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Home > Topics > Emerging Issues > Antiretroviral
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Antiretroviral Drug Dosing for Infants and Children: Calculation by Weight or Body Surface Area?

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Method 1
Use a table of surface area estimates based on a child's weight input alone. For an example, see the table here or in the Appendix .

Method 2
Use a nomogram, or graphical calculation device, including both height and weight inputs. See a PDF of a nomogram .

Method 3
Enter a patient's height and weight measurements into a formula. See an Internet-based formula .

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Why BSA?

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In June 2008, the U.S. Food and Drug Administration (FDA) issued an advisory recommending that the dosage of nevirapine for infants and children be determined according to estimated BSA rather than a child's weight.( 1 ) The revised recommendation was based on studies that compared weight-based dosing with BSA-based dosing and found that BSA-based dosing allowed a smoother transition between recommended drug dosages in various pediatric age groups.( 2-5 ) In general, determination of drug dosages for infants and children using BSA is felt to be more accurate than dosing based on weight.( 6 , 7 ) This largely explains the rationale for the new FDA recommendations, but it remains unclear why all pediatric drug dosages are not calculated on the basis of BSA.

The use of new drugs for children is of special concern because certain drugs behave quite differently in children than in adults, especially in prematurely born and young infants.( 6 ) The calculation of drug dosages for children using weight-based formulas with extrapolation from adult dosages can have devastating consequences (by either overdosing or underdosing). For example, chloramphenicol, a potent antibiotic given for control of many bacterial infections, has a very different metabolism in infants than it does in adults. In the mid 1950s, pediatricians began to use the drug in infants and children based on a dosage calculated from the recommended adult dosage. However, in newborn infants, especially prematurely born infants, a condition termed "gray baby syndrome" was observed.( 8-9 ) After 5-10 days of treatment with chloramphenicol, some infants developed cyanosis, hypotension, vomiting, limpness, hypothermia, and cardiovascular collapse. The syndrome was caused by a lethal accumulation of chloramphenicol in the blood as a result of immaturity of the liver enzyme UDP-glucuronyl transferase and inadequate renal excretion of the unconjugated drug. The gray baby syndrome was a consequence of excessive drug accumulation, which occurred even though the chloramphenicol dosage was adjusted on the basis of body weight.

At the opposite extreme, it is also possible that drug dosages calculated by weight might result in the administration of subtherapeutic levels and lead to ineffective treatment.( 10 )

Determining a drug dosage for infants and children is complicated by differences in metabolism, size, weight, race, and the condition being treated. Newborns and infants born prematurely pose difficulties related to incomplete development of the kidney and liver functions responsible for drug metabolism and elimination.( 11-16 ) Children with HIV infection may present additional difficulties for determining appropriate drug dosages, particularly in low-resource settings. For example, the administration of multiple drugs may interfere with the metabolism of each drug, and gastrointestinal infection along with diarrhea may result in malabsorption of orally administered drugs.( 12-19 )

When specific information based on pharmacokinetic studies of children is not available, clinicians are faced with difficult choices as they determine the appropriate drug dosage for a child. In many instances, even with drugs used to treat life-threatening conditions, precise pediatric dosing information may not be available. Under these circumstances, clinicians have several options:

  • Use age-adjusted drug dosing recommendations.
  • Calculate the pediatric drug dosage using weight, extrapolating from the recommended dosage for an average-size adult.
  • Calculate the pediatric drug dosage based on estimated BSA using one of three methods: nomogram, table, or data entered into an electronic-based formula.

