TIVA in childrenPeter SquireRCH, Melbourne

BENEFITSTYPES OF SURGERYDELIVERY SYSTEMS (and TCI)NEW TECHNOLOGY

TIVA in childrenPeter SquireRCH, Melbourne

Society of Intravenous Anaesthesia

Berlin 2009 Singapore 2011

~75 articles related to propofol/TIVA in last 5 years

Same number as the ten years preceeding

Growing enthusiasm

TIVA advantages

Simple delivery systems No pollution Portable PONV PAED MH proof Spinal surgery (controlled hypotension; motor-evoked

potentials) Neurosurgery (ICP,Cerebral metabolic protection) Shared airway procedures (eg. bronchoscopy) Cheaper? Less airway “spasms”?

Simple anaesthetic delivery systems

EASY TO USEVARIABLE RATESSYRINGE SIZES and MAKEALARMSDOWNLOAD DATAROBUSTBATTERY LIFE

Simple anaesthetic delivery systems...

Benefits:Post-operative nausea and vomiting

European Journal of Anaesthesiology 1998, 15, 433-570 trials (57 adult, 13 children)4074 vomiting as end-point; 3516 nausea; 742 n and v

“3.5 and 5.7-fold reductions in vomiting in adults and children respectively when propofol used at induction and maintenance”

PONV (ctd)

BJA 2002; 88(5):659-68 Volatile anaesthetics may be the main cause of early but not delayed postoperative vomiting: a randomized controlled trial of factorial design C.C Apfel et al

5 way factorial design (gender, type of surgery, anaesthetic maintenance, opiod use, antiemetic use)

1180 patients (593 children) elective ENT or strabismus surgery

Strongest risk factor for vomiting was use of volatile anaesthetics compared with propofol

(Odds ratio for Iso and Sevo were 3.4 and 2.8)

BJA 2002; Apfel et al (ctd)

Early post-op period (0-2 hrs) showed volatiles as also being the clear risk factor (40% PONV cw 10% PONV with propofol)

(Adjusted Odds ratios: Iso 19.8, Sevo 14.5)

Depends somewhat on degree of exposure

“Irrespective of volatile type this factor alone was several orders of magnitude stronger than all other factors (including antiemetics) in early post-op period”

PONV (ctd)Pediatric Anesthesia 2004 14:251-5

135 boys with Hx motion sickness/PONV

Sevo vs Prop/Ketamine; all had Ilioinguinal block. No premed or nitrous

No opiates

Anesth Analg 2003; 97:62

“PONV is debilitating, costly and prevalent”

2X incr vomiting in children

Adenotonsillectomy, squint repair, herniae, orchiopexy and penile surgery

Use of Propofol and avoiding volatiles was most efficacious measure (1A evidence)

Should we be extending the benefit to paediatric day-case?

Benefits:Post Anaesthesia Emergence Delirium (PAED)

Incidence Scoring systems Risk factors Prevention

16 retinoblastoma kids1-5 yoAll had Sevo inductionRandomised to Sevo or Propofol Had alternate agent for next exam

....good study but small numbers!

Paeds Anesthesia 2009; 19; 748-55

Prospective study of 179 dental patients

No difference in PAED scores

Sevo group significantly higher PONV and nursing interventions

Propofol group discharged 10 mins later

“...PAED is hard to quantify”

AANA JournalDec 2010Vol 78, p471

Benefits:Laryngospasm/ Bronchospasm

Lancet 2010; 376; p773Prospective multivariate analysis9297 questionnaires

Scoliosis surgery

SSSSSSEP’s

SSEP’s and MEP’s suppressed by volatile agentsSSEP’s and MEP’s suppressed by volatile agentsNo muscle relaxantsNo muscle relaxantsClonidine +/- KetamineClonidine +/- Ketamine

Types of surgery:

NeurosurgeryMaintain CO2 /CBF coupling

Avoid BP fluctuations

Clear-headed emergence

Avoid coughing/ICP surges

(TIVA interferes with mapping for epilepsy surgery)

Types of surgery:

Inhaled foreign body

ENT/Bronchoscopy

Tonsillectomy?

