Anticolinestherases 2004

Gli anticolinesterasici: quando,come e perché

Claudio Melloni

Anestesia e Rianimazione

Ospedale di Faenza(RA)

melloniclaudio@libero.it

Fisiologia e farmacologia degli anticolinesterasici

Colinesterasi• Colinesterasi vera:o acetilcolinesterasi

legata alle membr basali ,giunzioni colinergiche

• Pseudo o butirilcolinesterasi,plasmatica,libera nel plasma e presente anche nel fegato,rene,cervello ,pelle,musc liscio intest.

• Essa idrolizza anche SCC,mivacurium,AL esterei,diamorfina,aspirina

• (altre esterasi aspecifiche tissutali metabolizzano remif. e esmolol…)

Modello schematico del recettore Ach nicotinico(sec.Imoto,Alberts,Taylor)

Composizione delle subunità nel recettore Ach nicotinico

neostigmina

The active surface of the acetylcholinesterase is best viewed as having two subunits, the anionic site and esteratic site. The anionic site is concerned with binding and orienting the substrate molecule. The esteratic site is responsible for the hydrolytic process. A second “anionic” site, which became known as the “peripheral” anionic site, was proposed based on binding of bis-quaternary ammonium compounds. Binding of ligands to the peripheral anionic site causes inactivation of the enzyme, although the mechanism of inhibition is not clear. There is also evidence for a role of the peripheral anionic site of acetylcholinesterase in neurite regeneration and outgrowth and in the growth and differentiation of spinal motor neurons.

Neostigmine and edrophonium are the most commonly used anticholinesterases in the operating room. Edrophonium is a prosthetic inhibitor that binds to the anionic site on the acetylcholinesterase by electrostatic attachment and to the esteratic subsite by hydrogen bonding. The dissociation half-life of this reaction is less than 0.5 min. The in vivo activity of edrophonium is predicted to be rapid in onset, and, clinically, edrophonium has a more rapid onset of action than neostigmine. Neostigmine and pyridostigmine are oxydiaphoretic (acid transferring) inhibitors of acetylcholinesterase. Neostigmine and pyridostigmine transfer a carbamate group to the acetylcholinesterase, which forms a covalent bond at the esteratic site. The dissociation half-life of the carbamate-enzyme bond of neostigmine is at least 7 min. However, it should be noted that the pharmacologic actions of neostigmine and edrophonium are not limited to enzyme inhibition. Evidence suggests that the direct influences of the acetylcholinesterase inhibitors on neuromuscular transmission independent of enzyme inhibition involve at least three distinct, although possibly interacting mechanisms: (1) a weak agonist action, (2) the formation of desensitized receptor-complex intermediates, and (3) the alteration of the conductance properties of active channels.

Condizioni accompagnate da up o down regolazione del recettore per Ach.

• Up regulation• Traumi midollari• Ictus• Ustioni• Immobilità prolungata• Prolungata esposizione a

bloccanti nm.• Sclerosi multipla• Sindr di Guillain Barrè

• Down regulation• Myastenia gravis• Avvelenamento da

anticolinesterasici • Avvelenamento da

organofosforici

Tanito Y, Miwa T,Endou M, Hirose Y,Gamoh M,Nakaya H, Okumura F.Interaction of Edrophonium with Muscarinic Acetylcholine M2 and M3 Receptors .Anesthesiology 94:804-814, 2001• Background: It has been reported that edrophonium can antagonize the negative chronotropic effect of carbachol.

This study was undertaken to evaluate in detail the interaction of edrophonium with muscarinic M2 and M3 receptors.

• Methods: A functional study was conducted to evaluate the effects of edrophonium on the concentration–response curves for the negative chronotropic effect and the bronchoconstricting effect of carbachol in spontaneously beating right atria and tracheas of guinea pigs. An electrophysiologic study was conducted to compare the effects of edrophonium on carbachol-, guanosine triphosphate (GTP)g S-, and adenosine-induced outward K+ currents in guinea pig atrial cells by whole cell voltage clamp technique. A radioligand binding study was conducted to examine the effects of edrophonium on specific [3H]N-methyl-scopolamine (NMS) binding to guinea pig atrial (M2) and submandibular gland (M3) membrane preparations, and on atropine-induced dissociation of [3H]NMS.

• Results: Edrophonium shifted rightward the concentration–response curves for the negative chronotropic and bronchoconstricting effects of carbachol in a competitive manner. The pA2 values for cardiac and tracheal muscarinic receptors were 4.61 and 4.03, respectively. Edrophonium abolished the carbachol-induced outward current without affecting the GTPg S- and adenosine-induced currents in the atrial cells. Edrophonium inhibited [3H]NMS binding to M2 and M3 receptors in a concentration-dependent manner. The pseudo-Hill coefficient values and apparent dissociation constants of edrophonium for M2 and M3 receptors were 1.02 and 1.07 and 21 and 34 mm, respectively. Edrophonium also changed dissociation constant values of [3H]NMS without affecting its maximum binding capacities.

• Conclusion: Edrophonium binds to muscarinic M2 and M3 receptors nonselectively, and acts as a competitive antagonist.

Recettori per ACH

• Nicotinici:giunzione nm

• Muscarinici:M1cell ventric

• M2,cardiaci (musc liscio vie aeree,intest)

• M3musc liscio vie aeree,intest:tipica risp contrattile

• M4

CH3-CO-O-(CH2)2-N+(CH3)3

H3C C O

CH2 CH2 N CH3

Acetilcolina

Legame spezzato dall’Acetilcolinesterasi

Sito anionicoSito H donatore

Topologia dell’AchR visto dal lato sinaptico Lee C. Structure, conformation and action of neuromuscular blocking drugs. Br J Anaesth 2001; 87:755-69.

Canale ionico chiuso Canale ionico aperto da 2 molecole di Ach

Legame dell’ACH al substrato enzimatico,formazione dell’intermedio tetraedrale,perdita della colina e formazione dell’enzima acetilato ,idrolisi dell’enzima.

Il decametonio bloccaentrambi i siti anionici

Il vecuronium bloccasia il sito anionico che quello donante H di un unico recettore

Una grossa molecola Bisquaternaria blocca 2 siti anionici di 2 recettori

Modificazioni di forma;il decametonio preferisce una struttura lineare ,mentre Ach e SCC si piegano per le interazioni elettrostatiche fra i gruppi funzionali(methonium,gruppo carbonilico, O estereo).BJA 2001;87:755-69.

AntiChE

• Prevenzione dell’idrolisi dell’Ach a livello dei siti di trasmissione colinergica.

• Ne consegue che ACh rimane presente nella giunzione nm per un periodo di tempo + lungo e ciascuna molecola può legarsi ripetutamente con il recettore e quindi dare origine a maggiore corrente alla placca terminale …….

Legame dell’inibitore reversibile edrofonio e neostigmina,formazione dell’enzima carbamilato e idrolisi dell’enzima carbamilato

• L’azione degli antiChE passa attraverso una fase intermedia dopo il legame con l’enzima, con formazione di un complesso carbamilato relativamente stabile ,la cui decarbamilazione è lenta con emivita di circa 30 min. La cessazione degli effetti della neostigmina potrebbe essere dovuta proprio alla fase di decarbamilazione del complesso enzima/neostigmina piuttosto che solo dal decremento nella concentrazione plasmatica della neostigmina.A questo punto l’enzima è pronto a reagire nuovamente e il ciclo può riprendere.

t/12 (min)

T1/2 (min)

V1(lt/kg) Vdss(Lt/kg) Cl (ml/kg/min)

3,4 77 0,2 0,7 9,1 prostigmina

6,7 113 0,3 1,1 8,6 piridostigmina

7,2 110 9,3 1,1 9,5 edrofonio

Variabili farmacocinetiche medie dei principali antichE. (da 99 a 102 ref)

Matteo RS, Young WL, Ornstein E, et al. Pharmacokinetics and pharmacodynamics of edrophonium in elderly surgical patients. Anesth Analg 1990; 71:334-9.

• 7 pts 76-87 vs 7 27-57 years

• Elective intracranial surg.

• Tps/scc/N2O/Haloth 1 MAC age adiusted

• Force monit

• Metocurine bolus + inf aimed at 90% block

Matteo et al 1990

Matteo et al 1990.

• In elderly pts edrophonium exhibited a significant decrease in plasma clearance and a prolonged elimination hl.

• Plasma cl was correlated with age

• Plasma conc of edrophonium at equal response levels always greater in thr elderly than in the younger

Young WL, Matteo RS, Ornstein E. Duration of action of neostigmine and pyridostigmine in the elderly. Anesth Analg 1988; 67:775-8.

• 14 pts>60 years(68+/-2) vs young 38+/-5)

• Tps/scc/N2O/haloth 1 mac age adjiusted

• EMG monit

• Metoc bolus + cont infus

• Atropa 0.02+ neost 0.07 or pyrido 0.14 mg/kg

Young WL, Matteo RS, Ornstein E. Duration of action of neostigmine and pyridostigmine in the elderly. Anesth Analg 1988; 67:775-8.

prostigmina piridostigmina

onset risp maxdurata risp.maxT175%T150%T125%

Tempi * 10

giovani

anziani

giovani

anziani

• Dur risposta max + lunga negli anziani • Durate di ripresa 75,50,25% prolungate

negli anziani.• Durate di azione di neostigm e piridostigm

prolungate nell’anziano;poiché anche le durate di dtc,metoc,panc sono prolungate nell’anziano è meglio usare neo o pirido nell’antag dei miorila a lunga durata piuttosto che edrophonium….

Duration of action(max response) of antiChE

Matteoelderly

Matteoyoung

Youngelderly

Youngyoung

edrophonium

neostigmine

pyridostigmine

Cronnelly R, Stanski DR, Miller RD, et al. Renal function and the pharmacokinetics of neostigmine in

anesthetized patients. Anesthesiology 1979; 51:222-6.

Pazienti normali

Cronnelly R, Stanski DR, Miller RD, et al. Renal function and the pharmacokinetics of neostigmine in anesthetized patients. Anesthesiology 1979; 51:222-6.

Paz appena trapiantati di rene

Cronnelly R, Stanski DR, Miller RD, et al. Renal function and the pharmacokinetics of neostigmine in anesthetized patients. Anesthesiology 1979; 51:222-6.

Pazienti anefrici

Cronnelly R, Stanski DR, Miller RD, et al. Renal function and the pharmacokinetics of neostigmine in

anesthetized patients. Anesthesiology 1979; 51:222-6.

Morris RB,Cronnelly R,Miller RD,Stanski DR,Fahey MR.Pharmacokinetics of edrophonium and neostigmine

when antagonizing d-tubocurarine neuromuscular blockade in man.Anesthesiology 1981;54:399-402.

Morris 1981

Stone JG,Matteo RS, Ornstein E,Schwartz AE, Ostapkovich N,Jamdar SC,Diaz J.Aging Alters the Pharmacokinetics of Pyridostigmine. Anesthesia & Analgesia 81:773-776: 1995.

• tps 3–6 mg/kg /IV / isoflurane 0.5% /N2O

• Dtc 0.18 mg/kg + pancuronium 0.024 mg/kg T1 5% : atropine 1 mg +pyridostigmine 0.25 mg/kg.

Pyridostigmine and age Stone JG,Matteo RS, Ornstein E,Schwartz AE, Ostapkovich N,Jamdar SC,Diaz J.Aging Alters the Pharmacokinetics of Pyridostigmine. Anesthesia & Analgesia 81:773-776: 1995.

