Dr Ann E Rigby-Jones
email: ann.rigby-jones@pms.ac.uk

Robert Sneyd

we know and what we don't know

Keywords: propofol, children, pharmacokinetics, pharmacodynamics

The pharmacokinetics of propofol are relatively well-described in the pediatric population.

Recent work has confirmed the validity of allometric scaling for predicting propofol disposition across different species and for describing pediatric ontogenesis. In the first year of life, allometric models require adjustment to reflect ontogeny of maturation.

Pharmacodynamic data for propofol in children are scarcer, due to practical difficulties of data collection and the limitations of currently available depth of anesthesia monitors for pediatric use. Hence, questions relating to the comparative sensitivity of children to propofol, and differences in time to peak effect relative to adults, remain unanswered. K eo half-lives have been determined for pediatric kinetic models using time to peak effect techniques but are not currently incorporated into commercially available target controlled infusion pumps. Propofol injection pain remains a clinical problem, despite availability of propofol emulsions with a reduced free propofol concentration.

Pediatric pharmacokinetics

The pharmacokinetics of propofol are relatively well-described in children, having been investigated in healthy children [START_REF] Marsh | Pharmacokinetic model driven infusion of propofol in children[END_REF][START_REF] Saint-Maurice | Pharmacokinetics of propofol in young children after a single dose[END_REF][START_REF] Raoof | Propofol pharmacokinetics in children with biliary atresia[END_REF][START_REF] Jones | Pharmacokinetics of propofol in children[END_REF][START_REF] Kataria | The pharmacokinetics of propofol in children using three different data analysis approaches[END_REF], children with biliary atresia [START_REF] Raoof | Propofol pharmacokinetics in children with biliary atresia[END_REF], small children suffering from burns [START_REF] Murat | Pharmacokinetics of propofol after a single dose in children aged 1-3 years with minor burns. Comparison of three data analysis approaches[END_REF], critically ill ventilated [START_REF] Reed | A pharmacokinetically based propofol dosing strategy for sedation of the critically ill, mechanically ventilated pediatric patient[END_REF][START_REF] Rigby-Jones | Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit[END_REF] and non-ventilated children [START_REF] Peeters | Propofol pharmacokinetics and pharmacodynamics for depth of sedation in nonventilated infants after major craniofacial surgery[END_REF] and neonates [START_REF] Allegaert | Inter-individual variability in propofol pharmacokinetics in preterm and term neonates[END_REF][START_REF] Allegaert | Maturational pharmacokinetics of single intravenous bolus of propofol[END_REF]. Propofol disposition is generally best described by a 3-compartment mamillary model, with a rapidly equilibrating central compartment, a second larger peripheral compartment and a third, very large peripheral compartment. Propofol pharmacokinetics are altered in children, compared to adults. Comparative analyses have demonstrated that on a per kilogram body weight basis, children demonstrate increased clearance and larger volumes of distribution relative to adults. In particular, the volume of the central compartment is much greater than in adults [START_REF] Schuttler | Population pharmacokinetics of propofol: a multicenter study[END_REF]. Consequently, children require higher induction and maintenance doses than adults to achieve the same propofol blood concentration.

The influence of the larger central compartment volume in children can be explored using pharmacokinetic simulation. Figure 1 compares the concentration versus time profile resulting from a one hour propofol infusion (4mg kg -1 hr -1 ) administered to an adult (Diprifusor kinetics [START_REF] Marsh | Pharmacokinetic model driven infusion of propofol in children[END_REF][START_REF] Gepts | Disposition of propofol administered as constant rate intravenous infusions in humans[END_REF]) or to a 20kg child (Kataria kinetics (5)). The larger central compartment volume in children results in markedly reduced propofol plasma concentrations, relative to the adult.

Disentangling covariate effects

The evaluation of drug disposition in heterogeneous patients groups, such as those encountered in the pediatric ICU, can be complicated by the presence of confounding factors. How can one separate the influences that critical illness may have on pharmacokinetics, from the affects of body size and maturity? Body size and age are usually well correlated in pediatric populations. Allometric scaling is a useful and wellsupported [START_REF] Anderson | Population clinical pharmacology of children: modelling covariate effects[END_REF] approach to disentangle body size effects from other correlated covariables, such as age, in pediatric populations. Allometric scaling relates body mass to metabolic rate (and hence, to drug clearance) using Kleiber's Law. In 1932, Kleiber demonstrated that basal metabolic rate was proportional to body mass raised to the power 0.75, and that this relationship applied to animals ranging in size from a mouse to a whale [START_REF] Kleiber | Body size and metabolism[END_REF]. When deriving pharmacokinetic data from pediatric populations, if weight is selected as a initial covariate and the three-quarter power relationship applied a priori (to clearance parameters; volume parameters are scaled to the power of 1), this allows the influence of secondary covariates, which may be correlated to weight e.g. age, to be examined [START_REF] Anderson | Mechanistic basis of using body size and maturation to predict clearance in humans[END_REF]. Knibbe and colleagues explored the application of allometric scaling to propofol pharmacokinetic parameters obtained from rats, children (aged from 1 to 5 years) and adults [START_REF] Knibbe | Allometric relationships between the pharmacokinetics of propofol in rats, children and adults[END_REF]. This work demonstrated the validity of the allometric approach for predicting drug disposition across different species and for describing within-species ontogenesis, Figure 2.

A recent publication by the same group has focused on defining the human body weight range for which allometric scaling can accurately be applied to predict propofol clearance [START_REF] Peeters | Prediction of propofol clearance in children from an allometric model developed in rats, children and adults versus a 0.75 fixedexponent allometric model[END_REF]. Allometric scaling alone could accurately predict propofol clearance in children older than 2 years. However, adjustment of the model to reflect maturation was required to predict clearance in children younger than 24 months, a demonstration that simple allometric scaling reveals, but does not account for, age-related differences in pharmacokinetics.

Propofol in neonates

The work of Allegaert and colleagues in recent years has done much to inform propofol disposition and metabolism in term and pre-term neonates. Allegaert described markedly reduced clearance in a group of nine neonates (4-25 days postnatal age) after bolus injection of propofol [START_REF] Allegaert | Maturational pharmacokinetics of single intravenous bolus of propofol[END_REF]. After appropriate allometric scaling to 70kg to allow comparison, the clearance value was approximately 32%, and the volume of distribution at steady-state was approximately 44% of the corresponding values previously reported in infants . Scaled propofol clearance rates approach adult values within the first three months to one year of life [START_REF] Murat | Pharmacokinetics of propofol after a single dose in children aged 1-3 years with minor burns. Comparison of three data analysis approaches[END_REF][START_REF] Shangguan | Pharmacokinetics of a single bolus of propofol in chinese children of different ages[END_REF], mirroring ontogenic development of hepatic enzyme systems [START_REF] Alcorn | Ontogeny of hepatic and renal systemic clearance pathways in infants: part I[END_REF].

For infants and older children, the inclusion of body weight alone as a model covariate accounts for much of the observed inter-individual variability in propofol pharmacokinetics [START_REF] Kataria | The pharmacokinetics of propofol in children using three different data analysis approaches[END_REF][START_REF] Rigby-Jones | Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit[END_REF][START_REF] Peeters | Propofol pharmacokinetics and pharmacodynamics for depth of sedation in nonventilated infants after major craniofacial surgery[END_REF][START_REF] Shangguan | Pharmacokinetics of a single bolus of propofol in chinese children of different ages[END_REF]. Allegaert has demonstrated that for neonates post-menstrual and post-natal age as markers of maturity, rather than body weight, were the most influential factors, with the youngest babies having the smallest clearance values. Anderson (21) further explored this finding, combining Allegaert's neonatal clearance data with clearance values derived from older children [START_REF] Kataria | The pharmacokinetics of propofol in children using three different data analysis approaches[END_REF][START_REF] Murat | Pharmacokinetics of propofol after a single dose in children aged 1-3 years with minor burns. Comparison of three data analysis approaches[END_REF] and adults [START_REF] Gepts | Disposition of propofol administered as constant rate intravenous infusions in humans[END_REF][START_REF] Schnider | The influence of age on propofol pharmacodynamics[END_REF][START_REF] Struys | Influence of administration rate on propofol plasma-effect site equilibration[END_REF]. A sigmoid E max model was then applied to describe the maturation profile, Figure 3. In this analysis, the maturation half-time was calculated as 44 weeks. Anderson highlights the need for additional study of propofol disposition in infants to fully characterise the maturation profile in the first two years of life. Propofol infusion syndrome (PRIS) was first described in the literature in 1992 [START_REF] Parke | Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports[END_REF]. Shortly after, the syndrome was defined by Bray and colleagues as a sudden onset of treatmentresistant bradycardia leading to asystole, combined with at least one of the following symptoms; lipaemic plasma, clinically enlarged or fat infiltrated liver, metabolic acidosis or rhabdomylosis [START_REF] Bray | Propofol infusion syndrome in children[END_REF]. The syndrome was associated with long duration (more than 48 hours), high dose (more than 4 mg kg -1 hr -1 ) propofol infusions in children under 12 years old. In 2001, reports of the same propofol-related syndrome occurring in adult ICU patients [START_REF] Cremer | Long-term propofol infusion and cardiac failure in adult head-injured patients[END_REF] led to the UK Commission on Human Medicines (then Commission on Safety of Medicines) to recommend that propofol infusion rates for sedation did not exceed 4 mg kg -1 hr -1 [START_REF] Mca/Csm | Long term, high dose propofol (Diprivan) infusion[END_REF]. In the following year, the same committee announced the contraindication of propofol for the sedation of critically ill children [START_REF] Mca/Csm | Clarification: Propofol (Diprivan) infusion contraindication[END_REF].

