体表面积与儿童用药剂量英国BSA1997

体面积与儿童用药剂量英国BSA1997 The Calculation of Drug Dosage and Body Surface Area of Children 儿童体表面积和药物剂量计算 Alastair Lack and Malvena Stuart-Taylor Summary 简述 The British National Formulary (1) and many reference textbooks recommend that drug dosages for children be calculated according to body surface area (B.S.A.). Though many rules for drug dosage have been developed, based upon age, weight, and surface area, none have been both accurate and simple enough for routine use. These rules are described, and one for clinical use, that: 英国国家处方集( 1)和其 他参考资料，建议为儿童药物剂量根据体表面积( BSA)计算。虽然有很多计 算药物剂量的规则， 如年龄，体重，和表面积，但都不足够精确而实用的。描 述这些规则，和一个用于临床用途，即: Up to 30kg, a child‘s drug dose may be (Wt x2)% of adult, Over 30kg, (Wt +30)% of adult 一个体重达到30kg的儿童，用量可能是成人的(体重×2)%倍，大于30kg,(体 重+30)%倍 If this percentage of an ‘adult‘ dose of a drug is used, not only is the B.S.A. curve followed more closely than with the conventional mg/kg regime, but fewer major errors of prescription may be expected. 如果药物使用此―成人‖剂量的百分比，不仅(BSA体表面积)曲线更贴近传统 的毫克/公斤曲线，还将减少处方中错误。 Introduction 介绍 The British National Formulary (B.N.F.)(1), Martindale‘s Pharmacopoeia (2), and many other reference textbooks state that the most reliable methods for calculation of children‘s drug doses are those based on body surface area (B.S.A.). This principle has been commended for nearly ninety years, but there is still no consistency in the guidance offered, and the same B.N.F. uses a mixture of mg/kg , age and weight ranges in its recommendations. 英国国家处方集(BNF) [1]，马丁代尔药典[2]，和许多其他的参考书都表明 最可靠的儿童药物剂量的计算方法是基于体表面积(BSA) 。这一原则历经90 年，但目前提供的指导性文件中仍不一致， 如BNF中混合使用了毫克/公斤， 年龄和体重原则。 All dosage rules based upon a single physical dimension only hold good whilst that dimension is associated with normal other dimensions. Thus one could use an age based rule if associated height and weight for that age are were typical; however there is substantial normal variation of height and weight with age (see later) and so weight is more normally used as the dimension for calculations. This however is still relatively unreliable, so if one seeks better prediction of drug levels, a multidimensional rule is needed. Fortunately this is usually rather beyond clinical needs. 几乎所有用药剂量规则都基于保持一个单一的好的物理维度，而物理维度与其 他维度息息相关。因此，人们使用年龄规则时需将该年龄的身高和体重关联 为典型的(标准的)，但身高、体重与年龄的变化很大(见下文) ;这就是为什 么体重规则更常见。然而，体重也是不可靠的。为更好的预测药物浓度水平，需 建立多维度的规则。这不仅是临床的需要。 The therapeutic ratio (the ratio of toxic to effective doses) for most drugs is more than 50%, so that some approximation may usually be made with safety. It would appear that for routine practice, an ?accuracy‘ of 10-20% is reasonable; anything more than this complicates the mathematics substantially, and would not be justified because of individual differences in response. This generalisation excludes those drugs which are given according to known individual requirements (e.g. insulin or digoxin), for which a prescribing rule is inappropriate. 大部分药物的治疗比 (有毒剂量/有效剂量的比例)大于50%，即使近似于此值， 通常也视作安全。日常使用的 ?精确度‘在 10%-20%视为合理，因为在此范围内， 可用个体差异解释。这个说法不包括那些有个体化需求药物的(例如胰岛素或地 高辛)，他们不适用于处方规则。 