Pyridostigmine clearance and age Stone JG,Matteo RS, Ornstein E,Schwartz AE, Ostapkovich N,Jamdar SC,Diaz J.Aging Alters the Pharmacokinetics of Pyridostigmine. Anesthesia & Analgesia 81:773-776: 1995.

Pyridostigmine kineticsStone JG,Matteo RS, Ornstein E,Schwartz AE, Ostapkovich N,Jamdar SC,Diaz J.Aging Alters the Pharmacokinetics of Pyridostigmine. Anesthesia & Analgesia 81:773-776: 1995.

Antagonismo dei miorilassanti

Presenza dei vapori….

Recovery parameters following neostigmine administration(Reid J, Breslin DS,Mirakhur R, Hayes A.Neostigmine antagonism of rocuronium block during anesthesia with sevoflurane,isoflurane or propofol.Can.Anesth.J. 2001:48 :351-55)

propcont

propstop

sevocont

sevostop

isocont

isostop

Tof 0.80

pts at 0.8 tof at 15 min

6 groups ,20 eachRocuronium,Force,neo at tof 25%!

TOF vs time after neostigmine 40 gr/kg (from T1 25%);control(fent/N2O),isoflurane stopped,isoflurane continued (1.25%)Baurain MJ, d'Hollander AA,Melot C, Dernovoi BS,Barvais L.Effects of residual concentrations of isoflurane on the reversal of vecuronium induced neuromuscular blockade.Anesthesiology 1991:71:474- )

Valori del tetanic fade (stimolazione a 50 Hz sn,100 Hz dx)dopo 15 min dalla somministrazione di neostigmina 40 microgr/kg Baurain MJ, d'Hollander AA,Melot C, Dernovoi BS,Barvais L.Effects of residual concentrations of isoflurane on the reversal of vecuronium induced neuromuscular blockade.Anesthesiology 1991:71:474- )

• Insomma,continuare la soministraz del vapore ritarda la ripresa nm anche dopo rovesciamento……

Neostigmina vs edrofonio…..

Antagonism of atracurium or cisatracurium nm blockade(at T1 10%)with various dosages of neostigmine(fent,tps,N2O,isof anesth;Accel.) Naguib M,Riad W.Dose response relationship for edrophonijm and neostigmine antagonism of atracurium and cisatracurium induced neuromuscular block.Can.Anaesth.J 2000;47:1074-1081

Antagonism of atracurium or cisatracurium nm blockade(at T1 10%)with various dosages of edrophonium (fent,tps,N2O,isof anesth;Accel.) Naguib M,Riad W.Dose response relationship for edrophonijm and neostigmine antagonism of atracurium and cisatracurium induced neuromuscular block.Can.Anaesth.J 2000;47:1074-1081

Neostigmine vs edrophonium reversal of atracurium or cisatracuriun nm, blockade

Mean first twitch height vs time after administration of various doses of neostigmine and edrophonium starting from T 1 10% following atracurium and vecuronium Smith, CE, Donati F., Bevan DR.Dose‑Response Relationships for Edrophonium and Neostigmine as Antagonists of Atracurium and Vecuronium neuromuscular Blockade.Anesthesiology 1989;71: 37-43.

Inspired enflurane concentration maintained at 0.5-1%

Dose response relationship of first twitch and TOF assisted recovery 5 and 10 min. following administration of the antagonist as a function of the dose of neostigmine and edrophonium following atracurium and vecuronium. Smith, CE, Donati F., Bevan DR.Dose‑Response Relationships for Edrophonium and Neostigmine as Antagonists of Atracurium and Vecuronium Neuromuscular Blockade.Anesthesiology 1989;71: 37-43.

Effect on T1 of 2 doses of neostigmine and edrophonium following atracurium and vecuronium Smith, CE, Donati F., Bevan DR.Dose‑Response Relationships for Edrophonium and Neostigmine as Antagonists of Atracurium and Vecuronium Neuromuscular Blockade.Anesthesiology 1989;71: 37-43.

neo 0.02mg/kg

neo 0.04mg/kg

edroph 0.5mg/kg

edroph 1mg/kg

atrac at 5'

atrac at 10'

vecu at 5'

vecu at 10'

Effect on Tof of 2 doses of neostigmine and edrophonium following atracurium and vecuronium Smith, CE, Donati F., Bevan DR.Dose‑Response Relationships for Edrophonium and Neostigmine as Antagonists of Atracurium and Vecuronium Neuromuscular Blockade.Anesthesiology 1989;71: 37-43.

neo 0.02mg/kg

neo 0.04mg/kg

edroph 0.5 mg/kg

edroph 1mg/kg

atrac at 5'

atrac at 10'

vecu at 5'

vecu at 10'

Neo vs edrofonio e profondità del blocco nm.

Ist twitch height vs dose 10 min. after neostigmine or edrophonium administered at 90

or 99% block.

Conclusione 1

• La dose giusta di neostigmina è…………

• Meditate gente meditate………………

Relationship between dose of neostigmine and percentage recovery during continuous infusion of vecuronium(filled circle) or pancuronium(empty circle)

Insomma,l’antagonismo dipende da:

• Profondità di blocco al momento della somministrazione dell’antagonista

• Presenza o meno di potenzianti nmb.

• Tipo di antagonista somministrato

• Tipo di miorilassante somministrato

• Dose dell’antagonista somministrato

• end point scelto;T1/Tc,Tof,ecc.

Conclusione 2

• E’ meglio somministrare gli antidoti quando la ripresa nm è iniziata

• È meglio cessare la somministrazione degli alogenati ( e monitorizzare la % et)…….

BEEMER, G. H.; BJORKSTEN, A. R.; DAWSON, P. J.; DAWSON, R. J.; HEENAN, P. J.; ROBERTSON, B. A. Determinants of the reversal time of competitive nurmuscular block by anticholinesterases. BJA 1991;66:469-475.• • 200 patients• reversal time of competitive neuromuscular block by

anticholinesterase • alcuronium and atracurium neuromuscular block were • antagonized by neostigmine 0.04 and 0.08 mg kg-1 and

edrophonium 0.5 and 1.0 mg kg-1. A • biexponential relationship between the reversal time

(time from injection of anticholinesterase to a train-of-four ratio of 70%) and the degree of neuromuscular block at reversal (all groups; F ratio, P < 0.05).

BEEMER, G. H.; BJORKSTEN, A. R.; DAWSON, P. J.; DAWSON, R. J.; HEENAN, P. J.; ROBERTSON, B. A.

Determinants of the reversal time of competitive nurmuscular block by anticholinesterases. BJA

1991;66:469-475.• Reversal time was determined by two processes: direct antagonism

by the anticholinesterase and spontaneous recovery of the neuromuscular blocking agent, with the latter becoming the major determinant at profound levels of neuromuscular block (0–10% of control twitch height). Neostigmine, in the doses studied, appeared to have a higher “ceiling” of neuromuscular block which it completely antagonized, although edrophonium had a more rapid onset of action. The reversal time for alcuronium became progressively longer relative to atracurium as neuromuscular block increased because of the slower spontaneous recovery rate. Avoidance of profound neuromuscular block at the completion of surgery is required to ensure reliable antagonism of the block within 5–10 min by an anticholinesterase. Neostigmine 0.08 mg kg-1 was found to be the most effective agent in antagonizing profound neuromuscular block.

• The most important determinant of reversal time is the depth of neuromuscular block at the time of antagonism and this should determine the anticholinesterase and its dose. Another factor which should be considered is the type and dose of competitive neuromuscular blocking agent. When large doses of long acting competitive neuromuscular blocking agents are administered during surgery, it may be anticipated that antagonism of profound block by an anticholinesterase will be prolonged.

Mean Reversal times for the different nmb/antiAchE at deep (0-10%T1) and light (>30% T1) degrees of blockade BEEMER, G. H.; BJORKSTEN, A. R.; DAWSON, P. J.; DAWSON, R. J.; HEENAN, P. J.; ROBERTSON, B. A. Determinants of the reversal time of competitive nurmuscular block by anticholinesterases. BJA 1991;66:469-475.

profound block light block

atrac neo 0.04

atrac neo 0.08

atrac edroph 0.5

atrac neo 1

alcuronium neo 0.04

alcur neo 0.08

alcur edroph 0.5

alcur edroph 1

Reversal times for the different nmb/antiAchE BEEMER, G. H.; BJORKSTEN, A. R.; DAWSON, P. J.; DAWSON, R. J.; HEENAN, P. J.; ROBERTSON, B. A.

Determinants of the reversal time of competitive nurmuscular block by anticholinesterases. BJA 1991;66:469-475.

Perché la piridostigmina non è idonea…

Kim KS.,,Lew SH,Cho Y, Cheong Mi A.Residual paralysis induced by either vecuronium or rocuronium after reversal with pyridostigmine. Anesthesia & Analgesia 2002; 95:1656-1660• 602 pts without nm monitoring • vecuronium or rocuronium • reversal by pyridostigmine 10 or 20 mg/kg• RR TOF ( acceleromyography i)+ head-lift for >5 s + tongue-depressor test.• Postoperative residual curarization(PORC) defined as a TOF ratio <0.7:• vecuronium, 24.7%; rocuronium, 14.7%• no signif. Diff.in the TOFR between 10 mg and 20 mg of pyridostigmine. • The patients with residual block had several associated factors:

1) absence of perioperative neuromuscular monitoring2)the use of pyridostigmine, which is less potent than neostigmine, 3)a larger dose of vecuronium, 4)shorter time from the last neuromuscular blocker to TOF monitoringperipheral cooling.

• We conclude that significant residual neuromuscular block after vecuronium or rocuronium was not eliminated even with reversal by a large dose of pyridostigmine.

Kim KS.,,Lew SH,Cho Y, Cheong Mi A.Residual paralysis induced by either vecuronium or rocuronium after reversal with pyridostigmine. Anesthesia & Analgesia 2002; 95:1656-1660

21 % !!!

Kim KS.,,Lew SH,Cho Y, Cheong Mi A.Residual paralysis induced by either vecuronium or

rocuronium after reversal with pyridostigmine. Anesthesia & Analgesia 2002; 95:1656-1660

Effetti collaterali degli anti AchE

Effetti fisiologici della presenza di Ach

• Bradicardia

• Salivazione

• Iperperistalsi

• Secrezioni bronchiali

Effetto risvegliante !!!

Meuret P,Backman SB, Bonhomme V, Plourde G,Fiset P.Physostigmine Reverses Propofol-induced Unconsciousness and Attenuation of the Auditory Steady State Response and Bispectral Index in Human Volunteers . Anesthesiology 93:708-17, 2000• Background: It is postulated that alteration of central cholinergic transmission

plays an important role in the mechanism by which anesthetics produce unconsciousness. The authors investigated the effect of altering central cholinergic transmission, by physostigmine and scopolamine, on unconsciousness produced by propofol.

• Methods: Propofol was administered to American Society of Anesthesiologists physical status 1 (n = 17) volunteers with use of a computer-controlled infusion pump at increasing concentrations until unconsciousness resulted (inability to respond to verbal commands, abolition of spontaneous movement). Central nervous system function was assessed by use of the Auditory Steady State Response (ASSR) and Bispectral Index (BIS) analysis of electrooculogram. During continuous administration of propofol, reversal of unconsciousness produced by physostigmine (28 mg/kg) and block of this reversal by scopolamine (8.6 mg/kg) were evaluated.

