The Sophistication of Simplicity . . . Optimizing Emergency Dosing

There is probably nothing more stressful for the emergency physician than the management of cardiac arrest in a child. Major sources of stress, or “cognitive load,” identified during pediatric resuscitation include the need to know the appropriate equipment and drug doses based on age or size of the child.¹ The need to look up equipment and calculate drug doses results in potential error and time delay. Any activity that takes providers away from the patient, either physically or mentally, has potential ramifications. The discomfort clinicians experience in dealing with these issues should not be underestimated. To the extent that these resuscitation variables can be eliminated by prior preparation and precalculation, pediatric resuscitation can approximate adult resuscitation, in which efforts are principally expended performing “critical actions” such as therapeutic decision-making and ongoing patient evaluation, rather than noncontributory activities such as recall of formulas or elementary math.

Optimized dosing in pediatric emergencies requires the near simultaneous completion of multiple tasks to achieve a single endpoint . . . the delivery of a therapeutic drug dose. In addition to the logistics mandated by calculations, pediatric emergency dosing is complicated by a high-stress, time-limited, and often resource-limited environment. The critical factors related to pediatric resuscitation drug delivery are 1) knowledge of the weight-based dose, 2) estimation of patient weight, 3) calculation of the weight-based dose, 4) conversion of the calculated dose into the volume in milliliters, and 5) error-free administration based on knowledge of drug timing, route, and potential drug–drug interactions. These are expanded on in Table 1.

Table 1.   Optimizing Emergency Dosing by Modifying Factors Associated with Dosing

Factors	Issues When Applied Acutely	Optimized Emergency Dosing
Vd = volume of distribution. *i, ii, and iii become most relevant when dealing with the obese patient.
1. Knowledge of the weight-base dose	Memory unreliable.	Cannot be relied upon.
	Reference materials must be accessible; when available, it only solves a portion of total problem.	Dose ideally incorporated into precalculated dosing reference materials.
2. Estimating patient weight
A. Parents	Accurate, not always available.	Cannot be relied upon.
B. Formulas	Require calculations and variables not always available, e.g., age. Age-based estimate less accurate than most length-based methods.	Cannot be relied upon.
C. Length ± habitus qualifier	Length is the most accurate predictor of actual body weight and IBW. Actual body weight estimation improves with habitus qualifier.	A length-based method preferred, which can be modified based on assessment of body habitus if deemed appropriate.
3.Calculation of the weight-based dose. Dose per kg may vary according to age. Total dose may vary according to weight used for calculations (see i–iii)	Prone to high error rate and time delay. Diverts clinician’s attention from patient assessment and care.	Precalculated reference materials preferred.
	i. Based on IBW.* Can be accurately estimated from length.	Preferred for all medications in the nonobese patient.
	ii. Based on “dosing weight.”* Represents “IBW” in obese patients.	May be used for drugs dosed by IBW (low Vd meds).
	iii. Based on actual weight.* Caution not to “overdose” using this weight.	Titrate high Vd meds using lower than calculated dose.
4. Conversion of the dose to volume	Same calculation issues.	Precalculated reference materials preferred.
5. Error-free administration	Cannot spend time looking up information.	Use immediately accessible reference materials.

Initial efforts aimed at facilitating emergent dosing consisted of making the weight-based dose accessible at the point of care. This provides a false sense of security, as knowledge of the weight-based dose is only a small component of the total process of delivering an effective and safe medication dose in an emergency.

The second factor, estimating a weight used for dosing, has been the subject of multiple studies evaluating parental and provider ability to estimate a patient’s weight.^2–18 Although some studies suggest that parental estimate of weight is excellent,^2,3,17 depending on parental knowledge of weight in a stressful situation places an unfair burden on them, and in many acute situations is impractical, because parents may not be present at the point of care. Health care provider estimates, primarily studied in the nonacute environment, tend to be poor.^18,19 Attempts to better estimate weight have incorporated either a predicted or a known age or measured length. In an effort to maximize the ability of age to estimate weight, various formulas have been devised,^{5–7,9,11–14,16} but age-based formulas tend to be less accurate than length-based predicted weights,^2,11,15 because there is a greater variation of weight-versus-age compared to weight-versus-length.

The relationship of length to weight was incorporated into several dosing systems.^19,20 As an example, the initial kilogram color zones on the length-based Broselow tape were based on anthropometric data from the National Center for Health Statistics,²¹ and the current adjusted color zones are based on more recent National Health and Nutrition Examination Survey (NHANES) data.²² The zones are designed to predict the 50th percentile weight for height, which is considered an estimate of ideal body mass.²³ If one examines the NHANES data, for a given length there is a distribution of “normal” weights around that length that greatly exceeds 10% variation from the mean weight, a cutoff some authors chose in their studies to be representative of accurate predicted weight estimates. Similarly, examination of a standard growth chart illustrates substantial variation of weight for age. A major advantage of length-based weight estimates, however, is that length estimates the ideal body mass within a reasonable degree of precision,²³ and there is less variation of weight for length than observed for weight to age.