A large number of children‘s drug dosage rules have been described over the years(3-5), almost all using percentages of an adult dose to calculate an appropriate child‘s dose - the notable exception being the commonly used ‘n‘ mg kg -1 regime. An advantage of these rules is that modifications to adult doses to allow for sickness in adults are appropriately incorporated into calculations for children. An obvious requirement of these percentage methods is that adult doses of the drug are known, but for the majority of anaesthetists this does not present a problem, and certainly no more difficulty than the different dosages at different ages noted in the B.N.F. 近些年[3 – 5]，出现了大量的儿童药物剂量计算规则,几乎所有的规则都使用成 人剂量的百分比计算儿童用药的合适剂量——明显的例外是常用的毫克/公斤制 度。 这些规则的好处是,修改成人剂量便可适当的计算儿童用药。使用百分比计 算要求药物的成人剂量是已知的,这对麻醉类药品不是问题,但对于b n f中指出的 按年龄阶段给予不同剂量的药物来说困难重重。 Reports in the literature quote many examples of prescription errors for children of 2-10 times the recommended dosage(6-10). Many believe that the great majority of these errors would have been noticed if easily calculated percentages of a normal adult dose had been used, since the prescriber may readily check his mathematics by inspection of the figures involved. 在文献中很多儿童处方错误使用2-10倍的 推荐剂量[6-10]。许多人认为，如果使用成人剂量百分比计算，这些错误将会被 注意和避免，因为处方开具者可随时通过观察数字以检查处方计算。 Dosage rules may be described as those based on age, weight or body surface area. 基于年龄、体重、表面积的计算规则如下: Age Based Rules 年龄规则 The earliest rules used age as the base, giving the percentage of an adult dose. Augsberger (3) referred to D illing‘s rule (Age/20) as going back to the 8th. century. Those most commonly used are shown in figure 1 最早以年龄为基础计算成人剂量的百分比的规则，出现在公元8世纪时， Augsberger [3] ð解毒，阿莫西林的规则( Age/20 )。最常用的，如下表 Age/20, (4xAge)+20, and Age/(Age+12) 年龄/20, (4×年龄)+20，和年龄/年龄 +12 Figure 1 表1 Age based rules at ages shown for the calculation of childrens‘ drug dosages as a percentage of adult dose plotted using weights derived from standard growth tables 以年龄计算儿童用药成人剂量百分比的规则，使用来自标准增长表的体重绘 制。竖轴为成人用量百分比，横轴为体重，黑线体表面积百分比，粉线年龄/20， 红线(4×年龄)+20，蓝线年龄/(年龄+12) These are plotted using weights for ages obtained from standard tables(11,12). The normal variation of weight with age (from 3rd. to 97th. percentile) is very considerable, being least at one year (+25% to -20% at 10 kg), and reaching a maximum at about 13 years (+45% to -26% at 40 kg). The consequence is that these rules are highly unreliable. 这些绘制使用体重来自各年龄标准增长表 [11,12]。正常的体重随着年龄的变 化(从第3到第97百分位)是相当大的，在一年至少( +25 ,到-20,或者10 公斤)，在13年时达到最大值(+45,-26,，在40公斤) 。其结果是，这些规 则是非常不可靠的。 If weight is unavailable, then (4 x Age)+20 provides the best fit to the B.S.A. curve for normally sized children 假如体重不知，则用最贴近正常儿童的体表面积曲线的(4×年龄)+20计算规 则。 Weight Based Rules 体重规则 Prof. A.J. Clark of Edinburgh is said to have been the first to propose a weight-proportional regime for drug therapy(13). His first rule is 爱丁堡大学的教 授A.J.据说率先提出药物治疗的重量比例制度[13] 。规则如下 [Wt(lb)/150] fraction of an adult dose 成人剂量的[重量 (磅) / 150]分数 This was improved in accuracy by Augsberger(3), who substituted multiplication for division and added 10, suggesting 之后被Augsberger[3]改良，以×代替?并+ 10， 建议为 [(1.5 x Wt(kg))+10] percent of an adult dose 成人剂量的[ (1.5×体重(公斤) ) + 10] , However, this made it a little difficult to calculate, and this rule is not widely quoted. It is as good a linear fit as can be made to the B.S.A. curve, reaching 100% at 60kg (figure 2). 不过，由于难以计算，而这项规 则并未被广泛采用。它与 B.S.A.曲线很好的契合，在60 公斤时候达到100%， 可成线性， (图 2)。 The most common regime, mg/kg dosages, has an attractive simplicity which has given it widespread popularity despite its disadvantages, namely:- 最常见的规则是，mg/kg 剂量，因为简洁易操作被广泛 使用，尽管有它的缺点如: It requires a complete set of drug dosages (n mg/kg ) to be learned for its purpose, and indeed different doses at different ages(1) 它需要学习一套完整的药物剂量 (几 mg/kg)和在不同 年龄中的不同剂量[1] point sometimes being misplaced when tenths or hundredths of a mg/kg are being multiplied. 