Meuret P et al .Physostigmine Reverses Propofol-induced Unconsciousness and Attenuation of the Auditory Steady State Response and Bispectral

Index in Human Volunteers . Anesthesiology 93:708-17, 2000

• Results: Propofol produced unconsciousness at a plasma concentration of 3.2 ± 0.8 (± SD) mg/ml (n = 17). Unconsciousness was associated with reductions in ASSR (0.10 ± 0.08 mV [awake baseline 0.32 ± 0.18 mV], P < 0.001) and BIS (55.7 ± 8.8 [awake baseline 92.4 ± 3.9], P < 0.001). Physostigmine restored consciousness in 9 of 11 subjects, with concomitant increases in ASSR (0.38 ± 0.17 mV, P < 0.01) and BIS (75.3 ± 8.3, P < 0.001). In all subjects (n = 6) scopolamine blocked the physostigmine-induced reversal of unconsciousness and the increase of the ASSR and BIS (ASSR and BIS during propofol-induced unconsciousness: 0.09 ± 0.09 mV and 58.2 ± 7.5, respectively; ASSR and BIS after physostigmine administration: 0.08 ± 0.06 mV and 56.8 ± 6.7, respectively, NS).

• Conclusions: These findings suggest that the unconsciousness produced by propofol is mediated at least in part via interruption of central cholinergic muscarinic transmission.

Effetti della fisostigmina sul Auditory steady state response (ASSR) :basale,dopo propofol,dopo fisostigmina e al risveglio.

Effetti della fisostigmina sul BIS :basale,dopo propofol,dopo fisostigmina e al risveglio.

Pericoli degli AntiAchE: arresto cardiaco

• Bjerke, Richard J., MD; Mangione, Michael P.Asystole after intravenous neostigmine in a heart transplant recipient.Can.Anaesth.J. 2001;48:305-07.

• Purpose: To describe a heart transplant recipient who developed asystole after administration of neostigmine which suggests that surgical dennervation of the heart may not permanently prevent significant responses to anticholinesterases.

• Clinical features: A 67-yr-old man, 11 yr post heart transplant underwent left upper lung lobectomy. He developed asystole after intravenous administration of 4 mg neostigmine with 0.8 mg glycopyrrolate for reversal of the muscle relaxant. He had no history of rate or rhythm abnormalities either prior to or subsequent to the event.

• Conclusion: When administering anticholinesterase medications to heart transplant patients, despite surgical dennervation, one must be prepared for a possible profound cardiac response.

Pericoli degli ACHE:FA con rapida risposta ventricolare…..

• Kadoya, TSA, Aoyama K, Takenaka I.Development of rapid atrial fibrillation with wide QRS complex after neostigmine in a patient with intermittent WPW stndrome.BJA 1999;83:815-818

• 1Department of Anaesthesia, Nippon Steel Yawata Memorial Hospital, 1-1-1 Harunomachi, Yahatahigashi-ku,

• ABSTRACT: We report the case of a 67-yr-old man with intermittent Wolff-Parkinson-White (WPW) syndrome in whom neostigmine produced life-threatening tachyarrhythmias. The patient was scheduled for microsurgery for a laryngeal tumour. When he arrived in the operating room, the electrocardiogram showed normal sinus rhythm with a rate of 82 beat min-1 and a narrow QRS complex which remained normal throughout the operative period. On emergence from anaesthesia, the sinus rhythm (87 beat min-1) changed to atrial fibrillation with a rate of 80–120 beat min-1 and a normal QRS complex. We did not treat the atrial fibrillation because the patient was haemodynamically stable. Neostigmine 1 mg without atropine was then administered to antagonize residual neuromuscular block produced by vecuronium. Two minutes later, the narrow QRS complexes changed to a wide QRS complex tachycardia with a rate of 110–180 beat min-1, which was diagnosed as rapid atrial fibrillation. As the patient was hypotensive, two synchronized DC cardioversions of 100 J and 200 J were given, which restored sinus rhythm. No electrophysiological studies of anticholinesterase drugs have been performed in patients with WPW syndrome. We discuss the use of these drugs in this condition.

Caldwell JE. Reversal of residual nm block with neostigmine qt 1 to 4 hours after a single intubating dose of vecuronium.Anesth.Analg 1995;80:1168-74• The purpose of this study was to measure the degree of residual neuromuscular

block at different times after a single dose of vecuronium, and to evaluate the effectiveness of two different doses of neostigmine in antagonizing this residual block. Train-of-four (TOF) ratios were examined for up to 4 h after a single dose of vecuronium, 0.1 mg/kg, in 60 patients during nitrous oxide/isoflurane/fentanyl anesthesia. The effect of neostigmine, 40 mg/kg, was studied at 1, 2, 3, or 4 h. The effect of neostigmine, 20 mg/kg, was studied at 2 or 4 h after the vecuronium. Before neostigmine administration, the TOF ratio was less than 0.75 in 17 patients (including one patient at 4 h). Neostigmine produced an increase in TOF ratio in 52 patients and a decrease in 8. The TOF ratio decreased after neostigmine only, at 2, 3, or 4 h after vecuronium, when the TOF ratio was ³0.9 and when neostigmine 40 mg/kg was administered. One patient, at 1 h, had a TOF ratio of 0.00 and this did not reach 0.75 until 57 min after neostigmine, 40 mg/kg. There was a high incidence (50%) of adverse cardiovascular effects after both doses of neostigmine. In making the decision as to whether neostigmine should be administered, the risk to the patient of residual neuromuscular block must be balanced against the adverse cardiovascular effects of the neostigmine.

Caldwell JE. Reversal of residual nm block with neostigmine qt 1 to 4 hours after a single intubating dose of vecuronium.Anesth.Analg 1995;80:1168-74

• 10-20% incidenza di aritmie(ritmi giunzionali)• This study had three important findings: 1)

clinically significant residual neuromuscular block (TOF ratio <0.75) could be present for up to 4 h after a single dose of vecuronium 0.1 mg/kg; 2) neostigmine in a dose of 40 mg/kg, but not 20 mg/kg, could produce a decrease in the TOF ratio; 3) both doses of neostigmine and glycopyrrolate are associated with clinically significant cardiovascular effects.

Pericoli degli antiAchE:broncocostrizione

• Shibata O,Tsuda A,Makita T, Iwanaga S,Hara T,Shibata S,Sumikawa K. Contractile and phosphadytilinositol responses of rat trachea to anticholinesterase drugs.Can.Anaesth.J.1998;45:1190-95Purpose: Some anticholinesterases (anti-ChE) such as neostigmine and pyridostigmine but not edrophonium, stimulate phosphaticlylinositol (PI) response. Although a direct relationship was suggested between the increase in PI response and airway smooth muscle contraction, there are no data regarding the effects of anti-ChE drugs on airway smooth muscle. Thus, we examined the contractile properties and PI responses produced by anti-ChE drugs.

• Methods: Contractile response. Rat tracheal ring was suspended between two stainless hooks in Krebs-Henseleit (K-H) solution. (1) Carbachol (CCh), anti-ChE drugs (neostigmine, pyridostigmine, edrophonium) or DMPP (a selective ganglionic nicotinic agonist) were added to induce active contraction. (2) The effects of 4-diphenylacetoxy-N-methyl-piperidine methobromide (4-DAMP), an M3 muscarinic receptor antagonist, on neostigmine- or pyridostigmine-induced contraction of rat tracheal ring were examined. (3) Tetrodotoxin (TTX) was tested on the anti-ChE drugs-induced responses. PI response. The tracheal slices were incubated in K-H solution containing LiCl and 3[H]myo-inositol in the presence of neostigmine or pyridostigmine with or without 4-DAMP, an M3 muscarinic receptor antagonist. 3[H]inositol monophosphate (IP1) formed was counted with a liquid scintillation counter.

• Results: Carbachol (0.1 mM), neostigmine. (1 mM), pyridostigmine (10 mM) but not edrophonium or DMPP, caused tracheal ring contraction. 4-DAMP, but not tetrodotoxin, inhibited neostigmine and pyridostigmine-induced contraction. Neostigmine- or pyridostigmine-induced IP1 accumulation was inhibited by 4-DAMP.

• Conclusions: The data suggest that anti-ChE drugs activate the M3 receptors at the tracheal effector site.

Schema delle afferenze parasimpatiche a livello tracheale

Effetti contrattili di antiACHE,carbacolo e dimetilfenilpiperazinio sugli anelli tracheali di ratto.Shibata O,Tsuda A,Makita T, Iwanaga S,Hara T,Shibata S,Sumikawa K. Contractile and phosphadytilinositol responses of rat trachea to anticholinesterase drugs.Can.Anaesth.J.1998;45:1190-95

NEOSTIGMINE AND PONV

Tramèr, M. R. Fuchs-Buder, T..Omitting antagonism of nm block:effect on PONV and risk of residual paralysis.A systematic review.BJA 1999;82:379-386

• A systematic search (MEDLINE, EMBASE, Biological Abstracts, Cochrane library, reference lists and hand searching; no language restriction, up to March 1998) was performed for relevant randomized controlled trials. In eight studies (1134 patients), antagonism with neostigmine or edrophonium was compared with spontaneous recovery after general anaesthesia with pancuronium, vecuronium, mivacurium or tubocurarine. On combining neostigmine data, there was no evidence of an antiemetic effect when it was omitted. However, the highest incidence of emesis with neostigmine 1.5 mg was lower than the lowest incidence of emesis with 2.5 mg. These data suggested a clinically relevant emetogenic effect with the higher dose of neostigmine in the immediate postoperative period but not thereafter.

• Numbers-needed-to-treat to prevent emesis by omitting neostigmine compared with using it were consistently negative with 1.5 mg, and consistently positive (3–6) with 2.5 mg. There was a lack of evidence for edrophonium. In two studies, three patients with spontaneous recovery after mivacurium or vecuronium needed rescue anticholinesterase drugs because of clinically relevant muscle weakness (number-needed-to-harm, 30). Omitting neostigmine may have a clinically relevant antiemetic effect when high doses are used. Omitting antagonism, however, introduces a non-negligent risk of residual paralysis even with short-acting neuromuscular blocking agents.

Risk of omitting neostigmine….

• Residual paralysis!!!

Antagonism of mivacurium block

• Savarese et al:neo accelerates recovery form mivac by 40%

• Kaoo:neo may delay complete recovery from deep mivac block

• Baurain,Naguib:neo accelerates recovery fron mivac block by 7-9 min vs 15-17 spont.

• Devcic:mean recovery accelerated by neo,but variability high:

Antagonism of deep mivacurium block.

TOF25%

TOF50%

TOF75%

placebo

neostigmine

placebo

edrophonium

neostigmine

Dott. Melloni:

cDevcic et al.Anesthesia Analgesia,1995,81:1005-1009

Dott. Melloni:

cDevcic et al.Anesthesia Analgesia,1995,81:1005-1009

Lien CA,Belmont MR,Wray R, Doreen L,Okamoto M,Abalos A,Savarese JJ.Pharmacodynamics and the Plasma Concentration of Mivacurium during Spontaneous Recovery and Neostigmine-facilitated Recovery .Anesthesiology 91:119-26, 1999

• Background: The authors examined the plasma concentrations of the isomers of mivacurium and its pharmacodynamics during spontaneous and neostigmine-facilitated recovery after a mivacurium infusion.

• Methods: Sixteen patients receiving nitrous oxide—opioid anesthesia received 0.25 mg/kg mivacurium. Patient response to neuromuscular stimulation was determined using a mechanomyograph. Once T1 had recovered to 25% of its baseline height, a mivacurium infusion was begun and adjusted to maintain 95—99% neuromuscular block. The infusion was discontinued after 90 min and muscle strength allowed to recover either spontaneously or after neostigmine/glycopyrrolate (0.05/0.01 mg/kg). Plasma concentrations of the isomers of mivacurium after discontinuation of the infusion were determined using an HPLC assay. Differences between the groups were determined using a one-way analysis of variance with a Bonferroni-corrected t test or Student t test as appropriate. P £ 0.05 was considered significant.

