TIVA In Children

PIP Meeting Thursday 4 th 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 – issues Practical

    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 C p 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 0-10 25 20 15 10-20 20-30 30-40 20 15 10 15 10 10 10 10 10 40-50 50-60 >60 5 5 2.5

5 5 2.5

5 5 2.5

9-12 months 15 10 10 10 5 5 2.5

1-3 years 12 9 6 6 6 6 6 *mg/kg/hr Steur et al. Paediatr Anaesth 2004: 14: 462-7

11 10 7 6 9 8 3 2 5 4 1 0 0

Manual Infusion – 3m

10 20 30 40 50 60 70 80 90 100 110 120

Manual Infusion – 2y

3 2 1 0 0 9 8 11 10 5 4 7 6 10 20 30 40 50 60 70 80 90 100 110 120

10 9 8 7 6 5 4 3 2 1 0 0

Manual Infusion – 6y

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 V1 V2 V3 K 10 (min –1 ) K 12 (min –1 ) K 13 (min –1 ) K 21 (min –1 ) K 31 (min –1 )

Marsh

0.228 L/kg 0.463 L/kg 2.893 L/kg 0.119

0.112

0.042

0.055

0.0033

Kataria

0.52 L/kg 1.0 L/kg 8.2 L/kg 0.066

0.113

0.051

0.059

0.0032

Paedfusor

0.458 L/kg 1.34 L/kg 8.20 L/kg 70 x Weight -0.3

/458.4

0.12

0.034

0.041

0.0019

Why Paediatric models?

4 3 2 1 0 0 10 9 6 5 8 7 14 12 10 8 6 4 2 0 0 10 10 20 20 30 30 40 40 50 50 60 60 70 70 80 80 90 90 Paedfusor 100 110 Marsh 120 100 110 120

Plasma vs Effect Site Targeting

   C p C e = most commonly used depends on accuracy of PK models C e targeting leads to much higher plasma     Concentration gradient needed to drive drug into effect site Overshoot determined by model (k e0 ) Fast k e0 C e = less overshoot targeting more accurately predicts loss of consciousness

10 9 8 7 2 1 0 0 6 5 4 3

Plasma TCI

10 20 30 40 50 60

8 7 6 12 11 10 9 5 4 3 2 1 0 0

Effect site TCI

10 20 30 40 50 60

Adult propofol target concentrations (effect site)

Target (C e ) mcg/ml Plane of anaesthesia Clinical application <0.5

0.5-1.5

1.5-3.0

4.0-6.0

Light sedation Heavy sedation Light anaesthesia Insertion of lines, awake fibreoptic intubation Radiological imaging, endoscopy, surgery with LA Surgery with analgesia adjuncts General anaesthesia Major surgery

C p /C e 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

C p /C e 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) Calculated concentration Measured concentration No Bias 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) Calculated concentration Measured concentration Small Scatter

(No Bias)

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

Isobolograms Drug A

Propofol-Remifentanil Interaction 10 7 6 9 8 2 1 0 5 4 3 0 2

 7 min 

4 6

min

6 8



Blood propofol (µg/ml)

Vuyk et al. Anesthesiology 1997; 87: 1549-62

10 Adequate anesthesia Awakening

12 min

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

LOR Verbal LOR Eyelash LOR Noxious Struys. Anesthesiology 2003; 99: 802-12 Remifentanil 0 ng/ml 2.9  g/ml Remifentanil 2 ng/ml 2.4  g/ml Remifentanil 4 ng/ml 2.2  g/ml 2.8  g/ml 4.1  g/ml 1.8  g/ml 1.8  g/ml 1.7  g/ml 1.3  g/ml

Effect of remifentanil and RA on propofol C e

Propofol C e Nil Remifentanil Nitrous oxide Regional anaesthesia Sedation 1-1.5 mcg/ml <1 mcg/ml N/A <1 mcg/ml Maintenance of anaesthesia 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 ED 50 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

4 3 2 1 0 0 10 9 8 7 6 5 14 12 10 8 6 4 2 0 0

Propofol-remi interactions – effect on awakening (Cp50 – 2.2)

10 10 20 30 40 40 50 50 60 60

2 0 0 10 9 8 7 6 5 4 3 2 1 0 0 14 12 10 8 6 4

Propofol-remi interactions – effect on awakening (Cp50 – 2.7)

10 10 20 30 40 40 50 50 60 60

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 R x 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 – RD 50 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 – RD

50 0.2

0.192

0.15

0.1

0.05

0.095

0.075

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

0.15

0.1

0.05

0 0.167

0.166

6m-3yr 3yr-6yr 6yr-9yr

Barker N et al. Pediatr Anesth 2007; 17: 948-55

Remifentanil infusion rates – Adults vs Children

     Adults (20-60yrs) vs children (3-11yrs) IR 50 block somatic response to skin incision Propofol 6mcg/ml 3mcg/ml IR 50 IR 50 adults = 0.08mcg/kg/min 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 = 2 3g/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 (3 rd 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) 3 Diagnosis Prop dose (mg/kg/hr) 6.5

Prop duration (hours) 8 Signs of PRIS A, HT, ↑CPK 7 12 16 Cerebral aneurysm Osteogenesis imperfecta Mitral valve disease Mitral valve disease 13.5

<3 <3 2.5

15 8 LA LA 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 – 6 8mg/kg/min Monitor for lactic acidosis

Questions

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