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Commonly Used but Inferior Methods for Determining Pediatric Drug Dosage That Are Not Based on BSA

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Determination of Drug Dosage by Age

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It is generally agreed that basing a drug dosage on the age of a child is the most inaccurate and problematic solution.( 6 , 20-23 ) Many manufacturers of "over-the-counter" drugs provide dosing recommendations on that basis. In most cases, these drugs are used to treat clinical symptoms rather than to treat a disease. Because over-the-counter drugs are sold without a physician's prescription or guidance, age-based drug dosages are usually deliberately subtherapeutic and frequently ineffective. The FDA allows over-the-counter use of drugs because the lower dosage recommendations provide a higher margin of safety. Occasionally, however, an over-the-counter drug may be recalled for safety reasons when data indicate that the recommended dosage results in serious side effects.( 24 )

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Determination of Drug Dosage by Weight

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When a drug dosing recommendation for children is not available, clinicians most often determine the drug dosage by extrapolation from the recommend adult dosage using the following formula:

Dosage of drug for infant or child = adult dosage x (weight of infant or child ÷ weight of adult)
In this example, the average weight of an adult is assumed to be 70 kg. Thus, if the dosage of the drug for a 70 kg adult is 100 mg and the child weighs 30 kg, the dosage for the child would be 43 mg.
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Although this method is used frequently when there is no established pediatric dosage, extrapolation of pediatric drug dosages based on adult dosages and average adult weights presents many difficulties. In some instances, the calculated drug dosage could be correct, resulting in both efficacy and safety. On the other hand, as with the example of chloramphenicol, the dosage could be excessive, and result in drug toxicity. Alternatively, the dosage could be too low, and result in ineffective or incomplete therapy.( 9 )

If the determination of drug dosing for infants and children by weight is fraught with so many potential difficulties, why are there not more reports of drug toxicity or lack of drug efficacy with children? The numbers of reported drug-associated adverse events in children are low, for several reasons.

First, a majority of drugs have a high therapeutic index. The therapeutic index is the ratio of the amount of a drug that results in a therapeutic effect to the amount that results in toxicity.( 6 ) This allows for a "margin of error" for most drugs. Thus, drugs with a high therapeutic index can be both safe and efficacious even if some inaccuracies in calculations occur. Drugs with a low (narrow) therapeutic index generally require measurements of actual blood drug levels (therapeutic drug monitoring) to prevent fatal complications. Many antiretroviral medications and chemotherapy drugs have a low therapeutic index; that is one of the major reasons for recommending the use of BSA to calculate dosages of these drugs for children.

A second and more worrisome reason for limited reporting of drug toxicity or lack of efficacy in children, especially regarding problems related to drugs used for life-threatening diseases, is that toxic effects of a prescribed drug may be misinterpreted as abnormalities caused by disease rather than by the drug. For example, worsening liver function in a patient undergoing treatment for hepatitis could be either a result of advancing disease or a sign of drug toxicity. Whenever unexpected toxicity occurs, particularly in patients undergoing treatment for life-threatening diseases, an inappropriate drug dosage or a drug-related effect should be considered. Similarly, when treatment failure occurs, inappropriate drug dosage should be considered a possible cause.

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BSA-Based Methods for Determining Drug Dosages for Children

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Rationale for BSA-Based Drug Dosing

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Clinical experience indicates that calculating drug dosages for children according to estimated BSA is more appropriate than extrapolating from adult weights.( 6 , 21 , 22 , 25-30 ) BSA is more closely related to pharmacokinetic and physiologic parameters such as cardiac output, blood volume, glomerular filtration rate, body growth, and organ development. Several methods are used to estimate BSA for infants and children. These methods have been adapted to develop charts, tables, and nomograms that permit determination of appropriate drug dosages for children based on estimated BSA, using height and weight or weight alone.( 22 , 26 , 27 ) Mathematical formulations for determining BSA reflect the fact that changes in height and changes in weight result in different rates of change in surface area of the body. Thus, short-statured infants and children have greater surface areas in relation to their weight than an average adult. Table 1 shows the average BSA per kilogram of body weight at different ages, illustrating the fact that BSA on a per-kilogram basis is greater for infants than for adults.