• Results: Differences in the times for recovery to a train-of-four ratio of 70% did not achieve statistical significance (mean ± SD, 13.3 ± 6.0 vs. 16.3 ± 2.5 min for the neostigmine and spontaneous groups, respectively). Plasma cholinesterase activity decreased significantly from baseline values after administration of neostigmine (5.88 ± 0.21 vs. 0.43 ± 0.04 U/ml plasma). Plasma concentrations of the trans-trans isomer were significantly greater in the neostigmine group than in the spontaneous recovery group 5, 6, 8, and 10 min after discontinuation of the infusion. Differences in the plasma concentration of the cis-trans isomer did not achieve statistical significance.

• Conclusions: Although administration of neostigmine decreased plasma cholinesterase activity and caused the trans-trans isomer to remain in the plasma at higher concentration, it did not delay recovery from mivacurium-induced block.

Attività della colinesterasi plasmatica espressa come % rispetto al valore basale di attività al termine dell’infusione di mivacurium Lien CA,Belmont MR,Wray R, Doreen L,Okamoto M,Abalos A,Savarese JJ.Pharmacodynamics and the Plasma Concentration of Mivacurium during Spontaneous Recovery and Neostigmine-facilitated Recovery .Anesthesiology 91:119-26, 1999

Ripresa spontanea

Ripresa dopo neostigminSomm. A T1 25%

Ripresa spontanea

Farmacodinamica della ripresa dopo mivacurium ,spontanea e indotta da

neostigmina(somm al T1 25%) Lien CA,Belmont MR,Wray R, Doreen

L,Okamoto M,Abalos A,Savarese JJ.Pharmacodynamics and the Plasma Concentration of Mivacurium during Spontaneous Recovery and Neostigmine-facilitated Recovery .Anesthesiology 91:119-26, 1999

T1 25% T1 75% T! 95% TOF 70% TOF 90%

spontaneo

indotto daneostigmina

Concentrazioni degli isomeri del mivacurium al termine della infusione Lien CA,Belmont MR,Wray R, Doreen L,Okamoto M,Abalos A,Savarese

JJ.Pharmacodynamics and the Plasma Concentration of Mivacurium during Spontaneous Recovery and Neostigmine-facilitated Recovery .Anesthesiology 91:119-26, 1999

Baurain, M. J.; Dernovoi, B. S.; d'Hollander,A.; Hennart, D. A. Comparison of neostigmine induced recovery with spontaneous recovery from mivacurium induced block.BJA 1994;73:791-794.

• • In 24 ASA I–II adults anaesthetized with thiopentone, fentanyl and nitrous oxide in oxygen,

we studied neuromuscular transmission with isometric adductor pollicis monitoring. Patients received mivacurium 0.2 mg kg-1 followed by an infusion lasting at least 60 min and adjusted to maintain twitch height at 1–5%. After termination of the mivacurium infusion, when twitch height spontaneously regained 25% of its control value, the patients were allocated to two groups of 12 patients each. In group NEO patients received neostigmine 40 mg kg-1 and atropine 15 mg kg-1 and in group SPO neuromuscular transmission was allowed to recover spontaneously. Twitch height was measured every 10 s and train–of–four (TOF) (2 Hz) every 3 min. After 15 min, residual force after tetanic stimulation (50 and 100 Hz, 5–s duration (RF50HZ, RF100HZ), 1 min apart) were recorded sequentially. At 15 min, mean TOF ratio was greater in group NEO (0.94 (SEM 0.01)) than in group SPO (0.87 (0.02)) (P < 0.01). All patients in group NEO recovered to a TOF ratio greater than 0.7 after 6 min compared with 15 min in group SPO (P < 0.005). A TOF ratio greater than 0.9 was observed in all patients in group NEO compared with only six in group SPO (P < 0.025). Nevertheless, RF50HZ and RF100HZ did not differ significantly (0.92 (0.01) (group NEO), 0.91 (0.01) (group SPO) and 0.83 (0.02) (group NEO), 0.78 (0.03) (group SPO), respectively). We conclude that although there was a high degree of spontaneous recovery, administration of neostigmine–atropine accelerated the rate of recovery of neuromuscular transmission after mivacurium and greatly increased the number of patients satisfying the criteria for complete recovery of neuromuscular transmission (TOF ratio > 0.9) within 15 min.

Recovery indexes following discontinuation of mivacurium infusion;neostigmine vs spontaneous Baurain, M. J.; Dernovoi, B. S.; d'Hollander,A.; Hennart, D. A. Comparison of neostigmine induced recovery with spontaneous recovery from mivacurium induced block.BJA 1994;73:791-794.

endinfus-T125%

t1 25-75%

T1 25-90%

T1 25%tof 70%

T1 25%-Tof90%

Neostigm

TOFR Evolution at T1 25% following mivacurium discontinuation:neostigmine vs spontaneous recovery:Baurain, M. J.; Dernovoi, B. S.; d'Hollander,A.; Hennart, D. A. Comparison of neostigmine induced recovery with spontaneous recovery from mivacurium induced block.BJA 1994;73:791-794.

Naguib et al.Anesthesiology 1995;82:1288.

Purified human plasma cholinesterase

Effetti analgesici

• a muscarinic presynaptic inhibition of glutamatergic afferents, similar to how it has been described in the neostriatum. An important prerequisite for the effectiveness of neostigmine is a tonic cholinergic activity.

DTC PANC VECU ATRAC ROCU MIVA

Neostigmina

ED50 17±1 13±2 10±1 10±1 17±1 2±0.1

ED80 45±3 45±6 24±2 22±2 33±1 5±0.1

Edrofonio

ED50 270±27 170±24 180±50 110±30 161±10 3±0.1

ED80 880±93 680±102 460±13 440±110 690±10 9±0.1

Rapporti di potenza antagonistica per neostigmina e edrofonio (da Donati AA 1989,Smith

Anesthesiology 1989,Naguib Anesthesiology 1993,Naguib BJA 1993)

Comportamento suggerito per l’antagonismo dei miorilassanti a lunga e media durata di azione secondo le risposte al Tof

TOF esaurimento farmaco dose

Twitch visibili

nessuno Posponi antagonismo

Finchè almeno 1 o 2 contrazioni visibili!!

1-2 ++++ neostigmina 0.07 mg/kg

3-4 +++ neostigmina 0.04 mg/kg

4 ++ edrofonio 0.5 mg/kg

4 +/- edrofonio 0.25

Kirkegaard H,Heier T,Caldwell JE Efficacy of tactile guided reversal from cisatracurium induced neuromuscular block.Anesthesiology 2002;96:45-50

• Anest with fent/prop/N2O

• cisatrac 0.15 mg/kg

• neostigmine 0.07 mg/kg administered at reappearance of I,II,III,IV of TOF;tactile vs Meccanomyography contralateral.

Kirkegaard H,Heier T,Caldwell JE Efficacy of tactile guided reversal from cisatracurium induced neuromuscular block.Anesthesiology 2002;96:45-50

T im e f r o m n e o s t ig m in e a d m in is t r a t io na d m in is t r a t io n to T O F R 0 .7 0

0 , 0 0

5 , 0 0

1 0 , 0 0

1 5 , 0 0

2 0 , 0 0

2 5 , 0 0

I t w i t c h I I t w i t c h I I I t w i t c h I V t w i t c h

m e d i a n a

T im e f r o m n e o s t ig m in e a d m in is t r a t io n to T O F R 0 .8 0

I tw itch II tw itch III tw itch IV tw itch

m ed ian a

T im e f r o m n e o s t ig m in e a d m in is t r a t io n to T O F R 0 .9 0

I tw itch II tw itch II I tw itch IV tw itch

m ed ian a

M M G m a g n i t u d e o f t h e f i r s t T O F tw i tc h ( T 1 ) m e a s u r e d a t t h e r e a p p e a r a n c e o f e a c h o f t h e 4 t a c t i l e T O F r e s p o n s e s .

I t w i t c h I I t w i t c h I I I t w i t c h IV t w i t c h

m e d ia n a

Kirkegaard H,Heier T,Caldwell JE Efficacy of tactile guided reversal from cisatracurium induced

neuromuscular block.Anesthesiology 2002;96:45-50

• This study shows that achieving a TOFR of 0.90 in <10 min following neostigmine reversal is not a realistic goal;therefore counting the number of tactile responses to tof stimulation cannot be used as a guide for neostigmine admninistration if the end point of reversal is a TOFR of 0.90 or higher within 10

min;but is a good predictor of TOFR 0.70.

Kopman et al.Relationship of the train of four fade ratio to clinical signes and symptoms of residual paralysis in awake volunteers.Anesthesioloogy,1997;86:765-71.

• Volontari sani

• infusione di mivacurium

• monitoraggio Datex 221 NMT

• valutazione;stretta di mano

• sollev,testa & gamba per 5 sec.

• Ritenzione di abbassalingua

Clinical signs of residual weakness vs tof at the

AP(Kopman,Anesthesiology,1997;86:765-71)

0,000,100,200,300,400,500,600,700,800,90

lowest tof highest tof

at which test passed or failed

head lift

leg lift

retain tonguedepressor

Osservazioni cliniche sulla relazione fra tof e correlati di forza:

• disturbi visivi sempre con tof di 0.90(diplopia,diff.seguire oggetti in moto,ecc)

• forza dei masseteri ridotta sempre

• sollev.testa e gamba sempre possibile > 0.60

• stretta di mano variabile,ma 83% del basale a tof 0.90

• per tof < 0.75 tutti disturbati

Conclusioni delle correlazioni fra segni clinici di forza muscolare e tof

• Capacità di ritenzione dell’abbassalingua è un test più sensibile del sollevamento del capo

• tof <1 ancora residuano disturbi visivi e senso generalizzato di fatica

• tof = 1 (o altri monitoraggi) per dimissione in chirurgia ambulatoriale??

Assiomi della ripresa nm.

• TOF > 0.70 sicuro indice della ripresa nm……….. Ali HH, Wilson RS, Savarese JJ, Kitz RJ: The effect of tubocurarine on indirectly elicited train-of-four muscle response and respiratory measurements in humans. Br J Anaesth 47:570-4, 1975

• Brand JB, Cullen DJ, Wilson NE, Ali HH: Spontaneous recovery from nondepolarizing neuromuscular blockade: Correlation between clinical and evoked responses. Anesth Analg 56:55-8, 1977

Mutazioni occorse

• Esplosione della chirurgia ambulatoriale

• pressione per la diminuzione della spesa sanitaria

• aumento delle persone anziane e debilitate anche in chir amb.

• Disponibilità di nuovi farmaci

Implicazioni del lavoro di Kopman:1

• I paz chirurgici sono in genere più anziani e ammalati dei volontari sani dello studio di Kopman/( ASA 1, entro il 15% del peso ideale,tra 23—33 anni….)

• gli effetti residui dei miorilassanti è probabile possano essere + significativi nella pratica ambulatoriale con pazienti + anziani e debilitati.

• Si potrebbe arguire che i paz.con sedazione residua siano meno attenti a disturbi visivi e

• debolezza dei muscoli facciali;ma è anche vero che dal punto di vista della sicurezza i paz postop siano esposti a rischio maggiore di aumento della morbilità,poichè la debolezza residua nm può essere aggravata da residui dell’anestesia.

