Muscle relaxants and antagonists

in children

Lonneke Staals Erasmus MC- Sophia Children’s Hospital

Rotterdam

Conflicts of interest

MSD (formerly Organon NV)

financed research on sugammadex (PhD project).

Muscle relaxation in children

NMBA’s in children

PORC in children: is it a problem?

If you use muscle relaxation: monitor!

Do we really need to relax children?

Intubation: RSI

Working space

Reversal of NMB in children

E. Crins ©

Function of

Neuromuscular

Junction

Permeability of BBB

Plasma Protein Binding

Hepatic

function Renal

clearance

Volume of distribution

Volume of distribution

NMBAs in children

Depolarizing NMBA (succinylcholine):

Larger volume of distribution > lower concentration at NMJ

Higher dose is needed

Non-depolarizing NMBAs:

Larger volume of distribution > lower concentration at NMJ

Immature NMJ in neonates > less ACh release

Lower hepatic clearance in neonate

Shorter onset time

Longer duration of action Allegaert K, Pediatric Anesthesia 2014; 24: 30-38

PORC / residual NMB

Single intubating dose of NMBA

On recovery ward:

45% TOF ratio < 90%

After 2 hours:

37% TOF ratio < 90%

Debaene Anesthesiology 2003; 98:

1043-8

Higher risk on PORC

Renal insufficiency

Aminoglycoside antibiotics

Erythromycin

Gentamycin

In combination with steroids on the ICU

Premature children

Higher sensitivity of NMJ for non-depolarising NMBAs

Immature liver

PORC in children?

Observational study, for 1 month

TOF measured before extubation (and reported to anesthetist)

Choice up to anesthetist to antagonize or not

Postop to PACU: adverse events were noted

64 children, mean age 8.2 years; 35,1 kg Atracurium (41/ 10 continuous); Rocuronium (15, 2 continuous), Succinylcholine (6),

Vecuronium (1 continuous), Mivacurium (1 continuous)

Ledowski, Anesthesiology Research and Practice 2015

PORC in children?

23,4% routine TOF measurements during procedure

51,6% children antagonized with neostigmine (1 sugammadex)

TOF ratio < 90%: 28,1% After neostigmine: 37,5%

TOF ratio < 70%: 6,5% (2 patients) 1 x neostigmine; 1 no reversal

NO anesthetist changed his mind! TOF < 90% in 7 children, of which 2 < 70%

Few incidents on PACU (no difference)

PORC in children?

Higher incidence after administration of neostigmine: 37,5%

Deep NMB cannot be reversed by neostigmine

Long and variable onset time of neostigmine

False sense of safety!

Few anesthetists measure quantitative TOF routinely

No awareness for possible complications of PORC

Is PORC a problem?

Case control study

7500 Recovery patients, for 1 year

61 (0.8%) respiratory incidents on recovery ward Upper airway obstruction

Hypoxemia

Signs of respiratory distress

Inability to breath deeply

Complaints of respiratory or upper airway muscle weakness

Requiring re-intubation

Pulmonary aspiration

Matched controles Murphy, Anesth Analg 2008; 107 (1): 130-7

Murphy et al. Anesth Analg 2008; 107(1): 130-7

Is PORC a problem?

Incident group: mean TOF ratio 62% (± 20)

Control group: mean TOF ratio 98% (± 7)

Incident group: 9.5% acceptable TOF ratio

Control group: 90.5% acceptable TOF ratio

31 incidents: TOF ratio < 70%

TOF < 70% in none of the controles

Is PORC a problem?

All cases and controls:

NMB was reversed standard (neostigmine and glycopyrrolate)

Peripheral nerve stimulator with TOF was used!

Quantitative neuromuscular monitoring was not used

Monitoring NMB

Variability of duration of action NMBAs

Give repeated doses instead of continuous IV

Optimum level NMB!

Vital capacity?

Lifting the head?

Quantitative AMG!

TOF measuring in children

TOF bij kinderen

TOF monitors

Do we need muscle relaxation in children?

Intubation

Younger children?

Rapid sequence in children?

Improve surgical working conditions

Surgical working space?

Rapid sequence induction in children

Classic RSI:

Preoxygenation with 100% oxygen

No inflation of the lungs until ETT is placed

Application of cricoid pressure

Depolarizing NMBA (succinylcholine)

Apneic period of ± 60 sec

Intention to increase safety of patients considered at risk of

pulmonary aspiration of gastric content

Rapid sequence induction in children

Classic RSI:

Preoxygenation with 100% oxygen

No inflation of the lungs until ETT is placed

Application of cricoid pressure

Depolarizing NMBA (succinylcholine)

Apneic period of ± 60 sec

Intention to increase safety of patients considered at risk of

pulmonary aspiration of gastric content

Hypoxemia

Rapid sequence induction in children

Classic RSI in children = higher incidence of severe hypoxemia,

bradycardia and increased difficulties with intubation

Prevent hypoxia with gentle mask ventilation, pressure-limited

(not > 10-12 cm H2O)

Choice of muscle relaxant: depolarizing NMBA is NOT mandatory Engelhardt T, Pediatric Anesthesia 2015; 25: 5-8. Neuhaus D, Pediatric Anesthesia 2013; 23: 734-40

Effect of NMBAs during anesthesia

NMB

No change in ventilation pressures during thoracoscopy

Possibly more atalectasis in the lower regions of the lungs

Improved working conditions for the surgeon

Subjective impression of surgical conditions

Duration of surgical procedure

Children?

