Transcript Slide 1

Recovery from NMBA :
problems and solutions
Wirat Wasinwong
Anesthesia department
Faculty of Medicine
Prince of Songkla University
Muscle relaxant
• 1912 : curare
• 1970s : pancuronium
• 1980s : vecuronium, cisatracurium,
mivacurium, rocuronium
• rapacuronium
Ideal muscle relaxant
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Onset
Duration
Metabolite/accumulation
Safety
Reversibility
Cost
Rocuronium
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Dose 0.6-0.9 mg/kg
Onset 60-90 sec.
Duration 20-40 min.
Minimal cardiovascular effect
Hepatorenal excretion
Dam and Goldman
“ Today, the most common cause of
postoperative respiratory inadequacy is
the use and misuse of muscle relaxant
drugs”
Anesthesiology 1961; 22:699-707
Postoperative residual curarization
(PORC)
• 1979
– Residual postoperative weakness
– Incomplete recovery
– Ventilatory complications
• Kopman, Yee and Neuman
“ normal vital muscle function,
including normal pharyngeal
function, requires the TOF ratio at
the adductor pollicis to recover to
> 0.9 ”
Anesthesiology 1997; 86:765-71
relationship between receptor occupancy and
neuromuscular monitoring
receptor occupation (%)
125
no neuromuscular block
block
100
75
50
25
0
concentration
A.H. Bom , Dept. Pharmacology, Organon Newhouse, Scotland, UK
Minimal residual paralysis
• Impair pharyngeal muscle function
• Reduce lower esophageal sphincter
tone
• Increase risk
– Aspiration
– Upper airway obstruction
– Impair hypoxic ventilatory response
Eriksson LI, et al. Anesthesiology 1997;87: 1035-43.
Eikerman M, et al. Anesthesiology 2003; 98: 1333-7.
Eriksson LI, et al. Anesthesiology 1993;78: 693-9.
Incidence of residual block
Study
year
n
TOF
Cammu G
2002 30
<O.7
Gatke MR
2002 120 <0.8
Hayes AH
2001 150 <0.8
Baillaed C 2000 568 <O.7
Berg H
1997 691 <0.7
Shorten GD 1992
NDMR
cisatracurium
rocuronium
roc with TOF
without TOF
vecuronium
atracurium
rocuronium
vecuronium
pancuronium
atr, vec
panc with TOF
wthout TOF
PORC reverse
40 %
47
3
16.7
64
52
47
42
26
5.3
15
47
Y
N
Debeane B,et al. Anesthesiology,2003;98(5):1042-8
Naguib M, et al. Br J Anaesth 2007;98(3):302-16.
Murphy GS,et al. Anesth Analg 2004,98:193-200
Berg H,et al. Acta Anaesthesiol Scand 1997;41:1095
Pancuronium in cardiac surgery
• Increase duration of weaning and
tracheal extubation
• Significant muscle weakness after
tracheal extubation
Murphy GS, et al. Anesth Analg 2002;95:1534-9
Murphy GS, et al. Anesth Analg 2003;96:1301-7
Thomas R, et al. Anaesthsia 2003;58:265-70
How to avoid PORC
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Avoid long acting NMBA
Avoid unnecessary deep block
Antagonize block at the end
Do not initiate reversal before
– Spontaneous muscle activity presents
– 3 or 4 response of TOF
• Use reliable clinical evaluation
• Objective neuromuscular monitoring
• Objective neuromuscular monitoring
is evidence based practice
Ericksson LI. Anesthesiology 2003;98:1037-9.