Implicazioni del lavoro di Kopman:2

• mivacurium non è rappresentativo dei miorilassanti usati in chir amb;il mercato è dominato dai miorilassanti ad azione intermedia quali vecuronium, atracurium, rocuronium, cisatracurium

• se una paralisi residua permane per un’ora dopo interruzione del mivac,caratterizzato da un RI di pochi min,che succede dopo la somministrazione dei mioril a durata intermedia(RI 20-30 min )?

Conclusions form Kopman,Brull,Erikkson…..

• indicators of recovery of nm function should be changed.

• The TOF ratio <0.9 was also associated with functional impairment of the pharynx and upper correlated volunteers' subjective feelings of partial neuromuscular weakness with the clinical counterpart of neuromuscular recovery. All subjects had significant signs and symptoms of residual paralysis at a TOF ratio of 0.7 and satisfactory recovery of neuromuscular function after mivacurium-induced neuromuscular block required return of the TOF ratio to >0.9 . According to these studies, the absence of muscle relaxant-induced clinical effects may be defined as the return to a TOF ratio ³0.9 at the AP.

Ciclodestrine……….

• Gamma CD le + potenti

• Potenza di legame legata al diametro della cavità interna(> 7.5 A) lipofilica

• Elevata idrosolubilità

• Ottima tolleranza biologica

• Inclusione del miorilassante all’interno della cavità :incapsulazione

Infusion of Org 25969 at a rate of 50 nmol·kg-1·min-1 caused rapid reversal of neuromuscular block, combined with an increase in plasma concentration of rocuronium (free and

bound to Org 25969).

Gijsenberg F, Ramael S, De Bruyn S, Rietbergen, van Iersel T. Preliminary assessment of Org 25969 as a reversal agent for rocuronium in healthy male

volunteers. Anesthesiology 2002; 96: A1008

Placebo

ORG 259690,1 0,5 1,0 2,0 5,0 8,0

35-69 43 71 23-31 13-17 2,5-3,2 1-1,2

Min for TOF 0.90

Effect of Org 25969 on recovery from rocuronium-induced neuromuscular block after bilateral renal

ligation

onsettime

blockduration

50%recovery

90%recovery

25-75%

spont norm

spont art ren legate

org25969 norm

org 25969 art renlegate

Problems of tactile or visual assesmentProblems of tactile or visual assesmentusingusing

basalbasal

frequence..frequence..

TOFTOF

fade assessment needsexperiencefade assessment needsexperience

sensibility when IV reappears:whichis the IV/I ratio > 25-30%?sensibility when IV reappears:whichis the IV/I ratio > 25-30%?

tetanictetanic

fade assessmentneeds experiencefade assessmentneeds experience

do not repeat < 5min..do not repeat < 5min..

tactile assessmenttactile assessment

TetanusTetanus

DBSDBS

TOFTOF

Correlazione soggettiva-oggettiva(palpazione-meccanomiografia)

• 1 Twitch= T110%

• 3 twitches=T1 25%

Clinical signsClinical signscorrelation with residual forcecorrelation with residual force

patient cooperation!patient cooperation!

tonguedepressorclenching

head lift> 5 sechead lift> 5 sec

arm or leglift> 5 secarm or leglift> 5 sec

sustainedhand gripstrenght

clinical signsclinical signsreliable vs not reliablereliable vs not reliable

TV normalTV normal unreliableunreliable

Neg Press < 25 mmHgNeg Press < 25 mmHgunreliableunreliable

Neg press < 50 mmHgNeg press < 50 mmHgreliablereliable

coughcough unreliableunreliable

eye openingeye openingunreliableunreliable

tongue protrusiontongue protrusionunreliableunreliable

before patient cooperationri....before patient cooperationri....

Special neuromuscular monitoring

Mantiene quello che promette?

Servi zi o di Anestesia e Rianimazione Ospedale di Faenza(RA)

TOF,DBS , Tetanus

Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of residual curarization using double burst stimulation: A comparison with train-of-four. Anesthesiology 1989; 70:578-81• - Double burst stimulation (DBS) is a new mode of stimulation developed to

reveal residual neuromuscular blockade under clinical conditions. The stimulus consists of two short bursts of 50 Hz tetanic stimulation, separated by 750 ms, and the response to the stimulation is two short muscle contractions. Fade in the response results from neuromuscular blockade as with train-of-four stimulation (TOF). The authors compared the sensitivity of DBS and TOF in the detection of residual neuromuscular blockade during clinical anaesthesia. Fifty-two healthy patients undergoing surgery were studied. For both stimulation patterns the frequencies of manually detectable fade in the response to stimulation were determined and compared at various electromechanically measured TOF ratios. A total of 369 fade evaluations for DBS and TOF were performed. Fade frequencies were statistically significantly higher with DBS than with TOF, regardless of the TOF ratio level. Absence of fade with TOF implied a 48% chance of considerable residual relaxation as compared with 9% when fade was absent with DBS. The results demonstrate that DBS is more sensitive than TOF in the manual detection of residual neuromuscular blockade.

Probability of being within defined TOFR intervals when different clinical fade evaluations are given

(Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of residual curarization using double burst stimulation: A comparison with train-of-four.

Anesthesiology 1989; 70:578-81)

no tof fade no tof,no dbs fade fade in dbs,not tof

tof<0.4

tof 0.41-0.50

tof 051-0.60

tof 0.61-0.70

tof >0.70

Dbs 3-3 Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of residual curarization using double burst stimulation: A comparison with train-of-four. Anesthesiology

1989; 70:578-81)

• Absence of fade with tof implies a 52% probability than tof>0.60

• absence of fade with dbs implies a tof >0.60 in 91% of cases

• only tOFR<0.40 can be assessedd manually

• therefore,evaluation of DBS is relevant only when there is no fade to tof

Conclusions:Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of residual curarization using double burst stimulation: A comparison with train-of-four. Anesthesiology

1989; 70:578-81)

• absence of fade to DBS normally excludes severe residual nm blockade(tofr<0.60) BUT DOES NOT NECESSARILY INDICATE ADEQUATE CLINICAL RECOVERY.

Meccanomiographic vs tactileevaluation

Drenck et al.Anesthesiology 79;578:1989.Drenck et al.Anesthesiology 79;578:1989.

qualitative tofevaluation

48% chances ofevaluating a real fade48% chances ofevaluating a real fade

qualitative DBSevaluation

9% chances of nondiscerning a real fade9% chances of nondiscerning a real fade

Viby-Mogensen J, Jensen NH, Engbæk J, Ørding H, Skovgaard LT, Chæmmer-Jørgensen B. Tactile and visual evaluation of response to train-of-four nerve

stimulation. Anesthesiology 1985; 63:440-3.

• Diaz/tps/N2O 66%/haloth 0.75-1.5%

• IOT with SCC ,then panc

• simult MMG in one arm & visual/tactile evaluation in the opposite.

• Experienced and (inexperienced) anesthesiologists

• 6 different TOFR forn every patient

Viby-Mogensen et al Tactile and visual evaluation of response to train-of-four nerve stimulation.

Anesthesiology 1985; 63:440-3.

fade observed

inexp.observers exp.observers

true tofr <0.30

true tof 0.31-0.40

true tof 0.41-0.50

true tof 0.51-0.60

true tof 0.61-0.70

true tof>0.70

Threshold fade by 3 very experienced observers (Viby-Mogensen et al. Tactile and visual evaluation of

response to train-of-four nerve stimulation. Anesthesiology 1985; 63:440-3)

visual manual

offset

Threshold fade by 3 very experienced observers (Viby-Mogensen et al. Tactile and visual evaluation of

response to train-of-four nerve stimulation. Anesthesiology 1985; 63:440-3.)

visual onset visual recovery manual onset manual recovery

• Which is the TOFR level that can be reliably detected visually by observing tetanic fade of the AP in response to 100-Hz, 5-s tetanus in anesthetized patients.?

Baurain M,Hennart DA,Godschalx A,Huybrechts I,Nasrallah G,d'Hollander AA., Cantraine F.Visual Evaluation of Residual

Curarization in Anesthetized Patients Using One Hundred-Hertz, Five-Second Tetanic Stimulation at the Adductor Pollicis

Muscle .Anesth Analg 1998; 87:185–9• We were looking for a clinical test to indicate a train-of-four (TOF) ratio of approximately 0.9. We compared the adductor pollicis muscle (AP) visually evaluated response to ulnar nerve 100-Hz, 5-s tetanus (RF100 Hz) with the measured AP TOF ratio in 30 ASA physical status I or II adult anesthetized (propofol, sufentanil, N2O/O2) patients. After the induction of anesthesia, the left ulnar nerve was stimulated at the wrist (single twitch and TOF) and the resultant isometric force was measured. When TOF was assessed, the independent investigators, unaware of the left

AP-measured TOF ratios, visually evaluated the presence or absence of AP fading elicited by right ulnar nerve 100-Hz, 5-s tetanus. The 30 patients were randomly allocated to receive either 0.5 mg/kg atracurium (n = 15) or 0.1 mg/kg vecuronium (n = 15). The neuromuscular blockade was allowed to resolve spontaneously. A multiple logistic regression analysis was performed by computing the 771 visual observations. The probabilities of success of 100-Hz, 5-s tetanus to detect TOF ratios of 0.8, 0.85, and 0.9 were 99%, 96%, and 67%, respectively. The sensitivity and specificity of 100-Hz, 5-s tetanus as an indicator of TOF ratios of 0.85 and 0.9 are 100% and 75%, 54% and 67%, respectively. We conclude that RF100 Hz visual assessment seems to be highly sensitive in evaluating residual paralysis, as the absence of RF100 Hz visual fading at the AP is compatible with a TOF ratio >0.85. Implications: After the administration of muscle relaxants, the absence of visual fading at the adductor pollicis, elicited in anesthetized patients by 100-Hz, 5-s tetanus, is compatible with a train-of four ratio >0.85. Therefore, clinical observation of fading after 100-Hz, 5-s tetanus seems to be a highly sensitive test in evaluating residual paralysis.

Baurain et al.Visual Evaluation of Residual Curarization in Anesthetized Patients Using One Hundred-Hertz, Five-Second Tetanic Stimulation at the Adductor Pollicis Muscle .Anesth Analg 1998; 87:185–9

Saitoh, Y, Narumi Y,Fujii Y, Ueki M. Tactile evaluation of fade of the train-of-four and double-burst stimulation using the anaesthetist's non-dominant hand Br. J. Anaesth. 1999; 83:275-278• We have studied detection of fade in response to train-of-four (TOF),

double-burst stimulation3,3 (DBS3,3) or DBS3,2, assessed tactilely by the anaesthetist using the index finger of the non-dominant hand and the thumb of the patient, compared with that assessed when the index finger of the dominant hand was used. The probability of detection of any fade in response to TOF or DBS3,3 using the non-dominant hand was significantly less than when the dominant hand was used (P<0.05). The probability of identification of fade in response to DBS3,2 assessed using the non-dominant hand was comparable with that evaluated using the dominant hand when TOF ratios were 0–0.9, but when TOF ratios reached 0.91–1.00, detection using the non-dominant hand was significantly less common than with the dominant hand (12% vs 33%; P<0.05). Using the non-dominant hand, the probability of detection of fade in response to ulnar nerve stimulation was less than that with the dominant hand and only the absence of DBS3,2 fade ensured sufficient recovery of neuromuscular block.