Maracaja-Neto, Acta Anaesthesiol Scand 2009; Boon, Trials 2013; Lindekaer, J Vis Exp 2013; Hedenstierna,

Int Care Med 2005

Effect of NMB on laparoscopic working space

Animal experimental model

CT: dimensions of working space

16 female piglets, 20 kg

Propofol/ sufentanil anesthesia iv

Tracheotomy, ventilation with +5 PEEP

Stepwise abdominal CO2 insufflation: 0 – 5 – 10 – 15 mmHg

CT scan at end-expiratory hold

NMBA and reversal

TOF monitoring (quadriceps femoris)

Rocuronium 1.4 mg/kg bolus, continuous 4 mg/kg/h

Group A:

no NMB during run 1 and 2

NMB during run 3

Reversal (sugammadex) before run 4

Group B:

NMB during run 1 and 2

Reversal (sugammadex) before run 3

Results

Vlot J, et al. Surg Endosc 2015; 29(8): 2210-6

Smaller animals

3 weeks old, female piglets, 6 kg

Endotracheal intubation

0-3-5-6-8-10-15 mmHg

Group A: no NMB

Group B: rocuronium

Vlot J et al, J Pediatr Surg. 2015; 50(3): 465-71

Results

NMB: no significant effect on laparoscopic working space

Also no effect on mean volume insufflated CO2 in ml

Prestretching of the abdominal wall: greater effect

Deep NMB?

PTC versus TOF ratio?

How to measure this in young children???

Reversal?

Acetylcholinesterase inhibitors

Neostigmine, edrophonium, pyridostigmine

ACh concentration increases in the NMJ: competition

Ceiling effect: residual NMB may be present

Slow onset of action: 7 – 13 minutes

Not effective in deep NMB

Adverse effects

Combination with atropine

Sugammadex

Modified g-cyclodextrin

Encapsulation of aminosteroids

Rocuronium >> vecuronium > pancuronium

Recovery TOF ratio

Sugammadex

0 1 uur

0 1 uur

Sugammadex in children

ASA 1-2; 28 days old – 65 years

91 patients: Infants: 28 days – 23 months n=8 !

Children: 2 – 11 year n=24

Adolescents: 12-17 year n=31

Adults: 18-65 year n=28

Rocuronium 0.6 mg/kg iv

Sugammadex at reappearance of the 2nd twitch of the TOF:

0.5, 1.0, 2.0, 4.0 mg/kg or placebo iv

Plaud et al. Anesthesiology 2009; 110: 284-94

Sugammadex bij kinderen

Dose-response curve

Children n=22

Pharmacokinetics

Sugmmadex vs neostigmine in children

3 prospective trials, in total 180 children

Reversal with sugammadex 2 or 4 mg/kg vs neostigmine 40 or 60 mcg/kg

Shorter reversal time and

tracheal extubation times Tobias JD, Ped Anesthesia 2017

Reversal of rocuronium with sugammadex 2 mg/kg or •neostigmine 50 mg/kg in children Meretoja O, Pediatric Anesthesia 2010; 20: 591-604

Sugammadex in children

Dexamethason causes inhibition of sugammadex reversal in vitro: capturing / displacement interaction

Unclear which dose of dexamethason is required to inhibit reversal in humans

Dexamethason: 0,5 mg/kg IV: does not affect reversal time of sugammadex in pediatric patients undergoing (A)TE:

60 ASA I-II children 3-8 years old

97,7 sec (±23,9 sec) +dex vs 91,1 sec (±39,5 sec) in placebo group

Gulec E. Anesth Analg 2016; 122: 1147-52

Sugammadex in neonates

Case reports

Rocuronium may cross BBB if function is impaired

centrally acting NMBA: autonomic dysfunction, seizures, neuronal cell death

2 day old infant (3,3 kg) on PICU with esophageal atresia. Rocuronium infusion during repair.

Postop PORC and hypotonic, dilated pupils, possibly central accumulated rocuronium.

Sugammadex 16 mg/kg IV: 90 sec reversal. Pupils became reactive.

Cohort of 23 neonates (1-7 days old)

4 mg/kg sugammadex to reverse profound NMB: 1,2-1,3 min

No adverse events or changes in vital signs Langley RJ, Ped Anesth 2016; 26: 109-111. Alonso A, Eur J Anaesthesiol 2014; 31:163-5

Sugammadex in children

Limited data: few prospective trials

Neonates may need a higer dose: 4 mg/kg

No significant adverse effects were noted

No association with anaphylaxis in children

Toxicity / Long term?

Advice of Pediatric formulary in the Netherlands

1 month – 18 year: 2 mg/kg single dose

In emergency situations: higher dose (up to 16 mg/kg)

Tobias JD, Pediatric Anesthesia 2017; 27: 118-25; Tadokoro F, Pediatric Anesthesia 2018; 28: 654-9

Neuromuscular block in children

NMBAs in children:

Prolonged duration of action of non- depolarizing NMBAs

PORC and children: Underrecognized problem

Should we relax?

Not necessarily!

Modified RSI in children: no depolarizing NMBA needed

And if you relax….Use quantitative NMB monitoring

Sugammadex in children As effective as in adults