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Medical concerns about research in children (November 3, 2006).
| Gray Syndrome. Alternate Names : Chloramphenicol Toxicity in
Newborns, Gray Baby Syndrome.
Definition Chloramphenicol is an antibacterial medication used against
gram-positive and gram-negative bacteria and is often used for meningitis. If
given to a newborn, however, it can be toxic (poisonous) and fatal.
Overview, Causes, & Risk Factors "Gray syndrome" occurs if newborns
(especially premature babies) are given chloramphenicol for a bacterial infection.
Babies at that age do not have the necessary enzymes that allow the liver to be
able to metabolize this drug appropriately. The chloramphenicol accumulates in the
baby's blood stream, causing hypotension (low blood pressure), cyanosis (blue
coloring of lips, nail beds, and skin from lack of oxygen in the blood), and often
death.
(Source:
health.allrefer.com/health/gray-syndrome-info.html) |
Children are not little adults and you need to respect the important differences between
them. Some of the differences make research more difficult and some make the research easier.
Absorption, distribution, and elimination issues.
The tortuous path that drugs take is quite amazing when you think about it. The path is
different between children and adults, especially for infants in their first few months of
life.
There is a definitive resource for absorption, distribution, and elimination issues in
children:
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Developmental pharmacology--drug disposition, action, and therapy in infants and
children. G. L. Kearns, S. M. Abdel-Rahman, S. W. Alander, D. L. Blowey, J. S. Leeder,
R. E. Kauffman. N Engl J Med 2003: 349(12); 1157-67.
[Medline]
and all of the material discussed in this section is taken directly from this reference.
Stomach/Intestines. If a drug is ingested orally, it travels through the stomach
and the intestines. A young infact will have a higher stomach pH. This can lead to
differences in bioavailability of acid-labile drugs like penicillin G. Gastric emptying
increases during the first week of life. Absorption of lipophilic drugs is dependent on the
transport of bile salts into the intestinal lumen. This process is less efficient in
infants. Intestinal motility increases from birth through the first four months of
life. There are also changes in the splanchnic blood flow and intestinal microflora
during the first few weeks of life. Some metabolism of drugs occurs in the intestine, and
there are important age related differences in the activity of two key enzymes, CYP1A1
and glutathione-S-transferase.
Skin. Infants (especially pre-term infants) have an immature skin barrier, which
leads to substantial increases in percutaneous absorption of topically applied drugs. This
increased absorption is due to a thinner stratum corneum and greater hydration of
the epidermis.
Muscles. The physiology of the muscles has an important impact on intramuscular
injections. Infants have reduced blood flow and inefficient muscular contractions.
This may be more than offset, though, by a higher density of skeletal-muscle capillaries.
Lungs. Most drugs that are administered by inhalation are intended to stay in the
lungs, but some portion of these drugs will get absorbed into the blood stream leading to
various side effects. The lungs of infants and children are different in the vital
capacity and the respiratory rate.
Rectum. For drugs that are administered rectally, there are no apparent differences
in mucosal absorption, but the infant has a greater number of high-amplitude pulsatile
contractions which enhances the expulsion of solid drugs.
Body composition. Relative to their size, infants have a greater amount of
extracellular water and total-body water. In infants, there is a larger ratio
of water to lipid in the fat tissues. This can change the apparent volume of distribution
for some drugs.
Blood. For some drugs, the ratio of bound to unbound drugs is critical for
bioavailability. In young infants, there are fewer plasma proteins (especially albumin)
which will often leave a large proportion of the drug unbound. Infants also have a greater
degree of permeability of the blood-brain barrier, which can produce some serious side
effects that are not present in adults.
Liver. A variety of enzymes located predominantly in the liver are responsible for
biotransformation of drugs. Many of these enzymes (CYP3A7, CYP2C9, UGT1A6) are absent
or have low activity in the infant and competing metabolic pathways may predominate. Other
metabolic pathways (CYP1A2, UGT2B7) show substantial age-related variations.
Kidney. The kidneys play an important role in the elimination of certain drugs from
the bloodstream. There are rapid changes during the first few weeks of life and more gradual
changes during the remainder of childhood in the glomerular filtration rate and in
tubular secretion.
The Kearns et al review article stresses that most of the changes and differences in
absorption, distribution, and elimination occur in the first few weeks and months of life.
The differences can be even more exaggerated in pre-term infants. There is some continual
growth during the first few years of life that require disproportionate dosing, but by the
time children reach their eighth birthday, there is sufficient similarity between children
and adults to justify dosing proportional to body weight or body surface area. This reference
had relatively little discussion of the effect of puberty on absorption, distribution, and
elimination, and apparently this is not a major factor.
Compliance issues
I have two medication situations at home that remind me about the complexities of
compliance
The picture above is Newton, a 17 year old cat with a hyperthyroid condition. Down near
her front paws are her daily doses of Tapezole. She gets a half pill in the morning and a
quarter pill in the evening. She does not take these pills herself, but relies on me to open
her mouth and thrust the pill in. If she recognizes that I am about to pill her, she runs and
hides in the basement. When I catch her and try to pill her, she will try to spit out the
pill. Sometimes it takes three or four attempts before the pill goes down. Sometimes I think
it goes down but I find later that she had spit out the pill while I was not watching.
The second picture is Nicholas, a four year old boy that we adopted from Russia. He is
getting ready to brush his teeth with his Dora the Explorer toothbrush. Near the back of the
sink are two different types of children's toothpaste: a fluoride version for older children
and a fluoride-free version for younger children.