Eight years later, what have we learned about PRIS? We know that it is a real phenomenon, with the consistency of clinical reports of the syndrome, the dose-dependency and the temporal association to propofol administration cited as reasons to strongly support a causal relationship [START_REF] Fudickar | Propofol infusion syndrome: update of clinical manifestation and pathophysiology[END_REF]. Plausible mechanisms have been suggested supporting the implication of the lipid component of currently availably propofol formulations in the pathology of the syndrome [START_REF] Wolf | Impaired fatty acid oxidation in propofol infusion syndrome[END_REF][START_REF] Withington | A case of propofol toxicity: further evidence for a causal mechanism[END_REF]. Whether a lipid-free propofol formulation, such as fospropofol, would decrease the risk of PRIS, or avoid it entirely, is as yet unknown. However, the potential for direct toxicity related to propofol itself, rather than the vehicle, would remain [START_REF] Schenkman | Propofol impairment of mitochondrial respiration in isolated perfused guinea pig hearts determined by reflectance spectroscopy[END_REF].

In recent years, use of propofol sedation in critically ill children in the UK has been extremely limited in line with current recommendations [START_REF] Jenkins | Current United Kingdom sedation practice in pediatric intensive care[END_REF]. The knowledge base regarding the disposition of propofol in the critical care population is hence based on studies carried out prior to the 2002 contraindication. Reed and colleagues were first to study propofol disposition in a critically ill pediatric population, ranging from neonates to age 15 years [START_REF] Reed | A pharmacokinetically based propofol dosing strategy for sedation of the critically ill, mechanically ventilated pediatric patient[END_REF].

They concluded that the pharmacokinetics were not dissimilar to studies of healthy children but described substantial inter-patient variability that could not be attributed to age or other demographic effects. Rigby-Jones et al [START_REF] Rigby-Jones | Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit[END_REF] clearance values were reported to be twice as high as those previously described in paediatric intensive care unit (PICU) patients [START_REF] Rigby-Jones | Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit[END_REF], emphasising the impact that mechanical ventilation and cardiac bypass have on propofol elimination during post-operative sedation.

Pediatric Propofol Target Controlled Infusion (TCI)

There are at least two pediatric pharmacokinetic models for propofol available for use in commercially available TCI pumps; the Paedfusor [START_REF] Absalom | Accuracy of the 'Paedfusor' in children undergoing cardiac surgery or catheterization[END_REF][START_REF] Absalom | Paedfusor' pharmacokinetic data set[END_REF] and the Kataria kinetic set [START_REF] Kataria | The pharmacokinetics of propofol in children using three different data analysis approaches[END_REF]. [START_REF] Absalom | Accuracy of the 'Paedfusor' in children undergoing cardiac surgery or catheterization[END_REF]. In this small study, the Paedfusor model's predictive performance was well within acceptable limits for clinical use.

A formal prospective analysis of the predictive performance of the Kataria model in children has not been published to date. However, a study by Rigouzzo and colleagues involved TCI administration of propofol to children (aged 6 to 13 years) using the Kataria model. Blood samples for propofol plasma assay were collected [START_REF] Rigouzzo | The relationship between bispectral index and propofol during target-controlled infusion anesthesia: a comparative study between children and young adults[END_REF]. It was reported that measured concentrations of propofol were consistently higher than those predicted by the Kataria model, and that the margin of error increased with increasing propofol concentration.

The original analyses leading to the derivation of the Kataria and Paedfusor models were based on pharmacokinetic data only. However, values for K e0 , the blood-brain equilibration rate constant have been retrospectively generated for both models using the Time to Peak effect (t peak ) (37) technique [START_REF] Munoz | Estimation of the plasma effect site equilibration rate constant (ke0) of propofol in children using the time to peak effect: comparison with adults[END_REF]. T peak is a model-independent pharmacodynamic parameter that can be used to calculate a K e0 value for a given pharmacokinetic set, after administration of a sub-maximal dose. The K e0 value derived is one that accurately predicts t peak [START_REF] Minto | Using the time of maximum effect site concentration to combine pharmacokinetics and pharmacodynamics[END_REF]. Muñoz's analysis revealed that the peak effect of propofol in children (132s) occurs far later than in adults (80s). The explanation offered for this finding is that, relative to adults (Schnider model), simulations using the pediatric model demonstrate a much The experimentally derived t peak value of 132s extrapolated to a K e0 value for the Kataria model of 0.41min -1 and for the Paedfusor model, 0.91min -1 . However, current commercially available TCI devices incorporating the Kataria and Paedfusor models do not include K e0 i.e. plasma is the target of the infusion, rather than the effect site, thus depriving pediatric populations from the superior control offered by effect site targeting systems [START_REF] Wakeling | Targeting effect compartment or central compartment concentration of propofol: what predicts loss of consciousness?[END_REF][START_REF] Struys | Comparison of plasma compartment versus two methods for effect compartment--controlled target-controlled infusion for propofol[END_REF][START_REF] Mortier | Effect site modelling and its application in TCI[END_REF].

Pediatric Pharmacodynamics (PD)

Whilst the pharmacokinetics of propofol in the pediatric population are reasonably welldescribed, there is a relative paucity of pharmacodynamic data [START_REF] Peeters | Propofol pharmacokinetics and pharmacodynamics for depth of sedation in nonventilated infants after major craniofacial surgery[END_REF][START_REF] Munoz | Estimation of the plasma effect site equilibration rate constant (ke0) of propofol in children using the time to peak effect: comparison with adults[END_REF][START_REF] Cortinez | Pharmacodynamics of propofol in children and adults: comparison based on the auditory evoked potentials index[END_REF].

Limitations of Pediatric PD studies

Undertaking pharmacodynamic studies can be very difficult in children and particularly so in intensive care medicine. In a "real life" scenario, rather than a controlled volunteer study in adults, it is often difficult or impossible to obtain data describing a full drug concentration versus effect profile. This is required for adequately quantifying hysteresis and hence, the derivation of K e0 . Arterial blood, the gold-standard matrix for sampling during PK-PD studies of rapidly acting drug compounds, is highly unlikely to be available for children outside of critical care. The insertion of a peripheral arterial line in children purely for research purposes is classified as high risk and cannot be justified [START_REF] Hull | Guidelines for the ethical conduct of medical research in children[END_REF], further, arterial line insertion is typically done after induction of anesthesia and the opportunity to populate the rising phase of the hysteresis loop is lost. The use of venous blood sampling during pediatric pharmacodynamic studies of intravenous sedative-hypnotics presents a limitation that can in part be overcome by careful study design, such as the incorporation of equilibration stages to accompanying changes in infusion rate. This stabilises arterial and venous blood concentrations and minimises arterio-venous differences as far as possible.

The use of intermittent pharmacodynamic markers, such as sedation scores, can also make it more difficult to capture rapidly changing drug effects. However, for extended continuous infusion studies, COMFORT scores (44) can provide useful information and have been successfully utilised as pharmacodynamic markers for the development of complex but clinically informative models of propofol pharmacodynamics [START_REF] Peeters | Propofol pharmacokinetics and pharmacodynamics for depth of sedation in nonventilated infants after major craniofacial surgery[END_REF]. Other limitations of Additionally, researchers are unlikely to be able to study single drug effects in children.

Hence, there is a need for pragmatism regarding the concomitant administration of other drugs with sedating effects when evaluating propofol pharmacodynamics, such as maintaining opioids infusions at a constant rate, so adjunct drug contribution to pharmacodynamic effects are at least unchanging after a period of equilibration [START_REF] Murray | Electroencephalograph variables, drug concentrations and sedation scores in children emerging from propofol infusion anaesthesia[END_REF]. In another strategy to deal with multiple drug effects, Jeleazcov and colleagues assumed additive interactions between propofol and co-administered opioids to derive pharmacodynamic parameter values for each drug based on their combined sedative effect, when measured using bispectral index (BIS) [START_REF] Jeleazcov | Pharmacodynamic modelling of the bispectral index response to propofol-based anaesthesia during general surgery in children[END_REF]. They studied 59 children aged from 1 to 16 years undergoing general surgery. A two-stage pharmacodynamic analysis revealed an age-dependency of the K e0 value for propofol, with K e0 decreasing with increasing age. T peak , however, showed a trend of increasing with age. These findings may reflect true agedependent differences in propofol pharmacodynamics. Cortinez and colleagues have suggested that children may be more sensitive to propofol than adults, based on higher calculated CE 50 values in adults than in children (3 to 11 years), resulting from a study examining auditory evoked potentials (AEP) following a sub-maximal bolus propofol dose [START_REF] Cortinez | Pharmacodynamics of propofol in children and adults: comparison based on the auditory evoked potentials index[END_REF]. However, a second study by the same group which determined propofol effect site concentrations at BIS value = 50 in adults and in children aged 3 to 11 did not demonstrate significant differences in propofol requirements [START_REF] Munoz | Effect site concentrations of propofol producing hypnosis in children and adults: comparison using the bispectral index[END_REF]. In contrast, Rigouzzo et al suggested that children may be less sensitive than adults to propofol. In their study of 45 children (6 to 13 years) and 45 adults anaesthetised with TCI propofol, children demonstrated higher measured and predicted propofol plasma concentrations at a BIS value of 50 than the adult patients [START_REF] Rigouzzo | The relationship between bispectral index and propofol during target-controlled infusion anesthesia: a comparative study between children and young adults[END_REF]. Conflicting results from such studies may be in part related to the choice of depth of anesthesia monitor, and differences in the pharmacokinetic models used to administer propofol and/or predict effect site concentrations.

