Total Intravenous Anesthesia (TIVA) and Target Controlled Infusions (TCI) in Children

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1 Curr Anesthesiol Rep (2013) 3:37 41 DOI /s PEDIATRIC ANESTHESIA (J LERMAN, SECTION EDITOR) Total Intravenous Anesthesia (TIVA) and Target Controlled Infusions (TCI) in Children Neil S. Morton Published online: 18 December 2012 Ó Springer Science + Business Media New York 2012 Abstract Total intravenous anesthesia is increasingly used in children and in some situations is mandatory, for example in the child with malignant hyperthermia susceptibility. Propofol is most often used, either alone or concurrently with an opioid infusion. Pediatric dosing regimens have been calculated in small populations of healthy children and act as a guide for administration. Manual infusion schemes can be used quite effectively using conventional syringe drivers. Specifically programmed syringe drivers enable more careful titration to an estimated target concentration in blood or at the effect site using algorithms based upon pediatric pharmacokinetic data (target controlled infusion). In the future, more precise dosing and titration will be aided by near-real-time propofol analysis in blood or exhaled gases and further refinement of depth of anesthesia monitoring in children. Keywords Child Children Anesthesia Intravenous anesthesia TIVA Propofol Introduction It is important that pediatric anesthesiologists are able to safely use total intravenous anesthesia (TIVA) in children as there are clinical scenarios where its use is mandatory. This review describes the current state of knowledge about TIVA in children and highlights some advantages and problems. Drug regimens and delivery systems are N. S. Morton (&) Department of Anaesthesia, Royal Hospital for Sick Children, University of Glasgow, Glasgow G3 8SJ, Scotland, UK neilmorton@mac.com described and differences from adult practice are emphasised. Key references for further detailed reading are listed, which expand on pediatric pharmacokinetics of intravenous agents and the science underlying target-controlled infusion techniques. Potential Uses and Advantages of TIVA in Children TIVA techniques are mandatory where general anesthesia is to be given to a child with malignant hyperthermia susceptibility or where interpretation of evoked potential monitoring is crucial to outcome, for example use of motor evoked potentials during scoliosis correction. Propofol anesthesia, when properly managed, has the advantages of rapid smooth emergence with a minimum of airway complications and also provides a useful anti-emetic effect. So in those children at increased risk for postoperative nausea and vomiting or emergence delirium, a TIVA technique with propofol may be superior to one based on volatile anesthetic agents [1, 2]. Brief procedures and frequently repeated procedures are other indications. Some favour TIVA with propofol and opioids to control stress responses to major surgery, to control intracranial pressure and for endoscopic airway procedures. Problems with TIVA in Children An obvious practical problem in some children is gaining reliable venous access to deliver intravenous anesthesia. In some locations, topical local anesthetic may be applied before IV access is attempted whereas in others, anesthesia may have to be induced with sevoflurane (unless contraindicated) and IV access established only after anesthesia was induced [1].

2 38 Curr Anesthesiol Rep (2013) 3:37 41 Pain at the time of injection of propofol is a significant problem when TIVA is established in the awake child and preventative measures have been well researched now, although primarily in adults [3]. In children, admixture with or preinjection of lidocaine, preinjection of a short acting opioid, ketamine or thiopentone and the use of as large a vein as possible may attenuate the pain with injection. Of the newer formulations of propofol with different lipid compositions, microemulsions and cyclodextrins, only fospropofol has been shown to cause less pain on injection than the standard formulations. However, fospropofol is a water-soluble prodrug with a very slow onset of action. In some countries a 0.5 % (5 mg ml -1 ) concentration of propofol has recently become available, which has yet to be thoroughly researched in children. Prolonged propofol infusion at large doses can cause a syndrome of metabolic acidosis and myocardial toxicity due to lipid overload from the emulsion formulation (propofol infusion syndrome, PRIS) [4, 5]. To minimise the risks of PRIS in protracted cases, propofol and lipid sparing measures should be used, such as concurrent administration of opioids, other hypnotics such as midazolam