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Therapeutic drug monitoring principles in the neonate.

Although infants and toddlers are understood to be very different from adults in their disposition of and response to drugs, information relevant to this group is almost always collected after the drug has been tested in adults. Moreover, the accumulation of these data in young infants is often slow and incomplete: Ethical considerations hinder rigorous studies, and in many cases the lack of micro methods for drug analysis in small volumes hampers detailed trials in infants and small children. We now treat many high-risk, very-low-birth-weight infants with combinations of powerful drugs, and over the last decade this group of patients has prompted intensive research into the disposition of and response to drugs in preterm infants.

Here I will review differences in disposition and response to drugs in infants and children. Developmental changes will be dealt with, including specific problems associated with drug administration to this age group.

Pharmacokinetic Aspects


The two major determinants of gastrointestinal absorption, gastric acidity and gastric emptying time, differ between newborn infants and adults.

Gastric acidity. At birth, gastric pH is in the neutral range (between 6 and 8), owing to the presence of alkaline amniotic fluids. Within a day, the pH generally falls to between 1 and 3. However, gastric acidity is poorly maintained in neonates. Only by age 3 years does the production of acidity reach adult capacity ([H.sup.+] per hour, 0.15 mmol/10 kg body wt. in neonates vs 2 mmol/10 kg in adults after a stimulation test) [1, 2]. These age-dependent changes correspond closely to the development of the gastric mucosa. The relatively alkaline milk consumed by the infant further decreases gastric acidity.

These differences in gastric pH have been shown to affect the absorption of several drugs. For example, oral penicillin, ampicillin, and nafcillins (all acid labile) achieve higher concentrations in neonates than in children or adults [3-6]. Higher concentrations of these agents in neonates may also result from lower elimination rates (see below). The relative contributions of these two mechanisms have yet to be defined.

On the other hand, acidic drugs, such as nalidixic acid, are better absorbed in their nonionized form. In alkaline pH, a larger fraction of the drug is ionized and is therefore less well absorbed by the small infant [7].

Gastric emptying. In infants younger than 6 months, gastric emptying is much slower than in older children and adults. In normal adults, gastric emptying is biphasic, a rapid (10-20 min) first phase being followed by an exponentially slower phase. In the preterm infant, gastric emptying is slow and linear. The prolonged gastric emptying in the small infant (6-8 h) results in increased absorption of the penicillins (ampicillin, nafcillin) and decreased absorption of acidic drugs (e.g., nalidixic acid).

Theoretically, one would expect that drugs relatively poorly absorbed in adults might have an improved absorption rate in young infants, owing to prolonged contact with the gastrointestinal mucosa secondary to slow gastric emptying. However, limited data suggest that certain drugs, including amoxicillin, rifampin, chloramphenicol, and cephalosporins, demonstrate delayed and incomplete absorption in neonates and small infants [8-10]. After birth, there is a gradual improvement of gastrointestinal absorption of drugs, and by age 3 months, absorption may be comparable with or even more complete than that seen in adults [11].

Intramuscular absorption. The bioavailability of drugs after intramuscular injection depends on the perfusion in the area of injection, the rate of drug penetration through the capillary endothelium, and the apparent volume into which the drug has been distributed. Several physiological factors distinguish neonates from older children and adults, including vasomotor instability, less muscular mass and subcutaneous fat, and a higher proportion of water. In addition, the pathological states of hypovolemia, hypothermia, and hypoxemia may decrease perfusion and potentially decrease intramuscular bioavailability. Only sparse information exists comparing intramuscular administration of drugs in various age groups. Apparently, the time needed to achieve peak concentration ([T.sub.max]) for drugs administered by the intramuscular route is comparable for infants, children, and adults for aminoglycosides, ampicillin, and carbenicillin [11-14], whereas preterm infants exhibit delayed absorption of chloramphenicol, rifampicin, cephalexin, cephaloridine, and benzylpenicillin [10,11,15,16].

