In 115 patients (48%), there was one or more underlying disease, mostly diabetes mellitus (n = 55) and COPD (n = 51). Sixty patients (25%) had previously been treated with antibiotics.

The causative pathogen was found in 131 of the 240 patients (54.6%) [56 classic bacterial pathogens, 43 atypical pathogens, 16 viral pathogens, and 16 mixed]. In 154 patients (64.2%), the pneumonia resolved without complications, and the following complications developed in 49 patients (20.4%): septic shock, 6 patients (2.25%); mechanical ventilation requirement, 4 patients (1.7%); and empyema, 2 patients (0.8%). Seventeen of the 240 patients (7.1%) died.

Procalcitonin serum levels were measured in 185 patients (77.1%). In the remaining patients, the test was not performed because a serum sample obtained within the first 24 h of diagnosis of pneumonia was not available or was insufficient. There were no differences in age, sex, comorbidity, or PORT PSI scores between patients in whom procalcitonin was measured and those in whom it was not (data not shown). The etiologic distribution of the 185 cases is shown in Table 1. There were no significant differences in procalcitonin levels between major etiologic groups (Fig 1), although patients with bacterial pneumonia showed a wider interquartile range compared with the rest of the patients.

The severity of pneumonia was assessed using the POKT PSI. Overall, the median PSI score was 70.0 (range, 9 to 172) in the 185 patients. The median PSI score was lower in patients with pneumonia due to atypical organisms: 51.0 (range, 9 to 150) vs 77.0 (range, 15 to 172) in the rest of the pneumonias (p = 0.002). No significant differences were observed in median PSI scores among the other etiologic groups: 82.0 (range, 20 to 159) in bacterial pneumonia, 82.0 (range, 15 to 138) in viral pneumonias, 77.5 (range, 21 to 132) in mixed pneumonia, and 75 (range, 20 to 172) in pneumonias of unknown etiology. Mean procalcitonin levels were calculated according to PSI risk class. Mean procalcitonin value was 0.33 g/L (range, 0.10 to 8.95 g/L) in class I; 0.27 g/L (range, 0.10 to 3.45 g/L) in class II; 0.44 g/L (range, 0.10 to 10.57 g/L) in class III; 0.77 g/L (range, 0.10 to 6.80 g/L) in class IV; and 1.15 g/L (range, 0.10 to 5.47 g/L) in class V. Patients included in risk classes III- V (PORT PSI > 70) had a mean procalcitonin value of 0.67 g/L (range, 0.10 to 10.57 g/L), compared to 0.31 g/L (range, 0.10 to 8.95 g/L) in those included in classes I-II (p = 0.01). Likewise, patients with complications (including empyema, mechanical ventilation requirement, or septic shock) or who died had a higher procalcitonin level than those who did not (p = 0.03 and p

FIGURE 1. Box plots showing proculcitonin levels according to the etiology of CAP. The box plots show 25th, 50th, and 75th percentiles, maximal, extremes (*), and outliers ([white circle]).

Patients were stratified according to PSI-defined risk classes in those with a low risk (classes I-II) and with a higher risk (classes III-V). When procalcitonin serum levels were again evaluated according to the etiology, among patients classified into classes I- II, those with CAP caused by classic bacteria tended to have higher procalcitonin levels than patients with CAP of any other etiology, although differences did not reach statistical significance (p = 0.08) [Fig 2]. A cutoff point of procalcitonin of ≥0.15 g/L captured 37.5% of the patients with bacterial etiology and 13.3% of the patients with other etiologies (p = 0.03). No differences in procalcitonin levels were found between etiologic groups in patients included in classes III-V (Fig 2). Development of complications and death were significantly associated with higher procalcitonin levels in patients of PSI-defined risk classes III-V (p = 0.01 and p

In 21 patients, procalcitonin serum levels were ≥ 0.5 g/L. The clinical characteristics of these 21 patients were compared with those of the 164 patients with procalcitonin serum levels

Table 2-Procalcitonin Levels According to PORT PSI Risk Classes, Development of Complications, and Death*

FIGURE 2. Box plots showing procalcitonin levels according to the etiology of CAP in patients with low PSI risk classes (I-I1) [top], and in patients with higher PSI risk classes (III-V) [bottom]. The box plots show 25th, 50th, and 75th percentiles, maximal, extremes (*), and outliers ([white circle]).

DISCUSSION

The results of this study suggest that procalcitonin contribution to the evaluation of patients with CAP varies according to severity of pneumonia. While procalcitonin may have a role to predict the microbial etiology in patients with a low PSI score, in patients classified within high PSI risk classes it is a prognostic marker rather than a predictor of etiology.

To our knowledge, this is the largest study to date performed in adults with CAP in which procalcitonin serum levels have been evaluated as a predictor of etiology. Herein, strict criteria were used for the microbial diagnosis, and a final etiologic diagnosis was achieved \in a relatively high number of patients, compared to other studies6 in which procalcitonin levels were measured. In addition, biochemical testing for detection of procalcitonin was performed in a blinded fashion to avoid any classification bias. In the present study, no differences in procalcitonin levels were found between major etiologic groups when the whole sample of patients with CAP was considered. However, when patients were stratified according to PSI, the highest procalcitonin levels predicted bacterial etiology in patients with a low PSI score (risk classes I and II). No differences in procalcitonin levels were found between major etiologic groups in patients with higher PSI scores (risk classes III-V).

The results of this study corroborate that procalcitonin is a good predictor of seventy of pneumonia, as previously described.6,8,15 Patients with a higher PSI score or with complications or death had significantly higher procalcitonin levels than those with an uncomplicated clinical course. Additionally, patients with higher procalcitonin levels also had other markers of a more severe disease, such as higher WBC or neutrophil counts and respiratory rate.

CAP syndrome comprises a wide spectrum of seventy of disease, even when only bacterial pneumonia is considered.20 In our study, classic bacteria pneumonia was the most frequent etiology in the subset of patients with higher procalcitonin concentrations, but also atypical organisms and viruses were found in this group. Besides bacteria, severe cases of pneumonia due to atypical organisms and viruses have been reported,21 and distribution of pathogens in severe and nonsevere disease forms has been found to be comparable in a previous study20 of severe CAP. Our study showed that in CAP patients with a high PSI score, procalcitonin levels were elevated independently of the microorganism implicated, and there were no significant differences in procalcitonin values between main etiologic groups. Procalcitonin levels are raised in severe systemic inflammatory syndrome and sepsis and also in noninfectious marked systemic inflammation, such as inhalation burn injury22 or chemical pneumonitis.23 Therefore, high procalcitonin levels are not only a predictor of bacterial etiology. By contrast, in patients included in the lowest PSI risk classes (I and II), in which overall procalcitonin levels are also low, higher values of procalcitonin may be useful to predict bacterial etiology. This information can be used by clinicians to select targeted antimicrobial therapy in a proportion of patients with CAP. The discrepancies between the diverse studies of lower respiratory tract infections in which procalcitonin has been evaluated as a predictor of etiology might be explained by the spectrum of severity of disease of the population included in each study.

Table 3-Comparison of Clinical Characteristics of Patients With Procalcitonin Levels ge; 0.5 g/L and

Overall, we found lower procalcitonin serum concentrations than those described in patients with lower respiratory tract infections or CAP in other studies.6,7,10 However, in those studies, only patients admitted to the hospital were included and mean age was higher,6,7 both factors usually associated with a higher severity of infection and subsequently potentially higher values of procalcitonin. Our study was population based, with a wide spectrum of severity of disease and age range. When patients with CAP not admitted to the hospital have also been included, lower serum procalcitonin levels have been found.11,15

The present study has some limitations and potential biases that should be acknowledged. Unfortunately, as in most pneumonia studies, despite the extensive microbiological investigation carried out, the etiology remained unidentified in a considerable proportion of cases because of the low sensitivity of conventional microbiological tests. As a result, the sample size in some of the etiologic groups was small, and the lack of statistical power may have precluded us to detect significant differences among groups. An additional challenge facing all new laboratory techniques used lor the etiologic diagnosis of CAP relates to the lack of a satisfactory reference standard for the microbial diagnosis. Although the chosen criteria in this study were very strict, some microbiological tests may not have sufficient diagnosis accuracy to rule out etiologic misclassification, including the possibility of mixed infections in some cases (eg, bacterial superinfection in cases of viral pneumonia). Finally, a subset of patients had been previously treated with antibiotics, and this factor may have influenced the level of procalcitonin.

The limitation of procalcitonin as a diagnostic marker in patients with CAP may be related to the low sensitivity of the commercially available assay. This assay may be useful to detect markedly elevated procalcitonin in patients with severe systemic bacterial infection or sepsis, but it may not be sensitive enough to detect mildly or moderately elevated procalcitonin levels, which limits its diagnostic use in conditions other than overt sepsis.24 Christ-Grain et al,7 who employed a lower limit of detection (0.06 g/ L instead of 0.1 g/L) in their study, supported that diagnostic accuracy of procalcitonin depends on the sensitivity of the assay for its determination. A lower limit of detection should have helped to characterize better the differences between the major etiologic agents implicated in the patients with low PSI scores, in which many values were under the limit of detection. Further studies should evaluate whether more sensitive procalcitonin assays have a superior accuracy as diagnostic markers in patients with CAP.

In conclusion, the role of serum procalcitonin in adult patients with CAP differs among the PORT PSI score groups. Procalcitonin is mainly a marker of poorer outcome in patients with CAP classified into PSI high-severity risk classes, whereas in low-severity risk classes it may help clinicians to predict classic bacteria and subsequently to select empiric antimicrobial therapy.

* From the Infectious Diseases Unit, Internal Medicine Department (Drs. Masi, Gutirrez, and Padilla), Pneumology Section (Dr. Shum), and Biochemistry Section (Drs. Navarro and Flores), Hospital General Universitario de Elche, Alicante; and Public Health Department (Dr. Hernndez), Miguel Hernndez University, Alicante, Spain.

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2 Mullur B, Becker KL. Procalcitonin: how a hormone became a marker and mediator of sepsis. Swiss Med Wkly 2001; 131:595-602

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12 Whang KT, Steinwald PM, White [C, et al. Serum calcitonin precursors in sepsis and systemic inflammation. J Clin Endocrinol Metab 1998; 83:3296-3301

13 Muller B, Becker KL, Schachinger H, et al. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med 2000; 28:977-983

14 Castelli GP, Pognani C, Meisner M, et al. Procalcitonin and C- reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction. Crit Care 2004; 8:R234-242

15 Hausfater P, Garric S, Ayed SB, et al. Usefulness of procalcitonin as a marker of systemic infection in emergency department patients: a prospective study. Clin Infect Dis 2002; 34:895-901

16 Luna CM, Famiglietti A, Absi R, et al. Community-acquired pneumonia: etiology, epidemiology, and outcome at a teaching hospital in Argentina. Chest 2000; 118:1344-1354

17 Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997; 336:243-250

18 Gutirrez, F, Masi M, Rodrguez JC, et al. Evaluation of the immunochromatographic Binax NOW assay for detection of Streptococcus pneumoniae urinary antigen in a prospective study of community- acquired pneumonia in Spain. Clin Infect Dis 2003; 36:286-292

19 Meisner M, Tschaikowsky K, Schnabel S, et al. Procalcitonin- influence of temperature, storage, anticoagulation and arterial or venous asservation of blood sampl\es on procalcitonin concentrations. Eur J Clin Chem Clin Biochem 1997; 35:597-601

20 Oosterheert JJ, Bonten MJ, Hak E, et al. Severe community- acquired pneumonia: what’s in a name? Curr Opin Infect Dis 2003; 16:153-159

21 Ruiz M, Ewig S, Torres A, et al. Severe community-acquired pneumonia: risk factors and follow-up epidemiology. Am J Respir Crit Care Med 1999; 160:923-929

22 Nylen ES, O’Neill W, Jordan MH, et al. Serum procalcitonin as an index of inhalation injury in bums. Horm Metab Res 1992; 24:439- 443

23 Nylen ES, Snider RH Jr, Thompson KA, et al. Pneumonitis- associated hyperprocalcitoninemia. Am J Med Sci 1996; 312:12-18

24 Muller B, Christ-Crain M, Nylen ES, et al. Limits to the use of the procalcitonin level as a diagnostic marker. Clin Infect Dis 2004; 39:1867-1868

Mar Masi, MD; Flix Gutirrez, MD; Conrado Shum, MD; Sergio Padilla, MD; Juan Carlos Navarro, MD; Emilio Flores, MD; and Ildefonso Hernndez, MD

This work was performed at Hospital General Universitario de Elche, Alicante, Spain.

Manuscript received March 20, 2005; revision accepted April 7, 2005.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: Mar Masi, MD; Unidad de Enfermedades Infecciosas, Hospital General Universitario de Elche, Cam de la Almazara S/N; 03203 ELCHE, Alicante, Spain; e-mail: [email protected]

Copyright American College of Chest Physicians Oct 2005

By Moorman, Jonathan; Saad, Mustafa; Kosseifi, Semaan; Krishnaswamy, Guha

Hepatitis C virus (HCV) infection is a chronic blood-borne disease that affects > 4,000,000 individuals in the United States. The majority of individuals with HVC infection acquire a chronic hepatitis that predisposes them to the complications of cirrhosis and hepatoma. Chronic HCV infection is, however, associated with multiple extrahepatic manifestations as well, including recently recognized effects on the lung. These include primary effects on lung function, as well as secondary effects in the settings of progressive liver disease and drug treatment for HCV. In this article, we discuss the emerging clinical data that support a role for HCV infection in lung disease, describe the multiple pulmonary manifestations of this viral infection, and outline the therapies available for specific pulmonary complications of chronic HCV infection. (CHEST 2005; 128:2882-2892)

Key words: complications; hepatitis; lung diseases; review

Abbreviations: BALF = BAL fluid; BDP = beclomethasone dipropionate; BOOP = bronchiolitis obliterans/organizing pneumonia; DLCO = diffusing capacity of the lung for carbon monoxide; EMC = essential mixed cyroglobulinemia; HCV = hepatitis C virus; HPS = hepatopuhnonary syndrome; HRCT = high-resolution CT; IFN = interferon; IL = interleukin; IPF = idiopathic pulmonary fibrosis; PFT = pulmonary function test; PPHTN = portopulmonary hypertension

Hepatitis C virus (HCV), a small, single-stranded RNA virus classified in the Flaviviridae family, remains a major cause of hepatic cirrhosis and hepatocellular carcinoma worldwide.1 This virus is notorious for its ability to evade the host immune system and leads to persistent infection in the majority of the acutely infected patients.2-4 Persistent infection in turn is responsible for the direct and indirect effects of the virus on hepatic tissue, with chronic hepatic inflammation leading to cirrhosis and hepatocellular carcinoma.

Over the last decade, an increasing number of reports have suggested that chronic HCV infection is also associated with both direct and indirect effects on pulmonary tissue. While not all of these effects have been tightly linked to HCV infection, there are now sufficient studies available that warrant a review of the major pulmonary sequelae associated with chronic HCV infection. We first describe what appear to be primary/direct effects of the virus on the lung and the possible mechanisms underlying these effects. We subsequently outline the secondary effects of chronic HCV infection on lung parenchyma and the pulmonary vasculature, including those related to cirrhosis, cryoglobulinemia, and interferon (IFN) therapy. Finally, we discuss options for future clinical and molecular studies that might broaden our understanding of the mechanisms by which chronic HCV induces pulmonary pathology.

EFFECTS OF HEPATITIS C ON THE LUNG

Direct Effects of HCV on the Lung

The direct effects of HCV on the lung may present as worsening of lung function in some patients with preexisting asthma and/or COPD. In other patients, HCV may present with an interstitial pneumonitis and/or pulmonary fibrosis. These complications associated with HCV are discussed in greater detail in the sections that follow.

COPD: COPD and asthma are chronic inflammatory conditions of the airways and lung parenchyma with differing patterns of airflow obstruction with respect to reversibility, whether spontaneous or in response to treatment.5 Several reports6-9 have suggested an important role for latent viral infections, in particular adenovirus and HIV, in the etiology and/or progression of COPD. Based on these reports, investigators have hypothesized that chronic PICV infection might also function as a trigger for inflammation in the lungs, thereby either initiating or exacerbating the development of COPD. These data are limited by sample size but provide intriguing information that should urge investigators to pursue further trials.

The only prospective study10 to address the association between HCV and COPD was carried out by investigators from Japan, who randomly enrolled 30 HCV-positive and 29 HCV-negative patients with COPD and classified them into four groups: 15 HCV-negative ex- smokers, 14 HCV-negative current smokers, 14 HCV-positive ex- smokers, and 16 HCV-positive current smokers. Each patient underwent spirometric measurements and assessments of diffusion capacity of the lung for carbon monoxide (DLCO) every 4 months over a period of 5 years. Linear regression analysis was performed for each patient’s 5-year data to assess the decline in lung function. The annual rates of decline in FEV^sub 1^ and DLCO in current smokers and ex-smokers were significantly higher in HCV-positive patients. When the change in FEV^sub 1^ was assessed in patients who were treated for HCV infection with interferon (IFN)-α, IFN responders exhibited a slower progression of decline in FEV^sub 1^ than the IFN nonresponders. The authors10 suggested that the airway disease may be related to underlying chronic inflammation with emphasis on the possible effects mediated by HCV-specific T lymphocytes and latent viral infection.

Asthma: Several studies have now also documented an accelerated decline in lung function in asthmatic patients with chronic HCV infection associated with impaired responses to inhaled β^sub 2^-adrenoceptor agonists and corticosteroids and increased responses to inhaled anticholinergic agents. Kanazawa and colleagues11 assessed 40 asthmatic patients with chronic HCV infection for responses to the inhaled corticosteroid beclomethasone dipropionate (BDP) with and without IFN therapy. Patients were randomly selected, all were nonsmokers, and none of them were receiving steroid therapy. All patients received inhaled BDP therapy for 6 weeks, at which point 30 patients received therapy for HCV with IFN while all patients continued BDP therapy. Eleven patients responded to IFN therapy in terms of viral clearance, while 19 patients did not respond. Prebronchodilator and postbronchodilator FEV^sub 1^ values were obtained after 6 weeks of BDP therapy and at 1-year following the end of IFN therapy.

The study11 showed no significant differences in either prebroiichodilator or postbronchodilator FEV^sub 1^ among all patients at 6 weeks of BDP therapy. At 1 year after IFN treatment, however, these values were significantly higher in the IFN respondcr group than in the IFN nonresponders and the IFN nontreatment groups. Furthermore, the IFN responder group had significantly higher prebronchodilator and postbronchodilator FEV^sub 1^ values at 1 year after the end of IFN therapy compared to those obtained after 6 weeks of BDP therapy. As in the study10 examining the association of HCV with COPD, this study11 demonstrated declines in pulmonary function over time in individuals with HCV infection, which were reversible with successful control of viral replication by IFN treatment.

A prospective study12 with a 6-year follow-up was designed to determine whether chronic HCV infection affects declines in lung function and airway responses to the β^sub 2^-adrenoceptor agonist salbutamol in nonsmoking asthmatic patients. All HCV- positive patients received IFN for 6 months. One year after IFN therapy, patients were administered either inhaled salbutamol or oxitropium bromide in a doubleblind manner. FEV^sub 1^ values were then recorded, and measurements were repeated at 3 and 6 years after IFN therapy; 55 HCV-positive and 20 HCV-negative asthmatic patients completed the 6-year follow-up. Of the 55 HCV-positive patients, 18 were IFN responders and 37 were IFN nonresponders. Notably, all patients received rescue inhaled β^sub 2^-agonists for acute symptoms as well as inhaled corticosteroids, and their use was stable in all groups during the 6-year follow-up period.

