Practical pharmacology in paediatric emergencies

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4 Practical pharmacology in paediatric emergencies

Chapter Contents

Introduction

Overview

Pharmacokinetics in critical illness

Pharmacokinetics in the developing human

Methods of estimating drug doses in children

Dose modification for developmental stage, critical illness and abnormal body composition

Do not skip this chapter! It is not mind-numbing pharmacology and should offer some useful tips on drug dosing in paediatric emergency management. (Please refer to Chapters 5 and 6 for drug dosing tables.)

Introduction

Pharmacologists acknowledge that it is important to strike a balance between science and practicality when it comes to the clinical determination of drug dosages in children. While we understand many of the changes in pharmacokinetics that are related to growing up and to differences in body composition (body water and fatness), it is extremely unclear how to translate these into meaningful information when standing in front of the patient. There is even less information about emergency drug dose determination in a patient whose physiology is deranged from critical illness or injury. Fortunately, many of these issues have less application to initial or stat doses than to repeat or subsequent doses and can, to some degree, be avoided in drugs that can be titrated to clinical effect. This chapter contains some useful information and guidelines on how to modify drug dosage based on age or body composition, to ensure that the desired efficacy is achieved and overdosage is avoided.

Overview

Pharmacology in children is difficult primarily because of the differences in pharmacokinetics (what the body does to the drug) of any given drug between neonates, infants, children and adults, whereas the pharmacodynamics (what the drug does to the body) of that same drug will remain much the same across all developmental stages. An approach to paediatric drug dosing ideally needs to be based on the physiological and body composition characteristics of the child and the pharmacokinetic and pharmacodynamic qualities of a particular drug. In the few drugs that have been tested in children, there can be a 3- to 6-fold increase in the variability of the pharmacokinetics of a single drug dose for paediatric patients when compared to adults. This difference between adults and children is likely to remain unclear because of the difficulty in performing dose escalation studies in the paediatric population. This necessitates the initial dose estimation in paediatrics to be obtained via extrapolation approaches. The validity of such an extrapolation hinges on the similarity of disease progression and concentration-responses between adults and children for any particular pathological process. All of this leads to the off-label use of many drugs in the paediatric population group. About 75% of drugs used in paediatrics have never been studied in children.

Pharmacokinetics in critical illness

Some general pharmacokinetic principles that are relevant to emergency drug administration in critically ill children:

• Hypoxaemia as well as poor perfusion leads to decreased or unpredictable drug absorption from the GIT. This, in addition to variable first pass metabolism, is one of the reasons that intravenous administration is favoured to ensure optimum bioavailability of the drug.

• Rectal absorption can vary because of hypoperfusion and depending on how high in the rectum the medication is administered – higher up means absorption into the portal system and a greater enterohepatic first pass metabolism with a resultant decreased bioavailability. Drugs administered low in the rectum are delivered systemically via the inferior and middle rectal veins, before passing through the liver.

• Hepatic and renal function may be impaired because of decreased cardiac output, leading to diminished clearance of drugs and prolonged duration of action.

• Significant oedema may change the volume of distribution of hydrophilic drugs.

Pharmacokinetics in the developing human

An insight into the changes in pharmacokinetics of the developing child will give you an appreciation of how drug dosing can be tailored to these developmental periods. Simplistically, the age-related changes are:

• Changes in volume of distribution – neonates have a relatively higher proportion of body water, which reaches adult levels before 1 year of age.

• Changes in plasma protein levels – these reach adult levels in early infancy.

• Changes in drug metabolizing enzyme systems – Phase I and Phase II liver enzymes reach adult levels of function by about 2 years of age (with much variation between individual enzymes).

• Changes in renal function – glomerular filtration rate and drug excretion reach adult levels at about 1 year of age.

So then, how do we go about determining the correct dose to use in children at different developmental stages?

Methods of estimating drug doses in children

Various methods are used in order to estimate paediatric drug dosages, with each having its own advantages and disadvantages:

1. Age-based dosing regimens:

This method takes into account the differences in physiological development between neonates, infants, children and adolescents. Unfortunately, these differences are not absolute or specific to certain maturational stages of development and do not take into consideration the developmental differences and varied body composition of different children of the same age (fat vs. thin children).

2. Body weight-based dosing regimens:

Although there is a correlation between age and body weight, this does not apply to pharmacokinetics. Children between 2 and 6 years of age can potentially get under-dosed if using a body-weight dosing regimen, as they have an increased clearance of a drug. Attempting to compensate for this increase in clearance by increasing the dosage of the drug may compromise older children who do not have the increased clearance and thus may be potentially overdosed. Therefore a one-size-fits-all approach should not be used for all children.

3. Body surface area-based dosing regimens:

This method works on the premise that the physiology of the child is constant when expressed per unit of body surface area. The difference between the dosages calculated for BSA and body weight is more significant for paediatric patients in the younger age range. Dosing by BSA is more accurate for younger children as, for instance, children aged 2 years may have a dosage calculated by BSA of 1.7 times that calculated by weight. Unfortunately, this method requires complex calculations and may result in overdosing for certain drugs in neonates and infants. It also requires measurement of weight and length, is time-consuming and prone to errors in an emergency setting.

4. Allometric scaling:

This method works on the supposition that drug clearance and volume of distribution are scaled according to a body weight-based formula. It has similar disadvantages to BSA measurements and is inaccurate for children younger than 8 years of age.