Percutaneous absorption. Two major factors determine the rate and extent of percutaneous absorption and may cause excessive absorption of an agent applied to the skin in the neonate and small infants. The thickness of the epidermal stratum corneum is inversely related to absorption, whereas the state of skin hydration directly influences absorption. Several antiseptic agents have been implicated in cases of severe toxicity in neonates after percutaneous absorption. For many years, hexachlorophene (PHisohex) was used routinely for the "total body bath" to guard against skin bacteria, in the belief that absorption occurred only through wounds and burns. However, cases of severe central nervous system toxicity with generalized seizures reported in neonates with intact skin led to findings that 3% of infants so bathed had blood concentrations of hexachlorophene comparable with those causing seizures in animals [17]. Subsequently, the American Academy of Pediatrics recommended this compound not be used on extensive areas [18]. Similarly, increased skin permeability was shown with boric acid when used as a skin antiseptic in infants. Given the findings of severe intoxications and the existence of safer and less-penetrating antiseptic agents, it is now thought that boric acid should not be used at all.

The Eutectic Mixture of Local Anesthetics (EMLA) is the first effective noninvasive method for skin anesthesia. One of its components, prilocaine, is metabolized in the liver to o-toluidine, which can cause methemoglobinemia. The immature activity of the enzyme diaphorase in their erythrocytes makes infants more prone to methemoglobinemia in such circumstances; nonetheless, as my colleagues and I recently showed, even in preterm infants, applying EMLA before heel pricking does not produce methemoglobinemia [19].


Several determinants of drug distribution also are markedly different in neonates and infants compared with adults. Some of the factors influencing the distribution of antimicrobial drugs, such as protein binding and compartmentalization of body water, change continuously during the first years of life--as does, therefore, drug distribution in this group.

Protein binding. In general, protein binding of drugs is lower in newborns than in older children and adults-the result of lower albumin values, the lower affinity of fetal albumin for drugs, and the presence of endogenous compounds, such as bilirubin, that compete for protein binding. Examples of drugs for which lower protein binding has been documented in neonates are phenytoin, salicylates, ampicillin, nafcillin, sulfisoxazole, and sulfamethoxyphrazine [3, 20-22]. Consequently, greater free fractions of these drugs are circulating and thus are able to penetrate various tissue compartments, yielding higher distribution volumes ([V.sub.d]).

Body water. In the newborn infant, water makes up 70-75% of the body weight, compared with 50-55% in adults, and the extracellular water component is greater (40% of body weight vs 20% in adults). Infants have less fat tissue, 15% vs 20% of body weight in adults, and 25% less muscle tissue. These characteristics affect the [V.sub.d] of drugs that are mainly distributed in body water and, to a lesser extent, of lipophilic drugs. Gentamicin and amikacin have been shown to have a greater distribution in neonates, which tends to decrease gradually during childhood [11]. These changes are explained mainly by changes in the percentage of body water, given that the aminoglycosides bind minimally to plasma proteins.

The larger [V.sub.d] in infants and small children means that, at equal doses (per body weight), the peak concentrations produced in their blood will be lower than in adults. However, the mean serum concentration at steady state is independent of the [V.sub.d] and therefore is unaffected, according to the equation:

Mean concentration at steady state = dose

(mg/kg * h)/clearance


Hepatic metabolism. Although almost all liver metabolic processes can be demonstrated in infants, even in the fetus, their rates are by far slower in the newborn infant, especially if the infant is preterm, than in the older child and adult. The maturation of different phase 1 reactions (e.g., hydroxylation, deacetylation, and oxidation) and phase 2 reactions (e.g., conjugation) may vary extensively. For almost all the drugs studied that are metabolized by the liver, clearance rates are slower at birth than later. The deacetylation of rifampicin [9], glucuronidation of chloramphenicol [8], oxidation of nalidixic acid [7], and hydrolysis of clindamycin [23] appear to be much slower in newborn infants. Similarly, clearance rates for tetracyclines, phenobarbital, and phenytoin all appear to increase with age [24]. The direct result of this immaturity of metabolic degradation of drugs is a prolonged drug half-life ([T.sub.1/2]), which is inversely correlated with clearance rate:

[T.sub.1/2] = 0.69 [V.sub.d]/clearance rate

Clinically, this means that in newborns and small infants, drugs that are metabolically eliminated tend to stay in the body longer. As a result, therapeutic concentrations and prevention of toxicity are achieved with lower unit doses, longer dose intervals, or both.