CARDIAC SURGERY

Types of surgery

Radiology/ catheter lab

Cardiac

Burns baths

Hospital transfers

ICU sedation

...most surgery suited to TIVA really

Age Vd (ml/kg) Elimination t1/2 (min)

Clearance (ml/min/kg)

1-3 yo 9500 188 53

3-11yo 9700 398 34Adult 4700 312 28

Propofol differences between children & adults

DELIVERY SYSTEMS and PROPOFOL TCI

Why TCI?

Bolus: Ct x V1

Elimination: Ct x Cl = Ct x V1 x k10

Transfer: Ct x V1(k12e-k21t + k13e-k31t)

So the dose: Ct x V1(k10+k12e-k21t+k13e-k31t)

Do we need all this maths!!

TCI provides a simple way of adjusting the proportion of drug in a plasma or ‘effect-site’

Propofol pharmacokinetics

20 children, adult algorithmHigh targets required as model over-predictedRevised model 10 children, better accuracy

Diprifusor 1996

Anesthesiology 1994, 80(1):104

53 children age 3-11 yrsAnaesthesia maintained with Halothane/N2O658 Venous specimens20: 3mg/kg then nil else18: 3.5mg/kg then 9mg/kg/hr15: 3.5mg/kg then 12mg/kg/hr (30min) then 7.5mg/kg/hr until conclusion

....Complicated pharmacokinetic analyses to achieve “best”estimate of volumes and clearances to describe the observed concentrations in all the children

Anesthesiology 1994, 80(1):10453 children age 3-11 yrsAnaesthesia maintained with Halothane/N2O20: 3mg/kg then nil else18: 3.5mg/kg then 9mg/kg/hr15: 3.5mg/kg then 12mg/kg/hr (30min) then 7.5mg/kg/hr until conclusion

....Complicated pharmacokinetic analyses to achieve “best”estimate of volumes and clearances to describe the observed concentrations in all the children

NO FORMAL PROSPECTIVE ANALYSIS OF PREDICTIVE PERFORMANCE

Kataria’s model one of the most widely used (Anesthesia & Analgesia 2008; 106,no.4;p1109 Rigouzzo et al.The relationship between BIS and propofol during TCI))

Anesthesiology 2000; 92:727-38Pooled data from multiple small studies270 patients, 4,000 specimens (some arterial, some venous)(96 children, 1113 specimens including Kataria’s data of 657)Some bolus only, some with infusions

BJA 2003; 91(4): 507-13 Prospective evaluation of 29 patients Age 1-15 Cardiac surgery with CPB (22) or cardiac cath procedures (7) Maitre Alfentanil TCI for surgery group Arterial levels (up to 9 per patient) 212 specimens Performance errors 4-10%

Absalom et al; BJA 2003 91(4):507-13

Linking Pk and PD: the elusive ke0

BIS/ Entropy/ AAEP’s “more precise” targeting of where your drug works Bigger initial bolus

Anesthesiology 2004; 101:126925 adults, 25 childrenA-Line monitorSub-maximal propofol bolus“peak effect” recordedValues entered into Kataria & Paedfusor algorithms

results:

keo 0.41 min‾1 Katariakeo 0.91 min-1 Paedfusor

....what about inter-individual variability?

Our traditional skills in monitoring and titrating agents are still essential in TIVA

RCH study

40 patients aged 3-16

Kataria or Paedfusor

Arterial access

Specimens in a similar fashion to Absalom et al (2003)

Use a BIS where possible (many neurosurgical patients)

Look for accuracy and benefits

Patient 2

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Time after Start of TCI Propofol (minutes)

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ofol

pla

sma

leve

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cg/m

L)

AVGBIS

Cpred

Cmeas

2 per. Mov. Avg. (Cpred)

4 yo posterior fossa craniotomy & excision of ependymoma

(Hx of severe emergence agitation)

Patient 1

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Time after Start of TCI Propofol (minutes)

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ofol

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2 per. Mov.Avg. (Cpred)