Saitoh Y,Nakazawa K, Makita K,Tanaka H, Amaha K.Evaluation of Residual Neuromuscular Block

Using Train-of-Four and Double Burst Stimulation at the Index Finger Anesth Analg 1997; 84:1354• We examined the percentage of tactile detection of fade in response to train-of-four (TOF), double burst stimulation3,3 (DBS3,3), or DBS3,2 at the index finger compared with that at the thumb during continuous infusion of vecuronium. One hundred five adult patients were studied. At TOF ratios (T4/T1) of 0.41–0.70, fades in response to TOF were more frequently identified by tactile means at the index finger than at the thumb (58% vs 26%, P < 0.05). Similarly, at TOF ratios of 0.61–0.90, fades in response to DBS3,3 were more frequently detected at the index finger than at the thumb (55% vs 15%, P < 0.05), and at TOF ratios of 0.81–1.00, the percentage of detection of fade in response to DBS3,2 was higher at the index finger than at the thumb (72% vs 40%, P < 0.05). In addition, baseline displacement of the index finger or thumb during tactile assessment of fade in response to neurostimulation was measured videographically. The baseline displacement of the index finger was significantly less than that of the thumb (P < 0.05). In summary, the percentage of tactile detection of fade in response to neurostimulation at the index finger is higher than at the thumb, and the absence of fade in response to DBS3,3 at the index finger is a good indicator of adequate recovery from neuromuscular block. This is probably because of the smaller baseline displacement of the index finger.

Percentage of tactile detection of fade in response to TOF at the index finger compared with that at the thumb during continuous infusion of vecuronium (Saitoh Y,Nakazawa K, Makita K,Tanaka H, Amaha K.Evaluation of Residual Neuromuscular Block Using Train-of-Four and Double Burst Stimulation at the Index Finger Anesth Analg 1997; 84:1354)

020406080100

true TOFRindex

0,21--0.30

0,31-0,40

0,41-0,50

0,51-0,60

0,61-0,70

0,71-0,80

0,81-0,90

True tof

Percentage of tactile detection of fade in response to DBS 3,3 at the index finger compared with that at the thumb during continuous infusion of vecuronium (Saitoh Y,Nakazawa K, Makita K,Tanaka H, Amaha K.Evaluation of Residual Neuromuscular Block Using Train-of-Four and Double Burst Stimulation at the Index Finger Anesth Analg 1997; 84:1354)

020406080100

true TOFRindex

0-0,40 0,41-0,50

0,51-0.60

0,61-0,70

0,71-0,80

0,81-0,90

0-0,40

0,41-0,50

0,51-0.60

0,61-0,70

0,71-0,80

0,81-0,90

At TOFR>0.60 fade at index 55% vs thumb 15%

•THE END

Correlaz clinico-meccaniche del monitoraggio nm

• Pohihill SL BrJ Anaesth 1998

• Acta Anesth Belg.1999 Fezing AK

Fruergaard K, Viby-Mogensen J, Berg H, El-Mahdy AM. Tactile evaluation of the response to double burst stimulation decreases, but not

eliminates, the problem of postoperative residual paralysis. Acta Anaesthesiol Scand

1998; 42:1168-74• BACKGROUND: Routine perioperative monitoring with accelero-myography might prevent residual block,

whereas routine tactile evaluation of the response to train-of-four (TOF) nerve stimulation does not. The purpose of this prospective, randomised and blinded study was to evaluate the effect of manual evaluation of the response to double burst stimulation (DBS3.3) upon the incidence of residual block. METHODS: Sixty adult patients scheduled for elective abdominal surgery were included in the study. Pancuronium 0.08 to 0.1 mg kg-1 was given for relaxation and tracheal intubation. For maintenance of neuromuscular block, pancuronium 1-2 mg was administered. The patients were randomly allocated into two groups. In group DBS (double burst stimulation) the degree of block during anaesthesia was assessed by manual evaluation of the response to TOF nerve stimulation. During reversal, when no fade was detectable in the TOF response, the stimulation pattern was changed to DBS3.3. The trachea was extubated when the anaesthetist judged the neuromuscular function to have recovered adequately and no fade in the DBS3.3 response could be felt. In group CC (clinical criteria) patients were managed without the use of a nerve stimulator, and the level of neuromuscular block and reversal were evaluated solely on the basis of clinical criteria. In both groups, the TOF ratio was measured by mechanomyography immediately after tracheal extubation. Also, the ability to sustain head lift for 5 s, to protrude the tongue, to open the eyes, and to lift one arm to the opposite shoulder were tested. RESULTS: The TOF ratio, as measured immediately after tracheal extubation, was significantly lower in group CC than in group DBS (means: 0.68 and 0.78, respectively), and the incidence of residual neuromuscular block defined as a TOF ratio < 0.7 was significantly higher in group CC than in group DBS (57 and 24%, respectively). The time from the first TOF measurement until the TOF ratio reached 0.8 was significantly longer in group CC than in group DBs (means: 11.5 and 6.2 min, respectively). No significant differences between the two groups of patients were found in duration of anaesthesia, in times from end of surgery to injection of neostigmine, tracheal extubation or TOF ratio 0.8, in dose of pancuronium, or in any other postoperative variable. CONCLUSION: Routine perioperative manual evaluation of the responses to TOF and DBS3.3 decreased the incidence and the degree of residual block following the use of pancuronium. It did not, however, exclude clinically significant residual paralysis, nor did it influence the amount of pancuronium used during the operation, the duration of anaesthesia or the time from end of surgery to tracheal extubation or to sufficient recovery of neuromuscular function (TOF = 0.8).

Shorten GD, Merk H, Sieber T. Perioperative train-of-four monitoring and residual

curarization. Can J Anaesth 1995; 42:711-15• It has been suggested that perioperative train-of-four (TOF) monitoring does

not reduce the incidence of postoperative residual curarization (PORC). The purpose of this study was to examine whether the use of tactile assessment of the response of the adductor pollicis to supramaximal TOF stimulation of the ulnar nerve at the wrist during anaesthesia affected the incidence of PORC. Thirty-nine ASA I or II surgical patients were studied during thiopentone/fentanyl N2O/enflurane anaesthesia. Pancuronium (70-100 micrograms.kg-1) was used to facilitate tracheal intubation and additional pancuronium increments used to maintain surgical relaxation. The requirement for incremental doses of pancuronium and adequacy of recovery following reversal were assessed according to random allocation, either with (Group A; n = 20) or without (Group B; n = 19) access to TOF monitoring. Patients in the two groups received neostigmine in similar doses (Group A: 53 micrograms.kg-1 (5.9); Group B: 55 micrograms.kg-1 (5.4)). On arrival of the patient to the recovery area, neuromuscular function was assessed electromyographically (using the Datex NMT 221 to measure TOF ratio) and clinically. The incidence of PORC (TOF ratio < 70%) was greater in Group B (47%) than in Group A (15%) (P = 0.029). We conclude that the use of perioperative TOF monitoring decreases the incidence of pancuronium-induced PORC.

Cominciano le doppie….o le esplicative

• Fisher DM, Cronnelly R, Miller RD. The neuromuscular pharmacology of neostigmine in infants and children. Anesthesiology 1983; 59:220-5.

• 2: 3: Meyer HS, Lukey BJ, Gepp RT, et al. A radioimmunoassay for pyridostigmine. J Pharmacol Exp Ther 1988; 2:432-8.

• 7: Matteo RS. Use in the elderly. Clin Anesthesiol 1985; 3:421-34. • 8: Bevan DR, Donati F, Kopman AK. Reversal of neuromuscular blockade.

Anesthesiology 1992; 77:785-805. • 9: Cronnelly R, Stanski DR, Miller RD, et al. Pyridostigmine kinetics with and without

renal function. Clin Pharmacol Ther 1980; 28:78-81. • 10: Cronnelly R. Kinetics of anticholinesterases. Clin Anesthesiol 1985; 3:315-28. • 19: 20: Cronnelly R, Morris RB, Miller RD. Edrophonium: duration of action and atropine

requirement in humans during halothane anesthesia. Anesthesiology 1982; 57:261-6. • 22: Fisher DM, Cronnelly R, Miller RD. Clinical pharmacology of edrophonium in infants

and children. Anesthesiology 1984; 61:428-33. • 23: 24: Miller RD, Van Nyhuis LS, Eger EI II, et al. Comparative times to peak effect and

durations of action of neostigmine and pyridostigmine. Anesthesiology 1974; 41:27-33. • 25: Donati F, McCarroll SM, Antzaka C, et al. Dose-response curves for edrophonium,

neostigmine, and pyridostigmine after pancuronium and d-tubocurarine. Anesthesiology 1987; 66:471-6.

Chiu, Jen W. MBBS, MMed, DEAA; White, Paul F. PhD, MD,

FANZCA The Pharmacoeconomics of

Neuromuscular Blocking Drugs. Anesthesia & Analgesia. 90(5S) Supplement:S19-S23,

May 2000.

Zhou TJ,Chiu JW, White PF,Forestner JE,Murphy MT Reversal of rocuronium with edrophonium during propofol versus sevoflurane anesthesia. Acta

Anaesthesiologica Scandinavica. 45;246-249:2001.

Cutter TW. What is the role of neuromuscular blocking drugs in ambulatory anesthesia? Current

Opinion in Anaesthesiology. 15:635-639, 2002.

Young WL, Matteo RS, Ornstein E. Duration of action of neostigmine and pyridostigmine in

the elderly. Anesth Analg 1988; 67:775-8.

Young WL, Matteo RS, Ornstein E. Duration of action of neostigmine and pyridostigmine in

the elderly. Anesth Analg 1988; 67:775-8.

Rivalutazione della pratica clinica

• Età e stato di salute differiscono fra volontari sani e pazienti!

• La prassi clinica e l’utilizzo dei miorilassanti variano fra i diversi centri ambulatoriali

• il monitoraggio degli effetti nm non è praticato in ospedale,figurarsi nei centri ambulatoriali!

• I metodi di monitoraggio usati da Kopman et al si applicano ad una ampia gamma di situazioni cliniche.

• Esistono pesanti pressioni economiche per la diminuzione della spesa sanitaria.

Time from neostigmine administrationadministration to TOFR 0.70

I twitch II twitch III twitch IV twitch

mediana

Time from neostigmine administration to TOFR 0.80

mediana

Time from neostigmine administration to TOFR 0.90

mediana

MMG magnitude of the first TOF twitch(T1) measured at the reappearance of each of the 4 tactile TOF responses.

mediana

• Eventuale altra figura del file **90813

• Lavori su fx501…………

• Pyridostigmine, like neostigmine and many nondepolarizing muscle relaxants, has a prolonged duration of action in the elderly . This study demonstrates a decreased plasma clearance of pyridostigmine in the elderly which we believe to be the probable explanation.

• By comparing the elimination half-life of pyridostigmine in anephric patients and those with normal renal function, Cronnelly et al. . determined that approximately 75% of IV administered pyridostigmine is eliminated by the kidneys. Patients with normal renal function cleared pyridostigmine through the kidneys much faster than could be achieved by glomerular filtration alone . Consequently, renal tubular secretory function must play a major role in the excretion of pyridostigmine .

• Abnormal renal function has a profound effect on the excretion of pyridostigmine, and renal function declines with aging. In fact, deterioration occurs at a rate of approximately 1% per year after middle age . Parenchymal mass is lost as nephrons decrease in size and number. Sclerotic changes in renal vasculature limit the effective glomerular filtering surface and decrease renal cortical blood flow and glomerular filtration. Renal tubular function wanes to an even greater extent. Serum creatinine, however, usually remains within normal limits, because muscle atrophy and the creatinine load decrease comparably .