or ketamine, and appropriate local or regional anesthesia. A 2 % (20 mg ml -1 ) propofol formulation is available in some countries, which immediately halves the lipid load but causes more severe injection pain than the usual 1 % (10 mg ml -1 ) preparation so preventative measures are essential [2]. Few studies have investigated the use of TIVA in young or sick children. Hence, extreme caution is needed if TIVA is planned for these vulnerable patients. Propofol does cause vasodilatation, and this necessitates particular care in septic children, in those who are hypovolemic, in some patients with congenital heart defects, and when vasodilator medications are administered concurrently because dangerous hypotension may occur. In some countries, target controlled infusion (TCI) does not have regulatory approval and appropriate delivery systems and pediatric software are not available, which limit its more widespread use [1]. Delivery Systems for TIVA in Children Manual Infusion Schemes Conventional syringe drivers may be used to create manual infusion schemes (see Table 1). A loading dose or infusion is given to try to quickly establish a clinically useful concentration at the effect-site in the brain, which is then maintained by a continuous infusion. The infusion rate is then titrated against vital signs, depth of anesthesia estimates and surgical stimuli. The proportions of hypnosis and analgesia can be individualised. Several calculations have to be made manually, and this can lead to errors. Manual infusion schemes do perform quite well clinically and have been evaluated in healthy children [6 10]. However, the pharmacokinetics and pharmacodynamics of all intravenous agents change as the child develops due to changes in body proportions and composition, regional blood flow and organ maturity and function [11, 12]. For example, the propofol infusion rate in healthy children between age 1 and 10 years of age is much greater than that in adults to maintain a desired effect site concentration. Manual infusion schemes tend to be based solely on body weight with limited allowance for the morbidly obese child or for developmental changes in important parameters such as drug clearance. Recent evidence suggests that propofol infusion rates in the obese patient are better determined by EEG-feedback rather than total body weight [13]. Target Controlled Infusion (TCI) TCI systems are based on the concept that a syringe driver can be programmed with software containing the mathematical Table 1 Drugs and dosing regimens for TIVA in children Drug Loading dose Maintenance infusion Propofol [6] In older children and adults Propofol [29] In children 1 mg/kg 10 mg/kg/h for 10 min, then 8 mg/kg/h for 10 min, then 6 mg/kg/h thereafter 1 mg/kg 13 mg/kg/h for 10 min, then 11 mg/kg/h for 10 min, then 9 mg/kg/h thereafter Alfentanil [30] lg/kg 1 5 lg/kg/min Remifentanil [14] a 0.5 lg/kg/min 0.25 lg/kg/min for 3 min Remifentanil [14] a lg/kg lg/kg/min over 1 min Sufentanil [14, 31] b lg/kg lg/kg/min Sufentanil [14, 31] b 1 5 lg/kg lg/kg/min Fentanyl [30] 1 10 lg/kg lg/kg/min Ketamine [30] 1 2 mg/kg mg/kg/h Midazolam 0.1 mg/kg 0.1 mg/kg/h a These regimens for remifentanil will produce plasma concentrations of approximately 5 10 ng ml -1 with the slower loading infusion recommended for the less fit patient. Larger loading doses and infusion rates may cause bradycardia and a reduction in cardiac output and muscle rigidity, especially if administered rapidly to the awake child b The smaller dose infusion regimen for sufentanil produces plasma concentrations of 0.2 ng ml -1 which results in sedation and analgesia while the larger infusion rates produce anesthesia and stress control at plasma concentrations in the range ng ml -1

3 Curr Anesthesiol Rep (2013) 3: descriptors of a three-compartment pharmacokinetic model (Fig. 1) appropriate for each drug, but also automatically incorporates key parameters appropriate for developmental age and body weight as defined by the user. For example, the Paedfusor algorithm for propofol TCI adjusts for the increase in drug clearance in younger children (Table 2). Most TCI systems target a predicted blood concentration and then impute an effect site concentration. The compartment sizes and microconstants describing intercompartment movement and elimination of the drug are incorporated into the calculations (Fig. 1) [2]. These parameters are derived from studies of relatively small numbers of healthy children, and at present the software cannot take account of the wide variability in pharmacokinetics and pharmacodynamics in healthy children, much less the sick child and the grossly overweight child. Thus TCI systems do need to be controlled