In an emergency, the age used in prediction formulas is often estimated, since the parents may not be available. Length, however, is readily measured. With reference to the Broselow tape, examination of NHANES data reveals that approximately 60% of the time, the measured patient is placed in the correct zone for weight. Of the remaining ∼40%, 30% fall into the heavier zone above and 10% fall into the lighter zone below, with <1% outliers, falling greater than one zone from predicted. Adjusting the length-based prediction based on assessment of body habitus (i.e., observing whether a patient is normal, obviously overweight, or obviously underweight) would logically increase the accuracy in predicting actual patient weight.²⁰ The end result of adjusting the dose based on body habitus is a method of predicting actual patient weight that appears relatively accurate and accounts for ethnic trends in habitus. We are currently conducting a study to validate this approach. The article by Ramarajan and colleagues²⁴ in this issue of Academic Emergency Medicine notes that actual patient weight is overestimated in a sample of Indian children utilizing the Broselow tape. Another Indian study, however, demonstrated what was deemed acceptable accuracy utilizing the tape.¹¹ Conversely, the weights of children in a Pacific Rim population were underestimated by the Broselow tape.²⁵ Knowledge of a country’s or region’s childhood growth characteristics therefore becomes a necessary part of the assessment. As described below, ideal body weight (IBW) as predicted by length may be an acceptable weight for dosing many medications in overweight patients. One must use caution, however, when modifying length-based weight prediction for dosing, because other variables, such as fluid volumes, tidal volume, and equipment sizes (e.g., endotracheal tube sizes), correlate best with patient length regardless of actual weight.

A current controversial area in emergency dosing is determining whether the actual or predicted weight should be used to calculate drug dose and whether these decisions should be affected by the current “epidemic of obesity.” In clinical practice, conventional methods of dose adjustment by weight-based regimens assume that drug pharmacokinetics and pharmacodynamics are directly proportional to total body weight. However, the volume of distribution and clearance are more closely related to the lean body mass rather than actual body mass. Lean body mass is closely related to lean body weight, which is similar to IBW. Medications that are mainly metabolized in the central compartment (i.e., the plasma and extracellular water-soluble compartments) are characterized by a small volume of distribution and are best dosed by IBW. Lipid soluble drugs that are primarily distributed into the tissues (i.e., medications with a large volume of distribution) are best dosed by considering the actual body weight. In most normal individuals, considering the wide therapeutic range of most drugs, the difference between using actual body weight and IBW is clinically irrelevant. As body weight for age or length increases, primarily by increasing body fat, the difference between dosing by IBW versus actual weight becomes more relevant. In the overweight child, a medication such as theophylline, which has a small volume of distribution and a narrow therapeutic range, is best dosed based on IBW. If actual body weight is used in an obese child, toxicity may occur.

Theoretically, a medication with a large volume of distribution should be dosed using a calculation based on a weight close to actual weight. For these medications, using a length-based method that predicts IBW would lead to underdosing of these more fat-soluble medications. It is important to recognize, however, that most of these fat-soluble medications require time to distribute from the central to the fat compartment. Therefore, an initial bolus dose based on actual weight has the potential of producing acute toxic concentrations in the central compartment. For example, midazolam redistributes from the brain to the fat and tissues over several minutes, leading to its relatively short duration of action after a bolus dose. Terminal elimination is much slower and does not contribute to the duration of action from a single dose. The size of the fat compartment does not affect the initial brain concentration; instead the brain concentration is affected by the dose and the size of the central compartment. For example, if you give a 40-kg obese 6-year-old 4 mg of midazolam (0.1 mg/kg) for sedation, rather than 2.2 mg based on his or her ideal body mass, you greatly increase the risk of apnea. Therefore, using the obese child’s actual weight to dose medications that initially exert their effect based on the drug’s central compartment concentration may result in a greater potential for adverse effects. An exception is succinylcholine, which exerts its effect in the central compartment and whose concentration at the muscarinic receptor depends on its acute concentration in the plasma volume. Since the proportion of extracellular fluid is high in newborns, and decreases to the adult proportion in early childhood, the weight-based dose is higher in infants. Besides an increase in extracellular fluid, there is also an unexplained increase in pseudo-cholinesterase activity seen in obese patients, requiring a higher total dose in milligrams for full effect, and therefore actual body weight dosing has been recommended.^26,27 Since most resuscitation medications are given by bolus administration and distributed initially in lean body mass (e.g., epinephrine, sodium bicarbonate, calcium, magnesium, adenosine), we believe that IBW is preferable for resuscitation and most emergency dosing.

