Mon Sep 27, 2004 4:49 pm by Indy11
The New York Times
Nighttime, and Fevers Are Rising
By ABIGAIL ZUGER
Published: September 28, 2004
When bedtime comes, as all children and sick people know, the boogeymen come out of the closet. Darkness, silence and isolation can turn chairs into tigers, and make even trivial health problems seem ominous and hopeless.
But illness that goes bump in the night may not be just a patient's inner child coming out. Doctors have sensed for centuries that many diseases actually do get worse at night, and science has begun to confirm this impression.
The emotions nighttime elicits, although they certainly do not help matters, are not primarily to blame. Instead, it is the body's internal chemicals and hormones, cycling like the invisible gears of a giant cuckoo clock, that send diseases out to strut their stuff at night, then rotate into the background by dawn.
Fever burns in the evening. Asthma, ulcers and certain forms of arthritis worsen at night. Heart attacks and strokes brew in the predawn hours and often erupt after sunrise.
The study of how the time of day affects the body's functions, called chronobiology, is still a very new field, said Dr. Richard J. Martin, head of the pulmonary division at the National Jewish Medical and Research Center in Denver. Only when researchers understand it better are tests and treatments directed at nighttime illness likely to improve.
So many of the internal workings of the lungs change at night that lung diseases, particularly asthma, have become the best studied of the nighttime illnesses. As many as 75 percent of asthmatics have difficulty breathing one night a week, Dr. Martin said, and 50 to 60 percent report attacks three nights a week.
Rarely, people with asthma will develop symptoms exclusively at night, confounding doctors who try to make diagnoses during daytime office hours. Dr. Martin himself became interested in chronobiology after meeting such a patient, completely healthy during the day, who subsequently died of a nocturnal asthma attack.
Asthma is caused by narrowing and clogging of the small tubes called bronchi that carry air in and out of the lungs. At night, the bronchi naturally narrow in everyone, increasing resistance to air flow. In people without asthma this change is imperceptible, but in asthmatics the nocturnal constriction - which occurs whether or not they are asleep, although the increase is greater during sleep - may be enough to bring on an attack.
Researchers link the narrowing of airways at night to low nighttime levels of two important hormones: cortisol (a steroid hormone) and epinephrine, also known as adrenaline, which relaxes the airways, among its many important roles. Both these substances reach peak levels in the blood during the day, then taper off in the evening, reaching a nadir in the post-midnight hours.
Both cortisol and epinephrine may be considered the body's natural anti-asthma hormones: they are so powerful in helping to reverse the illness that hospitals give synthetic versions to break severe attacks. The nocturnal disappearance of these natural substances may be what tightens airways and provokes wheezing at night.
Other cycling body chemicals may also contribute. Melatonin, the hormone that induces sleep, can be "proinflammatory" in asthmatics, exacerbating the clogging of breathing tubes with cells and mucus, and contributing to nighttime breathing difficulties.
This finding leads to the still-unanswered question, Dr. Martin said, of whether asthmatics seeking to elude jet lag with melatonin tablets might be better advised to find another remedy. Other powerful substances that promote inflammation, including histamine, also rise at night and may further exacerbate symptoms.
For people with asthma, medication taken in the afternoon or evening will often control the disease better than the same pills taken in the morning. For instance, taking the steroid drug prednisone at 3 to 5 p.m. will have the best anti-inflammatory effect, Dr. Martin said, while the anti-asthma drug theophylline may work best when taken at 6 to 7 p.m. Afternoon ingestion means the drugs will peak in the bloodstream at night, when they are needed the most.
Why should the body close down its airways at night, like some small country under siege? It may actually be a matter of self-defense, Dr. Martin said: "With sleep, we lose a lot of protective mechanisms in regard to the lung."
The gag reflex that keeps large objects out of the windpipe is markedly reduced at night, and the small hairs called cilia that line the airways and rhythmically sweep tiny particles of dust and debris away from the lungs do not work as efficiently at night. Perhaps that is why the body evolved a mechanism for minimizing the damage microscopic intruders can do before dawn.