The prebronchodilator and postbronchodilator FEV^sub 1^ as well as the reversibility with salbutamol were significantly lower in the IFN nonresponder group when compared to the IFN responders and the HCV-negative group. Moreover, the study’s showed a steep decline in reversibility with salbutamol during the 6-year follow-up only in the IFN nonresponders, whereas there was a steep improvement in reversibility with the anticholinergic agent, oxitropium. These results suggested that chronic HCV infection is associated with an accelerated decline in lung function and impaired responses to salbutamol but not oxitropium in asthmatic patients. The authors12 suggested that chronic HCV infection might induce CD8+ T lymphocytes that cause asthma with a COPD-like inflammation, an effect that would explain the increased responses noted with the anticholinergic agent oxitropium.

This superior response to anticholinergic agents was further assessed in a recent study13 in which 36 HCV-positive asthmatic patients were administered IFN therapy followed by oxitropium bromide and compared to a group of 16 HCV-negative asthmatics. The study once again found significant increases in FEV^sub 1^ and forced expiratory flow between 25% and 75% of FVC after oxitropium bromide administration in IFN nonresponders (ie, those with active HCV infection) when compared to the HCV-negative and the IFN responder groups. The authors suggested the possibility that patients with asthma and HCV infection respond differently to the various bronch\odilator therapies than patients without HCV infection, and that HCV might modulate acetylcholine-mediated airway responses.

Mechanisms Regulating Declining Lung Function in HCV Infection: These clinical studies support an association between chronic HCV infection and obstructive airway diseases, but the exact role of HCV in the pathogenesis of declining pulmonary function is not well understood. Several mechanisms could be hypothesized (Fig 1), but the chronic immune activation and inflammation induced by HCV infection may play an important role. This has been shown with latent adenoviral infection in emphysematous smokers with COPD, who exhibit increased lung inflammation associated with increased expression of adenoviral EAl protein in alveolar epithelial cells9; patients with more severe emphysema were found to have absolute increases in neutrophils, macrophages, and CD4+ and CD8+ lymphocytes.

It is feasible that chronic HCV replication in pulmonary tissues may promote a similar result, but molecular studies to address this have been scant. The few studies analyzing BAL fluid (BALF) from groups with HCV infection have found varying results, with significant increases in neutrophils alone,14 lymphocytes and neutrophils,15 or lymphocytes and eosinophils.16 Increases in the numbers of CD2+ , CD3+ , CD4+ , and human leukocyte antigen-DR+ T lymphocytes were also noted15,16; these were, however, small studies that were done in asymptomatic patients with no clinical or radiologic evidence of respiratory disease.

FIGURE 1. Potential mechanisms for HCV-associated pulmonary disease. MCP = monocyte chemoattractant protein; NF = nuclear factor.

One candidate for a role in pulmonary inflammation may be the T lymphocyte, in particular the CD8+ T cell. During viral infections, cytotoxic CD8+ T lymphocytes are in general up-regulated and activate a cascade of inflammatory pathways leading to the release of inflammatory mediators.17 CD8+ cells are also believed to play a key role in the development of airway inflammation associated with COPD, being overrepresented in the lungs of patients with COPD in an inverse relationship to lung function.18 Cytotoxic CD8+ T lymphocytes were also found to contribute to the pathology of severe or persistent asthma (which is generally a CD4+ cellpredominant process).19 CD8+ T lymphocytes also contribute to dysregulation of muscarinic M2 receptors, the general function of which is to inhibit acetylcholine release and thereby limit airway bronchoconstriction.20 CD8+ lymphocyte expression of IFN-γ, for example, down-regulates M2 receptor expression in airway parasympathetic neurons and so exacerbates airway hyperreactivity.20,21 Thus far, however, no study has confirmed the presence of HCV-specific cytotoxic CD8+ (or CD4+) T lymphocytes in BALF. Future studies of cellular responses in the lung in the settings of chronic HCV infection are needed to clarify this issue.

Other strong candidates for a role in pulmonary inflammation in the setting of HCV include inflammatory cytokines. In COPD, increased levels of interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α have been found and increase further with exacerbations.22 Patients with persistent asthma and COPD have an influx of neutrophils and increased local pulmonary IL-8 levels, and both asthma and COPD are characterized by increased nuclear factor- κB and 15-lipoxygenase expression.23-25 In COPD, the bronchiolar epithelium also overexpresses monocyte chemoattractant protein-1 and IL-8, which act as leukocyte chemoattractants and thereby may contribute to the elevated neutrophil levels found in sputum.26

IL-8, because of its well-known chemotactic effects mediated by interaction with its receptor (CXCR 1 or 2) present on inflammatory cells such as neutrophils, can mediate cellular recruitment and propagate pulmonary inflammation (Fig 1).27 IL-8 has been shown to directly provoke bronchoconstriction28 and may contribute to the establishment of chronic reactive airway disease directly and indirectly by stimulating neutrophil recruitment and activation. Interestingly, studies29-30 in patients with chronic HCV infection have demonstrated increased levels of both serum and intrahepatic cytokines, in particular IL-8. Expression of IL-8 may inhibit the antiviral activity of IFN-γ and correlates with the degree of hepatic fibrosis and portal inflammation during HCV infection.31,32

It remains unclear if HCV is acting to exacerbate underlying pulmonary disease, to initiate disease, or both. Further clinical and basic studies are clearly needed to examine in particular the cellular and cytokine responses occurring within pulmonary tissues in individuals with HCV infection.

HCV Infection and Interstitial Lung Disease: Since HCV is well known to induce chronic inflammation and fibrosis in the liver, it was thought that HCV may play a similar role in the lung and be involved in the pathogenesis of pulmonary fibrosis. This idea put forth by investigators33 from Japan tests the presence of HCV antibodies in a cohort of patients with idiopathic pulmonary fibrosis (IPF); to their surprise, they found a higher prevalence of serum antibodies to HCV in patients with IPF (28.8%) than in age- matched control subjects (3.6%), which was statistically significant (p

Similarly, Ferri et al36 screened 300 patients with chronic HCV infection for the presence of lung disease by means of clinical symptoms and chest radiographs. Eight patients had evidence of interstitial lung involvement, which was further confirmed by high- resolution CT (HRCT). No patient had any obvious predisposing factors for pulmonary fibrosis. Four patients had severe interstitial lung fibrosis, while the other four patients had mild- to-moderate involvement. All of the patients had different degrees of DLCO reduction, and BALF showed an increased percentage of neutrophils in four of four patients. Lung involvement worsened in two patients slowly over time and remained stable in five patients; one patient died with rapidly progressive respiratory failure. The HCV genome was demonstrated in the lung biopsy specimen of one of the patients, a finding that might support a more direct pathogenic role for HCV in pulmonary fibrosis. Anecdotal reports37-41 have supported these findings as well.

Investigators have studied the association between HCV and pulmonary fibrosis in patients with and without known lung disease. In a recent prospective study in individuals with no known pulmonary disease, Okutan et al42 compared the results of pulmonary function tests (PFTs) and HRCT in 34 patients with chronic HCV infection and 10 healthy control subjects and found a trend toward decreased DLCO in patients with HCV. While the differences in DLCO were not statistically significant, patients with HCV exhibited statistically significant interstitial lung involvement as seen on the HRCT; this involvement did not correlate to the degree of liver impairment. The small size of the patient sample in this study likely influenced the statistical power of the results. In a retrospective study43 of 81 liver transplant candidates with hepatitis C-induced cirrhosis, the results of echocardiography, arterial blood gas analysis, and PFTs were reviewed. Pulmonary changes were found to be frequent in this cohort, with reduced DLCO being the most common (found in 43% of patients), followed by restrictive lung impairment (17%) and obstructive airway disease (11%).

Further evidence of interstitial involvement with chronic HCV infection was provided by a study44 that assessed lung function by measurement of epithelial permeability with ^sup 99m^Tc-labeled diethylenetriaminepentaacetic acid aerosol scintigraphy. In this study,44 26 HCV-positive patients with no clinical pulmonary symptoms were compared to 31 normal control subjects; significantly increased epithelial permeability was found in HCV-positive patients compared to control subjects, a finding that generally suggests early interstitial lung disease.45,46

In summary, several lines of evidence support a pathogenic role for chronic HCV infection in interstitial lung disease, but all are limited by sample size and the association remains controversial. Further larger, prospective trials are clearly needed to define the role of HCV in this process.

Secondary Effects of HCV Infection on the Lung

Table 1 lists the various other mechanisms by which the lung may be involved in HCV infection. Cirrhosis of the liver (due to HCV) with the added complications of portopulmonary hypertension (PPHTN) and hepatopulmonary syndrome (HPS), cryoglobulinemia, Sicca-like syndrome, malignant lymphomas, autoimmune thyroid disease, polymyositis, and hypocomplementemic urticarial vasculitis have all been reported in response to HCV infection and may indirectly affect the lung. The following sections discuss some of these secondary effects in greater detail.

Table 1-Overview of Pulmonary Complications Associated With HCV*

Cirrhosis-Related Pulmonary Effects: Secondary effects of HCV infection on pulmonary disease are either related to liver cirrhosis and portal hypertension or to the autoimmune disorders that are occasionally seen in association with chronic HCV infection. It is well established that chronic liver disease from any cause can lead to pulmonary derangements. These may arise from chan\ges in liver metabolism due to circulating inflammatory mediators and/or from circulatory changes related to pulmonary hypertension. Mild hypoxemia is a frequent finding in patients with chronic liver disease, occurring in approximately one third of all patients.55 The most common pulmonary problems occur due to impaired clearance of secretions and atelectasis that are associated with pleural effusions, ascites, and pulmonary edema.56 It is estimated that approximately 10% of patients with chronic liver disease acquire unilateral or bilateral pleural effusions, or the “hepatic hydrothorax.”57

In addition, two clinically distinct syndromes that represent a continuum of pulmonary vasculopathy have been defined in association with liver cirrhosis: HPS, representing extreme vasodilatation, and PPHTN, representing vasoconstriction. HPS is defined as the presence of intrapulmonary vasodilatations in conjunction with hypoxemia and chronic liver disease. PPHTN is defined by a mean pulmonary artery pressure > 25 mm Hg with a normal pulmonary capillary wedge pressure in the setting of portal hypertension. Although the two syndromes are the extremes of pulmonary vasculopathy, they may occasionally coexist in the same patient.58 They are discussed in the sections that follow.

HPS: HPS is characterized by the clinical triad of hepatic dysfunction, hypoxemia (PaO^sub 2^

The spectrum of clinical abnormalities is wide: impaired oxygenation may be subclinical, and patients may present with symptoms of liver disease rather than respiratory symptoms.55,59 A subset of patients present with typical respiratory symptoms that include exertional dyspnea and platypnea (dyspnea that occurs on arising from a supine to a standing position), cyanosis, finger clubbing, spider nevi, hypoxemia, and orthodeoxia (a decrease in PaO^sub 2^ > 3 mm Hg when a patient arises from a recumbent to a standing position).55,62-65 Platypnea and orthodeoxia are common in patients with HPS because the intrapulmonary vascular dilatations that underlie these two manifestations are predominantly found in the lower lung fields, where blood pools due to the effect of gravity on standing.56

Intrapulmonary vascular dilatations are the major cause of hypoxemia in HPS. These occur as vascular dilatations at the precapillary or capillary levels, or as larger arteriovenous communications. Ventilation/ perfusion mismatch then follows due to increased perfusion, while ventilation remains the same. This mismatch is thought to be due to inability of oxygen molecules to diffuse from the alveolar space to the center of these pathologically dilated capillaries to oxygenate the hemoglobin in the center.55-57,63 Finally, impaired hypoxic vasoconstriction in patients with chronic liver disease and the increased pulmonary blood flow may add to the ventilation/perfusion impairment48,63,66 The exact cause of the pulmonary vascular dilatations remains poorly understood.

Diagnosis can be established noninvasively by contrast echocardiography or ^sup 99m^Tc-labeled macroaggregated albumin scanning.55,56 Pulmonary angiography should be reserved for patients with severe hypoxemia and a poor response to 100% inspired oxygen, in whom vascular embolotherapy to obliterate arteriovenous communications (and eliminate the anatomic shunting) may be a therapeutic option.57

Several pharmacologic agents have been used to treat HPS, but the results have been disappointing. Plasma exchange and mechanical occlusion of the intrapulmonary vascular dilatations have also failed. Liver transplantation remains the only curative option, with resolution of the syndrome described to occur within days of transplant and up to 15 months after transplantation.55-57

PPHTN: PPHTN is characterized by a tetrad of elevated pulmonary artery pressure (> 25 mm Hg at rest), increased pulmonary vascular resistance (> 120 dyne.cm^sup 5^), a normal wedge pressure ( 10 mm Hg).67 It was first described in 1951 by Mantz and Craige,68 and its prevalence in patients with chronic liver disease is estimated to be between 1% and 5% in different studies.62,69-71 From 12 to 20% of patients undergoing orthotopic liver transplantation and those with decompensated cirrhosis may acquire this syndrome.49,64,72

In the majority of patients with PPHTN, portal hypertension precedes pulmonary hypertension by an average of 4 to 7 years.69,73 The pathogenesis of the structural changes in PPHTN is poorly understood, but the pathologic changes include pulmonary vasoconstriction, remodeling of muscular pulmonary artery walls, and in situ microthrombosis and/or thromboembolic lesions.63,74-76 Although the pathologic changes in PPHTN are similar to primary pulmonary hypertension, PPHTN is associated with a greatly increased cardiac output.77

The mean age at diagnosis is the fifth decade with a similar distribution in both sexes.63,77 The most common symptom on presentation is exertional dyspnea, but other less frequent symptoms include syncope, chest pain, orthopnea, fatigue, palpitations, and hemoptysis. In addition, a large proportion of patients with PPHTN may be asymptomatic. Physical signs of PPHTN include increased intensity of the pulmonary component of the second heart sound, and murmurs of tricuspid and pulmonic regurgitation. Arterial blood gases usually reveal mild hypoxemia and exaggerated respiratory alkalosis, while PFTs may show a mild restrictive pattern with reduction in DLCO.63,64,67,73,77,78

Echocardiography is a very helpful noninvasive tool to screen patients with suspected PPHTN. It may show right ventricular enlargement and signs of tricuspid and pulmonary regurgitation.77,79 In addition, Doppler echocardiography can give an indirect estimate of the pulmonary artery pressure. The diagnosis is usually established by right-heart catheterization with the direct measurement of the pulmonary artery and right ventricular pressures. Vasodilator responsiveness should be assessed at the time of catheterization to help guide future therapy.

Treatment with vasodilator therapy (prostacyclin or prostacyclin analogues) has been shown to improve survival in a subset of patients with a positive vasodilator response.63,67,80,81 Other pharmacologic agents have been used with variable results and include phosphodiesterase inhibitors, inhaled nitric oxide, nitrates, and β-blockers.50,81-85 In contrast to HPS, the role of liver transplantation in PPHTN is not clear because of the increased intraoperative and perioperative death, and reports57,62,63,67 of worsening pulmonary hypertension after transplantation. Prognosis is poor overall in the absence of an intervention, with a mean survival period of 15 months and a median survival of 6 months.73,74

Essential Mixed Cryoglobulinemia: Essential mixed Cryoglobulinemia (EMC) is a vasculitis characterized by the deposition of circulating immune complexes in small and medium- sized blood vessels and characteristically presents with a triad of arthralgias, purpura, and weakness.86 As the name implies, cryoglobulins are immune complexes that have the tendency to precipitate at cold temperatures. The link between EMC and chronic HCV infection is well established.87 It is estimated that approximately one third of patients with chronic hepatitis C infection have mixed cryoglobulinemia.47,86,88,89 In addition, cryoprecipitates were found to contain 10-fold and 1,000-fold levels of HCV antibody and RNA, respectively.86,89 EMC may present as a systemic vasculitis that can involve different organs, with renal and neurologic involvement being more commonly reported.

A large number of rheumatologic disorders and vasculitic syndromes can present with a range of pulmonary manifestations by means of immune-mediated injury and autoimmune mechanisms. Likewise, the immune-mediated vasculitic lesions are responsible for the clinical manifestations of EMC, including cutaneous and visceral organ involvement, and particularly pulmonary involvement. Fortunately, pulmonary involvement is usually mild and probably slowly progressive.91-93 Bombardieri and colleagues91 evaluated 23 patients with EMC for lung involvement and found that pulmonary symptoms were generally absent or moderate with the exception of 3 patients, who presented with asthma, hemoptysis, or pleurisy. Tests of small airway disease were markedly altered. Radiographic signs of interstitial lung involvement were present, albeit moderate, in 18 of 23 patients and were associated with inhomogeneities of regional blood flow on perfusion lung scanning.

Viegi et al92 found similar results and confirmed the findings documented by Bombardieri et al.91 A study93 of BALF in patients with EMC and HCV infection provided evidence for a subclinical T- lymphocyte alveolitis; patients with EMC were found to have a significantly lower percentage of alveolar macrophages but significantly higher percentages of CD3+ cells in their BALF than the control group. Also, PFTs done on the same patients showed significantly lower forced expiratory flow between 25% and 75% of FVC and DLCO in the EMC group than the control group. Following therapy with IFN, BALF analysis revealed a significant decrease in the percentage of lymphocytes.94 Whether the presence of T- lymphocyte alveolitis in this study is related to the EMC or to chronic HCV infection remains speculative.

Although the lung involvement in EMC is usually mild, several cases with severe lung involvement have \been reported. Roithinger et al95 reported a case of EMC complicated by immunologically mediated pulmonary vasculitis. The patient died from the progressive lung involvement, and autopsy revealed diffuse pulmonary vasculitis. Several other reported cases with EMC presented with diffuse alveolar hemorrhage,51,52,96,97 severe lung involvement,98,99 and bronchiolitis obliterans/organizing pneumonia (BOOP).53 IFN is now the treatment of choice for patients with EMC and probably the EMC- related pulmonary manifestations.53 Other lines of therapy include steroids and cytotoxic medications.

Miscellaneous Complications: Other disorders described in HCV infection that may contribute to pulmonary problems are listed in Table 1. Sicca-like syndrome,36 malignant lymphomas,37 autoimmune thyroid disease,87 polymyositis,41 and hypocomplementemic urticarial vasculitis54-100 have been described in HCV infection and may contribute to pulmonary disease. Appropriate testing and evaluation can lead to the diagnosis, affording specific therapies in addition to treatments directed against the virus.

PULMONARY COMPLICATIONS RELATED TO IFN THERAPY

IFN-α was documented to successfully treat chronic HCV infection very early after HCV was first isolated.101,102 This discovery was soon followed by reports of cases of IFN-associated pulmonary complications. Most of these were case reports, making it difficult to accurately estimate the incidence of such complications. However, interstitial pneumonitis, BOOP, ARDS, pulmonary hypertension, exacerbation of asthma, and sarcoid-like disease have been described in patients with hepatitis C undergoing treatment with IFN.

Okanoue and his colleagues103 evaluated the complications of IFN in 987 patients, 3 of whom acquired interstitial pneumonia related to IFN therapy. In one report,104 the incidence of interstitial pneumonia due to IFN therapy was thought to be approximately 0.2%. Table 2 summarizes the spectrum of pulmonary complications induced by IFN therapy as documented in the literature.103,105-132 While interstitial pneumonia and sarcoidosis are well-reported complications, the remainder represent rarely associated complications of IFN therapy.

Table 2-Spectrum of Pulmonary Complications Associated With IFN Therapy

CONCLUSIONS

Emerging clinical data suggest that chronic HCV infection can lead to multiple direct and indirect complications related to pulmonary function. The role that chronic inflammation might play in these complications remains unclear, but several lines of investigation should be pursued. Further, larger clinical studies of lung disease in patients with HCV infection are warranted, with particular attention being paid to viral and host determinants to predict progression of pulmonary disease. Future studies need to address the multifactorial effects that HCV might have on pulmonary function and control for these effects. Translational studies of cellular and cytokine responses in BALF cellular material from individuals with HCV infection with and without pulmonary disease can provide valuable insights into host responses to chronic HCV infection. Finally, in vitro molecular studies focusing on the role of T-lymphocyte activation, apoptosis, and the cytokine/chemokine responses to HCV gene products might shed light on the mechanisms by which pulmonary deterioration occurs and the role that available drug therapies might play in preventing this deterioration.