Recently, a second smaller study by Rigouzzo and colleagues attempted to identify the best model for describing propofol PK-PD in pre-pubertal children [START_REF] Rigouzzo | Pharmacokinetic-pharmacodynamic modeling of propofol in children[END_REF]. Propofol was administered to pre-pubertal children (n=16, 6-12 years) by TCI using the Kataria model ( 5), and to adults and post-pubertal children (n=13, 13-35 years) using the Schnider model [START_REF] Schnider | The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers[END_REF].

BIS was used as an effect measure. The recorded BIS data from the pre-pubertal group was then compared to predicted propofol concentrations generated using several pharmacokinetic models; the Kataria model used to administer propofol but also the Marsh (1), Schuttler [START_REF] Schuttler | Population pharmacokinetics of propofol: a multicenter study[END_REF] and Schnider models, to evaluate which model best described the data.

BIS data from the post-pubertal/adult cohort was compared to predicted concentrations generated by the Schnider model only. The analysis revealed that the pre-pubertal BIS versus predicted propofol concentration was best described by the adult Schnider model so in a second stage of the analysis, the two cohorts were pooled so that the influence of puberty on propofol pharmacodynamic parameter estimates could be examined. The authors hypothesise that the lack of early sampling in the studies that led to the derivation of the paediatric models tested, may explain their perceived weakness at describing the initial phase of propofol distribution kinetics, and hence, the effect on BIS. Additionally, the Schnider model is unique among those explored in Rigouzzo's analysis in that both age and lean body mass are included as covariates, thus allowing a more precise tailoring of individual predicted propofol concentrations. Analysis of the pooled data from both cohorts using the Schnider model revealed that pubertal status was a significant pharmacodynamic model covariate with both K eO and Ce 50 varying between children and adults. The typical value of Ce 50 was around 20% higher in children than in adults. Tpeak was subsequently derived and found to be significantly shorter in children at 0.71 min [0.37-1.64] median

[range] versus 1.73 [1.4-2.68] min in adults. This is in contrast to the findings by Munoz [START_REF] Munoz | Estimation of the plasma effect site equilibration rate constant (ke0) of propofol in children using the time to peak effect: comparison with adults[END_REF], which the authors suggest may relate to differences in effect measure (BIS versus AEP) and methodological differences, including the use of different pharmacokinetic models. The shorter T peak in younger children supports the findings of Jeleacov and colleagues [START_REF] Jeleazcov | Pharmacodynamic modelling of the bispectral index response to propofol-based anaesthesia during general surgery in children[END_REF].

Propofol, BIS & Children

The technology of BIS monitoring is based on an algorithm developed from adults, hence its usefulness as a measure of anaesthetic depth in children, and particularly in infants, has long been questioned [START_REF] Watcha | Investigations of the bispectral index monitor in pediatric anesthesia: first things first[END_REF]. Subsequent studies evaluating the relationship between the bispectral index and established sedation measures such as the Observer's Assessment of Alertness/Sedation (OAA/S) and the University of Michigan Sedation Scale (UMSS) have provided evidence that BIS monitoring can be a useful measure of intravenous sedation in children older than 2 years (51) [START_REF] Overly | Bispectral analysis during pediatric procedural sedation[END_REF]. Currently, evidence to suggest that any of the alternative depth of anesthesia monitors is more or less suitable than BIS for use in children is limited [START_REF] Davidson | Monitoring the anaesthetic depth in children -an update[END_REF][START_REF] Wallenborn | Comparative evaluation of Bispectral Index and Narcotrend Index in children below 5 years of age[END_REF][START_REF] Klockars | Spectral entropy as a measure of hypnosis in children[END_REF].

Prospective BIS monitoring of children (n=12, 1-12 years) in PICU was performed to investigate the incidence of over-sedation and periods of potential awareness during [START_REF] Tobias | Bispectral index monitoring during the administration of neuromuscular blocking agents in the pediatric intensive care unit patient[END_REF]. Children were sedated with either midazolam or propofol infusions, with supplemental doses of midazolam, fentanyl or morphine provided if additional sedation was deemed necessary, based on physiological parameters. The BIS monitor was concealed from clinical staff. During the 476 hours of sedation studied, over-sedation (BIS<50) occurred 35% of the time, and under-sedation (periods of potential awareness, BIS>71) comprised 8% of the time. Over-sedation was more likely to occur in patients sedated with propofol, than with midazolam (p<0.0001. There are several limitations to this study, not least the small cohort and the assumption that BIS is a 'gold standard' measure of sedation in the patients studied. However, the study results suggest the need for a larger prospective trial to establish the benefit of BIS-titrated sedation in pediatric patients during the use of neuromuscular blocking agents.

Recently, Tirel and colleagues (57) used TCI propofol to evaluate the relationship between age and BIS values, in a group of children aged from 3 to 15 years. Target propofol plasma concentrations were held at 6, 4 and 2µg mL -1 during periods without surgical stimulation to allow collection of BIS and raw EEG. In this study, there was no statistically significant difference in BIS values at 4 and 6µg mL -1 . BIS values at 2µg mL -1 were significantly different to those achieved at the higher target concentrations but were also correlated with the age of the children (r 2 =0.66), with the highest BIS values being recorded in the youngest children. Tirel et al suggest this may reflect a true pharmacodynamic difference between younger and older children, or could be influenced by the underlying pharmacokinetics. The Kataria model used for TCI does not include age as a covariate after it was demonstrated that its inclusion only marginally improved the model.

Park et al [START_REF] Park | Changes of bispectral index during recovery from general anesthesia with 2% propofol and remifentanil in children[END_REF] investigated the relationship between BIS values and predicted plasma propofol concentrations in 30 children aged from 2 to 7 years during emergence from anesthesia. The Marsh model was used to administer TCI propofol [START_REF] Marsh | Pharmacokinetic model driven infusion of propofol in children[END_REF]. On completion of surgery, the target propofol concentration was reduced from 3µg mL -1 in 0.2µg mL -1 steps and BIS values were recorded. The authors concluded that BIS was correlated with predicted propofol concentration during emergence from anesthesia but that the correlation was weaker than that observed with an adult population. Additionally, there was substantial interindividual variability in the recorded BIS values at each predicted concentration.

These studies suggest caution when using BIS to titrate propofol infusions in children and demonstrate a lack of sensitivity of the BIS system to discriminate at deep sedation levels in children.

Pain on injection

Whilst propofol injection pain is highly unpleasant for adults, it becomes a real clinical problem when the drug is administered to children. Injection pain causes severe distress to the patient and often to an accompanying parent. Children are more susceptible to propofol induced pain than adults, with younger children likely to experience more severe pain than older children [START_REF] Cameron | The minimum effective dose of lignocaine to prevent injection pain due to propofol in children[END_REF].

The addition of adjuvant drugs has been explored, with ketamine (60), lidocaine [START_REF] Cameron | The minimum effective dose of lignocaine to prevent injection pain due to propofol in children[END_REF] and thiopental [START_REF] Cheng | Injection pain with propofol: the effectiveness of thiopentone on induction[END_REF] all demonstrating some efficacy at reducing injection pain. It has been argued that if the use of adjuvant drugs for the reduction of propofol injection pain is to be recommended, their use must be evaluated from a medical risk-benefit perspective [START_REF] Akeson | Pain on injection of propofol -why bother?[END_REF] .

Propofol injection pain may be related to the concentration of free propofol in the formulation [START_REF] Klement | Pain on injection of propofol: effects of concentration and diluent[END_REF] and direct dilution of propofol prior to administration has been reported to reduce the incidence of injection pain in children [START_REF] Soltesz | Effect of a 0.5% dilution of propofol on pain on injection during induction of anesthesia in children[END_REF]. The free propofol concentration is reduced in medium chain triglyceride (MCT)/long chain triglyceride (LCT) mixtures, relative to formulations containing only LCT [START_REF] Yamakage | Changes in concentrations of free propofol by modification of the solution[END_REF]. Theoretically, this should lead to a reduction in injection pain. However, in practice, there have been contradictory findings in adults relating to the proposed reduction in pain [START_REF] Sundarathiti | A comparison of propofol-LCT with propofol-LCT/MCT on pain of injection[END_REF][START_REF] Burimsittichai | Pain on injection of propofol: propofol LCT vs propofol MCT/LCT with or without lidocaine pretreatment[END_REF][START_REF] Allford | Discomfort on injection: a comparison between two formulations of propofol[END_REF][START_REF] Suzuki | Propofol formulated with long-/medium-chain triglycerides reduces the pain of injection by target controlled infusion[END_REF][START_REF] Kinoshita | The injection pain of propofol with different emulsion[END_REF]. Certainly, MCT-LCT propofol is associated with pain in children when injected without an adjunct drug. Nyman and colleagues injected either a plain solution of 3mg/kg MCT-LCT propofol or LCT propofol with added lidocaine (1mL of 1%) randomly to a group of 83 children (2-18 years). The incidence of injection pain was higher with the MCT-LCT group (66.6%) than in the LCT-propofol/lidocaine group (39.0%) [START_REF] Nyman | Propofol injection pain in children: a prospective randomized double-blind trial of a new propofol formulation versus propofol with added lidocaine[END_REF]. A recent study of 84 children aged from 5 to 15 years reported no difference in the incidence or severity of pain when either pre-mixed lidocaine (1mL of 2%) and either a long chain triglyceride (LCT) propofol emulsion combination, a MCT/LCT propofol emulsion (20mL of 1%) combination were injected [START_REF] Varghese | Does the newer preparation of propofol, an emulsion of medium/long chain triglycerides cause less injection pain in children when premixed with lignocaine?[END_REF]. This indicates that in pediatric clinical practice, there may be little difference in the experience of injection pain with different propofol emulsions. There is, however, good evidence for the effectiveness lidocaine (1mL of 1%) combined with 10mL of a medium chain triglyceride (MCT) propofol formation for eliminating injection pain in pre-school children [START_REF] Rochette | Avoiding propofol injection pain in children: a prospective, randomized, double-blinded, placebo-controlled study[END_REF].