数学计算并不轻松，有时错放小数点将造使用药量成十倍、百倍的增 加或减少 prescriptions are not immediately obvious. 它不能立即与成人剂量关联比较，因此 不易发现不适当的处方 ‘underdoses‘ for much of its range(14). This varies from aboutat 15kg toat 40kg compared with the B.S.A. graph (figure 5). 化验显示药物浓度大多处于较低的范畴[14]。与BSA曲线的变化从15公斤时 -45%到40公斤时，-20%，(图 5)。 Figure 2 图2 Weight based rules for the calculation of childrens‘ drug dosages as a percentage of adult dose; markers at ages 以体重计算儿童用药成人剂量百分比的规则;标记年 龄。横轴体重，竖轴成人剂量百分比，黑线BSA%，红线体重/70，蓝线(1.5× 体重)+10 Body Surface Area Calculation 体表面积计算法 Body Surface Area is recommended as the principal basis for drug dosage(15,16) since the rate of metabolism or redistribution of a drug is proportional to metabolic rate, which in turn reflects heat losses which, as for any warm object, are generally proportional to surface area. Many measurements of organ size, fluid compartment volumes and assays of blood levels of drugs correlate well with B.S.A.(13,17-20). 身体表面面积被建议作为药物剂量的主要依 据[15,16]，因为药物的代谢和再分配与代谢率成正比，这反过来说明对于任何产 热物体，热量损失与表面积成正比。许多器官大小、 液体容量的测量和血药物 浓度均与 B.S.A.相关[13,17-20]。 Whilst this is valid for most ages, some drop below the B.S.A. proportional dose is in fact appropriate when prescribing for children of less than about eighteen months, typically 10kg, since below that age there are differences other than size that should be borne in mind i.e.:- 虽然这对大多数年龄是有效的，事实上对,18月的孩子来说，略低于 B.S.A. 比例剂量是合适的，通常 10 公斤，因为需要记住的是低于此年龄段除体型大小 外还有其他的差异:如 In the neonate, many enzyme systems are immature. 新生儿期酶系统的不成熟 about six months. 新生儿的肾脏清除率是约成年人的50,，在约6个月达到成人 水平 在新生 儿和婴儿中药物的半衰期较长 at 3 months, and 60% at 1 year, compared with about 55% for adults). This is of importance when considering the distribution volumes of drugs; in children less than one year old, the distribution volume is relatively large for drugs that are water soluble, and small for those that are fat soluble(14, 21- 儿童身体总水量的百分比高于成人(刚出生时80,，生后3个月，70, ，1 年后60 ,，成年人约55 ,)。关系到药物的分布体积时，应重点考虑。在小于 一岁的儿童，水溶性的药物分布容积是比较大，脂溶性较小[14 ，21-23]。 Moore , in 1909(19) was the first to recognise the importance of B.S.A., saying that:- ?stating dosage in reference to body weight is not only inaccurate, but rests entirely on a wrong principle‘, 摩尔，在1909年(19)是 首先认识到BSA的重要性:根据体重拟定起始剂量，不仅不精确，还是个错 误的方向。 that it should be ?proportionately instead to the body surfaces or, in other words, proportionately to the two thirds powers of their weights, which leads to quite different doses.‘ (1) 它应该是―与身体表面积成比例，或言之，与体重的2/3权重 成比例，导致不同剂量。[1] Moore is using the same formula as Meeh(24), who is widely quoted. Clark gave his name to his second rule by reporting Moore ?s work in 1937(13), again recommending dosage proportional to the two thirds power of the body weight. Moore和Meeh [24]使用相同的应用广泛的公式。1937年Clark出版了Moore 的工作报告并将之命名为第二个规则[13] ，再次推荐剂量与体重的2/3权重成比 例。 The history of actual measurements of surface area is fascinating, with examples of marvellous ingenuity, from covering surfaces with paper, plaster or lead, to ‘wrapping a man in silk tights, charging up the silk as one would a Leyden Jar, and calculating the surface by applying a metal plate of known area‘ (25). The power of 2/3 is the ratio of surface area to volume of cubes, spheres and other such solid objects, and in humans appears to be a quite reasonable approximation (figure 2) for those of normal build, using a proportionality constant of around 12 for kilograms, i.e. 12 x Wt2/3 (25). It is, however, unidimensional. 