Recovery from NMBA : problems and solutionsRecovery from NMBA : problems and solutions

Wirat WasinwongWirat WasinwongAnesthesia department

Faculty of MedicinePrince of Songkla University

Muscle relaxant

• 1912 : curare

• 1970s : pancuronium

• 1980s : vecuronium, cisatracurium, mivacurium, rocuronium

• rapacuronium

Ideal muscle relaxant

• Onset

• Duration

• Metabolite/accumulation

• Safety

• Reversibility

• Cost

Rocuronium

• 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

Anesthesiology 1997; 86:765-71

• 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 ”

relationship between receptor occupancy and neuromuscular monitoring

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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 blockStudy year n TOF NDMR PORC

reverse

Cammu G 2002 30 <O.7 cisatracurium 40 % Y

rocuronium 47Gatke MR 2002 120 <0.8 roc with TOF 3 without TOF 16.7Hayes AH 2001 150 <0.8 vecuronium 64 atracurium 52 rocuronium 47Baillaed C 2000 568 <O.7 vecuronium 42

NBerg H 1997 691 <0.7 pancuronium 26 atr, vec

5.3Shorten GD 1992 panc with TOF 15 wthout TOF 47

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

• 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

-cyclodextrin

6 glucose units

-cyclodextrin

7 glucose units

-cyclodextrin

8 glucose units

Hydrophilic exterior : polar hydroxyl group

O

S

OH

OH

O S

OH

OH

O

OS

OH O

O

S

OHOH OO

S

OH

OH

O

OS

OH

OH

O

OS

OH

OH

O

O

S

OHOHO

O

OH

CO2Na

CO2Na

NaO2C

NaO2C

NaO2C

NaO2C

CO2Na

CO2Na

Hydrophobic cavity

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 StudySorgenfrei IF. Anesthesiology 2006 10466; :7 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) ProfoundNeuromuscular Block by SugammadexA Multicenter, Dose-finding and Safety Study

de Boer, HD, et al. Anesthesiology 2007 107239; : –44

• phase II, multicenter,assessor-blinded, placebo-controlled, parallel study.

• 43 patients

• 5-min reversal after rocuronium

• Adverse effects : diarrhea, light anesthesia

Early Reversal of Profound Rocuronium-inducedNeuromuscular Blockade by Sugammadex in aRandomized Multicenter StudyEfficacy, Safety, and Pharmacokinetics

Sparr HJ , et al. Anesthesiology 2007 106935 4; : –3

• 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 • 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) -Update-

Co 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 youThank you