Conclusion

This review has sought to identify current gaps in the knowledge base of propofol use in the pediatric population, in particular, aspects relating to drug disposition and pharmacodynamic effect. Updated information on issues that impact on day-to-day clinical practice, such as injection pain and PRIS were also considered.

There are comprehensive data describing propofol disposition across the pediatric age range, as a result of much needed research in the neonatal population in recent years. In addition, based on demonstration of the applicability and limitations of allometric scaling, there is now better understanding of the mechanisms and predictability of changes in propofol pharmacokinetics from birth to maturity.

Given the practical restrictions described, and the continued lack of a gold-standard depth of anesthesia monitor for children, it is not surprising that much remains to be elucidated regarding the pharmacodynamics of propofol in the pediatric population. Indeed, the knowledge base relating to adult propofol pharmacodynamics has its own limitations, with genuine disagreement about the most appropriate values for time to peak effect and t 1/2 k eO (74,[START_REF] Absalom | Pharmacokinetic models for propofol--defining and illuminating the devil in the detail[END_REF].

5 Pediatric

 5 Critical Care & Propofol Infusion Syndrome

  described altered kinetics in very small babies (due to increased peripheral distribution volume) and reduced metabolic clearance in children recovering from cardiac surgery, both findings leading to prolonged propofol elimination times, see Figure2. Body weight was the most influential model covariate and although a broad age range was studied (1 week to 12 years), no additional influence of age could be supported. In a non-ventilated, post-neurosurgical pediatric population[START_REF] Peeters | Propofol pharmacokinetics and pharmacodynamics for depth of sedation in nonventilated infants after major craniofacial surgery[END_REF] propofol

The

  Kataria model is based on data from 53 healthy children, ranging in age from three to 11 years. Mean post-dose sampling duration was 214 minutes (range 52 to 811). The Paedfusor pharmacokinetic set was derived as a preliminary model (presumably based on pediatric data only) by Schuttler and Ihmsen during their development of a pharmacokinetic model based on pooled data from both adults and children (12). In Schuttler's analysis, pediatric data comprised 96 children aged from two to 11 years, including the patient population on which Kataria's model was based (5) and data from two further pediatric studies (1, 2). The Paedfusor model was prospectively validated in 29 children (1 to 15 years) undergoing cardiac surgery or cardiac catheterisation procedures

  initial decline in plasma propofol concentrations, Figure4. As the post-bolus t peak is the consequence of both decreasing plasma concentration and increasing effect site concentration, this is a plausible mechanism.

8 sedation

 8 scoring as a pharmacodynamic marker are inter-and intra-observer variance and the impact that stimulation required as part of a scoring system may have on the underlying depth of sedation.

14 Figure 2 Figure 3

 1423 Figures

Figure 4 F

 4 Figure 4

Figure 1 Simulation

 1 Figure 1Simulation of the concentration versus time profile resulting from a one hour propofol infusion (4mg kg -1 hr -1 ) administered to a 20kg child, using three different pharmacokinetic models. Diprifusor kinetics (adult)(1, 13), Kataria (pediatric)[START_REF] Kataria | The pharmacokinetics of propofol in children using three different data analysis approaches[END_REF] and Rigby-Jones (pediatric, post-cardiac surgery)[START_REF] Rigby-Jones | Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit[END_REF]. The Diprifusor kinetics are linearly weight-scaled, hence the predicted profile shown would apply to any given body weight, adult or child.

Figure 2 Evidence

 2 Figure 2 Evidence for applicability of allometric scaling of propofol pharmacokinetic parameters. Plots show clearance (upper left), intercompartmental clearance (upper right), volume of the central compartment (lower left) and volume of the peripheral compartment (lower right) of propofol versus body weight in rats (bolus injection), children (post-cardiac surgery, 6 hr infusion) and adults (post-CABG, 5 hr infusion). Figure from Knibbe et al (17).

Figure 3 Propofol

 3 Figure 3Propofol clearance rates, scaled to 70kg, derived from neonates, children and adults. The solid line describes the maturation process as a sigmoid E max function of post-menstrual age.Allegaert[START_REF] Allegaert | Inter-individual variability in propofol pharmacokinetics in preterm and term neonates[END_REF] hypothesises that the influence of post-natal age (PNA) on clearance reflects ontogeny of glucuronidation activity during the first week of postnatal life. Figurefrom

Figure 4 The

 4 Figure 4The unit disposition function of plasma versus time profile simulation with the Schnider model (adults)[START_REF] Schnider | The influence of age on propofol pharmacodynamics[END_REF] and both the Kataria and Paedfusor models. A shallower decline in plasma concentration, and a larger variability related to patient age, is observed with the pediatric models. Figure from Munoz et al[START_REF] Munoz | Estimation of the plasma effect site equilibration rate constant (ke0) of propofol in children using the time to peak effect: comparison with adults[END_REF].


Dr Philip Arnold
email: philip.arnold@alderhey.nhs.uk

Treatment and Monitoring of Coagulation Abnormalities in Children Undergoing Heart

Keywords: blood transfusion < Hematology, coagulation < blood transfusion < Hematology, massive transfusions < Hematology, congenital heart disease < Cardiac, antifibrinolytic

Introduction

Bleeding remains a major clinical problem during and after paediatric heart surgery. Young age, low weight, use of deep hypothermia, high preoperative haematocrit and complex surgery are risk factors for severe bleeding [START_REF] Szekely | Risks and predictors of blood transfusion in pediatric patients undergoing open heart operations[END_REF][START_REF] Williams | Factors associated with blood loss and blood product transfusions: a multivariate analysis in children after open-heart surgery[END_REF][START_REF] Miller | Predicting and treating coagulopathies after cardiopulmonary bypass in children[END_REF]. Bleeding occurs because of surgical trauma leading to opening of blood vessels; all bleeding is 'surgical bleeding'. However, achieving acceptable haemostasis is often complicated by the presence of coagulopathy of variable severity. All patients will have coagulation abnormalities if sensitive tests are applied and most patients will have coagulation abnormalities demonstrated by routine laboratory and point of care tests. Optimal care demands cooperation between the anaesthetist and surgeon to apply therapy which will give an acceptable level of haemostasis without additional risk of injury, either from bleeding or from adverse effects of therapy aimed at reducing bleeding. Therapy should be aimed neither at 'perfect' correction of coagulation abnormalities or unrealistic surgical haemostasis.

Models of coagulation

Traditional models of coagulation have presented coagulation as a linear cascade of proteolytic enzymes. The implication has been that each step is necessary and of equal importance. More recent descriptive models of coagulation have stressed the importance of platelet and cellular elements (such as white cells and endothelium) and have recognised that coagulation occurs not as a linear process but as a complex web of interactions between procoagulant factors, inhibitors and the fibrinolytic system (figure 1) [START_REF] Hoffman | A cell-based model of coagulation and the role of factor VIIa[END_REF]. This distinction has clinical relevance in explaining the observations that functionally normal coagulation can exist despite low levels of clotting proteins (in neonates and moderate liver dysfunction) [START_REF] Tripodi | Acquired coagulation disorders: revisited using global coagulation/anticoagulation testing[END_REF], that deficits in one part of coagulation can be compensated for by other parts of coagulation (use of fibrinogen to correct for thrombocytopenia [START_REF] Velik-Salchner | The effect of fibrinogen concentrate on thrombocytopenia[END_REF] or use of activated factor VIIa in haemophilia) and questions some approaches to acquired bleeding (use of laboratory coagulation tests [START_REF] Tripodi | Acquired coagulation disorders: revisited using global coagulation/anticoagulation testing[END_REF] and some use of fresh frozen plasma). A difficulty with this descriptive model of coagulation is its complexity. Complex systems may perform in unexpected ways, study of parts of such systems in isolation may be misleading and such a complex model is of little practical use when managing a bleeding patient. A simpler, more practical, approach to coagulation is illustrated by the thromboelastogram (figure 2). Coagulation is broken down into three stages representing initiation, clot strength and clot stability. Therapy can then be aimed specifically at each of these stages at which abnormalities exist. Ideally the ability of these interventions to stop bleeding can be studied in properly conducted prospective trials in specific patient populations. In reality few such studies have been performed and much of our therapy is based on much weaker evidence from laboratory data, observational studies, and expert opinion.

Coagulopathy and Cardiac Bypass

In the absence of anticoagulants blood will clot in extracorporeal circuits. This has been ascribed to activation of the 'intrinsic' pathway involving prekallikrein and factor XII upon contact with the artificial surface. However, patients deficient in factor XII or prekallikrein clot at the same rate as other patients and the 'intrinsic' pathway appears to play little role either in normal coagulation or in clotting inside extracorporeal circuits [START_REF] Paparella | Coagulation disorders of cardiopulmonary bypass: a review[END_REF][START_REF] Burman | Role of factor XII in thrombin generation and fibrinolysis during cardiopulmonary bypass[END_REF]. The lining of artificial circuits differs from endothelium in two respects: proteins will bind freely to their surface and they lack any inhibitory effect on coagulation. Binding of fibrinogen (together with fibronectin and von Willibrand factor) leads to adherence of white cells, red cells and platelets [START_REF] Paparella | Coagulation disorders of cardiopulmonary bypass: a review[END_REF]. The adherent platelets undergo activation encouraging further adhesion, releasing procoagulants and presenting a large phospholipid surface upon which further activation occurs. Adherent monocytes express tissue factor allowing coagulation to proceed as described above. Whilst heparin dramatically reduces thrombin formation and the formation of fibrin clots it is an imperfect anticoagulant and does not prevent initial protein binding or activation of coagulation or platelets. This leads to defects in platelet numbers, in function of platelets, in fibrinogen concentration and in activation of fibrinolytic systems. Activation of fibrinolysis will lead to dissolution of clots, further reduction of platelet function and to increased concentrations of fibrin degradation products, which inhibit coagulation further [START_REF] Williams | Fibrinolysis in pediatric patients undergoing cardiopulmonary bypass[END_REF].