实际表面积测量的历史是迷人的，奇妙匠心的例子，从用纸，石膏或铅覆盖面， 到―将人用绸缎紧身袜裹紧，用莱顿瓶充电，并计算通过应用已知金属板的表面 面积‖ [25]。2/3的比率是立方体，球体和其他这样的固体物体的体积的表面面积 )，对于正常体型，使用的比例常数12的比率，和用在人体中似乎也合理(图2 千克左右，即12× 体重2 / 3 [25] 。然而，它是单一维度的。 The first multidimensional formula for surface area to be widely used was proposed by DuBois and DuBois(26):- DuBois and DuBois是第一个被广泛使用的多维度计算公式。[26] S = W0.425 x H0.725 x 71.84 (2) S 体表面积(cm2)= 体重(kg)0.425 x 身 高(cm)0.725 x 71.84 (2) where S= Surface Area (sq.cm), W= Weight (Kg), H= Height (cm) The nomograms derived from this equation are those seen most often, as for example in Martindale‘s Pharmacopoeia(2) or Geigy Scientific Tables(27), despite the fact that the investigators only measured 9 subjects. The definitive work on surface area is a monograph by Edith Boyd(28), who improved the formula as follows:- S = 3.207W 0.7285-0.0188 LogW H0.3 (3) Where W= Weight (g). She quoted the standard deviation (S.D.) in her subjects as 7% Gehan and George(29) summarised all existing data, and suggested a further marginal improvement on the above equations, namely S = 0.0235 H0.42246 W0.51456 (5) In fact, equations 1 - 5 are within 5% of each other down to 15 kg in persons with a normal build. Thin people would appear to have about 10% more surface area than predicted by Equation 1, and fat people about 20% less(25), but unfortunately the literature does not provide reliable data about variations of B.S.A. with build. 事实上，公式(1) - 5是彼此间15公斤在一个正常体型在5,以内。由式(1) 瘦的人似乎多算了10,左右的表面积，胖的人低了20,左右[25] ，但不幸的是， 文献并没有提供BSA与体型的可靠数据变化。 B.S.A. Based Rules The nomograms constructed from these formulae provide the actual surface area, from which further mathematics will provide the fraction of an adult dose, and thence the required dose, but this is hardly a bedside calculation. The consensus has generally been that fixed tables of percentages of an adult dose derived from B.S.A.(3,20,30) are a lesser evil than calculations requiring such higher mathematical powers, though they do require interpolation and the consequent possibility of introducing further errors. This approach, first suggested by Butler & Richie(17) and further popularised by Catzel as ?The Percentage Method‘(31) again is difficult to use in a clinical situation: the figures may of course be learnt by heart, but this is little more use than nomograms or a calculator. They appear to be the basis of the table given in the B.N.F.(1) (which does not quote its source) and many current textbooks; Catzel‘s figures (Table 1, Figure 3) follow the B.S.A. curve up to 40kg, from which point they are 5% higher. Differences in the percentages recommended in different sources appear to arise from a combination of approximations and differences in the size of an ‘adult‘ - whether 140lb., 65kg or 70 kg. Much of this work was done in the early part of the century, since when the normal adult has increased in size. Catzel‘s Recommended Doses of Drugs for Children Catzel推荐儿童用药剂量 Age 2/52 2/12 4/12 8/12 12/12 18/12 3yrs 5 7 Weight(kg) 3.2 4.5 6.5 8.5 10 11 15 18 23 % Adult Dose 12.5 15 20 25 28 30 33 40 50 10 12 14 20 32 40 45 65 TABLE 1 60 75 80 100 Figure 3 