• The elderly patients in this study all appeared to have normal renal function, as every individual's blood chemistry screening test was within normal limits for our laboratory. Nevertheless, it was not unexpected that the mean blood urea nitrogen level was higher in the elderly group than in the younger controls. Had we measured urinary pyridostigmine clearance, a more specific and quantitative comparison would have been possible. Hepatic function, cardiac reserve, and blood volume also decline with advancing age, but these are relatively small changes and should have only minor effects on the kinetics of pyridostigmine, a drug excreted primarily by the kidneys .

• Although the elderly patients in this study demonstrated a decreased plasma clearance for pyridostigmine, significant differences between groups were not demonstrable for volumes of distribution or elimination half-life. The mean values indicated a tendency for the elderly population to have smaller volumes of distribution and a greater elimination half-life, and perhaps statistical significance would have been achieved if plasma sampling continued beyond 6 h or if group size had been larger. It is well established that elderly patients have a diminished body water content and a smaller cellular mass . Elimination half-life is derived from plasma clearance and volume of distribution , and since both are usually decreased in the elderly, elimination half-life may remain unchanged. Indeed, it has been pointed out that elimination half-life may not be an accurate reflection of drug excretion , and that plasma clearance is the best pharmacokinetic indicator of an organism's ability to eliminate a drug .

• In young adult patients with normal renal and hepatic function, there are not significant pharmacokinetic differences between pyridostigmine, neostigmine, and edrophonium . Nevertheless, elimination half-life and plasma clearance of the anticholinesterase drugs used in anesthesia tend to be influenced by age. For instance, Fisher et al. found that when neonates, children, and young adults received neostigmine or edrophonium to antagonize incomplete neuromuscular blockade, the younger patients demonstrated progressively shorter elimination half-life values and progressively faster plasma clearance values. The groups were small and, although a tendency was evident, differences did not always achieve statistical significance. Similarly, Matteo et al. compared kinetic variables in elderly patients and younger adults after they received edrophonium. Again aging was associated with a prolongation of the elimination half-life and a diminution of the plasma clearance. In the present study, pyridostigmine was administered to elderly and younger adults. The older group demonstrated a significantly slower plasma clearance and a tendency toward a longer elimination half-life. To date, no one has studied age-related kinetic variables for neostigmine.

• To accurately determine anticholinesterase onset times and peak action times, steady-state neuromuscular blockade should first be established by constant infusion . Our group has already done a full-fledged pharmacodynamic study of pyridostigmine . It required a time-consuming and cumbersome protocol which we elected not to repeat for this pharmacokinetic study. Nevertheless, pyridostigmine onset and peak action times were estimated for the two groups, and the validity of the data is confirmed by previous work . Both the young and the elderly patients demonstrated the same onset times and very similar initial volumes of distribution. As cardiac index decreases only slightly throughout adult life in healthy, fit individuals and as only such patients were included in this study, the delivery of pyridostigmine to the receptors should have been almost equal in the two groups. illustrates that the plasma pyridostigmine concentration-time relationships were similar for an hour after administration, and thus one might expect that the neuromuscular junctions of both groups were presented initially with equal concentrations of pyridostigmine. However, whether aging alters either drug distribution within the neuromuscular junction or the efficacy of pyridostigmine as an anticholinesterase were not examined, and we can only speculate that if the two groups had the same initial plasma concentrations then they might well have had equal initial responses.

Silverberg 1986

rocuronium after reversal with pyridostigmine.

Anesthesia & Analgesia 2002; 95:1656-1660

• patients were premedicated with midazolam 0.05 mg/kg IM approximately 1 h before the operation. Anesthesia was induced with thiopental 3–5 mg/kg and fentanyl 2 mg/kg until the patient was asleep and maintained with either 1%–2% enflurane or 1%–1.5% isoflurane and 50% N2O in oxygen. Endotracheal intubation was performed after the administration of either vecuronium 0.1 mg/kg or rocuronium 0.6 mg/kg. If required, relaxation was maintained with a supplementary dose of either vecuronium 2 mg or rocuronium 10 mg, respectively, according to the clinical judgement of the anesthesiologist. After completion of the surgical procedure, a bolus of pyridostigmine was administered in a dose of either 0.143 mg/kg (equivalent to 10 mg/70 kg) or 0.286 mg/kg (equivalent to 20 mg/70 kg) and glycopyrrolate 8 mg/kg, respectively. The timing and dose of administration of pyridostigmine were chosen by the participating anesthesiologist. Adequacy of recovery from neuromuscular block and the decision to extubate the endotracheal tube before arrival in the recovery room were based on clinical criteria only.

• There was no difference between adequate (TOF ratio >0.7) and inadequate (TOF ratio <0.7) groups concerning ASA physical status, sex, age, weight, and height. Inadequate recovery from neuromuscular block in the recovery room was found in 125 (20.8%) patients (). There were no differences in TOF ratio between 10 mg and 20 mg of pyridostigmine after the use of either vecuronium or rocuronium. Similarly, no differences were found between the enflurane or isoflurane groups. The recovery of TOF ratio was greater in patients who had received rocuronium than those who had received vecuronium with reversal with pyridostigmine 10 mg or 20 mg (P < 0.01) (). shows a similar pattern of the recovery of TOF ratio in vecuronium, rocuronium, enflurane, and isoflurane (P < 0.537).

• There was a similar incidence of residual block after reversal of pyridostigmine 10 mg (21.5%) and 20 mg (19.9%), respectively (). The incidence of residual block after vecuronium (24.7%) was more frequent than that after rocuronium (14.7%; P < 0.01). The patients with residual block had received a larger cumulative dose of vecuronium, and a shorter time had elapsed since the last NMB was injected in these patients. However, the time from the injection of pyridostigmine to TOF recording was similar in both groups. Tracheal extubation was performed in 93.4% of patients before arrival in the recovery room. The body core temperature in the patients with residual block was lower compared with that of adequate recovery (P < 0.001).

• Head-lift for 5 s and the tongue-depressor test could not be sustained by any patients at a TOF ratio of 0.5. Clinical testing was only possible in cooperative patients. The failed patients in the 5-s head-lift group were a larger proportion than those in the tongue-depressor test group after either vecuronium or rocuronium, respectively (P < 0.001). The TOF ratio of the recovered patients was greater than that of the failed patients in the 5-s head-lift group after either vecuronium or rocuronium, respectively (P < 0.001). There were no differences in the recovery of TOF ratio between the 5-s head-lift test and the tongue-depressor test of patients who were either recovered or failed in the recovery room ().

• Thirty-eight patients below 0.5 of TOF ratio were required further reversal in the recovery room with neostigmine 1.0 mg and atropine 0.5 mg for rapid clinical improvement.

• The onset of action of neostigmine was seven to 11 minutes. However, pyridostigmine took as long as 16 minutes to exert its full effect and had one-fifth the potency of neostigmine . In the present study, the average time from pyridostigmine administration to TOF recording was 28 minutes. Therefore, we suspect that the difference of potency might be the main reason for a more frequent incidence of postoperative residual neuromuscular block after reversal by pyridostigmine rather than neostigmine. However, pyridostigmine produced fewer complications such as bradycardia, increased salivation, and increased bowel motility than neostigmine . The antagonism produced by a large dose (20 mg) of pyridostigmine was similar to that produced by a small dose (10 mg) at 30 minutes after reversal injection . We also found similar results of no difference between 10 mg and 20 mg of pyridostigmine. The time of TOF recording was a fairly long interval (13–44 minutes) from pyridostigmine in the current study. If we had tested the TOF stimulation earlier with the strict criteria, we might have confirmed the difference between the doses. The residual block might be caused by too short a time between the last dose of NMB and pyridostigmine ().

• Diapo sull PONV seguono……

Nelskylä, K.; Yli-Hankala, A.; Soikkeli, A.; Korttila, K.Noestigmine with glycopirrolate does not increase the incidence and severity of PONV in outpatients undergoing gynecological laparoscopy.BJA 1998;81:757.-760

• • ABSTRACT: • We studied 100 healthy women undergoing outpatient gynaecological laparoscopy in

a randomized, double-blind and placebo-controlled study to evaluate the effect of neostigmine on post-operative nausea and vomiting (PONV). After induction of anaesthesia with propofol, anaesthesia was maintained with sevoflurane and 66% nitrous oxide in oxygen. Mivacurium was used for neuromuscular block. At the end of anaesthesia, neostigmine 2.0 mg and glycopyrrolate 0.4 mg, or saline, was given i.v. The incidence of PONV was evaluated in the postanaesthesia care unit, on the ward and at home. The severity of nausea and vomiting, worst pain, antiemetic and analgesic use, times to urinary voiding and home readiness were recorded. During the first 24 h after operation, 44% of patients in the neostigmine group and 43% in the saline group did not have PONV. We conclude that neostigmine with glycopyrrolate did not increase the occurrence of PONV in this patient group.

Watcha MF, Safavi FZ, McCulloch DA, et al. Effect of antagonism of mivacurium-induced

neuromuscular block on postoperative emesis in children. Anesth Analg 1995; 80:713-7.

PONV antiemeticinecess

Vomito entro24 ore

Incidenza di PONV nella PACU

neostigmine 70micrograms/kg +glycopyrrolate 10micrograms/kg,

edrophonium 1 mg/kg +atropine 10micrograms/kg.

saline

Ding Y,Fredman B, White PF.Use of mivacurium during laparoscopic surgery:effect of reversal

drungs on postoperaive recovery.Anesth Analg 1994; 78:450–4

• outpatient laparoscopic tubal ligation • 60 healthy, nonpregnant women. • midazolam / fentanyl/tps• succ 1 mg/kg (Group I) vs mivacurium 0.2 mg/kg

(Groups II and III)• Anesthesia maintained with isoflurane (0.5%-2%

+67% N2O• Muscle relaxation maintained in all three groups with

intermittent bolus doses of mivacurium, 2–4 mg, IV.• In Group III, residual neuromuscular block reversed

with neostigmine 2.5 mg +glycopyrrolate, 0.5 mg,

Effetti collat dello studio di Ding et al.

nausea vomit antiemetici neck pain shoulder pain

succi/miva/no antag

miva/miva/ no antag

miva/miva/antag

Boeke AJ, de Lange JJ, van Druenen B, Langemeijer JJM. Effect of antagonizing residual neuromuscular block by neostigmine and atropine on postoperative vomiting. Br J Anaesth 1994; 72:654-6.

• 80 patients undergoing outpatient surgery

• allocated randomly to two groups: in group A residual neuromuscular block was antagonized with a mixture of neostigmine 1.5 mg and atropine 0.5 mg; in group B spontaneous recovery was allowed.

• patients assessed after operation in hospital and 24 h after discharge.

Boeke AJ, de Lange JJ, van Druenen B, Langemeijer JJM. Effect of antagonizing residual neuromuscular block by neostigmine and atropine on postoperative vomiting. Br J Anaesth 1994; 72:654-6.

• inguinal hernia repair & stripping of the major saphenous vein of one leg.

• no premed• atropine 0.5 mg i.v.• anaesthesia : tps 5–8 mg/kg + fent 2 g/kg• vecu.0.1 mg kg-1. • 100% oxygen * 3 min• iot• IPPV 66% N2O/ haloth. 0.5%

Incid.di PONV nello studio di Boeke et al.

101214161820

num.paz

PONV RR PONV II

non antag

Boeke et al.;risultati e conclusioni.

• We found a significant difference (P < 0.05) in requirements for antiemetic therapy with a smaller need in the group which received neostigmine (in group A four of 40 patients received an antiemetic compared with 12 in group B).

