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TIVA In Children PIP Meeting Thursday 4th June 2009 Dr Oliver Bagshaw Definitions TIVA – anaesthetic technique involving no inhalational agents, including volatiles and nitrous oxide TCI - Infusion by a microprocessor-controlled syringe pump, which automatically and variably controls the rate of infusion of a drug to attain a user-defined target level in an effect site in the patient (usually blood) TIVA – Indications in Children Known MH patient MH susceptibility – central core disease, multiminicore disease, KD syndrome MH risk – muscular dystrophies, arthrogryposis, osteogenesis imperfecta Patients requiring muscle biopsy TIVA – Indications in Children Previous N&V post anaesthesia High risk of N&V post anaesthesia, e.g. strabismus, Ts&As, orchidopexy Scoliosis surgery Myasthenia gravis Reduce blood loss – e.g. FESS procedure TIVA in children Advantages Less pollution Less N&V Improved quality of recovery - delerium No laryngospasm No risk of MH Disadvantages Need IV access Can’t monitor blood levels Delivery problems may go unrecognised Requires ‘metabolism’ Risks of large doses of propofol – PRIS More ‘fiddly’ & wasteful TIVA in children – Practical issues Can’t always establish IV access prior to induction Propofol induction often prolonged with TCI – kids may squirm a bit! Try and avoid relaxants Can’t always have IV cannula exposed TIVA in children - Options Manual infusion regime TCI regime Manually Controlled Infusion Traditionally 10, 8, 6 regime – decreasing every 10 minutes Adapted in children – 15, 13, 11, 10, 9 regime – decreasing at variable intervals (15 mins to 1 hr)* Estimated Cp of 3mcg/ml *McFarlan et al. Paediatr Anaesth 1999; 9: 209-16 Manually Controlled Infusion – Effect of age Duration (mins) Age 0-3 months 3-6 months 6-9 months 9-12 months 1-3 years 0-10 25 20 15 15 12 10-20 20 15 10 10 9 20-30 15 10 10 10 6 30-40 10 10 10 10 6 40-50 5 5 5 5 6 50-60 5 5 5 5 6 >60 2.5 2.5 2.5 2.5 6 *mg/kg/hr Steur et al. Paediatr Anaesth 2004: 14: 462-7 Manual Infusion – 3m 100 11 10 9 8 7 6 5 4 3 2 1 0 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Manual Infusion – 2y 200 11 10 9 8 7 6 100 5 4 3 2 1 0 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Manual Infusion – 6y 1000 10 900 9 800 8 700 7 600 6 500 5 400 4 300 3 200 2 100 1 0 0 0 10 20 30 40 50 60 70 80 90 100 110 120 TCI Advantages: Uses valid pharmacokinetic data Bolus incorporated Can quickly adjust target level More accurate estimate of plasma/effect site concentrations Disadvantages: Need specific TCI pumps Data sometimes not available for younger children May be less accurate in younger patients Need some knowledge of appropriate targets Paediatric TCI models Paedfusor – developed in 1990s Showed need for larger bolus and greater infusion rates in children Can be used down to 5kg Kataria – also developed in 1990s Based on samples from >50 children Age range 3-16 years Minimum weight 15kg Marsh vs Kataria vs Paedfusor Marsh Kataria Paedfusor V1 0.228 L/kg 0.52 L/kg 0.458 L/kg V2 0.463 L/kg 1.0 L/kg 1.34 L/kg V3 2.893 L/kg 8.2 L/kg 8.20 L/kg K10 (min –1) 0.119 0.066 70 x Weight -0.3/458.4 K12 (min –1) 0.112 0.113 0.12 K13 (min –1) 0.042 0.051 0.034 K21 (min –1) 0.055 0.059 0.041 K31 (min –1) 0.0033 0.0032 0.0019 Why Paediatric models? 