Neuromuscular blockade reversal
Disadvantages of anticholinesterases
• Inability to antagonize profound block
• Relatively slow onset of action to peak1
–neostigmine (7–11 min)
–pyridostigmine (15–20 min)
• Muscarinic effects
–bradycardia and hypotension
–bronchoconstriction and excessive
secretions
–nausea and vomiting
1. Bevan DR et al. Anesthesiology. 1992; 77:785–805
Sugammadex
top / bottom view
side view
a-cyclodextrin
6 glucose units
b-cyclodextrin
7 glucose units
g-cyclodextrin
8 glucose units
Hydrophilic exterior : polar hydroxyl group
NaO 2C
CO 2Na
S
O
NaO 2C
S
O
O
HO
OH
S
O
OH
HO
O
OH
HO
OH
O
O
O S
OH
HO
S O
NaO 2C
O
OH
O
S
O
HO
OH
OH
OH
HO
O
HO
O
O
S
O
NaO 2C
S
CO 2Na
Hydrophobic cavity
CO 2Na
CO 2Na
Carboxyethyl group
Quaternary nitrogen
Sugammadex
• Water-soluble complex formation
1:1 ratio with steroidal muscle relaxants
• rocuronium > vecuronium >> pancuronium
Sugammadex
• No effects on acetylcholinesterase or any
other receptors (nicotinic, muscarinic)
• Acid-base change: no effects on
sugammadex efficacy
Pharmacokinetics
• Elimination half-life ≈100 min
• Clearance 120 mL/min
– similar to normal glomerular filtration rate
• Volume of distribution 18 L
– > blood volume, but substantially
< the volume of the extracellular space
• 59–80% of administered dose excreted
in the urine over 24 h
Gijsenbergh F et al. Anesthesiology. 2005; 103:695–703
Sugammadex increases renal
excretion of rocuronium
• 14% of an administered rocuronium dose
is excreted in the urine within 0–24 h
• With concomitant administration of
sugammadex (8.0 mg/kg at 3 min) renal
excretion of rocuronium within 0–24 h
increased to 39–68%
Gijsenbergh F et al. Anesthesiology. 2005; 103:695–703
Sugammadex
• Drugs that potentiate effects of
neuromuscular blocking agents (Mg2+,
aminoglycosides) may need higher
sugammadex dose
• Other steroids
– Cortisone, atropine, verapamil
– 120-700 time < rocuronium
– Clinical insignificant
Clinical studies
Reversal of Rocuronium-induced Neuromuscular Block
by the Selective Relaxant Binding Agent Sugammadex :
A Dose-finding and Safety Study
Sorgenfrei IF. Anesthesiology 2006;
104:667–74
• Randomized, placebo-controlled,
assessor-blinded trial
• 27 male patients.
• 0.6 mg/kg rocuronium
• Sugammadex 0.5, 1, 2, 3 ,4 mg/kg at T2
of TOF
Reversal of Rocuronium-induced (1.2 mg/kg) Profound
Neuromuscular Block by Sugammadex
A Multicenter, Dose-finding and Safety Study
de Boer, HD, et al. Anesthesiology 2007; 107:239–44
• phase II, multicenter,assessorblinded, placebo-controlled, parallel
study.
• 43 patients
• 5-min reversal after rocuronium
• Adverse effects : diarrhea, light
anesthesia
Early Reversal of Profound Rocuronium-induced
Neuromuscular Blockade by Sugammadex in a
Randomized Multicenter Study
Efficacy, Safety, and Pharmacokinetics
Sparr HJ, et al. Anesthesiology 2007; 106:935–43
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98 male adult patients
Reversal at 3,5 and 15 min
After rocuronium 0.6 mg/kg.
Adverse effect: sucking, moving,
glimace, cough
Anesth Analg 2007;104(3):569-74
Sugammadex
• 3 times more rapid than edrophonium
• 10 times more rapid than neostigmine
Side effects
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Hypotension
Cough
Vomitting
Dry mouth
Abnormal smell
Sensation of a changed temperature
Abnormal level of N-acetyl glucosaminidase in
urine
Safety
• Biologically inactive
• Not bind to plasma proteins
• Sugammadex well tolerated in studies to date
Gijsenbergh F et al. Anesthesiology. 2005; 103:695–703
Limitation
• succinylcholine, benzylisoquinolinium
– Ineffective
– After reversing with sugammadex
: difficult ,unpredictable dose of rocuronium,
vecuronium to re-establish block
: more intense block benzylisoquinolinium
: decrease dose
Limitation
• Cost
• Sugammadex-rocuronium complex in
renal disease : unclear
• Reverse profound block with inadequate
dose : incomplete recovery
Approval of Sugammadex 11-Mar-08 07:05 pm
• Schering-Plough announces the FDA Advisory
Committee unanimously recommends U.S.
approval of sugammadex, the first and only
selective relaxant binding agent (19.82 +0.17) UpdateCo announced that the U.S. Food and Drug
Administration (FDA) Advisory Committee on
Anesthetics and Life Support has recommended
sugammadex for approval. After reviewing data on
the safety
Gantacurium
• Lack of accumulation
• Dose 2.5-3 x ED95
– Maximum block onset within 90 sec.
• 25-75% recovery index = 3 min.
– 7 min. for mivacurium
– 9 min. for rapacuronium
– 14 min. for cisatracurium
• Clinical duration < 10 min.
• Complete recovery to TOF>0.9 within 15 min.
Thank
you