There is no evidence to suggest that one or other of these systems is more accurate when determining drug dosages for emergency care. The great majority of drug doses are currently based on body weight, which is also the least complex system, and this is how the doses are presented in this book. As with most issues in pharmacology, it is not quite that simple. There is vigorous debate about what form of weight measurement or calculation should be used for paediatric drug dose calculations.

Drug dose calculation based on body weight

In emergencies, drug dose calculation is always based on body weight. What form of body weight is best and what modification to drug dosing should we adopt in children with an unusually high or low weight-for-length: total body weight, lean body weight, ideal body weight or adjusted body weight?

Total body weight

This is the actual measured weight of the child. If the child is underweight, then the child’s actual body weight should be used to calculate the drug dosage. In obese children, if the patient weighs more than 20% above ideal body weight, adjusted body weight is often used.

Ideal body weight

There are three main ways to determine ideal body weight in children – the McLaren method, the Moore method and the body mass index method. The results obtained are similar for children under the age of 8 years old, but vary widely for older children.

The McLaren method (1972)

This method is based on McLaren and Read’s nomogram comparing weight and height in relation to a child’s age. It is the most commonly used method to calculate IBW in children. It is accomplished by plotting the child’s age and height, converting the height to the 50th percentile for age and then correlating it with the corresponding weight on the 50th percentile for weight on the chart.

The Moore method (1985)

This method was created to compensate for the fact that not all children will grow according to the 50th percentile. It thus compares the same percentile for height with its corresponding percentile for weight, i.e. if a child is on the 3rd percentile for height, the IBW would be obtained on the 3rd percentile for weight.

The body mass index method

IBW is calculated by using the predicted BMI for height at the 50th percentile

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Lean body weight

James’ equation:

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Adjusted body weight

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Adjusted body weight uses a factor to take the patient’s excess weight into account. The distribution is usually presumed to be approximately 20–50% of the excess weight. Therefore the factor is usually 0.2–0.5 of the excess weight added to the IBW. In general, if in doubt, use 0.4 unless another factor is specifically recommended.

Obese children

A useful rule of thumb in obese children is that 75% of their excess weight is fat mass and the remainder lean mass. The lean mass also has an increased hydration which has been attributed to an expanded extracellular water space. This over-hydration increases the lean mass value, which also needs to be taken into account when calculating body composition. If the patient weighs more than 20% above IBW, use ABW.

Table 4.1 shows the theoretical recommended dosing strategies for the major drug classes according to type of body weight.

Table 4.1 Theoretical recommended dosing strategies for the major drug classes according to type of body weight

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Dose modification for developmental stage, critical illness and abnormal body composition

General principles

• When a drug can be titrated to effect then this will eliminate many of these problems. Slow administration of a drug will also minimize unwanted side effects, especially in haemodynamically compromised patients, and allow for minimum effective doses to be used.

Developmental stage

• Drug doses for neonates and infants may need to be relatively higher in mg/kg values than for older children – be prepared to repeat a dose or to administer slightly higher doses than expected. On the contrary, drugs are cleared more slowly and so have a longer duration of action. Repeated drug doses must be given at longer intervals and infusions administered at slower rates than for older children.

• Percutaneous absorption of medications is much higher in infants and neonates (and even more so in preterm neonates) than older children and adults. Toxicity from dermal application of medication is a real danger in this group.

• Rectal administration of drugs in neonates and infants is subject to variable absorption and metabolism and should be used with care.

• Children of 2 to 6 years of age appear to clear drugs more rapidly than other developmental ages. Higher doses and shorter dosing intervals or higher infusion rates may be required in this group.

Critical illness

• Critically ill children often have renal dysfunction. The doses of drugs that are excreted via the kidneys should therefore be reduced for subsequent doses.

• Hepatic dysfunction should also be taken into account. Enzymes for Phase I and II reactions will be hindered in their functioning, leading to a decreased metabolism of certain drugs as well as decreased perfusion of the liver, which again affects subsequent doses rather than the initial one.

• Acidosis impedes the body’s ability to respond to catecholamines. Higher doses of these vasoactive drugs may be required in this setting, or the acidosis may require aggressive treatment.

Obesity

• Hydrophilic drugs – dose according to IBW or ABW in the obese patient, e.g. phenytoin, rocuronium, adrenaline, sodium bicarbonate.

• Lipophilic drugs – dose according to TBW, e.g. amiodarone, benzodiazepines, carbamazepine.

• Ventilator weight – There is no evidence to support which is the appropriate weight to use in obese children who are being ventilated. By extrapolating from adult studies, the most rational approach to ventilation in children would be to calculate tidal volume at 6 mL/kg using IBW or tape predicted weight based on length.

So what is the bottom line about drug dose modification in emergencies under these special circumstances?

1. Fortunately, there is little need to modify drug dosages for stat administration. Always use TBW for an initial drug dose if there is any doubt, and administer it slowly while observing for the desired clinical effect. Don’t let thoughts about dose modification impair your ability to manage the patient in an emergency– the paralysis by indecision of cognitive overload.

2. Use a tape-based weight prediction rather than any other form of weight estimation – it will probably offer the best indication of correct dosing. A system like the PAWPER tape will offer the best weight estimation and the least chance of under- or overdosing both in children with a higher and a lower than average weight-for-length.

3. Use a PAWPER tape-based weight estimation (with a habitus score of 5) for obese children – this will offer a weight close to an ABW and will pose little danger of overdosing.

4. Before subsequent doses are due in the ED or ICU there will be time to obtain a measured TBW, calculate IBW and plan the strategy for further dosing.

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