As well as the effects of interaction between blood and extracorporeal surfaces, other factors will add to coagulation anomalies. Blood spilt into the pericardial space and returned via 'pump' suction is a further (and possibly more important) cause of activation [START_REF] Chung | Pericardial blood activates the extrinsic coagulation pathway during clinical cardiopulmonary bypass[END_REF]. Clotting factors and platelets will undergo dilution on initiating bypass [START_REF] Kern | Coagulation defects in neonates during cardiopulmonary bypass[END_REF][START_REF] Chan | Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass[END_REF], red cells and platelets may be damaged from suction, blood loss and extensive surgical dissection will add to bleeding and many patients will have pre-existing coagulation abnormalities due to cyanotic heart disease [START_REF] Osthaus | Whole blood coagulation measured by modified thrombelastography (ROTEM) is impaired in infants with congenital heart diseases[END_REF][START_REF] Tempe | Coagulation abnormalities in patients with cyanotic congenital heart disease[END_REF][START_REF] Guay | Mediastinal bleeding after cardiopulmonary bypass in pediatric patients[END_REF], critical illness or medications.

Monitoring of Coagulation

Tests of coagulation are performed with the aim of identifying the coagulation abnormalities most likely to be contributing to bleeding. If results from these tests can be reported to the clinician in a short time, therapy can be directed more effectively at the specific cause of bleeding, leading to both more rapid correction of coagulopathy and avoiding unnecessary therapy. Tests can be divided between those conducted primarily in haematology laboratories and those available at the patient's bedside (point of care devices). The objective in using point of care tests is to make the results available to clinicians more rapidly, though as the tests available are also different they will have their own advantages and limitations.

i) Laboratory based coagulation tests

The most commonly performed laboratory tests relevant to coagulation are the full blood count (to give platelet concentration) and clotting studies (prothrombin time, activated partial thromboplastin time, thrombin time and fibrinogen concentration). Clotting studies are performed using patient's plasma so are insensitive to effects due to abnormalities of platelets or cellular elements. Citrated plasma is mixed with an excess of calcium and a reagent. Use of different reagents aims to test different parts of the coagulation pathway. The two most important tests used in acquired coagulopathy are the prothrombin time and fibrinogen concentration. Prothrombin time (PT) is widely used for monitoring acquired coagulopathy in a number of situations, including post cardiac surgery. The reagent used, thromboplastin, contains tissue factor and phospholipids; activation therefore occurs by the normal 'tissue factor' pathway. Problems arise in the interpretation of this test for two reasons. Firstly PT is prolonged in a number of situations despite functionally normal coagulation, including healthy neonates and in patients with moderate hepatic disease [START_REF] Tripodi | Acquired coagulation disorders: revisited using global coagulation/anticoagulation testing[END_REF]. In these patients the long PT reflects low concentrations of coagulation factors which, in vivo, are balanced by low concentrations of inhibitors. A long PT is also common in the absence of abnormal bleeding after paediatric heart surgery and this may reflect a similar situation. Secondly, deficiency of coagulation factors may not be the primary cause of bleeding. Congenital haemophilias are represented by profound deficiency of a single clotting factor. Acquired coagulopathy after surgery represents multiple coagulation defects with multiple origins. Not all these defects will be of equal importance and correction will not have an equal impact on bleeding. After cardiac surgery deficiencies of fibrinogen and functional platelets are likely to make a greater contribution to bleeding than deficiency of other factors [START_REF] Miller | Predicting and treating coagulopathies after cardiopulmonary bypass in children[END_REF][START_REF] Moganasundram | The relationship among thromboelastography, hemostatic variables, and bleeding after cardiopulmonary bypass surgery in children[END_REF][START_REF] Williams | Coagulation tests during cardiopulmonary bypass correlate with blood loss in children undergoing cardiac surgery[END_REF]. Basing treatment on PT may not lead to optimal correction of bleeding.

Thrombin time reflects fibrinogen activity but it is also prolonged by inhibition due to fibrinogen degradation products (FDP) or heparin. The most common method for determination of fibrinogen concentration, the Clauss method, is derived from the thrombin time. It is not interpretable in the presence of heparin and will be inaccurate in the presence of FDPs (common after heart surgery) [START_REF] Nieuwenhuizen | Biochemistry and measurement of fibrinogen[END_REF].

ii) Point of Care Monitoring

Point of care monitoring of coagulation may be aimed at the control of heparin administration or at the identification of coagulopathy. Devices available for monitoring of heparin have been reviewed previously [START_REF] Gruenwald | Management and monitoring of anticoagulation for children undergoing cardiopulmonary bypass in cardiac surgery[END_REF][START_REF] Prisco | Point-of-Care Testing of Hemostasis in Cardiac Surgery[END_REF]. For the purpose of this article only the latter will be discussed. Over the last few years improvement in design have allow a number of devices, previously suitable only for use in laboratories, to be developed for point of care use. Devices with potential for use during cardiac surgery include point of care equivalents of laboratory tests (such as APTT and PT), thromboelastography (TEG and ROTEM) and specific tests of platelet function (Sonoclot analyser, PFA-100 and MultiPlate platelet agrogometer) [START_REF] Enriquez | Point-of-care coagulation testing and transfusion algorithms[END_REF]. Currently only variations of thromboelastraphy have been widely employed and will be the focus of this discussion [START_REF] Miller | Rapid evaluation of coagulopathies after cardiopulmonary bypass in children using modified thromboelastography[END_REF][START_REF] Martin | Monitoring of coagulation status using thrombelastography during paediatric open heart surgery[END_REF]. The differences between the Thromboelastogram (TEG) and Rotational Thromboelastography (ROTEM) have been recently reviewed [START_REF] Jackson | The TEG vs the ROTEM thromboelastography/thromboelastometry systems[END_REF]. While important differences exist and results from these devices are not interchangeable [START_REF] Venema | An Assessment of Clinical Interchangeability of TEG (R) and RoTEM (R) Thromboelastographic Variables in Cardiac Surgical Patients[END_REF], the principle of their clinical application are similar. The discussion will focus on TEG whilst important differences in clinical application will be highlighted.

In conventional TEG a pin is lowered into a cup containing whole blood. The cup is rotated in each direction approximately 4 degrees. As the blood begins to clot the pin will begin to move with the cup, the force of the movement being a marker of the strength of the clot at that moment in time. This force is used to construct a graph of clot strength over time. A typical (Kaolin activated) TEG is shown in figure 1. Initially a straight line indicates no clot being present (the pin does not move), subsequently a clot begins to form and moves the pin to reach a maximum amplitude taken to indicate maximum clot strength. The stability of the clot is then indicated by the degree to which the clot retains this strength. An activator is usually added to the cup to speed up analysis and other substances may also be added to modify the test. Kaolin is the most common activator used with conventional TEG whilst the ROTEM is commonly performed as a battery of tests including kaolin (inTEM) and tissue factor (exTEM). A recent modification of TEG is 'rapid' TEG using a mixed activator aimed at giving information on clot strength more rapidly [START_REF] Chavez | A novel thrombelastograph tissue factor/kaolin assay of activated clotting times for monitoring heparin anticoagulation during cardiopulmonary bypass[END_REF].

The output of the TEG is primarily graphical. In order to allow comparison of results and to develop protocols based on TEG it is necessary to reduce this graphical output to numerical values (figure 2); computerisation has allowed for rapid calculation of these values. Similar values can be calculated for ROTEM though the values are not interchangeable and different nomenclature is used. Population 'normals' have been described for these values in adults, children [START_REF] Chan | Reference values for kaolin-activated thromboelastography in healthy children[END_REF] and in children with congenital heart disease [START_REF] Haizinger | Activated thrombelastogram in neonates and infants with complex congenital heart disease in comparison with healthy children[END_REF]. Some care is required in use of such reference values, as these will be different if different activators and additives are used. In interpretation of unmodified TEG values a prolonged R-time is an indication of residual anticoagulant or deficiency of clotting factors, a low maximum amplitude indicates poor clot strength and increased degrees of lysis (high Lys 30 or Lys [START_REF] Moganasundram | The relationship among thromboelastography, hemostatic variables, and bleeding after cardiopulmonary bypass surgery in children[END_REF][START_REF] Martin | Monitoring of coagulation status using thrombelastography during paediatric open heart surgery[END_REF]. A low MA may be the result of low platelet number, poor platelet function, low fibrinogen, poor function of fibrinogen or a combination of these factors. Moganasundram and colleagues demonstrated a close correlation between TEG MA and the product of platelet count and fibrinogen concentration in children [START_REF] Moganasundram | The relationship among thromboelastography, hemostatic variables, and bleeding after cardiopulmonary bypass surgery in children[END_REF]. Similar findings of an interaction between platelets and fibrinogen have been confirmed in adults [START_REF] Lang | The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia[END_REF].

Adaptation of the TEG can add further information. Addition of heparinase to the cup will neutralise any effect of heparin and comparison to an unmodified TEG will identify patients in which reversal of heparin has been inadequate. An estimate of fibrinogen activity can be made by addition of blockers of platelet function; the resulting clot will therefore reflect activity of fibrinogen alone.