Renal elimination. Many drugs, including penicillins, cephalosporins, digoxin, and the aminoglycosides, are eliminated unchanged by the kidney. All of them are filtered in the glomerulus, whereas some of them are also reabsorbed and secreted by the tubular cell (e.g., penicillins, cephalosporins, and phenobarbital). At birth, both the glomerular filtration rate (GFR) and tubular secretion processes are reduced; filtration, however, is relatively more developed. The preterm infant has fewer glomeruli than the full-term neonate, who in fact has the same number as an adult [25-28]. The maturation process of kidney structure and function is associated with prolongation and maturation of the tubules, increase in renal blood flow, and improvement of filtration efficiency. In addition, blood flow is shifted from the deeper to the more superficial nephrons. Improvement of the GFR depends on both gestational and postnatal age. The rate of tubular secretion is similarly impaired, owing to poor perfusion and undeveloped energy supply. Generally, it takes 6-12 months for the various renal functions to reach adult values.

Investigators often assume that drugs that are metabolically inactivated by the liver are not influenced by reduced renal function. However, in most cases the metabolite--whether inactive or active--is eliminated by filtration and (or) tubular secretion in the kidney. With chloramphenicol, for example, the conjugated metabolite is mainly secreted by the renal tubules. Reduced tubular secretion in preterm infants could result in increased serum concentrations of the inactivated (conjugated) drug, such that subsequent intestinal [beta]-glucuronidase hydrolysis of the inactive metabolite would lead to increased enterohepatic recycling of the parent drug.

Knowledge of these dynamic principles is crucial in planning a rational dose schedule for drugs. In general, the preterm infant will need lower doses or longer dose intervals (or both) than the full-term infant to maintain similar steady-state concentrations. In short, the clinician must consider both the degree of maturation of renal function and possible disease or drug-induced (e.g., by aminoglycosides) impairment of renal elimination of antimicrobial drugs.

Specific Problems Associated with Drug Administration in Neonates and Infants

It is generally assumed that the intravenous route of drug administration guarantees proper delivery of the intended dose. This assumption cannot be taken for granted in the neonate and small infant. Slow infusion rates, various injection sites, variable injection volumes, and different relative densities (specific gravities) of injected solutions are some of the factors that may influence the rate and extent of intravenous administration of antimicrobial drugs. In addition, medication errors are probably more common in this age group than is generally appreciated.


Roberts was the first to draw attention to the importance of the infusion rate and portal of injection on the speed and completeness of drug administration by the intravenous route [29]. A full-term neonate receiving 100-140 mL of water per kilogram of body weight per day generally will require an infusion rate of 10-20 mL/h in the absence of oral intake. A preterm infant weighing <1 kg often will be receiving intravenous fluids at a rate of 3-5 mL/h. Gould and Roberts demonstrated that, at an infusion rate of 3 mL/h, actual infusion of drug begins 160 min after injection into the system close to the reservoir and will be complete only after 12 h [30]. This delay in the administration of a drug may compromise therapy. Drug administration will be faster when the portal for injection is closer to the neonate. In addition, if serum concentrations of the drug are being monitored, accurate timing will be difficult. Attempts to increase the infusion rate are often not possible: Infants in intensive care units receive an average of 10 intravenous doses per day [31] and therefore cannot tolerate an excessive infusion rate. In the original observations [30], the injection portals were not necessarily as close as possible to the infant. This problem can be minimized by injecting the drug at a closer site.

Delivery of drugs to neonates should utilize pumps calibrated to accurately deliver very small volumes. If desired, these small volumes can then be infused at a rate much higher than the maintenance infusion rate, thus guaranteeing rapid delivery in only a small volume of fluid. The volume in which the drug is prepared is another important factor [29]: the greater the volume, the more time required to deliver the full dose. Consequently, flow rate in conjunction with dosage volume will dictate the time needed for full delivery of a given dose.


Gould and Roberts drew attention to the fact that, owing to frequent intravenous set replacement, multiple-dose administration, and slow infusion rates in neonates, as much as 38% of the total drug doses intended could be lost in the discarded sets [30]. When a drug is discontinued, the physician should keep in mind the amount of drug still in the line; flushing the set with drug-free solution or changing the set will guarantee discontinuation of the drug delivery.


Filters are often connected to the intravenous tubing in neonatal units to clean the infusion fluid of bubbles, particles, and microorganisms. In 1975, however, Wagman et al. documented the binding of antimicrobial agents to filter devices [32]. In 1981, Rajchgot et al. noticed that subtherapeutic serum concentrations of gentamicin and cloxacillin were achieved in neonates given these drugs intravenously through a site proximal to a filter chamber [33]. Subsequent analysis has shown that drugs delivered by slow infusion rates tend to be sequestered in the filter according to their specific gravity; the higher the specific gravity (e.g., that for cloxacillin), the more likely is the drug to stay in the filter chamber.