The morbidly obese patient is an outlier. We must distinguish between the “epidemic of obesity,” in which a larger proportion of children are moderately overweight, versus dosing of the morbidly obese. IBW probably suffices for most patients and for most medications, even for the mildly obese, especially considering the danger of overdosing these patients. In morbidly obese patients, the degree of adiposity carries with it an increase in “lean tissue” mass principally in the form of increased vasculature; therefore, investigators have suggested an alternative to a length-predicted IBW, termed the “dosing weight.”²⁸ In some studies, this dosing weight is approximated by adding 40% of the difference between IBW and actual weight to the IBW.²⁹ For moderately overweight patients, however, considering the wide therapeutic range of most medications, these dose adjustments are likely unnecessary. Knowledge of which patient weight (lean vs. actual) is best utilized for a given medication should be incorporated into dosing.

The third factor is calculation of a weight-based dose. The dose of some medications varies with age, for example; as noted, succinylcholine is dosed up to 3 mg/kg in the very young because of their relative increase in extracellular water as compared to older children and adults, in which it is dosed at 1 mg/kg. Midazolam is also often dosed incrementally, because the dose requirements in the young are generally higher than in older patients. The reverse is true for morphine, which is administered at a lower weight-based dose in the very young.³⁰ Besides eliminating the cognitive burden of routine calculations, the use of precalculated materials can imbed quite sophisticated individualized dose adjustments such as these, and yet not require additional time and decision-making during the evaluation and treatment process. The question is always raised however, “Is this dumbifying medicine?” To the contrary, sophisticated dosing practices such as described above are difficult to accommodate under the stress of an emergency. Instead, using a tool that automatically calculates, the dose considering these factors frees up time to better optimize care, such as noticing that a patient’s endotracheal tube has slipped further in, causing desaturation.

A corollary question is “Will clinicians lose the ability to calculate drug doses?” and “What if I do not have the precalculated materials at the beside when needed?” Although these are real concerns, a math-based system increases the likelihood that dedicated and conscientious health care professionals will make mistakes, since they are human and prone to error, and it diverts their attention away from the bedside. Basic drug calculation skills should be taught, but providers should minimize their dependence on mental math by utilizing standardized precalculated tools in emergencies. Just as we assure we have a defibrillator to defibrillate, a laryngoscope to intubate, and resuscitation bag to ventilate, we need to assure that we always have these materials accessible for dosing. The airline industry long ago realized the necessity of eliminating unnecessary, time-consuming, and error-prone activities to enhance the value of the pilot’s contribution.³¹ Paradoxically, many children requiring emergency care are managed by providers with limited experience in the care of critically ill pediatric patients, which highlights the need for simplification, but not simplification at the expense of function. Ironically, even the most experienced providers, who theoretically need these materials the least, lose precious time doing elementary math in a critical situation. Simplification by precalculation would thus be beneficial throughout the system of emergency care.

The fourth factor, conversion of a calculated dose into the correct volume to administer, produces the same difficulty for nurses as dose calculations for physicians. Most dosing aids do not address this area, concentrating primarily on dose calculation. The overall effect is less than optimal team effectiveness.

The last factor affecting drug dosing during an emergency is error-free medication administration. For those medications used infrequently, preparation and administration information should be immediately accessible at the point of care. Frequently more than one source must be consulted to provide information concerning dose, preparation, and administration, as well as drug–drug interactions and potential side effects. Having to look for this information at the point of care results in either valuable time being lost, or in the heat of a stressful emergency, not being done. This is an underappreciated cause of error and time delay in emergency dosing.³²

Summary

The barriers to safe and effective dosing are principally logistic and have less relevance to nonemergent dosing. To maximize dosing safety and efficiency, precalculated doses and critical dosing information should be available for immediate access at the point of care.

Instead of relying on an estimated weight, formulas requiring estimation of age, or any formula that requires calculation, the dose based on an estimate of IBW can be quickly accessed from a single rapid length measurement utilizing one of several published or commercial sources.^19,20,33 Alternatively, the ideal (50th percentile weight for age) may be readily obtained using a common centimeter measuring tape and a growth chart. Length-based estimated weight, which correlates well with IBW, can be modified by estimating habitus if judged necessary. During an emergency, time spent managing logistic issues should be minimized and effort focused on critical clinical issues.

Considering the wide therapeutic range of most medications, there is currently no evidence that for most resuscitation medications, giving a dose based on actual body weight is superior to giving an IBW dose and titrating to clinical effect if necessary. Indeed, using the actual weight could increase the risk of toxicity in certain clinical situations. Further study of the pharmacology of emergent dosing is needed.