by the anesthesiologist to individualise and titrate the target concentration to achieve the desired clinical endpoints, analogous to adjusting the inspired concentration for a volatile agent. The difficulty at present is that, unlike a volatile agent whose alveolar concentration can be easily measured and displayed in real time, there is no measure of the blood concentration of the IV drugs for display. For these drugs, we rely on estimates of the blood (and organ) concentrations derived from small populations, although for the individual child these estimates may not be precise [1, 10, 12, 14 17, 18, 19 21]. There have been great strides made to develop realtime propofol concentrations from the breath of patients similar to that used with volatile agents [22]. These remain under development. The current TCI delivery systems are not widely available for pediatric use despite having been evaluated in Table 2 Age-related pharmacokinetic parameters for propofol Age Vd (ml/ kg) detail and used frequently in centres in the UK and Europe. The available algorithms can be readily demonstrated using simulation software such as TivaTrainerÓ [23 ] which uses an animated hydraulic model to illustrate the pharmacokinetics and is a most useful teaching aid. TIVA and TCI in Practice Elimination half-life (min) 1 3 year 9, year 9, Adult 4, Clearance (ml/min/ kg) Propofol is the most commonly used drug, usually supplemented by an infusion of opioid. A loading infusion is given to induce anesthesia and the aim is to establish an anesthetic concentration at the effect site in the brain of around 3 lg ml -1. To do this expeditiously, an overpressure technique is used similar to that used with more soluble volatile agents. In a manual infusion technique, a bolus dose or infusion of 2 4 mg kg -1 propofol is administered during which time a TCI pump is infusing propofol to achieve a target blood concentration of 4 5 lg ml -1. Most TCI systems display the loading bolus dose as a useful cross-check. An excessive loading bolus will speed the induction of anesthesia, but it does so at the potential expense of causing hypotension and bradycardia. To minimise pain at the time of injection of propofol, one of the above strategies should Fig. 1 Three-compartment pharmacokinetic model

4 40 Curr Anesthesiol Rep (2013) 3:37 41 be used. If concerns exist that the patient s fitness or comorbidities may lead to side effects from the propofol, then a smaller bolus dose or reduced target concentration should be selected and the doses increased gradually as the vital signs tolerate and clinical endpoints are achieved. To maintain anesthesia, an effect site concentration of 3 lg ml -1 is reasonable, and this can be achieved by stepwise decrements in the manual infusion rate (see Table 1)or by adjusting the TCI pump to this target concentration, for which the pump would adjust automatically. Increases or decreases from the initial target are needed to accommodate changes in vital signs and surgical stimuli and towards the end of the case to ensure smooth, rapid recovery. For most drugs used for intravenous anesthesia, the greater the duration of an infusion, the more drug that accumulates in the poorly perfused body fat, which acts as a depot from which drug continuously and slowly is released into blood slowing the rate of recovery. The context-sensitive half-time (CSHT) describes this effect. A notable exception is remifentanil, for which the CSHT is independent of the duration of the infusion. Conclusions Anesthetic and analgesic agents act at effect sites in the brain and spinal cord, although it is important to appreciate that the effects do not have an instantaneous onset. A delay or lag in the delivery of the drug to the effect site is common when the intravenous route is used. This is described in TCI algorithms by the terms ke0, which is the rate constant for the effect-site compartment, or T1/2 ke0, which is the half-life for the effect-site. Recently, agespecific ke0 values have been described using bispectral index (BIS) and state entropy as a pharmacodynamic endpoints, which could be used to develop effect-site targeting of propofol in children [17, 24 28]. BIS has also been used in a prototype closed loop delivery system. Nearreal-time measurement of propofol in blood or exhaled gases is also currently under development and may allow for more accurate delivery and titration of IV propofol to individual patients by fine-tuning the TCI delivery system. Further refinement of pediatric depth of anesthesia monitoring is needed to improve the precision of titration of TIVA and TCI. TIVA and TCI competencies should be core competencies of all pediatric anesthesiologists and industry and regulatory authorities should support more widespread availability of TCI systems appropriate for pediatric patients. Disclosure No potential conflicts of interest relevant to this article were reported. References Papers of particular interest, published recently, have been highlighted as: Of importance 1. Lerman J. TIVA, TCI, and pediatrics: where are we and where are we going? Pediatr Anesth. 