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| The UK Society for Intravenous Anaesthesia |
| Based in the UK - as a resource for Anaesthesia Worldwide |
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TCI for children F. Engbers, MD, FRCA Leiden University Medical Center, The Netherlands Finding the appropriate dose of intravenous drugs in neonates and children is still a disputed area. Several approaches have been advocated to extrapolate the adult dose to the adequate dose for children. Many experts have pointed out that using the weight of the children as a lineair sizing model is probably the most inaccurate approach 3 4. Body composition and physiologic parameters like cardiac output and liver flow correlate better to Body Surface Area(BSA) and hence the BSA has been proposed many times as a better scaling parameter for intravenous drug dosing. The Dubois formula is used most widely for calculating the BSA, although it has been refined by others 4. For infants and neonates the relation between measured BSA and calculated BSA still seems to be less accurate because of the big morphologic differences between neonates and adults. Another method of scaling is based on allometric sizing models 3. This is derived from ecologic biology 1 where it has been shown that the metabolic rate of species is related to the weight of the subject raised to the power of ¾. Several attempts have been made to find a scientific base for this experimental rule and some biologists have even doubt that this rule is really universal. The allometric sizing model however is quite successful when applied to clearances of drugs as the clearance of a drug is metabolic rate related 3. But the approach will still fail when the elimination system is still immature like in neonates and infants. For opioids this is the first 3-6 months of live. Indeed if one looks at the clearance of for example morphine then the allometric sized clearance well corresponds with the adult clearance from 6 month on 3. The higher morphine requirements of children expressed as mg/kg disappears when the dose is normalized to BSA or using the allometric model. The same kind of relationship has been found for Fentanyl and Alfentanil. However clearance alone does not determine the appropriate dose of a drug. Distribution and steady state volumes may not follow allometric scaling rules and hence the allometric models may fail in predicting the appropriate dose3. For drugs that have matured elimination systems already at birth the relationship with the allometric size model must predict the clearance in even smaller subjects. We now have such a drug in anesthesia: Remifentanil. Remifentanil is hydrolyzed by non specific esterases in tissue and blood which are present abundantly even in newborns. We re-analyzed the data from one of the bigger pediatric pharmacokinetic studies involving 42 neonates, infants and children using a computer program for nonlinear mixed effect modeling (NONMEM).In the final outcome of the analysis the clearance for the whole population was best described by: 0.889*(weight/13.65)^0.76 Again a confirmation of the allometric sized model related to weight3/4 (=weight0.75) Whatever sizing model is selected it is considering neonates, infants and children as small adults which is not true because of the immaturity of many enzyme systems. Instead of trying to extrapolate intravenous drug dosing from adults to children using a scaling model it is much more logical to perform proper pediatric pharmacokinetic/pharmacodynamic research, build pharmacokinetic models and use computer controlled infusion devices like Target Controlled Infusion to use these models in clinical practice. The problem with pediatric pharmacological research apart from technical problems like limited blood sample size and difficult arterial/venous access is the problem with funding because it concerns a small sub population that is not very likely going to influence the market share of a pharmaceutical company. Furthermore it is often difficult to convince the medical ethical committees of the necessity of these kinds of studies. Last but not least experience with applying pharmacokinetic models for adult TCI systems teaches us that it is extremely important that models are scientifically validated in ‘TCI mode’ in clinical practice before they become publicly available. Most pharmacokinetic models that could be used for pediatric TCI have been developed for Propofol: The Kattaria8,Schuttler7 and ‘paedfusor’6 kinetic model. From these models only the paedfusor model has been prospectively tested in TCI mode5. Although pediatric pharmacokinetics have been investigated for the opioids used in anaesthesia: alfentanil fentanyl, sufentanil and remifentanil no scientific validation of using these drugs in TCI mode in pediatrics exists at this moment. Furthermore the way the pharmacokinetics are presented in most of the articles is not suitable for implementation in a TCI device. Apart from solving the pharmacokinetic problem there still exists the possible large difference in response to the drugs between the adult and pediatric population and maybe even a larger variability within the pediatric population. This is however a situation for which the anesthesiologist is trained to deal with. Furthermore using target controlled infusion will have an additional advantage as it will allow anesthesiologists to communicate information on the pharmacodynamic response of a specific pediatric subgroup in a much more sound and reproducible way. Drugs suitable for Target Controlled Infusion in children do not differ much from the selection in adults with the exception of remifentanil. Theoretically remifentanil should be the drug of choice for the very young: the neonates and infants9, when the elimation system for the other opioids is still in development phase. Like in adults good planning of how to deal with the postoperative pain is than important. The safety of the use of propofol in young children for longer periods like ICU sedation has been questioned after case reports of lethal acidosis and hyperlipaemia2. However in all of these reports propofol has been administered longer than 24 hours. The license of the drug for pediatric use hardly plays a role in this selection as there are only very few drugs licensed to be used in neonates and children and these licenses may vary from country to country. Of extreme importance in administering IV drugs in this population is the selection and care for the equipment. Using accurate pumps, small syringes one-way valves and multi-infusion access points to avoid dead space is of extreme importance for reliable and reproducible results. Experience with Target Controlled Infusion in adults and understanding the merits and limits of these devices is also important. Monitoring devices such as the Bispectral Index(BIS) have shown to decrease the incidence of awareness in adult patients while increasing the awareness of the anaesthesiologists for the effect of drug dosing and failure of equipment. It is certainly true that the BIS and most likely other ‘depth of hypnosis’ monitoring is less reliable in neonates and children11 and therefore not always suitable for guiding the target of a TCI system, but it will provide valuable information in the case of gross over- or underdosing of at least the hypnotic component and therefore in my opinion deserves serious consideration to be part of the monitoring.
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