Integration of monitoring into clinical care

A rational approach to bleeding after heart surgery should include a clinical assessment of bleeding at that point in time [START_REF] Mcewan | Aspects of bleeding after cardiac surgery in children[END_REF][START_REF] Nuttall | Coagulation tests predict bleeding after cardiopulmonary bypass[END_REF], an appreciation of risk factors, and use of specific tests to identify the presence and mechanisms of coagulopathy. In the absence of clinical bleeding, therapy is not required even if specific tests demonstrate an abnormality. In the presence of bleeding, tests can help to differentiate the specific cause. The most common causes of bleeding immediately after bypass are surgical causes, platelet abnormalities, fibrinogen insufficiency, inadequate reversal of heparin and combinations of these factors [START_REF] Moganasundram | The relationship among thromboelastography, hemostatic variables, and bleeding after cardiopulmonary bypass surgery in children[END_REF][START_REF] Shwea | Routine intraoperative thromboelastography reduces blood transfusions in paediatric cardiac surgery[END_REF]. In the absence of clotting abnormalities it is more likely that further surgical efforts will reduce bleeding than administration of blood products and early recognition of this can lead to more appropriate treatment [START_REF] Davidson | Can ROTEM thromboelastometry predict postoperative bleeding after cardiac surgery?[END_REF]. However, in small children this is an uncommon situation and abnormalities are likely to be present even if the primary cause of bleeding is surgical. If bleeding is persistent despite administration of appropriate clotting factors and normalisation of tests, then further surgical efforts are indicated.

Barriers exist to applying such an approach and it may not always be appropriate. Time is required to perform tests and to initiate treatment (in particular use of blood products) and delaying treatment while awaiting diagnostic information may be counterproductive. This can be minimised by use of tests that will give rapid results [START_REF] Chavez | A novel thrombelastograph tissue factor/kaolin assay of activated clotting times for monitoring heparin anticoagulation during cardiopulmonary bypass[END_REF] or by performing tests during bypass, which will predict coagulopathy after bypass [START_REF] Williams | Coagulation tests during cardiopulmonary bypass correlate with blood loss in children undergoing cardiac surgery[END_REF]. Inadequate reversal of heparin is an easily reversible cause of bleeding which can be rapidly confirmed by point of care tests such as heparinase modified TEG. Some patients, such as neonates undergoing complex procedures, are at very high risk of bleeding. If excessive bleeding is present, after reversal of heparin, initial empirical transfusion of platelets or cryoprecipitate is indicated [START_REF] Miller | Predicting and treating coagulopathies after cardiopulmonary bypass in children[END_REF][START_REF] Mcewan | Aspects of bleeding after cardiac surgery in children[END_REF] and waiting for coagulation tests may only lead to delay in treatment. If the patient fails to respond to initial treatment the cause for ongoing bleeding is likely to be less clear and coagulation tests can help to guide further therapy. Figure 3 demonstrates the ability of TEG to follow changes in coagulation during a case.

In other situations and when bleeding is of lesser severity, greater consideration can be given to the need for treatment. Approaches to bleeding based on clinical assessment of bleeding and results of coagulation tests can avoid unnecessary transfusion. Transfusion algorithms have been introduced to this end. Traditionally these algorithms have been based on laboratory tests (table 1) and have been developed primarily through clinical consensus [START_REF] Shaughnessy | Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant[END_REF][START_REF] Murphy | Guidelines for platelet transfusions. British Committee for Standards in Haematology, Working Party of the Blood Transfusion Task Force[END_REF][START_REF] Contreras | Guidelines for the use of fresh frozen plasma. British Committee for Standards in Haematology, Working Party of the Blood Transfusion Task Force[END_REF]. Often the clinical evidence (either for the chosen indication, the specific product or the dose) is weak. In addition, the guidelines are frequently applied to highly heterogeneous groups of patients; it is unlikely that the same management is appropriate for an elderly adult with liver disease or a neonate undergoing heart surgery. Algorithms based on point of care monitoring have also been introduced (table 2). These have been successful in limiting unnecessary transfusion in adults [START_REF] Anderson | An audit of red cell and blood product use after the institution of thromboelastometry in a cardiac intensive care unit[END_REF][START_REF] Ak | Thromboelastographybased transfusion algorithm reduces blood product use after elective CABG: a prospective randomized study[END_REF][START_REF] Avidan | Comparison of structured use of routine laboratory tests or near-patient assessment with clinical judgement in the management of bleeding after cardiac surgery[END_REF] and children [START_REF] Shwea | Routine intraoperative thromboelastography reduces blood transfusions in paediatric cardiac surgery[END_REF]. The algorithms introduced have largely been extrapolated from laboratory based guidelines and may not fully exploit the advantages of tests such as thromboelastograms. Table 2 gives advice on TEG guided transfusion. Evidence that introduction of transfusion algorithms based on point of care monitoring can improve outcome other than reducing unnecessary transfusion is limited [START_REF] Schochl | Goaldirected coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate[END_REF].

Specific Agents Blood Products

Platelet dysfunction and thrombocytopenia are common after cardiac bypass in infants. Hence, in the presence of bleeding, transfusion of platelets is logical. Coagulation variables which relate to platelet number and function (such as TEG MA) are corrected by infusion of platelets and clinical experience indicates that platelet transfusion is highly efficacious at reducing bleeding. This has been confirmed in a small study of children post cardiac surgery [START_REF] Miller | Predicting and treating coagulopathies after cardiopulmonary bypass in children[END_REF]. A platelet count of less than 108x10 9 /l have been identified as a predictor of bleeding whilst clot strength measured by TEG reduces steeply at platelet counts below 120x10 9 /l. The current recommendation of targeting a platelet count of approximately 100x10 9 /l appear reasonable. Use of platelets for initial treatment of presumed coagulopathic bleeding (in the absence of specific clotting tests) also seem reasonable.

The use of fresh frozen plasma (FFP) is based on the observation that concentration of clotting factors are often low immediately post bypass. The case for use of FFP either empirically or guided by coagulation tests is considerably weaker than for platelets. PT, APTT and TEG-R time are clotting tests which correlate best with factor deficiency. A PT greater than 1.5 times control is taken as an indication that FFP should be transfused [START_REF] Contreras | Guidelines for the use of fresh frozen plasma. British Committee for Standards in Haematology, Working Party of the Blood Transfusion Task Force[END_REF]. However, these tests are often significantly prolonged in the absence of bleeding and, when taken post bypass, correlate poorly with excessive bleeding. A meta-analysis of the use of FFP to treat acquired coagulopathy failed to demonstrate benefit, though the trials examined were small and conducted in heterogeneous populations [START_REF] Stanworth | Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials[END_REF]. In a small observational study a number of patients shad coagulopathic bleeding after transfusion of platelets; if these patients were then given FFP bleeding increased, whilst if cryoprecipitate was given bleeding improved [START_REF] Miller | Predicting and treating coagulopathies after cardiopulmonary bypass in children[END_REF]. The lack of efficacy may be related to dose. FFP is frequently given in doses below the recommended dose of 10-15ml/kg [START_REF] Kakkar | Improvement in fresh frozen plasma transfusion practice: results of an outcome audit[END_REF], though this dose may itself be inadequate to restore factor concentration. Modelling of FFP administration in major trauma suggests that much larger doses may be required to boast or retain factor levels [START_REF] Alam | Testing of blood products in a polytrauma model: results of a multi-institutional randomized preclinical trial[END_REF]. It is possible that a dose of 30-40ml/kg may be more appropriate, though administration of such a large volume is unlikely to be desirable except in the context of massive ongoing bleeding and dilution of platelets and red cells may exacerbate bleeding. Addition of FFP to the bypass circuit may allow administration of much larger doses, benefit appears to be confined to smaller patients [START_REF] Oliver | Blood loss in infants and children for open heart operations: albumin 5% versus freshfrozen plasma in the prime[END_REF][START_REF] Mccall | Fresh frozen plasma in the pediatric pump prime: a prospective, randomized trial[END_REF]. Not all coagulation factors are of equal importance during bleeding. Fibrinogen is normally present in much higher concentrations than other clotting factors and whilst other factors are mainly involved in initiating or amplifying thrombin formation, fibrinogen is a substrate for the production of fibrin. Deficiencies of fibrinogen are reflected in reduced strength of clot and are associated with increased bleeding [START_REF] Moganasundram | The relationship among thromboelastography, hemostatic variables, and bleeding after cardiopulmonary bypass surgery in children[END_REF]. Cryoprecipitate is the most concentrated fibrinogen replacement widely available with a fibrinogen concentration 4-8 times that of FFP; though a unit of cryoprecipiate contains less fibrinogen than a unit of FFP and multiple units will be required in larger patients. One unit for each 10kg should raise fibrinogen concentration by 0.5-1.0g/l. As well as fibrinogen, cryoprecipitate is a source of Von Willibrands factor, Factors VIII and XIII, though the clinical significance of this is unclear. Cryoprecipitate has been effective in treating bleeding resistant to platelet concentrates alone during paediatric heart surgery (3).

Human fractionated factor concentrates

Human fractionated factor concentrates are produced from pooled human plasma. They undergo pasteurisation, which will neutralise blood born viruses but (potentially) not prions. They are presented as a dried powder requiring reconstitution. They do not require cross matching and have a long shelf life avoiding some of the logistical problems with supply of other blood products.