• no significant difference in frequency of nausea or vomiting between the two groups.

• The incidence of postoperative nausea was 14 in group A and 18 in group B and the number of patients with postoperative vomiting was 10 in group A and 15 in group B.

• In conclusion, as there was an increase in the number of patients requiring antiemetics in group B compared with group A (P < 0.05), the results of this study may suggest an antiemetic effect of neostigmine.

Kao YJ, Mian T, McDaniel KE, et al. Neuromuscular blockade reversal agents induce postoperative nausea

and vomiting [abstract] Anesthesiology 1992; 77(Suppl):A1120.

Minilap per PPTL.Tps/succi/iot/fent/isof/N2O.Stomaco svuotato.Atrac 0.15 mg/kg.

no antag

A 0.15 micrG/kg + edroph 1mg/kg

A 0.15 micrg/kg+neo 0.05mg/kg

A 0.15 icrg/kg+pirido 0.25mg/KG

• Enzymatic Antagonism of Mivacurium-induced Neuromuscular Blockade by Human Plasma Cholinesterase. Anesthesiology. 83(4):694-701, October 1995.

Fisher, Dennis M. ,Szenohradszky, Janos , Hart, Paul S. .Antagonism of Residual Mivacurium Blockade: Setting the Record Straight. Anesthesiology. 84(6):1527-1528, June 1996.

• . Szenohradszky, Janos ,Fogarty, Declan Kirkegaard-Nielsen, Hans , Brown, Ronald, Sharma, Manohar L,Fisher, Dennis M. Effect of Edrophonium and Neostigmine on the Pharmacokinetics and Neuromuscular Effects of Mivacurium. Anesthesiology. 92(3):708-714, March 2000.

• Devcic A, Munshi CA, Gandhi SK, Kampine JP: Antagonism of mivacurium neuromuscular block: Neostigmine versus edrophonium. Anesth Analg 81:1005-9, 1995<ldn>!

• 12: Szenohradszky J, Lau M, Brown R, Sharma ML, Fisher DM: The effect of neostigmine on twitch tension and muscle relaxant concentration during infusion of mivacurium or vecuronium. ANESTHESIOLOGY 83:83-7, 1995<ldn>!

• 13: Kao YJ, Le ND: The reversal of profound mivacurium-induced neuromuscular blockade. Can J Anaesth 43:1128-33, 1996<ldn>!

• 14: Naguib M, Abdulatif M, Al-Ghamdi A, Hamo I, Nouheid R: Dose-response relationships for edrophonium and neostigmine antagonism of mivacurium-induced neuromuscular block. Br J Anaesth 71:709-14, 1993<ldn>!

• 15: Goldhill DR, Whitehead JP, Emmot RS, Griffith AP, Bracey BJ, Flynn PJ: Neuromuscular and clinical effects of mivacurium chloride in healthy adult patients during nitrous oxide-enflurane anaesthesia. Br J Anaesth 67:289-95, 1991<ldn>!

• 16: Caldwell JE, Heier T, Kitts JB, Lynam DP, Fahey MR, Miller RD: Comparison of the neuromuscular block induced by mivacurium, suxamethonium or atracurium during nitrous oxide-fentanyl anaesthesia. Br J Anaesth 63:393-9, 1989<ldn>!

• 21: Beemer GH, Bjorksten AR, Dawson PJ, Dawson RJ, Heenan PJ, Robertson BA: Determinants of the reversal time of competitive neuromuscular block by anticholinesterases. Br J Anaesth 66:469-75, 1991<ldn>!

• 22: Beemer GH, Goonetilleke PH, Bjorksten AR: The maximum depth of an atracurium neuromuscular block antagonized by edrophonium to effect adequate recovery. ANESTHESIOLOGY 82:852-8, 1995<ldn>!

Epemolu O,Bom A,Hope F,Mason R.Reversal of Neuromuscular Blockade and Simultaneous Increase in Plasma Rocuronium Concentration after the Intravenous Infusion of the Novel Reversal Agent Org 25969. Anesthesiology. 2003;99;632-637

. Bom A, Mason R, Hope F, van Egmond J, Muir A: The cyclodextrin derivative Org 25969, which forms complexes with steroidal neuromuscular blocking agents, causes selective reversal of normal and profound neuromuscular block. A nesthesiology 2001; 95: A1020

Mason R, Bom A: Org 25969 causes selective reversal of neuromuscular block induced steroidal NMBs in anaesthetised guinea pigs (abstract 18).

Eur J Anaesthesiol 2001; 18 (suppl 23): 100

. Hope F, Bom A: Org 25969 reverses rocuronium-induced neuromuscular blockade in the cat without important hemodynamic effects (abstract 17). Eur J

Anaesthesiol 2001; 18 (suppl 23): 99

. van Egmond J, van de Pol F, Booij L, Bom A: Neuromuscular blockade induced by steroidal NMBs can be rapidly reversed by Org 25969 in the anaesthetized monkey (abstract 19). Eur J Anaesthesiol 2001; 18 (suppl 23): 100

Bom A, Bradley M, Cameron K, Clark JK, van Egmond J, Feilden H, MacLean EJ, Muir A, Palin R, Rees

DC, Zhang M-Q: Chemical encapsulation of rocuronium by a cyclodextrin based synthetic host. Angew Chem 2002; 41: 265–70

[Context Link]

McGehee DS,Krasowski MD,Fung DL,Wilson B,Gronert GA, Moss J.Cholinesterase Inhibition by Potato Glycoalkaloids Slows Mivacurium Metabolism Anesthesiology 93:510-9, 2000

• ABSTRACT: Background: The duration of action for many pharmaceutical agents is dependent on their breakdown by endogenous hydrolytic enzymes. Dietary factors that interact with these enzyme systems may alter drug efficacy and time course. Cholinesterases such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) hydrolyze and inactivate several anesthetic drugs, including cocaine, heroin, esmolol, local ester anesthetics, and neuromuscular blocking drugs. Natural glycoalkaloid toxins produced by plants of the family Solanaceae, which includes potatoes and tomatoes, inhibit both AChE and BuChE. Here the authors assess the extent to which two solanaceous glycoalkaloids (SGAs), a-solanine and a-chaconine, can alter the effects of neuromuscular blocking drugs and cholinesterase inhibitors in vivo and in vitro.

• Methods: Inhibition of purified human AChE and BuChE by SGAs, neuromuscular blocking drugs, and cholinesterase inhibitors was assessed by an in vitro colorimetric cholinesterase assay. In vivo experiments were carried out using anesthetized rabbits to test whether SGAs affect recovery from mivacurium-induced paralysis.

• Results: SGAs inhibited human BuChE at concentrations similar to those found in serum of individuals who have eaten a standard serving of potatoes. Coapplication of SGAs (30—100 nM) with neuromuscular blocking drugs and cholinesterase inhibitors produced additive cholinesterase inhibition. SGA administration to anesthetized rabbits inhibited serum cholinesterase activity and mivacurium hydrolysis. In addition, SGA prolonged the time needed for recovery from mivacurium-induced paralysis (149 ± 12% of control; n = 12).

• Conclusions: These findings support the hypothesis that inhibition of endogenous enzyme systems by dietary factors can influence anesthetic drug metabolism and duration of action. Diet may contribute to the wide variation in recovery time from neuromuscular blockade seen in normal, healthy individuals.

• Testo sulla cinetica edrophonium/enzima…. Da Matteo

• Donati F, Lahoud J, McCready D, Bevan DR. Neostigmine, pyridostigmine and edrophonium and neostigmine as antagonists of deep pancuronium blockade. Can J Anaesth 1987; 34:589–93.<ldn>!

• Characterization of the Interactions Between Volatile Anesthetics and Neuromuscular Blockers at the Muscle Nicotinic Acetylcholine Receptor

• ANESTHETIC PHARMACOLOGY• • AUTHOR(S): Paul, Matthias, MD, DEAA*; Fokt, Ralf M.; Kindler, Christoph H., MD, DEAA†; Dipp, Natalie

C. J.; Yost, C. Spencer, MD*• Volatile anesthetics enhance the neuromuscular blockade produced by nondepolarizing muscle relaxants

(NDMRs). The neuromuscular junction is a postulated site of this interaction. We tested the hypothesis that volatile anesthetic enhancement of muscle relaxation is the result of combined drug effects on the nicotinic acetylcholine receptor. The adult mouse muscle nicotinic acetylcholine receptor (a2, b, d, e) was heterologously expressed in Xenopus laevis oocytes. Concentration-effect curves for the inhibition of acetylcholine-induced currents were established for vecuronium, d-tubocurarine, isoflurane, and sevoflurane. Subsequently, inhibitory effects of NDMRs were studied in the presence of the volatile anesthetics at a concentration equivalent to half the concentration producing a 50% inhibition alone. All individually tested compounds produced rapid and readily reversible concentration-dependent inhibition. The calculated 50% inhibitory concentration values were 9.9 nM (95% confidence interval [CI], 8.4–11.4 nM), 43.4 nM (95% CI, 33.6–53.3 nM), 897 mM (95% CI, 699–1150 mM), and 818 mM (95% CI, 685–1001 mM) for vecuronium, d-tubocurarine, isoflurane, and sevoflurane, respectively. Coapplication of either isoflurane or sevoflurane significantly enhanced the inhibitory effects of vecuronium and d-tubocurarine, especially so at small concentrations of NDMRs. Volatile anesthetics increase the potency of NDMRs, possibly by enhancing antagonist affinity at the receptor site. This effect may contribute to the clinically observable enhancement of neuromuscular blockade by volatile anesthetics.

• • Anesthesia & Analgesia 2002; 95:362-367

• PARASYMPATHOMIMETIC effects of acetylcholinesterase inhibitors such as neostigmine and edrophonium are thought to be theoretically inevitable, and side effects, including bradycardia, bronchoconstriction, and increased bowel movement, are encountered when used to reverse the muscle weakness induced by nondepolarizing muscle relaxants. In the clinical setting, however, the bradycardic effect of edrophonium was reported to be less potent than that of neostigmine, although the doses of the drugs to reverse the effects of the muscle relaxants to a comparable degree were used. Consistent with the clinical data, Backman et al. suggested that the bradycardic effect of edrophonium is solely a result of the anticholinesterase effect, whereas neostigmine possesses an additional effect on cholinergic receptors within the cardiac parasympathetic pathway, thereby producing profound bradycardia. Recently, we also demonstrated that neostigmine at clinically relevant concentrations decreased the spontaneously beating rate of isolated guinea pig right atria in an atropine-sensitive manner, whereas the therapeutic concentrations of edrophonium inhibited the negative chronotropic effect of carbachol without any direct chronotropic effects.

• Molecular cloning studies have identified five subtypes of muscarinic acetylcholine receptors (mAChRs) (m1–m5) expressed in various tissues, while pharmacologic studies revealed four different subtypes of mAChRs (M1–M4) based on their binding affinities to specific ligands.

• Although recent studies have shown the existence of M1 receptors in ventricular cells, M2 is thought to be the predominant subtype of cardiac mAChR and mediates the typical cardiodepressant effects of parasympathetic activation such as bradycardia. Coexpression of M2 and M3 receptors seems to be a common feature of smooth muscle cells in various tissues such as airway and intestinal smooth muscles. Although the amount of M3 receptors is less than that of M2 receptors in these tissues, the M3 receptors are usually responsible for the direct contractile effect of muscarinic agonists on smooth muscles, including guinea pig and human airway smooth muscles.

Anticolinestherases 2004

Health & Medicine

Transcript of Anticolinestherases 2004

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