After these findings, the manufacturer devised a new filter chamber to permit full delivery of injected drugs even with slow infusion rates. To avoid accumulation of the drug in the tubing during slow infusion rates, one injects the dose into a specially designed syringe chamber that permits any extra fluid to drain into a small additional bag. Only after the infusion volume first pushes the piston back to its original place is the infusion fluid able to pass the unidirectional valve; this guarantees propagation of the full dose without dilution through the filter chamber. Full recovery of injected doses of gentamicin and cloxacillin has been documented in studies in vitro [34]. In subsequent in vivo studies with 70 neonates serving as their own controls, we showed that concentrations produced by injecting the dose into the new device were comparable with those achieved by a direct intravenous bolus into the site nearest the neonate [35].


Neonates require very small doses of intravenous preparations. To meet the required dose, one often must dilute the stock solution. For example, if a neonate requires 2.5 mg of gentamicin from a 50 mg/mL stock solution (adult preparation), then 0.05 mL of the stock solution is required. Because dealing with such small injection volumes is difficult, the physician often dilutes this dose, e.g., by adding another 0.05 mL of isotonic saline. In such an instance, the dead space of the tuberculin syringe is filled as the 0.05-mL saline "pushes" gentamicin from the dead space into the syringe; the child is likely to receive more than the intended 2.5 mg. In a recent study, Berman et al. [36] demonstrated that, were digoxin to be diluted so, the dead space would increase an intended dose of 5 [micro]g to 12-18 [micro]g (average, 14 [micro]g). Thus, dilution of a very small-volume dose to increase accuracy results in potential overdosing. Similarly, a case of morphine toxicity attributable to "dilution intoxication" has been reported [37]. Roberts has calculated the effect of dilutional intoxication of several medications when prepared in this routine way [38].


The neglected problem of errors in administration of drug doses in pediatric patients has gained some publicity in the last decade. Perlstein et al. showed that ~8% of the calculations of drug volumes from a stock solution were erroneous, in many cases 10-fold higher or lower than the intended dose [39]. These results were confirmed in a subsequent study that demonstrated the existence of an "accident-prone" subgroup of health personnel who tended to perform significantly more computation errors than other staff members [40]. These subjects also had noticeably more errors in the 10-fold range. Although this finding of 3-6% for 10-fold calculation errors in a written test may seem excessive, a recent study from Britain reported a comparable incidence of 10-fold errors in administering intravenous acetylcysteine for acetaminophen toxicity [41].

Computational errors are not the only explanation for dosing errors. We recently reported a case of identical twins who, because the written order was misread, received two 50-mg doses of gentamicin instead of 5 mg. All appropriate staff should be aware of the appropriate dosages for neonates. The resulting acute renal failure took months to resolve, and it is too soon to evaluate the twins for potential ototoxicity [42]. Errors committed by parents of a sick infant are also likely if the intended dose is not clearly explained [42]. Pharmacy errors are less likely; pharmacists appear to be more knowledgeable and better trained in these matters than are nurses and physicians [39].

Because medication errors may result in morbidity and even mortality, various solutions to this issue have been suggested [42, 44]:

1) A written test for all personnel involved in the preparation of doses from stock solution. There is a good correlation between the results of these written tests [42] and the real-life occurrence rate [44]. Staff members who fail this test ought to be retrained before being allowed to prepare drug doses for infants.

2) Double-checking of calculations by two staff members. Statistically, if each person is computing the dose independently, the chance of an error should be decreased significantly; e.g., if each staff member has a 6% chance of making an error, the probability that both of them will make an error is 6% x 6% = 0.36%.

3) Use of standard tables of recommended dose and volume of stock solution of drugs given intravenously to neonates and small infants.

4) Preparation of patient-unit dose by clinical pharmacists, thus obviating errors by nursing staff and doctors. Although this system increases the financial burden, pharmacists are less likely to produce errors in their computations [41].

The common denominator of the specific problems delineated in this section is the very small doses of drugs given to neonates. Although the issues raised are not confined to antimicrobial drugs, antibiotics, in terms of number of doses, by far exceed all other medications used in the nursery [3]. Only well-trained personnel familiar with the appropriate doses for this age group and with effective methods to calculate them and to deliver them intravenously will be able to guarantee optimal antimicrobial therapy to small infants.