* From the Divisions of Infectious Diseases (Drs. Moorman and Saad) and Allergy and Immunology (Drs. Krishnaswamy and Kosseifi), Department of Internal Medicine, James H. Quillen VAMC and James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

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73 Robalino BD, Moodie DS. Association between primary pulmonary hypertension and portal hypertension: analysis of its pathophysiology and clinical, laboratory and hemodynamic manifestations. J Am Coll Cardiol 1991; 17:492-498

74 Budhiraja R, Hassoun PM. Portopulmonary hypertension: a tale of two circulations. Chest 2003; 123:562-576

75 Edwards BS, Weir EK, Edwards WD, et al. Coexistent pulmonary and portal hypertension: morphologic and clinical features. J Am Coll Cardiol 1987; 10:1233-1238

76 Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997; 336:111-117

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78 Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987; 107:216-223

79 Reeves JT, Grover RF, McMurtry I, et al. Pulmonary vascular reactivity. Bull Eur Physiopathol Respir 1985; 21:583-590

80 Fishinan AP. Epoprostenol (prostacyclin) and pulmonary hypertension. Ann Intern Med 2000; 132:500-502

81 Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a doubleblind, randomized, placebo- controlled trial. Am J Respir Crit Care Med 2002; 165:800-804

82 Wilkens H, Guth A, Konig J, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 2001; 104:1218-1222

83 Findlay JY, Harrison BA, Plevak DJ, et al. Inhaled nitric oxide reduces pulmonary artery pressures in portopulmonary hypertension. Liver Transpl Surg 1999; 5:381-387

84 Buchhorn R, Hulpke-Wette M, Wessel A, et al. β-Blocker therapy in an infant with pulmonary hypertension. Eur J Pediatr 1999; 158:1007-1008

85 Ribas J, Angrill J, Barbera JA, et al. Isosorbide-5- mononitrate in the treatment of pulmonary hypertension associated with portal hypertension. Eur Respir J 1999; 13:210-212

86 Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992; 327:1490- 1495

87 Nocente R, Ceccanti M, Bertazzoni G, et al. HCV infection and extrahepatic manifestations. Hepatogastroenterology 2003; 50:1149- 1154

88 Ferri C, Greco F, Longombardo G, et al. Association between hepatitis C virus and mixed cryoglobulinemia. Clin Exp Rheumatol 1991; 9:621-624

89 Misiani R, Bellavita P, Fenili D, et al. Hepatitis G virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 1992; 117:573-577

90 Lunel F, Musset L, Cacoub P, et al. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology 1994; 106:1291-1300

91 Bombardieri S, Paoletti P, Ferri C, et al. Lung involvement in essential mixed cryoglobulinemia. Am J Med 1979; 66:748-756

92 Viegi G, Fornai E, Ferri C, et al. Lung function in essential mixed cryoglobulinemia: a short-term follow-up. Clin Rheumatol 1989; 8:331-338

93 Manganelli P, Salaffi F, Subiaco S, et al. Bronchoalveolar lavage in mixed cryoglobulinaemia associated with hepatitis C virus. Br J Rheumatol 1996; 35:978-982

94 Salaffi F, Manganelli P, Carotti M, et al. Mixed cryoglobulinemia: effect of α-interferon on subclinical lymphocyte alveolitis. Clin Exp Rheumatol 1996; 14:219-220

95 Roithinger FX, Allinger S, Kirchgatterer A, et al. A lethal course of chronic hepatitis C, glomerulonephritis, and pulmonary vasculitis unresponsive to interferon treatment. Am J Gastroenterol 1995; 90:1006-1008

96 Rodriguez-Vidigal FF, Roig Figueroa V, Perez-Lucena E, et al. Alveolar hemorrhage in mixed cryoglobulinemia associated with hepatitis C virus infection [in Spanish]. An Med Interna 1998; 15:661-663

97 Gomez-Tello V, Onoro-Canaveral JJ, de la Casa Monje RM, et al. Diffuse recidivant alveolar hemorrhage in a patient with hepatitis C virus-related mixed cryoglobulinemia. Intensive Care Med 1999; 25:319-322

98 Monti G, Galli M, Cereda UG, et al. Mycosis fungoides with mixed cryoglobulinemia and pulmonary vasculitis: a case report. Boll Ist Sieroter Milan 1987; 66:324-328

99 Suzuki R, Monta H, Komukai D, et al. Mixed cryoglobulinemia due to chronic hepatitis C with severe pulmonary involvement. Intern Med 2003; 42:1210-1214

100 Pawlotsk\y JM, Dhumeaux D, Bagot M. Hepatitis C virus in dermatology: a review. Arch Dermatol 1995; 131:1185-1193

101 Davis GL, Balart LA, Schiff ER, et al. Treatment of chronic hepatitis C with recombinant interferon et: a multicenter randomized, controlled trial. Hepatitis Interventional Therapy Group. N Engl J Med 1989; 321:1501-1506

102 Di Bisceglie AM, Martin P, Kassianides C, et al. Recombinant interferon α therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled trial. N Engl J Med 1989; 321:1506- 1510

103 Okanoue T, Sakamoto S, Itoh Y, et al. Side effects of high- dose interferon therapy for chronic hepatitis C. J Hepatol 1996; 25:283-291

104 Karino Y, Hige S, Matsushima T, et al. Interstitial pneumonia induced by interferon therapy in type C hepatitis [in Japanese]. Nippon Rinsho 1994; 52:1905-1909

105 Kumar KS, Russo MW, Borczuk AC, et al. Significant pulmonary toxicity associated with interferon and ribavirin therapy for hepatitis C. Am J Gastroenterol 2002; 97:2432-2440

106 Yamamoto S, Shimabara M, Yamamoto R, et al. A case of chronic hepatitis C with pneumonitis during interferon therapy [in Japanese]. Nippon Shokakibyo Gakkai Zasshi 1993; 90:2142-2146

107 Karim A, Ahmed S, Khan A, et al. Interstitial pneumonitis in a patient treated with alpha-interferon and ribavirin for hepatitis C infection. Am J Med Sci 2001; 322:233-235

108 Rocca P, Dumortier J, Taniere P, et al. Induced interstitial pneumonitis: role of pegylated interferon α 2b [in French]. Gastroenterol Clin Biol 2002; 26:405-408

109 Rothfuss KS, Bode JC. Interstitial pneumonitis during combination therapy with interferon-alpha and ribavirin in a patient with chronic hepatitis C [in German]. Z Gastroenterol 2002; 40:807- 810

110 Rubinowitz AN, Naidich DP, Alinsonorin C. Interferon-induced sarcoidosis. J Comput Assist Tomogr 2003; 27:279-283

111 Chin K, Tabata C, Sataka N, et al. Pneumonitis associated with natural and recombinant interferon α therapy for chronic hepatitis C. Chest 1994; 105:939-941

112 Hizawa N, Kojima J, Kojima T, et al. A patient with chronic hepatitis C who simultaneously developed interstitial pneumonia, hemolytic anemia and cholestatic liver dysfunction after α- interferon administration. Intern Med 1994; 33:337-341

113 Sugiyama H, Nagai M, Kotajima F, et al. A case of interstitial pneumonia with chronic hepatitis C following interferon- α and sho-saiko-to therapy [in Japanese]. Arerugi 1995; 44: 711- 714

114 Moriya K, Yasuda K, Koike K, et al. Induction of interstitial pneumonitis during interferon treatment for chronic hepatitis C. J Gastroenterol 1994; 29:514-517

115 Ishizaki T, Sasaki F, Ameshima S, et al. Pneumonitis during interferon and/or herbal drug therapy in patients with chronic active hepatitis. Eur Respir J 1996; 9:2691-2696

116 Abi-Nassif S, Mark EJ, Fogel RB, et al. Pegylated interferon and ribavirin-induced interstitial pneumonitis with ARDS. Chest 2003; 124:406-410

117 Hoffmann RM, Jung MC, Motz R, et al. Sarcoidosis associated with interferon-α therapy for chronic hepatitis C. J Hepatol 1998; 28:1058-1063

118 Nakamura F, Andoh A, Minamiguchi H, et al. A case of interstitial pneumonitis associated with natural α-interferon therapy for myelofibrosis. Acta Haematol 1997; 97:222-224

119 Ikezoe J, Kohno N, Johkoh T, et al. Pulmonary abnormalities caused by interferon with or without herbal drug: CT and radiographie findings. Nippon Igaku Hoshasen Gakkai Zasshi 1995; 55:150-156

120 Nakajima M, Kubota Y, Miyashita N, et al. Recurrence of sarcoidosis following interferon alpha therapy for chronic hepatitis C. Intern Med 1996; 35:376-379

121 Teragawa H, Hondo T, Takahashi K, et al. Sarcoidosis after interferon therapy for chronic active hepatitis C. Intern Med 1996; 35:19-23

122 Perez-Alvarez R, Perez-Lopez R, Lombrana JL, et al. Sarcoidosis in two patients with chronic hepatitis C treated with interferon, ribavirin and amantadine. J Viral Hepat 2002; 9:75-79

123 Leveque L, de Boulard A, Bielefeld P, et al. Sarcoidosis during the treatment of hepatitis C by interferon-α and ribavirin: 2 cases [in French]. Rev Med Interne 2001; 22:1248-1252

124 Pohl J, Stremmel W, Kallinowski B. Pulmonal sarcoidosis: a rare side effect of interferon-α treatment for chronic hepatitis C infection [in German]. Z Gastroenterol 2000; 38:951-955

125 Salvio A, Mormile M, Giannattasio F, et al. Pulmonary sarcoidosis during interferon therapy: a rare or underestimated event? Ann Ital Med Int 2004; 19:58-62

126 Frankova H, Gaja A, Hejlova N. Pulmonary sarcoidosis in a patient with essential thrombocythemia treated with interferon a: a short case report. Med Sci Monit 2000; 6:380-382

127 Fiorani C, Sacchi S, Bonacorsi G, et al. Systemic sarcoidosis associated with interferon-α treatment for chronic myelogenous leukemia. Haematologica 2000; 85:1006-1007

128 Ogata K, Koga T, Yagawa K. Interferon-related bronchiolitis obliterans organizing pneumonia. Chest 1994; 106:612-613

129 Bini EJ, Weinshel EH. Severe exacerbation of asthma: a new side effect of interferon-α in patients with asthma and chronic hepatitis C. Mayo Clin Proc 1999; 74:367-370

130 Vander Els NJ, Gerdes H. Sarcoidosis and IFN-α treatment [letter]. Chest 2000; 117:294

131 Takeda A, Ikegame K, Kimura Y, et al. Pleural effusion during interferon treatment for chronic hepatitis C. Hepatogastroenterology 2000; 47:1431-1435

132 Fruehauf S, Steiger S, Topaly J, et al. Pulmonary artery hypertension during interferon-α therapy for chronic myelogenous leukemia. Ann Hematol 2001; 80:308-310

Jonathan Moorman, MD, PhD; Must of a Saas, MD; Semaan Kosseifi, MD; and Guha Krishnaswamy, MD, FCCP

Manuscript received March 2, 2005; revision accepted April 13, 2005.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: Jonathan P. Moorman, MD, PhD, Department of Internal Medicine, Division of Infectious Diseases, James H. Quillen College of Medicine, East Tennessee State University, Box 70622, Johnson City, TN 37614; e-mail: [email protected]

Copyright American College of Chest Physicians Oct 2005

By Duwe, Beau V; Sterman, Daniel H; Musani, Ali I

Tumors of the mediastinum represent a wide diversity of disease states. The location and composition of a mass is critical to narrowing the differential diagnosis. The most common causes of an anterior mediastinal mass include the following: thymoma; teratoma; thyroid disease; and lymphoma. Masses of the middle mediastinum are typically congenital cysts, including foregut and pericardial cysts, while those that arise in the posterior mediastinum are often neurogenic tumors. The clinical sequelae of mediastinal masses can range from being asymptomatic to producing symptoms of cough, chest pain, and dyspnea. This article will review the anatomy of the mediastinum as well as the different clinical, radiographic, and prognostic features, and therapeutic options of the most commonly encountered masses. (CHEST 2005; 128:2893-2909)

Keywords: bronchogenic; cysts; enterogenous; germ cell tumor; goiter; lymphoma; mediastinum; neuroblastoma; neurogenic tumor; pericardial; teratoma; thyroid; thymoma

Abbreviations: AFP = α-fetal protein; ALL = acute lymphoblastic leukemia; BMT = bone marrow transplant; GCT = germ cell tumor; hCG = human chorionic gonadotropin; HD = Hodgkin disease

The mediastinum is demarcated by the pleural cavities laterally, the thoracic inlet superiorly, and the diaphragm inferiorly. It is further compartmentalized into anterior, middle, and posterior divisions based on structural landmarks seen on the lateral radiograph. This has important implications for diagnosing suspected masses1 (Table 1). The anterior mediastinum contains the thymus, fat, and lymph nodes. The middle mediastinum contains the heart, pericardium, ascending and transverse aorta, brachiocephalic veins, trachea, bronchi, and lymph nodes, while the posterior mediastinum consists of the descending thoracic aorta, esophagus, azygous vein, autonomic ganglia and nerves, thoracic lymph nodes, and fat.

The likelihood of malignancy is influenced primarily by the following three factors: mass location; patient age; and the presence or absence of symptoms. Although more than two thirds of mediastinal tumors are benign, masses in the anterior compartment are more likely to be malignant.2 In the study by Davis et al3 of 400 patients with mediastinal masses, malignancy was seen in 59%, 29%, and 16%, respectively, of anterior, middle, and posterior mediastinal masses. Age is an important predictor of malignancy as well with many of the lymphomas and germ cell rumors (GCTs) presenting between the second and fourth decade of life. Last, symptomatic patients are more likely to have a malignancy. In Davis et al,3 85% of patients with a malignancy were symptomatic at presentation, compared to 46% of patients with benign neoplasms.

The most common symptoms at presentation were as follows: cough (60%); chest pain (30%); fevers/ chills (20%); and dyspnea (16%). Most symptoms can be categorized into the following two groups: localizing symptoms (Table 2); and systemic symptoms (Table 3). Localizing symptoms are secondary to tumor invasion. Common localizing symptoms include respiratory compromise; dysphagia; paralysis of the limbs, diaphragm, and vocal cords; Homer syndrome; and superior vena cava syndrome.4 Systemic symptoms are typically due to the release of excess hormones, antibodies, or cytokines. A classic example is hypercalcemia, which is caused by a parathyroid adenoma.

The initial workup of a suspected mediastinal mass involves obtaining posteroanterior and lateral chest radiographs. This can provide information pertaining to the size, anatomic location, density, and composition of the mass (Table 1). CT scanning is used to further characterize mediastinal masses and their relationship to surrounding structures as well as to identify cystic, vascular, and soft-tissue structures.4 In rare circumstances, fluoroscopy, barium swallow, angiograph, CT angiography, and three-dimensional reconstruction may provide additional information. The role of MRI is primarily in ruling out or evaluating a neurogenic tumor.5 MRI is also valuable to evaluate the extent of vascular invasion or cardiac involvement.

Table 1-Differential Diagnosis of a Mediastinal Mass by Anatomic Location*

Although nuclear scans and biochemical studies can be used to further characterize a lesion, tissue diagnosis is almost always required. If a mass is likely to be benign after initial workup, it can be removed surgically without biopsy. Otherwise, a diagnostic biopsy specimen can be obtained by transthoracic or transbronchial needle aspiration, mediastinoscopy, anterior mediastinotomy, or video-assisted thoracic surgery, depending on the anatomic location and radiographic appearance of the lesion.

TUMORS OF THE ANTERIOR MEDIASTINUM

Thymoma

Thymomas are the most common neoplasm of the anterior mediastinum with an incidence of 0.15 cases per 100,000.6-9 Although rare in children, thymomas represent 20% of anterior mediastinal neoplasms in adults.10,11

Table 2-Localizing Symptoms secondary to Tumor Invasion of Surrounding Structures*

Table 4-World Health Organization Classification of Thymomas*

Table 3-Systemic Syndromes secondary to Primary Mediastinal Tumors and Cysts*

Thymomas as a group have a wide spectrum of histologie diversity and are classified based on cell type predominance as lymphocytic, epithelial, or spindle cell variants. There is a strong association between histologic subtype and invasiveness as well as prognosis.12- 14 As a result, the World Health Organization15 devised a new classification system to group thymomas based on cytologie differences, which may be helpful in determining treatment regimens and predicting survival (Table 4).

Most thymomas are solid tumors, but up to one third may have components that are necrotic, hemorrhagic, or cystic.7,16 Thirty- four percent of thymomas invade through their own capsules, extending into surrounding structures.8,17-20 Likewise, transdiaphragmatic extension into the abdomen and metastasis into the ipsilateral pleura and pericardium can occur,7,9,18 although lymphogenous and hematogenous spread is rare.16,17

The Masaoka clinical staging system is based on the degree of invasion of the tumor through the capsule into the surrounding structures, which has important implications for prognosis21 (Table 5). In the study by Okumura et al,12 the Masaoka staging system was shown to be useful as an independent predictor of survival in patients with thymoma.

Typically, a thymoma is an incidental finding on a chest radiograph.10,22,23 One third of patients manifest symptoms of chest pain, cough, or dyspnea related to tumor compression or invasion.16 Metastasis is uncommon; however, parathymic syndromes, which include myasthenia gravis, hypogammaglobulinemia, and pure RBC aplasia, may develop.17

Myasthenia gravis is most frequent in women and is associated with thymoma. Symptoms include diploplia, ptosis, dysphagia, weakness, and fatigue. Thirty percent to 50% of patients with thymomas have myasthenia gravis, compared to 10 to 15% of patients with myasthenia gravis who have a thymoma.24,25 Pathogenesis is thought to occur via myloid cell lineages derived from the thymus that recognize antigens on the neuromuscular junction producing autoantibodies.26 These autoantibodies bind to acetylcholine receptors of the neuromuscular junction, causing muscle fatigue.26 Thymectomy can alleviate symptoms; however, this benefit is often delayed for months after surgery. Given the association between thymoma and myasthenia gravis, the serum antiacetylcholine receptor antibody level should be measured in all patients with a suspected thymoma to rule out myasthenia gravis before surgery.27,28

Hypogammaglobulinemia and pure RBC aplasia are present in 10% and 5% of patients with a thymoma, respectively.7 Good syndrome is diagnosed in patients with a thymoma and combined B-cell/T-cell immunodeficiency.29 Thymoma is also associated with various other autoimmune disorders, such as systemic lupus erythematosus, polymyositis, and myocarditis.3,7,18,30

Thymomas appear on a chest radiograph as a well-defined lobulated mass in the anterosuperior mediastinum, typically anterior to the aortic root.7,18 Further evaluation with contrast-enhanced thoracic CT scanning usually reveals an encapsulated, welldefined, soft- tissue mass, often with hemorrhage, necrosis, or cyst formation31 (Fig 1). They can also appear predominantly cystic with a nodular component.32

Table 5-Masaoka Staging System of Thymoma*

Surgical excision can be used for diagnosis; however, the sensitivity of ultrasonography and C]T scanguided fine-needle aspiration is increasing. Anderson and colleagues33 reported a success rate of 95% using ultrasonographically guided fine-needle aspiration. The success of fine-needle aspiration is operator- dependent and contingent on the skill of the immunohistologist. Thus, the results in the study by Anderson et al33 may overstate the true success of preoperative diagnosis. Tissue diagnosis may occur simultaneously with total resection of the mass if a thymoma is strongly suspected on the basis of clinical and radiologic evidence.34

Surgical resection remains the standard of care for both noninvasive and invasive thymomas as it provides the best prognosis. Adjunctive chemotherapy and radiation treatment is used for locally invasive or metastatic disease, or inoperable tumors. Additionally, although it is c\ommonly accepted that resection alone is sufficient treatment for stage I disease, there is no consensus regarding the role for postoperative radiation therapy in patients with stage II disease.35

According to Curran et al,36 of 117 patients, postoperative radiotherapy showed no survival benefit for those patients with stage I disease but did for patients with stage II and III disease. The 5-year mediastinal relapse rate for patients with stage II or III disease treated with surgery alone was 53%, while patients who received treatment with total resection and radiotherapy experienced no relapses. A smaller retrospective study by Eralp et al37 of 36 patients with stage II or III disease also showed a benefit for postoperative radiation therapy. While these studies had positive results, other institutional reviews35-38 have shown no benefit to postoperative radiotherapy. A larger randomized controlled trial would be useful to assess the benefit of postoperative radiation therapy in patients with stage II thymomas.