Prothrombin complex concentrates (PCCs) are mixtures of inactive factor II (prothrombin), VII, IX and X plus the coagulation inhibitors Protein S and C. A number of different brands of PCC are available which have different relative concentrations of these factors. In some older products low concentration of Protein S and C have been associated with increased thrombogenicity, whilst low concentration of factor VII have been associated with a lack of effect [START_REF] Hellstern | Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency[END_REF]. PCCs are currently considered safe and reliable for urgent reversal of oral anticoagulants [START_REF] Hanley | Warfarin reversal[END_REF][START_REF] Bershad | Prothrombin complex concentrates for oral anticoagulant therapy-related intracranial hemorrhage: a review of the literature[END_REF]. The use of these agents in other causes of acquired coagulopathy is less certain though case series in adult patients have been encouraging [START_REF] Fraser | A retrospective audit of the use of Prothrombinex-HT for refractory bleeding following adult cardiac surgery[END_REF][START_REF] Bruce | Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital[END_REF]. Widespread use in children after heart surgery requires more evaluation.

Fibrinogen concentrate has been available in continental Europe for over 20 years and appears to be a safe alternative to cryoprecipitate [START_REF] Bevan | Cryoprecipitate: no longer the best therapeutic choice in congenital fibrinogen disorders?[END_REF][START_REF] Dickneite | Animal model and clinical evidence indicating low thrombogenic potential of fibrinogen concentrate (Haemocomplettan P)[END_REF][START_REF] Tziomalos | Treatment of congenital fibrinogen deficiency: overview and recent findings[END_REF]. Use in cardiac surgery in children and adults has been increasing [START_REF] Weinkove | Fibrinogen concentrate for acquired hypofibrinogenaemic states[END_REF][START_REF] Solomon | Recovery of fibrinogen after administration of fibrinogen concentrate to patients with severe bleeding after cardiopulmonary bypass surgery[END_REF]. It is expected that this agent will be available in the USA and UK in 2010. Unlike cryoprecipitate it contains only fibrinogen and a direct comparison of these two agents in acquired coagulopathy has not been made. Potentially, it allows for more rapid correction of fibrinogen concentration as it will not require defrosting and can be administered in a smaller volume. Combining the availability of this agent with rapid measurement of fibrinogen concentration (using modified TEG) is an attractive approach [START_REF] Solomon | Recovery of fibrinogen after administration of fibrinogen concentrate to patients with severe bleeding after cardiopulmonary bypass surgery[END_REF][START_REF] Brenni | Successful rotational thromboelastometry-guided treatment of traumatic haemorrhage, hyperfibrinolysis and coagulopathy[END_REF][START_REF] Rahe-Meyer | Bleeding management with fibrinogen concentrate targeting a highnormal plasma fibrinogen level: a pilot study[END_REF][START_REF] Rahe-Meyer | Thromboelastometry-guided administration of fibrinogen concentrate for the treatment of excessive intraoperative bleeding in thoracoabdominal aortic aneurysm surgery[END_REF]. A small randomised study comparing prophylaxic administration of fibrinogen concentrate to placebo in adult cardiac patients demonstrated a reduction in bleeding [START_REF] Karlsson | Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. A prospective randomised pilot study[END_REF]. Recombinant fibrinogen is currently under development but it will be several years before it is available.

The ease of administration and low volume of fibrinogen concentrates compared to FFP or cryoprecipitate can allow targeting of higher fibrinogen concentrations than have been used previously [START_REF] Rahe-Meyer | Bleeding management with fibrinogen concentrate targeting a highnormal plasma fibrinogen level: a pilot study[END_REF][START_REF] Fenger-Eriksen | Fibrinogen concentrate--a potential universal hemostatic agent[END_REF]. It is possible that such use could reduce both bleeding and the need for platelet transfusion. In TEG studies high concentrations of fibrinogen can restore clot strength despite low platelet numbers. In animal models of bleeding and thrombocytopenia fibrinogen concentrates were superior to stored platelet concentrates in resolving bleeding [START_REF] Velik-Salchner | The effect of fibrinogen concentrate on thrombocytopenia[END_REF]. Such an approach requires further evaluation including assessment of effectiveness, safety and identification of appropriate targets.

Recombinant factor concentrates.

Use of factor VIIa in paediatric heart patients has been previously reviewed [START_REF] Warren | Defining the role of recombinant activated factor VII in pediatric cardiac surgery: where should we go from here?[END_REF]. Numerous case reports have shown effectiveness in treating severe bleeding in a number of situations including paediatric heart surgery. Significant questions concerning the indication for this agent, dose and safety remain. Prophylaxic use in a relatively low dose in children was ineffective in reducing bleeding [START_REF] Ekert | Elective administration in infants of low-dose recombinant activated factor VII (rFVIIa) in cardiopulmonary bypass surgery for congenital heart disease does not shorten time to chest closure or reduce blood loss and need for transfusions: a randomized, double-blind, parallel group, placebocontrolled study of rFVIIa and standard haemostatic replacement therapy versus standard haemostatic replacement therapy[END_REF]. In adults undergoing heart surgery rVIIa was effective in reducing bleeding, though the rate of serious adverse effects was higher than placebo [START_REF] Gill | Safety and efficacy of recombinant activated factor VII: a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery[END_REF]. Due to concern over thrombotic complications and ineffectiveness in preventing bleeding it would be reasonable to confine use to treatment of serious life threatening bleeding.

Human and recombinant factor XIII has been described for use during heart surgery [START_REF] Godje | The effect of factor XIII on bleeding in coronary surgery[END_REF][START_REF] Godje | Coagulation factor XIII reduces postoperative bleeding after coronary surgery with extracorporeal circulation[END_REF][START_REF] Levy | Repletion of factor XIII following cardiopulmonary bypass using a recombinant A-subunit homodimer. A preliminary report[END_REF] and is supported by animal work [START_REF] Ponce | Safety of recombinant human factor XIII in a cynomolgus monkey model of extracorporeal blood circulation[END_REF]. Factor XIII functions by stabilising and strengthening bonds in the fibrin polymer and would therefore be expected to contribute to clot strength and stability. Association between factor XIII concentration and bleeding have been inconsistent [START_REF] Blome | Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and postoperative bleeding in cardiopulmonary bypass surgery[END_REF][START_REF] Brody | Concentrations of factor VIII-related antigen and factor XIII during open heart surgery[END_REF]. Factor XIII also has a more general role in healing and may reduce myocardial oedema and pleural effusions in children after heart surgery [START_REF] Wozniak | Factor XIII prevents development of myocardial edema in children undergoing surgery for congenital heart disease[END_REF][START_REF] Schroth | Plasmatic [corrected] factor XIII reduces severe pleural effusion in children after openheart surgery[END_REF]. The role of factor XIII replacement is uncertain, though the development of a recombinant concentrate of this factor may lead to increased interest.

Other drugs

Treatment with antifibrinolytics such as aprotinin, tranexamic acid or epsilon-aminoamicroic acid is common during paediatric heart surgery. Use of aprotinin in children has reduced dramatically due to safety concerns in adults [START_REF] Fergusson | A comparison of aprotinin and lysine analogues in high-risk cardiac surgery[END_REF][START_REF] Mangano | Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery[END_REF][START_REF] Mangano | The risk associated with aprotinin in cardiac surgery[END_REF][START_REF] Henry | The safety of aprotinin and lysinederived antifibrinolytic drugs in cardiac surgery: a meta-analysis[END_REF], despite retrospective studies which show a lack of serious toxicity in children [START_REF] Guzzetta | The impact of aprotinin on postoperative renal dysfunction in neonates undergoing cardiopulmonary bypass: a retrospective analysis[END_REF]. Aprotinin is no longer available in many countries. Tranexamic acid and epsiolon aminocroic acid have evidence of efficacy in children though probably less than aprotinin [START_REF] Schouten | The effect of aprotinin, tranexamic acid, and aminocaproic acid on blood loss and use of blood products in major pediatric surgery: a meta-analysis[END_REF][START_REF] Breuer | Aprotinin is superior to tranexamic acid in paediatric cardiac surgery Journal of Cardiothoracic and Vascular Anesthesia[END_REF][START_REF] Arnold | Avoiding transfusions in children undergoing cardiac surgery: a meta-analysis of randomized trials of aprotinin[END_REF]. Only a single study has addressed dosing of tranexamic acid in children [START_REF] Chauhan | Dose comparison of tranexamic acid in pediatric cardiac surgery[END_REF] and dosing remains extremely variable (abstract APA 2010). Desmopressin increases plasma levels of von Willibrand factor with potential for reducing bleeding. In adults undergoing cardiac surgery, any benefit is confined to patients with high anticipated blood loss [START_REF] Cattaneo | The effect of desmopressin on reducing blood loss in cardiac surgery--a meta-analysis of double-blind, placebo-controlled trials[END_REF]. Trials of desmopression in children and adults undergoing surgery for congenital heart disease have failed to show a beneficial effect [START_REF] Seear | The effect of desmopressin acetate (DDAVP) on postoperative blood loss after cardiac operations in children[END_REF][START_REF] Oliver | Desmopressin does not reduce bleeding and transfusion requirements in congenital heart operations[END_REF][START_REF] Reynolds | Desmopressin does not decrease bleeding after cardiac operation in young children[END_REF].

Conclusion

Coagulopathy is a common cause of excess bleeding after heart surgery. Treatment should aim to reduce bleeding and should only be initiated in the presence of bleeding. 'Traditional' treatment using blood products is largely successful and empirical use of these products is often appropriate, particularly in the initial treatment of severe bleeding and in high risk patients. A strategy based on coagulation testing and application of specific therapies is likely to be more successful in patients who fail to respond to initial empirical treatment. Alternatively in lower risk patients the empirical use of blood products is likely to lead to excessive transfusion and an approach based on a clinical assessment of bleeding, an appreciation of risk factors and use of tests is likely to reduce transfusion. Points of care tests of coagulation, in particular the thromboelastogram, have theoretical and practical advantages over laboratory based tests.