Practical Guidelines for Therapeutic Drug Monitoring in Neonates

Because of obvious ethical constraints, therapeutic drug monitoring in the neonate has to be performed with extreme caution under strict guidelines, ensuring both the effectiveness and safety of the process.


With blood volume of 80 mL/kg, a preterm infant of 500 g has only ~40 mL of blood. Moreover, because of higher hematocrit in infants, more blood has to be harvested to obtain similar volumes of plasma. Repeated sampling has been associated with neonatal anemia; therefore, only laboratories possessing micromethods with samples limited to 75 [micro]L or less should perform these tests in neonates. New automated instruments usually require <75 [micro]L of serum (including the dead space of the sample containers). It is strongly recommended that laboratories inform clinicians of the absolute minimal blood volumes needed for therapeutic drug monitoring, and clinicians drawing blood should obtain only the minimum volume their laboratory requires. Moreover, the neonatal intensive care unit should maintain a record of the amount of blood being drawn daily for each infant, so that excessive blood loss can be avoided.


The most common tests necessitating therapeutic drug monitoring in neonates are those for aminoglycosides and vancomycin (in suspected or proven sepsis), theophylline/caffeine (in neonatal apneas), digoxin (in congestive heart failure and supraventricular arrhythmias), and phenobarbital (in neonatal seizures and ischemic encephalopathy). Of these, only the digoxin assay should be available on a stat basis, given the availability of an antidote in case of life-threatening toxicity. Table 1 lists the drugs for which monitoring should be routinely available for neonates.

This work was supported by a grant from the Medical Research Council of Canada.

Received September 19,1996; revised November 4,1996; accepted November 5, 1996.


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[35.] Koren G, Rajchgot P, Harding E, Perlman M, MacLeod SM. Evaluating a filter device used for intermittent intravenous drug delivery to newborn infants. Am J Hosp Pharm 1985;42:106-8.

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[37.] Zenk KE, Anderson S. Improving the accuracy of mini-volume injections. Infusion 1982;7:Jan-Feb.

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Department of Paediatrics, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1XS, Canada, and the University of Toronto, Toronto, Ontario, Canada.
Table 1. Drugs that should be routinely monitored in neonates.

Drug Clinical condition Assay
 availability (a)

Aminoglycosides: gentamicin/ Sepsis, proven or Routine
tobramycin, mg/L suspected


Vancomycin, mg/L Sepsis, proven or Routine

Chloramphenicol, mg/L Sepsis, proven or Routine

Theophylline/caffeine, Neonatal apnea Routine

Digoxin, nmol/L ([micro]g/L) Congestive heart Stat & routine

Phenobarbital, Seizures; ischemic Stat & routine
[micro]mol/L (mg/L) encephalopathy

Drug In-lab Peak sampling
 TAT,h time h

Aminoglycosides: gentamicin/ <2 0.5
tobramycin, mg/L


Vancomycin, mg/L <2 0.5-1.0

Chloramphenicol, mg/L <2 4

Theophylline/caffeine, <2

Digoxin, nmol/L (lag/L) <0.5


Phenobarbital, <2 2 (d)
[micro]mol/L (mg/L)

 Drug concn.

Drug Therapeutic Critical
 windows values

Aminoglycosides: gentamicin/ Peak 6-8 nL >12
tobramycin, mg/L Trough <2

Amikacin Peak 20-30
 Trough <2.5-10

Vancomycin, mg/L Peak 25-40 >50
 Trough 5-10

Chloramphenicol, mg/L 7.5-14 (b) >25

Theophylline/caffeine, 27-55

Digoxin, nmol/L (lag/L) 1-2.6 >3.1

 (0.5-2.0) (>2.4)

Phenobarbital, 40-160 >250
[micro]mol/L (mg/L)
 (10-40) (>60)

TAT, turnaround time; IV, intravenous.

(a) All should be available 24 h/day.

(b) Decreased protein binding in neonates results in increased
unbound drug. A 4-h post-dose concentration of 7.5-14 mg/L in
neonates would achieve an unbound chloramphenicol concentration
equivalent to 10-20 mg/L (Koup JR, et al. Chloramphenicol
pharmacokinetics in hospitalized patients. Antimicrob Agents
Chemother 1979;15:651-7).

(c) Requires treatment with FAB.

(d) Two hours after the post-IV loading dose trough on day 3.
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Title Annotation:NACB Symposium
Author:Koren, Gideon
Publication:Clinical Chemistry
Date:Jan 1, 1997
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