A good definition of compliance appears in the Wikipedia:
Compliance (or Adherence) in a medical context refers to a patient both agreeing
to and then undergoing some part of their treatment program as advised by their doctor
or other healthcare worker. Most commonly it is whether a patient takes their medication
(Drug compliance), but may also apply to use of surgical appliances (e.g. compression
stockings), chronic wound care, self-directed physiotherapy exercises, or attending for
a course of therapy (e.g. counselling). (Source:
en.wikipedia.org/wiki/Compliance_%28medicine%29
Researchers in this field have suggested that the word "compliance" be replaced with
"adherence."
The term "compliance" suggests a restricted medical-centered model of behavior,
while the alternative "adherence" implies that patients have more autonomy in defining
and following their medical treatments. (Source: Beyond "compliance" is
"adherence". Improving the prospect of diabetes care. KE Lutfey and WJ Wishner,
Diabetes Care; 22(4): 635-639.
[Abstract]
[PDF])
There are many reasons for poor compliance
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Prescription not collected or not dispensed
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Purpose of medicine not clear
-
Perceived lack of efficacy
-
Real or perceived side-effects
-
Patients' perception of the risk and severity of side-effects may differ from that
of the prescriber
-
Instructions for administration not clear
-
Physical difficulty in taking medicines (e.g. with swallowing the medicine, with
handling small tablets, or with opening medicine containers)
-
Unattractive formulation (e.g. unpleasant taste)
-
Complicated regimen
(Source: British National Formulary 52)
There is another reason not listed above, "I forgot." Researchers today are making a
distinction between "accidental noncompliance" (I forgot and related reasons) and "volitional
noncompliance" (I didn't want to and related reasons). These distinctions are helpful in
understanding how to improve compliance
A nice summary of the causes of poor compliance in children is
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How Do You Improve Compliance? Sheldon Winnick, David O. Lucas, Adam L. Hartman, and
David Toll. Vol. 115 No. 6 June 2005, pp. e718-e724.
[Abstract]
[Full text]
[PDF]
The article lists the various barriers to compliance in a paediatric patient.
Perhaps the most important barrier is the limited amount of time that a physician
has to spend with his/her patient. This lack of time is no different than with adult
patients, but the problem is that a pediatrician has to establish lines of communication with
both the patient and the parents/caregivers. Having the time to communicate with the parents
alone (without a restless child to distract their attention from the doctor) can be very
important.
If a family unit is dysfunctional, this can be a serious barrier to compliance. If
someone other than the primary caregiver brings the child in for an office visit, the
pediatrician has to rely on an intermediate source for relaying important information to the
primary caregiver. Just as bad is when there are multiple caregivers and complex medical
instructions have to be coordinated among these caregivers. Children who live in different
houses on the various days of the week because of shared custody arrangements may also have
problems with keeping medication readily available. Finally, rebellious adolescents (what
adolescent isn't rebellious?) can also cause trouble with compliance.
Medicines that taste bad or are hard to swallow are more of an issue in
children than adults. The differing dose requirements in children may require the
splitting or crushing of pills. It is unclear what impact splitting or crushing will
have. Does the presence of flavoring and coloring agents in mediation influence the safety
and efficacy profile? Frequency of administration can also create problems, especially
if it requires the cooperation of the child's school.
Although most of the barriers listed above are plausible and have anecdotal support, the
authors of this publication point out that there has been relatively little quantitative
research on these barriers and their effect on compliance.
Differential susceptibilities
The injuries and illnesses that children are susceptible to are quite different than the
susceptibilities in adults. An Institute of Medicine report on emergency medical care for
children,
highlights many of these issues in Table 1.1, starting on page 18. Children have a
greater body surface area to body mass ratio. This increases their heat loss and places
them at greater risk for hypothermia. They have less protective muscle around internal
organs, less fat, and a more pliable skeleton, so trauma is much more
likely to cause internal organ damage. The relatively large head size also contributes
to hypothermia and traumatic injuries. The increased respiratory rate makes children
more susceptible to effects of air pollution.
There are additional concerns in children. Children have a greater tendency for placing
foreign objects in their mouths, placing them at greater risk for choking and accidental
poisoning. Their inability to distinguish candy and medicine also places them at
greater risk for accidental poisoning.
Most of us have stopped growing (vertically, anyway), but the rapid growth in
children raises special concerns about drugs that might interfere with this growth.
Intellectual growth is just as important as physical growth. Any damage to the brain cells or
the nervous system can lead to serious developmental delays. While loss of hearing or vision
is traumatic at any age, the sensory deficit caused by hearing or vision loss during the
critical phase of brain development can produce serious deficits in intellectual
development.
The premature infant has many susceptibilities because of their immature organ systems:
cranial hemorrhages, bronchopulmonary dysplasia, and retinopathy of prematurity.
The character and nature of heart disease and cancer are quite different in
children. Most heart problems are congenital. Cancer is rarer in children than adults, but
the types of cancers in children are quite different.
On the positive side, children are less susceptible to diseases that are caused by
abuse of adult vices, such as cirrhosis of the liver and lung cancer. They also do not
have the burden of the aging process and have little or no risk for degenerative
diseases like Alzheimer's.
Another positive feature of paediatric diseases is their simplicity. Children, unlike
adults and especially unlike elderly patients, will have fewer co-medications and
fewer concurrent diseases. This is ideal from a research perspective because extra
medications and diseases can complicate the analysis and interpretation of research results.
This webpage was written on 2006-11-03
and was last modified on
2008-07-08.
Category: Children in research