Table 1. Comparison of BSA/kg of Adults and Children
Age BSA: (m 2 )/kg (x10 3 )
2 months 62
1 year 49
3 years 43
7 years 38
12 years 32
Adult 26
Adapted from Radde IC, MacLeod SM.( 6 )
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Methods for Determining BSA

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Method 1: Determination of BSA Using Weight Measurements Alone

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Several investigators have modified previously published formulas to develop BSA estimations and nomograms that permit identification of appropriate childhood dosages based upon weight alone.( 26 , 27 ) When appropriately formulated for children, use of weight alone is more convenient and theoretically subject to fewer errors than the use of both height and weight to determine dosages. Sharkey et al evaluated the use of weight alone to determine BSA and compared results with those derived from the use of both weight and height. The deviation in estimates from the two methods was <10%. Table 2 and Table 3, in the Appendix , provide nomograms for BSA determinations based on weights of children who were lighter than 10 kg and children who were heavier than 10 kg. Caution is suggested regarding use of the nomogram for calculating BSA of obese or malnourished children and of children weighing <10 kg.( 27 )

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Method 2: Determination of BSA Using Weight and Height Measurements

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BSA determinations are most accurate when both weight and height measurements are used, providing that the measuring instruments are accurate and that the measurements are determined carefully. Several nomograms and tables have been developed to assist in determining BSA without the need to use formulas. One of the most useful is that devised by Haycock et al (see Figure 1).( 21 )

Figure 1. Nomogram for Determining BSA in Children Using Weight and Height Measurements

Nomogram for Determining BSA in Children Using Weight and Height Measurements

Adapted from Haycock GB, Schwartz GJ, Wisotsky DH. Geometric method for measuring body surface area: a height-weight formula validated in infants, children, and adults . J Pediatr. 1978 Jul;93(1):62-6. Accessed January 7, 2009. See printable PDF . Note: Line up a ruler with the height on the left axis and the weight on the right axis. The point at which the center line is intersected (SA m 2 ) provides the value for the BSA.

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Method 3: Calculation of BSA Using Data Entry Forms Available on the Internet

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The most rapid and convenient method for calculating BSA is to use either a handheld calculator or an electronic tool on the Internet, an example of which may be found at http://www.halls.md/body-surface-area/bsa.htm . The patient's height (in centimeters or inches) and weight (in kilograms or pounds) can be entered into the electronic form, and the tool will calculate the BSA. The BSA can then be used to determine dosages for drugs that are available as dose/m 2 . Some electronic tools, including the one referenced above, also provide safety alerts if a drug dosage appears to exceed recommended levels. Although these electronic tools are rapid and accurate, limited access to the Internet may restrict their use in resource-poor settings. In addition, the electronic data entry method is effective only for weights >22 lb (10 kg). BSA for Infants who weigh less can be calculated using Table 2 or Figure 1.

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Summary

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Results from detailed pharmacokinetic studies are the only reliable determinants of appropriate drug dosage ranges for infants and children of various ages, weights, and heights. Errors in dosing decisions are more likely to occur when extrapolating a pediatric dosage from an adult dosage. Weight-based extrapolations may result in under- or over-dosing of a given drug, which can lead to decreased efficacy and treatment failure, or increased toxicity and adverse events. Legislative steps have been taken to encourage drug manufacturers to perform studies with infants and children to increase the accuracy of drug dosing recommendations. However, many drugs have not been evaluated, and clinicians often must use their best judgment in determining dosages. The FDA has been lax in requiring pharmacokinetic studies with children, even for life-saving medications.( 32 ) Of the more than 20 antiretroviral medications in use for the treatment of HIV infection, only zidovudine, nevirapine, lopinavir/ritonavir, and ritonavir have drug dosing recommendations based on BSA.( 33 )

Using formulas to calculate BSA for infants and children can be both time consuming and error prone. High patient volumes and a lack of handheld calculators and Internet access preclude widespread and consistent use of these formulas in resource-limited areas. Nomograms and tables with BSA based on weight alone or on both weight and height measurements provide a reasonable alternative, but also may be subject to error if the measurements are not performed carefully. In addition, these methods must be used with caution for infants and children who are malnourished or obese.( 27 )

There is no universal rule for dosage calculation that can be considered accurate under all circumstances. BSA is recommended as most closely meeting efficacy and safety requirements for infants and children. For each patient, however, the clinician should carefully monitor the patient's clinical status and any secondary end points that can be used to confirm efficacy. Laboratory monitoring of organ function should be performed to ensure that drug toxicity is not occurring. For example, evidence of efficacy in infants and children treated with antiretroviral drugs would include improved clinical status, weight gain, increased growth and development, and decreased opportunistic infections. Secondary end points would include increased CD4 counts and decreased viral loads. Toxicity should be monitored using hematologic, renal, and hepatic blood studies.