Thymoma is generally responsive to chemotherapy its well. In locally invasive or bulky disease, preoperative cisplatin-based chemotherapy, with or without postoperative radiotherapy, may offer the best prognosis.39 Kim et al40 examined 23 patients with locally advanced, unresectable disease who underwent three courses of induction chemotherapy with cisplatin, doxorubicin, cyclophosphamide, and prednisone. The 7-year disease-free and overall survival rates were 77% and 79%, respectively.40

FIGURE 1. A 36-year-old man with an invasive thymoma. A contrast- enhanced CT scan shows a heterogenons high-attenuated solid upper portion (arrow) with a small calcification in the left anterior aspect of the main pulmonary artery.

Other chemotherapeutic agents and regimens are less efficacious. Thus, these alternative regimens should only be used in patients who cannot tolerate cisplatin and doxorubicin or as second-line therapy in those who have relapsed.41

The following features are associated with poor prognosis: metastasis; large tumor size (ie, > 10 cm); tracheal or vascular compression; age

Thymic Carcinoma

Thymic carcinomas are a heterogeneous group of aggressive, invasive epithelial malignancies.3 Their incidence is rare, occurring predominantly in middle-aged men. Most patients present with cough, shortness of breath, and chest pain.43 Fatigue, weight loss, and anorexia are common, while superior vena cava syndrome and cardiac tamponade have been described.44-46

Histologically, thymic carcinomas are large, firm, infiltrating masses with areas of cystic change and necrosis. They are classified as low grade or high grade, with squamous cell-like and lymphoepithelioma-like variants being the most common cell types.47 In contrast to thymomas, thymic carcinomas are cytologically malignant, with typical features of cellular necrosis, atypia, and mitoses.44 Radiographically, thymic carcinomas are heterogeneous with necrosis and calcifications (Fig 2) and can be associated with pleural and pericardial effusions.

Treatment and prognosis depend on the cancer stage and grade. The Masaoka staging system used for thymomas is not useful as a prognostic tool in thymic carcinoma.48 Morphologic features that portend a poor prognosis include the following: infiltration of the tumor margin; absence of a lobular growth pattern; presence of high- grade atypia and necrosis; and > 10 mitoses per high-power field.21 Complete surgical resection is the treatment of choice and can be curative.49 Chemotherapy and radiation therapy have roles in treating unresectable tumors.36,40,50

Yoh et al51 examined 18 patients with thymic carcinomas. Patients with unresectable disease were treated with cisplatin, vincristine, doxorubicin, and etoposide. The overall response rate was 42% with 1- year and 2-year survival rates of 80% and 56%, respectively.51 Superior to previous chemotherapeutic regimens, the regimen of cisplatin, vincristine, doxorubicin, and etoposide warrants additional study by a randomized controlled trial for its use in the treatment of thymic carcinoma.

FIGURE 2. A 46-year-old man with a thymic carcinoma. A contrast- enhanced CT scan shows a necrotic mass with an irregularly shaped enhancing wall in the right anterior mediastinum.

Thymic Carcinoid

Thymic carcinoid is a malignant tumor, which is histologically similar to carcinoid tumors found at other sites. Its highest incidence is in the fourth and fifth decades of life.44 Thymic carcinoid is associated with Cushing syndrome and multiple endocrine neoplasia syndrome.7 According to a prospective study of patients with endocrine neoplasia syndrome type 1 by Gibil et al,52 thymic carcinoid developed in 8% of patients.

Thymic carcinoid presents as a large, lobulated, invasive mass of the anterior mediastinum with or without hemorrhage and necrosis.53 Metastasis is common, with spread to regional lymph nodes as well as distant metastasis developing in two thirds of patients.53 The treatment is complete surgical resection. For a locally invasive tumor, radiotherapy and chemotherapy are used despite minimal effect.53,54 The prognosis of these tumors is poor but difficult to assess. In a retrospective study by Tiffet et al,55 there was no association between prognosis and histologic features.

Thymolipoma and Nonneoplastic Thymic Cysts

Thymolipoma is a rare, benign, slowly growing tumor of the thymus gland that occurs in young adults of both sexes.2 CT scans and MRI studies show a characteristic fat density. The treatment of choice is surgical excision.

Thymic cysts are rare tumors of unclear etiology. They can be congenital or acquired, and are associated with inflammation or with an inflammatory neoplasm, such as Hodgkin disease (HD).56 Congenital thymic cysts are remnants of the thymopharyngeal duct.57 Inflammatory cysts probably arise from an inflamed thymic parenchyma. Radiographically, they appear as simple homogenous cysts (Fig 3). Microscopically, thymic cysts may be identical to cystic thymic neoplasms. Thus, thorough sampling and examination are essential.58 Surgical excision is curative.

MEDIASTINAL GCTs

Mediastinal GCTs are derived from primitive germ cells that fail to migrate completely during early embryonic development.59-61 GCTs are found in young adults and represent 15% of anterior mediastinal masses found in adults.2 Malignant GCTs are more common (> 90%) in men. A mediastinal GCT should prompt a search for a primary gonadal malignancy.

FIGURE 3. A 30-year-old woman with a unilocular thymic cyst. A contrast-enhanced CT scan shows a homogeneous cystic mass with a partially enhanced wall (arrows).

GCTs are classified into the following three groups based on cell type: benign teratomas; seminomas; and embryonal tumors. The embryonal tumors, also called malignant teratomas or nonseminomatous GCTS, are diverse and include choriocarcinomas, yolk sac carcinomas, embryonal carcinomas, and teratocarcinomas.62 These tumors often produce serologic markers such as α-fetal protein (AFP) and human chorionic gonadotropin (hCG), which can be useful in the diagnostic evaluation.2

Mediastical Teratomas (Benign)

Consisting of tissue from at least two of the three pnmitive germ layers, benign teratomas are the most common mediastinal GCT.63 Ectodermal tissues, which usually predominate, include skin, hair, sweat glands, and tooth-like structures. Mesodermal tissues, such as fat, cartilage, bone, and smooth muscle are less common, as are endodermal structures like respiratory and intestinal epithelium.64 The majority of mediastinal teratomas are mature teratomas that are histologically well-defined and benign.63 If a teratoma contains fetal tissue or neuroendocrine tissue, it is defined as immature and malignant. In children, the prognosis is favorable, but it can often recur or metastasize.65

Most patients are completely asymptomatic. Like other mediastinal masses, presenting symptoms include cough, dyspnea, and chest pain. Digestive enzymes secreted by intestinal mucosa or pancreatic tissue found in the teratoma can lead to the rupture of the bronchi, pleura, pericardium, or lung.2 A rare result of a ruptured mediastinal teratoma is the expectoration of hair or sebum.66,67 Mature teratomas do have the potential in rare circumstances to undergo malignant transformation into a variety of malignancies. Reports68 of rhabdomyosarcoma, adenocarcinoma, leukemia, and anaplastic small cell tumors have all been identified as arising from mature or immature teratomas.

Benign teratomas are well-defined, round, or lobulated masses when seen on a chest radiograph. Up to 26% are calcified, as they often have elements of bone or teeth.69 CT scanning and MRI are used to assess resectability (Fig 4), and may identify sebaceous elements and fat, supporting the diagnosis.70,71 Complete surgical resection is the treatment of choice; however, subtotal resection can relieve symptoms. Adjunctive chemotherapy may be useful after subtotal resection.72

FIGURE 4. A 16-year-old male patient with a mature cystic teratoma. A contrast-enhanced CT scan showsa multilocular cystic mass in the left anterior mediastinum. Histologie examination revealed a mature cystic teratoma with foreign-body reaction and dystrophic calcification.

Mediastinal Seminoma

Primary mediastinal seminomas, although uncommon, comprise 25 to 50% of malignant mediastinal GCTs occurring most frequently in men ages 20 to 40 years. Patients present with dyspnea, substernal pain, weakness, cough, fever, gynecomastia, or weight loss. Because of the tumor location, about 10% of patients present with superior vena cava syndrome.73 However, tumors can grow 20 to 30 cm before symptoms develop.74

Radiographically, seminomas are bulky, lobulated, homogenous masses. Local invasion is rare, but metastasis to lymph nodes and bone does occur.2 CT and gallium scanning is used to evaluate the extent of disease.75

Seminomas are uniquely sensitive to radiation therapy. In a study by Bush et al76 of 13 patients with localized disease who were treated with external beam radiation, the 10-year disease-free survival rate was 54%, with an actuarial survival rate of 69%. There is, however, debate as to the role of chemotherapy and surgical resection. A retrospective study by Bokemeyer et al77 showed that chemotherapy alone led to a 90% 5-year disease-free survival rate and that additional radiation offered only a slight survival advantage, while patients treated with just radiation initially had a much higher rate of disease recurrence. In patients with locally advanced disease, the preferred treatment includes chemotherapy followed by the surgical resection of residual disease.78

Mediastinal Nonseminomatous GCTs

Nonseminomatous malignant GCTs comprise a heterogeneous group of masses that includes embryonal cell carcinomas, endodermal thymus tumors, choriocarcinomas, yolk sac tumors, and mixed GCTs with multiple cellular components. These tumors are often symptomatic and malignant, and predominantly affect young men.2 In addition, they can be associated with hematologic malignancies, and 20% of patients have Kleinfelter syndrome.79,80

At diagnosis, 85% of patients are symptomatic, which includes complaints of chest pain, hemoptysis, cough, fever, or weight loss. Gynecomastia can develop as a result of β-hCG secretion from certain tumor types.62,81

These tumors are large, irregularly shaped, with areas of central necrosis, hemorrhage, or cyst formation82 (Fig 5). Measuring AFP and β-hCG levels is important in making the diagnosis. An elevated AFP level is suggestive of an endodermal sinus tumor or embryonal carcinoma and is sufficient, in the presence of a mediastinal mass, to establish the diagnosis.62,81

Chemotherapy with bleomycin, etoposide, and cisplatin is the current standard of care for patients with nonseminomatous malignant GCTs.83 Following chemotherapy,

Mediastinal Goiter

In patients undergoing thyroidectomy, the incidence of mediastinal goiter is 1 to 15%.86 Most goiters are euthyroid and are found incidentally during a physical examination. Radiographically, mediastinal goiters are encapsulated, tabulated, heterogeneous tumors.2 A classic finding on a CT scan is continuity of the cervical and mediastinal components of the thyroid. If the goiter contains functional thyroid tissue, then scintigraphy with a radioactive isotope of iodine can be diagnostic.2

FIGURE 5. A 59-year-old man with a nonseminatous malignant GCT. A contrast-enhanced CT scan shows a heterogeneous low-attenuating anterior mediastinal mass compressing the pulmonary artery.

Surgical resection is recommended since these lesions are not usually amenable to needle biopsy, and malignancy develops in a significant number. Nearly all substernal goiters can be removed easily through a cervical incision minimizing surgical morbidity.87

Mediastinal Parathyroid Adenoma

The mediastinum is the most common location at which an ectopic parathyroid tumor may develop. Overall, 20% of parathyroid adenomas develop in the mediastinum, with 80% occurring in the anterior mediastinum.88

These tumors are encapsulated, round, and usually

PRIMARY MEDIASTINAL LYMPHOMA

Primary mediastinal lymphoma is a rare entity comprising only 10% of lymphomas in the mediastinum. Lymphoma usually occurs in the anterior mediastinum and is part of more widespread disease. HD represents approximately 50 to 70% of mediastinal lymphomas, while non-Hodgkin lymphoma comprises 15 to 25%.90,91 The three most common types of mediastinal lymphoma include nodular sclerosing HD, large B- cell lymphoma, and lymphoblastic lymphoma.2

HD

HD has an incidence of approximately 2 to 4 cases per 100,000 people per year, with a bimodal distribution of incidence peaking in young adulthood and again after age 50 years.92 For mediastinal- predominant disease, prevalence peaks in young women during the third decade of life, while it is unaffected by age in men.93 HD is divided into four subtypes, including nodular sclerosing, lymphocyte- rich, mixed cellularity, and lymphocyte depleted HD, with the nodular sclerosing subtype representing more than two thirds of cases.94

Most patients experience constitutional symptoms (B symptoms), including fevers, night sweats, and weight loss. For patients with mediastinal involvement, cough, dyspnea, chest pain, pleural effusions, and superior vena cava syndrome may occur.93

The presence of Reed-Sternberg cells are pathognomonic of HD. These cells contain bilobed nuclei containing prominent eosinophilic nuclei. The classic immunohistochemical profile is biomarker positivity for CD15 and CD30 cells.95

The chest radiograph finding is abnormal in up to 76% of patients with HD, often showing enlargement of the prevascular and paratracheal nodes.96-98 A CT scan examination is usually sufficient to identify lymphoma; however, in certain circumstances, such as after radiation treatment, MRI may be better in distinguishing scars from residual disease96 (Fig 6). A positron emission tomography scan may also be useful in staging and following disease progression.99

Still widely used is the Ann Arbor staging system for HD. This system has important implications for determining prognosis and types of treatment (Table 6). In 1989, the Ann Arbor staging system was modified at a meeting in Cotswold, England, to separate out patients with bulky disease due to its prognostic significance.

The treatment of HD is separated into the treatment of early- stage disease (ie, stage I and II disease) and late-stage disease (ie, stage III and IV disease). Based on the Cotswold modifications, early-stage disease can be further subclassified into favorable and unfavorable, depending on the degree of tumor burden. For patients with favorable stage I or II disease, extended-field radiation alone used to be the standard of care. Hagenbeek et al100 conducted a randomized controlled trial in which 762 patients with favorable stage I or II HD were randomized to receive either combination therapy with six cycles of epirubicin, bleomycin, vinblastine, and prednisone, and involved field radiation, or to receive subtotal nodal irradiation alone. The complete remission rate was similar among patients in both groups, while the relapse rate was significantly higher in the radiation-alone group.100 Thus, the use of combined involved-field radiation and chemotherapy is quickly becoming the standard of care. For patients with stage I or II HD with bulky tumors, treatment consists of chemotherapy followed by radiation.101 Patients with stage III or IV HD are treated primarily with chemotherapy. Canellos et al102 showed that ABVD was superior to MOPP in preventing relapse.

FIGURE 6. A 39-year-old man with nodular sclerosis HD. A contrast- enhanced CT scan shows an anterior mediastinal mass in which the central portion is cystic (black arrow). The right paratracheal lymph node is enlarged (white arrow).

Table 6-Ann Arbor Staging System With Cotswold Modifications for HD*

Patients who relapse may benefit from a bone marrow transplant (BMT), while those who have had a good response to standard-dose second-line chemotherapy benefit the most.103 For patients with HD, autologous BMT is superior to allogeneic BMT since the relapse rate for both is similar, and the nonrelapse mortality rate is 48% for patients who have undergone allogeneic BMT and 27% for those who have undergone autologous BMT.104

Patients with stage I and II HD have cure rates of > 90%. Patients with stage IIIA HD have a cure rate of 30 to 90% with standard treatment. Stage IIIB HD offers a cure rate of 60 to 70%, while stage IV HD has a cure rate of 50 to 60% (2,101). Among patients with advanced disease, a prognostic index was created by the International Prognostic Factor Project on Advanced Hodgkin’s Disease that was based on the total number of unfavorable features from among seven potential features found at diagnosis, as follows: serum albumin level, 45 years; stage IV disease; WBC count, > 15,000 cells/L; and lymphocyte count,

Non-Hodgkin Lymphoma

Although there are many classes and grades of non-Hodgkin lymphoma, lymphoblastic lymphoma and large B-cell lymphoma are the most common subtypes to affect the medi\astinum.106 The overall incidence of non-Hodgkin lymphoma is greatest in white men with a mean age of 55 years.106 However, the mean ages of presentation for lymphoblastic lymphoma and primary large B-cell lymphoma are 28 and 30 to 35 years, respectively.106,107

Lymphoblastic lymphoma is highly aggressive, arising from thymic lymphocytes.108 Common symptoms include cough, wheezing, shortness of breath, superior vena cava syndrome, cardiac tamponade, or tracheal obstruction, and can involve the mediastinum, bone marrow, CNS, skin, or gonads.108 It is often confused with T-cell acute lymphoblastic leukemia (ALL) because bone marrow involvement with blasts is relatively common.109,110

Primary mediastinal B-cell lymphoma is a diffuse large B-cell lymphoma derived from the thymus. Common symptoms at presentation include chest pain, cough, dysphasia, superior vena cava syndrome, phrenic nerve palsy, and hoarseness.107 The involvement of extrathoracic structures and bone marrow is less common at presentation than for lymphoblastic lymphoma. However, on the recurrence of disease, involvement of the liver, kidneys, and brain can occur.111,112

Computer tomography scanning is used to characterize the lesion and to determine the extent of invasion. The middle and posterior mediastinal nodes are involved more often than the anterior ones.2 Tissue diagnosis should be obtained before treatment. Flow cytometry and cytogenetic analysis can be used to help render a definitive diagnosis.113

Treatment for mediastinal non-Hodgkin lymphoma depends on the stage, histologie subtype, and extent of the disease. For lymphomblastic lymphoma, the treatment regimens are often similar to ALL due to its propensity to involve the marrow. Treatment with intensive chemotherapy programs with maintenance-phase chemotherapy is superior to short-term chemotherapy without a maintenance phase. In a study by Kobayashi et al,114 patients with ALL and those with lymphoblastic lymphoma who received short-term chemotherapy had a cure rate of 78% but a relapse rate of 72% with only a 7% 7-year survival rate. Intrathecal chemotherapy is also necessary to prevent CNS relapse. CNS irradiation is often part of prophylactic treatment to prevent CNS recurrence, while mediastinal irradiation has been used as well. Many patients go on to relapse even after treatment. As a result, BMT is a commonly employed treatment for patients with lymphoblastic lymphoma. Levine et al115 demonstrated in a retrospective analysis of 204 patients with lymphoblastic lymphoma who had been treated with either allogeneic or autologous BMT that although there were fewer relapses at 5 years with allogeneic BMT (relapse rate, 46% vs 56%, respectively), the incidence of treatment- related mortality in patients who underwent allogeneic BMT made the overall survival benefit insignificant.

Patients with primary mediastinal B-cell lymphoma can be treated with conventional chemotherapy; however, there may be an additional benefit to treatment with high-dose chemotherapy and involved-field radiation.107,116 Currently, if patients fail to have a full response to standard chemotherapy, high-dose chemotherapy and/or radiation therapy are considered. After relapse, many patients are treated with high-dose chemotherapy and autologous BMT.107

TUMORS OF THE MIDDLE MEDIASTINUM

Mediastinal Cysts

Mediastinal cysts comprise 12 to 20% of mediastinal masses and are found in the middle compartment of the mediastinum.117-119 Despite a similar incidence, children are more often symptomatic at presentation due to compression on the surrounding structures.120 The most common type of mediastinal cyst are foregut cysts, which are derived as an embryonic abnormality, with enterogenous cysts (50 to 70%) and bronchogenic cysts (7 to 15%) being the most common subtypes.2

Bronchogenic Cysts

Bronchogenic cysts are formed during embryonic development as an anomalous budding of the laryngotracheal groove.121 These cysts are lined with ciliated, pseudostratified, columnar epithelium, and contain bronchial glands and cartilaginous plates.2 Approximately 40% of bronchogenic cysts are symptomatic resulting in cough, dyspnea, or chest pain.121

Radiographically, bronchogenic cysts can be identified on plain radiographs (Fig 7a) but are best defined by CT scanning. These cysts are well-defined round masses with a homogenous density similar to water; however, some bronchogenic cysts are mucoid and can give the impression of being a solid mass.120 Bronchogenic cysts are nonenhancing, and, when there is a direct communication with the tracheobronchial tree, air-fluid levels may be seen.122 MRI can differentiate the lesion from other masses (Fig 7, bottom, B, 8).