5 yo craniotomy for debulking glioma

Patient 1

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0 30 60 90 120 150 180 210 240

Time after Start of TCI Propofol (minutes)

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ofol

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AVGBIS

Cpred

Cmeas

Remi x10

2 per. Mov.Avg. (Cpred)

2 per. Mov.Avg. (Remix10)

5 yo craniotomy for debulking glioma (showing remifentanil)

Patient 5

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Time after Start of TCI Propofol (minutes)

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po

fol p

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a le

vel (

mcg

/mL)

AVGBIS Cpred Cmeas 2 per. Mov. Avg. (Cpred)

6 yo posterior fossa tumour resection (obstructive hydrocephalus)

Propofol synergists

Remifentanil

Ketamine/ “Ketofol”

Clonidine/ Dexmedetomidine

“low-dose”volatile agents

BZD’s

...remember to give a balanced anaesthetic! (Lundy)

Anesthesiology 2003; 99: 802Struys et al.

45 women

BIS, AAI

LORverbal LORlash LORnoxious

Minto’s Remi effect-site algorithm

..LOR at higher BIS levels and lower Ce propofol when adding Remi

Integrated anaesthetic tools

Propofol synergists...Remifentanil

“a drug that needs another drug” Remifentanil the obvious choice (effects on BIS-

Perth study Anesthesia & Analgesia 2007 104; 2; p325;

Anaesthesia 2009, 64, p 301; BJA 2003 90(5) p623-9 ; hyperalgesia?; rates for spont venting…(Pediatric Anesthesia 2007 17: 948-95)

Ketamine-great complement Dexmedetomidine/Clonidine

Double aortic arch (using PIVA)

6 kg, 4 mth old

Stridor and difficulty feeding.

Bronchoscopy and CT spiral angio

Left thoracotomy

Remi/Sevo then surgical intercostal LA plus 0.1mg/kg Morphine- extubate and feed

30 mcg/kg/50ml »» 10ml/hr = 0.1 mcg/kg/min

Propofol synergists.....Ketamine

Dexmedetomidine

TIVA disadvantages

Needs to be considered in the context of available alternative techniques

Awareness Vagal responses Involuntary movements Pain on injection Anaphylactoid/Anaphylactic reactions are rare (what do we

do with egg, peanut and food allergies?) PRIS Infection of infusion solutions Line dead space, Anti-reflux, flow rates, excess fluid loads in

small patients

Propofol Infusion Syndrome

Rare

Potentially fatal

May be preventable

Is it the drug or the carrier vehicle?

Mitochondria: respiratory chain inhibition or impaired fatty acid

metabolism

Anaesthesia 2007; 62 p690-701; PCA Kam, D Cardone

New propofol formulations

Involved study Similar pharmacokinetics/dynamics Reduced microbial contamination More pain on injection No difference in haematological or renal side effects

Pharmaceutics

Lipuro (MCT’s) Fospropofol Where’s the 2%? ....or 6%?

Closing the loop

BIS paediatric ,Entropy-need to correlate different levels with different Propofol levels Anesthesia & Analgesia 106; 4; April 2008 p1109 (cerebral pharmacodynamic feedback may help adapt Cpt and blunt interindividual variability)

Awareness could be 8X^ adults- does this matter? EEG study at RCH currently Children have different autonomic responses to

anaesthesia Effect of drugs

Expired propofol metabolites

Anesthesiology 2007 ; 106:659-6411 patientsElective surgery (with epidural) Constant rate manual infusions (3mg/kg/hr for one hr-then 6mg/kg/hr for one hr- then 9mg/kg/hr)Proton Transfer Mass Spectrometry plus blood levels

Rapid propofol analyser

Frequent sampling possible

Finally allows studies more efficiently?

Accuracy?

Cost?

Potential advances in TCI are huge

Conclusion

Choose your patient, list and procedure TCI Propofol as a mainstay Pick the model you’re comfortable with Add a synergist- must be titratable! Close the loop (BIS, Entropy, AEP’s) Enjoy the benefits START A TRIAL

THANK YOU!