The gastrointestinal tract may have evolved its nocturnal defenses for exactly the same reasons. Basal acid secretion in the stomach peaks in the early hours of sleep, possibly aimed to thwart nocturnal invaders.
As a result, ulcer pain and complications tend to peak then, too - and anti-ulcer medication is often most effective if taken before bedtime.
Fever, which is caused by some of the same internal chemicals that promote airway inflammation, and is also one of the body's defenses against attacking microbes, also tends to rise as night falls. Like normal body temperature, which is lowest in the morning and highest toward evening, most fevers peak near the end of the day. In fact, this pattern is so characteristic that even if a nighttime fever has eased by morning, doctors are trained to wait until the next evening before pronouncing the fever gone.
Of course, by escalating many of its defenses at night, the body sometimes does the equivalent of shooting itself in the foot.
People with rheumatoid arthritis know this error all too well. Their bodies mistakenly make antibodies against components of their own joints, causing painful inflammation and progressive deformity. Almost invariably, the pain of rheumatoid arthritis is worst in the morning and better as the day progresses.
"During the night, the inflammatory process exacerbates," said Dr. Michael Smolensky, a professor of environmental physiology at the University of Texas School of Public Health in Houston.
Low nighttime cortisol levels and high levels of the chemicals that promote inflammation may be responsible. The pattern of pain from rheumatoid arthritis stands in sharp contrast to that of a more common form of arthritis, osteoarthritis, which is exacerbated by activity and is often worse late in the day.
Sometimes, even illness that peaks after sunrise has its origins at night. Researchers think this is the case with heart attacks, which commonly occur during the first few hours after people wake up. Morning heart attacks may begin to brew during the period of R.E.M. sleep between 4 and 6 that is associated with a rise in heart rate and metabolic activity. The natural rise in blood pressure that occurs after awakening may further strain the heart. Finally, the body's clotting system works most efficiently in the early morning, so that clots may form then in narrowed coronary blood vessels. As a result, emergency rooms do a brisk business in heart attacks first thing in the morning.
Several time-release blood pressure and heart medications are now on the market that can be taken at bedtime, begin to work during the night and reach peak efficacy in the morning to counteract some of this process.
By and large, though, the study of circadian patterns of disease is still in its infancy, under study in the laboratory but not yet incorporated into medical practice. Polls find that most doctors and pharmacologists are unaware of these patterns, and the overriding message in medical education is that the body's workings are constant over time, Dr. Smolensky said.
Furthermore, for some medical conditions researchers have yet to make much sense of the cycles they uncover. This is particularly true in the case of pain, which, one might think, would be reliably escalated by nighttime demons.
But dozens of studies have uncovered dozens of different, contradictory pain cycles. One study found toothache pain to be worst in the early morning, peaking at 8 a.m. Another found a similar pattern for the pain of migraine headaches. But pain from gallstones was worst around midnight, and kidney stones seemed to throb unremittingly around the clock. End-stage cancer pain was worst in the predawn hours in one study, and in the afternoon in another.
Experts suggest that even if the daily cycles of many diseases are not yet fully understood, patients should still keep track of their own daily patterns, in hopes that their treatments can be customized accordingly. Dr. Smolensky favors a detailed diary that includes sleep, wake and medication times and, for women, menstrual cycles as well.
"Patients should be aware of these rhythms," he said, even if doctors are not.
It is possible to envision a day, though, when hospitals do become attuned to circadian cycles of disease. Asthma testing would take place in the middle of the night for the most telling results, and stress tests for heart disease would be conducted first thing in the morning. Cardiac patients would have life-threatening clots in their coronary arteries dissolved in the late afternoon, when the body's clotting system is at its weakest and, as an Israeli study recently suggested, the results are better than in the early morning. All medications would be dispensed in sync with the diseases they fight. And, of course, small night lights would burn in every corner to drive the spooks away.
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