TIVA In Children

1
TIVA In Children

• PIP Meeting
• Thursday 4th June 2009
• Dr Oliver Bagshaw

2
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)

3
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

4
TIVA Indications in Children

• Previous NV post anaesthesia
• High risk of NV post anaesthesia, e.g.
  strabismus, TsAs, orchidopexy
• Scoliosis surgery
• Myasthenia gravis
• Reduce blood loss e.g. FESS procedure

5
TIVA in children

• Advantages
• Less pollution
• Less NV
• Improved quality of recovery - delerium
• No laryngospasm
• No risk of MH

• Disadvantages
• Need IV access
• Cant monitor blood levels
• Delivery problems may go unrecognised
• Requires metabolism
• Risks of large doses of propofol PRIS
• More fiddly wasteful

6
TIVA in children Practical issues

• Cant always establish IV access prior to
  induction
• Propofol induction often prolonged with TCI
  kids may squirm a bit!
• Try and avoid relaxants
• Cant always have IV cannula exposed

7
TIVA in children - Options

• Manual infusion regime
• TCI regime

8
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
9
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
gt60 2.5 2.5 2.5 2.5 6
mg/kg/hr Steur et al. Paediatr
Anaesth 2004 14 462-7
10
Manual Infusion 3m
11
Manual Infusion 2y
12
Manual Infusion 6y
13
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

14
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 gt50 children
• Age range 3-16 years
• Minimum weight 15kg

15
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
16
Why Paediatric models?
Paedfusor
Marsh
17
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

18
Plasma TCI
19
Effect site TCI
20
Adult propofol target concentrations (effect site)
Target (Ce) mcg/ml Plane of anaesthesia Clinical application
lt0.5 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
21
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 lt2 mins

22
Cp/Ce Equilibration Times Targeted Infusions

• Propofol
• Plasma TCI 15-20 mins
• Effect site TCI lt5 mins
• Remifentanil
• Plasma TCI 5-7 mins
• Effect site TCI 1 min

23
How accurate are TCI systems?
24
Assessment of accuracyMeasurement 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
Significant bias
Calculated concentration Measured concentration
25
Assessment of accuracyMeasurement 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)
Large Scatter (No Bias)
Calculated concentration Measured concentration
26
(No Transcript)
27
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)

28
Arterial isoflurane tension 45 80 of
end-tidal!!!
29
Context Sensitive Half-time
30
Context Sensitive Half-time - propofol
31
Opioid hypnotic interactions
32
Isobolograms
Drug B
Drug A
33
(No Transcript)
34
Propofol-Remifentanil Interaction
Vuyk et al. Anesthesiology 1997 87 1549-62
35
Remifentanil

• May reduce clearance of propofol
• Can lead to under prediction of target
  concentrations
• Synergistic effect with propofol
• Does it produce tolerance?

36
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
37
Effect of remifentanil and RA on propofol Ce
Propofol Ce Nil Remifentanil Nitrous oxide Regional anaesthesia
Sedation 1-1.5 mcg/ml lt1 mcg/ml N/A lt1 mcg/ml
Maintenance of anaesthesia 4-6 mcg/ml 3-4 mcg/ml 4-5 mcg/ml 3-4 mcg/ml
38
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
39
Propofol-remi interactions
Drover D et al. Anesthesiology 2004 100 1382-86
40
Propofol-remi interactions effect on awakening
(Cp50 2.2)
41
Propofol-remi interactions effect on awakening
(Cp50 2.7)
42
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
43
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 lt10 best predictor of apnoea

Ansermino JM et al. Pediatric Anesthesia 2005
15 115-121
44
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
45
Remifentanil SV RD50
Barker N et al. Pediatr Anesth 2007 17 948-55
46
Remifentanil SV Maximum tolerated dose
Barker N et al. Pediatr Anesth 2007 17 948-55
47
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
48
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
15397-401
49
Remifentanil Timing of Morphine Bolus

• 120 adult patients lap chole
• Morphine bolus at various time intervals from end
  of surgery (lt20 mins to gt40 mins)
• Pain scores similar in all groups
• Least postoperative morphine consumption in gt40
  mins group

Munoz H et al. Br J Anaesth 2002 88 814-8
50
TIVA What I do

• Manual infusion regime
• Propofol 1 50mls/Remifentanil 1mg/Ketamine 25mg
• 15-12-10-8mg/kg/hr - lt6yo
• 12-10-8-6mg/kg/hr - gt6yo
• Aiming for target of about 3mcg/ml

51
TIVA What I do

• TCI
• Propofol 1 50mls/Ketamine 25mg
• Target 10-6-3mcg/ml - lt6yo
• Target 8-5-3mcg/ml - gt6yo
• Remifentanil 1-3mg in 50mls
• Target 6-4ng/ml - lt6yo
• Target 6-3ng/ml - gt6yo

52
Spontaneous breathing

• Avoid remifentanil
• Add ketamine to propofol
• Use local/regional anaesthesia
• Greater propofol requirements may need to start
  at 18-20mg/kg/hr dont go below 10-12mg/kg/hr

53
Ketamine TCI -Children

• Manual infusion regime to maintain target
  concentration of 3mg/l 11, 7, 5, 4 regime
• Context sensitive t½ less than adults 30mins at
  1hr, increasing to 55mins at 5hrs
• Prolonged awakening nearly 4hrs after 2hr
  infusion

54
Ketamine TCI - Adults

• Propofol/ketamine combination to provide clinical
  anaesthesia
• Ketamine target 0.3mg/l
• Mean ketamine dose 0.94mg/kg/hr (0.4-1.4)
• Mean propofol dose 9mg/kg/hr
• MDPE and MDAPE acceptable, but venous samples, so
  probably underestimating levels

Gray et al. Can J Anesth 1999 46 957-61
55
Ketofol ketamine/propofol combinations

• Mainly used in AE 11 ratio
• Tend to use lower doses of ketamine in TIVA
  101
• Can mix in same syringe
• Not much evidence that ketamine influences BIS,
  propofol requirements or need for opioids postop

56
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

57
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

58
PRIS Where is the Evidence? Case Report 1

• Wolf et al. Lancet 2001 357606
• 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

59
PRIS Where is the Evidence? Case Report 2

• Withington et al. Pediatr Anesth 2004 14505-8
• 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 lt3mg/kg/hr
• Child survived
• Samples showed elevated acylcarnitines normal
  at follow-up

60
PRIS Does it occur with Anaesthesia?

• 3 recent case reports in children
• A - Acidosis L Lactic, HT Hypotension CPK
  creatine phosphokinase

Age (yrs) Diagnosis Prop dose (mg/kg/hr) Prop duration (hours) Signs of PRIS
3 Cerebral aneurysm 6.5 8 A, HT, ?CPK
7 Osteogenesis imperfecta 13.5 2.5 LA
12 Mitral valve disease lt3 15 LA
16 Mitral valve disease lt3 8 LA
61
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

62
Questions

• ?

63
Use of BIS

• Adult-based algorithm
• Moderate correlation with predicted Cp in
  children
• Less if under 12 months age
• Does not always accurately predict Ce at higher
  propofol concentrations

64
BIS in TIVA

• Moderately correlated with propofol level not
  as good as adults
• Significant age variation less accurate lt1yo
• Often considerable individual variation
• Does not always accurately predict Ce at higher
  propofol concentrations
• Affected by adjuncts