Tissue is often required to make a definitive diagnosis of a bronchogenic cyst. This can be accomplished by tracheobronchial, endoscopic, or thoroscopic needle aspiration. Most bronchogenic cysts are removed surgically or are drained by needle aspiration. The treatment of asymptomatic cysts is controversial as surgery is not without risk, yet these cysts can grow to cause symptoms in the future.123

Enterogenous Cysts

Enterogenous cysts arise from the dorsal foregut and are lined by squamous or enteric (alimentary) epithelium and may contain gastric or pancreatic tissue. Esophageal duplication cysts are located in or are attached to the esophageal wall. Twelve percent of patients with esophageal duplication cysts have associated malformations, mostly of the GI tract.124

FIGURE 7. Top, A: a 49-year-old man with a bronehogenic cyst. A chest radiograph shows a rounded mass (arrow) that displaces the right primary bronchus superiorly. Bottom, B: a 49-year-old man with a bronehogenic cyst. A sagittal T1-weighted magnetic resonance image shows a high-signal intensity cyst with a fluid-fluid level due to infection (arrow).

FIGURE 8. A 37-year-old woman with a brochogenic cyst. A coronal T1-weighted magnetic resonance image shows a cyst with high-signal intensity contents (arrow).

Symptoms of enterogenous cysts are similar to those of other mediastinal cysts. They are often asymptomatic, but if they contain gastric or pancreatic mucosa, there is the added risk of hemorrhage or rupture of the cyst from mucosal secretions. Radiographically, it can be difficult to distinguish these from bronchogenic cysts, although they are more often calcified (Fig 9). The presence of cartilage suggests the presence of a bronchogenic cyst.121 Most cysts should be surgically excised, and videoassisted thoracic surgery is the treatment of choice.125

FIGURE 9. A 10-year-old female patient with a duplication cyst. A contrasted-enhanced CT scan shows a thin-walled water-attenuation cyst adjacent to the esophagus (arrow).

Neuroenteric Cysts

Neuroenteric cysts are characterized by the presence of both enteric and neural tissue in surgical specimens.126 Most of these cysts form in the posterior mediastinum above the level of the main carina. The close association of the foregut and notochord during embryogenesis possibly explains this anatomic location. Neuroenteric cysts are associated with multiple vertebral anomalies, such as scoliosis, spina bifida, hemivertebra, and vertebral fusion. Almost all are discovered by age 1 years due to symptoms from tracheobronchial compression.2 Neurologic symptoms may be caused by intraspinal extension. Complete surgical excision is curative.127

Pericardial Cysts

Pericardial cysts are part of a larger group of mesothelial cysts. They form as a result of a persistent parietal recess during embryogenesis.121 They are estimated to occur in 1 of 100,000 people. Although most are congenital, a few cases of acquired pericardial cysts do exist. They are often asymptomatic and are identified in the fourth to fifth decade of life. Rarely, cardiac compression may occur, causing hemodynamic compromise.95 Radiographically, pericardial cysts are well-marginated spherical or tear drop-shaped masses that characteristically abut the heart, anterior chest wall, and diaphragm.2 The most common location of pericardial cysts is at the right cardiophrenic angle (70%), followed by the left cardiophrenic angle (22%).128 On CT scans, these masses appear as unilocular and nonenhancing (Fig 10, 11). As with most mediastinal cysts, surgical removal is the treatment of choice, although clinically asymptomatic patients may be observed without intervention.

Lymphangiomas

Lymphangiomas are rare congenital abnormalities of the lymphatic vessels. Typically, they are isolated solitary masses, but they can be more widespread or associated with chromosomal abnormalities.129 These lesions are benign in nature and are found in the cervical region 75% of the time. In 10% of cases, the cysts extend into the mediastinum and are associated with chylothorax and hemangiomas.129 Although these tumors are commonly identified in children before the age of 2 years, when the mass is isolated to the mediastinum it is often not identified until it has gotten large enough to cause compressive symptoms.130 Such symptoms include chest pain, cough, mid dyspnea. Radiographically, these lesions appear cystic and can be confused with pericardial cysts, although lymphangiomas are more likely to have a loculated appearance.130 The use of lymphangiographic contrast media combined with CT scanning can also differentiate these lesions.129 Total resection is optimal; however, in cases complicated by chylothorax, there is some evidence suggesting that additional radiotherapy may be of some benefit.131 Lymphangiomatosis seen in young women is typically a more progressive form of disease in which multiple tumors are found and invade multiple organ structures, including the lung, heart, and bone.132

FIGURE 10. A 37-year-old man with a pericardial cyst. A contrastenhanced CT scan shows a thin-walled water-attenuation cyst (arrow).

TUMORS OF THE POSTERIOR MEDIASTINUM

Neurogenic Tumors

Neurogenic tumors \are derived from tissue of the neural crest, including cells of the peripheral, autonomie, and paraganglionic nervous systems. Ninety-five percent of posterior mediastinal masses arise in the intercostal nerve rami or the sympathetic chain region.133 They are classified on the basis of cell type and comprise approximately 12 to 21% of all mediastinal masses, although 95% occur in the posterior compartment.134 Seventy percent to 80% of neurogenic tumors are benign, and nearly half are asymptomatic; however, they can occasionally cause compressive or neurologic symptoms.133,135,136

Nerve Sheath Tumors

These benign, slowly growing tumors comprise 40 to 05% of neurogenic mediastinal masses. Neurilemomas or schwunnomas constitute 75% of this group of masses. These tumors are firm, encapsulated masses consisting of Schwann cells. Neurofibromas are nonencapsulated, soft, and friable, and are associated with Von Recklinghausen neurofibromatosis.137,138 They are often asymptomatic and are discovered incidentally.

FIGURE 11. A 54-year-old woman with a pericardial cyst. A contrast-enhanced CT scan shows a large thin-walled cystic mass at the level of the aortic arch (black arrow). The innominate vein is compressed by this mass (white arrow).

Radiographically, nerve sheath tumors are sharply marginated spherical masses. Being adjacent to the spine, they can cause erosion and deformity of the ribs and ventral bodies as they increase in size. Low attenuation on CT scans can indicate hypocellularity, cystic changes, hemorrhage, or the presence of lipid within myelin.2 Ten percent of these tumors grow through the intervertebral foramina and create a dumbbell appearance on radiographs.139 MRI is used to rule out intraspinal extension.

The surgery of choice for removal of these tumors is thoroscopy, or thorocotomy when the former is not an option.133,134 For tumors invading the vertebral body or foramina, en bloc resection can be achieved.140 There may be a role for postoperative chemotherapy or radiation therapy when total resection is not possible. Postoperative complications include Horner syndrome, partial sympathectomy, recurrent laryngeal nerve damage, and paraplegia.134

MALIGNANT TUMORS OF NERVE SHEATH ORIGIN

Malignant nerve sheath tumors are spindle cell sarcomas of the posterior mediastinum, and include malignant neurofibromas, malignant schwannomas, and neurogenic fibrosarcomas. They affect men and women equally in the third to fifth decade of life and are closely associated with neurofibromatosis, with a 5% risk of sarcomatous degeneration.141 Pain and nerve deficits are common. Complete surgical resection is the optimal treatment, but, in patients with unresectable tumors, adjuvant chemotherapy and radiation are options.

Autonomic Ganglionic Tumors

Tumors of the autonomic nervous system arise from neuronal cells rather than from the nerve sheath. They form a continuum ranging from benign encapsulated ganglioneuroma to aggressive malignant nonencapsulated neuroblastoma. Derived from embryologic origins, these tumors arise in the adrenal glands or in the sympathetic ganglia. However, ganglioneuromas and ganglioneuroblastomas arise mostly in the sympathetic ganglia of the posterior mediastinum.142 Fifty percent of neuroblastomas arise in the adrenal glands and up to 30% in the mediastinum.142,143

Ganglioneuroma: Ganglioneuromas are benign tumors composed of one or more mature ganglionic cells. Arising from the nerve ganglion cells, they are the most benign and differentiated of the autonomic ganglionic tumors.144 Most patients are asymptomatic and receive diagnoses in the second or third decade of life.145 Radiographically, the tumors are oblong and well-marginated, occurring along the anterolateral aspect of the spine and spanning three to five vertebrae145 (Fig 12). CT scanning is not particularly helpful as the mass can be homogenous or heterogeneous. Complete surgical resection is ideal.146

Ganglioneuroblastoma: Ganglioneuroblastomas have histologic features of both ganglioneuromas and neuroblastomas. They are the least common type of neurogenic tumor. Prognosis depends on histologic appearance.2 Both sexes are equally affected in the first decade of life.147 Symptoms may arise due to large tumor size, intraspinal extension, and metastasis. Staging is similar to that for neuroblastoma, as described in the following section.

FIGURE 12. A 20-year-old woman with a posterior mediastinal ganglioneuroma. Top, A: a contrast-enhanced CT scan image that shows a mass with mixed attenuation and calcifications. Bottom, B: acoronal T2-weighted magnetic resonance image that shows an 8-cm mass with heterogeneous signal intensity.

Neuroblastoma: Neuroblastoma is a disease of young children, with 95% occurring in patients

Grossly, these tumors appear as an elongated paraspinous mass, sometimes impinging on adjacent structures and causing skeletal damage.150,151 On CT scans, 80% of these tumors have calcification.151 As with all neurogenic tumors, MRI is useful to determine the extent of intraspinal involvement.146 Radionuclide imaging with 123I metaiodobenzylguanide can also be used to detect primary and metastatic disease.152

Table 7-Staging of Neuroblastoma and Ganglioneuroblastomas*

Treatment for neuroblastoma depends primarily on the stage of disease (Table 7). Treatment for limited-stage disease is surgical resection. For patients with stage I disease, resection is usually curative. For patients with partially resectable stage II and III disease, treatment includes postoperative chemotherapy and radiation. For patients with stage IV disease, there is much controversy over the role of surgery; however, some studies153 have suggested that delayed surgery after initial treatment with chemotherapy and radiation results in a better outcome than initial surgical intervention. In addition, there are ongoing studies looking at the role of radioactive 131I metaiodobenzylguanide therapy in combination with chemotherapy in patients with advanced- stage disease.154 Poor prognostic factors in neuroblastoma include large tumor size, poorly differentiated cell type, advanced stage, extrathoracic origin, and presentation in an elderly patient.138

ACKNOWLEDGMENT: We thank the following people for their contributions: Jin Mo Goo, MD, Department of Radiology, Seoul National University College of Medicine, for the contribution of Figures 1 to 6 and 11, which were originally published in the Journal of Computed Assisted Tomography in 2003; MiYoung Jeung, MD, Department of Radiology, University of Strasbourg, for the contribution of Figures 6 to 10, which were originally published in Radiographics in 2002; Allen Forsythe, MD, for the contribution of Figure 12, which was published in Radiographics in 2004. It was only through their contributions that we were able to produce this study.

* From the Departments of Internal Medicine (Dr. Duwe) and Pulmonary, Allergy, and Critical Care Medicine (Drs. Sternum and Musani), Hospital of the University of Pennsylvania, Philadelphia, PA.

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By Clark, Fr Peter

Some Have Questioned the Treatment’s Use in Catholic Facilities

Mercy Health System, Conshohocken, PA, has had inquiries concerning whether a new procedure, the NovaSure Impedance Controlled Endometrial Ablation System, can be used in a Catholic health care setting. The procedure is intended for the treatment of excessive menstrual bleeding-called menorrhagia-which sometimes occurs in premenopausal women who have completed childbearing. It is estimated that one in five women experience excessive menstrual bleeding that can result in fatigue, anemia, embarrassing accidents, and restricted activity.1

NovaSure is the newest endometrial ablation treatment option available to such women. Following preclinical and clinical studies, the U.S. Food and Drug Administration (FDA), on September 28, 2001, declared the procedure to be safe and effective.

However, some people say that NovaSure is a form of direct sterilization. Others wonder whether it should be performed in a Catholic medical facility, since the women who undergo it are warned that future pregnancies should be avoided. Pregnancies following endometrial ablation can be dangerous to both the mother and the fetus. Accordingly, women who choose NovaSure are urged to use some form of birth control afterward.

It therefore seems appropriate to conduct a complete ethical evaluation of the procedure to determine whether it can be utilized in a Catholic health care facility. In this article, I will give a medical evaluation of the procedure and then ethically analyze it in light of the Ethical and Religious Directives for Catholic Health Care Services.

MEDICAL EVALUATION

CAUSES AND TREATMENTS

The word menorrhagia comes from the Greek roots men (meaning “month”) and rhegnyai (meaning “to burst forth”). It is a medical term that refers to menstrual bleeding that is excessive or prolonged, or both. (The condition is also known as hypermenorrhea.)

The menstrual cycle is not the same for every woman. Normal menstrual flow occurs about every 28 days, lasts four to five days, and produces a total blood loss of from 60 to 250 milliliters (four tablespoons to about one cup). A woman’s period may be regular or irregular, light or heavy, painful or pain-free, and long or short, and still be considered normal. Statistically, although about a third of premenopausal women complain of heavy menstrual bleeding, only one in 10 experiences blood loss severe enough to be defined as menorrhagia.2

The signs and symptoms of menorrhagia include menstrual periods that last longer than seven days, menstrual flow that includes large blood clots, heavy menstrual flow that interferes with one’s regular lifestyle, constant pain in the lower abdomen during the menstrual period, irregular menstrual periods, tiredness, fatigue or shortness of breath (symptoms of anemia), and a menstrual flow that soaks through one or more sanitary pads or tampons every hour for several consecutive hours.3

In some cases, the causes of heavy menstrual bleeding are unknown, but there are several conditions that may cause menorrhagia. About 80 percent result from one of two causes.

Hormonal Imbalance In a normal menstrual cycle, a balance between the hormones estrogen and progesterone regulates the buildup of the lining of the uterus (endometrium), which a woman sheds during menstruation. If a hormonal imbalance occurs, the endometrium develops in excess and eventually sheds by way of heavy menstrual bleeding. Hormonal imbalance occurs most often in adolescent girls experiencing their menstrual periods for the first time or in women approaching menopause. Menorrhagia caused by certain conditions involving hormonal imbalance (such as thyroid disease) often can be controlled with hormone medications. However, improper use of hormone medications can itself be a direct cause of menorrhagia.

Uterine Fibroids These noncancerous (benign) tumors of the uterus appear during childbearing years. Uterine fibroids may cause heavier than normal or prolonged menstrual bleeding.4

Other causes of menorrhagia are polyps; ovarian cysts; dysfunction of the ovaries; adenomyosis (a condition that occurs when glands from the endometrium become embedded in the uterine muscle, often causing heavy bleeding and pain); intrauterine device (IUD) use; pregnancy complications; certain medications (including anticoagulants and anti-inflammatory drugs); and such medical conditions as pelvic inflammatory disease, thyroid problems, endometriosis, lupus, kidney disease, some uncommon blood disorders, and certain cancers; and chemotherapy.s

To diagnose menorrhagia, physicians take a complete medical history of the woman’s menstrual cycle, perform a physical examination, and recommend one or more of the following tests: blood tests, Pap test, endometrial biopsy, ultrasound scan, sonohysterogram (an ultrasound done after fluid is injected through a tube into the uterus by way of the vagina and cervix), hysteroscopy, dilation and curettage (D & C), and a hysterosalpingography (in which, after a dye is injected into the uterus and fallopian tubes through the cervix, X-rays are taken to determine the shape and size of those organs). Excessive and prolonged menstrual bleeding can lead to other medical conditions, including iron deficiency anemia, severe pain, infertility, and toxic shock syndrome.6

OTHER TREATMENTS

It is estimated that as many as 7 million premenopausal women between the ages of 35 and 55 suffer from menorrhagia and that 2.5 million women seek treatment for this condition every year.7 A number of practices and procedures are currently available to them.

Drug Therapy Estrogen-progestogen combinations (such as those found in oral contraceptives) or progestogens (progesterone) alone are frequently employed in the treatment of menorrhagia. Other classes of drugs include androgens, such as Danocrine; gonadotropin- releasing hormone agonists; and nonsteroidal anti-inflammatory drugs. Drug therapy is typically the first order of treatment in alleviating excessive menstrual bleeding. Drug therapies usually require long-term treatment. They are successful for about 50 percent of patients; for others they are ineffective and may introduce unpleasant side effects. This treatment does allow the woman to maintain her fertility.

D & C This is typically the first surgical step if drug therapy is unsuccessful. In it, the cervix is dilated and the uterine contents are either scraped away or removed through vacuum aspiration. This may reduce bleeding for a few cycles. If a polyp is present and removed, the bleeding may stop. In most cases, a D & C does not provide the patient with long-term definitive results. It is useful, however, for those women who desire to maintain their fertility.

Hysteroscopic Endometrial Ablation This is a surgical procedure that uses a resectoscope or operating hysteroscope; a video monitor; a fluid distention medium such as glycine or sorbitol; and a surgical ablation device, such as an electrode loop, rollerball, or laser, to destroy the endometrium. The procedure is typically performed under general or epidural anesthesia. The cervix must be dilated to accommodate the hysteroscopic instrument, and the uterus must be properly distended. The most common risks associated with the procedure are hyponatremia from fluid overload, which is a lifethreatening condition, and uterine perforation. This treatment is intended for women who no longer desire to maintain their fertility.

Thermal Endometrial Ablation In this surgical procedure, the endometrium is treated with heat for a predetermined period of time. hot fluid may be injected directly into the uterine cavity or into a balloon-like device in the uterine cavity. The procedure may be performed under general or local anesthesia with intravenous (W) sedation. Dilation of the cervix of from 5 to 8 millimeters may be required. This treatment is intended for women who no longer desire to maintain their fertility.

Cryosurgical Ablation In this procedure, a surgical device is used to destroy tissues on the uterus employing extreme cold. A probe is inserted into the uterus under ultrasound guidance for predetermined periods of time, and the tip of the probe is cooled to a temperature ranging from 100 degrees to 120 degrees Celsius. The procedure may be performed under general or local anesthesia with IV sedation. Dilation of the cervix of from 6 to 7 millimeters may be required. This treatment is intended for women who no longer desire to maintain their fertility.

Hysterectomy Historically, this is the most common and definitive surgical treatment for menorrhagia. It is, however, a major surgical procedure and one performed in the hospital under general anesthesia and associated with the risks and complications of such surgery. Among the risks are possible damage to the urinary tract, bladder, or rectum during surgery (all of which can require further surgical repair), loss of ovarian function, and early onset of menopause.s Depending on the technique, a hysterectomy can require a recovery period as long as six weeks.9

NOVASURE

The newest endometrial ablation alternative is NovaSure. To perform it, the physician uses a RF (radio frequency) controller, carbon dioxide canister, desiccant, foot switch, power cord, and what the manufacturer calls a “Disposable Device.””The Disposable Device consists of a … bipolar electrode array mounted on \a frame that expands into a triangle-like shape when deployed in the uterus.” 10 According to a spokesperson at Cytyc Corporation, Marlborough, MA, NovaSure’s parent company, the RF controller costs $16,000 and the Disposable Device unit costs $850. 11 The NovaSure System treats the entire inside of the uterus at the same time.