Management of bleeding after paediatric heart surgery using strategies based on infusion of more specific factor concentrates and fibrinogen is promising. As yet, these approaches are largely untested either for efficacy or safety. Trials of therapy aimed at treatment of bleeding are challenging, though these problems are not insurmountable and the benefits from such trials will be considerable. is initiated by leakage of factor VIIa and platelets from traumatised blood vessels. When platelets come into contact with von Willibrands factor (VWF) and collagen they undergo a process of activation; which includes the release of procoagulants, a dramatic increase on surface area and expression of adhesion molecules (for other platelets and fibrin). Factor VIIa , usually present in low concentrations within blood vessels, makes contact with tissue factor (TF) bound to cells (principally fibroblasts but subsequently white cells). This leads to the production of a small quantity of thrombin which initiates a positive feed back loop (involving a number of factors, further conversion of factor VII to VIIa and activation of platelets) producing large quantities of thrombin. This leads to production of fibrin (from fibrinogen), which together with activated platelets, forms clot. The major inhibitor is the Protein C (PC) system which inactivates factor VIII and V. In the absence of endothelium bound thrombomodulin (TM ) (for example in invitro blood tests) little active protein C is produced. Subsequent stabilisation of the clot by factor XII, inhibitors other than protein C and the fibrinolytic system are not shown for simplicity. Platelet concentrate 10mls/kg Fibrinogen <0.8-1.0 g/l Cryoprecipitate 1 unit per 10Kg Coagulation is initiated by leakage of factor VIIa and platelets from traumatised blood vessels. When platelets come into contact with von Willibrands factor (VWF) and collagen they undergo a process of activation; which includes the release of procoagulants, a dramatic increase on surface area and expression of adhesion molecules (for other platelets and fibrin). Factor VIIa , usually present in low concentrations within blood vessels, makes contact with tissue factor (TF) bound to cells (principally fibroblasts but subsequently white cells). This leads to the production of a small quantity of thrombin which initiates a positive feed back loop (involving a number of factors, further conversion of factor VII to VIIa and activation of platelets) producing large quantities of thrombin. This leads to production of fibrin (from fibrinogen), which together with activated platelets, forms clot. The major inhibitor is the Protein C (PC) system which inactivates factor VIII and V. In the absence of endothelium bound thrombomodulin (TM ) (for example in invitro blood tests) little active protein C is produced. Subsequent stabilisation of the clot by factor XII, inhibitors other than protein C and the fibrinolytic system are not shown for simplicity.

<<4057 Words>>

  presence of fibrinolysis. Low amplitude (MA) is the TEG value most closely correlated with bleeding after heart surgery

Figure 1 :

 1 Figure 1: This figure demonstrates the major pathways involved in normal coagulation. Coagulationis initiated by leakage of factor VIIa and platelets from traumatised blood vessels. When platelets come into contact with von Willibrands factor (VWF) and collagen they undergo a process of activation; which includes the release of procoagulants, a dramatic increase on surface area and expression of adhesion molecules (for other platelets and fibrin). Factor VIIa , usually present in low concentrations within blood vessels, makes contact with tissue factor (TF) bound to cells (principally fibroblasts but subsequently white cells). This leads to the production of a small quantity of thrombin which initiates a positive feed back loop (involving a number of factors, further conversion of factor VII to VIIa and activation of platelets) producing large quantities of thrombin. This leads to production of fibrin (from fibrinogen), which together with activated platelets, forms clot. The major inhibitor is the Protein C (PC) system which inactivates factor VIII and V. In the absence of endothelium bound thrombomodulin (TM ) (for example in invitro blood tests) little active protein C is produced. Subsequent stabilisation of the clot by factor XII, inhibitors other than protein C and the fibrinolytic system are not shown for simplicity. 214x171mm (72 x 72 DPI)

Figure 2 :Figure 3 :

 23 Figure 1: This figure demonstrates the major pathways involved in normal coagulation. Coagulationis initiated by leakage of factor VIIa and platelets from traumatised blood vessels. When platelets come into contact with von Willibrands factor (VWF) and collagen they undergo a process of activation; which includes the release of procoagulants, a dramatic increase on surface area and expression of adhesion molecules (for other platelets and fibrin). Factor VIIa , usually present in low concentrations within blood vessels, makes contact with tissue factor (TF) bound to cells (principally fibroblasts but subsequently white cells). This leads to the production of a small quantity of thrombin which initiates a positive feed back loop (involving a number of factors, further conversion of factor VII to VIIa and activation of platelets) producing large quantities of thrombin. This leads to production of fibrin (from fibrinogen), which together with activated platelets, forms clot. The major inhibitor is the Protein C (PC) system which inactivates factor VIII and V. In the absence of endothelium bound thrombomodulin (TM ) (for example in invitro blood tests) little active protein C is produced. Subsequent stabilisation of the clot by factor XII, inhibitors other than protein C and the fibrinolytic system are not shown for simplicity. 214x171mm (72 x 72 DPI)

Figure 1 :

 1 Figure 1: This figure demonstrates the major pathways involved in normal coagulation. Coagulation is initiated by leakage of factor VIIa and platelets from traumatised blood vessels. When platelets come into contact with von Willibrands factor (VWF) and collagen they undergo a process of activation; which includes the release of procoagulants, a dramatic increase on surface area and expression of adhesion molecules (for other platelets and fibrin).Factor VIIa , usually present in low concentrations within blood vessels, makes contact with tissue factor (TF) bound to cells (principally fibroblasts but subsequently white cells). This leads to the production of a small quantity of thrombin which initiates a positive feed back loop (involving a number of factors, further conversion of factor VII to VIIa and activation of platelets) producing large quantities of thrombin. This leads to production of fibrin (from fibrinogen), which together with activated platelets, forms clot. The major inhibitor is the Protein C (PC) system which inactivates factor VIII and V. In the absence of endothelium bound thrombomodulin (TM ) (for example in invitro blood tests) little active protein C is produced. Subsequent stabilisation of the clot by factor XII, inhibitors other than protein C and the fibrinolytic system are not shown for simplicity.

Figure 2 :

 2 Figure 2: A normal thromboelastogram (TEG) trace is shown. The output of TEG is graphical, however a number of numerical values can be derived to describe the curve. Rtime is the time from beginning the sample until the amplitude of the trace reaches 1mm; it describes the initiation of clotting. Maximum Amplitude (MA) is the largest amplitude reached; it describes the strength of the clot formed. The α angle describes the steepness of the initial part of the curve; this is often referred to as the 'clot kinetics'. Lys 30 is the ratio of the amplitude of the trace 30 minutes after the maximum amplitude to the maximum amplitude; this describes the stability of the clot.

Figure 3 :

 3 Figure 3: The ability of thromboelastogram to follow changes in coagulation through a case is demonstrated. Dotted lines show a 'normal' trace. The patient was a newborn who had undergone an aortic arch repair. The baseline trace (A) demonstrates a mildly elongated R time but is otherwise normal. After bypass platelets were administered empirically due to excessive bleeding. Bleeding continued and a TEG was performed to identify the cause of bleeding. This demonstrated a low amplitude and excess fibrinolysis (B). Tranexamic acid was given with some effect (C) followed by infusion of cryoprecipitate (D). Following this bleeding reduced dramatically and the TEG returned to the baseline.

Table 1 :

 1 Guidelines for transfusion of blood products. Following bypass it is assumed that significant platelet dysfunction will be present and the higher target for platelet transfusion (100*10 9 ) is used.

	TEG	Additive	'normal'	Interpretation	Suggested Action
	parameter		value
	MA (kaolin) Kaolin	54-72mm	Reflects platelet number, platelet function,	>48mm platelets or cryoprecipitate are not
				fibrinogen concentration and dysfunction.	indicated
					<43 and if patient is bleeding, there is likely
					benefit from platelet or cryoprecipiate infusion
	R time	Kaolin	4-8 minutes	Similar to ACT is a complex parameter	If long consider residual heparin (check
	(kaolin)			affected by anticoagulation, factor	heparinase TEG) or factor deficiency.
				deficiency and presence of inhibitors. Also	FFP may be indicated if >15minutes but other
				operator variable.	abnormalities should be corrected first.
					If severe bleeding and long R time consider use
					of Prothrombin Complex Concentrates
	Lys 30/ Lys	Kaolin	0-8%	High levels diagnostic of abnormal	Treat with antifibrinolytic drugs
	60		0-15%	fibrinolysis
	Heparinase	Kaolin	As R-time	Useful in heparinised patient. TEG MA on	If unmodified R time is >1.5 times heparinase
	modified R	Heparinase	Compare to	bypass shows correlation with bleeding post	modified R time, further protamine should be
	time		plain kaolin R	bypass.	given
			time	If ran together with unmodified TEG a
				shorter R time indicates residual heparin or
				contamination.
	Functional	Tissue factor	Expressed as	Identifies portion of clot strength due to	"Traditional" management is to supplement
	Fibrinogen	Platelet	a fibrinogen	fibrinogen to give estimate of fibrinogen	fibrinogen until greater than 1g/l in the presence
		blocker	concentration	activity.	of bleeding. If active bleeding likely to be
		(ReoPro)			further benefit in targeting concentration 2g/l or
					higher. Can be achieved with cryoprecipitate or
					fibrinogen concentrate.

F o r P e e r R e v i e w

Table 1 :

 1 Commonly measured thromboelastogram (TEG) parameters, with guidance on their significance and suggested action. Thresholds for transfusion or other treatments should be seen only as a guide and treatment should be guided by the clinical situation and known risk factors for coagulopathy. Treatment is only indicated in the presence of active bleeding.