2010;20: Mani V, Morton NS. Overview of total intravenous anesthesia in children. Pediatr Anesth. 2010;20: Jalota L, Kalira V, George E, et al. Prevention of pain on injection of propofol: systematic review and meta-analysis. British Medical Journal, 2011:d Wolf A, Weir P, Segar P, et al. Impaired fatty acid oxidation in propofol infusion syndrome. Lancet. 2001;357: Vasile B, Rasulo F, Candiani A, et al. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med. 2003;29: Roberts FL, Dixon J, Lewis GT, et al. Induction and maintenance of propofol anaesthesia. A manual infusion scheme. Anaesthesia. 1988;43: McFarlan CS, Anderson BJ, Short TG. The use of propofol infusions in paediatric anaesthesia: a practical guide. Paediatr Anaesth. 1999;9: Engelhardt T, McCheyne AJ, Morton N, et al. Clinical adaptation of a pharmacokinetic model of plasma propofol concentrations in children. Pediatr Anesth. 2008;18: Schuttler JJ, Ihmsen H. Population pharmacokinetics of propofol: a 17 multicenter study. Anesthesiology. 2000;92: Sepulveda P, Cortinez LI, Saez C, et al. Performance evaluation of paediatric propofol pharmacokinetic models in healthy young children. Br J Anaesth. 2011;107: Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology. 1997;86: Rigby-Jones AE, Sneyd JR. Propofol in children what we know and what we do not know. Pediatr Anesth. 2011;21: La Collal L, et al. No adjustment vs. adjustment formula as input weight for propofol target-controlled infusion in morbidly obese patients. Eur J Anaesth. 2009;26: Absalom A, Struys MMRF. An overview of TCI and TIVA. Gent: Academia Press; Marsh B, White M, Morton N, et al. Pharmacokinetic model driven infusion of propofol in children.[see comment]. Br J Anaesth. 1991;67: Kataria BK, Ved SA, Nicodemus HF, et al. The pharmacokinetics of propofol in children using three different data analysis approaches. Anesthesiology. 1994;80: Rigouzzo A, Servin F, Constant I. Pharmacokinetic-pharmacodynamic modeling of propofol in children. Anesthesiology. 2010;113: Constant I, Rigouzzo A. Which model for propofol TCI in children. Pediatr Anesth. 2010;20: This is an excellent review of the available pharmacokinetic models for propofol in children. 19. Anderson BJ, Hodkinson B. Are there still limitations for the use of target-controlled infusion in children? Curr Opin Anesthesiol. 2010;23: Absalom A, Kenny GNC. Paedfusor pharmacokinetic data set. Br J Anaesth. 2005;95: Amutike D, Lal A, Absalom A, et al. Accuracy of the Paedfusor: a new propofol target-controlled infusion system for children. 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5 Curr Anesthesiol Rep (2013) 3: Hornuss C, et al. Time course of expiratory propofol after bolus injection as measured by ion molecule reaction mass spectrometry. Anal Bioanal Chem. 2012;403: Engbers F, Sutcliffe N, Kenny GNC. TIVA Trainer. 8.5 edn; This software is an excellent teaching aid and allows uploading of pediatric parameters to illustrate the subtelties of the three compartment pharmacokinetic model. It is available to download at main.htm 24. Jeleazcov C, Ihmsen H, Schmidt J, et al. Pharmacodynamic modelling of the bispectral index response to propofol-based anaesthesia during general surgery in children. British Journal of Anaesthesia. 2008;100: Hahn J-O, Khosravi S, Dumont G, et al. Two-stage vs mixedeffects approach to pharmacodynamic modeling of propofol in children using state entropy. Pediatric Anesthesia. 2011;21: Limb J, Morton NS. Age-specific effect-site TCI in children: modelling using TivaTrainer. Anaesthesia. 2010;65: Munoz HR, Cortinez LI, Ibacache ME, et al. Estimation of the plasma effect site equilibration rate constant (ke0) of propofol in children using the time to peak effect: comparison with adults. Anesthesiology. 2004;101: Tirel O, Wodey E, Harris R, et al. Variation of bispectral index under TIVA with propofol in a paediatric population. British Journal of Anaesthesia. 2008;100: Browne BL, Prys-Roberts C, Wolf AR. Propofol and alfentanil in children: infusion technique and dose requirement for total i.v. anaesthesia. Br J Anaesth. 1992;69: Shann F. Drug doses. 13th ed. Melbourne: Royal Children s Hospital; Glass PSA, Shafer SL, Reves JG. Intravenous drug delivery systems. In: Miller RD, editor. Anesthesia. 5th ed. New York: Churchill-Livingstone; p