This procedure requires neither incisions nor hospitalization. About an hour before the therapy, a doctor may give the patient a medication to minimize cramping during and after it. After giving the patient a local anesthetic in or around her cervix, the surgeon places the Disposable Device-a sheath containing an electrode- through the cervix. The sheath is pulled back, allowing the electrode (a wand-like device) to expand and conform to the shape of the uterine cavity. The uterus is inflated with a small amount of carbon dioxide to ensure proper placement of the device. During the ablation process, the device is activated and RF energy desiccates and coagulates the endometrium and the underlying, superficial myometrium. As tissue destruction progresses, electrical impedance of the tissue increases.

The device automatically turns off when impedance at the tissue- electrode interface reaches 50 ohms or the total treatment has lasted two minutes, whichever comes first. Usually it takes 90 seconds. The electrode is formed from stretchable, porous, silver- and gold-plated fabric or nylon and spandex. Suction drawn through the disposable device during ablation serves to maintain good contact between tissue and the electrode, and to remove liquids, steam, and other gases generated during treatment. After ablation is complete, the electrode safely retracts into the sheath for easy removal. As the name implies, the Disposable Device is then discarded. Most women are able to go home within an hour of the procedure’s completion. One advantage of NovaSure is that it requires neither concomitant hysteroscopic visualization nor endometrial pretreatment. 12

Contraindications exist for patients who:

* Are pregnant or want to become pregnant in the future. Pregnancies following ablation are possible but, because the uterine tissue has been compromised, can be dangerous for both the mother and unborn child.

* Have known or suspected endometrial carcinoma (uterine cancer) or premalignant change of the endometrium, such as unresolved adenomatous hyperplasia.

* Have any anatomic or pathologic condition, such as history of previous classical caesarian or transmural myomectomy, that could weaken the myometrium.

* Have an active genital or urinary tract infection (e.g., cervicitis, vaginitis, endometritis, salpingitis, or cystitis) at the time of the procedure.

* Have IUDs in place.

* Have a uterine cavity length less than 4 centimeters, the minimum length of the electrode array. Treatment of the uterine cavity with a length less than that could result in thermal injury to the endocervical canal.

* Have active pelvic inflammatory disease.13

The primary advantage of NovaSure is that it has been shown, in approximately 78 percent of the women in a randomized clinical study, to reduce menstrual bleeding to normal or belownormal levels a year after treatment. 14 In approximately 36 percent of women in the study, menstrual bleeding was totally eliminated. The FDA has also certified that both preclinical and clinical data provide reasonable assurance that NovaSure is safe. 15 Moreover, many women have experienced a significant reduction in painful menstruation, as well as a meaningful reduction in premenstrual syndrome (PMS) symptoms.

However, NovaSure is not without its risks. Possible surgical risks include perforation of the uterus, bleeding, infection, injury to organs within the abdomen and pelvis, and accumulation of blood within the uterus caused by scarring. The procedure may also be hazardous for women with cardiac pacemakers or other active implants. Another rare, but important, risk of any endometrial ablation procedure is that it may reduce a physician’s ability to make an early diagnosis of cancer of the endometrium. That is because bleeding is one of the warning signs of endometrial cancer, and endometrial ablation procedures are of course designed to reduce or eliminate bleeding. 16

It is clear that the procedure does not directly or indirectly sterilize women. Even though a woman’s chances of pregnancy are reduced after it, pregnancy is still possible. Because pregnancy after ablation can be very dangerous, it is recommended that women who have had the procedure use birth control afterward.

ETHICAL ANALYSIS

POST-FDA APPROVAL RESULTS

Having approved NovaSure as both safe and effective, the FDA nevertheless asked that postapproval studies be done to follow all subjects of the original clinical study for three years after treatment, in the interest of assessing long-term safety and effectiveness.

The results thus far have been positive. Three post-approval, long-term studies, reported at the 52nd Annual Clinical Meeting of the American College of Obstetricians and Gynecologists in May 2004, describe a range of benefits that include improved patient outcomes, improved patient satisfaction rates, and reduced operating room time and recovery time. 17 One study indicated that patients treated with NovaSure experience significantly less intraoperative and postoperative pain than patients treated with another system, called ThermaChoice UBT. ‘8 A second study compared four of the commercially available endometrial devices; the results suggested that, of the devices, NovaSure yields the highest rates of clinical success and patient satisfaction. 19

However, NovaSure is only one option among many that women with menorrhagia can use. As noted, women who have had the procedure may conceive afterward. Physicians therefore recommend that such women use birth control to avoid future pregnancies. I will argue that under three ethical principles-respect for persons, beneficence, and nonmaleficence-the procedure is ethical and can be performed in Catholic hospitals.

RESPECT FOR PERSONS

This principle concerns a person’s right to exercise self- determination and to be treated with dignity and respect. One of the fundamental elements of a physicianpatient relationship is the right of a patient to receive information from physicians and to discuss with them the benefits, risks, and costs of appropriate treatment alternatives. This element includes a physician’s obligation to inform patients of all current medical options available to them for a particular condition.

NovaSure is one option open to women who are experiencing menorrhagia. Because of the risks and benefits associated with the other options, the first option should always be drug therapy, using estrogen-progestogen combinations or progestogens alone. This is the safest therapy, and one that also allows a woman to maintain her fertility. However, should the drug-therapy option be unsuccessful, the D & C would be the next step. A D & C does not provide the patient with long-term definitive results; but, in combination with drug therapy, it allows women to maintain their fertility. Of the ablation methods, NovaSure appears to be the safest and most effective. It is also less risky and invasive than a hysterectomy- which should be the last option.

Birth control is an issue with NovaSure. Directive 52 of the Ethical and Religious Directives for Catholic Health Care Services states clearly that “Catholic health institutions may not promote or condone contraceptive practices but should provide, for married couples and the medical staff who counsel them, instruction both about the Church’s teaching on responsible parenthood and in methods of natural family planning.” 20

The NovaSure procedure is for women who have excessive uterine bleeding that can cause serious health problems. Many such women are celibate; birth control would not be an issue for them. Married women should be instructed about both the dangers of becoming pregnant after having had NovaSure and on the proper use of natural family planning (NFP). In good conscience, however, the physician should explain to the women that there are available to them other methods of birth control that may also reduce their chances of becoming pregnant. Patients have a right to be informed about the advantages and disadvantages of any treatment, as well as about all viable alternatives. Unless patients are told about the other birth control options available to them, they cannot give informed consent.

Giving each person this information does not violate Directive 52 because the physician can clearly state that the Catholic Church approves only of NFP and that, if used correctly and consistently, it can help the woman avoid possible pregnancies in the future. A failure to give the woman all the options available to protect her health and that of her unborn child, should she become pregnant, would violate the basic dignity and respect that all people deserve.

BENEFICENCE

This principle involves the obligation to prevent and remove harm to a person, and to promote his or her good, by minimizing possible harms and maximizing possible benefits. Beneficence includes nonmaleficence, which prohibits the infliction of harm, injury, or death on others. In medical ethics, this principle has been closely associated with the maxim Primum non nocere: “Above all, do no harm.”

We have seen that NovaSure appears to be both the most effective and the safest of the new generation of endometrial ablation devices. As noted, drug therapy should be the first treatment option, but it is effective only about 50 percent of the time and usually must be continued in order to remain effective. The D & C procedure can be a second-tier option if drug therapy is ineffective, but it is only a temporary solution that reduces bleeding for a few cycles.

Conventional endometrial ablation removes the lining of the uteru\s with an electrosurgical tool or laser and effectively reduces the bleeding in approximately 85 percent of patients. However, the risks include perforation of the uterus, bleeding, infection, and even heart failure due to fluids used to open or distend the uterus.21 The new generation of endometrial ablation devices destroy the endometrium by using either heated fluid or freezing temperatures. These options are intended for women who no longer desire to maintain their fertility.22 NovaSure’s benefits clearly outweigh those of the alternative options; the procedure is safer, more effective, less invasive, and does not destroy the endometrium and thereby cause the woman to become sterilized. In addition, women undergoing one of the other endometrial ablation procedures often need, for a month or two, to take a pretreatment drug such as Lupron to thin the lining of the uterus. No pretreatment drugs are needed with NovaSure.23

The only other treatment alternative is a hysterectomy. As noted, a hysterectomy is a major surgical procedure performed in the hospital under general anesthesia and is associated with the risks and complications of major surgery, whereas NovaSure is minimally invasive, can be done on an outpatient basis, and is more beneficial than a hysterectomy.

Certain post-procedure complications can be associated with NovaSure, including possible fever, nausea, vomiting, shortness of breath, dizziness, bowel or bladder problems, and vaginal discharge. However, clinical studies have shown these complications to be minimal. Most women can return to normal activities within a day or two of their treatment. Sexual activity can be resumed after the patient’s first checkup, usually a week to 10 days after the procedure. Possible surgical risks are perforation of the uterus, bleeding, infection, injury to organs within the abdomen and pelvis, and the accumulation of blood within the uterus due to scarring. Another important risk, as noted above, is the possibility that NovaSure will reduce a physician’s ability to diagnose cancer of the endometrium.24

SAFE AND ETHICAL

The NovaSure ablation procedure is not only an effective and safe modality in the treatment of patients suffering from excessive menstrual bleeding; it also has a very low complication rate and does not require endometrial pretreatment. NovaSure treatment can be accomplished in 90 seconds under IV sedation and paracervical block anesthesia in an office setting. The procedure’s medical benefits and cost-effectiveness make it a very viable option to a hysterectomy, which, under most circumstances, is the last option for a woman with menorrhagia.

It is true that women who undergo NovaSure should avoid future pregnancies, in the interest of their own health and that of the unborn child. However, pregnancy is often not an issue, particularly for celibate women. For a sexually active woman, the physician should explain the option of NFP, along with other options, to satisfy the ethical principle of informed consent. This should satisfy the birth control issue, thereby reassuring people concerned about allowing the procedure in a Catholic health care facility. Under the circumstances, it appears that the NovaSure system is not only ethical; it should be utilized in Catholic facilities for the good of women suffering from menorrhagia.

The NovaSure procedure requires neither incisions nor hospitalization.

Birth control is an issue with the use of NovaSure.

Beneficence includes nonmaleficence, which prohibits the infliction of harm.

NOTES

1. Cytyc Corporation, “NovaSure,” p. 1, available at www.novasure.com/

2. Mayo Clinic Staff, “Menorrhagia,” Mayo Clinic Health Information, October 3, 2003, pp. 1-6, available at www.mayoclinic.com/invoke.cfm? id=DS00394.

3. Mayo Clinic Staff, p. 2.

4. Mayo Clinic Staff.

5. Mayo Clinic Staff, pp. 2-3.

6. Mayo Clinic Staff, pp. 3-4.

7. Cytyc Corporation, “Three Studies Evaluating Cytyc’s NovaSure System Presented at ACOG Annual Meeting,” Investor Information, May 10, 2004, pp. 1-3, available at http://ir.cytyc.com/ ReleaseDetail.cfm? ReleaselD=134858.

8. Mayo Clinic Staff, “Hysterectomy: Benefits and Alternatives,” Mayo Clinic Health Information, March 15, 2004, pp. 1-5, available at www.mayoclinic.com/ invoke.cfm?id=HQ00905.

9. Center for Devices and Radiological Health, “Summary of Safety and Effectiveness Data: NovaSure Impedance Controlled Endometrial Ablation System,” New Device Approval: NovaSure Impedance Controlled Endometrial Ablation System-P010013, U.S. Food and Drug Administration, Washington, DC, September 28, 2001, p. 2.

10. Center for Devices and Radiological Health.

11. Anne Rivers, Investor Relations, Cytyc Corporation, Marlborough, MA, telephone conversation with author, December 30, 2004.

12. Center for Devices and Radiological Health, pp. 1-2. see also “NovaSure: The 90 second Endometrial Ablation,” at the website of Paul lndman, MD, www.egyn.com/novasure_system.htm.

13. Center for Devices and Radiological Health.

14. Center for Devices and Radiological Health, pp. 1320.

15. Center for Devices and Radiological Health. see also T. Fulop, I. Rakoczi, and I. Barna, “NovaSure Impedance Controlled Endometrial Ablation System: Long-Term Follow-Up Results,” Proceedings of the 2nd World Congress on Controversies in Obstetrics, Gynecology and Infertility, Paris, France, September 6- 9, 2001, pp. 149-155; P. Laberge, “NovaSure Technology Overview,” Proceedings, pp. 301-310; and J. Cooper, “NovaSure GEA Technology Overview: Analysis of Worldwide Clinical Results,” Proceedings, pp. 311-318.

16. Novacept, “NovaSure Ablation Procedure Overview,” Information and Fact Sheet, PaIo Alto, CA, 2004, pp. 1-5. Novacept was acquired by Cytyc in 2004.

17. Cytyc Corporation, p. 1. see also, J. Cooper and R. J. Gimpelson, “Summary of Safety and Effectiveness Data from FDA: A Valuable Source of Information on the Performance of Global Endometrial Ablation Devices,” Journal of Reproductive Medicine, vol. 49, no. 4, April 2004, pp. 267-273; A. Gallinat, “NovaSure Impedance Controlled System for Endometrial Ablation: Three-Year Follow-Up on 107 Patients,” American Journal of Obstetrics and Gynecology, vol. 191, no. 5, November 2004, pp. 1,585-1, 589; M. Y. Bongers, P. Bourdrez, B. W. Mol, et al., “Randomized Controlled Trial of Bipolar Radio-Frequency Endometrial Ablation and Balloon Endometrial Ablation,” British Journal of Obstetrics and Gynaecology, vol. Ill, no. 10, October 2004, pp. 1,095-1,102; and P. Y. Laberge, R. Sabbah, C. Fortin, et al., “Assessment and Comparison of lntraoperative and Postoperative Pain Associated with NovaSure and ThermaChoice Endometrial Ablation Systems,” Journal of the American Association of Gynecological Laparoscopy, vol. 10, no. 2, May 2003, pp. 223-232.

18. Laberge, Sabbah, Fortin, et al.

19. Cooper and Gimpelson.

20. U.S. Conference of Catholic Bishops, Ethical and Religious Directives for Catholic Health Care Services, 4th edition, Washington, DC, 2001, p. 28.

21. Novacept, p. 4.

22. Novacept.

23. Novacept, p. 2.

24. Novacept, p. 5.

BY FR. PETER CLARK, SJ, PhD

Fr. Clark is associate professor, theology and health administration, Saint Joseph’s University, Philadelphia, and bioethicist, Mercy Health System, Conshohocken, PA.

His article “Prejudice and the Medical Profession” (Health Progress, September-October 2003) won the 2005 Dean Conley Article of the Year Award.

Copyright Catholic Health Association of the United States Nov/Dec 2005

By Holguin, Fernando; Folch, Erik; Redd, Stephen C; Mannino, David M

Study objectives: COPD is one of the leading causes of mortality and morbidity in the United States, yet little is known about the prevalence of comorbid conditions and mortality in hospitalized patients with COPD.

Design: From the National Hospital Discharge Survey, 1979 to 2001, we evaluated whether or not COPD in adults ≥ 25 years old is associated with increased prevalence and in-hospital mortality of several comorbidities.

Results: During 1979 to 2001, there were an estimated total of 47,404,700 hospital discharges (8.5% of all hospitalizations in adults > 25 years old) of patients with COPD; 37,540,374 discharges (79.2%) were made with COPD as a secondary diagnosis, and 9,864,278 discharges (20.8%) were made with COPD as the primary diagnosis. The prevalence and in-hospital mortality for pneumonia, congestive heart failure, ischemic heart disease, thoracic malignancies, and respiratory failure were larger in hospital discharges with any mention of COPD.

Conclusions: In a nationally representative sample of hospitalizations, any mention of COPD in the discharge diagnosis is associated with higher hospitalization prevalence and in-hospital mortality from other comorbidities. These results highlight the fact that the burden of disease associated with COPD is likely underestimated. (CHEST 2005; 128:2005-2011)

Key words: COPD; comorbidity; in-hospital mortality

Abbreviations: ICD-9 = International Classification of Diseases, Ninth Revision; NHDS = National Hospital Discharge Survey

COPD is the fourth-most-common cause of death in adults in the United States and is projected to be the third-most-common cause of death in both men and women by the year 2020.1 COPD is also a leading cause of hospitalisations in adults in the United States, particularly in older populations.2 Even though the prevalence of COPD has increased in the last 20 years,3 COPD is infrequently mentioned as a contributing or underlying cause of death even in patients with severe disease.4,5 Although this has been attributed to an underreporting bias, it is also possible that COPD increases the risk of dying from other comorbid conditions. Since nonrespiratory diseases account for > 50% of the underlying causes of death in COPD,5 it is likely that the impact of COPD as a health burden is substantially underestimated. We hypothesized that patients discharged from the hospital with a diagnosis of COPD have a higher prevalence and in-hospital mortality from comorbidities when compared to patients discharged without a diagnosis of COPD. To determine this, we analyzed the prevalence and mortality from selected comorbidities in patients with and without a diagnosis of COPD using the National Hospital Discharge Survey (NHDS) [1979 to 2001].

MATERIALS AND METHODS

The NHDS is a national survey that has heen conducted continuously since 1965, and it provides data on inpatient utilization of non-Federal, short-stay hospitals in the United States. NHDS data are collected from a sample of inpatient records acquired from a national prolmhility sample of hospitals. Because persons with multiple discharges during the year can be sampled more than once, the NHDS produces estimates for discharges, not persons. Only general hospitals, children’s general hospitals, or hospitals with an average length of stay

Analysis

We used ICD-9 codes 490-492 and 496 to define COPD. and included COPD as either primary (first diagnosis listing) or secondary discharge diagnosis (from the second to the seventh diagnosis listing). We evaluated whether having a primary or secondary diagnosis of COPD in adults ≥ 25 years old was associated with increased prevalence and mortality from the following selected comorbidibcs: pneumonia (ICD-9 480-487.8); hypertension (ICD-9 401- 406); diabetes (ICD-9 250); heart failure (ICD-9 428); ischemic heart disease (ICD-9 410-414); pulmonary vascular disease (ICD9 415- 417, which includes acute cor pulmonale, pulmonary embolism, primary and secondary pulmonary hypertension, and cor pulmonale not otherwise specified); thoracic malignancies (ICD-9 160-165); and ventilatory failure (defined as acute respiratory failure [ICD-9 518.81]; pulmonary insufficiency following trauma or surgery [ICD-9 518.5]; asphyxia and respiratory arrest [ICD-9 799], respiratory distress [ICD-9 786.09]); acute renal failure (ICD-9 584); chronic renal failure (ICD-9 585-586); HIV (ICD-9 042); cerebrovascular accident (ICD-9 430-438); and GI bleeding (ICD-9 578). To evaluate for any possible time-trend effects, we performed these analysis in five periods: 1979 to 1984, 1985 to 1988, 1989 to 1992, 1993 to 1996, and 1997 to 2001. Relative SEs were calculated using the weight for all-listed diagnosis provided in the 2000 NHDS data file documentation. We used the χ^sup 2^ test for differences between proportions and the Cochrane-Armitage test for trend using categorical data. For direct age adjustment using 2000 US population weights, a software program (PROC DESCRIPT in SUDAAN; Research Triangle Institute; Research Triangle Park, NC) was used. For analysis, we used statistical software (SAS version 8.0; SAS Institute; Cary, NC; and SUDAAN; Research Triangle Institute); p

RESULTS

During 1979 to 2001, there were an estimated total of 47,404,700 hospital discharges with a diagnosis of COPD its either the primary or secondary discharge diagnosis (8.5% of all hospitalisations in adults > 25 years old), of which 37,540,374 discharges (79.2%) were listed with COPD as a secondary diagnosis and 9,864,278 discharges (20.8%) were listed with COPD as the primary discharge diagnosis. From 1979 to 2001, the yearly prevalence of hospital discharges with a diagnosis of COPD increased significantly (p for trend

DISCUSSION

COPD is one of the leading causes for mortality and morbidity in the United States, yet little is known about the prevalence of comorbid conditions and specific causes of death in hospitalized patients with COPD.” In this analysis, hospital discharges with primary or secondary COPD were also more frequently diagnosed with other comorbid conditions, including cardiac and pulmonary vascular disease, pneumonia, and thoracic malignancies. Also, the in- hospital mortalityfrom congestive heart failure, hypertension, ischemic heart disease, and thoracic malignancies was higher among hospital discharges with any mention of COPD.