Table 4 lists the advantages and disadvantages of the various methods for calculating BSA.

Table 4. Comparison of Various Methods for Calculating BSA
Method Advantages Disadvantages Comments
Weight alone: Dosage based on extrapolation from dosage and weight of average adult Readily available. Not subject to the inaccuracies of height measurements. More likely to result in inaccurate dosage calculations for infants and children. Best used for drugs with a high therapeutic index. Most widely used method for calculating drug dosing for children.
BSA based on a table using weight only (Method 1) Weight measurements and tables for calculation of BSA are readily available. Bypasses potential inaccuracies in height measurements. Does not take into account height measurements that may be important for accurate BSA estimations. Use with caution for malnourished or obese infants and children weighing <10 kg.
BSA based on nomogram using height and weight (Method 2) Weight and height measurements are usually available along with tables to calculate BSA. Printed copies are easy to use. Height measurements are subject to greater inaccuracies than are weight measurements. Generally felt to more accurately reflect BSA.
BSA determined using electronic entry of height and weight (Method 3) Easy to use. Reduces errors resulting from inaccurate calculations. Requires programming formula into handheld devices or having access to the Internet. Widespread use in resource-poor areas not feasible until handheld devices and Internet access become more readily available.
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Appendix

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Table 2. BSA Estimation for Patients Weighing ≤10 kg
Values are calculated using the Boyd formula.( 31 )
Body Weight (kg) Surface Area (m 2 )
2 0.16
2.5 0.19
3 0.21
3.5 0.24
4 0.26
4.5 0.28
5 0.3
5.5 0.32
6 0.34
6.5 0.36
7 0.38
7.5 0.4
8 0.42
8.5 0.44
9 0.46
9.5 0.47
10 0.49
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Table 3. BSA Estimation for Patients Weighing >10 kg
Values are calculated using the Boyd formula.( 31 )
Body Weight (kg) Surface Area (m 2 ) Body Weight (kg) Surface Area (m 2 )
11 0.53 51 1.5
12 0.56 52 1.5
13 0.59 53 1.5
14 0.62 54 1.6
15 0.65 55 1.6
16 0.68 56 1.6
17 0.71 57 1.6
18 0.74 58 1.6
19 0.77 59 1.7
20 0.79 60 1.7
21 0.82 61 1.7
22 0.85 62 1.7
23 0.87 63 1.7
24 0.9 64 1.7
25 0.92 65 1.8
26 0.95 66 1.8
27 0.97 67 1.8
28 1.0 68 1.8
29 1.0 69 1.8
30 1.1 70 1.9
31 1.1 71 1.9
32 1.1 72 1.9
33 1.1 73 1.9
34 1.1 74 1.9
35 1.2 75 1.9
36 1.2 76 2.0
37 1.2 77 2.0
38 1.2 78 2.0
39 1.3 79 2.0
40 1.3 80 2.0
41 1.3 81 2.0
42 1.3 82 2.1
43 1.3 83 2.1
44 1.4 84 2.1
45 1.4 85 2.1
46 1.4 86 2.1
47 1.4 87 2.1
48 1.4 88 2.2
49 1.5 89 2.2
50 1.5 90 2.2
From Sharkey I, Boddy AV, Wallace H, et al. Body surface area estimation in children using weight alone: application in paediatric oncology . Br J Cancer. 2001 Jul 6;85(1):23-8. Accessed January 7, 2009.
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References

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