1000 10 9 7 600 6 5 400 Concentration µg/ml 800 Paedfusor 8 4 3 200 2 1 0 0 0 10 20 30 40 50 60 70 80 90 100 110 120 1000 14 800 Marsh 10 600 8 400 Concentration µg/ml 12 6 200 4 2 0 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Plasma vs Effect Site Targeting Cp = most commonly used Ce depends on accuracy of PK models Ce targeting leads to much higher plasma concentrations initially Concentration gradient needed to drive drug into effect site Overshoot determined by model (ke0) Fast ke0 = less overshoot Ce targeting more accurately predicts loss of consciousness Plasma TCI 600 10 9 500 8 400 7 6 300 5 4 200 3 100 2 1 0 0 0 10 20 30 40 50 60 Effect site TCI 600 12 11 500 10 9 400 8 7 300 6 5 200 4 3 100 2 1 0 0 0 10 20 30 40 50 60 Adult propofol target concentrations (effect site) Target (Ce) mcg/ml Plane of anaesthesia Clinical application <0.5 Light sedation Insertion of lines, awake fibreoptic intubation 0.5-1.5 Heavy sedation Radiological imaging, endoscopy, surgery with LA 1.5-3.0 Light anaesthesia Surgery with analgesia adjuncts 4.0-6.0 General anaesthesia Major surgery Cp/Ce Equilibration Times – Manual Infusions Propofol: Manual infusion alone – 20-30 mins Bolus & manual infusion ≈5 mins Remifentanil: Manual infusion alone – 5-10 mins Bolus & manual infusion <2 mins Cp/Ce Equilibration Times – Targeted Infusions Propofol: Plasma TCI – 15-20 mins Effect site TCI <5 mins Remifentanil: Plasma TCI – 5-7 mins Effect site TCI ≈1 min How accurate are TCI systems? Assessment of accuracy Measurement or predictive performance of a TCI system Bias This value represents the direction (over or under-prediction) of the performance error (median performance error) No Bias Calculated concentration Measured concentration Significant bias Assessment of accuracy Measurement or predictive performance of a TCI system Precision This is an indication of the size of the typical error from the predicted concentration (median absolute performance error) Small Scatter (No Bias) Calculated concentration Measured concentration Large Scatter (No Bias) Accuracy of Paedfusor Bias (MPE) – 4.1% (10%) Precision (MAPE) – 9.7% (20%) ‘Wobble’ – 8.3% Performs better than adult models Also better than ET volatile concentration monitoring (20% bias) Arterial isoflurane tension = 45 – 80% of end-tidal!!! Context Sensitive Half-time Context Sensitive Half-time - propofol Opioid – hypnotic interactions Drug B Isobolograms Drug A Plasma remifentanil (ng/ml) Propofol-Remifentanil Interaction 10 9 8 7 6 7 min Adequate anesthesia Awakening 6 min 5 4 3 2 1 0 12 min 0 2 4 6 8 10 Blood propofol (µg/ml) Vuyk et al. Anesthesiology 1997; 87: 1549-62 12 14 16 Remifentanil May reduce clearance of propofol Can lead to under prediction of target concentrations Synergistic effect with propofol Does it produce tolerance? Influence of remifentanil on propofol Cp50 Remifentanil 0 ng/ml Remifentanil 2 ng/ml Remifentanil 4 ng/ml LOR Verbal 2.9 g/ml 2.4 g/ml 2.2 g/ml LOREyelash 2.8 g/ml 1.8 g/ml 1.7 g/ml LORNoxious 4.1 g/ml 1.8 g/ml 1.3 g/ml Struys. Anesthesiology 2003; 99: 802-12 Effect of remifentanil and RA on propofol Ce Propofol Ce Sedation Maintenance of anaesthesia Nil Remifentanil Nitrous oxide Regional anaesthesia 1-1.5 mcg/ml <1 mcg/ml N/A <1 mcg/ml 4-6 mcg/ml 3-4 mcg/ml 4-5 mcg/ml 3-4 mcg/ml Propofol-remi interactions 32 children; 3-10yrs UGIE Three remi groups – 0.025, 0.05 and 0.1 mcg/kg/min Propofol ED50 decreased from 3.7 to 2.8 mcg/ml with addition of remi No benefit from increasing dose above 0.025mcg/kg/min – more complications Drover D et al. Anesthesiology 2004; 100: 1382-86 Propofol-remi interactions Drover D et al. Anesthesiology 2004; 100: 1382-86 Propofol-remi interactions – effect on awakening (Cp50 – 2.2) 1000 14 800 12 600 10 8 400 6 200 4 2 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 1000 0 10 800 9 8 600 7 6 400 5 4 200 3 2 1 0 0 Propofol-remi interactions – effect on awakening (Cp50 – 2.7) 1000 14 800 12 600 10 8 400 6 200 4 2 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 1000 0 10 800 9 8 600 7 6 400 5 4 200 3 2 1 0 0 Propofol-remi interactions – effect on recovery propofol 6mg/kg/hr and remi 0.15mcg/kg/min vs propofol 3mg/kg/hr and remi 0.45mcg/kg/min No significant difference in recovery times if propofol or remi pronounced Less variation in recovery times if remi pronounced Hackner C et al. BJA 2003; 91: 580-2 Remifentanil – Spontaneously breathing 32 children (2-7 yrs); dental Rx Big variation in