Progressive respiratory failure accounts for approximately one third of the COPD-related mortality; therefore, factors other than progression of lung disease must play a substantial role.9,10 For example, a long-standing history of tobacco abuse in COPD patients may increase the risk for comorbidities such as cardiovascular disease and cancer. Some of the most common comorbid conditions that have been described in association with COPD include hypertension, diabetes, coronary artery disease,10,11 heart failure,12 pulmonary infections, cancer, and pulmonary vascular disease.13 In a study14 of 312,664 decedents from England and Wales during 1993 to 1999, COPD was mentioned in 8.0% of all death certificates. In these death certificates, obstructive lung disease comprised 59.8% of the underlying cause of death. When obstructive lung disease was not the underlying cause of death, the most common causes of death were similar to those presented in our analysis (ischemic heart diseases, heart failure, malignant neoplasms of the lung, and bronchopneumonia).14

FIGURE 1. Percentage of hospital discharges with COPD as the underlying cause for hospitalization and for hospital discharges with COPD as secondary diagnosis, NHDS 1979 to 2001. Upper bar segment with white bars represent hospital discharges with COPD listed as a secondary hospital discharge diagnosis. Lower black segments represent hospital discharges with COPD listed as a primary hospital discharge diagnosis (p for trend

Table 1-Age Distribution of Hospital Discharges and In-hospital Mortality by a Primary or Secondary Discharge Diagnosis of COPD, NHDS 1979 to 2001

The number of preexisting comorbidities in patients with COPD has been associated with increased in-hospital mortality in a cross- sectional study15 of 71,130 patients admitted for COPD exacerbation. The in-hospital mortality from COPD exacerbations was 2.5%, which is considerably lower than the 5.9% in this study; this difference is probably explained by our broader inclusion of any mention of COPD in the discharge diagnoses. Comorbid conditions that have been associated with an increased mortality risk in COPD patients include chronic renal failure, cor pulmonale, and pulmonary vascular disease16; underlying heart diseases have not been consistently associated with a higher mortality risk.10 However, since COPD is frequently underreported, it is difficult to have an adequate estimate of how comorbid conditions influence COPD mortality or, inversely, how COPD affects the outcome of other diagnosis.4 For example, in a 22-year follow-up study of 5,542 adults in the first National Health and Nutrition Examination Survey, only 47.7% of patients with severe COPD at baseline had COPD listed in the death certificate, and only 23.1% had COPD listed as the underlying cause of death.”5

FIGURE 2. Estimated prevalence of hospital discharges with selected comorbidities in patients with and without COPD, NHDS 1979 to 2001. Bars represent the age-adjusted percentage with SE bars. Black burs show patients with COPD (either as primary or secondary discharge diagnosis). White bars show patients without any mention of a COPD discharge diagnosis. IHD = ischemic heart disease; CHF = congestive heart failure; RF = respiratory failure; PVD = pulmonary vascular disease; TM = thoracic malignancy. The prevalence of all listed comorbidities is different across COPD categories (p

The results from this study have several implications. First, this study shows that the burden of disease associated with COPD is largely underestimated, since having a diagnosis of COPD is associated with increase risk for hospitalisation and inhospital mortality from other common diagnoses. Second, the increase in the number of COPD-related hospital discharges since 1979 hits been largely due to COPD discharges listed as secondary diagnosis relative to COPD discharges listed as primary diagnosis. We believe that any combination of the following factors could account for this finding: (1) outpatient treatment may reduce the incidence of COPD exacerbations requiring hospitalization17 (which are also more likely to be labeled as a primary discharge diagnosis); however, outpatient treatment may not reduce the effect that COPD has on the risk of being hospitalized for other comorbid conditions; (2) only the most severe cases of COPD are recognized during hospitalization,18 thereby underestimating the number of hospital discharges where moderate or mild COPD could also be labeled as primary diagnosis; and (3) even in patients with severe COPD, a large proportion of patients are admitted to the hospital for other comorbidities,10 and therefore COPD is labeled as a secondary diagnosis.

Third, after adjusting for age, patients with COPD appear to have an increasing trend in the hospitalization and mortality prevalence for pneumonia, congestive heart failure, and ischemic heart disease when compared to patients without COPD (Fig 4). This finding might have important implications for developing prevention strategies such as influenza and pneumonia vaccination, and long-term oxygen treatment.

FIGURE 3. Estimated in-hospital mortality of hospital discharges associated with selected comorbidities in patients with and without COPD, NHDS 1979 to 2001. Bars represent the age-adjusted percentage with SE bars. Black bars show patients with COPD (either as primary or secondary discharge diagnosis). White bars show patients without any mention of a COPD discharge diagnosis. The in-hospital mortality for all listed comorbidities is dillerent across COPD categories (p

Several limitations must be considered when interpreting the results From this study. Our study has several potential sources for exposure misclassification: first, the use of ICD-9 codes and the ability of physicians to adequately diagnose COPD in hospitalized patients. Since ICD-9 coding for COPD has a low degree of sensitivity (29 to 53%)19 and physicians often fail to recognize mild-to-moderate cases of COPD in hospitalized patients,18 this would result in a selection bias that would underestimate the true prevalence of COPD-related hospital discharges; however, this bias would not affect the relationship between COPD and comorbid conditions observed in our analysis since this is nondifferential with regards to the presence of comorbidities. The association between COPD must be taken with caution due to residual confounding from a lack of adjustment for other covariates (gender, disease severity, medications used, and occupational exposure, among others). Further studies are needed to characterize the association of COPD and how it relates to the prevalence and in-hospital mortality from other comorbidities (ie, degree of airway obstruction, smoking history, functional status, and body mass index). Third, our study cannot address whether or not there is a causal association between a diagnosis of COPD and the selected comorbidities used in the analysis. Fourth, no stratified analyses were done to determine the effect of COPD according to race, type of hospital, and insurance; therefore, these results may not be applicable across all ethnic groups, which differ in health-care access and socioeconomic status. Fifth, the increasing trends in the hospitalisation prevalence and in-hospital mortality for ischemic heart disease, congestive heart failure, and pneumonia in patients with COPD should be taken with caution, since it is not possible to determine the extent to which other factors, such as changes in ICD coding patterns over time, could have affected these estimates.

FIGURE 4. Prevalence of hospitalization and in-hospital mortality for pneumonia, congestive heart failure, and ischemic heart disease in patients with and without COPD, NHDS 1971 to 2001. Prevalence and in-hospital mortality are age standardized to the 2000 US population. Relative SEs are

As shown in this study, a discharge diagnosis of COPD is associated with higher prevalence and inhospital mortality from selected comorbid conditions. Efforts toward earlier detection and treatment of COPD may result in decreasing the burden of disease.

* From the Division of Pulmonary, Allergy and Critical Care Medicine (Dr. Holguin) and Department of Medicine (Dr. Folch), Emory University School of Medicine; and Air Pollution and Respiratory Health Branch (Drs. Mannino and Redd), Division of Environmental Hazards and Health Effects, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA.

REFERENCES

1 Petty TL. Definition, epidemiology, course, and prognosis of COPD. Clin Cornerstone 2003; 5:1-10

2 Mannino DM. COPD; epidemiology, prevalence, morbidity and mortality, and disease heterogeneity. Chest 2002; 121(suppl):121S- 126S

3 Mannino DM, Homa DM, Akimbami LJ, et al. Chronic obstructive pulmonary disease surveillance-United States, 1971-2000. MMWR Morb Mortal Wkly Rep 2002; 51:1-16

4 Camilli AE, Rabbins DR, Lebowitz MD. Death certificate reporting of confirmed airways obstructive disease. Am J Epidemiol 1991; 133:795-800

5 Mannino DM, Brown C, Giovino GA. Obstructive lung disease in the United States from 1979 to 1993; an analysis using multiple- cause mortality data. Am J Respir Crit Care Med 1997; 156:814-818

6 Dennison CF, Pokras R. Design and operation of the National Hospital Discharge Survey: 1988 redesign. National Center for Health Statistics. Vital Health Stat 2000; 1:39

7 World Health Organization. International classification of dis\eases, ninth revision, clinical modification. (ICD-9-CM). Geneva, Switzerland: World Health Organization, 1978

8 Anto JM, Vermeire P, Vestbo J, et al. Epidemiology of chronic obstructive pulmonary disease. Eur Respir J 2001; 17:982-994

9 Vilkman S, Keistinen T, Tuuponen T, et al. Survival and cause of death among elderly chronic obstructive pulmonary disease patients after first admission to hospital. Respiration 1997; 64:281- 284

10 Zielinski J, MacNee W, Wedzicha J, et al. Causes of death in patients with COPD and chronic respiratory failure. Monaldi Arch Chest Dis 1997; 52:43-47

11 Behar S, Panosh A, Reicher-Reiss H, et al. Prevalence and prognosis of chronic obstructive pulmonary disease among 5,839 consecutive patients with acute myocardial infarction. SPRINT Study Group. Am J Med 1992; 93:637-641

12 Havranek EP, Masoudi FA, Westfall KA, et al. Spectrum of heart failure in older patients: results from the National Heart Failure project. Am Heart J 2002; 143:412-417

13 van Manen JG, Bindels FJ, Ijzennans CJ, et al. Prevalence of comorbidity in patients with a chronic airway obstruction and controls over the age of 40. J Clin Epidemiol 2001; 54:287-293

14 Hansell AL, Walk JA, Soriano JB. What do chronic pulmonary disease patients die from? A multiple cause coding analysis. Eur Respir J 2003; 22:809-814

15 Paul SP, Krishnan AJ, Lechtzin N, et al. In-hospital mortality following acute exacerbations of chronic obstructive pulmonary disease. Arch Intern Med 2003; 163:1180-1186

16 Antonelli I, Fuso L, De Rosa M, et al. Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease. Eur Respir J 1997; 10:2794-2800

17 Cidulka RK, McFadden ER, Emerman CL, et al. Patterns of hospitalization in elderly patients with asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1997; 156:1807-1812

18 Zaas D, Wise R, Wiener C. Airway obstruction is common but unsuspected in patients admitted to a general medicine service. Chest 2004; 125:106-111

19 Wilchesky M, Tamblyn RM, Huang A. Validation of diagnostic codes within medical service claims. J Clin Epidemiol 2004; 57:131- 141

Fernando Holguin, MD; Erik Folch, MD; Stephen C. Redd, MD; and David M. Mannino, MD, FCCP

This work was performed at the Centers for Disease Control and Prevention, Air Pollution and Respiratory Health Branch.

Manuscript received June 6, 2004; revision accepted March 23, 2005.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: Fernando Holguin, MD, CDC/NCEH, 1600 Clifton Rd, NE MS E-17, Atlanta GA 30333; e-mail: [email protected]

Copyright American College of Chest Physicians Oct 2005

WINDSOR, Ont. (CP) – A doctor faces a charge of first-degree murder in the brazen stabbing death of a nurse who was attacked in the recovery room of a southwestern Ontario hospital while stunned colleagues worked nearby.

Police said Monday they laid the charge against Marc Daniel, 50, an anesthesiologist who was romantically involved with slain nurse Lori Dupont, 37. An autopsy concluded the single mother died almost instantly from multiple stab wounds to her chest and back after Saturday morning’s attack at Hotel-Dieu Grace hospital. Daniel was later found unconscious in his car, suffering from an apparent drug overdose.

“The root of this whole thing is there was a past relationship between the victim and the suspect in this case,” said Windsor police Staff Sgt. Ed McNorton.

“There was a break-up in that relationship and that’s what caused, basically, what happened.”

McNorton said the weapon – a military-type dagger with a 15-centimetre blade – was left at the crime scene.

But McNorton said Daniel has not been officially charged because he remains in critical condition in an unnamed hospital. McNorton said a lot hinges on the man’s health.

“There is still a lot of information that we have to gather,” McNorton said.

“There are still witnesses that we’d like to speak to and, of course, it’s a waiting game as far as his condition is. If he improves to the point where he can be taken before the courts, then a formal charge will be laid, but until then it is just a waiting game.”

It was unknown to what extent Daniel, who had worked at the hospital for 11 years, may have suffered brain damage or what his prognosis will be.

Stan Dupont, an Amherstburg, Ont., dentist, said his sister met Daniel at the hospital and began dating him about two years ago.

He said the couple bought a home together, but the relationship soured about a year ago and his sister asked Daniel to leave.

He said she tried to give Daniel back money he contributed to the purchase of the home, but he refused it and then tried to sue for additional money, claiming the house appreciated in value.

“He would not let go and would not take no for an answer,” Dupont told the Windsor Star.

“He needed to prove something to everybody, and unfortunately my sister got caught in the middle.”

Hospital colleagues have said that Dupont, who had worked at Hotel-Dieu Grace for five years, feared for her safety and had applied for a restraining order against her former boyfriend.

Dupont was so afraid that she asked security guards to walk her to her car after her shifts at the hospital. Besides providing Dupont with a security escort and helping her apply for the peace bond, the hospital also reserved her a parking spot on the first floor of the garage next to the security office, hospital officials said.

The Registered Nurses’ Association of Ontario said Monday the nursing community was in mourning following the attack.

“This tragic event is a grisly reminder of the pervasive abuse and violence that women face in our society – inside and outside the workplace,” said association president Joan Lesmond.

“It reinforces the critical importance of effective sexual harassment and violence prevention programs everywhere, including health-care facilities.”

Linda Haslam-Stroud, president of the Ontario Nurses’ Association, said nurses are three times more likely to experience violence in the workplace than any other professional group.

By URVAKSH KARKARIA

Blue Cross and Blue Shield of Florida’s chief executive drew $4.7 million in total compensation last year — making him among the top paid Blue Cross CEOs nationwide. This as the Jacksonville-based insurer pink-slips some rank-and-file employees and trims administrative costs.

Robert Lufrano’s pay topped that of CEOs at not-for-profit Blue Plans or subsidiaries, some of which reported higher 2004 revenues, according to an analysis of 27 Blue Cross plans by Atlantic Information Services.

Lufrano’s package included $808,635 in salary, $2.35 million in bonuses and $1.56 million in other compensation, the Washington, D.C.-based health care publishing and information company said.

The CEO was not made available for comment, but Randy Kammer, vice president of regulatory affairs and public policy at Blue Cross Florida, defended the compensation as “fair and equitable” in a “complex market.”

The pay package, approved by the board, was determined by an independent consultant after reviewing executive compensation surveys and the financials of publicly traded competitors.

The notion of CEOs earning lucrative paychecks even as workers face the brunt of cost-reductions is not unique.

Winn-Dixie Stores Inc. chief Peter Lynch received $2.5 million in salary and bonus in fiscal 2005 even as the Jacksonville-based retailer is in the midst of slashing 22,000 jobs as part of its Chapter 11 bankruptcy reorganization.

The Florida Times-Union last week reported Blue Cross Florida is undergoing a corporate overhaul — including job cuts — aimed at trimming administrative costs and improving efficiency.

Internal documents obtained by the newspaper reveal plans to cut $50 million in administrative costs for 2006. The insurer is hoping for a 25 percent reduction in administrative costs through 2007, the document said.

The cost-cutting goals are not set in stone, Kammer said.

“Our budget planning process is very fluid,” she said, adding that if the initiative hurts customer service, the scale of cuts could be rolled back.

The cost-cutting extends beyond employees. Blue Cross is jacking health insurance premiums for retirees by about 25.5 percent on average.

Health insurance premiums for the general population have increased an average of 8 percent to 12 percent annually, said Patrick Hays, former president and chief executive of BlueCross BlueShield Association, which represents 40 independent, locally operated Blue Cross and Blue Shield companies. Retiree health insurance premiums can be expected to increase at a greater rate than the general population, he said.

Corporate shakeups are a competitive necessity, industry analysts say, as health insurers find themselves bracketed by rising medical costs and customers clamoring for competitive premiums. While unable to completely control medical costs, i.e. the claims paid out, Blue Cross executives say they can better manage administrative expenses.

Lufrano’s compensation was second only to WellPoint Inc. chief Larry Glasscock who pulled in $5.4 million, the Atlantic Information Services survey showed. Glasscock also owns WellPoint stock valued at $26.7 million on Dec. 31.

WellPoint is a for-profit, publicly traded company that owns Blues-branded subsidiaries in 13 states. WellPoint said in September it will buy WellChoice Inc. for $6.5 billion giving the combined company more than 33 million medical members across 14 states.

CEO pay at Blue Cross Florida “is indicative of a broader issue among executive salaries in this country,” Hays said.

“The ratio of what a CEO can expect to make and what a key professional employee makes . . . is way out of whack,” he said.

Part of the reason for the escalation of salaries in recent years is that even though many of the Blues are incorporated as not-for profits they have to compete for talent with investor-owned insurers, Hays said.

Blue Cross’s Kammer echoes that sentiment: Lufrano’s pay is justified because that’s what it takes to attract and retain top talent in a hypercompetitive market.

The compensation is worth it, Kammer said, because it translates into customers receiving the “the best bang for the buck.”

“What [policyholders] are getting for their premium,” she said, “is the best service and the best product and the best network, because we have the best people running our company.”

While Blue Cross is a not-for-profit, Kammer said it operates like a for-profit and should be compared with publicly traded rivals.

“We are regulated in a way that’s much more closer to a commercial company,” she said.

Unlike not-for-profit Blue Cross plans in some other states, Blue Cross Florida does not receive tax breaks or state-authorized discounted rates on reimbursements to health care providers such as hospitals, Kammer said. But like a not-for-profit, profits go back into the company and not to shareholders.

Kenneth McNabb, a Blue Cross Florida policyholder doesn’t have a problem with Lufrano’s pay package. But the 55-year-old Jacksonville stock trader would like some financial clarity as to where the company’s profits are being spent.

“They’ve got record revenues coming in on the front end and yet they are now on a campaign to cut costs,” McNabb said. “This means that profits should be larger in the future and so the question is where are all these profits going?”

Kammer would not say if Lufrano and other top officers would take pay cuts as part of the push to reduce administrative expenses. But she said all employees were sharing in the pain.

“Everybody is making do with more work and less resources,” Kammer said.

Starting this year employee health insurance contributions are tied to pay. This means higher paid workers contribute proportionately more in health insurance premiums than workers lower on the pay scale.

Expecting companies to force top executives to share in the pain of corporate cost cutting is not realistic, said John Challenger, chief executive of Challenger, Gray & Christmas, a Chicago-based outplacement firm.

Cutting pay of senior officers could result in the loss of top talent, he said.

It is easier for a company to eliminate or reduce pay for a lower- level job because the task can be consolidated among other employees, Challenger said.

“Usually there’s one person in each senior management position,” he said. “So you have to cut the whole function.” [email protected], (904) 359-4367COMING SUNDAYBlue Cross consolidationBlue Cross plans nationwide are consolidating. Is Blue Cross and Blue Shield of Florida a takeover target or potential acquirer?BY THE NUMBERS2004 CEO pay at selected Blues PlansBlue Cross and Blue Shield of Florida’s chief Robert Lufrano was among the highest paid among Blue Cross plans last year.Publicly Traded, For-Profit Blues PlanCOMPANY CEO SALARY BONUS OTHER TOTAL COMPENSATION COMPENSATION WellPoint Inc. Larry Glasscock $1,081,600 $4,081,498 $283,445 $5,446,543Multistate Not-for-Profit or Mutual Blues PlansCareFirst Inc. William Jews $1,140,606 $1,793,199 $0 $2,933,805Highmark Inc. Kenneth Melani 805,326 634,502 231,197 1,671,025Single State Not-for-Profit or Mutual Blues PlansBCBS of Florida Robert Lufrano $808,635 $2,350,000 $1,566,150 $4,724,785Horizon BCBS of N.J. William Marino 824,000 2,614,455 0 3,438,455BCBS of Michigan Richard Whitmer 826,315 1,295,421 183,728 2,305,464Source: State insurance department documents and U.S. Securities and Exchange Commission filings, compiled by Atlantic Information Services Inc.