Catzel‘s recommended dose of drugs for children as a percentage of adult dose SALISBURY RULE None of the rules described above are both simple and accurate enough for clinical use. A rule is needed that will allow a dosage calculation that is approximately ‘correct‘, rather than having complicated mathematics in order to achieve academic accuracy, but getting the point wrong. Since a curve cannot be calculated easily with bedside mathematics; it was decided to use two straight lines crossing over at an appropriate point. As pointed out, the Wt/70 (mg/kg) rule falls substantially below the B.S.A. curve throughout its range, with consequent underdosing. Wt/50, which is the same as double the body weight as a percentage of the adult dose, makes for easier calculation and provides reasonable results up to 30 kg, though still deviating to the low side at low weights (thereby accommodating the reservations concerning infants described above). Over 30 kg, one may simply add 30 to the body weight to obtain the graph shown in figure 4, following the B.S.A. curve closely. Figure 4 The Salisbury rule for drug dosage for children compared with B.S.A. and Wt/70 ( mg/kg ) The difference of the Wt/70 (mg/kg) and Salisbury rules from the B.S.A. curve may be seen in Figure 5 Figure 5 The deviation from the B.S.A. of the Wt/70 ( mg kg) rule and the Salisbury rule Thus, we propose that children should have:- Less than 30 kg : Weight x 2 More than 30 kg : Weight + 30 percentage of the adult dose of a drug. Expressed colloquially, this is: Under 30 double it, Over 30, add 30‖ ―To obtain the B.S.A.% from the weight, Examples of drug dosage calculations using different rules Most doses rounded to nearest mg: n/r = not recommended Weight (kg) Atracurium 3.2 8.5 18 45 adult dose assumed to be 35mg 0.5 mg/kg n/r 3 9 23 Salisbury Rule n/r 6 13 26 Catzel/BNF n/r 9 14 28 Thiopentone 4 mg/kg Catzel/BNF 13 35 34 48 70 73 101 112 180 252 224 ‘Adult‘ dose assumed to be 280mg Salisbury Rule 18 Morphine ‘Adult‘ dose assumed to be 10mg. ‘B.N.F.‘ follows B.N.F. guidance for different age/weight groupings 0.1- 0.2 mg/kg 0.3-0.6 0.9-1.7 1.8-3.6 4.5-9 BNF mg/kg Catzel/BNF 0.5 1.25 1.7 1.7 2.5 ~4 3.6 5 10 9 8 Salisbury Rule 0.6 Table 2 The results from the Salisbury Rule fall in a safe area close to those recommended by the B.N.F. It is particularly useful that it removes the need to learn different doses at different ages. So, for example, the dose for Morphine is quoted in the B.N.F. as: ‘<1 month, 150 micrograms/kg; 1-12 months 200 micrograms/kg; 1-5 years 2.5-5 mg; 6-12 years 5-10 mg‘. The Salisbury Rule tracks these different doses accurately, so eliminating the need for different dosage recommendations at different ages. The authors have been using this rule now for nearly ten years. It has proved easy to use, and there has been no clinical evidence of inappropriate dosage. SUMMARY Nearly ninety years ago the following suggestion was made:- ?For the great majority of drugs the method of stating dosage as so much per kilogram should be abandoned‘ Moore ,1909 It has often been repeated, and in order to facilitate this the Salisbury rule is that Children should have, if they are Less than 30 kg, double the body weight. More than 30 kg, add 30 to the body weight. percentage of the adult dose of a drug. 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