dose tolerated – 0.05 0.3mcg/kg/min Median 0.127mcg/kg/min RR <10 = best predictor of apnoea Ansermino JM et al. Pediatric Anesthesia 2005; 15: 115-121 Remifentanil – Spont breathing & effect of age 45 children for stabismus surgery – 6m to 9yrs Propofol – State entropy value 40-45 Final propofol rate about 12mg/kg/hr Remifentanil – RD50 to RR ≤10 (mcg/kg/min) No obvious relationship to age, weight or height Barker N et al. Pediatr Anesth 2007; 17: 948-55 Remifentanil SV – RD50 0.2 0.192 0.15 0.095 0.1 0.075 0.05 0 6m-3yr 3yr-6yr 6yr-9yr Barker N et al. Pediatr Anesth 2007; 17: 948-55 Remifentanil SV – Maximum tolerated dose 0.35 0.35 0.3 0.25 0.2 0.167 0.166 3yr-6yr 6yr-9yr 0.15 0.1 0.05 0 6m-3yr Barker N et al. Pediatr Anesth 2007; 17: 948-55 Remifentanil infusion rates – Adults vs Children Adults (20-60yrs) vs children (3-11yrs) IR50 block somatic response to skin incision Propofol 6mcg/ml 3mcg/ml IR50 adults = 0.08mcg/kg/min IR50 children = 0.15mcg/kg/min Munoz H et al. Anesth Analg 2007; 104: 77-80 Propofol/remifentanil – spontaneously breathing 100 children for MRI – mean age about 3 yr Propofol (10mg/ml) and remifentanil (10mcg/ml) Tsui BC et al. Pediatric Anaesthesia 2007; 15:397-401 Remifentanil – Timing of Morphine Bolus 120 adult patients – lap chole Morphine bolus at various time intervals from end of surgery (<20 mins to >40 mins) Pain scores similar in all groups Least postoperative morphine consumption in >40 mins group Munoz H et al. Br J Anaesth 2002; 88: 814-8 TIVA – What I do Manual infusion regime: Propofol 1% 50mls/Remifentanil 1mg/Ketamine 25mg 15-12-10-8mg/kg/hr - <6yo 12-10-8-6mg/kg/hr - >6yo Aiming for target of about 3mcg/ml TIVA – What I do TCI: Propofol 1% 50mls/Ketamine 25mg Target 10-6-3mcg/ml - <6yo Target 8-5-3mcg/ml - >6yo Remifentanil 1-3mg in 50mls Target 6-4ng/ml - <6yo Target 6-3ng/ml - >6yo Spontaneous breathing Avoid remifentanil Add ketamine to propofol Use local/regional anaesthesia Greater propofol requirements – may need to start at 18-20mg/kg/hr; don’t go below 10-12mg/kg/hr Propofol Infusion Syndrome (PRIS) First reported in children in 1992 Age 4 weeks to 6 years All had respiratory illnesses Propofol 7.4-10.0 mg/kg/hr Metabolic acidosis, bradycardia, myocardial failure, lipaemic blood, enlarged liver PRIS - Pathophysiology Like mitochondial cytopathy Impaired fatty acid oxidation Accumulation of acylcarnitine esters Propofol 1% at 4mg/kg/hr = 23g/kg/day lipid Worse if inadequate glucose supplemention (6-8mg/kg/min), steroids and catecholamines PRIS – Where is the Evidence? – Case Report 1 Wolf et al. Lancet 2001; 357:606 2yo head injury mean propofol dose 5.2mg/kg/hr Developed signs of PRIS on D4 Propofol stopped and CVVH instigated High levels of carnitines (malonyl and acyl) Mean glucose intake ≈ 2.5mg/kg/min Child survived – markers of fatty acid oxidation normal at 9 month follow-up PRIS – Where is the Evidence? – Case Report 2 Withington et al. Pediatr Anesth 2004; 14:505-8 5m old post cleft lip repair (3rd attempt) Mean propofol dose 11.7mg/kg/hr Developed signs of PRIS on D3 Propofol stopped and charcoal HP instigated Glucose intake <3mg/kg/hr Child survived Samples showed elevated acylcarnitines – normal at follow-up PRIS – Does it occur with Anaesthesia? 3 recent case reports in children: Age (yrs) Diagnosis Prop dose (mg/kg/hr) Prop duration Signs of PRIS (hours) 3 Cerebral aneurysm 6.5 8 A, HT, ↑CPK 7 Osteogenesis imperfecta 13.5 2.5 LA 12 Mitral valve disease <3 15 LA 16 Mitral valve disease <3 8 LA A - Acidosis; L – Lactic, HT – Hypotension; CPK – creatine phosphokinase PRIS – What can we do to prevent it? Avoid propofol! Avoid in high risk cases – PICU patients, steroids, catecholamines, fatty acid oxidation disorder Use 2% propofol Limit dose – adjuncts, avoid for postoperative sedation Maintain adequate glucose intake – 68mg/kg/min Monitor for lactic acidosis Questions ?