Exercise capacity, as measured in terms of VO2max, is a powerful predictor of death in patients with coronary artery disease, not just patients with heart failure. That is the finding of Mayo Clinic research presented today at the American Heart Association’s Scientific Sessions 2005 in Dallas.

VO2max is the maximum amount of oxygen a person can take in during exercise. In a VO2max study, a patient walks on a treadmill for about 5 to 15 minutes and breathes through a valve; the oxygen and carbon dioxide in the expired air are measured. Results are given in milliliters of oxygen per kilogram of body weight per minute (ml/kg/min).

“The best predictor of survival in cardiac patients is their capacity for exercise,” says Thomas Allison, Ph.D., the lead author of the study, who is from Mayo Clinic in Rochester, Minn. “When we considered all of the measurable clinical variables — such as whether they had bypass surgery or whether they have diabetes or high blood pressure — the patient’s capacity for exercise as measured by VO2max stood clear as the best predictor for 10-year survival.”

In this study, the significance of low VO2max levels was examined in patients with coronary artery disease — the top cause of death in the United States and often a precursor to a heart attack and heart failure.

A group of 282 patients, 17 percent of them women, underwent cardiopulmonary treadmill testing at the end of cardiac rehabilitation and were followed for an average of 9.8 years. The average age was 61 at the time of the test.

In the first two years there were few deaths, but after that mortality was significantly higher in patients with low VO2max. Fifty-five patients had a low VO2max (less than 18 ml/kg/min); at 10 years, almost half (42 percent) had died. Of the 227 patients who had a VO2max above or equal to 18 ml/kg/min, only 11.6 percent had died at the 10-year mark. Even after adjusting for age, sex and ventricular function, VO2max was a strong predictor of mortality.

The results confirm that poor functional capacity — specifically a VO2max of less than 18 ml/kg/min — is a major predictor of long-term mortality, even in a group of cardiac rehabilitation patients with good medical management, close follow-up and excellent short-term prognosis.

“This research suggests that physicians should strongly consider looking at VO2max for heart patients, not just those with heart failure, and help them preserve their exercise capacity,” Dr. Allison says. “Patients can do things, too, like exercising regularly and losing weight, to maintain their VO2max.

“It remains to be seen whether improving VO2max through better medical care or surgical intervention versus weight loss and a better exercise program will be the key to improving survival, but we suspect both are important,” he says.

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Mayo Clinic

BOSTON ““ Foot ulcerations are one of the most serious complications of diabetes, resulting in more than 80,000 lower-leg amputations each year in the U.S. alone. A new study led by researchers at the Joslin-Beth Israel Deaconess Foot Center and Microcirculation Laboratory finds that early changes in the oxygenation of the skin could help foretell the development of ulcerations and enable doctors to treat patients at an earlier stage, before the onset of serious complications.

Reported in the Nov. 12 issue of the medical journal The Lancet, the study is part of a special issue devoted to diabetic foot disease to coincide with World Diabetes Day, also Nov.12th.

“Nearly one in 40 diabetes patients will develop foot ulcers every year and more than 15 percent of these individuals will have to undergo amputation,” explains Aristidis Veves, MD, DSc, research director of the Joslin-Beth Israel Deaconess Foot Center and Microcirculation Laboratory and associate professor of surgery at Harvard Medical School. “And, unfortunately, an amputation is often the beginning of a rapid downward cycle from which the patient never recovers.”

The root of the problem is often a condition known as peripheral neuropathy, which develops when uncontrolled high blood sugar damages the nerves of the legs and feet, resulting in greatly decreased sensitivity.

“Peripheral neuropathy causes extreme numbness and a loss of protective sensation,” explains Veves. “As a result, even a minor foot injury [such as a corn or callus, a splinter, or pressure from an improperly fitting shoe] can go undetected by the patient until it has escalated into a chronic wound that won’t heal.” Once an ulcer has become infected it can lead to the onset of gangrene, and in the most serious cases, to amputation of the limb.

Knowing that changes in large vessels and the microcirculation of the diabetic foot play a central role in the development of ulcers and their subsequent failure to heal, the authors set out to specifically identify what these changes are.

Using a novel technology known as medical hyperspectral imaging (MHSI), Veves and his colleagues studied a total of 108 patients ““ 21 control subjects who did not have diabetes, 36 diabetes patients who did not have neuropathy and 51 patients with both diabetes and neuropathy. They also measured foot muscle energy reserves using a magnetic spectroscopy, a new method that is based on magnetic resonance imaging (MRI).

As predicted, their results found that there are indeed measurable differences in the skin of diabetes patients ““ and, in particular, diabetes patients with peripheral neuropathy ““ that can be detected before ulcerative foot disease develops.

“Our results indicated that the amount of oxygen that is available is reduced in the skin of patients with diabetes, and that this impairment is accentuated in the presence of neuropathy in the foot,” write the authors. Furthermore, says Veves, their findings showed that energy reserves of the foot muscles are reduced in the presence of diabetes, suggesting that microcirculatory changes could [also] have a major role.

“Foot problems are the most common reason for hospitalization among patients with diabetes,” notes Veves. “But they are also among the most preventable. If problems can be diagnosed early, then interventions can be made that will have important effects on clinical management of the diabetic foot.”

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Shire Pharmaceuticals Group

By Phil Galewitz, The Palm Beach Post, Fla.

Nov. 11–Good Samaritan Medical Center in West Palm Beach, which lost $16 million last year, laid off 12 managers this week, hospital officials confirmed Thursday.

“Like most hospitals in the area, we continually evaluate our staffing to make sure it is aligned with our volumes and the services we provide,” the hospital said in a statement. “We anticipate that approximately twelve positions not related to direct patient care will be affected.”

The layoffs at 326-bed Good Samaritan come less than a week after Jupiter Medical Center said it was cutting 23 administrative positions in a $2 million cost-cutting move.

Employees who were laid off at Good Sam — including some who have been with the hospital for more than 20 years — were immediately escorted from the hospital, sources said. Among those positions cut were the director of physical therapy and director of obstetrics, sources said. The laid off employees were told they could apply to work at other Tenet hospitals.

Good Sam is one of five Palm Beach County hospitals owned by Dallas-based Tenet Healthcare Corp., which has seen its stock plummet the past two years as it tried to rebound from an accounting scandal. Last week, Tenet said it lost $408 million in the third quarter, compared with a $70 million loss in the same period a year ago.

Good Sam is one of the most visible hospitals in the county because of its location on Flagler Drive where patients on upper floors enjoy views of the Atlantic Ocean and the town of Palm Beach. But the hospital has suffered in the past few years as the population has moved west, north and south.

The hospital’s average occupancy has hovered at about 40 percent the past five years, compared with 65 percent average occupancy hospital rate in Palm Beach County and the Treasure Coast, according to the Treasure Coast Health Council. Only Columbia Hospital in West Palm Beach had a lower occupancy level last year.

Good Sam’s scenic location along the Intracoastal Waterway is not always good for business. That’s because it sits in a flood zone.

The hospital had to close for a few days in September 2004 as Hurricane Frances approached the county. It was the first time the hospital closed in its 85-year history.

—–

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Copyright (c) 2005, The Palm Beach Post, Fla.

Distributed by Knight Ridder/Tribune Business News.

For information on republishing this content, contact us at (800) 661-2511 (U.S.), (213) 237-4914 (worldwide), fax (213) 237-6515, or e-mail [email protected].

THC,

By Amy Norton

NEW YORK — Smarter children may enjoy longer lives, the results of a new study suggest.

The study, which followed elderly adults deemed gifted by childhood IQ tests, found that the higher their early IQs were, the longer they lived — up to a point, at least. The survival advantage began to plateau after a childhood IQ of 163, an intelligence level few people reach.

Dr. Laurie T. Martin and Laura D. Kubzansky of the Harvard School of Public Health report these findings in the American Journal of Epidemiology.

Though the reasons for the link between IQ and longevity are not clear, it does not appear to be merely a reflection of income and social position. As children, the participants were from affluent families and most were white. Yet childhood IQ was still a factor in their lifespan.

Similarly, in an earlier study of Americans with more varied childhood IQs and family incomes, Martin found that IQ was related to health problems independently of socioeconomics.

This, she told Reuters Health, suggests that IQ affects longevity among lower-income people as well.

As research has already linked IQ to mortality, the current study, according to Martin, was in part an attempt to see how far the IQ-health advantage extends. The researchers expected there to be a cutoff at which a high IQ no longer brought any extra health benefits.

And there was. But, Martin said, they were surprised at how high that cutoff turned out to be.

IQs of 163 or higher are not often seen; the average IQ score in the general population is 100 (by definition), and children who score above 130 are considered “gifted.”

The current study is based on data from 862 men and women followed since childhood, starting in 1922, until 1986. All had childhood IQs of 135 or higher, with the average being 151.

The researchers found that, up to the cutoff point of 163, participants’ risk of dying during a given period decreased as their IQ increased; for example, those with a childhood IQ of 150 had a 44 percent lower risk of death than those with an IQ of 135.

Though it’s not clear why childhood IQ itself might affect a person’s lifetime health, Martin and Kubzansky point to several possibilities. For one, these children may be more likely to take up healthy habits like regular exercise, while shunning health risks like smoking. They are also more likely to get high-paying, prominent jobs as adults, with all the advantages that confers.

And in general, Martin noted, IQ scores reflect a “set of skills,” like reasoning, planning and communication, that affect how people manage their health — from talking with their doctors to dealing with a complex healthcare system.

Understanding exactly why IQ affects longevity, according to Martin, could ultimately help improve health and healthcare for everyone.

SOURCE: American Journal of Epidemiology, November 2005.

By Kreiter, Ted

The Aztec civilization may never rise again, but part of its ancient legacy may be a gift of better health to those who have rediscovered the secret of its prized “running food.”

In the annals of nutrition history, the last half-century may well be considered the age of the supergrains. Starting in the 1960s, Dr. Norman Borlaug developed disease-resistant dwarf wheat and sparked the “Green Revolution” in Asia; Purdue University researchers discovered opaque-2 maize, with the mutation that doubles the protein value of corn; and Canadian researchers developed triticale, the long-sought cross between barley and wheat. But what may be the most functional of all the supergrains still remains virtually unknown. It is the tiny seed of the Salvia hispanica L. plant, better known as chia, the same plant family used to grow furry foliage on those popular chia pets.

White blossoms of Salvia hispanica L., better known as Salba, carpet a Peruvian field. Scientists believe reintroduction of the omega-3-rich grain once used by the ancient Aztecs might significantly improve nutrition and health around the world.

In chia’s previous, more glorious existence, it served as the power food of the ancient Aztec civilization. According to Spanish manuscripts, the Aztecs ate the seeds of this semitropical plant to improve their endurance. They called chia their “running food” because messengers reportedly could run all day on just a handful. The Aztecs prized chia more highly than gold. They even used it as medicine. When the Aztec civilization ended, the much-vaunted grain fell into relative obscurity. Now, after half a millennium, chia is poised for a comeback in something other than a pottery animal.

White chia seeds are nature’s richest and most stable plant source of omega-3 fatty acids.

Scientists investigating chia since the 1990s have found the grain surprisingly nutritious. Superior in protein quality to wheat, corn, rice, oats, barley, amaranth and soy, chia also offers a disease-fighting arsenal of antioxidants, including chlorogenic acid, caffeic acid, myricetin, quercetin and flavonols. Of keenest interest at present, however, is chia’s abundance of omega-3 fatty acids, which studies have shown promote a wide range of cardiovascular and mental health benefits. Chia turns out to be the highest known wholefood source of omega-3s.

An ancient Aztec calendar indicates when chia must be sown.

Dr. Vladimir Vuksan, a pioneer of the functional foods movement in Europe and one of the developers of the revolutionary glycemic index at the University of Toronto, recently conducted the first long-term study of chia’s health effects. He and his colleagues used a commercial variety of chia called Salba, developed especially to produce white, rather than the original black, seed and a more reliable omega-3 content of about 60 percent.

In their six-month study of type 2 diabetes patients, the researchers found impressive health effects from eating Salba daily. In patients who already were on diets or medication to control their disease, Salba lowered systolic blood pressure by 10 and diastolic by five mm mercury. It also reduced c-reactive protein (CRP) levels by 32 percent and lowered fibrinolytic (blood thickening) factors, which can trigger cardiovascular disease.

“These were huge discoveries rarely seen in medical literature, even with the most powerful and combined pharmacological therapies,” Dr. Vuksan explains. “Ten over five is a major blood pressure reduction; there aren’t many studies showing this effect.”

“We asked ourselves, why is this happening?” Dr. Vuksan says. “Then we remembered one of the things from history, that Aztecs used chia seeds as a ‘running food.’ So we thought that maybe something [about chia] was helping the body to function better. We measured the body inflammation, the so-called c-reactive protein, which has been discovered as a major risk factor for heart disease, even more important than cholesterol, according to studies from Harvard. This was one of the rarest studies in the world, showing that CRP dropped about 32 percent in type 2 diabetics who were heavily medicated and well controlled,” he continues. “The only other major studies showing a reduction in CRP have been done with statin drugs.”

The researchers also looked at fibrinolytic factors. “The thickness of blood can determine heart problems,” Dr. Vuksan says. “We actually found some of the major fibrinorytic factors, like factor VIII (linked to von Willebrand’s disease) and flbrinogen, were significantly reduced after Salba. We also measured bleeding time because, as you know, if you are thinning blood, you want to see whether the patient will bleed more. We measured three factors, and there was no change with Salba whatsoever. We concluded that basically Salba is a functional food that has a health effect in diabetic individuals.”

In the beginning, Dr. Vuksan says, he only looked at the main nutrients in Salba. He knew that the seed’s protein quality was higher than soy and that it had the highest fiber content of any food, higher than wheat bran. But to explain some of the effects he and his team had seen in their study, they had to look more closely at the seeds’ makeup. And there they found a nutritional goldmine. They calculate that 3 ounces of Salba contain the same amount of omega-3 as 28 ounces of Atlantic salmon, as much calcium as 3 cups of milk, as much fiber as 1 cups of All-Bran cereal, as much iron as 5 cups of raw spinach, as much vegetable protein as 1 cups of kidney beans, as much potassium as 1 bananas, and as much vitamin C as seven oranges!

“When we started analyzing, we just couldn’t believe it,” Dr. Vuksan says. “For us in nutrition, this is like a dream food. This is an ideal composition.” At first reluctant to study the seeds at all, Dr. Vuksan is now an advocate. “My family sprinkles ground Salba on our cereal every morning,” he says.

Dr. Vuksan hopes to do further studies of the nutritious seeds. “I think Salba has great potential in regulating human health,” he says. “We would like to do more studies in different categories-in people with hypertension, arthritis, and for weight loss.” The diabetic patients in the study had no problem eating Salba, except that it made them feel full, he says. In fact, following the study, a number have continued asking for supplies of the seed.

The researchers may also look into a phenomenon reported by some study participants who had been lactose intolerant, but who on Salba found they could again drink milk without side effects.

In a summary of their findings, the scientists noted that Salba “could be considered the world’s most nutritious food crop and thus can be used as a global remedy for world hunger.”

“There’s no other food that can say that,” says Larry Brown, a nutritional foods entrepreneur and president of Salba Research and Development Inc. in Toronto. “But it’s going to take a while,” he adds. Brown is working to introduce the product in North America. This year, in collaboration with Neutraceutical, a Utah-based manufacturer of nutritional supplements, the first product with chia has been made available in North America, a tortilla chip that contains over 400 mg of omega-3 per serving and has no trans fats. The chips, called Taste Waves, may also be the only food product in North America made with organically grown high-lysine corn, a modified version of the opaque-2 maize supergrain discovered by Dr. Edwin Mertz and his Purdue colleagues in 1964.

Brown’s company is planning to offer more Salba products soon, including a salsa, a nutrition bar, and possibly a Salba drink. “Many companies have contacted us,” he says. “We’re talking to bakeries now to do bread and other baked goods with Salba. We’ve also been contacted by cereal companies. In fact, a company in Germany is doing a cereal with Salba now. So Salba is going to be around the world.”

Still, Brown says, it’s an uphill battle to convince people of the food value nestled in the tiny Salba seeds. “When we first started Salba,” he says, “we hired a consultant [from one of the world’s largest food makers] to advise us for a month and tell us what the biggest hurdle was going to be. He said, ‘Fellows, your biggest hurdle is, NO ONE IS GOING TO BELIEVE YOU.’ We laughed,” Brown says. “But you know what? He was right. If we didn’t have the University of Toronto researchers backing us up, saying that yes, what they’re saying is true, nobody would believe us.”

Copyright Benjamin Franklin Literary and Medical Society Nov/Dec 2005

Large portions push people to overeat — even to overeat foods they don’t like.

According to a new Cornell University study, when moviegoers were served stale popcorn in big buckets, they ate 34 percent more than those given the same stale popcorn in medium-sized containers. Tasty food created even larger appetites: Fresh popcorn in large tubs resulted in people eating 45 percent more than those given fresh popcorn in medium-sized containers.

“We’re finding that portion size can influence intake as much as taste,” said Brian Wansink, the John S. Dyson Professor of Marketing and of Applied Economics at Cornell. “Large packages and containers can lead to overeating foods we do not even find appealing.”

There is, however, a silver lining to the findings — that portion sizes can be used to increase the consumption of less appetizing, but healthy foods, such as raw vegetables, said Wansink. “While a small bowl of raw carrots might make for a good afternoon snack, a large bowl might be even better.”

The study is published in the September/October issue of the Journal of Nutrition Education and Behavior (Vol. 37:5).

Wansink and Junong Kim, assistant professor of marketing at the University of Central Florida, gave 158 moviegoers either medium (4.2 oz) or large (8.4 oz) tubs of free popcorn that was either fresh or 14 days old. The researchers asked the moviegoers to describe the popcorn after the movie, and they weighed how much popcorn was left in the containers. As expected, the 14-day-old popcorn was described with such remarks as “stale” and “it was terrible.”

When the moviegoers were asked if they thought they ate more because of the size of the container, 77 percent of those given the large tubs said they would have eaten the same amount if given a medium container. “This means that the moviegoers were unaware that the exceptional amount they ate was due to the size of the container,” said Wansink, who also is the author of the new book, “Marketing Nutrition: Soy, Functional Foods, Biotechnology, and Obesity,” and director of the Cornell Food and Brand Lab, made up of a group of interdisciplinary researchers who have conducted more than 200 studies on the psychology behind what people eat and how often they eat it.

Several of Wansink’s previous studies show that larger portions prompt people to eat more not because of a clean-your-plate mentality, but because large packages and portions suggest larger consumption norms. “They implicitly suggest what might be construed as a ‘normal’ or ‘appropriate’ amount to consume,” said Wansink, who tested this concept in 1996 with volunteers given different-sized bags of M&Ms that were too large to be finished while watching a videotape; those given larger bags ate twice as much as those with smaller bags.

In another similar 2001 study of popcorn and moviegoers, Wansink found that people not only significantly underestimate the calorie content of what they eat, but discount even more the calorie content of food they eat but don’t like. “When asked how many ounces or calories they had eaten, both groups — those given either medium or really large buckets of popcorn — reported about the same amount,” Wansink said.

Another factor is that while people tend to acknowledge that portion size and container size may influence other people, they often wrongly believe they themselves are unaffected, Wansink found in a 2004 study. “This suggests that portion and package size may insidiously influence people at a basic level of which they are not aware or do not monitor,” Wansink warned.

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Cornell University News Service