StATS: Medical concerns about research in children (created 2006-11-03).

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:

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

(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

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 page was written by Steve Simon while working at Children's Mercy Hospital. Although I do not hold the copyright for this material, I am reproducing it here as a service, as it is no longer available on the Children's Mercy Hospital website. Need more information? I have a page with general help resources. You can also browse for pages similar to this one at Category: Children in research.